CN1759095A - N,N'-substituted-1,3-diamino-2-hydroxypropane derivatives - Google Patents
N,N'-substituted-1,3-diamino-2-hydroxypropane derivatives Download PDFInfo
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- CN1759095A CN1759095A CN 02826786 CN02826786A CN1759095A CN 1759095 A CN1759095 A CN 1759095A CN 02826786 CN02826786 CN 02826786 CN 02826786 A CN02826786 A CN 02826786A CN 1759095 A CN1759095 A CN 1759095A
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Abstract
Disclosed are compounds of the formula I, wherein the variables RN, RC, R1, R25, R2, and R3 are as defined herein. These compounds have activity as inhibitors of betasecretase and are therefore useful in treating a variety of discorders such as Alzheimer's Disease.
Description
Background of invention
1. invention field
The present invention relates to be used for the treatment of the compound of Alzheimer's disease and similar disease.
2. description of Related Art
Alzheimer's disease (AD) is the disease that a kind of mainly relevant with aging brain is progressively degenerated.The AD clinical manifestation is characterised in that the forfeiture of memory, cognition, reasoning, judgement and orientation property.Along with sb.'s illness took a turn for the worse, motion, sensation and language ability also are affected, until the comprehensive damage that produces multiple cognitive function.The forfeiture of these cognitive powers produces gradually, but meeting cause serious harm in 4 to 20 years and finally cause death usually.
Alzheimer's disease is characterised in that the pathological observation result that two kinds in the brain are main: neurofibrillary tangles and amyloid beta (or neuritis) spot, they mainly are made of the aggregate of the peptide fragment that is known as A β.Except neurofibrillary tangles, distinctive amyloid-beta deposition (for the amyloid beta spot, being the beta-amyloyd cerebrovascular disease in the cerebrovascular in brain) has also appearred in AD patient's the brain and the cerebrovascular.Neurofibrillary tangles not only occurs in the Alzheimer's disease, also appears at other and brings out in the dull-witted disease.When necrotomy, common this a large amount of to discovery in the very important zone of memory and cognition in human brain class damage.
In not suffering from most of elderly brains of clinical AD, found a spot of these damages, and its anatomic distribution is more limited.Amyloid generates (Amyloidogenic) spot and vascular amyloid angiopathy, and to become also be Trisomy21 (Down's syndrome), with the feature of patient's brain of the hereditary cerebral hemorrhage (HCHWA-D) of Dutch type amyloidosis and other neurodegenerative disease.Amyloid beta is the definition feature of AD, is considered to pathogenic precursor or factor in this disease progression now.The deposition of A β in the brain region of being responsible for cognitive activities is the developing principal element of AD.The amyloid beta spot mainly is made of amyloid beta (A β is also referred to as β A4 sometimes).A β peptide produces by the proteolysis of amyloid precursor protein (APP), and contains 39-42 amino acid.Some proteolytic enzyme that are known as Secretases have participated in the treating processes of APP.
APP has constituted amyloid-beta generation (amyloidogenic) approach, i.e. the formation approach of A β in the cracking of the N-terminal generation of A β peptide with by one or more gamma secretases in the cracking that C-terminal produces by beta-secretase.APP cracking under the effect of α Secretases produces α-sAPP, a kind of APP secretion form that can not cause β starch spot to form.This alternative route has stoped the formation of A β peptide.
Confirmed that a kind of aspartyl protease is the enzyme that causes APP to change at the beta-secretase cracking site.Use multiple different title to disclose beta-secretase, comprised BACE, Asp and Memapsin.
Several evidences show that amyloid beta peptide (A β) being deposited on gradually in brain brought into play basic effect in the AD pathogeny, and can produce than Zao several years of cognitive symptom or many decades.Verified: as from the neurone of substratum, growing, discharge A β, and A β to be present in normal people and AD patient's the celiolymph (CSF).
The someone proposes, and the gathering of A β peptide is to be produced by the effect of beta-secretase to APP, and therefore, the activity that suppresses this kind of enzyme is that treatment AD is required.In vivo, APP is considered to the rate-limiting step that A β generates in the reaction of beta-secretase cracking site, therefore is the therapeutic goal in the AD treatment.
The ruined mouse of BACE1 (β position APP lyase 1) does not produce A β, and shows normal phenotype.When showing the mouse mating of too much APP, the comparison of the content of A β is according to animal few (Luo etc., 2001 Nature Neuroscience 4:231-232) in its offspring's the big brain extract.This evidence has further been supported following opinion, i.e. minimizing to A β in active inhibition of beta-secretase and the brain provides a kind of AD and other beta-amyloyd treatment of diseases method.
At present, there is not effective methods of treatment in order to end, to prevent or reverse the in-depth of Alzheimer's disease.Therefore, press for the in-depth that can slow down Alzheimer's disease and/or can prevent the medicament of its generation at the very start.
Treatment and prevention are the following compound of disease (for example AD) needs of feature with amyloid beta deposition or spot: effective inhibitor of beta-secretase; Suppressing APP is that media carries out the cracked compound with the beta-secretase; Effective inhibitor that A β produces; And/or can effectively reduce the compound of amyloid beta deposition or spot.
Summary of the invention
Generally, the invention provides the compound that chemical formula is X:
And can be used for the salt of pharmacy, wherein
R
1Be-(CH
2)
1-2-S (O)
0-2-(C
1-C
6Alkyl) or
Optional by 1,2 or 3 be independently selected from halogen ,-OH ,=O ,-SH ,-C ≡ N ,-CF
3,-C
1-C
3Alkoxyl group, amino, list or dialkyl amido ,-N (R)-C (O) R '-,-OC (=O)-amino and-OC (=O)-C that the group of list or dialkyl amido replaces
1-C
10Alkyl or
Optional by 1,2 or 3 be independently selected from halogen ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3The C that the group of alkoxyl group, amino and list or dialkyl amido replaces
2-C
6Alkenyl or C
2-C
6Alkynyl or
Aryl, heteroaryl, heterocycle ,-C
1-C
6Alkyl-aryl ,-C
1-C
6Alkyl-heteroaryl or-C
1-C
6Alkyl-heterocycle, wherein loop section is separately all chosen wantonly by 1,2,3 or 4 substituting group that is independently selected from following groups and is replaced: halogen ,-OH ,-SH ,-C ≡ N ,-NR
105R '
105,-CO
2R ,-N (R) COR ' or-N (R) SO
2R ' ,-C (=O)-(C
1-C
4) alkyl ,-SO
2-amino ,-SO
2-list or dialkyl amido ,-C (=O)-amino ,-C (=O)-list or dialkyl amido ,-SO
2-(C
1-C
4) alkyl or
Optional by 1,2 or 3 C that is independently selected from the group replacement of halogen
1-C
6Alkoxyl group or
Optional by 1,2 or 3 be independently selected from halogen ,-OH ,-SH ,-C ≡ N ,-CF
3,-C
1-C
3Alkoxyl group, amino ,-C
1-C
6The C that the group of alkyl and list or dialkyl amido replaces
3-C
7Cycloalkyl or
Optional by 1,2 or 3 be independently selected from halogen ,-OH ,-SH ,-C ≡ N ,-CF
3,-C
1-C
3Alkoxyl group, amino, list or dialkyl amido and-C
1-C
3The C that the group of alkyl replaces
1-C
10Alkyl or
Each optional by 1,2 or 3 be independently selected from halogen ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group, amino, C
1-C
6The C that the group of alkyl and list or dialkyl amido replaces
2-C
10Alkenyl or C
2-C
10Alkynyl; Heterocyclic group can also be chosen wantonly by=O and replace;
R
2Be hydrogen, optional by one, two or three are independently selected from C
1-C
3Alkyl, halogenated hydroxyl ,-SH, cyano group ,-CF
3, C
1-C
3Alkoxyl group, amino, list (C
1-C
6) alkylamino or two (C
1-C
6) C that replaces of the substituting group of alkylamino
1-C
6Alkyl;
R
3Be selected from hydrogen, optional by one, two or three are independently selected from C
1-C
3Alkyl, halogenated hydroxyl ,-SH, cyano group ,-CF
3, C
1-C
3Alkoxyl group, amino, list (C
1-C
6) alkylamino or two (C
1-C
6) C that replaces of the substituting group of alkylamino
1-C
6Alkyl;
Or R
2And R
3Form 3 or 4 yuan of carbocyclic rings with the carbon atom that links to each other with them;
Each R
25All be selected from hydrogen or C independently of one another
1-C
6Alkyl;
R
CBe hydrogen ,-(CR
245R
250)
0-4-aryl ,-(CR
245R
250)
0-4-heteroaryl ,-(CR
245R
250)
0-4-heterocycle ,-(CR
245R
250)
0-4-aryl-heteroaryl ,-(CR
245R
250)
0-4-aryl-heterocycle ,-(CR
245R
250)
0-4-aryl-aryl ,-(CR
245R
250)
0-4-heteroaryl-aryl ,-(CR
245R
250)
0-4-heteroaryl-heterocycle ,-(CR
245R
250)
0-4-heteroaryl-heteroaryl ,-(CR
245R
250)
0-4-heterocycle-heteroaryl ,-(CR
245R
250)
0-4-heterocycle-heterocycle ,-(CR
245R
250)
0-4-heterocycle-aryl ,-[C (R
255) (R
260)]
1-3-CO-N-(R
255)
2,-CH (aryl)
2,-CH (heteroaryl)
2,-CH (heterocycle)
2,-CH (aryl) (heteroaryl) ,-(CH
2)
0-1-CH ((CH
2)
0-6-OH)-(CH
2)
0-1-aryl ,-(CH
2)
0-1-CH ((CH
2)
0-6-OH)-(CH
2)
0-1-heteroaryl ,-CH (aryl or-heteroaryl)-CO-O (C
1-C
4Alkyl) ,-CH (CH
2-OH)-CH (OH)-phenyl-NO
2, (C
1-C
6Alkyl)-O-(C
1-C
6Alkyl)-OH;-CH
2-NH-CH
2-CH (O-CH
2-CH
3)
2,-(CH
2)
0-6-C (=NR
235) (NR
235R
240) or
Choose wantonly and be independently selected from R by 1,2 or 3
205,-OC=ONR
235R
240,-S (=O)
0-2(C
1-C
6Alkyl) ,-SH ,-NR
235C=ONR
235R
240,-C=ONR
235R
240With-S (=O)
2NR
235R
240The C that replaces of group
1-C
10Alkyl or
-(CH
2)
0-3-(C
3-C
8) cycloalkyl, wherein cycloalkyl is optional is independently selected from R by 1,2 or 3
205,-CO
2H and-CO
2-(C
1-C
4Alkyl) group replace or
With aryl, heteroaryl or heterocyclic fused cyclopentyl, cyclohexyl or suberyl ring, wherein in cyclopentyl, cyclohexyl or the suberyl, two or three carbon are chosen wantonly and are independently selected from NH, NR by one
215, O or S (=O)
0-2Heteroatoms replace, and wherein cyclopentyl, cyclohexyl or suberyl can be chosen wantonly by one or two and be independently selected from R
205,=O ,-CO-NR
235R
240, or-SO
2-(C
1-C
4Alkyl) group replace or
Optional by 1,2 or 3 R
205The C that group replaces
2-C
10Alkenyl or C
2-C
10Alkynyl, wherein
Each aryl and heteroaryl are all chosen wantonly by 1,2 and 3 R
200Replace, wherein each heterocycle is all chosen wantonly by 1,2,3 or 4 R
210Replace.
R under each situation
200All be independently selected from-OH ,-NO
2, halogen ,-CO
2H, C ≡ N ,-(CH
2)
0-4-CO-NR
220R
225,-(CH
2)
0-4-CO-(C
1-C
12Alkyl) ,-(CH
2)
0-4-CO-(C
2-C
12Alkenyl) ,-(CH
2)
0-4-CO-(C
2-C
12Alkynyl) ,-(CH
2)
0-4-CO-(C
3-C
7Cycloalkyl) ,-(CH
2)
0-4-CO-aryl ,-(CH
2)
0-4-CO-heteroaryl ,-(CH
2)
0-4-CO-heterocycle ,-(CH
2)
0-4-CO-O-R
215,-(CH
2)
0-4-SO
2-NR
220R
225,-(CH
2)
0-4-SO-(C
1-C
8Alkyl) ,-(CH
2)
0-4-SO
2-(C
1-C
12Alkyl) ,-(CH
2)
0-4-SO
2-(C
3-C
7Cycloalkyl) ,-(CH
2)
0-4-N (H or R
215)-CO-O-R
215,-(CH
2)
0-4-N (H or R
215)-CO-N (R
215)
2,-(CH
2)
0-4-N-CS-N (R
215)
2,-(CH
2)
0-4-N (H or R
215)-CO-R
220,-(CH
2)
0-4-NR
220R
225,-(CH
2)
0-4-O-CO-(C
1-C
6Alkyl) ,-(CH
2)
0-4-O-P (O)-(OR
240)
2,-(CH
2)
0-4-O-CO-N (R
215)
2,-(CH
2)
0-4-O-CS-N (R
215)
2,-(CH
2)
0-4-O-(R
215) ,-(CH
2)
0-4-O-(R
215)-COOH ,-(CH
2)
0-4-S-(R
215) ,-(CH
2)
0-4-O-(the optional C that is replaced by 1,2,3 or 5-F
1-C
6Alkyl), C
3-C
7Cycloalkyl ,-(CH
2)
0-4-N (H or R
215)-SO
2-R
220,-(CH
2)
0-4-C
3-C
7Cycloalkyl or
Optional by 1,2 or 3 R
205The C that group replaces
1-C
10Alkyl or
Each is optional by 1 or 2 R
205The C that group replaces
2-C
10Alkenyl or C
2-C
10Alkynyl, wherein
Aryl under each situation and heteroaryl are all chosen wantonly by 1,2 or 3 following group and are replaced: R
205, R
210Or it is optional by 1,2 or 3 R
205Or R
210The C that group replaces
1-C
6Alkyl,
Wherein the heterocyclic group under each situation is all chosen wantonly by 1,2 or 3 R
210Group replaces;
R under each situation
205Be independently selected from C
1-C
6Alkyl, halogen ,-OH ,-the O-phenyl ,-SH ,-C ≡ N ,-CF
3, C
1-C
6Alkoxyl group, NH
2, NH (C
1-C
6Alkyl) or N-(C
1-C
6Alkyl) (C
1-C
6Alkyl);
R under each situation
210Be independently selected from halogen, C
1-C
6Alkoxyl group, C
1-C
6The halogen alkoxyl group ,-NR
220R
225, OH, C ≡ N ,-CO-(C
1-C
4Alkyl) ,-SO
2-NR
235R
240,-CO-NR
235R
240,-SO
2-(C
1-C
4Alkyl) ,=O or
C
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl or C
3-C
7Cycloalkyl, wherein each is all chosen wantonly by 1,2 or 3 R
205Group replaces;
R under each situation
215Be independently selected from C
1-C
6Alkyl ,-(CH
2)
0-2-(aryl), C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
3-C
7Cycloalkyl and-(CH
2)
0-2-(heteroaryl) ,-(CH
2)
0-2-(heterocycle), wherein the aryl under each situation is all chosen wantonly by 1,2 or 3 R
205Or R
210Group replaces, and heterocycle under each situation and heteroaryl are all chosen wantonly by 1,2 and 3 R
210Replace;
R under each situation
220And R
225Be independently selected from independently-H ,-C
3-C
7Cycloalkyl ,-(C
1-C
2Alkyl)-(C
3-C
7Cycloalkyl) ,-(C
1-C
6Alkyl)-O-(C
1-C
3Alkyl) ,-C
2-C
6Alkenyl ,-C
2-C
6Alkynyl, contain two keys and a triple-linked-C
1-C
6Alkyl chain ,-aryl ,-heteroaryl and-heterocycle or
Optional quilt-OH ,-NH
2, or halogen replace-C
1-C
10Alkyl, wherein
Aryl under each situation, heterocycle and heteroaryl are all chosen wantonly by 1,2 or 3 R
270Group replaces;
R under each situation
235And R
240All be H or C
1-C
6Alkyl;
R under each situation
245And R
250Be independently selected from-H, C
1-C
4Alkyl, C
1-C
4Alkylaryl, C
1-C
4Miscellaneous alkyl aryl, C
1-C
4Hydroxyalkyl, C
1-C
4Alkoxyl group, C
1-C
4The halogen alkoxyl group ,-(CH
2)
0-4-C
3-C
7Cycloalkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl and phenyl; Or
R
245And R
250Form a carbocyclic ring that contains 3,4,5,6 or 7 carbon atoms with the carbon that links to each other with them, one of them carbon atom can choose wantonly by one be independently selected from-O-,-S-,-SO
2-and-NR
220-heteroatoms replace;
R under each situation
255And R
260Be independently selected from-H ,-(CH
2)
1-2-S (O)
0-2-(C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-aryl ,-(C
1-C
4Alkyl)-heteroaryl ,-(C
1-C
4Alkyl)-heterocycle ,-aryl ,-heteroaryl ,-heterocycle ,-(CH
2)
1-4-R
265-(CH
2)
0-4-aryl ,-(CH
2)
1-4-R
265-(CH
2)
0-4-heteroaryl ,-(CH
2)
1-4-R
265-(CH
2)
0-4-heterocycle or
C
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl or-(CH
2)
0-4-C
3-C
7Cycloalkyl, wherein each is all chosen wantonly by 1,2 or 3 R
205Group replaces, wherein,
Each aryl or phenyl are all chosen wantonly by 1,2 or 3 following group and are replaced: R
205, R
210, or by 1,2 or 3 R
205Or R
210The C that group replaces
1-C
6Alkyl,
Wherein each heterocycle is all chosen wantonly by 1,2,3 or 4 R
210Replace;
R under each situation
265All be-O-,-S-or-N (C
1-C
6Alkyl)-;
R under each situation
270All be R
205, halogen, C
1-C
6Alkoxyl group, C
1-C
6Halogen alkoxyl group, NR
235R
240,-OH ,-C ≡ N ,-CO-(C
1-C
4Alkyl) ,-SO
2-NR
235R
240,-CO-NR
235R
240,-SO
2-(C
1-C
4Alkyl) ,=O or
C
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl or-(CH
2)
0-4-C
3-C
7Cycloalkyl, wherein each is all chosen wantonly by 1,2 or 3 R
205Group replaces;
R
NBe R '
100, SO
2R '
100,-(CRR ')
1-6R '
100,-C (=O)-(CRR ')
0-6R
100,-C (=O)-(CRR ')
1-6-O-R '
100,-C (=O)-(CRR ')
1-6-S-R '
100,-C (=O)-(CRR ')
1-6-C (=O)-R
100,-C (=O)-(CRR ')
1-6-SO
2-R
100Or-C (=O)-(CRR ')
1-6-NR
100-R '
100
R
100And R '
100Be independently aryl, heteroaryl ,-aryl-W-aryl ,-aryl-W-heteroaryl ,-aryl-W-heterocycle ,-heteroaryl-W-aryl ,-heteroaryl-W-heteroaryl ,-heteroaryl-W-heterocycle ,-heterocycle-W-aryl ,-heterocycle-W-heteroaryl ,-heterocycle-W-heterocycle ,-CH[(CH
2)
0-2-O-R
150]-(CH
2)
0-2-aryl ,-CH[(CH
2)
0-2-O-R
150]-(CH
2)
0-2-heterocycle or-CH[(CH
2)
0-2-O-R
150]-(CH
2)
0-2-heteroaryl, wherein the loop section of each is all chosen wantonly and is independently selected from following group by 1,2 or 3 and replaces :-OR ,-NO
2, halogen ,-C ≡ N ,-OCF
3,-CF
3,-(CH
2)
0-4-O-P (=O) (OR) (OR ') ,-(CH
2)
0-4-CO-NR
105R '
105,-(CH
2)
0-4-O-(CH
2)
0-4-CONR
102R '
102,-(CH
2)
0-4-CO-(C
1-C
12Alkyl) ,-(CH
2)
0-4-CO-(C
2-C
12Alkenyl) ,-(CH
2)
0-4-CO-(C
2-C
12Alkynyl) ,-(CH
2)
0-4-CO-(CH
2)
0-4(C
3-C
7Cycloalkyl) ,-(CH
2)
0-4-R
110,-(CH
2)
0-4-R
120,-(CH
2)
0-4-R
130,-(CH
2)
0-4-CO-R
110,-(CH
2)
0-4-CO-R
120,-(CH
2)
0-4-CO-R
130,-(CH
2)
0-4-CO-R
140,-(CH
2)
0-4-CO-O-R
150,-(CH
2)
0-4-SO
2-NR
105R '
105,-(CH
2)
0-4-SO-(C
1-C
8Alkyl) ,-(CH
2)
0-4-SO
2-(C
1-C
12Alkyl) ,-(CH
2)
0-4-SO
2-(CH
2)
0-4-(C
3-C
7Cycloalkyl) ,-(CH
2)
0-4-N (R
150)-CO-O-R
150,-(CH
2)
0-4-N (R
150)-CO-N (R
150)
2,-(CH
2)
0-4-N (R
150)-CS-N (R
150)
2,-(CH
2)
0-4-N (R
150)-CO-R
105,-(CH
2)
0-4-NR
105R '
105,-(CH
2)
0-4-R
140,-(CH
2)
0-4-O-CO-(C
1-C
6Alkyl) ,-(CH
2)
0-4-O-P (O)-(O-R
110)
2,-(CH
2)
0-4-O-CO-N (R
150)
2,-(CH
2)
0-4-O-CS-N (R
150)
2,-(CH
2)
0-4-O-(R
150) ,-(CH
2)
0-4-O-R
150'-COOH ,-(CH
2)
0-4-S-(R
150) ,-(CH
2)
0-4-N (R
150)-SO
2-R
105,-(CH
2)
0-4-C
3-C
7Cycloalkyl, (C
2-C
10) alkenyl or (C
2-C
10) alkynyl or
R
100Be optional by 1,2 or 3 R
115The C that group replaces
1-C
10Alkyl or
R
100Be-(C
1-C
6Alkyl)-O-(C
1-C
6Alkyl) or-(C
1-C
6Alkyl)-S-(C
1-C
6Alkyl), each is optional by 1,2 or 3 R
115Group replace or
R
100Be optional by 1,2 or 3 R
115The C that group replaces
3-C
8Cycloalkyl.
W is-(CH
2)
0-4-,-O-,-S (O)
0-2-,-N (R
135)-,-CR (OH)-or-C (O)-;
R
102And R
102' be independently halogen or optional by 1,2 or 3 halogen, aryl or-R
110The C that replaces
1-C
10Alkyl;
R
105And R
105' be independently-H ,-R
110,-R
120,-C
3-C
7Cycloalkyl ,-(C
1-C
2Alkyl)-(C
3-C
7Cycloalkyl) ,-(C
1-C
6Alkyl)-O-(C
1-C
3Alkyl) ,-C
2-C
6Alkenyl ,-C
2-C
6Alkynyl, contain two keys and a triple-linked-C
1-C
6Alkyl chain or optional quilt-OH or-NH
2The C that replaces
1-C
6Alkyl or optional by one, two or three are independently selected from that the group of halogen replaces-C
1-C
6Alkyl, or
R
105And R '
105Forming a carbocyclic ring that contains 3 to 7 atoms with the carbon that links to each other with them, one of them atom is optional to be one and to be independently selected from-O-,-S (O)
0-2-and-N (R
135)-heteroatoms, this ring is optional by 1,2 or 3 R
140Group replaces;
R under each situation
115Be independently halogen ,-OH ,-CO
2-R
102,-C
1-C
6Thio alkoxy ,-CO
2-phenyl ,-NR
105R '
135,-SO
2-(C
1-C
8Alkyl) ,-C (=O) R
180, R
180,-CONR
105R '
105,-SO
2NR
105R '
105,-NH-CO-(C
1-C
6Alkyl) ,-NH-C (=O)-OH ,-NH-C (=O)-OR ,-NH-C (=O)-the O-phenyl ,-O-C (=O)-(C
1-C
6Alkyl) ,-O-C (=O)-amino ,-O-C (=O)-list or dialkyl amido ,-O-C (=O)-phenyl ,-O-(C
1-C
6Alkyl)-CO
2H ,-NH-SO
2-(C
1-C
6Alkyl), C
1-C
6Alkoxyl group or C
1-C
6The halogen alkoxyl group;
R
135Be C
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
3-C
7Cycloalkyl ,-(CH
2)
0-2-(aryl) ,-(CH
2)
0-2-(heteroaryl) or-(CH
2)
0-2-(heterocycle);
R
140Be optional by 1,2,3 or 4 heterocycle that is independently selected from the group replacement of following group: C
1-C
6Alkyl, C
1-C
6Alkoxyl group, halogen, hydroxyl, cyano group, nitro, amino, list (C
1-C
6) alkylamino or two (C
1-C
6) alkylamino, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
1-C
6Alkylhalide group, C
1-C
6Halogen alkoxyl group, amino (C
1-C
6) alkyl, list (C
1-C
6) alkylamino (C
1-C
6) alkyl, two (C
1-C
6) alkylamino (C
1-C
6) alkyl and=O;
R
150Be halogen, C
3-C
7Cycloalkyl ,-(C
1-C
2Alkyl)-(C
3-C
7Cycloalkyl), C
2-C
6Alkenyl, C
2-C
6Alkynyl, contain two keys and a triple-linked C
1-C
6Alkyl ,-R
110,-R
120, or optional by 1,2,3 or 4 be independently selected from-OH ,-NH
2, C
1-C
3Alkoxyl group, R
110The C that replaces with the group of halogen
1-C
6Alkyl;
R
150' be C
3-C
7Cycloalkyl ,-(C
1-C
3Alkyl)-(C
3-C
7Cycloalkyl), C
2-C
6Alkenyl, C
2-C
6Alkynyl, contain two keys and a triple-linked C
1-C
6Alkyl ,-R
110,-R
120, or optional by 1,2,3 or 4 be independently selected from-OH ,-NH
2, C
1-C
3Alkoxyl group, R
110The C that replaces with the group of halogen
1-C
6Alkyl;
R
180Be independently selected from morpholinyl, thio-morpholinyl, piperazinyl, piperidyl, high morpholinyl, high-sulfur for morpholinyl, high-sulfur for morpholinyl S-oxide compound, high-sulfur for morpholinyl S, S-dioxide, pyrrolinyl and pyrrolidyl, wherein each is all chosen wantonly by 1,2,3 or 4 group that is independently selected from following group and replaces: C
1-C
6Alkyl, C
1-C
6Alkoxyl group, halogen, hydroxyl, cyano group, nitro, amino, list (C
1-C
6) alkylamino, two (C
1-C
6) alkylamino, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
1-C
6Alkylhalide group, C
1-C
6Halogen alkoxyl group, amino (C
1-C
6) alkyl, list (C
1-C
6) alkylamino (C
1-C
6) alkyl, two (C
1-C
6) alkylamino (C
1-C
6) alkyl and=O;
R
110Be optional by 1 or 2 R
125The aryl that group replaces;
R under each situation
125All be halogen, amino, list or dialkyl amido ,-OH ,-C ≡ N ,-SO
2-NH
2,-SO
2-NH-C
1-C
6Alkyl ,-SO
2-N (C
1-C
6Alkyl)
2,-SO
2-(C
1-C
4Alkyl) ,-CO-NH
2,-CO-NH-C
1-C
6Alkyl or-CO-N (C
1-C
6Alkyl)
2, or
C
1-C
6Alkyl, C
2-C
6Alkenyl or C
2-C
6Alkynyl, wherein each is chosen wantonly and is independently selected from C by 1,2 or 3
1-C
3Alkyl, halogen ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3The group of alkoxyl group, amino and list or dialkyl amido replaces, or
The optional C that is replaced by, two or three halogens
1-C
6Alkoxyl group;
R
120Be optional by 1 or 2 R
125The heteroaryl that group replaces; With
R
130Be optional by 1 or 2 R
125The heterocycle that group replaces.
Another wide in range aspect, the invention provides chemical formula is the compound of X and the salt that can be used for pharmacy thereof, wherein
R
1Be:
(I) C
1-C
6Alkyl can be chosen wantonly by one, two or three the substituting group replacement that is selected from following groups: C
1-C
3Alkyl, C
1-C
7Alkyl is (optional by C
1-C
3Alkyl and C
1-C
3Alkoxyl group replaces) ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group ,-NR
1-aR
1-b, and-OC=O-NR
1-aR
1-b, the R under each situation wherein
1-aAnd R
1-bBe independently-H or C
1-C
6Alkyl,
(II)-CH
2-S (O)
0-2-(C
1-C
6Alkyl),
(III)-CH
2-CH
2-S (O)
0-2-(C
1-C
6Alkyl),
(IV) contain the C of one or two pair key
2-C
6Alkenyl, can choose wantonly by one, two or three substituting group that is selected from following groups and replace :-F ,-Cl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group ,-NR
1-aR
1-b, R wherein
1-aAnd R
1-bBe-H or C
1-C
6Alkyl,
(V) contain one or two triple-linked C
2-C
6Alkynyl, can choose wantonly by one, two or three substituting group that is independently selected from following groups and replace :-F ,-Cl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group ,-NR
1-aR
1-b, R wherein
1-aAnd R
1-bBe-H or C
1-C
6Alkyl,
(VI)-(CH
2)
N1-(R
The 1-aryl), wherein n1 is 0 or 1, and R wherein
The 1-arylBe phenyl, naphthyl, 2,3-indanyl, indenyl, dihydro naphthyl or tetrahydro naphthyl, wherein each is all chosen wantonly on aromatic ring and is replaced by one, two, three, four or five following substituting group:
(A) C
1-C
6Alkyl can be chosen wantonly by one, two or three and be selected from C
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-NR
1-aR
1-b,-C ≡ N ,-CF
3And C
1-C
3The substituting group of alkoxyl group replaces,
(B) C
2-C
6Alkenyl, can choose wantonly by one, two or three be selected from-F ,-Cl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bSubstituting group replace;
(C) C
2-C
6Alkynyl, can choose wantonly by one, two or three and be selected from :-F ,-Cl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bSubstituting group replace,
(D)-F, Cl ,-Br and-I,
(E)-C
1-C
6The halogen alkoxyl group,
(F)-C
1-C
6Alkoxyl group,
(G)-NR
N-2R
N-3，
(H)-OH，
(I)-C≡N，
(J) C
3-C
7Cycloalkyl, can choose wantonly by one, two or three be selected from-F ,-Cl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bSubstituting group replace,
(K)-CO-(C
1-C
4Alkyl),
(L)-SO
2-NR
1-aR
1-b，
(M)-CO-NR
1-aR
1-b，
(N)-SO
2-(C
1-C
4Alkyl),
(VII)-(CH
2)
N1-(R
The 1-heteroaryl), R wherein
The 1-heteroarylBe selected from pyridyl, pyrimidyl, quinoline beautiful jade base, benzothienyl, indyl, indolinyl, pyridazinyl, pyrazinyl, pseudoindoyl, different quinoline beautiful jade base, quinazolyl, quinoxalinyl, 2, the 3-phthalazinyl, imidazolyl isoxazolyl, pyrazolyl oxazolyl, thiazolyl, the indolizine base, indazolyl, benzothiazolyl, benzimidazolyl-, benzofuryl, furyl, thienyl, pyrryl oxadiazole base, thiadiazolyl group, triazolyl, tetrazyl oxazole and pyridyl, imidazopyridyl, isothiazolyl, 1, the 5-phthalazinyl, 1, the 2-phthalazinyl, carbazyl, the β-Ka Lin base, the isochroman base, chromanyl, Tetrahydroisoquinoli-beautiful jade base, dihydro-iso indolyl, different benzo tetrahydrofuran base, different benzo tetrahydro-thienyl, isobenzo-thienyl benzoxazolyl, the pyridopyridine base, the benzo tetrahydrofuran base, the benzo tetrahydro-thienyl, purine radicals, the benzodioxole base, triazinyl phenoxazinyl, phenothiazinyl, pteridyl, benzothiazolyl, imidazopyridyl, the Imidazothiazole base, dihydrobenzo Yi oxazinyl, Ben Bing Yi oxazinyl benzoxazinyl, dihydrobenzo isothiazine base, benzopyranyl, the benzo thiapyran base, the tonka bean camphor base, isocoumarinyl, the chromone base, the chromanone base, tetrahydrochysene quinoline beautiful jade base, dihydro quinoline beautiful jade base, dihydro quinoline beautiful jade ketone group, the different quinoline beautiful jade of dihydro ketone group, the melilotine base, the dihydro isocoumarinyl, the isoindoline ketone group, benzodioxan base benzoxazolinone base, pyridyl-N-oxide compound, pyrryl N-oxide compound, pyrimidyl N-oxide compound, pyridazine N-oxide compound, pyrazine N-oxide compound, quinoline beautiful jade N-oxide compound, indoles N-oxide compound, indolinyl N-oxide compound, different quinoline beautiful jade base N-oxide compound, quinazolyl N-oxide compound, quinoxalinyl N-oxide compound, 2,3-phthalazinyl N-oxide compound, imidazolyl N-oxide compound isoxazolyl N-oxide compound oxazolyl N-oxide compound, thiazolyl N-oxide compound, indolizine base N-oxide compound, indazolyl N-oxide compound, benzothiazolyl N-oxide compound, benzimidazolyl-N-oxide compound, pyrryl N-oxide compound oxadiazole base N-oxide compound, thiadiazolyl group N-oxide compound, triazolyl N-oxide compound, tetrazyl N-oxide compound, benzo thiapyran base S-oxide compound, and benzo thiapyran base S, the S-dioxide
R wherein
The 1-heteroarylBy precursor group R
The N-heteroarylAny annular atoms that is replaced by hydrogen and-(CH
2)
N1-link to each other, be connected to R like this
The 1-heteroarylOn new key substituted hydrogen atom and key thereof, wherein heteroaryl can be chosen wantonly by one, two, three, four or five following groups and replace:
(1) C
1-C
6Alkyl can be chosen wantonly by one, two or three and be selected from C
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-NR
1-aR
1-b,-C ≡ N ,-CF
3And C
1-C
3The substituting group of alkoxyl group replaces,
(2) contain the C of one or two pair key
2-C
6Alkenyl, can choose wantonly by one, two or three be independently selected from-F ,-Cl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bSubstituting group replace,
(3) contain one or two triple-linked C
2-C
6Alkynyl, can choose wantonly by one, two or three be independently selected from-F ,-Cl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bSubstituting group replace,
(4)-F ,-Cl ,-Br and-I,
(5)-C
1-C
6The halogen alkoxyl group,
(6)-C
1-C
6Alkoxyl group,
(7)-NR
N-2R
N-3，
(8)-OH，
(9)-C≡N，
(10) C
3-C
7Cycloalkyl, can choose wantonly by one, two or three be independently selected from-F ,-Cl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bSubstituting group replace,
(11)-CO-(C
1-C
4Alkyl),
(12)-SO
2-NR
1-aR
1-b，
(13)-CO-NR
1-aR
1-b，
(14)-SO
2-(C
1-C
4Alkyl), condition is to work as n
1When being zero, R
The 1-heteroarylDo not link to each other with carbochain by nitrogen-atoms,
(VIII)-(CH
2)
N1-(R
The 1-heterocycle), n wherein
1Definition as above and R
The 1-heterocycleBe selected from morpholinyl, thio-morpholinyl, thio-morpholinyl S-oxide compound, thio-morpholinyl S, the S-dioxide, piperazinyl, high piperazinyl, pyrrolidyl, pyrrolinyl, THP trtrahydropyranyl, piperidyl, tetrahydrofuran base, tetrahydro-thienyl, homopiperidinyl, high morpholinyl, high-sulfur is for morpholinyl, high-sulfur is for morpholinyl S, S-dioxide; oxazolidine ketone group, the pyrazoline base, the pyrrolin base, the dihydro pyrazinyl, the dihydropyridine base, the dihydro-pyrimidin base, the dihydrofuran base, dihydro pyranyl, tetrahydro-thienyl S-oxide compound, tetrahydro-thienyl S, the S-dioxide, high-sulfur is for morpholinyl S-oxide compound, the dithiane base, pyranyl, the dihydrofuran base, the pyrroline ketone group, the tetrahydroglyoxaline ketone group, the imidazolinedione base, wherein each above-mentioned group is all chosen wantonly and is fused to benzene, on pyridine or the pyrimidine ring, and
R
The 1-heterocycleBy precursor group R
The 1-heterocycleAny atom that is replaced by hydrogen connect, be connected to R like this
The 1-heterocycleOn new key substituted hydrogen atom and key thereof, wherein heterocycle can be chosen wantonly by one, two, three or four following groups and replace:
(1) C
1-C
6Alkyl can be chosen wantonly by one, two or three and be independently selected from C
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-NR
1-aR
1-b,-C ≡ N ,-CF
3And C
1-C
3The substituting group of alkoxyl group replaces,
(2) C
2-C
6Alkenyl, can choose wantonly by one, two or three be selected from-F ,-Cl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group ,-NR
1-aR
1-bSubstituting group replace,
(3) C
2-C
6Alkynyl, can choose wantonly by one, two or three be independently selected from-F ,-Cl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C-oxygen base and-NR
1-aR
1-bSubstituting group replace,
(4)-F ,-Cl ,-Br and-I,
(5)-C
1-C
6Alkoxyl group,
(6)-C
1-C
6The halogen alkoxyl group,
(7)-NR
N-2R
N-3，
(8)-OH，
(9)-C≡N，
(10) C
3-C
7Cycloalkyl, can choose wantonly by one, two or three be independently selected from-F ,-Cl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bSubstituting group replace,
(11)-CO-(C
1-C
4Alkyl),
(12)-SO
2-NR
1-aR
1-b，
(13)-CO-NR
1-aR
1-b，
(14)-SO
2-(C
1-C
4Alkyl),
(15)=and O, condition is to work as n
1When being zero, R
The 1-heterocycleDo not link to each other with carbochain by nitrogen-atoms; R wherein
2Be selected from:
(I)-H
(II) C
1-C
6Alkyl can be chosen wantonly by one, two or three and be independently selected from C
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bSubstituting group replace,
(III)-(CH
2)
0-4-R
30, R wherein
30Be R
The 1-aryl, R
The 1-hetero-aromatic ring, or R
The 1-heterocycle,
(IV) has the C of one or two pair key
2-C
6Alkenyl, can choose wantonly by one, two or three be independently selected from-F ,-Cl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bSubstituting group replace,
(V) C
2-C
6Alkynyl, can choose wantonly by one, two or three be independently selected from-F ,-Cl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bSubstituting group replace,
(VI)-(CH
2)
0-4-C
3-C
7Cycloalkyl, can choose wantonly by one, two or three be independently selected from-F ,-Cl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bSubstituting group replace,
R wherein
3Be independently selected from:
(I)-H
(II) C
1-C
6Alkyl can be chosen wantonly by one, two or three and be selected from C
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bSubstituting group replace,
(III)-(CH
2)
0-4-R
30，
(IV) C
2-C
6Alkenyl,
(V) C
2-C
6Alkynyl,
(VI)-(CH
2)
0-4-C
3-C
7Cycloalkyl, can choose wantonly by one, two or three be independently selected from-F ,-Cl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bSubstituting group replace,
Perhaps R
2And R
3Forming the carbocyclic ring that contains three, four, five, six and seven carbon atoms with the carbon atom that links to each other with them, one of them carbon atom can choose wantonly and be selected from-O-,-S-,-SO
2-,-NR
N-2-heteroatoms replace;
R
NBe:
(I) R
N-1-X
N-, X wherein
NBe independently selected from:
(A)-CO-
(B)-SO
2-
(C)-(CR ' R ")
1-6, wherein
R ' under each situation and R " identical or different, and be-H or C
1-C
4Alkyl,
(D)-CO-(CR ' R ")
1-6-X
N-1, X wherein
N-1Be independently selected from-O-,-S-and-NR '-,
(E) singly-bound, and
(F)-CO-(CR′R″)
1-6-
R wherein
N-1Be selected from:
(A) R
The N-aryl, the R under each situation wherein
The N-arylAll be phenyl independently; Naphthyl; Tetrahydro naphthyl; 2, the 3-indanyl; Indenyl; The dihydro naphthyl; Or 6,7,8,9-tetrahydrochysene-5H-benzo [a] cycloheptenyl; Wherein each group all can be chosen wantonly by one, two or three following groups and replace:
(1) C
1-C
6Alkyl can be chosen wantonly by one, two or three and be selected from C
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bSubstituting group replace the R under each situation wherein
1-aAnd R
1-bBe H or C independently
1-C
6Alkyl,
(2)-OH，
(3)-NO
2，
(4)-F、-Cl、-Br、-I，
(5)-CO
2H，
(6)-C≡N，
(7)-(CH
2)
0-4-CO-NR
N-2R
N-3, the R of each situation wherein
N-2And R
N-3Identical or different, it is selected from:
(a)-H，
(b)-C
1-C
8Alkyl, it is optional by a substituting group replacement, and substituting group is selected from:
(i)-OH，
(ii)-NH
2
(iii) phenyl,
(c)-C
1-C
8Alkyl, its can choose wantonly by 1,2 or 3-F ,-Cl ,-Br or-I replaces,
(d)-C
3-C
8Cycloalkyl,
(e)-(C
1-C
2Alkyl)-(C
3-C
8Cycloalkyl),
(f)-(C
1-C
6Alkyl)-O-(C
1-C
3Alkyl),
(g)-C
2-C
6Alkenyl,
(h)-C
2-C
6Alkynyl,
(i) contain two keys and a triple-linked-C
1-C
6Alkyl chain,
(j)-R
The 1-aryl,
(k)-R
The 1-heteroaryl,
(1)-R
The 1-heterocycle, or
(m) R
N-2, R
N-35,6 or 7 yuan of Heterocyclylalkyls that form with the nitrogen that links to each other with them or heteroaryl, wherein said Heterocyclylalkyl or heteroaryl are optional to be fused on phenyl ring, pyridine ring or the pyrimidine ring, and described group is unsubstituted or is C by 1,2,3,4 or 5 independently in various situations
1-C
6Alkyl, C
1-C
6Alkynyloxy group, halogen, halogen C
1-C
6Alkyl, halogen C
1-C
6Alkoxyl group ,-CN ,-NO
2,-NH
2, NH (C
1-C
6Alkyl), N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-OH ,-C (O) NH
2,-C (O) NH (C
1-C
6Alkyl) ,-C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl), C
1-C
6Alkoxy C
1-C
6Alkyl, C
1-C
6Thio alkoxy and C
1-C
6Thio alkoxy C
1-C
6The group of alkyl replaces;
(B)-R
The N-heteroaryl, R wherein
The N-heteroarylBe independently selected from pyridyl, pyrimidyl, quinoline beautiful jade base, benzothienyl, indyl, indolinyl, pyridazinyl, pyrazinyl, pseudoindoyl, different quinoline beautiful jade base, quinazolyl, quinoxalinyl, 2, the 3-phthalazinyl, imidazolyl isoxazolyl, pyrazolyl oxazolyl, thiazolyl, the indolizine base, indazolyl, benzothiazolyl, benzimidazolyl-, benzofuryl, furyl, thienyl, pyrryl oxadiazole base, thiadiazolyl group, triazolyl, tetrazyl oxazole and pyridyl, imidazopyridyl, isothiazolyl, 1, the 5-phthalazinyl, 1, the 2-phthalazinyl, carbazyl, the β-Ka Lin base, different coumaran base, the coumaran base, Tetrahydroisoquinoli-beautiful jade base, dihydro-iso indolyl, different benzo tetrahydrofuran base, different benzo tetrahydro-thienyl, isobenzo-thienyl benzoxazolyl, the pyridopyridine base, the benzo tetrahydrofuran base, the benzo tetrahydro-thienyl, purine radicals, the benzodioxole base, triazinyl phenoxazinyl, phenothiazinyl, pteridyl, benzothiazolyl, the Imidazothiazole base, dihydrobenzo Yi oxazinyl, Ben Bing Yi oxazinyl benzoxazinyl, dihydrobenzo isothiazine base, benzopyranyl, the benzo thiapyran base, the tonka bean camphor base, isocoumarinyl, the chromone base, the chromanone base, tetrahydrochysene quinoline beautiful jade base, dihydro quinoline beautiful jade base, dihydro quinoline beautiful jade ketone group, the different quinoline beautiful jade of dihydro ketone group, the melilotine base, the dihydro isocoumarinyl, the isoindoline ketone group, benzodioxan base benzoxazolinone base, pyridyl-N-oxide compound, pyrryl N-oxide compound, pyrimidyl N-oxide compound, pyridazine N-oxide compound, pyrazine N-oxide compound, quinoline beautiful jade N-oxide compound, indoles N-oxide compound, indoline base N-oxide compound, different quinoline beautiful jade base N-oxide compound, quinazolyl N-oxide compound, quinoxalinyl N-oxide compound, 2,3-phthalazinyl N-oxide compound, imidazolyl N-oxide compound isoxazolyl N-oxide compound oxazolyl N-oxide compound, thiazolyl N-oxide compound, indolizine base N-oxide compound, indazolyl N-oxide compound, benzothiazolyl N-oxide compound, benzimidazolyl-N-oxide compound, pyrryl N-oxide compound oxadiazole base N-oxide compound, thiadiazolyl group N-oxide compound, triazolyl N-oxide compound, tetrazyl N-oxide compound, benzo thiapyran base S-oxide compound, benzo thiapyran base S, the S-dioxide, the imidazolopyrazole base, the quinazoline ketone group, Pyrazolopyridine base Ben Bing oxadiazole base, the dihydro-pyrimidin ketone group, with the Dihydrobenzofuranes ketone group, the optional benzene that is fused to of wherein above-mentioned each substituting group, on pyridine or the pyrimidine ring
R wherein
The N-heteroarylBy parent R
The N-heteroarylAny atom that is replaced by hydrogen of group connects, and is connected to R like this
The N-heteroarylOn new key substituted hydrogen atom and key thereof, wherein heteroaryl can be chosen wantonly by one, two, three or four following groups and replace:
(1) C
1-C
6Alkyl can be chosen wantonly by one, two or three and be independently selected from C
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bSubstituting group replace,
(2)-OH，
(3)-NO
2，
(4)-F、-Cl、-Br、-I，
(5)-CO
2H，
(6)-C≡N，
(7)-(CH
2)
0-4-CO-NR
N-2R
N-3，
(8)-(CH
2)
0-4-CO-(C
1-C
12Alkyl),
(9)-(CH
2)
0-4-CO-(C
2-C
12Alkenyl),
(10)-(CH
2)
0-4-CO-(C
2-C
12Alkynyl),
(11)-(CH
2)
0-4-CO-(C
3-C
8Cycloalkyl),
(12)-(CH
2)
0-4-CO-R
The 1-aryl,
(13)-(CH
2)
0-4-CO-R
The 1-heteroaryl,
(14)-(CH
2)
0-4-CO-R
The 1-heterocycle,
(15)-(CH
2)
0-4-CO-R
N-4，
(16)-(CH
2)
0-4-CO
2-R
N-5，
(17)-(CH
2)
0-4-SO
2-NR
N-2R
N-3，
(18)-(CH
2)
0-4-SO-(aryl C
1-C
8Alkyl),
(19)-(CH
2)
0-4-SO
2-(C
1-C
12Alkyl),
(20)-(CH
2)
0-4-SO
2-(C
3-C
8Cycloalkyl),
(21)-(CH
2)
0-4-N (H or R
N-5)-CO-O-R
N-5,
(22)-(CH
2)
0-4-N (H or R
N-5)-CO-N (R
N-5)
2,
(23)-(CH
2)
0-4-N-CS-N(R
N-5)
2，
(24)-(CH
2)
0-4-N (H or R
N-5)-CO-R
N-2,
(25)-(CH
2)
0-4-NR
N-2R
N-3，
(26)-(CH
2)
0-4-R
N-4
(27)-(CH
2)
0-4-O-CO-(C
1-C
6Alkyl),
(28)-(CH
2)
0-4-O-P(O)-(OR
100)
2，
(29)-(CH
2)
0-4-O-CO-N(R
N-5)
2，
(30)-(CH
2)
0-4-O-CS-N(R
N-5)
2，
(31)-(CH
2)
0-4-O-(R
N-5)，
(32)-(CH
2)
0-4-O-(R
N-5)-COOH，
(33)-(CH
2)
0-4-S-(R
N-5)，
(34)-(CH
2)
0-4-O-(the optional C that is replaced by one, two, three, four or five-F
1-C
6Alkyl),
(35) C
3-C
8Cycloalkyl,
(36) C
2-C
6Alkenyl can be chosen wantonly by C
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group or-NR
1-aR
1-bSubstituting group replace,
(37) C
2-C
6Alkynyl can be chosen wantonly by C
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group or-NR
1-aR
1-bReplace,
(38)-(CH
2)
0-4-N (H or R
N-5)-SO
2-R
N-2
(39)-(CH
2)
0-4-C
3-C
8Cycloalkyl,
(C) R
The N-aryl-W-R
The N-aryl,
(D) R
The N-aryl-W-R
The N-heteroaryl,
(E) R
The N-aryl-W-R
The N-heterocycle,
(F) R
The N-heteroaryl-W-R
The N-aryl,
(G) R
The N-heteroaryl-W-R
The N-heteroaryl,
(H) R
The N-heteroaryl-W-R
The 1-heterocycle,
(I) R
The N-heterocycle-W-R
The N-aryl,
(J) R
The N-heterocycle-W-R
The N-heteroaryl,
(K) R
The N-heterocycle-W-R
The 1-heterocycle,
Wherein W is
(1)-(CH
2)
1-4-，
(2)-O-，
(3)-S(O)
0-2-，
(4)-N(R
N-5)-，
(5)-CO-; Or
(6) one keys
(II)-CO-(C
1-C
10Alkyl), wherein alkyl can be chosen wantonly by one, two or three substituting group replacement that is independently selected from following groups:
(A)-OH，
(B)-C
1-C
6Alkoxyl group,
(C)-C
1-C
6Thio alkoxy,
(D)-CO
2-R
N-8, the R under each situation wherein
N-8All be-H, C
1-C
6Alkyl or optional be halogen, C independently by 1 or 2
1-C
4Alkoxyl group, C
1-C
4Alkyl or-C (O) NH
2The phenyl that replaces of group,
(E)-CO-NR
N-2R
N-3，
(F)-CO-R
N-4，
(G)-SO
2-(C
1-C
8Alkyl),
(H)-SO
2-NR
N-2R
N-3，
(I)-NH-CO-(C
1-C
6Alkyl),
(J)-NH-CO-O-R
N-8，
(K)-NR
N-2R
N-3，
(L)-R
N-4，
(M)-O-CO-(C
1-C
6Alkyl),
(N)-O-CO-NR
N-8R
N-8，
(O)-O-(C
1-C
5Alkyl)-COOH,
(P)-O-(can choose wantonly by one, two or three-F ,-Cl ,-Br or-C that the I group replaces
1-C
6Alkyl),
(Q)-NH-SO
2-(C
1-C
6Alkyl),
(R) halogen,
(S)-N (H or R
N-5)-SO
2-R
N-2,
(T)-N (H or R
N-5)-CO-(R
N-2), and
(U)-SO
2-R
N-2，
(V) R
The N-aryl
(III)-CO-(C
1-C
6Alkyl)-O-(C
1-C
6Alkyl), wherein each alkyl all is unsubstituted, or is replaced by one, two or three substituting group that is independently selected from following groups:
(A)-OH，
(B)-C
1-C
6Alkoxyl group,
(C)-C
1-C
6Thio alkoxy,
(D)-CO
2-R
N-8，
(E)-CO-NR
N-2R
N-3，
(F)-CO-R
N-4，
(G)-SO
2-(C
1-C
8Alkyl),
(H)-SO
2-NR
N-2R
N-3，
(I)-NH-CO-(C
1-C
6Alkyl),
(J)-NH-CO-O-R
N-8，
(K)-NR
N-2R
N-3，
(L)-R
N-4，
(M)-O-CO-(C
1-C
6Alkyl),
(N)-O-CO-NR
N-8R
N-8，
(O)-O-(C
1-C
5Alkyl)-CO
2H,
(P)-O-(can choose wantonly by one, two or three be independently-F ,-Cl ,-Br or-C that the group of I replaces
1-C
6Alkyl),
(Q)-NH-SO
2-(C
1-C
6Alkyl),
(R) halogen,
(S)-N (H or R
N-5)-SO
2-R
N-2,
(T)-N (H or R
N-5)-CO-(R
N-2),
(U)-SO
2-R
N-2, and
(V) R
The N-aryl
(IV)-CO-(C
1-C
6Alkyl)-S-(C
1-C
6Alkyl), wherein each alkyl all is unsubstituted, or is replaced by one, two or three substituting group that is independently selected from following groups:
(A)-OH，
(B)-C
1-C
6Alkoxyl group,
(C)-C
1-C
6Thio alkoxy,
(D)-CO
2-R
N-8，
(E)-CO-NR
N-2R
N-3，
(F)-CO-R
N-4，
(G)-SO
2-(C
1-C
8Alkyl),
(H)-SO
2-NR
N-2R
N-3，
(I)-NH-CO-(C
1-C
6Alkyl),
(J)-NH-CO-O-R
N-8，
(K)-NR
N-2R
N-3，
(L)-R
N-4，
(M)-O-CO-(C
1-C
6Alkyl),
(N)-O-CO-NR
N-8R
N-8，
(O)-O-(C
1-C
5Alkyl)-CO
2H,
(P)-O-(can choose wantonly by one, two or three be independently-F ,-Cl ,-Br ,-C that the group of I replaces
1-C
6Alkyl),
(Q)-NH-SO
2-(C
1-C
6Alkyl),
(R) halogen,
(S)-N (H or R
N-5)-SO
2-R
N-2,
(T)-N (H or R
N-5)-CO-(R
N-2),
(U)-SO
2-R
N-2, and
(V) R
The N-aryl
(V)-CO-CH ((CH
2)
0-2-O-R
N-10)-(CH
2)
0-2-(R
The N-arylOr R
The N-heteroaryl)), wherein
R
N-10Be independently selected from following groups:
(1)-H
(2) C
1-C
6Alkyl
(3) C
3-C
8Cycloalkyl
(4) C
2-C
6Alkenyl
(5) C
2-C
6Alkynyl
(6) R
The 1-aryl
(7) R
The N-heteroaryl
(8) R
The N-heterocycle
(VI)-CO-(C
3-C
8Cycloalkyl), wherein cycloalkyl is optional is replaced by one or two substituting group that is independently selected from following groups:
(A)-(CH
2)
0-4-OH，
(B)-(CH
2)
0-4-C
1-C
6Alkoxyl group,
(C)-(CH
2)
0-4-C
1-C
6Thio alkoxy,
(D)-(CH
2)
0-4-CO-O-R
N-8，
(E)-(CH
2)
0-4-CO-NR
N-2R
N-3，
(F)-(CH
2)
0-4-CO-R
N-4，
(G)-(CH
2)
0-4-SO
2-(C
1-C
8Alkyl),
(H)-(CH
2)
0-4-SO
2-NR
N-2R
N-3，
(I)-(CH
2)
0-4-NH-CO-(C
1-C
6Alkyl),
(J)-NH-CO-O-R
N-8，
(K)-(CH
2)
0-4-NR
N-2R
N-3，
(L)-(CH
2)
0-4-R
N-4，
(M)-O-CO-(C
1-C
6Alkyl),
(N)-O-CO-NR
N-8R
N-8，
(O)-O-(C
1-C
6Alkyl)-CO
2H,
(P)-O-(can choose wantonly by one, two or three be independently-F ,-Cl ,-Br ,-C that the group of I replaces
1-C
6Alkyl),
(Q)-NH-SO
2-(C
1-C
6Alkyl),
(R) halogen,
(S)-N (H or R
N-5)-SO
2-R
N-2,
(T)-N (H or R
N-5)-CO-(R
N-2),
(U)-SO
2-R
N-2, and
(V) R
The N-aryl
Wherein, R
CBe:
(I) optionally be selected from C by one, two or three
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
6Alkoxyl group ,-the O-phenyl ,-NR
1-aR
1-b,-C=O-NR
1-aR
1-b,-S (=O)
0-2R
1-a,-NR
1-aC=ONR
1-aR
1-b,-C=O-NR
1-aR
1-bWith-S (=O)
2NR
1-aR
1-bThe C that replaces of substituting group
1-C
10Alkyl,
(II)-(CH
2)
0-3-(C
3-C
8) cycloalkyl, wherein cycloalkyl can be chosen wantonly by one, two or three and be independently selected from C
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
6Alkoxyl group ,-the O-phenyl ,-CO
2H ,-CO
2-(C
1-C
4Alkyl) and-NR
1-aR
1-bSubstituting group replace,
(III)-(CR
C-XR
C-Y)
0-4-R
The C-aryl, be phenyl, naphthyl, tetrahydro naphthyl independently under each situation; 2, the 3-indanyl; Indenyl; The dihydro naphthyl; Or 6,7,8,9-tetrahydrochysene-5H-benzo [a] cycloheptenyl; The group that it is following groups independently that each group is all chosen wantonly by 1,2 or 3 every kind of situation replaces:
(1) C
1-C
6Alkyl can be chosen wantonly by one, two or three and be selected from C
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bSubstituting group replace,
(2)-OH
(3)-NO
2，
(4)-F、-Cl、-Br、-I，
(5)-CO
2H，
(6)-C ≡ N and
(7)-(CH
2)
0-4-CO-NR
N-2R
N-3；
R wherein
C-XAnd R
C-YBe independently
-H，
Can choose the C that is replaced by one or two-OH wantonly
1-C
4Alkyl,
Can choose the C that is replaced by 1,2 or 3-F wantonly
1-C
4Alkoxyl group,
-(CH
2)
0-4-C
3-C
8Cycloalkyl,
C
2-C
6Alkenyl,
C
2-C
6Alkynyl, and
Phenyl,
Or R
C-XAnd R
C-YForming the carbocyclic ring that contains three, four, five, six and seven carbon atoms with the carbon atom that links to each other with them, a carbon atom in this carbocyclic ring is optional to be selected from-O-,-S-,-SO
2-,-NR
N-2-heteroatoms replace and R
The C-arylDefinition as above;
(IV)-(CR
C-XR
C-Y)
0-4-R
The C-heteroaryl, the R under each situation wherein
The C-heteroarylAll be independently selected from pyridyl, pyrimidyl, quinoline beautiful jade base, benzothienyl, indyl, indolinyl, pyridazinyl, pyrazinyl, pseudoindoyl, different quinoline beautiful jade base, quinazolyl, quinoxalinyl, 2, the 3-phthalazinyl, imidazolyl isoxazolyl, pyrazolyl oxazolyl, thiazolyl, the indolizine base, indazolyl, benzothiazolyl, benzimidazolyl-, benzofuryl, furyl, thienyl, pyrryl oxadiazole base, thiadiazolyl group, triazolyl, tetrazyl oxazole and pyridyl, isothiazolyl, 1, the 5-phthalazinyl, 1, the 2-phthalazinyl, carbazyl, the β-Ka Lin base, different coumaran base, the coumaran base, Tetrahydroisoquinoli-beautiful jade base, dihydro-iso indolyl, different benzo tetrahydrofuran base, different benzo tetrahydro-thienyl, isobenzo-thienyl benzoxazolyl, the pyridopyridine base, the benzo tetrahydrofuran base, the benzo tetrahydro-thienyl, purine radicals, the benzodioxole base, triazinyl phenoxazinyl, phenothiazinyl, pteridyl, benzothiazolyl, imidazopyridyl, the Imidazothiazole base, dihydrobenzo Yi oxazinyl, Ben Bing Yi oxazinyl benzoxazinyl, dihydrobenzo isothiazine base, benzopyranyl, the benzo thiapyran base, the tonka bean camphor base, isocoumarinyl, the chromone base, the chromanone base, tetrahydrochysene quinoline beautiful jade base, dihydro quinoline beautiful jade base, dihydro quinoline beautiful jade ketone group, the different quinoline beautiful jade of dihydro ketone group, the melilotine base, the dihydro isocoumarinyl, the isoindoline ketone group, benzodioxan base benzoxazolinone base, the imidazolopyrazole base, the quinazoline ketone group, pyrazolopyridines base Ben Bing oxadiazole base, the dihydro-pyrimidin ketone group, the Dihydrobenzofuranes ketone group, pyridyl-N-oxide compound, pyrryl N-oxide compound, pyrimidyl N-oxide compound, pyridazine N-oxide compound, pyrazine N-oxide compound, quinoline beautiful jade N-oxide compound, indoles N-oxide compound, indoline base N-oxide compound, different quinoline beautiful jade base N-oxide compound, quinazolyl N-oxide compound, quinoxalinyl N-oxide compound, 2,3-phthalazinyl N-oxide compound, imidazolyl N-oxide compound isoxazolyl N-oxide compound oxazolyl N-oxide compound, thiazolyl N-oxide compound, indolizine base N-oxide compound, indazolyl N-oxide compound, benzothiazolyl N-oxide compound, benzimidazolyl-N-oxide compound, pyrryl N-oxide compound oxadiazole base N-oxide compound, thiadiazolyl group N-oxide compound, triazolyl N-oxide compound, tetrazyl N-oxide compound, benzo thiapyran base S-oxide compound, benzo thiapyran base S, the S-dioxide
R wherein
The C-heteroarylBy parent R
The C-heteroarylAny atom that is replaced by hydrogen of group connects, and is connected to R like this
The C-heteroarylOn new key substituted hydrogen atom and key thereof, wherein heteroaryl can be chosen wantonly by 1,2,3 or 4 following groups and replace:
(1) C
1-C
6Alkyl can be chosen wantonly by one, two or three and be independently selected from C
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bSubstituting group replace,
(2)-OH，
(3)-NO
2，
(4)-F、-Cl、-Br、-I，
(5)-CO-OH，
(6)-C≡N，
(7)-(CH
2)
0-4-CO-NR
N-2R
N-3，
(8)-(CH
2)
0-4-CO-(C
1-C
12Alkyl),
(9)-(CH
2)
0-4-CO-(C
2-C
12Alkenyl),
(10)-(CH
2)
0-4-CO-(C
2-C
12Alkynyl),
(11)-(CH
2)
0-4-CO-(C
3-C
7Cycloalkyl),
(12)-(CH
2)
0-4-CO-R
The 1-aryl,
(13)-(CH
2)
0-4-CO-R
The 1-heteroaryl,
(14)-(CH
2)
0-4-CO-R
The 1-heterocycle,
(15)-(CH
2)
0-4-CO-R
N-4，
(16)-(CH
2)
0-4-CO-O-R
N-5，
(17)-(CH
2)
0-4-SO
2-NR
N-2R
N-3，
(18)-(CH
2)
0-4-SO-(C
1-C
8Alkyl),
(19)-(CH
2)
0-4-SO
2-(C
1-C
12Alkyl),
(20)-(CH
2)
0-4-SO
2-(C
3-C
7Cycloalkyl),
(21)-(CH
2)
0-4-N (H or R
N-5)-CO-O-R
N-5,
(22)-(CH
2)
0-4-N (H or R
N-5)-CO-N (R
N-2)
2,
(23)-(CH
2)
0-4-N-CS-N(R
N-5)
2，
(24)-(CH
2)
0-4-N (H or R
N-5)-CO-R
N-2,
(25)-(CH
2)
0-4-NR
N-2R
N-3，
(26)-(CH
2)
0-4-R
N-4，
(27)-(CH
2)
0-4-O-CO-(C
1-C
6Alkyl),
(28)-(CH
2)
0-4-O-P(O)-(OR
100)
2，
(29)-(CH
2)
0-4-O-CO-N(R
N-5)
2，
(30)-(CH
2)
0-4-O-CS-N(R
N-5)
2，
(31)-(CH
2)
0-4-O-(R
N-5)，
(32)-(CH
2)
0-4-O-(R
N-5)-COOH，
(33)-(CH
2)
0-4-S-(R
N-5)，
(34)-(CH
2)
0-4-O-(the optional C that is replaced by one, two, three, four or five-F
1-C
6Alkyl),
(35) C
3-C
8Cycloalkyl,
(36) can choose wantonly by C
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group or-NR
1-aR
1-bThe C that replaces
2-C
6Alkenyl,
(37) can choose wantonly by C
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group or-NR
1-aR
1-bThe C that replaces
2-C
6Alkynyl,
(38)-(CH
2)
0-4-N (H or R
N-5)-SO
2-R
N-2, and
(39)-(CH
2)
0-4-(C
3-C
8Cycloalkyl),
(V)-(CR
C-XR
C-Y)
0-4-R
The C-aryl-R
The C-aryl,
(VI)-(CR
C-XR
C-Y)
0-4-R
The C-aryl-R
The C-heteroaryl,
(VII)-(CR
C-XR
C-Y)
0-4-R
The C-heteroaryl-R
The C-aryl,
(VIII)-(CR
C-XR
C-Y)
0-4-R
The C-heteroaryl-R
The C-heteroaryl,
(IX)-(CR
C-XR
C-Y)
0-4-R
The C-aryl-R
The C-heterocycle, R wherein
The C-heterocycleBe independently selected from morpholinyl, thio-morpholinyl, thio-morpholinyl S-oxide compound, thio-morpholinyl S, the S-dioxide, piperazinyl, high piperazinyl, pyrrolidyl, pyrrolinyl, THP trtrahydropyranyl, piperidyl, tetrahydrofuran base, tetrahydro-thienyl, homopiperidinyl, high morpholinyl, high-sulfur is for morpholinyl, high-sulfur is for morpholinyl S, S-dioxide; oxazolidine ketone group, the pyrazoline base, the pyrrolin base, the dihydro pyrazinyl, the dihydropyridine base, the dihydro-pyrimidin base, the dihydrofuran base, dihydro pyranyl, tetrahydro-thienyl S-oxide compound, tetrahydro-thienyl S, the S-dioxide, high-sulfur is for morpholinyl S-oxide compound, the dithiane base, pyranyl, the dihydrofuran base, the pyrroline ketone group, the tetrahydroglyoxaline ketone group, the imidazolinedione base, wherein above-mentioned each group can be chosen wantonly and be fused to benzene, on pyridine or the pyrimidine ring, and
R wherein
The 1-heterocycleBy precursor group R
The 1-heterocycleAny atom that is replaced by hydrogen connect, be connected to R like this
The 1-heterocycleOn new key substituted hydrogen atom and key thereof, wherein heterocycle can be chosen wantonly by one, two, three or four following groups and replace:
(1) C
1-C
6Alkyl can be chosen wantonly by one, two or three and be independently selected from C
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-NR
1-aR
1-b,-C ≡ N ,-CF
3And C
1-C
3The substituting group of alkoxyl group replaces,
(2) C
2-C
6Alkenyl, can choose wantonly by one, two or three be independently selected from-F ,-C1 ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group ,-NR
1-aR
1-bSubstituting group replace,
(3) C
2-C
6Alkynyl, can choose wantonly by one, two or three be independently selected from-F ,-Cl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C-oxygen base and-NR
1-aR
1-bSubstituting group replace,
(4)-F ,-Cl ,-Br and-I,
(5)-C
1-C
6Alkoxyl group,
(6)-C
1-C
6The halogen alkoxyl group,
(7)-NR
N-2R
N-3，
(8)-OH，
(9)-C≡N，
(10) C
3-C
7Cycloalkyl, can choose wantonly by one, two or three be independently selected from-F ,-Cl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bSubstituting group replace,
(11)-CO-(C
1-C
4Alkyl),
(12)-SO
2-NR
1-aR
1-b，
(13)-CO-NR
1-aR
1-b，
(14)-SO
2-(C
1-C
4Alkyl),
(15)=and O, condition is to work as n
1When being zero, R
The 1-heterocycleDo not link to each other with carbochain by nitrogen-atoms;
(X)-(CR
C-XR
C-Y)
0-4-R
The C-heteroaryl-R
The C-heterocycle,
(XI)-(CR
C-XR
C-Y)
0-4-R
The C-heterocycle-R
The C-aryl,
(XII)-(CR
C-XR
C-Y)
0-4-R
The C-heterocycle-R
The C-heteroaryl,
(XIII)-(CR
C-XR
C-Y)
0-4-R
The C-heterocycle-R
The C-heterocycle,
(XIV)-(CR
C-XR
C-Y)
0-4-R
The C-heterocycle,
(XV)-[C (R
C-1) (R
C-2)]
1-3-CO-N-(R
C-3)
2, R wherein
C-1And R
C-2Identical or different, and be selected from:
(A)-H，
(B) C
1-C
6Alkyl can be chosen wantonly by one, two or three and be selected from C
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
6Alkoxyl group ,-the O-phenyl and-NR
1-aR
1-bSubstituting group replace,
(C) C
2-C
6Alkenyl can be chosen wantonly by one, two or three and be selected from C
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
6Alkoxyl group ,-the O-phenyl and-NR
1-aR
1-bSubstituting group replace,
(D) C
2-C
6Alkynyl can be chosen wantonly by one, two or three and be selected from C
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
6-alkoxyl group ,-the O-phenyl and-NR
1-aR
1-bSubstituting group replace,
(E)-(CH
2)
1-2-S (O)
0-2-(C
1-C
6Alkyl),
(F)-(CH
2)
0-4-C
3-C
8Cycloalkyl can be chosen wantonly by one, two or three and be selected from C
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
6Alkoxyl group ,-the O-phenyl and-NR
1-aR
1-bSubstituting group replace,
(G)-(C
1-C
4Alkyl)-R
The C-aryl,
(H)-(C
1-C
4Alkyl)-R
The C-heteroaryl,
(I)-(C
1-C
4Alkyl)-R
The C-heterocycle,
(J)-R
The C-heteroaryl,
(K)-R
The C-heterocycle,
(M)-(CH
2)
1-4-R
C-4-(CH
2)
0-4-R
The C-aryl, R wherein
C-4Be-O-,-S-or-NR
C-5-, R here
C-5Be C
1-C
6Alkyl,
(N)-(CH
2)
1-4-R
C-4-(CH
2)
0-4-R
The C-heteroaryl,
(O)-R
The C-aryl,
And the R under each situation wherein
C-3Identical or different, and be:
(A)-H，
(B) C
1-C
6Alkyl can be chosen wantonly by one, two or three and be independently selected from C
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
6Alkoxyl group ,-the O-phenyl and-NR
1-aR
1-bSubstituting group replace,
(C) has the C of one or two pair key
2-C
6Alkenyl can be chosen wantonly by one, two or three and be independently selected from C
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
6Alkoxyl group ,-the O-phenyl and-NR
1-aR
1-bSubstituting group replace,
(D) has one or two triple-linked C
2-C
6Alkynyl can be chosen wantonly by one, two or three and be independently selected from C
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
6-oxygen base ,-the O-phenyl and-NR
1-aR
1-bSubstituting group replace,
(E)-(CH
2)
0-4-C
3-C
8Cycloalkyl can be chosen wantonly by one, two or three and be independently selected from C
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
6Alkoxyl group ,-the O-phenyl ,-NR
1-aR
1-bSubstituting group replace,
(F)-R
The C-aryl,
(G)-R
The C heteroaryl,
(H)-R
The C-aromatic ring,
(I)-(C
1-C
4Alkyl)-R
The C-aryl,
(J)-(C
1-C
4Alkyl)-R
The C-heteroaryl,
(K)-(C
1-C
4Alkyl)-R
The C-heterocycle,
(XVI)-CH (R
The C-aryl)
2,
(XVII)-CH (R
The C-heteroaryl)
2,
(XVIII)-CH (R
The C-aryl) (R
The C-heteroaryl),
(XIX) be fused to R
The C-arylOr R
The C-heteroarylOr R
The C-heterocycleOn-cyclopentyl ,-cyclohexyl or-the suberyl ring, wherein cyclopentyl, cyclohexyl or suberyl carbon is optional by NH, NR
N-5, O, S (=O)
0-2Replace, and wherein cyclopentyl, cyclohexyl or suberyl can be chosen wantonly by one or two-C
1-C
3Alkyl ,-F ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
6Alkoxyl group ,-O-and-NR
1-aR
1-bReplace,
(XX) C
2-C
10Alkenyl can be chosen wantonly by one, two or three and be selected from C
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
6Alkoxyl group ,-the O-phenyl and-NR
1-aR
1-bSubstituting group replace,
(XXI) C
2-C
10Alkynyl can be chosen wantonly by one, two or three and be selected from C
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
6Alkoxyl group ,-the O-phenyl and-NR
1-aR
1-bSubstituting group replace,
(XXI)-(CH
2)
0-1-CHR
C-6-(CH
2)
0-1-R
The C-aryl, R wherein
C-6Be-(CH
2)
0-6-OH,
(XXII)-(CH
2)
0-1-CHR
C-6-(CH
2)
0-1-R
The C-heteroaryl,
(XXIII)-CH (R
The C-arylOr R
The C-heteroaryl)-CO
2(C
1-C
4Alkyl),
(XXIV)-CH(-CH2-OH)-CH(-OH)-NO
2，
(XXV) (C
1-C
6Alkyl)-O-(C
1-C
6Alkyl)-OH,
(XXVII)-CH
2-NH-CH
2-CH(-O-CH
2-CH
3)
2，
(XXVIII)-H，
(XXIX)-(CH
2)
0-6-C(＝NR
1-a)(NR
1-aR
1-b)；
R under each situation
25All be independently selected from hydrogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
6Alkoxy C
1-C
6Alkyl, hydroxyl C
1-C
6Alkyl, halo C
1-C
6Alkyl, C
1-C
6Alkyloyl, each group all are unsubstituted, or are independently selected from halogen, alkyl, hydroxyl, alkoxyl group and NH by 1,2,3 or 4
2Group replace, and-R
26-R
27, wherein
R
26Be independently selected from-C (O)-,-O-,-S-,-SO-,-SO
2-,-CO
2-,-C (O) NH-and-C (O) N (C
1-C
6Alkyl)-;
R
27Be independently selected from alkyl, alkoxyl group, phenyl, pyridyl and cyclopropyl.
Disclose a kind of methods of treatment, this method is used for the treatment of the patient of Alzheimer's disease and similar disease or prevents it to produce these diseases; Help to prevent or delay the outbreak of Alzheimer's disease; Treatment mild cognitive damage (MCI) patient also prevents or delays Alzheimer's disease to show effect from the person that MCI develops into AD in those meetings; The treatment mongolism; Treatment is with the hereditary cerebral hemorrhage patient of Dutch type amyloidosis; The treatment study on cerebral amyloid angiopathy becomes, and prevents its latent consequences, i.e. single and recurrent cerebral lobar hemorrhage; Treat other degenerative dementia disease, comprise the dementia that has the blood vessel and the degenerative cause of disease concurrently, the dementia relevant with Parkinson's disease, with stein-leventhal syndrome relevant dementia, with cortex degenerate substantially relevant dementia or diffusion thunder dimension corpusculum (Lewy body) type Alzheimer's disease; This method also can be used for treating the patient who needs this class treatment, and it comprises compound of the present invention or its salt that can be used for pharmacy that uses dose therapeutically effective.
The active method of inhibition beta-secretase is also disclosed; Amyloid precursor protein in the inhibited reaction mixture (APP) between Met596 and Asp597 (the isostructural numbering of APP-695 amino acid) the site or in the corresponding site of its homotype or mutant cracked method; Suppress to produce in the cell method of amyloid beta (A β); Suppress to produce in the animal body method of amyloid beta spot; And the method for the treatment of or preventing to be deposited as with the amyloid-beta in the brain disease of feature, these methods comprise compound of the present invention or its salt that can be used for pharmacy that uses dose therapeutically effective.
The invention also discloses the pharmacy composite that contains compound of the present invention.
The invention provides inhibition amyloid precursor protein (APP) is that media carries out cracked compound, composition, test kit and method with the beta-secretase.More specifically, compound of the present invention, composition and method can suppress generation of A β peptide and treatment effectively and prevent the relevant mankind or the Animal diseases of pathomorphism any and A β peptide.
Compound of the present invention, composition and method can be used for treating Alzheimer's disease (AD) patient, help prevention or delay the AD outbreak, treatment mild cognitive damage (MCI) patient also prevents or delays AD to show effect from the person that MCI develops into AD in those meetings, the treatment mongolism, treatment is with the hereditary cerebral hemorrhage of Dutch type amyloidosis, treatment beta-amyloyd cerebrovascular disease also prevents its latent consequences, for example single and recurrent cerebral lobar hemorrhage, treat other degenerative dementia disease, comprise the dementia that has the blood vessel and the degenerative cause of disease concurrently, treat the dementia relevant with Parkinson's disease, the dementia relevant with stein-leventhal syndrome, with the cortex relevant dementia of degenerating substantially, diffusion thunder dimension small body type AD.
Compound of the present invention has the beta-secretase enzyme inhibition activity.The inhibition activity of compound of the present invention be easy to the demonstration, for example, can use described herein or this field in known one or more analytical methods prove.
Detailed Description Of The Invention
Under a kind of particular case of chemical formula X, the invention provides chemical formula is the compound of Z1:
Or it can be used for the salt of pharmacy, wherein
R
30Be selected from phenyl, the pyrazolopyrimidine base, oxa--azepine-benzo Azulene base isoxazolyl, the Triazolopyridine base, pyrrolidone-base (pyrrolidinony), tetrahydrochysene thiophene-azepine-fluorenyl, pyridyl, piperidyl, dihydro ring penta quinolyl, furyl, the naphthalene thienyl, 2,3-naphthyridine ketone group, thiadiazolyl group, the Thienopyrimidine ketone group, oxa--diaza-ring penta naphthyl, dihydrobenzo dioxepinyl, the chromanone base, the chromene ketone group, oxazolidinyl, benzophenone, pyrazinyl list N-oxide compound, cumarone, pyrazolyl,-isoxazolyls-phenyl, phenyl-triazolyl, benzimidazolyl-, indyl, phenyl-pyrryl, chromanyl, isoquinolyl,-thienyl-thienyl, benzothienyl,-phenyl-thiadiazolyl group, the chromanone base, quinolyl,-pyrryl-C (O)-phenyl,-phenyl-O-phenyl,-phenyl-oxazolyls,-pyrrolidone-base-phenyl,-phenyl-pyrimidine base,-phenyl-oxadiazole bases, two ring [2.2.1] heptenyls, cyclopentyl, thieno-[2,3-b] thiophene, cyclohexyl,-phenyl-imidazolyl benzoxazole, dihydro-1H-indyl, 2,3-dihydro-benzo [b] thiophene 1, the 1-dioxide, benzo [b] thiophene 1, the 1-dioxide, 2,3-dihydro-benzo [d] isothiazole 1, the 1-dioxide,-phenyl-thiazolyl,-phenyl-pyrazole base,-phenyl-C (O)-piperidyl,-phenyl-C (O)-pyrrolidyl,-phenyl-isoxazolyls, pseudoindoyl, purine radicals, oxaxolyl, thiazolyl, the pyridazine ketone group, thiazolyl, pyranyl, dihydropyrane and pyridyl, diazepanyl, cyclopropyl, the dihydro-naphtho isoxazolyl, the benzo indazolyl, dihydro ring penta chromene ketone group, the imidazolopyrazole base, tetrahydro cyclopentyl chromene ketone group, the dihydroquinoline ketone group, pyridyl N-oxide compound, the isochroman base, the quinazoline ketone group, the Pyrazolopyridine base, dihydrobenzo thiophene dioxide, dihydro furan benzoisoxazole base, the dihydro-pyrimidin diketo, thieno-pyrazolyl oxazolyl, the tetrahydro cyclopentyl pyrazolyl, dihydro naphthalenonyl, the Dihydrobenzofuranes ketone group, dihydro monodral base, the tetrahydro cyclopentyl pyrazolyl, tetrahydro-pyrazole and azepine base, indazolyl, the tetrahydro cyclopentyl isoxazolyl, the tetrahydro indole base, pyrrolidyl, the thienopyridine base, dioxy dihydrobenzo isothiazole ketone group, triazolopyrimidinyl, thienyl, the dihydrothieno pyrimidines ketone group, with Ben Bing oxadiazole base, wherein above-mentioned each group is unsubstituted or by 1,2,3,4 or 5 substituting groups that are independently selected from following groups replace:
Optional by 1 phenyl or 1 C that CN replaces
1-C
10Alkyl; OH, optional by phenyl or (C
1-C
4Alkyl) the hydroxyl C of phenyl replacement
1-C
10Alkyl; Optional is the C that hydroxyl or phenyl groups replace by 1 or 2 independently
1-C
6Alkoxyl group; Alkylhalide group, halogen alkoxyl group, (CH
2)
0-4C (O) NR
31R
32NR
31-SO
2-(C
1-C
6Alkyl), wherein alkyl is optional is halogen or R by 1,2 or 3 independently
33Group replace;-SO
2-NH (C
1-C
6Alkyl), wherein alkyl is optional is halogen, OH, alkoxyl group or R by 1 or 2 independently
33Group replace;-(C
1-C
6Alkyl)-SO
2-(C
1-C
6Alkyl), wherein alkyl is optional is halogen, OH, C by 1 or 2 independently
1-C
4Alkoxyl group or R
33Group replace;-SO
2-(C
1-C
6Alkyl), wherein alkyl is optional is OH or C by 1 or 2 independently
1-C
4The group of alkoxyl group replaces;-SO
2-N (C
1-C
6Alkyl) (C
1-C
6Alkyl), wherein each alkyl is optional is halogen, OH or R by 1 or 2 independently
33Group replace;-SO
2-NH (C
1-C
6Alkyl)-and phenyl, wherein phenyl is optional is C by 1 or 2 independently
1-C
4The group of alkoxy or halogen replaces;-O-(C
1-C
6Alkyl)-phenyl ,-(C
1-C
6Alkyl)-the O-phenyl ,-(C
1-C
6Alkyl)-O-(C
1-C
6Alkyl)-phenyl, triazolidine-3,5-diketone, halogen ,-NHC (O) NH
2,-NHC (O) NH (C
1-C
6Alkyl) ,-NHC (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl) C (O) NH
2,-N (C
1-C
6Alkyl) C (O) NH (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl) C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl) thienyl ,-(C
1-C
6Alkyl) furyl ,-S-(C
1-C
6Alkyl) phenyl ,-SO
2NR
31R
32,-C (O)-NR
31R
32,-NR
31R
32, dithiane ,-NHC (S) NH
2,-NHC (S) NH (C
1-C
6Alkyl) ,-NHC (S) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-CO
2(C
1-C
6Alkyl), tetrahydropyrans, optional be the phenyl of F, Cl or Br replacement independently by 1 or 2; Pyridine ,-C
2-C
4Alkynyl-phenyl ,-O-C
3-C
8Cycloalkyl ,-O-(C
1-C
6Alkyl)-R
33Optional by one or two methyl substituted pyrroles; 2,3-dihydro-cumarone, benzo [1,2,5] oxadiazoles;-C (O)-(C
1-C
10Alkyl), wherein alkyl is optional by NH
2, N (C
1-C
6Alkyl) or N (C
1-C
6Alkyl) (C
1-C
6Alkyl) replaces;-C (O) NH-phenyl ,-C (O) N (C
1-C
6Alkyl)-and phenyl, 4,4-dimethyl-4,5-dihydro-oxazoles ,-(C
1-C
6Alkyl)-the S-pyridine ,-(C
1-C
6Alkyl)-SO
2-pyridine ,-(C
1-C
6Thio alkoxy)-pyridine, optional by 1 or 2 methyl substituted thiazole; Pyrazoles, S-(C
1-C
6Alkyl), indoles, (C
1-C
6Thio alkoxy)-(C
1-C
6Alkyl), C
2-C
8Alkynyl ,-CO
2-(C
1-C
6Alkyl), C
1-C
10Alkyloyl;-(CH
2)
0-4-SO
2-(C
1-C
10Alkyl), wherein alkyl is optional is replaced by OH;
R wherein
31And R
32Be independently selected from hydrogen, C in each case
1-C
8Alkyl, C
2-C
8Alkenyl, hydroxyl C
1-C
6Alkyl, C
1-C
6Alkylhalide group, C
1-C
6Alkoxy C
1-C
6Alkyl;-(CH
2)
0-4-SO
2-(C
1-C
6Alkyl), wherein alkyl is optional is replaced by the group of 1,2,3 or 4 independently selected from halogen atoms;-(CH
2)
0-4-SO
2-imidazolyl ,-(C
1-C
6Alkyl)-C (O) NH
2,-(C
1-C
6Alkyl)-C (O) NH (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-NH
2,-(C
1-C
6Alkyl)-NH (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl) phenyl ,-(C
1-C
6Alkyl) pyridyl ,-C (O) furyl, (C
1-C
6Alkyl)-tetrahydrofuran (THF), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl ,-CO
2-(C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-furyl ,-(CH
2)
0-4-SO
2-thienyl, wherein phenyl and pyridyl be unsubstituted or by 1,2,3,4 or 5 independently for C
1-C
4Alkyl, hydroxyl, C
1-C
4The group of alkoxyl group, halogen replaces, or
R
31, R
32Form 5,6 or 7 yuan of Heterocyclylalkyls or 6 yuan of hetero-aromatic rings with the nitrogen that links to each other with them, wherein each is chosen wantonly and is fused on benzene, pyridine or the pyrimidine ring, and each is optional by C
1-C
6Alkoxyl group, hydroxyl, hydroxyl C
1-C
6Alkyl, C
1-C
4Alkoxy C
1-C
6Alkyl ,-C (O) NH
2,-C (O) NH (C
1-C
6Alkyl)-the phenyl replacement;
R
33Be H, NH in each case independently
2, NH (C
1-C
6Alkyl), N (C
1-C
6Alkyl) (C
1-C
6Alkyl), N (C
1-C
6Alkyl) (phenyl), N (C
1-C
6Alkyl) (benzyl);
R
35Be phenyl, C
3-C
8Cycloalkyl ,-the S-phenyl ,-benzo dioxole, thienyl, C
1-C
6Alkyl, furyl, imidazolyl, wherein each group be unsubstituted or by 1,2,3,4 or 5 independently for C
1-C
4Alkyl, C
1-C
4Alkoxyl group, OH, hydroxyl C
1-C
6Alkyl, halogen, halogen C
1-C
6Alkyl, halogen C
1-C
6Alkoxyl group ,-O-(C
1-C
6Alkyl)-phenyl ,-CO
2-(C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-(C
5-C
6Cycloalkyl) or (CH
2)
0-4The group of CN replaces;
R
40Be phenyl ,-phenyl-pyridyl, xenyl ,-phenyl-benzothienyl ,-phenyl-thienyl ,-phenyl-furyl ,-the phenyl-pyrimidine base ,-phenyl-isoxazolyls ,-C (O)-pyridyl;-(C
1-C
4Alkyl)-and O-C (O) NH-phenyl, wherein phenyl is optional is replaced by 1,2 or 3 halogen atom;-(C
1-C
4Alkyl)-O-C (O) N (C
1-C
6Alkyl)-phenyl ,-(C
1-C
6Alkyl)-phenyl ,-(C
1-C
4Alkyl)-SO
2NH
2,-(C
1-C
4Alkyl)-SO
2NH (C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-SO
2N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-SO
2NH
2,-SO
2NH (C
1-C
6Alkyl) ,-SO
2N (C
1-C
6Alkyl) (C
1-C
6Alkyl), CN ,-(CH
2)
0-4-(C
3-C
8Cycloalkyl) ,-(C
1-C
4Alkyl)-C (O) O-(C
1-C
4Alkyl) ,-(C
1-C
4Alkyl)-R
33, C
1-C
10Alkyl, C
2-C
8Alkenyl ,-(C
1-C
4Alkyl)-NHC (O)-(C
1-C
4Alkyl) ,-(CH
2)
0-4-C (O) NH
2,-(CH
2)
0-4-C (O) NH (C
1-C
6Alkyl) ,-(CH
2)
0-4-C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl), naphthyl, tetralyl, dihydro naphthyl ,-(CH
2)
0-4-imidazolyl ,-(CH
2)
0-4-pyrrolidyl, oxazolidone 3,4-dihydro-benzo [e] [1,2] oxathiin 2,2-dioxide, pyrimidyl, 3,4-dihydro-2H-benzo [e] [1,2] thiazine 1,1-dioxide, pyridyl; Or pyrimidyl, alkoxyalkyl ,-phenyl-benzothienyl ,-phenyl-cyclohexyl ,-phenyl-cyclopentyl ,-phenyl-(C
1-C
6Alkyl)-cyclopentyl ,-phenyl-(C
1-C
6Alkyl)-cyclohexyl ,-phenyl-oxazolyls, furyl, tetrahydrofuran base, wherein above-mentioned each be unsubstitutedly or optional to be replaced for the substituting group of following groups independently by 1,2,3,4 or 5: halogen, optional by 1 or 2 C that replaces for the group of CN or OH independently
1-C
8Alkyl, C
1-C
6Alkoxyl group, halogen (C
1-C
8Alkyl), halogen (C
1-C
4Alkoxyl group); Wherein phenyl optional by 1 or 2 halogen replace-O-(C
1-C
4Alkyl)-phenyl, CN ,-CHO, C
1-C
4Thio alkoxy ,-NHSO
2-(C
1-C
6Alkyl), alkyl wherein optional by 1,2 or 3 halogen replace-N (C
1-C
4Alkyl) SO
2-(C
1-C
4Alkyl); OH;-SO
2R
33R
33C
2-C
8Alkynyl; C
2-C
8Alkenyl; The thio alkoxy alkyl;-SO
2-(C
1-C
10Alkyl); NR
31R
32-C (O)-NR
31R
32-OC (O) R
33C
1-C
8Alkyloyl;-(C
1-C
6Alkyl)-C (O)-(C
1-C
6Alkoxyl group);
R
41aAnd R
41Be H, cyclohexyl, phenyl or optional independently by 1 or 2 phenyl, hydroxyl, C
1-C
4Thio alkoxy, C
1-C
4Thio alkoxy C
1-C
6The C that alkyl replaces
1-C
6Alkyl; Or-C
1-C
6Alkyl-SO
2-C
1-C
6Alkyl;
R
40, R
41Form an optional C who is replaced by following group with the atom that links to each other with them
3-C
8Cycloalkyl ring: C
1-C
4Alkyl, C
1-C
4Alkoxyl group, halogen ,-CO
2NH
2,-CO
2NH (C
1-C
6Alkyl) ,-CO
2N (C
1-C
6Alkyl) (C
1-C
6Alkyl), optional by C
1-C
6The thiazolyl that alkyl replaces, optional by C
1-C
6Alkyl replaces the De isoxazolyl or chooses wantonly by 1,2 or 3 is halogen or C independently
1-C
6The phenyl that the group of alkyl replaces;
And
R
42Be H, the optional C that is replaced by OH
1-C
6Alkyl; Benzyl;-NHC (O)-(C
1-C
6Alkyl);-NHC (O)-phenyl, wherein phenyl is optional is replaced by 1 and 2 alkyl.
The compound that preferred chemical formula is Z1 comprises that chemical formula is the compound of Z2:
Or it can be used for the salt of pharmacy, wherein
R
51Be C in each case independently
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NHSO
2-(C
1-C
4Alkyl), wherein alkyl optional by 1,2 or 3 halogen replace ,-SO
2-NH-(C
1-C
6Alkyl)-NH
2,-SO
2-NH-(C
1-C
6Alkyl)-NH (C
1-C
4Alkyl) ,-SO
2-NH-(C
1-C
6Alkyl)-N (C
1-C
4Alkyl) (C
1-C
4Alkyl), [1,2,4] triazolidine-3, the 5-diketone ,-NHC (O) NH
2,-NHC (O) NH (C
1-C
6Alkyl) ,-NHC (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl) C (O) NH
2,-N (C
1-C
6Alkyl) C (O) NH (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl) C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl), halogen ,-CF
3, OH ,-SO
2NR
31R
32,-C (O)-NR
31R
32,-NR
31R
32, optional by phenyl or (C
1-C
4Alkyl) the hydroxyl C of phenyl replacement
1-C
10Alkyl ,-O-(C
1-C
4Alkyl)-phenyl ,-NHC (S) NH
2,-NHC (S) NH (C
1-C
6Alkyl) ,-NHC (S) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-the O-phenyl ,-C (O)-(C
1-C
6Alkyl), wherein alkyl is optional by NH
2, N (C
1-C
6Alkyl) or N (C
1-C
6Alkyl) (C
1-C
6Alkyl) replaces;-O-C
3-C
6Cycloalkyl, optional be C independently by 1 or 2
1-C
4The group of alkyl or phenyl replaces the De oxazole; Hydroxyl C
1-C
4Alkoxyl group, aminoalkoxide, NH (C
1-C
6Alkyl)-alkoxyl group, N (C
1-C
6Alkyl) (C
1-C
6Alkyl)-alkoxyl group,
R wherein
31And R
32Be independently selected from hydrogen, C in each case
1-C
6Alkyl, hydroxyl C
1-C
6Alkyl, C
1-C
6Alkylhalide group, (C
1-C
6Alkyl) C (O) NH
2,-(C
1-C
6Alkyl) C (O) NH (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl) C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-NH
2,-(C
1-C
6Alkyl)-NH (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl) phenyl ,-(C
1-C
6Alkyl) pyridyl ,-C (O) furyl, (C
1-C
6Alkyl)-tetrahydrofuran (THF), wherein phenyl and pyridyl be unsubstituted or by 1,2,3,4 or 5 independently for C
1-C
4Alkyl, hydroxyl, C
1-C
4The group of alkoxyl group, halogen replaces, or
Wherein in each case, R
31, R
32Form a pyrrolidyl, piperazinyl, piperidyl, azepanyl, pyridyl, pyrimidine-ring independently with the nitrogen that links to each other with them, wherein each is chosen wantonly and is fused on benzene, pyridine or the pyrimidine ring, and each is optional by C
1-C
6Alkoxyl group, C
1-C
6Alkyl, hydroxyl, hydroxyl C
1-C
6Alkyl, C
1-C
4Alkoxy C
1-C
6Alkyl ,-C (O) NH
2, or-C (O) NH (C
1-C
6Alkyl)-the phenyl replacement.
Preferred Z2 compound is R wherein
41And R
42It is the compound of hydrogen.
Other preferred Z2 compound is R wherein
35Compound for following groups: phenyl, cyclohexyl ,-S-phenyl, benzo dioxole, thienyl, C
3-C
6Alkyl, furyl, wherein each group be unsubstituted or by 1,2,3,4 or 5 independently for C
1-C
4Alkyl, C
1-C
4Alkoxyl group, OH, hydroxyl C
1-C
6Alkyl, halogen, halogen C
1-C
6Alkyl, halogen C
1-C
6Alkoxyl group ,-O-(C
1-C
6Alkyl)-phenyl ,-CO
2-(C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-(C
5-C
6Cycloalkyl) group replaces.
Other preferred Z1 compound is following compound, promptly wherein,
R
35Be phenyl, cyclohexyl ,-S-phenyl, benzo dioxole, thienyl, C
3-C
6Alkyl, furyl, wherein each group be unsubstituted or by 1,2,3,4 or 5 independently for C
1-C
4Alkyl, C
1-C
4Alkoxyl group, OH, hydroxyl C
1-C
6Alkyl, halogen, halogen C
1-C
6Alkyl, halogen C
1-C
6Alkoxyl group ,-O-(C
1-C
6Alkyl)-phenyl ,-CO
2-(C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-(C
5-C
6Cycloalkyl) group replaces.
R
40Be phenyl ,-phenyl-pyridyl, xenyl ,-phenyl-benzothienyl ,-phenyl-thienyl ,-phenyl-furyl ,-the phenyl-pyrimidine base ,-phenyl-isoxazolyls ,-C (O)-pyridyl ,-(C
1-C
4Alkyl)-O-C (O) NH-phenyl ,-(C
1-C
4Alkyl)-O-C (O) N (C
1-C
6Alkyl)-phenyl ,-(C
1-C
4Alkyl)-phenyl ,-(C
1-C
4Alkyl)-SO
2NH
2,-(C
1-C
4Alkyl)-SO
2NH (C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-SO
2N (C
1-C
6Alkyl) (C
1-C
6Alkyl), CN ,-(CH
2)
0-4-(C
3-C
8Cycloalkyl) ,-(C
1-C
4Alkyl)-C (O) O-(C
1-C
4Alkyl) ,-(C
1-C
4Alkyl)-R
33, C
1-C
8Alkyl ,-(C
1-C
4Alkyl)-NHC (O)-(C
1-C
4Alkyl) ,-(CH
2)
0-4-C (O) NH
2,-(CH
2)
0-4-C (O) NH (C
1-C
6Alkyl) ,-(CH
2)
0-4-C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl), tetralyl, dihydro naphthyl, above-mentioned each be unsubstituted or replaced for the substituting group of following groups independently by 1,2,3,4 or 5: halogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, halogen (C
1-C
4Alkyl); Wherein phenyl optional by 1 or 2 halogen replace-O-(C
1-C
4Alkyl)-phenyl ,-CHO, C
1-C
4Thio alkoxy ,-NHSO
2-(C
1-C
4Alkyl), alkyl wherein optional by 1,2 or 3 halogen replace-N (C
1-C
4Alkyl) SO
2-(C
1-C
4Alkyl), OH ,-SO
2R
33, R
33
R
41Be H, cyclohexyl, phenyl or optional by 1 or 2 phenyl, hydroxyl or C
1-C
4The C that thio alkoxy replaces
1-C
6Alkyl; And
R
42Be hydrogen or CH
2CN.
Preferred Z2 compound comprises following compound, promptly wherein,
R
35Be phenyl, C
3-C
8Cycloalkyl ,-S-phenyl, benzo dioxole, thienyl, C
3-C
6Alkyl, furyl, wherein each group be unsubstituted or by 1,2,3,4 or 5 independently for C
1-C
4Alkyl, C
1-C
4Alkoxyl group, OH, hydroxyl C
1-C
6Alkyl, halogen, CF
3, OCF
3,-O benzyl ,-CO
2-(C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-(C
5-C
6Cycloalkyl) group replaces;
R
40Be phenyl ,-phenyl-pyridyl, xenyl ,-phenyl-benzothienyl ,-phenyl-thienyl ,-phenyl-furyl ,-the phenyl-pyrimidine base ,-phenyl-isoxazolyls ,-C (O)-pyridyl ,-(C
1-C
4Alkyl)-O-C (O) NH-phenyl ,-(C
1-C
4Alkyl)-O-C (O) N (C
1-C
6Alkyl)-phenyl ,-(C
1-C
4Alkyl)-phenyl ,-(C
1-C
4Alkyl)-SO
2NH
2,-(C
1-C
4Alkyl)-SO
2NH (C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-SO
2N (C
1-C
6Alkyl) (C
1-C
6Alkyl), CN ,-(C
1-C
4Alkyl)-(C
3-C
6Cycloalkyl) ,-(C
1-C
4Alkyl)-C (O) O-(C
1-C
4Alkyl) ,-(C
1-C
4Alkyl)-R
33, C
1-C
8Alkyl ,-(C
1-C
4Alkyl)-NHC (O)-(C
1-C
4Alkyl) ,-C (O) NH
2, wherein above-mentioned each ring is unsubstituted or is replaced for the substituting group of following groups independently by 1,2 or 3: halogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, CF
3,-O-(C
1-C
4Alkyl)-phenyl, wherein phenyl optional by 1 or 2 halogen replace-O-(C
1-C
4Alkyl)-phenyl ,-CHO ,-NHSO
2-(C
1-C
4Alkyl), alkyl wherein optional by 1,2 or 3 halogen replace-N (C
1-C
4Alkyl) SO
2-(C
1-C
4Alkyl);
R
41Be H, cyclohexyl, phenyl or optional by 1 or 2 phenyl, hydroxyl or C
1-C
4The C that thio alkoxy replaces
1-C
6Alkyl; And
R
42Be hydrogen or CH
2CN;
R
51Be C in each case independently
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NHSO
2-(C
1-C
4Alkyl), wherein alkyl optional by 1,2 or 3 halogen replace ,-SO
2-NH-(C
1-C
6Alkyl)-NH
2,-SO
2-NH-(C
1-C
6Alkyl)-NH (C
1-C
4Alkyl) ,-SO
2-NH-(C
1-C
6Alkyl)-N (C
1-C
4Alkyl) (C
1-C
4Alkyl), [1,2,4] triazolidine-3, the 5-diketone ,-NHC (O) NH
2,-NHC (O) NH (C
1-C
6Alkyl) ,-NHC (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl) C (O) NH
2,-N (C
1-C
6Alkyl) C (O) NH (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl) C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl), halogen ,-CF
3, OH ,-SO
2NR
31R
32,-C (O)-NR
31R
32,-NR
31R
32, the optional hydroxyl C that is replaced by phenyl or 2-aminomethyl phenyl
1-C
10Alkyl ,-O-(C
1-C
4Alkyl)-phenyl ,-NHC (S) NH
2,-NHC (S) NH (C
1-C
6Alkyl) ,-NHC (S) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-the O-phenyl;-C (O)-(C
1-C
6Alkyl), wherein alkyl is optional by NH
2, N (C
1-C
6Alkyl) or N (C
1-C
6Alkyl) (C
1-C
6Alkyl) replace ,-O-C
3-C
6Cycloalkyl, optional be C independently by 1 or 2
1-C
4Azoles, hydroxyl C that the group of alkyl or phenyl replaces
1-C
4Alkoxyl group, aminoalkoxide, NH (C
1-C
6Alkyl)-alkoxyl group, N (C
1-C
6Alkyl) (C
1-C
6Alkyl)-alkoxyl group,
R wherein
31And R
32Be independently selected from hydrogen, C in each case
1-C
6Alkyl, hydroxyl C
1-C
6Alkyl ,-(C
1-C
6Alkyl) C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-NH (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl) phenyl ,-(C
1-C
6Alkyl) pyridyl ,-C (O) furyl, (C
1-C
6Alkyl)-tetrahydrofuran (THF), wherein phenyl be unsubstituted or by 1,2 or 3 independently for C
1-C
4The group of alkoxy or halogen replaces, or
R in each case wherein
31, R
32Form a pyrrolidyl, piperazinyl, piperidyl or nitrogen Zhuo Ji (azepanyl) independently with the nitrogen that links to each other with them, wherein each is chosen wantonly and is fused on benzene, pyridine or the pyrimidine ring, and each is optional by hydroxyl, C
1-C
6Alkyl, hydroxyl C
1-C
6Alkyl, C
1-C
4Alkoxy C
1-C
6Alkyl ,-C (O) NH
2, or-C (O) NH-benzyl replaces.
Also preferred Z2 compound is following compound, promptly wherein,
R
35It is phenyl; Halogenophenyl, dihalogenated phenyl; The trihalogenated benzene base; The tetrahalogeno-benzene base; The phenyl-pentahalide base; Halogen, benzyl oxy phenyl; Halogen, alkyl phenyl; Benzyl oxy phenyl; Cyclohexyl; (C
1-C
4Alkoxyl group) carbonyl phenyl; (C
1-C
4Alkoxyl group) phenyl;-S-phenyl; Or benzo dioxole;
R
41Be H, cyclohexyl, phenyl or optional by 1 or 2 phenyl, hydroxyl or C
1-C
4The C that thio alkoxy replaces
1-C
6Alkyl; And
R
42Be hydrogen or-CH
2CN.
Other preferred Z2 compound is following compound, promptly wherein,
R
35Be 3, the 5-dihalogenated phenyl;
R
40Be phenyl ,-phenyl-pyridyl, xenyl ,-phenyl-benzothienyl ,-phenyl-thienyl ,-phenyl-furyl ,-the phenyl-pyrimidine base ,-phenyl-isoxazolyls ,-(C
1-C
4Alkyl)-O-C (O) NH-phenyl ,-(C
1-C
4Alkyl)-O-C (O) N (C
1-C
6Alkyl)-phenyl ,-(C
1-C
4Alkyl)-SO
2NH
2, CN ,-(C
1-C
4Alkyl)-(C
3-C
6Cycloalkyl) ,-(C
1-C
4Alkyl)-C (O) O-(C
1-C
4Alkyl) ,-(C
1-C
4Alkyl)-R
33Or C
1-C
8Alkyl, wherein above-mentioned each be unsubstituted or replaced for the group of following groups independently by 1,2 or 3: halogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, CF
3Wherein phenyl optional by 1 or 2 halogen replace-O-(C
1-C
4Alkyl)-phenyl ,-CHO or-NHSO
2-(C
1-C
4Alkyl).
Also preferred Z2 compound is following compound, promptly wherein,
R
35Be 3, the 5-difluorophenyl; 3, the 5-dichlorophenyl; Or 3-chlorine, the 5-fluorophenyl; And
R
40Be unsubstituted or be fluorine-based, chloro, bromo, iodo, methyl, ethyl, methoxyl group, oxyethyl group, CF independently by 1,2 or 3
3Or-phenyl that the group of O benzyl replaces, the phenyl in-O benzyl optional by 1 or 2 be independently halogen or-NHSO
2CH
3Group replace.
Also preferred Z2 compound is following compound, promptly wherein,
R
51Be C in each case independently
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NHSO
2CH
3,-SO
2-NH-(ethyl)-NH (CH
3), [1,2,4] triazolidine-3, the 5-diketone ,-NHC (O) NH
2,-CF
3, OH ,-SO
2NR
31R
32,-C (O)-NR
31R
32, the hydroxyl octyl group ,-CH (OH)-2-aminomethyl phenyl ,-the O benzyl or-NHC (S) NH (CH
3);
R wherein
31And R
32Be independently selected from hydrogen, C in each case
1-C
6Alkyl, hydroxyl C
1-C
6Alkyl ,-(CH
2) C (O) N (CH
3)
2,-CH
2CH
2N (CH
3)
2, benzyl, styroyl ,-CH
2CH
2Pyridyl ,-C (O) furyl or
R in each case
31, R
32Form a pyrrolidyl, piperazinyl, piperidyl or nitrogen Zhuo Ji independently with the nitrogen that links to each other with them, each optional by methylol, hydroxyethyl, methoxymethyl or-C (O) NH
2Replace.
Also preferred Z2 compound is following compound, promptly wherein,
R
40Be 3-ethylphenyl or 3-p-methoxy-phenyl; And
R
42Be hydrogen.
Preferred Z2 compound comprises following compound, promptly wherein
R
51Be C in each case independently
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-C (O)-NR
31R
32,-C (O) CH
2NH
2, cyclopentyloxy ,-NHC (O) NH (ethyl), optional be C independently by 1 or 2
1-C
4Alkyl or phenyl replaces De oxazole, hydroxy ethoxy, diethylamino oxyethyl group,
R wherein
31And R
32Be independently selected from hydrogen, C in each case
1-C
6Alkyl, hydroxyl C
1-C
6Alkyl ,-CH
2Tetrahydrofuran (THF).
Other preferred Z2 compound comprises R wherein
35Compound for cyclohexyl.
Preferred compound comprises following compound, promptly wherein
R
40Be phenyl or C
1-C
8Alkyl, wherein each is unsubstituted or is halogen, C independently by 1,2,3,4 or 5
1-C
4Alkyl, C
1-C
4Alkoxyl group, halogen (C
1-C
4Alkyl) group replaces; And
R
42And R
41Be hydrogen.
Preferred compound comprises following compound, promptly wherein
R
40Be phenyl, 3-p-methoxy-phenyl, 4-p-methoxy-phenyl, 3-ethoxyl phenenyl, 4-ethoxyl phenenyl, 3-trifluoromethyl, 4-trifluoromethyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 2-ethylphenyl, 3-ethylphenyl or C
3-C
6Alkyl; And
R
51Be C in each case independently
1-C
6Alkyl, C
1-C
6Alkoxy or halogen,
R wherein
31And R
32Be independently selected from hydrogen, C in each case
1-C
6Alkyl, hydroxyl C
1-C
6Alkyl and-(C
1-C
6Alkyl) phenyl, wherein phenyl be unsubstituted or by 1,2 or 3 independently for C
1-C
4The group of alkoxy or halogen replaces,
R in each case wherein
31, R
32Form a pyrrolidyl, piperazinyl, piperidyl or nitrogen Zhuo Ji independently with the nitrogen that links to each other with them, wherein each is chosen wantonly and is fused on benzene, pyridine or the pyrimidine ring, and each is optional by hydroxyl, hydroxyl C
1-C
6Alkyl, C
1-C
4Alkoxy C
1-C
6Alkyl ,-C (O) NH
2, or-C (O) NH-phenyl replaces.
Preferred compound comprises following compound, promptly wherein
R
35Be 3-halogen, 5-benzyloxy phenyl; 3-benzyloxy phenyl; Or 4-benzyloxy phenyl;
R
41Be H, cyclohexyl, phenyl or optional by 1 or 2 phenyl, hydroxyl or C
1-C
4The C that thio alkoxy replaces
1-C
6Alkyl; And
R
42Be hydrogen or-CH
2CN.
Preferred compound comprises following compound, promptly wherein
R
40Be phenyl ,-phenyl-pyridyl, xenyl ,-(C
1-C
4Alkyl)-O-C (O) NH-phenyl ,-(C
1-C
4Alkyl)-O-C (O) N (C
1-C
6Alkyl)-phenyl ,-(C
1-C
4Alkyl)-SO
2NH
2,-(C
1-C
4Alkyl)-(C
3-C
6Cycloalkyl) ,-(C
1-C
4Alkyl)-C (O) O-(C
1-C
4Alkyl) ,-(C
1-C
4Alkyl)-R
33Or C
1-C
8Alkyl, wherein above-mentioned each be unsubstituted or be halogen, C independently by 1,2 or 3
1-C
4Alkyl, C
1-C
4Alkoxyl group, CF
3The group of ,-O benzyl replaces, the phenyl the in-O benzyl optional by 1 or 2 halogen ,-CHO or-NHSO
2-(C
1-C
4Alkyl) replaces.
Preferred compound comprises following compound, promptly wherein
R
40Be phenyl or C
1-C
8Alkyl, wherein above-mentioned each be unsubstituted or be halogen, C independently by 1,2 or 3
1-C
4Alkyl, C
1-C
4Alkoxyl group, CF
3The group of ,-O benzyl replaces, the phenyl the in-O benzyl optional by 1 or 2 halogen ,-CHO or-NHSO
2-(C
1-C
4Alkyl) replaces;
R
41Be hydrogen or optional by 1 or 2 phenyl, hydroxyl or C
1-C
4The C that thio alkoxy replaces
1-C
6Alkyl;
R
42Be hydrogen; And
R
51Be C in each case independently
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NHSO
2-(C
1-C
4Alkyl), wherein alkyl optional by 1,2 or 3 halogen replace ,-SO
2-NH-(C
1-C
6Alkyl)-NH
2,-SO
2-NH-(C
1-C
6Alkyl)-NH (C
1-C
4Alkyl) ,-SO
2-NH-(C
1-C
6Alkyl)-N (C
1-C
4Alkyl) (C
1-C
4Alkyl) ,-NHC (O) NH
2,-NHC (O) NH (C
1-C
6Alkyl) ,-NHC (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl) C (O) NH
2,-N (C
1-C
6Alkyl) C (O) NH (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl) C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl), halogen ,-CF
3, OH ,-SO
2NR
31R
32,-C (O)-NR
31R
32,-NR
31R
32, hydroxyl C
1-C
10Alkyl;-O benzyl ,-NHC (S) NH
2,-NHC (S) NH (C
1-C
6Alkyl) ,-NHC (S) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-the O-phenyl;-C (O)-(C
1-C
6Alkyl) ,-the O-cyclopentyl ,-O-cyclohexyl, hydroxyl C
1-C
4Alkoxyl group, aminoalkoxide, NH (C
1-C
6Alkyl)-alkoxyl group, N (C
1-C
6Alkyl) (C
1-C
6Alkyl)-alkoxyl group,
R wherein
31And R
32Be independently selected from hydrogen, C in each case
1-C
6Alkyl, hydroxyl C
1-C
6Alkyl ,-(C
1-C
6Alkyl)-NH (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-N (C
1-C
6Alkyl) (C
1-C
6Alkyl) and benzyl, the phenyl in the benzyl is unsubstituted or is C independently by 1 or 2
1-C
4The group of alkoxy or halogen replaces,
R in each case wherein
31, R
32Form pyrrolidyl, piperazinyl or a piperidyl independently with the nitrogen that links to each other with them, wherein each is optional by hydroxyl, hydroxyl C
1-C
6Alkyl, C
1-C
4Alkoxy C
1-C
6Alkyl ,-C (O) NH
2, or-C (O) NH-benzyl replaces.
Preferred compound comprises following compound, promptly wherein
R
40Be phenyl or C
1-C
8Alkyl, wherein above-mentioned each be unsubstituted or be halogen, C independently by 1,2 or 3
1-C
4Alkyl, C
1-C
4Alkoxyl group or CF
3Group replace; And
R
51Be C in each case independently
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NHSO
2CH
3,-NHSO
2CF
3, halogen ,-CF
3, OH ,-SO
2NR
31R
32,-C (O)-NR
31R
32,-NR
31R
32, hydroxyl C
1-C
10Alkyl, hydroxyl C
1-C
4Alkoxyl group, aminoalkoxide, NH (C
1-C
6Alkyl)-alkoxyl group, N (C
1-C
6Alkyl) (C
1-C
6Alkyl)-alkoxyl group,
R wherein
31And R
32Be independently selected from hydrogen, C in each case
1-C
6Alkyl, hydroxyl C
1-C
6Alkyl and benzyl, the phenyl in the benzyl be unsubstituted or by 1 or 2 independently for the group of methoxyl group, oxyethyl group or halogen replaces,
R in each case wherein
31, R
32Form a pyrrolidyl, piperazinyl or piperidines basic ring independently with the nitrogen that links to each other with them, wherein each is optional by hydroxyl, hydroxyl C
1-C
6Alkyl, C
1-C
4Alkoxy C
1-C
6Alkyl or-C (O) NH
2Replace.
Preferred compound comprises wherein R
35Be that 3-is fluorine-based, 5-benzyloxy phenyl or 3-chloro, the compound of 5-benzyloxy phenyl.
Preferred compound comprises following compound, promptly wherein
R
35Be-the S-phenyl, benzo [1,3] dioxole, furyl or thienyl;
R
41Be H, cyclohexyl, phenyl or optional by 1 or 2 phenyl, hydroxyl or C
1-C
4The C that thio alkoxy replaces
1-C
6Alkyl; And
R
42Be hydrogen or-CH
2CN.
Preferred compound comprises following compound, promptly wherein
R
40Be phenyl ,-phenyl-pyridyl, xenyl ,-the phenyl-pyrimidine base ,-(C
1-C
4Alkyl)-O-C (O) NH-phenyl ,-(C
1-C
4Alkyl)-O-C (O) N (C
1-C
6Alkyl)-phenyl ,-(C
1-C
4Alkyl)-SO
2NH
2,-(C
1-C
4Alkyl)-(C
3-C
6Cycloalkyl) ,-(C
1-C
4Alkyl)-C (O) O-(C
1-C
4Alkyl) ,-(C
1-C
4Alkyl)-R
33Or C
1-C
8Alkyl, wherein above-mentioned each be unsubstituted or be halogen, C independently by 1,2 or 3
1-C
4Alkyl, C
1-C
4Alkoxyl group, CF
3The group of ,-O benzyl replaces, the phenyl the in-O benzyl optional by 1 or 2 halogen ,-CHO or-NHSO
2-(C
1-C
4Alkyl) replaces.
Preferred again compound comprises following compound, promptly wherein
R
40Be phenyl or C
1-C
8Alkyl, wherein above-mentioned each be unsubstituted or be halogen, C independently by 1,2 or 3
1-C
4Alkyl, C
1-C
4Alkoxyl group, CF
3The group of ,-O benzyl replaces, the phenyl the in-O benzyl optional by 1 or 2 halogen ,-CHO or-NHSO
2-(C
1-C
4Alkyl) replaces; And
R
41Be hydrogen or optional by 1 or 2 phenyl, hydroxyl or C
1-C
4The C that thio alkoxy replaces
1-C
6Alkyl; And
R
42Be hydrogen; And
R
51Be C in each case independently
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NHSO
2-(C
1-C
4Alkyl), wherein alkyl optional by 1,2 or 3 halogen replace ,-SO
2-NH-(C
1-C
6Alkyl)-NH
2,-SO
2-NH-(C
1-C
6Alkyl)-NH (C
1-C
4Alkyl) ,-SO
2-NH-(C
1-C
6Alkyl)-N (C
1-C
4Alkyl) (C
1-C
4Alkyl) ,-NHC (O) NH
2,-NHC (O) NH (C
1-C
6Alkyl) ,-NHC (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl) C (O) NH
2,-N (C
1-C
6Alkyl) C (O) NH (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl) C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl), halogen ,-CF
3, OH ,-SO
2NR
31R
32,-C (O)-NR
31R
32,-NR
31R
32, hydroxyl C
1-C
10Alkyl ,-the O benzyl ,-NHC (S) NH
2,-NHC (S) NH (C
1-C
6Alkyl) ,-NHC (S) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-the O-phenyl;-C (O)-(C
1-C
6Alkyl) ,-the O-cyclopentyl ,-O-cyclohexyl, hydroxyl C
1-C
4Alkoxyl group, aminoalkoxide, NH (C
1-C
6Alkyl)-alkoxyl group, N (C
1-C
6Alkyl) (C
1-C
6Alkyl)-alkoxyl group;
R wherein
31And R
32Be independently selected from hydrogen, C in each case
1-C
6Alkyl, hydroxyl C
1-C
6Alkyl ,-(C
1-C
6Alkyl)-NH (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-N (C
1-C
6Alkyl) (C
1-C
6Alkyl) and benzyl, the phenyl in the benzyl is unsubstituted or is C independently by 1 or 2
1-C
4The group of alkoxy or halogen replaces,
R in each case wherein
31, R
32Form pyrrolidyl, piperazinyl or a piperidyl independently with the nitrogen that links to each other with them, wherein each is optional by hydroxyl, hydroxyl C
1-C
6Alkyl, C
1-C
4Alkoxy C
1-C
6Alkyl ,-C (O) NH
2, or-C (O) NH-benzyl replaces.
Preferred again compound comprises following compound, promptly wherein
R
40Be phenyl or C
1-C
8Alkyl, wherein above-mentioned each be unsubstituted or be halogen, C independently by 1,2 or 3
1-C
4Alkyl, C
1-C
4Alkoxyl group or CF
3Group replace; And
R
51Be C in each case independently
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NHSO
2CH
3,-NHSO
2CF
3, halogen ,-CF
3, OH ,-SO
2NR
31R
32,-C (O)-NR
31R
32,-NR
31R
32, hydroxyl C
1-C
10Alkyl, hydroxyl C
1-C
4Alkoxyl group, aminoalkoxide, NH (C
1-C
6Alkyl)-alkoxyl group, N (C
1-C
6Alkyl) (C
1-C
6Alkyl)-alkoxyl group,
R wherein
31And R
32Be independently selected from hydrogen, C in each case
1-C
6Alkyl, hydroxyl C
1-C
6Alkyl and benzyl, the phenyl in the benzyl be unsubstituted or by 1 or 2 independently for the group of methoxyl group, oxyethyl group or halogen replaces,
R in each case wherein
31, R
32Form a pyrrolidyl, piperazinyl or piperidines basic ring independently with the nitrogen that links to each other with them, wherein each is optional by hydroxyl, hydroxyl C
1-C
6Alkyl, C
1-C
4Alkoxy C
1-C
6Alkyl or-C (O) NH
2Replace.
Particularly preferred chemical formula is that the compound of X is R wherein
1Be 3, the compound of 5-difluorophenyl.
Under another particular case of chemical formula X, the invention provides the compound that chemical formula is Z3
Or it can be used for the salt of pharmacy, wherein
R
30Be selected from phenyl, the pyrazolopyrimidine base, oxa--azepine-benzo Azulene base isoxazolyl, the Triazolopyridine base, pyrrolidone-base, tetrahydrochysene sulfo--azepine-fluorenyl, pyridyl, piperidyl, dihydro ring penta quinolyl, furyl, the naphthalene thienyl, 2,3-naphthyridine ketone group, thiadiazolyl group, the Thienopyrimidine ketone group, oxa--diaza-ring penta naphthyl, dihydrobenzo dioxepinyl, the chromanone base, the chromene ketone group, oxazolidinyl, purine radicals, oxaxolyl, thiazolyl, the pyridazine ketone group, thiazolyl, pyranyl, dihydropyrane and pyridyl, diazepanyl, cyclopropyl, the dihydro-naphtho isoxazolyl, the benzo indazolyl, dihydro ring penta chromene ketone group, the imidazolopyrazole base, tetrahydro cyclopentyl chromene ketone group, the dihydroquinoline ketone group, pyridyl, the isochroman base, the quinazoline ketone group, the Pyrazolopyridine base, dihydrobenzo thiophene dioxide, dihydro furan benzoisoxazole base, the dihydro-pyrimidin diketo, thieno-pyrazolyl oxazolyl, the tetrahydro cyclopentyl pyrazolyl, dihydro naphthalenonyl, the Dihydrobenzofuranes ketone group, dihydro monodral base, the tetrahydro cyclopentyl pyrazolyl, tetrahydro-pyrazole and azepine base, indazolyl, the tetrahydro cyclopentyl isoxazolyl, the tetrahydro indole base, pyrrolidyl, the thienopyridine base, dioxy dihydrobenzo isothiazole ketone group, triazolopyrimidinyl, thienyl, the dihydrothieno pyrimidines ketone group, with Ben Bing oxadiazole base
Wherein above-mentioned each group is unsubstituted or is replaced by 1,2,3,4 or 5 group that is independently selected from following groups:
The optional C that is replaced by phenyl
1-C
10Alkyl; Hydroxyl; Optional by phenyl or (C
1-C
4Alkyl) the hydroxyl C of phenyl replacement
1-C
10Alkyl; The optional C that is replaced by 1 or 2 hydroxyl
1-C
6Alkoxyl group;-C (O) NR
31R
32NR
31-SO
2-(C
1-C
6Alkyl), wherein alkyl is optional by 1,2 or 3 R
33Group replace;-SO
2-NH (C
1-C
6Alkyl), wherein alkyl is optional by 1 or 2 R
33Group replaces;-SO
2-N (C
1-C
6Alkyl) (C
1-C
6Alkyl), wherein each alkyl is optional by 1 or 2 R
33Group replaces;-SO
2-NH (C
1-C
6Alkyl)-and phenyl, wherein phenyl is optional is C by 1 or 2 independently
1-C
4The group of alkoxy or halogen replaces;-O-(C
1-C
6Alkyl)-phenyl;-(C
1-C
6Alkyl)-the O-phenyl;-(C
1-C
6Alkyl)-O-(C
1-C
6Alkyl)-phenyl; Triazolidine-3, the 5-diketone; Halogen;-NHC (O) NH
2-N (C
1-C
6Alkyl) C (O) NH
2-N (C
1-C
6Alkyl) C (O) NH (C
1-C
6Alkyl);-N (C
1-C
6Alkyl) C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl);-(C
1-C
6Alkyl) thienyl;-(C
1-C
6Alkyl) furyl;-S-(C
1-C
6Alkyl) phenyl;-SO
2NR
31R
32-C (O)-NR
31R
32-NR
31R
32Dithiane :-NHC (S) NH
2-NHC (S) NH (C
1-C
6Alkyl);-NHC (S) N (C
1-C
6Alkyl) (C
1-C
6Alkyl);-CO
2(C
1-C
6Alkyl); Tetrahydropyrans; Optional is F by 1 or 2 independently; The phenyl that the group of Cl or Br replaces; Pyridine;-C
2-C
4Alkynyl-phenyl;-O-C
3-C
8Cycloalkyl;-O-(C
1-C
6Alkyl)-R
33Benzo [1,2,5] oxadiazoles;-C (O)-(C
1-C
10Alkyl), wherein alkyl is optional by NH
2N (C
1-C
6Alkyl) or N (C
1-C
6Alkyl) (C
1-C
6Alkyl) replaces;-C (O) NH-phenyl;-C (O) N (C
1-C
6Alkyl)-phenyl; 4,4-dimethyl-4,5-dihydro-oxazoles;-(C
1-C
6Alkyl)-the S-pyridine;-(C
1-C
6Alkyl)-SO
2-pyridine;-(C
1-C
6Thio alkoxy)-pyridine,
R wherein
31And R
32Be independently selected from hydrogen, C in each case
1-C
6Alkyl, hydroxyl C
1-C
6Alkyl, C
1-C
6Alkylhalide group ,-(C
1-C
6Alkyl)-C (O) NH
2,-(C
1-C
6Alkyl)-C (O) NH (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-NH
2,-(C
1-C
6Alkyl)-NH (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl) phenyl ,-(C
1-C
6Alkyl) pyridyl ,-C (O) furyl, (C
1-C
6Alkyl)-tetrahydrofuran (THF), wherein phenyl and pyridyl be unsubstituted or by 1,2,3,4 or 5 independently for C
1-C
4Alkyl, hydroxyl, C
1-C
4The group of alkoxyl group, halogen replaces, or
R
31, R
32Form 5,6 or 7 yuan of Heterocyclylalkyls or 6 yuan of hetero-aromatic rings with the nitrogen that links to each other with them, wherein each is chosen wantonly and is fused on benzene, pyridine or the pyrimidine ring, and each is optional by C
1-C
6Alkoxyl group, hydroxyl, hydroxyl C
1-C
6Alkyl, C
1-C
4Alkoxy C
1-C
6Alkyl ,-C (O) NH
2,-C (O) NH (C
1-C
6Alkyl)-the phenyl replacement;
R
33Be H, NH in each case independently
2, NH (C
1-C
6Alkyl), N (C
1-C
6Alkyl) (C
1-C
6Alkyl), N (C
1-C
6Alkyl) (phenyl);
R
35Be phenyl, C
3-C
8Cycloalkyl ,-the S-phenyl ,-benzo dioxole, thienyl, C
1-C
6Alkyl, furyl, wherein each group be unsubstituted or by 1,2,3,4 or 5 independently for C
1-C
4Alkyl, C
1-C
4Alkoxyl group, OH, hydroxyl C
1-C
6Alkyl, halogen, halogen C
1-C
6Alkyl, halogen C
1-C
6Alkoxyl group ,-O-(C
1-C
6Alkyl)-phenyl ,-CO
2-(C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-(C
5-C
6Cycloalkyl) group replaces;
R
42Be H, C
1-C
6Alkyl; Benzyl ,-NHC (O)-(C
1-C
6Alkyl) or-NHC (O)-phenyl (wherein phenyl is optional is replaced by 1 and 2 alkyl).
R
55It is cyclohexyl; Cyclopentyl; The tall and erect ketone of nitrogen; Phenyl; Piperidyl;-SO
2-phenyl, pyrrolidyl; Or 4,5,6,7-tetrahydrochysene-thiazole [5,4-c] pyridine; Wherein each chooses quilt-C (O) NH wantonly
2Replace;-C (O) NH (C
1-C
6Alkyl);-C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl); C
1-C
6Alkoxy carbonyl;-O-(C
1-C
6Alkyl)-C (O)-NR
31R
32-(C
1-C
6Alkyl)-phenyl; 4,5-dihydro-2H-pyridazin-3-one; It is optional that (wherein phenyl is chosen quilt-NHC (O) C wantonly by a CN group, phenoxy group
1-C
6Alkyl ,-N (C
1-C
6Alkyl)-C (O) C
1-C
6The alkyl replacement) C that replaces
5-C
6Cycloalkyl, wherein
R
31, R
32Form tetramethyleneimine, piperidines, piperazine, morpholine or a thiomorpholine ring with the nitrogen that links to each other with them, wherein each ring is unsubstituted or is OH, C independently by 1,2 or 3
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-(C
1-C
6Alkyl)-(wherein imidazoles is optional by 1 or 2 C for imidazoles
1-C
4Alkyl replaces) or hydroxyl (C
1-C
6Alkyl) group of (wherein alkyl is optional is replaced by 1 phenyl ring) replaces;
Or
R
42, R
55Forming a tetrahydro isoquinolyl, dihydro-isoquinoline base or choose wantonly by 1,2,3 or 4 with the nitrogen that links to each other with them is halogen, C independently
1-C
4Alkyl, C
1-C
4The isoquinolyl that alkoxyl group, CN, OH and phenyl groups replace, wherein phenyl is optional by halogen, hydroxyl, C
1-C
4Alkoxyl group and C
1-C
4Alkyl replaces.
Preferred Z3 compound comprises following compound, promptly wherein
R
30Be selected from phenyl, pyrrolidone-base, pyridyl, piperidyl, furyl, cyclopropyl and thienyl, wherein above-mentioned each group is unsubstituted or is replaced by 1,2,3,4 or 5 substituting group that is independently selected from following groups:
C
1-C
10Alkyl, hydroxyl, hydroxyl C
1-C
10Alkyl C
1-C
6Alkoxyl group ,-NR
31-SO
2-(C
1-C
6Alkyl) ,-SO
2-NH (C
1-C
6Alkyl) ,-SO
2-N (C
1-C
6Alkyl) (C
1-C
6Alkyl), halogen ,-NHC (O) NH
2,-N (C
1-C
6Alkyl) C (O) NH
2,-N (C
1-C
6Alkyl) C (O) NH (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl) C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-SO
2NR
31R
32,-C (O)-NR
31R
32,-NR
31R
32,-C
2-C
4Alkynyl-phenyl ,-O-C
3-C
8Cycloalkyl ,-O-(C
1-C
6Alkyl)-R
33, benzo [1,2,5] oxadiazoles;-C (O)-(C
1-C
10Alkyl);
R wherein
31And R
32Be independently selected from hydrogen, C in each case
1-C
6Alkyl, hydroxyl C
1-C
6Alkyl, C
1-C
6Alkylhalide group ,-(C
1-C
6Alkyl)-C (O) NH
2,-(C
1-C
6Alkyl)-C (O) NH (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-NH
2,-(C
1-C
6Alkyl)-NH (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-N (C
1-C
6Alkyl) (C
1-C
6Alkyl), benzyl and-C (O) furyl, wherein phenyl and pyridyl be unsubstituted or by 1,2 or 3 independently for C
1-C
4Alkyl, hydroxyl, C
1-C
4The group of alkoxyl group, halogen replaces, or
R
31, R
32Form 5,6 or 7 yuan of Heterocyclylalkyls or 6 yuan of hetero-aromatic rings with the nitrogen that links to each other with them, wherein each is optional by C
1-C
6Alkoxyl group, hydroxyl, hydroxyl C
1-C
6Alkyl, C
1-C
4Alkoxy C
1-C
6Alkyl or-C (O) NH
2Replace;
R
35Be phenyl, C
3-C
6Cycloalkyl or-the S-phenyl, wherein each group be unsubstituted or by 1,2 or 3 independently for C
1-C
4Alkyl, C
1-C
4Alkoxyl group, CF
3, OCF
3, halogen ,-the O benzyl ,-CO
2-(C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-(C
5-C
6Cycloalkyl) group replaces;
R
42Be H, C
1-C
6Alkyl; Benzyl ,-NHC (O)-(C
1-C
6Alkyl) or-NHC (O)-phenyl (wherein phenyl is optional is replaced by 1 and 2 alkyl).
R
55It is cyclohexyl; The tall and erect ketone of nitrogen; Phenyl; Piperidyl;-SO
2-phenyl, pyrrolidyl; Or 4,5,6,7-tetrahydrochysene-thiazole [5,4-c] pyridine; Wherein each chooses quilt-C (O) NH wantonly
2Replace; C
1-C
6Alkoxy carbonyl;-O-(C
1-C
6Alkyl)-C (O)-NR
31R
32-(C
1-C
6Alkyl)-phenyl; 4,5-dihydro-2H-pyridazin-3-one; It is optional that (wherein phenyl is chosen quilt-NHC (O) C wantonly by a CN, phenoxy group
1-C
6The alkyl replacement) cyclopentyl that replaces, wherein
R
31, R
32Form tetramethyleneimine, piperidines, piperazine or a morpholine ring with the nitrogen that links to each other with them, wherein each ring be unsubstituted or by 1,2 or 3 independently for OH ,-(C
1-C
6Alkyl)-(wherein imidazoles is optional by 1 or 2 C for imidazoles
1-C
4Alkyl replaces) or hydroxyl (C
1-C
6Alkyl) group of (wherein alkyl is optional is replaced by 1 phenyl ring) replaces;
Or
R
42, R
55Forming a tetrahydro isoquinolyl with the nitrogen that links to each other with them, choosing wantonly by 1,2,3 or 4 is halogen, C independently
1-C
4Alkyl, C
1-C
4The group that alkoxyl group, CN, OH and phenyl groups replace, wherein phenyl is optional by halogen, hydroxyl, C
1-C
4Alkoxyl group and C
1-C
4Alkyl replaces.
Also preferred Z3 compound comprises following compound, promptly wherein
R
30Be selected from phenyl, pyridyl or piperidyl, wherein above-mentioned each group is unsubstituted or is independently selected from C by 1,2,3,4 or 5
1-C
10Alkyl, hydroxyl, hydroxyl C
1-C
10Alkyl C
1-C
6Alkoxyl group, halogen ,-SO
2NR
31R
32,-C (O)-NR
31R
32,-NR
31R
32,-O-C
3-C
6Cycloalkyl ,-C (O)-(C
1-C
6Alkyl) group replaces;
R wherein
31And R
32Be independently selected from hydrogen, C in each case
1-C
6Alkyl, hydroxyl C
1-C
6Alkyl ,-(C
1-C
6Alkyl)-NH
2,-(C
1-C
6Alkyl)-NH (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-N (C
1-C
6Alkyl) (C
1-C
6Alkyl), benzyl and-C (O) furyl, wherein phenyl be unsubstituted or by 1,2 or 3 independently for C
1-C
4Alkyl, hydroxyl, C
1-C
4The group of alkoxy or halogen replaces, or
R
31, R
32Form tetramethyleneimine, piperidines, morpholine, pyridine or a pyrimidine ring with the nitrogen that links to each other with them, wherein each is optional by C
1-C
6Alkoxyl group, hydroxyl, hydroxyl C
1-C
6Alkyl, C
1-C
4Alkoxy C
1-C
6Alkyl or-C (O) NH
2Replace;
R
35Be phenyl, cyclohexyl, cyclopentyl or-the S-phenyl, wherein each group is unsubstituted or is C independently by 1,2 or 3
1-C
4Alkyl, C
1-C
4Alkoxyl group, CF
3, OCF
3, halogen ,-the O benzyl ,-CO
2-(C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-(C
5-C
6Cycloalkyl) group replaces.
Under a kind of particular case, the invention provides the compound that chemical formula is X100:
And can be used for the salt of pharmacy, wherein
N, p and q are 0,1 or 2 independently;
Dotted line is represented a singly-bound or two key;
R
1, R
2, R
3And R
4Be independently selected from
Hydrogen, halogen, C
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl group, halogen (C
1-C
6) alkyl, hydroxyl (C
1-C
6) alkyl, halogen (C
1-C
6) alkoxyl group, sulfo-(C
1-C
6) alkyl, (C
1-C
6) alkoxyl group (C
1-C
6) alkyl, amino (C
1-C
6) alkyl, list (C
1-C
6) alkylamino (C
1-C
6) alkyl, two (C
1-C
6) alkylamino (C
1-C
6) alkyl,
-(CH
2)
0-4-aryl or-(CH
2)
0-4-heteroaryl,
C
2-C
6Alkenyl or C
2-C
6Alkynyl, wherein each group optional by one, two or three be independently selected from halogen, hydroxyl ,-SH, cyano group ,-CF
3, C
1-C
3Alkoxyl group, amino, list (C
1-C
6) alkylamino and two (C
1-C
6) substituting group of alkylamino replaces,
-(CH
2)
0-4-C
3-C
7Cycloalkyl, wherein cycloalkyl optional by one, two or three be independently selected from halogen, hydroxyl ,-SH, cyano group ,-CF
3, C
1-C
3Alkoxyl group, amino, list (C
1-C
6) alkylamino and two (C
1-C
6) substituting group of alkylamino replaces;
R
z, R
z', R
z" and R
z_ representative independently
C
1-C
6Alkyl, optional by one, two or three are independently selected from C
1-C
3Alkyl, halogen ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
6Alkoxyl group, amino, list (C
1-C
6) alkylamino and two (C
1-C
6) substituting group of alkylamino replaces,
Hydroxyl, nitro, halogen ,-CO
2H, cyano group,
-(CH
2)
0-4-CO-NR
142R
144, R wherein
142And R
144Represent hydrogen, C independently
1-C
6Alkyl, hydroxyl (C
1-C
6) alkyl, amino (C
1-C
6) alkyl, alkylhalide group, C
3-C
7Cycloalkyl ,-(C
1-C
2Alkyl)-(C
3-C
7Cycloalkyl) ,-(C
1-C
6Alkyl)-O-(C
1-C
3Alkyl), contain one or two pair key-C
2-C
6Alkenyl, contain one or two triple-linked C
2-C
6Alkynyl, contain two keys and a triple-linked-C
1-C
6Alkyl chain ,-R
The 1-aryl, R wherein
The 1-arylDefinition as above or R
The 1-heteroaryl, R wherein
The 1-heteroarylDefinition as above,
-(CH
2)
0-4-CO-(C
1-C
12Alkyl) ,-(CH
2)
0-4-CO-(C
2-C
12Alkenyl) ,-(CH
2)
0-4-CO-(C
2-C
12Alkynyl) ,-(CH
2)
0-4-CO-(C
3-C
7Cycloalkyl) ,-(CH
2)
0-4-CO-R
The 1-aryl, R wherein
The 1-arylDefinition as above ,-(CH
2)
0-4-CO-R
The 1-heteroaryl, R wherein
The 1-heteroarylDefinition as above ,-(CH
2)
0-4-CO-R
The 1-heterocycle,-(CH
2)
0-4-CO-R
146, R wherein
146Be Heterocyclylalkyl, wherein Heterocyclylalkyl is optional by 1-4 C
1-C
6The alkyl replacement,
-(CH
2)
0-4-CO-O-R
148, R wherein
148Be selected from: C
1-C
6Alkyl ,-(CH
2)
0-2-(R
The 1-aryl), C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
3-C
7Cycloalkyl and-(CH
2)
0-2-(R
The 1-heteroaryl),
-(CH
2)
0-4-SO
2-NR
142R
144,-(CH
2)
0-4-SO-(C
1-C
8Alkyl) ,-(CH
2)
0-4-SO
2-(C
1-C
12Alkyl) ,-(CH
2)
0-4-SO
2-(C
3-C
7Cycloalkyl) ,-(CH
2)
0-4-N (H or R
148)-CO-O-R
148,-(CH
2)
0-4-N (H or R
148)-CO-N (R
148)
2,-(CH
2)
0-4-N-CS-N (R
148)
2,-(CH
2)
0-4-N (H or R
148)-CO-R
142,-(CH
2)
0-4-NR
142R
144-(CH
2)
0-4-R
146, R wherein
N-4Definition as above,
-(CH
2)
0-4-O-CO-(C
1-C
6Alkyl) ,-(CH
2)
0-4-O-P (O)-(OR
150)
2, each R wherein
150Be hydrogen or C independently
1-C
4Alkyl ,-(CH
2)
0-4-O-CO-N (R
148)
2,-(CH
2)
0-4-O-CS-N (R
148)
2,-(CH
2)
0-4-O-(R
148)
2,-(CH
2)
0-4-O-(R
148)
2-CO
2H ,-(CH
2)
0-4-S-(R
148)
2,-(CH
2)
0-4-O-halogen (C
1-C
6) alkyl ,-(CH
2)
0-4-O-(C
1-C
6) alkyl, C
3-C
7Cycloalkyl,
C
2-C
6Alkenyl or C
2-C
6Alkynyl, each is optional by C
1-C
3Alkyl, halogen, hydroxyl ,-SH, cyano group ,-CF
3, C
1-C
3Alkoxyl group, amino, list (C
1-C
6) alkylamino and two (C
1-C
6) the alkylamino replacement,
-(CH
2)
0-4-N (H or R
148)-SO
2-R
142, or-(CH
2)
0-4-C
3-C
7Cycloalkyl;
R
35Be phenyl, cyclohexyl ,-S-phenyl, benzo dioxole, thienyl, C
3-C
6Alkyl, furyl, wherein each group be unsubstituted or by 1,2,3,4 or 5 independently for C
1-C
4Alkyl, C
1-C
4Alkoxyl group, OH, hydroxyl C
1-C
6Alkyl, halogen, halogen C
1-C
6Alkyl, halogen C
1-C
6Alkoxyl group ,-O-(C
1-C
6Alkyl)-phenyl ,-CO
2-(C
1-C
6Alkyl) or-(C
1-C
4Alkyl)-(C
5-C
6Cycloalkyl) group replaces;
X and Y are independently selected from O, NR
5, C (O), CR
1R
2, SO
2And S,
R wherein
5Be hydrogen, C
1-C
6Alkyl, SO
2R
5', C (O) R
5', R wherein
5' be hydrogen, halogen, C
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl group, halogen (C
1-C
6) alkyl, halogen (C
1-C
6) alkoxyl group, sulfo-(C
1-C
6) alkyl, (C
1-C
6) alkoxyl group (C
1-C
6) alkyl, amino (C
1-C
6) alkyl, list (C
1-C
6) alkylamino (C
1-C
6) alkyl, two (C
1-C
6) alkylamino (C
1-C
6) alkyl,
-(CH
2)
0-4-aryl or-(CH
2)
0-4-heteroaryl,
C
2-C
6Alkenyl or C
2-C
6Alkynyl, each optional by one, two or three be independently selected from halogen, hydroxyl ,-SH, cyano group ,-CF
3, C
1-C
3Alkoxyl group, amino, list (C
1-C
6) alkylamino and two (C
1-C
6) substituting group of alkylamino replaces,
-(CH
2)
0-4-C
3-C
7Cycloalkyl, wherein cycloalkyl optional by one, two or three be independently selected from halogen, hydroxyl ,-SH, cyano group ,-CF
3, C
1-C
3Alkoxyl group, amino, list (C
1-C
6) alkylamino and two (C
1-C
6) substituting group of alkylamino replaces.
R
140Represent phenyl or naphthyl, wherein each is optional by 1-5 substituting group replacement that is independently selected from following groups:
C
1-C
6Alkyl, optional by one, two or three are selected from C
1-C
3Alkyl ,-halogen, hydroxyl ,-SH, cyano group ,-CF
3, C
1-C
3Alkoxyl group, amino, list (C
1-C
6) alkylamino and two (C
1-C
6) substituting group of alkylamino replaces,
Hydroxyl, nitro, halogen ,-CO
2H, cyano group,
-(CH
2)
0-4-CO-NR
142R
144, R wherein
142And R
144Represent hydrogen, C independently
1-C
6Alkyl, hydroxyl (C
1-C
6) alkyl, amino (C
1-C
6) alkyl, alkylhalide group, C
3-C
7Cycloalkyl ,-(C
1-C
2Alkyl)-(C
3-C
7Cycloalkyl) ,-(C
1-C
6Alkyl)-O-(C
1-C
3Alkyl), contain one or two pair key-C
2-C
6Alkenyl, contain one or two triple-linked C
2-C
6Alkynyl, contain two keys and a triple-linked-C
1-C
6Alkyl chain ,-R
The 1-aryl, R wherein
The 1-arylDefinition as above or R
The 1-heteroaryl, R wherein
The 1-heteroarylDefinition as above,
-(CH
2)
0-4-CO-(C
1-C
12Alkyl) ,-(CH
2)
0-4-CO-(C
2-C
12Alkenyl) ,-(CH
2)
0-4-CO-(C
2-C
12Alkynyl) ,-(CH
2)
0-4-CO-(C
3-C
7Cycloalkyl) ,-(CH
2)
0-4-CO-R
The 1-aryl, R wherein
The 1-arylDefinition as above ,-(CH
2)
0-4-CO-R
The 1-heteroaryl, R wherein
The 1-heteroarylDefinition as above ,-(CH
2)
0-4-CO-R
The 1-heterocycle,-(CH
2)
0-4-CO-R
146, R wherein
146Be Heterocyclylalkyl, wherein Heterocyclylalkyl is optional by 1-4 C
1-C
6The alkyl replacement,
-(CH
2)
0-4-CO-O-R
148, R wherein
148Be selected from: C
1-C
6Alkyl ,-(CH
2)
0-2-(R
The 1-aryl), C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
3-C
7Cycloalkyl and-(CH
2)
0-2-(R
The 1-heteroaryl),
-(CH
2)
0-4-SO
2-NR
142R
144,-(CH
2)
0-4-SO-(C
1-C
8Alkyl) ,-(CH
2)
0-4-SO
2-(C
1-C
12Alkyl) ,-(CH
2)
0-4-SO
2-(C
3-C
7Cycloalkyl) ,-(CH
2)
0-4-N (H or R
148)-CO-O-R
148,-(CH
2)
0-4-N (H or R
148)-CO-N (R
148)
2,-(CH
2)
0-4-N-CS-N (R
148)
2,-(CH
2)
0-4-N (H or R
148)-CO-R
142,-(CH
2)
0-4-NR
142R
144,-(CH
2)
0-4-R
146, R wherein
N-4Definition as above,
-(CH
2)
0-4-O-CO-(C
1-C
6Alkyl);-(CH
2)
0-4-O-P (O)-(OR
150)
2, each R wherein
150Be hydrogen or C independently
1-C
4Alkyl ,-(CH
2)
0-4-O-CO-N (R
148)
2,-(CH
2)
0-4-O-CS-N (R
148)
2,-(CH
2)
0-4-O-(R
148)
2,-(CH
2)
0-4-O-(R
148)
2-CO
2H ,-(CH
2)
0-4-S-(R
148)
2,-(CH
2)
0-4-O-halogen (C
1-C
6) alkyl ,-(CH
2)
0-4-O-(C
1-C
6) alkyl, C
3-C
7Cycloalkyl,
C
2-C
6Alkenyl or C
2-C
6Alkynyl, each is optional by C
1-C
3Alkyl, halogen, hydroxyl ,-SH, cyano group ,-CF
3, C
1-C
3Alkoxyl group, amino, list (C
1-C
6) alkylamino and two (C
1-C
6) the alkylamino replacement,
-(CH
2)
0-4-N (H or R
148)-SO
2-R
142, or-(CH
2)
0-4-C
3-C
7Cycloalkyl.
In a preferred specific embodiment, q is 1.
In a preferred specific embodiment, R
z, R
z', R
z" and R
z_ in two or three be hydrogen, and
R
z, R
z', R
z" and R
z_ middle another one or two be hydroxyl, nitro, halogen ,-CO
2H, cyano group or C
1-C
6Alkyl, wherein alkyl optional by one, two or three are independently selected from C
1-C
3Alkyl, halogen ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
6Alkoxyl group, amino, list (C
1-C
6) alkylamino and two (C
1-C
6) substituting group of alkylamino replaces.
Preferred chemical formula is that the compound of X100 comprises following compound, i.e. R wherein
z, R
z', R
z" and R
z_ in three be that hydrogen and another are (C
1-C
6) alkyl, halogen or (C
1-C
6) alkoxyl group.
The compound that other preferred chemical formula is X100 comprises following compound, i.e. R wherein
140The phenyl that is replaced by 1,2 or 3 substituting group that is independently selected from following groups:
Optional by one, two or three are independently selected from C
1-C
3Alkyl ,-halogen, hydroxyl ,-SH, cyano group ,-CF
3, C
1-C
3Alkoxyl group, amino, list (C
1-C
6) alkylamino and two (C
1-C
6) C that replaces of the group of alkylamino
1-C
6Alkyl,
Hydroxyl, nitro, halogen ,-CO
2H, cyano group,
-(CH
2)
0-4-CO-NR
142R
144, R wherein
142And R
144Represent hydrogen, C independently
1-C
6Alkyl, hydroxyl (C
1-C
6) alkyl, amino (C
1-C
6) alkyl and C
3-C
7Cycloalkyl.
Other preferred chemical formula is X100 compound comprises following compound again, i.e. R wherein
140By hydroxyl, nitro, halogen ,-CO
2H, cyano group or C
1-C
6In the alkyl one and-(CH
2)
0-4-CO-NR
142R
144In the phenyl of a replacement, wherein alkyl optional by one, two or three are independently selected from C
1-C
3Alkyl ,-halogen, hydroxyl ,-SH, cyano group ,-CF
3, C
1-C
3Alkoxyl group, amino, list (C
1-C
6) alkylamino and two (C
1-C
6) group of alkylamino replaces.
The compound that other preferred chemical formula is X100 is following compound, i.e. R wherein
140By-(CH
2)
0-4-CO-NR
142R
144Monobasic phenyl, and R
142And R
144Be hydrogen or C independently
1-C
6Alkyl.
Preferred chemical formula is that the compound of X100 comprises R wherein
142And R
144Identical and be the compound of propyl group.
The compound that other specific chemical formula is X100 comprises following compound, i.e. R wherein
35That replaced by 1-5 halogen or be independently selected from (C by 1,2 or 3
1-C
6) alkyl, hydroxyl, halogen, (C
1-C
6) alkoxyl group, amino, list (C
1-C
6) alkylamino and two (C
1-C
6) phenyl that replaces of the group of alkylamino.
Preferred chemical formula is that the compound of X100 comprises following compound, i.e. R wherein
35By the phenyl of 2 halogens replacements.
Other preferred chemical formula compound that is X100 is R wherein again
35Be 3, the compound of 5-difluorophenyl.
The compound that other specific chemical formula is X100 comprises following compound, i.e. R wherein
140By hydroxyl, nitro, halogen ,-CO
2H, cyano group or C
1-C
6In the alkyl one and-(CH
2)
0-4-CO-NR
142R
144In the phenyl of a replacement, wherein alkyl optional by one, two or three are independently selected from C
1-C
3Alkyl ,-halogen, hydroxyl ,-SH, cyano group ,-CF
3, C
1-C
3Alkoxyl group, amino, list (C
1-C
6) alkylamino and two (C
1-C
6) group of alkylamino replaces.
Preferred chemical formula is that the specific compound of X100 is following compound, i.e. R wherein
140By-(CH
2)
0-4-CO-NR
142R
144Monobasic phenyl, and R
142And R
144Be hydrogen or C independently
1-C
6Alkyl.
The specific compound that other preferred chemical formula is X100 is R wherein
142And R
144Identical and be the compound of propyl group.
Preferred chemical formula be the compound of X100 be wherein n be 1 and p be 0 compound.
The compound that other preferred chemical formula is X100 is that wherein dotted line is represented single bonded compound.
At other preferred chemical formula is in the compound of X100, R
1Be that hydrogen and X are SO
2
In other preferred Z100 compound, Y is a methylene radical.
Preferred X100 compound is that wherein Z ' is the compound of 2-propyl group.
Other preferred X100 compound is that wherein Y is methylene radical and R
2Be hydrogen, hydroxyl (C
1-C
3) alkyl or (C
1-C
3) compound of alkyl.
Preferred R
2Group is a methyl.
Under the another kind of particular case of chemical formula X100, R
1Be hydrogen;
X is SO
2And Y is NR
5, or X is NR
5And Y is SO
2, each R wherein
5Be hydrogen, (C
1-C
6) alkyl or hydroxyl (C
1-C
6) alkyl.
Under a kind of preferable case of X100,
R
1Be hydrogen;
X is that C (O) and Y are NR
5, or X is NR
5And Y is C (O), wherein each R
5Be R
5Be hydrogen, (C
1-C
6) alkyl or hydroxyl (C
1-C
6) alkyl.
The compound that preferred chemical formula is X100 comprises that chemical formula is the compound of X101
The compound that other preferred chemical formula is X100 comprises that chemical formula is the compound of X102
The compound that preferred chemical formula is X100 comprises that chemical formula is the compound of X103
The compound that other preferred chemical formula is X100 comprises that chemical formula is the compound of X104
The compound that preferred chemical formula is X103 comprises R wherein
2Be (C
1-C
3) compound of alkyl.
The compound that other preferred chemical formula is X103 comprises R wherein
2Compound for methyl.
Other preferred chemical formula compound that is X103 comprises R wherein again
2Be hydroxyl (C
1-C
3) compound of alkyl.
The compound that preferred chemical formula is X104 comprises R wherein
2Be (C
1-C
3) compound of alkyl.
The compound that other preferred chemical formula is X104 comprises R wherein
2Compound for methyl.
Other preferred chemical formula compound that is X104 comprises R wherein again
2Be hydroxyl (C
1-C
3) compound of alkyl.
Under a kind of particular case, the invention provides the compound that chemical formula is Z4:
Wherein
R
100Be H, C
1-C
8Alkoxy carbonyl, phenyl C
1-C
6Alkyl or phenyl C
1-C
6Alkoxy carbonyl;
R
110Be phenyl C
1-C
6Alkyl, thienyl ,-S-phenyl, furyl or benzo dioxolyl, wherein each optional be halogen, C independently by 1,2,3,4 or 5
1-C
4Alkyl, C
1-C
4Alkoxyl group or phenyl C
1-C
6The group of alkoxyl group replaces; And
R
120Be H, phenyl C
1-C
6Alkyl, optional by C
1-C
6The C that alkyl or phenyl replaces
3-C
8Cycloalkyl, C
3-C
8Cycloalkyl C
1-C
4Alkyl or optional quilt-C (O) NR
121R
122The C that replaces
1-C
6Alkyl, wherein above-mentioned each optional be C independently by 1,2 or 3
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, halogen or C
1-C
6The group of alkoxyl group replaces; Wherein
R
121And R
122Be H or C independently
1-C
6Alkyl.
Preferred Z4 compound comprises following compound, promptly wherein
R
100It is tert-butoxycarbonyl.
Preferred Z4 compound comprises following compound, i.e. R wherein
110Be to choose wantonly by 1,2,3,4 or 5 to be halogen, C independently
1-C
4Alkyl, C
1-C
4Alkoxyl group or phenyl C
1-C
6The phenyl C that the group of alkoxyl group replaces
1-C
6Alkyl.
Preferred Z4 compound comprises R wherein
110Compound for phenyl-monohalide base, dihalogenated phenyl or trihalogenated benzene base.
Preferred Z4 compound comprises following compound, i.e. R wherein
110Be thienyl or-the S-phenyl, each is optional to be halogen, C by 1,2,3,4 or 5 independently
1-C
4Alkyl, C
1-C
4The group of alkoxyl group, benzyloxy replaces.
Preferred Z4 compound comprises following compound, i.e. R wherein
110Be furyl or benzo dioxolyl, each is optional to be halogen, C by 1,2,3,4 or 5 independently
1-C
4Alkyl, C
1-C
4The group of alkoxyl group, benzyloxy replaces.
Preferred Z4 compound comprises following compound, i.e. R wherein
120Be to choose wantonly by 1,2 or 3 to be C independently
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, halogen or C
1-C
6The benzyl that the group of alkoxyl group replaces.
Preferred Z4 compound comprises following compound, i.e. R wherein
120Be optional by C
1-C
6The cyclopropyl that alkyl or phenyl replaces; Or cyclopropyl C
1-C
4Alkyl, wherein above-mentioned each optional be C independently by 1,2 or 3
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, halogen or C
1-C
6The group of alkoxyl group replaces.
Preferred Z4 compound comprises following compound, promptly wherein
R
110Be to choose wantonly by 1,2,3,4 or 5 to be halogen, C independently
1-C
4Alkyl, C
1-C
4Alkoxyl group or phenyl C
1-C
6The phenyl C that the group of alkoxyl group replaces
1-C
6Alkyl; And
R
120Be H or optional be C independently by 1,2 or 3
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, halogen or C
1-C
6The benzyl that the group of alkoxyl group replaces.
The Z4 compound that other is more preferably comprises following compound, promptly wherein
R
110Be to choose wantonly by 1,2,3,4 or 5 to be halogen, C independently
1-C
4Alkyl, C
1-C
4Alkoxyl group or phenyl C
1-C
6The phenyl C that the group of alkoxyl group replaces
1-C
6Alkyl; And
R
120Be optional by C
1-C
6The cyclopropyl that alkyl or phenyl replaces; Or cyclopropyl C
1-C
4Alkyl, wherein above-mentioned each optional be C independently by 1,2 or 3
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, halogen or C
1-C
6The group of alkoxyl group replaces.
The Z4 compound that other is more preferably comprises following compound, promptly wherein
R
110Be thienyl or-the S-phenyl, each is optional to be halogen, C by 1,2,3,4 or 5 independently
1-C
4Alkyl, C
1-C
4The group of alkoxyl group, benzyloxy replaces; And
R
120Be H or optional be C independently by 1,2 or 3
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, halogen or C
1-C
6The benzyl that the group of alkoxyl group replaces.
The Z4 compound that other is more preferably comprises following compound, promptly wherein
R
110Be thienyl or-the S-phenyl, each is optional to be halogen, C by 1,2,3,4 or 5 independently
1-C
4Alkyl, C
1-C
4The group of alkoxyl group, benzyloxy replaces; And
R
120Be optional by C
1-C
6The cyclopropyl that alkyl or phenyl replaces; Or cyclopropyl C
1-C
4Alkyl, wherein above-mentioned each optional be C independently by 1,2 or 3
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, halogen or C
1-C
6The group of alkoxyl group replaces.
The Z4 compound that other is more preferably comprises following compound, promptly wherein
R
110Be furyl or benzo dioxolyl, each is optional to be halogen, C by 1,2,3,4 or 5 independently
1-C
4Alkyl, C
1-C
4The group of alkoxyl group, benzyloxy replaces.
R
120Be H or optional be C independently by 1,2 or 3
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, halogen or C
1-C
6The benzyl that the group of alkoxyl group replaces.
Even preferred Z4 compound comprises following compound, promptly wherein
R
110Be furyl or benzo dioxolyl, each is optional to be halogen, C by 1,2,3,4 or 5 independently
1-C
4Alkyl, C
1-C
4The group of alkoxyl group, benzyloxy replaces;
R
120Be optional by C
1-C
6The cyclopropyl that alkyl or phenyl replaces; Or cyclopropyl C
1-C
4Alkyl, wherein above-mentioned each optional be C independently by 1,2 or 3
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, halogen or C
1-C
6The group of alkoxyl group replaces.
The compound that other is more preferably of the present invention is following compound, promptly wherein
R
51Be independently in each case H ,-SO
2NH-propyl group-OH ,-SO
2NH-ethyl-OH ,-SO
2NH-ethyl-OCH
3,-SO
2NH-CH (CH
3)
2-CH
2OH ,-SO
2NH-(CH
2CH (OH) CH
3) ,-SO
2NH-ethyl-NH (CH
3) ,-SO
2NH-(CH
2CH
2OH)
2,-SO
2NHCH (CH
3) CH
2OH ,-SO
2N (CH
3)
2,-SO
2NH (CH
2CH (OH) CH
3) ,-SO
2-tetramethyleneimine ,-SO
2-(lupetidine) ,-SO
2-(2-propyl group piperidines) ,-SO
2-(hydroxypropyl),-C (O)-(2-methoxymethyl tetramethyleneimine),-C (O)-(2-crassitude),-C (O)-(2, the 6-dimethyl pyrrolidine),-C (O)-(2-hydroxymethyl pyrrolidine),-C (O) N (methyl) (ethyl),-C (O) N (methyl) (propyl group),-C (O) N (methyl) (butyl),-C (O) N (propyl group) (butyl),-C (O) N (allyl group) (cyclopentyl),-C (O) N (allyl group) (cyclohexyl),-C (O) N (methyl) (methyl),-C (O) N (ethyl) (ethyl),-C (O) N (butyl) (butyl),-C (O) N (sec.-propyl) (sec.-propyl),-C (O) N (propyl group) (propyl group),-C (O) N (methyl) (cyclohexyl),-C (O) N (ethyl) (cyclohexyl),-C (O) NH (cyclobutyl),-C (O) NH (cyclopentyl),-C (O) N (CH
3) (cyclopentyl) ,-C (O) NH (2-methylcyclohexyl) ,-C (O) NH (amyl group) ,-C (O) N (amyl group) (amyl group) ,-C (O) NH (isopentyl) ,-C (O) NH (ethoxyethyl group) ,-C (O) N (CH
3) (methoxy ethyl) ,-C (O) N (propyl group) (methoxy ethyl) ,-C (O) N (methoxy ethyl) (methoxy ethyl) ,-C (O) N (ethoxyethyl group) (ethoxyethyl group) ,-C (O) N (ethyl) (methoxy ethyl) ,-C (O) N (propyl group) (hydroxyethyl) ,-C (O) N (hydroxyethyl) (ethyl), ethynyl, methyl, bromo ,-N (CH
3) SO
2(CH
3) ,-N (CH
3) SO
2-thienyl ,-N (hydroxypropyl) SO
2CH
3,-(CH
2)-SO
2-(CH
3) or-C (O)-CH (CH
3) CH
2CH
2CH
3
Two R are more preferably wherein arranged
51The compound of group.
Wherein R more preferably also
51Group is at 3 and 5 compound of phenyl.
The preferred compound of the present invention is following compound, promptly wherein
In each case, R
51Be independently selected from C
1-C
4Alkyl ,-C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-C (O) NH
2,-C (O) N (C
2-C
6Alkenyl) (C
3-C
8Cycloalkyl) ,-C (O) NH (C
3-C
8Cycloalkyl) ,-C (O) NH (C
1-C
6Alkyl), optional by 1 and 2 be independently the group replacement of alkoxyalkyl or hydroxyl C (O)-(tetramethyleneimine), halogen ,-C (O) N (C
1-C
6Hydroxyalkyl) (C
1-C
6Alkyl) ,-C (O) NH (alkoxyalkyl) ,-C (O) N (alkoxyalkyl) (alkoxyalkyl) ,-C (O) N (C
1-C
6Alkyl) (alkoxyalkyl) ,-C (O) N (C
1-C
6Hydroxyalkyl) (alkyl) ,-NHSO
2CF
3,-N (C
1-C
6Alkyl)-SO
2-thienyl ,-N (C
1-C
6Hydroxyalkyl) SO
2-(C
1-C
6Alkyl) ,-NHC (O) C
1-C
4Alkyl, optional by 1 or 2 methyl substituted De oxazolyl, optional by 1 or 2 methyl substituted thiazolyl, optional by 1 or 2 methyl substituted pyrazolyl, optional by 1 or 2 methyl substituted imidazolyl, optional by 1 or 2 methyl substituted isoxazolyl, the optional pyrimidyl that is replaced by 1 or 2 methyl or halogen group ,-NHSO
2CH
3,-NHSO
2-imidazolyl (wherein imidazole ring is optional by 1 or 2 methyl substituted) ,-N (C
1-C
6Alkyl) SO
2(C
1-C
6Alkyl) ,-SO
2NH-C
1-C
6Hydroxyalkyl ,-SO
2NH-C
1-C
6Alkyl-NH (C
1-C
4Alkyl), optional by 1 or 2 methyl substituted-SO
2-piperazinyl, optional by 1 or 2 methyl substituted-SO
2-tetramethyleneimine, optional by 1 or 2 C
1-C
4Alkyl replaces-SO
2-piperidines ,-SO
2N (C
1-C
4Hydroxyalkyl) (C
1-C
4Hydroxyalkyl) ,-SO
2NH
2,-SO
2N (C
1-C
6Alkyl) (C
1-C
6Alkyl), C
2-C
6Alkynyl ,-SO
2-(C
1-C
6Hydroxyalkyl) ,-SO
2NH (C
1-C
6Hydroxyalkyl) ,-SO
2N (C
1-C
6Alkyl) (C
1-C
6Hydroxyalkyl) ,-(C
1-C
4Alkyl) SO
2-(C
1-C
4Alkyl) or-C (O)-(C
1-C
10Alkyl).
The also preferred compound of the present invention is following compound, i.e. R wherein
51Be independently selected from each case-SO
2NH-propyl group-OH ,-SO
2NH-ethyl-OH ,-SO
2NH-ethyl-OCH
3,-SO
2NH-CH (CH
3)
2-CH
2OH ,-SO
2NH-(CH
2CH (OH) CH
3) ,-SO
2NH-ethyl-NH (CH
3) ,-SO
2NH-(CH
2CH
2OH)
2,-SO
2NHCH (CH
3) CH
2OH ,-SO
2N (CH
3)
2,-SO
2NH (CH
2CH (OH) CH
3) ,-SO
2-tetramethyleneimine ,-SO
2-(lupetidine) ,-SO
2-(2-propyl group piperidines) ,-SO
2-(hydroxypropyl),-C (O)-(2-methoxymethyl tetramethyleneimine),-C (O)-(2-crassitude),-C (O)-(2, the 6-dimethyl pyrrolidine),-C (O)-(2-hydroxymethyl pyrrolidine),-C (O) N (methyl) (ethyl),-C (O) N (methyl) (propyl group),-C (O) N (methyl) (butyl),-C (O) N (propyl group) (butyl),-C (O) N (allyl group) (cyclopentyl),-C (O) N (allyl group) (cyclohexyl),-C (O) N (methyl) (methyl),-C (O) N (ethyl) (ethyl),-C (O) N (butyl) (butyl),-C (O) N (sec.-propyl) (sec.-propyl),-C (O) N (propyl group) (propyl group),-C (O) N (methyl) (cyclohexyl),-C (O) N (ethyl) (cyclohexyl),-C (O) NH (cyclobutyl),-C (O) NH (cyclopentyl),-C (O) N (CH
3) (cyclopentyl) ,-C (O) NH (2-methylcyclohexyl) ,-C (O) NH (amyl group) ,-C (O) N (amyl group) (amyl group) ,-C (O) NH (isopentyl) ,-C (O) NH (ethoxyethyl group) ,-C (O) N (methoxy ethyl) (methoxy ethyl) ,-C (O) N (CH
3) (methoxy ethyl) ,-C (O) N (propyl group) (methoxy ethyl) ,-C (O) N (ethoxyethyl group) (ethoxyethyl group) ,-C (O) N (ethyl) (methoxy ethyl) ,-C (O) N (propyl group) (hydroxyethyl) ,-C (O) N (hydroxyethyl) (ethyl), ethynyl, methyl, bromo ,-N (CH
3) SO
2(CH
3) ,-N (CH
3) SO
2-thienyl ,-N (hydroxypropyl) SO
2CH
3,-(CH
2)-SO
2-(CH
3) or-C (O)-CH (CH
3) CH
2CH
2CH
3
The preferred compound of the present invention is following compound, promptly wherein
R
30Be pyridyl, it is unsubstituted or is replaced by 1 or 2 substituting group that is independently selected from following radicals: C
1-C
4Alkyl ,-C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-C (O) NH
2,-C (O) N (C
2-C
6Alkenyl) (C
3-C
8Cycloalkyl) ,-C (O) NH (C
3-C
8Cycloalkyl) ,-C (O) NH (C
1-C
6Alkyl), optional by 1 and 2 be independently the group replacement of alkoxyalkyl or hydroxyl C (O)-(tetramethyleneimine), halogen ,-C (O) N (C
1-C
6Hydroxyalkyl) (C
1-C
6Alkyl) ,-C (O) NH (alkoxyalkyl) ,-C (O) N (alkoxyalkyl) (alkoxyalkyl) ,-C (O) N (C
1-C
6Alkyl) (alkoxyalkyl) ,-C (O) N (C
1-C
6Hydroxyalkyl) (alkyl) ,-NHSO
2CF
3,-N (C
1-C
6Alkyl)-SO
2-thienyl ,-N (C
1-C
6Hydroxyalkyl) SO
2-(C
1-C
6Alkyl) ,-NHC (O) C
1-C
4Alkyl, optional by 1 or 2 methyl substituted De oxazolyl, optional by 1 or 2 methyl substituted thiazolyl, optional by 1 or 2 methyl substituted pyrazolyl, optional by 1 or 2 methyl substituted imidazolyl, optional by 1 or 2 methyl substituted isoxazolyl, the optional pyrimidyl that is replaced by 1 or 2 methyl or halogen group ,-NHSO
2CH
3,-NHSO
2-imidazolyl (wherein imidazole ring is optional by 1 or 2 methyl substituted) ,-N (C
1-C
6Alkyl) SO
2(C
1-C
6Alkyl) ,-SO
2NH-C
1-C
6Hydroxyalkyl ,-SO
2NH-C
1-C
6Alkyl-NH (C
1-C
4Alkyl), optional by 1 or 2 methyl substituted-SO
2-piperazinyl, optional by 1 or 2 methyl substituted-SO
2-tetramethyleneimine, optional by 1 or 2 C
1-C
4Alkyl replaces-SO
2-piperidines ,-SO
2N (C
1-C
4Hydroxyalkyl) (C
1-C
4Hydroxyalkyl) ,-SO
2NH
2,-SO
2N (C
1-C
6Alkyl) (C
1-C
6Alkyl), C
2-C
6Alkynyl ,-SO
2-(C
1-C
6Hydroxyalkyl) ,-SO
2NH (C
1-C
6Hydroxyalkyl) ,-SO
2N (C
1-C
6Alkyl) (C
1-C
6Hydroxyalkyl) ,-(C
1-C
4Alkyl) SO
2-(C
1-C
4Alkyl) or-C (O)-(C
1-C
10Alkyl).
The also preferred compound of the present invention is following compound, promptly wherein
R
30Be pyridyl, it is unsubstituted or is replaced by at least one following groups :-SO
2NH-propyl group-OH ,-SO
2NH-ethyl-OH ,-SO
2NH-ethyl-OCH
3,-SO
2NH-CH (CH
3)
2-CH
2OH ,-SO
2NH-(CH
2CH (OH) CH
3) ,-SO
2NH-ethyl-NH (CH
3) ,-SO
2NH-(CH
2CH
2OH)
2,-SO
2NHCH (CH
3) CH
2OH ,-SO
2N (CH
3)
2,-SO
2NH (CH
2CH (OH) CH
3) ,-SO
2-tetramethyleneimine ,-SO
2-(lupetidine) ,-SO
2-(2-propyl group piperidines) ,-SO
2-(hydroxypropyl),-C (O)-(2-methoxymethyl tetramethyleneimine),-C (O)-(2-crassitude),-C (O)-(2, the 6-dimethyl pyrrolidine),-C (O)-(2-hydroxymethyl pyrrolidine),-C (O) N (methyl) (ethyl),-C (O) N (methyl) (propyl group),-C (O) N (methyl) (butyl),-C (O) N (propyl group) (butyl),-C (O) N (allyl group) (cyclopentyl),-C (O) N (allyl group) (cyclohexyl),-C (O) N (methyl) (methyl),-C (O) N (ethyl) (ethyl),-C (O) N (butyl) (butyl),-C (O) N (sec.-propyl) (sec.-propyl),-C (O) N (propyl group) (propyl group),-C (O) N (methyl) (cyclohexyl),-C (O) N (ethyl) (cyclohexyl),-C (O) NH (cyclobutyl),-C (O) NH (cyclopentyl),-C (O) N (CH
3) (cyclopentyl) ,-C (O) NH (2-methylcyclohexyl) ,-C (O) NH (amyl group) ,-C (O) N (amyl group) (amyl group) ,-C (O) NH (isopentyl) ,-C (O) NH (ethoxyethyl group) ,-C (O) N (CH
3) (methoxy ethyl) ,-C (O) N (propyl group) (methoxy ethyl) ,-C (O) N (methoxy ethyl) (methoxy ethyl) ,-C (O) N (ethoxyethyl group) (ethoxyethyl group) ,-C (O) N (ethyl) (methoxy ethyl) ,-C (O) N (propyl group) (hydroxyethyl) ,-C (O) N (hydroxyethyl) (ethyl), ethynyl, methyl, bromo ,-N (CH
3) SO
2(CH
3) ,-N (CH
3) SO
2-thienyl ,-N (hydroxypropyl) SO
2CH
3,-(CH
2)-SO
2-(CH
3) or-C (O)-CH (CH
3) CH
2CH
2CH
3
The compound that other preferred chemical formula is X is that chemical formula is the compound of Z5
Or it can be used for the salt of pharmacy, wherein
R
1Be C
1-C
4Alkyl, C
2-C
4Alkynyl or CF
3
R
2And R
3Be hydrogen; Or
R
2And R
3Form a cyclopropyl rings with the carbon that links to each other with them;
R
4Be optional by methyl, thiazolyl, C
2-C
4Alkynyl or C
1-C
4Alkyl replaces the De oxazolyl;
R
5Be C
1-C
4Alkyl;
R
6Be C
1-C
4Alkyl;
X and Y are halogen independently;
Z is CH or N.
Preferred compound is that Z wherein is the compound of CH among the chemical formula Z5.In these compounds, R wherein more preferably
2And R
3It is the compound of H.
Other preferred compound of the present invention is that chemical formula is the compound of Z6
The compound that preferred chemical formula is Z6 comprises following compound, promptly wherein
R
1Be ethyl, ethynyl or CF
3And R
4Be optional, hereinafter these compounds be called the Z6-1 compound by methyl, 2-thiazolyl, ethynyl or methyl substituted 2-oxazolyl.Preferred Z6-1 compound is R wherein
5Be propyl group and R
6Compound for propyl group.More preferably, R
1It is ethyl; R
4Be optional by methyl substituted 2-oxazolyl; And X and Y are F.
Other preferred Z6-1 compound is R wherein
1Be ethyl or CF
3And R
4Compound for the 2-thiazolyl.More preferably, R
5It is propyl group; And R
6It is propyl group; Or R
5It is methyl; And R
6Be propyl group or butyl; And X and Y are F.R wherein more preferably again
1Compound for ethyl.Particularly preferred compound is R wherein
1Be CF
3R
5Be propyl group; And R
6Compound for propyl group.
Other preferred Z6-1 compound is R wherein
1Be ethynyl and R
4Compound for ethynyl, methyl and 2-oxazolyl.More preferably, R
5It is propyl group; And R
6It is propyl group; And X and Y are F.R wherein more preferably also
4Compound for ethynyl or methyl.
Other preferred compound of the present invention is that chemical formula is the compound of Z7
Preferred Z7 compound is R wherein
1Be ethyl or ethynyl; R
4Be the compound of methyl or 2-oxazolyl, hereinafter referred to as formula Z7-1 compound.
Preferred Z7-1 compound comprises wherein R
5And R
6It is propyl group; And X and Y are the compounds of F.More preferably, Z is N; And R
4It is methyl.Also more preferably wherein Z be CH; And R
6It is the Z7-1 compound of methyl or 2-oxazolyl.
Other preferred compound of the present invention is that chemical formula is the compound of Z8
Or it can be used for the salt of pharmacy, wherein
R
1Be C
2-C
3Alkyl;
R
2And R
3Be hydrogen; Or
R
fAnd R
gBe halogen independently;
R
5Be C
1-C
2Alkyl sulphonyl;
R
6Be hydroxyl (C
1-C
4Alkyl), be preferably hydroxyethyl or (C
1-C
4) alkoxyl group (C
1-C
4) alkyl, be preferably methoxy ethyl.
Other preferred compound more of the present invention is that chemical formula is the compound of Z9
Or it can be used for the salt of pharmacy, wherein
R
1Be C
2-C
3Alkyl;
R
2And R
3Be hydrogen; Or
R
fAnd R
gBe halogen independently;
R
5And R
6Be C independently
3-C
4Alkyl; Or
R
5, R
6Form an optional pyrrolidine ring that is replaced by methoxymethyl with the nitrogen that links to each other with them; And
R
sBe C
1-C
2Alkyl, hydroxyl (C
2-C
4Alkyl), N-[hydroxyl (C
2-C
4Alkyl)]-N-(C
1-C
2) alkylamino, N-methyl-N-(C
4(tertiary butyl) alkyl) amino ,-NH (C
1-C
4Hydroxyalkyl) ,-N (C
1-C
3Hydroxyalkyl) (C
1-C
3Hydroxyalkyl) ,-N (C
1-C
2Alkyl) (C
1-C
2Alkyl), the tetramethyleneimine of person's north methylol or methoxymethyl replacement-1-base C
1-C
2Alkoxy C
2-C
3Alkyl, 1-piperazinyl ,-NH
2,-NH (C
2-C
3Alkyl-NH (C
1-C
2Or C alkyl))
1-C
4Alkylamino.
The compound that preferred chemical formula is Z9 comprises wherein R
sBe N-[hydroxyl (C
4-alkyl)]-the N-methylamino-,-N (C
1-C
3Hydroxyalkyl) (C
1-C
3Hydroxyalkyl) or-NH (C
1-C
4Hydroxyalkyl) compound hereinafter is called the Z9-1 compound.
The compound that preferred chemical formula is Z9-1 comprises that wherein hydroxyalkyl is a 2-hydroxyl-1, the 1-dimethyl ethyl; The 2-hydroxyethyl; The 3-hydroxypropyl; 1 (R)-2-hydroxyl-1-methylethyl; 1 (S)-2-hydroxyl-1-methylethyl; 1 (S)-2-hydroxyl-1-methylethyl; 2 (R)-2-hydroxypropyls; Or the compound of 2 (S)-2-hydroxypropyls.
The compound that preferred chemical formula is Z9 comprises wherein R
sIt is the compound of 3-hydroxypropyl, 4-hydroxyl butyl.
The compound that other preferred chemical formula is Z9 comprises wherein R
sBe the compound of 2 (R)-2-methoxymethyl tetramethyleneimine-1-base, 2 (R)-2-hydroxymethyl pyrrolidine-1-base, 2 (S)-2-hydroxymethyl pyrrolidine-1-bases, tetramethyleneimine-1-base or 1-piperazinyl, hereinafter be called Z9-1A.More preferably, R
sBe 2 (R)-2-methoxymethyl tetramethyleneimine-1-base, 2 (R)-2-hydroxymethyl pyrrolidine-1-base, 2 (S)-2-hydroxymethyl pyrrolidine-1-bases.
Other preferred chemical formula is Z9 compound comprises wherein R again
5, R
6Compound with one 2 (the S)-2-methoxymethyl tetramethyleneimine-1-base of nitrogen formation that links to each other with them hereinafter is called the Z9-2 compound.
The compound that preferred chemical formula is Z9-2 comprises wherein R
sBe-NH (tertiary butyl) ,-N (CH
3) (CH
2CH
3) ,-N (CH
3)
2, or the compound of 2 (S)-2-methoxymethyl tetramethyleneimine-1-bases, hereinafter be called Z9-3.
The compound that preferred chemical formula is Z9 comprises wherein R
sBe N-[hydroxyl (C
4Alkyl)]-compound of N-methylamino-.Particularly preferably be wherein R
sIt is the compound of N-(the hydroxyl tertiary butyl)-N-methylamino-." the hydroxyl tertiary butyl " is meant 1-hydroxyl-1-methyl-ethyl.
Other preferred compound comprises the compound of Z9, Z9-1, Z9-1A, Z9-2 and Z9-3, wherein R
1Be ethyl or sec.-propyl.More preferably, R
1It is ethyl.
Other preferred compound of the present invention is that chemical formula is the compound of Z10
Or it can be used for the salt of pharmacy, wherein
R
1Be C
2-C
3Alkyl;
R
2And R
3Be hydrogen; Or
R
fAnd R
gBe halogen independently;
R
5And R
6Be C independently
1-C
4Alkyl; And
R
dBe C
1-C
2Alkyl (being preferably methyl), N-hydroxyl (C
2-C
3Alkyl)-N-(C
1-C
2) alkylamino or C
1-C
2Alkylamino.
Other preferred compound of the present invention is that chemical formula is the compound of Z11
Or it can be used for the salt of pharmacy, wherein
X is nitrogen or CH;
R
1Be C
2-C
3Alkyl, amino, list (C
1-C
3) alkylamino, two (C
1-C
3) alkylamino, amino (C
1-C
3) alkyl, list (C
1-C
3) alkylamino (C
1-C
2) alkyl or two (C
1-C
3) alkylamino (C
1-C
2) alkyl;
R
2And R
3Be hydrogen; Or
R
fAnd R
gBe hydrogen or independently for halogen;
R
5And R
6Be methyl or C independently
2-C
3-C
4Alkyl, wherein R
5And R
6In at least one is not a methyl.
Preferred Z11 compound comprises R wherein
5And R
6In at least one is C
3The compound of alkyl hereinafter is called the Z11-1 compound.Preferred again Z11 compound is each R wherein
5And R
6It is the compound of propyl group.
Preferred Z11 and Z11-1 compound are that wherein X is the compound of CH.More preferably, R
1Be two (C
1-C
2) alkylamino.Wherein R more preferably again
5And R
6In at least one is the compound of propyl group.
Other preferred Z11-1 compound is that wherein X is a nitrogen compound.More preferably, R
5And R
6It or not methyl.Other more preferably the Z11-1 compound be R wherein
1Be two (C
1-C
2) alkylamino (C
1-C
2) compound of alkyl.More preferably, this two (C
1-C
2) alkylamino (C
1-C
2) alkyl is N, N-dimethyl-(C
1-C
2) alkyl.
Other preferred compound of the present invention is that chemical formula is the compound of Z12
Or it can be used for the salt of pharmacy, wherein
R
1Be C
2-C
3Alkyl;
R
2And R
3Be hydrogen; Or
R
2, R
3Form a cyclopropyl rings with the carbon that links to each other with them;
R
fAnd R
gBe halogen independently;
R
5And R
6Be C independently
3-C
4Alkyl (more preferably, R
5And R
6In at least one is a propyl group); And
R
jBe hydrogen or C
1-C
2Alkoxy methyl.
Other preferred compound of the present invention is that chemical formula is the compound of Z13
Or it can be used for the salt of pharmacy, wherein
R
1Be C
2-C
4Alkynyl, C
2-C
4Alkyl is preferably ethyl, sec.-propyl or trifluoromethyl;
R
2And R
3Be hydrogen; Or
R
2, R
3Form a triatomic ring with the carbon atom that links to each other with them;
R
fAnd R
gBe halogen independently;
R
5And R
6Be C independently
3-C
4Alkyl; Or
R
5And R
6In at least one is methyl or ethyl, and another is C
3Or C
4,5(butyl) alkyl.
Preferred chemical formula is that the compound of Z13 comprises wherein R
1Be ethyl, n-propyl, sec.-propyl or trifluoromethyl, more preferably the compound of ethyl or sec.-propyl.R wherein more preferably also
5And R
6Be the compound of propyl group or butyl independently.R wherein more preferably again
2And R
3It is the compound of hydrogen.Particularly preferably be wherein R
fAnd R
gBe chloro or fluorine-based compound.
Other preferred Z13 compound is R wherein
1Be the compound of ethyl or trifluoromethyl, hereinafter be called the Z13-1 compound.In these compounds, R wherein
5Be methyl, ethyl or propyl group and R
6Be C
3-C
4The compound of alkyl is preferred.R wherein more preferably also
6It is the compound of propyl group or butyl.Particularly preferably be wherein R
6Be butyl and R
5It is the compound of methyl.
The compound that other preferred chemical formula is Z13 is R wherein
5Be the compound of methyl, hereinafter be called the Z13-2 compound.Preferred Z13-2 compound comprises wherein R
fAnd R
gBe chloro or fluorine-based compound.More preferably, R
2And R
3Be hydrogen.
The compound that other preferred chemical formula is Z13 is R wherein
2And R
3Be hydrogen and R
1Be C
2-C
3The compound of alkynyl.
The compound that preferred again chemical formula is Z13 is R wherein
5And R
6Be the compound of propyl group or butyl independently, hereinafter be called Z13-3.More preferably, be in the compound of Z13-3 at chemical formula, R
2And R
3Be hydrogen.Again more preferably, R
fAnd R
gIt is chloro or fluorine-based.Also more preferably, R
2, R
3Form a triatomic ring with the carbon atom that links to each other with them.
Other preferred compound of the present invention is that chemical formula is the compound of Z14
And can be used for the salt of pharmacy, wherein
X and X
1In one be nitrogen or N
+-O
-, and another is CH;
R
1Be C
2-C
4Alkynyl, cyano group or C
1-C
3Alkyl;
R
2And R
3Be hydrogen; Or
R
2, R
3Form a triatomic ring with the carbon atom that links to each other with them;
R
fAnd R
gBe halogen independently;
R
pBe hydrogen, C
1-C
2Wan Ji Huo oxazolyl; And
R
5And R
6Be C independently
3-C
4Alkyl.
The compound that preferred chemical formula is Z14 comprises that wherein X is a nitrogen; R
1Be C
1-C
2Alkyl; R
2And R
3Be hydrogen; And R
pBe hydrogen, C
1-C
2The compound of Wan Ji Huo oxazole-2-base.
Other preferred Z14 compound is that wherein X is a nitrogen; R
1Be C
2-C
3Alkynyl; R
2And R
3Form a triatomic ring with the carbon atom that links to each other with them; And R
pBe C
1-C
2The compound of alkyl.More preferably wherein X is a nitrogen; And R
1Be C
2The compound of alkynyl.
Other preferred Z14 compound is that wherein X is a nitrogen; R
1Be C
1-C
2Alkyl is preferably ethyl; R
2And R
3Be hydrogen; And R
pBe hydrogen, C
1-C
2The compound of Wan Ji Huo oxazole-2-base.
Other preferred Z14 compound is that wherein X is a nitrogen again; R
1Be C
1-C
2Alkyl; R
2And R
3Be hydrogen; And R
pBe hydrogen, C
1-C
2The compound of alkyl, oxazole-2-base or cyano group.More preferably, R
pBe cyano group, Jia Ji Huo oxazole-2-base.Also more preferably, R
pIt is methyl.Equally preferably, R
pShi oxazole-2-base.Equally preferably, R
pBe cyano group.
Also having other preferred Z14 compound is that wherein X is a nitrogen; R
1Be C
2-C
3Alkyl; R
2And R
3Form a triatomic ring with the carbon atom that links to each other with them; And R
pBe C
1-C
2The compound of alkyl.
Preferred Z14 compound comprises wherein R
fAnd R
gBe chloro or fluorine-based compound.Other preferred Z14 compound is R wherein again
5And R
6Be the compound of propyl group or butyl independently.
Also have other Z14 compound to comprise wherein R
fAnd R
gBe chloro or fluorine-based and R
5And R
6Be the compound of propyl group or butyl independently.
Other preferred chemical formula is Z14 compound comprises that wherein X is that CH and X ' are the compounds of N again.More preferably, R
pBe cyano group, Jia Ji Huo oxazole-2-base.More preferably, R
fAnd R
gBe chloro or fluorine-based, and R
5And R
6Be the compound of propyl group or butyl independently.Equally preferably, the compound of Z14 comprises wherein R
2And R
3Form the compound of a triatomic ring with the carbon atom that links to each other with them.
Other preferred compound more of the present invention is that chemical formula is the compound of Z15
Or it can be used for the salt of pharmacy, wherein
R
cIt is the following group of chemical formula
R
fAnd R
gBe halogen independently;
R
pBe C
1-C
2Alkyl; And
R
5And R
6Be hydrogen or C independently
3-C
4(sec-butyl) alkyl.
Preferred Z15 compound comprises that wherein X is a nitrogen; X ' is CH; And R
5And R
6Be the compound of propyl group or butyl independently.
Other preferred Z15 compound is that wherein X is CH; X ' is a nitrogen; And R
5And R
6Be the compound of propyl group or butyl independently.More preferably, R
1Be-CH
2N (CH
3) CH
3Or ethyl.Again more preferably, R
1Be-CH
2N (CH
3) CH
3
Particularly preferred Z15 compound comprises wherein R
5And R
6In one be that hydrogen and another are C
4The compound of butyl (sec-butyl more preferably).
Other preferred compound of the present invention is that chemical formula is the compound of Z16
Or it can be used for the salt of pharmacy, wherein
R
sBe methylamino-, ethylamino, C
3Alkylamino, two (C
3-alkyl) the amino or following group of chemical formula
R wherein
qBe C
1-C
2Alkoxyl group (C
1-C
2) alkyl;
R
1Be C
2-C
3Alkyl;
R
2And R
3Be hydrogen; And
R
fAnd R
gBe halogen independently;
Other preferred compound of the present invention is that chemical formula is the compound of Z17
Or it can be used for the salt of pharmacy, wherein
When dotted line was represented a singly-bound or CH or a hydrogen atom, Z was CH
2, or when dotted line was represented one pair of key, Z was CH or a nitrogen-atoms;
R
1Be C
2-C
3Alkyl;
R
2And R
3Be hydrogen; Or
R
2, R
3Form a cyclopropyl rings with the carbon that links to each other with them;
R
fAnd R
gBe halogen independently;
R
pBe hydrogen, cyano group, C
1-C
3Alkyl, amino, N-(C
1-C
3Alkyl sulphonyl)-N-((C
1-C
3) alkyl) amino (when Z=CH, being suitable for), 2-oxazolyl or choose wantonly on 2 and 5 by C
1-C
2The 1-pyrryl that alkyl replaces; And
R
jBe C
1-C
5Alkyl.
The compound that preferred chemical formula is Z17 comprises wherein R
pBe N-(CH
3) SO
2(C
1-C
2Alkyl); And R
1It is the compound of ethyl.
The compound that other preferred chemical formula is Z17 comprises that wherein Z is CH
2Compound, hereinafter be called the Z17-1 compound.Preferred Z17-1 compound comprises wherein R
pBe N-(C
1-C
3Alkyl sulphonyl)-N-((C
1-C
3) alkyl) amino compound.
Other preferred Z17 compound is R wherein
jIt is the compound of methyl.
Other preferred Z17-1 compound is R wherein again
pBe N-(methyl sulphonyl)-N-((C
1-C
2) alkyl) amino; And R
jBe C
1-C
3The compound of alkyl (being preferably butyl) hereinafter is called Z17-2.
Preferred Z17-2 compound comprises wherein R
pBe-N-(CH
3) SO
2(C
1-C
2Alkyl); And R
1It is the compound of ethyl.
Other preferred Z17 compound is R wherein
pThe compound of Shi oxazolyl.In these compounds, Z is preferably CH
2Or CH.More preferably, Z is CH.
Other preferred Z17 compound is R wherein
pBe cyano group; Z is CH
2Or CH; And R
jBe C
3-C
4The compound of alkyl.Preferably, Z is CH and R
jIt is butyl.
Other preferred Z17, Z17-1 and Z17-2 compound are R wherein again
fAnd R
gIn at least one is the compound of fluorine.More preferably, two is fluorine.
Other preferred Z17, Z17-1 and Z17-2 compound are R wherein again
2, R
3Form the compound of a cyclopropyl rings with the carbon atom that links to each other with them.
Other preferred compound of the present invention is that chemical formula is the compound of Z18
Or it can be used for the salt of pharmacy, wherein
X and X ' be among CH or X and the X ' one be nitrogen and another is CH;
R
1Be C
2-C
3Alkynyl, C
1,2-C
3Alkyl, amino, list (C
1-C
3) alkylamino or two (C
1-C
3) alkylamino, aminoalkyl group, list (C
1-C
3) alkylamino (C
1-C
2) alkyl, two (C
1-C
3) alkylamino (C
1-C
2) alkyl, CF
3, C
1-C
2Alkoxyl group, halogen ,-NHSO
2(C
1-C
2Alkyl);
R
2And R
3Be hydrogen; Or
R
2, R
3Form a triatomic ring with the carbon atom that links to each other with them;
R
fAnd R
gBe halogen independently;
R
5And R
6Be C independently
1,2,3-C
4Alkyl; Or
R
5And R
6In one be methyl or ethyl, and another is C
3Or C
4Alkyl, be preferably butyl.
The compound that preferred chemical formula is Z18 comprises wherein R
1It is the compound of bromo or chloro.
Other preferred Z18 compound comprises the Z18-1 compound, i.e. R wherein
1Be C
2-C
3The Z18 compound of alkyl.
Other preferred Z18 compound comprises the Z18-2 compound, i.e. R wherein
1Be two (C
1-C
3) alkylamino and R
fAnd R
gAll be chloro or fluorine-based Z18 compound.
Other preferred Z18 compound comprises the Z18-3 compound again, i.e. R wherein
1Be two (C
1-C
3) alkylamino (C
1-C
2) alkyl and R
fAnd R
gBe chloro or fluorine-based Z18 compound.
Preferred chemical formula is that the compound of Z18 comprises that wherein X is a nitrogen; R
fAnd R
gBe fluorine-based; R
1Be C
1-C
3Alkyl; And R
2, R
3Form the compound of a triatomic ring with the carbon atom that links to each other with them.
Preferred Z18-1 compound comprises that wherein X and X ' are CH; And R
fAnd R
gBe chloro or fluorine-based compound, hereinafter be called the compound that chemical formula is Z18-1-A.Preferred Z18-1 and Z18-1-A compound are R wherein
5And R
6In one be methyl or ethyl, and another is C
3Or C
4The compound of alkyl (being preferably butyl).
Other preferred Z18-1 compound comprises that chemical formula is the compound of Z18-1-B again, i.e. R wherein
5And R
6Be C independently
2-C
4The Z18-1 compound of alkyl.Preferred Z18-1-B compound comprises wherein R
5Be C
2-C
4Alkyl and R
6Compound for ethyl.
Other preferred Z18-1-A compound is R wherein
5And R
6In one be methyl or ethyl, and another is C
3Or C
4The compound of alkyl (being preferably butyl).More preferably, R
5And R
6In one be methyl.Other preferred Z18-1-A compound is R wherein again
5And R
6Be the compound of propyl group or butyl independently.
The compound that other preferred chemical formula is Z18 is that chemical formula is the compound of Z18-4, i.e. R wherein
1Be C
2The Z18 compound of alkynyl.Preferred Z18-4 compound comprises that wherein X and X ' are CH and R
fAnd R
gBe chloro or fluorine-based compound.
Other preferred Z18-4 compound comprises that wherein X is that nitrogen and X ' are CH
3Compound.
Other preferred Z18-1-A compound is R wherein
5And R
6Be the compound of propyl group or butyl independently.
Other preferred Z18 compound comprises wherein R again
1Be CF
3Or-NHSO
2CH
3R
2And R
3Be H; And R
5And R
6Be C independently
3Or C
4The compound of alkyl hereinafter is called Z18-5.
Other preferred Z18 compound comprises that wherein X is that CH and X ' are nitrogen compounds more again, hereinafter is called Z18-6.
Z18, Z18-1-A ,-preferred compound of any specific embodiment of 1-B, Z18-2, Z18-3, Z18-4, Z18-5, Z18-6 is R wherein
2, R
3Form the compound of a triatomic ring with the carbon atom that links to each other with them, hereinafter be called Z18-7.
Preferred Z18-7 compound comprises wherein R
fAnd R
gIn at least one is fluorine-based compound.More preferably, R
fAnd R
gBe fluorine-based.
Other preferred compound of the present invention is that chemical formula is the compound of Z19
Or it can be used for the salt of pharmacy, wherein
R
1Be C
2-C
3Alkyl or C
1-C
2Alkoxyl group;
R
2And R
3Be hydrogen;
R
fAnd R
gBe halogen independently;
R
sBe C
3-C
9Alkyl (is preferably C
3-C
4Alkyl), thiazolinyl or thiazolidyl.
The compound that preferred chemical formula is Z19 comprises wherein R
sBe 2-thiazolidyl or 2-thiazolinyl and R
1Be C
2-C
3The compound of alkyl.
Other preferred Z19 compound is R wherein
sBe methyl, propyl group or the compound of the tertiary butyl more preferably.Again more preferably, R
fAnd R
gIn at least one is fluorine-based.Also more preferably, R
1Also be C
2-C
3Alkyl.
Other preferably chemical formula be that the compound of Z19 comprises wherein R
sBe C
8The compound of alkyl.More preferably, this C
8Alkyl is-CH
2CH (n-propyl) (n-propyl).Also more preferably, R
1Also be C
1-C
2Alkoxyl group.Also more preferably, R
1It is methoxyl group.
Other preferred compound of the present invention is that chemical formula is the compound of Z20
Or it can be used for the salt of pharmacy, wherein
R
1Be C
2-C
3Alkyl, CF
3, or-NH (C
3-C
6Cycloalkyl);
R
2And R
3Be hydrogen; Or
R
2, R
3Form a triatomic ring with the carbon atom that links to each other with them;
R
pBe pyridyl, piperazinyl, amino, amino (C
1-C
5 (3)) alkyl, list (C
1-C
2) alkylamino (C
1-C
5) alkyl, two (C
1-C
2) alkylamino (C
1-C
(4) 5) alkyl, list (C
1-C
3) alkylamino, two (C
1-C
3) alkylamino, amino (C
3-C
4) alkynyl, list (C
1-C
2) alkylamino (C
3-C
4) alkynyl, two (C
1-C
2) alkylamino (C
3-C
5) alkynyl ,-N (C
1-C
2Alkyl)-SO
2(C
1-C
2Alkyl) ,-NH-SO
2(C
1-C
2Alkyl) ,-N (C
1-C
2Alkyl)-SO
2-thienyl ,-N (C
1-C
2Alkyl)-SO
2(C
1-C
2Alkylhalide group), two (C
1-C
2) alkylamino (C
3-C
4) alkynyl, pyrimidyl, pyrazolyl, imidazolyl or C
2-C
4Alkynyl;
R
fAnd R
gBe halogen independently;
R
5And R
6Be C independently
3-C
4Alkyl.
Preferred chemical formula is that the compound of Z20 comprises that chemical formula is the compound of Z20-1, i.e. R wherein
5And R
6Be C
3The Z20 compound of alkyl.
The compound that other preferred chemical formula is Z20 comprises that chemical formula is the compound of Z20-2, i.e. R wherein
2And R
3It is the Z20 compound of hydrogen.
Other preferred Z20 compound is that chemical formula is the compound of Z20-3 again, i.e. R wherein
2, R
3Form the compound of a triatomic ring with the carbon atom that links to each other with them.
Preferred Z20-1 ,-2 and-3 compounds are R wherein
pBe 4-pyridyl, 2-pyrimidyl, 4-pyrazolyl or 4-imidazolyl, more preferably the compound of 4-pyridyl hereinafter is called Z20-3A.Other preferred chemical formula is that Z20-1 ,-2 and-3 compound are R wherein
pBe the compound of diethylin or dimethylamino, hereinafter be called Z20-3B.Other preferred chemical formula is that Z20-1 ,-2 and-3 compound are R wherein again
pBe amino or C
1-C
6The compound of alkylamino hereinafter is called Z20-3C.Other preferred Z20-1 ,-2 and-3 compounds are R wherein more again
pBe the compound of 1-piperazinyl, hereinafter be called Z20-3D.Other preferred Z20-1 ,-2 and-3 compounds comprise wherein R again
pBe amino (C
2-C
4) alkyl (wherein amino choosing wantonly by C
1-C
2The alkyl monosubstitution) compound hereinafter is called Z20-3E; Or R wherein
pFor-N (CH
3)-SO
2CH
3,-NH-SO
2CH
3,-N (CH
3)-SO
2-thiophene-2-base or-N (CH
3)-SO
2CF
3Compound, hereinafter be called Z20-3F.
Other preferred Z20 compound is R wherein
pBe two (C
1-C
2) alkylamino (C
3-C
5) alkyl, N more preferably, N-dimethylamino (C
3-C
5Alkyl) compound hereinafter is called Z20-3G.
Particularly preferred Z20-1 ,-2 and-3 compounds are R wherein
pBe 3-(single (C
1-C
2) alkylamino) compound of propine-1-base, hereinafter be called Z20-3H.Other particularly preferred Z20 compound is R wherein
pBe 3-(single (C
1-C
2) alkylamino) propine-1-base, 3-(two (C
1-C
2) alkylamino) propine-1-base or 4-(two (C
1-C
2) alkylamino) compound of propine-1-base, hereinafter be called Z20-3I.
Other preferred Z20-1 ,-2 and-3 compounds are R wherein
pBe two (C
1-C
2) alkylamino (C
3-C
5) alkyl; And R
5And R
6Be C
3The compound of alkyl hereinafter is called Z20-J.
Other preferred Z20, Z20-1 ,-2 and-3 compounds are R wherein again
pBe C
2-C
3The compound of alkynyl hereinafter is called Z20-4.More preferably, R
pBe C
2Alkynyl.
Equally preferably work as R
1For-NH (C
3-C
6Cycloalkyl), be preferably-chemical formula during the NH cyclopropyl be Z20, Z20-1 ,-2 ,-3 ,-3A is to the compound of-3J and Z20-4.More preferably, R
fAnd R
gIn at least one is fluorine-based.Also more preferably, be fluorine-based.
Equally preferably work as R
1Be CF
3The time chemical formula be Z20, Z20-1 ,-2 ,-3 ,-3A is to the compound of-3J and Z20-4.More preferably, R
fAnd R
gIn at least one is fluorine-based.Also more preferably, be fluorine-based.
Other preferred Z20, Z20-1 ,-2 ,-3 ,-3A comprises wherein R to-3J and Z20-4 compound
1Compound for ethyl or sec.-propyl.Preferably, R
1Be sec.-propyl.More preferably, R
1Be ethyl.More preferably, R
fAnd R
gIn at least one is fluorine-based.Also more preferably, be fluorine-based.Again more preferably, R
fAnd R
g(position 1 is and CH to be connected to 3 and 5 of phenyl ring
2The position that group links to each other).
Other preferred compound of the present invention is that chemical formula is the compound of Z21
Or it can be used for the salt of pharmacy, wherein
R
1Be C
2-C
3Alkynyl;
R
2And R
3Be hydrogen;
R
pBe C
1-C
3Alkyl;
R
fAnd R
gBe halogen independently;
R
5And R
6Be C independently
3-C
4Alkyl; Or
R
5And R
6In one be methyl, and another is C
3Or C
4Alkyl.
The compound that preferred chemical formula is Z21 comprises wherein R
5And R
6In one be methyl, and another is the compound of butyl, hereinafter is called Z21-1.
The compound that other preferred chemical formula is Z21 and Z21-1 comprises wherein R
pCompound for methyl.
Other preferred compound of the present invention is that chemical formula is the compound of Z22
Or it can be used for the salt of pharmacy, wherein
R
1Be C
1-C
2Alkyl, C
2-C
4Alkynyl or C
3(sec.-propyl)-C
4Alkyl;
R
2And R
3Be hydrogen; Or
R
2, R
3Form a triatomic ring with the carbon atom that links to each other with them;
R
fAnd R
gBe halogen independently;
R
pBe C
1-C
3Alkyl or chemical formula are R
sSO
2-group, wherein
R
sBe R
51R
61N-, and R
51And R
61Represent hydrogen or C independently
1-C
4Alkyl; Or
R
sBe the following group of chemical formula:
R wherein
tBe C
1-C
2Alkoxyl group (C
1-C
2) alkyl; And
R
qBe C
1-C
3Alkoxyl group (C
1-C
2) alkyl, C
1-C
4Alkyl ,-C (O) NH
2, or H.
Preferred chemical formula is that the compound of Z22 comprises following compound, i.e. R wherein
1Be C
2Alkynyl; R
2, R
3Form a triatomic ring with the carbon atom that links to each other with them; And R
pBe R
sSO
2-, R wherein
sBe
The compound that other preferred chemical formula is Z22 comprises following compound, i.e. R wherein
1Be C
1-C
2Alkyl; R
2And R
3Be hydrogen; And R
pBe R
sSO
2-, R wherein
sBe C
3-C
4Amino is preferably propyl group, more preferably uncle's fourth amino.
Other preferred chemical formula is Z22 compound comprises following compound again, i.e. R wherein
1Be C
1-C
2Alkyl; R
2And R
3Be hydrogen; R
pBe C
1-C
2Alkyl; And R
qBe C
3-C
4Alkyl is preferably propyl group or butyl.
Other preferred chemical formula is Z22 compound comprises wherein R more again
1Be C
1-C
2Alkyl; R
2And R
3Be hydrogen; R
pBe C
1-C
2Alkyl; And R
qBe propoxy-(C
1-C
2) compound of alkyl.
The compound that other preferred chemical formula is Z22 comprises wherein R
1Be C
1-C
2Alkyl; R
2And R
3Be hydrogen; R
pBe C
1-C
2Alkyl; And R
qBe methoxyl group (C
1-C
2) compound of alkyl.
The compound that other preferred chemical formula is Z22 comprises wherein R
1Be C
1-C
2Alkyl; R
2, R
3Form a triatomic ring with the carbon atom that links to each other with them; R
pBe C
1-C
2Alkyl; And R
qBe C
1-C
2The compound of alkyl.
The compound that other preferred chemical formula is Z22 comprises wherein R
1Be C
1-C
2Alkyl; R
2And R
3Be hydrogen; R
pBe C
1-C
2Alkyl; And R
qBe C
1-C
2The compound of alkyl.
Particularly preferred Z22 compound is R wherein
1Compound for sec.-propyl.
Other preferred Z22 compound comprises wherein R
qIt is (R)-methoxymethyl, methyl, propyl group, (S)-propyl group, (R)-propyl group, butyl, (R)-butyl, (S)-butyl, (R)-2-methoxymethyl or (R)-2-methoxy ethyl.
Other preferred compound of the present invention is that chemical formula is the compound of Z23
Or it can be used for the salt of pharmacy, wherein
Z is oxygen, nitrogen or sulphur;
R
1Be chloro, bromo, hydrogen or C
1-C
2Alkyl;
R
fAnd R
gBe halogen independently; And
R
5And R
6Be C independently
3-C
4Alkyl; Or
R
5And R
6In one be methyl, and another is C
3Or C
4Alkyl.
The compound that preferred chemical formula is Z23 comprises that wherein Z is a nitrogen; And R
1Be C
1-C
3The compound of alkyl.
Preferred chemical formula is that the compound of Z23 is R wherein
1Be that bromo and Z are the compounds of oxygen, hereinafter be called Z23-1.The compound that other preferred chemical formula is Z23 is that wherein Z is a nitrogen compound, hereinafter is called Z23-2.Other preferred chemical formula is Z23 compound is that wherein Z is the compound of sulphur again, hereinafter is called Z23-3.
Particularly preferred Z23, Z23-1, Z23-2 and Z23-3 compound are R wherein
5And R
6In one be methyl, and another is the compound of butyl.R equally preferably
5And R
6In at least one is the compound of propyl group.Again more preferably, R
1Be C
1-C
3Alkyl.Also more preferably, R
1Be C
2-C
3Alkyl.R
1It also can be ethyl.
Other preferred compound of the present invention is that chemical formula is the compound of Z24
Or it can be used for the salt of pharmacy, wherein
R
1Be C
1-C
2-C
3Alkyl;
R
2And R
3Be hydrogen; Or
R
pBe C
1-C
2Alkyl;
R
fAnd R
gBe hydrogen or independently for halogen; And
R
5And R
6Be C independently
3-C
4Alkyl.
The compound that preferred chemical formula is Z24 comprises wherein R
1Compound for ethyl.More preferably, R
pIt also is methyl.Again more preferably, R
fAnd R
gIt is halogen.
Other preferred compound of the present invention is that chemical formula is the compound of Z25
Or it can be used for the salt of pharmacy, wherein
One is that nitrogen and another are CH or CR among X and the X '
1
R
1Be C
1-C
2-C
3Alkyl;
R
2And R
3Be hydrogen; Or
R
2, R
3Form a cyclopropyl rings with the carbon that links to each other with them;
R
pBe C
1-C
2Alkyl;
R
fAnd R
gBe halogen independently; And
R
5And R
6Be C independently
3-C
4Alkyl.
The compound that preferred chemical formula is Z25 comprises that wherein X is that CH and X ' are nitrogen compounds, and particularly preferred chemical formula is that the compound of Z25 comprises wherein R
1It is the compound of ethyl.More preferably work as R
2And R
3When being hydrogen.
Other preferred compound of the present invention is that chemical formula is the compound of Z26
Or it can be used for the salt of pharmacy, wherein
R
1Be the following group of chemical formula:
Wherein, R
S11And R '
S11In one be that hydrogen and another are C
1-C
3Acyl group, C
1-C
2Alkyl or CHO; Or
R
S11And R '
S11In one be that methyl and another are CHO or methyl,
Each R
S21Be C
1-C
3Alkoxyl group, halogen, H, C
1-C
2Alkyl or cyano group; Or
R
1Be cyclopentyl, cyclohexyl, oxazolyl, optional by one or two C
1-C
2Alkyl replaces De isoxazolyl, phenyl, optional thiophene-2-base, the unsubstituted thiene-3-yl-that is replaced by CHO;
R
2And R
3Be hydrogen;
R
pBe C
1-C
2Alkyl;
R
fAnd R
gBe halogen independently; And
R
5And R
6Be C independently
3-C
4Alkyl.
The compound that preferred chemical formula is Z26 comprises wherein R
1Be 6-(C
1-C
2) the Z26 compound of alkoxy pyridines-2-base.
The compound that other preferred chemical formula is Z26 comprises wherein R
1It is the Z26 compound of 2-formyl thiene-3-yl-.
Other preferred chemical formula is Z26 compound comprises wherein R again
1It is the Z26 compound of 5-formyl thiene-3-yl-.
The compound that other preferred chemical formula is Z26 comprises wherein R
S21It is the compound of cyano group.
Other preferred chemical formula is Z26 compound comprises wherein R again
1It is the Z26 compound of 5-cyanopyridine-3-base.
The compound that other preferred chemical formula is Z26 is that chemical formula is the compound of Z26-1, i.e. R wherein
1It is the Z26 compound of 6-haloperidid-3-base.Particularly preferred Z26-1 compound is R wherein
1In halogen be the compound of fluorine-based or chloro.
Other preferred chemical formula is Z26 compound is following compound again, i.e. R wherein
1For choosing wantonly by R
S11Or R '
S11The thienyl that replaces, cyclopentyl, cyclohexyl, oxazolyl, optional by one or two C
1-C
2Alkyl replaces De isoxazolyl, phenyl or the optional thiophene-2-base that is replaced by CHO.More preferably, unsubstituted thienyl is thiene-3-yl-or thiophene-2-base.
Other preferred compound of the present invention is that chemical formula is the compound of Z27
Or it can be used for the salt of pharmacy, wherein
Z is
Pyridyl or pyridyl N-oxide compound, wherein pyridyl or pyridyl N-oxide compound are by C (O) NR
5R
6Replace, wherein
R
5And R
6Be C independently
3-C
4Alkyl; Or
R
5Be methyl or ethyl and R
6Be C
3Alkyl;
R
1Be C
1-C
3Alkyl or halogen;
R
2And R
3Be hydrogen;
R
sBe C
1-C
3Alkyl sulphonyl, C
1-C
3Alkyl sulphonyl (C
1-C
3) alkyl ,-NHSO
2(C
1-C
2Alkyl) or-N (C
1-C
2Alkyl) SO
2(C
1-C
2Alkyl); And
R
fAnd R
gBe halogen independently;
Preferably, chemical formula is the R in the compound of Z27
1It is ethyl.More preferably, Z is
Equally preferably, R
sBe C
1-C
3Alkyl sulphonyl, C
1-C
3Alkyl sulphonyl (C
1-C
3) alkyl ,-NHSO
2CH
3, or-NCH
3SO
2CH
3
Other preferred compound comprises following compound, promptly wherein Z by C (O) NR
5R
6The pyridyl that replaces, wherein R
5And R
6Be C independently
3-C
4Alkyl; Or R
5Be methyl or ethyl and R
6Be C
3Alkyl.More preferably, R
5And R
6It is propyl group.Again more preferably, Z is
Or its N-oxide compound.
Other preferred compound of the present invention is that chemical formula is the compound of Z28
Or it can be used for the salt of pharmacy, wherein
R
1Be C
2-C
3Alkyl;
R
2And R
3Be hydrogen;
R
5And R
6The C that is replaced by phenyl is chosen in representative (a) wantonly independently
1-C
3Alkyl and (b) the optional phenyl that is replaced by halogen; And
R
fAnd R
gBe halogen independently.
The compound that preferred chemical formula is Z28 comprises wherein R
5Be optional methyl and the R that is replaced by phenyl
6Compound for phenyl.
The compound that other preferred chemical formula is Z28 comprises wherein R
5Be C
1-C
2Alkyl and R
6Be 4-halobenzene base, be preferably the compound of 4-chloro-phenyl-.
Other preferred compound of the present invention is that chemical formula is the compound of Z29
Or it can be used for the salt of pharmacy, wherein
X is nitrogen or N
+-O
-
R
1Be C
2-C
4Alkynyl or C
1-C
3Alkyl;
R
2And R
3Be hydrogen; Or
R
2, R
3Form a triatomic ring with the carbon atom that links to each other with them;
R
fAnd R
gBe halogen independently;
R
pBe hydrogen or C
1-C
2Alkyl; And
R
5And R
6Be C independently
3-C
4Alkyl.
The compound that preferred chemical formula is Z29 comprises wherein R
1Compound for ethyl.Preferred chemical formula
For the compound of Z29 comprises that wherein X is a nitrogen; R
pBe C
1-C
2Alkyl (being preferably methyl) and R
1It is the compound of ethyl;
Other preferred compound of the present invention is that chemical formula is the compound of Z30
Or it can be used for the salt of pharmacy, wherein
R
1Be hydrogen or C
1-C
3Alkyl;
R
2And R
3Be hydrogen;
R
pBe C
1-C
2Alkyl;
R
fAnd R
gBe halogen independently; And
R
5And R
6Be C independently
3-C
4Alkyl.
The present invention another to organize preferred compound be the compound shown in the chemical formula Z31
Or it can be used for the salt of pharmacy, wherein
R
sBe NR
S31R
S41, wherein
R
S31Be C
1-C
2Alkyl; And
R
S41Be C
1-C
6Alkyl, allyl group, cyano group (C
1-C
3) alkyl, (C
4-7) cycloalkyl, pyridine (C
1-C
3) alkyl, phenyl, phenyl (C
1-C
3) alkyl, amino (C
1-C
3) alkyl, list (C
1-C
3) alkylamino (C
1-C
2) alkyl or two (C
1-C
3) alkylamino (C
1-C
2) alkyl; Or
R
sBe CH
3,-N (C
1-C
2Alkyl) phenyl or-N (C
2-C
3Alkyl) (C
3-C
4Alkyl);
R
1Be C
2-C
3Alkyl;
R
2And R
3Be hydrogen; And
R
fAnd R
gBe halogen independently;
The compound that other preferred chemical formula is Z31 comprises wherein R
S41It is the compound of pyridine ethyl or styroyl.
The compound that other preferred chemical formula is Z31 is R wherein
S41Be diethylin (C
1-C
2) alkyl, the more preferably compound of diethylin methyl.
Other preferred chemical formula compound that is Z31 is R wherein again
S41Be C
3-5The compound of alkyl.
Particularly preferred chemical formula is that the compound of Z31 comprises wherein R
sBe (2-cyanoethyl) (methyl) amino compound.
The compound that other particularly preferred chemical formula is Z31 comprises wherein R
sBe the amino compound of (cyclohexyl) (methyl).
In a kind of preferred situation of chemical formula Z31, R
S41Be C
1-C
6Alkyl, allyl group, cyano group (C
1-C
3) alkyl, (C
4-7) cycloalkyl, pyridine (C
1-C
3) alkyl, phenyl or phenyl (C
1-C
3) alkyl.
In the another kind of preferred situation of chemical formula Z31, R
S41Be phenyl or cyclohexyl.
In another preferred situation of chemical formula Z31, R
sBe-N (CH
3) phenyl or-N (ethyl) (C
3-C
4Alkyl).
Other preferred compound of the present invention is that chemical formula is the compound of Z32
Or it can be used for the salt of pharmacy, wherein
R
1Be C
2-C
3Alkynyl or C
1-C
3Alkyl;
R
fAnd R
gBe halogen independently;
R
5And R
6Be C independently
1-C
4Alkyl.
The compound that preferred chemical formula is Z33 comprises wherein R
5And R
6Be C
3The compound of alkyl.
The compound that other preferred chemical formula is Z33 comprises wherein R
5Be methyl and R
6Be C
3The compound of alkyl.
Particularly preferred chemical formula is that the compound of Z33 comprises wherein R
1Compound for ethyl.
The compound that other particularly preferred chemical formula is Z33 comprises wherein R
5And R
6Be propyl group or R
5Be methyl and R
6Be the compound of propyl group, hereinafter be called Z33-1.
Other preferred chemical formula is Z33 and Z33-1 compound comprises wherein R again
1Be C
2-C
3Alkynyl (is preferably C
2Alkynyl) compound.
Other preferred compound of the present invention is that chemical formula is the compound of Z33
Or it can be used for the salt of pharmacy, wherein
R
sBe C
1-C
4Alkyl;
R
mBe C
1-C
4Alkyl;
R
1Be C
2-C
3Alkyl;
R
2And R
3Be hydrogen; And
R
fAnd R
gBe halogen independently.
Other preferred compound of the present invention is that chemical formula is the compound of Z34
Or it can be used for the salt of pharmacy, wherein
R
mBe C
1-C
4Alkyl;
R
1Be C
2-C
3Alkyl;
R
2And R
3Be hydrogen; And
R
fAnd R
gBe halogen independently;
Z is S, S (O), S (O)
2Or O.
The compound that preferred chemical formula is Z34 comprises that wherein Z is the compound of S or S (O).More preferably, R
1Be C
2Alkyl.
Other preferred compound of the present invention is that chemical formula is the compound of Z35
Or it can be used for the salt of pharmacy, wherein
One is that CH and another are N among X and the X ';
R
1Be C
2-C
4Alkynyl; Amino (C
1-C
3) alkyl, list (C
1-C
3) alkylamino (C
1-C
2) alkyl or two (C
1-C
3) alkylamino (C
1-C
2) alkyl;
R
2And R
3Be hydrogen; Or
R
2, R
3Form a triatomic ring with the carbon atom that links to each other with them;
R
fAnd R
gBe halogen independently;
R
5And R
6Be C independently
1-C
3-C
4Alkyl.
The compound that preferred chemical formula is Z35 comprises wherein R
2, R
3Form a triatomic ring with the carbon atom that links to each other with them; X is N; And X ' is the compound of CH, hereinafter is called Z35-1.
The compound that other preferred chemical formula is Z35 comprises that chemical formula is the compound of Z35-1, i.e. R wherein
2And R
3Be hydrogen; X ' is N; And X is the Z35 compound of CH, hereinafter is called Z35-2.
Preferred Z35, Z35-1 and Z35-2 compound comprise wherein R
1Be C
2The compound of alkynyl.More preferably, R
1Also can be two (C
1-C
3) alkylamino (C
1-C
3) alkyl.Again more preferably, R
1Be dimethylamino (C
1-C
2) alkyl.
Other preferred compound of the present invention is that chemical formula is the compound of Z36
Or it can be used for the salt of pharmacy, wherein
R
1Be C
2-C
3Alkyl;
R
2And R
3Be hydrogen;
R
fAnd R
gBe halogen independently;
R
pBe hydrogen, cyano group, C
1-C
3Alkyl, amino, N-(C
1-C
3Alkyl sulphonyl)-N-((C
1-C
3) alkyl) amino, 2-oxazolyl or choose wantonly at 2 and 5 by C
1-C
2The pyrryl that alkyl replaces;
R
aBe C
1-C
3Alkyl, H or trifluoromethyl; And
R
jBe C
1-C
5Alkyl.
Preferred Z36 compound comprises wherein R
jBe methyl or ethyl and R
pIt is the compound of hydrogen, methyl or ethyl.
Other preferred Z35 compound comprises wherein R
jBe methyl and R
pIt is the compound of hydrogen.
Other preferred compound of the present invention is that chemical formula is the compound of Z37
Or it can be used for the salt of pharmacy, wherein
X is nitrogen or N
+-O
-
R
1Be C
2-C
4Alkynyl, cyano group, C
1-C
3Alkyl or CF
3
R
2And R
3Be hydrogen; Or
R
2, R
3Form a triatomic ring with the carbon atom that links to each other with them;
R
fAnd R
gBe halogen independently;
R
pBe hydrogen, cyano group or C
1-C
2Alkyl; And
R
5And R
6Be C independently
1-C
4Alkyl.
The compound that preferred chemical formula is Z37 comprises that chemical formula is the compound of Z37-1, and promptly wherein X is the Z37 compound of N.Preferred Z37-1 compound comprises wherein R
pCompound for cyano group.Preferred Z37-1 compound is R wherein
5Be methyl and R
6Be C
2-C
4The compound of alkyl.Particularly preferred Z37-1 compound is R wherein
6Compound for propyl group.
The compound that other preferred chemical formula is Z37 comprises wherein R
1Be C
2-C
3Alkyl; R
pBe methyl or ethyl; And R
5And R
6Be C independently
3-C
4The compound of alkyl.More preferably, R
2And R
3Also be hydrogen.
Other preferred Z37 compound comprises wherein R
1Be C
2-C
3Alkynyl or C
2Alkyl; And R
pCompound for methyl.
Other preferred Z37 compound comprises wherein R again
1Be CF
3Compound.More preferably, R
pIt also is methyl.Also more preferably, X is CH.
Other preferred compound of the present invention is that chemical formula is the compound of Z38
Or it can be used for the salt of pharmacy, wherein
R
1Be hydrogen, methyl or-CH
2OH;
R
2And R
3Be hydrogen; Or
R
2, R
3Form a triatomic ring with the carbon atom that links to each other with them;
R
pBe C
2-C
3Alkynyl or C
1-C
3Alkyl;
R
fAnd R
gBe halogen independently;
R
5And R
6Be C independently
3-C
4Alkyl, or
R
5Be methyl and R
6Be C
3-C
4Alkyl.
The compound that preferred chemical formula is Z38 comprises wherein R
pBe the compound of methyl, hereinafter be called Z38-1.
The compound that other preferred chemical formula is Z38 comprises wherein R
pBe C
2The compound of alkynyl hereinafter is called Z38-2.
Other preferred Z38, Z38-1 and Z38-2 compound comprise wherein R
1Be hydrogen and R
2And R
3Be the compound of hydrogen, hereinafter be called Z38-3.Preferred Z38-3 compound comprises wherein R
5And R
6Be C
3-C
4The compound of alkyl.Again more preferably, be C
3Compound.
Other preferred Z38, Z38-1 and Z38-2 compound comprise wherein R again
1Be hydrogen and R
2And R
3Form the compound of a triatomic ring, hereinafter be called Z38-4.
Other preferred Z38, Z38-1 and Z38-2 compound comprise wherein R
1Be-CH
2The compound of OH.Preferably, R
2And R
3Also be hydrogen, hereinafter be called Z38-4A.
Also preferred Z38 compound is R wherein
1Be hydrogen and R
2And R
3Form the compound of a triatomic ring with the carbon atom that links to each other with them, hereinafter be called Z38-5.
Preferred chemical formula is that the compound of Z38-5 comprises wherein R
pBe C
2-C
3Alkynyl (is preferably C
2Alkynyl) or the compound of methyl.More preferably, R
5And R
6In at least one is C
3Alkyl.Again more preferably, R
5Be methyl or propyl group and R
6Be propyl group, hereinafter be called Z38-5A.
Other preferred Z38, Z38-1, Z38-2, Z38-3, Z38-4, Z38-4A, Z38-5 and Z38-5A compound comprise wherein R again
fAnd R
gBe chloro or fluorine-based compound.Particularly preferably be wherein R in the Z38 compound
fAnd R
gBe that position fluorine-based and that link to each other with phenyl is the compound at 3 and 5.
Other preferred compound of the present invention is that chemical formula is the compound of Z39
Or it can be used for the salt of pharmacy, wherein
R
1Be C
2-C
3Alkyl;
R
2And R
3Be hydrogen; Or
R
2, R
3Form a cyclopropyl rings with the carbon that links to each other with them;
R
fAnd R
gBe halogen independently;
R
5And R
6Be C independently
3-C
4Alkyl; And
R
sBe-NH (C
1-C
4Hydroxyalkyl).
Preferred Z39 compound comprises that wherein hydroxyalkyl is a 2-hydroxyl-1,1, the compound of dimethyl ethyl.More preferably, R
1It also is ethyl.
Preferably, R
2And R
3It is methyl.Equally preferably, R
2, R
3Form a cyclopropyl with the carbon that links to each other with them.
Other preferred compound of the present invention is that chemical formula is the compound of Z40
Or it can be used for the salt of pharmacy, wherein
R
1Be C
2-C
3Alkynyl;
R
2And R
3Be hydrogen; Or
R
fAnd R
gBe halogen independently;
R
5And R
6Be C independently
3-C
4Alkyl; And
R
sBe-NH (C
2-C
4Hydroxyalkyl).
Preferred Z40 compound comprises that wherein hydroxyalkyl is a 2-hydroxyl-1,1, the compound of dimethyl ethyl or 2-hydroxyethyl.
Other preferred compound of the present invention is that chemical formula is the compound of Z41
Or it can be used for the salt of pharmacy, wherein
R
cBe C
4-C
5Alkyl; Cyclopropyl; The tetrahydrochysene naphthylidene;-CH (C
2Alkyl-S-(C
1-C
2) alkyl) C (O) NH (C
4Alkyl);-CH (C
2Alkyl-SO
2-(C
1-C
2) alkyl) C (O) NH (C
4Alkyl); Optional by C
3-C
4The pyrimidyl that alkyl replaces; Thiochroman 1, the 1-dioxide; Optional by C
3-C
4Alkyl replaces-CH
2-thiazolyl or optional by C
1-C
5Alkyl replaces-CH
2-isoxazolyls;
R
fAnd R
gBe halogen independently;
R
pBe-NHSO
2CF
3,-SO
2NH (C
3-C
4Hydroxyalkyl) ,-NHSO
2CH
3, oxazole-2-base or C
2-C
4Alkynyl; And
R
5And R
6Be C independently
3-C
4Alkyl.
Preferred Z41 compound comprises the compound that hereinafter is called Z41-1, i.e. R wherein
cBe C
4-C
5Alkyl (being preferably isobutyl-or isopentyl); Cyclopropyl; The tetrahydrochysene naphthylidene;-CH (C
2Alkyl-S-(C
1-C
2) alkyl) C (O) NH (C
4Alkyl);-CH (C
2Alkyl-SO
2-(C
1-C
2) alkyl) C (O) NH (C
4Alkyl); Optional by C
3-C
4The pyrimidyl that alkyl replaces; Thiochroman 1, the 1-dioxide; Optional by C
3-C
4Alkyl replaces-CH
2-thiazolyl.
Preferred Z41-1 compound comprises the compound that hereinafter is called Z41-2, i.e. R wherein
cIt is isobutyl-; 1,2,3,4-tetrahydrochysene naphthylidene-1-base;-CH (CH
2CH
2-S-CH
3) C (O) NH (C
1-C
5Alkyl) (wherein alkyl is preferably isobutyl-) or 2-tertiary butyl pyrimidine-4-base.
Other preferred Z41 compound comprises wherein R
pBe-SO
2The compound of NH (2-hydroxyl-1,1-dimethyl ethyl) hereinafter is called Z41-3.
Other preferred Z41, Z41-1, Z41-2 and Z41-3 compound comprise wherein R
5And R
6Be C
3The compound of alkyl.
Other preferred Z41 compound comprises wherein R
pShi oxazole-2-base; And R
cBe-CH
2The compound of-(2-isobutyl thiazole-5-yl).
Other preferred Z41 compound comprises wherein R again
pBe C
2-C
3Alkynyl (is preferably C
2Alkynyl) and R
cBe-CH
2The compound of-(2-isobutyl thiazole-5-yl).
Other preferred chemical formula is Z41 compound comprises wherein R again
pBe optional by C
1-C
5Alkyl replaces-CH
2The compound of-isoxazolyls.More preferably, R
pBe-CH
2-isoxazole-5-bases.Also more preferably, it is-CH
2-(3-isobutyl-isoxazole-5-base).Also more preferably, R
pAlso be C
2-C
3Alkynyl.Again more preferably, R
5And R
6Be C
3Alkyl.
Other preferred compound of the present invention is that chemical formula is the compound of Z42
Or it can be used for the salt of pharmacy, wherein
R
1Be C
2-C
3Alkyl or halogen;
R
2And R
3Be hydrogen; Or
R
2, R
3Form a cyclopropyl rings with the carbon that links to each other with them;
R
fAnd R
gBe halogen independently; And
R
mBe-NH-SO
2CF
3, oxazole-2-base ,-N (CH
3) SO
2CH
3,-N (C
3-C
4Hydroxyalkyl) SO
2(C
1-C
2And R alkyl),
pBe H; Or
R
mBe H and R
pBe-NH-SO
2CF
3,-NH
2SO
2(C
1-C
2Alkyl), wherein alkyl is preferably methyl; Or
R
mBe-C (O) pyrrolidyl and R
pBe OH.
The compound that preferred chemical formula is Z42 comprises wherein R
mBe H and R
pBe-NH-SO
2CF
3,-NH
2SO
2(C
1-C
2Alkyl) compound hereinafter is called Z42-1.R wherein equally preferably
mBe-NH-SO
2CF
3, oxazole-2-base ,-N (CH
3) SO
2CH
3,-N (C
3-C
4Hydroxyalkyl) SO
2(C
1-C
2And R alkyl),
pBe the Z42 compound of H, hereinafter be called Z42-2.
Preferred Z42, Z42-1 and Z42-2 compound comprise R
1It is the compound of ethyl, bromo or iodo.More preferably work as R
2And R
3When also being hydrogen;
Other preferred compound of the present invention is that chemical formula is the compound of Z43
Or it can be used for the salt of pharmacy, wherein
R
1Be C
2-C
5Alkyl, C
3-C
6Qing Wanji, C
3-C
6Alkenyl ,-NH
2SO
2(C
1-C
2Alkyl), C
4-C
5Alkylhalide group ,-C
3Alkyl-CO
2-(C
1-C
2Alkyl), CN ,-N (C
1-C
2Alkyl) SO
2(C
1-C
2Alkyl) ,-SO
2(C
1-C
2Alkyl) ,-S (O) (C
1-C
6Alkyl) ,-NH-(C
3-C
6Cycloalkyl) or-OC (O) N (C
1-C
2Alkyl) (C
1-C
2Alkyl),
R
2And R
3Be hydrogen;
R
fAnd R
gBe halogen independently;
R
pBe C
1-C
2Alkyl;
R
5And R
6Be C independently
3-C
5Alkyl, C
1-C
2Alkoxy C
1-C
3Alkyl or C
3-C
5Alkenyl (is preferably C
3Alkenyl) or
R
5Be hydrogen and R
6Be C
4-C
6Alkyl or (C
1-C
2Alkoxyl group)-(C
2-C
3Alkyl);
R
5Be ethyl and R
6Be C
2-C
3Hydroxyalkyl or-(C
1-C
2Alkyl)-N (C
1-C
2Alkyl) (C
1-C
2Alkyl); Or
R
5Be CH
3And R
6Be C
4-C
5Alkyl, cyclohexyl ,-(C
1-C
2Alkyl)-phenyl ,-(C
1-C
2Alkyl)-pyridyl or-CH
2-furyl; Or
R
5Be methyl or ethyl and R
6Be (C
1-C
2Alkoxyl group)-(C
2-C
3Alkyl) or-CH
2-(C
3-C
6Cycloalkyl), or
R
5, R
6Forming one with the nitrogen that links to each other with them chooses wantonly by C
3-C
4The piperidines basic ring of alkyl or OH, azepanyl, tetramethyleneimine-2-carboxylic acid amide, 3-hydroxy piperidine-1-base replacement.
The compound that preferred chemical formula is Z43 comprises wherein R
1Be C
2-C
4The compound of alkyl hereinafter is called Z43-1.Preferably, R
1Be ethyl, sec.-propyl, isobutyl-, sec-butyl or isopentyl.More preferably ethyl or sec.-propyl.Ethyl more preferably again.
The compound that other preferred chemical formula is Z43 and Z43-1 comprises wherein R
5And R
6Be the compound of ethoxyethyl group (hereinafter being called Z43-1A), R wherein simultaneously
5Be propyl group and R
6Be the compound (hereinafter being called Z43-1B) of butyl, R wherein
5Be ethyl and R
6Be the compound (hereinafter being called Z43-1C) of butyl, R wherein
5Be methyl or ethyl and R
6For-CH
2-(cyclopropyl), isobutyl-or C
2-C
4Compound of alkynyl (hereinafter being called Z43-1D) or R wherein
5Be ethyl and R
6Be the compound (hereinafter being called Z43-1E) of propyl group or R wherein
5Be hydrogen and R
6Compound (hereinafter being called Z43-1F) for sec-butyl.
The compound of also preferred Z43, Z43-1, Z43-1A, Z43-1B, Z43-1C, Z43-1D, Z43-1E and Z43-1F is R wherein
pBe methyl or C
2The compound of alkynyl.
The compound that other preferred chemical formula is Z43 comprises wherein R
5, R
6Compound with a 2-propyl group piperidines-1-basic ring of nitrogen formation that links to each other with them.
Other preferred chemical formula is Z43 compound comprises the compound that hereinafter is called Z43-2 again, i.e. R wherein
1Be cyclopentyl, cyclohexyl, propenyl, allyl group or-(C
3-C
6Alkyl)-CN, 4-chlorobutyl, 3-pyridyl, 2 Methylpropionic acid methyl esters, oneself-5-thiazolinyl, CN ,-N (CH
3) SO
2CH
3,-SO
2CH
2CH
3, 3-picoline-2-Ji, oxazole-2-base, 3,5-dimethyl isoxazole-4-base, 3 methyl thiophene-2-base, 2-pyridyl, 4-carbonyl aldehyde (carbaldehyde) furyl-5-base and 2-carbonyl aldehyde furans thienyl-5-base, 2-carbonyl aldehyde-3 methyl thiophene-5-base, 2-methoxypyridine-4-base ,-the NH-cyclopropyl ,-NHSO
2CH
3And R
pIt is methyl.The compound that preferred chemical formula is Z43-2 comprises wherein R
5And R
6Also be C
3The compound of alkyl.Equally preferably work as R
5Be ethyl and R
6During for butyl.
Preferred Z43, Z43-1 and Z43-2 compound comprise wherein R
1Be C
2-C
3Alkynyl (is preferably C
2Alkynyl) compound hereinafter is called Z43-3.
Preferred Z43, Z43-1, Z43-2 and Z43-3 compound comprise wherein R
5And R
6Be C independently
3-C
5Alkyl, C
1-C
2Alkoxy C
1-C
3The compound of alkyl.Other preferred Z43, Z43-1, Z43-2 and Z43-3 compound comprise wherein R
5Be H and R
6Be C
4,5-C
6Alkyl or (C
1-C
2Alkoxyl group)-(C
2-C
3Alkyl) compound.Other preferred Z43, Z43-1, Z43-2 and Z43-3 compound comprise wherein R again
5Be ethyl and R
6Be C
2-C
3Hydroxyalkyl or-(C
1-C
2Alkyl)-N (C
1-C
2Alkyl) (C
1-C
2Alkyl) compound.More preferably, be somebody's turn to do-(C
1-C
2Alkyl)-N (C
1-C
2Alkyl) (C
1-C
2Alkyl) is-(C
1-C
2Alkyl)-N (CH
3)
2
Other preferred Z43, Z43-1, Z43-2 and Z43-3 compound comprise wherein R more again
5Be CH
3And R
6Be C
4-C
5Alkyl, cyclohexyl ,-(C
1-C
2Alkyl)-phenyl ,-(C
1-C
2Alkyl)-pyridyl or-CH
2The compound of-furyl.Preferably, R
5Be CH
3And R
6Be C
4-C
5Alkyl hereinafter is called Z43-4.Other preferred Z43, Z43-1, Z43-2 and Z43-3 compound comprise wherein R more again
5Be methyl or ethyl and R
6Be (C
1-C
2Alkoxyl group)-(C
2-C
3Alkyl) compound.
Other preferred Z43, Z43-1, Z43-2 and Z43-3 compound comprise wherein R
5, R
6Forming one with the nitrogen that links to each other with them chooses wantonly by C
3-C
4The compound of alkyl or OH, azepanyl, tetramethyleneimine-2-carboxylic acid amide, 3-hydroxy piperidine-piperidines basic ring that the 1-base replaces.
Further preferred Z43, Z43-1, Z43-2, Z43-3 and Z43-4 compound comprise wherein R
pIt is the compound of methyl.
Other preferred compound of the present invention is that chemical formula is the compound of Z44
Wherein
R
1Be C
2-C
3Alkyl, halogen ,-NH (C
3-C
6Cycloalkyl), preferred cycloalkyl is a cyclopropyl,
R
fAnd R
gBe halogen independently;
R
pBe C
1-C
2Alkyl, oxazolyl, thiazolyl or C
2-C
3Alkynyl;
R
2, R
3Form a cyclopropyl rings with the carbon that links to each other with them; Or
R
2And R
3It is methyl;
R
5And R
6Be C independently
3-C
4Alkyl; Or
R
5Be methyl and R
6Be C
3-C
5Alkyl.
The compound that preferred chemical formula is Z44 comprises wherein R
2And R
3It is methyl; And R
5And R
6Be C independently
3-C
4The compound of alkyl hereinafter is called the Z44-1 compound.
The compound that preferred chemical formula is Z44 and Z44-1 comprises wherein R
pThe compound of Shi oxazole-2-base or thiazol-2-yl.
The compound that preferred chemical formula is Z44 comprises wherein R
pBe C
2-C
3Alkynyl; And R
5And R
6Be C independently
3-C
4The compound of alkyl.
R wherein equally preferably
1Be bromo, chloro or iodo or-compound of NH (cyclopropyl).
Other preferred compound of the present invention is that chemical formula is the compound of Z45
Wherein
R
cBe optional by C
3-C
5Alkyl replaces De isoxazolyl, optional by C
3-C
4The thiazolyl that alkyl replaces or-C
1-C
3Alkyl-C (O) NH (C
1-C
3Alkyl);
R
fAnd R
gBe halogen independently;
R
pBe C
1-C
2Alkyl, oxazolyl, thiazolyl or C
2-C
4Alkynyl;
R
5And R
6Be C independently
3-C
4Alkyl.
The compound that preferred chemical formula is Z45 comprises wherein R
pThe compound of Shi oxazole-2-base or thiazol-2-yl hereinafter is called the Z45-1 compound.Preferred Z45-1 compound comprises wherein R
cIt is 3-isobutyl-isoxazole-5-base or N-isobutyl--2 Methylpropionic acid (methylpropion)-2-base acid amides; And R
fAnd R
gBe the compound of Cl or F independently.
The compound that other preferred chemical formula is Z45 comprises wherein R
cIt is 2-isobutyl thiazole-2-base; And R
fAnd R
gBe the compound of Cl or F independently.
Other preferred chemical formula is Z45 compound comprises wherein R again
cIt is 3-isobutyl-isoxazole-5-base or N-isobutyl--2 Methylpropionic acid (methylpropion)-2-base acid amides; R
fAnd R
gBe Cl or F independently; And R
pBe C
2-C
3The compound of alkynyl.
Other preferred compound of the present invention is that chemical formula is the compound of Z46
Wherein
Hal is a halogen;
R
1Be C
1-C
2Alkyl or halogen;
R
2And R
3Be hydrogen;
R
fAnd R
gBe halogen independently;
R
zBe C
1-C
2Alkyl;
R
5And R
6Be C independently
3-C
4Alkyl.
The compound that preferred chemical formula is Z46 comprises that wherein Hal is the compound of bromo or chloro.More preferably, R
1Also be methyl, ethyl, bromo or iodo.More preferably, R
1Be methyl or ethyl.Again more preferably, it is an ethyl.
Other preferred compound of the present invention is that chemical formula is the compound of Z47
Wherein
N is 0,1 or 2;
R
1Be C
1-C
2Alkyl;
R
2And R
3Be hydrogen;
R
fAnd R
gBe halogen independently;
R
sBe (C
1-C
2Alkoxyl group) (C
1-C
2Alkyl).
Preferred Z47 compound comprises wherein R
sIt is the compound of methoxymethyl.Preferably, n is 1.
Other preferred compound of the present invention is that chemical formula is the compound of Z48
Wherein
R
1Be C
1-C
2Alkyl;
R
2And R
3Be hydrogen;
R
fAnd R
gBe halogen independently;
R
pBe optional by C
1-C
2Alkyl replaces the De isoxazole;
R
5And R
6Be C independently
3-C
4Alkyl.
The compound that preferred chemical formula is Z48 comprises wherein R
pBe 3-methyl-isoxazole-4-base, 5-oxazolyl, 3-oxazolyl, 3-Jia Ji oxazole-2-base, 3-Yi Ji oxazole-2-base.
Preferred chemical formula is Z
1-Z
48Compound comprise wherein R
fAnd R
gIn at least one is fluorine-based compound.More preferably, be fluorine-based.Also more preferably, R
fAnd R
gThe position that links to each other with phenyl is at 3 and 5.
In another case, the present invention includes the compound that chemical formula is Z49:
Wherein Ya is
Or-N (CH
2CH
2CH
3)
2
R
fAnd R
gBe hydrogen or form a carbonyl with the carbon that links to each other with them;
X
aBe a covalent linkage or a carbonyl;
R
nBe hydrogen or hydroxyl;
R
iAnd R
jBe hydrogen or the halogen that is selected from Br, F, Cl or I independently;
R
kBe-C
1-6Alkyl;
R
1Be-C
1-6Alkyl or optional by C
1-C
6Alkyl, C
1-C
6Alkoxyl group, halogen, hydroxyl, amino, list (C
1-C
6) alkylamino, two (C
1-C
6) phenyl that replaces of alkylamino, trifluoromethyl; And
M is 0 or 1.
In this specific embodiment, R
fAnd R
gPreferably form a carbonyl, X with the carbon that links to each other with them
aBe preferably a covalent linkage, R
hBe preferably hydrogen, m is preferably 1, and R
iAnd R
jBe preferably hydrogen.More preferably, R
kBe ethyl and R
cAn ethylphenyl that is replaced by position ,-CH
2CH
2CH (CH
3)
2, methyl or phenyl.R
1Be preferably phenyl.
Under another preferable case of Z49, R
fAnd R
gBe hydrogen, X
aBe a carbonyl, R
hBe hydroxyl, R
iAnd R
jBe hydrogen and R
kIt is ethyl.In another case and according to these preferred group, R
eBe preferably the ethylphenyl that replaced by position ,-CH
2CH
2CH (CH
3)
2Or methyl.
According to this specific embodiment, R
aBe preferably methyl and R
dBe preferably ethyl, X is preferably O, and R
bAnd R
cBe preferably hydrogen.In another case, and according to these preferred group, R
eBe preferably the ethylphenyl that replaced by position ,-CH
2CH
2CH (CH
3)
2, methyl or phenyl.Perhaps, according to this specific embodiment, X is preferably S, R
bAnd R
cBe hydrogen, and R
eBy the ethylphenyl or a methyl of position replacement.R
eBe preferably phenyl.
In another case, the invention provides the compound that chemical formula is Z50:
Wherein
R
aAnd R
dBe C
1-6Alkyl;
X is O or S;
R
bAnd R
cBe hydrogen or the halogen that is selected from Br, F, Cl or I independently; And
R
eBe-C
1-6Alkyl or optional by C
1-C
6Alkyl, C
1-C
6Alkoxyl group, halogen, hydroxyl, amino, list (C
1-C
6) alkylamino, two (C
1-C
6) phenyl that replaces of alkylamino, trifluoromethyl.
In another case, the invention provides chemical formula is the compound of Z51 and the salt that can be used for pharmacy thereof:
Wherein
M is 0-5;
B chooses wantonly to be independently selected from R by one or two
6, R '
6, R "
6And R_
6The group aryl or the heteroaryl that replace, or
B chooses wantonly to be independently selected from R by one, two, three, four, five, six, seven or eight
6a, R
6b, R '
6a, R '
6b, R "
6a, R "
6b, R_
6a, R_
6bThe group cycloalkyl or the Heterocyclylalkyl that replace;
Optional by one, two or three are selected from-NRR ' ,-SR ,-CN ,-OCF
3,-CF
3,-CONRR ' ,-CO
2R ,-SO
2NRR ' ,-O-P (=O) (OR) (OR ') ,-N (R)-C (=O) (R ') ,-N (R)-(SO
2R ') ,-SO
2R ,-C (=O) R ,-NO
2, halogen ,-(CH
2)
0-4-aryl or-(CH
2)
0-4The C that the group of-heteroaryl replaces
1-C
8Alkyl, C
2-C
7Alkenyl or C
2-C
7Alkynyl, or
R and R ' be independently-H ,-(C
1-C
10) alkyl ,-(CH
2)
0-4-R
Aryl,-(CH
2)
0-4-R
Heteroaryl,-(CH
2)
0-4-R
Heterocycle, or
Optional by one, two or three be selected from halogen ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group, amino, list or dialkyl amido and C
1-C
6The C that the substituting group of alkyl replaces
2-C
7Alkenyl or C
2-C
7Alkynyl or
Optional by one, two or three be selected from halogen ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group, amino, list or dialkyl amido and C
1-C
6The substituting group of alkyl replaces-(CH
2)
0-4-C
3-C
7Cycloalkyl;
Benzyl, wherein benzyl ring optional by 1-3 be independently selected from halogen ,-OH ,-SH ,-C ≡ N, list or dialkyl amido, C
1-C
6The group of alkyl or trifluoromethyl replaces;
R
6, R '
6, R "
6, R_
6, R
6a, R
6b, R '
6a, R '
6b, R "
6a, R "
6b, R_
6aAnd R_
6bBe independently-OR ,-NO
2, halogen ,-CO
2R ,-C ≡ N ,-NRR ' ,-SR ,-SO
2R ,-C (=O) R ,-OCF
3,-CF
3,-CONRR ' ,-SO
2NRR ' ,-O-P (=O) (OR) (OR ') ,-N (R) (COR ') ,-N (R) (SO
2R ') ,-(CH
2)
0-4-CO-NR
7R '
7,-(CH
2)
0-4-O-(CH
2)
0-4-CONRR ' ,-(CH
2)
0-4-CO-(C
1-C
12Alkyl) ,-(CH
2)
0-4-CO-(C
2-C
12Alkenyl) ,-(CH
2)
0-4-CO-(C
2-C
12Alkynyl) ,-(CH
2)
0-4-CO-(C
3-C
7Cycloalkyl) ,-(CH
2)
0-4-R
Aryl,-(CH
2)
0-4-R
Heteroaryl,-(CH
2)
0-4-R
Heterocycle,-(CH
2)
0-4-CO-R
Aryl,-(CH
2)
0-4-CO-R
Heteroaryl,-(CH
2)
0-4-CO-R
Heterocycle,-(CH
2)
0-4-CO-R
10,-(CH
2)
0-4-CO-O-R
11,-(CH
2)
0-4-SO
2-NR
7R '
7,-(CH
2)
0-4-SO-(C
1-C
8Alkyl) ,-(CH
2)
0-4-SO
2-(C
1-C
12Alkyl) ,-(CH
2)
0-4-SO
2-(C
3-C
7Cycloalkyl) ,-(CH
2)
0-4-N (H or R
11)-CO-O-R
11,-(CH
2)
0-4-N (H or R
11)-CO-N (R
11)
2,-(CH
2)
0-4-N (H or R
11)-CS-N (R
11)
2,-(CH
2)
0-4-N (H or R
11)-CO-R
7,-(CH
2)
0-4-NR
7R '
7,-(CH
2)
0-4-R
10,-(CH
2)
0-4-O-CO-(C
1-C
6Alkyl) ,-(CH
2)
0-4-O-P (O)-(O-R
Aryl)
2,-(CH
2)
0-4-O-CO-N (R
11)
2,-(CH
2)
0-4-O-CS-N (R
11)
2,-(CH
2)
0-4-O-(R
11) ,-(CH
2)
0-4-O-(R
11)-COOH ,-(CH
2)
0-4-S-(R
11), C
3-C
7Cycloalkyl ,-(CH
2)
0-4-N (H or R
11)-SO
2-R
7, or-(CH
2)
0-4-C
3-C
7Cycloalkyl,
Or optional by one, two or three are independently selected from the C that the substituting group of following groups replaces
1-C
8Alkyl: C
1-C
6Alkyl ,-F ,-Cl ,-Br ,-I ,-OR ,-NO
2,-F ,-Cl ,-Br ,-I ,-CO
2R ,-C ≡ N ,-NRR ' ,-SR ,-SO
2R ,-C (=O) R ,-OCF
3,-CF
3,-CONRR ' ,-SO
2NRR ' ,-O-P (=O) (OR) (OR ') ,-N (R) (COR ') ,-N (R) (SO
2R ') ,-(CH
2)
0-4-CO-NR
7R '
7,-(CH
2)
0-4-CO-(C
1-C
12Alkyl) ,-(CH
2)
0-4-CO-(C
2-C
12Alkenyl) ,-(CH
2)
0-4-CO-(C
2-C
12Alkynyl) ,-(CH
2)
0-4-CO-(C
3-C
7Cycloalkyl) ,-(CH
2)
0-4-R
Aryl,-(CH
2)
0-4-R
Heteroaryl,-(CH
2)
0-4-R
Heterocycle,-(CH
2)
0-4-CO-R
Aryl,-(CH
2)
0-4-CO-R
Heteroaryl,-(CH
2)
0-4-CO-R
Heterocycle,-(CH
2)
0-4-CO-R
10,-(CH
2)
0-4-CO-O-R
11,-(CH
2)
0-4-SO
2-NR
7R '
7,-(CH
2)
0-4-SO-(C
1-C
8Alkyl) ,-(CH
2)
0-4-SO
2-(C
1-C
12Alkyl) ,-(CH
2)
0-4-SO
2-(C
3-C
7Cycloalkyl) ,-(CH
2)
0-4-N (H or R
11)-CO-O-R
11,-(CH
2)
0-4-N (H or R
11)-CO-N (R
11)
2,-(CH
2)
0-4-N (H or R
11)-CS-N (R
11)
2,-(CH
2)
0-4-N (H or R
11)-CO-R
7,-(CH
2)
0-4-NR
7R '
7,-(CH
2)
0-4-R
10,-(CH
2)
0-4-O-CO-(C
1-C
6Alkyl) ,-(CH
2)
0-4-O-P (O)-(O-R
Aryl)
2,-(CH
2)
0-4-O-CO-N (R
11)
2,-(CH
2)
0-4-O-CS-N (R
11)
2,-(CH
2)
0-4-O-(R
11) ,-(CH
2)
0-4-O-(R
11)-COOH ,-(CH
2)
0-4-S-(R
11), C
3-C
7Cycloalkyl ,-(CH
2)
0-4-N (H or R
11)-SO
2-R
7, or-(CH
2)
0-4-C
3-C
7Cycloalkyl or each optional by one, two or three be independently selected from halogen or-C that the group of OH replaces
2-C
7Alkenyl or C
2-C
7Alkynyl,
Or each optional by one, two or three are independently selected from halogen, C
1-C
3Alkyl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3The C that the group of alkoxyl group, amino and list or dialkyl amido replaces
2-C
7Alkenyl or C
2-C
7Alkynyl or
-(CH
2)
0-4-O-(C
1-C
6Alkyl), wherein moieties is optional by one, two, three, four or five halogens replacements, or
R
6a, R
6b, R '
6a, R '
6b, R "
6a, R "
6b, R_
6aAnd R_
6bIn any two be oxo altogether;
R
7And R '
7Can be identical or different, and the representative be-H ,-C
3-C
7Cycloalkyl ,-(C
1-C
2Alkyl)-(C
3-C
7Cycloalkyl) ,-(C
1-C
6Alkyl)-O-(C
1-C
3Alkyl) ,-C
2-C
6Alkenyl ,-C
2-C
6Alkynyl, contain two keys and a triple-linked-C
1-C
6Alkyl or optional quilt-OH or-NH
2Replace-C
1-C
6Alkyl; Or optional by one, two or three are independently selected from that the group of halogen replaces-C
1-C
6Alkyl; Or
The optional heterocycle that is replaced by following group: halogen, amino, list or dialkyl amido ,-OH ,-C ≡ N ,-SO
2-NH
2,-SO
2-NH-G
1-C
6Alkyl ,-SO
2-N (C
1-C
6Alkyl)
2,-SO
2-(C
1-C
4Alkyl) ,-CO-NH
2,-CO-NH-C
1-C
6Alkyl, oxo and-CO-N (C
1-C
6Alkyl)
2Or optional by one, two or three are independently selected from C
1-C
3Alkyl, halogen ,-OH ,-SH ,-C ≡ N ,-CF
3,-C
1-C
3The C that the group of alkoxyl group, amino and list or dialkyl amido replaces
1-C
6Alkyl; Or each optional by one, two or three are independently selected from C
1-C
3Alkyl, halogen ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3The C that the group of alkoxyl group, amino and list or dialkyl amido replaces
2-C
6Alkenyl or C
2-C
6Alkynyl; Or the optional C that is replaced by, two or three halogens
1-C
6Alkoxyl group;
Or each optional aryl or heteroaryl that is replaced by following group: halogen, amino, list or dialkyl amido ,-OH ,-C ≡ N ,-SO
2-NH
2,-SO
2-NH-C
1-C
6Alkyl ,-SO
2-N (C
1-C
6Alkyl)
2,-SO
2-(C
1-C
4Alkyl) ,-CO-NH
2,-CO-NH-C
1-C
6Alkyl and-CO-N (C
1-C
6Alkyl)
2Or optional by one, two or three are independently selected from C
1-C
3Alkyl, halogen ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3The C that the group of alkoxyl group, amino and list or dialkyl amido replaces
1-C
6Alkyl; Or each optional by one, two or three are independently selected from C
1-C
3Alkyl, halogen ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3The C that the group of alkoxyl group, amino and list or dialkyl amido replaces
2-C
6Alkenyl or C
2-C
6Alkynyl; Or the optional C that is replaced by, two or three halogens
1-C
6Alkoxyl group;
R
10Be to choose wantonly to be independently selected from C by one, two, three or four
1-C
6The heterocycle that the group of alkyl replaces;
R
11Be C
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
3-C
7Cycloalkyl ,-(CH
2)
0-2-R
ArylOr-(CH
2)
0-2-R
Heteroaryl
R
ArylBe the optional aryl that is replaced by following group: halogen, amino, list or dialkyl amido ,-OH ,-C ≡ N ,-SO
2-NH
2,-SO
2-NH-C
1-C
6Alkyl ,-SO
2-N (C
1-C
6Alkyl)
2,-SO
2-(C
1-C
4Alkyl) ,-CO-NH
2,-CO-NH-C
1-C
6Alkyl or-CO-N (C
1-C
6Alkyl)
2Or
Optional by one, two or three are independently selected from C
1-C
3Alkyl, halogen ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3The C that the group of alkoxyl group, amino and list or dialkyl amido replaces
1-C
6Alkyl; Or
Optional by one, two or three are independently selected from C
1-C
3Alkyl, halogen ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3The C that the group of alkoxyl group, amino and list or dialkyl amido replaces
2-C
6Alkenyl or C
2-C
6Alkynyl; Or
The optional C that is replaced by, two or three halogens
1-C
6Alkoxyl group;
R
HeteroarylBe the optional heteroaryl that is replaced by following group: halogen, amino, list or dialkyl amido ,-OH ,-C ≡ N ,-SO
2-NH
2,-SO
2-NH-C
1-C
6Alkyl ,-SO
2-N (C
1-C
6Alkyl)
2,-SO
2-(C
1-C
4Alkyl) ,-CO-NH
2,-CO-NH-C
1-C
6Alkyl or-CO-N (C
1-C
6Alkyl)
2Or optional by one, two or three are independently selected from C
1-C
3Alkyl, halogen ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3The C that the group of alkoxyl group, amino and list or dialkyl amido replaces
1-C
6Alkyl; Or optional by one, two or three are independently selected from C
1-C
3Alkyl, halogen ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3The C that the group of alkoxyl group, amino and list or dialkyl amido replaces
2-C
6Alkenyl or C
2-C
6Alkynyl; Or the optional C that is replaced by, two or three halogens
1-C
6Alkoxyl group;
R
HeterocycleBe the optional heterocycle that is replaced by following group: halogen, amino, list or dialkyl amido ,-OH ,-C ≡ N ,-SO
2-NH
2,-SO
2-NH-C
1-C
6Alkyl ,-SO
2-N (C
1-C
6Alkyl)
2,-SO
2-(C
1-C
4Alkyl) ,-CO-NH
2,-CO-NH-C
1-C
6Alkyl ,=O or-CO-N (C
1-C
6Alkyl)
2Or optional by one, two or three are independently selected from C
1-C
3Alkyl, halogen ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3The C that the group of alkoxyl group, amino and list or dialkyl amido replaces
1-C
6Alkyl; Or optional by one, two or three are independently selected from C
1-C
3Alkyl, halogen ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3The C that the group of alkoxyl group, amino and list or dialkyl amido replaces
2-C
6Alkenyl or C
2-C
6Alkynyl; Or the optional C that is replaced by, two or three halogens
1-C
6Alkoxyl group;
R
2And R
3Be hydrogen or C independently
1-C
6Alkyl; Or
R
2, R
3Form 3 or 4 yuan of rings with the carbon atom that links to each other with them;
R
CBe hydrogen or optional by C
1-C
3Alkyl, C
2-C
4Alkynyl, trifluoromethyl or C
1-C
2The phenyl that alkoxyl group replaces.
In another case, the invention provides the compound that chemical formula is Z52:
Or it can be used for the salt of pharmacy, wherein
N is 0,1,2 or 3 (being preferably 1);
R
1Be C
1-C
3Alkoxyl group (being preferably methoxyl group), halogen (being preferably iodo), C
1-C
3Alkyl (being preferably ethyl or sec.-propyl) or C
2-C
3Alkynyl (is preferably C
2Alkynyl);
R
fAnd R
gBe halogen independently, or hydrogen; And
Alk is C
1-C
6Alkyl (being preferably methyl, ethyl, isobutyl-or isopentyl).
The example of preferred Z52 comprises that wherein n is 1 and R
1Be methoxyl group, C
2The compound of alkynyl or ethyl.More preferably, R
1It is methoxyl group.
Compound of the present invention has suppressed beta-secretase and therefore can be used for treatment and the prevention Alzheimer's disease.Compound of the present invention is by well known to a person skilled in the art method, using starting compound well known by persons skilled in the art to make.Its process chemistry is well known to a person skilled in the art.Graph A has been illustrated the method for the most general preparation compound of the present invention.Usually, amino acid (I) is protected on amino, generates protected amino acid (II).Compound (II) is changed into a kind of ester intermediate, and this intermediate and a kind of carbon nucleophile reacting generating compound (III).Ketone partial reduction in the compound (III) is generated alcohol (IV), and it forms epoxide (V).Add amine R
C-NH
2(VI) open epoxide (V), form and protected alcohol (VII).Remove amine protecting group, this deprotection amine (VIII) is (R with a kind of chemical formula
N-1-X
N)
2O or R
N-1-X
N-X
2Or R
N-1-X
NThe acid amides of-OH (IX) forms the agent reaction, makes the target compound of chemical formula for (X).
The main chain of compound of the present invention is an ethylol amine part ,-NH-CH (R)-CH (OH)-.It can easily make by disclosed in the document and method known to those skilled in the art.For example, J.Med.Chem., 36,288-291 (1992), Tetrahedron Letters, 28,5569-5572 (1987), J.Med.Chem., 38,581-584 (1994) and Tetrahedron Letters, 38,619-620 (1997) discloses the method for preparing ethylol amine type compound.
Graph A has been illustrated the universal method of the amine (X) that preparation suitably replaces among the present invention.Use corresponding amino acid (I) as feedstock production compound of the present invention.This amino acid (I) well known to a person skilled in the art, or can be by well known to a person skilled in the art what method was made easily by compound known.Replacement amine of the present invention (X) has at least two mapping centers, and it produces four enantiomorphs.In these mappings in the heart first from amino acid starting material (I).Preferably obtain or make required enantiomorph (S) by commercial sources, but not make a kind of on the mapping structure non-single mixture have to isolate required enantiomorph (S) then.This method preferably use the mapping structure single and also with replace amine (X) product and have (the S)-amino acid (I) of identical configuration as starting raw material.
The first step of this method is by well known to a person skilled in the art the free amino group of method with amino protecting group protection (S)-amino acid (I), to make (S)-protected amino acid (II).The ammonia protecting group is well known to a person skilled in the art.Referring to for example, " Protecting Groups in Organic Synthesis ", John Wiley and sons, New York, N.Y, 1981, chapter 7; " Protecting Groups in Organic Chemistry ", PlenumPress, New York, N.Y, 1973, chapter 2.The function of amino protecting group is the (NH of free amino group functional group on protection (S)-amino acid (I) in the subsequent reaction process
2), subsequent reaction can because following two kinds former thereby can not proceed well: promptly amino reacts in some way and functionalised, and this mode and reaction pair amino subsequently be free radical require inconsistent; Or because free amino group can disturb this reaction.When no longer needing amino protecting group, can it be removed by well known to a person skilled in the art method.As qualification, this amino protecting group must can be removed by well known to a person skilled in the art method as those skilled in the art understand easily.The amino protecting group that is fit to is selected from tert-butoxycarbonyl; carbobenzoxy-(Cbz); formyl radical; trityl; ethanoyl; the tribromo-acetyl base; dichloro-acetyl; chloracetyl; trifluoroacetyl group; the difluoro ethanoyl; the acetyl fluoride base; 4-phenyl carbobenzoxy-(Cbz); 2-methyl carbobenzoxy-(Cbz); 4-oxyethyl group benzyloxy carbonyl; 4-fluorine carbobenzoxy-(Cbz); 4-benzyloxycarbonylchloride base; 3-benzyloxycarbonylchloride base; 2-benzyloxycarbonylchloride base; 2; 4-dichloro carbobenzoxy-(Cbz); the 4-bromo-benzyloxycarbonyl; the 3-bromo-benzyloxycarbonyl; 4-nitro carbobenzoxy-(Cbz); 4-cyano group carbobenzoxy-(Cbz); 2-(4-xenyl)-isopropoxy carbonyl; 1; 1-phenylbenzene second-1-base oxygen carbonyl; 1; 1-diphenylprop-1-base oxygen carbonyl; 2-phenyl third-2-base oxygen carbonyl; 2-(to toluyl) third-2-base oxygen carbonyl; pentamethylene base oxygen carbonyl; 1-methylcyclopentane base oxygen carbonyl; cyclohexyl oxygen carbonyl; 1-methyl cyclohexane alkyl oxygen carbonyl; 2-methyl cyclohexane alkyl oxygen carbonyl; 2-(4-toluyl alkylsulfonyl) ethoxy carbonyl; 2-(methyl sulphonyl)-ethoxy carbonyl; 2-(triphenylphosphinyl) ethoxy carbonyl; the fluorenyl methoxy carbonyl; 2-(trimethyl silyl) ethoxy carbonyl; allyloxy carbonyl; 1-(trimethyl silyl methyl) third-1-thiazolinyl oxygen carbonyl; 5-benzoisoxazole ylmethoxy carbonyl; 4-acetoxyl group carbobenzoxy-(Cbz); 2; 2,2-trichlorine ethoxy carbonyl; 2-ethynyl-2-propoxycarbonyl; the cyclo propyl methoxy carbonyl; 4-(oxygen base in the last of the ten Heavenly stems) carbobenzoxy-(Cbz); isobornyl oxygen carbonyl and piperidino oxygen carbonyl; carbonic acid 9-fluorenyl methyl esters;-CH-CH=CH
2And phenyl-C (=N-)-H.This protecting group is preferably tert-butoxycarbonyl (BOC) and carbobenzoxy-(Cbz) (CBZ), and this protecting group is tert-butoxycarbonyl more preferably.Those skilled in the art understand the preferred method that adds tert-butoxycarbonyl or carbobenzoxy-(Cbz) protecting group; in addition can also with reference to T.W.Green and P.G.M.Wuts " Protective Groups inOrganic Chemistry; " John Wiley and sons, 1991 as instructing.
At first (S)-protected amino acid (II) is changed into corresponding alkyl ester according to sophisticated method in this field (for example by with diazonium compound reaction), thus will (S)-protected compound (II) to change into (S) that chemical formula is (III)-quilt and protected compound.Making the reaction of ester intermediate and a kind of carbanion nucleophile well known by persons skilled in the art (nucleofile) then, is X by chemical formula for example
1-C (R
2) (R
3)-X
1Compound and the organometallic compound that makes of strong metal alkali reaction, wherein should reaction produce halogen-metal exchange, and wherein-X
1It is the halogen that is selected from chlorine, bromine or iodine.In the ester intermediate, add this carbanion nucleophile, generate (S)-protected compound (III).The alkali that is suitable for includes, but not limited to lithium alkylide, comprises, for example, s-butyl lithium, n-Butyl Lithium and tert-butyl lithium.Described reaction is preferably carried out in low temperature, for example-78 ℃.Suitable reaction conditions is included in inert solvent or its mixture (for example but be not only ether, tetrahydrofuran (THF) or its mixture) and reacts.Work as R
2And R
3When all being hydrogen, X
1-C (R
2) (R
3)-X
1Example comprise methylene bromide, methylene iodide, chloroiodomethane, bromoiodomethane and bromochloromethane.The required optimum condition of this reaction is carried out in those skilled in the art's understanding.In addition, if R
2And/or R
3Be not-H, so by general-C (R
2) (R
3)-X
1(S)-when being protected compound (III), the another one chiral centre is introduced in meeting to the ester of adding (S)-protected amino acid (II) in product to make, and prerequisite is R
2And R
3Different.
By well known to a person skilled in the art ketone is reduced to the method reduction (S) of correspondent alcohol (IV)-protected compound (III) then.With (S)-protected reagent and the reaction conditions that compound (III) is reduced to correspondent alcohol (IV) to comprise, for example, sodium borohydride, lithium borohydride, borine, diisobutyl aluminium hydride and lithium aluminum hydride.Sodium borohydride is preferred reductive agent.This reduction reaction is approximately-78 ℃ to carrying out between the reflux temperature of reaction mixture 1 hour to 3 days.Preferably approximately-78 ℃ and between about 0 ℃ reducing.Can use borane complex, for example, borine-methyl-sulfide complex compound, borine-piperidines complex compound or borine-tetrahydrofuran complex.The preferably combination of required reductive agent combination and reaction conditions is that those of ordinary skills are known, referring to for example Larock, and R.C., Comprehensive Organic Transformations, VCH Publisher, 1989.(S)-protected the reaction that compound (III) is reduced to correspondent alcohol (IV) to have generated second chiral centre (if R
2And R
3Difference then is the 3rd chiral centre).(S)-reduction reaction of being protected compound (III) generates mixture of enantiomers at second center, (S, R/S)-alcohol (IV).Then by method known to those skilled in the art, for example selectivity low temperature recrystallize or chromatography (for example by HPLC, the chiral stationary phase that use can obtain by commercial sources) separate this mixture of enantiomers.The enantiomorph that uses at the remainder of method shown in the graph A be (S, S)-alcohol (IV) because this enantiomorph be required biologically active Kang Aercihaimoshi disease (S, R)-replace the parent of amine (X).
By method known to those skilled in the art make (S, S)-alcohol (IV) in intramolecular reaction to generate corresponding epoxide (V).In epoxide (V), keep the middle carbon of compound (IV) to be attached to-OH stereochemistry partly.Preferred reaction conditions comprises makes compound (III) contact alkali, such as but not limited to, sodium hydroxide, potassium hydroxide or lithium hydroxide.Reaction conditions comprises use C
1-C
6Alcoholic solvent; Ethanol is preferred.Also can use common cosolvent, for example ethyl acetate.Reaction preferably approximately-45 ℃ is being carried out between the reflux temperature of reaction mixture; Preferred temperature is approximately-20 ℃ and approximately between 20-25 ℃.
Then under reaction conditions well known by persons skilled in the art, with epoxide (V) and the C-terminal amine that is suitably replaced, R
c-NH
2(VI) reaction, thus make the epoxide open loop with make the mapping structure single (S, R)-protected alcohol (VII).Replacement C-terminal amine of the present invention, R
c-NH
2(VI), can obtain by commercial sources, or well known by persons skilled in the art and can make easily by known compound.In addition, preferably, work as R
cDuring for phenyl, it is in 3-position or 3, and the 5-position is substituted.
It is a kind of organic that the appropriate reaction condition of epoxide (V) open loop is included in, and is preferably among the inert w and reacts.C
1-C
6Alcoholic solvent is preferred, and Virahol is most preferred.This reaction can approximately 20-25 ℃ carry out between the reflux temperature of reaction mixture, preferred temperature of reaction is about 50 ℃ of reflux temperatures to reaction mixture.When the C-terminal amine (VI) that replaces is 1-amino-3,5-is suitable-and during the Dimethylcyclohexyl dicarboxylic ester, it is preferably according to following method preparation.In a bomb, will the rhodium in aluminum oxide be added in the amino isophthalic ester of dimethyl-5-in acetate and the methyl alcohol.Bottle is full of the hydrogen of 55psi and one week of shake.Then with mixture by one deck diatomite filtration, and with methanol rinse three times, decompression (heating) removal solvent obtains concentrate.This concentrate is ground with ether, and filtration obtains required C-terminal amine (VI) once more.When replacing C-terminal amine (VI) is 1-amino-3, and 5-is suitable-during the dimethoxy hexanaphthene, and it is according to above-mentioned universal program and except with 3, and the 5-anisidine is that raw material does not carry out key change outward and is prepared.When replacing C-terminal amine (VI) is aminomethyl, and wherein the substituting group on the methyl is an aryl, for example NH
2-CH
2-R
The C-aryl, and NH
2-CH
2-R
The C-arylBe not when obtaining by commercial sources, it preferably is prepared according to following method.The starting material that are suitable for are (by suitably replacing) aralkyl compounds.The first step be by method known to those skilled in the art with the alkyl substituent bromination, referring to for example R.C., Larock, Comprehensive OrganicTransformations, VCH Publisher, 1989, P.313.Subsequently, alkylogen and trinitride prepared in reaction aryl-(alkyl)-trinitride.By hydrogen/catalyzer this trinitride being reduced into corresponding amine at last, is NH thereby make chemical formula
2-CH
2-R
The C-arylC-terminal amine (VI).Those skilled in the art need not to do major change and just can easily make suitably functionalized C-terminal amine (VI) by known method in the document.Selected reference comprises 1) people such as Calderwood, Tet.Lett., 1997,38,1241,2) Ciganek, J.Org.Chem., 1992,57,4521,3) people such as Thurkauf, J.Med.Chem., 1990,33,1452,4) people such as Wemer, Org.Syn., Coll.Vol.5,273,5) J.Med.Chem., 1999,42,4193,6) Chem.Rev.1995,95,2457,7) J.Am.Chem.Soc., 1986,3150,8) people such as Felman, J.Med.Chem., 1992,35,1183,9) J.Am.Chem.Soc.1970,92,3700,10) J.Med.Chem., 1997,40,2323.
Chart B disclose another kind of by (S)-protected synthetic mapping structure single (enantiomerically pure) of compound (III) (S, R)-protected the method for alcohol (VII).In the method, (S)-by protected compound (III) under above-mentioned preferred reaction conditions with the C-terminal amine R that is suitably replaced
C-NH
2(VI) reaction generates (S)-is protected ketone (XI), its under above-mentioned optimum condition, reduce generation (S, R)-quilt protected alcohol (VII).
Chart C disclose another kind of by the synthetic mapping structure of epoxide (V) single (S, R)-protected the method for alcohol (VII).The reaction of epoxide (V) and trinitride, generate the mapping structure single (S, R)-protected trinitride (XII), its reaction conditions is well known by persons skilled in the art, for example, and J.March, Advanced OrganicChemistry, the third edition, John Wiley ﹠amp; Sons Publisher, 1985, p.380.By well known by persons skilled in the art under the condition that has tert-butoxycarbonyl N-protected base the method for reduction azido-, catalytic hydrogenation for example, will (S, R)-protected trinitride (XII) to be reduced into and to be protected amine (XIII).It is well known by persons skilled in the art that other that can be used for avoiding the N-deprotection uses the reductive condition of non-tert-butoxycarbonyl protecting group, referring to for example, and R.C.Larock; Comprehensive Organic Transformations; VCH Publisher, 1989, p.409.
By the method for removal amine protecting group well known by persons skilled in the art, will (S, R)-protected compound (XIII) deprotection, generate (S, R)-amine (VII).Be applicable to that the reaction conditions of removing amine protecting group depends on the type of protecting group.For example, preferably by will (S, R)-protected alcohol (VII) to contact with the mixture (for example trifluoroacetic acid/dichloromethane mixture) of organic solvent with acid and remove preferred protecting group BOC, generation (S, R)-the protonated salt of amine (VII).Randomly, can pass through method known to those skilled in the art (for example recrystallize) purify (S, R)-amine (VII).This alkali-free (S, R)-amine (VII) makes by method known to those skilled in the art, for example, prepares this alkali-free amine by making salt contact weak base environment.At T.W.Green and P.G.M.Wuts, " ProtectiveGroups in Organic Chemistry ", John Wiley and sons, 1991, can find the additional BOC deprotection condition and the deprotection condition of other protecting group in p.309.The typical salt that chemically is suitable for comprises trifluoroacetate, muriate, vitriol, phosphoric acid salt; Preferably trifluoroacetate and muriate.
Under reaction conditions well known by persons skilled in the art, make (S, R)-acylating reagent (IX) that amine (VIII) and a kind of quilt suitably replace, for example acid anhydride, carboxylic acid halides or chemical formula are (R
N-1-X
N)
2O or R
N-1-X
N-X
2Or R
N-1-X
NThe acid-respons of-OH (IX), with make (S, R)-replace amine (X).Can, for example, R.C.Larock, Comprehensive Organic Transformations, VCH Publisher, 1989, p.981, find reaction conditions well known by persons skilled in the art in 979 and 972.R
NBe preferably selected from:
R
N-1-X
N-, X wherein
NBe-CO-, R
N-1Be R
The N-arylOr R
The N-heteroaryl, R wherein
The N-arylBe phenyl, wherein the replacement on the phenyl is 1,3-, and R wherein
The N-arylOr R
The N-heteroarylBy one-CO-NR
N-2R
N-3Replace,
R
N-1-X
N-, X wherein
NBe-CO-, R
N-1Be R
The N-arylOr R
The N-heteroaryl, R wherein
The N-arylBy a C
1The phenyl that alkyl replaces, wherein the replacement on the phenyl is 1,3,5-, and R wherein
The N-arylOr R
The N-heteroarylBy one-CO-NR
N-2R
N-3Replace,
R
N-1-X
N-, X wherein
NBe-CO-, R
N-1Be R
The N-heteroaryl, R wherein
The N-heteroarylBy one-CO-NR
N-2R
N-3Replace R
N-2And R
N-3Preferred identical and be C
3Alkyl,
R
N-1-X
N-, X wherein
NBe-CO-, R
N-1Be R
The N-aryl, R wherein
The N-arylBy one-CO-NR
N-2R
N-3The phenyl that replaces, wherein the replacement on the phenyl is 1,3-.
R
N-1-X
N-, X wherein
NBe-CO-, R
N-1Be R
The N-aryl, R wherein
The N-arylBy a C
1Alkyl and one-CO-NR
N-2R
N-3The phenyl that replaces, wherein the replacement on the phenyl is 1,3,5 ,-.X
NBe preferably (A)-CO-and (B)-SO
2-; X
NMore preferably-CO-.X
2Be selected from-Cl ,-Br; More preferably, X
2Be-Cl.
Acylating reagent, (R
N-1-X
N)
2O or R
N-1-X
N-X
2Or R
N-1-X
N-OH (IX) is well known by persons skilled in the art and can obtains or can be made easily by disclosed method in the document by known raw material by commercial sources.Preferred acylating reagent is that chemical formula is R
N-2R
N-3M-phthalic acid derivative (IX) or the chemical formula of N-CO-phenyl-CO-are R
N-2R
N-3N-CO-(CH
3-) the methyl isophthalic acid derivative (IX) of phenyl-CO-, wherein substituting group is the 5-methyl isophthalic acid, the 3-m-phthalic acid.Most preferred 5-methyl isophthalic acid, 3-m-phthalic acid derivative is 3-[(N, N-dipropyl amino) carbonyl]-5-tolyl acid (IX).These compounds are preferably synthetic according to following method.A kind of ester is preferably the mono-methyl or the 5-methyl isophthalic acid of m-phthalic acid, and 3-m-phthalic acid methyl esters is dissolved in a kind of organic solvent or the solvent mixture, is preferably the THF/DMF mixture.At approximately 20-25 ℃ of adding 1,1 '-carbonyl dimidazoles.Add a kind of preferred amines (H-NR
N-2R
N-3).About 20 ℃ to stirring between the reflux temperature of reaction mixture about 1 hour to about 24 hours, make reaction mixture phase-splitting between saturated aqueous ammonium chloride and water organic solvent immiscible (for example ethyl acetate) then.Separate water layer and with organic solvent extracting twice again.Merge organic extract liquid, and with the saturated bicarbonate aqueous solution and salt water washing, and through anhydrous sodium sulphate or dried over mgso.Solvent is removed in filtration drying agent and decompression, obtains required R
N-2R
N-3N-CO-phenyl-CO-O-CH
3-or methyl isophthalic acid acylating agent (IX) R
N-2R
N-3N-CO-(CH
3-) phenyl-CO-O-CH
3Methyl esters.Should can pass through silica gel chromatography, purify by (methyl) ester with the ethyl acetate and the hexanes mixtures wash-out of moving phase.Use alkaline aqueous solution, the solution of lithium hydroxide in minimum THF/ methane/water is for example handled the isophthalic ester or the m-phthalic acid methyl esters of monoalkyl or dialkyl amide, and at 20 ℃ to stirring 3-24 hour between the reaction mixture refluxed temperature.Solvent is removed in decompression then, makes the phase-splitting between Shui Heshui immiscible solvent (for example ethyl acetate) of this product.If the formation of milk sap has hindered the separation of these two kinds of phases, add a small amount of salt solution to help separation.Water water immiscible solvent (for example ethyl acetate) extracts one time again.Add a kind of acid then, be preferably hydrochloric acid, make aqueous phase as acidified to pH≤3.The mixture water immiscible solvent (for example ethyl acetate) that makes is extracted three times.With the blended organic extract liquid through anhydrous sodium sulphate or dried over mgso.Filter and remove siccative, and decompression removal organic solvent, product obtained.Single or two-alkylamide isophthalic ester/m-phthalic acid methyl esters with (S, R)-amine (VIII) reaction with preparation (S, R)-replace amine (X).
If R
N-2And R
N-3All be-H that following method is preferred.A kind of ester is preferably the mono-methyl or the 5-methyl isophthalic acid of m-phthalic acid, and 3-m-phthalic acid methyl esters is dissolved in a kind of organic solvent or the solvent mixture, is preferably the THF/DMF mixture.Add CDI at about 20-25 ℃.After five to 30 minutes, ammonia was blasted in this mixture 1 hour.During ammonia bubbles, mixture is cooled to about 0 ℃.Under about 20-25 ℃, allow reaction mixture under ammonia atmosphere, stir and spend the night, and phase-splitting between saturated aqueous ammonium chloride and water immiscible solvent (for example ethyl acetate).Separate this phase, and with twice of ethyl acetate extraction water.With the saturated bicarbonate aqueous solution and salt water washing organic extract liquid, and through anhydrous sodium sulphate or dried over mgso.Solvent is removed in filtration drying agent and decompression, obtains the ester of required m-phthalic acid or m-phthalic acid deutero-acylating reagent (IX).Should (methyl) ester can be by silica gel chromatography, purify with the isopropanol/chloroform elution mixture.Use alkaline aqueous solution, the solution of lithium hydroxide in THF/ methane/water is for example handled the isophthalic ester or the m-phthalic acid methyl esters of this primary amide, and spends the night in about 20-25 ℃ of stirring, after this solvent is removed in decompression, makes the phase-splitting between Shui Heshui immiscible solvent (for example ethyl acetate) of this solid.If the formation of milk sap has hindered the separation of these two kinds of phases, add the small amounts of salts aqueous solution to promote separation.Water phase separated and water immiscible solvent (for example ethyl acetate) extraction.Use acid then, be preferably hydrochloric acid, make aqueous phase as acidified to pH≤3.The mixture that makes with ethyl acetate extraction.With the blended organic extract liquid through anhydrous sodium sulphate or dried over mgso.Filter and remove siccative, and decompression removal organic solvent, product obtained.This acid amides m-phthalic acid derivative with (VIII) reaction with the preparation (X).
When amine moiety is a cyclic group, when for example the part of morpholinyl, piperazinyl, piperidyl and pyrrolidyl etc. is preferable case, preferably use following method.A kind of ester is preferably the methyl esters or the 5-methyl isophthalic acid of m-phthalic acid, and 3-m-phthalic acid methyl esters is dissolved in a kind of anhydrous solvent, methylene dichloride for example, and add a small amount of dipolar aprotic solvent, for example DMF.Mixture is cooled to about 0 ℃, and adds oxalyl chloride.This mixture was stirred about 30 minutes to about 2 hours at about 0 ℃, and solvent is removed in decompression after this.This rough chloride of acid placed under vacuum spend the night, be dissolved in anhydrous methylene (methylene) and be cooled to about 0 ℃, add a kind of cyclammonium and a kind of tertiary amine base then, for example the N-methyl piperidine.Reaction mixture was stirred about 1 to about 6 hours at about 0 ℃, and solvent is removed in decompression then.Water and water immiscible solvent (for example ethyl acetate) dilution resistates, and water phase separated.Water immiscible solvent (for example ethyl acetate) aqueous phase extracted, and with saturated bicarbonate solution washing blended organic extract liquid, and through anhydrous sodium sulphate or dried over mgso.Filter and remove siccative, and decompression removal organic solvent, the cyclic amide product obtained.Use alkaline aqueous solution, for example the solution of lithium hydroxide in THF/ methane/water is handled this cyclic amide, and spends the night in about 20-25 ℃ of stirring, and solvent is removed in decompression after this, makes the phase-splitting between Shui Heshui immiscible solvent (for example ethyl acetate) of this resistates.Use the ethyl acetate extraction water.Remove water from the aqueous phase decompression, obtain target cyclic amide product (IX).
R in target product
N-1Part is a carbocyclic ring, during such as but not limited to hexanaphthene, raw material reagent can be a kind of suitably functionalized dimethyl isophthalate, by document (Meyers, A.I., Org.Syn., 1971,51,103) one of method of instruction in, can be under the condition that has acetate and methane, under nitrogen atmosphere, use reductive agent such as rhodium (5%)-aluminium to reduce these 6 yuan of rings, so that corresponding cyclohexane dicarboxylic acid dimethyl ester to be provided.
Chart D illustrated another kind of by (S, R)-protected trinitride (XII) preparation (S, R)-replace the method for amine (X), should (S, R)-protected trinitride (XII) to make by corresponding epoxide (V) among the chart C.By in the aforementioned graph A will (S, R)-protected alcohol (VII) to change into accordingly that (S, R)-method of amine (VIII), the removal amino protecting group is to make corresponding unprotect trinitride (XIV).To then (S, R)-unprotect trinitride (XIV) acidylate on nitrogen, corresponding to prepare (S, R)-trinitride (XV).Next, as described above will (S, R)-protected trinitride (XII) change into accordingly (S R)-protected the method for amine (XIII), can reduce the trinitride official, make (S, R)-unhindered amina (XVI).At last, use chemical formula to be R
C-X
3Compound by azanylization will (S, R)-unhindered amina (XVI) change into accordingly (S, R)-replace amine (X), thereby make corresponding (S, R)-replacement amine (X).X
3Be suitable leavings group, such as but not limited to ,-Cl ,-Br ,-I ,-the O-methanesulfonates ,-O-tosylate, O-triflate etc.X
3Also can be aldehyde; Corresponding by known reduction amination program and (XVI) coupling generated (S, R)-replacement amine (X).
The present invention also provides the carbocyclic ring acid amides to form agent (IX).For example, the following carbocyclic ring acid amides of chemical formula forms agent
|-----------------------------|
R '-CH-C (R ") (R_)-CH-X
N-OH (IX) is prepared by the disclosed and method known to those skilled in the art (for example, J.Med.Chem., 1998,41,1581, J.Org.Chem., 2000,65,1305) of document by known raw material easily.What it is also understood that is to use carboxylic acid halides (wherein this halogenide is preferably chlorine) or suitable group to replace carboxylic acid to make mixed anhydride easily; Graph A has been set forth these methods.The guidance that other relevant carbocyclic ring (being preferably cyclopropane) forms can be with reference to M.P.Doyle; M.A.McKervery; T.Ye, Modem Catalytic Methods for Organic Synthesis with Diazo Compounds FromCyclopropanes to Ylides, Wiley-Interscience, 1998, PP.163-279.
Chart E, F, G and H disclose the R that multiple manufacturing replaces amine (X)
NThe method of part, wherein R
N1,3-two replaces the benzyl ring of part, and-CO-phenyl-CO-is further replaced by various groups such as acid amides, nitrile, halogenide and amine in the 5-position.Prepare these compounds by method known to those skilled in the art.The process chemistry of each reaction all is well known by persons skilled in the art.Novel part of the present invention is the order of each step and/or used concrete reagent.It is at least a by using the method for known this required product of feedstock production to understand one skilled in the art will recognize that of required product.Therefore, following discussion is optional, but is used for the people that further help intends to prepare The compounds of this invention.
Figure E discloses other and aniline (XVII) or acid ester (XVIII) has been changed into the method for corresponding acid (IX-XXIII).A kind of method is a raw material with the aniline (XVII) that can obtain by commercial sources.(XVII) uses a kind of diazo reagent with this aniline, and for example Sodium Nitrite or potassium nitrite are handled in mineral acid, and then handles with a kind of halogen source such as copper halide (II) or alkali metal halide; Perhaps use a kind of organic diazo reagent, for example alkyl nitrite is handled in strong acid (for example acetate or trifluoroacetic acid), and then handles with a kind of halogen source such as copper halide (II) or alkali metal halide, thereby makes halo acid ester (XIX).
Perhaps, handle acid ester (XVIII) to make halo acid ester (XIX) with N-halo succinimide and trifluoromethanesulfonic acid.Use a kind of chemical formula to be H-NG then
1G
2(G wherein
1And G
2Identical or different or can be by cyclisation) primary amine or secondary amine this halo acid ester (XIX) is changed into esteramides (XXI).G
1And G
2Become the part that replaces amine (X) and be included in R
NDefinition in.R
NComprise R
N-1-X
N-, wherein connect base-X
N-comprise-CO-, and R
N-1Comprise R
The N-arylR
The N-arylBe defined as comprise optional by one or two acid amides :-CO-NR
N-2R
N-3With-CO-R
N-4The phenyl (phenyl) that replaces.
Perhaps, use method known to those skilled in the art that halo acid ester (XIX) is changed into chloride of acid halogen ester (XX).Those skilled in the art will appreciate that also and can use other acyl halide.With chemical formula is H-NG
1G
2Primary amine or secondary amine handle dihalogenated ester (XX) to make esteramides (XXI).Use those methods (Palladium Reagents in Organic Synthesis then as the Heck comment, 1985 pp.342-365), exist under the condition of palladium catalyst, esteramides (XXI) is reacted with a kind of amine in carbon monoxide atmosphere, making diamide (XXII).Use well known to a person skilled in the art method, makes the ester moiety hydrolysis of diamide (XXII), makes diamide acid (XXIII).
In chart F, shown that another kind be the approach that raw material is made intermediate diamide (XXII) with the phenol (XXIV) that can obtain by commercial sources.Handle this phenol (XXIV) with a kind of fluoroform sulfonated reagent, make triflate (XXV) such as trifluoromethanesulfanhydride anhydride.As among the chart E esteramides (XXI) being changed into the used method of corresponding diamide (XXII), under the palladium catalytic condition, be H-NR having carbon monoxide and chemical formula
N αR
N βUnder the situation of (AMINE (amine)), make triflate (XXV) reaction, make diester (XXVI).Use method known to those skilled in the art with this diester (XXVI) hydrolysis, make monoprotic acid (XXVII).Use as among the chart E halo acid ester (XIX) being changed into the used condition of esteramides (XXI) then, this monoprotic acid (XXVII) is changed into diamide (XXII).
Chart G discloses the approach of another kind of preparation esteramides (XXI).This reaction be a raw material with the nitro-compound (XXVIII) that can obtain by commercial sources, use coupling method well known by persons skilled in the art with this nitro-compound and a kind of amine (AMINE) condensation to make nitro acid amides (XXX).Also can be prepared as follows this nitro acid amides (XXX): at first use reagent such as thionyl chloride or DMF and oxalyl chloride, or other method well known by persons skilled in the art is handled this nitro-compound (XXVIII), obtain acyl chlorides (XXIX), this acyl chlorides is handled through amine (AMINE) and is made nitro acid amides (XXX).The use method known to those skilled in the art (referring to, for example, Smith and March, Advanced Organic Chemistry, the 5th edition) reduction nitro acid amides (XXX), make acid amides aniline (XXXI).Then this acid amides aniline (XXXI) is used diazo reagent, for example Sodium Nitrite or potassium nitrite are handled in mineral acid, use a kind of halogen source such as copper halide (II) or alkali metal halide to handle subsequently again; Perhaps use a kind of organic diazo reagent, for example alkyl nitrite is handled in strong acid (for example acetate or trifluoroacetic acid), and then handles with a kind of halogen source such as copper halide (II) or alkali metal halide, thereby makes esteramides (XXI).
Chart H discloses and has a kind ofly prepared the method for diamide acid (IX-XXIII) by esteramides (XXI), and wherein in the acid amides is unsubstituted and is-CO-NH
2This method is a raw material with ester or acid, for example at N-Methyl pyrrolidone or DMF, (CuCN) handles esteramides (XXI) with cupric cyanide (I) in the preferred N-Methyl pyrrolidone, makes nitrile (XXXII).Use urea-hydrogen peroxide complex thing (referring to Synth.Commum. (1993) 3149) or Synth.Commum. (1990) 1445, Synth.Commum. (1997) 3119, J.Org.Chem. (1992) 2521, Tet.Lett. (1996) 6555, Ind.J.Chem., Sect.B, (1999) 974, method or other method of Tet.Lett. (1995) 3469, Tet.Lett. (1998) 3005 change into primary amide (XXXIII) with this nitrile (XXXII).If esteramides (XXI) is an ester-formin, use lithium hydroxide, sodium hydroxide, potassium hydroxide, hydrated barta or other hydrolysis method well known by persons skilled in the art additionally to carry out a hydrolysing step, thereby diamide ester (XXXIII) is changed into diamide acid (IX-XXIII).
The figure Table I discloses another kind of by being protected the synthetic approach that replaces amine (X) of alcohol (VII), and this approach has used the intermediate (XXXIV) of the two protections of a kind of quilt, wherein is connected to R
CNitrogen-atoms on the substituting group is protected.Use the method for figure Table I, single alcohol (VII) that protected is reacted to form by (XXXIV) of orthogonally protect with new protecting group.This is a kind of strategy that those skilled in the art use always in traditional chemistry of peptides, referring to M.Bodansky, and Principles of Peptide Chemistry.If single alcohol (VII) that protected is with the CBZ protection, those skilled in the art can with its with (BOC)
2O reacts in methylene dichloride or similar organic solvent in methylene dichloride or similar organic solvent or with FOMC-C1, thereby preparation is by (XXXIV) of orthogonally protect.Then in alcoholic solvent (for example methane or ethyl acetate), the CBZ group is removed in hydrogenation under the condition of the palladium-carbon that has catalytic amount, or as is known to persons skilled in the art, in alcoholic solvent, use palladium catalyst-hydrocarbonize to remove the CBZ group under the condition of ammonium formiate existing.Make R thus
C-N is protected (XXXV).Similarly, if single alcohol (VII) that protected is protected with BOC, it can react with CBZ-OSu with the CBZ-C1 reaction or in THF under the Schotten-Bauman condition, thereby prepares anti-phase (XXXIV).Can be used in the hydrochloric acid (4N) in methyl alcohol, the ethanol Huo diox then or be used in the trifluoroacetic acid in the methylene dichloride or use as The Peptides, Analysis, Synthesis, Biology, volume 3, other method cracking BOC group described in the Ed.E.Gross and J.Meinenhofer (1981) is to discharge CBZ R
C-N is protected (XXXV).It will be apparent to those skilled in the art that the processing of this functional group can produce the multiple arrangement to (XXXV) by (VII) to (XXXIV).As R suitably
CThe acid amides that-N is protected compound (XXXV) and sour form forms agent (IX) under the standard peptide coupling condition during (for example, EDC/HOBt is in methylene dichloride or DMF or activatory acid in advance) reaction, (R
N-)
2O produces corresponding R
NThe R of-replacement
C-N is protected (XXXVI).R
NThe R of-replacement
CThe simple deprotection that-N is protected (XXXVI) generates required replacement amine (X).Thus, if R
NThe R of-replacement
C-N is protected (XXXVI) and is protected with BOC, and the hydrochloric acid (4N) that is used in diox or above-mentioned other reagent is handled, and obtains replacing amine (X).If R
NThe R of-replacement
C-N is protected (XXXVI) and is protected with CBZ, and the hydrogen with 10-50psi in alcoholic solvent (for example methane) is also handled with the palladium-carbon of catalytic amount, will obtain required replacement amine (X) after the aftertreatment.Similarly, if R
NThe R of-replacement
C-N is protected (XXXVI) with the FMOC protection, uses secondary amine, and preferred piperidines (10%) or diethylamine (10%) are handled in inert solvent (for example methylene dichloride), will obtain required replacement amine (X) after the aftertreatment.
Chart J discloses a kind of method for preparing following compound, in described compound, and the R of-CO-phenyl-CO-
NSubstituent benzyl ring is replaced by a sulfamyl in the 5-position.This method is a raw material with halogen acid amide ester (XXI, chart E), and this halogen acid amide ester is by J.Med.Chem., and 42,3797 (1999) middle disclosed method and Sodium Nitrite, sulfurous gas, cupric chloride (II) and acetic acidreactions are with preparation SULPHURYL CHLORIDE (XXXVII).This SULPHURYL CHLORIDE (XXXVII) prepares corresponding sulphonamide (XXXVIII) by method known to those skilled in the art and AMINE reaction as defined above then.At last, pass through method known to those skilled in the art, for example use lithium hydroxide, sodium hydroxide, potassium hydroxide, hydrated barta or other method for hydrolysis well known by persons skilled in the art, sulphonamide (XXXVIII) is changed into corresponding thionamic acid (XXXIX).
Chart K discloses how to prepare R
NSubstituting group, wherein R
NBe R
N-1-X
N-, X wherein
NBe-CO-and R
N-1Be R
The N-aryl, R wherein
The N-arylBy an alkyl and one-CO-NR
N-2R
N-3Or-CO-R
N-4The phenyl that replaces.Referring to above among the chart E about being used for making acid amides R
NSubstituent amine, H-NR
N αR
N β(AMINE) explanation.This method is a raw material with halogen acid amide ester (XXI), uses J.Med.Chem. then, and there is palladium catalyst in 4288 (2000) the middle general methods of describing, for example Pd (PPH
3) Cl
2Condition under, with this halogen acid amide ester and the alkylboronic acids reaction that contains required alkyl.This alkylboronic acids is maybe can pass through J.Am.Chem.Soc. by what commercial sources obtained, and 60,105 (1938) described methods are prepared.R
N-bBe preferably bromo.This step produces alkyl ester (XL), and it by the method known to those skilled in the art hydrolysis, generates required alkyl acid (XLI) then.
Chart L discloses a kind of method that acid amides forms agent (IX-XLVII), wherein R of preparing
NSubstituting group is R
N-1-X
N-, wherein connect base-X
N-be-CO-R wherein
N-1Be R
The N-aryl, and R wherein
The N-arylThe phenyl (phenyl) that is replaced by following groups:
Optional by one, two or three are selected from C
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group ,-NR
1-aR
1-b(R wherein
1-aAnd R
1-bDefinition as above) and-N (H and C
1-C
3Alkyl)-CO-R
N-5The C that replaces of substituting group
1-C
6Alkyl.This concrete acid amides forms agent, is that raw material is prepared with phenyl nitro-compound (XILII) (IX-XLVII), uses borine-methyl sulfide or the borine in THF that this raw material is reduced into corresponding phenyl nitro oxy-compound (XLIII).Using as is known to persons skilled in the art, hydrogen and palladium catalyst are reduced into corresponding phenyl amino oxy-compound (XLIV) with this phenyl nitro oxy-compound (XLIII).Under the condition that exists such as the reductive agent of cyano group sodium borohydride or triacetyl oxygen base sodium borohydride, with this phenyl amino oxy-compound (XLIV) and aldehyde reaction to make the hydroxy amino compound (XLV) that phenyl replaces.By method known to those skilled in the art, hydroxy amino compound (XLV) acidylate that this phenyl is replaced with chloride of acid or acid anhydrides is to make the disubstituted hydroxy amino compound of phenyl (XLVI).Use alkali-metal oxyhydroxide with the disubstituted hydroxy amino compound of phenyl (XLVI) hydrolysis, acidifying then obtains acid amides and forms agent (IX-XLVIIA).Use method known to those skilled in the art and previously described method (for example, using diethyl phosphorocyanidate) then, make this acid amides form agent (IX-XLVIIA) and amine (VIII) coupling, make replacement amine (X).Further handle with the cyano group phosphinic acid ethyl ester and to replace amine (X), the hydroxyalkyl substituting group that obtains on the benzyl ring wherein has the substituent replacement amine of phosphoric acid ester.
Chart M discloses a kind of method that acid amides forms agent (IX-L), wherein R of preparing
NSubstituting group is R
N-1-X
N-, wherein connect base-X
N-be-CO-R wherein
N-1Be R
The N-aryl, and R wherein
The N-arylBy the phenyl (phenyl) of two groups replacements.Being positioned at first substituting group of locating common mark work position " 5-" can be:
-R
The N-arylOr
-R
The N-heteroarylBeing positioned at second substituting group locating common mark work position " 3-" can be:
-CO-NR
N-2R
N-3Or
-CO-R
N-4。R
N αAnd R
N βAll comprise the non-annularity acid amides ,-CO-NR
N-2R
N-3And cyclic amide-CO-R
N-4, R wherein
N-2, R
N-3And R
N-4Define as claims.This method is raw material, wherein R with trisubstituted benzene based compound (XLVIII)
N-dBe-Cl ,-Br ,-I or-O-triflate.In inert solvent, existence contain or the condition of alkali free metal catalyst under, with aryl or heteroaryl boric acid or heteroaryl or aryl-boric acid ester, for example (aryl or heteroaryl)-B (OH)
2Or (aryl or heteroaryl)-B (OR
a) (OR
b) (R wherein
aAnd R
bBe low alkyl group, i.e. C
1-C
6, or R
aAnd R
bLumping together is low-grade alkylidene, i.e. C
2-C
12) handle, produce (XLIX).Metal catalyst in these conversion reactions includes, but not limited to salt or phosphine complex compound (for example, the Cu (OAc) of Cu, Pd or Ni
2, PdCl
2(pph
3)
2, NiCl
2(pph
3)
2).Alkali includes but not limited to, alkaline earth metal carbonate, alkali metal bicarbonates, alkaline earth metal hydroxides, alkaline carbonate, alkali metal hydrocarbonate, alkali metal hydroxide, alkalimetal hydride (being preferably sodium hydride), alkali metal alcoholates (being preferably sodium methylate or sodium ethylate), alkaline earth metal hydride, basic metal dialkyl amide (being preferably the diisopropylaminoethyl lithium), basic metal two (trialkylsilkl) acid amides (being preferably two (trimethyl silyl) sodium amide), trialkylamine (being preferably diisopropylethylamine or triethylamine) or aromatic amine (being preferably pyridine).Inert solvent can include but not limited to, acetonitrile, dialkyl ether (being preferably diethyl ether), cyclic ethers (are preferably tetrahydrofuran (THF) or 1, the 4-diox), N, N-dialkyl acetamides (being preferably N,N-DIMETHYLACETAMIDE), N, N-dialkylformamide (being preferably dimethyl formamide), dialkyl sulphoxide (being preferably methyl-sulphoxide), aromatic hydrocarbons (being preferably benzene or toluene) or alkyl halide (being preferably methylene dichloride).Preferred temperature of reaction is the boiling point of room temperature to solvent for use.These reactions can be carried out in traditional glassware or carry out in one of many parallel synthesizers of buying.The boric acid that can not buy and boric acid ester can be as Tetrahedron, and 50, described in the 979-988 (1994), make by the corresponding optional aryl halide that replaces.Use alkali metal hydroxide (for example lithium hydroxide, sodium hydroxide, potassium hydroxide) with intermediate (XLIX) hydrolysis then, acidifying then makes aryl or heteroaryl coupling acid (IX-L).Perhaps, as Tetrahedron, 50,978-988 (1994) is described, can be with R
N-dChange into corresponding boric acid or boric acid ester (OH)
2B-or (OR
a) (OR
b) B-, and by handling to make product same as described above with suitable aryl or heteroaryl halogen or triflate.
Chart N discloses a kind of method that acid amides forms agent (IX-LII), wherein R of preparing
NSubstituting group is R
N-1-X
N-, wherein connect base-X
N-be-CO-R wherein
N-1Be R
The N-aryl, and R wherein
The N-arylBy the phenyl (phenyl) of two groups replacements.Being positioned at first substituting group of locating common mark work position " 5-" is C ≡ C-R.Being positioned at second substituting group locating common mark work position " 3-" can be-CO-NR
N-2R
N-3Or-CO-R
N-4Use method known to those skilled in the art, use PdCl
2(P phenyl
3)
2Handle halogen ester (XXI) with trimethyl silyl acetylene, make ethynyl ester (LI).Use alkali metal hydroxide hydrolysis ethynyl ester (LI) then, acidifying then makes acetylene acid (IX-LII).
Chart O and O ' disclose an acid amides that contains the methylene radical of elongation and have formed agent (IX-LX) and preparation method (IX-LXIII), wherein R
NSubstituting group is R
N-1-X
N-, wherein connect base-X
N-be-CO-R wherein
N-1Be R
The N-aryl, and R wherein
The N-arylBy the phenyl (phenyl) of two groups replacements.Being positioned at the substituting group of locating common mark work position " 3-" can be-CO-NR
N-2R
N-3Or-CO-R
N-4In the method for chart O, the substituting group that is positioned at the 5-position is-CH
2CO-NH
2, in the method for chart O ', the substituting group that is positioned at the 5-position is-CH
2C ≡ N.In such as the THF equal solvent, reduce raw material diester acid (LIII) with borine, make corresponding diester alcohol (LIV).Use bromizating agent, for example PBr
3, CBr
4Or other halogenating agent for example well known by persons skilled in the art changes into corresponding diester bromo compound (LV) with this diester alcohol (LIV).Replace the bromine of this diester bromo compound (LV) then with prussiate, make corresponding nitrile (LVI).In figure O ', again this nitrile (LVI) is hydrolyzed into corresponding cyano group ester (LXI).Use method known to those skilled in the art then, with this cyano group ester (LXI) and foregoing H-NR
N αR
N β(AMINE) coupling makes corresponding cyano group acid amides (LXII).Then this cyano group acid amides (LXII) is hydrolyzed into corresponding cyano group acid (IX-LXIII),, makes and replace amine (X) again with itself and amine (VIII) coupling.If the substituting group on the methylene radical of elongation is-CO-NH
2, just use the method for chart O.At this moment, by method known to those skilled in the art nitrile (LVI) is changed into corresponding two esteramides (LVII).Identical among next step and the chart O ', wherein two esteramides (LVII) are hydrolyzed into corresponding ester amine (LVIII), then this ester amine is changed into corresponding diamide ester (LIX), again it is hydrolyzed into corresponding diamide acid (IX-LX).Then with this diamide acid (IX-XL) and suitable amine (VIII) coupling to make required substituted amide (X).
Chart P discloses the preparation method of the acid amides formation agent (IX-LXVII) of the hydroxyl methylene radical that contains an elongation, wherein R
NSubstituting group is R
N-1-X
N-, wherein connect base-X
N-be-CO-R wherein
N-1Be R
The N-aryl, R wherein
The N-arylBy the phenyl (phenyl) of two groups replacements.Being positioned at the substituting group of locating common mark work position " 3-" can be-CO-NR
N-2R
N-3Or-CO-R
N-4This method is with halogen acid amide (LXIV), and being preferably the iodo acid amides is raw material, passes through Synth.Commun.28, the method of describing in 4270 (1998), choose wantonly and carry out change well known by persons skilled in the art, this feedstock conversion is become corresponding aldehyde (LXV), change into corresponding alcohol (LXVI) then.Use the alkali metal hydroxide hydrolysis should alcohol (LXVI), acidifying then obtains required alcohol acid (IX-LXVII).With this alcohol acid (IX-LXVII) and suitable amine (VIII) coupling, make required replacement amine (X) then.
Chart Q discloses the preparation method that the acid amides that contains an alkyl or a halogen atom or an amino in the 5-position forms agent (IX-LXXII), wherein R
NSubstituting group is R
N-1-X
N-, wherein connect base-X
N-be-CO-R wherein
N-1Be R
The N-aryl, R wherein
The N-arylBy the phenyl (phenyl) of two groups replacements.Being positioned at the substituting group of locating common mark work position " 3-" can be-CO-NR
N-2R
N-3Or-CO-R
N-4This method is a raw material with the diacid (LXVIII) that suitable 5-replaces, and with its esterification, obtains corresponding diester (LXIX) by method known to those skilled in the art.Use alkali metal hydroxide with this diester (LXIX) hydrolysis then, acidifying then obtains corresponding monoprotic acid (LXX).Perhaps, can be by currently known methods directly by diacid (LXVIII) preparation monoprotic acid (LXX).Then with this monoprotic acid (LXX) and H-NR
N αR
N β(AMINE) coupling obtains corresponding amide ester (LXXI).Use this carboxylic acid amide esters of alkali metal hydroxide hydrolysis (LXXI) then, acidifying then makes corresponding amide (IX-LXXII).
Chart R discloses the universal method that a kind of preparation acid amides forms agent (IX-LXXVII), and this acid amides forms agent and is being called that there is an alkyl at place, 5-position and a ketone is arranged in the 3-position.These acid (IX-LXXVII) are that raw material forms with acid (LXXIII), use method known to those skilled in the art that this feedstock conversion is become corresponding acyl halide (LXXIV).This acyl halide (LXXIV) is preferably chloride of acid.Under the condition that has cupric bromide (I) and tetrahydrofuran (THF) and at-78 ℃ to 0 ℃, with Grignard reagent (aryl-Mg-X, or alkyl-Mg-X, wherein X be-Cl or-Br) handle this acyl halide (LXXIV), make ketone ester (LXXVI and LXXVI ').Many Grignard reagents can be buied; Can making of other by method known to those skilled in the art.Another kind of preparation ketone ester (LXXVI; LXXVI ') method is a preparation Weinreb acid amides (LXXV); perhaps directly prepare or use acyl halide (LXXIV) to use N subsequently by acid (LXXIII); O-dimethyl hydroxyl amine is handled to make Weinreb acid amides (LXXV); by method known to those skilled in the art, handle this Weinreb acid amides (LXXV) then with a kind of Grignard reagent.Use alkali metal hydroxide hydrolysis ketone ester (LXXVI, LXXVI ') then, acidifying then makes ketone acid (LXXVII, LXXVII ').
Chart S discloses the R that multiple change replaces amine (X)
NThe method of part, wherein R
NThe aryl rings of part is further replaced by various groups such as aryl and heteroaryl in the 3-position.Prepare these compounds by method known to those skilled in the art.The process chemistry of each reaction all is well known by persons skilled in the art.Novel part of the present invention is the order of each step and/or used concrete reagent.It is at least a by using the method for known this required product of feedstock production to understand one skilled in the art will recognize that of required product.Therefore, following discussion is optional, but is used for the people that further help intends to prepare The compounds of this invention.
Chart S has illustrated the universal method of a kind of preparation replacement amine (X) of the present invention's use, wherein R
N=R
The N-aryl-R
The N-aryl-X
NOr R
The N-heteroaryl-R
The N-aryl-X
NAccording to method mentioned above, with acid amides form agent (IX) handle (S, R)-amine (VIII), wherein for chart S, R
N-1Be Br-R
The N-aryl, generate thus accordingly (S, R)-replacement amine (X), wherein R
NBe Br-R
The N-aryl-X
NIn inert solvent, existence contain or the condition of alkali free metal catalyst under, with aryl boric acid or aryl-boric acid ester, (aryl or heteroaryl)-B (OH) for example
2Or (aryl or heteroaryl)-B (OR
a) (OR
b) (R wherein
aAnd R
bBe low alkyl group, i.e. C
1-C
6, or R
aAnd R
bLumping together is low-grade alkylidene, i.e. C
2-C
12) further handle, produce (S, R)-replacement amine (X), wherein R
NBe N
The R-aryl-N
The R-aryl-X
NOr R
The N-heteroaryl-R
The N-aryl-X
NMetal catalyst in these conversion reactions includes, but not limited to salt or phosphine complex compound (for example, the Cu (OAc) of Cu, Pd or Ni
2, PdCl
2(pph
3)
2, NiCl
2(pph
3)
2).Alkali includes but not limited to, alkaline earth metal carbonate, alkali metal bicarbonates, alkaline earth metal hydroxides, alkaline carbonate, alkali metal hydrocarbonate, alkali metal hydroxide, alkalimetal hydride (being preferably sodium hydride), alkali metal alcoholates (being preferably sodium methylate or sodium ethylate), alkaline earth metal hydride, basic metal dialkyl amide (being preferably the diisopropylaminoethyl lithium), basic metal two (trialkylsilkl) acid amides (being preferably two (trimethyl silyl) sodium amide), trialkylamine (being preferably diisopropylethylamine or triethylamine) or aromatic amine (being preferably pyridine).Inert solvent can include but not limited to, acetonitrile, dialkyl ether (being preferably diethyl ether), cyclic ethers (are preferably tetrahydrofuran (THF) or 1, the 4-diox), N, N-dialkyl acetamides (being preferably N,N-DIMETHYLACETAMIDE), N, N-dialkylformamide (being preferably dimethyl formamide), dialkyl sulphoxide (being preferably methyl-sulphoxide), aromatic hydrocarbons (being preferably benzene or toluene) or alkyl halide (being preferably methylene dichloride).Preferred temperature of reaction is the boiling point of room temperature to solvent for use.These reactions can be carried out in traditional glassware or carry out in one of many parallel synthesizers of buying.The boric acid that can not buy and boric acid ester can be as Tetrahedron, and 50, described in the 979-988 (1994), make by the corresponding optional aryl halide that replaces.
When top chemical process with (S, R)-replace amine (X) (R wherein
NBe Br-R
The N-aryl-X
N) other functional group when incompatible, those skilled in the art are readily appreciated that needs another serial coupling step.For example, handle the acid amides that suitably replaces with boric acid or boric acid ester under these conditions and form agent (IX) R
N-1-X
N-OH, wherein R
N-1Be Br-R
The N-aryl, the acid amides that can suitably be replaced forms agent (IX), wherein R
N-1Be N
The R-aryl-N
The R-arylOr R
The N-heteroaryl-R
The N-arylWhen use (S, R)-amine (VIII) handles this acid amides and form agent (IX) (R wherein
N-1Be N
The R-aryl-N
The R-arylOr R
The N-heteroaryl-R
The N-aryl) time, can obtain listed identical replacement amine (X) with chart S.
The example of above-mentioned chart S is not intended to limit the scope of its chemical process.Except bromine, suitable group can also comprise iodine or triflate.Perhaps, as Tetrahedron, 50, described in the 979-988 (1994), by handling with suitable aryl or heteroaryl halogen or triflate, can be with Br-R
The N-arylChange into corresponding boric acid or boric acid ester (OH)
2B-R
The N-arylOr (OR
a) (OR
b) B-R
The N-aryl, and obtain product same as described above.In addition, in above-mentioned chemical process, each-R
The N-arylAnd R
The N-heteroarylCan exchange in each case.
Chart T discloses a kind of method that acid amides forms agent (IX-LXXIX), wherein R of preparing
NSubstituting group is R
N-1-X
N-, wherein connect base-X
NBe-CO-, wherein R
N-1Be R
The N-aryl, and R wherein
The N-arylBy-CO-NR
N αR
N β(AMINE) and chemical formula be-(CH
2)
0-4-N (H and R
N-5)-CO-R
N-2,-(CH
2)
0-4-N (H and R
N-5)-SO
2-R
N-2The phenyl that replaces of acid amides.
This method is a raw material with acid amides aniline (XXXI), itself and corresponding acyl halide or sulfonic acid halide or acid anhydrides or sulphonyl anhydride reactant, preparation corresponding amide ester (LXXVIII).Suitable solvent is included in-78 ℃ to 100 ℃ THF or methylene dichloride.By method known to those skilled in the art this carboxylic acid amide esters (LXXVIII) is hydrolyzed into corresponding amide acid (IX-LXXIX) then.When acid amides forms agent (IX-LXXIX) with suitable amine (VIII) reaction, obtain required compound (X).
Chart U discloses the universal method of a kind of multiple C-terminal amine of preparation (VI), is called the preparation of C-terminal amine (LXXXIV).Use method known to those skilled in the art, can understand the method for this class amine of preparation well, perhaps can reference: 1) JACS, 1970,92,3700 and 2) United States Patent (USP) 4,351,842.
The figure Table V further discloses the universal method of the multiple C-terminal amine of preparation (VI), is called the preparation of C-terminal amine (LXXXIX).Can obtain many cases heterocyclic carboxylic acid or chloride of acid by commercial sources.Randomly, can use reagent that this carboxylic acid (LXXXV) is changed into chloride of acid (LXXXVI) such as but not limited to thionyl chloride.Replace with ammonia, generate common midbody acid amide (LXXXVII), the several different methods of using preamble to describe in detail can easily become these reduction of amide amine (VI-LXXXIX).Perhaps, other heteroaryl obtains by commercial sources with the form of methyl halide (LXXXVIII), and it is used ammonia treatment, makes the C-terminal amine (VI-LXXXVIII) of title.
Chart W discloses the universal method for preparing the C-terminal amine that contains thiazolyl, is called the preparation of C-terminal amine (LXXXXI).Chart W has summarized the synthetic of thiazole; These programs have detailed description in the literature and are by Mashraqui, SH; Keehn, PM.J.Am.Chem.Soc.1982,104, generalized method is revised and is got among the 4461-4465.By 5-hydroxymethylthiazole (XC) by Alterman etc., J.Med.Chem.1998,41, the program described in the 3782-3792 realizes replacing the synthetic of 5-amino methyl thiazole (XCI).Other thiazole analogue changes into hydroxymethyl derivative with all to use chart W, and changes into the aminomethyl derivative by the Alterman program of not doing obviously to change.
The figure Table X discloses the universal method for preparing the C-terminal amine that contains isoxazolyl, is called the preparation of C-terminal amine (XCII).To Felman, SW etc., J.Med.Chem.1992,35, the program among the 1183-1190 is made amendment, the synthesizing isoxazole derivative, those skilled in the art can understand this synthetic at an easy rate, and need not to carry out any tangible change and just can obtain title compound.Use Bousquet, EW.Org.Synth.Coll. rolls up II, the synthetic substituted hydroxy amine parent of the program that 313-315 discloses.Can use propargyl amine that several different methods known in the art protection can buy (referring to Greene, TW; Wuts, PGM.Protective Groups inOrganic Synthesis, the third edition, New York:John Wiley, 1999. chapter 7) BOC protecting group preferably.Replacing propargyl amine can make by many methods of this area notice.
Chart Y discloses the general approach of preparation oxyethylamine, wherein carbon atom in the peptide main chain and R
2And R
3Form a ring together.Be appreciated that the present invention can also incorporate heteroatoms into this ring.In a word, R wherein
2And R
3The compound that can form ring can be synthesized by amino acid aldehyde that is suitably protected and cycloalkyl lithium class material, and these two kinds of materials all are to be known in the art by commercial sources currently known methods that obtain or that wherein make these compounds.Relevant universal program also is the existing precedent in the document, for example referring to Klumpp etc., and J.Am.Chem.Soc., 1979,101,7065, and be intended that and need not to carry out material alterations, just can obtain the title compound that chart Y provides.Suitably the processing of protected amino acid aldehyde and cycloalkyl lithium class material obtains alcohol (XCIII).These are reflected at inert solvent, for example carry out in tetrahydrofuran (THF) or the diethyl ether.The reaction optimum carries out at low temperatures, for example is lower than 0 ℃.The carbonylation that is undertaken by the Klumpp program produces acid (XCIV), with Ku Ertisi or when well known to a person skilled in the art that dependent program is handled this acid, produces primary amine (XCV).By chart C﹠amp; The listed condition of D is carried out the C-terminal end-blocking with this primary amine (XCV), then nitrogen deprotection and carry out the C-terminal end-blocking by the listed condition of graph A.
Compound of the present invention can contain how much or optically active isomer and tautomer.Therefore, the present invention includes all tautomers and pure geometrical isomer, for example E and Z geometrical isomer and their mixture.In addition, the present invention includes pure enantiomorph and diastereomer and their mixture, comprise racemic mixture.Each geometrical isomer, enantiomorph or diastereomer can or separate by the methods known in the art preparation.
Having the specified stereochemical The compounds of this invention of chemical formula X can be included in the mixture with other enantiomorph, diastereomer, geometrical isomer or tautomer, comprises racemic mixture.Have the content of the specified stereochemical The compounds of this invention of chemical formula X in these mixtures and surpass 50% usually.Preferably, have the content of the specified stereochemical The compounds of this invention of chemical formula X in these mixtures and surpass 80%.Most preferably, have the content of the specified stereochemical The compounds of this invention of chemical formula X in these mixtures and surpass 90%.
Compound of the present invention is amine normally, forms salt during therefore with acid-respons.The salt that can be used for pharmacy than (S, R)-replace amine (X) and R
NPreferred by the replacement amine of cyclisation (X ') because their generate water-soluble better, the more stable and/or better compound of crystallinity.The salt that can be used for pharmacy is anyly to have kept the active of parent compound and can not produce any harmful or dysgenic salt to subject and applying environment thereof.The salt that can be used for pharmacy comprises inorganic and organic acid salt.The salt that preferably can be used for pharmacy comprises the salt of following acid: acetate, aspartic acid, Phenylsulfonic acid, phenylformic acid, heavy carbonic, heavy sulfuric acid, liquor epinephrinae bitartratis ophthalmicus, butyric acid, Ca-EDTA, camsylic, carbonic acid, chloro-benzoic acid, citric acid, ethylenediamine tetraacetic acid (EDTA), edisylic, estolic, esyl, esylic, formic acid, fumaric acid, gluceptic, glyconic acid, L-glutamic acid, the glycolyl arsanilic acid, the hexanoyl amino acid, hexylresorcinoic, hydrabamic, Hydrogen bromide, spirit of salt, hydroiodic acid HI, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, toxilic acid, oxysuccinic acid, propanedioic acid, amygdalic acid, methylsulfonic acid, methyl nitric acid, methyl sulfuric acid, glactaric acid, muconic acid, naphthene sulfonic acid, nitric acid, oxalic acid, to the nitro methylsulfonic acid, pamoic, pantothenic acid, phosphoric acid, one hydrogen phosphoric acid, dihydrogen phosphoric acid, phthalic acid, polygalacturonic acid, propionic acid, Whitfield's ointment, stearic acid, succsinic acid, succsinic acid, thionamic acid, Sulphanilic Acid, sulfonic acid, sulfuric acid, Weibull, tartrate, teoclic and toluenesulphonic acids.Other available salt is referring to Int.J.Pharm., and 33,201-217 (1986) and J.Pharm.Sci., 66 (1), 1, (1977).
The invention provides and suppress compound, composition, medicine box and the method that beta-secretase is active and A β peptide forms.Active inhibition is ended or has reduced by APP to generate A β to beta-secretase, and has reduced or eliminated the sedimentary formation of amyloid beta in the brain.
Method of the present invention
It is the human and animal of the disease of feature that compound of the present invention and the salt that can be used for pharmacy thereof can be used for treating the pathomorphism of suffering from beta amyloid peptide (for example amyloid-beta spot), and can be used for helping to prevent or delay the outbreak of this class disease.Compound of the present invention and composition are particularly useful for treatment or prevention Alzheimer's disease.Compound of the present invention can use separately or be used in combination, and this depends on which kind of situation is the most favourable to the patient.
Term used herein " treatment " is meant that compound of the present invention can be used for having the people of at least a medical diagnosis on disease qualitatively temporarily.Compound of the present invention can postpone or slow down the deterioration of disease, thereby gives individual more effective the natural duration of life.
Term " prevention " is meant also not to be diagnosed as may suffer from this disease but when being considered to suffer from this disease usually or suffering from the patient that the risk of this disease raise, compound of the present invention is effective when being used to use.Compound of the present invention can slow down disease symptoms development, postpone the outbreak of disease or fundamentally prevent individuality to suffer from this disease.Prevention also comprises those owing to age, family's medical history, gene or chromosome abnormalty and/or owing to there is the biological marker of one or more these diseases, the transgenation in cerebral tissue or brain liquid of for example famous APP or APP split product, and the individuality that is considered to easily to suffer from this disease uses compound of the present invention.
When treating or preventing above-mentioned disease, use compound of the present invention with dose therapeutically effective.Dose therapeutically effective is along with used particular compound and route of administration is different and different, and this is that those skilled in the art are known.
In addition, compound of the present invention also can use with P-glycoprotein (P-gp) inhibitor.The use of P-gp inhibitor is well known by persons skilled in the art.Referring to for example Cancer Research, 53,4595-4602 (1993), Clin.Cancer Res., 2,7-12 (1996), Cancer Research, 56,4171-4179 (1996), international open text WO99/64001 and WO01/10387.Importantly the blood content of P-gp inhibitor should make it bring into play restraining effect to P-gp by the brain blood content that reduces compound of the present invention.Realize this purpose, P-gp inhibitor and compound of the present invention can be used simultaneously or at different time by identical or different route of administration.Important is not administration time but have effective blood content of P-gp inhibitor.
The P-gp inhibitor that is suitable for comprises Ciclosporin A, Verapamilum, triphen oxygen peace, Quinidine, vitamin-E-TGPS, ritonavir, megestrol acetate, progesterone, rapamycin, 10,11-methylene radical dibenzocycloheptane, thiodiphenylamine, acridine derivatives (for example GF120918, FK506, VX-710, LY335979, PSC-833, GF-102,918 and other steroid).It will be appreciated that, can also find function identical and be considered to useful additive.
The P-gp inhibitor can be oral, parenterai administration, (IV, IM, IM-depo, SQ and SQ-depo), topical, sublingual administration, per rectum administration, intranasal administration, intrathecal drug delivery and pass through drug delivery implant.
The dose therapeutically effective of P-gp inhibitor is about 0.1 to about 300mg/kg/ day, is preferably about 0.1 to about 150mg/kg/ day.It will be appreciated that though a patient may begin with a dosage, this dosage need change every now and then along with this patient's change of illness state.
If oral, the form of medication of P-gp inhibitor can be to well known to a person skilled in the art oral administration form commonly used.These form of medication comprise solid unit dose forms commonly used, as tablet and capsule, also comprise the liquid form of medication, for example solution, suspension and elixir.If use the solid form of medication, they are preferably slow release type so that only need use P-gp inhibitor once or twice every day.Use one to four time oral administration form to the patient every day.Divide three times preferred every day or still less time use the P-gp inhibitor, once a day or twice more preferably.Therefore the P-gp inhibitor preferably uses with the solid form of medication, and more preferably this solid form of medication is to allow to be administered once in one day or twice slow release type.Preferably no matter use which kind of form of medication, it all should be designed to protect the P-gp inhibitor to avoid the erosion of stomach inner acidic environment.The tablet that scribbles the enteric solubility medicine is well known to a person skilled in the art.In addition, the capsule (each bead all has anti-hydrochloric acid in gastric juice coating) of filling bead also well known to a person skilled in the art.
In addition, the P-gp inhibitor can be at the enteron aisle external administration.If parenterai administration, they can pass through IV, IM, depo-IM, SQ or depo SQ administration.
The P-gp inhibitor can sublingual administration.If sublingual administration, the P-gp inhibitor should be with the amount every day administration identical with the IM dosage one to four time.
The P-gp inhibitor can intranasal administration.If adopt this route of administration, suitable form of medication is nasal spray well known by persons skilled in the art or dry powder.The intranasal administration dosage of P-gp inhibitor is identical with the IM dosage.
The P-gp inhibitor can intrathecal drug delivery.If adopt this route of administration, suitable form of medication is a parenterai administration form well known by persons skilled in the art.
The P-gp inhibitor can topical.If adopt this route of administration, suitable form of medication is emulsifiable paste, ointment or adhesive plaster.Because the amount of the P-gp inhibitor that need use, adhesive plaster is preferred.Yet, limited by the amount that adhesive plaster is used, therefore perhaps need two or more adhesive plasters.The quantity of adhesive plaster and size are unimportant, importantly as is known to the person skilled in the art, use the P-gp inhibitor of dose therapeutically effective.
The P-gp inhibitor can be as is known to persons skilled in the art like that by the administration of suppository per rectum.
The P-gp inhibitor can pass through drug delivery implant as is known to persons skilled in the art like that.
On the route of administration of P-gp inhibitor and form of medication, all there is not any fresh content.Given a kind of concrete P-gp inhibitor and required form of medication, those skilled in the art will know how to prepare the form of medication that is fit to this P-gp inhibitor.
It is evident that to those skilled in the art, the accurate dosage of administration and frequency depend on that the severity of the disease specific of used concrete The compounds of this invention, treatment, the disease for the treatment of, concrete patient's age, body weight, general physical condition and individual may treat by ongoing other medicines, and this is well known to a person skilled in the art.
Formulation and dosage
Compound of the present invention can be oral, (suction) administration in the parenterai administration, (IV, IM, depo-IM, SQ and depo SQ), sublingual administration, nose, intrathecal drug delivery, topical or per rectum administration.Form of medication well known by persons skilled in the art is applicable to using of The compounds of this invention.
The invention provides the composition of the The compounds of this invention that contains dose therapeutically effective.These compounds preferably are mixed with suitable medicinal preparations, tablet for example for oral use, capsule or elixir, or be used for the sterile solution or the suspension of parenterai administration.Usually technique known and program are mixed with pharmacy composite with above-claimed cpd in this field of use.
With so-called a kind of unit dosage form in the pharmacy practice of generally acknowledging, with the mixture of about 1 to 500mg a kind of compound of the present invention or compound or on acceptable salt or ester on the physiology and a kind of physiology acceptable vehicle, carrier, vehicle, tackiness agent, sanitas, stablizer, seasonings etc. allocate together.The amount of the active substance in composition or preparation should make it can obtain suitable dosage in stated limit.Said composition is preferably prepared with a unit dosage form, and every dose contains about 2 to about 100mg, more preferably about activeconstituents of 10 to about 30mg.Term " unit dosage form " is meant and is suitable as physical division the unit human and unitary dose that other animal is used, contain the active material of the predetermined amount that the required result of treatment of promising generation calculates in the per unit, also contain suitable pharmaceutical purpose vehicle.
In order to prepare composition, one or more compounds of the present invention are mixed with a kind of suitable carrier that can be used for pharmacy.When mixing or add compound, the mixture that makes can be solution, suspension, milk sap or analogue.Lipid suspension also is suitable as the carrier that can be used for pharmacy.These can be prepared according to method known to those skilled in the art.The form that makes mixture depends on many factors, comprises predetermined administering mode and the solubleness of this compound in selected carrier or vehicle.Effective concentration is enough to alleviate or improve at least a symptom of disease, imbalance or the indication of being treated, and can rule of thumb measure.
For using of compound provided herein, suitable pharmacy carrier or vehicle comprise any carrier that is applicable to concrete administering mode well known by persons skilled in the art.In addition, these active materials also can mix with other active material that can not weaken required effectiveness or with the material mixing that can strengthen required effectiveness or have another effect, these compounds can be used as pharmacy activeconstituents unique in the composition and prepare, and also can mix with other activeconstituents.
When the solubleness of compound is not enough, can use the method for solubilization.These methods are known, include but not limited to, use solubility promoter, for example methyl-sulphoxide (DMSO); Use tensio-active agent, for example Tween_; And in sodium bicarbonate aqueous solution, dissolve.The derivative of these compounds, for example salt or prodrug also can be used for preparing effective pharmacy composite.
This compound concentrations is enough to transmit certain dosage, this amount can alleviate or improve this compound at least a symptom of disease.Usually, preparation is used for the composition of single agent administration.
Compound of the present invention can with the carrier of avoiding them to discharge rapidly in the body, for example slowly-releasing formulation or dressing, preparation together.Such carrier comprises long-acting formulation, such as but not limited to, microencapsulation drug delivery system.Contain a certain amount of active compound in can be used for the carrier of pharmacy, this amount should be enough to produce effective result of treatment and can not produce unacceptable side effect to patient.By at the external of treatment disease and body internal schema system these compounds of build-in test, can determine effectively to treat concentration by rule of thumb.
Compound of the present invention and composition can be encapsulated in compound or the single medicine container.The compound or the composition of encapsulation can provide with kit form, for example, comprise the integral part that can be used in combination.For example, can provide a kind of compound inhibitor and a kind of suitable thinner of freeze-drying form, they are as independently component mixing before using mutually.Medicine box can comprise a kind of compound inhibitor and common second therapeutical agent that uses.This inhibitor and second therapeutical agent can be used as mutually independently, and integral part exists.Medicine box can comprise a plurality of containers, contains the The compounds of this invention of one or more unitary doses in each container.Container preferably is applicable to required administering mode, includes but not limited to be used for oral tablet, capsule, slow releasing capsule and analogue; The long-acting product, prefilled syringe, ampoule, phial and the analogue that are used for parenterai administration; And the adhesive plaster, medipad, emulsifiable paste and the analogue that are used for topical.
Activity compound concentration in composite medicine depends on absorption, deactivation and discharge rate, dosage regimen, dosage and other factor well known by persons skilled in the art of this active compound.
Activeconstituents can once use, and also can be divided into the certain hour gradation use at interval of many smaller doses.Accurate dose and treatment time length and the disease for the treatment of have substantial connection, and they can use known test procedure, or according in vivo or external test data infer, definite by rule of thumb thus.It is to be noted that concentration and dose value also can change along with the severity of the disease that will alleviate.Also to further be understood that; for any concrete object; should be according to individual need and use or supervise the people's that said composition uses professional judgement; adjust concrete dosage every now and then; here the concentration range of listing just illustrates, and is not scope or practice for the composition of requirement for restriction protection.
Oral if desired, this compound should be present in a kind of can the protection in its sour environment erosive composition of avoiding stomach.For example, said composition can be formulated in a kind of enteric coatings, with keep its under one's belt integrity and in intestines, discharge active compound.Said composition also can be prepared with a kind of antacid or other specific examples of such components.
Oral compositions generally includes inert diluent or edible carrier, and can be pressed into tablet or be encapsulated in the capsule.In order to carry out oral administration, one or more active compounds can with mixed with excipients, and use with tablet, capsule or lozenge form.Can comprise tackiness agent compatible in the pharmacy and batching a part as said composition.
The compound that tablet, pill, capsule, lozenge and analogue can contain following any composition or have similar quality: tackiness agent, such as but not limited to, tragacanth gum, Sudan Gum-arabic, W-Gum or gelatin; Vehicle, for example Microcrystalline Cellulose, starch or lactose; Disintegrating agent, such as but not limited to, alginic acid and W-Gum; Lubricant, such as but not limited to, Magnesium Stearate; Gildant, such as but not limited to, colloidal silica; Sweeting agent, for example sucrose or asccharin; And seasonings, for example peppermint, wintergreen oil or fruit flavour.
If unit dosage form is a capsule, except the material of the above-mentioned type, it can also contain a kind of liquid vehicle, for example fatty oil.In addition, unit dosage form can contain various other materials, and they have changed the physical aspect of this dose unit, for example sugar-coat and other enteric solubility reagent.These compounds can also carry out administration as the component of elixir, suspension, syrup, wafer, chewing gum and analogue.Except active compound, syrup can also contain as the sucrose of sweeting agent and some sanitas, dyes and dyestuffs and seasonings.
Active substance can not weaken the active substance of required effectiveness with other yet or mix with the material that can strengthen required effectiveness.
Be used for non-enteron aisle, intracutaneous, solution or suspension subcutaneous or topical and can contain following any component: a kind of sterile diluent, for example water of injection, salts solution, fixed oil, a kind of vegetables oil (for example sesame oil, Oleum Cocois, peanut oil, Oleum Gossypii semen and analogue) or a kind of synthetic fat vehicle (for example ethyl oleate and analogue), polyoxyethylene glycol, glycerine, propylene glycol or other synthetic that forms naturally; Antiseptic-germicide, for example benzylalcohol and para methyl paraben; Antioxidant, for example xitix and sodium bisulfite; Sequestrant, for example ethylenediamine tetraacetic acid (EDTA) (EDTA); Buffer reagent, for example acetate, Citrate trianion and phosphoric acid salt; With adjustment tensile reagent, for example sodium-chlor and dextrose.Parenteral formulation can be encapsulated in ampoule, disposable syringe or the multi-agent phial that is made by glass, plastics or other suitable material.Buffer reagent, sanitas, antioxidant and analogue can add according to need.
During intravenously administrable, suitable carrier comprises physiological saline, phosphate buffered saline (PBS) (PBS) and contains thickening material and the solution of solubilizing agent (for example glucose, polyoxyethylene glycol, polypropylene glycol and their mixture).The lipid suspension that contains at the liposome of organizing also is suitable as the carrier that can be used for pharmacy.These can be prepared in accordance with known methods, and for example United States Patent (USP) 4,522, the method described in 811.
Active compound can with the carrier of avoiding this compound to discharge in the body rapidly, for example slowly-releasing formulation or dressing, preparation together.Such carrier comprises long-acting formulation, such as but not limited to, implant and microencapsulation drug delivery system and biodegradable, biocompatible polymkeric substance, for example osso-albumin, ethylene vinyl acetate, polyanhydride, polyglycolic acid, poe, poly(lactic acid) and analogue.The method for preparing these formulation is well known by persons skilled in the art.
Compound of the present invention can be oral, (suction) administration in the parenterai administration (IV, IM, depo-IM, SQ and depo-SQ), sublingual administration, nose, intrathecal drug delivery, topical or per rectum administration.Form of medication well known by persons skilled in the art is applicable to using of The compounds of this invention.
Compound of the present invention can interior administration of intestines or parenterai administration.If oral, the form of medication of The compounds of this invention can be to well known to a person skilled in the art oral administration form commonly used.These form of medication comprise solid unit dose forms commonly used, as tablet and capsule, also comprise the liquid form of medication, for example solution, suspension and elixir.If use the solid form of medication, they are preferably slow release type so that only need use compound of the present invention once or twice every day.
Use 1,2,3 or 4 time oral administration form to the patient every day.Divide three times preferred every day or still less time use compound of the present invention, once a day or twice more preferably.Therefore compound of the present invention preferably uses with the oral administration form.Preferably no matter use which kind of oral administration form, the sour environment that it all is designed to protect compound of the present invention to avoid in the stomach corrodes.The tablet that scribbles the enteric solubility medicine is well known to a person skilled in the art.In addition, the capsule of filling bead (each bead all has anti-hydrochloric acid in gastric juice dressing) also well known to a person skilled in the art.
If oral, the dosage that in treatment, effectively suppress the beta-secretase activity, suppresses A β and form, suppress A β deposition or treatment or prevention AD be about 0.1mg/ days to about 1,000mg/ days.Preferred oral dosage is about 1mg/ days to approximately 100mg/ days.Preferred oral dosage is about 5mg/ days to approximately 50mg/ days.It will be appreciated that though a patient may begin with a dosage, dosage can change every now and then along with this patient's change of illness state.
Compound of the present invention also can advantageously disperse to be used in the formulation at a kind of nanocrystal.For example at United States Patent (USP) 5,145, the preparation of this formulation has been described in 684.At United States Patent (USP) 6,045, the nanocrystal dispersion and the using method thereof of hiv protease inhibitor described in 829.The nanocrystal formulation makes pharmaceutical compounds have higher bioavailability usually.
Compound of the present invention can parenterai administration, for example by IV, IM, depo-IM, SC and depo-SC.If parenterai administration, the dose therapeutically effective that should use is about 0.5 to about 100mg/ day, more preferably about 5 to about 50mg/ days.If used long-acting formulation every month or every fortnight injection once, dosage should be approximately 0.5mg/ days to approximately 50mg/ days, or month dosage is about 15mg to about 1,500mg.Part is owing to the Alzheimer's disease patient's is forgetful, and preferred parenterai administration form is long-acting formulation.
Compound of the present invention can sublingual administration.If sublingual administration, compound of the present invention should be according to above-mentioned IM dosage administration every day one to four time.
Compound of the present invention can intranasal administration.If by this administration, as is known to the person skilled in the art, nasal spray that suitable form of medication is or dry powder.The intranasal administration dosage of compound of the present invention is above-mentioned IM dosage.
Compound of the present invention can also intrathecal drug delivery.If by this administration, suitable administering mode is a parentemal form of medication as is known to the person skilled in the art.The intrathecal drug delivery dosage of compound of the present invention is above-mentioned IM dosage.
Compound of the present invention can also topical.If by this administration, suitable form of medication is emulsifiable paste, ointment or adhesive plaster.Because the dosage of compound of the present invention, adhesive plaster is preferred.If topical, dosage are about 0.5mg/ days to approximately 200mg/ days.Since limited by the amount that adhesive plaster is used, two or more adhesive plasters can be used.The quantity of adhesive plaster and size are unimportant, importantly as is known to the person skilled in the art, use the compound of the present invention of dose therapeutically effective.Compound of the present invention can be as is known to persons skilled in the art like that by the administration of suppository per rectum.If by the suppository administration, dose therapeutically effective is that about 0.5mg is to about 500mg.
Compound of the present invention can also pass through drug delivery implant as is known to persons skilled in the art like that.If use compound of the present invention by implantation, dose therapeutically effective is the amount of above-mentioned long-acting administration.
The present invention is novel cpd of the present invention and the novel method of using The compounds of this invention.Given a kind of concrete The compounds of this invention and required form of medication, those skilled in the art will know how to prepare and use this suitable form of medication.
With with identical mode mentioned above, by identical route of administration, use identical therapeutic dosage forms and identical administration arrangement, use compound of the present invention, with preventing disease or treatment MCI (mild cognitive damage) patient and prevent or delay Alzheimer's disease to understand on the person that develop into AD by MCI at those and show effect; The treatment mongolism; Treatment is with the hereditary cerebral hemorrhage patient of Dutch type amyloidosis; The change of treatment study on cerebral amyloid angiopathy also prevents its latent consequences, i.e. single and recurrent cerebral lobar hemorrhage; Treat other degenerative dementia disease, comprise the dementia that has the blood vessel and the degenerative cause of disease concurrently, the dementia relevant with Parkinson's disease, with stein-leventhal syndrome relevant dementia, with cortex degenerate substantially relevant dementia, follow Parkinsonian volume temporal lobe type dementia (FTDP) and diffusion thunder to tie up the small body type Alzheimer's disease.
The compound of the present invention use of can interosculating also can or prevent the therapeutical agent of above-listed symptom or method to be used in combination with other treatment.Such reagent and method comprise: acetylcholinesterase depressant, for example: bright (trade mark is Exelon_) of tacrine (tetrahydroaminoacridine, trade mark are COGNEX_), E 2020 (trade mark is Aricept_) and Li Fansi; Inhibitors of gamma-secretase; Antiphlogistic, for example cyclo-oxygenase II inhibitor; Antioxidant, for example vitamin-E and bilobalide; Immunization method for example obtains immunity with A β peptide, or uses anti-A β peptide antibody; Si Dading; And directly or indirectly neuralward agent, for example Cerebrolysin_, AIT-082 (Emilieu, 2000, Arch.Neurol.57:454) and other neuralward agent in the future.
It is evident that to those skilled in the art, the accurate dosage of administration and frequency depend on that the severity of the disease specific of used concrete The compounds of this invention, treatment, the disease for the treatment of, concrete patient's age, body weight, general physical condition and individual may ongoing other medicines treatments, and this is that to be familiar with the administration doctor of this area known.
The APP cracking suppresses
Compound of the present invention has suppressed be numbered Met595 and Asp596 between the cracking of APP at APP695 homotype or its mutant, or goes up cracking in the corresponding site (being called " beta-secretase site " sometimes) of a different homotype (for example APP751 or APP770) or its mutant.Suppress active with a kind of confirmation in the multiple inhibition assay method, when having the inhibition compound, be enough under beta-secretase cracking position generation cracked condition, to analyze the APP substrate usually thus in the cracking that exists under the condition of beta-secretase.APP in the cracking of beta-secretase cracking position than unprocessed or reduce when not having active contrast, this minimizing with suppress active relevant.Can be used to prove that the mensuration system of The compounds of this invention inhibitor effectiveness is known.Representational mensuration system is for example being described in United States Patent (USP) 5,942, No. 400,5,744, No. 346 and the following examples to some extent.
Can use natural, sudden change and/or synthetic APP substrate, natural, sudden change and/or synthetic enzyme and test compound are external or analyze the enzymic activity of beta-secretase and the generation of A β in vivo.This analysis may comprise expresses natural, sudden change and/or the primary cell of synthetic APP substrate and enzyme and the animal model of passage cell, expression natural A PP and enzyme, maybe can use the transgenic animal model of expressing this substrate and enzyme.Can for example carry out enzyme assay by analysis to one or more split products by immunoassay, fluorometric assay or chromogenic assay, HPLC or other assay method.It is to compare with contrast that the inhibition compound is confirmed as, and can reduce the compound of the amount of beta-secretase split product, in contrast, observes and detect the cracking of beta-secretase mediation in the reaction system under not having the condition that suppresses compound.
Beta-secretase
The various forms of beta-secretase is known, and can obtain, and can be used for enzymic activity and enzymic activity inhibition mensuration.These comprise enzyme natural, the reorganization and synthesized form.Human beta-secretase is known as β position APP lyase (BACE), Asp2 and memapsin2, its feature is described in following document to some extent: for example, United States Patent (USP) 5,744, No. 346 and PCT patent application WO98/22597, WO00/03819, WO01/23533 and the WO00/17369 and the document publication (Hussain etc. that have announced, 1999, Mol.Cell.Neurosci.14:419-427; Vassar etc., 1999, Science 286:735-741; Yah etc., 1999, Nature 402:533-537; Sinha etc., 1999, Nature 40:537-540; With Lin etc., 2000, PNAS USA 97:1456-1460).The synthesized form of enzyme has also been described (WO98/22597 and WO00/17369) to some extent.Beta-secretase can extract and purifying from the human brain tissue, and can generate in cell, for example the newborn zooblast of muttering of express recombinant enzyme.
Effectively suppress compound and be lower than 50 micromoles in concentration, be preferably 10 micromoles or lower, 1 micromole or lower more preferably most preferably is 10 nanometer moles or when lower, can effectively suppresses 50% beta-secretase activity.
The APP substrate
The APP cracked assay method of confirmation inhibition beta-secretase mediation can adopt the APP of any form known, be included in people such as Kang, 1987, the homotype (isotype) of 695 amino acids " normally " described in the Nature 325:733-6, Kitaguchi etc., 1981, the homotype of 770 amino acids described in the Nature 331:530-532, and varient, for example swedish mutant body (KM670-1NL) (APP-SW), London mutant (V7176F), and other.Referring to, for example, United States Patent (USP) 5,766, No. 846 and Hardy, 1992, Nature Genet.1:233-234 is to the summary of known variation mutant.Other effective substrate comprises the dibasic aminoacid variant, as disclosed APP-KK, APP segment among the WO00/17369, contain the synthetic peptide of beta-secretase cracking position, as United States Patent (USP) 5,942, No. 400 and the described wild-type of WO00/03819 (WT) or sudden change form, for example SW.
The APP substrate contains the beta-secretase cracking position of APP (KM-DA or NL-DA), for example complete APP peptide or varient, APP segment, reorganization or synthetic APP or fusogenic peptide.Preferably, this fusogenic peptide comprises the beta-secretase cracking position that is fused on the peptide, and this peptide contains the part that can be used for enzymatic determination, for example, has segregation and/or detects characteristic.Useful part can be epitope, mark or other test section, the bound substrates that is used for antibodies, and analogue.
Antibody
Can use as Pirttila etc., 1999,5,612, No. 486 described various antibody of Neuro.Lett.249:21-4 and United States Patent (USP) are measured the feature of APP cracked product by immunoassay.The antibody that can be used for detecting A β comprises, for example, the monoclonal antibody 6E10 of the epitope on the 1-16 amino acids of specific recognition A β peptide (Senetek, St.Louis, MO); Respectively to people A β 1-40 and 1-42 have specific antibody 162 and 164 (New York State Institute for Basic Research, Staten Island, NY); With as United States Patent (USP) 5,593, No. 846 are described, the antibody of connecting area (position between 16 and 17 residues just) of identification beta-amyloyd peptide.As United States Patent (USP) 5,604, No. 102 and 5,721, No. 130 described, at the antibody of the synthetic peptide of 591 to 596 residues of APP with also can be used for the immunoassay of APP and split product thereof at the SW192 antibody of the 590-596 position of swedish mutant body.
The mensuration system
Measuring the cracked method of APP in beta-secretase cracking position is being known in the art.For example, United States Patent (USP) 5,744 No. 346 and 5,942, has been described exemplary assay method among No. 400 and the following embodiment.
Cell-less measurement
In for example WO00/17369, WO00/03819 and United States Patent (USP) 5,942, No. 400 and 5,744, No. 346, the active exemplary assay method of inhibition that can be used to prove compound of the present invention has been described.Can use cell of expressing beta-secretase and the cell that contains the APP substrate of beta-secretase cracking position, carry out these mensuration at acellular culture or in cell culture.
Have beta-secretase, its segment or have a beta-secretase active and be enough under the condition of polypeptide variants of synthetic or reorganization of beta-secretase cracking position of cracking APP, be suitable under the active culture condition of enzymatic lysis, cultivation contains the APP substrate of the beta-secretase cracking position of APP, for example, complete APP or varient, APP segment or contain aminoacid sequence: the recombinant chou of KM-DA or NL-DA or synthetic APP substrate.Suitable substrate is optional to comprise it can being the derivative that condenses protein or peptide, and wherein peptide contains peptide substrate and a kind ofly helps making things convenient for the purifying of this peptide or its beta-secretase split product or the modification of detection.Useful modification comprises inserts the known epitope that is used for antibodies; The connection of mark or other test section, the connection of bound substrates and analogue.
External cell-less measurement suitable culture condition is comprised, for example: the enzyme of the micromolar substrate of about 200 nanometer moles to 10, about 10 to 200 pmols, the micromolar inhibitor compound of about 0.1 nanometer mole to 10, in the aqueous solution, the pH value is approximately 4-7, about 37 ℃, the time is about 10 minutes to 3 hours.These culture condition only are to show illustratively, can change according to the requirement of concrete mensuration component and/or required mensuration system.For concrete mensuration component, the optimization of culture condition should be considered used specific beta-secretase and suitable pH value thereof, any other the enzyme and/or marker that may use in mensuration, and analogue.Such optimization is conventional, need not undue experimentation.
A kind of effective assay method has adopted a kind of fusogenic peptide, and maltose binding protein in this fusogenic peptide (MBP) is fused on the C-terminal of 125 amino acids of APP-SW.This MBP part is caught by anti-MBP capture antibodies on the mensuration substrate.Condense protein existing under the condition of beta-secretase to cultivate to catch, cause the cracking on beta-secretase cracking position of this substrate thus.Of course, for example, by the immunoassay analytical pyrolysis activity of split product.Antibody SW192 is for example used in such immunoassay, detects to be exposed to unique epitope that cracked condenses proteinic C-terminal.This assay method is described in No. 5,942,400, United States Patent (USP) for example to some extent.
Raji cell assay Raji
Can use many raji cell assay Rajis to analyze the activity of beta-secretase and/or APP changes and discharges the process of A β.Existing or not existing under the condition of compound inhibitor of the present invention, the APP substrate is contacted in cell with beta-secretase, this method can be used for proving the beta-secretase enzyme inhibition activity of this compound.Preferably, compare, exist mensuration when effectively suppressing compound to provide about at least 30%, most preferably be about at least 50% enzymic activity and suppress with the contrast that does not possess inhibition.
In a specific embodiments, use the cell of natural expression beta-secretase.Perhaps, with beta-secretase or the synthetic variant enzyme of cell modification for the above-mentioned reorganization of expression.The APP substrate can add in the substratum, and preferably expresses in cell.Can use the cell of natural expression APP, APP varient or mutant, or be transformed into the proteinic cell that condenses of expressing APP homotype, APP mutant or varient, reorganization or synthetic APP, APP segment or synthetic APP peptide or containing beta-secretase APP cracking position, prerequisite is that the APP that gives expression to can contact with enzyme, and can the enzyme analysis lytic activity.
A kind of active means of inhibition of effective mensuration The compounds of this invention are provided by the human cell system of APP generation A β usually.Can by immunoassay for example (for example Western blot or with enzyme-linked immunoassay (EIA), for example pass through ELISA), measure A β and/or formation and the release of other split product in substratum.
Can be at the cell that has culture expression APP substrate and active beta-secretase under the condition of compound inhibitor, with the enzymic activity restraint that proves that it is compared with contrast.By analyzing one or more split products of APP substrate, can measure the activity of beta-secretase.For example, suppress the activity of beta-secretase, be considered to reduce the release of specific beta-secretase inductive APP split product (for example A β) substrate A PP.
Although neural and non-neurocyte is all handled and discharged A β, the active level of endogenous beta-secretase is very low, and usually is difficult to detect by EIA.Therefore, the preferred use is considered to the variation that strengthens the beta-secretase activity, strengthens APP to A β and/or strengthens the cell type that A β generates.For example, use the swedish mutant body (APP-SW) of APP; APP-KK; Or the APP-SW-KK transfectional cell, consequent cell has enhanced beta-secretase activity, and the amount of the A β of its generation can be easily measured.
In such mensuration, for example, be suitable for beta-secretase under the condition of the enzymic activity of the cracking position of APP substrate, the cell of culture expression APP and beta-secretase in substratum.In this cells contacting when the compound inhibitor, be discharged in the substratum A β amount and/or in cell pyrolysis liquid the segmental amount of the CTF99 of APP reduced compared with the control.Can pass through, for example, use the immune response of specific antibody as mentioned above, analyze the split product of APP.
The cell that preferably is used for the beta-secretase activation analysis comprises that nascent human neural cells, transgenosis are nascent transgenic animal neurocyte and other cells of APP, for example expresses 293 cell strains of stablizing of APP (for example APP-SW).
Measure in the body: animal model
Can use various animal models, analyze the activity of beta-secretase and/or APP as mentioned above and change and discharge the process of A β.For example, can use the transgenic animal of expressing APP substrate and beta-secretase to prove the inhibition activity of The compounds of this invention.For example at United States Patent (USP) 5,877,399,5,612,486,5,387,742,5,720,936,5,850,003,5,877,015 and 5,811,633 and Ganes etc., 1995, some transgenic animal model has been described among the Nature 373:523.Preferably show animal with the pathologic, physiologic correlated characteristic of AD.Compound inhibitor of the present invention is used for transgenosis mouse as herein described, provides a kind of this compound of proof to suppress active alternative method thus.Preferably in pharmacy, use these compounds in the effective carrier and by a kind of route of administration with suitable therapeutic dose arrival destination organization.(preferably award simultaneously the described compound in the medicine effective carrier and the medicine of appropriate therapeutic amount and arrive destination organization by route of administration.)
By measuring the cracking segment in animal body fluid (for example brain liquid) or the tissue, can in these animals, analyze APP that beta-secretase mediates in the cracking of beta-secretase cracking position with to the inhibition of the release of A β.Preferred A β deposition or the A β spot of analyzing in the cerebral tissue.
Under the situation that has inhibition compound of the present invention, and in the APP cracking that is enough to carry out the enzyme mediation and/or from substrate, discharge under the condition of A β, the APP substrate is contacted with beta-secretase, and the APP that compound of the present invention can effectively reduce beta-secretase mediation is in the cracking of beta-secretase cracking position and/or effectively reduce the burst size of A β.If this contact is that aforesaid animal model is used inhibition compound of the present invention, then this compound effectively reduces the A β deposition in the animal brain, and effectively reduces the quantity and/or the size of amyloid beta spot.If subject is the people, then this compound effectively suppresses or slows down the deterioration that increases the disease that is feature with the quantity of A β, effectively slow down AD and worsen on one's body the patient, and/or prevention AD shows effect on one's body or develops the patient that may suffer from this disease.
Unless otherwise indicated, the implication of all Science and Technology terms used herein and those skilled in the art in the invention's common sense is identical.All patents of reference and publication are all incorporated herein by reference fully among the application.
Definition
" alkyl " and " C among the present invention
1-C
6Alkyl " be meant the straight or branched alkyl that contains 1-6 carbon atom; for example, methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, amyl group, 2-amyl group, isopentyl, neo-pentyl, hexyl, 2-hexyl, 3-hexyl and 3-methyl amyl.(when for example, alkyl, alkoxyl group and alkenyl) alkyl chain was shorter than or is longer than 6 carbon, it can show in second " C ", for example " C when substituting group
1-C
10" expression has 10 carbon atoms at most.
" alkoxyl group " and " C among the present invention
1-C
6Alkoxyl group " be meant contain 1-6 carbon atom, by at least one bivalent oxygen atom banded straight or branched alkyl, for example methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy, sec-butoxy, tert.-butoxy, pentyloxy, isopentyloxy, neopentyl oxygen, hexyloxy and 3-methyl pentyloxy.
Term among the present invention " halogen " is meant fluorine, bromine, chlorine and iodine.
" alkenyl " and " C
2-C
6Alkenyl " be meant the straight or branched alkyl that contains the two keys of 2 to 6 carbon atoms and to three, comprise, for example vinyl, propenyl, 1-fourth-3-thiazolinyl, 1-penta-3-thiazolinyl, 1-oneself-the 5-thiazolinyl, and analogue.
" alkynyl " and " C
2-C
6Alkynyl " be meant and contain 2 to 6 carbon atoms and one or two triple-linked straight or branched alkyl, comprise ethynyl, proyl, butynyl, pentyne-2-base, and analogue.
Term used herein " cycloalkyl " is meant the saturated carbon cyclic group that contains three to 12 carbon atoms.Cycloalkyl can be that monocycle or many rings condense system.The example of this free radical comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl.The cycloalkyl here is unsubstituted or as described belowly to be replaced by multiple group in one or more commutable positions.For example, this class cycloalkyl can be chosen wantonly by C
1-C
6Alkyl, C
1-C
6Alkoxyl group, halogen, hydroxyl, cyano group, nitro, amino, list (C
1-C
6) alkylamino, two (C
1-C
6) alkylamino, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
1-C
6Alkylhalide group, C
1-C
6Halogen alkoxyl group, amino (C
1-C
6) alkyl, list (C
1-C
6) alkylamino (C
1-C
6) alkyl or two (C
1-C
6) alkylamino (C
1-C
6) the alkyl replacement.
" aryl " is meant optional coverlet, two or the trisubstituted aromatic carbocyclic group that contains monocycle (for example phenyl), many rings (for example biphenyl) or many fused rings, and at least one ring is aromatic ring (for example 1,2,3,4-tetralin base, a naphthyl) in many fused rings.Preferred aryl groups of the present invention is phenyl, 1-naphthyl, 2-naphthyl, 2,3-indanyl, indenyl, dihydro naphthyl, 1,2,3,4-tetralin base or 6,7,8,9-tetrahydrochysene-5H-benzo [a] cycloheptenyl.The aryl here is unsubstituted or as described belowly to be replaced by multiple group in one or more commutable positions.For example, this class aryl can be chosen wantonly by following group and replace, for example C
1-C
6Alkyl, C
1-C
6Alkoxyl group, halogen, hydroxyl, cyano group, nitro, amino, list (C
1-C
6) alkylamino, two (C
1-C
6) alkylamino, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
1-C
6Alkylhalide group, C
1-C
6Halogen alkoxyl group, amino (C
1-C
6) alkyl, list (C
1-C
6) alkylamino (C
1-C
6) alkyl, two (C
1-C
6) alkylamino (C
1-C
6) alkyl ,-COOH ,-C (=O) O (C
1-C
6Alkyl) ,-C (=O) NH
2,-C (=O) N is (single-or two-C
1-C
6Alkyl) ,-S (C
1-C
6Alkyl) ,-SO
2(C
1-C
6Alkyl) ,-O-C (=O) (C
1-C
6Alkyl) ,-NH-C (=O)-(C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl)-C (=O)-(C
1-C
6Alkyl) ,-NH-SO
2-(C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl)-SO
2-(C
1-C
6Alkyl) ,-NH-C (=O) NH
2,-NH-C (=O) N is (single-or two-C
1-C
6Alkyl) ,-NH (C
1-C
6Alkyl)-C (=O)-NH
2Or-NH (C
1-C
6Alkyl)-C (=O)-N-(single-or two-C
1-C
6Alkyl).
" heteroaryl " is meant one or more aromatic ring systems of 5,6 or 7 yuan of rings, and it comprises the condensed ring system of 9-11 atom, and this condensed ring system contains at least one and reaches four heteroatomss that are selected from nitrogen, oxygen or sulphur.The preferred heteroaryl of the present invention comprises pyridyl, pyrimidyl, quinolyl, benzothienyl, indyl, indolinyl, pyridazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolyl, quinoxalinyl, 2, the 3-phthalazinyl, imidazolyl isoxazolyl, pyrazolyl oxazolyl, thiazolyl, the indolizine base, indazolyl, benzothiazolyl, benzimidazolyl-, benzofuryl, furyl, thienyl, pyrryl oxadiazole base, thiadiazolyl group, triazolyl, tetrazyl oxazole and pyridyl, imidazopyridyl, isothiazolyl, 1, the 5-phthalazinyl, the cinnolines base, carbazyl, the β-Ka Lin base, the isochroman base, chromanyl, tetrahydro isoquinolyl, isoindolinyl, different benzo tetrahydrofuran base, different benzo tetrahydro-thienyl, isobenzo-thienyl benzoxazolyl, the pyridopyridine base, the benzo tetrahydrofuran base, the benzo tetrahydro-thienyl, purine radicals, the benzo dioxolyl, triazinyl phenoxazinyl, phenothiazinyl, pteridyl, benzothiazolyl, imidazopyridyl, the Imidazothiazole base, dihydrobenzo Yi oxazinyl, Ben Bing Yi oxazinyl benzoxazinyl, dihydrobenzo isothiazine base, benzopyranyl, the benzo thiapyran base, the tonka bean camphor base, isocoumarinyl, the chromone base, the chromanone base, pyridyl-N-oxide compound, tetrahydroquinoline, dihydroquinoline, the dihydroquinoline ketone group, the dihydro-isoquinoline ketone group, the melilotine base, the dihydro isocoumarinyl, the isoindoline ketone group, benzodioxan base benzoxazolinone base, pyrryl N-oxide compound, pyrimidyl N-oxide compound, pyridazinyl N-oxide compound, pyrazinyl N-oxide compound, quinolyl N-oxide compound, indyl N-oxide compound, indolinyl N-oxide compound, isoquinolyl N-oxide compound, quinazolyl N-oxide compound, quinoxalinyl N-oxide compound, 2,3-phthalazinyl N-oxide compound, imidazolyl N-oxide compound isoxazolyl N-oxide compound oxazolyl N-oxide compound, thiazolyl N-oxide compound, indolizine base N-oxide compound, indazolyl N-oxide compound, benzothiazolyl N-oxide compound, benzimidazolyl-N-oxide compound, pyrryl N-oxide compound oxadiazole base N-oxide compound, thiadiazolyl group N-oxide compound, triazolyl N-oxide compound, tetrazyl N-oxide compound, benzo thiapyran base S-oxide compound, benzo thiapyran S, the S-dioxide.The heteroaryl here is unsubstituted or as described belowly to be replaced by multiple group in one or more commutable positions.For example, this class heteroaryl can be chosen wantonly by following groups and replace: C
1-C
6Alkyl, C
1-C
6Alkoxyl group, halogen, hydroxyl, cyano group, nitro, amino, list (C
1-C
6) alkylamino, two (C
1-C
6) alkylamino, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
1-C
6Alkylhalide group, C
1-C
6Halogen alkoxyl group, amino (C
1-C
6) alkyl, list (C
1-C
6) alkylamino (C
1-C
6) alkyl or two (C
1-C
6) alkylamino (C
1-C
6) alkyl ,-COOH ,-C (=O) O (C
1-C
6Alkyl) ,-C (=O) NH
2,-C (=O) N is (single-or two-C
1-C
6Alkyl) ,-S (C
1-C
6Alkyl) ,-SO
2(C
1-C
6Alkyl) ,-O-C (=O) (C
1-C
6Alkyl) ,-NH-C (=O)-(C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl)-C (=O)-(C
1-C
6Alkyl) ,-NH-SO
2-(C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl)-SO
2-(C
1-C
6Alkyl) ,-NH-C (=O) NH
2,-NH-C (=O) N is (single-or two-C
1-C
6Alkyl) ,-NH (C
1-C
6Alkyl)-C (=O)-NH
2Or-NH (C
1-C
6Alkyl)-C (=O)-N-(single-or two-C
1-C
6Alkyl).
" heterocycle ", " Heterocyclylalkyl " or " heterocyclic radical " are meant one or more carbocyclic ring systems of 4-, 5-, 6-or 7-unit ring, it comprises the condensed ring system of 9-11 atom, and this condensed ring system contains at least one and reaches four heteroatomss that are selected from nitrogen, oxygen or sulphur.The preferred heterocycle of the present invention comprises morpholinyl, thio-morpholinyl, thio-morpholinyl S-oxide compound, thio-morpholinyl S, the S-dioxide, piperazinyl, high piperazinyl, pyrrolidyl, pyrrolinyl, THP trtrahydropyranyl, piperidyl, tetrahydrofuran base, tetrahydro-thienyl, homopiperidinyl, high morpholinyl, high-sulfur is for morpholinyl, high-sulfur is for morpholinyl S, S-dioxide; oxazole ketone group, the pyrazoline base, the pyrrolin base, the dihydro pyrazinyl, the dihydropyridine base, the dihydro-pyrimidin base, the dihydrofuran base, dihydro pyranyl, tetramethylene sulfide S-oxide compound, tetramethylene sulfide S, S-dioxide and high-sulfur are for morpholinyl S-oxide compound.Heterocycle can be fused on the aromatic ring.Example comprises tetrahydroisoquinoline and indoline.The heterocyclic group here is unsubstituted or as described belowly to be replaced by multiple group in one or more commutable positions.For example, this class heterocyclic group can be chosen wantonly by following groups and replace: C
1-C
6Alkyl, C
1-C
6Alkoxyl group, halogen, hydroxyl, cyano group, nitro, amino, list (C
1-C
6) alkylamino, two (C
1-C
6) alkylamino, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
1-C
6Alkylhalide group, C
1-C
6Halogen alkoxyl group, amino (C
1-C
6) alkyl, list (C
1-C
6) alkylamino (C
1-C
6) alkyl, two (C
1-C
6) alkylamino (C
1-C
6) alkyl or=O.
All temperature all be degree centigrade (℃).
TLC is meant tlc.
Psi is meant pound/square inch.
HPLC is meant high pressure lipuid chromatography (HPLC).
THF is meant tetrahydrofuran (THF).
DMF is meant dimethyl formamide.
EDC is meant ethyl-1-(3-dimethylamino-propyl) carbon imide or 1-(3-dimethylamino-propyl)-3-ethyl carbon imide hydrochloride.
HOBt is meant the I-hydroxybenzotriazole hydrate.
NMM is meant N-methylmorpholine.
NBS is meant N-bromosuccinimide.
TEA is meant triethylamine.
BOC is meant 1,1-dimethyl ethoxy carbonyl or tert-butoxycarbonyl ,-CO-O-C (CH
3)
3
CBZ is meant benzyloxycarbonyl ,-CO-O-CH
2-phenyl.
FMOC is meant carbonic acid 9-fluorenyl methyl esters.
TFA is meant trifluoroacetic acid.
CDI is meant 1,1 '-carbonyl dimidazoles.
Salt solution is meant the saturated aqueous solution of sodium-chlor.
Chromatography (column chromatography and flash chromatography) is meant the purification/separate with the compound of (carrier, elutriant) expression.It will be appreciated that, suitable cut is compiled concentrated, make one or more required compounds.
CMR is meant the C-13 nuclear magnetic resonance spectroscopy, is the chemical transformation of unit from the report of TMS downfield with ppm (δ).
NMR is meant nuclear (proton) nuclear magnetic resonance spectroscopy, is the chemical transformation of unit from the report of TMS downfield with ppm (δ).
IR is meant infrared spectra.
MS is meant the mass spectroscopy that is expressed as m/e, m/z or mass unit.MH
+Be meant that parent adds the positively charged ion that a hydrogen atom constitutes.EI is meant electron bombardment.CI is meant chemi-ionization.FAB is meant fast atom bombardment(FAB).
HRMS is meant the high resolution mass spec method.
Ether is meant diethyl ether.
" can be used for pharmacy " and be meant, see from pharmacy/toxicity angle and can be accepted and see character and/or the material that to be accepted by the pharmaceutical chemistry man by patient from the physical/chemical angle about composition, preparation, stability, patient's acceptability and bioavailability.
If use solvent pairs, the ratio of solvent for use are volume/volume (v/v).
If use the solubleness of solid in solvent, then solid is weight/volume (wt/v) with the ratio of solvent.
BOP is meant benzotriazole-1-base oxygen base-three (dimethylamino) phosphofluoric acid phosphine.
TBDMSCl is meant chlorination tertiary butyl dimethylsilane.
TBDMSOTf is meant tertiary butyl dimethylsilane trifluoro sulphonate.
Trisomy21 is meant mongolism.
Following term (at embodiment 321 and above) is used for acid amides and forms agent (IX):
" PHTH " is meant (CH
3-CH
2-CH
2-)
2N-CO-phenyl-CO-OH, wherein with-being connected of phenyl-ring is 1,3-;
" 5-Me-PHTH " is meant (CH
3-CH
2-CH
2-)
2N-CO-(CH
3-) phenyl-CO-OH, wherein-and phenyl-ring is 1, and 3-connects carbonyl, connects methyl at 5-;
" 3, the 5-pyridyl " are meant (CH
3-CH
2-CH
2-)
2N-CO-(pyridyl)-CO-OH, wherein-pyridyl-ring is 3, and 5-connects carbonyl;
" SO
2" be meant (CH
3-CH
2-CH
2-)
2CH-SO
2-phenyl-CO-OH, wherein with-being connected of phenyl-ring is 1,3-;
" 5-OMe-PHTH " is meant (CH
3-CH
2-CH
2-)
2N-CO-(CH
3-O-) phenyl-CO-OH, wherein-phenyl-ring is 1, and 3-connects carbonyl, connects methoxyl group at 5-;
" 5-Cl-PHTH " is meant (CH
3-CH
2-CH
2-)
2N-CO-(Cl-) phenyl-CO-OH, wherein-phenyl-ring is 1, and 3-connects carbonyl, connects the chlorine atom at 5-;
" 5-F-PHTH " is meant (CH
3-CH
2-CH
2-)
2N-CO-(F-) phenyl-CO-OH, wherein-phenyl-ring is 1, and 3-connects carbonyl, connects fluorine atom at 5-;
" thienyl " is meant (CH
3-CH
2-CH
2-)
2N-CO-thienyl-CO-OH is-2,5 with being connected of thiphene ring wherein;
" 2, the 4-pyridyl " are meant (CH
3-CH
2-CH
2-)
2N-CO-(pyridyl)-CO-OH, wherein-pyridyl-ring is 2, and 4-connects carbonyl;
" 4, the 6-pyrimidyl " are meant (CH
3-CH
2-CH
2-)
2N-CO-(pyrimidyl) phenyl-CO-OH, wherein-pyrimidyl-ring is 4, and 6-connects carbonyl;
" morpholinyl " is meant morpholinyl-CO-phenyl-CO-OH, wherein-phenyl-ring is 1, and 3-connects carbonyl.
APP, amyloid precursor protein are defined as any APP polypeptide, comprise APP varient, mutant and body of the same race (isoform), and be for example as United States Patent (USP) 5,766, disclosed in 846.
A β, amyloid beta are defined as any peptide that is produced by the APP cracking that with the beta-secretase is media, comprise 39,40,41,42 and 43 amino acid whose peptides, and extend to 39,40,41,42 or 43 amino acid from beta-secretase cracking position.
Beta-secretase (BACE1, Asp2, Memapsin2) is the aspartyl protease of a kind of N-terminal at A β as APP cracking media.Human beta-secretase has for example been described in WO00/17369.
" can be used for pharmacy " and be meant, see from pharmacy/toxicity angle and can be accepted and see character and/or the material that to be accepted by the pharmaceutical chemistry man by patient from the physical/chemical angle about composition, preparation, stability, patient's acceptability and bioavailability.
Dose therapeutically effective is meant and can effectively reduces or alleviate by at least a symptom of treatment disease or effectively reduce or delay one or more clinical manifestations of this disease or the amount of paresthesia epilepsy.
The invention provides and suppress compound, composition and the method that beta-secretase is active and A β peptide produces.Active inhibition is ended or has reduced by APP to generate A β to beta-secretase, and has reduced or eliminated the sedimentary formation of amyloid beta in the brain.
Embodiment
The following example has been described and how to be prepared all cpds of the present invention and/or implement the whole bag of tricks of the present invention, and it is explanation as an example only, rather than to aforementioned disclosed restriction.Those skilled in the art can be by the rapid suitable change of confirming about reactant and reaction conditions and technological method of these programs.
Goods 1 3-amino-5-(methoxycarbonyl) phenylformic acid (XVII)
Under nitrogen atmosphere (50psi), the shake 3 hours in hydrogenation apparatus of the suspension in methyl alcohol (100 milliliters) with 5-nitro-m-phthalic acid mono-methyl (22.5 gram, 100 mmoles) and palladium-carbon (5%, 2.00 restrains).Then mixture is also concentrated by diatomite filtration, make title compound, NMR (300MHz, CDCl
3) δ 7.67,7.41,7.40 and 3.83; C
9H
9NO
4MS (ESI-) m/z (M-H)
-=194.
Goods 2 3-bromo-5-(methoxycarbonyl) phenylformic acid (XIX)
Place the round-bottomed flask of the water-bath that is added with several thick ice to stir cupric bromide (II) (1.85 grams at one, 8.30 n-Butyronitrile (1.07 grams mmole),, 10.4 mmole) and the mixture of acetonitrile (30 milliliters), with 15 fens clock times, add 3-amino-5-(methoxycarbonyl) phenylformic acid (XVII, goods 1,1.35 gram, 6.92 the slurry in warm acetonitrile (70 milliliters) mmole), with this mixture 20-25 ℃ of restir 2 hours, the phase-splitting between methylene dichloride and hydrochloric acid (3N) of mixture this moment.Separate organic phase, and through dried over sodium sulfate and be concentrated into dried.The chromatographic separation of suitable cut (silica gel, 125 milliliters; Ethanol/methylene, 15/85) and concentrate a kind of solid of generation, it is crystallization in methyl alcohol, obtains two batches of title compounds, NMR (DMSO-d
6) δ 3.90,8.26 and 8.65.
Goods 3 3-bromo-5-[(dipropyl amino) carbonyl] methyl benzoate (XXI)
Carbonyl dimidazoles (3.0 grams, 18 mmoles) is added in THF (30 milliliters) solution of 3-bromo-5-(methoxycarbonyl) phenylformic acid (XIX, goods 2,3.9 grams, 15 mmoles).Mixture was stirred 0.5 hour.In mixture, add dipropyl amine (AMINE, 4.2 milliliters, 30 mmoles), stirred then 24 hours.Solvent is removed in decompression then, and makes mixture phase-splitting between ethyl acetate and water.Clean organic phase with salt solution then, through anhydrous magnesium sulfate drying, filtration and concentrated.Column chromatography is separated (silica gel; Ethyl acetate/hexane, 15/85) obtains title compound, IR (diffuse-reflectance) 2968,2958,1714,1637,1479,1440,1422,1321,1310,1288,1273,1252,889,772 and 718cm
-1NMR (300MHz, CDCl
3) δ 8.21,7.96,7.70,3.95,3.46,3.15,1.69,1.57,1.00 and 0.78; C
15H
20BrNO
3MS (ESI+) m/z (M+H)
+=344.1.
Goods 4 3-bromo-5-[(dipropyl amino) carbonyl] phenylformic acid
At 3-bromo-5-[(dipropyl amino) carbonyl] add lithium hydroxide monohydrate (0.17 gram, 4.05 mmoles) in THF/ water/methyl alcohol (4/2/2,8 milliliter) solution of methyl benzoate (XXI, goods 3,1.4 gram, 4.1 mmoles).This mixture was stirred 1 hour at 20 ℃-25 ℃, and solvent is removed in decompression then.With resistates water-soluble (50 milliliters), and add hydrochloric acid (1N) adjusting pH value to about 3.With this mixture aqueous solution of ethyl acetate extraction, separate organic phase and, make title compound through dried over mgso.C
14H
18BrNO
3The analytical calculation value: C, 51.23; H, 5,53; N, 4.27; Br, 24.35.Measured value: C, 51.37; H, 5.56; N, 4.28.
Goods 5 3-(aminocarboxyl)-5-[(dipropyl amino) carbonyl] methyl benzoate (XXII)
Under carbon monoxide atmosphere, at 3-bromo-5-[(dipropyl amino) carbonyl] methyl benzoate (XXI, goods 3,0.5 gram, 1.47 mmoles) in the mixture in anhydrous N-Methyl pyrrolidone, add acid chloride (II) (0.017 gram, 0.074 mmole), 1,3-two (diphenylphosphino) propane (0.045 gram, 0.11 mmole), hexamethyldisilazane are (1.0 milliliters, 4.7 mmole) and diisopropylethylamine (0.38 gram, 2.94 mmoles).This mixture was heated 24 hours at 100 ℃.Mixture is cooled to 20-25 ℃, and phase-splitting between water and ethyl acetate.Separate each layer, with ethyl acetate back scrubbing water.Merge organic phase, and clean three times,, filter and concentrate through anhydrous magnesium sulfate drying with salt solution.Column chromatography is separated (silica gel, 75 milliliters; Ethanol/methylene 2.5/97.5) makes title compound, NMR (CDCl
3) δ 0.77,1.02,1.57,1.71,3.17,3.49,3.98,5.78,6.34,8.07,8.20 and 8.48.
Goods 6 3-(aminocarboxyl)-5-[(dipropyl amino) carbonyl] phenylformic acid (XXIII)
At 3-(aminocarboxyl)-5-[(dipropyl amino) carbonyl] add sodium hydroxide (1N, 3.0 milliliters) in the mixture of methyl benzoate (XXII, goods 5,0.197 gram, 0.64 mmole) in methyl alcohol (5.0 milliliters).This mixture was stirred 24 hours at 20-25 ℃.With hydrochloric acid (10%) this mixture is acidified to about pH5.Add entry (50 milliliters) and use ethyl acetate (2 * 50 milliliters) to clean twice.Merge organic extract liquid,, make title compound, NMR (DMSO-d through anhydrous magnesium sulfate drying and concentrated
6) δ 0.66,0.930,1.48,1.62,3.12,3.35,7.54,7.98,8.22 and 8.51.
Goods 7 3-cyano group-5-[(dipropyl amino) carbonyl] phenylformic acid (IX/XXXII)
With 3-bromo-5-[(dipropyl amino) carbonyl] phenylformic acid (goods 4,0.596 gram, 1.82 mmole) and nitrilation copper (0.325 the gram, 3.63 mmole) mixture in N-Methyl pyrrolidone (1.5 milliliters) stirred 2.5 hours at 175 ℃, this moment is with mixture cooling and phase-splitting between ethyl acetate and hydrochloric acid (3N).Organic layer is cleaned twice again with hydrochloric acid (3N), use then and cleaned again twice by small amount of hydrochloric acid (3N) acidifying salt solution.Through the dried over mgso organic layer, and under high vacuum, concentrate, make title compound, NMR (CDCl
3) δ 0.80,1.02,1.60,1.73,3.17,3.51,7.90,8.31 and 8.41; Crystallization goes out aliquots containig-IR (diffuse-reflectance) 3017,2970,2937,2898,2877,2473,2432,2350,2318,2236,1721,1608,1588,1206 and 1196cm from ether/dichloromethane/hexane
-1
Goods 8 3-(aminocarboxyl)-5-[(dipropyl amino) carbonyl] phenylformic acid (XXXIII)
With 3-cyano group-5-[(dipropyl amino) carbonyl] phenylformic acid (IX/XXXII, goods 7,0.602 gram, 2.19 mmoles), salt of wormwood (0.212 gram, 1.53 mmoles) and acetone (2.5 milliliters) is 20-25 ℃ of stirring.Add entry (2.5 milliliters) and urea-hydrogen peroxide adduct (0.825 gram, 8.78 mmoles), and mixture was stirred 15 hours at 20-25 ℃, add other urea-hydrogen peroxide adduct (0.204 gram) this moment; Behind the restir 3 hours, add 0.205 gram urea-hydrogen peroxide adduct again.After amounting to past 39 hours, acetone is removed in decompression, and with hydrochloric acid (3N) resistates is acidified to pH=2-4.With this mixture of dichloromethane extraction, separate organic layer and, use the anhydrous magnesium sulfate drying organic phase with hydrochloric acid (0.5N) cleaning, obtain solid.The crystallization in dichloromethane/hexane/methyl alcohol of this solid obtains title compound, C
15H
20N
2O
4MS (ESI+) m/z (M+H)
+=293.2.
Goods 9 3-[(dipropyl amino) carbonyl]-5-nitrobenzoic acid methyl esters (XXX)
In the mixture of 5-nitro m-phthalic acid mono-methyl (XXVIII, 4.50 grams, 20.0 mmoles) in anhydrous THF (50 milliliters), add carbonyl dimidazoles (3.90 grams, 24.0 mmoles).Mixture was stirred 0.5 hour.In mixture, slowly add dipropyl amine (3.28 milliliters, 24.0 mmoles).Then reaction mixture was stirred 4 hours.Solvent is removed in decompression then, and makes mixture phase-splitting between ethyl acetate and water.Separate organic phase and clean, through anhydrous magnesium sulfate drying, filtration and concentrate with salt solution.Column chromatography is separated (silica gel; Ethyl acetate/hexane, 15/85) obtains title compound, NMR (300MHz, CDCl
3) δ 8.88,8.41,8.35,4.00,3.48,3.15,1.72,1.57,1.00 and 0.77; C
15H
20N
2O
5MS (ESI+) m/z (M+H)
+=309.2.
Goods 10 3-amino-5-[(dipropyl amino) carbonyl] methyl benzoate (XXXI)
Under nitrogen atmosphere (45psi), with 3-[(dipropyl amino) carbonyl]-5-nitrobenzoic acid methyl esters (XXX, goods 9,6.00 gram, 20.0 mmoles) and the suspension of palladium-carbon (5%, 0.600 restrains) in methyl alcohol (40 milliliters) shake 3 hours in hydrogenation apparatus.Then mixture is also concentrated by diatomite filtration, make title compound, NMR (300MHz, CDCl
3) δ 7.27,6.77,4.10,3.82,3.38,3.10,1.62,1.46,0.91 and 0.68.
Goods 11 3-(chlorosulfonyl)-5-[(dipropyl amino) carbonyl] methyl benzoate (XXXVII)
With 3-amino-5-[(dipropyl amino) carbonyl] methyl benzoate (XXXI, goods 10,1.11 gram, 4 mmoles) adds in the mixture of entry (5 milliliters) and concentrated hydrochloric acid (1 milliliter).At 0 ℃ Sodium Nitrite (0.276 gram, 4 mmoles) is slowly added in this mixture.Then mixture is added with the saturated CuCl of sulfurous gas
22H
2In the acetic acid solution of O (5 milliliters).Mixture was stirred 0.5 hour, and pour in the frozen water.With this mixture of ethyl acetate extraction.Separate organic phase and use saturated sodium bicarbonate, water and salt solution to clean, and through anhydrous sodium sulfate drying, filtration also concentrates, and makes title compound, NMR (300MHz, CDCl
3) δ 8.69,8.38,8.20,4.01,3.49,3.14,1.72,1.59,1.01 and 0.79; C
15H
20C1NO
5The MS of S (ESI+) m/z (M+H)
+=362.2.
Goods 12 3-(amino-sulfonyl)-5-[(dipropyl amino) carbonyl] methyl benzoate (XXXVIII)
At 3-(chlorosulfonyl)-5-[(dipropyl amino) carbonyl] add ammonia (the 7N solution in methyl alcohol, 0.214 milliliter, 1.50 mmoles) in anhydrous THF (3 milliliters) solution of methyl benzoate (XXXVII, goods 11,0.100 gram, 0,300 mmole).Mixture was stirred 18 hours, remove solvent then.Make resistates phase-splitting between ethyl acetate and water.Separate organic phase and clean,, filter also and concentrate, make title compound, NMR (300MHz, CDCl through anhydrous sodium sulfate drying with salt solution
3) δ 8.45,8.07,8.01,6.05,3.93,3.44,3.09,1.67,1.52,0.96 and 0.73; C
12H
22N
2O
5The MS of S (ESI+) m/z (M+H)
+=343.3.
Goods 13 3-(amino-sulfonyl)-5-[(dipropyl amino) carbonyl] phenylformic acid (XXXVIII)
At 3-(amino-sulfonyl)-5-[(dipropyl amino) carbonyl] methyl benzoate (XXXVIII, goods 12,0.090 grams; 0.263 mmole) in THF/ methanol (2/1/1; 2 milliliters) in the solution in the mixture, add lithium hydroxide monohydrate (0.011 gram, 0.263 mmole).This mixture was stirred 3 hours at 20-25 ℃.This mixture of dilute with water then, and add hydrochloric acid (1N) and make pH be lower than 3.The aqueous solution with this mixture of ethyl acetate extraction.Separate organic phase and clean,, filter also and concentrate, make title compound through anhydrous sodium sulfate drying with salt solution.
1H NMR(300MHz，CDCl
3)δ10.36(s，1H)、8.39(s，1H)、8.09(s，2H)、6.06(s，2H)、3.48(t，J＝7Hz，2H)、3.15(t，J＝7Hz，2H)、1.71(m，2H)、1.55(m，2H)、0.97(t，J＝7Hz，3H)、0.74(t，J＝7Hz，3H)。C
11H
20N
2O
5The MS of S (ESI+) m/z 329.2 (M+H)
+
Goods 14 3-[(dipropyl amino) carbonyl]-5-(1-pyrrolidyl alkylsulfonyl)-methyl benzoate (XXXVIII)
According to the general procedure of goods 12, remove and use outer key change, acquisition title compound, the C of not doing of tetramethyleneimine (0.347 milliliter, 4.16 mmoles)
19H
28N
2O
5The MS of S (ESI+) m/z (M+H)
+=397.1.
Goods 15 3-[(dipropyl amino) carbonyl]-5-(1-pyrrolidyl alkylsulfonyl)-phenylformic acid (XXXIX)
According to the general procedure of goods 13 and do not do key change, obtain title compound, C
18H
26N
2O
5The MS of S (ESI+) m/z (M+H)
+=383.3.
Goods 16 3-[(dipropyl amino) carbonyl]-the 5-[(methylamino-)-alkylsulfonyl]-methyl benzoate (XXXVIII)
According to the general procedure of goods 12, remove and use outer key change, acquisition title compound, the C of not doing of methylamine (the 2N solution in THF, 0.692 milliliter, 1.38 mmoles)
16H
24N
2O
5The MS of S (ESI+) m/z (M+H)
+=357.1.
Goods 17 3-[(dipropyl amino) carbonyl]-the 5-[(methylamino-)-alkylsulfonyl]-phenylformic acid (XXXIX)
According to the general procedure of goods 13 and do not do key change, obtain title compound, C
15H
22N
2O
5The MS of S (ESI+) m/z (M+H)
+=343.1.
Goods 18 3-[(dimethylaminos) alkylsulfonyl]-5-[(dipropyl amino)-carbonyl]-methyl benzoate (XXXVIII)
According to the general procedure of goods 12, remove and use outer key change, acquisition title compound, the C of not doing of dimethylamine (the 2N solution in THF, 0.692 milliliter, 1.38 mmoles)
17H
26N
2O
5The MS of S (ESI+) m/z (M+H)
+=371.1.
Goods 19 3-[(dimethylaminos) alkylsulfonyl]-5-[(dipropyl amino) carbonyl]-phenylformic acid (XXXIX)
According to the general procedure of goods 13 and do not do key change, obtain title compound, C
16H
24N
2O
5The MS of S (ESI+) m/z (M+H)
+=375.1.
Goods 20 3-[(dipropyl amino) carbonyl]-5-ethyl benzoate methyl esters (IX)
At 3-bromo-5-[(dipropyl amino) carbonyl]-methyl benzoate (1.23 grams, 3.60 mmole) in the mixture in dry DMF (20 milliliters), add ethyl-boron dihydroxide (0.800 gram, 10.8 dichloro two (triphenyl phosphine)-palladium (II) (0.252 gram mmole),, 0.360 saleratus (2.50 grams mmole),, 18.0 mmole) and lithium chloride (0.151 gram, 3.60 mmoles).This mixture was heated 18 hours at 100 ℃.Make the phase-splitting between ethyl acetate and water of this mixture then.Separate each phase, clean the ethyl acetate phase with salt solution, and through anhydrous sodium sulfate drying and concentrated.Concentrate is carried out column chromatography separate (silica gel; Ethyl acetate/hexane, 15/85) makes title compound, C
17H
25NO
3MS (ESI+) m/z (M+H)
+=292.2.
Goods 21 3-[(dipropyl amino) carbonyl]-5-ethyl benzoate (IX)
At 3-[(dipropyl amino) carbonyl]-5-ethyl benzoate methyl esters (goods 20,0.450 gram, 1.6 mmoles) in the mixture in THF/ methanol (2/1/1, the 8 milliliter) mixed solvent, add lithium hydroxide monohydrate (0.0680 gram, 1.6 mmoles).Mixture was stirred 3 hours at 20-25 ℃.Water (20 milliliters) dilutes this mixture then, and adding hydrochloric acid (1N) makes pH be lower than 3.The aqueous solution with this mixture of ethyl acetate extraction.Separate organic phase and clean,, filter also and concentrate, make title compound, C through anhydrous sodium sulfate drying with salt solution
16H
23NO
3MS (ESI+) m/z (M+H)
+=278.2.
Embodiment 1 (1S)-3-bromine (3, the 5-difluorobenzyl)-2-oxopropyl t-butyl carbamate (III)
With N-methyl-morpholine (5.83 milliliters, 53 mmoles 1.05eq.) are added in (2S)-2-[(tert-butoxycarbonyl among the THF (100 milliliters)) amino]-3-(3, the 5-difluorophenyl) propionic acid (II, 15 grams, 50 mmoles) in, reactant is cooled to-78 ℃.Rapid adding isobutyl chlorocarbonate (6.87 milliliters, 53 mmoles, 1.05eq.).Remove cooling bath then, mixture was stirred 1 hour.React completely guaranteeing by the TLC monitoring reaction, then mixture is filtered and clean with anhydrous THF (50 milliliters), and the low temperature of-20 ℃ of maintenances in filtering flask.
500 milliliters of graduated cylinders that ether (200 milliliters) and potassium hydroxide aqueous solution (40%, 60 milliliter) will be housed place cryosel to bathe.(5.6 grams, 106 mmoles 2.1eq.), and remain on temperature below 0 ℃ slowly to add 1-methyl-3-nitro-1-nitrosoguanidine when stirring.This mixture becomes yellow, and continues to bubble 10 minutes.Stop to stir, do not mix each layer, the diazomethane ether layer at top is transferred to-20 ℃ mixing in the acid anhydride with the unpolished transfer pipet of mouth.By TLC (ethyl acetate/hexane, 50/50; R
f=0.69) monitoring reaction.After 1 hour, nitrogen is blasted in the mixture.Solvent is removed in decompression (heating), and makes mixture phase-splitting between ether and water.Separate each phase, clean organic phase with supercarbonate, salt solution, through anhydrous sodium sulfate drying, and solvent is removed in decompression (heating).Resistates is dissolved in ether (100 milliliters) and adds Hydrogen bromides at-20 ℃ (48%, 15 milliliter, 135 mmoles 2.7eq), are removed cooling bath and with mixture restir 0.5 hour.By TLC (ethyl acetate/hexane, 50/50; R
f=0.88) monitoring reaction.Make the phase-splitting between ether and water of this mixture, clean,, and remove solvent through anhydrous sodium sulfate drying with supercarbonate, salt solution.This resistates recrystallization in ethanol obtains title compound, TCL (ethyl acetate/hexane, 50/50) R
f=0.88; MS (MH
+)=379.3.
Embodiment 2 (1S, 2S)-3-bromo-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl t-butyl carbamate (IV)
(1.32 grams, 34.9 mmoles 1.1eq.) add in (1S)-3-bromine (3, the 5-the difluorobenzyl)-2-oxopropyl t-butyl carbamate (III, embodiment 1,12 gram, 31.75 mmoles) that is dissolved in raw spirit (500 milliliters) with sodium borohydride at-78 ℃.Reaction mixture was stirred 0.5 hour, and by TLC (ethyl acetate/hexane, 20/80; R
f=0.2).Water (10 milliliters) is with this mixture quenching, and decompression heating (being no more than 30 ℃) is removed solvent to doing.Make the phase-splitting between methylene dichloride and water of this solid, clean with salt solution, through anhydrous sodium sulfate drying.Solvent is removed in decompression, makes title compound, TLC (ethyl acetate/hexane, 20/80) R
f=0.2; MS (MH
+)=381.2.
Embodiment 3 (1S)-2-(3, the 5-difluorophenyl)-1-[(2S)-Oxyranyle] the ethyl carbamic acid tert-butyl ester (V)
With (1S, 2S)-3-bromo-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl t-butyl carbamate (IV, embodiment 2) be dissolved in raw spirit (150 milliliters) and the ethyl acetate (100 milliliters), and (2.3 restrain to add potassium hydroxide at-20 ℃, 34.9 mmole, ethanol 1.1eq.) (85%, 5 milliliter) solution.Remove cooling bath then, and mixture was stirred 0.5 hour.By TLC (ethyl acetate/hexane, 20/80) monitoring reaction.When reaction is finished, it is diluted also water and salt solution extraction, washs with methylene dichloride, through anhydrous sodium sulfate drying, and decompression removal solvent.Separate the raw product of purifying by on silica gel, carrying out flash chromatography, obtain title compound, TLC (ethyl acetate/hexane, 20/80) R
f=0.3; MS (MH
+)=300.4.
Embodiment 4 (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] the propyl carbamic acid tert-butyl ester (VII)
With (1S)-2-(3, the 5-difluorophenyl)-1-[(2S)-and Oxyranyle] the ethyl carbamic acid tert-butyl ester (V, embodiment 3,245 milligrams, 0.82 mmole) be suspended in the Virahol (6 milliliters), and when stirring, add 3-methoxy-benzyl amine (160 microlitres, 1.22 mmoles) at 20-25 ℃.Under nitrogen atmosphere, this compound is heated to mild backflow (bathing 85 ℃ of temperature) 2 hours, with the mixture concentrating under reduced pressure that makes, make title compound thereupon.Title compound is passed through flash chromatography (2-5% ethanol/methylene; Gradient elution) purifies, make the title compound of purifying.
Embodiment 5 (2R, 3S)-3-amino-4-(3, the 5-difluorobenzyl)-1-[(3-methoxy-benzyl) amino]-2-butanols trifluoro-acetate (VIII)
Under 20-25 ℃, will (1S, 2R)-1-(3, the 5-difluorobenzyl)-and 2-hydroxyl-3-[(3-methoxy-benzyl) amino] the propyl carbamic acid tert-butyl ester (VII, 4,258 milligrams of embodiment, 0.59 mmole) be dissolved in methylene dichloride (1 milliliter), under nitrogen atmosphere, stir adding trifluoroacetic acid (1 milliliter).Reaction mixture was stirred 1 hour at 20-25 ℃, with the reaction mixture concentrating under reduced pressure, make title compound thereupon.This title compound promptly is used for next reaction without further purification.
Embodiment 6 N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine (isophthalamide) (X)
Will (2R, 3S)-3-amino-4-(3, the 5-difluorobenzyl)-1-[(3-methoxy-benzyl) amino]-2-butanols trifluoro-acetate (VIII, embodiment 5) is dissolved in dry DMF (3 milliliters) and is cooled to 0 ℃.Add triethylamine (500 microlitres, 3.6 mmoles) and 5-methyl-N, N-dipropyl m-phthalic acid (156 milligrams, 0.59 mmole) when stirring.This mixture is warmed to 20-25 ℃, mainly is for carboxylic acid is dissolved fully, and then is cooled to 0 ℃.Add I-hydroxybenzotriazole (157 milligrams, 1.2 mmoles) when stirring, add 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (229 milligrams, 1.2 mmoles) then.The mixture of making was stirred 5 minutes at 0 ℃, be warmed to 20-25 ℃ then and reach 15 hours.Use aqueous citric acid solution (10%) with the reaction mixture quenching then, with ethyl acetate extraction three times of this mixture.Clean the organic extract liquid that merges with saturated sodium bicarbonate, salt solution,, filter and concentrating under reduced pressure, make the raw product of title compound through dried over sodium sulfate.By flash chromatography (2-10% ethanol/methylene gradient elution) this material is purified, make the title compound of purifying, MS (MH
+)=582.3.
Embodiment 7-9
According to the general procedure of embodiment 1 and do not do key change, just the protecting group with hurdle A is raw material and the acid of using hurdle B, and the quilt that makes hurdle C thus protects compound (III):
| Embodiment | Hurdle A | Hurdle B | Hurdle C |
| 7 | BOC | Hydrochloric acid | (1S)-3-chloro-1-(3, the 5-difluorobenzyl)-2-oxopropyl t-butyl carbamate |
| 8 | CBZ | Hydrogen bromide | (1S)-3-bromo-1-(3, the 5-difluorobenzyl)-2-oxopropyl carboxylamine benzyl ester |
| 9 | CBZ | Hydrochloric acid | (1S)-3-chloro-1-(3, the 5-difluorobenzyl)-2-oxopropyl carboxylamine benzyl ester |
Embodiment 10-12
According to the general procedure of embodiment 2, and be the raw material except the quilt with hurdle A protects compound (III), do not do key change, the quilt that makes hurdle B thus protects compound:
| Embodiment | Hurdle A | Hurdle B |
| 10 | 7 | (1S, 2S)-3-chloro-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl t-butyl carbamate |
| 11 | 8 | (1S, 2S)-3-bromo-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl carboxylamine benzyl ester |
| 12 | 9 | (1S, 2S)-3-chloro-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl carboxylamine benzyl ester |
Embodiment 13 (1S)-2-(3, the 5-difluorophenyl)-1-[(2S)-Oxyranyle] ethyl carbamic acid benzyl ester (V)
According to the general procedure of embodiment 3, and, do not do key change, make this title compound thus except being the raw material with alcohol (IV).
Embodiment 14-107
According to the general procedure of embodiment 4 and do not do key change, just with (1S, 2S)-and C-terminal amine (VI) reaction of 1-(2-Oxyranyle)-2-phenylethyl t-butyl carbamate (V can obtain by commercial sources) and hurdle A, the quilt that makes hurdle B thus protects alcohol (VII):
| Embodiment number | Hurdle A C-terminal amine (VI) | Hurdle B is protected alcohol (VII) |
| 14 | H 2N-CH 2CH 3 | (1S, 2R)-1-benzyl-3-(ethylamino)-2-hydroxypropyl t-butyl carbamate |
| 15 | H 2N-CH 2-phenyl | (1S, 2R)-1-benzyl-3-(benzyl amino)-2-hydroxypropyl t-butyl carbamate |
| 16 | H 2N-CH(CH 3) 2 | (1S, 2R)-1-benzyl-3-(isopropylamino)-2-hydroxypropyl t-butyl carbamate |
| 17 | H 2N-CH 2-phenyl-4-CH 3 | (1S, 2R)-1-benzyl-2-hydroxyl-3-[(4-xylyl) amino] the propyl carbamic acid tert-butyl ester |
| 18 | H 2N-(CH 2) 2-phenyl-4-OCH 3 | (1S, 2R)-1-benzyl-2-hydroxyl-3-{[2-(4-methoxyphenyl) ethyl] amino } the propyl carbamic acid tert-butyl ester |
| 19 | H 2N-CH 2-phenyl-3-OCH 3 | (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxybenzyl) amino] the propyl carbamic acid tert-butyl ester |
| 20 | H 2N-CH (phenyl)-CO-OC 2H 5 | ((2R, 3S)-the 3-[(tert-butoxycarbonyl) amino]-2-hydroxyl-4-benzene butyl } amino) (phenyl) ethyl acetate |
| 21 | H 2N-(CH 2) 2-phenyl | (1S, 2R)-1-benzyl-2-hydroxyl-3-[(2-styroyl) amino] the propyl carbamic acid tert-butyl ester |
| 22 | H 2N-CH(-CH 2OH)-CH (OH)-phenyl-4-NO 2 | (1S, 2R)-1-benzyl-2-hydroxyl-3-{[(1S)-2-hydroxyl-1-(methylol)-2-(4-nitre phenyl) ethyl] amino } the propyl carbamic acid tert-butyl ester |
| 23 | H 2N-CH 2-phenyl-2-chlorine | (1S, 2R)-1-benzyl-3-[(2-benzyl chloride base) amino]-2-hydroxypropyl t-butyl carbamate |
| 24 | H 2N-CH 2-phenyl-4-chlorine | (1S, 2R)-1-benzyl-3-[(4-benzyl chloride base) amino]-2-hydroxypropyl t-butyl carbamate |
| 25 | H 2N-(CH 2) 2-O-(CH 2) 2-OH | (1S, 2R)-1-benzyl-2-hydroxyl-3-{[2-(2-hydroxyl-oxethyl) ethyl] amino } the propyl carbamic acid tert-butyl ester |
| 26 | H 2The N-1-indanyl | (1S, 2R)-1-benzyl-3-(2,3-dihydro-1H-indenes-1-base is amino)-2-hydroxypropyl t-butyl carbamate |
| 27 | H 2N-CH 2-CH(OH)-CH 3 | (1S, 2R)-1-benzyl-2-hydroxyl-3-[(2-hydroxypropyl) amino] the propyl carbamic acid tert-butyl ester |
| 28 | H 2N-CH 2-tetrahydrofuran base | (1S, 2R)-1-benzyl-2-hydroxyl-3-[(tetrahydrochysene-2-furyl methyl) amino] the propyl carbamic acid tert-butyl ester |
| 29 | H 2N-CH 2-CH(-OCH 2CH 3) | (1S, 2R)-1-benzyl-3-[(2,2-diethoxy ethyl) amino]-2-hydroxypropyl t-butyl carbamate |
| 30 | H 2N-(CH 2) 4-CH 3 | (1S, 2R)-1-benzyl-2-hydroxyl-3-(penta amino) propyl carbamic acid tert-butyl ester |
| 31 | H 2The N-cyclohexyl | (1S, 2R)-1-benzyl-3-(hexamethylene amino)-2-hydroxypropyl t-butyl carbamate |
| 32 | H 2N-CH 2-pyridine-2-base | (1S, 2R)-1-benzyl-2-hydroxyl-3-[(2-pyridylmethyl) amino] the propyl carbamic acid tert-butyl ester |
| 33 | H 2N-CH 2-phenyl-2-NH 2 | (1S, 2R)-the 3-[(2-aminobenzyl) amino]-1-benzyl-2-hydroxypropyl t-butyl carbamate |
| 34 | H 2N-CH 2-pyridin-3-yl | (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-pyridylmethyl) amino] the propyl carbamic acid tert-butyl ester |
| 35 | H 2N-(CH 2) 2-tetramethyleneimine-1-base | (1S, 2R)-1-benzyl-2-hydroxyl-3-{[2-(1-pyrrolidyl) ethyl] amino } the propyl carbamic acid tert-butyl ester |
| 36 | H 2N-CH 2-CH (OH)-phenyl | (1S, 2R)-1-benzyl-2-hydroxyl-3-[(2-hydroxyl-2-styroyl) amino] the propyl carbamic acid tert-butyl ester |
| 37 | H 2N-(CH 2) 3-O-(CH 2) 3-CH 3 | (1S, 2R)-1-benzyl-3-[(3-butoxy propyl group) amino]-2-hydroxypropyl t-butyl carbamate |
| 38 | H 2N-(CH 2) 3-O-CH(CH 3) 2 | (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-isopropoxide propyl) amino] the propyl carbamic acid tert-butyl ester |
| 39 | H 2N-(CH 2) 2-CH(CH 3) 2 | (1S, 2R)-1-benzyl-2-hydroxyl-3-(isoamylamino) propyl carbamic acid tert-butyl ester |
| 40 | H 2N-(CH 2) 3-phenyl | (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-phenyl propyl) amino] the propyl carbamic acid tert-butyl ester |
| 41 | H 2N-(CH 2) 2-OCH 3 | (1S, 2R)-1-benzyl-2-hydroxyl-3-[(2-methoxy ethyl) amino] the propyl carbamic acid tert-butyl ester |
| 42 | H 2N-(CH 2) 2-O-phenyl | (1S, 2R)-1-benzyl-2-hydroxyl-3-[(2-phenoxy group ethyl) amino] the propyl carbamic acid tert-butyl ester |
| 43 | H 2N-(CH 2) 2-O-(CH 2) 2-CH 3 | (1S, 2R)-1-benzyl-2-hydroxyl-3-[(2-propoxy-ethyl) amino] the propyl carbamic acid tert-butyl ester |
| 44 | H 2N-(CH 2) 2-C(CH 3) 3 | (1S, 2R)-1-benzyl-3-[(3, the 3-dimethylbutyl) amino]-2-hydroxypropyl t-butyl carbamate |
| 45 | H 2N-(CH 2) 4-phenyl | (1S, 2R)-1-benzyl-2-hydroxyl-3-[(4-phenyl butyl) amino] the propyl carbamic acid tert-butyl ester |
| 46 | H 2N-CH 2-phenyl-3-iodine | (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-iodine benzyl) amino] the propyl carbamic acid tert-butyl ester |
| 47 | H 2N-CH 2-phenyl-4-NO 2 | (1S, 2R)-1-benzyl-2-hydroxyl-3-[(4-nitrobenzyl) amino] the propyl carbamic acid tert-butyl ester |
| 48 | H 2N-CH 2-phenyl-3-chlorine | (1S, 2R)-1-benzyl-3-[(3-benzyl chloride base) amino]-2-hydroxypropyl t-butyl carbamate |
| 49 | H 2N-(CH 2) 2-phenyl-4-chlorine | (1S, 2R)-1-benzyl-3-{[2-(4-chloro-phenyl-) ethyl] ammonia |
| Base }-2-hydroxypropyl t-butyl carbamate | ||
| 50 | H 2N-(CH 2) 2-pyridine-2-base | (1S, 2R)-1-benzyl-2-hydroxyl-3-{[2-(2-pyridyl) ethyl] amino } the propyl carbamic acid tert-butyl ester |
| 51 | H 2N-CH 2-pyridin-4-yl | (1S, 2R)-1-benzyl-2-hydroxyl-3-[(4-picolyl) amino] the propyl carbamic acid tert-butyl ester |
| 52 | H 2N-(CH 3) 2-(N-methylpyrrolidin-2-yl) | (1S, 2R)-1-benzyl-2-hydroxyl-3-{[2-(1-methyl-2-pyrrolidyl) ethyl] amino } the propyl carbamic acid tert-butyl ester |
| 53 | H 2N-CH 2-phenyl-2, the 3-dimethyl | (1S, 2R)-1-benzyl-3-[(2, the 3-dixylyl) amino]-2-hydroxypropyl t-butyl carbamate |
| 54 | H 2N-CH 2-phenyl-2-OCF 3 | (1S, 2R)-1-benzyl-2-hydroxyl-3-{[2-(trifluoromethoxy) benzyl] amino } the propyl carbamic acid tert-butyl ester |
| 55 | H 2N-CH 2-phenyl-2-chloro-6-O-phenyl | (1S, 2R)-1-benzyl-2-hydroxyl-3-[(2-chloro-6-phenoxy benzyl) amino]-2-hydroxypropyl t-butyl carbamate |
| 56 | H 2N-CH 2-phenyl-4-CF 3 | (1S, 2R)-1-benzyl-2-hydroxyl-3-{[4-(trifluoromethyl) benzyl] amino } the propyl carbamic acid tert-butyl ester |
| 57 | H 2N-CH 2-phenyl-2, the 3-dichloro | (1S, 2R)-1-benzyl-3-[(2, the 3-dichloro benzyl) amino]-2-hydroxypropyl t-butyl carbamate |
| 58 | H 2N-CH 2-phenyl-3, the 5-dichloro | (1S, 2R)-1-benzyl-3-[(3, the 5-dichloro benzyl) amino]-2-hydroxypropyl t-butyl carbamate |
| 59 | H 2N-CH 2-phenyl-3, the 5-difluoro | (1S, 2R)-1-benzyl-3-[(3, the 5-difluorobenzyl) amino]-2-hydroxypropyl t-butyl carbamate |
| 60 | H 2N-CH 2-phenyl-4-OCF 3 | (1S, 2R)-1-benzyl-2-hydroxyl-3-{[4-(trifluoromethoxy) benzyl] amino } the propyl carbamic acid tert-butyl ester |
| 61 | H 2N-(CH 2) 2-phenyl-4-SO 2-NH 2 | (1S, 2R)-3-{[4-(amino-sulfonyl) benzyl] amino }-1-benzyl-2-hydroxypropyl t-butyl carbamate |
| 62 | H 2N-CH 2-phenyl-4-OCH 3 | (1S, 2R)-1-benzyl-2-hydroxyl-3-[(4-methoxy-benzyl) amino] the propyl carbamic acid tert-butyl ester |
| 63 | H 2N-CH 2-phenyl-4-CH 3 | (1S, 2R)-1-benzyl-2-hydroxyl-3-[(4-methyl-benzyl) amino] the propyl carbamic acid tert-butyl ester |
| 64 | H 2N-CH 2-phenyl-(3,4, the 5-trimethoxy) | (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3,4,5-trimethoxy benzyl) amino] the propyl carbamic acid tert-butyl ester |
| 65 | H 2N-CH 2-phenyl-3-OCF 3 | (1S, 2R)-1-benzyl-2-hydroxyl-3-{[3-(trifluoromethoxy) benzyl] amino } the propyl carbamic acid tert-butyl ester |
| 66 | H 2N-CH 2-phenyl-3, the 5-dimethoxy | (1S, 2R)-1-benzyl-3-[(3, the 5-dimethoxy-benzyl) amino]-2-hydroxypropyl t-butyl carbamate |
| 67 | H 2N-CH 2-phenyl-2, the 4-dimethoxy | (1S, 2R)-1-benzyl-3-[(2, the 4-dimethoxy-benzyl) amino]-2-hydroxypropyl t-butyl carbamate |
| 68 | H 2N-CH 2-phenyl-phenyl | (1S, 2R)-1-benzyl-3-[([1,1 '-phenylbenzene)]-the 3-ylmethyl) amino]-2-hydroxypropyl t-butyl carbamate |
| 69 | H 2N-CH 2-phenyl-3, the 4-dichloro | (1S, 2R)-1-benzyl-3-[(3, the 4-dichloro benzyl) amino]-2-hydroxypropyl t-butyl carbamate |
| 70 | H 2N-CH 2-phenyl-4-fluorine | (1S, 2R)-1-benzyl-3-[(4-luorobenzyl) amino]-2-hydroxypropyl t-butyl carbamate |
| 71 | H 2N-CH 2-phenyl-3-CF 3 | (1S, 2R)-1-benzyl-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } the propyl carbamic acid tert-butyl ester |
| 72 | H 2N-CH 2-phenyl-2-CH 3 | (1S, 2R)-1-benzyl-2-hydroxyl-3-[(2-methyl-benzyl) amino] the propyl carbamic acid tert-butyl ester |
| 73 | H 2N-CH((R)-CH 3)-phenyl | (1S, 2R)-1-benzyl-2-hydroxyl-3-{[(1R)-the 1-styroyl] amino } the propyl carbamic acid tert-butyl ester |
| 74 | H 2N-CH((S)-CH 3)-phenyl | (1S, 2R)-1-benzyl-2-hydroxyl-3-{[(1S)-the 1-styroyl] amino } the propyl carbamic acid tert-butyl ester |
| 75 | H 2N-CH 2-phenyl-3,5-(two) trifluoromethyl | (1S, 2R)-1-benzyl-3-{[3, two (trifluoromethyl) benzyls of 5-] amino }-2-hydroxypropyl t-butyl carbamate |
| 76 | H 2N-CH 2-phenyl-2-CF 3 | (1S, 2R)-1-benzyl-2-hydroxyl-3-{[2-(trifluoromethyl) benzyl] amino } the propyl carbamic acid tert-butyl ester |
| 77 | H 2N-CH((S)-CH 3)-(naphthalene-1-yl) | (1S, 2R)-1-benzyl-2-hydroxyl-3-{[(1S)-1-(1-naphthyl) ethyl] amino } the propyl carbamic acid tert-butyl ester |
| 78 | H 2N-CH((R)-CH 3)-(naphthalene-1-yl) | (1S, 2R)-1-benzyl-2-hydroxyl-3-{[(1R)-1-(1-naphthyl) ethyl] amino } the propyl carbamic acid tert-butyl ester |
| 79 | H 2N-CH 2-phenyl-3-OCH 3-4-OH | (1S, 2R)-1-benzyl-2-hydroxyl-3-[(4-hydroxyl-3-methoxy-benzyl) amino] the propyl carbamic acid tert-butyl ester |
| 80 | H 2N-CH 2-phenyl-3, the 4-dihydroxyl | (1S, 2R)-1-benzyl-3-[(3, the 4-dihydroxy benzyl) amino]-2-hydroxypropyl t-butyl carbamate |
| 81 | H 2N-(CH 2) 3-OCH 3 | (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-propyl) amino] the propyl carbamic acid tert-butyl ester |
| 82 | H 2N-CH((S)-CH 3)-CH 2-OH | (1S, 2R)-1-benzyl-2-hydroxyl-3-{[(1S)-2-hydroxyl-1-methylethyl] amino } the propyl carbamic acid tert-butyl ester |
| 83 | H 2N-CH((R)-CH 3)-CH 2-OH | (1S, 2R)-1-benzyl-2-hydroxyl-3-{[(1R)-2-hydroxyl-1-methylethyl] amino } the propyl carbamic acid tert-butyl ester |
| 84 | H 2N-CH 2-C≡CH | (1S, 2R)-1-benzyl-2-hydroxyl-3-(2-propynyl amino) third |
| The aminocarbamic acid tert-butyl ester | ||
| 85 | H 2N-(CH 2) 2-phenyl-2-fluorine | (1S, 2R)-1-benzyl-2-hydroxyl-3-{[2-(2-fluorophenyl) ethyl] amino }-2-hydroxypropyl t-butyl carbamate |
| 86 | H 2N-(CH 2) 2-phenyl-3-fluorine | (1S, 2R)-1-benzyl-3-{[2-(3-fluorophenyl) ethyl] amino }-2-hydroxypropyl t-butyl carbamate |
| 87 | H 2N-(CH 2) 2-phenyl-4-fluorine | (1S, 2R)-1-benzyl-3-{[2-(4-fluorophenyl) ethyl] amino }-2-hydroxypropyl t-butyl carbamate |
| 88 | H 2N-(CH 2) 2-phenyl-3-bromine | (1S, 2R)-1-benzyl-3-{[2-(4-bromophenyl) ethyl] amino }-2-hydroxypropyl t-butyl carbamate |
| 89 | H 2N-(CH 2) 2-phenyl-3-OCH 3 | (1S, 2R)-1-benzyl-2-hydroxyl-3-{[2-(3-p-methoxy-phenyl) ethyl] amino } the propyl carbamic acid tert-butyl ester |
| 90 | H 2N-(CH 2) 2-phenyl-2, the 4-dichloro | (1S, 2R)-1-benzyl-3-{[2-(2,4 dichloro benzene base) ethyl] amino }-2-hydroxypropyl t-butyl carbamate |
| 91 | H 2N-(CH 2) 2-phenyl-3-chlorine | (1S, 2R)-1-benzyl-3-{[2-(3-chloro-phenyl-) ethyl] amino }-2-hydroxypropyl t-butyl carbamate |
| 92 | H 2N-(CH 2) 2-phenyl-2, the 5-dimethoxy | (1S, 2R)-1-benzyl-3-{[2-(2, the 5-Dimethoxyphenyl) ethyl] amino }-2-hydroxypropyl t-butyl carbamate |
| 93 | H 2N-(CH 2) 2-phenyl-4-CH 3 | (1S, 2R)-1-benzyl-3-{[2-(4-aminomethyl phenyl) ethyl] amino }-2-hydroxypropyl t-butyl carbamate |
| 94 | H 2N-CH(-(R)CH 2-OH)-CH 2-phenyl | (1S, 2R)-the 1-benzyl-3-{[(1R)-1-benzyl-2-hydroxyethyl] amino }-2-hydroxypropyl t-butyl carbamate |
| 95 | H 2N-(CH 2) 3-(1-morpholinyl) | (1S, 2R)-1-benzyl-2-hydroxyl-3-{[3-(4-morpholinyl) propyl group] amino } the propyl carbamic acid tert-butyl ester |
| 96 | H 2N-CH 2-C(CH 3) 2 | (1S, 2R)-1-benzyl-3-[(3, the 3-dimethylbutyl) amino]-2-hydroxypropyl t-butyl carbamate |
| 97 | H 2N-(CH 2) 2-(1-morpholinyl) | (1S, 2R)-1-benzyl-2-hydroxyl-3-{[2-(4-morpholinyl) ethyl] amino } the propyl carbamic acid tert-butyl ester |
| 98 | H 2N-CH(OH)-CH 2-CH 3 | (1S, 2R)-1-benzyl-2-hydroxyl-3-[(1-hydroxypropyl) amino] the propyl carbamic acid tert-butyl ester |
| 99 | H 2N-(CH 2) 2-(thiophene-2-yl) | (1S, 2R)-1-benzyl-2-hydroxyl-3-[(2-thienyl methyl) amino] the propyl carbamic acid tert-butyl ester |
| 100 | H 2N-(CH 2) 4-OH | (1S, 2R)-1-benzyl-2-hydroxyl-3-[(4-hydroxybutyl) amino] the propyl carbamic acid tert-butyl ester |
| 101 | H 2N-CH(-(S)CH 2-OH)-phenyl | (1S, 2R)-1-benzyl-2-hydroxyl-3-{[(1S)-2-hydroxyl-1-styroyl] amino } the propyl carbamic acid tert-butyl ester |
| 102 | H 2N-CH 2-phenyl-2, the 4-dichloro | (1S, 2R)-1-benzyl-3-[(2, the 4-dichloro benzyl) amino]-2-hydroxypropyl t-butyl carbamate |
| 103 | H 2N-CH(-(R)CH 2-OH)-phenyl | (1S, 2R)-1-benzyl-2-hydroxyl-3-{[(1R)-2-hydroxyl-1-styroyl] amino } the propyl carbamic acid tert-butyl ester |
| 104 | H 2N-CH 2-phenyl-4-C (CH 3) 3 | (1S, 2R)-1-benzyl-3-[(4-benzyl) amino]-2-hydroxypropyl t-butyl carbamate |
| 105 | H 2N-CH(CH 3)-phenyl | (1S, 2R)-1-benzyl-2-hydroxyl-3-[(1-styroyl) amino] the propyl carbamic acid tert-butyl ester |
| 106 | H 2N-(1R, 2S)-2-hydroxyl indenes-1-base | (1S, 2R)-1-benzyl-2-hydroxyl-3-{[(1R, 2S)-and 2-hydroxyl-2,3-dihydro-1H-indenes-1-yl] amino } the propyl carbamic acid tert-butyl ester |
| 107 | H 2N-CH 2-phenyl-3, the 4-dimethyl | (1S, 2R)-1-benzyl-3-[(3, the 4-dixylyl) amino]-2-hydroxypropyl t-butyl carbamate |
Embodiment 108-164
According to the general procedure of embodiment 4 and do not do key change, just with (1S)-2-(3, the 5-difluorophenyl)-1-[(2S)-and Oxyranyle] C-terminal amine (VI) reaction of the ethyl carbamic acid tert-butyl ester (V, embodiment 3) and hurdle A, the quilt that makes hurdle B thus protects alcohol (VII):
| Embodiment | Hurdle A C-terminal amine (VI) | Hurdle B is protected alcohol (VII) |
| 108 | H 2N-(CH 2) 6-CO-O-CH 3 | Methyl-7-{[(2R, 3S)-the 3-[(tert-butoxycarbonyl) amino]-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl] amino } heptanoate |
| 109 | H 2N-CH(-CH 3)-CO-NH-C H 2-CH(CH 3) 2r/s | (1S, 2R)-and 1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[2-(isobutylamino)-1-methyl-2-oxoethyl] amino } the propyl carbamic acid tert-butyl ester |
| 110 | H 2N-CH((S)-CH 3)-CO-N H-CH 2-CH(CH 3) 2 | (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1S)-2-(isobutylamino)-1-methyl-2-oxoethyl] amino } the propyl carbamic acid tert-butyl ester |
| 111 | H 2N-C(-CH 3) 2-CO-NH-C H 2-CH(CH 3) 2 | (1S, 2R)-1-(3, the 5-difluorobenzyl)-and 2-hydroxyl-3-{[2-(isobutylamino)-1,1-dimethyl-2-oxoethyl] amino } the propyl carbamic acid tert-butyl ester |
| 112 | H 2N-CH 2-CO-NH-CH 2-C H(CH 3) 2 | (1S, 2R)-and 1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[2-(isobutylamino)-2-oxoethyl] amino } the propyl carbamic acid tert-butyl ester |
| 113 | H 2N-CH((S)-CH 2CH 3)-C O-NH-CH 2-CH(CH 3) 2 | (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-((1S)-and the 1-[(isobutylamino) carbonyl] propyl group } amino) third |
| -3-((1S)-and the 1-[(isobutylamino) carbonyl] propyl group } amino) the propyl carbamic acid tert-butyl ester | ||
| 114 | H 2N-CH((R)-CH 2CH 3)-C O-NH-CH 2-CH(CH 3) 2 | (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-((1R)-and the 1-[(isobutylamino) carbonyl] propyl group } amino) the propyl carbamic acid tert-butyl ester |
| 115 | H 2N-CH 2-phenyl | (1S, 2R)-3-(benzylamino)-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl t-butyl carbamate |
| 116 | H 2N-CH 2-CH 3 | (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-(ethylamino)-2-hydroxypropyl t-butyl carbamate |
| 117 | H 2N-CH 2-CH(CH 3) 2 | (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(isobutylamino) propyl carbamic acid tert-butyl ester |
| 118 | H 2N-CH 2-CH(CH 3)-CON H-CH 2-CH(CH 3) 2 | (1S, 2R)-and 1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(isobutylamino)-2-methyl-3-oxopropyl] amino } the propyl carbamic acid tert-butyl ester |
| 119 | H 2N-CH 2-phenyl-4-N (CH 3) 2 | (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[4-(dimethylamino) benzyl] amino }-2-hydroxyl-propyl carbamic acid tert-butyl ester |
| 120 | H 2N-CH((S)-CH 2-phenyl)-CO-NH-CH 2-CH(CH 3 ) 2 | (1S, 2R)-3-{[(1S)-1-(3, the 5-difluorobenzyl)-and 2-(isobutylamino)-2-oxoethyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxyl-propyl carbamic acid tert-butyl ester |
| 121 | H 2N-CH((S)-CH(CH 3) 2)- CO-NH-CH 2-CH(CH 3) 2 | (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-((1S)-and the 1-[(isobutylamino) carbonyl]-the 3-methyl butyl } amino) the propyl carbamic acid tert-butyl ester |
| 122 | H 2N-CH 2-CH 2-N(CH 3) 2 | (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[2-(dimethylamino) ethyl] amino }-2-hydroxypropyl t-butyl carbamate |
| 123 | H 2N-CH 2-(pyridin-3-yl) | (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-pyridylmethyl) amino] the propyl carbamic acid tert-butyl ester |
| 124 | H 2N-CH((S)-CH 2-O-CH 2-phenyl)-CO-NH-CH 2-CH(CH 3 ) 2 | (1S, 2R)-3-{[(1S)-and the 1-[(benzyloxy) methyl]-2-(isobutylamino)-2-oxoethyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl t-butyl carbamate |
| 125 | H 2N-C(-CH 3) 2-phenyl | (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(1-methyl isophthalic acid-styroyl) amino] the propyl carbamic acid tert-butyl ester |
| 126 | H 2N-CH((R)-CH(CH 3) 2)- CO-NH-CH 2-CH(CH 3) 2 | (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-((1R)-and the 1-[(isobutylamino) carbonyl]-the 3-methyl butyl } amino) the propyl carbamic acid tert-butyl ester |
| 127 | H 2N-CH((S)-CH 2-CH 2-C H 3)-CO-NH-CH 2-CH(CH 3 ) 2 | (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-((1S)-and the 1-[(isobutylamino) carbonyl] butyl } amino) the propyl carbamic acid tert-butyl ester |
| 128 | H 2N-CH((S)-CH 2-OH)-C O-NH-CH 2-CH(CH 3) 2 | (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1S)-1-(methylol)-2-(isobutylamino)-2-oxoethyl] amino } the propyl carbamic acid tert-butyl ester |
| 129 | H 2N-CH 2-CH 2-phenyl | (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(2-styroyl) amino] the propyl carbamic acid tert-butyl ester |
| 130 | H 2N-CH((S)-CH 3)-CO-N H-CH 2-phenyl | (1S, 2R)-and 3-{[2-(benzyl amino)-1-methyl-2-oxoethyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl t-butyl carbamate |
| 131 | H 2N-CH((S)-CH 2-CH 3)-phenyl | (1S, 2R)-and 1-(3, the 5-difluorobenzyl)-3-{[(1S)-2-(benzyl amino)-1-methyl-2-oxoethyl] amino }-2-hydroxypropyl t-butyl carbamate |
| 132 | H 2N-CH 2-phenyl-3-OCH 3 | (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] the propyl carbamic acid tert-butyl ester |
| 133 | H 2N-CH ((S)-phenyl) CO-NHCH 2CH(CH 3) 2 | (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1S)-2-(isobutylamino)-2-oxo-1-styroyl] amino } the propyl carbamic acid tert-butyl ester |
| 134 | H 2N-CH 2-CH 2-CH(CH 3) 2 | (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(isopentyl amino) propyl carbamic acid tert-butyl ester |
| 135 | H 2The N-cyclohexyl | (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-(cyclohexyl amino)-2-hydroxypropyl t-butyl carbamate |
| 136 | H 2N-(CH 2) 3-CH 3 | (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-(fourth amino)-2-hydroxyl-propyl carbamic acid tert-butyl ester |
| 137 | H 2N-(CH 2) 3-O-CH 3 | (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methoxy-propyl) amino] the propyl carbamic acid tert-butyl ester |
| 138 | H 2N-CH 2-CH (OH)-phenyl | (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(2-hydroxyl-2-styroyl) amino] the propyl carbamic acid tert-butyl ester |
| 139 | H 2N-cyclohexyl-3, the 5-dimethoxy | (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(3R, 5S)-3,5-dimethoxy cyclohexyl] amino }-2-hydroxypropyl t-butyl carbamate |
| 140 | H 2N-cyclohexyl-3,5-two-(CO-OCH 3) | Dimethyl (1R, 3S)-5-({ (2R, 3S)-and the 3-[(tert-butoxycarbonyl) amino]-2-hydroxy-4-phenyl butyl } amino)-1,3-cyclohexane cyclohexanedimethanodibasic ester |
| 141 | H 2N-cyclohexyl-3,5-two-(COOH) | (1R, 3S)-5-({ (2R, 3S)-and the 3-[(tert-butoxycarbonyl) amino]-2-hydroxy-4-phenyl butyl } amino)-1, the 3-cyclohexane cyclohexanedimethanodibasic |
| 142 | H 2N-CH((R)-CH 2-CH 3)-phenyl | (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1R)-the 1-hydrocinnamyl] amino } the propyl carbamic acid tert-butyl ester |
| 143 | H 2N-CH 2-phenyl-3-chlorine | (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-benzyl chloride base) amino]-2-hydroxypropyl t-butyl carbamate |
| 144 | H 2N-CH 2-phenyl-3-OCH 3 | (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] the propyl carbamic acid tert-butyl ester |
| 145 | H 2N-CH 2-phenyl-phenyl | (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[{[1,1 '-phenylbenzene]-the 3-ylmethyl } amino]-2-hydroxypropyl t-butyl carbamate |
| 146 | H 2N-CH 2-phenyl-3-iodine | (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] the propyl carbamic acid tert-butyl ester |
| 147 | H 2N-CH 2-phenyl-3-CH 3 | (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methyl-benzyl) amino] the propyl carbamic acid tert-butyl ester |
| 148 | H 2N-CH 2-CH(-CH 3)-phenyl | (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(2-hydrocinnamyl) amino] the propyl carbamic acid tert-butyl ester |
| 149 | H 2N-CH 2-(thiazole-5-yl) | (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(1,3-thiazole-5-ylmethyl) amino] the propyl carbamic acid tert-butyl ester |
| 150 | H 2N-CH 2-(thiophene-2-yl) | (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(2-thienyl methyl) amino] the propyl carbamic acid tert-butyl ester |
| 151 | H 2N-4-methoxyl group-1,2,3,4-tetralin-1-base | (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(5-methoxyl group-1,2,3,4-tetrahydrochysene-1-naphthyl) amino] the propyl carbamic acid tert-butyl ester |
| 152 | H 2N-CH 2-pyrazine-2-base | (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(2-pyrazinyl methyl) amino] the propyl carbamic acid tert-butyl ester |
| 153 | H 2N-CH 2-phenyl-3, the 5-difluoro | (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3, the 5-difluorobenzyl) amino]-2-hydroxypropyl t-butyl carbamate |
| 154 | H 2N-CH 2-phenyl-3, the 4-methylene-dioxy | (1S, 2R)-3-[(1,3-benzo dioxole-5-ylmethyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl t-butyl carbamate |
| 155 | H 2N-CH 2-phenyl-3, the 5-dimethoxy | (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3, the 5-dimethoxy-benzyl) amino]-2-hydroxypropyl t-butyl carbamate |
| 156 | H 2N-CH 2-phenyl-3-CF 3 | (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } the propyl carbamic acid tert-butyl ester |
| 157 | H 2N-CH 2-(furans-2-yl) | (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(2-furyl methyl) amino]-2-hydroxypropyl t-butyl carbamate |
| 158 | H 2N-(7-methoxyl group-1,2,3,4-tetralin-1-yl) | (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(7-methoxyl group-1,2,3,4-tetrahydrochysene-1-naphthyl) amino] the propyl carbamic acid tert-butyl ester |
| 159 | H 2N-CH 2-phenyl-3-O-CF 3 | (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(trifluoromethoxy) benzyl] amino } the propyl carbamic acid tert-butyl ester |
| 160 | H 2N-CH 2-phenyl-3-fluorine | (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-luorobenzyl) amino]-2-hydroxypropyl t-butyl carbamate |
| 161 | H 2N-CH 2-phenyl-3-O-CH (CH 3) 2 | (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-isopropoxide benzyl) amino] the propyl carbamic acid tert-butyl ester |
| 162 | H 2N-CH 2-phenyl-3-bromine | (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-bromobenzyl) amino]-2-hydroxypropyl t-butyl carbamate |
| 163 | H 2N-CH 2-(5-methyl furan-2-yl) | (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(5-methyl-2-furyl) methyl] amino } the propyl carbamic acid tert-butyl ester |
| 164 | H 2N-(5-methoxyl group-1,2,3,4-tetralin-1-yl) | (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(5-methoxyl group-1,2,3,4-tetrahydrochysene-1-naphthyl) amino] the propyl carbamic acid tert-butyl ester |
Embodiment 165 tertiary butyls-(1S, 2R)-3-azido--1-(3, the 5-difluorobenzyl)-2-hydroxypropyl carbamate (XII)
At the tertiary butyl (1S)-2-(3, the 5-difluorophenyl)-1-[(2S)-Oxyranyle] ethyl carbamate (V, embodiment 3,0.6 can, 2 mmoles) in add sodiumazide (0.22 gram, 4 mmoles) and ammonium chloride (2eq).With 75-80 ℃ of the reactant heating and stirred 16 hours.React completely guaranteeing by the TLC monitoring reaction.Solvent is removed in decompression.Make concentrate phase-splitting between ethyl acetate and water, separate each phase and clean organic phase,, make title compound, TLC (ethyl acetate/hexane) R through anhydrous sodium sulfate drying and concentrated with supercarbonate and salt solution
f=0.45; MS (MH
+)=343.
Embodiment 166 (2R, 3S)-3-amino-1-azido--4-(3, the 5-difluorophenyl)-2-butanols (XIV)
With the tertiary butyl-(1S, 2R)-3-azido--1-(3, the 5-difluorobenzyl)-2-hydroxypropyl carbamate (XII, embodiment 165,0.48 gram, 1.41 mmoles) is dissolved in methylene dichloride (20 milliliters), adds trifluoroacetic acid (5 milliliters) therein.Reactant was stirred 16 hours at 20-25 ℃, and decompression adds the heat abstraction solvent.Add ethyl acetate twice, and can evaporate twice, make the title compound of trifluoroacetic acid salt form, it promptly is used for next reaction without further purification; MS (MH
+)=242.
Embodiment 167 N
1-[(1S, 2R)-3-azido--1-(3, the 5-difluorobenzyl)-2-hydroxypropyl] 5-methyl-N
3, N
3-dipropyl isophthaloyl amine (XV)
At (2R, 3S)-and 3-amino-1-azido--4-(3, the 5-difluorophenyl)-2-butanols (XIV, embodiment 166,0.34 gram, 1.4 add N in methylene dichloride mmole) (20 milliliters) solution, N-two propionamido m-phthalic acids (IX, 0.53 gram, 2 mmoles), the trimethyl carbinol (0.27 gram, 2 mmoles) and triethylamine (0.84 milliliter, 6 mmoles) and ethyl-1-(3-dimethylamino-propyl) carbodiimide (0.58 gram, 3 mmoles).This mixture was stirred 16 hours at 20-25 ℃.By TLC (ethanol/methylene, 20/80+ ethyl acetate/hexane, 50.50; R
f=0.76) monitoring reaction.When the TLC assaying reaction is finished, make reaction mixture phase-splitting between methylene dichloride and water, clean with hydrochloric acid (0.5N), supercarbonate, salt solution, through anhydrous sodium sulfate drying, and decompression adds the heat abstraction solvent, makes concentrate.On silica gel,, make title compound by column chromatography separating and concentrating thing; MS (MH
+)=488.
Embodiment 168 N
1-[(1S, 2R)-3-amino-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine acetate (XVI)
With N
1-[(1S, 2R)-3-azido--1-(3, the 5-difluorobenzyl)-2-hydroxypropyl] 5-methyl-N
3, N
3The mixed solution of-dipropyl isophthaloyl amine (XV, embodiment 167,0.3 grams, 0.62 mmole) in ethyl acetate (20 milliliters) and acetate (5 milliliters) adds a Pa Er pressure bottle.Add palladium-carbon (10%, 5 gram), and with mixture shake 2 hours under the nitrogen atmosphere of 50psi.Concentrate through this mixture of diatomite filtration and with filtrate, make title compound; MS (MH
+)=462.
Embodiment 169 N
1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(2-furyl methyl) amino]-the 2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine (X)
With N
1-[(1S, 2R)-3-amino-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine acetate (XVI, 168,76 milligrams of embodiment, 0.146 mmole) is dissolved in raw spirit (2 milliliters).Under 20-25 ℃, when stirring, add 3-furfural (20 microlitres, 0.231 mmole) and triethylamine (30 microlitres by syringe, 0.215 mmole), after 10 minutes, add palladium-carbon (122 milligrams 5wt%) and with mixture placed nitrogen atmosphere (50psi) under also shake 20 minutes.Then with the mixture that makes through diatomite filtration, clean with ethanol simultaneously.By flash chromatography (2-10% ethanol/methylene) purification filtrate, make the title compound of purifying, MS (MH
+)=542.2.
Embodiment 169a (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(1S)-2-(ethylamino)-1-methyl-2-oxoethyl] amino }-2-hydroxypropyl t-butyl carbamate (VII)
General procedure according to embodiment 4 and 14-164, do not do key change and with (1S)-2-(3, the 5-difluorophenyl)-1-[(2S)-Oxyranyle] the ethyl carbamic acid tert-butyl ester (V, embodiment 3) with (2S)-reaction of 2-amino-N-ethyl propionic acid amide (VI), make title compound.
Embodiment 170-320
According to the general procedure of embodiment 5, do not do key change, just protecting alcohol (VII) with the quilt of hurdle A is raw material, makes the amine (VIII) of hurdle B thus.
The quilt that hurdle A has listed with number expression of above-mentioned specific embodiment protects alcohol (VII).
| Embodiment | A | Hurdle B amine (VIII) |
| 170 | 14 | (2R, 3S)-3-amino-1-(ethylamino)-4-phenyl-2-butanols |
| 171 | 15 | (2R, 3S)-3-amino-1-(benzylamino)-4-phenyl-2-butanols |
| 172 | 16 | (2R, 3S)-3-amino-1-(isopropylamino)-4-phenyl-2-butanols |
| 173 | 17 | (2R, 3S)-3-amino-1-[(4-xylyl) amino]-4-phenyl-2-butanols |
| 174 | 18 | (2R, 3S)-3-amino-1-{[2-(4-p-methoxy-phenyl) ethyl] amino }-4-phenyl-2-butanols |
| 175 | 19 | (2R, 3S)-3-amino-1-[(3-methoxy-benzyl) amino]-4-phenyl-2-butanols |
| 176 | 20 | Ethyl [(2R, 3S)-3-amino-2-hydroxy-4-phenyl butyl] amino } (phenyl) acetic ester |
| 177 | 21 | (2R, 3S)-3-amino-4-phenyl-1-[(2-styroyl) amino]-the 2-butanols |
| 178 | 22 | (2S)-2-{[(2R, 3S)-3-amino-2-hydroxy-4-phenyl butyl] amino }-1-(4-nitrophenyl)-1, ammediol |
| 179 | 23 | (2R, 3S)-3-amino-1-[(2-benzyl chloride base) amino]-4-phenyl-2-butanols |
| 180 | 24 | (2R, 3S)-3-amino-1-[(4-benzyl chloride base) amino]-4-phenyl-2-butanols |
| 181 | 25 | (2R, 3S)-3-amino-1-{[2-(2-hydroxyl-oxethyl) ethyl] amino }-4-phenyl-2-butanols |
| 182 | 26 | (2R, 3S)-3-amino-1-(2,3-dihydro-1H-indenes-1-base is amino)-4-phenyl-2-butanols |
| 183 | 27 | (2R, 3S)-3-amino-1-[(2-hydroxypropyl) amino]-4-phenyl-2-butanols |
| 184 | 28 | (2R, 3S)-3-amino-4-phenyl-1-[(tetrahydrochysene-2-furyl methyl) amino] the 2-butanols |
| 185 | 29 | (2R, 3S)-3-amino-1-[(2,2-diethoxy ethyl) amino]-4-phenyl-2-butanols |
| 186 | 30 | (2R, 3S)-3-amino-1-(fourth amino)-4-phenyl-2-butanols |
| 187 | 31 | (2R, 3S)-3-amino-1-(hexamethylene amino)-4-phenyl-2-butanols |
| 188 | 32 | (2R, 3S)-3-amino-4-phenyl-1-[(2-pyridylmethyl) amino]-the 2-butanols |
| 189 | 33 | (2R, 3S)-3-amino-1-[(2-aminobenzyl) amino]-4-phenyl-2-butanols |
| 190 | 34 | (2R, 3S)-3-amino-4-phenyl-1-[(3-pyridylmethyl) amino]-the 2-butanols |
| 191 | 35 | (2R, 3S)-3-amino-4-phenyl-1-{[2-(1-pyrrolidyl) ethyl] amino }-the 2-butanols |
| 192 | 36 | (2R, 3S)-3-amino-1-[(2-hydroxyl-2-styroyl) amino]-4-phenyl-2-butanols |
| 193 | 37 | (2R, 3S)-3-amino-1-[(3-butoxy propyl group) amino]-4-phenyl-2-butanols |
| 194 | 38 | (2R, 3S)-3-amino-1-[(3-isopropoxide propyl) amino]-4-phenyl-2-butanols |
| 195 | 39 | (2R, 3S)-3-amino-1-(isoamylamino)-4-phenyl-2-butanols |
| 196 | 40 | (2R, 3S)-3-amino-4-phenyl-1-[(3-hydrocinnamyl) amino]-the 2-butanols |
| 197 | 41 | (2R, 3S)-3-amino-1-[(2-methoxy ethyl) amino]-4-phenyl-2-butanols |
| 198 | 42 | (2R, 3S)-3-amino-1-[(2-phenoxy group ethyl) amino]-4-phenyl-2-butanols |
| 199 | 43 | (2R, 3S)-3-amino-4-phenyl-1-[(2-propoxy-ethyl) amino]-the 2-butanols |
| 200 | 44 | (2R, 3S)-3-amino-1-[(3, the 3-dimethylbutyl) amino]-4-phenyl-2-butanols |
| 201 | 45 | (2R, 3S)-3-amino-4-phenyl-1-[(4-benzene butyl) amino]-the 2-butanols |
| 202 | 46 | (2R, 3S)-3-amino-1-[(3-iodine benzyl) amino]-4-phenyl-2-butanols |
| 203 | 47 | (2R, 3S)-3-amino-1-[(4-nitrobenzyl) amino]-4-phenyl-2-butanols |
| 204 | 48 | (2R, 3S)-3-amino-1-[(3-benzyl chloride base) amino]-4-phenyl-2-butanols |
| 205 | 49 | (2R, 3S)-3-amino-1-{[2-(4-chloro-phenyl-) ethyl] amino }-4-phenyl-2-butanols |
| 206 | 50 | (2R, 3S)-3-amino-4-phenyl-1-{[2-(2-pyridyl) ethyl] amino }-the 2-butanols |
| 207 | 51 | (2R, 3S)-3-amino-4-phenyl-1-[(4-pyridylmethyl) amino]-the 2-butanols |
| 208 | 52 | (2R, 3S)-3-amino-1-{[2-(1-methyl-2-pyrrolinyl) ethyl] amino }-4-phenyl-2-butanols |
| 209 | 53 | (2R, 3S)-3-amino-1-[(2, the 3-dimethyl benzyl) amino]-4-phenyl-2-butanols |
| 210 | 54 | (2R, 3S)-3-amino-4-phenyl-1-{[2-(trifluoromethoxy) benzyl] amino }-the 2-butanols |
| 211 | 55 | (2R, 3S)-3-amino-1-[(2-chloro-6-phenoxy benzyl) amino]-4-phenyl-2-butanols |
| 212 | 56 | (2R, 3S)-3-amino-4-phenyl-1-{[4-(trifluoromethyl) benzyl] amino } the 2-butanols |
| 213 | 57 | (2R, 3S)-3-amino-1-[(2, the 3-dichloro benzyl) amino]-4-phenyl-2-butanols |
| 214 | 58 | (2R, 3S)-3-amino-1-[(3, the 5-dichloro benzyl)]-4-phenyl-2-butanols |
| 215 | 59 | (2R, 3S)-3-amino-1-[(3, the 5-difluorobenzyl)]-4-phenyl-2-butanols |
| 216 | 60 | (2R, 3S)-3-amino-4-phenyl-1-{[4-(trifluoromethoxy) benzyl] amino }-the 2-butanols |
| 217 | 61 | 4-([(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl] amino } methyl) benzsulfamide |
| 218 | 62 | (2R, 3S)-3-amino-1-[(4-methoxy-benzyl) amino]-4-phenyl-2-butanols |
| 219 | 63 | (2R, 3S)-3-amino-1-[(4-methyl-benzyl) amino]-4-phenyl-2-butanols |
| 220 | 64 | (2R, 3S)-3-amino-4-phenyl-1-[(3,4,5-trimethoxy benzyl) amino]-the 2-butanols |
| 221 | 65 | (2R, 3S)-3-amino-4-phenyl-1-{[3-(trifluoromethoxy) benzyl] amino }-the 2-butanols |
| 222 | 66 | (2R, 3S)-3-amino-1-[(3, the 5-dimethoxy-benzyl) amino]-4-phenyl-2-butanols |
| 223 | 67 | (2R, 3S)-3-amino-1-[(2, the 4-dimethoxy-benzyl) amino]-4-phenyl-2-butanols |
| 224 | 68 | (2R, 3S)-3-amino-1-[([1,1 '-phenylbenzene]-the 3-ylmethyl) amino]-4-phenyl-2-butanols |
| 225 | 69 | (2R, 3S)-3-amino-1-[(3, the 4-dichloro benzyl) amino]-4-phenyl-2-butanols |
| 226 | 70 | (2R, 3S)-3-amino-1-[(2-luorobenzyl) amino]-4-phenyl-2-butanols |
| 227 | 71 | (2R, 3S)-3-amino-4-phenyl-1-{[3-(trifluoromethyl) benzyl] amino }-the 2-butanols |
| 228 | 72 | (2R, 3S)-3-amino-1-[(2-methyl-benzyl) amino]-4-phenyl-2-butanols |
| 229 | 73 | (2R, 3S)-3-amino-4-phenyl-1-{[(1R)-the 1-styroyl] amino } the 2-butanols |
| 230 | 74 | (2R, 3S)-3-amino-4-phenyl-1-{[(1S)-the 1-styroyl] amino }-the 2-butanols |
| 231 | 75 | (2R, 3S)-3-amino-1-{[3, two (trifluoromethyl) benzyls of 5-] amino }-4-phenyl-2-butanols |
| 232 | 76 | (2R, 3S)-3-amino-4-phenyl-1-{[2-(trifluoromethyl) benzyl] amino }-the 2-butanols |
| 233 | 77 | (2R, 3S)-3-amino-1-{[(1R)-1-(1-naphthyl) ethyl] amino }-4-phenyl-2-butanols |
| 234 | 78 | (2R, 3S)-3-amino-1-{[(1S)-1-(1-naphthyl) ethyl] amino }-4-phenyl-2-butanols |
| 235 | 79 | 4-([(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl] amino } methyl)-the 2-methoxyphenol |
| 236 | 80 | 4-([(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl] amino } methyl)-1, the 2-dihydroxy-benzene |
| 237 | 81 | (2R, 3S)-3-amino-1-[(3-methoxy-propyl) amino]-4-phenyl-2-butanols |
| 238 | 82 | (2R, 3S)-3-amino-1-{[(1S)-2-hydroxyl-1-methylethyl] amino }-4-phenyl-2-butanols |
| 239 | 83 | (2R, 3S)-3-amino-1-{[(1R)-2-hydroxyl-1-methylethyl] amino }-4-phenyl-2-butanols |
| 240 | 84 | (2R, 3S)-3-amino-4-phenyl-1-(2-propynyl amino)-2-butanols |
| 241 | 85 | (2R, 3S)-3-amino-1-{[2-(2-fluorophenyl) ethyl] amino }-4-phenyl-2-butanols |
| 242 | 86 | (2R, 3S)-3-amino-1-{[2-(3-fluorophenyl) ethyl] amino }-4-phenyl-2-butanols |
| 243 | 87 | (2R, 3S)-3-amino-1-{[2-(4-fluorophenyl) ethyl] amino }-4-phenyl-2-butanols |
| 244 | 88 | (2R, 3S)-3-amino-1-{[2-(4-bromophenyl) ethyl] amino }-4-phenyl-2-butanols |
| 245 | 89 | (2R, 3S)-3-amino-1-{[2-(3-p-methoxy-phenyl) ethyl] amino }-4-phenyl-2-butanols |
| 246 | 90 | (2R, 3S)-3-amino-1-{[2-(2,4 dichloro benzene base) ethyl] amino }-4-phenyl-2-butanols |
| 247 | 91 | (2R, 3S)-3-amino-1-{[2-(3-chloro-phenyl-) ethyl] amino }-4-phenyl-2-butanols |
| 248 | 92 | (2R, 3S)-3-amino-1-{[2-(2, the 5-Dimethoxyphenyl) ethyl] amino }-4-phenyl-2-butanols |
| 249 | 93 | (2R, 3S)-3-amino-1-{[2-(4-aminomethyl phenyl) ethyl] amino }-4-phenyl-2-butanols |
| 250 | 94 | (2R, 3S)-3-amino-1-{[(1R)-1-benzyl-2-hydroxyethyl] amino }-4-phenyl-2-butanols |
| 251 | 95 | (2R, 3S)-3-amino-1-{[3-(4-morpholinyl) propyl group } amino }-4-phenyl-2-butanols |
| 252 | 96 | (2R, 3S)-3-amino-1-(isobutylamino)-4-phenyl-2-butanols |
| 253 | 97 | (2R, 3S)-3-amino-1-{[2-(4 morpholinyl) ethyl] amino }-4-phenyl-2-butanols |
| 254 | 98 | (2R, 3S)-3-amino-4-phenyl-1-[2-hydroxyl butyl] amino]-the 2-butanols |
| 255 | 99 | (2R, 3S)-3-amino-4-phenyl-1-{[2-(2-thienyl) ethyl] amino }-the 2-butanols |
| 256 | 100 | 4-{[(2R, 3S)]-3-amino-2-hydroxyl-4-benzene butyl] amino }-the 1-butanols |
| 257 | 101 | (2R, 3S)-3-amino-1-{[(1S)-2-hydroxyl-1-styroyl] amino }-4-phenyl-2-butanols |
| 258 | 102 | (2R, 3S)-3-amino-1-[(2, the 4-dichloro benzyl) amino]-4-phenyl-2-butanols |
| 259 | 103 | (28,3S)-3-amino-1-{[(1R)-2-hydroxyl-1-styroyl] amino }-4-phenyl-2-butanols |
| 260 | 104 | (2R, 3S)-3-amino-1-[(4-tertiary butyl benzyl) amino]-4-phenyl-2-butanols |
| 261 | 105 | (2R, 3S)-3-amino-4-phenyl-1-[(1-styroyl) amino]-the 2-butanols |
| 262 | 106 | (1R, 2S)-1-{[(2R, 3S)-3-amino-2-hydroxy-4-phenyl butyl] amino }-2,3-dihydro-1H-indenes-2-alcohol |
| 263 | 107 | (2R, 3S)-3-amino-1-[(3, the 4-dimethyl benzyl) amino]-4-phenyl-2-butanols |
| 264 | 108 | 7-{[(2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl] amino } Methylheptanoate |
| 265 | 109 | 2-{[(2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl] amino }-N-isobutyl-propionic acid amide |
| 266 | 110 | (2S)-2-{[(2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl] amino }-N-isobutyl-propionic acid amide |
| 267 | 111 | 2-{[(2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl] amino }-N-isobutyl--2-methyl propanamide |
| 268 | 112 | 2-{[(2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl] amino }-N-isobutyl-ethanamide |
| 269 | 113 | (2S)-2-{[(2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl] amino }-N-isobutyl-butyramide |
| 270 | 114 | (2R)-2-{[(2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl] amino }-N-isobutyl-butyramide |
| 271 | 115 | (2R, 3S)-3-amino-1-(benzyl amino)-4-(3, the 5-difluorophenyl)-2-butanols |
| 272 | 116 | (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-(ethylamino)-2-butanols |
| 273 | 117 | (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-(isobutylamino)-2-butanols |
| 274 | 118 | 3-{[(2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl] amino }-N-isobutyl--2-methyl propanamide |
| 275 | 119 | (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-{[4-(dimethylamino) benzyl] amino }-the 2-butanols |
| 276 | 120 | (2S)-2-{[(2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl] amino }-N-isobutyl--3-Phenylpropionamide |
| 277 | 121 | (2S)-2-{[(2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl] amino }-N-isobutyl--3-methyl propanamide |
| 278 | 122 | (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-{[2-(dimethylamino) ethyl] amino }-the 2-butanols |
| 279 | 123 | (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(3-pyridylmethyl) amino]-the 2-butanols |
| 280 | 124 | (2S)-2-{[(2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl] amino }-3-(benzyloxy)-N-isobutyl-propionic acid amide |
| 281 | 125 | (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(1-methyl isophthalic acid-styroyl) amino]-the 2-butanols |
| 282 | 126 | (2R)-2-{[(2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl] amino }-N-isobutyl--3-methylbutyryl amine |
| 283 | 127 | (2S)-2-{[(2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl] amino }-N-isobutyl-valeramide |
| 284 | 128 | (2S)-2-{[(2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl] amino }-the 3-hydroxyl |
| Base-N-isobutyl-propionic acid amide | ||
| 285 | 129 | (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(2-styroyl) amino]-the 2-butanols |
| 286 | 130 | (2S)-2-{[(2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl] amino }-N-benzyl propionic acid amide |
| 287 | 131 | (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-{[(1S)-1-hydrocinnamyl] amino }-the 2-butanols |
| 287a | 169a | (2S)-2-{[(2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl] amino }-N-ethyl propionic acid amide |
| 288 | 132 | (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(3-methoxy-benzyl) amino]-the 2-butanols |
| 289 | 133 | (2S)-2-{[(2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-2-hydroxybutyl] amino }-N-isobutyl--2-phenyl-acetamides |
| 290 | 134 | (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-(isopentyl amino)-2-butanols |
| 291 | 135 | (2R, 3S)-3-amino-1-(hexamethylene amino)-4-(3, the 5-difluorophenyl)-2-butanols |
| 292 | 136 | (2R, 3S)-3-amino-1-(fourth amino)-4-(3, the 5-difluorophenyl)-2-butanols |
| 293 | 137 | (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(3-methoxy-propyl) amino]-the 2-butanols |
| 294 | 138 | (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(2-hydroxyl-2-styroyl) amino]-the 2-butanols |
| 295 | 139 | (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-{[(3R, 5S)-3,5-dimethoxy cyclohexyl] amino }-the 2-butanols |
| 296 | 140 | (1R, 3S)-5-{[(2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-2-hydroxybutyl] amino }-1, the 3-dimethyl hexahydrophthalate |
| 297 | 141 | Dimethyl (1R, 3S)-5-{[(2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-2-hydroxybutyl] amino }-1, the 3-cyclohexane cyclohexanedimethanodibasic |
| 298 | 142 | (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-{[(1R)-1-hydrocinnamyl] amino }-the 2-butanols |
| 299 | 143 | (2R, 3S)-3-amino-1-[(3-benzyl chloride base) amino]-4-(3, the 5-difluorophenyl)-2-butanols |
| 300 | 144 | (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(3-methoxy-benzyl) amino]-the 2-butanols |
| 301 | 145 | (2R, 3S)-3-amino-1-[([1,1 '-phenylbenzene]-the 3-ylmethyl) amino]-4-(3, the 5-difluorophenyl)-2-butanols |
| 302 | 146 | (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(3-iodine benzyl) amino]-the 2-butanols |
| 303 | 147 | (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(3-methyl-benzyl) amino]-the 2-butanols |
| 304 | 148 | (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(2-hydrocinnamyl) amino]-the 2-butanols |
| 305 | 149 | (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(1,3-thiazole-5-ylmethyl) amino]-the 2-butanols |
| 306 | 150 | (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(2-thienyl methyl) amino]-the 2-butanols |
| 307 | 151 | (2R, 3S)-3-ammonia-4-(3, the 5-difluorophenyl)-1-[(5-methoxyl group-1,2,3,4-tetrahydrochysene-1-naphthyl) amino]-the 2-butanols |
| 308 | 152 | (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(2-pyrazinyl methyl) amino]-the 2-butanols |
| 309 | 153 | (2R, 3S)-3-amino-1-[(3, the 5-difluorobenzyl) amino]-4-(3, the 5-difluorophenyl)-2-butanols |
| 310 | 154 | (2R, 3S)-3-amino-1-[(1,3-benzo dioxole-5-yl) amino]-4-(3, the 5-difluorophenyl)-2-butanols |
| 311 | 155 | (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(3, the 5-dimethoxy-benzyl) amino]-the 2-butanols |
| 312 | 156 | (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-{[3-(trifluoromethyl) benzyl] amino }-the 2-butanols |
| 313 | 157 | (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(2-furyl methyl) amino]-the 2-butanols |
| 314 | 158 | (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(7-methoxyl group-1,2,3,4-tetrahydrochysene-1-naphthyl) amino]-the 2-butanols |
| 315 | 159 | (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-{[3-(trifluoromethoxy) benzyl] amino }-the 2-butanols |
| 316 | 160 | (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(3-luorobenzyl) amino]-the 2-butanols |
| 317 | 161 | (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(3-isopropoxide benzyl) amino]-the 2-butanols |
| 318 | 162 | (2R, 3S)-3-amino-1-[(3-bromobenzyl) amino]-4-(3, the 5-difluorophenyl)-2-butanols |
| 319 | 163 | (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(5-methyl-2-furyl methyl) amino]-the 2-butanols |
| 320 | 164 | (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(5-methoxyl group-1,2,3,4-tetrahydrochysene-1-naphthyl) amino]-the 2-butanols |
Embodiment 587 N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
3, N
3-dipropyl-1,3,5-benzene triamide (X)
At 3-(aminocarboxyl)-5-[(dipropyl amino) carbonyl] phenylformic acid (IX, goods 6,0.18 gram, 0.616 mmole) in the mixture in dry DMF (16 milliliters), add EDC (0.182 gram, 0.9 mmole), HOBT (0.127 gram, 0.9 mmole), triethylamine (0.062 gram, 0.616 mole) and (2R, 3S)-and 3-amino-1-[(3-methoxy-benzyl) amino]-4-phenyl-2-butanols (VIII, embodiment 175,0.185 grams, 0.616 mmole).This mixture was stirred 3 days at 20-25 ℃.Make the phase-splitting between water and ethyl acetate of this mixture.Separating each cleans three times mutually and with the organic phase water.Organic phase is filtered and is concentrated through anhydrous magnesium sulfate drying.Column chromatography is separated (silica gel, 75 milliliters; Ethanol/methylene, 10/90) makes title compound, IR (diffuse-reflectance) 3306,3301,3270,2962,1676,1667,1663,1645,1638,1627,1615,1550,1537,1450 and 1439cm
-1NMR (CDCl
3) δ 0.645,0.968,1.20,1.43,1.67,2.8,2.97,3.38,3.47,3.73,3
Embodiment 588 (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3[(3-iodine benzyl) amino] the propyl carbamic acid 1-tert-butyl ester (VII)
With (1S)-2-(3, the 5-difluorophenyl)-1-[(2S)-Oxyranyle] the ethyl carbamic acid tert-butyl ester (V, embodiment 3,1.75 gram, 5.8 mmoles) mixes with Virahol (30 milliliters).In reaction flask, add 3-iodine benzyl amine (VI).With reaction mixture reflux 45 minutes, HPLC analysis revealed epoxide (V) completely dissolve.With the reaction mixture concentrating under reduced pressure, and make resistates phase-splitting between ethyl acetate (150 milliliters) and aqueous hydrochloric acid (3%, 35 milliliter).Separate organic phase and use aqueous hydrochloric acid (3%, 20 milliliter), supercarbonate, salt solution to clean, and through dried over sodium sulfate.Concentrating under reduced pressure obtains title compound, M+H=535.
Embodiment 589 (2R, 3S)-3-(3-tert-butoxycarbonyl) amino-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl (3 '-iodine benzyl) carboxylamine 1-9H-fluorenes-9-base methyl ester hydrochloride (XXXIV)
Will (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3[(3-iodine benzyl) amino] the propyl carbamic acid 1-tert-butyl ester (VII, embodiment 588,2.5 grams, 4.7 mmoles) and triethylamine (0.72 milliliter, 5.1 mmoles) mix in THF (10 milliliters).Reactant is cooled to 0 ℃ and by THF (2 milliliter) solution-treated of feed hopper with FMOC-C1 (1.2 gram, 4.7 mmoles).After 15 minutes, HPLC shows the starting material completely dissolve.With ethyl acetate diluting reaction thing, and clean with aqueous potassium hydrogen sulfate, supercarbonate saturated aqueous solution, salt solution, and through dried over sodium sulfate.Concentrating under reduced pressure obtains crude product, by the flash chromatography partition method, use eluent ethyl acetate again with ethyl acetate/hexane (20/80), thereby crude product is purified, and makes title compound, M+H=757.Embodiment 590 (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl (3-iodine benzyl) carboxylamine 1-9H-fluorenes-9-base methyl ester hydrochloride (XXXV)
Will (2R, 3S)-3-(3-tert-butoxycarbonyl) amino-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl (3 '-iodine benzyl) carboxylamine 1-9H-fluorenes-9-base methyl ester hydrochloride (XXXIV, embodiment 589,2.9 grams) adds in the hydrochloric acid/diox (4N, 10 milliliters).This mixture was stirred 1 hour, slowly pour into then in the ether (200 milliliters) of quick stirring.This product is filtered and drying, make title compound, M+H=657.
Embodiment 591 (2R, 3S)-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl-{ [5-oxo-5-(piperidino) pentanoyl] amino } butyl (3-iodine benzyl) carboxylamine 1-9H-fluorenes-9-base methyl esters (XXXIV)
HOBt (81 milligrams, 0.6 mmole) and EDC (105 milligrams, 0.55 mmole) are added in DMF (2 milliliters) solution of 1-carboxyl-5-piperidyl glutaramide (IX, 100 milligrams, 0.5 mmole).With this acid activation 60 minutes, use then (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl (3-iodine benzyl) carboxylamine 1-9H-fluorenes-9-base methyl ester hydrochloride (XXXV, 590,300 milligrams of embodiment, 0.43 mmole) and NMM (0.19 milliliter, 1.72 mmoles) handle.Reactant was stirred 3 hours, then concentrating under reduced pressure.Make resistates phase-splitting in the ethyl acetate and the saturated bicarbonate aqueous solution.Clean organic phase with saturated sal enixum, salt solution,, make crude product through dried over sodium sulfate and final concentrating under reduced pressure.By use methanol/ethyl acetate (10/90) to purify then with ethyl acetate/hexane (50/50), make title compound, M+H=838 by flash chromatography.Embodiment 5921-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-5-oxo-5-(piperidino) valeramide trifluoro-acetate (X)
1-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-5-oxo-5-(piperidino) valeramide trifluoro-acetate (XXXVI, embodiment 591,240 milligrams, 0.29 mmole) be dissolved in the dichloromethane solution of diethylamine (10%, 9 milliliter).This reactant is spent the night 20-25 ℃ of stirring.With the reactant concentrating under reduced pressure, and be dissolved in methylene dichloride again with resistates second day morning, and by preparation reversed-phase HPLC purifying.Suitable cut is compiled, and concentrating under reduced pressure, and phase-splitting between ethyl acetate and the salt solution again.Separate organic phase and, make title compound, M+H=614 through dried over sodium sulfate and concentrated.
Embodiment 593 5-(amino-sulfonyl)-N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
3, N-dipropyl isophthaloyl amine (X)
At 3-(amino-sulfonyl)-5-[(dipropyl amino)-carbonyl] phenylformic acid (XXXIX, goods 13,0.0800 grams; 0.244 mmole) and (2R, 3S)-3-amino-1-[(3-methoxy-benzyl) amino]-4-phenyl-2-butanols (VIII, embodiment 175; 0.0732 gram; 0.244 mmole) in the mixture in dry DMF (3 milliliters), add O-(7-azepine benzo triazol-1-yl)-N, N; N '; N '-tetramethyl-urea hexafluorophosphate (HATU, 0.0928 gram, 0.244 mmole).This mixture was stirred 18 hours at 20-25 ℃, make its phase-splitting between ethyl acetate and water then.Separate organic phase and,, filter also concentrated through anhydrous sodium sulfate drying with the salt solution cleaning.This concentrate is carried out column chromatography (silica gel; Ethanol/methylene, 5/95) separate, make title compound, C
32H
42N
4O
6The MS of S (ESI+) m/z (M+H)
+=611.5; To C
32H
42N
4O
6S+H
1RMS (FAB) calculated value=611.2903, measured value=611.2904.
Embodiment 620 N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-5-ethyl-N
3, N
3-dipropyl isophthaloyl amine (X)
At 3-[(dipropyl amino) carbonyl]-5-ethyl benzoate (IX, goods 21,0.200 gram, 0.720 mmole), (2R, 3S)-3-amino-1-[(3-methoxy-benzyl) amino]-4-phenyl-2-butanols (VIII, embodiment 175,0.216 the milligram, 0.720 mmole) and the mixture of triethylamine (0.121 milliliter, 0.870 mmole) in methylene dichloride (3 milliliters) in, add diethyl phosphorocyanidate (0.132 milliliter, 0.870 mmole).This mixture was stirred 1 hour at 20-25 ℃.Methylene dichloride is removed in decompression then.Make resistates phase-splitting between ethyl acetate and water.Separate organic phase and,, filter also concentrated through anhydrous sodium sulfate drying with the salt solution cleaning.This concentrate is carried out column chromatography (silica gel; Ethanol/methylene, 5/95) separate, make title compound, C
34H
45N
3O
4MS (ESI+) m/z (M+H)
+=560.4; To C
34H
45N
3O
4The HOURMS of+H (FAB) calculated value=560.3488, measured value=560.3487.
Embodiment 629 N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-[butyryl radicals (propyl group) amino]-5-methyl benzamide (X)
According to the program of embodiment 570 and do not do key change; at 3-[butyryl radicals (propyl group) amino]-5-tolyl acid (IX; 0.120 gram; 0.460 mmole), (2R, 3S)-3-amino-1-[(3-methoxy-benzyl) amino]-4-phenyl-2-butanols (VIII, 0.137 gram; 0.460 mmole) and (0.0760 milliliter of triethylamine; 0.550 mmole) in the mixture in methylene dichloride (5 milliliters), add diethyl phosphorocyanidate (0.0760 milliliter, 0.550 mmole).This mixture was stirred 1 hour at 20-25 ℃.Methylene dichloride is removed in decompression then.Make resistates phase-splitting between ethyl acetate and water.Separate organic phase and,, filter also concentrated through anhydrous sodium sulfate drying with the salt solution cleaning.This concentrate is carried out column chromatography (silica gel; Ethanol/methylene, 5/95) separate, make title compound, NMR (400MHz, CDCl
3) δ 7.09,4.15,3.80,3.79,3.60,3.02,2.84,2.36,1.94,1.56,1.49,0.87 and 0.81; C
33H
43N
3O
4MS (ESI+) m/z (M+H)
+=546.3; To C
33H
43N
3O
4The HRMS of+H (FAB) calculated value=546.3331, measured value=546.3331.
Embodiment 631 N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-1-propyl group-1H-indoles-6-acid amides (X)
Embodiment 682 N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-ethynyl-N
3, N
3-dipropyl isophthaloyl amine (X), (M+H)
+=590
Embodiment 739 N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-5-(cyanogen methyl)-N
3, N
3-dipropyl isophthaloyl amine (X)
Step 1. 20-25 ℃ with 1,3,5-benzene tricarbonic acid diethyl ester (5.2 gram) and borine methyl sulfide complex compound (6.1 restrain) stir in THF (150 milliliters) and spend the night.Handle this mixture with methyl alcohol then, be concentrated into driedly, the circumstances in which people get things ready for a trip of going forward side by side spectrums is separated (silica gel), makes 5-(methylol) m-phthalic acid diethyl ester.Use lithium hydroxide monohydrate (0.57 gram) in 20-25 ℃ of hydrolysis 3.5 hours in the second alcohol and water 5-(methylol) m-phthalic acid diethyl ester (3.4 gram), this moment, solvent was removed in decompression.Add entry (100 milliliters) and this mixture is acidified to pH=4 with concentrated hydrochloric acid.With this mixture of ethyl acetate extraction and through anhydrous magnesium sulfate drying, filter and concentrate, make 3-(ethoxy carbonyl)-5-(methylol) phenylformic acid, high resolving power MS MH+=225.0769.3-(ethoxy carbonyl)-5-(methylol) phenylformic acid (2.3 gram), EDC (3.0 gram), 1-HOBT (2.1 gram), diisopropylethylamine (2.7 milliliters), dipropyl amine (2.8 milliliters) and DMF (50 milliliters) are spent the night 20-25 ℃ of stirring.Make mixture phase-splitting between ethyl acetate, water and salt solution then.Separate organic phase and through anhydrous magnesium sulfate drying, filter also and concentrate.Chromatographic separation (silica gel) makes 3-[(dipropyl amino) carbonyl]-5-(methylol) ethyl benzoate, NMR (CDCl
3) δ 0.77,1.0,1.4,1.6,1.7,3.2,3.5,4.4,4.8,7.6,8.0 and 8.1.
Step 2. stirs 3-[(dipropyl amino in methylene dichloride (10 milliliters)) carbonyl]-mixture of 5-(methylol) ethyl benzoate (1.5 gram) and phosphorus tribromide (0.95 milliliter), and in 50 ℃ of heating 4 hours, cooling and phase-splitting between methylene dichloride and water then.Separate organic phase and,, obtain 3-(brooethyl)-5-[(dipropyl amino then through dried over mgso and to drying regime with the sodium bicarbonate aqueous solution cleaning) carbonyl] ethyl benzoate, high resolving power MS MH+=370.1020.With 3-(brooethyl)-5-[(dipropyl amino) carbonyl] ethyl benzoate (1.4 gram) and sodium cyanide (0.2 gram) in 20-25 ℃ of stirring 3.5 hours, make mixture phase-splitting between ethyl acetate, water and salt solution then in anhydrous DMSO (25 milliliters).Separate organic layer, and through dried over mgso and be decompressed to driedly, obtain 3-(cyano methyl)-5-[(dipropyl amino) carbonyl] ethyl benzoate.With 3-(cyanogen methyl)-5-[(dipropyl amino) carbonyl] ethyl benzoate (0.6 gram) spends the night in 20-25 ℃ of hydrolysis with lithium hydroxide monohydrate (0.1 restrains) in the second alcohol and water, adds then in the entry (50 milliliters).With concentrated hydrochloric acid the pH value is transferred to 4, and make mixture phase-splitting between ethyl acetate, water and salt solution.Separate organic phase and through anhydrous magnesium sulfate drying, and be decompressed to driedly, make 3-(cyanogen methyl)-5-[(dipropyl amino) carbonyl] phenylformic acid, MS M+H=287.2.
Step 3. is with 3-(cyanogen methyl)-5-[(dipropyl amino) carbonyl] phenylformic acid (IX, 0.13 (2R gram),, 3S)-and 3-amino-1-[(3-methoxy-benzyl) amino]-4-phenyl-2-butanols (VIII, 0.14 gram), HATU (0.17 gram) and methylene dichloride (10 milliliters) spend the night 40 ℃ of stirrings.After the cooling, the water washed mixture separates organic phase and through dried over mgso and be decompressed to dried.Chromatographic separation (silica gel) makes title compound, M+H=571.2.
Embodiment 710 N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-5-(methylol)-N
3, N
3-dipropyl isophthaloyl amine (X)
Program according to chart P and embodiment 739, remove and use 3-[(dipropyl amino) carbonyl]-5-(methylol) phenylformic acid (IX) and (2R, 3S)-and 3-amino-1-[(3-methoxy-benzyl) amino]-4-phenyl-2-butanols (VIII) is outer does not do key change, make title compound thus, HRMS (FAB)=615.3571.
Embodiment 741 N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-5-ethynyl-N
3, N
3-dipropyl isophthaloyl amine (X)
Step l: with 3-bromo-5-[(dipropyl amino) carbonyl] methyl benzoate (XXI, 200 milligrams, 0.58 mmole), PdCl
2(16 milligrams, 0.03mol%) and cupric iodide (I) (6 milligrams, 0.05mol%) mixture heating up in triethylamine (1.2 milliliters) is to refluxing.Add (trimethyl silyl) acetylene (100 microlitres, 0.7 mmole), and mixture was stirred 3 hours, be cooled to 20-25 ℃, water (20 milliliters) dilution is with chloroform (3 * 15 milliliters) extraction.Clean the organic extract liquid that merges with salt solution (20 milliliters),, make 3-[(dipropyl amino through dried over sodium sulfate and concentrating under reduced pressure) carbonyl]-5-acetylenylbenzene methyl-formiate (XXXII, 185.5 milligrams), NMR (300MHz, CDCl
3): δ 7.95,7.75,7.43,3.74,3.25,2.95,1.49,1.34,0.79,0.56 and 0.06.
Step 2: protect 3-[(dipropyl amino) carbonyl at quilt through stirring]-5-acetylenylbenzene methyl-formiate (XXXII, step 1,185.3 milligrams, 0.49 mmole) in the mixture in methyl alcohol (2.5 milliliters), add potassium hydroxide (2.9 milliliters of 1M mixtures in water, 2.9 mmoles) mixture.With reaction mixture stirring 4 hours, with chloroform (40 milliliters) dilution, separate each phase and concentrating under reduced pressure organic phase, make 3-[(dipropyl amino) carbonyl]-5-acetylenylbenzene formic acid, NMR (300MHz, CDCl
3): δ 8.22,8.05,7.71,3.48,3.17,3.16,1.7l, 1.55,1.00 and 0.78.
Step 3: at 3-[(dipropyl amino) carbonyl through stirring]-(70 milligrams in 5-acetylenylbenzene formic acid, 0.24 mmole) in the mixture in DMF (2.5 milliliters), add (2R, 3S)-and 3-amino-1-[(3-methoxy-benzyl) amino]-4-phenyl-2-butanols dihydrochloride (VIII, 81 milligrams, 0.24 mmole), HOBt (36 milligrams, 0.26 mmole) and diisopropylethylamine (170 microlitres, 0.96 mmole).In this reaction mixture, add EDC (51 milligrams, 0.26 mmole), and the reaction mixture stirring is spent the night.This reaction mixture is diluted with ethyl acetate (30 milliliters), and water (3 * 50 milliliters), hydrochloric acid (1N, 30 milliliters), saturated sodium bicarbonate (30 milliliters), salt solution (30 milliliters) clean, through dried over sodium sulfate and concentrating under reduced pressure.Purify by flash chromatography (silicon-dioxide, ethyl acetate-methyl alcohol/chloroform, 1/10), obtain title compound, IR (KBr): 3276,2956,2921,1610,1450 and 1264cm
-1ESI-MS (m/z) [M+H]
+=556.
Embodiment 742 N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-N
3, N
3-dipropyl-5-third-1-alkynyl isophthaloyl amine (X)
General procedure according to embodiment 741, do not do key change, only be to use propine to replace (trimethyl silyl) acetylene and use (2R, 3S)-and 3-amino-1-[(3-iodine benzyl) amino]-4-phenyl-2-butanols dihydrochloride (VIII) replacement (2R, 3S)-and 3-amino-1-[(3-methoxy-benzyl) amino]-4-phenyl-2-butanols dihydrochloride (VIII), make title compound thus.IR (ATR): 3305,2930,2872,1613 and 1537cm
-1ESI-MS (m/z) [M+H]
+=666.
Embodiment 743 N
1-((1S, 2R)-1-benzyl-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-5-ethynyl-N
3, N
3-dipropyl isophthaloyl amine (X)
Step 1: with (1S)-1-[(2S)-Oxyranyle]-2-styroyl t-butyl carbamate (V, 2.3 gram, 8.7 mmole) and the mixture heating up of 3-(trifluoromethyl) benzyl amine (VI, 1.9 milliliters, 13.1 mmoles) in 2-propyl alcohol (70 milliliters) refluxed 4 hours.Reaction mixture is cooled to 20-25 ℃, and concentrating under reduced pressure, make solid state (1S, 2R)-1-benzyl-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino the propyl carbamic acid tert-butyl ester (VII, 3.1 grams), ESI-MS (m/z) [M+H]
+=439.
Step 2: stir (1S at 20-25 ℃, 2R)-and 1-benzyl-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } the propyl carbamic acid tert-butyl ester (VII, step 1,2.5 grams, 5.7 mmole) and the mixture of hydrochloric acid (the 4.0M mixture in 29 milliliters of Zai dioxs, 114 mmoles).Form precipitation and pass through to filter collection, clean with ether, drying under reduced pressure, make (2R, 3S)-3-amino-4-phenyl-1-{[3-(trifluoromethyl) benzyl] amino }-2-butanols dihydrochloride (VIII, 2.13 grams), ESI-MS (m/z) [M+H]
+=339.
Step 3:
With 3-[(dipropyl amino) carbonyl]-5-acetylenylbenzene formic acid (IX, 231 milligrams, 0.8 (2R mmole),, 3S)-and 3-amino-4-phenyl-1-{[3-(trifluoromethyl) benzyl] amino }-2-butanols dihydrochloride (VIII, step 2,493.5 milligram, 1.2 mmole), HOBt is (162 milligrams, 1.2 mmole) and diisopropylethylamine (820 microlitres, 4.8 mixture mmole) stirred 15 minutes in methylene dichloride (4 milliliters), add EDC (206 milligrams, 1.2 mmoles), and the reaction mixture stirring is spent the night.This reaction mixture of dilute with water, and extract with methylene dichloride (3 * 25 milliliters).Water hydrochloric acid (1N, 25 milliliters), saturated sodium bicarbonate (25 milliliters), salt solution clean organic phase, through dried over sodium sulfate and concentrating under reduced pressure.Purify by flash chromatography (silicon-dioxide, 100% ethyl acetate-methyl alcohol/chloroform, 1/9), obtain title compound, IR (ATR): 3302,2963,2932 and 1615cm
-1MS (m/z) [M+H]
+=549.
Embodiment 744 N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-5-ethynyl-N
3, N
3-dipropyl isophthaloyl amine (X)
According to the general procedure of embodiment 744, except that using 3-iodine benzyl amide salt acidify salt (VI), do not do key change, make title compound thus, IR (ATR): 3295,2960,2927 and 1616cm
-1APCI-MS (m/z) [M+H]
+=652.
Embodiment 745 N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-luorobenzyl) amino]-the 2-hydroxypropyl }-5-ethynyl-N
3, N
3-dipropyl isophthaloyl amine (X)
According to the general procedure of embodiment 744, except that using 3-luorobenzyl acid amides (VI), do not do key change, make title compound thus, IR (ATR): 3217,2961,2918 and 1615cm
-1APCI-MS (m/z) [M+H]
+=544.
Embodiment 746 N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
3, N
3-dipropyl-5-(8-quinolyl) isophthaloyl amine (X)
Step 1: with methyl-3-bromo-5-[(dipropyl amino) carbonyl] benzoic ether (XLVIII, 200 milligrams, 0.58 mmole), 8-quinolineboronic acid (200.6 milligrams, 1.2 mmoles), yellow soda ash (the 2M mixture in water of 870 microlitres; 1.74 mmole) decompression of the mixture in toluene (6 milliliters) outgased 15 minutes and used argon purge.Add tetrakis triphenylphosphine palladium (139 milligrams, 0.12 mmole), and with the reaction mixture decompression degassing 15 minutes, and use argon purge.With reaction mixture heated overnight under refluxing, be cooled to 20-25 ℃ and dilute with chloroform.Separate organic phase and water (3 * 50 milliliters) and salt solution and clean, through dried over sodium sulfate and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, ethyl acetate/hexane, 1.3/1), obtain 3-[(dipropyl amino) carbonyl]-5-(8 quinolyl) methyl benzoate (XLIX, 176 milligrams), NMR (300MHz, CDCl
3): δ 8.91,8.42,8.21,8.09,7.95,7.86,7.77,7.64,3.94,3.49,3.34,1.64,0.99 and 0.84.
Step 2: at 3-[(dipropyl amino) carbonyl]-5-(8 quinolyl) methyl benzoate (XLIX, step 1,175.5 milligrams, 0.45 mmole) in the mixture in methyl alcohol (2 milliliters), the mixture that adds lithium hydroxide (32.3 milligrams, 1.4 mmoles) and water (500 microlitre).After stirring is spent the night, make reaction mixture phase-splitting between ethyl acetate (10 milliliters) and water (10 milliliters).Water phase separated, and with hydrochloric acid (1N) acidifying, and extract with chloroform (3 * 40 milliliters).Clean organic phase with salt solution, dry (sodium sulfate) and concentrating under reduced pressure make 3-[(dipropyl amino) carbonyl]-5-(8-quinolyl) phenylformic acid (IX-L, 130 milligrams), NMR (300MHz, CD
3OD): δ 8.84,8.39,8.35,8.05,7.96,7.90,7.87,7.79,7.68,3.50,3.37,1.76-1.61,0.99 and 0.84.
Step 3: with 3-[(dipropyl amino) carbonyl]-5-(8-quinolyl) phenylformic acid (IX-L, step 2,130 milligrams, 0.35 (2R mmole),, 3S)-and 3-amino-1-[(3-methoxy-benzyl) amino]-4-phenyl-2-butanols dihydrochloride (VIII, 117 milligrams, 0.35 mmole), HOBt is (70 milligrams, 0.52 mmole) and diisopropylethylamine (241 microlitres, 1.4 mmole) mixture in methylene dichloride (2 milliliters) stirred 15 minutes, add EDC (89 milligrams, 0.52 mmole), and the reaction mixture stirring is spent the night.With this reaction mixture dilute with water, and extract with methylene dichloride (3 * 25 milliliters).Clean organic phase with hydrochloric acid (1N, 25 milliliters), saturated sodium bicarbonate (25 milliliters), salt solution, dry (sodium sulfate), and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, methyl alcohol/chloroform, 1/9), obtain title compound, IR (NaCl): 3301,2916,2365 and 1613cm
-1APCI-MS (m/z) [M+H]
+=659.
Embodiment 747 N
3-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-4 '-methoxyl group-N
5, N
5-dipropyl [1,1 '-xenyl]-3,5-diamide hydrochloride (X)
Step 1: with (463 milligrams of 4-anisole ylboronic acids, 3.05 carbonyl 3-bromo-5-[(dipropyl amino mmole))] phenylformic acid (XLVIII, 1.02 gram, 3.05 mmole) and potassiumphosphate (1.29 the gram, 6.10 mmole) 1, the mixture in 2-glycol dimethyl ether (10 milliliters) and the water (5 milliliters) is used argon-degassed 15 minutes.Add chlorination two (triphenylphosphine) palladium (II) (21 milligrams, 0.03 mmole), again with the reaction mixture argon-degassed, and 85 ℃ of heated overnight.Reaction mixture is cooled to 20-25 ℃, and the filtration over celite plug.
(1N) is acidified to pH=4 with filtrate with hydrochloric acid, and uses ethyl acetate extraction.Water and salt solution clean organic phase, and dry (sal epsom).By flash column chromatography (silica gel; Ethyl acetate/acetate, 99/1) with purification of products, make 5-[(dipropyl amino) carbonyl] and-4 '-methoxyl group [1,1 '-xenyl]-3-carboxylic acid (IX-L, 667 milligrams), ESI-MS (m/z) [M+H]
+=356.
Step 2: with 5-[(dipropyl amino) carbonyl]-4 '-methoxyl group [1,1 '-xenyl]-3-carboxylic acid (IX-L, step 1,316 milligrams, 0.89 mmole), (2R, 3S)-and 3-amino-1-[(3-methoxy-benzyl) amino]-4-phenyl-2-butanols dihydrochloride (VIII, 316 milligrams, 0.89 mmole), (181 milligrams of HOBt, 1.34 mmole) and the mixture of N-methylmorpholine (0.37 gram, 3.56 mmoles) in methylene dichloride (8 milliliters) and dimethyl formamide (2 milliliters) stirred 15 minutes (257 milligrams of adding EDC at 20-25 ℃, 1.34 mmole), and with reaction mixture stirred 4.5 hours.Make the phase-splitting between methylene dichloride and water of this reaction mixture.Clean organic phase with hydrochloric acid (1N), water and salt solution, dry (sal epsom), and concentrate.Concentrate is dissolved in the minimum methyl alcohol, handles with hydrochloric acid (3 milliliters the 1.0M mixture in ether, 3 mmoles), and stirred 10 minutes.Add ether again with the precipitation resultant product.Filter the collecting precipitation thing, and dry in 50 ℃ vacuum drying oven, obtain title compound, mp=205-209 ℃; IR (ATR): 2964 and 1649cm
-1APCI-MS (m/z) [M+H]
+=638.
Embodiment 748 N
3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
5, N
5-dipropyl [1,1 '-xenyl]-3,5-diamide hydrochloride (X)
Step 1: with (1S)-2-(3, the 5-difluorophenyl)-1-[(2S)-and Oxyranyle] the ethyl carbamic acid tert-butyl ester (V, 500 milligrams, 1.67 mmole) and 3-methoxy-benzyl amine (VI, 0.34 gram, 2.51 the heated overnight under refluxing of the mixture in 2-propyl alcohol (3 milliliters) mmole), it is cooled to 20-25 ℃ and concentrating under reduced pressure, make resistates crystallization in ethyl acetate/hexane, filter and collect, obtain solid state (1S, 2R)-1-(3, the 5-difluorobenzyl)-and 2-hydroxyl-3-[(3-methoxy-benzyl) amino] the propyl carbamic acid tert-butyl ester (VII, 575 milligrams), ESI-MS (m/z): 437[M+H]
+
Step 2: with hydrochloric acid (3.2 milliliters the 1.0M mixture in ether, 3.2 mmole) handle (1S, 2R)-1-(3, the 5-difluorobenzyl)-and 2-hydroxyl-3-[(3-methoxy-benzyl) amino] the propyl carbamic acid tert-butyl ester (VII, step 1,535 milligrams, 1.23 mmoles) mixture in methyl alcohol (2 milliliters), and stirred 30 minutes at 20-25 ℃.Add ether until forming precipitation.Filter the collecting precipitation thing, this throw out is (2R, 3S)-3 amino-4-(3, the 5-difluorophenyl)-1-[(3-methoxy-benzyl) amino]-2-butanols dihydrochloride (VIII).
Step 3: with 5-[(dipropyl amino) carbonyl] [1,1 '-xenyl]-3-carboxylic acid (IX, 188 milligrams, 0.56 (2R mmole),, 3S)-3 amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-methoxy-benzyl) amino]-2-butanols dihydrochloride (VIII, step 2,230 milligrams, 0.56 mmole), HOBt is (114 milligrams, 0.84 mmole) and the mixture of N-methylmorpholine (0.23 gram, 2.24 mmoles) in methylene dichloride (6 milliliters) and dimethyl formamide (1 milliliter) 20-25 ℃ of stirring 15 minutes.Add EDC (161 milligrams, 0.84 mmole), and reaction mixture is spent the night 20-25 ℃ of stirring.Water, 1N hydrochloric acid, water and salt solution cleaning reaction mixture, dry (sodium sulfate), and concentrating under reduced pressure obtain title compound, mp=230-233 ℃; IR (ATR): 2965,1651,1596 and 1267cm
-1ESI-MS (m/z) [M+H]
+=644.
Embodiment 749 N
3-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
5, N
5-dipropyl [1,1 '-xenyl]-3,5-diamide hydrochloride (X)
General procedure according to embodiment 748, do not do key change, only be to use (2R, 3S)-and 3 amino-1-[(3-methoxy-benzyl) amino]-4-phenyl-2-butanols dihydrochloride (VIII) replacement (2R, 3S)-3 amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-methoxy-benzyl) amino]-2-butanols dihydrochloride (VIII), make title compound thus, mp=214-219 ℃; IR (KBr): 3227,2961,1632 and 1605cm
-1ESI-MS (m/z) [M+H]
+=608.
Embodiment 750 N
3-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-4 '-[(dimethylamino) alkylsulfonyl]-N
5, N
5-dipropyl-1,1 '-xenyl-3,5-diamide (X)
Step 1: in a flask, add 1, (37 milligrams in 1: 1 complex compound of 1 '-two (diphenylphosphino) ferrocene-palladium chloride, 0.05 mmole), potassium acetate is (492 milligrams, 4.5 mmole) and (408 milligrams of two (pinacolato), two boron, 1.6 mmole), decompression outgased 15 minutes and used argon purge.In this mixture, add methyl-3-bromo-5-[(dipropyl amino) carbonyl] mixture of benzoic ether (XXI, 500 milligrams, 1.5 mmoles) in anhydrous dimethyl sulphoxide (9 milliliters), and reaction mixture stirred 4 hours at 80 ℃.Reaction mixture is cooled to 20-25 ℃, with toluene (50 milliliters) dilution, water, salt solution (3 * 150 milliliters) clean, dry (sal epsom), and concentrating under reduced pressure, make 3-[(dipropyl amino) carbonyl]-5-(4,4,5,5-tetramethyl--1,3, the 2-dioxaborolan-2-yl) methyl benzoate, ESI-MS (m/z) [M+H]
+=390.
Step 2: with 3-[(dipropyl amino) carbonyl]-5-(4,4,5,5-tetramethyl--1,3, the 2-dioxaborolan-2-yl) methyl benzoate (step 1,534 milligrams, 1.4 mmoles), 4-bromobenzene dimethyl-sulphonamide (363 milligrams, 1.4 mmoles) and yellow soda ash (2 milliliters of 2M mixtures in water, 4.1 mmole) decompression of the mixture in toluene (10 milliliters) degassing is 15 minutes, uses argon purge then.Add tetrakis triphenylphosphine palladium (40 milligrams, 0.025 mmole) and, use argon purge then the reaction mixture decompression degassing 15 minutes.Reaction mixture was heated 4 hours under refluxing, be cooled to 20-25 ℃, filter by diatomite and sodium sulfate plug, and filtrate decompression is concentrated.Purify by flash column chromatography (silicon-dioxide, ethyl acetate/hexane, 1/1), obtain 4 '-[(dimethylamino) alkylsulfonyl]-5-[(dipropyl amino) carbonyl] [1,1 '-xenyl]-3-carboxylate methyl ester (XXXVIII), ESI-MS (m/z) [M+H]
+=447.
Step 3: with 4 '-[(dimethylamino) alkylsulfonyl]-5-[(dipropyl amino) carbonyl] [1; 1 '-xenyl]-3-carboxylate methyl ester (XXXVIII; step 2; 555 milligrams; 1.24 mmole) mixture in methyl alcohol (6 milliliters) and sodium hydroxide (2 milliliters of 6M mixtures in water, 12 mmoles) stirred 4 hours in 20-25 ℃.Make the phase-splitting between ethyl acetate (40 milliliters) and water (40 milliliters) of this reaction mixture.With hydrochloric acid (1N) with aqueous phase as acidified to pH=4, with ether (3 * 100 milliliters) extraction, and with the organic phase concentrating under reduced pressure that merges; make methyl 4 '-[(dimethylamino) alkylsulfonyl]-5-[(dipropyl amino) carbonyl] [1; 1 '-xenyl]-3-carboxylic acid (IX-XXXIX), NMR (300MHz, CD
3Cl): δ 8.37,8.12,7.89,7.80,3.51,3.22,2.76,1.74,1.59,1.02 and 0.79.
Step 4: with acid (IX-XXXIX, step 3,150 milligrams, 0.35 mmole), (2R, 3S)-and 3 amino-1-[(3-methoxy-benzyl) amino]-4-phenyl-2-butanols dihydrochloride (VIII, 129 milligrams, 0.35 mmole), HOBt (47 milligrams, 0.35 mmole) and N-methylmorpholine are (122 milliliters, 1.1 mixture mmole) stirred 15 minutes in methylene dichloride (4 milliliters), add EDC (107 milligrams, 0.62 mmole), and the reaction mixture stirring is spent the night.With this reaction mixture dilute with water, and extract with methylene dichloride (3 * 25 milliliters).Clean organic phase with hydrochloric acid (1N, 25 milliliters), saturated sodium bicarbonate (25 milliliters), salt solution, dry (sodium sulfate), and concentrating under reduced pressure.By flash column chromatography (silicon-dioxide; 100% ethyl acetate-methyl alcohol/chloroform, 1/9) purifies, obtain title compound, IR (ATR): 2932,2837 and 1593cm
-1APCI-MS (m/z) [M+H]
+=715.
Embodiment 751 N
3-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-4 '-[(dimethylamino) alkylsulfonyl]-N
5, N
5-dipropyl-1,1 '-xenyl-3,5-diamide (X)
General procedure according to embodiment 750, do not do key change, only be to use (2R, 3S)-3 amino-1-[(3-iodine benzyl) amino]-4-phenyl-2-butanols dihydrochloride (VIII), make title compound thus, IR (ATR): 3303,2930,2872 and 1614cm
-1APCI-MS (m/z) [M+H]
+=811.
Embodiment 752 N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
3, N
3-dipropyl-5-(3-thienyl) isophthaloyl amine hydrochlorate (X)
Step 1: at ice-cold 3-amino-5-[(dipropyl amino) carbonyl] (48wt% is at H at the aqueous solution of Tetrafluoroboric acid hydrogen salt for methyl benzoate (XLVIII, 1.0 grams, 3.60 mmoles)
2Among the O, 12.9 mmoles) in the mixture in, dropwise add refrigerative sodium nitrite in aqueous solution mixture (0.25 gram, 3.60 mmoles).This mixture was stirred 10 minutes, use ethyl acetate extraction then.Water cleans organic phase, through dried over mgso, filters and concentrating under reduced pressure, makes the diazonium salt that can use without further purification, NMR (500MHz, CD
3OD): δ 9.26,8.86,8.71,4.03,3.50,3.22,1.75,1.60,1.01 and 0.79.
Step 2: in the mixture of thiophene-3-boric acid (1.0 grams, 7.82 mmoles) in methyl alcohol, dropwise add Fremy condensed water phase mixture (2.01 grams, 25.8 mmoles).Reaction mixture was stirred 10 minutes and concentrating under reduced pressure.The solid that makes with acetone extract, and concentrating under reduced pressure make raw product, make its recrystallization in acetone/ether, make trifluoro (3-thiophene) boric acid sylvite, ESI-MS (m/z) [M+H]
+=151.
Step 3: trifluoro (3-thiophene) boric acid sylvite (step 2,0.69 gram, 1.82 mmoles), diazonium salt (XLVIII, step 1,0.42 gram, 2.19 mmoles) and lead acetate (0.02 gram, 0.09 mmole) were in the dark used argon purge 15 minutes.Add diox (8 milliliters) and reaction mixture is spent the night with argon-degassed and 20-25 ℃ of stirring.Dilute this reaction mixture with ether, clean,, make through flash chromatography (silicon-dioxide through dried over mgso and concentrating under reduced pressure with salt solution; Ethyl acetate/hexane, 1/1) the carbonyl 3-[(dipropyl amino of purifying)]-5-(3-thiophene) methyl benzoate, ESI-MS (m/z) [M+H]
+=346.
Step 4: with 3-[(dipropyl amino) carbonyl]-mixture of 5-(3-thiophene) methyl benzoate (XLIX, step 3,0.31 gram, 0.88 mmole) in THF/ methanol/sodium hydroxide (3/1/1,5 milliliter) stirred 2 hours at 40 ℃.Reactant is cooled to 20-25 ℃, and dilute with water is also used ethyl acetate extraction.With aqueous phase as acidified to pH=4 and use ethyl acetate extraction.Water and salt solution clean organic phase, through dried over mgso and concentrating under reduced pressure, make 3-[(dipropyl amino) carbonyl]-5-(3-thiophene) phenylformic acid (IX-L), ESI-MS (m/z) [M+H]
+=332.
Step 5: with 3-[(dipropyl amino) carbonyl]-5-(3-thiophene) phenylformic acid (IX-L, step 4,0.26 gram, 0.79 (2R mmole),, 3S)-and 3-amino-1-[(3-methoxy-benzyl) amino]-4-phenyl-2-butanols dihydrochloride (VIII, 0.26 gram, 0.71 HOBt (0.16 gram mmole),, 1.18 mmole) and (0.44 milliliter of triethylamine, 3.15 mmole) mixture in DMF (4 milliliters) stirred 10 minutes at 20-25 ℃, add EDC (0.23 gram, 1.18 mmoles), and reaction mixture was stirred 4 hours.With this reaction mixture dilute with water, and use ethyl acetate extraction.Clean organic phase with hydrochloric acid (1N), water and salt solution, through dried over mgso and and concentrating under reduced pressure.Recrystallization (dichloromethane/hexane, 1/1) obtains title compound, mp=199-201 ℃; IR (KBr): 3278,2961,2874 and 2837cm
-1ESI-MS (m/z) [M+H]
+=614.
Embodiment 753 N-{ (1R, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(methoxy-benzyl) amino] propyl group }-3-methyl-5-pentanoyl benzamide (X)
Step 1: in the mixture of oxalyl chloride (733 milligrams, 5.77 mmoles) in methylene dichloride (5 milliliters) ice-cold,, add 3 dimethyl formamides through stirring.After 10 minutes, add 3-(methoxycarbonyl)-5-tolyl acid (LXXIII, 560 milligrams, 2.89 mmoles).Reaction mixture was stirred 1 hour and concentrating under reduced pressure, make a kind of chloride of acid (LXXIV), it can use without further purification.
Step 2: at-78 ℃, chloride of acid (LXXIV through stirring; step 1; 612 milligrams; 2.89 mmole) and (415 milligrams of cuprous bromides (I); 2.89 mmole) in the mixture in tetrahydrofuran (THF) (5 milliliters); add butylmagnesium chloride (1.44 milliliters, the mixture of 2.0M in tetrahydrofuran (THF), 2.89 mmoles).Reaction mixture is warmed to 20-25 ℃, adds saturated ammonium chloride and make its quenching, and dilute with ether.Separate organic phase, clean, dry (sodium sulfate), filtration and concentrating under reduced pressure with salt solution.By flash column chromatography (silicon-dioxide; Hexane/ethyl acetate, 6.5/1) purify, make 3-methyl-5-pentanoyl methyl benzoate (LXXVI), NMR (300MHz, CD
3OD): δ 8.43,8.05,3.96,3.01,1.77,1.55 and 1.22.
Step 3: the mixture of 3-methyl-5-pentanoyl methyl benzoate (LXXVI, step 2,133 milligrams, 0.605 mmole) in methyl alcohol (1 milliliter) stirred 3 days with tetrahydrofuran (THF)/methanol/sodium hydroxide (2N) (3/1/1,3 milliliter).With ethyl acetate reaction mixture dilution and water are cleaned.Water phase separated and with hydrochloric acid (1N) acidifying and use dichloromethane extraction.With organic phase drying (sodium sulfate), filter and concentrating under reduced pressure, make 3-methyl-5-pentanoyl phenylformic acid (IX-LXXVII), NMR (300MHz, CD
3OD): δ 8.44,8.03,3.10,2.33,1.78,1.64 and 1.34.
Step 4: at 3-methyl-5-pentanoyl phenylformic acid (IX-LXXVII; 112 milligrams; 0.589 (2R mmole); 3S)-and 3-amino-4-(3, the 5-difluorophenyl)-1-[(3-methoxy-benzyl) amino]-2-butanols dihydrochloride (VIII, 239 milligrams; 0.589 mmole), HOBt is (80 milligrams; 0.589 mmole) and in the mixture of N-methylmorpholine (250 milligrams, 2.47 mmoles) in methylene dichloride (3 milliliters) add EDC (203 milligrams, 1.06 mmoles).Phase-splitting between ethyl acetate and water is then spent the night in the reaction mixture stirring.Clean organic phase with hydrochloric acid (1N), saturated sodium bicarbonate, salt solution, dry (sodium sulfate) filters and concentrating under reduced pressure.By flash column chromatography (silicon-dioxide; Methylene chloride, 12/1) purifies, obtain title compound, IR (ATR): 3297,2957,1687 and 1628cm
-1APCI-MS (m/z) [M+H]
+=539.
Embodiment 754 N
1-(4-hydroxyl butyl)-N
3-(1S)-and 2-hydroxyl-1-(4-hydroxybenzyl)-3-[(3-methoxy-benzyl) amino] propyl group }-5-methyl-N
1-propyl group isophthaloyl amine (X)
Step 1: at (2S)-3-[4-(benzyloxy) phenyl]-2-(tert-butoxycarbonyl) alanine methyl esters (1.79 grams, 4.65 mmole) in THF/ methanol (1/2/1,16 milliliters) in mixture in, add (340 milligrams of lithium hydroxides, 13.9 mmole), and with this mixture stirred 12 hours at 20-25 ℃.With citric acid (10%) quenching of this mixture.Extract the mixture that makes with ethyl acetate (3 * 15 milliliters).The organic extract liquid water that merges is cleaned three times,, filters and concentrating under reduced pressure, obtain (2S)-3-[4-(benzyloxy) phenyl through dried over sodium sulfate]-the 2-[(tert-butoxycarbonyl) amino] propionic acid, it can use without purifying.At-78 ℃, (2S)-3-[4-(benzyloxy) phenyl through stirring]-the 2-[(tert-butoxycarbonyl) amino] propionic acid (10.0 grams, 27.0 mmole) in the mixture in THF (200 milliliters), add (3.20 milliliters of NMM, 29.0 mmole) and chloroformic acid isobutyl (3.8 milliliters, 29.0 mmoles).Remove cooling bath, reaction mixture was stirred 1 hour, filter then.Make filtrate maintenance cooling and be used for next step.In the mixture of ice-cold, ether (110 milliliters) and potassium hydroxide (40%, 35 milliliter), slowly add 1-methyl-3-nitro-1-nitrosoguanidine (8.40 restrain 57.0 mmoles) through stirring.Stirred reaction mixture is until no longer emitting gas.Separate organic phase and slowly join ice-cold, going on foot in the mixed anhydride filtrate mixture that obtains through stirring by second.Reaction mixture was stirred 1 hour, in mixture, blasted nitrogen 10 minutes.With the mixture concentrating under reduced pressure that makes, clean with ethyl acetate (200 milliliters) dilution and water (100 milliliters).Clean organic phase with saturated sodium bicarbonate and salt solution, through dried over sodium sulfate, filter and concentrating under reduced pressure, make diazo-ketones, it is without purifying or identifying and can use.In ice-cold, the mixture of diazo-ketones in ether (100 milliliters), add Hydrogen bromide (48%, 4 milliliter, 73 mmoles) through stirring.Remove cooling bath, reaction mixture was stirred 30 minutes, and phase-splitting between ether and water.Separate organic phase and use saturated sodium bicarbonate and the salt solution cleaning, through dried over sodium sulfate, filter and concentrating under reduced pressure, make (1S)-1-[4-(benzyloxy) benzyl]-3-bromo-2-oxopropyl t-butyl carbamate (IV), it is without further purifying or identifying and can use.At-78 ℃, (1S)-1-[4-(benzyloxy) benzyl through stirring]-3-bromo-2-oxopropyl t-butyl carbamate (IV) in the mixture among Virahol/THF (2/1,150 milliliter), slowly add sodium borohydride (1.15 grams, 30.0 mmoles).Reaction mixture was stirred 30 minutes, add entry (30 milliliters) then.With the mixture that makes be warmed to 20-25 ℃ and in being no more than 30 ℃ water-bath concentrating under reduced pressure.Be dissolved in the resistates crude product in the ethyl acetate and water and salt solution cleaning.Through the dried over mgso organic phase, filter and concentrating under reduced pressure, make the solid state bromhydrin.In ice-cold, the mixture of bromhydrin in ethanol (150 milliliters) and ethyl acetate (100 milliliters) through stirring, adding potassium hydroxide (1N) alcohol mixture (36 milliliters, 36 mmoles).Remove cooling bath, and reaction mixture was stirred 30 minutes.Make the mixture phase-splitting between ethyl acetate and water that makes.Separate organic phase and,, filter also concentrating under reduced pressure through dried over mgso with the salt solution cleaning.By flash chromatography (silicon-dioxide; Hexane/ethyl acetate, 5/1) purify, obtain (1S)-2-[4-(benzyloxy) benzyl]-1-[(2S)-and Oxyranyle] the ethyl carbamic acid tert-butyl ester (V is as 8/1 mixture of diastereomer), NMR (500MHz, CDCl
3): δ 7.44-7.32,7.14,6.93,5.07,4.45,3.61,3.00-2.60 and 1.39.
Step 2: with 4-benzyloxy butyric acid (2.69 grams, 13.8 propylamine (0.82 gram mmole),, 13.8 HOBt (2.05 grams mmole),, 15.2 N-methylmorpholine (1.68 grams mmole),, 16.6 mmole) and the mixture of EDC (2.91 gram, 15.2 mmoles) in DMF (6 milliliters) stirred 18 hours at 20-25 ℃.This mixture is diluted also water (10 milliliters), hydrochloric acid (1N with ethyl acetate (40 milliliters), 10 milliliters), saturated sodium bicarbonate (10 milliliters) and salt solution (10 milliliters) cleans, separate organic phase, through dried over mgso, filter and concentrating under reduced pressure, make 4-(benzyloxy)-N-propyl group butyramide (2.59 gram), APCI-MS (m/z) [M+H]
+=236.
Step 3: in ice-cold, the mixture of 4-(benzyloxy)-N-propyl group butyramide (2.59 grams, 11.0 mmoles) in THF (8 milliliters), add lithium aluminium hydride (0.54 gram, 14.3 mmoles) through stirring.This reaction mixture is heated to 40-50 ℃ reaches 5 hours.Water (0.5 milliliter), sodium hydroxide (2N, 1.0 milliliters) and salt solution (0.5 milliliter) quenching refrigerative reaction mixture are used ether (30 milliliters) dilution then.With the throw out filtering that forms, and, filter and concentrating under reduced pressure, make N-[4-(benzyloxy) butyl through dried over mgso ether phase]-N-propylamine (2.41 gram), APCI-MS (m/z): 222[M+H]
+
Step 4: with N-[4-(benzyloxy) butyl]-N-propylamine (2.31 grams, 10.44 3-(ethoxy carbonyl)-5-tolyl acid (2.18 grams mmole),, 10.44 HOBt (1.56 grams mmole),, 11.49 mmole), N-methylmorpholine is (1.37 milliliters, 12.52 mmole) and the mixture of EDC (2.20 gram, 11.49 mmoles) in DMF (12 milliliters) stirred 18 hours at 20-25 ℃.Reaction mixture is cleaned with ethyl acetate (80 milliliters) dilution and water (2 * 20 milliliters), hydrochloric acid (1N, 20 milliliters), saturated sodium bicarbonate (20 milliliters) and salt solution (20 milliliters),, filter and concentrating under reduced pressure through dried over mgso.By flash chromatography (silicon-dioxide; Hexane/ethyl acetate, 1/1) purify, obtain 3-{[[4-(benzyloxy) butyl] (propyl group) amino] carbonyl }-5-tolyl acid ethyl ester (1.79 gram), NMR (500MHz, DMSO-d
6): δ 7.80,7.64,7.40,7.38-7.16,4.50-4.43,4.34-4.29,3.53-3.30,3.20-3.06,2.41-2.36,1.70-1.40,1.36-1.29,0.94-0.84 and 0.82-0.72; APCI-MS (m/z) [M+H]
+=412.
Step 5: at 3-{[[4-(benzyloxy) butyl] (propyl group) amino] carbonyl }-5-tolyl acid ethyl ester (1.75 gram, 4.25 mmoles) adds lithium hydroxide (0.31 gram, 12.76 mmoles) in the mixture in the THF/ ethanol/water (1/2/1,30 milliliter).Reaction mixture was stirred 2 hours, use concentrated hydrochloric acid (0.5 milliliter) to be acidified to pH=3 then.With ethyl acetate (2 * 30 milliliters) extractive reaction mixture, through dried over mgso, filter and concentrating under reduced pressure, make 3-{[[4-(benzyloxy) butyl] (propyl group) amino] carbonyl }-5-tolyl acid (IX, 1.63 grams), ESI-MS (m/z) [M+H]
+=384.
Step 6: with (1S)-2-[4-(benzyloxy) phenyl]-1-[(2S)-and Oxyranyle] the ethyl carbamic acid tert-butyl ester (V, 1.58 gram, 4.28 mmole) and 3-methoxy-benzyl amine (VI, 825 microlitres, 6.42 mmoles) mixture heating up to 90 in Virahol (45 milliliters) ℃ reaches 4 hours.When being cooled to 20-25 ℃, with the reaction mixture concentrating under reduced pressure.By flash chromatography (silicon-dioxide; Methylene chloride/ammonium hydroxide 98/1/1 to 95/4/1) purify, obtain (1S, 2R)-1-[4-(benzyloxy) benzyl]-2-hydroxyl-3-[(3-methoxy-benzyl)-amino] the propyl carbamic acid tert-butyl ester (VII, 1.97 grams), NMR (300MHz, MeOH-d
4): δ 7.41-6.79,5.05,4.33-3.33,3.74,3.54,3.03-2.46 and 1.29; ESI-MS (m/z) [M+H]
+=507.
Step 7 the: with (1S in the Zai diox (10 milliliters), 2R)-1-[4-(benzyloxy) benzyl]-2-hydroxyl-3-[(3-methoxy-benzyl)-amino] the propyl carbamic acid tert-butyl ester (VII, step 6,2.34 gram, 4.62 mmole) with (12 milliliters of hydrochloric acid, 4.M the mixture in the Zai diox, 48 mmoles) handled 2 hours, filter and collect the throw out that forms, clean with ether, and drying under reduced pressure spends the night, make (2R, 3S)-3-amino-4[4-(benzyloxy) phenyl]-the 1-[(3-methoxy-benzyl) amino]-2-Kauri-butanol hydrochloric salt (VIII), NMR (300MHz, MeOH-d
4): δ 7.44-6.96,5.05,4.21,3.83,3.65 and 3.21-2.77; ESI-MS (m/z) [M+H]
+=407.
Step 8: at 3-{[[4-(benzyloxy) butyl ice-cold, through stirring] (propyl group) amino] carbonyl }-5-tolyl acid (IX, 310 milligrams, 0.809 (2R mmole),, 3S)-3-amino-4[4-(benzyloxy) phenyl]-the 1-[(3-methoxy-benzyl) amino]-2-Kauri-butanol hydrochloric salt (VIII, 359 milligrams, 0.809 mmole) and (415 milligrams of bromine tripyrrole alkylphosphines hexafluorophosphates, 0.890 mmole) mixture in methylene dichloride (10 milliliters) dropwise adds diisopropylethylamine (285 microlitres, 1.62 mmoles).The mixture that makes was stirred 30 minutes at 0 ℃, be warmed to 20-25 ℃ then.After 4 hours, with reactant concentrating under reduced pressure and phase-splitting between ethyl acetate and water.Water phase separated and with ethyl acetate (3 * 15 milliliters) extraction, with the organic phase that merges through dried over mgso, and concentrating under reduced pressure.By flash chromatography (silicon-dioxide; Methylene chloride/ammonium hydroxide 96/3/0.5) concentrate is purified, make N
1-(1S, 2R)-1-[4-(benzyloxy) benzyl]-2-hydroxyl-3-[(methoxy-benzyl) amino] propyl group }-N
3-[4-(benzyloxy) butyl]-5-methyl-N
3-propyl group isophthaloyl amine (X), NMR (300MHz, acetone-d
6): δ 7.99-6.74,5.01,4.51-4.29,4.36,4.01,3.80,3.55-3.16,2.98-2.82,2.65-2.62,2.36,1.85-1.29,1.01 and 0.68; ESI-MS (m/z) [M+H]
+=772.
Step 9: at N
1-(1S, 2R)-1-[4-(benzyloxy) benzyl]-2-hydroxyl-3-[(methoxy-benzyl) amino] propyl group }-N
3-[4-(benzyloxy) butyl]-5-methyl-N
3Shake is 5 hours under-propyl group isophthaloyl amine (X, 100 milligrams, 0.130 mmole) and the nitrogen atmosphere of mixture at 35psi of palladium-carbon (10%, 100 milligram) in anhydrous Glacial acetic acid (5 milliliters).With the mixture filtration over celite that makes, and use washed with methanol.The filtrate decompression that merges is concentrated.Concentrate is passed through flash column chromatography (silicon-dioxide; The graded of methylene chloride/ammonium hydroxide 97/3/0.05 to 93/7/0.05) purifies, make title compound: NMR (300MHz, CD
3OD): δ 7.55-6.64,4.19,3.99-3.72,3.63-3.36,3.21-3.09,2.79-2.69,2.39,1.90-1.40,1.29 and 1.02-0.6; ESI-MS (m/z) [M+H]
+=592.
Embodiment 756 N
1-(1S, 2R)-2-hydroxyl-1-(4-hydroxybenzyl)-3-[(methoxy-benzyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine (X)
Step 1: at 3-[(dipropyl amino) through stirring-carbonyl]-5-tolyl acid (IX, 150 milligrams, 0.570 (2R mmole),, 3S)-3-amino-4-[4-(benzyloxy) phenyl]-the 1-[(3-methoxy-benzyl) amino]-2-Kauri-butanol hydrochloric salt (VIII, 274 milligrams, 0.571 N mmole),, N-diisopropylethylamine (400 microlitres, 2.28 mmole) and (116 milligrams of HOBt, 0.857 mmole) add EDC (160 milligrams, 0.857 mmole) in the mixture in methylene dichloride (10 milliliters).The mixture that makes was stirred 16 hours at 20-25 ℃.Make reaction mixture phase-splitting between methylene dichloride and water.Water phase separated is also used methylene dichloride (3 * 15 milliliters) extraction.The organic phase water that merges is cleaned dry (sal epsom), and concentrating under reduced pressure.By flash column chromatography (silicon-dioxide; Methylene chloride/ammonium hydroxide, 97/3/0.05) purify, obtain N
1-(1S, 2R)-1-[4-(benzyloxy) benzyl] 2-hydroxyl-3-[(methoxy-benzyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine, ESI-MS (m/z) [M+H]
+=652.
Step 2: with N
1-(1S, 2R)-1-[4-(benzyloxy) benzyl] 2-hydroxyl-3-[(methoxy-benzyl) amino] propyl group }-5-methyl-N
3, N
3Shake is 5 hours under-dipropyl isophthaloyl amine (140 milligrams, 0.215 mmole) and the nitrogen atmosphere of mixture at 35psi of palladium-carbon (10%, 140 milligram) in anhydrous Glacial acetic acid (5 milliliters).The mixture that makes through diatomite filtration, and is used washed with methanol.The filtrate decompression that merges is concentrated.Concentrate is passed through flash column chromatography (silicon-dioxide; Methylene chloride/ammonium hydroxide is by 97/3/0.05 to 93/7/0.05 graded) purify, make title compound, IR (KBr) 2962,2931,1611,1594 and 1263cm
-1ESI-MS (m/z) [M+H]
+=562.
Embodiment 757 N
1-((1S, 2R)-1-benzyl-3{[3-(2, the 4-dimethyl benzyl) propyl group] amino }-the 2-hydroxypropyl)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine (X)
Step 1: (1S)-1-[(2S)-Oxyranyle that will be through stirring]-2-phenylethyl t-butyl carbamate (V, 247 milligrams, 0.939 mmole), yellow soda ash is (299 milligrams, 2.82 mmole) and 3-(2, the 4-3,5-dimethylphenyl) propylamine (VI, 628 milligrams, 2.82 mmoles) mixture is heated overnight under refluxing.Reaction mixture is cooled to 20-25 ℃ and concentrating under reduced pressure.By flash column chromatography (silicon-dioxide; Methylene chloride/ammonium hydroxide, 98/2/1) purify, make (1S, 2R)-1-benzyl-3-{[3-(2, the 4-3,5-dimethylphenyl) propyl group] amino }-2-hydroxypropyl t-butyl carbamate (VII), NMR (300MHz, CD
3OD): δ 7.22-7.16,3.81,3.18,2.77,2.54,2.15,2.13,1.89 and 1.23.
Step 2: at (1S through stirring, 2R)-1-benzyl-3-{[3-(2, the 4-3,5-dimethylphenyl) propyl group] amino }-2-hydroxypropyl t-butyl carbamate (VII, 180 milligrams, 0.423 in the mixture in the mmole) Zai diox (2 milliliters), add hydrochloric acid (0.32 milliliter, the 4N mixture in the Zai diox, 1.27 mmoles).Reaction mixture is stirred the also concentrating under reduced pressure that spends the night, make (2R, 3S)-3-amino-1-{[3-(2, the 4-3,5-dimethylphenyl) propyl group] amino }-4-phenyl-2-Kauri-butanol hydrochloric salt (VIII), NMR (300MHz, CDCl
3): δ 7.14,3.73,2.70,2.32 and 1.86.
Step 3: at (2R through stirring, 3S)-3-amino-1-{[3-(2, the 4-3,5-dimethylphenyl) propyl group] amino }-4-phenyl-2-Kauri-butanol hydrochloric salt (VIII, 163 milligrams, 0.411 mmole), carbonyl 3-[(dipropyl amino)]-5-tolyl acid (IX, 108 milligrams, 0.411 mmole), HOBt is (55 milligrams, 0.411 mmole) and in the mixture of N-methylmorpholine (133 milligrams, 1.32 mmoles) in methylene dichloride (5 milliliters) add EDC (142 milligrams, 0.740 mmole).Reaction mixture is stirred the phase-splitting between ethyl acetate and water then of spending the night.Clean organic phase with hydrochloric acid (1N), saturated sodium bicarbonate, salt solution, dry (sodium sulfate), filtration and concentrating under reduced pressure.By flash column chromatography (silicon-dioxide; Methylene chloride/ammonium hydroxide, 95/5/1) purify, obtain title compound, IR (ATR) 3299,2930 and 1614cm
-1APCI-MS (m/z) [M+H]
+=572.
Embodiment 765 N
3-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-4-methyl-N
1, N
1-dipropyl isophthaloyl amine (X)
The mixture heating up to 160 of 3-bromo-4-tolyl acid (10.94 gram, 43.25 mmoles), cuprous cyanide (I) (7.75 grams, 86.5 mmoles) and 1-Methyl-2-Pyrrolidone (75 milliliters) ℃ is spent the night.With mixture cooling and vacuum distilling, obtain resistates, it was stirred 10 minutes in hydrochloric acid (6N, 60 milliliters).Filter and collect the solid that makes, water, ether clean, and dry.This solid is heated to 90 ℃ reaches 3 hours in sodium hydroxide (2N, 250 milliliters), spend the night with this mixture cooling and 20-25 ℃ of stirring then.With concentrated hydrochloric acid reactant is acidified to about pH3, obtains throw out thus.Solid collected by filtration and water clean, and grind in boiling water then, filter and drying in 60 ℃ vacuum drying oven.This solid is dissolved in methyl alcohol (75 milliliters), and adds concentrated hydrochloric acid (5 milliliters), mixture is refluxed spend the night.Then with this mixture cooling and concentrating under reduced pressure.Chromatography (silica gel; Ethanol/methylene, 8/92) makes 5-(methoxycarbonyl)-2-tolyl acid.
When stirring (250 milligrams of 5-(methoxycarbonyl)-2-tolyl acid, 1.3 mmole) and (0.72 milliliter of triethylamine, 5.2 mmole) add cyano group diethylpyrocarbonate (90%, 0.24 milliliter, 1.4 mmoles) in the solution in methylene dichloride (14 milliliters).After 1 minute, add (2R, 3S)-3-amino-1-[(3-methoxy-benzyl) amino]-4-phenyl-2-Kauri-butanol hydrochloric salt (VIII, 485 milligrams, 1.3 mmoles), and reactant stirred spend the night.This mixture is concentrated, carry out chromatographic separation (silicon-dioxide then; Ethanol/methylene 8/92), obtain 3-[({ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } amino) carbonyl]-the 4-methyl benzoic acid ester.
With (39 milligrams of lithium hydroxides, 0.96 mmole) in tetrahydrofuran (THF)/methanol (2/1/1,2 milliliters) the middle 3-[({ (1S that handles, 2R)-and 1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } amino) carbonyl]-(200 milligrams of 4-methyl benzoic acid esters, 0.42 mmole), and with this mixture spend the night 20-25 ℃ of stirring.With this mixture decant and with supernatant concentration, make 3-[({ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } amino) carbonyl]-the 4-tolyl acid.
With 3-[({ (1S, 2R)-and 1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } amino) carbonyl]-(124 milligrams of 4-tolyl acids, 0.27 mmole) be dissolved in (0.07 milliliter of triethylamine, 0.54 mmole) and in the methylene dichloride (3 milliliters), and with cyano group diethylpyrocarbonate (90%, 0.06 milliliter, 0.32 mmole) handle, stirred simultaneously 2 minutes.Adding dipropyl amine (0.04 milliliter, 0.32 mmole) also continues to stir to spend the night.Clean with methylene dichloride dilution organic phase and with saturated sodium bicarbonate (2 * 50 milliliters) and salt solution (50 milliliters), then through anhydrous sodium sulfate drying, filtration also concentrates chromatography (silica gel; Ethanol/methylene, 8/92) makes title compound, MS[M+H]
+=546.3.
Embodiment 766 N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-(2-furyl)-5 methyl benzamides (X)
With N-{ (1S, 2R)-and 1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-bromo-5 methyl benzamide (X, embodiment 761,295 milligrams, 0.95 mmole), 2-furyl boric acid is (133 milligrams, 1.19 mmole) and yellow soda ash (366 milligrams, 2.95 mmoles) in dimethyl formamide (5 milliliters), mix, and under nitrogen gas stream, stirred 15 minutes.Add four (triphenylphosphinyl) palladium (136 milligrams, 0.12 mmole) and mixture heating up to 100 ℃ is spent the night.Mixture is cooled to 20-25 ℃, with chloroform (50 milliliters) dilution and water (3 * 100 milliliters) extraction.Separate organic phase and use saturated sodium bicarbonate (2 * 100 milliliters) and salt solution (100 milliliters) cleaning,, filter and concentrating under reduced pressure through anhydrous sodium sulfate drying.Resistates is carried out chromatographic separation (silica gel; Ethanol/methylene, 8/92), make title compound, MS[M+H]
+=485.3.
Embodiment 792 2-butyl cyclopropylamine hydrochlorides (VI)
The solution of phosphine acyl acetic acid three ethyl (22.4 grams, 0.1 mole) in 13 milliliters of diglymes is added 13 milliliters of diglymes and sodium hydride (60﹠amp; , 5.7 grams, 0.12 mole) and in the mixture in mineral oil.When stopping to generate hydrogen, add 1, the solution of 2-epoxy hexane (12 grams, 0.12 mole) in diglyme (12 milliliters).This mixture was stirred 1 day and stirred 3 hours at 140 ℃ at 20-25 ℃.Add cold sodium hydroxide (15 grams are in 25 milliliters water) mixture.This mixture was refluxed 15 hours, dilute, and clean with ether (3 * 50 milliliters) with cold water (100 milliliters).Be acidified to pH=2 with sulfuric acid (25%),, with the ether drying, filter and concentrate, make 2-butyl cyclopropane-carboxylic acid with anhydrous sodium sulphate with ether (5 * 25 milliliters) extraction.Should heat 15 hours with thionyl chloride (5.1 grams, 3.1 milliliters) at 60 ℃ by the mixed solution of acid (5.0 grams, 0.035 mmole) in methylene dichloride (15 milliliters).With reaction mixture distillation (76 ℃-80 ℃), obtain chloride of acid, it is dissolved in acetone (15 milliliters), be cooled to-10 ℃ of water (5 milliliters) solution-treated of also using sodiumazide (2.2 grams, 33.8 mmoles).Reaction mixture-10 ℃ of restir 1 hour, is poured on ice/waterborne then, with ether (3 * 10 milliliters) extraction, dry and 20-25 ℃ carefully reduction vaporization to doing.Resistates is dissolved in toluene (15 milliliters) and is warmed to 100 ℃ of while vigorous stirring 1 hour carefully.Add concentrated hydrochloric acid (7 milliliters) and with reaction mixture refluxed 15 minutes.Acid layer is evaporated to dried, obtains compound, MH
+=114.2.
Embodiment 793 2-amino methyl-3-methyl furan (VI)
At 20-25 ℃ 3-methyl furancarboxylic acid (4.0 grams, 32 mmoles) is dissolved in DMF (10 milliliters), adds 1,1-carbonyl dimidazoles (5.7 grams, 35 mmoles).After 15 minutes, in mixture, blast about 2 minutes ammonia.This mixture was stirred 2 hours at 20-25 ℃, then with this mixture concentrating under reduced pressure.Make resistates phase-splitting between ethyl acetate and 10% aqueous citric acid solution.Separate each layer, use ethyl acetate (2 *) aqueous layer extracted again.Clean the organic phase of merging and, filter also concentrated with saturated sodium bicarbonate, salt solution through dried over mgso.Form crystal in the put procedure, clean with its filtering separation and with amount of ethyl acetate/hexane (80/20).MS(ESI)：MH+：126.1。3-methyl furoamide (317 milligrams, 2.5 mmoles) is dissolved in anhydrous THF (5 milliliters).Disposable adding lithium aluminium hydride (230 milligrams, 6.0 mmoles), and mixture heating up refluxed spend the night.This mixture is cooled to 0 ℃, and makes its quenching by adding THF/ water (50/50).Then this mixture is diluted with THF, and through diatomite filtration.Filtrate is concentrated, make title compound, MS (ESI): (M-H)+: 109.1.
Embodiment 794 4-amino methyls-3,5-dimethyl isoxazole (VI)
Under 20-25 ℃, make 4-chloromethyl-3,5-dimethyl isoxazole (700 milligrams, 4.8 mmoles) is suspended in the strong aqua, and vigorous stirring is spent the night.With isopropanol/chloroform (10/90,2 *) extractive reaction mixture.Under nitrogen gas stream, the organic phase that merges is concentrated.Resistates is purified by flash chromatography ethanol/methylene (5-20%, 1% triethylamine), make title compound, NMR (CDCl
3, 300MHz): δ 3.62,2.37,2.29 and 1.44.
Embodiment 795 5-methylol-2-(2-methyl-propyl) thiazoles (VI)
According to J.Med.Chem.41, the program among the 602-617 (1998) is synthesized the isoamyl thioamides.Isovaleramide (10 grams, 9.9 mmoles) is suspended in the anhydrous ether (400 milliliters), and gradation adds phosphoric sulfide (V) (4.4 grams, 0.99 mmole) then.It 20-25 ℃ of vigorous stirring 2 hours, is filtered then.Filtrate decompression is concentrated, and promptly use this resistates: MS (ESI): MH+:118.1 without further filtration.
Isoamyl thioamides (6.0 gram, 51 mmoles) and formyl radical ethyl chloroacetate ((1991), 5.0 restrain 33 mmoles for Heterocycles32 (4), 693-701) are dissolved in dry DMF (20 milliliters), and are heated to 95 ℃ and reach 4 hours.Reactant is cooled to 0 ℃ subsequently, and adds cold water (50 milliliters).With solid sodium bicarbonate this mixture is alkalized to pH=8, use ether (3 * 35 milliliters) extraction then.Water cleans the organic extract liquid that merges with salt solution then, through dried over mgso, filters and concentrates.Resistates is purified by flash chromatography (ethyl acetate/hexane 4-10% wash-out), obtain required product.NMR (CDCl
3, 300MHz): δ 8.27,4.45-4.30,3.70-3.50,3.00-2.80,2.30-2.10,1.40-1.20 and 1.10-0.90.
When stirring, with 2-(2-methyl-propyl) thiazole-5-carboxylic acid ethyl ester (2.05 grams, 9.6 mmole) solution in THF (10 milliliters) dropwise adds under 0 ℃ in the suspension of lithium aluminium hydride (730 milligrams, 19 mmoles) in anhydrous THF (50 milliliters).After interpolation is finished, at 20-25 ℃ of stirred reaction mixture.Reaction mixture is cooled to 0 ℃, and adds entry (0.75 milliliter), aqueous sodium hydroxide solution (15%, 0.75 milliliter) and water (2.25 milliliters) in regular turn.This mixture was stirred 1 hour at 0 ℃, filter by diatomite (THF and chloroform) then.Filtrate is concentrated, make 5-methylol-2-(2-methyl-propyl) thiazole, MS (ESI): MH+:172.1.
Embodiment 796 3-(2-methyl-propyl)-5-amino methyl isoxazole (VI)
The vigorous stirring in water (6 milliliters) with isovaleric aldehyde (5.4 milliliters, 50 mmoles) and hydroxylamine hydrochloride (3.5 grams, 50.4 mmoles).Water (15 milliliters) solution that adds yellow soda ash (2.65 grams, 25 mmoles) therein.Its vigorous stirring is spent the night.Extract this mixture with ether.Water cleans organic layer, then through dried over sodium sulfate, filters and concentrates.Being about to it without further purifying is used for afterreaction: MS (ESI): MH+:102.1.
Propargyl amine (8.0 milliliters, 117 mmoles) is dissolved in methylene dichloride (60 milliliters), and adds tert-Butyl dicarbonate (25 grams, 114 mmoles).Its stirring is spent the night, concentrate then and make the propargyl amine that BOC-is protected, it can use without further purification: MS (ESI): MNa+:178.0.
BOC-propargyl amine (6.2 grams, 39.7 mmoles) and isopentyl oxime (3.97 grams, 39.3 mmoles) are dissolved in methylene dichloride (60 milliliters), and add triethylamine (0.55 milliliter, 3.95 mmoles).It is cooled to 0 ℃, and dropwise adds SYNTHETIC OPTICAL WHITNER (5% aqueous solution, 59.1 grams), vigorous stirring simultaneously.After interpolation is finished, this mixture was warmed to 20-25 ℃ above 22 hours.Separate each layer, and with methylene dichloride (2 *) aqueous layer extracted.Clean the organic extract liquid that merges with salt solution,, filter and concentrate through dried over mgso.Resistates is purified by chromatography (silica gel, ethyl acetate/hexane 5-10%), make the title compound that BOC-is protected, MS (ESI): MH+:255.3.
3-(2-methyl-propyl)-5-amino methyl isoxazole that BOC-is protected (2.4 grams, 9.3 mmoles) is dissolved in methylene dichloride (10 milliliters), and with trifluoroacetic acid (10 milliliters) 20-25 ℃ of processing.It was stirred 70 minutes at 20-25 ℃, concentrate then.Product is dissolved in methylene dichloride, and cleans, until being alkalescence (pH=11) with wet chemical (1M).Separating has basic unit, through dried over sodium sulfate, filters and concentrates, and makes title compound: MS (ESI): MH+:155.2.
Embodiment 797 (3R)-2-oxo-1-propyl group azepan t-butyl carbamate (VI)
In the solution of DMF (4 liters), add benzotriazole-Ji oxygen tripyrrole alkyl-phosphine hexafluorophosphate (BOP, 18.3 grams, 41.4 mmoles) and sodium bicarbonate (17.4 grams, 206.8 mmoles) at N-t-Boc-D-Lys-OH (10 grams, 41.4 mmoles); Reactant was stirred 12 hours at 20-25 ℃.Then reactant is concentrated into 50 ml volumes and with ethyl acetate dilution, and with sodium bicarbonate 3 *, water, 1M sal enixum and salt solution cleans, and is dry and concentrated.Purify by chromatographic separation on silica gel, make 5.05 gram solid state (3R)-2-oxo azepan t-butyl carbamates; The program that adopts is similar to J.Med.Chem.1999, the program of describing in 4193.M+H-(t-Boc)(m/3＝129.2)，M+Na(m/3＝251.1)。
Under-78 ℃, in the solution of anhydrous THF (20 milliliters), add n-Butyl Lithium/hexane (2.5M at above-mentioned lactan (2 grams, 8.77 mmoles), 5.3 milliliter, 13.2 mmoles), reactant was stirred 1 hour, and adding 1-N-PROPYLE BROMIDE (3.2 milliliters, 35.1 mmoles).Reactant was stirred 1 hour, remove cooling bath and continued restir 16 hours.Add tetrabutylammonium iodide (0.49 gram, 2.63 mmoles), and with reactant restir 16 hours.Make reactant phase-splitting between ethyl acetate/hydrochloric acid+ice+water, water and salt solution clean this mixture, and it is concentrated.Purify by chromatographic separation on silica gel, make title compound, MS (M+Na+) 293.3.
Embodiment 798 N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-ethynyl benzyl) amino]-the 2-hydroxypropyl }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine (X)
According to J.Am.Med.Chem.Soc.1986, the program of describing in 3150 is with N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-5-methyl-N
3, N
3The trifluoroacetate of-dipropyl isophthaloyl amine (92.9 milligrams, 0.117 mmole) is dissolved in triethylamine (0.2M, 0.6 milliliter), adds PdCl then
2(PPh
3)
2(3.3 milligrams, 0.005 mmole) and cupric iodide (I) (1.1 milligrams, 0.006 mmole).Reactant is heated to backflow.When reactant refluxes, add trimethyl silyl acetylene (0.02 milliliter, 0.14 mmole) by syringe.With reactant at N
2(g) refluxed 3 hours down, and reactant is cooled to 20-25 ℃, make its phase-splitting between sodium bicarbonate and ethyl acetate then.Extract this product with ethyl acetate (3 *), clean with salt solution, through dried over sodium sulfate, and filter, solvent is removed in decompression then.
The acetylene (0.117 mmole) that TMS is protected is dissolved in methyl alcohol (0.2M, 0.5 milliliter), adds potassium hydroxide (1M, 0.7 milliliter, 0.7 mmole) then.Reactant was stirred 6 hours at 20-25 ℃, at this moment make the phase-splitting between sodium bicarbonate and ethyl acetate of this mixture.Product with ethyl acetate (3 *) extraction, is cleaned with salt solution, through dried over sodium sulfate, and filter, solvent is removed in decompression then.Column chromatography is separated (silica gel; The 1.5-2% isopropanol/chloroform is under alkaline condition; Add several ammonium hydroxide in per 100 milliliters of eluting solvents), obtain title compound, MS m/z:(M+H)
+=576.3.
Embodiment 799 1-phenycyclopropyl amine (VI)
According to N.W.Werner etc., J.Org.Syn.Coll. roll up 5, the program of describing among the 273-276 is with sodiumazide (0.915 gram, 14.1 mmole) slowly add the solution of 1-phenyl-cyclopropane-carboxylic acid (1.0 grams, 6.1 mmoles) in the vitriol oil (5 milliliters) and methylene dichloride (10 milliliters).Sodium sulfate is precipitated out from solution.Reaction mixture is heated to 50 ℃ reaches 17 hours, be cooled to 0 ℃ then.This mixture is alkalized to pH=11 and usefulness methylene dichloride (2 *) extraction with sodium hydroxide (1N).Merge organic layer,, filter and concentrate through dried over sodium sulfate.Resistates is passed through chromatography (silica gel; Isopropanol/chloroform/ammonium hydroxide 4/95/1) purify, obtain title compound, C
9H
11The MS of N (ESI+) m/z (M+H)
+=134.
Embodiment 800 7-methoxyl groups-1,2,3,4-tetrahydrochysene-naphthalidine (VI)
7-methoxyl group-1-Tetralone an intermediate of Sertraline (2.0 grams, 11.3 mmoles), hydroxylamine hydrochloride (1.56 grams, 22.6 Bo moles) and sodium acetate (1.8 grams, 22.6 mmoles) are suspended in the ethanol/water (3/1,40 milliliter), this mixture was heated 45 minutes at 100 ℃.Make this mixture cool overnight and the throw out that makes filtered and water cleans, make the intermediate oxime, MS (ES) (M+H): 192.1.This oxime is dissolved in Glacial acetic acid (25 milliliters) and adds palladium/carbon (500 milligrams), and this mixture is spent the night in 20-25 ℃ of hydrogenation at 50psi.Through the diatomite filtration catalyzer and use washed with methanol.The filtrate that merges is concentrated.Grind concentrate with ether, make title compound, MS (CI) (M+H)
+: 178.2.
Embodiment 1208-1214 and 1226
1,208 N
1-(tertiary butyl)-N
3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the oreinol diformamide
1.209 5-bromo-N
1-(tertiary butyl)-N
3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } isophthaloyl amine
1.210 3-tert.-butoxy-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide
1.211 3-tert.-butoxy-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-methyl benzamide
1.212 N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-{[(trifluoromethyl) alkylsulfonyl] amino } benzamide
1,213 N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(trifluoromethoxy) benzamide
1,213 N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl-5-(trifluoromethoxy) benzamide
1.226 N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(4-methyl isophthalic acid, 3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine (M+H)
+=647.5
Compound in the following table is that the main method of setting forth in the above-described and following diagram of using prepares.
Compound among the application is to use the Chemdraw Ultra 6.0.2 version (can be available from Cambridgesoft.co, 100 Cambridge Park Drive, Cambridge, MA 02140), Namepro 5.09 editions (can be available from ACDlabs, 90 Adelaide Street West, Toronto, Ontario, M5H, 3V9, Canada) name, or come from the title of using those rules to produce.
Compound in the following table is that the main method of setting forth in the above-described and following diagram of using prepares.
Following compounds is to use the Advanced Chemistry Development Inc. (ACD) nomenclature, and IUPAC Name Batch 4.5. version is named.The network address of ACD is www.acdlabs.com.
| Compound title (IUPAC title) | |
| 1441 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-{[(2-hydroxyethyl) amino] sulphonyl }-N 3，N 3-dipropyl isophthaloyl amine |
| 1442 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(2-isobutyl--1,3-thiazoles-5-yl) methyl] amino } propyl group)-5-ethynyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1443 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-isopropyl benzyl) amino] propyl group }-5-ethynyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1444 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-isopropyl benzyl) amino] propyl group }-5-(1,3-oxazole-2-yl)-N 3，N 3-dipropyl isophthaloyl amine |
| 1445 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-{[(2-hydroxyl-1, the 1-dimethyl ethyl) amino] alkylsulfonyl }-N 3，N 3-dipropyl isophthaloyl amine |
| 1446 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(4-methyl isophthalic acid, 3-oxazole-2-yl)-N 3，N 3-dipropyl isophthaloyl amine |
| 1447 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(2-isobutyl--1,3-thiazoles-5-yl) methyl] amino } propyl group)-5-(1,3-oxazole-2-yl)-N 3，N 3-dipropyl isophthaloyl amine |
| 1448 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-{[(3-hydroxypropyl) amino] alkylsulfonyl }-N 3，N 3-dipropyl isophthaloyl amine |
| 1449 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-propyl group benzyl) amino] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1451 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-ethynyl benzyl) amino]-the 2-hydroxypropyl }-5-ethynyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1452 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(3-isobutyl-isoxazole-5-base) methyl] amino } propyl group)-5-ethynyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1453 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-[(dimethylamino) alkylsulfonyl]-N 3，N 3-dipropyl isophthaloyl amine |
| 1454 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1,3-Evil azoles-2-yl)-N 3，N 3-dipropyl isophthaloyl amine hydrochlorate |
| 1455 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[3-(5-formyl radical thiophene-2-yl) benzyl] amino }-the 2-hydroxypropyl)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1456 | 5-bromo-N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-benzyl iodide) amino] propyl group }-N 3，N 3-dipropyl isophthaloyl amine |
| 1457 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-([(1R)-and 2-hydroxyl-1-methylethyl] amino } alkylsulfonyl)-N 3，N 3-dipropyl isophthaloyl amine |
| 1458 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-isobutyl-benzyl) amino] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1459 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-5-ethynyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1460 | N-{ (1S, 2R)-and 1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(2R)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] carbonyl }-5-toluyl amine hydrochlorate |
| 1461 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-([(1S)-and 2-hydroxyl-1-methylethyl] amino } alkylsulfonyl)-N 3，N 3-dipropyl isophthaloyl amine |
| 1462 | N 1-butyl-N 3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-N 1-propyl group isophthaloyl amine |
| 1463 | N 1，N 1-dibutyl-N 3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the oreinol diformamide |
| 1464 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(3-hydroxyl third-1-alkynyl) benzyl] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1465 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-{[(2S)-and 2-(methylol) tetramethyleneimine-1-yl] alkylsulfonyl }-N 3，N 3-dipropyl isophthaloyl amine |
| 1467 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1,3-Evil azoles-2-yl)-N 3，N 3-dipropyl isophthaloyl amine |
| 1469 | N 1-[(1S, 2R)-3-{[3-(cyclopropyl amino) benzyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-ethynyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1470 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-thiene-3-yl-benzyl) amino] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1471 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-5-(1,3-oxazole-2-yl)-N 3，N 3-dipropyl isophthaloyl amine |
| 1472 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(piperazine-1-base alkylsulfonyl)-N 3，N 3-dipropyl isophthaloyl amine |
| 1473 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[1-(3-iodophenyl) cyclopropyl] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1474 | N 1-(1S, 2R)-the 3-[(3-sec-butyl) benzyl]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1475 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(3-methyl |
| Isoxazole-4-base)-N 3，N 3-dipropyl isophthaloyl amine | |
| 1476 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[1-(3-isobutyl-isoxazole-5-base) cyclopropyl] amino } propyl group)-N 3，N 3-dipropyl isophthaloyl amine |
| 1477 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylbenzene base) cyclopropyl] amino }-the 2-hydroxypropyl)-5-(1,3-oxazole-2-yl)-N 3，N 3-dipropyl isophthaloyl amine |
| 1478 | N 4-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-6-methyl-N 2，N 2-dipropyl pyridine-2, the 4-diformamide |
| 1480 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-5-(1,3-oxazole-2-yl)-N 3，N 3-dipropyl isophthaloyl amine |
| 1481 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-5-(1,3-oxazole-2-yl)-N 3，N 3-dipropyl isophthaloyl amine |
| 1482 | 5-(amino-sulfonyl)-N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3，N 3-dipropyl isophthaloyl amine |
| 1483 | N 1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(3-[(1Z)-third-1-thiazolinyl] benzyl } amino) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1484 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3，N 3-dipropyl-5-(1H-pyrazoles-4-yl) isophthaloyl amine |
| 1485 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylbenzene base)-1-methylethyl] amino }-the 2-hydroxypropyl)-5-ethynyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1487 | N 1-[(1S, 2R)-3-[(3-allyl group benzyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1488 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylbenzene base) cyclopropyl] amino }-the 2-hydroxypropyl)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1489 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-Ethylbenzyl)-1-methylethyl] amino }-the 2-hydroxypropyl)-5-(1,3-oxazole-2-yl)-N 3，N 3-dipropyl isophthaloyl amine |
| 1490 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3-ethyl-5-methyl-N 3-propyl group isophthaloyl amine |
| 1491 | N 1-[(1S, 2R)-3-{[3-(cyclopropyl amino) benzyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1492 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-5-ethynyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1493 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[1-(3-isobutyl-isoxazole-5-base) cyclopropyl] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1494 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[3-(5-formyl radical-4-thiotolene-2-yl) benzyl] amino }-the 2-hydroxypropyl)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1496 | N 1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(the 3-[(methyl sulphonyl) and amino] benzyl } amino) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1498 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-isopentyl benzyl) amino] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1500 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1501 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-({ [2-(methylamino-) ethyl] amino } alkylsulfonyl)-N 3，N 3-dipropyl isophthaloyl amine dihydrochloride |
| 1502 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[1-(3-isobutyl-isoxazole-5-base) cyclopropyl] amino } propyl group)-5-ethynyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1504 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[1-(2-isobutyl--1,3-thiazoles-5-yl) cyclopropyl] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1505 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylbenzene base)-1-methylethyl] amino }-the 2-hydroxypropyl)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1506 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-{[(2-hydroxyethyl) amino] alkylsulfonyl }-N 3-propyl group isophthaloyl amine |
| 1507 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3, 5-dimethyl-N 3-propyl group isophthaloyl amine |
| 1508 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 2-(phenyl sulfonyl)-3-[(1-propyl group butyl) alkylsulfonyl] amino propionic acid amide |
| 1509 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3，N 3-diethyl-5-(1,3-oxazole-2-yl) isophthaloyl amine |
| 1510 | N 2-[(benzylamino) carbonyl]-N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(1-propyl group butyl) alkylsulfonyl] amino propionic acid amide |
| 1511 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-pyridin-3-yl benzyl) amino] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1512 | N 2-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 5，N 5-dipropyl pyridine-3,5-diformamide 1-oxide compound |
| 1513 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[3-(3-formyl radical-2-furyl) benzyl] amino }-the 2-hydroxypropyl)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1514 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1-methyl isophthalic acid H-imidazoles-2-yl)-N 3，N 3-dipropyl isophthaloyl amine |
| 1515 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3，N 3-diethyl-oreinol diformamide |
| 1516 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[3-(ethyl sulfinyl) benzyl] amino }-the 2-hydroxypropyl |
| Base)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | |
| 1517 | 3-{[butyl (ethyl) amino] alkylsulfonyl }-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } propionic acid amide |
| 1519 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(1-propyl group butyl) alkylsulfonyl] propionamide hydrochloride |
| 1520 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3-isobutyl--N 3, 5-dimethyl isophthaloyl amine |
| 1521 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-pyridine-2-base benzyl) amino] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1523 | N 1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(3-[methyl (methyl sulphonyl) amino] and benzyl } amino) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1524 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 2-(3-phenyl propanol base)-3-[(1 propyl group butyl) alkylsulfonyl] amino propionic acid amide trifluoroacetate |
| 1525 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[3-(ethylsulfonyl) benzyl] amino }-the 2-hydroxypropyl)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1526 | N 2-[(5-chlorothiophene-2-yl) alkylsulfonyl]-N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(1-propyl group butyl) alkylsulfonyl] amino propionic acid amide |
| 1527 | N 1-[(1S, 2R)-3-{[3-(5-acetyl thiophene-2-yl) benzyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1529 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(1,3-oxazole-2-yl) benzamide hydrochloride salt |
| 1530 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3, 5-dimethyl-N 3-(2-styroyl) isophthaloyl amine |
| 1531 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[3-(3,5-dimethyl isoxazole-4-yl) benzyl] amino }-the 2-hydroxypropyl)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1532 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3, 5-dimethyl-N 3-Propargyl isophthaloyl amine |
| 1533 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3-ethyl-N 3, 5-dimethyl isophthaloyl amine |
| 1535 | N 1-benzyl-N 3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 1, 5-dimethyl isophthaloyl amine |
| 1536 | N 1-(sec-butyl)-N 3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-N 1-propyl group isophthaloyl amine |
| 1537 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(4-thiotolene-2-yl) benzyl] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1538 | 3-({ [(2R; 3S)-4-(3, the 5-difluorophenyl)-3-(3-[(dipropyl amino) carbonyl]-the 5-methyl benzoyl } amino)-2-hydroxyl butyl] amino } methyl) phenyl (methyl) Urethylane |
| 1539 | N 1-((1S, 2R)-2-hydroxyl-1-(2,3, the 5-trifluoro-benzyl)-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1540 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3，N 3-diisobutyl-oreinol diformamide |
| 1541 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3, 5-dimethyl-N 3-(2-pyridine-2-base ethyl) isophthaloyl amine |
| 1542 | N 1-(1S, 2R)-1-(3-fluoro-5-hydroxybenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine hydrochlorate |
| 1544 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-hydroxyl-3-(tetramethyleneimine-1-base carbonyl) benzamide |
| 1545 | 5-oxo-right type prolyl-N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(1-propyl group butyl) alkylsulfonyl] amino propionamide hydrochloride |
| 1546 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-{[(trifluoromethyl) alkylsulfonyl] amino } benzamide |
| 1547 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl) }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1549 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(6-methoxyl group-1,2,3,4-tetralin-1-yl) amino] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1550 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 2-(phenyl acetyl)-3-[(1-propyl group butyl) alkylsulfonyl] amino propionic acid amide |
| 1552 | 3-([(2R, 3S)-4-(3, the 5-difluorophenyl)-3-(3-[(dipropyl amino) carbonyl]-the 5-methyl benzoyl } amino)-2-hydroxyl butyl] amino } methyl) the phenylcarbamic acid methyl esters |
| 1553 | 5-oxo-levorotation prolyl-N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(1-propyl group butyl) alkylsulfonyl] amino propionamide hydrochloride |
| 1554 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3-isobutyl--oreinol diformamide |
| 1555 | 4-({ (1S; 2R)-and 1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino)-4-oxo-3-{[(1-propyl group butyl) alkylsulfonyl] amino } the butyric acid trifluoroacetate |
| 1556 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[methyl (methyl sulphonyl) amino] benzamide |
| 1557 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3-ethyl-N 3-sec.-propyl-oreinol diformamide |
| 1558 | N 1-[(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(thiophene-2-ylmethyl) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1559 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-{[(2-hydroxyethyl) (propyl group) amino] alkylsulfonyl } propionic acid amide |
| 1560 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3-sec.-propyl-N 3, 5-dimethyl isophthaloyl amine |
| 1561 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-[(methyl sulphonyl) amino]-1,3-thiazoles-4-methane amide |
| 1562 | N 1-allyl group-N 1-cyclopentyl-N 3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the oreinol diformamide |
| 1563 | N-(3-({ (1S; 2R)-and 1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino-3-oxo-2-{[(1-propyl group butyl) alkylsulfonyl] methyl } propyl group) benzamide |
| 1564 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(isopentyl alkylsulfonyl) propionic acid amide |
| 1565 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(5-thiotolene-2-yl) benzyl] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1567 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(1-methyl hexyl) amino] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1568 | N 1-[(1S, 2R)-3-{[1-(aminocarboxyl) cyclohexyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1569 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(2E)-oneself-the 2-alkenyl amino]-the 2-hydroxypropyl }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1571 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-hydoxyisoxazole-5-methane amide |
| 1572 | N 1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-(3-[(1E)-oneself-the 1-thiazolinyl] benzyl } amino)-the 2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1573 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3-sec.-propyl-oreinol diformamide |
| 1574 | N 1-[(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(thiophene-2-ylmethyl) propyl group]-N 3，N 3-dipropyl-1,3, the 5-trimethamide |
| 1575 | 2-[3-(2-amino-2-oxo oxyethyl group) phenyl]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-benzyl iodide) amino] propyl group } ethanamide |
| 1576 | N 1-(1S, 2R)-1-(3-bromobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1577 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(2-ethylhexyl) amino]-the 2-hydroxypropyl }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1578 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(6-methoxypyridine-3-yl) benzyl] ammonia |
| Base } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | |
| 1579 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[3-(2,4-dimethoxypyridin-5-yl) benzyl] amino }-the 2-hydroxypropyl)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1580 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(2-ethyl butyryl radicals) benzamide |
| 1581 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(4-hydroxy piperidine-1-yl) carbonyl]-the 5-methyl benzamide |
| 1582 | N 1-(1S, 2R)-1-(3-bromobenzyl)-2-hydroxyl-3-[(3-ethoxy benzyl) amino] propyl group }-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1583 | 4 '-[4-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-benzyl iodide) amino] propyl group } amino)-the 4-oxobutanoyl]-1,1 '-phenylbenzene-2-methane amide |
| 1585 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(3-hydroxy piperidine-1-yl) carbonyl]-the 5-methyl benzamide |
| 1586 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl-3-[(3-hydroxyl-1-phenyl propyl) amino] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1587 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3-[2-(dimethylamino) ethyl]-N 3-ethyl-oreinol diformamide |
| 1588 | N-{ (1S, 2R)-and 1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-methyl isophthalic acid H, 6H-pyrrolo-[1,2-a] [4,1] benzoxazine (benzoxazepine)-4-methane amides |
| 1589 | 2-(5-acetyl thiophene-2-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide |
| 1591 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3，N 3-di-isopropyl-oreinol diformamide |
| 1592 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-[(methyl sulphonyl) amino] benzamide |
| 1594 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-benzyl iodide) amino] propyl group }-2-[4-(2-oxo-pyrrolidine-1-yl) phenyl] ethanamide |
| 1595 | N-{ (1S, 2R)-1-(3-chloro-5-luorobenzyl)-2-hydroxyl-3-[(3-Ethylbenzyl) amino] propyl group }-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 1596 | N 1-[(1S, 2R)-1-(3-chloro-5-luorobenzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1597 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(1-methyl isophthalic acid H-imidazol-4 yl) alkylsulfonyl] amino } benzamide four hydrochlorides |
| 1598 | N 1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(penta amino) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1599 | N 1-(1S, 2R)-1-(4-luorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1600 | N 1-[(1S, 2R)-3-(benzylamino)-1-(3-chloro-5-luorobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1601 | N 1-cyclohexyl-N 3-(1S, 2R)-1-(3, the 5-difluorophenyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 1-ethyl-oreinol diformamide |
| 1602 | 2-{[(2R; 3S)-4-(3; the 5-difluorobenzyl)-3-(3-[(dipropyl amino) carbonyl]-the 5-methyl benzoyl } amino)-2-hydroxyl butyl] amino } butyl 2,4 difluorobenzene aminocarbamic acid ester |
| 1603 | N-{ (1S, 2R)-and 1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(2S)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] carbonyl }-5-toluyl amine hydrochlorate |
| 1605 | N 1-[(1S, 2R)-1-(3-bromobenzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1606 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,8-dimethyl quinoline beautiful jade-3-methane amide |
| 1607 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(6-hydroxyl hexyl) amino] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1608 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(2R)-the 2-hydroxypropyl] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1609 | N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-[(1-propyl group butyl) alkylsulfonyl] propionic acid amide |
| 1610 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(2-hydroxyl-1, the 1-dimethyl ethyl) amino] alkylsulfonyl } benzamide |
| 1611 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(4-phenyl butyl) amino] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1612 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-benzyl iodide) amino] propyl group }-7-(1H-imidazoles-1-yl)-5,6-dialin-2-methane amide |
| 1613 | 3-(kharophen)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-methyl benzamide |
| 1614 | N 1-[(1S, 2R)-3-{[2-(amino-sulfonyl) ethyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1615 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[2-(ethylmercapto group) ethyl] amino }-the 2-hydroxypropyl)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1617 | N 1-[(1S, 2R)-3-[benzyl (cyano methyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1618 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-hydroxypropyl) amino] propyl group }-the 5-methyl |
| -N 3，N 3-dipropyl isophthaloyl amine | |
| 1619 | N 1-[(1S, 2R)-3-[(3-butoxy propyl group) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1620 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[2-(2-hydroxyethyl) piperidines-1-yl] carbonyl }-the 5-methyl benzamide |
| 1621 | N-[(2S, 3R)-4-(3, the 5-difluorophenyl)-3-(3-[(dipropyl amino) carbonyl]-the 5-methyl benzoyl } amino)-2-hydroxyl butyl]-the β-An Jibingsuan methyl esters |
| 1622 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(1-hydroxyl-2-propyl group amyl group) benzamide |
| 1623 | N 1-[(1S, 2R)-3-(benzyl amino)-1-(3-chloro-5-luorobenzyl)-2-hydroxypropyl]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1624 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-[(methyl sulphonyl) amino] butyramide |
| 1625 | N 1-[(1S, 2R)-3-{[3-(1-thionaphthene-2-yl) benzyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1626 | 3-(benzyloxy)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } isoxazole-5-methane amide |
| 1627 | The 2-{[(benzyloxy) carbonyl] amino }-7-[(cyclopropyl methyl) amino]-1; 2; 4; 5; 7-pentadecyl oxygen (pentadeoxy)-5-(3, the 5-difluorobenzyl)-1-[(1-propyl group butyl) alkylsulfonyl]-right type-threo form-heptan-3-ketose (ulose) trifluoro-acetate |
| 1629 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1H-pyrazol-1-yl) valeramide |
| 1630 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-(2-furyl methyl)-5-oxo-pyrrolidine-3-methane amide |
| 1632 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(5-hydroxyl amyl group) amino] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1633 | 3-[({ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(1-methyl)-the 1-styroyl] amino } propyl group } amino) alkylsulfonyl]-N, N-dipropyl benzamide |
| 1634 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N 3，N 3-dipropyl piperidines-1, the 3-diformamide |
| 1635 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N 3，N 3-diethyl piperidines-1, the 3-diformamide |
| 1636 | 5-bromo-N 1-((1S, 2R)-2-hydroxyl-1-(PFBBR)-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-N 3，N 3-dipropyl isophthaloyl amine |
| 1637 | N-{[1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-[(methyl sulphur |
| Acyl group) amino] benzamide | |
| 1638 | N-{ (1S, 2R)-1-(3-bromobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 1639 | 3-[(dipropyl amino) alkylsulfonyl]-N-[(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(thiophene-2-ylmethyl) propyl group } propionic acid amide |
| 1640 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-ethoxycarbonyl propyl) amino]-the 2-hydroxypropyl }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1641 | N 1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(thiophene-2-ylmethyl) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1642 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl-4-(phenyl sulfonyl) butyramide |
| 1643 | N 1-[(1S, 2R)-1-(3, the 5-dichloro benzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1645 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3, the 3-dimethylbutyl) amino]-the 2-hydroxypropyl }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1646 | N 1-[(1S, 2R)-3-(benzyl amino)-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1647 | N 1-[(1S, 2R)-1-(3-chloro-5-luorobenzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1648 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(1, the 3-diphenyl propyl) amino]-the 2-hydroxypropyl }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1649 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(1S)-1-(methylol) propyl group] amino } propyl group)-N 3，N 3-dipropyl isophthaloyl amine |
| 1650 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(3S)-2-oxo nitrogen Zhuo (oxoazepan)-3-yl] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1651 | N 1-cyclohexyl-N 5-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } valeramide |
| 1652 | N 1-[(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(3-methyl-benzyl) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1653 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3-[(2-propyl group amyl group) alkylsulfonyl]-beta-amino propionic acid amide |
| 1654 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(1,3-thiazoles-2-yl) benzamide hydrochloride salt |
| 1656 | N 1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(3-[methyl (phenyl) amino] and propyl group } amino) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1657 | N 1-[(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(4-methyl-benzyl) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1658 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-oxo-1-(thiophene-2-ylmethyl) tetramethyleneimine-3-methane amide |
| 1659 | The 4-[(butylthio) methyl]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-2-furoamide |
| 1660 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-{[(2-hydroxyethyl) amino] alkylsulfonyl } benzamide |
| 1661 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methylcyclohexyl) amino] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1662 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2-oxo-1,3-oxazolidine-3-yl) benzamide |
| 1663 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(1H-pyrroles-1-yl) benzamide |
| 1665 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,3,4,5-tetrahydro-thiapyran is [4,3-b] indoles-8-methane amide also |
| 1666 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 4-[2-(trifluoromethyl) phenyl] succinic diamide |
| 1667 | N 1-[(1S, 2R)-1-(3-bromobenzyl)-2-hydroxyl-3-(isoamylamino) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1668 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4,5-dimethyl-2-(1H-pyrroles-1-yl) thiophene-3-methane amide |
| 1669 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(2, the 3-dihydroxypropyl) amino]-the 2-hydroxypropyl }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1670 | N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(2S)-the 2-hydroxypropyl] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1671 | N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1R)-the 1-methyl-propyl] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1672 | 2-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(methyl sulphonyl) benzamide |
| 1673 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(2-hydroxyethyl) amino] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1674 | 3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S, 2R)-2-hydroxyl-1-(3-methoxy-benzyl)-3-[(3-methoxy-benzyl) amino] propyl group } propionic acid amide |
| 1675 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-{ methyl |
| [(trifluoromethyl) alkylsulfonyl] amino } benzamide | |
| 1676 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-hydroxyl-6-(1-hydroxyl-2,2-dimethyl propyl) pyridine-2-carboxamide |
| 1677 | N 1-[(1S, 2R)-3-[(1,3-dicyclohexyl propyl group) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1678 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,2 '-two thiophene-5-methane amide |
| 1679 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(1H-imidazoles-1-yl) butyramide |
| 1680 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,3-dihydroxyl-N 4-(4-p-methoxy-phenyl) succinic diamide |
| 1682 | N 1-(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-[3-(trifluoromethyl) benzyl] propyl group }-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1683 | N 1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(thiophene-2-ylmethyl) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1684 | N 1-[(1S, 2R)-3-{[2-(aminocarboxyl)-1H-indoles-6-yl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1685 | N 1-[(1S, 2R)-3-(benzyl amino)-1-(3-bromobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1686 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(1-oxo-1,3-dihydro-H-isoindole-2-yl) butyramide |
| 1687 | 3-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(methyl sulphonyl) thiophene-2-carboxamide derivatives |
| 1688 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(1-ethyl propyl) amino]-the 2-hydroxypropyl }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1689 | N 1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-([(5R)-and 3-ethyl-2-oxo-1,3-oxazolidine-5-yl] methyl } amino)-the 2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1690 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-7-(trifluoromethyl) pyrazolo [1,5-a] pyrimidine-2-methane amide |
| 1691 | N 1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N 2-[(methylthio group) ethanoyl]-3-[(1-propyl group butyl) alkylsulfonyl] amino propionamide hydrochloride |
| 1692 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(2, the 3-Dimethylcyclohexyl) amino]-the 2-hydroxypropyl }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1693 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4,5-dimethoxy-1-thionaphthene-2-methane amide |
| 1694 | N 1-[(1S, 2R)-1-[3-fluoro-5-(trifluoromethyl) benzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1695 | N 1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-([(5S)-and 3-ethyl-2-oxo-1,3-oxazolidine-5-yl] methyl } amino)-the 2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1696 | N 1-(1S, 2R)-1-(1,3-benzo dioxole-5-ylmethyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1697 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3,5-dioxo-1,2,4-triazolidine-4-yl) benzamide |
| 1698 | N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-2-hydroxyl-3-[(3-p-methoxy-phenyl) alkylsulfonyl] propionamide hydrochloride |
| 1699 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(2-methylcyclohexyl) amino] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1700 | N 1-(1S, 2R)-3-[(2-{4-[(3-benzyl chloride base) oxygen] phenyl } ethyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1701 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-2-hydroxypropyl-2-hydroxyl-4-oxo-4-thiene-3-yl-butyramide |
| 1702 | N 1-(1S, 2R)-1-[3-(benzyloxy)-5-luorobenzyl]-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1703 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl-4-oxo-4-[3-(trifluoromethyl) phenyl] butyramide |
| 1704 | N 1-(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-[3-(trifluoromethoxy) benzyl] propyl group }-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1705 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[1-(methylol)-3-(methylthio group) propyl group] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1706 | 2-(1H-1,2,3-benzotriazole-1-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } hexanamide |
| 1707 | N 1-[(1S, 2R)-1-(3-fluoro-4-methyl-benzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1708 | N-{ (1S; 2R)-1-(3; the 5-difluorobenzyl)-and the 3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl)-2-{[(1-propyl group butyl) alkylsulfonyl] methyl } propionic acid amide |
| 1709 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-{[(trifluoromethyl) alkylsulfonyl] amino } butyramide |
| 1710 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(5-methyl isophthalic acid, 3-dioxo-1,3-dihydro-2H-isoindole-2-yl) ethanamide |
| 1712 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[1-(methylol) propyl group] amino } propyl group)-5- |
| Methyl-N 3，N 3-dipropyl isophthaloyl amine | |
| 1713 | N 1-[(1S, 2R)-3-(benzylamino)-1-(3, the 5-dichloro benzyl)-2-hydroxypropyl]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1714 | N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-the 3-{[(2-hydroxyethyl) (propyl group) amino] alkylsulfonyl } propionamide hydrochloride |
| 1715 | 5-(benzylthio)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } niacinamide |
| 1716 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-pyrazoles-5-methane amide |
| 1717 | 6-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazole-5-methane amide |
| 1718 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-benzimidazolyl-2 radicals-methane amide |
| 1719 | N 1-(1S, 2R)-1-(cyclohexyl methyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1720 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-6-hydroxyl-4,7-dimethoxy-1-cumarone-5-methane amide |
| 1721 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(4-methylcyclohexyl) amino] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1722 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } [1,2,4] triazolo [4,3-a] pyridine-6-methane amide |
| 1723 | N-{[1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl-4-oxo-4-thiophene-2-base butyramide |
| 1724 | N 1-[(1S, 2R)-3-(benzyl amino)-1-(3, the 5-dichloro benzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1725 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2-hydroxy-5-methyl base phenyl)-4-oxo butyramide |
| 1726 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-phenoxy benzamide |
| 1727 | The 4-[(aminocarboxyl) amino]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide |
| 1728 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1S)-1-(methylol)-3-(methylthio group) propyl group] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1729 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-7-hydroxyl-4-oxo look alkane (oxochromane)-2-methane amide |
| 1730 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1S)-1-(methylol)-3-methyl butyl] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1731 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1R)-1-(methylol) propyl group] amino } propyl group)-N 3，N 3-dipropyl isophthaloyl amine |
| 1732 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(1-methyl-3-phenyl propyl) amino] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1733 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2,3-dihydro-1-cumarone-5-yl)-1,3-thiazoles-4-methane amide |
| 1734 | N 1-(1S, 2R)-1-[3-(benzyloxy) benzyl]-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1735 | N-{ (1S, 2R)-1-(4-benzyl chloride base)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 1736 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3-amyl group Malonamide |
| 1737 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(trifluoromethoxy) benzamide |
| 1738 | 3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S, 2R)-1-(3-fluoro-4-methyl-benzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } propionic acid amide |
| 1739 | N-[(1S, 2R)-1-(3-chloro-5-luorobenzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-3-[(3-dipropyl amino) alkylsulfonyl] propionic acid amide |
| 1740 | N-{ (1S; 2R)-1-(3; the 5-difluorobenzyl)-and the 3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl)-2-{[(1-propyl group butyl) alkylsulfonyl] methyl } propionic acid amide |
| 1741 | N 1-[4-(acetylamino) phenyl]-N 4-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } succinic diamide |
| 1742 | 3-(1-cyanoethyl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide |
| 1743 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 4-(5-phenyl-1,3,4-thiadiazoles-2-yl) succinic diamide |
| 1744 | N 1-(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-[3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1745 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[2-(2-oxo-2-tetramethyleneimine-1-base oxethyl) phenyl] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1746 | N 1-[(1S, 2R)-1-(4-benzyl chloride base)-2-hydroxyl-3-(isopentyl amino) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1747 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(1, the 1-dioxy |
| Change tetramethylene sulfide-2-yl) ethanamide | |
| 1748 | N 1-[(1S, 2R)-3-(benzyl amino)-1-(4-benzyl chloride base)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1749 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl-5-oneself-1-alkynyl niacinamide |
| 1750 | N-[(1S, 2R)-1-(3-bromobenzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 1751 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-first oxygen isoxazole-5-methane amide |
| 1752 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,3-dimethyl-1H-indoles-7-methane amide |
| 1753 | 4-(3-chloro-phenyl-)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl-4-oxo butyramide |
| 1755 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(1-Methyl-1H-indole-3-yl)-2-oxo ethanamide |
| 1756 | N 1-[(1S, 2R)-1-(3-fluoro-4-methyl-benzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1757 | 3-[(dipropyl amino) alkylsulfonyl]-N-[(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(4-methyl-benzyl) propyl group] propionic acid amide |
| 1758 | N 1-[(1S, 2R)-3-(benzyl amino)-1-(3-fluoro-4-methyl-benzyl)-2-hydroxypropyl]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1759 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[5-(4-aminomethyl phenyl)-2H-tetrapyrrole-2-yl] ethanamide |
| 1760 | N-{ (1S, 2R)-1-(3, the 5-dichloro benzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 1761 | N 1-(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(thiophene-2-ylmethyl) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1762 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-3-phenyl-isoxazole azoles-4-methane amide |
| 1764 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 2-[(methyl sulphonyl) ethanoyl]-N 2-amyl group G-NH2 |
| 1765 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(1H-indol-3-yl)-4-oxo butyramide |
| 1766 | N 1-(5-benzyl-1,3,4-thiadiazoles-2-yl)-N 4-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } succinic diamide |
| 1767 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3-fluoro-4-p-methoxy-phenyl)-4-oxo butyramide |
| 1768 | 4-{[(2R, 3S)-4-(3, the 5-difluorophenyl)-3-(3-[(dipropyl amino) carbonyl]-the 5-methyl benzoyl } amino)-2-hydroxyl butyl] amino } piperidines-1-ethyl formate |
| 1769 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2-fluoro benzoyl)-1H-pyrroles-2-methane amide |
| 1770 | N 1-[(1S, 2R)-3-(benzyl amino)-1-(4-benzyl chloride base)-2-hydroxypropyl]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1772 | N 1-[(1S, 2R)-2-hydroxyl-1-(4-hydroxybenzyl)-3-(isopentyl amino) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1773 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(4-morpholine-4-base phenyl) ethanamide |
| 1774 | 3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-[3-(trifluoromethoxy) benzyl] propyl group } propionic acid amide |
| 1775 | N 1-benzyl-N 1-(1-cyclopropyl ethyl)-N 4-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } succinic diamide |
| 1776 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-(2, the 5-dimethylbenzoyl)-5-methyl benzamide |
| 1777 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 4-(2-methoxyl group-5-aminomethyl phenyl) succinic diamide |
| 1778 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-the 2-hydroxypropyl }-2-(3-hydroxy phenyl) ethanamide |
| 1779 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[hydroxyl (2-aminomethyl phenyl) methyl]-the 5-methyl benzamide |
| 1780 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(ethylmercapto group) niacinamide |
| 1781 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-[4-(2-furoyl base) piperazine-1-yl]-4-oxo butyramide |
| 1782 | N 1-[(1S, 2R)-3-(benzyl amino)-1-(3-fluoro-4-methyl-benzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1783 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-oxoisoindoline diindyl-1-methane amide |
| 1784 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(ethylmercapto group) benzamide |
| 1785 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } thieno- |
| [2,3-b] quinoline-2-formamide | |
| 1786 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(4-methyl isophthalic acid, 3-oxazole-2-yl) benzamide |
| 1788 | N-{2-[({ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino) carbonyl] phenyl }-N-methyl-2-furoamide |
| 1789 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl-4-(3-p-methoxy-phenyl)-4-oxo butyramide |
| 1790 | N 1-[(1S, 2R)-3-(suberyl amino)-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1791 | N 1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(4-methyl-benzyl) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1792 | 1,3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S, 2R)-1-(3-fluoro-5-hydroxybenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } propionic acid amide |
| 1793 | 3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S, 2R)-1-(3-fluoro-5-hydroxybenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } propionamide hydrochloride |
| 1794 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-hydroxyl-1H-indoles-2-methane amide |
| 1795 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,2-dimethyl chromane-8-methane amide |
| 1796 | 6-benzyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } piperazine-2-methane amide 4-oxide compound |
| 1797 | 2-{[({ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-methoxy-benzyl) amino] propyl group } amino) carbonyl] amino }-N, N-dipropyl ethane sulphonamide |
| 1798 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1R)-1-(methylol)-2-methyl-propyl] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1799 | N-[(1S, 2R)-3-(benzyl amino)-1-(3-chloro-5-luorobenzyl)-2-hydroxypropyl]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 1800 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(4-p-methoxy-phenyl)-4-oxo butyramide |
| 1802 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl-4-oxo-3,4-dihydro naphthyridine-1-methane amide |
| 1803 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3,4-dihydro-2H-1,5-benzo dioxepine-7-methane amide |
| 1804 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[4-(2,5-dioxo tetramethyleneimine-1-yl) phenoxy group] ethanamide |
| 1806 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-4-oxo-3, the 4-dihydro-thiophene is [2,3-d] pyrimidine-6-methane amide also |
| 1807 | N 1-[(1S, 2R)-1-(1,3-Ben Bing Er oxazole-5-ylmethyl)-2-hydroxyl-3-(3-isopentyl amino) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1808 | N 1-(1S, 2R)-1-(3-chloro-5-luorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N 5，N 5-glutaramide |
| 1809 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-6-fluoro-2-hydroxyl quinoline beautiful jade-4-methane amide |
| 1810 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-oxo-4-thiophene-2-base butyramide |
| 1811 | N 3-[((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } amino) carbonyl]-N 1，N 1-dipropyl-beta-amino propionic acid amide |
| 1812 | N 1-(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-the 1-[(thiophenyl) methyl] propyl group }-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1814 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1R, 2S)-1-(methylol)-2-methyl butyl] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1815 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(phenoxymethyl) benzamide |
| 1816 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 5-(2,4 difluorobenzene base) glutaramide |
| 1817 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 5-(4.6-dimethyl pyrimidine-2-yl) glutaramide |
| 1818 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-(3-anisoyl)-5-methyl benzamide |
| 1819 | N 1-(1S, 2R)-1-[3-(benzyloxy) benzyl]-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1820 | 4-(3, the 4-dichlorophenyl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-oxo butyramide |
| 1821 | 4-{ (2R, 3R)-2-(3-[(dipropyl amino) carbonyl]-the 5-methyl benzoyl } amino)-3-hydroxyl-4-[(3-methoxy-benzyl) amino] butyl } methyl benzoate |
| 1822 | N 1-(4-acetylphenyl)-N 5-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } glutaramide |
| 1824 | N 1-(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-the 1-[(thiophenyl) methyl] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1825 | 2-{[3-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ammonia |
| Base)-and the 3-oxopropyl] sulfenyl }-N-methyl-benzamide | |
| 1826 | N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-[(1-propyl group butyl) sulfenyl] propionic acid amide |
| 1827 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 4-(4-ethoxyl phenenyl) succinic diamide |
| 1828 | N 1-[(1S, 2R)-1-[3-(benzyloxy)-5-luorobenzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1829 | 2-{[(2R; 3S)-4-(3, the 5-difluorophenyl)-3-(3-[(dipropyl amino) carbonyl]-the 5-methyl benzoyl } amino)-2-hydroxyl butyl]-amino } ethyl 3-p-methoxy-phenyl carbamate |
| 1830 | 3-(benzyloxy)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide |
| 1831 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1S)-2-hydroxyl-1-methylethyl] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1832 | N 1-(1S, 2R)-2-hydroxyl-1-(PFBBR)-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1833 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(4-hydroxy phenyl)-4-oxo butyramide |
| 1834 | 3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-[3-(trifluoromethyl) benzyl] propyl group } propionic acid amide |
| 1835 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(piperidines-3-base alkylsulfonyl) benzamide |
| 1836 | 6-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-hydroxyl quinoline beautiful jade-2-methane amide |
| 1837 | N 1-[(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(thiophene-2-ylmethyl) propyl group]-N 5，N 5-dipropyl glutaramide |
| 1838 | N 1-((1S)-1-{ (1R)-1-hydroxyl-2-[(3-methoxy-benzyl) amino] ethyl }-the 3-methyl butyl)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1839 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(6-oxo-3-phenylpiperazine-1 (6H)-yl) ethanamide |
| 1840 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-{4-[(methyl sulphonyl) amino] phenyl } propionic acid amide |
| 1842 | N 1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(4-methyl-benzyl) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1843 | 3-(2-chlorophenoxy)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group } propionic acid amide |
| 1844 | N 1-[(1S, 2R)-1-(4-luorobenzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1845 | May contain unsupported peptide in the existing version in the structure |
| 1846 | 1N-{ (1S, 2R)-1-[3-(benzyloxy)-5-luorobenzyl]-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-[(dipropyl amino) alkylsulfonyl] propionamide hydrochloride |
| 1847 | N-{ (1S, 2R)-1-[3-(benzyloxy)-5-luorobenzyl]-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-[(dipropyl amino) alkylsulfonyl] propionamide hydrochloride |
| 1848 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(4-aminomethyl phenyl)-4-oxo butyramide |
| 1849 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 4-[3-(trifluoromethyl) phenyl] succinic diamide |
| 1850 | N 1-(1S, 2R)-1-(1,3-benzodiazole-5-ylmethyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1851 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(5-piperidines-2-base-2H-tetrapyrrole-2-yl) ethanamide |
| 1852 | May contain unsupported peptide in the existing version in the structure |
| 1853 | 3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(3-methyl-benzyl) propyl group] propionic acid amide |
| 1854 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-2-hydroxypropyl } isoxazole-5-methane amide |
| 1855 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(3,5-dimethoxy phenoxy group) ethanamide |
| 1856 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2,5-dimethyl-1H-pyrroles-1-yl)-3-hydroxybenzamide |
| 1857 | N 1-(1S, 2R)-1-(3-bromobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N 5，N 5-dipropyl glutaramide |
| 1858 | N1-[5-(cyclopentyl-methyl)-1,3,4-thiadiazoles-2-yl]-N 4-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } succinic diamide |
| 1859 | N 1-(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-[3-(trifluoro-benzyl) benzyl] propyl group }-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1860 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(3-oxo-1,2-benzisothiazole-2 (3H)-yl) ethanamide |
| 1861 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[1-methyl-5-(tetramethyleneimine-1-base carbonyl)-1H-pyrroles-3-yl] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1862 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3, the 4-difluoro |
| Phenyl)-4-oxo butyramide | |
| 1863 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2-naphthyl)-4-oxo butyramide |
| 1864 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4,6-diethoxy pyridine-2-carboxamide |
| 1865 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(5-methyl isophthalic acid H-pyrroles-2-yl)-4-oxo butyramide |
| 1866 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-({ [2-(methylamino) ethyl] amino } alkylsulfonyl) benzamide dihydrochloride |
| 1867 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3，N 3-dipropyl isophthaloyl amine |
| 1868 | N-[(1S, 2R)-1-(1,3-benzo dioxole-1-ylmethyl)-3-(benzylamino)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1869 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(piperazine-1-base alkylsulfonyl) benzamide |
| 1870 | N 1-[(1S, 2R)-3-(2-[4-(amino-sulfonyl) phenyl] and ethyl } amino)-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1871 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[2-hydroxyl]-1-(methylol) ethyl } amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1872 | N 1-[(1S, 2R)-1-(4-fluoro-3-methyl-benzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1873 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(3-oxo-2,1-benzisothiazole-1 (3H)-yl) propionic acid amide |
| 1874 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2,6-dihydroxy-pyrimidine-4-yl) ethanamide |
| 1875 | N 1-(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-[3-(trifluoromethyl) benzyl] propyl group }-N 5，N 5-dipropyl glutaramide |
| 1876 | N-{ (1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(4-hydroxybenzyl) propyl group]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 1877 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3, the 4-difluorophenyl)-2-methyl-4-oxo butyramide |
| 1878 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 5-(2-pyridine-2-base ethyl) glutaramide |
| 1879 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[2-(4-fluorophenyl)-1,3-benzoxazole-5-yl] ethanamide |
| 1880 | N 2-(anilino carbonyl)-N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } G-NH2 |
| 1881 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(1,3-dithiane-2-yl)-3-furoamide |
| 1882 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[2-oxo-2-(propyl group amino) ethyl] benzamide |
| 1883 | N-[(1S, 2R)-3-(benzylamino)-1-(3-bromobenzyl)-2-hydroxypropyl]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 1884 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-3-(2-fluorophenyl) propionic acid amide |
| 1885 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-thiotolene-2-methane amide |
| 1886 | 2-[4-(benzyloxy) phenyl]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group } ethanamide |
| 1887 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[(5,7-dimethyl [1,2,4] sulfenyl triazolo [4,3-a] pyrimidin-3-yl)] ethanamide |
| 1888 | N 1-(1-ethanoyl-2,3-dihydro-1H-indoles-7-yl)-N 4-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } succinic diamide |
| 1889 | N 1-(3-acetylphenyl)-N 5-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } glutaramide |
| 1890 | 3-(4-chlorophenoxy)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl propionic acid amide |
| 1891 | N 1-[(1S, 2R)-3-(benzyl amino)-1-(3-fluoro-4-methoxy-benzyl)-2-hydroxypropyl]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1892 | N 1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(3-methyl-benzyl) propyl group]--N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1893 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-indoles-7-methane amide |
| 1894 | N 1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(3-methyl-benzyl) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1895 | N-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(1,2,3-thiadiazoles-4-yl) benzamide |
| 1896 | N-{ (1S, 2R)-1-[3-(benzyloxy)-5-luorobenzyl]-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 1897 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(4, the 4-diformazan |
| Base-2,5-dioxo alkyl imidazole-1-yl)-2-{[(1-propyl group butyl) alkylsulfonyl] methyl } propionic acid amide | |
| 1898 | N 1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(4-methyl-benzyl) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1899 | N 1-(1S, 2R)-3-(benzylamino)-1-[3-fluoro-5-(trifluoromethyl) benzyl]-the 2-hydroxypropyl }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1900 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[1-methyl-3-(methylthio group)-1H-indoles-2-yl] ethanamide |
| 1901 | N 1-[(1S, 2R)-1-(3, the 5-dichloro benzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1902 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2-furyl)-4-oxo butyramide |
| 1903 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(3-pyridine-2-base-1,2,4-oxadiazole-5-yl) propionic acid amide |
| 1904 | 2-[2-(acetylamino)-1,3-thiazoles-4-yl]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide |
| 1905 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[(4-methyl-4H-1,2,4-triazole-3-yl) sulfenyl]-the 2-phenyl-acetamides |
| 1906 | N 1-[(1S, 2R)-1-(4-benzyl chloride base)-2-hydroxyl-3-(isopentyl amino) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1907 | 4-(1,3-benzothiazole-2-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } butyramide |
| 1908 | N 1-(3-chloro-4-fluorophenyl)-N 4-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } succinic diamide |
| 1909 | N 1-[(1S, 2R)-1-[3-(benzyloxy)-5-luorobenzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1910 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[(2-oxo-2,3-dihydro quinoline beautiful jade-4-yl) sulfenyl] ethanamide |
| 1911 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-methyl-5-(2-methyl benzoyl) benzamide |
| 1913 | N 1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(4-methyl-benzyl) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1914 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-propoxy-benzamide |
| 1915 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-methyl isophthalic acid H-indoles-2-methane amide |
| 1916 | 5-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(3-methyl-4H-1,2,4-triazole-4-yl) benzamide |
| 1917 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3, the 4-difluorophenyl)-2-methoxyl group-4-oxo butyramide |
| 1918 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(3-thiophene-2-base-1H-is pyrazol-1-yl not) ethanamide |
| 1919 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino }-the 2-hydroxypropyl }-N 5-phenyl glutaramide |
| 1920 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2-sulfo--1,3-benzothiazole-3 (2H)-yl) ethanamide |
| 1923 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(3-hydroxy-4-methyl phenyl) ethanamide |
| 1924 | N 1-[(1S, 2R)-1-[3-fluoro-5-(trifluoromethyl) benzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1925 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-7-fluoro-4H-imidazo [5,1-c] [1,4] benzoxazine-3-methane amide |
| 1926 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3,4-dihydro-2H-1,5-benzo dioxepin-7-yl)-4-oxo butyramide |
| 1927 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-cumarone-3-methane amide |
| 1928 | N 1-(3, the 4-dichlorophenyl)-N 3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } Malonamide |
| 1929 | N 1-(1S, 2R)-3-(benzyl amino)-1-[3-fluoro-5-(trifluoromethyl) benzyl]-the 2-hydroxypropyl }-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1930 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1R)-2-hydroxyl-1-methylethyl] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1931 | N 1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(3-methyl-benzyl) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1932 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 5-pyridin-3-yl glutaramide |
| 1933 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-methyl-4-oxo-4H-chromene-6-methane amide |
| 1934 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(1H-imidazoles-1-yl) propyl group] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1935 | 3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S, 2R)-1-[3-fluoro-5-(trifluoromethyl) benzyl]-the 2-hydroxyl |
| -3-[(3-methoxy-benzyl) amino] propyl group } propionic acid amide | |
| 1936 | 3-[(dipropyl amino) alkylsulfonyl]-N-[(1S, 2R)-2-hydroxyl-1-(4-hydroxybenzyl)-3-(isopentyl amino) propyl group] propionic acid amide |
| 1937 | N 1-[(1S, 2R)-1-(1,3-benzo dioxole-5-ylmethyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1938 | 3-[(dipropyl amino) alkylsulfonyl]-N-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(thiophene-2-ylmethyl) propyl group] propionic acid amide |
| 1939 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-[(2,2-dimethyl propylene acyl group) amino]-the 2-hydroxybenzamide |
| 1940 | N 1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(3-methoxy-benzyl) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1941 | N-((1S, 2R)-1-(4-luorobenzyl)-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-the 3-{[(3-methoxy-benzyl) amino] alkylsulfonyl } benzamide |
| 1943 | N-[6-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino)-the 6-oxo-hexyl]-the 2-furoamide |
| 1944 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[(1-phenyl-4,5-dihydro-1H-tetrapyrrole-5-yl) sulfenyl] ethanamide |
| 1945 | 4-ethanoyl-4-amino-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } hexamethylene-1,5-diene-1-sulphonamide |
| 1946 | N-((1S, 2S)-1-benzyl-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-the 3-{[(3-methoxy-benzyl) amino] alkylsulfonyl } benzamide |
| 1947 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3,4-dihydro-2H-chromene-6-yl)-4-oxo butyramide |
| 1948 | N 1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(3-methoxy-benzyl) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1949 | N 1-(1S, 2R)-1-(3-fluoro-4-methyl-benzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N 5，N 5-dipropyl glutaramide |
| 1950 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } indolizine-2-methane amide |
| 1951 | N 1-(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-[3-(trifluoromethoxy) benzyl] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1952 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } niacinamide 1-oxide compound |
| 1953 | N-[(1S, 2R)-1-[3-(benzyloxy)-5-luorobenzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 1954 | 2-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group } amino)-2-oxoethyl carbamate |
| 1955 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,3-dihydro-1H-cyclopenta [b] quinoline beautiful jade-9-methane amide |
| 1956 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl isophthalic acid H-pyrroles-5-methane amide |
| 1957 | N-[5-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino)-5-oxo amyl group] benzamide |
| 1958 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-[(methoxymethyl) sulfenyl] benzamide |
| 1959 | 3-(1,3-benzothiazole-2-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methoxy propyl acid amides |
| 1960 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-{[(methylamino-) carbonyl] amino }-3-thiene-3-yl-propionic acid amide |
| 1961 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-pyridine-2-base thiophene-2-carboxamide derivatives |
| 1962 | N 1-(1S, 2R)-3-(benzyl amino)-1-[3-(benzyloxy)-5-luorobenzyl]-the 2-hydroxypropyl }-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1963 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(5,6-dimethyl-2,4-dioxy-1,2,3,4-tetrahydropyridine-3-yl) ethanamide |
| 1964 | N 1-[(1S, 2R)-1-(3-fluoro-4-methoxy-benzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1965 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-isobutyl--1,3-dioxoisoindolin-5-methane amide |
| 1967 | 5-(acetylamino)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-furoamide |
| 1968 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 2-[(4-p-methoxy-phenyl) ethanoyl] G-NH2 |
| 1969 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } different quinoline beautiful jade-4-methane amide |
| 1970 | N 1-[(1S, 2R)-1-[3-(benzyloxy) benzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1971 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(4-hydroxy 3-methoxybenzene base) ethanamide |
| 1972 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-[(4-phenyl |
| -4H-1,2,4-triazole-3-yl) sulfenyl] ethanamide | |
| 1973 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(3, the 5-Dimethoxyphenyl) ethanamide |
| 1974 | N 1-[(1S, 2R)-3-(benzylamino)-2-hydroxyl-1-(3-methoxy-benzyl) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 1975 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2-ethyl-4H-[1,2,4] triazolo [1,5-a] benzoglyoxaline-4-yl) ethanamide |
| 1977 | 7-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 1-benzofuran-2-carboxamides |
| 1978 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl) propionic acid amide |
| 1979 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(2-oxo-2H-1,3-benzoxazine-3 (4H)-yl) propionic acid amide |
| 1980 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(pyrimidine-2-base sulfenyl) ethanamide |
| 1981 | N 1-[3-(aminocarboxyl)-4,5,6,7-tetrahydrochysene-1-thionaphthene-2-yl]-N 4-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } succinic diamide |
| 1982 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[(5-phenyl-1,3,4-oxadiazole-2-yl) sulfenyl] ethanamide |
| 1983 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } quinoline beautiful jade-6-methane amide |
| 1985 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2,3-dihydro-1,4-benzo dioxin-6-yl)-4-oxo butyramide |
| 1986 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(1H-indol-3-yl)-1H-pyrroles-5-methane amide |
| 1987 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl-4-{[(methylamino-) carbonothioyl] amino } benzamide |
| 1988 | 6-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } niacinamide |
| 1989 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3-hydroxy phenyl)-4-oxo butyramide |
| 1990 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2-2-base sulfenyl) ethanamide |
| 1991 | N-{[1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[(1-pyridine oxide-2-yl) sulfenyl] ethanamide |
| 1992 | 3-(acetylamino)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-fluoro-1H-indoles-2-methane amide |
| 1993 | N-((1S, 2R)-1-benzyl-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-3-{[(3-benzyl chloride base) amino] alkylsulfonyl } benzamide |
| 1995 | N 1-[(1S, 2R)-1-(1,3-benzo dioxole-5-ylmethyl)-3-(benzylamino)-2-hydroxypropyl]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 1996 | 4-(3, the 4-dichlorophenyl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxy-3-methyl-4-oxo butyramide |
| 1997 | 3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-[3-(trifluoromethoxy) benzyl] propyl group } propionic acid amide |
| 1998 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 4-(5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl) succinic diamide |
| 1999 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2-ethyl-1H-benzoglyoxaline-1-yl) ethanamide |
| 2000 | N-{ (1S, 2R)-1-(1,3-benzodioxole-5-ylmethyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 2001 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(2-oxo-1,3-benzoxazole-3 (2H)-yl) propionic acid amide |
| 2002 | N-[(1S, 2R)-1-(3, the 5-dichloro benzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 2003 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 4-(6-picoline-2-yl) succinic diamide |
| 2004 | (4R)-4-[({ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino) carbonyl]-1,3-oxazolidine-3-ethyl formate |
| 2005 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-glycyl benzamide dihydrochloride |
| 2006 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(1-methyl isophthalic acid H-imidazoles-2-yl) benzamide |
| 2007 | 4-(acetylamino)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } the butyramide trifluoroacetate |
| 2008 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 2-[(3S)-and tetrahydrofuran (THF)-3-base oxo] carbonyl }-right type-leucyl amine |
| 2009 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(tetramethyleneimine-3-base alkylsulfonyl) benzamide |
| 2010 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-[(two |
| Propyl group amino) methyl] benzamide dihydrochloride | |
| 2011 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1R)-1-(methylol)-3-methyl butyl] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2012 | N 1-[(1S, 2R)-the 3-[tertiary butyl (cyclohexyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2013 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1S)-1-(methylol)-2, the 2-dimethyl propyl] amino } propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2014 | N 1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-([(2R)-and 1-ethyl pyrrolidine-2-yl] methyl } amino)-the 2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2015 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[3-(dimethylamino)-2, the 2-dimethyl propyl] amino }-the 2-hydroxypropyl)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2016 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[2-(diisopropylaminoethyl) ethyl] amino }-the 2-hydroxypropyl)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2017 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(1-ethyl pyrrolidine-2-yl) methyl] amino }-the 2-hydroxypropyl)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2018 | N 1-[(1S, 2R)-3-[(1-benzyl-pyrrole alkane-3-yl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2019 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-tetramethyleneimine-1-base propyl group) amino] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2020 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[3-(dimethylamino) propyl group] amino }-the 2-hydroxypropyl)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2021 | N 1-[(1S, 2R)-3-{[2-(acetylamino) ethyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2022 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[2-(6-oxo-1,4,5,6-tetrahydro pyridazine-3-yl) phenyl] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2023 | N 1-[(1S, 2R)-3-[7-chloro-1-(2-hydroxy 3-methoxybenzene base)-3, the different quinoline beautiful jade-2 of 4-dihydro (1H)-yl]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2024 | N 1-[(1S, 2R)-3-{[4-(1-cyano group cyclopentyl) phenyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2025 | N 1-[(1S, 2R)-3-(4-[4-(acetylamino) phenoxy group] and phenyl } amino)-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2026 | N 1-[(1S, 2R)-3-[(4-benzoyl-2, the 3-3,5-dimethylphenyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2027 | N 1-[(1S, 2R)-3-[(2-amino-2-oxo-1-styroyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2028 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{4-[(1-methyl isophthalic acid H-imidazoles-2-yl) methyl] piperazine-1-yl } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2029 | N 1-((1S, 2R)-1-[3, two (trifluoromethyl) benzyls of 5-]-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2030 | (1S，2R)-N 1-[2-(tertiary butyl sulfenyl) ethyl]-N 2-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } cyclopropane-1, the 2-diformamide |
| 2031 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4, the 5-dihydro-naphtho [2,1-d] isoxazole-3-methane amide |
| 2032 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-methyl isophthalic acid H-benzo [g] indazole-3-methane amide |
| 2033 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-methyl isophthalic acid, the 3-thiazole-4-carboxamide |
| 2034 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-methoxyl group-1H-pyrrole-3-carboxamide |
| 2035 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-9-oxo-1,2,3,9-tetrahydro cyclopentyl diene is [b] chromene-7-methane amide also |
| 2036 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2-oxo-2,3-dihydro-1H-benzoglyoxaline-5-yl) ethanamide |
| 2037 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2-oxo-2,3-dihydro-1,3-benzoxazole-5-yl) ethanamide |
| 2038 | 2-[2-(1,3-benzoxazole-2-yl) phenoxy group]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide |
| 2039 | 5-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-morpholine-4-yl-benzamide |
| 2040 | 3-(3-Lv isoxazole-5-base)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } propionic acid amide |
| 2041 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(6-methoxyl group-1,1 '-phenylbenzene-3-yl)-4-oxo butyramide |
| 2042 | 4-(1-cumarone-2-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-oxo butyramide |
| 2043 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-oxo-1,2,3,4-tetrahydrochysene quinoline beautiful jade-3-methane amide |
| 2044 | 2-(1-cumarone-2-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-methyl propanamide |
| 2045 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 6-methoxyl group |
| -1-benzofuran-2-carboxamides | |
| 2046 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[4-(1H-pyrroles-1-yl) phenyl] propionic acid amide |
| 2047 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-imidazo [1,2-b] pyrazoles-6-methane amide |
| 2048 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-[(4-methyl isophthalic acid, the 3-thiazol-2-yl) sulfenyl] ethanamide |
| 2049 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-methoxyl group-4-(methylthio group) benzamide |
| 2050 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl-4-(propionamido) benzamide |
| 2051 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 6-{[(4-aminomethyl phenyl) alkylsulfonyl] amino }-4-oxo hexanamide |
| 2052 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-benzoglyoxaline-5-carboxamide |
| 2053 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-methyl-2-(1-oxo-1,3-dihydro-2H-isoindole-2-yl) propionic acid amide |
| 2054 | 7-(acetylamino)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-methyl quinoline beautiful jade-5-methane amide |
| 2054A | N 3-(tert-butoxycarbonyl)-N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the amino propionic acid amide of b- |
| 2055 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-hydroxyl-3-propyl group hexanamide |
| 2056 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-phenyl-2-(1H-pyrroles-1-yl) ethanamide |
| 2057 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-methyl-5-phenyl-1H-pyrazole-3-formamide |
| 2058 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(3-oxo-2,3-dihydro-1H-isoindole-1-yl) ethanamide |
| 2059 | 4-[2-(acetylamino)-4, the 5-3,5-dimethylphenyl]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-oxo butyramide |
| 2060 | 6-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } pyrazine-2-methane amide 4-oxide compound |
| 2061 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } methoxypyrazine-2-methane amide 4-oxide compound |
| 2062 | 22-(1H, 1 ' H-2,2-diimidazole-1-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide |
| 2063 | 5-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,3-dihydro-1-cumarone-7-methane amide |
| 2064 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-([1,2,4] triazolo [4,3-b] pyrazine-6-base sulfenyl) ethanamide |
| 2065 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl isophthalic acid-pyridin-4-yl-1H-1,2,3-triazole-4-methane amide |
| 2066 | 2-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-oxo-3,4-dihydroquinazoline-6-methane amide |
| 2067 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(7-methoxyl group-1-cumarone-2-yl)-4-oxo butyramide |
| 2068 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[(2-ethyl-1-oxo-2,3-dihydro-1H-isoindole-5-yl) oxo] propionic acid amide |
| 2069 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } pyrazine-2-methane amide 4-oxide compound |
| 2070 | 7-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } quinoline beautiful jade-2-methane amide |
| 2071 | 2-cyano group-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(3, the 4-Dimethoxyphenyl)-2-methyl propanamide |
| 2072 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl-5-(propionyl amino) benzamide |
| 2073 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[2-oxo-5-(trifluoromethyl) pyridine-1 (2H)-yl] propionic acid amide |
| 2074 | 5-(4-chloro-phenyl-)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-furoamide |
| 2075 | 4-cyano group-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(1H-pyrroles-1-yl) thiophene-2-carboxamide derivatives |
| 2076 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3, two (methylthio group) isothiazole of 5--4-methane amide |
| 2077 | 2-chloro-4-cyano group-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide |
| 2078 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(methoxyl group ethanoyl) amino]-the 3-Phenylpropionamide |
| 2079 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-fluoro-4- |
| Quinoline-4-yl-benzamide | |
| 2080 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(1-epoxy thiomorpholine-4-yl) butyramide |
| 2081 | 4-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
| 2082 | N-{2-[({ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino) carbonyl] phenyl }-5-methyl-2-furoamide |
| 2083 | 1-(cyano methyl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-pyrroles-2-methane amide |
| 2084 | N 1-(2-chloropyridine-3-yl)-N 4-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } succinic diamide |
| 2085 | 3-(cyclopentyloxy)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-methoxy benzamide |
| 2086 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(5-tetramethyleneimine-1-base-2H-tetrazolium-2-yl) ethanamide |
| 2087 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,5-dimethyl-1-phenyl-1H-pyrrole-3-carboxamide |
| 2088 | 1-(4-acetylphenyl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } piperidines-4-methane amide |
| 2089 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-methyl-2-(1H-1,2,4-triazol-1-yl) propionic acid amide |
| 2090 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(piperidines-1-ylmethyl)-2-furoamide |
| 2091 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-methyl-2,3-dihydro-1-thionaphthene-2-methane amide-1,1-dioxide |
| 2092 | 2-(2,1,3-Ben Bing oxadiazole-5-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,3-thiazoles-4-methane amide |
| 2093 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4, the 5-dihydrofuran is [2,3-g] [2,1] benzoisoxazole-8-methane amide also |
| 2094 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-[(4-methyl isophthalic acid, 2,3-thiadiazoles-5-yl) sulfenyl] ethanamide |
| 2095 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-(2-furoyl base)-4-hydroxyl prolineamide |
| 2096 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-oxo-4,5,6,7-tetrahydrochysene-1-cumarone-3-methane amide |
| 2097 | 4,5-two chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } isothiazole-3-methane amide |
| 2098 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 5-(1,3-thiazoles-2-yl) glutaramide |
| 2099 | N-ethanoyl-4-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } the phenyl amino propionic acid amide |
| 2100 | 8-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-hydroxyl cinnolines-3-methane amide |
| 2101 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,6-dioxo pentahydro-pyrimidine-4-methane amide |
| 2102 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(5-methyl-4-phenyl-1,3-oxazole-2-yl) benzamide |
| 2103 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-phenylimidazole [1,2-a] pyridine-6-methane amide also |
| 2104 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[3-(4-p-methoxy-phenyl)-1,2,4-oxadiazole-5-yl] propionic acid amide |
| 2105 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-yl)-1,3-thiazoles-4-methane amide |
| 2106 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-2-phenyl-2H-1,2,3-triazole-4-methane amide |
| 2107 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3-pyridine-2-base-1,2,4-oxadiazole-5-yl) butyramide |
| 2108 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,3-dimethyl-1H-thieno-[2,3-c] pyrazoles-5-methane amide |
| 2109 | 4-(1,3-benzo dioxole-5-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } butyramide |
| 2110 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl-5-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base) isoxazole-4-methane amide |
| 2111 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[2-(dimethylamino)-1-methylethyl] amino }-the 2-hydroxypropyl)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2112 | N 1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(2-methylmorpholine-4-yl) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2113 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{2-[hydroxyl (phenyl) methyl]-4-methylpiperazine-1-yl } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2114 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(2R)-the 2-methyl butyl] amino } propyl group)-5- |
| Methyl-N 3，N 3-dipropyl isophthaloyl amine | |
| 2115 | N 1-[(1S, 2R)-3-{[4-(diethylamino)-1-methyl butyl] amino }-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2116 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(2-hydroxyl-1, the 1-dimethyl ethyl) amino] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2117 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(pipecoline-1-yl) propyl group] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2118 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[5-(trifluoromethyl)-1,3,4-thiadiazoles-2-yl] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2119 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methyl-4,5,6,7-tetrahydrochysene-3H-3 λ 4-[1,3] thiazole also [5,4-c] pyridine-2-yl) amino] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2120 | N 1-[(1S, 2R)-the 3-[(3-Ethylbenzyl) amino]-2-hydroxyl-1-(1H-pyrazol-1-yl methyl) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2121 | 3, two (the kharophen)-N-{ of 5-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide |
| 2122 | N 1-[4-(amino-sulfonyl) phenyl]-N 4-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } succinic diamide |
| 2123 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-[methyl (methyl sulphonyl) amino] benzamide |
| 2124 | 1-ethanoyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-piperidines-4-methane amide |
| 2125 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(4-methoxyl group phenoxy group) propionic acid amide |
| 2126 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 4-methyl succinic diamide |
| 2127 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 4-(2, the 6-3,5-dimethylphenyl) succinic diamide |
| 2128 | N-ethanoyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-right type-phenyl amino propionic acid amide |
| 2129 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-[(4-aminomethyl phenyl) alkylsulfonyl] ethanamide |
| 2130 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-{[(ethylamino) carbonyl] amino } benzamide |
| 2131 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 1-phenyl |
| -1,4,5,6-tetrahydro cyclopentyl diene is [c] pyrazole-3-formamide also | |
| 2132 | 4-(cyclopentyloxy)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide |
| 2133 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 4-pyridin-3-yl succinic diamide |
| 2134 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 4-phenyl succinic diamide |
| 2135 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3, the 4-dihydroxy benzoyl amine |
| 2136 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1H-1,2,4-triazol-1-yl) valeramide |
| 2137 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-phenyl-1,3-oxazole-4-methane amide |
| 2138 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-7-methoxyl group-4-oxo-1,2,3,4-tetralin-2-methane amide |
| 2139 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-{4-[(methyl sulphonyl) amino] phenyl }-4-oxo butyramide |
| 2140 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-hydroxyl-7-methoxyl group-1-cumarone-5-methane amide |
| 2141 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-hydroxyl-7-methoxyl group-1-thionaphthene-5-methane amide |
| 2142 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3,6,6-trimethylammonium-4-oxo-4,5,6,7-tetrahydrochysene-1-benzofuran-2-carboxamides |
| 2143 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5,6-dihydro-4H-cyclopenta [b] thiophene-2-carboxamide derivatives |
| 2144 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,3-thiazoles-4-methane amide |
| 2145 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2-pyridine-2-base-1,3-thiazoles-4-yl) ethanamide |
| 2146 | N 1-[5-(amino-sulfonyl)-1,3,4-thiadiazoles-2-yl]-N 4-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } succinic diamide |
| 2147 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-hydroxyl-6-neo-pentyl pyridine-2-carboxamide |
| 2148 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-(4-fluorophenyl)-1,4,5,6-tetrahydro cyclopentyl diene is [c] pyrazole-3-formamide also |
| 2149 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-methyl-5,6,7,8-tetrahydrochysene-4H-pyrazolo [1,5-a] azepine-3-methane amide |
| 2150 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-methyl-3-furoamide |
| 2151 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-furoamide |
| 2152 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2-hydroxyl-oxethyl) benzamide |
| 2153 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } thiophene-2-carboxamide derivatives |
| 2154 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 2，N 2-dimethyl phthalamide |
| 2155 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-2-phenyl-1,3-oxazole-4-methane amide |
| 2156 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)-2-maloyl group amine |
| 2157 | 2-(2H-1,2,3-benzotriazole-2-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } butyramide |
| 2158 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-indazole-3-formyl radical |
| 2159 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-hydroxy quinoxaline-2-methane amide |
| 2160 | 2-(kharophen)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4,5-thioxene-3-methane amide |
| 2161 | N 1-(2-cyano-phenyl)-N 4-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } succinic diamide |
| 2162 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-ethyl-1H-indoles-2-methane amide |
| 2163 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 1-benzofuran-2-carboxamides |
| 2164 | 1-benzyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3,5-dimethyl-1H-pyrazole-4-carboxamide |
| 2165 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 2-[(4-aminomethyl phenyl) alkylsulfonyl] G-NH2 |
| 2166 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4,8-dihydroxyl quinoline beautiful jade-2-methane amide |
| 2167 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(1,1-titanium dioxide tetramethylene sulfide-3-yl) ethanamide |
| 2168 | 5-[({ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino) carbonyl]-1H-benzimidazolyl-2 radicals-aminocarbamic acid methyl esters |
| 2169 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2-methyl isophthalic acid, 3-benzoxazole-5-yl) ethanamide |
| 2170 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[ethyl (methyl) amino]-4-hydroxy pyrimidine-5-methane amide |
| 2171 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2-pyridin-4-yl-1,3-benzoxazole-5-yl) ethanamide |
| 2172 | 4-[2-(diethylamino) oxyethyl group]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide |
| 2173 | 3-(amino-sulfonyl)-4-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide |
| 2174 | 2-(diethylamino)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-hydroxy pyrimidine-5-methane amide |
| 2175 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5,6,7,8-tetrahydrochysene-4H-cyclopenta [c] isoxazole-3-methane amide |
| 2176 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 4，N 4-phenylbenzene succinic diamide |
| 2177 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-6-hydroxyl-4-picoline-2-methane amide |
| 2178 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-phenylimidazole [1,2-a] pyridine-7-methane amide also |
| 2179 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } quinoline beautiful jade-4-methane amide |
| 2180 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydrochysene-9H-purine-9-yl) ethanamide |
| 2181 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methoxyl group-1H-indoles-2-formyl radical |
| 2182 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3,5-dimethyl-1H-pyrazol-1-yl) benzamide |
| 2183 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-isoxazole-3-methane amide |
| 2184 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-methyl is different |
| Oxazole-5-methane amide | |
| 2185 | 2-(1-thionaphthene-4-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide |
| 2186 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-2-methane amide |
| 2187 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-thionaphthene-2-methane amide |
| 2188 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 6-hydroxy nicotinoyl amine |
| 2189 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3-[(4-aminomethyl phenyl) alkylsulfonyl]-beta-amino propionic acid amide |
| 2190 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl quinoline beautiful jade-4-methane amide |
| 2191 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(5-phenyl-1H-tetrapyrrole-1-yl) ethanamide |
| 2192 | The 4-{[(cyclobutyl carbonyl) amino] methyl }-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide |
| 2193 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2-oxo-1,3-benzoxazole-3 (2H)-yl) butyramide |
| 2194 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(1,3-dioxo octahydro-2H-isoindole-2-yl) butyramide |
| 2195 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 2-(tetrahydrofuran (THF)-2-ylmethyl) phthalamide |
| 2196 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2,3-dihydro-1H-indoles-1-yl)-4-oxo butyramide |
| 2197 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } thieno-[3,2-b] pyridine-6-methane amide |
| 2198 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-sulfenyl of 2-[(6-methoxyl group-1H-benzimidazolyl-2 radicals-yl)] ethanamide |
| 2199 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } thieno-[2,3-c] pyridine-2-carboxamide |
| 2200 | 2-(1H-benzimidazolyl-2 radicals-Ji sulfenyl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } propionic acid amide |
| 2201 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(2, the 4-difluorobenzyl) the oxygen base] propionic acid amide |
| 2202 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5,6-dimethyl-4-oxo-3,4-dihydro-thiophene be [2,3-d] pyrimidine-2-methane amide also |
| 2203 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-(2-fluorophenyl)-5-oxo-pyrrolidine-3-methane amide |
| 2204 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(5-methyl isophthalic acid H-tetrapyrrole-1-yl) benzamide |
| 2205 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(4,4-dimethyl-4,5-dihydro-1,3-oxazole-2-yl) thiophene-3-methane amide |
| 2206 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(trifluoromethoxy)-1H-indoles-2-methane amide |
| 2207 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-phenyl-5-propyl group-1H-pyrazole-4-carboxamide |
| 2208 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-[(pyridine-2-base sulfenyl) methyl]-the 2-furoamide |
| 2209 | 5-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-morpholine-4-yl pyrimidines-4-methane amide |
| 2210 | 5-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl isophthalic acid-phenyl-1H-pyrazole-4-carboxamide |
| 2211 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-methyl isophthalic acid, 2,3-thiadiazoles-5-methane amide |
| 2212 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,1,3-Ben Bing oxadiazole-5-methane amide |
| 2213 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[(imidazo [1,2-a] pyridine-2-ylmethyl) sulfenyl] ethanamide |
| 2214 | 2-(kharophen)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-1,3-oxazole-4-methane amide |
| 2215 | N-{ (1S, 2R)-1-[3-(cyclohexyl methyl) benzyl]-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } ethanamide |
| 2216 | 12-{[({ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } amino) carbonyl] amino }-N, N-dipropyl ethane sulphonamide hydrochloride |
| 2217 | 2-(3-azabicyclo [3,2,2] non-3-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group } ethanamide |
| 2218 | 2-(4-benzoyl phenoxy group)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group } propionic acid amide |
| 2219 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-4-(7-methoxy |
| Base-2,3-dihydro-1-cumarone-4-yl)-4-oxo butyramide | |
| 2220 | N-{ (1S, 2R)-1-[3-(cyclohexyl methyl) benzyl]-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-the 3-{[(trifluoromethyl) alkylsulfonyl] amino } benzamide hydrochloride salt |
| 2221 | N 1-(1S, 2R)-1-[3-(cyclohexyl methyl) benzyl]-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine hydrochlorate |
| 2222 | 3-chloro-N-((1S, 2R)-1-(4-luorobenzyl)-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group) benzamide |
| 2223 | 3-chloro-N-{ (1S, 2R)-1-(4-luorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } benzamide |
| 2224 | 3-chloro-N-((1S, 2R)-1-(cyclohexyl methyl)-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group) benzamide |
| 2225 | 3-chloro-N-{ (1S, 2R)-1-(cyclohexyl methyl)-2-hydroxyl-3-[(3-second methoxy-benzyl) amino] propyl group } benzamide |
| 2226 | N-((1S, 2R)-1-benzyl-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-the 3-chlorobenzamide |
| 2227 | N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-the 3-chlorobenzamide |
| 2228 | 3-{[(3-benzyl chloride base) amino] alkylsulfonyl }-N-((1S, 2R)-1-(4-luorobenzyl)-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group) benzamide |
| 2229 | 3-{[(3-benzyl chloride base) amino] alkylsulfonyl }-N-{ (1S, 2R)-1-(4-luorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } benzamide |
| 2230 | 3-{[(3-benzyl chloride base) amino] alkylsulfonyl }-N-((1S, 2R)-1-(cyclohexyl methyl)-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group) benzamide |
| 2231 | 3-{[(3-benzyl chloride base) amino] alkylsulfonyl }-N-{ (1S, 2R)-1-(cyclohexyl methyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } benzamide |
| 2232 | N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-{[(3-benzyl chloride base) amino] alkylsulfonyl } benzamide |
| 2233 | N-{ (1S, 2R)-1-(4-luorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-the 3-{[(3-methoxy-benzyl) amino] alkylsulfonyl } benzamide |
| 2234 | N-((1S, 2R)-1-(cyclohexyl methyl)-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-the 3-{[(3-methoxy-benzyl) amino] alkylsulfonyl } benzamide |
| 2235 | N-{ (1S, 2R)-1-(cyclohexyl methyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-the 3-{[(3-methoxy-benzyl) amino] alkylsulfonyl } benzamide |
| 2236 | N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-the 3-{[(3-methoxy-benzyl) amino] alkylsulfonyl } benzamide |
| 2237 | N 1-[(1R, 2S)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(4-methyl-benzyl) propyl group]-N 3，N 3- |
| Dipropyl benzene-1,3, the 5-trimethamide | |
| 2238 | N 1-[(1R, 2S)-2-hydroxyl-3-(isopentyl amino)-1-(4-methyl-benzyl) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 2239 | N 1-[(1R, 2S)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(4-methyl-benzyl) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2240 | N 1-[(1R, 2S)-2-hydroxyl-3-(isopentyl amino)-1-(4-methyl-benzyl) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2241 | N 1-[(1R, 2S)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(4-methyl-benzyl) propyl group]-N 5，N 5-dipropyl glutaramide |
| 2242 | N 1-[(1R, 2S)-2-hydroxyl-3-(isopentyl amino)-1-(4-methyl-benzyl) propyl group]-N 5，N 5-dipropyl glutaramide |
| 2243 | 3-[(dipropyl amino) alkylsulfonyl]-N-[(1R, 2S)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(4-methyl-benzyl) propyl group] propionic acid amide |
| 2244 | 3-[(dipropyl amino) alkylsulfonyl]-N-[(1R, 2S)-2-hydroxyl-3-(isopentyl amino)-1-(4-methyl-benzyl) propyl group] propionic acid amide |
| 2245 | N 1-[(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(4-methyl-benzyl) propyl group]-N 5，N 5-dipropyl glutaramide |
| 2246 | N 1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(4-methyl-benzyl) propyl group]-N 5，N 5-dipropyl glutaramide |
| 2247 | N 1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(4-methyl-benzyl) propyl group]-N 5，N 5-dipropyl glutaramide |
| 2248 | N-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(4-methyl-benzyl) propyl group]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 2249 | 3-[(dipropyl amino) alkylsulfonyl]-N-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(4-methyl-benzyl) amino] propionic acid amide |
| 2250 | N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-(4,5-dimethyl-2-furoyl base)-5-methyl benzamide |
| 2251 | N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-2-hydroxyl-3-(isopentyl alkylsulfonyl) propionamide hydrochloride |
| 2252 | N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-the 3-{[(2-methoxy ethyl) (propyl group) amino] alkylsulfonyl } propionamide hydrochloride |
| 2253 | N 1-(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-[(phenyl sulfenyl) methyl] propyl group }-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 2254 | N 1-(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-[(phenyl sulfenyl) methyl] propyl group }-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 2255 | N 1-(1S, 2R)-3-(benzyl amino)-1-[4-(benzyloxy) benzyl]-the 2-hydroxypropyl }-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 2256 | N 1-[(1S, 2R)-1-[4-(benzyloxy) benzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 2257 | N 1-[(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(1-naphthyl methyl) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 2259 | N 1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(1-naphthyl methyl) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 2260 | N 1-[(1S, 2R)-1-(2-furyl methyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 2261 | N 1-(1S, 2R)-3-(benzyl amino)-1-[3-(benzyloxy) benzyl]-the 2-hydroxypropyl }-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 2262 | N 1-[(1S, 2R)-2-hydroxyl-1-(4-hydroxybenzyl)-3-(isopentyl amino) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 2263 | N 1-((1S)-1-{ (1R)-1-hydroxyl-2-[(3-methoxy-benzyl) amino] ethyl } fourth-3-alkynyl)-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 2264 | N 1-(1S)-1-[(1R)-and 2-(benzyl amino)-1-hydroxyethyl] fourth-3-alkynyl }-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 2265 | N 1-(1S)-1-[(1R)-and 1-hydroxyl-2-(isopentyl amino) ethyl] fourth-3-alkynyl }-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 2266 | N 1-[(1S, 2R)-3-(benzyl amino)-1-(cyclohexyl methyl)-2-hydroxypropyl]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 2267 | N 1-[(1S, 2R)-1-(cyclohexyl methyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 2268 | N 1-((1S)-1-{ (1R)-1-hydroxyl-2-[(3-methoxy-benzyl) amino] ethyl }-the 3-methyl butyl)-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 2270 | N 1-(1S)-1-[(1R)-1-hydroxyl-2-(isopentyl amino) ethyl]-the 3-methyl butyl }-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 2271 | N 1-(1R, 2R)-3-(benzyl amino)-2-hydroxyl-1-[(phenyl sulfenyl) methyl] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2272 | N 1-(1R, 2R)-2-hydroxyl-3-(isopentyl amino)-1-[(phenyl sulfenyl) methyl] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2273 | N 1-(1S, 2R)-3-(benzyl amino)-1-[4-(benzyloxy) benzyl]-the 2-hydroxypropyl }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2274 | N 1-[(1S, 2R)-1-[4-(benzyloxy) benzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-the 5-methyl |
| -N 3，N 3-dipropyl isophthaloyl amine | |
| 2275 | N 1-[(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(1-naphthyl methyl) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2277 | N 1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(1-naphthyl methyl) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2278 | N 1-[(1S, 2R)-1-(2-furyl methyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2279 | N 1-(1S, 2R)-3-(benzyl amino)-1-[3-(benzyloxy) benzyl]-the 2-hydroxypropyl }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2280 | N 1-[(1S, 2R)-1-[3-(benzyloxy) benzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2281 | N 1-[(1S, 2R)-1-(4-luorobenzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2282 | N 1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(thiophene-2-ylmethyl) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2283 | N 1-((1S)-1-{ (1R)-1-hydroxyl-2-[(3-methoxy-benzyl) amino] ethyl } fourth-3-alkynyl)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2284 | N 1-(1S)-1-[(1R)-and 2-(benzyl amino)-1-hydroxyethyl] fourth-3-alkynyl }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2285 | N 1-(1S)-1-[(1R)-and 1-hydroxyl-2-(isopentyl amino) ethyl] fourth-3-alkynyl }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2286 | N 1-[(1S, 2R)-1-(cyclohexyl methyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2288 | N 1-(1S)-1-[(1R)-1-hydroxyl-2-(isopentyl amino) ethyl]-the 3-methyl butyl }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2289 | N 1-(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-{ (phenyl sulfenyl) methyl } propyl group }-N 5，N 5-dipropyl glutaramide |
| 2290 | N 1-(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-[(phenyl sulfenyl) methyl] propyl group }-N 5，N 5-dipropyl glutaramide |
| 2291 | N 1-(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-[(phenyl sulfenyl) methyl] propyl group }-N 5，N 5-dipropyl glutaramide |
| 2292 | N 1-(1S, 2R)-3-(benzyl amino)-1-[4-(benzyloxy) benzyl]-the 2-hydroxypropyl }-N 5，N 5-dipropyl glutaramide |
| 2293 | N 1-[(1S, 2R)-1-[4-(benzyloxy) benzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-N 5，N 5-dipropyl glutaramide |
| 2295 | N 1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(1-naphthyl methyl) propyl group]-N 5，N 5-dipropyl glutaramide |
| 2296 | N 1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(1-naphthyl methyl) propyl group]-N 5，N 5-dipropyl glutaramide |
| 2298 | N 1-[(1S, 2R)-3-(benzyl amino)-1-(2-furyl methyl)-2-hydroxypropyl]-N 5，N 5-dipropyl glutaramide |
| 2299 | N 1-[(1S, 2R)-1-(2-furyl methyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N 5，N 5-dipropyl glutaramide |
| 2300 | N 1-(1S, 2R)-1-[3-(benzyloxy) benzyl]-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N 5，N 5-dipropyl glutaramide |
| 2301 | N 1-(1S, 2R)-3-(benzyl amino)-1-[3-(benzyloxy) benzyl]-the 2-hydroxypropyl }-N 5，N 5-dipropyl isophthaloyl amine |
| 2302 | N 1-[(1S, 2R)-1-[3-(benzyloxy) benzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-N 5，N 5-dipropyl glutaramide |
| 2304 | N 1-[(1S, 2R)-3-(benzyl amino)-1-(4-luorobenzyl)-2-hydroxypropyl]-N 5，N 5-dipropyl glutaramide |
| 2305 | N 1-[(1S, 2R)-1-(4-luorobenzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N 5，N 5-dipropyl glutaramide |
| 2306 | N 1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(thiophene-2-ylmethyl) propyl group]-N 5，N 5-dipropyl glutaramide |
| 2307 | N 1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(thiophene-2-ylmethyl) propyl group]-N 5，N 5-dipropyl glutaramide |
| 2308 | N 1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(4-hydroxybenzyl) propyl group]-N 5，N 5-dipropyl glutaramide |
| 2309 | N 1-[(1S, 2R)-2-hydroxyl-1-(4-hydroxybenzyl)-3-(isopentyl amino) propyl group]-N 5，N 5-dipropyl glutaramide |
| 2310 | N 1-((1S)-1-{ (1R)-1-hydroxyl-2-[(3-methoxy-benzyl) amino] ethyl } fourth-3-alkynyl)-N 5，N 5-dipropyl glutaramide |
| 2311 | N 1-(1S)-1-[(1R)-and 2-(benzyl amino)-1-hydroxyethyl] fourth-3-alkynyl }-N 5，N 5-dipropyl glutaramide |
| 2312 | N 1-(1S)-1-[(1R)-and 1-hydroxyl-2-(isopentyl amino) ethyl] fourth-3-alkynyl }-N 5，N 5-dipropyl glutaramide |
| 2313 | N 1-(1S, 2R)-1-(cyclohexyl methyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N 5，N 5-dipropyl glutaramide |
| 2314 | N 1-[(1S, 2R)-3-(benzyl amino)-1-(cyclohexyl methyl)-2-hydroxypropyl]-N 5，N 5-dipropyl glutaramide |
| 2315 | N 1-[(1S, 2R)-1-(cyclohexyl methyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N 5，N 5-dipropyl glutaramide |
| 2316 | N 1-((1S)-1-{ (1R)-1-hydroxyl-2-[(3-methoxy-benzyl) amino] ethyl }-the 3-methyl butyl)-N 5，N 5-dipropyl glutaramide |
| 2317 | N 1-(1S)-1-[(1R)-2-(benzyl amino)-1-hydroxyethyl]-the 3-methyl butyl }-N 5，N 5-dipropyl glutaramide |
| 2318 | N 1-(1S)-1-[(1R)-1-hydroxyl-2-(isopentyl amino) ethyl]-the 3-methyl butyl }-N 5，N 5-dipropyl glutaramide |
| 2319 | 3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-[(phenyl sulfenyl) methyl] propyl group } propionic acid amide |
| 2320 | N-{ (1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-[(phenyl sulfenyl) methyl] propyl group }-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 2321 | 3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-[(phenyl sulfenyl) methyl] propyl group } propionic acid amide |
| 2322 | N-{ (1S, 2R)-3-(benzyl amino)-1-[4-(benzyloxy) benzyl]-the 2-hydroxypropyl }-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 2323 | N-[(1S, 2R)-1-[4-(benzyloxy) benzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 2324 | N-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(1-naphthyl methyl) propyl group]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 2325 | 3-[(dipropyl amino) alkylsulfonyl]-N-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(1-naphthyl methyl) propyl group] propionic acid amide |
| 2326 | N-[(1S, 2R)-3-(benzyl amino)-1-(2-furyl methyl)-2-hydroxypropyl]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 2327 | 3-[(dipropyl amino) alkylsulfonyl]-N-[(1S, 2R)-1-(2-furyl methyl)-2-hydroxyl-3-(isopentyl amino) propyl group] propionic acid amide |
| 2328 | N-{ (1S, 2R)-1-[3-(benzyloxy) benzyl]-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 2329 | N-{ (1S, 2R)-3-(benzyl amino)-1-[3-(benzyloxy) benzyl]-the 2-hydroxypropyl }-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 2330 | N-[(1S, 2R)-1-[3-(benzyloxy) benzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 2331 | N-[(1S, 2R)-3-(benzyl amino)-1-(4-luorobenzyl)-2-hydroxypropyl]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 2332 | 3-[(dipropyl amino) alkylsulfonyl]-N-[(1S, 2R)-1-(4-luorobenzyl)-2-hydroxyl-3-(isopentyl amino) propyl group] propionic acid amide |
| 2333 | N-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(thiophene-2-ylmethyl) propyl group]-3-[(dipropyl amino) sulphur |
| Acyl group] propionic acid amide | |
| 2334 | 3-[(dipropyl amino) alkylsulfonyl]-N-((1S)-1-{ (1R)-1-hydroxyl-2-[(3-methoxy-benzyl) amino] ethyl } fourth-3-alkynyl) propionic acid amide |
| 2335 | N '-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(3-[(1Z)-third-1-alkene-1-yl] benzyl } amino) propyl group]-5-methyl-N, N-dipropyl isophthaloyl amine |
| 2335 | N-{ (1S)-1-[(1R)-2-(benzyl amino)-1-hydroxyethyl] fourth-3-alkynyl }-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 2336 | 3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S)-1-[(1R)-1-hydroxyl-2-(isopentyl amino) ethyl] fourth-3-alkynyl } propionic acid amide |
| 2337 | N-{ (1S, 2R)-1-(cyclohexyl methyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 2338 | N-[(1S, 2R)-3-(benzyl amino)-1-(cyclohexyl methyl)-2-hydroxypropyl]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 2339 | [3-({ [(2R, 3S)-4-(3, the 5-difluorophenyl)-3-(3-[(dipropyl amino) carbonyl]-the 5-methyl benzoyl } amino)-2-hydroxyl butyl] amino } methyl) phenyl] methylene dicarbamate |
| 2339 | N-[(1S, 2R)-1-(cyclohexyl methyl)-2-hydroxyl-3-(amine 21F81 amino) propyl group]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 2340 | 3-[(dipropyl amino) alkylsulfonyl]-N-((1S)-1-{ (1R)-1-hydroxyl-2-[(3-methoxy-benzyl) amino] ethyl }-the 3-methyl butyl) propionic acid amide |
| 2341 | N-{ (1S)-1-[(1R)-2-(benzyl amino)-1-hydroxyethyl]-the 3-methyl butyl }-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 2342 | 3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S)-1-[(1R)-1-hydroxyl-2-(isopentyl amino) ethyl]-the 3-methyl butyl } propionic acid amide |
| 2343 | N 1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(3-methoxy-benzyl) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 2346 | N 1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(4-sec.-propyl amino) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 2348 | N 1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(4-methoxy-benzyl) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 2349 | N 1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(4-methoxy-benzyl) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 2350 | N 1-[(1S, 2R)-3-(benzyl amino)-1-(4-fluoro-3-methyl-benzyl)-2-hydroxypropyl]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 2351 | N 1-[(1S, 2R)-1-(3-fluoro-4-methoxy-benzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 2352 | N 1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(4-isopropyl benzyl) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2353 | N 1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(4-isopropyl benzyl) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2354 | N 1-(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-[3-(trifluoromethoxy) benzyl] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2355 | N 1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(4-methoxy-benzyl) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2356 | N 1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(4-methoxy-benzyl) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2357 | N 1-[(1S, 2R)-3-(benzyl amino)-1-(4-fluoro-3-methyl-benzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2358 | N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(4R)-2,2-titanium dioxide (dioxido)-3,4-dihydro-1H-2,1-benzothiazine-4-yl] amino }-the 2-hydroxypropyl)-5-methyl-N, N-dipropyl isophthaloyl amine |
| 2359 | N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(4S)-2,2-titanium dioxide-3,4-dihydro-1H-2,1-benzothiazine-4-yl] amino }-the 2-hydroxypropyl)-5-methyl-N, N-dipropyl isophthaloyl amine |
| 2358 | N 1-[(1S, 2R)-1-(4-fluoro-3-methyl-benzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2359 | N 1-(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-[3-(trifluoromethyl) benzyl] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2360 | N 1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(3-methyl-benzyl) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2361 | N 1-(1S, 2R)-3-(benzyl amino)-1-[3-(benzyloxy)-5-luorobenzyl]-the 2-hydroxypropyl }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2362 | N 1-[(1S, 2R)-3-(benzyl amino)-1-(3-fluoro-4-methoxy-benzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2363 | N 1-(1S, 2R)-2-hydroxyl-1-(3-methoxy-benzyl)-3-[(3-methoxy-benzyl) amino] propyl group }-N 5，N 5-dipropyl glutaramide |
| 2364 | N 1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(3-methoxy-benzyl) propyl group]-N 5，N 5-dipropyl glutaramide |
| 2365 | N 1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(3-methoxy-benzyl) propyl group]-N 5，N 5-dipropyl glutaramide |
| 2366 | N 1-[(1S, 2R)-3-(benzyl amino)-1-(3-chloro-5-luorobenzyl)-2-hydroxypropyl]-N 5，N 5-dipropyl glutaramide |
| 2367 | N 1-[(1S, 2R)-1-(3-chloro-5-luorobenzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N 5，N 5-dipropyl glutaramide |
| 2368 | N 1-(1S, 2R)-1-(3, the 5-dichloro benzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N 5，N 5-dipropyl glutaramide |
| 2369 | N 1-[(1S, 2R)-3-(benzyl amino)-1-1-(3, the 5-dichloro benzyl)-2-hydroxypropyl]-N 5，N 5-dipropyl glutaramide |
| 2370 | N 1-[(1S, 2R)-1-(3, the 5-dichloro benzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N 5，N 5-dipropyl glutaramide |
| 2371 | N 1-(1S, 2R)-2-hydroxyl-1-(4-isopropyl benzyl)-3-[(3-methoxy-benzyl) amino] propyl group }-N 5，N 5-dipropyl glutaramide |
| 2311 | N 1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(4-isopropyl benzyl) propyl group]-N 5，N 5-dipropyl glutaramide |
| 2312 | N 1-[(1S, 2R)-2-hydroxyl-3-(sec.-propyl amino)-1-(4-isopropyl benzyl) propyl group]-N 5，N 5-dipropyl glutaramide |
| 2313 | N 1-(1S, 2R)-1-[3-fluoro-5-(trifluoromethyl) benzyl]-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N 5，N 5-dipropyl glutaramide |
| 2314 | N 1-(1S, 2R)-3-(benzyl amino)-1-[3-fluoro-5-(trifluoromethyl) benzyl]-the 2-hydroxypropyl }-N 5，N 5-dipropyl glutaramide |
| 2315 | N 1-[(1S, 2R)-1-[3-fluoro-5-(trifluoromethyl) benzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-N 5，N 5-dipropyl glutaramide |
| 2316 | N 1-(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-[3-(trifluoromethoxy) benzyl] propyl group }-N 5，N 5-dipropyl glutaramide |
| 2317 | N 1-(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-[3-(trifluoromethoxy) benzyl] propyl group }-N 5，N 5-dipropyl glutaramide |
| 2318 | N 1-(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-[3-(trifluoromethoxy) benzyl] propyl group }-N 5，N 5-dipropyl glutaramide |
| 2319 | N 1-[(1S, 2R)-3-(benzyl amino)-1-(3-fluoro-4-methyl-benzyl)-2-hydroxypropyl]-N 5，N 5-dipropyl glutaramide |
| 2320 | N 1-[(1S, 2R)-1-(3-fluoro-4-methyl-benzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N 5，N 5-dipropyl glutaramide |
| 2321 | N 1-(1S, 2R)-2-hydroxyl-1-(4-methoxy-benzyl)-3-[(3-methoxy-benzyl) amino] propyl group }-N 5，N 5-dipropyl glutaramide |
| 2322 | N 1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(4-methoxy-benzyl) propyl group]-N 5，N 5-dipropyl glutaramide |
| 2323 | N 1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(4-methoxy-benzyl) propyl group]-N 5，N 5-dipropyl |
| Glutaramide | |
| 2324 | N 1-(1S, 2R)-1-(4-benzyl chloride base)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N 5，N 5-dipropyl glutaramide |
| 2325 | N 1-[(1S, 2R)-3-(benzyl amino)-1-(4-benzyl chloride base)-2-hydroxypropyl]-N 5，N 5-dipropyl glutaramide |
| 2326 | N 1-[(1S, 2R)-1-(4-benzyl chloride base)-2-hydroxyl-3-(isopentyl amino) propyl group]-N 5，N 5-dipropyl glutaramide |
| 2327 | N 1-(1S, 2R)-1-(1,3-benzo dioxole-5-ylmethyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N 5，N 5-dipropyl glutaramide |
| 2328 | N 1-[(1S, 2R)-1-(1,3-benzo dioxole-5-ylmethyl)-3-(benzyl amino)-2-hydroxypropyl]-N 5，N 5-dipropyl glutaramide |
| 2329 | N 1-[(1S, 2R)-1-(1,3-benzo dioxole-5-ylmethyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N 3，N 3-dipropyl isophthaloyl amine |
| 2330 | N 1-(1S, 2R)-1-(4-fluoro-3-methyl-benzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N 5，N 5-dipropyl glutaramide |
| 2331 | N 1-[(1S, 2R)-3-(benzyl amino)-1-(4-fluoro-3-methyl-benzyl)-2-hydroxypropyl]-N 5，N 5-dipropyl glutaramide |
| 2332 | N 1-[(1S, 2R)-1-(4-fluoro-3-methyl-benzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N 5，N 5-dipropyl glutaramide |
| 2333 | N 1-(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-[3-(trifluoromethyl) benzyl] propyl group }-N 5，N 5-dipropyl glutaramide |
| 2335 | N 1-[(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(3-xylyl) propyl group]-N 5，N 5-dipropyl glutaramide |
| 2336 | N 1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(3-xylyl) propyl group]-N 5，N 5-dipropyl glutaramide |
| 2337 | N 1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(3-xylyl) propyl group]-N 5，N 5-dipropyl glutaramide |
| 2338 | N 1-(1S, 2R)-1-[3-(benzyloxy)-5-luorobenzyl]-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N 5，N 5-dipropyl glutaramide |
| 2339 | N 1-(1S, 2R)-3-(benzyl amino)-1-[3-(benzyloxy)-5-luorobenzyl)]-the 2-hydroxypropyl }-N 5，N 5-dipropyl glutaramide |
| 2340 | N 1-[(1S, 2R)-1-[3-(benzyloxy)-5-luorobenzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-N 5，N 5-dipropyl glutaramide |
| 2341 | N 1-(1S, 2R)-1-(3-fluoro-4-methoxy-benzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N 5，N 5-dipropyl glutaramide |
| 2342 | N 1-[(1S, 2R)-3-(benzyl amino)-1-(3-fluoro-4-methoxy-benzyl)-2-hydroxypropyl]-N 5，N 5-dipropyl glutaramide |
| 2343 | N 1-[(1S, 2R)-1-(3-fluoro-4-methoxy-benzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N 5，N 5-dipropyl glutaramide |
| 2344 | N 1-[(1S, 2R)-3-(benzyl amino)-1-(3-bromobenzyl)-2-hydroxypropyl]-N 5，N 5-dipropyl glutaramide |
| 2345 | N 1-[(1S, 2R)-1-(3-bromobenzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N 5，N 5-dipropyl glutaramide |
| 2346 | N-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(3-methoxy-benzyl) propyl group]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 2347 | 3-[(dipropyl amino) alkylsulfonyl] N-[(1S, 2R)-and 2-hydroxyl-3-(isopentyl amino)-1-(3-methoxy-benzyl) propyl group] propionic acid amide |
| 2348 | N-[(1S, 2R)-3-(benzyl amino)-1-(3, the 5-dichloro benzyl)-2-hydroxypropyl]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 2349 | 3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S, 2R)-2-hydroxyl-1-(4-isopropyl benzyl)-3-[(3-methoxy-benzyl) amino] propyl group } propionic acid amide |
| 2350 | N-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(4-isopropyl benzyl) propyl group]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 2351 | 3-[(dipropyl amino) alkylsulfonyl] N-[(1S, 2R)-and 2-hydroxyl-3-(isopentyl amino)-1-(4-isopropyl benzyl) propyl group] propionic acid amide |
| 2352 | N-{ (1S, 2R)-3-(benzyl amino)-1-[3-fluoro-5-(trifluoromethyl) benzyl]-the 2-hydroxypropyl }-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 2353 | 3-[(dipropyl amino) alkylsulfonyl]-N-[(1S, 2R)-1-[3-fluoro-5-(trifluoromethyl) benzyl]-2-hydroxyl-3-(isopentyl amino) propyl group] propionic acid amide |
| 2354 | N-{ (1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-[3-(trifluoromethoxy) benzyl] propyl group }-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 2355 | N-[(1S, 2R)-3-(benzyl amino)-1-(3-fluoro-4-methyl-benzyl)-2-hydroxypropyl]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 2356 | 3-[(dipropyl amino) alkylsulfonyl] N-[(1S, 2R)-and 1-(3-fluoro-4-methyl-benzyl)-2-hydroxyl-3-(isopentyl amino) propyl group] propionic acid amide |
| 2357 | 3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S, 2R)-2-hydroxyl-1-(4-methoxy-benzyl)-3-[(3-methoxy-benzyl) amino] propyl group } propionic acid amide |
| 2358 | N-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(4-methoxy-benzyl) propyl group]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 2359 | 3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(4-methoxy-benzyl) propyl group] propionic acid amide |
| 2360 | N-[(1S, 2R)-3-(benzyl amino)-1-(4-benzyl chloride base)-2-hydroxypropyl]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 2314 | N-[(1S, 2R)-1-(4-benzyl chloride base)-2-hydroxyl-3-(isopentyl amino) propyl group]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 2315 | N-[(1S, 2R)-1-(1,3-benzo dioxole-5-ylmethyl)-3-(benzyl amino)-2-hydroxypropyl]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 2316 | N-[(1S, 2R)-1-(1,3-benzo dioxole-5-ylmethyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 2317 | 3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S, 2R)-1-(4-fluoro-3-methyl-benzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } propionic acid amide |
| 2318 | N-[(1S, 2R)-3-(benzyl amino)-1-(4-fluoro-3-methyl-benzyl)-2-hydroxypropyl]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 2319 | 3-[(dipropyl amino) alkylsulfonyl]-N-[(1S, 2R)-1-(4-fluoro-3-methyl-benzyl)-2-hydroxyl-3-(isopentyl amino) propyl group] propionic acid amide |
| 2320 | N-{ (1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-[3-(trifluoromethyl) benzyl] propyl group }-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 2321 | 3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-[3-(trifluoromethyl) benzyl] propyl group } propionic acid amide |
| 2322 | N-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(3-methyl-benzyl) propyl group]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 2323 | 3-[(dipropyl amino) alkylsulfonyl]-N-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(3-methyl-benzyl) propyl group]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 2324 | N-{ (1S, 2R)-3-(benzyl amino)-1-[3-(benzyloxy)-5-luorobenzyl]-the 2-hydroxypropyl }-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 2325 | 3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S, 2R)-1-(3-fluoro-4-methoxy-benzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } propionic acid amide |
| 2326 | N-[(1S, 2R)-3-(benzyl amino)-1-(3-fluoro-4-methoxy-benzyl)-2-hydroxypropyl]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide |
| 2327 | 3-[(dipropyl amino) alkylsulfonyl]-N-[(1S, 2R)-1-(3-fluoro-4-methoxy-benzyl)-2-hydroxyl-3-(isopentyl amino) propyl group] propionic acid amide |
| 2328 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-phenyl-2-(4H-1,2,4-triazole-3-base sulfenyl) ethanamide |
| 2329 | 1-ethanoyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-phenyl prolineamide |
The compound that a kind of chemical formula is following:
Compound in the following table mainly is to use the method preparation of setting forth in the above-described and following diagram.
Following compounds is to use the Advanced Chemistry Development Inc. (ACD) nomenclature, and IUPAC Name Batch 4.5. version is named.The network address of ACD is www.acdlabs.com.
| 2332 | N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(3R, 4S)-3-(methylol)-6-sec.-propyl-2,2-titanium dioxide-3, the different sulfenyl chromene of 4-dihydro-1H--4-yl] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine |
| 2333 | N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(3R, 4S)-6-sec.-propyl-3-methyl-2,2-titanium dioxide-3, the different sulfenyl chromene of 4-dihydro-1H--4-yl] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine |
| 2334 | N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(3R, 4S)-6-sec.-propyl-2,2-titanium dioxide-3-propyl group-3, the different sulfenyl chromene of 4-dihydro-1H--4-yl] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine |
| 2336 | N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(3S, 4R)-3-(methylol)-6-sec.-propyl-2,2-titanium dioxide-3, the different sulfenyl chromene of 4-dihydro-1H--4-yl] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine |
| 2337 | N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(3S, 4R)-3-(2-hydroxyethyl)-6-sec.-propyl-2,2-titanium dioxide-3, the different sulfenyl chromene of 4-dihydro-1H--4-yl] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine |
| 2339 | N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(3S, 4S)-6-sec.-propyl-2,2-titanium dioxide-3-propyl group-3, the different sulfenyl chromene of 4-dihydro-1H--4-yl] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine |
| 2340 | N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(3S, 4S)-6-sec.-propyl-3-methyl-2,2-titanium dioxide-3, the different sulfenyl chromene of 4-dihydro-1H--4-yl] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine |
| 2341 | N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-the 2-hydroxyl-3-{[(4R)-6-sec.-propyl-2,2-titanium dioxide-3, the different sulfenyl chromene of 4-dihydro-1H--4-yl] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine |
Compound in the following table mainly is to use the method preparation of setting forth in the above-described and following diagram.
Following compounds is to use the Advanced Chemistry Development Inc. (ACD) nomenclature, and IUPAC Name Batch 4.5. version is named.The network address of ACD is www.acdlabs.com.
| 2342 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-[(3-methoxy-propyl) (methyl sulphonyl) amino] benzamide |
| 2343 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-[(3-methoxy-propyl) (methyl sulphonyl) amino] benzamide |
| 2344 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-[(2-methoxy ethyl) (methyl sulphonyl) amino] benzamide |
| 2345 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 6-[(2-methoxy ethyl) (methyl sulphonyl) amino] niacinamide |
| 2346 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 6-[(3-hydroxypropyl) (methyl sulphonyl) amino] niacinamide |
| 2347 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 6-[(2-hydroxyethyl) (methyl sulphonyl) amino] niacinamide |
| 2348 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 6-[(2-methoxy ethyl) (methyl sulphonyl) amino] niacinamide |
| 2349 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-[(2-methoxy ethyl) (methyl sulphonyl) amino] Isonicotinamide |
| 2350 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-[(2-methoxy ethyl) (methyl sulphonyl) amino] niacinamide |
| 2351 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-[(3-hydroxypropyl) (methyl sulphonyl) amino] Isonicotinamide |
| 2352 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-[(2-hydroxyethyl) (methyl sulphonyl) amino] Isonicotinamide |
| 2353 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-[(2-hydroxyethyl) (methyl sulphonyl) amino] niacinamide |
| 2354 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-[(3-hydroxypropyl) (methyl sulphonyl) amino] niacinamide |
| 2355 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-[(3-methoxy-propyl) (methyl sulphonyl) amino] Isonicotinamide |
| 2356 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-[(3-methoxy-propyl) (methyl sulphonyl) amino] niacinamide |
| 2357 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-(methyl sulphur |
| Acyl group)-1H-indoles-5-methane amide | |
| 2358 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-(methyl sulphonyl) indoline-5-methane amide |
| 2359 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-(methyl sulphonyl) indoline-4-methane amide |
| 2360 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-(methyl sulphonyl) indoline-6-methane amide |
| 2361 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-(methyl sulphonyl)-1H-indoles-4-methane amide |
| 2362 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[1-methyl isophthalic acid-(methyl sulphonyl) ethyl] benzamide |
| 2363 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-[1-methyl isophthalic acid-(methyl sulphonyl) ethyl] benzamide |
| 2364 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(ethylsulfonyl) benzamide |
| 2365 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(sulfonyl propyl base) benzamide |
| 2366 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(amyl group alkylsulfonyl) benzamide |
| 2367 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-[(2-hydroxyethyl) alkylsulfonyl] benzamide |
| 2368 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-[(2-methoxy ethyl) alkylsulfonyl] benzamide |
| 2369 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-[(2-ethoxyethyl group) alkylsulfonyl] benzamide |
| 2370 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-[(3-hydroxypropyl) alkylsulfonyl] benzamide |
| 2371 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,3-dihydro-1-thionaphthene-5-methane amide; 1, the 1-dioxide |
| 2372 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-thionaphthene-5-methane amide; 1, the 1-dioxide |
| 2374 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,3-dihydro-1-thionaphthene-6-methane amide; 1, the 1-dioxide |
| 2375 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-thionaphthene-6-methane amide; 1, the 1-dioxide |
| 2376 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-methyl-2,3-dihydro-1,2-benzisothiazole-6-methane amide; 1, the 1-dioxide |
| 2377 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-methyl-2,3-dihydro-1,2-benzisothiazole-5-methane amide; 1, the 1-dioxide |
| 2378 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 1-methyl isophthalic acid, 3-dihydro-2,1-benzisothiazole-6-methane amide; 2, the 2-dioxide |
| 2343 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 1-methyl isophthalic acid, 3-dihydro-2,1-benzisothiazole-5-methane amide; 2, the 2-dioxide |
| 2344 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,2-dimethylbiphenyl pyrans-6-methane amide |
| 2345 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,2-dimethylbiphenyl pyrans-7-methane amide |
Compound in the following table mainly is to use the method preparation of setting forth in the above-described and following diagram.
Following compounds is to use the Advanced Chemistry Development Inc. (ACD) nomenclature, and IUPAC Name Batch 4.5. version is named.The network address of ACD is www.acdlabs.com.
| Compound title (s) | |
| 2346 | (3R)-4-((1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } amino)-2,2,3-trimethylammonium-4-ketobutyric acid benzyl ester |
| 2347 | N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-4-(phenyl sulfonyl) butyramide |
| 2348 | (3S)-and tetrahydrofuran (THF)-3-base (1S, 2R)-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl carbamate |
| 2349 | N 1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N 3-(phenyl sulfonyl)-beta-amino propionic acid amide |
| 2350 | N 1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N 3-[(4-aminomethyl phenyl) alkylsulfonyl]-beta-amino propionic acid amide |
| 2351 | N 1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N 3-[(4-fluorophenyl) alkylsulfonyl]-beta-amino propionic acid amide |
| 2352 | N 1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N 3-[(4-p-methoxy-phenyl) alkylsulfonyl]-beta-amino propionic acid amide |
| 2353 | N 1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N 2-[(4-aminomethyl phenyl) alkylsulfonyl] G-NH2 |
| 2354 | N 1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N 2-[(4-fluorophenyl) alkylsulfonyl] G-NH2 |
| 2355 | N 1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N 2-[(4-p-methoxy-phenyl) alkylsulfonyl] G-NH2 |
| 2356 | N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-the 3-[(4-chloro-phenyl-) alkylsulfonyl] propionic acid amide |
| 2357 | N 1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N 2-(benzyl alkylsulfonyl) G-NH2 |
| 2358 | N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-the 3-[(4-fluorophenyl) alkylsulfonyl] propionic acid amide |
| 2359 | N 1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N 3-[(4-chloro-phenyl-) alkylsulfonyl]-beta-amino propionic acid amide |
| 2360 | N 1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N 3-(benzyl alkylsulfonyl)-beta-amino propionic acid amide |
| 2361 | N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-the 3-[(4-p-methoxy-phenyl) alkylsulfonyl] propionic acid amide |
| 2362 | N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-the 3-[(4-aminomethyl phenyl) alkylsulfonyl] propionic acid amide |
| 2363 | N 1-benzyl-N 4-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-2,2-dimethyl succinic diamide |
| 2364 | N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-(1,1-titanium dioxide-3-oxo-1,2-benzisothiazole-2 (3H)-yl) propionic acid amide |
| 2365 | N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl) propionic acid amide |
| 2366 | (2R)-N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-2-methyl-3-(phenyl sulfonyl) propionic acid amide |
| 2367 | (2S)-N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-2-methyl-3-(phenyl sulfonyl) propionic acid amide |
| 2368 | N 1-benzyl-N 5-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } glutaramide |
| 2369 | N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-the 2-[(phenyl sulfonyl) methyl] acrylamide |
| 2370 | N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-2-[(isopentyl alkylsulfonyl) methyl] acrylamide |
| 2371 | N 1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N 3-[(dipropyl amino) carbonyl]-beta-amino propionic acid amide |
| 2372 | N 1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N 2-[(dipropyl ammonia |
| Base) carbonyl] G-NH2 | |
| 2373 | Benzyl (4R)-4-{[((1S, 2R)-1-benzyl-3-{[3-(dimethylamino)-2, the 2-dimethyl propyl] amino }-the 2-hydroxypropyl) amino] carbonyl }-1,3-oxazolidine-3-formic acid ester compound and methyl hydroperoxide (1: 2) |
| 2374 | (2R, 3S)-2-hydroxyl-3-(2-hydroxyl-3-[(3-p-methoxy-phenyl) and alkylsulfonyl] the propyl alcohol base } amino)-4-phenyl butyl (3-methoxy-benzyl) t-butyl carbamate |
| 2383 | N 1-[(1S, 2R)-1-[3-(benzyloxy)-5-luorobenzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2386 | N 1-[(1S, 2R)-1-[3-(benzyloxy)-5-luorobenzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 2405 | N 1-[(1S, 2R)-1-(cyclohexyl methyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2406 | N 1-[(1S, 2R)-3-(benzyl amino)-1-(cyclohexyl methyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2411 | N 1-[(1S, 2R)-1-[4-(benzyloxy) benzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2413 | N 1-[(1S, 2R)-1-(cyclohexyl methyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 2414 | N 1-[(1S, 2R)-3-(benzyl amino)-1-(cyclohexyl methyl)-2-hydroxypropyl]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 2419 | N 1-[(1S, 2R)-1-[4-(benzyloxy) benzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 2421 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-[hydroxyl (2-aminomethyl phenyl) methyl]-the 5-methyl benzamide |
| 2426 | N 1-[(1R, 2S)-2-hydroxyl-3-(isopentyl amino)-1-(4-methyl-benzyl) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2427 | N 1-[(1R, 2S)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(4-methyl-benzyl) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2428 | N 1-[(1R, 2S)-2-hydroxyl-3-(isopentyl amino)-1-(4-methyl-benzyl) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 2429 | N 1-[(1R, 2S)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(4-methyl-benzyl) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide |
| 2440 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl-4-(phenyl sulfonyl) butyramide |
| 2442 | (2R, 3S)-4-(3, the 5-difluorophenyl)-3-[(3-(4,4-dimethyl-2,5-dioxo alkyl imidazole-1- |
| Base)-and 2-{[(1-propyl group butyl) alkylsulfonyl] methyl } the propyl alcohol base) amino]-2-hydroxyl butyl (3-Ethylbenzyl) benzyl carbamate | |
| 2445 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-7-(1H-imidazoles-1-yl)-5,6-dihydronaphthalene-2-methane amide |
| 2446 | 2-{[({ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } amino) carbonyl] amino }-N, N-dipropyl ethane sulphonamide hydrochloride |
| 2447 | (2R, 3S)-1-benzyl-2-hydroxyl-3-(N-(3-phenyl propanol base)-3-[(1-propyl group butyl) and alkylsulfonyl] alanyl } amino) butyl (3-Ethylbenzyl) benzyl carbamate |
| 2448 | N 1-[(1S, 2R)-the 3-[[(benzyloxy) carbonyl] (3-Ethylbenzyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-N 2-[(3S)-and tetrahydrofuran (THF)-3-base oxygen base] carbonyl }-right type-leucyl amine |
| 2449 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-([1,3] Evil azoles is [4,5-b] pyridine-2-base sulfenyl also) ethanamide |
| 2450 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[(imidazo [1,2-a] pyridine-2-ylmethyl) sulfenyl] ethanamide |
| 2451 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[(5,7-dimethyl [1,2,4] sulfenyl triazolo [4,3-a] pyrimidin-3-yl)] ethanamide |
| 2452 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,3-dihydro-1H-ring five [b] quinoline beautiful jade-9-methane amide |
| 2453 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-hydroxyl-6-oxygen-1-phenyl-1,6-dihydrogen dazin-3-methane amide |
| 2454 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,3-dioxy isoindoline-5-methane amide |
| 2455 | 1-benzyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-imidazoles-2-methane amide |
| 2456 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(4,4-dimethyl-4,5-dihydro-1,3-oxazole-2-yl) thiophene-3-methane amide |
| 2457 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-isobutyl--1,3-dioxy isoindoline-5-methane amide |
| 2458 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-oxygen-2-phenylpyrazole alkane-3-methane amide |
| 2459 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5,6-dimethyl-4-oxygen-3,4-dihydro-thiophene be [2,3-d] pyrimidine-2-methane amide also |
| 2460 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(2, the 4-difluorobenzyl) the oxygen base] propionic acid amide |
| 2461 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } thieno- |
| [2,3-c] pyridine-2-carboxamide | |
| 2463 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2-methyl isophthalic acid H-benzoglyoxaline-1-yl)-4-oxo butyramide |
| 2464 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(2,5-dioxo tetramethyleneimine-1-yl)-4-oxo butyramide |
| 2465 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } thieno-[3,2-b] pyridine-6-methane amide |
| 2466 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2,3-dihydro-1H-indoles-1-yl)-4-oxo butyramide |
| 2468 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(1,3-dioxo octahydro-2H-isoindole-2-yl) butyramide |
| 2469 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3-[(4-aminomethyl phenyl) alkylsulfonyl]-beta-amino propionic acid amide |
| 2470 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(1H-indol-3-yl)-4-oxo butyramide |
| 2471 | N 2-(anilino carbonyl sulfenyl (carbonothioyl))-N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } G-NH2 |
| 2472 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl-4-oxygen-4,5,6,7-tetrahydrochysene-1H-indoles-2-methane amide |
| 2473 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5,6,7,8-tetrahydrochysene-4H-encircles seven [c] isoxazoles-3-methane amide |
| 2475 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 2-[(4-aminomethyl phenyl) alkylsulfonyl] G-NH2 |
| 2477 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3,5-dioxy-1,2,4-triazolidine-4-yl) benzamide |
| 2478 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2-hydroxyl-oxethyl) benzamide |
| 2479 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(1,3-dithiane-2-yl)-3-furoamide |
| 2481 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-methyl-5,6,7,8-tetrahydrochysene-pyrazolo [1,5-a] azepine-3-methane amide |
| 2482 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-(4-fluorophenyl)-1,4,5,6-tetrahydrochysene ring five [c] pyrazole-3-formamide |
| 2484 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5,6-dihydro-4H-encircles five [b] thiophene-2-carboxamide derivatives |
| 2485 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3,6,6-trimethylammonium-4-oxo-4,5,6,7-tetrahydrochysene-1-benzofuran-2-carboxamides |
| 2486 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-7-methoxyl group-4-oxo-1,2,3,4-naphthane-2-methane amide |
| 2487 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-methane amide |
| 2488 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4,5,6,7-tetrahydrochysene-2H-indazole-3-methane amide |
| 2489 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-4-oxo-3, the 4-dihydro-thiophene is [2,3-d] pyrimidine-6-methane amide also |
| 2490 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-7-fluoro-4H-imidazo [5,1-c] [1,4] benzoxazine-3-methane amide |
| 2491 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3-fluoro-4-p-methoxy-phenyl)-4-oxo butyramide |
| 2492 | 4-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino)-4-oxo butyl-(dithiocarbamic acid methyl esters) |
| 2494 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } [1,2,4] triazolo [4,3-a] pyridine-6-methane amide |
| 2495 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-[(4-aminomethyl phenyl) alkylsulfonyl] ethanamide |
| 2496 | 3-(2-chloro-phenyl-)-2-cyano group-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } propionic acid amide |
| 2498 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(4-aminomethyl phenyl)-4-oxo butyramide |
| 2499 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2-hydroxy-5-methyl base phenyl)-4-oxo butyramide |
| 2500 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(2,5-dioxo-2,5-dihydro-1H-pyrroles-1-yl) benzamide |
| 2501 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-oxo-4-thiophene-2-base butyramide or 2379 |
| 2502 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2,5-dioxo-2,5-dihydro-1H-pyrroles-1-yl)-2-hydroxybenzamide |
| 2503 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2,5-dioxo tetramethyleneimine-1-yl) benzamide |
| 2507 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-[(trifluoro second |
| Acyl group) amino] butyramide | |
| 2510 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[(1-hydroxycyclopent base) sulfo-] ethanamide |
| 2511 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(2-oxo cyclohexyl) propionic acid amide |
| 2512 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2-naphthyl)-4-oxo butyramide |
| 2513 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-oxo-2,3-dihydro-1H-indazole-4-methane amide |
| 2514 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,3-dimethyl-1H-thieno-[2,3-c] pyrazoles-5-methane amide |
| 2515 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 2-[(dimethylamino) alkylsulfonyl] valine amide |
| 2516 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2-furyl)-4-oxo butyramide |
| 2517 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(5-methyl-4-phenyl-1,3-oxazole-2-yl) benzamide |
| 2518 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,6-dioxo hexahydropyrimidine-4-methane amide |
| 2519 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5,7-dimethoxy-1-oxo-dihydro indenes-2-methane amide |
| 2521 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 5-(2-pyridine-2-base ethyl) glutaramide |
| 2522 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-[4-(2-furoyl) piperazine-1-yl]-4-oxo butyramide |
| 2523 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-oxo-4,5,6,7-tetrahydrochysene-1-cumarone-3-methane amide |
| 2524 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-oxo-1-(thiophene-2-ylmethyl) tetramethyleneimine-3-methane amide |
| 2525 | The 2-[(cyano methyl) sulfo-]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } niacinamide |
| 2526 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-(2-furoyl)-4-hydroxyl prolineamide |
| 2527 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4,5-dihydro furo[2,3-g] [2,1] benzoisoxazole-8-methane amide |
| 2528 | 3-[({ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino) carbonyl]-5 thiotolenes-2--sulfinic acid methyl esters- |
| 2529 | 2-(acetylamino)-2-(1H-1,2,3-benzotriazole-1-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide |
| 2530 | 1-{[(cyclohexyl amino) carbonyl] amino }-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } cyclopropane carboxamide |
| 2531 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2-ethyl-4H-[1,2,4] triazolo [1,5-a] benzoglyoxaline-4-yl) ethanamide |
| 2532 | (2E)-N 1-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 4-[4-(1,3-oxazole-5-yl) phenyl] but-2-ene diamide |
| 2533 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,3,4,5-tetrahydrochysene sulfo-pyrans is [4,3-b] indoles-8-methane amide also |
| 2535 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-and the 3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3,4-dihydro-2H-1,5-Benzodiazepine (dioxepin)-7-yl)-4-oxo butyramide |
| 2536 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(1-oxidation thiomorpholine-4-yl) butyramide |
| 2537 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-oxo-4-(2-sulfo--1,3-benzothiazole-3 (2H)-yl) butyramide |
| 2538 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-8H-thieno-[2,3-b] indoles-2-methane amide |
| 2539 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3,4-dihydro-2H-1,5-Benzodiazepine-7-methane amide |
| 2540 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl-the 4H-chromene also [3,4-d] isoxazole-4-methane amide |
| 2542 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3, the 4-difluorophenyl)-4-oxo butyramide |
| 2543 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3, the 4-difluorophenyl)-2-methyl-4-oxo butyramide |
| 2544 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3, the 4-difluorophenyl)-2-methoxyl group-4-oxo butyramide |
| 2545 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl-4-oxo-4-[3-(trifluoromethyl) phenyl] butyramide |
| 2546 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl-4-oxo-4-thiophene-2-base butyramide |
| 2548 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-[(2-ethyl |
| -1-oxo-2,3-dihydro-1H-isoindole-5-yl) oxo] propionic acid amide | |
| 2549 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-oxoisoindoline diindyl-1-methane amide |
| 2550 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(7-methoxyl group-1-cumarone-2-yl)-4-oxo butyramide |
| 2551 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl-the 4H-chromene also [3,4-d] isoxazole-8-methane amide |
| 2552 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-methyl-4-oxo-4H-chromene-6-methane amide |
| 2553 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-([1,2,4] triazolo [4,3-b] pyridazine-6-base sulfo-) ethanamide |
| 2554 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(1,1-titanium dioxide tetramethylene sulfide-2-yl) ethanamide |
| 2555 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3,4-dihydro-2H-chromene-6-yl)-4-oxo butyramide |
| 2556 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-ethyl-3-oxoisoindoline diindyl-1-methane amide |
| 2558 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(4-hydroxy phenyl)-4-oxo butyramide |
| 2559 | 2-[(6-chlorine [1,2,4] triazolo [4,3-b] pyridazine-3-yl) oxo]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide |
| 2560 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl-4-(3-p-methoxy-phenyl)-4-oxo butyramide |
| 2561 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl-4-oxo-4-thiene-3-yl-butyramide |
| 2562 | 4-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino)-4-ketobutyric acid-3-chlorobenzene ester |
| 2563 | 4-(4-chloro-2-hydroxyphenyl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-oxo butyramide |
| 2565 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 6-{[(4-aminomethyl phenyl) alkylsulfonyl] amino }-4-oxo hexanamide |
| 2566 | N-{ (1S, 2R)-and 1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(6-hydroxyl-3-oxo-2,3-glyoxalidine also [2,1-b] [1,3] thiazol-2-yl) ethanamide |
| 2567 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(4,5-dihydro-1,3-thiazoles-2-base sulfo-) ethanamide |
| 2568 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-imidazo [1,2-b] pyrazoles-6-methane amide |
| 2570 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(6-methoxyl group-1,1 '-phenylbenzene-3-yl)-4-oxo butyramide |
| 2571 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(4-p-methoxy-phenyl)-4-oxo butyramide |
| 2572 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2,3-dihydro-1,4-benzo dioxine-6-yl)-4-oxo butyramide |
| 2573 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2-oxo-2,3-dihydro-1,3-benzoxazole-5-yl) ethanamide |
| 2574 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2-oxo-2,3-dihydro-1H-benzoglyoxaline-5-yl) ethanamide |
| 2575 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-9-oxo-1,2,3,9-tetrahydrochysene ring five [b] chromene-7-methane amide |
| 2576 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-methyl isophthalic acid H-benzo [g] indazole-3-methane amide |
| 2577 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4, the 5-dihydro-naphtho [1,5-b] isoxazole-3-methane amide |
| 2578 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(tetrazolium [1,5-b] pyridazine-6-base sulfo-) ethanamide |
| 2580 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(5-methyl isophthalic acid H-pyrroles-2-yl)-4-oxo butyramide |
| 2581 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-{[(trifluoromethyl) alkylsulfonyl] amino } butyramide |
| 2582 | N-[(1S, 2R)-3-(2-ethanoyl-1-ethyl diazanyl)-1-benzyl-2-hydroxypropyl]-the 2-[(methyl sulphonyl) amino]-1,3-thiazoles-4-methane amide |
| 2583 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(1-hydroxyl-2-propyl group phenyl) benzamide |
| 2587 | N 1-[(1S, 2R)-3-[(2-{4-[(3-benzyl chloride base) oxo] phenyl } ethyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2589 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-morpholine-4-base propyl group) amino] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2597 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 2-[(methyl sulphonyl) ethanoyl]-N 2-amyl group G-NH2 |
| 2598 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl |
| Base }-3-{[(2R)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] alkylsulfonyl } propionic acid amide | |
| 2599 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(2S)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] alkylsulfonyl } propionic acid amide |
| 2600 | 4-{ (1S, 2R)-3-(3-[(dipropyl amino) and carbonyl] benzoyl } amino)-2-hydroxy-4-phenyl butyl] amino } piperidines-1-ethyl formate |
| 2601 | N 1-((1S, 2R)-the 1-benzyl-3-{[(3R)-1-benzyl-pyrrole alkane-3-yl] amino }-the 2-hydroxypropyl)-N 3，N 3-dipropyl isophthaloyl amine |
| 2602 | (2E)-2-[2-((1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } amino)-2-oxygen ethyl]-4-methylpent olefin(e) acid methyl esters |
| 2603 | N 1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N 4-(4-methoxy-benzyl) succinic diamide |
| 2604 | N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-the 3-{[(4-fluorophenyl) alkylsulfonyl] amino }-3-methylbutyryl amine |
| 2605 | N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-9,10-dioxo-9,10-dihydroanthracene-2-methane amide |
| 2606 | N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-4-(phenoxy group) benzamide |
| 2607 | N '-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N-methyl-N-phenylurea |
| 2608 | N '-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N, N-diisopropyl urea |
| 2609 | N '-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N, the N-sym-diphenylurea |
| 2610 | N '-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N, the N-Dimethylurea |
| 2611 | 2-{[({ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } amino) carbonyl] amino } methyl benzoate |
| 2613 | (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl carbamic acid-2-methoxyl group ethyl ester |
| 2612 | (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] the propyl carbamic acid phenyl ester |
| 2614 | (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl carbamic acid-2-(benzyloxy) ethyl ester |
| 2615 | (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl carbamic acid Propargyl ester |
| 2616 | (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl carbamic acid-(1R, 2S, 5R)-2-sec.-propyl-5-methylcyclohexyl ester |
| 2617 | (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] the propyl carbamic acid pentyl ester |
| 2618 | (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] the propyl carbamic acid peopentyl ester |
| 2621 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(4-oxo-4H-chromene-3-yl) methyl] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2622 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(1,7,7-trimethylammonium two rings [2.2.1] heptan-2-yl) amino] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2623 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-4-(3-methyl-5-oxo-4,5-dihydro-1 h-pyrazole-1-yl) benzamide |
| 2625 | N 1-[(1S, 2R)-3-[(1-ethanoyl piperidines-3-yl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2627 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3-oxyethyl group-oreinol diformamide |
| 2628 | N 1-(allyloxy)-N 3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the oreinol diformamide |
| 2629 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3-isobutoxy-oreinol diformamide |
| 2630 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-N 3-(2,2,3,3,3-five fluoropropyls) isophthaloyl amine |
| 2631 | 4-(3-[({ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino) carbonyl]-the 5-methyl benzoyl } amino) ethyl butyrate |
| 2632 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-N 3，N 3-two (2,2, the 2-trifluoroethyl) isophthaloyl amine |
| 2633 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3-ethyl-N 3-[(1-ethyl piperidine-4-yl) carbonyl]-oreinol diformamide |
| 2634 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3-(2,2,3,3,4,4,4-seven fluorine butyl)-oreinol diformamide |
| 2635 | N 1-(1-benzyl-pyrrole alkane-3-yl)-N 3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 1-ethyl-oreinol diformamide |
| 2636 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-N 3-(tetrahydrofuran (THF)-2-ylmethyl) isophthaloyl amine |
| 2638 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(3R)-2-oxo nitrogen Zhuo-3-yl] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2639 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(1,1-titanium dioxide-3,4-dihydro-2H-1,2-benzothiazine-4-yl) amino]-the 2-hydroxypropyl }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2640 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[2-(4-methylpent acyl group) diazanyl] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine |
| 2641 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-[(3-ethylphenyl) alkylsulfonyl] propionic acid amide |
| 2642 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl |
| Base }-2,2,3,3,4,4-hexafluoro-N 3，N 3-dipropyl isophthaloyl amine | |
| 2643 | N 5-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-phenyl-N 1，N 1-dipropyl isophthaloyl amine |
| 2644 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-[(3-hydroxypropyl) (methyl sulphonyl) amino] benzamide |
| 2645 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-[(2-hydroxyethyl) (methyl sulphonyl) amino] benzamide |
| 2646 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-{[(2R)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] alkylsulfonyl }-N 3，N 3-dipropyl isophthaloyl amine |
| 2647 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-[(3-hydroxypropyl) (methyl sulphonyl) amino] benzamide |
Compound in the following table mainly is to use the method preparation of setting forth in the above-described and following diagram.
Following compounds is to use the Advanced Chemistry Development Inc. (ACD) nomenclature, and IUPAC Name Batch 4.5. version is named.The network address of ACD is www.acdlabs.com.
| The compound title | Mass spectrum | |
| 2648 | 5-bromo-N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-N 3，N 3-dipropyl isophthaloyl amine | |
| 2649 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-{[(trifluoromethyl) alkylsulfonyl] amino } benzamide | 586.1 |
| 2657 | N 1-(1S, 2R)-1-(3, the 5-dichloro benzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide | 643.2 |
| 2664 | N 1-[(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(thiophene-2-ylmethyl) propyl group]-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide | 581.3 |
| 2665 | N 1-(1S, 2R)-1-(4-luorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N 3，N 3-dipropyl benzene-1,3, the 5-trimethamide | 593.3 |
| 2666 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(4-methyl isophthalic acid, 3-oxazole-2-yl)-N 3，N 3-dipropyl isophthaloyl amine | 647 |
| 2667 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3，N 3-dipropyl-5-(1,3-thiazoles-2-yl) isophthaloyl amine | 649 |
| 2668 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-[(methyl sulphonyl) amino] benzamide | 532.2 |
| 2671 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl | 633 |
| Base }-5-(1,3-oxazole-2-yl)-N 3，N 3-dipropyl isophthaloyl amine | ||
| 2672 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1,3-oxazole-2-yl)-N 3，N 3-dipropyl isophthaloyl amine hydrochlorate | 633.4 |
| 2675 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(1-propyl group butyl) alkylsulfonyl] propionamide hydrochloride | 553 |
| 2677 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-5-(1,3-oxazole-2-yl)-N 3，N 3-dipropyl isophthaloyl amine | 635 |
| 2678 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-the 2-[(methyl sulphonyl) amino]-1,3-thiazoles-4-methane amide | 637.6 |
| 2679 | N 1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N 3，N 3-dipropyl-5-{[(trifluoromethyl) alkylsulfonyl] amino } isophthaloyl amine | 665 |
| 2680 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(isopentyl alkylsulfonyl) propionic acid amide | 525 |
| 2681 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(1-methyl isophthalic acid H-imidazol-4 yl) alkylsulfonyl] amino } the benzamide tri hydrochloride | 598.1 |
| 2682 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-{[(trifluoromethyl) alkylsulfonyl] amino } benzamide | 586 |
| 2684 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-{[(2-hydroxyethyl) (propyl group) amino] alkylsulfonyl } propionic acid amide | 556 |
| 2685 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(1,3-oxazole-2-yl) benzamide hydrochloride salt | 506 |
| 2686 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-{[(2-hydroxyl-1, the 1-dimethyl ethyl) amino] alkylsulfonyl }-N 3，N 3-dipropyl isophthaloyl amine | 717 |
| 2687 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(2-hydroxyl-1, the 1-dimethyl ethyl) amino] alkylsulfonyl } benzamide | 590 |
| 2688 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-{[(3-hydroxypropyl) amino] alkylsulfonyl }-N 3，N 3-dipropyl isophthaloyl amine | 703 |
| 2689 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-[(methyl sulphonyl) amino]-1,3-thiazoles-4-methane amide | 539.1 |
| 2690 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 2-(phenyl formyl radical)-3-[(1-propyl group butyl) alkylsulfonyl] amino propionic acid amide | 686 |
| 2709 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-{[(2-hydroxyethyl) amino] alkylsulfonyl }-N 3-propyl group isophthaloyl amine | 647 |
| 2710 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-([(1S)-and 2-hydroxyl-1-methylethyl] amino } alkylsulfonyl)-N 3，N 3-dipropyl isophthaloyl amine | 703 |
| 2711 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3，N 3-diethyl-5-(1,3-oxazole-2-yl) isophthaloyl amine | 605.4 |
| 2712 | N-{ (1S, 2R)-and 1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(2S)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] carbonyl }-5-toluyl amine hydrochlorate | 594.3 |
| 2713 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-{[(2S)-and 2-(methylol) tetramethyleneimine-1-yl] alkylsulfonyl }-N 3，N 3-dipropyl isophthaloyl amine | 729 |
| 2714 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-([(1R)-and 2-hydroxyl-1-methylethyl] amino } alkylsulfonyl)-N 3，N 3-dipropyl isophthaloyl amine | 703 |
| 2716 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(2-ethyl-1-hydroxyl butyl) benzamide | 539.3 |
| 2717 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-[(dimethylamino) alkylsulfonyl]-N 3，N 3-dipropyl isophthaloyl amine | 673.1 |
| 2719 | N 1-[(1S, 2R)-3-{[2-(amino-sulfonyl) ethyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | 569.6 |
| 2723 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(4-phenyl butyl) amino] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | 594.5 |
| 2729 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3-ethyl-N 3-methyl-5-(1,3-oxazole-2-yl) isophthaloyl amine | 591.4 |
| 2730 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3-methyl-5-(1,3-oxazole-2-yl)-N 3-propyl group isophthaloyl amine | 605.4 |
| 2731 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3，N 3-dipropyl-5-(tetramethyleneimine-1-base alkylsulfonyl) isophthaloyl amine hydrochlorate | 699.1 |
| 2732 | N 1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-5-{[(2-hydroxyl-1, the 1-dimethyl ethyl) amino] alkylsulfonyl }-N 3，N 3-dipropyl isophthaloyl amine | 669 |
| 2733 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1,3-oxazole-5-yl)-N 3，N 3-dipropyl isophthaloyl amine hydrochlorate | 633 |
| 2734 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1,3-oxazole-2-yl)-N 3，N 3-dipropyl isophthaloyl amine hydrochlorate | 629 |
| 2735 | N 1-butyl-N 3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 1-methyl-5-(1,3-oxazole-2-yl) isophthaloyl amine | 619.4 |
| 2736 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3，N 3-dimethyl-5-(1,3-oxazole-2-yl) isophthaloyl amine | 577.3 |
| 2737 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3-ethyl-5-(1,3-oxazole-2-yl)-N 3-propyl group isophthaloyl amine | 619.4 |
| 2738 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3，N 3-dipropyl-5-(1,3-thiazoles-2-yl) isophthaloyl amine hydrochlorate | 645 |
| 2739 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(1-propyl group butyl) amino] alkylsulfonyl } propionic acid amide | 568 |
| 2740 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-{[(2R)-and 2-(methylol) tetramethyleneimine-1-yl] alkylsulfonyl }-N 3，N 3-dipropyl isophthaloyl amine | 729 |
| 2741 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-{[(2-hydroxyl-1, the 1-dimethyl ethyl) amino] alkylsulfonyl }-N 3，N 3-dipropyl isophthaloyl amine | 713 |
| 2742 | N 1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(isobutylamino) propyl group]-5-(1,3-oxazole-2-yl)-N 3，N 3-dipropyl isophthaloyl amine hydrochlorate | 571 |
| 2743 | 5-bromo-N 1-((1S, 2R)-1-[3-fluoro-4-(trifluoromethyl) benzyl]-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-N 3，N 3-dipropyl isophthaloyl amine | 734-1 |
| 2744 | 5-bromo-N 1-((1S, 2R)-2-hydroxyl-1-(2,3, the 4-trifluoro-benzyl)-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-N 3，N 3-dipropyl isophthaloyl amine | |
| 2745 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(2-ethyl butyryl radicals)-5-toluyl amine hydrochlorate | 551.3 |
| 2746 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl-5-[(2-propyl group piperidines-1-yl) carbonyl] benzamide hydrochloride salt | 606.3 |
| 2747 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl-5-[(2-methylpyrrolidin-1-yl) carbonyl] benzamide hydrochloride salt | 564.4 |
| 2748 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(2,6-lutidine-1-yl) carbonyl]-5-toluyl amine hydrochlorate | 592.3 |
| 2749 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-{[(2-methoxy ethyl) amino] alkylsulfonyl }-N 3，N 3-dipropyl isophthaloyl amine | 703 |
| 2766 | N 1-[(1S, 2R)-3-{[3-(1-thionaphthene-2-yl) benzyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | 684.5 |
| 2767 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-5-ethynyl-N 3，N 3-dipropyl isophthaloyl amine | 630.2 |
| 2768 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-thiene-3-yl-benzyl) amino] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | 633.0 |
| 2769 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(5-thiotolene-2-yl) benzyl] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | 647.0 |
| 2770 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-pyridin-4-yl benzyl) amino] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | 629.6 |
| 2771 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(4-thiotolene-2-yl) benzyl] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | 648.5 |
| 2772 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[3-(2,4-dimethoxypyridin-5-yl) benzyl] amino }-the 2-hydroxypropyl)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | 690.6 |
| 2773 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[3-(3,5-dimethyl isoxazole-4-yl) benzyl] amino }-the 2-hydroxypropyl)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | 647.6 |
| 2774 | N 4-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-6-methyl-N 2，N 2-dipropyl pyridine-2, the 4-diformamide | 581.3 |
| 2775 | N 1-[(1S, 2R)-3-{[3-(cyclopropyl amino) benzyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | 607.3 |
| 2776 | N 1-[(1S, 2R)-3-{[3-(cyclopropyl amino) benzyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-ethynyl-N 3，N 3-dipropyl isophthaloyl amine | 617.3 |
| 2777 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[1-(2-isobutyl--1,3-thiazoles-5-yl) cyclopropyl] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | 641.3 |
| 2778 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-5-(1,3-oxazole-2-yl)-N 3，N 3-dipropyl isophthaloyl amine | 659.3 |
| 2779 | 3-({ [(2R; 3S)-4-(3, the 5-difluorophenyl)-3-(3-[(dipropyl amino) carbonyl]-the 5-methyl benzoyl } amino)-2-hydroxyl butyl] amino } methyl) phenyl (methyl) Urethylane | 639.3 |
| 2780 | N 1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(3-[methyl (methyl sulphonyl) amino] and benzyl } amino) propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | 659.3 |
| 2781 | N 1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-(the 3-[(dimethylamino) and alkylsulfonyl] benzyl } amino)-the 2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | 659.3 |
| 2782 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | 606.3 |
| 2783 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(2-isobutyl--1,3-thiazoles-5- | 668.2 |
| Benzyl)-the 2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | ||
| 2801 | N 1-[(1S, 2R)-3-[(3-allyl group benzyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | 592.6 |
| 2802 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(6-methoxypyridine-3-yl) benzyl] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | 659.6 |
| 2803 | N 1-[(1S, 2R)-3-{[(2-tertiary butyl pyrimidine-4-yl) methyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | 610.3 |
| 2804 | N 4-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-isopropyl benzyl) amino] propyl group }-6-methyl-N 2，N 2-dipropyl pyridine-2, the 4-diformamide | 595.3 |
| 2805 | N 1-[(1S, 2R)-the 3-[(3-butyl benzyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | 608.6 |
| 2806 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-amyl group benzyl) amino] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | 622.6 |
| 2807 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-penta-4-thiazolinyl benzyl) amino] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | 620.6 |
| 2808 | N 1-[(1S, 2R)-3-[(3-cyclopentyl benzyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | 620.6 |
| 2809 | N 1-[(1S, 2R)-the 3-[(3-cyclohexyl benzyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | 634.6 |
| 2810 | N 1-[(1S, 2R)-3-{[3-(cyclohexyl methyl) benzyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | 648.6 |
| 2811 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-oneself-5-thiazolinyl benzyl) amino]-the 2-hydroxypropyl-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | 634.6 |
| 2812 | (2S)-3-[3-({ [(2R; 3S)-4-(3, the 5-difluorophenyl)-3-(3-[(dipropyl amino) carbonyl]-the 5-methyl benzoyl } amino)-2-hydroxyl butyl] amino } methyl) phenyl]-the 2 Methylpropionic acid methyl esters | 2812 |
| 2813 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(3 methyl thiophene-2-yl) benzyl] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | 648.5 |
| 2814 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2 hydroxyls-3-{[3-(3-picoline-2-yl) benzyl] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | 643.6 |
| 2815 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(4-picoline-2-yl) benzyl] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | 643.6 |
| 2816 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(5-picoline-2-yl) benzyl] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | 643.6 |
| 2817 | N 1-[(1S, 2R)-3-{[3-(4-chlorobutyl) benzyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxyl | 642.6 |
| Propyl group]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | ||
| 2818 | N 1-[(1S, 2R)-3-{[3-(3-cyano group butyl) benzyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | 619.6 |
| 2819 | N 1-[(1S, 2R)-3-{[3-(4-cyano group butyl) benzyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | 633.6 |
| 2820 | N 1-[(1S, 2R)-3-{[3-(6-cyano group hexyl) benzyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | 661.6 |
| 2821 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(6-picoline-2-yl) benzyl] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | 643.6 |
| 2822 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(1,3-oxazole-2-yl) benzyl] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | 619.2 |
| 2823 | 3-{[((2R; 3S)-4-(3; the 5-difluorophenyl)-and 3-{[3-[(dipropyl amino) carbonyl]-5-(1,3-oxazole-2-yl) benzoyl] amino }-2-hydroxyl butyl) amino] methyl } phenyl (methyl) Urethylane | |
| 2824 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1S)-the 1-[(isobutylamino) carbonyl]-3-(methyl sulphonyl) propyl group] amino } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | 681.0 |
| 2825 | N 1-butyl-N 3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-isopropyl benzyl) amino] propyl group }-N 1, 5-dimethyl isophthaloyl amine | 580.3 |
| 2826 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-and 3-{[1-(3-ethylphenyl)-1-methylethyl] amino }-the 2-hydroxypropyl)-5{[(2-hydroxyl-1, the 1-dimethyl ethyl) amino] alkylsulfonyl }-N 3，N 3-dipropyl isophthaloyl amine | 745.1 |
| 2827 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-{ methyl [(trifluoromethyl) alkylsulfonyl] amino }-N 3，N 3-dipropyl isophthaloyl amine | 727 |
| 2828 | N 1-[(1S, 2R)-3-(cyclopropyl amino)-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-{[(2-hydroxyl-1, the 1-dimethyl ethyl) amino] alkylsulfonyl }-N 3，N 3-dipropyl isophthaloyl amine | 639 |
| 2829 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl)-1-methylethyl] amino }-the 2-hydroxypropyl)-N 3，N 3-dipropyl-5-(1,3-thiazoles-2-yl) isophthaloyl amine | 677.1 |
| 2830 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-[methyl (methyl sulphonyl) amino]-N 3，N 3-dipropyl isophthaloyl amine | 673.2 |
| 2831 | N 1-butyl-N 3-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl)-1-methylethyl] amino }-the 2-hydroxypropyl)-N 1, 5-dimethyl isophthaloyl amine | 594.3 |
| 2832 | N 1-((1S, 2R)-1-(2, the 4-difluorobenzyl)-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] ammonia | 620.2 |
| Base } propyl group)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | ||
| 2833 | 5-bromo-N 1-((1S, 2R)-1-(2, the 4-difluorobenzyl)-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-N 3，N 3-dipropyl isophthaloyl amine | 684.1 |
| 2834 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(2-ethyl piperidine-1-yl) alkylsulfonyl] propionic acid amide | 566 |
| 2835 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-5-ethynyl-N 3，N 3-dipropyl isophthaloyl amine | 616.3 |
| 2836 | N 1-cyclobutyl-N 3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the oreinol diformamide | 550.1 |
| 2837 | N 1-cyclopentyl-N 3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the oreinol diformamide | 564.1 |
| 2838 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-N 3-amyl group isophthaloyl amine | 566.1 |
| 2839 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3-isopentyl-oreinol diformamide | 566.1 |
| 2840 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3-ethyl-N 3-(2-hydroxyethyl)-oreinol diformamide | 568.1 |
| 2841 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3-(2-ethoxyethyl group)-oreinol diformamide | 568.1 |
| 2842 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3-(2-methoxy ethyl)-N 3, 5-dimethyl isophthaloyl amine | 568.1 |
| 2843 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3-(2-furyl methyl)-N 3, 5-dimethyl isophthaloyl amine | 590.1 |
| 2844 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(2R, 5R)-2,5-dimethyl pyrrolidine-1-yl] carbonyl }-the 5-methyl benzamide | 578.1 |
| 2845 | N 1-cyclopentyl-N 3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 1, 5-dimethyl isophthaloyl amine | 578.1 |
| 2846 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3, 5-dimethyl-N 3-amyl group isophthaloyl amine | 580.1 |
| 2847 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3-(2-hydroxyethyl)-5-methyl-N 3-propyl group isophthaloyl amine | 582.1 |
| 2848 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3-ethyl-N 3-(2-methoxy ethyl)-oreinol diformamide | 582.1 |
| 2849 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-N 3-(2-methylcyclohexyl) isophthaloyl amine | 592.1 |
| 2850 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3-(2-methoxy ethyl)-5-methyl-N 3-propyl group isophthaloyl amine | 596.1 |
| 2851 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3，N 3-two (2-methoxy ethyl)-oreinol diformamides | 612.1 |
| 2852 | N 1-allyl group-N 1-cyclohexyl-N 3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the oreinol diformamide | 618.1 |
| 2853 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-N 3，N 3-diamyl isophthaloyl amine | 636.2 |
| 2854 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3，N 3-two (2-ethoxyethyl group)-oreinol diformamides | 640.1 |
| 2855 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1,3-oxazole-2-yl)-N 3，N 3-dipropyl isophthaloyl amine | 655.2 |
| 2856 | N 1-butyl-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-2-hydroxypropyl-N, 5-dimethyl isophthaloyl amine | 592.3 |
| 2857 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-and 3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-5-{[(2-hydroxyl-1, the 1-dimethyl ethyl) amino] alkylsulfonyl }-N 3，N 3-dipropyl isophthaloyl amine | 743.2 |
| 2860 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-[(3-hydroxypropyl) alkylsulfonyl]-N 3，N 3-dipropyl isophthaloyl amine | 688 |
| 2861 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1H-imidazol-4 yl)-N 3，N 3-dipropyl isophthaloyl amine tri hydrochloride | 632 |
| 2862 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-isoxazole-3-base-N 3，N 3-dipropyl isophthaloyl amine | 633 |
| 2863 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-and the 3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(2R)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] carbonyl }-5-(1,3-oxazole-2-yl) benzamide | 647 |
| 2864 | N 4-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-6-methyl-N 2，N 2-dipropyl pyridine-2, the 4-diformamide | 577.2 |
| 2865 | N 4-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-6-methyl-N 2，N 2-dipropyl pyridine-2, the 4-diformamide | 621.2 |
| 2866 | N 4-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-6-methyl-N 2，N 2-dipropyl pyridine-2, the 4-diformamide | 607.3 |
| 2867 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl }-N 3，N 3-dipropyl-5-(1,3-thiazoles-2-yl) isophthaloyl amine | 675.4 |
| 2868 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl | 741 |
| The base propionamide hydrochloride | ||
| 2892 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-{[(2R)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] alkylsulfonyl }-N 3，N 3-dipropyl isophthaloyl amine | 743 |
| 2893 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-[(3-hydroxypropyl) (methyl sulphonyl) amino] benzamide | 590.0 |
| 2894 | N 2-ethanoyl-N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(1-propyl group butyl) alkylsulfonyl]-the amino propionamide hydrochloride of right type | 610 |
| 2895 | 2-[allyl group (methyl sulphonyl) amino]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl)-1,3-thiazoles-5-methane amide | 579.2 |
| 2896 | 3-(butyl alkylsulfonyl)-N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the amino propionic acid amide of right type two (trifluoroacetate) | 526 |
| 2897 | N 1-{ (1S; 2R)-and 1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-3-[(1-propyl group butyl) alkylsulfonyl]-the amino propionic acid amide of right type two (trifluoroacetate) | 594 |
| 2898 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 2-isobutyryl-3-[(1-propyl group butyl) alkylsulfonyl]-the amino propionamide hydrochloride of right type | 638 |
Compound in the following table mainly is to use the method preparation of setting forth in the above-described and following diagram.
Following compounds is to use the Advanced Chemistry Development Inc. (ACD) nomenclature, and IUPAC Name Batch 4.5. version is named.The network address of ACD is www.acdlabs.com.
| The compound title | Mass spectrum | |
| 2899 | N-[(1S, 2R)-3-(fourth amino)-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-4-(ethylenebis dithiocarbamate) benzamide | |
| 2900 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-(2-fluorophenyl)-5-oxo-pyrrolidine-3-methane amide | 540.2 |
| 2901 | N 1-(the 4-tertiary butyl-1,3-thiazoles-2-yl)-N 4-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } succinic diamide | |
| 2902 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-hydroxyl-6-(1-hydroxyl-2,2-dimethyl propyl) pyridine-2-carboxamide | 542.3 |
| 2903 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-{[(ethylamino) carbonyl] amino } benzamide | 525.3 |
| 2908 | 3-ethanoyl-N-[(1S, 2R)-3-(benzylamino)-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl] |
| Benzamide | ||
| 2909 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(7-methoxyl group-1,2,3,4-naphthane-1-yl) amino] propyl group }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | |
| 2913 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(2,2-titanium dioxide-3,4-dihydro-1,2-benzo oxathiin-4-yl) amino]-the 2-hydroxypropyl }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | |
| 2916 | N 1-(1S, 2R)-1-{[5-(cyano methyl)-1H-imidazoles-1-yl] methyl }-the 3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | |
| 2918 | N 1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(2-ethyl-pyrimidine-4-yl) methyl] amino }-the 2-hydroxypropyl)-5-methyl-N 3，N 3-dipropyl isophthaloyl amine | |
| 2920 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-{[ethyl (methyl) amino] alkylsulfonyl }-N 3，N 3-dipropyl isophthaloyl amine | 687.3 |
| 2921 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-[(2-hydroxyethyl) (methyl sulphonyl) amino] benzamide | 575.9 |
| 2922 | 5-bromo-N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3，N 3-dipropyl isophthaloyl amine | 646.4 |
| 2923 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(2-first and second bases) (methyl sulphonyl) amino] benzamide hydrochloride salt | 590.0 |
| 2924 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-[(methyl sulphonyl) methyl] benzamide | 531.2 |
| 2925 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-[(4-hydroxyl butyl) alkylsulfonyl]-N 3，N 3-dipropyl isophthaloyl amine hydrochlorate | 702.4 |
| 2926 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the different quinoline beautiful jade of 1-(dipropyl amino)-7-methane amide | 589.4 |
| 2927 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-{[(2-hydroxyethyl) (methyl) amino] alkylsulfonyl }-N 3，N 3-dipropyl isophthaloyl amine | 703.4 |
| 2928 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-[(ethylamino) alkylsulfonyl]-N 3，N 3-dipropyl isophthaloyl amine | 673.4 |
| 2929 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl)-N 3，N 3-dipropyl isophthaloyl amine hydrochlorate | 648.4 |
| 2930 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[methyl (methyl sulphonyl) amino]-1,3-oxazole-4-methane amide | |
| 2931 | 3-(butyl alkylsulfonyl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) | 511 |
| Amino]-the 2-hydroxypropyl } propionic acid amide | ||
| 2932 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3，N 3-dipropyl Malonamide | |
| 2933 | N 2-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-2-hydroxypropyl }-N, N-dipropyl two rings [2.2.1] heptan-5-alkene-2,3-diformamide | |
| 2934 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 3，N 3-dipropyl pentamethylene-1, the 3-diformamide | |
| 2935 | N 2-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3,4-dimethyl-N 5，N 5-dipropyl thieno-[2,3-b] thiophene-2, the 5-diformamide | |
| 2936 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-phenyl-N 5，N 5-dipropyl glutaramide | |
| 2937 | N 2-benzyl-N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 2-[2-(dipropyl amino)-2-oxygen ethyl] G-NH2 | |
| 2938 | 3-(4-chloro-phenyl-)-N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 5，N 5-dipropyl glutaramide | |
| 2939 | (2E)-N 5-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(methoxyimino)-N 1，N 1-dipropyl glutaramide | |
| 2940 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 2-[2-(dipropyl amino)-2-oxygen ethyl]-N 2-phenylglycinamide | |
| 2941 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N 2，N 2-dipropyl hexanaphthene-1, the 2-diformamide | |
| 2942 | N 1-[(1S, 2R)-the 3-[(benzyloxy) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-(1,3-oxazole-2-yl)-N 3，N 3-dipropyl Malonamide | |
| 2943 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-Phenylpropionamide | |
| 2945 | N 1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1H-imidazoles-2-yl)-N 3，N 3-dipropyl Malonamide | 632.3 |
| 2946 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(1-hydroxyl-2-propyl group phenyl) benzamide | 567.3 |
| 2947 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-phenyl isopropyl ketone carboxamide hydrochloride | 536.2 |
| 2948 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(2-propyl group pentanoyl (pentanoyl)) benzamide | 565.3 |
| 2949 | N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(2-ethyl butyryl radicals (butanoyl)) benzamide hydrochloride salt | 537.3 |
Compound in the following table mainly is to use the method preparation of setting forth in the above-described and following diagram.
Following compounds is to use the Advanced Chemistry Development Inc. (ACD) nomenclature, and IUPAC Name Batch 4.5. version is named.The network address of ACD is www.acdlabs.com.
Embodiment SP-131
Step 1: will be at the iodide 1 in the N-crassitude (10 milliliters) (1.70 grams, 4.36 mmoles), Pd
2Dba
3(80 milligrams, 0.087 mmole), dppf (193 milligrams, 0.349 mmole) and triethylamine (882 milligrams, 8.72 mmoles) solution outgased 15 minutes under nitrogen atmosphere.Add 3-sulfydryl-1-propyl alcohol (402 milligrams, 4.36 mmoles) and with reaction mixture 60 ℃ of heating 2 hours.Reaction mixture is cooled to room temperature, then phase-splitting between ethyl acetate and saturated sodium-chloride.With saturated sodium-chloride washing (2 *) organic layer, dry (sodium sulfate) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 1: 1 hexane/ethyl acetate), obtain yellow oily sulfide 2 (880 milligrams, 57%):
1H NMR (300MHz, CDCl
3) δ 8.00 (and s, 1H), 7.85 (s, 1H), 7.50 (s, 1H), 3.92 (s, 3H), 3.77 (m, 2H), 3.47 (m, 4H), 3.11 (m, 4H), 1.92 (m, 2H), 1.70 (m, 2H), 0.98 (m, 3H), 0.78 (m, 3H); ESI MS m/z 354[M+H]
+
Step 2: in the solution of the sulfide 2 (880 milligrams, 2.49 mmoles) through stirring in 1: 1 acetic acid/water (15 milliliters), add excessive 30% hydrogen peroxide.Phase-splitting between ethyl acetate and water is then spent the night in the reaction mixture stirring.Wash organic layer with water, dry (sodium sulfate) filters, and concentrating under reduced pressure, makes light yellow oily sulfone (912 milligrams, 95%):
1HNMR (300MHz, CDCl
3) δ 9.51 (and s, 1H), 8.28 (s, 1H), 8.11 (s, 1H), 3.99 (s, 3H), 3.71 (m, 2H), 3.55 (m, 2H), 3.44 (m, 2H), 3.38 (m, 2H), 2.11 (m, 2H), 1.88 (m, 2H), 1.78 (m, 2H), 0.77 (m, 3H), 0.56 (m, 3H); APCI MS m/z 387[M+H]
+
Step 3: sulfone (912 milligrams, the 2.36 mmoles) solution that will make in the step 2 in 3: 1: 1 methyl alcohol/tetrahydrofuran (THF)/1N sodium hydroxide (20 milliliters) was stirring at room 2 hours.Make reaction mixture phase-splitting between ethyl acetate and water.With 1N hydrochloric acid water layer is acidified to pH3, and uses chloroform extraction.With organic layer drying (sodium sulfate), filter and concentrate, make white foam shape acid 3 (860 milligrams, 98%):
1H NMR (300MHz, CDCl
3) δ 8.48 (and s, 1H), 8.24 (s, 1H), 8.08 (s, 1H), 4.11 (m, 2H), 3.69 (m, 2H), 3.33 (m, 2H), 3.13 (m, 2H), 1.98 (m, 2H), 1.75 (m, 2H), 1.58 (m, 2H), 1.03 (m, 3H), 0.79 (m, 3H).
Step 4: (630 milligrams of the acid 3 in methylene dichloride (15 milliliters) through stirring, 1.69 mmole), amine 4 is (688 milligrams, 1.69 mmole), HOBt is (251 milligrams, 1.86 mmole) and (855 milligrams of N-methylmorpholines, 8.45 mmole) add EDC (583 milligrams, 3.04 mmoles) in the solution.Phase-splitting between ethyl acetate and water is then spent the night in the reaction mixture stirring.With 1N hydrochloric acid, saturated sodium bicarbonate and saturated sodium-chloride washing organic layer, dry (sodium sulfate), filtration and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 93: 7: 1 methylene chloride/ammonium hydroxide), obtain the ALB 8198 (5) (400 milligrams, 34%) of white solid: mp 62-66 ℃; IR (ATR) 3293,2964,2874,1614cm
-1,
1H NMR (300MHz, CDCl
3) δ 8.18 (and s, 1H), 8.06 (s, 1H), 7.85 (s, 1H), 7.28 (m, 2H), 7.15 (m, 2H), 6.85 (m, 2H), 6.62 (m, 1H), 4.31 (m, 1H), 3.79 (m, 2H), 3.67 (m, 2H), 3.55 (m, 2H), 3.24 (m, 2H), 3.05 (m, 2H), 2.91 (m, 4H), 2.86 (m, 1H), 2.60 (m, 2H), 1.95 (m, 2H), 1.73 (m, 2H), 1.56 (m, 2H), 1.22 (m, 3H), 1.03 (m, 3H), 0.72 (m, 3H); APCI MS m/z 688[M+H]
+HPLC: method A, 8.36 minutes (＞99%, AUC).C
36H
47F
2N
3O
6S0.25H
2The Anal. calculated value of O: C, 62.45; H, 6.92; N, 6.07.Measured value: C, 62.21; H, 6.69; N, 5.97.
Embodiment SP-132
Step 1: under 40 ℃, in THF (20 milliliters), stir the mixture of benzoate 6 (870 milligrams, 3.79 mmoles) and sulfo-methylate (292 milligrams, 4.18 mmoles).After 48 hours, reaction mixture is cooled to room temperature, then phase-splitting between ethyl acetate and water.With organic layer drying (sodium sulfate), filter and concentrating under reduced pressure, obtain white foam shape sulfide 7 (650 milligrams, 87%):
1H NMR (300MHz, CDCl
3) δ 7.97 (and s, 1H), 7.88 (d, J=8Hz, 1H), 7.40 (d, J=8Hz, 1H), 7.27 (m, 1H), 3.92 (s, 3H), 3.71 (s, 2H), 1.99 (s, 3H).
Step 2: add excessive 30% hydrogen peroxide in sulfide 7 (650 milligrams, the 3.31 mmoles) solution in 1: 1 acetic acid/water (25 milliliters) through stirring.Phase-splitting between ethyl acetate and water is then spent the night in the reaction mixture stirring.With sodium bicarbonate, water and saturated sodium-chloride washing organic layer, dry (sodium sulfate) filters, and concentrating under reduced pressure, makes transparent oily sulfone 8 (540 milligrams, 72%):
1H NMR (500MHz, DMSO-d
6) δ 8.12 (and s, 1H), 8.04 (d, J=7Hz, 1H), 7.74 (d, J=7Hz, 1H), 7.54 (m, 1H), 4.62 (s, 2H), 3.98 (s, 3H), 2.98 (s, 3H).
Step 3: will stir at sulfone 8 (540 milligrams, the 2.37 mmoles) mixture in 3: 1: 1 methyl alcohol/tetrahydrofuran (THF)/2N sodium hydroxide (10 milliliters) and spend the night.Make reaction mixture phase-splitting between ethyl acetate and water.With 1N hydrochloric acid water layer is acidified to pH3, and uses chloroform extraction.With organic layer drying (sodium sulfate), filter and concentrating under reduced pressure, make white solid acid (406 milligrams, 80%):
1H NMR (300MHz, DMSO-d
6) δ 8.02 (and s, 1H), 7.96 (d, J=7Hz, 1H), 7.64 (d, J=7Hz, 1H), 7.57 (m, 1H), 4.59 (s, 2H), 2.92 (s, 3H).
Step 4: from (260 milligrams of the acid of step 3,1.21 mmole), HOBt (163 milligrams, 1.21 mmoles), amine 4 (495 milligrams, 1.21 mmoles) and N-methylmorpholine are (612 milligrams, 6.05 add EDC (418 milligrams, 2.18 mmoles) in solution mmole) through stirring.The reaction mixture stirring is spent the night, be divided into ethyl acetate layer and water layer then.With 1N hydrochloric acid, saturated sodium bicarbonate and saturated sodium-chloride washing organic layer, dry (sodium sulfate), filtration and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 93: 7: 1 methylene chloride/ammonium hydroxide), obtain ALB 8653 (9) (308 milligrams, 48%): mp 147-149 ℃; IR (ATR) 3286,2961,1633,1596cm
-1 1H NMR (300MHz, DMSO-d
6) δ 8.39 (and d, J=9Hz, 1H), 7.77 (s, 1H), 7.72 (d, J=7Hz, 1H), 7.54 (d, J=7Hz, 1H), 7.48 (m, 1H), 7.18-6.93 (m, 7H), 5.03 (br s, 1H), 4.51 (s, 2H), 4.18 (br s, 1H), 3.68 (s, 2H), 3.67 (m, 1H), 3.12 (m, 1H), 2.91 (s, 3H), 2.88 (m, 1H), 2.61 (m, 1H), 2.45 (m, 2H), 2.43 (m, 2H), 1.13 (m, 3H); ESI MS m/z531[M+H]
+HPLC: method A, 6.81 minutes (＞99%, AUC).C
31H
40F
2N
4O
40.25H
2The Anal. calculated value of O: C, 62.85; H, 6.12; N, 5.23.Measured value: C, 62.96; H, 5.83; N, 5.09.
Embodiment SP-132
Step 1: with oxyhydroxide 10 (2.5 grams, 11.1 mmoles) and POCl
3The solution of (10.4 milliliters, 111 mmoles) stirred 2.5 hours at 70 ℃.Reaction mixture is cooled to room temperature, pours in the frozen water, and solution stirring is spent the night.Use CHCl
3Dilute this aqueous mixture, use saturated NaHCO
3Solution, saturated NaCl washing, dry (MgSO
4), filter and concentrating under reduced pressure, make brown solid shape muriate 11 (2.3 grams, 85%):
1HNMR (300MHz, DMSO-d
6) δ 8.39-8.36 (and m, 2H), 8.09-8.02 (m, 2H), 7.95 (d, J=6Hz, 1H).
Step 2: the solution of muriate 11 (500 milligrams, 2.1 mmoles) and dipropyl amine (2.8 milliliters, 21 mmoles) was heated 2 days with 150 ℃ in sealed tube.With the reaction mixture cooling, solvent is removed in decompression, makes brown oily amine 12 (400 milligrams, 63%):
1H NMR (300MHz, DMSO-d
6) δ 8.55 (and s, 1H), 7.90 (d, J=6Hz, 1H), 7.75-7.64 (m, 2H), 6.87 (d, J=6Hz, 1H), 3.42 (q, J=7Hz, 4H), 1.65 (q, J=7Hz, 4H), 0.94 (t, J=7Hz, 6H).
Step 3: will under backflow, stir 24 hours at amine 12 among the DMF (2 milliliters) (350 milligrams, 1.1 mmoles) and CuCN (204 milligrams, 2.2 mmoles) solution.This reaction mixture is cooled to room temperature, dilute with water, and extract with EtOAc (3 * 50 milliliters).The organism that merges is washed dry (MgSO with saturated NaCl
4), filter and concentrating under reduced pressure, make brown oily nitrile (279 milligrams, 100%), it can use without any further sign.
Step 4: will in sealed tube, heat 14 hours at the nitrile in the concentrated hydrochloric acid (4 milliliters) (279 milligrams, 1.1 mmoles) solution from step 4 with 150 ℃.Reaction mixture is cooled to room temperature, and solvent is removed in decompression, and resistates is dissolved in 25%NH
4OH/H
2O solution, and stirred 1 hour.Solution is acidified to pH 4, and uses CHCl
3Extraction (3 * 50 milliliters).With the organism drying (NaSO that merges
4), filter and concentrating under reduced pressure, make the acid 13 (104 milligrams, 35%) of white solid:
1H NMR (300MHz, CDCl
3) δ 8.85 (and s, 1H), 8.15 (d, J=8Hz, 1H), 8.01 (d, J=6Hz, 1H), 7.79 (d, J=7Hz, 1H), 7.21 (d, J=6Hz, 1H), 3.47 (m, 4H), 1.68 (m, 4H), 0.83 (m, 6H); ESI MS m/z273[M+H]
+
Step 5: (103 milligrams of the acid 13 in methylene dichloride (4 milliliters) through stirring, 0.38 mmole), amine 4 is (154 milligrams, 0.38 mmole), HOBt is (77 milligrams, 0.57 mmole) and (0.2 milliliter of DIPEA, 1.1 the Bo mole) add HATU (216 milligrams, 0.57 mmole) in the solution.The reaction mixture stirring is spent the night, be divided into dichloromethane layer and 1N hydrochloric acid layer then.With saturated sodium bicarbonate, saturated sodium-chloride washing organic layer, dry (sodium sulfate), filtration and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 9: 1 methylene chloride), obtain ALB 8655 (70 milligrams, 31): mp 142-151 ℃; IR (ATR) 3222,1621,1585,1114,848,700cm
-1 1H NMR (500MHz, DMSO-d
6) δ 9.46 (s, 1H), 9.09 (s, 2H), 8.57 (s, 1H), 8.35 (s, 1H), 8.09 (s, 1H), 7.29 (s, 1H), 7.46 (d, J=6Hz, 1H), 7.40 (s, 1H), 7.35 (d, J=7Hz, 1H), 7.27 (t, J=7Hz, 1H), 7.19 (d, J=7Hz, 1H), 7.04-6.97 (m, 3H), 4.24-4.08 (m, 4H), 3.73 (br s, 4H), 3.54 (br s, 8H), 3.18 (d, J=8Hz, 1H), 3.10 (br s, 1H), 3.00 (m, 1H), 2,87 (d, J=8Hz, 1H), 2.56-2.50 (m, 2H), 1.75 (d, J=6Hz, 4H), 1.12 (t, J=7Hz, 3H), 0.88 (t, J=7Hz, 6H); APCI MS m/z 589[M+H]
+HPLC: method A, 7.21 minutes (99%, AUC).C
35H
42F
2N
4O
22HCl0.5H
2The Anal. calculated value of O: C, 62.68; H, 6.76; N, 8.35.Measured value: C, 62.60; H, 6.89; N, 8.29.
Embodiment SP-134
The ketone that is used for this embodiment is prepared shown in chart U usually.
Step 1.
In halogenide in dry toluene (10 milliliters) (4.68 grams, the 20 mmoles) solution, add (α-vinyl ethyl ether base)-tributyl tin (7.66 milliliters, 22 mmoles) and dichloro two (triphenylphosphine) palladium (0.715 gram, 1 mmole) through stirring.Under nitrogen, reactant was heated 14 hours in 100 ℃.With the reaction mixture hydrolysis, wash organic layer with 1N HCl (100 milliliters), use potassium fluoride aqueous solution (10%, 100 milliliter) washing then, concentrate through dried over mgso and under vacuum with ether.Crude product is passed through flash column chromatography (10-20% ethyl acetate: hexane) purify, obtain the 3-ethanoyl-5-methyl-methyl benzoate (65% productive rate) of 2.5 gram white solid.IR (drift) 3090,3078,3019,2998,2952,2920,1716,1681,1608,1596,1448,1435,1273,1237,1234,1197,1118,893cm
-1 1H NMR (CDCl
3) δ 8.44 (and s, 1H), 8.10 (s, 1H), 8.01 (s, 1H), 3.99 (s, 3H), 2.68 (s, 3H), 2.51 (s, 3H); C
11H
12O
3+ H
+HRMS (FAB) calculated value=193.0865, measured value is 193.0868.
Step 2.
At room temperature; potassium hydroxide (pill shape) in methyl-sulphoxide (10 milliliters) (5.0 grams through stirring; 90.0 mmole) add 3-ethanoyl-5-methyl-methyl benzoate (0.8 gram, 4.5 mmoles) and propyl iodide (2.9 milliliters, 36 mmoles) in the suspension.Reaction mixture was heated to 50-60 ℃ and restir 1 hour.After being cooled to room temperature, reactant is poured in the 1N HCl aqueous solution (100 milliliters).Extract this aqueous solution with ether (80 milliliters * 2).Organic layer with salt solution (80 milliliters * 2) washing merges through dried over mgso, and concentrates under vacuum.By flash column chromatography (30-40% ethyl acetate: hexane) crude product is purified, obtain 0.316 gram light yellow solid shape phenylformic acid (30% productive rate).
Step 3
At room temperature, in the solution of phenylformic acid (138.2 milligrams, 0.59 mmole) in DMF (3 milliliters) through stirring, add HATU (281 milligrams, 0.74 mmole), diisopropylethylamine (0.31 milliliter, 1.77 mmoles), add amine (240 milligrams, 0.59 mmole) then.After at room temperature stirring 1 hour, reaction mixture is poured in 40 ml waters.Extract this aqueous solution with chloroform (50 milliliters * 2), collected organic layer then, water (40 milliliters * 2), 1NHCl (40 milliliters * 2), saturated sodium bicarbonate aqueous solution (40 milliliters * 2) and salt solution (40 milliliters * 2) washing through dried over sodium sulfate, and concentrate under vacuum.(10% methyl alcohol: purification crude product methylene dichloride) obtains 198 milligrams of required light yellow solid shape products (61% productive rate) by flash column chromatography.
Embodiment SP-135
Compound 14b (1 equivalent, 0.064 mmole, 37.6 milligrams) is dissolved in EtoAc, adds PtO (catalyzer) and H then
2Bubble.Reactant was at room temperature stirred 4 hours, and LC-MS measures two kinds of products then: 15 and 16.Filter crude compound through C salt, and remove solvent in a vacuum, separate every kind of product by HPLC then: 15 (13 milligrams, 34%, M+H
+=59.3) and 16 (16 milligrams, 42%, M+H
+=594.3).
Embodiment SP-136
Compound 17 (1 equivalent, 0.46 mmole, 0.31 gram) is dissolved in CH
2Cl
2And be cooled to 0 ℃, add Boc then
2O (1 equivalent, 0.46 mmole, 0.1 gram) and catalyzer DMAP.Finish (4 hours) by TLC judgement reaction, simply remove solvent then in a vacuum, in next step, use this crude product.
In a sealed tube, add iodine compound (1 equivalent, 0.13 mmole, 100 milligrams), Pd
2Dba
3(0.02 equivalent, 0.002 mmole, 2.4 milligrams), dppf (0.08 equivalent, 0.01 mmole, 5.8 milligrams), Et
3N (2 equivalents, 0.26 mmole, 0.04 milliliter) and NMP (0.3M, 0.4 milliliter), and use N
2(gas) purge/bubbling 15 minutes.Adding sulfur alcohol then also stirred 3 hours with this seal of tube and at 60 ℃.Be cooled to room temperature with reaction this moment, with salt solution dilution, and with EtOAc extraction 3 *.The organic extract of using salt solution (2 *) washing to merge then is through Na
2SO
4Drying is filtered and rotary evaporation, makes required brown thioether raw product.Pass through SiO
2In hexane, carry out column chromatography with 25%EtOAc and separate, make purified product (71.5 milligrams, 0.1 mmole, 77%).
This thioether (1 equivalent, 0.08 mmole, 56.3 milligrams) is dissolved in AcOH (0.4 milliliter) and uses 30%H2O2 (0.2 milliliter) to handle.This reactant was stirred 2 hours.At this moment, make this crude mixture at EtOAc and H
2Phase-splitting between the O, with this product with EtOAc extraction 3 *.Through Na
2SO
4Dry organic extract filters and rotary evaporation, passes through SiO then
2In hexane, carry out column chromatography with 50%EtOAc and purify, make isolating Boc and protected sulfone and sulfoxide.After TFA deprotection and HPLC purify, obtain final product 18 (17 milligrams, 33%, M+H
+=644.2) and 19 (18 milligrams, 35%, M+H
+=628.3).
Embodiment SP-137
P424
Embodiment SP-138
Or
Embodiment SP-139
Aniline (1 equivalent, 8.46 mmoles, 1 gram) is dissolved in pyridine (1M, 8.5 milliliters), and is cooled to 0 ℃, add chloro-formic ester (1.2 equivalents, 10.2 Bo moles, 0.96 gram, 0.78 milliliter) then.Make reactant when stirring, be warmed to ambient temperature overnight.Then with the reaction mixture rotary evaporation, and in irreducible oil, add H
2O is settled out a kind of white solid this moment.This white precipitate is filtered and uses H
2The O washing, dried overnight on vacuum pump makes purified carbamate raw product (1.4 grams, 93%) then.
This carbamate (1 equivalent, 3.98 mmoles, 0.70 gram) is dissolved in THF (8 milliliters) and is cooled to 0 ℃, add the 1M THF solution (1.1 equivalents, 4.37 mmoles, 4.37 milliliters) of KOtBu then.When adding KOtBu, starting material are gone out from solution, so add (5 milliliters) THF again Yu diox (1 milliliter).At this moment, not enough although solubility continues, add MeI (1.1 equivalents, 4.37 mmoles, 0.62 gram, 0.27 milliliter) and make reactant when stirring, be warmed to ambient temperature overnight.After 12 hours, reactant is not dissolving still, and TLC shows that starting material do not exhaust fully.Therefore, add DMF (5 milliliters), reactant finally dissolves.At room temperature restir reacted completely after 5 hours.Filter crude reaction mixture by C salt, rotary evaporation is at H
2Phase-splitting between O and the EtOAc, with EtOAc extraction 3 *, and use the salt water washing.Organic extract is through Na
2SO
4Drying is filtered and rotary evaporation.Pass through SiO
2Short plug is purified in hexane with 30%EtOAc, obtains the required carbamate that methylates, and it still contains a kind of not by the foreign pigment of TLC and NMR discovery.(0.76 gram, quantitatively)
Nitrile (1 equivalent, 3.98 mmoles, 0.76 gram) is dissolved in ethanol, and with N
2(gas) fed solution 5 minutes, added AcOH (1 equivalent, 3.98 mmoles, 2.27 milliliters) and 5%DeGussa Pd/C (1 spoonful) then.Feed 5 minutes N again
2(gas) is then at 55psiH
2Shake spends the night on the Pa Er wobbler down.Filter this reactant and rotary evaporation through C salt, make the acetate of required product.Make the phase-splitting between 10%NaOH (aqueous solution) and 20% isopropanol/chloroform of this product then, and with 20% isopropanol/chloroform extraction 3 *, make required free alkali.
Use this rough free alkali to open epoxide.The M+H of final product
+Amount is 639.3.
Embodiment SP-140
Aniline (1 equivalent, 16.9 mmoles, 2 grams) is dissolved in pyridine, and is cooled to 0 ℃, add SULPHURYL CHLORIDE (1.5 equivalents, 25.4 mmoles, 2.91 grams, 1.97 milliliters) then.When adding SULPHURYL CHLORIDE, reactant becomes bright orange.Make reactant when stirring, be warmed to ambient temperature overnight.After 12 hours, with the reaction mixture rotary evaporation, at CH
2Cl
2And NaHCO
3Phase-splitting between (aqueous solution), and use CH
2Cl
2Extraction 3 *.With the organic extract KHSO that merges
4(aqueous solution) and salt water washing are through Na
2SO
4Drying is filtered and rotary evaporation, makes purified rough sulphonamide.(3.34 grams, quantitatively)
Rough sulphonamide is dissolved in acetone, adds levigated Cs then
2CO
3, add Me then
2SO
4Cs
2CO
3Not dissolving fully.Reactant at room temperature stirred spend the night.After 12 hours, rotary evaporation browning reaction mixture in stink cupboard is at EtOAc and H
2Phase-splitting between the O, and with EtOAc extraction 3 *.Then with the organic extract NaHCO that merges
3(aqueous solution) and KHSO
4(aqueous solution) washing is through Na
2SO
4Drying is filtered and rotary evaporation, makes the rough sulphonamide that methylates.By TLC, the R of sulphonamide raw material and final product
fBe worth identical, yet spot is a different colours.Pass through SiO
2Plug is purified in hexane fast with 30%-40%EtOAc, obtains required product.(1.88 grams, 93%)
Nitrile (1 equivalent, 8.94 mmoles, 1.88 grams) is dissolved in methyl alcohol, and with N
2(gas) fed solution 5 minutes, added AcOH (1 equivalent, 8.94 mmoles, 0.51 milliliter) and 5%DeGussa Pd/C (1 spoonful) then.Feed 5 minutes N again
2(gas) is then at 55psi H
2Following shake 2 hours on the Pa Er wobbler.Filter this reactant and rotary evaporation through C salt, make the acetate of required product.Make the phase-splitting between 10%NaOH (aqueous solution) and 20% isopropanol/chloroform of this product then, and with 20% isopropanol/chloroform extraction 3 *, make required free alkali.
Use this rough free alkali to open epoxide.The M+H of final product
+Amount is 659.3.
Embodiment SP-141
The dimethylamine solution (1.2 equivalents, 11.88 mmoles, 5.94 milliliter) of 2M in THF is dissolved in pyridine, and is cooled to 0 ℃, add SULPHURYL CHLORIDE (1 equivalent, 9.9 mmoles, 2 grams) then.Make reactant when stirring, be warmed to ambient temperature overnight.After 12 hours, with the reaction mixture rotary evaporation, at CH
2Cl
2And NaHCO
3Phase-splitting between (aqueous solution), and use CH
2Cl
2Extraction 3 *.With the organic extract KHSO that merges
4(aqueous solution) and salt water washing are through Na
2SO
4Drying is filtered and rotary evaporation, makes purified rough sulphonamide.(2.04 grams, 98%)
Nitrile (1 equivalent, 9.7 mmoles, 2.04 grams) is dissolved in the mixture of ethanol, methyl alcohol and THF, until its final dissolving.With N
2(gas) fed solution 5 minutes, added AcOH (1 equivalent, 9.7 mmoles, 0.56 milliliter) and 5%DeGussa Pd/C (1 spoonful) then.Feed 5 minutes N again
2(gas) is then at 55psiH
2Shake spends the night on the Pa Er wobbler down.Filter this reactant and rotary evaporation through C salt, make the acetate of required product.Make the phase-splitting between 10%NaOH (aqueous solution) and 20% isopropanol/chloroform of this product then, and with 20% isopropanol/chloroform extraction 3 *, make required free alkali.
Use this rough free alkali to open epoxide.The M+H of final product
+Amount is 659.3.
Embodiment SP-142
Aniline (1 equivalent, 8.46 mmoles, 1 gram) is dissolved in pyridine (1M, 8.5 milliliters), and is cooled to 0 ℃, add chloro-formic ester (1.2 equivalents, 10.2 mmoles, 0.96 gram, 0.78 milliliter) then.Make reactant when stirring, be warmed to ambient temperature overnight.Then with the reaction mixture rotary evaporation, and in irreducible oil, add H
2O is settled out a kind of white solid this moment.This white precipitate is filtered and uses H
2The O washing, dried overnight on vacuum pump makes purified carbamate raw product (1.4 grams, 93%) then.
Nitrile (1 equivalent, 3.43 mmoles, 0.604 gram) is dissolved in ethanol, and with N
2(gas) fed solution 5 minutes, added AcOH (1 equivalent, 3.43 mmoles, 0.2 milliliter) and 5%DeGussa Pd/C (1 spoonful) then.Feed 5 minutes N again
2(gas) is then at 55psiH
2Shake spends the night on the Pa Er wobbler down.Filter this reactant and rotary evaporation through C salt, make the acetate of required product.Make this product contain NH then
4The H of OH
2Phase-splitting between O and 20% isopropanol/chloroform, and with 20% isopropanol/chloroform extraction 3 *, make required free alkali.
Use this rough free alkali to open epoxide.The M+H of final product
+Amount is 625.2.
Embodiment SP-143
Aniline (1 equivalent, 16.9 mmoles, 2 grams) is dissolved in pyridine, and is cooled to 0 ℃, add SULPHURYL CHLORIDE (1.5 equivalents, 25.4 mmoles, 2.91 grams, 1.97 milliliters) then.When adding SULPHURYL CHLORIDE, reactant becomes bright orange.Make reactant when stirring, be warmed to ambient temperature overnight.After 12 hours, with the reaction mixture rotary evaporation, at CH
2Cl
2And NaHCO
3Phase-splitting between (aqueous solution), and use CH
2Cl
2Extraction 3 *.With the organic extract KHSO that merges
4(aqueous solution) and salt water washing are through Na
2SO
4Drying is filtered and rotary evaporation, makes purified rough sulphonamide.(3.34 grams, quantitatively)
Nitrile (1 equivalent, 7.40 mmoles, 1.45 grams) is dissolved in methyl alcohol, and with N
2(gas) fed solution 5 minutes, added AcOH (1 equivalent, 7.40 mmoles, 0.42 milliliter) and 5%DeGussa Pd/C (1 spoonful) then.Feed 5 minutes N again
2(gas) is then at 55psi H
2Following shake 2 hours on the Pa Er wobbler.Filter this reactant and rotary evaporation through C salt, make the acetate of required product.Make this product contain NH then
4The H of OH
2Phase-splitting between O and 20% isopropanol/chloroform, and with 20% isopropanol/chloroform extraction 3 *, make required free alkali.
Use this rough free alkali to open epoxide.The M+H of final product
+Amount is 645.2.
Embodiment SP-144
Aldehyde (1 equivalent, 2.29 mmoles, 0.3 gram) and amine (1.05 equivalents, 2.40 mmoles, 0.76 gram) are dissolved in 1,2 ethylene dichloride (40 milliliters), and handle with molecular sieve (little spoon) and several AcOH.Reactant was stirred 1 hour, add Na (OAc) then
3BH (1.3 equivalents, 2.98 mmoles, 0.63 gram).Reactant at room temperature stirred spend the night.After 12 hours, reaction mixture is filtered and rotary evaporation.Make resistates at EtOAc and H
2Phase-splitting between the O, and with product with EtOAc extraction 3 *.Then with the organic extract that merges through Na
2SO
4Drying is filtered and rotary evaporation, obtains purified rough required amine (quantitatively)
This raw material also is coupled to the N-end as a rule with the TFA deprotection.The M+H of final product
+Amount is 577.2.
Embodiment SP-145
Phenol (1 equivalent, 16.8 mmoles, 2 grams) is added CH
2Cl
2In, therefore but not dissolving adds THF and acetone fails to dissolve phenol.This mixture is cooled to 0 ℃, adds NEt then
3(1 equivalent, 16.8 mmoles, 1.7 grams, 2.3 milliliters), DMAP (1 equivalent, 16.8 mmoles, 2.05 grams) and dimethylcarbamyl chloride (1 equivalent, 16.8 mmoles, 1.81 grams, 1.55 milliliters).Add NEt
3The time, this agent dissolves.Stir after 2 hours, judge as TLC, reaction is finished.Yet, reactant was stirred 2 days.After 2 days, reactant is at CH
2Cl
2And NaHCO
3CH is used in phase-splitting between (aqueous solution)
2Cl
2Extraction 3 *.With organic extract 1N HCl and the salt water washing that merges, through Na
2SO
4Drying is filtered and rotary evaporation, obtains purified rough carbamate (3.04 grams, 95%)
Nitrile (1 equivalent, 16.0 mmoles, 3.04 grams) is dissolved in ethanol, and with N
2(gas) fed solution 5 minutes, added 5%DeGussa Pd/C (1 spoonful) then.Feed 5 minutes N again
2(gas), then under 55psi on the Pa Er wobbler shake 1 hour.Filter this reactant and rotary evaporation through C salt, make required free alkali.
Use this rough free alkali to open epoxide.The M+H of final product
+Amount is 639.3.
Embodiment SP-146
Oxazole (3.15 equivalents, 1.89 mmoles, 0.13 gram) is weighed in the round-bottomed flask of oven dry, is dissolved in THF (3 milliliters) and is cooled to-78 ℃, add the nBuLi solution (3.48 equivalents, 2.09 mmoles, 1.3 milliliter) of 1.6M in hexane then.After 30 minutes, dropwise add the ZnCl of 1.0M in THF-78 ℃ of stirrings
2Solution (9.06 equivalents, 5.4 mmoles, 5.4 milliliters).At this moment, because viscosity or adhesive increase in the reactor, stirring stops.This solution is warmed to 0 ℃ reaches 1 hour, add HCI salt (1 equivalent, 0.6 mmole, 0.429 gram) and the Pd (PPh of AN 104574-7 then
3)
4With this mixture heating up to refluxing 1 hour.Make reactant at EtOAc and H then
2Phase-splitting between the O, with EtOAc extraction 3 *, use the salt water washing, through Na
2SO
4Drying is filtered and rotary evaporation.At SiO
2Last with containing several NH
4The 2-5%MeOH/CH of OH
2Cl
2Carry out chromatographic separation, produce purified required product (95%, 0.35 gram, M+H
+=619.2).
Embodiment SP-147
2-dipropyl formamyl-6-methyl-Yi Yansuan
23.7 mmoles (1.0 equivalent) the 2-chloro-6-methyl Yi Yansuan solution of preparation in 32 milliliters of 30%MeOH/THF.In this reaction mixture, dropwise add 30.0 mmoles (1.3 equivalent) (trimethyl silyl diazonium) methane.After at room temperature stirring was spent the night, reaction was finished.In this reaction mixture, add several Glacial acetic acid,, quantitatively obtain product 2 then by rotary evaporation concentration.
In through 100 milliliters of round-bottomed flasks of exsiccant, add 22.0 mmoles (1.0 equivalent) methyl esters 2,0.45 mmole (0.02 equivalent) three (dibenzalacetones), two palladiums (0), (0.90 0.04 equivalent) 1,1-two (diphenyl phosphine) ferrocene, 28.3 mmoles (0.13 equivalent) zinc metallic dusts and 10.7 (0.5 equivalent) zinc cyanide.Reaction flask is used purging with nitrogen gas 5 minutes, add 45 milliliters of N,N-dimethylacetamide by syringe.Refluxing, vigorous stirring is after 4 hours simultaneously, and reaction is finished.Reaction mixture is used EtOAc (50 milliliters) dilution and used 2N NH
4Saturated NaCl (50 milliliters) washing is used in OH (3 * 50 milliliters) washing again.With the organic extract that merges through Na
2SO
4Dry also vacuum filtration.By rotary evaporation concentration filtrate, and, make product 3,34% productive rates by column chromatography Hex/EtOAc (8: 2) purification.
1.2 mmoles (1.0 equivalent) nitrile 3 solution of preparation in 5 ml methanol.In this reaction mixture, add 6.7 mmoles (5.7 equivalent) sodium hydroxide.After at room temperature stirring 1 hour, in this reaction mixture, add 5 milliliters of H
2O.Behind the restir 1.5 hours, reaction is finished.Use CHCl
3Dilute this mixture, and wash with 2N HCl.Collect organic extract and through Na
2SO
4Dry also vacuum filtration.By rotary evaporation concentration filtrate, obtain product 4,61% productive rates.
0.7 mmole (1.0 equivalent) formic acid 4 solution of preparation in 6 milliliters of methylene dichloride.In this reaction mixture, add 1.8 mmoles (2.6 equivalent) 4-methylmorpholine.Reaction flask is placed cooled on ice in advance, add 0.8 mmole (1.1 equivalent) HBTU and 0.8 mmole (1.2 equivalent) dipropyl amine then.Be warmed to ambient temperature overnight, stir simultaneously, this afterreaction is finished.Reaction mixture diluted with EtOAc (25 milliliters) and use H
2Saturated NaHCO is used in O (2 * 25 milliliters) washing again
3(2 * 25 milliliters) washing.With the organic extract that merges through Na
2SO
4Dry also vacuum filtration.By rotary evaporation concentration filtrate, obtain product 5,64%.
0.5 gram (1.0 equivalent) isophalate 5 solution of preparation in 2 ml methanol.In this reaction mixture, add 4.5 mmoles (9.3 equivalent) sodium hydroxide.After at room temperature stirring 2 hours, in reaction mixture, add 2 milliliters of H
2O.Behind the restir 1.5 hours, reaction is finished.With reaction mixture with EtOAc dilution and use H
2Saturated NaHCO is used in O (2 *) washing again
3(2 *) washing.Collect the water extraction liquid also with dense HCl acidifying.With CHCl
3The solution of/iPA (1: 3) is used for extraction.Collect organic extract, with saturated NaCl washing, and through Na
2SO
4Dry also vacuum filtration.By rotary evaporation concentration filtrate, obtain product 6.
Embodiment SP-148
Bredereck, H., Sell, R. and Effenberger, F.; Chem.Ber.; 1964,97,3407.
Embodiment SP-149
(2-ethyl-pyrimidine-4-yl)-methylamine
As described in following reference, adopt experimental step to prepare product 1 to 3.
Bumess，D.M.；J.Org.Chem.，1956，21，97。
Daves, GD., O ' Brien, D.E., Lewis, L. and Cheng, C.C.; J.Heterocycl.Chem., 1963,1.130.
In 50 milliliters of round-bottomed flasks of oven dry, add 3.6 mmoles (1.0 equivalent) halogenated pyrimidine 3,5.4 mmoles (1.5 equivalent) tributyls (vinyl) tin, 0.09 mmole (0.03 equivalent) chlorination two (triphenyl phosphine) palladium (II), 4.1 mmoles (1.1 equivalent) tetraethylammonium chloride, 3.8 mmoles (0.9 equivalent) salt of wormwood and 7.5 milliliters of dry DMF.Have under the condenser of nitrogen inlet refluxed 2 hours after, reaction is finished.Reaction mixture diluted with EtOAc (30 milliliters) and use H
2Saturated NaCl (30 milliliters) washing is used in O (2 * 30 milliliters) washing again.With the organic extract that merges through Na
2SO
4Dry also vacuum filtration.By rotary evaporation concentration filtrate, and, make product 4,42% productive rates by column chromatography Hex/EtOAc (9: 1) purifying.
In a little phial, by being dissolved in the solution that minimum EtOH prepares 1.53 mmoles (1.0 equivalent) vinylbenzene 4.Add 0.1 milliliter of Glacial acetic acid in this reaction mixture, the 10%wt that adds catalytic amount then carries palladium carbon.After placing 30 minutes on the hydrogenator of 50psi, reaction is finished.Reaction mixture is also used the EtOAc rinsing by the vacuum filtration of C salt.By rotary evaporation concentration filtrate, make product 5.
Embodiment SP-150
In a 1dram phial, under-5.0 ℃, raw material diamines (big 18 milligrams, about 0.05 mmole) and 1 equivalent SULPHURYL CHLORIDE are dissolved in 1 milliliter of pyridine.Make this mixture reaction 18 hours.After this reaction times, the pyridine dissolving, the preparation mix products uses the Hewlett-Packard1050 series HPLC that is connected with Thermo-Finnigan LCQ Deca MS to carry out LC-MS and analyzes.According to LC-MS result, use VarianPro Star Preparative HPLC that final product is purified.
Embodiment SP-151
N-end dipropyl amine metathetical is synthetic
Embodiment SP-152
Synthesizing of N-end pentanedioic acid
By 11 compounds that make in this storehouse, make 2 with the dioctyl phthalate raw material, another 9 has been the Pyroglutaric acid form.In order to prevent that dioctyl phthalate from forming hydrazine, every kind of acid of 0.1 mmole was at room temperature reacted 1 hour in 1 milliliter of methylene dichloride with 1 equivalent EDC.When all raw material all is the Pyroglutaric acid form, at room temperature every kind of Pyroglutaric acid of 0.1 mmole was mixed 2 hours in 1.5 milliliters of methylene dichloride with 0.1 mmole dipropyl amine.Acid and the reaction of 1 equivalent HEA sheet of using 1.1 equivalent HATU will make then as coupling agent.Use 3 equivalents in conjunction with the diisopropylethylamine of polystyrene as alkali.These are reflected among 1.5 milliliters of DMF and at room temperature carried out 4 hours.Pass through Varian Pro Star Preparative HPLC then with purification of products.
Embodiment SP-153: the exemplary steps of chart Y (R=I)
The preparation (R=I) of 1-aryl rings propane nitrile (2)
Org.Prep.Proc.Inter.1995，27(3)，355-59
Iodine Bian Jiqing 1 (3 grams in vigorous stirring, 12.35 benzyl triethylammonium chloride (TEBAC mmole),, 100 milligrams) and the mixture of 1-bromo-2-monochloroethane (BCE, 15 milliliters) in, with dropwise adding the 50%NaOH aqueous solution (20 milliliters) (50 ℃ of temperature) in 35 minutes.Add finish after, reactant 50 ℃ of restir 2 hours, was at room temperature stirred 2 hours then.Adding entry to total amount is 100 milliliters, with methylene dichloride (3 * 25 milliliters) extraction.Water, the 5%HCl aqueous solution and water washing organic extract are then through Na
2SO
4Drying, and concentrate.Purify as if distillation method by the Tim Koogle.Produce
2-3.3 grams (99%); MH+ (CI) 269.9.
Amine
3Preparation. will
2(13.3 mmole), the 25%KOH aqueous solution (0.34 milliliter), 30%H
2O
2The mixture of (17.5 milliliters) and MeOH (100 milliliters) was 55 ℃ of heating 7 hours.TCL shows does not have SM.Reaction mixture is concentrated and drying under vacuum.Productive rate 95%; MH+ (CI) 288.0.
3Hydrolysis. with amine
3(14 mmole) is dissolved in a small amount of MeOH (5 milliliters) and the 10%NaOH aqueous solution (80 milliliters), and refluxes 6 hours.With the cooling of this mixture and be acidified to pH with 15%HCl and be about 2.Solvent is partly evaporated, collect white solid by filtering.Acid
4Productive rate---85%; MH+ (CI) 288.9.
Chloride of acid
5Preparation. with reaction mixture: acid
4(8 mmole) and thionyl chloride (2.0 grams, 1.23 milliliters) are at CH
2Cl
250 ℃ of heated overnight (backflow) in (10 milliliters).Second day, at rotary evaporator Shanghai Automobile Factory extraction solvent and resistates is dry under vacuum.Directly use without purifying.
Ku Ertisi resets. with chloride of acid
5(6.5 mmole) is dissolved in acetone (15 milliliters), is cooled to-10 ℃ and also handles with sodiumazide (1.8 grams are in 5 ml waters).-10 ℃ stir 1 hour after, reaction mixture poured in 100 milliliters of cold water and with trinitride be extracted in the toluene.Toluene layer is washed with water and drying.With this toluene solution partial concentration (to 15 milliliters) and remainder is heated to 100 ℃ carefully reaches 1 hour.Add dense HCl (8-10 milliliter) and with the reaction mixture vigorous stirring and refluxed 15 minutes.Decant goes out white crystal and is dry under vacuum.
6Productive rate be 84% (R=I); MH+ (CI) 260.2.
Embodiment SP-154:2-isobutyl--5-(the amino ring of 1-third-1-yl) thiazole:
Amino ring third-1-yl) thiazole
This step is adapted certainly: Wilk, BK.Synth.Commun.1993,23,2481-4.Under 0 ℃, in thiazole methyl alcohol in anhydrous THF (10 milliliters) (753 milligrams, 4.2 mmoles) and triphenyl phosphine (1.74 grams, the 6.63 mmoles) solution, when stirring, dropwise add diethyl azodiformate (EDAD, 1.0 milliliters, 6.4 mmoles).After 10 minutes, when stirring, dropwise add acetone cyanohydrin (Aldrich, 0.6 milliliter, 6.6 mmoles).The solution that makes was stirred 10 minutes at 0 ℃, at room temperature stirred then 3 hours, subsequently with this mixture concentrating under reduced pressure, by flash chromatography (EtOAc/ hexane wash-out; Product R in the 60%EtOAc/ hexane
f=0.73) resistates is purified, obtain yellow oil product (516 milligrams, 65%).
This step is adapted certainly: Org.Prep.Proc.Int.1995,27,355-9.Under 50 ℃, 50% sodium hydroxide (aqueous solution amounts to 5.0 milliliters) is added in the solution of prussiate (516 milligrams, 2.9 mmoles), 1-bromo-2-monochloroethane (3.5 milliliters, 42 mmoles) and benzyl triethylammonium chloride (25 milligrams, 0.09 mmole).This kept 2 hours at 50 ℃, at room temperature kept then 2 hours.Adding entry, to make cumulative volume be 20 milliliters, uses CH
2Cl
2(3 * 10 milliliters) extract this mixture.With the organic extract washing (water, 1N HCl, water) that merges, dry (Na
2SO
4), filter and concentrating under reduced pressure.By flash chromatography (20%EtOAc/ hexane wash-out) resistates is purified, obtain oily product (403 milligrams, 68%); MH+ (CI) 207.1.
This step is adapted certainly: Org.Prep.Proc.Int.1995,27,355-9.Cyclopropyl aryl cyanogen (403 milligrams, 1.96 mmoles) is dissolved in MeOH (15 milliliters), at room temperature adds 30% hydrogen peroxide (2.7 milliliters) and 25%KOH (aqueous solution, 0.05 milliliter).This solution is heated to 55 ℃ reaches 7 hours.Then reaction mixture is concentrated and store overnight in refrigerator in a vacuum.This raw product promptly is used for next reaction without further purification.
This rough acid amides is dissolved among the MeOH (1 milliliter) of minimum, and adds 2.5N NaOH (aqueous solution, 10 milliliters).This suspension is heated to backflow (bathing 105 ℃ of temperature) 6 hours, mixture is cooled to 0 ℃ then, and is acidified to pH 3 with 3N HCl (aqueous solution).With its partial concentration, use CHCl then
3(3 *) extraction.With the extraction liquid drying (Na that merges
2SO
4), filter and concentrate, obtain a kind of solid (189 milligrams, 43%); MH+ (CI) 226.1.
Formic acid (189 milligrams, 0.84 mmole) is dissolved in CH
2Cl
2(5 milliliters) at room temperature add thionyl chloride (0.2 milliliter, 2.7 mmoles).Be heated to backflow (bathing 55 ℃ of temperature) 3.5 hours, then with this mixture concentrating under reduced pressure.Rough chloride of acid is dissolved in acetone (4 milliliters), and at-15 ℃ of sodiumazide (270 milligrams, 4.2 mmoles) solution that are added in the water (1 milliliter)., add entry (20 milliliters), and acylazide is extracted in the toluene (3 *) after 1 hour-15 ℃ of maintenances.With the organic extract drying (Na that merges
2SO
4), filter and partial concentration (to the ca.30 milliliter).Solution is warmed to 100 ℃ then and reaches 1 hour.Add dense HCl (aqueous solution, 2 milliliters) then, and this mixture heating up is reached 15 minutes to refluxing.This mixture is cooled to 0 ℃,, uses CHCl then with 10N NaOH (aqueous solution) alkalization
3(3 *) extraction.With the organic layer drying (Na that merges
2SO
4), filter and concentrate, obtain a kind of oil (at 5%MeOH/CH
2Cl
2Middle R
f=0.37; The ninidrine colour developing); MH+ (CI) 197.1.
Embodiment SP-155 steps A: 2 synthetic:
2,2-dioxo-1,2,3,4-tetrahydrochysene-2 λ
6-benzo [c] [1,2] thiazine-4-base amine
Will be at 13 milliliters of tetrahydrofuran aqueous solution (THF: H
2O, 10: 1) in 0.58 gram (2.7 mmole) oxime 1 (according to J.Heterocyclic.Chem.17,1281 (1980) preparations, what describe herein is identical compound) solution under argon atmospher, stir.By some little (is restrained from 0.52,19 mmoles, 7 normal Reynolds heavy anticorrosive aluminium foils) handle (every kind handle 10-20 second) with 1N KOH, distilled water, 0.5% mercury chloride, distilled water and anhydrous THF in regular turn, make aluminium amalgam, with 3 hours it is joined in 1 this solution then.Reaction mixture stirred spend the night, on one deck C salt, filter then and, produce 510 milligrams of orange buttery that slowly solidify 2 (94%) solvent evaporation.mass spec(CI)(MH+)：199.1。
Embodiment SP-155A
The compound of embodiment SP-155 can be used for making suitable boc to be protected the amino epoxide open loop, to generate the compound of embodiment SP-155A.Use method well known in the art with this compound deprotection then, to generate unhindered amina, it can further be handled then.
Embodiment SP-156: step B:4's is synthetic:
2,2-dioxo-3,4-dihydro-2H-2 λ
6-benzo [e] [1,2] oxathiin-4-base amine
According to above-mentioned steps A with 1H-2,1-benzothiazine-4 (3H)-ketone, oxime, 2,2-dioxide 3 be feedstock production amine 4 (mass spec (CI) (MH+): 200.0).With can by commercial sources obtain 1,2-benzo oxathiin-4 (3H) ketone, 2,2-dioxide [49670-47-5] makes oxime 3 for raw material.
Embodiment SP-156A:
The compound of embodiment SP-156 can be used for making suitable boc to be protected the amino epoxide open loop, to generate the compound of embodiment SP-156A.Use method well known in the art with this compound deprotection then, to generate unhindered amina, it can further be handled then.
Embodiment SP-156-B
R
cAnd R
dBe H, halogen, alkoxyl group or alkyl independently.R
1Be 3,5-two fluorobenzene; Z be with the resistates of amine link coupled group, comprise, for example, carboxylic acid derivatives (for example isophthaloyl amine), sulfonic acid (for example tosic acid), alkyl halide derivative (for example iodopentane) and aryl halide alkyl derivative (for example benzyl bromide).
Embodiment SP-157:(2R, 3S)-4-(3, the 5-difluorophenyl)-2-hydroxyl-3-(3-[(1-propyl group butyl) and alkylsulfonyl] alanyl } amino) butyl (3-Ethylbenzyl) t-butyl carbamate
The A part.
Be furnished with magnetic stirring bar and N at one
2In 250 milliliters of round-bottomed flasks of inlet, add 5.0 gram (34 mmole) 2-acetamidoacrylic acid methyl esters, 4.6 gram (34 mmole) 4-sulfydryl heptane in 50 ml methanol.Add 3.6 gram (36 mmole) triethylamines third and at room temperature stirred 45 minutes in reactor, HPLC showed and reacted completely this moment.In reactor, add 47.2 gram (77 mmole) oxones then.After 90 minutes, HPLC shows and is completely oxidized to required sulfone.This reactant is filtered and concentrates in a vacuum.Make resistates be divided into ethyl acetate layer and water layer,,, and be condensed into 9.2 gram (86%) colorless oil N-ethanoyl-3-[(1-propyl group butyl in a vacuum through dried over sodium sulfate with salt water washing organic layer) alkylsulfonyl] alanine methyl ester.M+H＝308g/m。
The B part.
Be furnished with magnetic stirring bar, reflux exchanger and N at one
2In 250 milliliters of round-bottomed flasks of inlet, be added in 9.2 gram N-ethanoyl-3-[(1-propyl group butyl among 50 milliliters of acetate and the 50 milliliters of dense HCl) alkylsulfonyl] alanine methyl ester solution.This solution was refluxed 4 hours, concentrate in a vacuum then.With toluene (2 *) chased, vacuum-drying is spent the night then, makes the required 3-[(1-propyl group butyl of 7.8 grams) alkylsulfonyl] the L-Ala hydrochloride.
The C part.
Be furnished with magnetic stirring bar and N at one
2In 250 milliliters of round-bottomed flasks of inlet, be added in the gram of 7.8 in 100 milliliters of methylene dichloride (27 mmole) 3-[(1-propyl group butyl) alkylsulfonyl] L-Ala and 7.4 gram (30 mmole) N-Cbz succinic diamide solution.This reactant is cooled to 0 ℃, and third dropwise adds 6.9 gram NMM.This reactant is warmed to room temperature and stirred 4 hours, this moment, the HPLC analysis revealed reacted completely.Reactant is concentrated and phase-splitting between ethyl acetate and 1N HCl in a vacuum.Water, salt water washing organic layer through dried over sodium sulfate, and concentrate in a vacuum, obtain 11.4 gram N-[(benzyloxies) carbonyl]-3-[(1-propyl group butyl) alkylsulfonyl] L-Ala, it can use without further purification.M+H＝386。
The D part.
Be furnished with magnetic stirring bar and N at one
2In 250 milliliters of round-bottomed flasks of inlet; be added in the gram of 4.0 in 50 milliliters of anhydrous methylene chlorides (10 mmole) N-[(benzyloxy) carbonyl]-3-[(1-propyl group butyl) alkylsulfonyl] L-Ala and 1.2 gram (12 mmole) (2R; 3S)-and 3-amino-4-(3, the 5-difluorophenyl)-1-[(3-Ethylbenzyl) amino] fourth-2-alcohol dihydrochloride solution.In this reaction mixture, add 5.6 milliliters of (51 mmole) NMM, 1.7 gram (13 mmole) Qiang base Ben Bing trioazole and add 3.1 gram (16 mmole) 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochlorides at last.After at room temperature stirring 3 hours, HPLC analysis revealed complete reaction.With this reactant with methylene dichloride dilution and with saturated sodium bicarbonate solution, 0.5M citric acid and salt water washing.Organic layer through dried over sodium sulfate, is filtered and concentrates in a vacuum, make N
2-[(benzyloxy) carbonyl]-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(1-propyl group butyl) alkylsulfonyl] alanimamides.Be furnished with magnetic stirring bar and N at one
2In 50 milliliters of round-bottomed flasks of inlet, be added in the rough resistates in the anhydrous methylene chloride.This reactant is cooled to 0 ℃ and add 2.5 gram (12 mmole) hydrogen-carbonate di tert butyl carbonate and 1.2 milliliters of (11 mmole) N-methylmorpholines.Make this reactant be warmed to room temperature and stirred 18 hours, this moment HPLC analysis revealed complete reaction.With this reactant with methylene dichloride dilution and with saturated sodium bicarbonate solution and salt water washing.Organic layer through dried over sodium sulfate, is filtered and concentrates in a vacuum.Using the 5-40% ethyl acetate gradient solvent in hexane this raw product to be purified on the silica gel, making 3.4 gram N by flash chromatography
2-[(benzyloxy) carbonyl]-N
1-(1S, 2R)-the N-[(tert.-butoxy) carbonyl]-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(1-propyl group butyl) alkylsulfonyl]-D, the L-alanimamides.M+Na＝824。
The E part.
In a Fisher-Porter bottle, be added in the gram of 3.4 in 50 ml methanol (4.2 mmole) N
2-[(benzyloxy) carbonyl]-N
1-(1S, 2R)-the N-[(tert.-butoxy) carbonyl]-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(1-propyl group butyl) alkylsulfonyl] alanimamides.After the nitrogen degassing, add 1.6 gram 5%Pd/C (Degussa E10150% water).Clean this reactor with 40psi nitrogen (4 *), then with pressurized with hydrogen to 50psi.After 15 minutes, HPLC analysis revealed complete reaction.Filter the removal catalyzer by C salt, and filtrate is concentrated in a vacuum, make 2.4 gram N
1-(1S, 2R)-the N-[(tert.-butoxy) carbonyl]-1.-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(1-propyl group butyl) alkylsulfonyl]-D, the L-L-Ala.M+H＝668。
Embodiment SP-158
2,2-dioxy-1,2,3,4-tetrahydrochysene-2 λ
6-benzo [c] [1,2] thiazine-4-base amine
Steps A preparation 2 according to embodiment SP-155.Equally, according to Bennett, Frank.Synlett 1933, and the step described in the 703-704 makes epoxide open loop (referring to the steps A of embodiment SP-155) with 2.Massspec(CI)(MH+)：643.7。
Embodiment SP-159
2,2-dioxy-1,2,3,4-tetrahydrochysene-2 λ
6-benzo [c] [1,2] thiazine-4-base amine
Steps A preparation 2 according to embodiment SP-155.Equally, according to Bennett, Frank.Synlett 1933, and the step described in the 703-704 makes epoxide open loop (referring to steps A) with 2.Mass spec(CI)(MH+)：643.7。
Embodiment SP-160
Synthetic t-Boc-NH-two-F-Phe-oxyethylamine (HEA)-O-Bn
Add 20 milliliters of 1N KOH in 2.4 gram (15 mmoles, 3 equivalents) O-benzyl hydroxy amine hydrochloric acid salt solution in 20 milliliters of EtOAc, stir simultaneously.The extraction organic layer is also dry, and solvent stripping at room temperature adds the two F-Phe-epoxide of 1.5 gram (5 mmole) erythros and 0.62 gram (1 mmole, 0.2 equivalent) trifluoromethayl sulfonic acid ytterbium (III) also with 20 milliliters of DCM reduction.This mixture stirred spend the night and progressively wash with 1N HCl, supercarbonate and salt solution, drying with solvent stripping, obtains 1.23 gram raw product, it is carried out post purify, and obtains 0.76 and restrains (1.8 mmoles, 36%) shallow white solid target compound.
Embodiment SP-161
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(5-methyl isophthalic acid, 2,4-Evil Er oxazole-3-yl)-N
3, N
3-dipropyl isophthaloyl amine hydrochlorate
Step 1:3-[(dipropyl amino) carbonyl]-5-(5-methyl isophthalic acid, 2,4-Evil Er oxazole-3-yl) methyl benzoate
3-cyano group-5-[(dipropyl the amino that makes in method) carbonyl according to embodiment S-2510] methyl benzoate (2.3 grams, 7.9 mmole) in methyl alcohol (26 milliliters) in the solution through stirring, add hydroxylamine hydrochloride (1.1 grams, 16 mmoles) and salt of wormwood (2.2 grams, 16 mmoles).With the reaction mixture refluxed that makes 20 hours, be cooled to room temperature then.Filtering inorganic salt, and filtrate decompression concentrated, make the amidoxim of quantitative production.
Add acetate (0.21 milliliter, 4 mmoles) among amidoxim in 2-methoxy ethyl ether (8 mmole) solution (1.3 grams, 4 mmoles) and the EDC (1.5 grams, 8 mmoles).The reaction mixture that makes was stirred 24 hours, refluxed then 3 hours.This reaction mixture is cooled to room temperature, with ethyl acetate dilution, water, 1N hydrochloric acid, saturated sodium bicarbonate and salt water washing, dry (sodium sulfate), filtration and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 50% ethyl acetate isohexane), obtain title compound.
1H NMR(500MHz，CDCl
3)δ8.69(s，1H)、8.18(m，1H)、8.11(s，1H)、3.91(s，3H)、3.43(t，J＝7Hz，2H)、3.12(t，J＝7Hz，2H)、2.63(s，3H)、1.66(t，J＝7Hz，2H)、1.50(t，J＝7Hz，2H)、0.95(t，J＝7Hz，3H)、0.70(t，J＝7Hz，3H)。
Step 2
3-[(dipropyl amino) carbonyl]-5-(5-methyl isophthalic acid, 2,4-Evil Er oxazole-3-yl) phenylformic acid
3-[(dipropyl amino that will be in pyridine (7 milliliters)) carbonyl through stirring]-5-(5-methyl isophthalic acid, 2,4-Evil Er oxazole-3-yl) methyl benzoate (629 milligrams, 1.8 mmoles) and lithium iodide (2.4 grams, 18 mmoles) solution backflow 18 hours.This reaction mixture is cooled to room temperature and with the solvent concentrating under reduced pressure.Resistates is water-soluble, with the ethyl acetate washing, water layer is acidified to pH 3 and uses chloroform (3 * 100 milliliters) extraction with 1N hydrochloric acid.With organic layer drying (sodium sulfate), filter and concentrate, make title compound.
1H NMR(500MHz，CDCl
3)δ11.11(br s，1H)、8.85(t，J＝1Hz，1H)、8.31(t，J＝1Hz，1H)、8.23(t，J＝1Hz，1H)、3.51(s，2H)、3.19(s，2H)、2.72(s，3H)、1.73(d，J＝7Hz，2H)、1.56(d，J＝7Hz，2H)、1.01(t，J＝7Hz，3H)、0.76(t，J＝7Hz，3H)。
Step 3
N
1-(1S, 2R)-l-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(5-methyl isophthalic acid, 2,4-Evil Er oxazole-3-yl)-N
3, N
3-dipropyl isophthaloyl amine hydrochlorate
With 3-[(dipropyl amino) carbonyl]-5-(5-methyl isophthalic acid, 2,4-Evil Er oxazole-3-yl) phenylformic acid is (209 milligrams, 0.63 mmole), HATU is (359 milligrams, 0.95 mmole), HOBt is (128 milligrams, 0.95 mmole) and the solution of diisopropylethylamine (165 milliliters, 0.95 mmole) in methylene dichloride (2.0 milliliters), stirred 15 minutes.(the 2R that adding makes according to the method for embodiment SP-272,3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] (252 milligrams of fourth-2-alcohol dihydrochlorides, 0.63 mmole) and (165 milliliters of diisopropylethylamine in methylene dichloride (2.0 milliliters), 0.95 solution mmole), and reaction mixture stirred spend the night.Reaction mixture is diluted with methylene dichloride, with 1N hydrochloric acid (25 milliliters), saturated sodium bicarbonate (25 milliliters) and salt water washing, dry (sal epsom), filtration and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 1: 9 methyl alcohol/chloroform), make title compound as free alkali.This solid is dissolved in methyl alcohol (1 milliliter), and handles with hydrochloric acid (0.3 milliliter, the 1.0M solution in diethyl ether, 0.3 mmole).Filter and collect the precipitation that produces, obtain title compound.APCI MS m/z 648.4[M+H]
+。
Embodiment SP-162
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1H-imidazoles-2-yl)-N
3, N
3-dipropyl isophthaloyl amine hydrochlorate
Step 1:3-[(dipropyl amino) carbonyl]-5-(1H-imidazoles-2-yl) methyl benzoate
In 1-t-butyldimethylsilyl imidazoles (602 milligrams, the 3.3 mmoles) solution in the tetrahydrofuran (THF) (10 milliliters) of-70 ℃ of stirrings, add n-Butyl Lithium (the 1.6M solution in hexane, 2.3 milliliters, 3.63 mmoles).After 30 minutes, add zinc chloride (the 1M solution in diethyl ether, 9.9 milliliters, 9.9 mmoles), and reaction mixture is warmed to 0 ℃ reaches 1 hour.In this mixture, add according to embodiment SP-281 the 3-[(dipropyl amino that the method in the step 2 makes then) carbonyl]-5-iodo-benzoic acid methyl esters (1.17 grams, 3 mmoles), add palladium (O) four (triphenyl phosphine) (173 milligrams, 0.15 mmole) subsequently.With reaction mixture refluxed heating 15 hours.This reaction mixture is diluted water and salt water washing, dry (sodium sulfate), filtration and concentrating under reduced pressure with ethyl acetate (50 milliliters).Purify by flash column chromatography (silica gel, 1-5% ethanol/methylene), obtain the title compound of its pure state.
1H NMR(300MHz，CDCl
3)δ8.64(s，1H)、8.14(s，1H)、7.97(s，1H)、7.19(s，2H)、3.96(s，3H)、3.51(m，2H)、3.32(m，2H)、1.73(m，2H)、1.57(m，2H)、1.01(m，3H)、0.73(m，3H)。
Step 2
3-[(dipropyl amino) carbonyl]-5-(1H-imidazoles-2-yl) phenylformic acid
In the solution of the ester (260 milligrams, 0.79 mmole) that makes in the step 1 in 2: 1: 1 tetrahydrofuran (THF)/methanol (8 milliliters) through stirring, add lithium hydroxide (140 milligrams, 3.3 mmoles).With reaction mixture stirring at room 2 hours, and concentrating under reduced pressure.Make resistates phase-splitting between water (10 milliliters) and ether (10 milliliters).With 1N hydrochloric acid water layer is acidified to pH 4-5, and with 3: 1 chloroform/2-propyl alcohol (3 * 30 milliliters) extraction.With the organic layer drying (sodium sulfate) that merges, filter and concentrating under reduced pressure, obtain title compound.
1H NMR(300MHz，CDCl
3)δ8.64(s，1H)、8.10(s，1H)、8.01(s，1H)、7.28(s，2H)、3.52(m，2H)、3.26(m，2H)、1.75(m，2H)、1.59(m，2H)、1.02(t，J＝7Hz，3H)、0.75(t，J＝7Hz，3H)。
Step 3
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1H-imidazoles-2-yl)-N
3, N
3-dipropyl isophthaloyl amine
3-[(dipropyl amino in methylene dichloride (5 milliliters)) carbonyl through stirring]-(250 milligrams in 5-(1H-imidazoles-2-yl) phenylformic acid, 0.79 mmole), diisopropylethylamine is (103 milligrams, 0.8 mmole) and (330 milligrams of HBTU, 0.87 mmole) in the solution, (the 2R in methylene dichloride (5 milliliters) that adding makes according to the method for embodiment SP-272,3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] (322 milligrams of fourths-2-alcohol, 0.79 mmole) and diisopropylethylamine (206 milligrams, 1.6 mmoles) mixture.Reaction mixture is at room temperature stirred 4 hours, and concentrating under reduced pressure.Resistates with ethyl acetate (20 milliliters) dilution, is used saturated sodium bicarbonate and salt water washing, dry (sodium sulfate), filtration and concentrating under reduced pressure.Purify by flash column chromatography (silica gel, 5: 95 ethanol/methylene), make the title compound of its pure state.APCI MS m/z 632.3[M+H]
+。
Embodiment SP-163
N
1-(1S, 2R)-1-benzyl-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-methyl-5-(1,3-oxazole-2-yl)-N
3-propyl group isophthaloyl amine
Step 1
3-iodo-5-{[methyl (propyl group) amino] carbonyl } methyl benzoate
In DMF (10 milliliters) as embodiment SP-181 step 1 in make 3-iodo-5-(methoxycarbonyl) phenylformic acid (1.0 the gram, 3.3 mmole) and (1.7 milliliters of diisopropylethylamine, 9.8 mmole) in the solution, add O-(7-azepine benzo trioazole-1-yl)-N, N, N ', N '-tetramethyl-uronium hexafluorophosphate (HATU, 1.5 grams, 3.9 mmoles), add N methyl pmpyl amine (503 microlitres, 4.9 mmoles) then.This solution was at room temperature stirred 2 hours.This solution is diluted water, saturated sodium bicarbonate and salt water washing in ethyl acetate.Through the dried over sodium sulfate organic layer, filter and concentrating under reduced pressure, make rough title compound.By flash column chromatography (40% ethyl acetate/hexane) this material is purified, obtain the title compound of purifying.MS(ESI)[M+H]
+＝362.4。
Step 2
3-{[methyl (propyl group) amino] carbonyl }-5-(1,3-oxazole-2-yl) phenylformic acid
In tetrahydrofuran (THF) (4 milliliters) solution of-70 ℃ of stirring De oxazoles (330 milligrams, 4.8 mmoles), add n-Butyl Lithium (the 1.6M solution in hexane, 3.3 milliliters, 5.3 mmoles).After 30 minutes, add zinc chloride (solution in the 1M ether, 14.5 milliliters, 14.5 mmoles), and reaction mixture is warmed to 0 ℃ reaches 1 hour.In this mixture, add 3-iodo-5-{[methyl (propyl group) amino] carbonyl } solution of methyl benzoate (1.6 grams, 4.5 mmoles) in anhydrous tetrahydro furan (3 milliliters), add palladium (O) four (triphenyl phosphine) (221 milligrams, 0.19 mmole) subsequently.With reaction mixture refluxed heating 2 hours.With this reaction mixture cooling, with ethyl acetate dilution, water and salt water washing, dry (sodium sulfate), filtration and concentrating under reduced pressure.Purify by flash column chromatography (silica gel, 60% ethyl acetate/hexane), obtain a kind of solid.This solid is dissolved in 1: 1: 1 tetrahydrofuran (THF)/methanol (9 milliliters) again, adds a hydronium(ion) oxidation lithium (331 milligrams, 7.4 mmoles) and at room temperature stirred 2 hours.With chloroform dilution and with 1N hydrochloric acid (aqueous solution), water and salt water washing, dry (sodium sulfate) filters also concentrating under reduced pressure, obtains title compound with reactant.ESI MS m/z287.3[M-H]
+。
Step 3
N
1-(1S, 2R)-1-benzyl-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-methyl-5-(1,3-oxazole-2-yl)-N
3-propyl group isophthaloyl amine
At 3-{[methyl (propyl group) amino] carbonyl }-5-(1,3-oxazole-2-yl) phenylformic acid is (206 milligrams, 0.71 in DMF mmole) (5 milliliters) solution, add diisopropylethylamine (174 microlitres, 1.1 mmole), HATU (323 milligrams, 0.85 mmole), add (the 2R that makes according to the method among the embodiment SP-272 then, 3S)-and 3-amino-1-[(3-Ethylbenzyl) amino]-4-phenyl fourth-2-alcohol dihydrochloride (292 milligrams, 0.79 mmole).Reactant was at room temperature stirred 4 hours.Make reactant phase-splitting between chloroform and water.With 1N hydrochloric acid, saturated sodium bicarbonate and salt water washing organic layer, dry (sodium sulfate), filtration and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 8% methyl alcohol/chloroform), make title compound.ESI MS m/z 569.3[M+H]
+。
Embodiment SP-164
Step 1
N
1-isobutyl--L-alanimamides
To stir 15 minutes at the Boc-L-L-Ala in the dry DMF (15 milliliters) (5.0 grams, 26.4 mmoles), isobutylamine (2.9 milliliters, 29.1 mmoles), diisopropylethylamine (11.5 milliliters, 66 mmoles) and HOBt (3.6 grams, 26.4 mmoles).Add EDC, reactant was at room temperature stirred 16 hours.With ethyl acetate dilution and with 1N hydrochloric acid, saturated sodium bicarbonate and salt water washing, dry (sal epsom) filters also concentrating under reduced pressure with reactant.Resistates is dissolved in the 4N hydrochloric acid in the Zai diox (30 milliliters) again, and stirred 2 hours.This solution decompression is concentrated, be dissolved in chloroform and use 1N NaOH (aqueous solution) washing.Use the chloroform extraction water layer, the organism drying (sodium sulfate) that will compile is filtered and concentrating under reduced pressure, makes title compound.ESI MS m/z 145.2[M+H]
+。
Step 2
[1-(3,5-two fluoro-benzyls)-2-hydroxyl-3 (1-isobutylamino formyl radical-ethylamino)-propyl group 1-t-butyl carbamate
With N
1-isobutyl--L-alanimamides (3.8 grams, 26 mmoles) and (the 1S)-2-(3 in Virahol (50 milliliters) that makes according to the method among the embodiment S-3, the 5-difluorophenyl)-1-[(2S)-and oxyethane-2-yl] the ethyl carbamic acid tert-butyl ester (3.1 gram, 10.4 mmoles) refluxed 4 hours.With reactant cooling and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 8% methyl alcohol/chloroform), make title compound.ESI MS m/z444.1[M+H]
+。
Step 3
N
2-[(2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl]-N
1-isobutyl--L-alanimamides dihydrochloride
[1-(3,5-two fluoro-benzyls)-2-hydroxyl-3 (1-isobutylamino formyl radical-ethylamino)-propyl group]-t-butyl carbamate (2.7 grams, 6 mmoles) is dissolved in the dioxane solution of excessive 4N hydrochloric acid, and reactant was at room temperature stirred 2 hours.This solution decompression is concentrated, make title compound.ESI MS m/z 344.3[M+H]
+。
Step 4
3-[(dipropyl amino) carbonyl]-5-(1,3-oxazole-2-yl) methyl benzoate
With 3-[(dipropyl amino) carbonyl]-5-iodo-benzoic acid (12 gram, 32 mmoles) is dissolved in 20% methyl alcohol/benzene (480 milliliters), slowly is added in the 2M trimethyl silyl two azomethane liquid (19 milliliters, 38 mmoles) in the hexane.Add when finishing, this solution decompression concentrated, make 3-[(dipropyl amino) carbonyl]-5-iodo-benzoic acid methyl esters, it promptly is used for next reaction without further purification.In tetrahydrofuran (THF) (4 milliliters) solution of-70 ℃ of stirring De oxazoles (120 milligrams, 1.7 mmoles), add n-Butyl Lithium (the 1.6M solution in hexane, 1.2 milliliters, 1.9 mmoles).After 30 minutes, add zinc chloride (the 1M solution in diethyl ether, 5.2 milliliters, 5.2 mmoles), and reaction mixture is warmed to 0 ℃ reaches 1 hour.In this mixture, be added in the 3-[(dipropyl amino in the anhydrous tetrahydro furan (3 milliliters)) carbonyl]-5-iodo-benzoic acid methyl esters (643 milligrams, 1.6 mmoles) solution, add palladium (0) four (triphenyl phosphine) (80 milligrams, 0.07 mmole) subsequently.With reaction mixture refluxed heating 3 hours.This reaction mixture is cooled off,, filter with the ethyl acetate dilution, with saturated sodium bicarbonate, water and salt water washing, dry (sodium sulfate), filtration and concentrating under reduced pressure.Purify by flash column chromatography (silica gel, 60% ethyl acetate/hexane), obtain the title compound of its pure state.
1H NMR(400MHz，CDCl
3)δ8.77(s，1H)、8.27(s，1H)、8.14(s，1H)、7.80(s，1H)、7.32(s，1H)、3.52(t，2H)、3.22(t，2H)、1.75(m，2H)、1.30(m，2H)、0.97(t，3H)、0.79(t，3H)。
Step 5
N-[1-(3,5-two fluoro-benzyls)-2-hydroxyl-3-(1-isobutylamino formyl radical-ethylamino)-propyl group]-5-oxazole-2-base-N ', N '-dipropyl-isophthaloyl amine
With 3-[(dipropyl amino) carbonyl]-5-(1,3-oxazole-2-yl) methyl benzoate (430 milligrams, 1.3 mmoles) is dissolved in 1: 1: 1 tetrahydrofuran (THF)/methanol (9 milliliters), adds (110 milligrams of hydronium(ion) oxidation lithiums, 2.6 mmole), and at room temperature stirred 2 hours.With the reactant concentrating under reduced pressure, and add chloroform.Wash this solution with 1N hydrochloric acid (aqueous solution).Water layer is stripped with chloroform, and the organism that compiles with the salt water washing.This solution decompression is concentrated.
In the resistates that is dissolved in DMF (5 milliliters) again, add diisopropylethylamine (438 microlitres, 2.52 mmoles), HATU (289 milligrams, 0.76 mmole), add N then
2-[(2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl]-N
1-isobutyl--L-alanimamides dihydrochloride (288 milligrams, 0.69 mmole).This reactant was at room temperature stirred 4 hours.Make reactant phase-splitting between chloroform and water.With 1N hydrochloric acid, saturated sodium bicarbonate and salt water washing organic layer, dry (sodium sulfate) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 8% methyl alcohol/chloroform), obtain title compound.ESI MS m/z 642.3[M+H]
+。
Embodiment SP-165
N-[1-(3,5-two fluoro-benzyls)-2-hydroxyl-3-(1-isobutylamino formyl radical-ethylamino)-propyl group]-N '-methyl-5-oxazole-2-base-N '-propyl group-isophthaloyl amine
At the 3-{ methyl that makes according to the method among the embodiment SP-163 [(propyl group) amino] carbonyl }-5-(1,3-oxazole-2-yl) in benzoic DMF (5 milliliters) solution, add diisopropylethylamine (361 microlitres, 2.1 mmole), HATU is (237 milligrams, 0.62 mmole), add the dihydrochloride hydrochloride (237 milligrams, 0.57 mmole) that makes according to the method among the embodiment SP-164 then.Reactant was at room temperature stirred 2 hours.Make reactant phase-splitting between chloroform and water.With 1N hydrochloric acid, saturated sodium bicarbonate and salt water washing organic layer, dry (sodium sulfate) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 8% methyl alcohol/chloroform), obtain title compound.ESI MS m/z 614.4[M+H]
+。
Embodiment SP-166
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-[1-(ethoxyl methyl)-1H-imidazoles-2-yl]-N
3, N
3-dipropyl isophthaloyl amine
Step 1
3-[(dipropyl amino) carbonyl]-5-[1-(ethoxyl methyl)-1H-imidazoles-2-yl] methyl benzoate
In tetrahydrofuran (THF) (10 milliliters) solution of the 1-of-70 ℃ of stirrings ethoxyl methyl imidazoles (J.Am.Chem.Soc.1978,100,3918) (420 milligrams, 3.3 mmoles), add n-Butyl Lithium (solution of 1.6M in hexane, 2.3 milliliters, 3.6 mmoles).After 30 minutes, add zinc chloride (9.9 milliliters, the solution of 1M in diethyl ether, 9.9 mmoles), and reaction mixture is warmed to 0 ℃ reaches 1 hour.In this mixture, add 3-[(dipropyl amino then) carbonyl]-5-iodo-benzoic acid methyl esters (1.17 grams, 3 mmoles), add palladium (0) four (triphenyl phosphine) (173 milligrams, 0.15 mmole) subsequently.With reaction mixture refluxed heating 2 hours.This reaction mixture is diluted water and salt water washing, dry (sodium sulfate), filtration and concentrating under reduced pressure with ethyl acetate (50 milliliters).Purify by flash column chromatography (silica gel, 1-5% ethanol/methylene), obtain the title compound of its pure state.
1H NMR(300MHz，CDCl
3)δ8.52(s，1H)、8.10(s，1H)、8.03(s，1H)、8.19(s，2H)、5.28(s，2H)、3.95(s，3H)、3.59(q，J＝7Hz，2H)、3.49(m，2H)、3.21(m，2H)、1.70(m，2H)、1.54(m，2H)、1.25(t，J＝7Hz，3H)、0.99(m，3H)、0.74(m，3H)。
Step 2
3-[(dipropyl amino) carbonyl]-5-[1-(ethoxyl methyl)-1H-imidazoles-2-yl] phenylformic acid
In the solution through stirring of the ester that in step 1, makes (756 milligrams, 1.95 mmoles) in 2: 1: 1 tetrahydrofuran (THF)/methanol (12 milliliters), add lithium hydroxide (170 milligrams, 4 mmoles).With reaction mixture stirring at room 42 hours, and concentrating under reduced pressure.Make resistates phase-splitting between water (10 milliliters) and chloroform (10 milliliters).With 1N hydrochloric acid water layer is acidified to pH4-5, and with 3: 1 chloroform/2-propyl alcohol (3 * 30 milliliters) extraction.With the organic layer drying (sodium sulfate) that merges, filter and concentrating under reduced pressure, obtain title compound.
1H NMR(300MHz，CD
3OD)δ8.51(s，1H)、8.06(s，1H)、8.00(s，1H)、7.49(s，1H)、7.17(s，1H)、5.39(s，2H)、3.62(q，J＝7Hz，2H)、3.51(m，2H)、3.27(m，2H)、1.72(m，2H)、1.59(m，2H)、1.21(t，J＝7Hz，3H)、1.00(m，3H)、0.75(m，3H)。
Step 3
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-[1-(ethoxyl methyl)-1H-imidazoles-2-yl]-N
3, N
3-dipropyl isophthaloyl amine
At 3-[(dipropyl amino through stirring) carbonyl]-5-[1-(ethoxyl methyl)-1H-imidazoles-2-yl] (177 milligrams in phenylformic acid, 0.47 mmole), (651 milligrams of diisopropylethylamine, 0.5 mmole) and (209 milligrams of HBTU, 0.55 mmole) in the solution in methylene dichloride (5 milliliters), (the 2R that adding makes according to the method for embodiment SP-272,3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] (196 milligrams of fourths-2-alcohol, 0.48 mmole) and the diisopropylethylamine in methylene dichloride (5 milliliters) (130 milligrams, 1.0 mmoles).Reaction mixture is at room temperature stirred 15 hours, and concentrating under reduced pressure.Resistates with ethyl acetate (20 milliliters) dilution, is used saturated sodium bicarbonate and salt water washing, dry (sodium sulfate), filtration and concentrating under reduced pressure.Purify by flash column chromatography (silica gel, 5: 95 ethanol/methylene), make title compound.APCI MS m/z 690.3[M+H]
+。
Embodiment SP-168
3-[({ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino) carbonyl] methyl benzoate
At m-phthalic acid hydrogen methyl esters (1.0 grams, 5.6 DMF/ chloroform mmole) (1: 2,15 milliliters) add (3.9 milliliters of diisopropylethylamine in the solution, 22 mmoles), HATU (2.5 grams, 6.7 mmole), add then that method according to embodiment SP-272 makes (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] fourth-2-alcohol dihydrochloride (2.5 grams, 6.1 mmoles).Reactant was at room temperature stirred 1 hour.Make reactant be divided into ethyl acetate layer and water layer.With 1N hydrochloric acid, saturated sodium bicarbonate and salt water washing organic layer, dry (sodium sulfate) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 8% methyl alcohol/chloroform), obtain title compound.ESI MS m/z 497.3[M+H]
+。
Embodiment SP-169 N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[4-(2-hydroxyethyl)-1,3-oxazole-2-yl]-benzamide
Step 1
O-benzyl-N-(tert-butoxycarbonyl) homoserine methyl esters
The high silk amino acid of O-benzyl-N-(tert-butoxycarbonyl) in 20% methyl alcohol/benzene (72 milliliters) (5.8 grams, 18.9 mmole) in the solution, the hexane solution (12.3 milliliters, 24.5 mmoles) that adds 2M trimethyl silyl diazomethane, and reactant at room temperature stirred 1.5 hours.Solution decompression is concentrated, make the title compound of its pure state.ESI MS m/z 324.2[M+H]
+。
Step 2
3-(benzyloxy)-1-(methylol) the propyl carbamic acid tert-butyl ester
In dehydrated alcohol (100 milliliters) solution of ice-cold O-benzyl-N-(tert-butoxycarbonyl) homoserine methyl esters (6 grams, 18.6 mmoles), add sodium borohydride (2.8 grams, 74.2 mmoles), and reactant was refluxed 2 hours.With the solution cooling, add excessive saturated potassium carbonate, and at room temperature stirred 16 hours.Ethanol is removed in decompression, with this aqueous solution of chloroform extraction.With saturated sodium bicarbonate, saturated sodium sulfate washing organic layer, dry (sal epsom) filters, and concentrating under reduced pressure, obtains title compound.ESI MS m/z 296.2[M+H]
+。
Step 3
2-amino-4-(benzyloxy) fourth-1-alcohol hydrochloride
3-(benzyloxy)-1-(methylol) propyl carbamic acid tert-butyl ester (5 grams, 17 mmoles) is dissolved in 4N hydrochloric acid De diox (21 milliliters) solution, and at room temperature stirred 3 hours.Solution decompression is concentrated, obtain the title compound of its pure state.ESI MS m/z 196.1[M+H]
+。
Step 4
3-({ [3-(benzyloxy)-1-(methylol) propyl group] amino } carbonyl) methyl benzoate
At room temperature, with (4.2 milliliters of m-phthalic acid hydrogen methyl esters (1.5 gram, 8.2 mmoles), 2-amino-4 (benzyloxy) fourth-1-alcohol hydrochloride (2 grams, 8.6 mmoles), diisopropylethylamine, 24.7 mmole) and HATU (3.8 milligrams, 9.9 mmoles) in DMF (15 milliliters), stirred 1 hour.This reactant is diluted also water, 1N hydrochloric acid (aqueous solution), saturated sodium bicarbonate, salt water washing with ethyl acetate, and dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (silica gel, 4% methyl alcohol/chloroform), make title compound.
1H NMR(400MHz，CDCl
3)δ8.44(s，1H)、8.18(d，1H，J＝7.9Hz)、7.86(d，1H，J＝7.9Hz)、7.43(t，1H，J＝7.6Hz)、7.42-7.35(m，5H)、4.59(s，2H)、4.33(m，1H)、3.96(s，3H)、3.88-3.72(m，4H)、3.53(s，1H)、2.08(m，2H)。
Step 5
3-{4-[2-(benzyloxy) methyl]-1,3-oxazole-2-yl } methyl benzoate
3-in water saturation methylene dichloride (20 milliliters) ({ [3-(benzyloxy)-1-(methylol) propyl group] amino } carbonyl) methyl benzoate (1,3 grams, 3.6 mmole) in the solution, add (187 milligrams of Sodium Bromides, 1.8 mmole) and water (2.75 milliliters), add TEMPO (6 milligrams, 0.04 mmole) then, simultaneously vigorous stirring.Adding sodium bicarbonate (115 milligrams) and 6% clorox (5 milliliters) also stirred 1 hour.In 3 hours, per hour add 6% clorox (1 milliliter).Add excessive saturated sodium thiosulfate, and stirred 30 minutes.With this mixture phase-splitting, and with salt water washing organic layer, dry (sodium sulfate) filters and concentrating under reduced pressure.Resistates is dissolved in anhydrous tetrahydro furan (4 milliliters) and hydroxide (methoxycarbonyl sulphonamide) three second ammoniums, inner salt (670 milligrams, 2.8 mmoles).Handle this reactant with microwave (100W, 2 minutes) in sealer, cooling is filtered, and concentrating under reduced pressure.Purify (silica gel, 40% ethyl acetate/hexane) by flash column chromatography, obtain title compound.ESI MS m/z 338.3[M+H]
+。
Step 6
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[4-(2-hydroxyethyl)-1,3-oxazole-2-yl]-benzamide
With 3-{4-[2-(benzyloxy) methyl]-1,3-oxazole-2-yl } dehydrated alcohol (3 milliliters) solution of methyl benzoate (300 milligrams, 0.9 mmole), 20% palladium hydroxide (II)-carbon (65 milligrams) and tetrahydrobenzene (3 milliliters) refluxed 1 hour.With the reactant cooling, through diatomite filtration, and concentrating under reduced pressure.Resistates is dissolved in 2: 1: 1 tetrahydrofuran (THF)/methanol (4 milliliters) again, adds lithium hydroxide (75 milligrams, 1.8 mmoles).Reaction mixture is at room temperature stirred 3 hours, and concentrating under reduced pressure.Resistates is dissolved in DMF (5 milliliters), and adding diisopropylethylamine (625 microlitres, 3.6 mmole), HATU is (540 milligrams, 1.4 mmole) and (2R that makes according to the method among the embodiment SP-272,3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] fourth-2-alcohol dihydrochloride (407 milligrams, 1 mmole).Reactant was at room temperature stirred 16 hours.Use the chloroform diluted reaction mixture, water, 1N hydrochloric acid (aqueous solution), saturated sodium bicarbonate and salt water washing, dry (sodium sulfate) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 8% methyl alcohol/chloroform), obtain title compound.ESI MS m/z 550.3[M+H]
+。
Embodiment SP-170
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-isopropyl benzyl) amino] propyl group }-N
3, N
3-dipropyl-5-(1,3-thiazoles-2-yl) isophthaloyl amine
Step 1
3-pseudoallyl benzonitrile
In the solution of the 3-hydroxy phenyl boric acid that is dissolved in DME (340 milliliters) (10.0 grams, 68.05 mmoles), add 2-bromine third rare (6.86 grams, 56.7 mmoles) and the yellow soda ash (62.3 milliliters, the 2M aqueous solution, 124.7 mmoles) through stirring.With nitrogen reaction mixture was outgased 20 minutes.Add four (triphenyl phosphine) palladium (O) (2.54 grams, 2.2 mmoles), with the reaction mixture degassing 10 minutes, and reflux spent the night.Reaction mixture is cooled to room temperature, then phase-splitting between hexane and water.With hexane (3 * 75 milliliters) aqueous layer extracted.With the organic phase salt water washing that merges, dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (9: 1 hexane/ethyl acetate), obtain title compound.
1H NMR(300MHz，DMSO-d
6)δ7.96(m，1H)、7.85(d，J＝8Hz，1H)、7.75(d，J＝8Hz，1H)、7.56(m，1H)、5.58(s，1H)、5.23(m，1H)、2.13(s，3H)。
Step 2
3-isopropyl benzylamine hydrochloride
3-pseudoallyl benzonitrile (6.0 gram, 41.9 mmoles) and the solution of 10%Pa/C (600 milligrams) in ethanol (65 milliliters) and acetate (2.4 milliliters) were outgased 15 minutes with nitrogen, and under the nitrogen atmosphere of 50psi shake 12 hours.Reaction mixture through diatomite filtration and concentrating under reduced pressure, is made a kind of oil.This oil is dissolved in methyl alcohol (5 milliliters), and adds hydrochloric acid (15 milliliters, the solution of 1M in ether).Filter and collect the precipitation that generates, obtain title compound.APCI MS m/z 149[M+H]
+。
Step 3
(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-isopropyl benzyl) amino] the propyl carbamic acid tert-butyl ester
Will be at (the 1S)-2-in the Virahol (60 milliliters) (3, the 5-difluorophenyl)-1-[(2S)-oxyethane-2-yl] the ethyl carbamic acid tert-butyl ester (2.0 grams, 6.7 mmoles) and 3-isopropyl benzylamine hydrochloride (2.5 grams, 13.5 mmoles) backflow 3 hours.With reactant cooling and stirred 16 hours.This solution decompression is concentrated, be dissolved in chloroform again, with 1N hydrochloric acid, saturated sodium bicarbonate, salt water washing, dry (sodium sulfate), filtration and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 7% methyl alcohol/chloroform), obtain the title compound of its pure state.ESI MSm/z 449.3[M+H]
+。
Step 4
(2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(3-isopropyl benzyl) amino] fourth-2-alcohol dihydrochloride
Will (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-isopropyl benzyl) amino] the propyl carbamic acid tert-butyl ester (1.5 grams, 3.3 mmoles) is dissolved in 4N hydrochloric acid De diox (20 milliliters) solution, and reactant at room temperature stirred 3 hours.With this mixture concentrating under reduced pressure, make title compound.ESI MS m/z 349.2[M+H]
+。
Step 5
3-[(dipropyl amino) carbonyl]-5-(1,3-thiazoles-2-yl) methyl benzoate
Tetrahydrofuran (THF) (45 milliliters) solution of 0.5M thiazole zinc bromide is added 3-[(dipropyl amino) carbonyl]-5-iodo-benzoic acid methyl esters (8.6 grams, 21.4 anhydrous tetrahydro furan mmole) (130 milliliters) solution, add four (triphenyl phosphine) palladium (0) (2 grams, 1.7 mmoles) again.With reaction mixture refluxed heating 16 hours.Reaction mixture is diluted with ethyl acetate (50 milliliters), water, saturated sodium bicarbonate and salt water washing, dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (silica gel, 35% ethyl acetate/hexane), obtain title compound.ESI MS m/z 347.1[M+H]
+。
Step 6
3-[(dipropyl amino) carbonyl]-5-(1,3-thiazoles-2-yl) phenylformic acid
With 3-[(dipropyl amino) carbonyl]-5-(1,3-thiazoles-2-yl) methyl benzoate (4.4 gram, 12.8 mmoles) is dissolved in 1: 1: 1 tetrahydrofuran (THF)/methanol (60 milliliters), and adds a hydronium(ion) oxidation lithium (1.1 grams, 25.6 mmoles).Reactant was stirred 15 minutes, and concentrating under reduced pressure.Resistates is diluted also water, salt water washing with chloroform, and dry (sal epsom) filters and concentrating under reduced pressure, makes title compound.ESI MS m/z 333.1[M+H]
+。
Step 7
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-isopropyl benzyl) amino] propyl group }-N
3, N
3-dipropyl-5-(1,3-thiazoles-2-yl) isophthaloyl amine
With 3-[(dipropyl amino) carbonyl]-5-(1, the 3-thiazol-2-yl) phenylformic acid is dissolved in DMF (8 milliliters), and adding diisopropylethylamine (456 microlitres, 2.6 mmole), HATU is (342 milligrams, 0.9 mmole) and (2R, 3S)-and 3-amino-4-(3, the 5-difluorophenyl)-1-[(3-Ethylbenzyl) amino] fourth-2-alcohol dihydrochloride (350 milligrams, 0.83 mmole).Reactant was at room temperature stirred 1 hour.Make reactant be divided into ethyl acetate layer and water layer.With 1N hydrochloric acid, saturated sodium bicarbonate and salt water washing organic layer, dry (sodium sulfate) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 8% methyl alcohol/chloroform), obtain title compound as free alkali.Purify by flash column chromatography (silica gel, 8% methyl alcohol/chloroform), obtain title compound as free alkali.Resistates is dissolved in ether (5 milliliters), and adds ether (2 milliliters) solution of 1N hydrochloric acid.With this mixture concentrating under reduced pressure, make title compound.ESI MS m/z 663.3[M+H]
+。
Embodiment SP-171
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-isopropyl benzyl) amino] propyl group }-N
3, N
3-dipropyl-5-(1,3-thiazoles-2-yl) isophthaloyl amine hydrochlorate
With N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-isopropyl benzyl) amino] propyl group }-N
3, N
3-dipropyl-5-(1,3-thiazoles-2-yl) isophthaloyl amine (180 milligrams, 0.27 mmole) is dissolved in ether (5 milliliters), and adds ether (2 milliliters) solution of 1N hydrochloric acid.With this mixture concentrating under reduced pressure, make title compound.ESI MS m/z 663.3[M+H]
+。
Embodiment SP-172
3-(2-{3-[({ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino) carbonyl] phenyl }-1,3-oxazole-5-yl) methyl propionate
Step 1
3-{[(5-methoxyl group-2,5-dioxo amyl group) amino] carbonyl } methyl benzoate
With m-phthalic acid hydrogen methyl esters (1.8 grams, 10.2 mmole) be dissolved in methylene dichloride (10 milliliters) and DMF (10 milliliters), and add diisopropylethylamine (4.4 milliliters, 25.5 mmoles), HATU (4.6 grams, 12.2 mmole) and 5-aminolevulinic acid methyl ester hydrochloride (2 gram, 11.2 mmoles).Reactant was at room temperature stirred 1 hour.Make reactant be divided into ethyl acetate layer and water layer.With 1N hydrochloric acid, saturated sodium bicarbonate and salt water washing organic layer, dry (sodium sulfate) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 4% methyl alcohol/chloroform), obtain title compound.ESI MS m/z 306.1[M-H]
+。
Step 2
3-[5-(3-methoxyl group-3-oxopropyl)-1,3-oxazole-2-yl] methyl benzoate
With 3-{[(5-methoxyl group-2,5-dioxo amyl group) amino] carbonyl } methyl benzoate (520 milligrams, 1.7 mmoles) is dissolved in anhydrous tetrahydro furan (4 milliliters) and hydroxide (methoxycarbonyl sulphonamide) three second ammoniums, inner salt (810 milligrams, 3.4 mmoles).Reactant is carried out microwave (100W, 2 minutes) handle in sealer, cooling is filtered and concentrating under reduced pressure.Purify by flash column chromatography (silica gel, 40% ethyl acetate/hexane), obtain title compound.ESI MS m/z 290.1[M+H]
+。
Step 3
3-[5-(2-propyloic)-1,3-oxazole-2-yl] phenylformic acid
At 3-[5-(3-methoxyl group-3-oxopropyl)-1,3-oxazole-2-yl] (400 milligrams of methyl benzoate, 1.3 in 2: 1: 1 tetrahydrofuran (THF)/methanol mmole) (8 milliliters) solution, add (112 milligrams of hydronium(ion) oxidation lithiums, 2.7 mmole), and with reactant at room temperature stirred 2 hours.Add a hydronium(ion) oxidation lithium (225 milligrams, 5.4 mmoles) again and reactant was at room temperature stirred 16 hours.Handle this reactant with excessive concentrated hydrochloric acid, produce precipitation.Filtering-depositing obtains title compound.ESI MS m/z 260.1[M-H]
+。
Step 4
3-[5-(3-methoxyl group-3-oxopropyl)-1,3-oxazole-2-yl] phenylformic acid
At 3-[5-(2-propyloic)-1,3-oxazole-2-yl] add thionyl chloride (4.4 microlitres, 0.06 mmole) in methyl alcohol (5 milliliters) solution of phenylformic acid (317 milligrams, 1.2 mmoles), and reactant was at room temperature stirred 16 hours.Solution decompression is concentrated, obtain title compound.ESI MS m/z 274.1[M-H]
+。
Step 5
3-(2-{3-[({ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino) carbonyl] phenyl }-1,3-oxazole-5-yl) methyl propionate
With 3-[5-(3-methoxyl group-3-oxopropyl)-1,3-oxazole-2-yl] (285 milligrams in phenylformic acid, 1.0 mmole) be dissolved in methylene dichloride (5 milliliters) and DMF (5 milliliters), add diisopropylethylamine (695 microlitres, 4.0 mmole), HATU (472 milligrams, 1.2 mmoles) and according to the method for embodiment SP-272 make (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] fourth-2-alcohol dihydrochloride (448 milligrams, 1.1 mmoles).Reactant was at room temperature stirred 1 hour.Make reactant phase-splitting between ethyl acetate and saturated sodium bicarbonate.With 1N hydrochloric acid, saturated sodium bicarbonate and salt water washing organic layer, dry (sodium sulfate) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 8% methyl alcohol/chloroform), make title compound.ESI MS m/z 591.9[M+H]
+。
Embodiment SP-173
3-(2-{3-[({ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino) carbonyl] phenyl }-1,3-oxazole-5-yl) propionic acid
Will be at the 3-(2-{3-[({ (1S in 2: 1: 1 tetrahydrofuran (THF)/methanol (6 milliliters), 2R)-1-(3, the 5-difluorobenzyl)-and the 3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino) carbonyl] phenyl }-1,3-oxazole-5-yl) methyl propionate is (70 milligrams, 0.12 mmole) and a hydronium(ion) oxidation lithium (10 milligrams, 0.24 mmole) at room temperature stirred 1.5 hours.With the reactant concentrating under reduced pressure.Resistates with 1N hydrochloric acid (aqueous solution) washing, with the chloroform washing, with the solid drying under reduced pressure, is obtained title compound then.ESI MS m/z 578.2[M+H]
+。
Embodiment SP-174
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(1,3-oxazole-2-yl) benzamide
Step 1
4-(1,3-oxazole-2-yl) methyl benzoate
In tetrahydrofuran (THF) (10 milliliters) solution of-70 ℃ of stirring De oxazoles (190 milliliters, 3.8 mmoles), add n-Butyl Lithium (2.6 milliliters, the solution of 1.6M in hexane, 4.2 mmoles).After 30 minutes, add zinc chloride (11.5 milliliters, the solution of 1.0M in ether, 11.5 mmoles).Reaction mixture is warmed to 0 ℃ reaches 1 hour, and add 4-iodo-benzoic acid methyl esters (1 gram, 3.8 mmoles) and palladium (0) four (triphenyl phosphine) (530 milligrams, 0.4 mmole).With reaction mixture under argon gas in 70 ℃ the heating 20 hours, be cooled to room temperature, be divided into ethyl acetate layer and water layer then.Water and salt water washing organic layer, dry (sodium sulfate), filtration and concentrating under reduced pressure.Purify by flash column chromatography (3: 1 hexane/ethyl acetate), obtain title compound.
1H NMR(300MHz，CDCl
3)δ8.14(s，4H)、8.07-8.05(m，1H)、7.36-7.35(m，1H)、3.95(s，3H)。
Step 2
4-(1,3-oxazole-2-yl) phenylformic acid
In 4-(1, the 3-oxazole-2-yl) methyl benzoate (690 milligrams, 3.4 mmoles) in 2: 1: 1 tetrahydrofuran (THF)/methanol (20 milliliters), add lithium hydroxide (430 milligrams, 3 mmoles) through stirring.Reaction mixture was at room temperature stirred 2 hours.Decompression is removed solvent and is made resistates phase-splitting between ether and water.With 1N hydrochloric acid water layer is acidified to pH 1, observes precipitation.Filter and collect this solid, obtain title compound.
1H NMR(300MHz，CD
3OD)δ8.14(s，4H)、8.05(s，1H)、7.36(s，1H)。
Step 3
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(1,3-oxazole-2-yl) benzamide
With 4-(1,3-oxazole-2-yl) phenylformic acid is (105 milligrams, 0.6 (2R mmole),, 3S)-and 3-amino-4-(3, the 5-difluorophenyl)-1-[(3-Ethylbenzyl) amino] (210 milligrams of fourth-2-alcohol dihydrochloride (220 milligrams, 0.6 mmole) and HATU, 0.6 mmole) stirring makes solution in methylene dichloride (5 milliliters), in this solution, add N, N-diisopropylethylamine (340 milliliters, 1.9 mmoles).This reaction mixture was at room temperature stirred 18 hours.Make reaction mixture phase-splitting between methylene dichloride and water.Organic layer is washed with water, and dry (sodium sulfate) filters and concentrating under reduced pressure, makes rough solid.Purify by flash column chromatography (silicon-dioxide, the methylene chloride of 96: 4 to 93: 7 graded), obtain title compound.ESI MS m/z 506.2[M+H]
+。
Embodiment SP-175
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(1,3-thiazoles-2-yl) benzamide
Step 1
4-(1,3-thiazoles-2-yl) methyl benzoate
In tetrahydrofuran (THF) (10 milliliters) solution of the thiazole (270 milliliters, 3.8 mmoles) of-70 ℃ of stirrings, add n-Butyl Lithium (2.6 milliliters, the solution of 1.6M in hexane, 4.2 mmoles).After 30 minutes, add zinc chloride (11.4 milliliters, the solution of 1.0M in ether, 11.4 mmoles).Reaction mixture is warmed to 0 ℃, and adds 4-iodo-benzoic acid methyl esters (1 gram, 3.8 mmoles) and palladium (O) four (triphenyl phosphine) (530 milligrams, 0.4 mmole).With reaction mixture under argon gas in 70 ℃ the heating 20 hours, be cooled to room temperature, be divided into ethyl acetate layer and water layer then.Water and salt water washing organic layer, dry (sodium sulfate), filtration and concentrating under reduced pressure.Purify by flash column chromatography (3: 1 hexane/ethyl acetate), obtain title compound.
1H NMR(300MHz，CDCl
3)δ8.14-8.03(s，4H)、7.93-7.92(m，1H)、7.42-7.41(m，1H)、3.95(s，3H)。
Step 2
4-(1,3-thiazoles-2-yl) phenylformic acid
In 4-(1,3-thiazoles-2-yl) methyl benzoate (560 milligrams, the 2.6 mmoles) solution in 2: 1: 1 tetrahydrofuran (THF)/methanol (20 milliliters), add lithium hydroxide (322 milligrams, 3 mmoles) through stirring.Reaction mixture was at room temperature stirred 2 hours.Decompression is removed solvent and is made resistates phase-splitting between ether and water.With 1N hydrochloric acid water layer is acidified to pH1, observes precipitation.Solid collected by filtration obtains title compound.
1HNMR(300MHz，CD
3OD)δ8.14-8.05(s，4H)、7.95-7.93(m，1H)、7.71-7.69(m，1H)。
Step 3
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(1,3-thiazoles-2-yl) benzamide
With 4-(1, the 3-thiazol-2-yl) phenylformic acid is (110 milligrams, 0.6 (2R mmole),, 3S)-and 3-amino-4-(3, the 5-difluorophenyl)-1-[(3-Ethylbenzyl) amino] (210 milligrams of fourth-2-alcohol dihydrochloride (220 milligrams, 0.6 mmole) and HATU, 0.6 mmole) stirring makes solution in methylene dichloride (5 milliliters), in this solution, add N, N-diisopropylethylamine (340 milliliters, 1.9 mmoles).This reaction mixture was at room temperature stirred 18 hours.Make reaction mixture phase-splitting between methylene dichloride and water.Organic layer is washed with water, and dry (sodium sulfate) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, the methylene chloride of 95: 5 to 92: 8 graded), obtain title compound.ESI MS m/z 522.2[M+H]
+。
Embodiment SP-176
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(3H-[1,2,3] trioazole [4,5-b] pyridin-3-yl oxygen) methyl] benzamide
In DMF (5 milliliters) solution of 3-(brooethyl) phenylformic acid (200 milligrams, 0.93 mmole) and diisopropylethylamine (566 microlitres, 3.26 mmoles), add HATU (424 milligrams, 1.12 mmoles), and reactant was stirred 5 minutes.(2R, 3S)-3-amino-4-(3, the 5-the difluorophenyl)-1-[(3-Ethylbenzyl) amino that adds in reactant that method according to embodiment SP-272 makes] fourth-2-alcohol dihydrochloride (379 milligrams, 0.93 mmole), and reactant stirred 30 minutes.Reaction mixture is diluted with methylene dichloride, with 1N hydrochloric acid (15 milliliters), saturated sodium bicarbonate (15 milliliters) and salt water washing.With organic layer drying (sodium sulfate), filter and concentrating under reduced pressure then.Purify by flash column chromatography (silicon-dioxide, 8% methyl alcohol/chloroform), make title compound.ESI MS m/z 587.4[M+H]
+。
Embodiment SP-177
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-the 3-{[(2-hydroxyethyl) (propyl group) amino] methyl }-5-methyl benzamide dihydrochloride
Step 1
3-bromo-5-(methylol) phenylformic acid
In the benzoic anhydrous tetrahydro furan of 3-bromo-5-(methoxycarbonyl) (100 milliliters) solution that the ice-cold method according in the preparation 2 makes, by a part adding lithium borohydride (12 grams, 550 mmoles).Reactant was stirred 4 hours under this temperature.Dropwise add dehydrated alcohol (20 milliliters), and reactant was stirred 1.5 hours.This reactant slowly is poured on ice, adds 10% hydrochloric acid (aqueous solution) up to stopping to generate gas.Use the chloroform extraction water layer, and with organic layer salt water washing, dry (sal epsom) filters and concentrating under reduced pressure, makes title compound.ESI MS m/z 229，231[M-H]
+。
Step 2
3-bromo-5-(methylol) methyl benzoate
In 3-bromo-5-(methylol) phenylformic acid in 20% methyl alcohol/benzene (100 milliliters) (7.0 grams, the 30 mmoles) solution, add trimethyl silyl diazomethane (2M is in hexane), and reactant was stirred 16 hours.With the reactant concentrating under reduced pressure, make title compound.ESI MS m/z 244.0[M+H]
+。
Step 3
3-(methylol)-5-methyl-toluate
At (3.0 grams of 3-bromo-5-(methylol) methyl benzoate through stirring, 12.2 in mmole) De diox (27 milliliters) solution, add cesium carbonate (4.0 grams, 12.2 salt of wormwood (34 grams mmole),, 24.4 mmole) and (704 milligrams of palladiums (0) four (triphenyl phosphine), 0.61 mmole), add trimethylboroxin (1.7 milliliters, 12.2 mmoles) then.With this reaction mixture refluxed 5 hours, be cooled to room temperature, then phase-splitting between water and ethyl acetate.Water, saturated sodium bicarbonate and salt water washing organic layer, dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 20% ethyl acetate/hexane), make title compound.ESI MS m/z 181.2[M+H]
+。
Step 4
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-the 3-{[(2-hydroxyethyl) (propyl group) amino] methyl }-5-methyl benzamide dihydrochloride
In 3-(methylol)-5-methyl-toluate (1.25, the 7 mmole) solution in methylene dichloride (30 milliliters) of-30 ℃ of stirrings, add methylsulfonyl chloride (752 microlitres, 9.7 mmoles), add triethylamine (1.95 milliliters, 14 mmoles) then.Reaction mixture was stirred 15 minutes at 0 ℃.Reactant is diluted with ether and water and cool brine washing, and dry (sal epsom) filters also concentrating under reduced pressure, makes a kind of oil.Resistates is dissolved in anhydrous methylene chloride (22 milliliters) again.From this liquid storage, get in anhydrous methylene chloride (1 milliliter) solution of 2 milliliters of adding N-hydroxyethyl propylamine (115 microlitres, 1 mmole), and reaction mixture was at room temperature stirred 5 hours.Reaction mixture with methylene dichloride (10 milliliters) dilution, is washed with 1N hydrochloric acid and saturated sodium bicarbonate, and dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 4% methyl alcohol/chloroform), obtain amine.This amine is dissolved in 1: 1: 1 tetrahydrofuran (THF)/methanol (3 milliliters), and adds a hydronium(ion) oxidation lithium (33 milligrams, 0.75 mmole).Reactant was stirred 2 hours and concentrating under reduced pressure.Resistates is dissolved in DMF (3 milliliters) again, and adding diisopropylethylamine (261 microlitres, 1.5 mmole), HATU is (214 milligrams, 0.56 mmole) and (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and 1-[(3-iodine benzyl) amino] fourth-2-alcohol dihydrochloride (189 milligrams, 0.37 mmole).Reactant was at room temperature stirred 16 hours.Purify by flash column chromatography (silicon-dioxide, 8% methyl alcohol/chloroform), make title compound as free alkali.Resistates is dissolved in ether (3 milliliters) and adds ether (1 milliliter) solution of 1N hydrochloric acid.With this mixture concentrating under reduced pressure, make title compound.ESI MS m/z 666.2[M+H]
+。
Embodiment SP-178
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-3-{[ethyl (propyl group) amino] methyl }-5-methyl benzamide dihydrochloride
With embodiment SP-177, the method for describing in the step 4 is similar, 2 milliliters of liquid storages is added in anhydrous methylene chloride (1 milliliter) solution of N-ethyl propylamine (143 microlitres, 1 mmole), and reaction mixture was at room temperature stirred 5 hours.Reaction mixture with methylene dichloride (10 milliliters) dilution, is washed with 1N hydrochloric acid and saturated sodium bicarbonate, and dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 4% methyl alcohol/chloroform), obtain amine.This amine is dissolved in 1: 1: 1 tetrahydrofuran (THF)/methanol (3 milliliters), and adds a hydronium(ion) oxidation lithium (42 milligrams, 1 mmole).Reactant was stirred 2 hours and concentrating under reduced pressure.Resistates is dissolved in DMF (5 milliliters) again, and adding diisopropylethylamine (265 microlitres, 1.5 (2R mmole),, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and 1-[(3-iodine benzyl) amino] (252 milligrams of fourth-2-alcohol dihydrochlorides, 0.5 mmole) and HATU (237 milligrams, 0.62 mmole).Reactant was at room temperature stirred 16 hours.Purify by flash column chromatography (silicon-dioxide, 10% methyl alcohol/chloroform), make title compound as free alkali.Resistates is dissolved in ether (3 milliliters) and adds ether (1 milliliter) solution of 1N hydrochloric acid.With this mixture concentrating under reduced pressure, make title compound.ESI MS m/z 650.2[M+H]
+。
Embodiment SP-179
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-the 3-{[(2-hydroxyethyl) (propyl group) amino] methyl } benzamide dihydrochloride
Step 1
The 3-{[(2-hydroxyethyl) (propyl group) amino] methyl } methyl benzoate
In chloroform (20 milliliters) solution of 2-third amino methanol (505 microlitres, 4.4 mmoles), add bromomethyl-benzoic acid methyl ester (1 gram, 4.4 mmoles), and reactant was at room temperature stirred 16 hours.With reactant saturated sodium bicarbonate and salt water washing.With organic layer drying (sodium sulfate), filter and concentrating under reduced pressure then.Purify by flash column chromatography (silicon-dioxide, 80% ethyl acetate/hexane), make title compound.ESI MSm/z 252.3[M+H]
+。
Step 2
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-the 3-{[(2-hydroxyethyl) (propyl group) amino] methyl } benzamide dihydrochloride
At room temperature, with the 3-{[(2-hydroxyethyl) (propyl group) amino] methyl } methyl benzoate (500 milligrams, 2 mmoles) and a hydronium(ion) oxidation lithium (170 milligrams, 4 mmoles) stirred 16 hours in tetrahydrofuran (THF)/methanol (4 milliliters) at 2: 1: 1.With this reactant concentrating under reduced pressure, be dissolved in again among the DMF (15 milliliters).In this solution, add (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(3-iodine benzyl) amino] fourth-2-alcohol dihydrochloride (1 gram, 2 mmoles), diisopropylethylamine (1.4 milliliters, 8 mmoles), add then HATU (1.1 the gram, 3 mmoles), and with reactant stirred 2 hours.Purify by flash column chromatography (silicon-dioxide, 10% methyl alcohol/chloroform), make title compound as free alkali.Resistates is dissolved in ether (5 milliliters) and adds ether (3 milliliters) solution of 1N hydrochloric acid.With this mixture concentrating under reduced pressure, make title compound.ESI MS m/z 652.2[M+H]
+。
Embodiment SP-180
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-3-methyl-5-{[methyl (propyl group) amino] methyl } benzamide dihydrochloride
With embodiment SP-177, the method for describing in the step 4 is similar, 2 milliliters of liquid storages is added in anhydrous methylene chloride (1 milliliter) solution of N methyl pmpyl amine (103 microlitres, 1 mmole), and reaction mixture was at room temperature stirred 5 hours.Reaction mixture with methylene dichloride (10 milliliters) dilution, is washed with 1N hydrochloric acid and saturated sodium bicarbonate, and dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 4% methyl alcohol/chloroform), obtain amine.This amine is dissolved in 1: 1: 1 tetrahydrofuran (THF)/methanol (3 milliliters), and adds a hydronium(ion) oxidation lithium (33 milligrams, 0.75 mmole).Reactant was stirred 2 hours and concentrating under reduced pressure.Resistates is dissolved in DMF (3 milliliters) again, and adding diisopropylethylamine (261 microlitres, 1.5 mmole), HATU is (214 milligrams, 0.56 mmole) and (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and 1-[(3-iodine benzyl) amino] fourth-2-alcohol dihydrochloride (189 milligrams, 0.37 mmole).Reactant was at room temperature stirred 16 hours.Purify by flash column chromatography (silicon-dioxide, 8% methyl alcohol/chloroform), make title compound as free alkali.Resistates is dissolved in ether (3 milliliters) and adds ether (1 milliliter) solution of 1N hydrochloric acid.With this mixture concentrating under reduced pressure, make title compound.ESI MS m/z 636.2[M+H]
+。
Embodiment SP-181
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-3-[(dipropyl amino) methyl 1-5-methyl benzamide dihydrochloride
With embodiment SP-177, the method for describing in the step 4 is similar, 2 milliliters of liquid storages is added in anhydrous methylene chloride (1 milliliter) solution of dipropyl amine (137 microlitres, 1 mmole), and reaction mixture was at room temperature stirred 5 hours.Reaction mixture with methylene dichloride (10 milliliters) dilution, is washed with 1N hydrochloric acid and saturated sodium bicarbonate, and dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 4% methyl alcohol/chloroform), obtain amine.This amine is dissolved in 1: 1: 1 tetrahydrofuran (THF)/methanol (3 milliliters), and adds a hydronium(ion) oxidation lithium (33 milligrams, 0.75 mmole).Reactant was stirred 2 hours and concentrating under reduced pressure.Resistates is dissolved in DMF (3 milliliters) again, and adding diisopropylethylamine (261 microlitres, 1.5 mmole), HATU is (214 milligrams, 0.56 mmole) and (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and 1-[(3-iodine benzyl) amino] fourth-2-alcohol dihydrochloride (189 milligrams, 0.37 mmole).Reactant was at room temperature stirred 16 hours.Purify by flash column chromatography (silicon-dioxide, 8% methyl alcohol/chloroform), make title compound as free alkali.Resistates is dissolved in ether (3 milliliters) and adds ether (1 milliliter) solution of 1N hydrochloric acid.With this mixture concentrating under reduced pressure, make title compound.ESI MS m/z 664.2[M+H]
+。
Embodiment SP-182
3-{[butyl (methyl) amino] methyl }-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-5-methyl benzamide dihydrochloride
With embodiment SP-177, the method for describing in the step 4 is similar, 2 milliliters of liquid storages is added in anhydrous methylene chloride (1 milliliter) solution of N-methylbutylamine (118 microlitres, 1 mmole), and reaction mixture was at room temperature stirred 5 hours.Reaction mixture with methylene dichloride (10 milliliters) dilution, is washed with 1N hydrochloric acid and saturated sodium bicarbonate, and dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 4% methyl alcohol/chloroform), obtain amine.This amine is dissolved in 1: 1: 1 tetrahydrofuran (THF)/methanol (3 milliliters), and adds a hydronium(ion) oxidation lithium (33 milligrams, 0.75 mmole).Reactant was stirred 2 hours and concentrating under reduced pressure.Resistates is dissolved in DMF (3 milliliters) again, and adding diisopropylethylamine (261 microlitres, 1.5 mmole), HATU is (214 milligrams, 0.56 mmole) and (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and 1-[(3-iodine benzyl) amino] fourth-2-alcohol dihydrochloride (189 milligrams, 0.37 mmole).Reactant was at room temperature stirred 16 hours.Purify by flash column chromatography (silicon-dioxide, 8% methyl alcohol/chloroform), make title compound as free alkali.Resistates is dissolved in ether (3 milliliters) and adds ether (1 milliliter) solution of 1N hydrochloric acid.With this mixture concentrating under reduced pressure, make title compound.ESI MS m/z 650.2[M+H]
+。
Embodiment SP-183
3-[(hexamethylene amino) methyl]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-5-methyl benzamide dihydrochloride
With embodiment SP-177, the method for describing in the step 4 is similar, 2 milliliters of liquid storages is added in anhydrous methylene chloride (1 milliliter) solution of hexahydroaniline (114 microlitres, 1 mmole), and reaction mixture was at room temperature stirred 5 hours.Reaction mixture with methylene dichloride (10 milliliters) dilution, is washed with 1N hydrochloric acid and saturated sodium bicarbonate, and dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 4% methyl alcohol/chloroform), obtain amine.This amine is dissolved in 1: 1: 1 tetrahydrofuran (THF)/methanol (3 milliliters), and adds a hydronium(ion) oxidation lithium (33 milligrams, 0.75 mmole).Reactant was stirred 2 hours and concentrating under reduced pressure.Resistates is dissolved in DMF (3 milliliters) again, and adding diisopropylethylamine (261 microlitres, 1.5 mmole), HATU is (214 milligrams, 0.56 mmole) and (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and 1-[(3-iodine benzyl) amino] fourth-2-alcohol dihydrochloride (189 milligrams, 0.37 mmole).Reactant was at room temperature stirred 16 hours.Purify by flash column chromatography (silicon-dioxide, 8% methyl alcohol/chloroform), make title compound as free alkali.Resistates is dissolved in ether (3 milliliters) and adds ether (1 milliliter) solution of 1N hydrochloric acid.With this mixture concentrating under reduced pressure, make title compound.ESI MS m/z 662.2[M+H]
+。
Embodiment SP-184
3-{[benzyl (methyl) amino] methyl }-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-5-methyl benzamide dihydrochloride
Similar to the method for describing among the embodiment SP-177, at the 3-of-30 ℃ of stirrings (methylol)-5-methyl-toluate (1.0,5.6 in methylene dichloride mmole) (9 milliliters) solution, add methylsulfonyl chloride (600 microlitres, 7.8 mmole), add triethylamine (1.55 milliliters, 11 mmoles) then.Reaction mixture was stirred 1 hour at 0 ℃, filter then.From this liquid storage, get in 2 milliliters of anhydrous methylene chloride (1 milliliter) solution that are added to N-methylbenzylamine (538 microlitres, 4.2 mmoles), and reaction mixture was at room temperature stirred 16 hours.Reaction mixture with methylene dichloride (10 milliliters) dilution, with saturated sodium bicarbonate and salt water washing, dry (sal epsom), is filtered and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 4% methyl alcohol/chloroform), obtain amine.This amine is dissolved in 2: 1: 1 tetrahydrofuran (THF)/methanol (4 milliliters), and adds a hydronium(ion) oxidation lithium (90 milligrams, 2 mmoles).Reactant was stirred 16 hours and concentrating under reduced pressure.Resistates is dissolved in DMF (5 milliliters) again, and adds (570 milligrams of diisopropylethylamine (695 microlitres, 4 mmoles), HATU, 1.5 mmole) and (2R, 3S)-and 3-amino-4-(3, the 5-difluorophenyl)-1-[(3-iodine benzyl) amino] fourth-2-alcohol dihydrochloride (505 milligrams, 1 mmole).Reactant was at room temperature stirred 16 hours.Purify by flash column chromatography (silicon-dioxide, 7% methyl alcohol/chloroform), make title compound as free alkali.Resistates is dissolved in ether (3 milliliters) and adds ether (1 milliliter) solution of 1N hydrochloric acid.With this mixture concentrating under reduced pressure, make title compound.ESI MS m/z 684.2[M+H]
+。
Embodiment SP-185
2-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,2,3,4-tetrahydroisoquinoline-7-methane amide dihydrochloride
Step 1
2-butyl-1,2,3,4-tetrahydroisoquinoline-7-nitrile
Ice-cold, through 1,2,3 of stirring, 4-tetrahydroisoquinoline-7-nitrile (J.Med.Chem.1997,40,3997) (485 milligrams, 3.1 mmoles) and triethylamine are (0.47 milliliter, 3.4 in methylene dichloride mmole) (5 milliliters) solution, add DMAP (37 milligrams, 0.3 mmole) and n-butyl bromide (0.5 milliliter, 4.6 mmoles).Reaction mixture was stirred 20 hours, and with methylene dichloride dilution, water and salt water washing, dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 50% ethyl acetate/hexane), obtain title compound.ESI MS m/z 215[M+H]
+。
Step 2
2-butyl-1,2,3,4-tetrahydroisoquinoline-7-formic acid
At a 2-butyl-1,2,3 that is equipped with in concentrating hydrochloric acid (10 milliliters), be added in 90 ℃ in the sealed tube of 4-tetrahydroisoquinoline-7-nitrile (480 milligrams, 2.2 mmoles) solution and stirred 16 hours.Reaction mixture is cooled to room temperature, and adds dense ammonium hydroxide, filter then and collect the precipitation that forms, obtain title compound.ESI MSm/z 234[M+H]
+。
Step 3
2-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,2,3,4-tetrahydroisoquinoline-7-methane amide dihydrochloride
With 2-butyl-1,2,3, (190 milligrams of 4-tetrahydroisoquinolines-7-formic acid, 0.81 mmole), HATU is (465 milligrams, 1.2 mmole), the solution of HOBt (162 milligrams, 1.2 mmoles) and diisopropylethylamine (250 microlitres, 1.6 mmoles) stirred 15 minutes in methylene dichloride (2.0 milliliters).(the 2R that adding makes according to the method among the embodiment SP-272,3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] (332 milligrams of fourths-2-alcohol, 0.81 mmole) and diisopropylethylamine (250 microlitres in methylene dichloride (2.0 milliliters), 1.6 solution mmole), and reaction mixture stirred spend the night.Reaction mixture is diluted with methylene dichloride, with 1N hydrochloric acid (15 milliliters), saturated sodium bicarbonate (15 milliliters) and salt water washing.Organic layer drying (sal epsom) is filtered and concentrating under reduced pressure then.Purify by flash column chromatography (silicon-dioxide, 1: 9 methyl alcohol/chloroform), make title compound as free alkali.This solid is dissolved in methyl alcohol (1 milliliter), and handles with hydrochloric acid (0.2 milliliter, 1.0M ether, 0.2 mmole).Filter and collect the precipitation that generates, obtain title compound.ESI MS m/z550.3[M+H]
+。
Embodiment SP-186
3-{[cyclohexyl (methyl) amino] methyl }-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-5-methyl benzamide dihydrochloride
Similar to the method for describing among the embodiment SP-184,2 milliliters of liquid storages are added in anhydrous methylene chloride (1 milliliter) solution of N-methylcyclohexylamine (545 microlitres, 4.2 mmoles), and reaction mixture was at room temperature stirred 16 hours.Reaction mixture with methylene dichloride (10 milliliters) dilution, with saturated sodium bicarbonate and salt water washing, dry (sal epsom), is filtered and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 4% methyl alcohol/chloroform), obtain amine.This amine is dissolved in 2: 1: 1 tetrahydrofuran (THF)/methanol (4 milliliters), and adds a hydronium(ion) oxidation lithium (60 milligrams, 1.4 mmoles).Reactant was stirred 16 hours and concentrating under reduced pressure.Resistates is dissolved in DMF (4 milliliters) again, and adding diisopropylethylamine (465 microlitres, 2.7 mmole), HATU is (380 milligrams, 1 mmole) and (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and 1-[(3-iodine benzyl) amino] fourth-2-alcohol dihydrochloride (340 milligrams, 0.67 mmole).Reactant was at room temperature stirred 16 hours.Purify by flash column chromatography (silicon-dioxide, 7% methyl alcohol/chloroform), make title compound as free alkali.Resistates is dissolved in ether (3 milliliters) and adds ether (1 milliliter) solution of 1N hydrochloric acid.With this mixture concentrating under reduced pressure, make title compound.ESI MS m/z 676.2[M+H]
+。
Embodiment SP-187
5-{[butyl (methyl) amino] methyl }-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } the thiophene-2-carboxamide derivatives dihydrochloride
Step 1
5-(brooethyl) thiophene-2-carboxylic acid methyl esters
In methylene dichloride (9.0 milliliters) solution of ice-cold 5-(methylol) thiophene-2-carboxylic acid methyl esters (375 milligrams, 2.17 mmoles), add phosphorus tribromide (100 microlitres, 1.08 mmoles), and reaction mixture was stirred 0.5 hour at 0 ℃.In this reaction mixture, add saturated sodium bicarbonate (10 milliliters) carefully, and separate each phase.Organic phase is washed with water, and dry (sodium sulfate) filters and concentrating under reduced pressure, makes the title compound of its pure state.ESI MS m/z 235[M+H]
+。
Step 2
5-{[butyl (methyl) amino] methyl } the thiophene-2-carboxylic acid methyl esters
In anhydrous propanone (6.0 milliliters) solution of 5-(brooethyl) thiophene-2-carboxylic acid methyl esters (350 milligrams, 1.49 mmoles), add N-methylbutylamine (533 microlitres, 4.47 mmoles), and this solution at room temperature stirred spend the night.With the reactant concentrating under reduced pressure, be dissolved in again in the methylene dichloride then, with saturated sodium bicarbonate, water and salt water washing.With organic phase drying (sodium sulfate), filter and concentrating under reduced pressure then, make the title compound of its pure state.
1H NMR(300MHz，CDCl
3)δ7.65(d，J＝3Hz，1H)、6.88(d，J＝3Hz，1H)、3.86(s，3H)、3.69(s，2H)。2.41-2.36(m，2H)、2.25(s，3H)、1.53-1.43(m，2H)、1.34-1.25(m，2H)、0.91(t，J＝7Hz，3H)。
Step 3
5-{[butyl (methyl) amino] methyl } thiophene-2-carboxylic acid
5-{[butyl (methyl) amino in 2: 1: 1 diox/methanol (8.0 milliliters)] methyl } (280 milligrams of thiophene-2-carboxylic acid methyl esters, 1.16 mmole) in the solution, add a hydronium(ion) oxidation lithium (146 milligrams, 3.38 mmoles), and reaction mixture at room temperature stirred spend the night.With the reaction mixture concentrating under reduced pressure and make solid residue be divided into ethyl acetate layer and water layer.With 1N hydrochloric acid with aqueous phase as acidified to pH 1 and with 3: 1 chloroform/2-propyl alcohol extracted several times.With organic phase water and the salt water washing that merges, dry (sodium sulfate) filters and concentrating under reduced pressure, makes the title compound of its pure state.
1H NMR(300MHz，CD
3OD)δ7.75(d，J＝4Hz，1H)、7.41(d，J＝4Hz，1H)、4.63(s，2H)、3.20-3.14(m，2H)、2.85(s，3H)、1.82-1.72(m，2H)、1.42(tq，J＝8，7Hz，2H)、0.99(t，J＝7Hz，3H)。
Step 4
5-{[butyl (methyl) amino] methyl }-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } the thiophene-2-carboxamide derivatives dihydrochloride
5-{[butyl (methyl) amino in methylene dichloride (5.0 milliliters)] methyl } (171 milligrams of thiophene-2-carboxylic acids, 0.75 mmole) and N, add (285 milligrams of HBTU in N-diisopropylethylamine (250 microlitres, the 1.43 mmoles) solution, 0.75 mmole), and with reactant stirred 0.5 hour.To wherein adding (the 2R that makes according to the method among the embodiment SP-272,3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] (306 milligrams of fourths-2-alcohol, 0.75 methylene dichloride mmole) (5.0 milliliters) solution, contain N in this solution, N-diisopropylethylamine (250 microlitres, 1.43 mmoles).Then reaction mixture is at room temperature stirred and spend the night.Reaction mixture is diluted with methylene dichloride, with saturated sodium bicarbonate and salt water washing.With organic layer drying (sodium sulfate), filter and concentrating under reduced pressure then.Purify by flash column chromatography (silicon-dioxide, 95: 5 chloroform/methanol), make title compound as free alkali.This solid is dissolved in methyl alcohol (1 milliliter), and handles with hydrochloric acid (1.0M ether).Filter and collect the precipitation that generates, obtain title compound.ESI MS m/z 544.3[M+H]
+。
Embodiment SP-188
3-{[butyl (methyl) amino] methyl }-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-5-methyl benzamide dihydrochloride
Step 1
3-{[butyl (methyl) amino] methyl }-the 5-methyl-toluate
At-30 ℃, in 3-(methylol)-5-methyl-toluate that the method according among the embodiment SP-177 in anhydrous methylene chloride (10 milliliters) makes (1.1 grams, 6.1 mmoles) solution, be added to methylsulfonyl chloride (663 microlitres, 8.6 mmole), reactant is warmed to 0 ℃.Reactant was stirred 1 hour, filter then.Filtrate is added in the N-methylbutylamine (2.1 milliliters, 18.3 mmoles), and reactant was at room temperature stirred 16 hours.This solution decompression is concentrated.Purify by flash chromatography, make the title compound of its pure state.ESI MS m/z 250.2[M+H]
+。
Step 2
3-{[butyl (methyl) amino] methyl }-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-5-methyl benzamide dihydrochloride
With 3-{[butyl (methyl) amino] methyl }-(122 milligrams of 5-methyl-toluates, 0.49 mmole) be dissolved in 2: 1: 1 tetrahydrofuran (THF)/methanol (4 milliliters), and add a hydronium(ion) oxidation lithium (41 milligrams, 1 mmole), and reactant was stirred 16 hours.This solution decompression is concentrated.Resistates is dissolved in DMF (5 milliliters) again, and adding diisopropylethylamine (350 microlitres, 2 mmoles), HATU is (240 milligrams, 0.63 mmole) and (2R that makes according to the method among the embodiment SP-272,3S)-3-amino-4-(3, the 5-difluorophenyl)-and 1-{[1-(3-ethynyl phenyl) cyclopropyl] amino } fourth-2-alcohol dihydrochloride (215 milligrams, 0.5 mmole).Reactant was at room temperature stirred 16 hours.Reaction mixture is diluted with ethyl acetate, water, saturated sodium bicarbonate, salt water washing, dry (sodium sulfate) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 8% ethanol/methylene), make title compound as free alkali.Resistates is dissolved in ether (3 milliliters) and adds ether (1 milliliter) solution of 1N hydrochloric acid.With this mixture concentrating under reduced pressure, make title compound.ESI MS m/z574.3[M+H]
+。
Embodiment SP-189
3-{[butyl (methyl) amino] methyl }-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-5-methyl benzamide dihydrochloride
Similar to the method among the embodiment SP-188, with 3-{[butyl (methyl) amino] methyl }-(112 milligrams of 5-methyl-toluates, 0.45 mmole) be dissolved in 2: 1: 1 tetrahydrofuran (THF)/methanol (4 milliliters), and add (38 milligrams of hydronium(ion) oxidation lithiums, 0.9 mmole), and with reactant stirred 16 hours.This solution decompression is concentrated.Resistates is dissolved in DMF (5 milliliters) again, and adding diisopropylethylamine (350 microlitres, 2 mmoles), HATU is (240 milligrams, 0.63 mmole) and (2R that makes according to the method among the embodiment SP-272,3S)-3-amino-4-(3, the 5-difluorophenyl)-and 1-{[1-(3-ethynyl phenyl) cyclopropyl] amino } fourth-2-alcohol dihydrochloride (201 milligrams, 0.44 mmole).Reactant was at room temperature stirred 16 hours.Reaction mixture is diluted with ethyl acetate, water, saturated sodium bicarbonate, salt water washing, dry (sodium sulfate) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 8% ethanol/methylene), make title compound as free alkali.Resistates is dissolved in ether (3 milliliters) and adds ether (1 milliliter) solution of 1N hydrochloric acid.With this mixture concentrating under reduced pressure, make title compound.ESI MS m/z 592.3[M+H]
+。
Embodiment SP-190
3-bromo-5-{[butyl (methyl) amino] methyl }-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl) benzamide dihydrochloride
Step 1
3-bromo-5-{[butyl (methyl) amino] methyl } methyl benzoate
In-30 ℃ 3-bromo-5-(methylol) methyl benzoate in anhydrous methylene chloride (35 milliliters) (4.1 grams, the 16.8 mmoles) solution, add methylsulfonyl chloride (1.82 milliliters, 23.5 mmoles), add triethylamine (4.7 milliliters, 33.6 mmoles) then.Reaction mixture was stirred 45 minutes at 0 ℃, filter then.Filtrate is added in the N-methylbutylamine (6 milliliters, 50.4 mmoles), and at room temperature stirred 16 hours.This solution decompression is concentrated, and resistates is purified by flash chromatography (silicon-dioxide, 8% ethyl acetate/hexane), make title compound.ESI MS m/z 314.1[M+H]
+。
Step 2
3-bromo-5-{[butyl (methyl) amino] methyl }-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl) benzamide dihydrochloride
With 3-bromo-5-{[butyl (methyl) amino] methyl } (113 milligrams of methyl benzoate, 0.36 mmole) be dissolved in 2: 1: 1 tetrahydrofuran (THF)/methanol (4 milliliters), and add a hydronium(ion) oxidation lithium (30 milligrams, 0.72 mmole), and reactant was stirred 16 hours.This solution decompression is concentrated.Resistates is dissolved in DMF (5 milliliters) again, and adding diisopropylethylamine (250 microlitres, 1.44 mmole), HATU is (170 milligrams, 0.45 mmole) and (2R that makes according to embodiment SP-264,3S)-3-amino-4-(3, the 5-difluorophenyl)-and 1-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-3-methyl fourth-2-alcohol dihydrochloride (170 milligrams, 0.4 mmole).Reactant was at room temperature stirred 16 hours.Purify by flash column chromatography (silicon-dioxide, 8% ethanol/methylene), make title compound as free alkali.Resistates is dissolved in ether (3 milliliters) and adds ether (1 milliliter) solution of 1N hydrochloric acid.With this mixture concentrating under reduced pressure, make title compound.ESI MS m/z 638.2[M+H]
+。
Embodiment SP-191
3-{[butyl (methyl) amino] methyl }-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-5-methyl benzamide dihydrochloride
Similar to the method among the embodiment SP-188, with 3-{[butyl (methyl) amino] methyl }-(132 milligrams of 5-methyl-toluates, 0.53 mmole) be dissolved in 2: 1: 1 tetrahydrofuran (THF)/methanol (4 milliliters), and add (45 milligrams of hydronium(ion) oxidation lithiums, 1.06 mmole), and with reactant stirred 16 hours.This solution decompression is concentrated.Resistates is dissolved in DMF (5 milliliters) again, and adding diisopropylethylamine (350 microlitres, 2 mmoles), HATU is (240 milligrams, 0.63 mmole) and (2R that makes according to the method among the embodiment SP-272,3S)-3-amino-4-(3, the 5-difluorophenyl)-and 1-{[1-(3-ethynyl phenyl) cyclopropyl] amino } fourth-2-alcohol (191 milligrams, 0.5 mmole).Reactant was at room temperature stirred 16 hours.Reaction mixture is diluted with ethyl acetate, water, saturated sodium bicarbonate, salt water washing, dry (sodium sulfate) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 8% ethanol/methylene), make title compound as free alkali.Resistates is dissolved in ether (3 milliliters) and adds ether (1 milliliter) solution of 1N hydrochloric acid.With this mixture concentrating under reduced pressure, make title compound.ESI MS m/z 578.4[M+H]
+。
Embodiment SP-192
3-{[butyl (methyl) amino] methyl }-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl benzamide dihydrochloride
Similar to the method among the embodiment SP-188, with 3-{[butyl (methyl) amino] methyl }-(122 milligrams of 5-methyl-toluates, 0.49 mmole) be dissolved in 2: 1: 1 tetrahydrofuran (THF)/methanol (4 milliliters), and add (41 milligrams of hydronium(ion) oxidation lithiums, 1.0 mmole), and with reactant stirred 16 hours.This solution decompression is concentrated.Resistates is dissolved in DMF (5 milliliters) again, and adding diisopropylethylamine (350 microlitres, 2 mmoles), HATU is (240 milligrams, 0.63 mmole) and (2R that makes according to the method among the embodiment SP-272,3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] fourth-2-alcohol dihydrochloride (203 milligrams, 0.5 mmole).Reactant was at room temperature stirred 16 hours.Reaction mixture is diluted with ethyl acetate, water, saturated sodium bicarbonate, salt water washing, dry (sodium sulfate) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 8% ethanol/methylene), make title compound as free alkali.Resistates is dissolved in ether (3 milliliters) and adds ether (1 milliliter) solution of 1N hydrochloric acid.With this mixture concentrating under reduced pressure, make title compound.ESI MS m/z 552.3[M+H]
+。
Embodiment SP-193
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-3-{[isopentyl (methyl) amino] methyl }-5-methyl benzamide dihydrochloride
Similar to the method for describing among the embodiment SP-184,2 milliliters of liquid storages are added in anhydrous methylene chloride (1 milliliter) solution of N-isopentyl methylamine (526 microlitres, 4.2 mmoles), and reaction mixture was at room temperature stirred 16 hours.Reaction mixture with methylene dichloride (10 milliliters) dilution, with saturated sodium bicarbonate and salt water washing, dry (sal epsom), is filtered and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 4% methyl alcohol/chloroform), obtain amine.This amine is dissolved in 2: 1: 1 tetrahydrofuran (THF)/methanol (4 milliliters), and adds a hydronium(ion) oxidation lithium (42 milligrams, 1 mmole).Reactant was stirred 16 hours and concentrating under reduced pressure.Resistates is dissolved in DMF (5 milliliters) again, and adding diisopropylethylamine (355 microlitres, 2 mmoles), HATU is (242 milligrams, 0.64 mmole) and (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and 1-[(3-iodine benzyl) amino] fourth-2-alcohol dihydrochloride (257 milligrams, 0.5 mmole).Reactant was at room temperature stirred 16 hours.Purify by flash column chromatography (silicon-dioxide, 7% methyl alcohol/chloroform), make title compound as free alkali.Resistates is dissolved in ether (3 milliliters) and adds ether (1 milliliter) solution of 1N hydrochloric acid.With this mixture concentrating under reduced pressure, make title compound.ESI MS m/z 664.2[M+H]
+。
Embodiment SP-194
3-{[butyl (methyl) amino] methyl }-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(1-phenycyclopropyl) amino] propyl group }-5-methyl benzamide dihydrochloride
Similar to the method among the embodiment SP-188, with 3-{[butyl (methyl) amino] methyl }-(170 milligrams of 5-methyl-toluates, 0.68 mmole) be dissolved in 2: 1: 1 tetrahydrofuran (THF)/methanol (4 milliliters), and add (57 milligrams of hydronium(ion) oxidation lithiums, 1.4 mmole), and with reactant stirred 2 hours.This solution decompression is concentrated.Resistates is dissolved in DMF (3 milliliters) again, and adding diisopropylethylamine (472 microlitres, 2.7 mmole), HATU is (322 milligrams, 0.85 mmole) and (2R that makes according to the method among the embodiment SP-XYZ, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(1-phenycyclopropyl) amino] fourth-2-alcohol dihydrochloride (275 milligrams, 0.68 mmole).Reactant was at room temperature stirred 16 hours.Reaction mixture is diluted with ethyl acetate, water, saturated sodium bicarbonate, salt water washing, dry (sodium sulfate) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 8% ethanol/methylene), make title compound as free alkali.Resistates is dissolved in ether (3 milliliters) and adds ether (1 milliliter) solution of 1N hydrochloric acid.With this mixture concentrating under reduced pressure, make title compound.ESI MS m/z 550.3[M+H]
+。
Embodiment SP-195
3-{[butyl (methyl) amino] methyl }-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-isopropyl benzyl) amino] propyl group }-5-methyl benzamide dihydrochloride
Similar to the method among the embodiment SP-188, with 3-{[butyl (methyl) amino] methyl }-(50 milligrams of 5-methyl-toluates, 0.2 mmole) be dissolved in 2: 1: 1 tetrahydrofuran (THF)/methanol (4 milliliters), and add (17 milligrams of hydronium(ion) oxidation lithiums, 0.4 mmole), and with reactant stirred 16 hours.This solution decompression is concentrated.Resistates is dissolved in DMF (2 milliliters) again, and adding diisopropylethylamine (140 microlitres, 0.8 mmole), HATU is (95 milligrams, 0.25 mmole) and (2R that makes according to the method among the embodiment SP-170,3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-isopropyl benzyl) amino] fourth-2-alcohol dihydrochloride (85 milligrams, 0.2 mmole).Reactant was at room temperature stirred 16 hours.Reaction mixture is diluted with ethyl acetate, water, saturated sodium bicarbonate, salt water washing, dry (sodium sulfate) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 8% ethanol/methylene), make title compound as free alkali.Resistates is dissolved in ether (3 milliliters) and adds ether (1 milliliter) solution of 1N hydrochloric acid.With this mixture concentrating under reduced pressure, make title compound.ESI MS m/z 566.3[M+H]
+。
Embodiment SP-196
3-{[butyl (methyl) amino] methyl }-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-5-(1,3-oxazole-2-yl) benzamide dihydrochloride
Step 1
3-(methoxycarbonyl)-5-(1,3-oxazole 2-yl) phenylformic acid
In-70 ℃ of tetrahydrofuran (THF) (10 milliliters) solution, add n-Butyl Lithium (the 2.5M solution in hexane, 2.75 milliliters, 6.9 mmoles) through stirring De oxazole (432 milligrams, 6.3 mmoles).After 30 minutes, add zinc chloride (the 1M solution in ether, 18.75 milliliters, 18.75 mmoles), and reaction mixture is warmed to 0 ℃ reaches 1 hour.In this mixture, be added in the anhydrous tetrahydro furan (10 milliliters) according to embodiment SP-281,3-iodo-5-(methoxycarbonyl) phenylformic acid that method in the step 1 makes (1.8 grams, 6 mmoles) solution adds palladium (0) four (triphenyl phosphine) (291 milligrams, 0.25 mmole) subsequently.With reaction mixture refluxed heating 15 hours.With this reaction mixture cooling, through diatomite filtration, with ethyl acetate (50 milliliters) dilution, water and salt water washing, dry (sodium sulfate), filtration and concentrating under reduced pressure.Purify by flash column chromatography (silica gel, 5% ethanol/methylene), obtain the title compound of its pure state.ESI MS m/z 246.1[M-H]
+。
Step 2
3-{[butyl (methyl) amino] methyl }-5-(1,3-oxazole-2-yl) methyl benzoate
In anhydrous tetrahydro furan (10 milliliters) solution of ice-cold 3-(methoxycarbonyl)-5-(1,3-oxazole 2-yl) phenylformic acid (340 milligrams, 1.4 mmoles), slowly add lithium borohydride (250 milligrams, 11 mmoles).Reactant was stirred 30 minutes, add dehydrated alcohol (4 milliliters) then, and reactant was stirred 1 hour.This solution is poured on contains excessive hydrochloric acid on ice, and use ethyl acetate extraction.With organic layer water, salt water washing, dry (sodium sulfate) filters and concentrating under reduced pressure.Resistates is dissolved in 20% methyl alcohol/benzene (50 milliliters) again, and adds hexane (0.9 milliliter, the 1.8 mmoles) solution of 2M trimethyl silyl diazomethane.Reactant was at room temperature stirred 2 hours, then concentrating under reduced pressure.Resistates is dissolved in anhydrous methylene chloride (10 milliliters) again, is cooled to-30 ℃, add methylsulfonyl chloride (150 microlitres, 1.9 mmoles) and triethylamine (380 microlitres, 2.7 mmoles) then.Reactant was stirred 15 minutes at 0 ℃, add N-methylbutylamine (480 microlitres, 4 mmoles) then, and reactant was at room temperature stirred 16 hours.This solution decompression is concentrated.Purify by flash column chromatography (silica gel, 40-100% ethyl acetate/hexane gradient), make the title compound of its pure state.ESIMS m/z 303.3[M+H]
+。
Step 3
3-{[butyl (methyl) amino] methyl }-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-5-(1,3-oxazole-2-yl) benzamide dihydrochloride
With 3-{[butyl (methyl) amino] methyl }-5-(1,3-oxazole-2-yl) methyl benzoate (30 milligrams, 0.1 mmole) is dissolved in 2: 1: 1 tetrahydrofuran (THF)/methanol (4 milliliters), and adds (10 milligrams of hydronium(ion) oxidation lithiums, 0.2 mmole), and with reactant stirred 16 hours.This solution decompression is concentrated.Resistates is dissolved in DMF (1 milliliter) again, and adding diisopropylethylamine (70 microlitres, 0.4 mmole), HATU is (57 milligrams, 0.15 mmole) and (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and 1-{[1-(3-ethynyl phenyl) cyclopropyl] amino } fourth-2-alcohol dihydrochloride (203 milligrams, 0.5 mmole).Reactant was at room temperature stirred 2 hours.Reaction mixture is diluted with ethyl acetate, water, saturated sodium bicarbonate, salt water washing, dry (sodium sulfate) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 9-10% ethanol/methylene), make title compound as free alkali.Resistates is dissolved in ether (3 milliliters) and adds ether (1 milliliter) solution of 1N hydrochloric acid.With this mixture concentrating under reduced pressure, make title compound.ESI MS m/z 627.3[M+H]
+。
Embodiment SP-197
3-{[butyl (methyl) amino] methyl }-5-cyano group-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl) benzamide dihydrochloride
Will be at 3-bromo-5-(methoxycarbonyl) phenylformic acid in the methyl-2-pyrrolidone (20 milliliters) (4 grams, 15.4 mmoles) and cupric cyanide (I) (4.1 grams, 89.5 mmoles) and 175 ℃ of heating 4 hours.With the reactant cooling, add entry.With this aqueous solution dichloromethane extraction,, filter and concentrating under reduced pressure with 1N hydrochloric acid (aqueous solution), salt water washing, dry (sodium sulfate).Resistates is dissolved in tetrahydrofuran (THF) (20 milliliters), in ice bath, cools off, and slowly add lithium borohydride (475 milligrams, 22 mmoles).Under this temperature, reactant was stirred 2 hours.Dropwise add dehydrated alcohol (4 milliliters), and reactant was stirred 30 minutes.This mixture is poured on contains excessive hydrochloric acid on ice.After stopping to generate gas, with this solution of dichloromethane extraction, and concentrating under reduced pressure.
Resistates is dissolved in 20% methyl alcohol/benzene (20 milliliters), and adds hexane (1.3 milliliters, the 2.6 mmoles) solution of 2M trimethyl silyl diazomethane.Reactant is at room temperature stirred 2 hours, and concentrating under reduced pressure.Then resistates is dissolved in anhydrous methylene chloride (10 milliliters), is cooled to-30 ℃, add methylsulfonyl chloride (216 microlitres, 2.8 mmoles) and triethylamine (556 microlitres, 4 mmoles) then.Reactant is warmed to 0 ℃ and stirred 15 minutes, filters then.Filtrate is added N-methylbutylamine (5 milliliters), and stirred 16 hours.This solution decompression is concentrated and purify, make a kind of oil by flash chromatography (silica gel, 40% ethyl acetate/hexane).Should oil (107 milligrams) be dissolved in 2: 1: 1 tetrahydrofuran (THF)/methanol (4 milliliters), and add a hydronium(ion) oxidation lithium (35 milligrams, 0.8 mmole), and reactant was stirred 1.5 hours.This solution decompression is concentrated.
Resistates is dissolved in DMF (3 milliliters) again, and adding diisopropylethylamine (280 microlitres, 1.6 mmole), HATU is (230 milligrams, 0.6 mmole) and (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and 1-{[1-(3-ethynyl phenyl) cyclopropyl] amino } fourth-2-alcohol dihydrochloride (206 milligrams, 0.5 mmole).Reactant was at room temperature stirred 16 hours.Reaction mixture is diluted with ethyl acetate, water, saturated sodium bicarbonate, salt water washing, dry (sodium sulfate) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 8% ethanol/methylene), make title compound as free alkali.Resistates is dissolved in ether (3 milliliters) and adds ether (1 milliliter) solution of 1N hydrochloric acid.With this mixture concentrating under reduced pressure, make title compound.ESI MS m/z585.3[M+H]
+。
Embodiment SP-198
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-{[(2-furyl methyl) (methyl) amino] methyl }-5-methyl benzamide dihydrochloride
Step 1
3-bromo-5-(methylol) methyl benzoate
Ice-cold, in tetrahydrofuran (THF) (77.2 milliliters) solution of 3-bromo-5-(methoxycarbonyl) phenylformic acid through stirring (5.0 grams, 19.3 mmoles), add borine-methyl-sulfide complex compound (10.6 milliliters, 2.0M tetrahydrofuran (THF), 21.1 mmoles).Reaction mixture was heated 2 hours at 50 ℃.Make the reaction mixture stopped reaction with methyl alcohol (50 milliliters), and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 50% ethyl acetate/hexane), make title compound.
1H NMR(300MHz，CDCl
3)δ8.03(s，1H)、7.90(s，1H)、7.69(s，1H)、4.69(s，1H)、3.91(s，3H)、2.83(br s，1H)。
Step 2
3-(methylol)-5-methyl-toluate
At (4.53 grams of 3-bromo-5-(methylol) methyl benzoate through stirring, 18.5 in mmole) De diox (74 milliliters) solution, add cesium carbonate (6.0 grams, 18.5 salt of wormwood (5.1 grams mmole),, 37 mmoles) and palladium (0) four (triphenyl phosphine) (2.1 the gram, 1.85 mmole), add trimethylboroxin (5.1 milliliters, 37 mmoles) then.With this reaction mixture refluxed 12 hours, be cooled to room temperature, then phase-splitting between water and ethyl acetate.Water and salt water washing organic layer, dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 25% ethyl acetate/hexane), absorbed dirty oil on the silica gel,, make title compound.
1H NMR(300MHz，CDCl
3)δ7.75(s，1H)、7.65(s，1H)、7.39(s，1H)、5.31(br s，1H)、4.53(s，1H)，3.84(s，3H)、2.36(s，3H)。
Step 3
The 3-{[(2-furyl methyl) (methyl) amino] methyl }-the 5-methyl-toluate
Ice-cold, in methylene dichloride (2.2 milliliters) solution of 3-(methylol)-5-methyl-toluate (200 milligrams, 1.1 mmoles), add (0.304 milliliter of triethylamine through stirring, 2.2 mmole) add methylsulfonyl chloride (0.116 milliliter, 1.5 mmoles) then.Reaction mixture was stirred 15 minutes and filtered.In filtrate, add N methyl furfuryl amine (367 milligrams, 3.3 mmoles), and reaction mixture was at room temperature stirred 5 hours.Reaction mixture with methylene dichloride (10 milliliters) dilution, is washed with 1N hydrochloric acid, saturated sodium bicarbonate, and dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 50% ethyl acetate/hexane), make title compound.
1H NMR(300MHz，CDCl
3)δ7.76(d，J＝11Hz，2H)、3.79(d，J＝6Hz，2H)、6.32(d，J＝2Hz，2H)、6.21(d，J＝3Hz，1H)、3.90(s，3H)、3.59(s，3H)、3.53(s，2H)、2.39(s，3H)、2.23(s，3H)。
Step 4
The 3-{[(2-furyl methyl) (methyl) amino] methyl }-the 5-tolyl acid
3-{[(2-furyl methyl in methyl alcohol (2 milliliters), tetrahydrofuran (THF) (1 milliliter) and water (1 milliliter)) (methyl) amino through stirring] methyl }-(180 milligrams of 5-methyl-toluates, 0.66 mmole) in the solution, add (277 milligrams of lithium hydroxides, 6.6 mmole), and with this reaction mixture at room temperature stirred 2 hours.With the reaction mixture concentrating under reduced pressure, be dissolved in methylene dichloride, filter and filtrate decompression is concentrated, make title compound.ESI MS m/z 258[M+H]
+。
Step 5
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-{[(2-furyl methyl) (methyl) amino] methyl }-5-methyl benzamide dihydrochloride
At 3-{[(2-furyl methyl through stirring) (methyl) amino] methyl }-(170 milligrams of 5-tolyl acids, 0.66 in methylene dichloride mmole) (3 milliliters) solution, add (375 milligrams of HBTU, 0.99 mmole), (134 milligrams of HOBt, 0.99 mmole) and N, (0.334 milliliter of N-diisopropylethylamine, 1.98 mmole), add (the 2R that makes according to the method among the embodiment SP-272 then, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] fourth-2-alcohol (269 milligrams, 0.66 mmole), and reaction mixture at room temperature stirred 12 hours.Reaction mixture is diluted with methylene dichloride, water and saturated sodium bicarbonate washing, dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 10% methyl alcohol/chloroform), make title compound as free alkali.This compound is dissolved in methyl alcohol (2 milliliters), and in this solution, adds hydrochloric acid (5 milliliters, 4N diox, 20 mmoles).Reaction mixture was at room temperature stirred 1 hour.Then this reaction mixture is diluted with ethyl acetate (10 milliliters).Filter and collect the precipitation that forms, obtain title compound.ESI MS m/z 576[M+H]
+。
Embodiment SP-199
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-{[(2-methoxy ethyl) (methyl) amino] methyl }-5-methyl benzamide dihydrochloride
Step 1
The 3-{[(2-methoxy ethyl) (methyl) amino] methyl }-the 5-methyl-toluate
Ice-cold, in methylene dichloride (2.2 milliliters) solution of 3-(methylol)-5-methyl-toluate (200 milligrams, 1.1 mmoles), add (0.304 milliliter of triethylamine through stirring, 2.2 mmole) add methylsulfonyl chloride (0.116 milliliter, 1.5 mmoles) then.Reaction mixture was stirred 15 minutes and filtered.In filtrate, add 2-methoxyl group-N-benzylidene amino (0.354 milliliter, 3.3 mmoles), and reaction mixture was at room temperature stirred 5 hours.Reaction mixture with methylene dichloride (10 milliliters) dilution, is washed with 1N hydrochloric acid and saturated sodium bicarbonate, and dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 50% ethyl acetate/hexane), make title compound.
1H NMR(300MHz，CDCl
3)δ7.75(d，J＝5Hz，2H)、7.37(s，3H)、3.90(s，1H)、3.56(s，2H)、3.52(t，J＝6Hz，2H)、3.34(s，3H)、2.61(t，J＝6Hz，2H)、2.39(s，3H)、2.26(s，3H)。
Step 2
The 3-{[(2-methoxy ethyl) (methyl) amino] methyl }-the 5-tolyl acid
3-{[(2-methoxy ethyl in methyl alcohol (2 milliliters), tetrahydrofuran (THF) (1 milliliter) and water (1 milliliter)) (methyl) amino through stirring] methyl }-(180 milligrams of 5-methyl-toluates, 0.72 mmole) in the solution, add (302 milligrams of lithium hydroxides, 7.2 mmole), and with this reaction mixture at room temperature stirred 2 hours.With the reaction mixture concentrating under reduced pressure, be dissolved in methylene dichloride, filter and filtrate decompression is concentrated, make title compound.ESI MS m/z 238[M+H]
+。
Step 3
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-{[(2-methoxy ethyl) (methyl) amino] methyl }-5-methyl benzamide dihydrochloride
At 3-{[(2-methoxy ethyl through stirring) (methyl) amino] methyl }-(140 milligrams of 5-tolyl acids, 0.56 in methylene dichloride mmole) (3 milliliters) solution, add (318 milligrams of HBTU, 0.84 mmole), HOBt is (114 milligrams, 0.84 mmole) and N, (0.284 milliliter of N-diisopropylethylamine, 1.68 mmole), add (the 2R that makes according to the method among the embodiment SP-272 then, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] fourth-2-alcohol (228 milligrams, 0.56 mmole).Reaction mixture was at room temperature stirred 24 hours, with the methylene dichloride dilution, water and saturated sodium bicarbonate washing, dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 10% methyl alcohol/chloroform), make title compound as free alkali.This compound is dissolved in methyl alcohol (2 milliliters), and in this solution, adds hydrochloric acid (5 milliliters, 4N diox, 20 mmoles).Reaction mixture was at room temperature stirred 1 hour.Then this reaction mixture is diluted with ethyl acetate (10 milliliters).Filter and collect the precipitation that forms, obtain title compound.ESI MS m/z 554[M+H]
+。
Embodiment SP-200
3-{[[2-(diethylin) ethyl] (methyl) amino] methyl }-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl benzamide tri hydrochloride
Step 1
3-{[[2-(diethylin) ethyl] (methyl) amino] methyl }-the 5-methyl-toluate
Ice-cold, in 3-(the methylol)-5-methyl-toluate (200 milligrams, 1.19 mmoles) through stirring and methylene dichloride (5 milliliters) solution of triethylamine (241 milligrams, 2.38 mmoles), add methylsulfonyl chloride (191 milliliters, 1.67 mmoles).Reaction mixture was stirred 15 minutes, remove the precipitation that forms by filtering, and add N, N-diethyl-N '-methyl ethylenediamine (465 milligrams, 3.57 mmoles).This reaction mixture was at room temperature stirred 2 hours, then concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 9: 1 chloroform/methanol), make title compound.
1H NMR(300MHz，CDCl
3)δ8.02(s，2H)、7.33(s，1H)、3.56(s，3H)、3.48(s，2H)、2.95(m，4H)、2.75(m，4H)、2.41(s，3H)、2.31(s，3H)、1.21(m，6H)。
Step 2
3-{[[2-(diethylin) ethyl] (methyl) amino] methyl }-the 5-tolyl acid
With 3-{[[2-(diethylin) ethyl] (methyl) amino] methyl }-(296 milligrams of 5-methyl-toluates, 1.01 mmole) and 3: 1: 1 methyl alcohol/tetrahydrofuran (THF)/2N sodium hydroxide (10 milliliters) mixture stir and to spend the night, be divided into ethyl acetate layer and water layer then.With 1N hydrochloric acid water layer is acidified to pH3 and uses chloroform extraction.With the water layer concentrating under reduced pressure, make title compound.
1H NMR(300MHz，DMSO-d
6)δ7.99(s，1H)、7.82(s，1H)、7.80(s，1H)、4.56(m，2H)、4.31(m，2H)、3.98(m，2H)、3.17(m，4H)、2.51(s，3H)、2.50(s，3H)、1.27(m，6H)。
Step 3
3-{[[2-(diethylin) ethyl] (methyl) amino] methyl }-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl benzamide tri hydrochloride
3-{[[2-(diethylin) ethyl in methylene dichloride (5 milliliters) through stirring] (methyl) amino] methyl }-(267 milligrams of 5-tolyl acids, 0.959 (the 2R that makes according to the method among embodiment SP-272 mmole),, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] (391 milligrams of fourths-2-alcohol, 0.959 mmole), HOBt is (129 milligrams, 0.959 mmole) and N, (496 milligrams of N-diisopropylethylamine, 3.84 mmole) in the solution, add EDC (331 milligrams, 1.73 mmoles).The reaction mixture stirring is spent the night, be divided into ethyl acetate layer and water layer then.With 1N hydrochloric acid, saturated sodium bicarbonate and salt water washing organic layer, dry (sodium sulfate) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 9: 1: 1 methylene chloride/ammonium hydroxide), make title compound.ESI MS m/z 595.4[M+H]
+。
Embodiment SP-201
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-oxo 1,2-indane-5-methane amide
In 3-oxo 1,2-indane-5-formic acid (2.0 grams, 11.5 in DMF mmole) (10 milliliters) solution, add diisopropylethylamine (8 milliliters, 46 mmoles), HATU (5.5 grams, 14.4 mmoles), add (the 2R that makes according to the method among the embodiment SP-272 then, 3S)-and 3-amino-4-(3, the 5-difluorophenyl)-1-[(3-Ethylbenzyl) amino] fourth-2-alcohol dihydrochloride (5.6 grams, 13.8 mmoles).Reactant was at room temperature stirred 1 hour.Make reactant anti-phase between ethyl acetate and water.With 1N hydrochloric acid, saturated sodium bicarbonate and salt water washing organic layer, dry (sodium sulfate) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 8% methyl alcohol/2 methyl chloride), make title compound.ESI MS m/z 493.2[M+H]
+。
Embodiment SP-202
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-hydroxyl 1,2-indane-5-methane amide
N-{ (the 1S that is making according to the method among the embodiment SP-201,2R)-1-(3, the 5-difluorobenzyl)-and the 3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-oxo 1, (66 milligrams of 2-indane-5-methane amide, 0.13 in ice cold methanol mmole) (3 milliliters) solution, add sodium borohydride (20 milligrams, 0.52 mmole).Reactant was at room temperature stirred 3 hours.With the reactant concentrating under reduced pressure, water-soluble again (3 milliliters) and phase-splitting in ethyl acetate.Water, saturated sodium bicarbonate and salt water washing organic layer, dry (sodium sulfate) filters and concentrating under reduced pressure, makes title compound.ESI MS m/z 495.2[M+H]
+。
Embodiment SP-203
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[isobutyl-(methyl) amino] methyl }-5-toluyl amine hydrochlorate
Step 1
3-{[isobutyl-(methyl) amino] methyl }-the 5-methyl-toluate
Ice-cold, in methylene dichloride (2.2 milliliters) solution of 3-(methylol)-5-methyl-toluate (200 milligrams, 1.1 mmoles), add (0.304 milliliter of triethylamine through stirring, 2.2 mmole) add methylsulfonyl chloride (0.116 milliliter, 1.5 mmoles) then.Reaction mixture was stirred 15 minutes and filtered.In filtrate, add N-methyl isobutylamine (287 milligrams, 3.3 mmoles), and reaction mixture was at room temperature stirred 5 hours.Reaction mixture with methylene dichloride (10 milliliters) dilution, is washed with 1N hydrochloric acid and saturated sodium bicarbonate, and dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 15% ethyl acetate/hexane), make title compound.
1H NMR(300MHz，CDCl
3)δ7.77(s，1H)、7.73(s，1H)、7.36(s，1H)、3.90(s，3H)、3.44(s，2H)、2.38(s，3H)、2.41(s，3H)、2.10(d，J＝8Hz，2H)、1.81(m，1H)、0.90(d，J＝7Hz，6H)。
Step 2
3-{[isobutyl-(methyl) amino] methyl }-the 5-tolyl acid
At 3-{[isobutyl-(methyl) amino through stirring] methyl }-(120 milligrams of 5-methyl-toluates, 0.48 mmole) in the solution in methyl alcohol (2 milliliters), tetrahydrofuran (THF) (1 milliliter) and water (1 milliliter), add (200 milligrams of lithium hydroxides, 4.8 mmole), and with this reaction mixture at room temperature stirred 2 hours.With the reaction mixture concentrating under reduced pressure, be dissolved in methylene dichloride, filter and filtrate decompression is concentrated, make title compound.ESI MS m/z 236[M+H]
+。
Step 3
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[isobutyl-(methyl) amino] methyl }-5-toluyl amine hydrochlorate
At 3-{[isobutyl-(methyl) amino through stirring] methyl }-(110 milligrams of 5-tolyl acids, 0.48 in methylene dichloride mmole) (3 milliliters) solution, add (273 milligrams of HBTU, 0.72 mmole), (97 milligrams of HOBt, 0.72 mmole) and N, (0.243 milliliter of N-diisopropylethylamine, 1.44 mmole), add (the 2R that makes according to the method among the embodiment SP-272 then, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] fourth-2-alcohol (196 milligrams, 0.48 mmole), and reaction mixture at room temperature stirred 12 hours.Reaction mixture is diluted with methylene dichloride, water and saturated sodium bicarbonate washing, dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 10% methyl alcohol/chloroform), make a kind of clean oil, it is dissolved in methyl alcohol (2 milliliters).In this solution, add hydrochloric acid (5 milliliters, 4N diox, 20 mmoles), and reaction mixture was at room temperature stirred 1 hour.Then this reaction mixture is diluted with ether (10 milliliters).Filter and collect the precipitation that forms, obtain title compound.ESI MS m/z 552.5[M+H]
+。
Embodiment SP-204
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl-5-{[methyl (amyl group) amino] methyl } benzamide dihydrochloride
Step 1
3-methyl-5-{[methyl (amyl group) amino] methyl } methyl benzoate
Ice-cold, in methylene dichloride (2.2 milliliters) solution of 3-(methylol)-5-methyl-toluate (200 milligrams, 1.1 mmoles), add (0.304 milliliter of triethylamine through stirring, 2.2 mmole) add methylsulfonyl chloride (0.116 milliliter, 1.5 mmoles) then.Reaction mixture was stirred 15 minutes and filtered.In filtrate, add N-dimethylpentylamine (333 milligrams, 3.3 mmoles), and reaction mixture was at room temperature stirred 5 hours.Reaction mixture with methylene dichloride (10 milliliters) dilution, is washed with 1N hydrochloric acid and saturated sodium bicarbonate, and dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 15% ethyl acetate/hexane), make title compound.
1H NMR(300MHz，CDCl
3)δ7.75(d，J＝4Hz，2H)、7.36(s，1H)、3.90(s，3H)、3.47(s，2H)、3.13(t，J＝9Hz，3H)、2.39(s，2H)、2.34(d，J＝8Hz，2H)、2.18(s，3H)、1.45(m，5H)、1.32(m，2H)。
Step 2
3-methyl-5-{[methyl (amyl group) amino] methyl } phenylformic acid
At 3-methyl-5-{[methyl (amyl group) amino through stirring] methyl } (120 milligrams of methyl benzoate, 0.46 mmole) in the solution in methyl alcohol (2 milliliters), tetrahydrofuran (THF) (1 milliliter) and water (1 milliliter), add (191 milligrams of lithium hydroxides, 4.6 mmole), and with this reaction mixture at room temperature stirred 2 hours.With the reaction mixture concentrating under reduced pressure, be dissolved in methylene dichloride, filter and filtrate decompression is concentrated, make title compound.ESIMS m/z 250[M+H]
+。
Step 3
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl-5-{[methyl (amyl group) amino] methyl } benzamide dihydrochloride
At 3-methyl-5-{[methyl (amyl group) amino through stirring] methyl } (110 milligrams in phenylformic acid, 0.44 in methylene dichloride mmole) (3 milliliters) solution, add (250 milligrams of HBTU, 0.66 mmole), (90 milligrams of HOBt, 0.66 mmole) and N, (0.222 milliliter of N-diisopropylethylamine, 1.32 mmole), add (the 2R that makes according to the method among the embodiment SP-272 then, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] fourth-2-alcohol (180 milligrams, 0.44 mmole), and reaction mixture at room temperature stirred 12 hours.Reaction mixture is diluted with methylene dichloride, water and saturated sodium bicarbonate washing, dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 10% methyl alcohol/chloroform), make a kind of clean oil, it is dissolved in methyl alcohol (2 milliliters).In this solution, add hydrochloric acid (5 milliliters, 4N diox, 20 mmoles), and reaction mixture was at room temperature stirred 1 hour.Then this reaction mixture is diluted with ether (10 milliliters).Filter and collect the precipitation that forms, obtain title compound.ESI MS m/z 566.5[M+H]
+。
Embodiment SP-205
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(2R)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] methyl }-5-methyl benzamide dihydrochloride
Step 1
3-{[(2R)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] methyl }-the 5-methyl-toluate
Ice-cold, in methylene dichloride (2.2 milliliters) solution of 3-(methylol)-5-methyl-toluate (200 milligrams, 1.1 mmoles), add (0.304 milliliter of triethylamine through stirring, 2.2 mmole) add methylsulfonyl chloride (0.116 milliliter, 1.5 mmoles) then.Reaction mixture was stirred 15 minutes and filtered.In filtrate, add (R)-2-(methoxymethyl) tetramethyleneimine (380 milligrams, 3.3 mmoles), and reaction mixture was at room temperature stirred 5 hours.Reaction mixture with methylene dichloride (10 milliliters) dilution, is washed with 1N hydrochloric acid and saturated sodium bicarbonate, and dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 50% ethyl acetate/hexane), make title compound.
1H NMR(300MHz，CDCl
3)δ7.77(s，1H)、7.73(s，1H)、7.37(s，1H)、4.11(d，J＝13Hz，1H)、3.90(d，J＝6Hz，2H)、3.41(m，2H)、3.34(m，3H)、2.89(m，1H)、2.71(m，1H)、2.38(s，3H)、2.19(m，3H)、1.93(m，1H)、1.54(m，3H)。
Step 2
3-{[(2R)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] methyl }-the 5-tolyl acid
At 3-{[(2R through stirring)-2-(methoxymethyl) tetramethyleneimine-1-yl] methyl }-(120 milligrams of 5-methyl-toluates, 0.43 mmole) in the solution in methyl alcohol (2 milliliters), tetrahydrofuran (THF) (1 milliliter) and water (1 milliliter), add (180 milligrams of lithium hydroxides, 4.3 mmole), and with this reaction mixture at room temperature stirred 2 hours.With the reaction mixture concentrating under reduced pressure, be dissolved in methylene dichloride, filter and filtrate decompression is concentrated, make title compound.ESI MS m/z 264[M+H]
+。
Step 3
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(2R)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] methyl }-5-methyl benzamide dihydrochloride
At 3-{[(2R through stirring)-2-(methoxymethyl) tetramethyleneimine-1-yl] methyl }-(113 milligrams of 5-tolyl acids, 0.43 in methylene dichloride mmole) (3 milliliters) solution, add (165 milligrams of HBTU, 0.66 mmole), (89 milligrams of HOBt, 0.66 mmole) and N, (0.220 milliliter of N-diisopropylethylamine, 1.30 mmole), add (the 2R that makes according to the method among the embodiment SP-272 then, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] fourth-2-alcohol (175 milligrams, 0.43 mmole), and reaction mixture at room temperature stirred 12 hours.Reaction mixture is diluted with methylene dichloride, water and saturated sodium bicarbonate washing, dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 10% methyl alcohol/chloroform), make a kind of clean oil, it is dissolved in methyl alcohol (2 milliliters).In this solution, add hydrochloric acid (5 milliliters, 4N diox, 20 mmoles), and reaction mixture was at room temperature stirred 1 hour.Then this reaction mixture is diluted with ether (10 milliliters).Filter and collect the precipitation that forms, obtain title compound.ESI MS m/z580.4[M+H]
+。
Embodiment SP-206
3-bromo-5-{[butyl (methyl) amino] methyl }-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide dihydrochloride
Will be according to embodiment SP-190,3-bromo-5-{[butyl (methyl) amino that method in the step 1 makes] methyl } (170 milligrams of methyl benzoate, 0.54 mmole) be dissolved in 2: 1: 1 tetrahydrofuran (THF)/methanol (4 milliliters), and add (45 milligrams of hydronium(ion) oxidation lithiums, 1.1 mmole), and with reactant stirred 16 hours.This solution decompression is concentrated.Resistates is dissolved in DMF (5 milliliters) again, and adding diisopropylethylamine (375 microlitres, 2.16 mmole), HATU is (256 milligrams, 0.68 mmole) and (2R that makes according to the method among the embodiment SP-272,3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] fourth-2-alcohol dihydrochloride (265 milligrams, 0.65 mmole).Reactant was at room temperature stirred 1 hour.Reaction mixture is diluted with methylene dichloride, water and saturated sodium bicarbonate washing, dry (sodium sulfate) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 8% ethanol/methylene), make title compound as free alkali.Resistates is dissolved in ether (3 milliliters) and adds ether (1 milliliter) solution of 1N hydrochloric acid.With this mixture concentrating under reduced pressure, make title compound.ESI MS m/z 616.2[M+H]
+。
Embodiment SP-207
3-[(fourth amino) methyl]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl benzamide dihydrochloride
Step 1
3-[(fourth amino) methyl]-the 5-methyl-toluate
Ice-cold, in methylene dichloride (2.2 milliliters) solution of 3-(methylol)-5-methyl-toluate (200 milligrams, 1.1 mmoles), add (0.304 milliliter of triethylamine through stirring, 2.2 mmole) add methylsulfonyl chloride (0.116 milliliter, 1.5 mmoles) then.Reaction mixture was stirred 15 minutes and filtered.In filtrate, add butylamine (0.543 milliliter, 5.5 mmoles), and reaction mixture was at room temperature stirred 5 hours.Reaction mixture with methylene dichloride (10 milliliters) dilution, is washed with 1N hydrochloric acid and saturated sodium bicarbonate, and dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 89: 10: 1 chloroform/methanol/ammonium hydroxide), make title compound.
1H NMR(300MHz，CDCl
3)δ7.75(s，1H)、7.70(s，1H)、7.24(br s，1H)、4.42(d，J＝9Hz，2H)、3.90(m，3H)、3.16(m，2H)、2.38(s，3H)、1.64(s，2H)、1.44(m，9H)、1.27(m，2H)、0.89(t，J＝7Hz，3H)。
Step 2
The 3-{[(tert-butoxycarbonyl) (butyl) amino] methyl }-the 5-methyl-toluate
At 3-[(fourth amino through stirring) methyl]-(70 milligrams of 5-methyl-toluates, 0.30 in dichloromethane solution mmole), add (0.046 milliliter of triethylamine, 0.33 mmole) and (4.0 milligrams of 4-Dimethylamino pyridines, 0.03 mmole), add tert-Butyl dicarbonate (72 milligrams, 0.30 mmole) then.Reaction mixture was at room temperature stirred 24 hours, with the methylene dichloride dilution, with 1N hydrochloric acid and salt water washing.With this organic solution drying (sal epsom), filter and concentrating under reduced pressure, make title compound.
1H NMR(300MHz.CDCl
3)δ7.75(s，1H)、7.70(s，1H)、7.24(br s，1H)、4.42(d，J＝9Hz，2H)、3.90(m，3H)、3.16(m，2H)、2.38(s，3H)、1.64(s，2H)、1.44(m，9H)、1.27(m.2H)、0.89(t.J＝7Hz，3H)。
Step 3
The 3-{[(tert-butoxycarbonyl) (butyl) amino] methyl }-the 5-tolyl acid
At 3-{[(tert-butoxycarbonyl through stirring) (butyl) amino] methyl }-(70 milligrams of 5-methyl-toluates, 0.21 mmole) in the solution in methyl alcohol (2 milliliters), tetrahydrofuran (THF) (1 milliliter) and water (1 milliliter), add (88 milligrams of lithium hydroxides, 2.1 mmole), and with this reaction mixture at room temperature stirred 2 hours.With the reaction mixture concentrating under reduced pressure, be dissolved in methylene dichloride, filter and filtrate decompression is concentrated, make title compound.
Step 4
3-[(fourth amino) methyl]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl benzamide dihydrochloride
At 3-{[(tert-butoxycarbonyl through stirring) (butyl) amino] methyl }-(90 milligrams of 5-tolyl acids, 0.28 in methylene dichloride mmole) (3 milliliters) solution, add (160 milligrams of HBTU, 0.42 mmole), (57 milligrams of HOBt, 0.42 mmole) and N, (0.142 milliliter of N-diisopropylethylamine, 0.84 mmole), add (the 2R that makes according to the method among the embodiment SP-272 then, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] fourth-2-alcohol (114 milligrams, 0.28 mmole), and reaction mixture at room temperature stirred 12 hours.Reaction mixture is diluted with methylene dichloride, water and saturated sodium bicarbonate washing, dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 10% methyl alcohol/chloroform), make a kind of clean oil, it is dissolved in methyl alcohol (2 milliliters).In this solution, add hydrochloric acid (5 milliliters, 4N diox, 20 mmoles), and reaction mixture was at room temperature stirred 1 hour.Then this reaction mixture is diluted with ether (10 milliliters).Filter and collect the precipitation that forms, obtain title compound.ESI MS m/z538.5[M+H]
+。
Embodiment SP-208
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(2S)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] methyl }-5-methyl benzamide dihydrochloride
Step 1
3-{[(2S)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] methyl }-the 5-methyl-toluate
Ice-cold, in methylene dichloride (2.2 milliliters) solution of 3-(methylol)-5-methyl-toluate (200 milligrams, 1.1 mmoles), add (0.304 milliliter of triethylamine through stirring, 2.2 mmole) add methylsulfonyl chloride (0.116 milliliter, 1.5 mmoles) then.Reaction mixture was stirred 15 minutes and filtered.In filtrate, add (S)-(+)-2-(methoxymethyl) tetramethyleneimine (380 milligrams, 3.3 mmoles), and reaction mixture was at room temperature stirred 5 hours.Reaction mixture with methylene dichloride (10 milliliters) dilution, is washed with 1N hydrochloric acid and saturated sodium bicarbonate, and dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 15% ethyl acetate/hexane), make title compound.
1H NMR(300MHz，CDCl
3)δ7.77(s，1H)、7.73(s，1H)、7.37(s，1H)、4.12(d，J＝17Hz，1H)、3.90-(s，3H)、3.85(m，2H)、3.51(m，2H)、3.44(m，2H)、3.15(s，1H)、2.38(s，3H)、1.94(m，3H)、1.72(m，3H)。
Step 2
3-{[(2S)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] methyl }-the 5-tolyl acid
At 3-{[(2S through stirring)-2-(methoxymethyl) tetramethyleneimine-1-yl] methyl }-(170 milligrams of 5-methyl-toluates, 0.50 mmole) in the solution in methyl alcohol (2 milliliters), tetrahydrofuran (THF) (1 milliliter) and water (1 milliliter), add (211 milligrams of lithium hydroxides, 5.0 mmole), and with this reaction mixture at room temperature stirred 2 hours.With the reaction mixture concentrating under reduced pressure, be dissolved in methylene dichloride, filter and filtrate decompression is concentrated, make title compound.ESI MS m/z 264[M+H]
+。
Step 3
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(2S)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] methyl }-5-methyl benzamide dihydrochloride
At 3-{[(2S through stirring)-2-(methoxymethyl) tetramethyleneimine-1-yl] methyl }-(110 milligrams of 5-tolyl acids, 0.42 in methylene dichloride mmole) (3 milliliters) solution, add (240 milligrams of HBTU, 0.63 mmole), HOBt is (85 milligrams, 0.63 mmole) and N, (0.212 milliliter of N-diisopropylethylamine, 1.26 mmole), add (the 2R that makes according to the method among the embodiment SP-272 then, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] fourth-2-alcohol (171 milligrams, 0.42 mmole).Reaction mixture was at room temperature stirred 12 hours.Reaction mixture is diluted with methylene dichloride, water and saturated sodium bicarbonate washing, dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 10% methyl alcohol/chloroform), make a kind of clean oil, it is dissolved in methyl alcohol (2 milliliters).In this solution, add hydrochloric acid (5 milliliters, 4N diox, 20 mmoles), and reaction mixture was at room temperature stirred 1 hour.Then this reaction mixture is diluted with ether (10 milliliters).Filter and collect the precipitation that forms, obtain title compound.ESI MS m/z580.4[M+H]
+。
Embodiment SP-209
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-{[(2-hydroxyethyl) (methyl) amino] methyl }-5-methyl benzamide dihydrochloride
Step 1
The 3-{[(2-hydroxyethyl) (methyl) amino] methyl }-the 5-methyl-toluate
Ice-cold, in methylene dichloride (2.2 milliliters) solution of 3-(methylol)-5-methyl-toluate (200 milligrams, 1.1 mmoles), add (0.304 milliliter of triethylamine through stirring, 2.2 mmole) add methylsulfonyl chloride (0.116 milliliter, 1.5 mmoles) then.Reaction mixture was stirred 15 minutes and filtered.In filtrate, add 2-methoxyl group-N-benzylidene amino (0.354 milliliter, 3.3 mmoles), and reaction mixture was at room temperature stirred 5 hours.Reaction mixture with methylene dichloride (10 milliliters) dilution, is washed with 1N hydrochloric acid and saturated sodium bicarbonate, and dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (50% ethyl acetate/hexane), make title compound.ESI MS m/z 238[M+H]
+。
Step 2
The 3-{[(2-hydroxyethyl) (methyl) amino] methyl }-the 5-tolyl acid
At 3-{[(2-hydroxyethyl through stirring) (methyl) amino] methyl }-(180 milligrams of 5-methyl-toluates, 0.72 mmole) in the solution in methyl alcohol (2 milliliters), tetrahydrofuran (THF) (1 milliliter) and water (1 milliliter), add (302 milligrams of lithium hydroxides, 7.2 mmole), and with this reaction mixture at room temperature stirred 2 hours.With the reaction mixture concentrating under reduced pressure, be dissolved in methylene dichloride, filter and filtrate decompression is concentrated, make title compound.ESI MS m/z 224[M+H]
+。
Step 3
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-{[(2-hydroxyethyl) (methyl) amino] methyl }-5-methyl benzamide dihydrochloride
At 3-{[(2-hydroxyethyl through stirring) (methyl) amino] methyl }-(140 milligrams of 5-tolyl acids, 0.56 in methylene dichloride mmole) (3 milliliters) solution, add (318 milligrams of HBTU, 0.84 mmole), HOBt is (114 milligrams, 0.84 mmole) and N, (0.284 milliliter of N-diisopropylethylamine, 1.68 mmole), add (the 2R that makes according to the method among the embodiment SP-272 then, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] fourth-2-alcohol (228 milligrams, 0.56 mmole).Reaction mixture was at room temperature stirred 24 hours, with the methylene dichloride dilution, water and saturated sodium bicarbonate washing, dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (10% methyl alcohol/chloroform), make a kind of clean oil, it is dissolved in methyl alcohol (2 milliliters).In this solution, add 4N in the hydrochloric acid (Zai diox, 5 milliliters, 20 mmoles).Reaction mixture was at room temperature stirred 1 hour.This reaction mixture is diluted with ether (10 milliliters).Filter and collect the precipitation that forms, obtain title compound.ESI MS m/z 540.4[M+H]
+。
Embodiment SP-210
3-bromo-5-{[butyl (methyl) amino] methyl }-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group) benzamide dihydrochloride
Will be according to embodiment SP-190,3-bromo-5-{[butyl (methyl) amino that method in the step 1 makes] methyl } (200 milligrams of methyl benzoate, 0.64 mmole) be dissolved in 2: 1: 1 tetrahydrofuran (THF)/methanol (4 milliliters), and add (60 milligrams of hydronium(ion) oxidation lithiums, 1.3 mmole), and with reactant stirred 16 hours.This solution decompression is concentrated.Resistates is dissolved in DMF (5 milliliters) again, and adding diisopropylethylamine (445 microlitres, 2.6 mmole), HATU is (304 milligrams, 0.8 mmole) and (2R that makes according to the method among the embodiment SP-2511,3S)-3-amino-4-(3, the 5-difluorophenyl)-and 1-{[3-(trifluoromethyl) benzyl] amino } fourth-2-alcohol dihydrochloride (315 milligrams, 0.7 mmole).Reactant was at room temperature stirred 16 hours.Reaction mixture is diluted with ethyl acetate, water and saturated sodium bicarbonate, salt water washing, dry (sodium sulfate) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 9% ethanol/methylene), make title compound as free alkali.Resistates is dissolved in ether (3 milliliters) and adds ether (1 milliliter) solution of 1N hydrochloric acid.With this mixture concentrating under reduced pressure, make title compound.ESI MS m/z 656.2[M+H]
+。
Embodiment SP-211
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-3-{[isopentyl (methyl) amino] methyl }-5-methyl benzamide dihydrochloride
Step 1
3-{[isopentyl (methyl) amino] methyl }-the 5-methyl-toluate
-30 ℃ according to embodiment SP-198, in the anhydrous methylene chloride solution of the 3-that the method in the step 2 makes (methylol)-5-methyl-toluate, add methylsulfonyl chloride (601 microlitres, 7.8 mmole), add (1.5 milliliters of triethylamines then, 11.1 mmole), then reactant was stirred 15 minutes at 0 ℃.With the sedimentation and filtration that generates, and filtrate added in the N-methyl isobutylcarbylamine (2.1 milliliters, 16.7 mmoles).Reactant was at room temperature stirred 16 hours.This solution decompression is concentrated, be dissolved in ethyl acetate again and use saturated sodium bicarbonate, salt water washing, dry (sodium sulfate) filters and concentrating under reduced pressure.Purify by flash chromatography (silicon-dioxide, 20% ethyl acetate/hexane), make title compound.ESI MS m/z 264.2[M+H]
+。
Step 2
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-3-{[isopentyl (methyl) amino] methyl }-5-methyl benzamide dihydrochloride
At 3-{[isopentyl (methyl) amino] methyl }-(250 milligrams of 5-methyl-toluates, 0.95 in tetrahydrofuran (THF)/methanol mmole) (2: 1: 1,8 milliliters) solution, add (80 milligrams of hydronium(ion) oxidation lithiums, 1.9 mmole), and with reactant at room temperature stirred 16 hours.This solution decompression is concentrated, be dissolved in DMF (5 milliliters) again, and adding diisopropylethylamine (660 microlitres, 3.8 mmole), HATU is (540 milligrams, 1.4 mmole) and (2R, 3S)-and 3-amino-4-(3, the 5-difluorophenyl)-1-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-3-methyl fourth-2-alcohol dihydrochloride (450 milligrams, 1.05 mmoles).Reactant was at room temperature stirred 2 hours.Reaction mixture is diluted with ethyl acetate, water, saturated sodium bicarbonate, salt water washing, dry (sodium sulfate) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 9% ethanol/methylene), make title compound as free alkali.Resistates is dissolved in ether (3 milliliters) and adds ether (2 milliliters) solution of 1N hydrochloric acid.With this mixture concentrating under reduced pressure, make title compound.ESI MS m/z 588.3[M+H]
+。
Embodiment SP-212
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-3-{[isopentyl (methyl) amino] methyl }-5-methyl benzamide dihydrochloride
According to embodiment SP-211,3-{[isopentyl (methyl) amino that step 1 makes] methyl }-(160 milligrams of 5-methyl-toluates, 0.61 tetrahydrofuran (THF)/methanol mmole) (2: 1: 1,8 milliliters) in the solution, add (51 milligrams of hydronium(ion) oxidation lithiums, 1.2 mmole), and with reactant at room temperature stirred 16 hours.This solution decompression is concentrated, be dissolved in DMF (5 milliliters) again, and adding diisopropylethylamine (424 microlitres, 2.4 mmole), HATU is (290 milligrams, 0.8 mmole) and (2R that makes according to the method among the embodiment SP-272,3S)-and 3-amino-4-(3, the 5-difluorophenyl)-1-{[1-(3-ethylphenyl) cyclopropyl] amino }-3-methyl fourth-2-alcohol dihydrochloride (291 milligrams, 0.7 mmole).Reactant was at room temperature stirred 2 hours.Reaction mixture is diluted with ethyl acetate, water, saturated sodium bicarbonate, salt water washing, dry (sodium sulfate) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 8% ethanol/methylene), make title compound as free alkali.Resistates is dissolved in ether (3 milliliters) and adds ether (2 milliliters) solution of 1N hydrochloric acid.With this mixture concentrating under reduced pressure, make title compound.ESI MS m/z 592.3[M+H]
+。
Embodiment SP-213
1-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-indoles-6-methane amide
Step 1:1H-indole-5-carboxylic acid methyl esters
Add 1,1-carbonyl dimidazoles (3.08 gram) in indole-5-carboxylic acid in anhydrous THF (100 milliliters) (3.0 gram) and triethylamine (1.9 gram) mixture.This mixture was at room temperature stirred 30 minutes, add methyl alcohol (25 milliliters) this moment.This mixture was at room temperature stirred 1 hour, make its phase-splitting between water and ethyl acetate.Separate each layer and wash organic layer with water twice,, filter and concentrating under reduced pressure through anhydrous magnesium sulfate drying.Go up use CH at silica gel (200 milliliters)
2Cl
2Carry out column chromatography as elutriant and separate, obtain 0.794 gram title compound:
1H NMR (CDCl
3) δ 3.93,6.66,7.28,7.41,7.91,8.34,8.42.
Step 2:1-butyl-1H-indole-5-carboxylic acid methyl esters
In 1H-indole-5-carboxylic acid methyl esters in methyl-sulphoxide (30 milliliters) (6.0 gram) mixture, add potassium tert.-butoxide (3.88 gram).This mixture was at room temperature stirred 10 minutes, add 1-butyl iodide (1.8 milliliters) this moment.This mixture was at room temperature stirred 5 hours, then phase-splitting between water and methylene dichloride.Separate each layer, and with organic layer salt water washing three times, through anhydrous magnesium sulfate drying and concentrating under reduced pressure.Go up the hexane solution that uses 10% ethyl acetate at silica gel (100 milliliters) and carry out the column chromatography separation, obtain 6.18 gram title compounds as elutriant:
1H NMR (CDCl
3) δ 0.923,1.38,1.83,3.9,4.14,6.58,7.15,7.34,7.9,8.39.
Step 3:1-butyl-1H-indoles-6-formic acid
In 1-butyl-1H-indoles-6-formic acid in methyl alcohol (25.0 milliliters) and water (5.0 milliliters) (0.52 gram) mixture, add a hydronium(ion) oxidation lithium (2.0 gram).This mixture heating up to 60 ℃ is reached 6 hours, be cooled to room temperature, pour among the 1N HCl (50 milliliters) and be extracted in the ethyl acetate.Acetic acid ethyl acetate extract through anhydrous magnesium sulfate drying and concentrating under reduced pressure, is made 0.496 gram (72%) title compound:
1H NMR (CDCl
3) δ 0.98 (and t, J=7.3Hz, 3H), 1.4 (m, 2H), 1.9 (m, 2H), 4.2 (m, 2H), 6.57 (ss, J=2.6Hz, 1H), 7.31 (ss.J=3.1Hz, 1H), 7.68 (d, J=8.4Hz, 1H), 7.89 (dd, J=1.4,8.4Hz, 1H), 8.24 (s, 1H).
Step 4:1-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-indoles-6-methane amide
In 1-butyl in methylene dichloride (10 milliliters)-1H-indoles-6-formic acid (0.278 gram) mixture, add triethylamine (0.129 gram), HOBT (0.175 gram) and HATU (0.486 gram).This mixture was at room temperature stirred 30 minutes, add this moment (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(3-Ethylbenzyl) amino 1 fourth-2-alcohol (0.408 gram).The mixture that makes was at room temperature stirred 18 hours, then phase-splitting between water and methylene dichloride.Separate each layer and, use the salt water washing then the organic layer water, and through anhydrous magnesium sulfate drying.Go up the dichloromethane solution that uses 3% methyl alcohol at silica gel (100 milliliters) and carry out the column chromatography separation, make 0.256 gram title compound: C as elutriant
32H
37F
2N
3O
2MS (ESI+) m/z 542.2 (M+H)
+
Embodiment SP-214
1-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } indoline-6-methane amide dihydrochloride
Step 1:1-butyl indoline-6-methyl-formiate
Add cyano group sodium borohydride (2.28 gram) in 1-butyl in Glacial acetic acid (25 milliliters)-1H-indoles-6-methyl-formiate (2.1 gram) mixture.This mixture 40 ℃ of heating 3 hours, is cooled to room temperature then, phase-splitting between water and ethyl acetate, and separate each layer.Organic layer with salt water washing three times, through anhydrous sodium sulfate drying and concentrated, is made 1.64 gram title compounds:
1H NMR (CDCl
3) δ 0.969,1.43,1.59,2.99,3.1,3.4,3.88,7.07,7.34.
Step 2:1-butyl indoline-6-carboxylic acid
In 1-butyl indoline-6-carboxylate methyl ester in methyl alcohol (20 milliliters) (1.6 gram) mixture, add 1N NaOH (5.0 milliliters).With 60 ℃ of heating of this mixture 2 hours, be cooled to room temperature then, pour among the 1N HCl, and be extracted in the ethyl acetate.Acetic acid ethyl acetate extract through anhydrous magnesium sulfate drying and concentrated, is made 1.16 gram title compounds:
1H NMR (CDCl
3) δ 0.974,1.43,1.60,3.01,3.11,3.42,7.1,7.43.
Step 3:1-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } indoline-6-carboxamide hydrochloride
In the mixture of 1-butyl indoline-6-formic acid (0.2 gram) in methylene dichloride, add triethylamine (0.27 gram), HOBT (0.125 gram) and HATU (0.347 gram).This mixture was stirred 15 minutes at 40 ℃, add this moment (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(3-Ethylbenzyl) amino] fourth-2-alcohol (0.346 gram).The mixture that makes was stirred phase-splitting between water and methylene dichloride then 5 hours at 40 ℃.Separate each layer and, use the salt water washing then the organic layer water, and through anhydrous magnesium sulfate drying.Go up the dichloromethane solution that uses 5% methyl alcohol at silica gel (100 milliliters) and carry out the column chromatography separation, make 0.100 gram title compound: C as elutriant
32H
39F
2N
3O
2MS (ESI+) m/z 535.9 (M+H)
+
Embodiment SP-215
1-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-indazole-6-methane amide
Step 1:3-[(E)-(tertiary butyl sulphur) diazenyl]-the 4-tolyl acid
Add concentrated hydrochloric acid (15 milliliters) in 3-amino-4-tolyl acid in water (50 milliliters) (5.0 gram) mixture.This mixture is cooled to 0 ℃ in ice/acetone bath.Slowly add in this mixture with Sodium Nitrite (2.28 gram) water-soluble (10 milliliters) and at 0 ℃.With saturated sodium acetate the pH value is adjusted to 6, and adds 2-methyl-2-propylmercaptan (1.8 milliliters).This mixture was stirred 1 hour and, washes with water and drying under reduced pressure, make 5.7 gram title compounds by filtering the solid that collection generates:
1H NMR (CDCl
3) δ 1.61,2.20,7.38,7.55,9.67.
Step 2:1H-indazole-6-formic acid
3-[(E in nitrogen degassing methyl-sulphoxide (90 milliliters))-(tertiary butyl sulphur) diazenyl]-4-tolyl acid (5.7 gram) mixture in, add potassium tert.-butoxide (25.0 gram).This mixture was at room temperature stirred 24 hours, be poured on then on ice and be acidified to pH 4 with concentrated hydrochloric acid.This mixture is also used salt water washing organic layer with extracted with diethyl ether.Through anhydrous magnesium sulfate and decolorizing charcoal drying, concentrating under reduced pressure then obtains 1.2 gram title compounds with organic layer:
1H NMR (CDCl
3) δ 0.963,1.36,1.95,4.48,7.81,7.88,8.08,8.29.
Step 3:1H-indazole-6-methyl-formiate
In the mixture of 1H-indazole-6-formic acid (1.0 gram) in methylene dichloride (15 milliliters), add EDC (1.8 gram), HOBT (1.27 gram) and triethylamine (1.29 milliliters).(2 heating 30 minutes add methyl alcohol (10.0 milliliters) this moment with 40 ℃ in this mixture.This mixture was stirred 18 hours at 40 ℃.This mixture is withdrawn thermal source, be cooled to room temperature and pour methylene dichloride into.With this mixture water, use the salt solution washed twice then, through anhydrous sodium sulfate drying and concentrating under reduced pressure, make 0.955 gram title compound:
1H NMR (CDCl
3) δ 3.98,7.81,7.86,8.16,8.29,10.6.
Step 4:1-butyl-1H-indazole-6-methyl-formiate
In the mixture of 1H-indazole-6-methyl-formiate (0.95 gram) in DMF (10 milliliters), add 60%NaH (0.216 gram).With this mixture heating up to 60 ℃ and add 1-butyl iodide (0.61 milliliter).60 ℃ of heating of this mixture were added 1-butyl iodide (0.61 milliliter) in 72 hours and per 24 hours.Mixture is withdrawn thermal source and is cooled to room temperature, make its phase-splitting between water and ethyl acetate.Separate each layer and with organic layer with salt water washing three times, through anhydrous magnesium sulfate drying and concentrating under reduced pressure.Go up the hexane solution that uses 5% ethyl acetate at silica gel (100 milliliters) and carry out the column chromatography separation, make 0.356 gram title compound as elutriant:
1H NMR (CDCl
3) δ 0.938,1.34,1.92,3.97,4.43,7.73,7.79,8.03,8.18.
Step 5:1-butyl-1H-indazole-6-formic acid
In the mixture of 1-butyl-1H-indazole-6-methyl-formiate (0.356 gram) in methyl alcohol (10 milliliters), add saturated sodium bicarbonate (5 milliliters).With 60 ℃ of heating of this mixture 2 hours, add 1N NaOH (5 milliliters) this moment also with 80 ℃ of heating of this mixture 18 hours.This mixture is cooled to room temperature, pours 1N HCl (50 milliliters) into, and use ethyl acetate extraction.Acetic acid ethyl acetate extract through anhydrous magnesium sulfate drying and concentrating under reduced pressure, is made 0.310 gram title compound:
1H NMR (CDCl
3) δ 0.964,1.96,4.48,7.81,7.89,8.29,8.46.
Step 6:1-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-indazole-6-methane amide
In the mixture of 1-butyl-1H-Yin indazole-6-formic acid (0.2 gram) in methylene dichloride (20 milliliters), add triethylamine (0.182 gram), HOBT (126 gram) and HATU (0.348 gram).This mixture was stirred 10 minutes at 40 ℃, add this moment (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(3-Ethylbenzyl) amino] fourth-2-alcohol (0.35 gram).Mixture was stirred 3 hours at 40 ℃, pour into then (50 milliliters) in the methylene dichloride, water is used the salt water washing then, concentrates through anhydrous magnesium sulfate drying and under vacuum.Go up the dichloromethane solution that uses 5% methyl alcohol at silica gel (100 milliliters) and carry out the column chromatography separation, make 0.2 gram title compound: C as elutriant
31H
36F
2N
4O
2MS (ESI+) m/z 534.9 (M+H)
+
Embodiment SP-216
1-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-[methyl (methylsulfonyl) amino]-1H-indoles-6-methane amide
Step 1:4-methyl-3, the 5-dinitro-methyl benzoate
In the mixture of 3,5 dinitrobenzene toluic acids (16 gram) in methyl alcohol (10 milliliters), add sulfuric acid.This mixture heating up to 75 ℃ is reached 72 hours, withdraw thermal source and be cooled to room temperature.Decompression is removed solvent and is made resistates phase-splitting between water and ethyl acetate.Separate each layer and wash organic layer then with water with 2N NaOH.Organic layer through anhydrous magnesium sulfate drying, is filtered and concentrates, obtain 16.28 gram (96%) title compounds:
1H NMR (CDCl
3) δ 2.65 (and s, 3H), 4.02 (s, 3H), 8.61 (s, 2H)
Step 2:4-[(E)-and 2-(dimethylamino) ethynyl]-3, the 5-dinitro-methyl benzoate
At 4-methyl-3, add dimethylformamide dimethyl acetal (4.17 gram) and 5-sulfo group salycylic acid hydrate (0.1 gram) in the mixture of 5-dinitro-methyl benzoate (5.6 gram) in toluene (20 milliliters).This mixture heating up to 110 ℃ is reached 19 hours, withdraw thermal source and be cooled to room temperature.Solvent is removed in decompression, adds hexane this moment and with the resistates filtration, obtain 6.85 gram title compounds in resistates:
1H NMR (CDCl
3) δ 2.97,3.96,5.54,6.74,8.33.
Step 3:4-amino-1H-indoles-6-methyl-formiate
At 4-[(E)-2-(dimethylamino) ethynyl]-3, in the mixture of 5-dinitro-methyl benzoate (19.3 gram) in ethyl acetate (200 milliliters), add 5% year palladium carbon (1.5 gram).This mixture is placed 45PSI H
2Also shake spends the night down.Mixture is filtered and concentrates through C salt.This resistates is dissolved in CH
2Cl
2, add (1: 1) water therein: concentrated hydrochloric acid (250 milliliters).Filter and collect the solid that makes, be dissolved in ethyl acetate and use 2N NaOH washing.With the ethyl acetate layer anhydrous magnesium sulfate drying, filter and concentrate, obtain 7.4 gram title compounds:
1H NMR (CDCl
3) δ 3.91,4.01,6.51,7.09,7.27,8.40.
Step 4:4-[(methylsulfonyl) amino]-1H-indoles-6-methyl-formiate
In the mixture of 4-amino-1H-indoles-6-methyl-formiate (1.0 gram) in DMF (10 milliliters), add 4-Dimethylamino pyridine (1.46 gram) and methylsulfonyl chloride (0.6 gram).With 60 ℃ of heating of this mixture 3 hours, be cooled to room temperature, and phase-splitting between water and ethyl acetate.Separate each layer and,, make 0.71 gram title compound through anhydrous sodium sulfate drying and concentrated with organic layer salt water washing three times:
1H NMR (CDCl
3) δ 3.02,3.94,6.69,7.42,7.81,8.04.
Step 5:4-[methyl (methylsulfonyl) amino]-1H-indoles-6-methyl-formiate
At the 4-[(methylsulfonyl) amino]-add salt of wormwood (0.309 gram) and methyl iodide (0.63 milliliter) in the mixture of 1H-indoles-6-methyl-formiate (0.6 gram) in THF (10 milliliters).This mixture was at room temperature stirred 4 hours, be heated to 40 ℃ then and spend the night.Add methyl iodide (0.3 milliliter) and with mixture reheat 3 hours.This mixture is cooled to room temperature, and phase-splitting between water and ether is through anhydrous sodium sulfate drying and concentrated.Resistates is dissolved in ether and adds decolorizing charcoal (2 gram), filter through C salt while hot then also with this mixture backflow 5 minutes.Ether is removed in decompression, obtains 0.437 gram title compound: C
12H
14N
2O
4S
1MS (ESI+) m/z321.1 (M+K).
Step 6:1-butyl-4-[methyl (methylsulfonyl) amino]-1H-indoles-6-formic acid
At 4-[methyl (methylsulfonyl) amino]-add potassium hydroxide (0.087 gram) and butyl iodide (0.34 milliliter) in the mixture of 1H-indoles-6-methyl-formiate (0.437 gram) in DMF (15 milliliters).This mixture heating up to 70 ℃ is reached 6 hours, at room temperature stirred then 72 hours.Make the phase-splitting between water and ethyl acetate of this mixture, separate each layer and organic layer is washed with water three times.Organic layer through anhydrous sodium sulfate drying, is filtered and concentrates.Resistates is dissolved in methyl alcohol (5 milliliters), adds 1N NaOH (2 milliliters) therein and mixture heating up to 50 ℃ is reached 1 hour.Mixture is cooled to room temperature and pours in the water and and wash with ether.Water layer is acidified to pH4 with 1N HCl, and product is extracted in the ethyl acetate, with it through anhydrous sodium sulfate drying, filter and be concentrated into dried, make 0.377 the gram title compound:
1H NMR (CDCl
3) δ 0.973,1.38,1.87,3.01,3.45,4.21,6.71,7.36,7.82,8.18.
Step 7:1-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-[methyl (methylsulfonyl) amino]-1H-indoles-6-methane amide
At 1-butyl-4-[methyl (methylsulfonyl) amino]-mixture of 1H-indoles-6-formic acid (0.2 gram) in methylene dichloride (15 milliliters) in, add triethylamine (0.156 gram), HOBT (0.105 gram) and HATU (0.293 restrains).This mixture was stirred 10 minutes at 39 ℃, add this moment (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(3-Ethylbenzyl) amino] fourth-2-alcohol (0.293 gram).Mixture was stirred 4 hours at 40 ℃, pour into then (50 milliliters) in the methylene dichloride, water is used the salt water washing then, then through anhydrous magnesium sulfate drying and concentrating under reduced pressure.Silica gel (100 milliliters) _ on use 5% methyl alcohol dichloromethane solution carry out column chromatography as elutriant and separate, make 0.21 gram title compound: C
34H
42F
2N
4O
2S
1MS (ESI+) m/z 640.8 (M+H).
Embodiment SP-217
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(dipropyl amino) Isonicotinamide hydrochloride
The different cigarette nitrile of step 1:2-chlorine
N-oxidation 4-cyanopyridine (10.0 gram) is added phosphorus oxychloride (85 milliliters), and be heated to 110 ℃ and reach 2.5 hours.This mixture is cooled to room temperature and decompression removal excess chlorine phosphorus oxide.With resistates water-soluble and with strong aqua make its be alkalescence.Product is extracted in the methylene dichloride, through anhydrous magnesium sulfate drying and concentrating under reduced pressure.Go up the use methylene dichloride at silica gel (100 milliliters) and carry out the column chromatography separation, obtain 7.19 gram title compounds as elutriant:
1H NMR (CDCl
3) δ 7.48,7.6,8.6.
The different cigarette nitrile of step 2:2-(dipropyl amino)
The different cigarette nitrile of 2-chlorine (1.0 gram) and dipropyl amine (10 milliliters) placed seal thick-walled tube, and be heated to 100 ℃ and reach 18 hours.This mixture is withdrawn thermal source and is cooled to room temperature.Decompression is removed dipropyl amine and is used the hexane solution of 2% ethyl acetate to carry out chromatographic separation as elutriant on silica gel resistates, obtains 1.06 gram title compound: C
12H
17N
3MS (ESI+) m/z 204.1 (M+H)
+
Step 3:2-(dipropyl amino) Yi Yansuan hydrochloride
The different cigarette nitrile of 2-(dipropyl amino) (1.0 gram) is dissolved in concentrated hydrochloric acid (30 milliliters) and 65 ℃ of heating 3 hours.Solvent is removed in decompression, obtains 1.27 gram title compound: C
13H
10N
2O
2MS (ESI+) m/z 237.3 (M+H)
+
Step 4:N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(dipropyl amino) Isonicotinamide hydrochloride
The mixture of 2-(dipropyl amino) Yi Yansuan hydrochloride (0.2 gram) in methylene dichloride (15 milliliters) adds triethylamine (0.195 gram), HOBT (0.105 gram) and HATU (0.293 gram).This mixture was stirred 10 minutes at 39 ℃, add this moment (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(3-Ethylbenzyl) amino] fourth-2-alcohol (0.285 gram).This mixture was stirred 4 hours at 40 ℃, pour methylene dichloride (50 milliliters) then into, water is used the salt water washing then, concentrates through anhydrous magnesium sulfate drying and under vacuum.Go up the dichloromethane solution that uses 5% methyl alcohol at silica gel (100 milliliters) and carry out the column chromatography separation, and change into hydrochloride, obtain 0.105 gram title compound: C as elutriant
31H
40F
2N
4O
2MS (ESI+) m/z 539.3 (M+H)
+
Embodiment SP-218
1-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(1,3-oxazole-2-yl)-1H-indoles-6-methane amide
Step 1:4-iodo-1H-indoles-6-methyl-formiate
(embodiment SP-216 in the mixture of step 3) (3.2 gram) in water (50 milliliters), adds concentrated hydrochloric acid (5 milliliters) at 4-amino-1H-indoles-6-methyl-formiate.Adding ice is cooled to this mixture below 5 ℃.To. wherein add the Sodium Nitrite (1.16 gram) in water-soluble (10 milliliters).This mixture was stirred 1 hour under the state of cooling, add water (20 milliliters) solution of sodium iodide (3 gram) then.This mixture was stirred 30 minutes, filter, and filter that the solid of collecting washes with water and 50 ℃ of dryings.This solid becomes black, and discharges gas rapidly when drying.Go up the CH that uses 20% hexane at silica gel (200 milliliters)
2Cl
2Solution carries out column chromatography as elutriant to be separated, and obtains 0.82 gram title compound:
1H NMR (CDCl
3) δ 3.94,6.55,7.43,8.14,8.22,8.62.
Step 2:1-butyl-4-iodo-1H-indoles-6-methyl-formiate
In the mixture of 4-iodo-1H-indoles-6-methyl-formiate (1.0 gram) in DMF (10 milliliters), add potassium hydroxide (0.392 gram) and 1-butyl iodide (0.8 milliliter).This mixture heating up to 80 ℃ is reached 18 hours.This mixture is cooled to room temperature, and phase-splitting between water and ethyl acetate.Separate each layer and wash organic layer with water secondary, through anhydrous magnesium sulfate drying and concentrating under reduced pressure.Go up the hexane solution that uses 20% ethyl acetate at silica gel (100 milliliters) and carry out the column chromatography separation, obtain 0.73 gram title compound as elutriant:
1H NMR (CDCl
3) δ 0.940,1.32,1.81,3.95,4.15,6.45,7.31,8.09,8.18.
Step 3:1-butyl-4-(1,3-oxazole-2-yl)-1H-indoles-6-formic acid
In-72 ℃ of solution of Zai oxazole (0.069 gram) in anhydrous THF (20 milliliters), dropwise add 1.6M n-Butyl Lithium (0.68 milliliter).This mixture was stirred 30 minutes at-72 ℃, add 1.0M zinc chloride (3.3 milliliters) this moment.Make this mixture be warmed to 0 ℃, add 1-butyl-4-iodo-1H-indoles-6-methyl-formiate (0.37 gram) and four triphenyl phosphine palladiums (0) (0.07 restrains) this moment, and with this mixture heating up to 85 ℃.This mixture was cooled to room temperature and phase-splitting between water and ethyl acetate in 20 hours then 85 ℃ of heating.Separate each layer and organic layer is washed with water, through anhydrous sodium sulfate drying and concentrating under reduced pressure.Go up the hexane solution that uses 20% ethyl acetate at silica gel (100 milliliters) and carry out the column chromatography separation as elutriant.Resistates is dissolved in methyl alcohol (10 milliliters) and 1N NaOH (3 milliliters), and 60 ℃ of heating 2 hours.This mixture is acidified to pH4 and uses ethyl acetate extraction with 1N HCl.With acetic acid ethyl acetate extract through anhydrous sodium sulfate drying and be evaporated to dried, obtain 0.2 the gram title compound: C
16H
16N
2O
3MS (ESI+) m/z 283.16 (M+H)
+
Step 4:1-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(1,3-oxazole-2-yl)-1H-indoles-6-methane amide
In 1-butyl-4-(1,3-oxazole-2-the yl)-mixture of 1H-indoles-6-formic acid (0-2 gram) in methylene dichloride (20 milliliters), add 1,1-carbonyl dimidazoles (0-114 gram).This mixture was at room temperature stirred 1 hour, adds (2R, 3S)-3-amino-4-(3, the 5-the difluorophenyl)-1-[(3-Ethylbenzyl) amino be dissolved in methylene dichloride (10 milliliters) this moment] fourth-2-alcohol (0.265 gram).This mixture was at room temperature stirred 18 hours, pour into then in the methylene dichloride (50 milliliters), water is used the salt water washing then, through anhydrous magnesium sulfate drying and concentrating under reduced pressure.Upward use 65% methylene dichloride, 30% hexane to carry out column chromatography with 5% methyl alcohol as elutriant and separate at silica gel (100 milliliters), make 0.0985 gram title compound: C
35H
38F
2N
4O
3MS (ESI+) m/z 601.99 (M+H)
+
Embodiment SP-219
1-butyl-4-cyano group-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-indoles-6-methane amide
Step 1:1-butyl-4-cyano-1 H-indol--6-methyl-formiate
(embodiment SP-218 in the mixture of step 4) (1.47 gram) in N-Methyl pyrrolidone (15 milliliters), adds cupric cyanide (I) (1.1 gram) at 1-butyl-4-iodo-1H-indoles-6-methyl-formiate.With 150 ℃ of heating of this mixture 6 hours, withdraw thermal source and be cooled to room temperature.Make the phase-splitting and separate each layer between water and ethyl acetate of this mixture.Organic layer is washed with water three times, through anhydrous sodium sulfate drying and concentrating under reduced pressure.(100 milliliters) use 20% ethyl acetate to carry out the column chromatography separation as elutriant on silica gel, make 0.5 gram title compound:
1H NMR (CDCl
3) δ 0.995,1.32,1.85,3.98,4.23,6.76,7.43,8.16,8.30.
Step 2:1-butyl-4-cyano-1 H-indol--6-formic acid
In the mixture of 1-butyl-4-cyano-1 H-indol--6-methyl-formiate (10.5 gram) in methyl alcohol (15 milliliters), add 1NNaOH (3.0 milliliters).This mixture 40 ℃ of heating 2 hours, is cooled to room temperature then.Pour this mixture into 1N HCl and be extracted in the ethyl acetate.This acetic acid ethyl acetate extract through anhydrous magnesium sulfate drying and concentrated, is made 0.45 gram title compound:
1H NMR (CDCl
3) δ 0.973,1.38,1.88,4.27,6.79,7.48,8.24,8.38.
Step 3:1-butyl-4-cyano group-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-indoles-6-methane amide
In the mixture of 1-butyl-4-cyano-1 H-indol--6-formic acid (0.29 gram) in methylene dichloride (10 milliliters), add 1,1-carbonyl dimidazoles (0.194 gram) and triethylamine (0.267 gram).This mixture was at room temperature stirred 45 minutes, adds (2R, 3S)-3-amino-4-(3, the 5-the difluorophenyl)-1-[(3-Ethylbenzyl) amino be dissolved in methylene dichloride (10 milliliters) this moment] fourth-2-alcohol (0.5 gram).This mixture was at room temperature stirred 18 hours, pour into then in the methylene dichloride (50 milliliters), water is used the salt water washing then, concentrates through anhydrous magnesium sulfate drying and under vacuum.Go up the dichloromethane solution that uses 5% methyl alcohol at silica gel (100 milliliters) and carry out the column chromatography separation, make 0.47 gram title compound: C as elutriant
33H
36F
2N
4O
2MS (ESI+) m/z 559.0 (M+H)
Embodiment SP-220
4-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-8-(1,3-oxazole-2-yl)-3,4-dihydro-2H-1,4-benzoxazine-6-methane amide
Step 1:4-hydroxyl-3-iodo-5-nitrobenzoic acid methyl esters
In acetate (15 milliliters) solution of 4-hydroxyl-3-nitrobenzoic acid methyl esters (2.0 gram), add the acetic acid solution of iodine monochloride (1.65 milligrams), and this mixture was stirred 1.5 hours at 100 ℃.After being cooled to room temperature, this mixture being poured in the water (200 milliliters), and stirred 30 minutes.This mixture is filtered, and water and hexane wash.Filter to collect yellow powder, and in vacuum drying oven dried overnight, obtain 2.99 gram title compounds:
1H NMR (300Hz, CDCl
3) δ 11.68,8.81,8.72,3.96.
Step 2:3-amino-4-hydroxy-5-iodo-benzoic acid methyl esters
In the mixture of 4-hydroxyl-3-iodo-5-nitrobenzoic acid methyl esters (2.99 gram) in ethanol (40 milliliters), by a part adding tin chloride (II) (10 gram).Under refluxing, stir after 1 hour, this mixture is cooled to 0 ℃ also makes its stopped reaction with saturated potassium carbonate (100 milliliters).This mixture is extracted filtrate through diatomite filtration and with ethyl acetate (4 * 100 milliliters).With the organic extract drying (sodium sulfate) that merges, filter and concentrating under reduced pressure, make 2.5 gram title compounds:
1H NMR (300Hz, DMSO-d
6) δ 7.50,7.24,3.75.
Step 3:8-iodo-3-oxygen-3,4-dihydro-2H-1,4-benzoxazine-6-methyl-formiate
Ice-cold, add chloroacetyl chloride (1.1 gram) in 3-amino-4-hydroxy-5-iodo-benzoic acid methyl esters through stirring (2.3 gram) and sodium bicarbonate (1.5 gram) solution in 1: 1 isobutyl methyl ketone/water (80 milliliters), and with reaction mixture stirring 1 hour.This mixture was warmed to room temperature and reflux 18 hours.After spending the night, form a kind of beige solid.This mixture is filtered, and water and hexane wash, obtain 2.4 gram title compounds:
1H NMR (300Hz, DMSO-d
6) δ 10.98,7.89,7.47,4.79,3.82.
Step 4:4-butyl-8-iodo-3-oxygen-3,4-dihydro-2H-1,4-benzoxazine-6-methyl-formiate
At 8-iodo-3-oxygen-3,4-dihydro-2H-1 in DMSO (20 milliliters) solution of 4-benzoxazine-6-methyl-formiate (2.64 gram) and salt of wormwood (5 gram), adds n-butyl bromide (5 gram), and reaction mixture was stirred 1 hour at 80 ℃.This mixture is cooled to room temperature,, and separates with 1: 1 ethyl acetate/hexane (100 milliliters) and water (160ml) dilution.With organic layer water and salt water washing, dry (sal epsom) filters, and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 1: 10 ethyl acetate/hexane), obtain 2.24 gram title compounds:
1H NMR (300Hz, CDCl
3) δ 8.13,7.63,4.74,3.96,3.92,1.64,1.42,0.97.
Step 5:4-butyl-8-iodo-3,4-dihydro-2H-1,4-benzoxazine-6-methyl-formiate
With 4-butyl-8-iodo-3-oxygen-3,4-dihydro-2H-1, tetrahydrofuran (THF) (30 milliliters) the solution reflux of 4-benzoxazine-6-methyl-formiate (680 milligrams) and 9-BBN (900 milligrams) 1.5 hours.This mixture is cooled to room temperature, adds thanomin (0.22 milliliter) and the solution decompression that makes is concentrated.With the resistates hexane wash, filter, and filtrate decompression is concentrated.Purify by flash column chromatography (silicon-dioxide, 10% ethyl acetate/hexane), obtain 600 milligrams of title compounds:
1H NMR (300Hz, CDCl
3) δ 7.75,7.28,4.34,3.86,3.36,3.28,1.58,1.40,0.96.
Step 6:4-butyl-8-(1,3-oxazole-2-yl)-3,4-dihydro-2H-1,4-benzoxazine-6-methyl-formiate
In tetrahydrofuran (THF) (10 milliliters) solution of-70 ℃ De oxazoles (227 milligrams), add n-Butyl Lithium (the 2.5M solution in hexane, 2 milliliters).After 30 minutes, add zinc chloride (solution of 1M in ether, 13 milliliters)-70 ℃ of stirrings.This mixture is warmed to 0 ℃ reaches 1 hour.In this mixture, add 4-butyl-8-iodo-3 then, 4-dihydro-2H-1, THF (5 milliliters) solution of 4-benzoxazine-6-ethyl formate (600 milligrams, 1.6 mmoles) adds four (triphenyl phosphine) palladium (0) (115 milligrams) then.With this mixture reflux 3 hours, with ethyl acetate (300 milliliters) dilution, and water, use the salt water washing then.With this organic solution drying (sodium sulfate) and concentrating under reduced pressure.Purify by silica gel plug (1: 1 acetate/hexane), obtain 363 milligrams of title compounds:
1H NMR (300MHz, CDCl
3) δ 7.96,7.73,7.40,7.28,4.44,3.90,3.43,3.34,1.61,1.41,0.98.
Step 7:4-butyl-8-(1,3-oxazole-2-yl)-3,4-dihydro-2H-1,4-benzoxazine-6-formic acid
At the 4-butyl-8-(1,3-oxazole-2-yl)-3 through stirring, 4-dihydro-2H-1 adds potassium hydroxide (15 milliliters, the 1.0M aqueous solution) in methyl alcohol (20 milliliters) solution of 4-benzoxazine-6-methyl-formiate (474 milligrams).This mixture at room temperature stirred spend the night, then concentrating under reduced pressure.Wash with residue diluted with water and with ethyl acetate.With 1N hydrochloric acid water layer is acidified to pH 4 and uses chloroform extraction (4 * 100 milliliters).With the organic extract drying (sodium sulfate) that merges, filter and concentrating under reduced pressure, make 450 milligrams of title compounds:
1H NMR (300MHz, CDCl
3) δ 11.60,8.08,7.74,7.46,7.37,4.46,3.43,3.34,1.62,1.41,0.98.
Step 8:4-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-8-(1,3-oxazole-2-yl)-3,4-dihydro-2H-1,4-benzoxazine-6-methane amide
With 4-butyl-8-(1,3-oxazole-2-yl)-3,4-dihydro-2H-1,4-benzoxazine-6-formic acid (450 milligrams), HBTU (853 milligrams) and diisopropylethylamine (580 milligrams) stirred 15 minutes in methylene dichloride (15 milliliters).Add (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(3-Ethylbenzyl) amino] methylene dichloride (7 milliliters) solution of fourth-2-alcohol (606 milligrams), and reaction mixture stirred spend the night.This mixture is filtered dry (sal epsom), and concentrating under reduced pressure with methylene dichloride.Purify by flash column chromatography (silicon-dioxide, 1: 9 methyl alcohol/chloroform), obtain 400 milligrams of title compounds: ESI MS m/z 619[M+H]
+
Embodiment SP-221
4-butyl-8-cyano group-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3,4-dihydro-2H-1,4-benzoxazine-6-methane amide
Step 1:3-bromo-5-(fourth amino)-4-methoxyl methyl benzoate
At Pd (OAc) through stirring
2In (144 milligrams), BINAP (1.2 gram) and the solution of cesium carbonate (8.4 gram) in toluene (100 milliliters), add butylamine (1.6 milliliters), and this mixture was heated 15 minutes at 80 ℃.Dropwise added 3, toluene (30 milliliters) solution of 5-two bromo-4-methoxyl methyl benzoates (4.2 gram) with 20 minutes.This mixture backflow is spent the night.This mixture is cooled to room temperature, through diatomite filtration, and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 1: 9 ethyl acetate/hexane), obtain 3.5 gram title compounds:
1H NMR (300MHz, CDCl
3) δ 7.52,7.19,3.90,3.88,3.18,1.66,1.46,0.97.
Step 2:3-bromo-5-(fourth amino)-4-methyl hydroxybenzoate
In methylene dichloride (10 milliliters) solution of-78 ℃ 3-bromo-5-(fourth amino)-4-methoxyl methyl benzoate (520 milligrams), dropwise add BBr
3(8 milliliters, the solution of 1M in methylene dichloride), and with reaction mixture stirring 18 hours.With this mixture concentrating under reduced pressure, and resistates is dissolved in the methylene dichloride, adds saturated sodium bicarbonate.Mixture is cooled to 0 ℃ also dropwise adds methyl alcohol.Stir after 30 minutes, this mixture was at room temperature stirred 1 hour.Remove solvent, and resistates is dissolved in methylene dichloride, water, saturated sodium bicarbonate (15 milliliters) and salt water washing, drying is filtered and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 1: 20 ethyl acetate/hexane), obtain 440 milligrams of title compounds:
1H NMR (300MHz, CDCl
3) δ 7.52,7.19,3.88,3.18,1.65,1.46,0.97.
Step 3:8-bromo-4-butyl-3,4-dihydro-2H-1,4-benzoxazine-6-methyl-formiate
Ice-cold, add chloroacetyl chloride (226 milligrams) in 3-bromo-5-(fourth amino)-4-methyl hydroxybenzoate (440 milligrams) through stirring and sodium bicarbonate (280 milligrams) solution in 1: 1 isobutyl methyl ketone/water (10 milliliters).Reaction mixture was stirred 1 hour, be warmed to room temperature and reflux 14 hours.This mixture is cooled to room temperature, with the chloroform dilution, and layering.With organic layer water and salt water washing, dry (sal epsom) filters and concentrating under reduced pressure, makes-kind of white solid:
1H NMR (300Hz, CDCl
3) δ 7.94,7.62,4.76,3.98,3.93,1.65,1.43,0.97, it promptly can be used for next step without further purifying or characterizing.Step 4: acid amides that step 3 is made and the solution reflux of 9-BBN (780 milligrams) in tetrahydrofuran (THF) (10 milliliters) 1.5 hours.This mixture is cooled to room temperature, adds thanomin (0.2 milliliter), and the solution decompression that makes is concentrated.With the resistates hexane wash, filter and filtrate decompression is concentrated.Purify by flash column chromatography (silicon-dioxide, 10% ethyl acetate/hexane), obtain (330 milligrams) title compound through 2 steps:
1H NMR (300Hz, CDCl
3) δ 7.55,7.27,4.36,3.87,3.37,3.30,1.60,1.41,0.97.
Step 5:4-butyl-8-cyano group-3,4-dihydro-2H-1,4-benzoxazine-6-methyl-formiate
Containing 8-bromo-4-butyl-3,4-dihydro-2H-1 adds NMP (7 milliliters) in the flask of 4-benzoxazine-6-methyl-formiate (0.33 gram), adds cupric cyanide (0.18 gram) then.Then with this mixture heating up to 175 ℃ and stir and spend the night.The mixture that makes is cooled to room temperature and pours in the 1N hydrochloric acid.With the acid water layer of ethyl acetate extraction, with 1N hydrochloric acid (15 milliliters), saturated sodium bicarbonate (15 milliliters) and salt water washing, dry (sal epsom) filters, and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 1: 9 ethyl acetate/hexane), obtain 184 milligrams of title compounds:
1H NMR (300Hz, CDCl
3) δ 7.55,7.43,4.41,3.89,3.39,3.31,1.58,1.40,0.97.
Step 6:4-butyl-8-cyano group-3,4-dihydro-2H-1,4-benzoxazine-6-formic acid
At the 4-butyl-8-cyano group-3 through stirring, 4-dihydro-2H-1 adds potassium hydroxide (7 milliliters, the 1.0M aqueous solution) in methyl alcohol (3 milliliters) solution of 4-benzoxazine-6-methyl-formiate (184 milligrams).This mixture at room temperature stirred spend the night, then concentrating under reduced pressure.Wash with residue diluted with water and with ethyl acetate.With 1N hydrochloric acid water layer is acidified to pH4 and uses chloroform extraction (4 * 100 milliliters).With the organic extract drying (sodium sulfate) that merges, filter and concentrating under reduced pressure, make 154 milligrams of title compounds:
1H NMR (300MHz, CDCl
3) δ 7.62,7.46,4.44,3.41,3.33,1.60,1.41,0.98.
Step 7:4-butyl-8-cyano group-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3,4-dihydro-2H-1,4-benzoxazine-6-methane amide
With 4-butyl-8-cyano group-3,4-dihydro-2H-1,4-benzoxazine-6-formic acid (129 milligrams), HBTU (284 milligrams) and diisopropylethylamine (0.26 gram) stirred 15 minutes in methylene dichloride (6 milliliters).Add (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(3-Ethylbenzyl) amino] methylene dichloride (4 milliliters) solution of fourth-2-alcohol (204 milligrams), and reaction mixture stirred spend the night.This mixture is diluted with methylene dichloride, and with 1N hydrochloric acid (15 milliliters), saturated sodium bicarbonate (15 milliliters) and salt water washing, dry (sal epsom) filters, and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 1: 9 methyl alcohol/chloroform), obtain 20 milligrams of title compounds: ESI MS m/z 577[M+H]
+
Embodiment SP-222
4-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-(methylsulfonyl)-1,2,3,4-tetrahydroquinoxaline-6-methane amide
Step 1:4-nitro-3-{[(trifluoromethyl) alkylsulfonyl] oxygen } methyl benzoate
Ice-cold, in 3-hydroxyl-4-nitrobenzoic acid methyl esters through stirring (1.5 gram) and the solution of triethylamine (1.1 milliliters) in methylene dichloride (15 milliliters), add trifluoromethanesulfanhydride anhydride (1.4 milliliters), and reaction mixture was stirred 30 minutes.This mixture is diluted with methylene dichloride,, filters and concentrating under reduced pressure, make 2.4 gram title compounds with saturated sodium bicarbonate and salt water washing, dry (sal epsom):
1H NMR (300Hz, DMSO-d
6) δ 8.47,8.27,8.15,3.99.
Step 2:3-(fourth amino)-4-nitrobenzoic acid methyl esters
At Pd through stirring
2(dba)
3In (139 milligrams), BINAP (284 milligrams) and cesium carbonate (2.0 gram) solution in toluene (50 milliliters), add butylamine (0.45 milliliter), and this reaction mixture was heated 15 minutes at 80 ℃.With dropwise adding 4-nitro-3-{[(trifluoromethyl in 1 hour) alkylsulfonyl] oxygen } toluene (15 milliliters) solution of methyl benzoate (1.0 gram).This mixture is cooled to room temperature, through diatomite filtration, and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 3: 1 ethyl acetate/hexane), obtain the title compound of 670 milligrams of yellow oilies: ESI MS m/z 550[M+H]
+
Step 3:4-amino-3-(fourth amino) methyl benzoate
With shake under 3-(fourth amino)-4-nitrobenzoic acid methyl esters (1.1 gram) and the nitrogen atmosphere of solution at 50psi of 10%Pd/C (110 milligrams) in methyl alcohol (20 milliliters) 2 hours.Through diatomite filtration, and concentrating under reduced pressure makes 940 milligrams of title compounds with this mixture:
1H NMR (300Hz, DMSO-d
6) 67.13,6.94,6.52,3.72,3.02,1.60,1.42,0.93.
Step 4:4-butyl-3-oxygen-1,2,3,4-tetrahydroquinoxaline-6-methyl-formiate
Ice-cold, in 4-amino-3-(fourth amino) methyl benzoate (950 milligrams) through stirring and sodium bicarbonate (862 milligrams) solution in 1: 1 isobutyl methyl ketone/water (20 milliliters), add chloroacetyl chloride (0.41 milliliter), and this mixture was stirred 1 hour.This mixture was warmed to room temperature and reflux 14 hours.This mixture is cooled to room temperature, with the chloroform dilution, and layering.With organic layer water and salt water washing, dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 1: 1 ethyl acetate/hexane), obtain 850 milligrams of title compounds:
1H NMR (300Hz, CDCl
3) δ 7.89,7.72,6.80,3.97,3.88,3.30-3.25,1.68-1.58,1.47-1.35,0.94-0.88.
Step 5:4-butyl-1,2,3,4-tetrahydroquinoxaline-6-methyl-formiate
Ice-cold, the 4-butyl-3-oxygen-1,2 through stirring, 3, in the solution of the tetrahydrofuran (THF) (32 milliliters) of 4-tetrahydroquinoxaline-6-methyl-formiate (840 milligrams), add (3.2 milliliters of borines-methyl-sulfide complex compound, 2.0M tetrahydrofuran (THF)), and with the mixture that makes refluxed 24 hours.This mixture is cooled to room temperature, uses the methyl alcohol stopped reaction, and solvent is removed in decompression.Purify by flash column chromatography (silicon-dioxide, 1: 1 ethyl acetate/hexane), obtain 364 milligrams of title compounds:
1H NMR (300Hz, CDCl
3) δ 7.27,7.22,6.41,3.84,3.47-3.45,3.32-3.23,1.60-1.58,1.42-1.37,0.99-0.94.
Step 6:4-butyl-1-(methylsulfonyl)-1,2,3,4-tetrahydroquinoxaline-6-methyl-formiate
Ice-cold, the 4-butyl-1,2,3 through stirring in 4-tetrahydroquinoxaline-6-methyl-formiate (180 milligrams) and the solution of triethylamine (62 microlitre) in methylene dichloride (2 milliliters), adds chloroacetyl chloride (101 microlitre), and this mixture was stirred 1 hour.This mixture is warmed to room temperature, with the methylene dichloride dilution, with 1N hydrochloric acid and salt water washing.With organic layer drying (sal epsom), filter then, and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 1: 3 ethyl acetate/hexane), obtain 150 milligrams of title compounds:
1H NMR (300Hz, CDCl
3) δ 7.57,7.41,7.32,3.90,3.84,3.45,3.38,1.61,1.41,0.98.
Step 7:4-butyl-1-(methylsulfonyl)-1,2,3,4-tetrahydroquinoxaline-6-formic acid
At 4-butyl-1-(methylsulfonyl)-1,2,3, in methyl alcohol (1.3 milliliters) solution of 4-tetrahydroquinoxaline-6-methyl-formiate (144 milligrams), add 1M potassium hydroxide (13 milliliters) through stirring.This mixture is at room temperature stirred 48 hours, and concentrating under reduced pressure.Wash with residue diluted with water and with ethyl acetate.With 1N hydrochloric acid organic layer is acidified to pH 4, and extracts with chloroform (4 * 100 milliliters).With the organic extract drying (sodium sulfate) that merges, filter, and concentrating under reduced pressure, make 99 milligrams of title compounds:
1H NMR (300Hz, CDCl
3) δ 7.43,7.39,7.24,3.77,3.39,3.32,1.56,1.33,0.90.
Step 8:4-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-(methylsulfonyl)-1,2,3,4-tetrahydroquinoxaline-6-methane amide
With 4-butyl-1-(methylsulfonyl)-1,2,3, the solution of 4-tetrahydroquinoxaline-6-formic acid (99 milligrams), HATU (181 milligrams), HOBt (64 milligrams) and diisopropylethylamine (100 microlitre) stirred 15 minutes in methylene dichloride (1.0 milliliters).Add (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(3-Ethylbenzyl) amino] fourth-2-alcohol (129 milligrams) and the solution of diisopropylethylamine (100 microlitre) in methylene dichloride (1.0 milliliters), and this mixture stirring spent the night.This mixture is diluted with methylene dichloride, with 1N hydrochloric acid (10 milliliters), saturated sodium bicarbonate (10 milliliters) and salt water washing.With organic layer drying (sal epsom), filter then, and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 1: 9 methyl alcohol/chloroform), make a kind of transparent solid.This solid is dissolved in methyl alcohol (1 milliliter), and handles with hydrochloric acid (0.5 milliliter, the 1.0M ether).Filter and collect the precipitation that generates, obtain 90 milligrams of title compounds: ESI MS m/z 629[M+H]
+
Embodiment SP-223
4-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,2,3,4-tetrahydroquinoxaline-6-carboxamide hydrochloride
Step 1:1-tertiary butyl 6-methyl 4-butyl-3-oxygen-3,4-dihydro-quinoxaline-1,6 (2H)-dicarboxylic acid esters P571
Ice-cold, 4-butyl-3-oxygen-1 through stirring, 2,3, in 4-tetrahydroquinoxaline-6-methyl-formiate (1.1 gram) and the solution of triethylamine (0.9 milliliter) in methylene dichloride (10 milliliters), add DMAP (51.3 milligrams) and tert-Butyl dicarbonate (1.4 gram), and the mixture that makes was stirred 4 days.This mixture is diluted water and salt water washing with methylene dichloride.With organic layer drying (sal epsom), filter then, and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 1: 1 ethyl acetate/hexane), obtain 440 milligrams of title compounds: ESI MS m/z 363[M+H]
+
Step 2:1-tertiary butyl 6-methyl 4-butyl-3,4-dihydro-quinoxaline-1,6 (2H)-dicarboxylic acid esters P572
With 1-tertiary butyl 6-methyl 4-butyl-3-oxygen-3,4-dihydro-quinoxaline-1,6 (2H)-dicarboxylic acid esters (440 milligrams) and the solution of 9-BBN dimer (600 milligrams) in tetrahydrofuran (THF) (10 milliliters) were 65 ℃ of heating 10 hours.This mixture is cooled to room temperature, adds thanomin (0.15 milliliter), and the solution decompression that makes concentrates.With the resistates hexane wash, filter, and filtrate decompression is concentrated.Purify by flash column chromatography (silicon-dioxide, 1: 9 ethyl acetate/hexane), obtain 158 milligrams of title compounds:
1H NMR (300Hz, CDCl
3) δ 7.50,7.34,7.28,3.88,3.77,3.38-3.30,1.65-1.51,1.42-1.34,0.99-0.94.
Step 3:1-(tert-butoxycarbonyl)-4-butyl-1,2,3,4-tetrahydroquinoxaline-6-formic acid P572
At 1-tertiary butyl 6-methyl 4-butyl-3, in methyl alcohol (1.4 milliliters) solution of 4-dihydro-quinoxaline-1,6 (2H)-dicarboxylic acid esters (158 milligrams), add 1M potassium hydroxide (1.4 milliliters) through stirring.This mixture was stirred 12 hours at 40 ℃, then concentrating under reduced pressure.Wash with this residue diluted with water and with ethyl acetate.With 1N hydrochloric acid water layer is acidified to pH 4, and extracts with chloroform (4 * 100 milliliters).With the organic extract drying (sodium sulfate) that merges, filter, and concentrating under reduced pressure, make 120 milligrams of title compounds:
1H NMR (300Hz, CDCl
3) δ 7.55,7.40,7.37,3.79,3.38,3.34,1.60,1.53,1.39,0.97.Step 4:4-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,2,3,4-tetrahydroquinoxaline-6-carboxamide hydrochloride
With 1-(tert-butoxycarbonyl)-4-butyl-1,2,3, the solution of 4-tetrahydroquinoxaline-6-formic acid (120 milligrams), HBTU (204 milligrams) and diisopropylethylamine (100 microlitre) stirred 15 minutes in methylene dichloride (2.0 milliliters).Add (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(3-Ethylbenzyl) amino] fourth-2-alcohol (146 milligrams) and the solution of diisopropylethylamine (100 microlitre) in methylene dichloride (2.0 milliliters), and this mixture stirring spent the night.This mixture is diluted with methylene dichloride, with 1N hydrochloric acid (10 milliliters), saturated sodium bicarbonate (10 milliliters) and salt water washing.With organic layer drying (sal epsom), filter then, and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 1: 9 methyl alcohol/chloroform), make-kind of transparent solid.This solid is dissolved in methyl alcohol (1 milliliter), and handles with hydrochloric acid (0.5 milliliter, 1.0M ether, 0.5 mmole).Filter and collect the precipitation that generates, obtain 45 milligrams of title compounds: ESI MS m/z 551[M+H]
+
Embodiment SP-224
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 6-[(methylsulfonyl) methyl] niacinamide
Step 1:6-[(acetoxyl group) methyl] nicotinic acid methyl ester
In methylene dichloride (100 milliliters) solution of 6-methylnicotinic acid methyl esters (6.05 gram), add metachloroperbenzoic acid (77%, 13.5 gram).Reaction mixture was at room temperature stirred 2 hours, use chloroform (100 milliliters) dilution then.Mixture is used sulfite solution, saturated sodium bicarbonate and salt water washing in regular turn.With organism drying (sodium sulfate), filter then, and concentrating under reduced pressure, make 6.21 gram 1-oxidation 6-methylnicotinic acid methyl esters.Diacetyl oxide (50 milliliters) solution of 1-oxidation 6-methylnicotinic acid methyl esters (4.35 gram) was heated 2 hours at 120 ℃, then concentrating under reduced pressure.Purify by flash column chromatography (silica gel, 1: 2 to 3: 5 ethyl acetate/hexane), make 3.3 gram title compounds:
1H NMR (300Hz, CDCl
3) δ 9.18,8.31,7.44,5.29,3.96,2.19.
Step 3:6-[(methylsulfonyl) methyl] nicotinic acid
At the 6-[(acetoxyl group) methyl] in anhydrous methanol (100 milliliters) solution of nicotinic acid methyl ester (3.0 gram), add salt of wormwood (4.56 gram).This mixture was at room temperature stirred 2 hours, use the dilution of methylene dichloride (200 milliliters) and water (200 milliliters) then.With organic layer salt water washing, dry (sodium sulfate) filters, and concentrating under reduced pressure, obtains 1.70 gram alcohol.This material is used without further purification.In methylene dichloride (40 milliliters) solution of ice-cold 6-(methylol) nicotinic acid methyl ester (1.6 gram), add diisopropylethylamine (1.5 gram), add methylsulfonyl chloride (1.21 gram) then.Mixture was at room temperature stirred 1 hour, use methylene dichloride (100 milliliters) dilution then.This mixture is used 0.5N sal enixum, water and salt water washing in regular turn.With organic layer drying (sodium sulfate), filter then, and concentrating under reduced pressure, make methylsulfonyl ester 2.34 grams.This methylsulfonyl ester can use without further purification.
At the 6-{[(methylsulfonyl) oxygen] methyl } N of nicotinic acid methyl ester (2.34 gram), in dinethylformamide (10 milliliters) solution, add sulphur methylate (850 milligrams).This mixture was stirred 15 hours at 50 ℃.This mixture is diluted and water, saturated sodium bicarbonate and salt water washing in regular turn with ethyl acetate (100 milliliters).With organic layer drying (sodium sulfate), filter then, and concentrating under reduced pressure, make 1.61 gram methyl thioethers.This material can use without further purification.At ice-cold 6-[(methylthio group) methyl] in methyl alcohol (35 milliliters) solution of nicotinic acid methyl ester (1.61 gram), add water (35 milliliters) solution of oxone (7.52 gram).The water slurry that makes was at room temperature stirred 2 hours.Extract with the dilution of the mixture water (50 milliliters) that makes and with chloroform (3 * 100 milliliters).With the organic extract salt water washing of merging, dry (sodium sulfate) filters and concentrating under reduced pressure, makes 1.77 gram methyl sulfones, and it can use without further purification.
At 6-[(methylsulfonyl through stirring) methyl] nicotinic acid methyl ester (800 milligrams) 1: 1: 1 tetrahydrofuran (THF)/methanol (30 milliliters) solution in, add lithium hydroxide (440 milligrams).Mixture is at room temperature stirred 1 hour, and concentrating under reduced pressure.Make resistates phase-splitting between water (10 milliliters) and chloroform (10 milliliters).With 1N hydrochloric acid water layer is acidified to pH 4, and with 3: 1 chloroform/2-propyl alcohol (3 * 30 milliliters) extraction.With the organic layer drying (sodium sulfate) that merges, filter, and concentrating under reduced pressure, make 700 milligrams of title compounds:
1H NMR (300Hz, CD
3OD) δ 9.07,8.33,7.65,4.77,3.06.
Step 4:N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 6-[(methylsulfonyl) methyl] niacinamide
At 6-[(methylsulfonyl through stirring) methyl] in nicotinic acid (181 milligrams), diisopropylethylamine (116 milligrams) and the solution of HBTU (341 milligrams) in methylene dichloride (5 milliliters); add (2R; 3S)-3-amino-4-(3; the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] fourth-2-alcohol (326 milligrams) and N, the mixture of N-diisopropylethylamine (233 milligrams) in methylene dichloride (5 milliliters).This mixture is at room temperature stirred 15 hours, and concentrating under reduced pressure.Resistates with ethyl acetate (50 milliliters) dilution, with saturated sodium bicarbonate and salt water washing, dry (sodium sulfate), is filtered, and concentrating under reduced pressure.Purify by flash column chromatography (silica gel, 5: 95 to 10: 90 ethanol/methylene), obtain 165 milligrams of title compounds: ESI MS m/z 532[M+H]
+
Embodiment SP-225
3-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-Methyl-1H-indole-5-methane amide
Step 1:4-hydrazino-benzoic acid carbethoxy hydrochloride
In the mixture of 0 ℃ 4-ethylamino benzoic ether (10.0 gram) in water (56 milliliters) and concentrated hydrochloric acid (20 milliliters), by water (20 milliliters) solution of a part adding Sodium Nitrite (4.25 gram).This mixture was stirred 15 minutes at 0 ℃, and pour this mixture in tin chloride (II) water (34 milliliters) solution (50gm) into this moment.The mixture that makes is shifted out from ice bath, make it slowly go back up to room temperature with 1 hour, filtration this moment is collected the solid that makes and is washed with ether then with cold concentrated hydrochloric acid (30 milliliters).This solid is dry under vacuum, make 13 gram title compounds:
1H NMR (DMSO-d
6) δ 1.29,4.25,7.03,7.85,9.0,9.06,10.6.
Step 2:3-butyl-1H-indole-5-carboxylic acid ethyl ester
At 4-hydrazino-benzoic acid carbethoxy hydrochloride (10gm) at ethanol: in the mixture in the water (5: 1,100 milliliters), add hexanal (4.62gm).This mixture was refluxed 3 hours at 100 ℃.Remove solvent and add toluene (100 milliliters) and tosic acid (0.1 gram).This mixture was refluxed 18 hours at 120 ℃, be cooled to room temperature and concentrating under reduced pressure.Silica gel (100 milliliters) go up to use 90: 9: 1 (hexane: methylene dichloride: ethyl acetate) carry out column chromatography and separate, make 0.8 gram title compound as elutriant:
1H NMR (CDCl
3) δ 0.957,1.44,1.72,2.78,4.40,7.02,7.34,7.90,8.13,8.38.
Step 3:3-butyl-1-Methyl-1H-indole-5-ethyl formate
In the mixture of 3-butyl-1H-indole-5-carboxylic acid ethyl ester (0-6 gram) in methyl-sulphoxide (10 milliliters), add potassium tert.-butoxide (0.29 gram) and methyl iodide (2.0 milliliters).This mixture was stirred 18 hours at 50 ℃ 2, and pour this mixture in the water (50 milliliters) into this moment.With this solution with ethyl acetate extraction and with organic extract with salt water washing three times, through anhydrous sodium sulfate drying, and concentrating under reduced pressure.Go up the hexane solution that uses 5% ethyl acetate at silica gel (100 milliliters) and carry out the column chromatography separation, make 0.294 gram title compound as elutriant:
1HNMR (CDCl
3) δ 0.953,1.44,1.69,2.77,3.76,4.40,6.87,7.26,7.91,8.35.
Step 4:3-butyl-1-Methyl-1H-indole-5-formic acid
In the mixture of 3-butyl-1-Methyl-1H-indole-5-ethyl formate (0.294 gram) in methyl alcohol (20 milliliters), add 1N NaOH (10 milliliters).This mixture was stirred 18 hours at 50 ℃, be cooled to room temperature and pour 1N HCl (50 milliliters) into.With this mixture ethyl acetate extraction, and with acetic acid ethyl acetate extract through anhydrous sodium sulfate drying and be evaporated to dried, make 0.234 the gram (89%) title compound:
1H NMR (300Hz, CD
3OD) δ 0.965,1.42,1.69,2.76,3.77,7.02,7.35,7.84,8.29.
Step 5:3-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-Methyl-1H-indole-5-methane amide
In the mixture of 3-butyl-1-Methyl-1H-indole-5-formic acid (0.15 gram) in methylene dichloride (5 milliliters) and tetrahydrofuran (THF) (10 milliliters), add 1,1-carbonyl dimidazoles (0.105 gram).This mixture 40 ℃ of stirrings, is added (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(3-Ethylbenzyl) amino this moment] methylene dichloride (5 milliliters) solution of fourth-2-alcohol (0.2 gram).This mixture was stirred 18 hours at 40 ℃, pour into then in the methylene dichloride (50 milliliters).With this mixture water, use the salt water washing then, through anhydrous sodium sulfate drying and concentrating under reduced pressure.Go up use 85: 10: 5 (methylene dichloride: hexane: methyl alcohol) carry out column chromatography and separate, make 0.102 gram title compound: C at silica gel (100 milliliters) as elutriant
33H
39F
2N
3O
2MS (ESI+) m/z 547.9[M+H]
+
Embodiment SP-226
3-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-indoles-5-methane amide
Step 1:3-butyl-1H-indole-5-carboxylic acid
At 3-butyl-1H-indole-5-carboxylic acid ethyl ester, embodiment SP-225 in the mixture of step 2 (0.4 gram) in methyl alcohol (15 milliliters), adds 1N NaOH (5 milliliters).This mixture was stirred 18 hours at 50 ℃, be cooled to room temperature and pour among the 1N HCl (50 milliliters).With this mixture ethyl acetate extraction.With acetic acid ethyl acetate extract through anhydrous sodium sulfate drying, and be evaporated to dried, make 0.145 the gram title compound: C
13H
15N
1O
2MS (ESI+) m/z 216.12 (M+H)
+
Step 2:3-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-indoles-5-methane amide
In the mixture of 3-butyl-1H-indole-5-carboxylic acid (0.145 gram) in methylene dichloride (15 milliliters), add triethylamine (0.068 gram) and HATU (0.255 gram).This mixture was at room temperature stirred 15 minutes, add this moment (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(3-Ethylbenzyl) amino] fourth-2-alcohol (0.224 gram).This mixture was at room temperature stirred 72 hours, pour into then in the methylene dichloride (50 milliliters), water with the saturated sodium bicarbonate washing, concentrates through anhydrous magnesium sulfate drying and under vacuum then.
The solution of going up in the methylene dichloride that uses 5% methyl alcohol containing 0.15%HOAc at silica gel (100 milliliters) carries out the column chromatography separation as elutriant, makes 0.247 gram title compound: C
32H
37F
2N
3O
2MS (ESI+) m/z 534.3 (M+H)
+
Embodiment SP-227
4-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3,4-dihydro-2H-1,4-benzoxazine-6-methane amide
Step 1:4-butyl-3-oxygen-3,4-dihydro-2H-1,4-benzoxazine-6-methyl-formiate
Ice-cold, add chloroacetyl chloride (1.7 milliliters) in 3-amino-4-hydroxy methyl benzoate through stirring (3.0 gram) and sodium bicarbonate (3.3 gram) solution in 1: 1 isobutyl methyl ketone/water (40 milliliters), and with reaction mixture stirring 1 hour.This mixture is warmed to room temperature and refluxed 14 hours, be cooled to room temperature, with the chloroform dilution, and layering.With organic layer water and salt water washing, dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash chromatography (silicon-dioxide, 1: 9 methyl alcohol/chloroform), make 3.2 gram white solid phenoxazine, it can use without further purifying or characterizing.In step 1, make in methyl alcohol (8 milliliters) solution of De phenoxazine (700 milligrams) and salt of wormwood (934 milligrams) and add n-butyl bromide (1.8 milliliters), and this mixture was refluxed 6 days.This mixture is cooled to room temperature, and concentrating under reduced pressure also makes resistates be divided into ethyl acetate layer and water layer.With organic layer salt water washing, dry (sal epsom) filters and concentrating under reduced pressure, makes 800 milligrams of title compounds:
1H NMR (300Hz, CDCl
3) δ 7.72-7.68,7.02-6.99,4.66,4.00-3.92,1.69-1.64,1.46-1.38,1.01-0.95.
Step 2:4-butyl-3,4-dihydro-2H-1,4-benzoxazine-6-methyl-formiate
At 4-butyl-3-oxygen-3,4-dihydro-2H-1, tetrahydrofuran (THF) (13 milliliters) the solution reflux of 4-benzoxazine-6-methyl-formiate (800 milligrams) and 9-BBN (1.6 gram) 1.5 hours.This mixture is cooled to room temperature, adds thanomin (0.4 milliliter) and the solution decompression that makes is concentrated.With the resistates hexane wash, filter, and filtrate decompression is concentrated.Purify by flash column chromatography (silicon-dioxide, 25% ethyl acetate/hexane), obtain 607 milligrams of title compounds:
1H NMR (300Hz, DMSO-d
6) δ 7.21,7.16,6.75,4.24-4.21,3.78,3.34-3.24,1.55-1.47,1.38-1.30,0.95-0.90.
Step 3:4-butyl-3,4-dihydro-2H-1,4-benzoxazine-6-formic acid
At the 4-butyl-3 through stirring, 4-dihydro-2H-1 adds 1M potassium hydroxide (17 milliliters) in methyl alcohol (5 milliliters) solution of 4-benzoxazine-6-methyl-formiate (412 milligrams).This mixture is at room temperature stirred 5 hours, and concentrating under reduced pressure.Wash with residue diluted with water and with ethyl acetate.With 1N hydrochloric acid water layer is acidified to pH 4 and uses chloroform extraction (4 * 50 milliliters).With the organic extract drying (sodium sulfate) that merges, filter and concentrating under reduced pressure, make 384 milligrams of title compounds: ESI MS m/z 236[M+H]
+
Step 4
4-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl)-3,4-dihydro-2H-1,4-benzoxazine-6-methane amide
With 4-butyl-3,4-dihydro-2H-1,4-benzoxazine-6-formic acid (43 milligrams), HATU (104 milligrams),
HOBt(37 milligrams) and diisopropylethylamine (47 milliliters) stirred 15 minutes in methylene dichloride (1.0 milliliters).Add (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(3-Ethylbenzyl) amino] methylene dichloride (1.0 milliliters) solution of fourth-2-alcohol dihydrochloride (62 milligrams) and diisopropylethylamine (47 milliliters), and the reaction mixture stirring spent the night.This mixture is diluted with methylene dichloride, and with 1N hydrochloric acid (15 milliliters), saturated sodium bicarbonate (15 milliliters) and salt water washing, dry (sal epsom) filters, and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 1: 9 methyl alcohol/chloroform), obtain 15 milligrams of title compounds: APCI MS m/z 552[M+H]
+
Embodiment SP-228
3-ethanoyl-1-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-indoles-6-methane amide
Step 1.1-butyl-1H-indoles-6-methyl-formiate
1H-indoles-6-methyl-formiate (4.17 gram) is dissolved in DMSO (30 milliliters), and adds potassium tert.-butoxide (2.93 gram).This mixture was at room temperature stirred 10 minutes.Add butyl iodide (3.0 milliliters).With this mixture restir 3 hours, make the phase-splitting between ethyl acetate and water and salt solution of this mixture, through anhydrous sodium sulfate drying, filter also and concentrate, make 1-butyl-1H-indoles-6-methyl-formiate (4.53 gram).C
14H
17NO
2+ H
1MS (ESI+) m/z 232.12 (M+H)
+
Step 2.3-ethanoyl 1-butyl-1H-indoles-6-methyl-formiate
1-butyl-1H-indoles-6-methyl-formiate (4.53 gram) is dissolved in methylene dichloride (25 milliliters).This mixture is cooled to 0 ℃.Dropwise adding diethyl aluminum chloride (29.5 milliliters) also stirs this mixture 30 minutes at 0 ℃.The solution that dropwise adds methylene dichloride (25 milliliters) and Acetyl Chloride 98Min. (2.1 milliliters), and this mixture stirred 2 hours at 0 ℃.Make mixture phase-splitting between methylene dichloride, water and salt solution then,, filter and concentrate through dried over sodium sulfate.On silica gel, use ethyl acetate/heptane (40/60) to carry out chromatographic separation concentrate, make 3-ethanoyl 1-butyl-1H-indoles-6-methyl-formiate (3.38 gram).C
16H
19N
1O
3+ H
1MS (ESI+) m/z 274.14 (M+H)
+
Step 3. 3-ethanoyl 1-butyl-1H-indoles-6-formic acid
3-ethanoyl 1-butyl-1H-indoles-6-methyl-formiate (2.00 gram) is dissolved in methyl alcohol (100 milliliters).Add sodium hydroxide (1N) until the mixture slight haze that becomes.Add methyl alcohol (20 milliliters) again until this solution clarification.Add sodium hydroxide again until this mixture slight haze.This mixture at room temperature stirred spend the night.With this solution concentration half, and add hydrochloric acid (2N) and have until water layer and be approximately 1 pH value to original volume.With this mixture dichloromethane extraction, and,, filter and concentrate through dried over sodium sulfate with organic layer salt water washing.On silica gel, use MeOH/ heptane/methylene dichloride (4/20/76) to carry out chromatographic separation the material that makes, make 3-ethanoyl-1-butyl-1H-indoles-6-formic acid (1.60 gram).C
15H
17N
1O
3+ H
1MS (ESI+) m/z 260.13 (M+H)
+
Step 4.3-ethanoyl-1-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-indoles-6-methane amide
3-ethanoyl-1-butyl-1H-indoles-6-formic acid (0.322 gram) is dissolved in methylene dichloride (15 milliliters).Add 1,1 '-carbonyl dimidazoles (0.171 gram).This mixture was stirred 2 hours, add then (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(3-Ethylbenzyl) amino] mixture of fourth-2-alcohol (0.250 gram) in methylene dichloride (15 milliliters).After stirring is spent the night, with the phase-splitting between methylene dichloride, water and salt solution of this mixture.Organic layer through dried over sodium sulfate, is filtered, and concentrate.Resistates is carried out chromatographic separation with MeOH/ methylene dichloride (4/96) on silica gel; make 3-ethanoyl-1-butyl-N-{ (1S; 2R)-and 1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-indoles-6-methane amide (0.335 gram).C
34H
39F
2N
3O
3+ H
1MS (ESI+) m/z 576.30 (M+H)
+
Embodiment SP-229
1-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(trifluoroacetyl group)-1H-indoles-6-methane amide
Step 1.1-butyl-1H-indoles-6-butyl formate
1-butyl-1H-indoles-6-formic acid (0.450 gram) is dissolved in methylene dichloride (10 milliliters).Add potassium tert.-butoxide (0.317 gram), and this mixture was at room temperature stirred 10 minutes.Add butyl iodide (0.33 milliliter).This mixture was at room temperature stirred 6 hours.Add entry then, make the phase-splitting between ethyl acetate, water and salt solution of this mixture, and, filter and concentrate through dried over mgso.Use heptane/methylene dichloride (30/70) to carry out silica gel chromatography and separate, make 1-butyl-1H-indoles-6-butyl formate (0.429 gram).C
17H
23NO
2+ H
1MS (ESI+) m/z 274.20 (M+H)
+
Step 2. 1-butyl-3-(trifluoroacetyl group)-1H-indoles-6-butyl formate
Boron trifluoride-methyl-sulfide complex compound (0.238 gram) is dissolved in methylene dichloride (10 milliliters).This solution is cooled to-78 ℃, and adds methylene dichloride (2 milliliters) solution of trifluoroacetic anhydride (0.384 gram).This mixture was stirred 10 minutes at-78 ℃, add methylene dichloride (3 milliliters) solution of 1-butyl-1H-indoles-6-butyl formate (0.250 gram) this moment.This mixture was stirred 15 minutes at-78 ℃, be warmed to ambient temperature overnight then.Then this mixture is poured in the sodium bicarbonate aqueous solution, and used dichloromethane extraction.Organic layer through dried over sodium sulfate, is filtered, and concentrate, and on silica gel, use ethyl acetate/heptane (20/80) to carry out chromatographic separation the material that makes, make 1-butyl-3-(trifluoroacetyl group)-1H-indoles-6-butyl formate (0.302 gram).C
19H
22F
3N
1O
3+ H
1MS (ESI+) m/z 370.16 (M+H)
+
Step 3. 1-butyl-3-(trifluoroacetyl group)-1H-indoles-6-formic acid
With 1-butyl-3-(trifluoroacetyl group)-1H-indoles-6-butyl formate (0.277 gram), LiOHH
2O (0.040 gram), THF (1.5 milliliters) water (0.5 milliliter) and methyl alcohol (0.5 milliliter) at room temperature stir and spend the night.Solvent is removed in decompression then, and adds HCl (2N, 0.5 milliliter) in resistates.With the resistates ethyl acetate extraction,, filter and concentrate through dried over mgso.On silica gel, use ethanol/methylene (6/94) to carry out chromatographic separation, make 1-butyl-3-(trifluoroacetyl group)-1H-indoles-6-formic acid (0.166 gram).C
15H
14F
3N
1O
3+ H
1MS (ESI+) m/z 314.10 (M+H)
+
Step 4.1-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(trifluoroacetyl group)-1H-indoles-6-methane amide
1-butyl-3-(trifluoroacetyl group)-1H-indoles-6-formic acid (0.141 gram) is dissolved in methylene dichloride (10 milliliters).Add 1,1 '-carbonyl dimidazoles (0.080 gram), and this mixture at room temperature stirred 2 hours.Add (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(3-Ethylbenzyl) amino] mixture of fourth-2-alcohol (0.166 gram) in methylene dichloride, and this mixture at room temperature stirred spend the night.Make the phase-splitting between methylene dichloride and water of this mixture then, through dried over sodium sulfate, filter, and concentrate.On silica gel, carry out chromatographic separation with methanol/ethyl acetate/heptane/methylene dichloride (3/10/10/77 to 6/10/10/74); make 1-butyl-N-{ (1S; 2R)-and 1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(trifluoroacetyl group)-1H-indoles-6-methane amide (0.155 gram).C
34H
36F
5N
3O
3+ H
1MS (ESI+) m/z 630.28 (M+H)
+
Embodiment SP-230
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-2-(dipropyl amino) Isonicotinamide
2-(dipropyl amino) Yi Yansuan (0.206 gram) is dissolved in methylene dichloride (10 milliliters).Add 1,1 '-carbonyl dimidazoles (0.142 gram), and this mixture at room temperature stirred 2 hours, add (2R this moment, 3S)-and 3-amino-4-(3, the 5-difluorophenyl)-1-{[1-(3-ethynyl phenyl) cyclopropyl] amino } mixture of fourth-2-alcohol (0.284 gram) in methylene dichloride.This mixture stirring is spent the night, and phase-splitting between methylene dichloride, water and salt solution then through dried over sodium sulfate, is filtered, and concentrating under reduced pressure.Enriched material is carried out chromatographic separation with ethanol/methylene (4/96) on silica gel, make N-((1S, 2R)-and 1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-2-(dipropyl amino) Isonicotinamide (0.268 gram).C
33H
38F
2N
4O
2+ H
1MS (ESI+) m/z 561.30 (M+H)
+
Embodiment SP-231
1-butyl-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-1H-indoles-6-methane amide
According to N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-and 3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-2-(dipropyl amino) method that Isonicotinamide is identical, use 1-butyl-1H-indoles-6-formic acid (0.119 gram) to make 1-butyl-N-((1S, 2R)-and 1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-1H-indoles-6-methane amide (0.076 gram).C
34H
35F
2N
3O
2+ H
1MS (ESI+) m/z 556.28 (M+H)
+
Embodiment SP-231
3-(allyl sulfide)-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl) benzamide
Step 1. 3-(allyl sulfide) phenylformic acid
3-thiobenzoic acid (Aldrich, 4.3 grams, 28 mmoles) is dissolved in THF (100 milliliters), is cooled to 0 ℃, and, use allyl bromide 98 (2.4 milliliters, 28 mmoles) to handle then with KO-tBu (6.3 grams, 56 mmoles).From this reaction mixture, remove solvent, and with resistates phase-splitting between 3M HCl and EtOAc.Separate organic layer, dry (MgSO
4) and concentrate, make title compound (5.3 gram).(LRMS(M-H)m/z 193.2)。
Step 2. 3-(allyl sulfide)-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl) benzamide
With (717 milligrams in 3-(allyl sulfide) phenylformic acid, 3.69 (2R mmole),, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and 1-{[1-(3-ethylphenyl) cyclopropyl] amino } (247 milligrams of fourths-2-alcohol, 0.685 mmole) and HATU (Aldrich, 2.1 grams, 5.54 mmoles) at room temperature be dissolved in methylene dichloride (35 milliliters), and handle with diisopropylethylamine (1.6 milliliters, 9.225 mmoles).After finishing, reaction mixture is concentrated the circumstances in which people get things ready for a trip spectrum of going forward side by side separate (SiO
2, 2: 1 to 1: 1 hexanes: EtOAc), make required compound (650) milligram.(LRMS(M+H)m/z 537.8)。
Embodiment SP-232
3-(allyl group sulfinyl)-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl) benzamide
With 3-(allyl sulfide)-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino-the 2-hydroxypropyl) benzamide (325 milligrams, 0.606 mmole) is dissolved in CH
2Cl
2(10 milliliters) and AcOH (1 milliliter), and handle with mCPBA (104 milligrams, 0.606 mmole).This reaction mixture was stirred 2.5 hours, add mCPBA (20 milligrams, 0.11 mmole) this moment again, and continued restir 30 minutes.With organic layer Et
2O dilution and with 15% sodium thiosulfite solution washing.With organism salt water washing, dry then (MgSO
4) and concentrate, make-kind of oil, it is used in 25% in the hexane carries out chromatographic separation to 50%EtOAc, obtain title compound.(LRMS(M+H)m/z 553.8)。
Embodiment SP-233
3-(allyl group alkylsulfonyl)-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl) benzamide
With 3-(allyl sulfide)-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino-the 2-hydroxypropyl) benzamide (245 milligrams, 0.456 mmole) is dissolved in MeOH: H
2O (9: 1,6 milliliters), and handle with oxone (561 milligrams, 0.931 mmole).When reaction is finished, this mixture is concentrated into 0.5 times of volume, and is poured on the EtOAc.With it with 15% sodium thiosulfite solution washing, dry (MgSO
4) and concentrate, make title compound.(LRMS(M+H)m/z 569.8)。
Embodiment SP-234
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(dipropyl amino)-6-methyl Isonicotinamide
Step 1. 2-chloro-6-methyl Isonicotinamide
Use the method for Org.Prep.Proceed.Intern. (1982) 396,2-chloro-6-methyl Yi Yansuan (0.405 gram, 2.36 mmoles) is changed into the different cigarette nitrile of 2-chloro-6-methyl (0.241 gram).
Step 2. 2-(dipropyl the amino)-different cigarette nitrile of 6-methyl
In the different cigarette nitrile of 2-chloro-6-methyl (0.230 gram, 1.51 mmoles), add di-n-propylamine (5 milliliters).In a sealing, heavy wall Glass Containers, this mixture 80 ℃ of heating 12 hours, was at room temperature heated 17 hours then.Excessive di-n-propylamine is removed in decompression, and with resistates phase-splitting between methylene dichloride and sodium bicarbonate aqueous solution.Through dried over sodium sulfate and after concentrating, on silica gel, use ethyl acetate-hexane (10/90) to carry out chromatographic separation resistates, make the 0.14 gram 2-chloro-different cigarette nitrile of 6-methyl and 0.059 gram 2-(dipropyl amino)-different cigarette nitrile of 6-methyl.Use above-mentioned condition, the different cigarette nitrile of 2-chloro-6-methyl (0.14 gram) is changed into 2-(dipropyl the amino)-different cigarette nitrile of 6-methyl of other 0.043 gram.
Step 3. 2-(dipropyl amino)-6-methyl Yi Yansuan hydrochloride
In 2-(dipropyl amino)-different cigarette nitrile of 6-methyl (0.094 gram, 0.433 mmole), add 4N HCl (2 milliliters) and THF (1 milliliter).This mixture was stirred 12 hours 100 ℃ (THF is distilled out), reduce pressure then and use the methylbenzene azeotropic thing to remove water layer, obtain 2-(dipropyl amino)-6-methyl Yi Yansuan hydrochloride, it promptly is used for next step without further purification.
Step 4. N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(dipropyl amino)-6-methyl Isonicotinamide
In THF (3 milliliters) solution of 2-(dipropyl amino)-6-methyl Yi Yansuan hydrochloride (about 0.4 mmole), add triethylamine (0.17 microlitre), add methylene dichloride (2 milliliters) then, add CDI (0.071 gram, 0.44 mmole) then.Stir after 1 hour, in this CDI mixture, add (2R, 3S)-and 3-amino-4-(3, the 5-difluorophenyl)-1-[(3-ethylphenyl) amino] fourth-2-alcohol dihydrochloride (0.163 gram, 0.400 mmole), triethylamine (0.11 milliliter) and methylene dichloride (about 2 milliliters).This mixture stirred spends the night, after this add 0.12 milliliter of triethylamine and 0.045 gram (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(3-ethylphenyl) amino again] fourth-2-alcohol dihydrochloride.Restir is after a few hours, with the phase-splitting between methylene dichloride and sodium bicarbonate aqueous solution of this mixture.With the organic layer dried over sodium sulfate, concentrate, and on silica gel, use MeOH-methylene dichloride (5/95) to carry out chromatographic separation resistates, make 0.04 gram title compound.
Embodiment SP-235
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(dipropyl amino)-6-methylpyrimidine-4-methane amide
Step 1. 2-(dipropyl amino)-6-methylpyrimidine-4-methyl-formiate
With 2-chloro-6-methylpyrimidine-4-methyl-formiate (0.411 gram, 2.20 di-n-propylamine (0.668 gram mmole),, 6.60 stirring 1.3 hours under refluxing then milliliter), triethylamine (0.267 gram, 2.64 mmoles) and the mixture of THF (5 milliliters) at room temperature stirred 55 minutes.This moment is with its cooling, and phase-splitting between the mixture of ethyl acetate and salt solution and sodium bicarbonate aqueous solution.Through dried over mgso and concentrated, on silica gel, use ethyl acetate-hexane (90/10) to carry out chromatographic separation then organic layer, make light yellow liquid 2-(dipropyl amino)-6-methylpyrimidine-4-methyl-formiate (0.457 gram).
Step 2. 35137-ret-1352-(dipropyl amino)-6-methylpyrimidine-4-formic acid
In 2-(dipropyl amino)-6-methylpyrimidine-4-methyl-formiate in MeOH (2 milliliters), water (1 milliliter) and THF (1 milliliter) (0.450 gram, 1.79 mmoles) solution, add a hydronium(ion) oxidation lithium (0.113 gram, 2.68 mmoles).This mixture was at room temperature stirred 1 hour, and MeOH and THF are removed in decompression then.The pH value of regulating resistates is to about 5, then with the mixture dichloromethane extraction that makes, through dried over sodium sulfate, and concentrated, makes 2-(dipropyl the amino)-6-methylpyrimidine-4-formic acid (0.351 restrains) of yellow solid shape.
Step 3.N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(dipropyl amino)-6-methylpyrimidine-4-methane amide
In THF (0.5 milliliter) solution of 2-(dipropyl amino)-6-methylpyrimidine-4-formic acid (0.101 gram, 0.426 mmole), add 1,1 '-carbonyl dimidazoles (CDI) (0.076 gram, 0.468 mmole).After 50 minutes, this CDI mixture is added (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-ethylphenyl) amino] fourth-2-alcohol dihydrochloride (1.173 grams, 0.425 mmole) and in the mixture of triethylamine (0.18 milliliter, 1.28 mmoles) in THF (6 milliliters) and methylene dichloride (2 milliliters).Stirring is spent the night, and decompression is removed solvent and made resistates phase-splitting between methylene dichloride, sodium bicarbonate aqueous solution and sodium bicarbonate aqueous solution-saline mixture.Organic layer through dried over sodium sulfate, is filtered and concentrates, and use MeOH-methylene dichloride (5/95) to carry out chromatographic separation on silica gel resistates, make the title compound of 0.199 gram solid state.
Embodiment SP-236
3-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } imidazoles [1,2-a] pyridine-6-methane amide
Step 1. 3-butyl imidazole [1,2-a] pyridine-6-formic acid
At hexanal (1.02 gram, 10.2 mmoles) at 15 milliliters of Virahol-water (4: in solution 1v/v), add CuCl
2(1.37 grams, 10.2 mmoles).With 80 ℃ of heating of this mixture 2.5 hours, cooling then.Filter and remove solid, and filtrate is added in the amino hydrochloric acid of 6-(1.35 grams, 10 mmoles).This mixture at room temperature stirred spend the night, then reflux 32 hours.After the cooling, decompression is removed solvent and will add MeOH in resistates.Filter and remove the solid that generates, and filtrate is concentrated into dried.Add MeOH again, and filter and remove the solid that generates.After filtrate concentrated, on silica gel, uses MeOH-methylene dichloride (33/67) to carry out chromatographic separation resistates, make 0.26 and restrain 3-butyl imidazole [1,2-a] pyridine-6-formic acid.3-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } imidazoles [1,2-a] pyridine-6-methane amide
Step 2. according to N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-and the 3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(dipropyl amino)-6-methylpyrimidine-4-methane amide (embodiment SP-235), the method that step 3 is identical, 3-butyl imidazole [1,2-a] pyridine-6-formic acid (0.16 gram) is changed into 0.30 gram title compound.
Embodiment SP-237
2-[butyl (methyl) amino]-6-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } Isonicotinamide
Step 1. 2-[butyl (methyl) amino]-6-chloroisonicotinic acid methyl esters
According to N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-and the 3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(dipropyl amino)-6-methyl Isonicotinamide (embodiment SP-234, step 2) identical method, with 2,6-dichloro-isonicotinic acid methyl esters (1.0 gram) changes into 2-[butyl (methyl) amino]-6-chloroisonicotinic acid methyl esters (0.87 gram).
Step 2. 2-[butyl (methyl) amino]-the 6-chloroisonicotinic acid
According to N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-and the 3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(dipropyl amino)-6-methylpyrimidine-4-methane amide (embodiment S-2435), the method that step 2 is identical is with 2-[butyl (methyl) amino]-6-chloroisonicotinic acid methyl esters (0.17 gram) changes into 2-[butyl (methyl) amino]-6-chloroisonicotinic acid (0.15 gram).
Step 3. 2-[butyl (methyl) amino]-6-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } Isonicotinamide
According to N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-and the 3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(dipropyl amino)-6-methylpyrimidine-4-methane amide (embodiment S-2435), the method that step 3 is identical is with 2-[butyl (methyl) amino]-6-chloroisonicotinic acid (0.15 gram) changes into 0.13 gram title compound.
Embodiment SP-238
2-[butyl (methyl) amino]-6-cyano group-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } Isonicotinamide
Step 1. 2-[butyl (methyl) amino]-6-cyano group iso methyl nicotinate
With one of purging with nitrogen gas 2-[butyl (methyl) amino is housed]-6-chloroisonicotinic acid methyl esters (0.306 gram, 1.19 mmoles), zinc cyanide (0.0839 gram, 0.714 mmole), Pd
2Dba
3The flask of (0.0218 gram, 0.024 mmole), dppf (0.0264 gram, 0.048 mmole) and zinc powder dirt (0.0093 gram, 0.143 mmole).Add N-Methyl pyrrolidone (2 milliliters) and with mixture 120 ℃ of heating 2 hours, then with its cooling and phase-splitting between ethyl acetate and ammonium hydroxide aqueous solution and salt solution.Organic layer through dried over mgso, and is concentrated, uses ethyl acetate-hexane (10/90) to carry out silica gel chromatography then and separate, obtain 0.161 gram 2-[butyl (methyl) amino]-6-cyano group iso methyl nicotinate.
Step 2. 2-[butyl (methyl) amino]-6-cyano group Yi Yansuan
According to N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-and the 3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(dipropyl amino)-6-methylpyrimidine-4-methane amide (embodiment S-2435), the method that step 2 is identical is with 2-[butyl (methyl) amino]-6-cyano group iso methyl nicotinate (0.157 gram) changes into 2-[butyl (methyl) amino]-6-cyano group Yi Yansuan (0.151 gram).
Step 3. 2-[butyl (methyl) amino]-6-cyano group-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } Isonicotinamide
According to N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-and the 3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(dipropyl amino)-6-methylpyrimidine-4-methane amide (embodiment S-2435), the method that step 3 is identical is with 2-[butyl (methyl) amino]-6-cyano group Yi Yansuan (0.135 gram) changes into title compound (0.223 gram).
Embodiment SP-239
2-cyano group-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-6-[methyl (propyl group) amino] Isonicotinamide
According to N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-and the 3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(dipropyl amino)-6-methylpyrimidine-4-methane amide (embodiment S-2435), the method that step 3 is identical is with 2-cyano group-6-[methyl (butyl) amino] Yi Yansuan (0.13 gram) changes into 0.23 gram title compound.
Embodiment SP-240
Preparation 1-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,2,3, the reaction scheme of 4-tetrahydroquinoline-7-methane amide
1-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,2,3,4-tetrahydroquinoline-7-methane amide
Step 1: ice-cold, (1.0 milliliters of 7-hydroxyl-quinoline through stirring (1.0 grams, 6.9 mmoles) and triethylamines, 7.6 mmole) in the solution in methylene dichloride (14 milliliters), add trifluoromethanesulfanhydride anhydride (1.3 milliliters, 7.6 mmoles), and reaction mixture was stirred 30 minutes.This mixture is diluted with methylene dichloride,, filter and concentrating under reduced pressure, make quinoline-7-base trifluoro-acetate (1.5 gram): ESI MS m/z 278[M+H] with saturated sodium bicarbonate and salt water washing, dry (sal epsom)
+
Step 2: will be: the quinoline among the 2DMF/MeOH (39 milliliters)-7-base trifluoro-acetate (750 milligrams, 2.7 mmoles), PdCl through stirring 1
2(Ph
3P) (95 milligrams, 0.14 mmole) and triethylamine (1.2 milliliters, 8.4 mmoles) solution outgases, and sweeps with the CO spray, and this mixture was heated 48 hours at 60 ℃.This mixture is cooled to room temperature, through diatomite filtration and concentrating under reduced pressure.With resistates 5%LiCl solution dilution, use CHCl
3(3 * 250 milliliters) washing.With the organism drying (Na that merges
2SO
4), filter and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 3: 1 ethyl acetate/hexane), obtain quinoline-7-methyl-formiate (185 milligrams): ESI MS m/z 188[M+H]
+
Step 3: with quinoline-7-methyl-formiate (185 milligrams, 1.0 mmoles) and PtO
2(20 milligrams) solution in methyl alcohol (10 milliliters) shake 2 hours under nitrogen atmosphere.Through diatomite filtration, and concentrating under reduced pressure makes 1,2,3,4-tetrahydroquinoline-7-methyl-formiate (189 milligrams): ESI MS m/z 192[M+H with reaction mixture]
+
Step 4: through stirring 1,2,3, (180 milligrams of 4-tetrahydroquinolines-7-methyl-formiate, 0.94 mmole) and in the solution of cesium bicarbonate (1.5 gram, 4.7 mmoles) in THF (2 milliliters), add (1.0 milliliters of n-butyl bromides, 9.4 mmole), and with reaction mixture refluxed heated 48 hours.Reaction mixture is cooled to room temperature, and dilutes with EtOAc.With organic layer water and salt water washing, dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 1: 3 ethyl acetate/hexane), obtain 1-butyl-1,2,3,4-tetrahydroquinoline-7-methyl-formiate (156 milligrams): ESI MS m/z 248[M+H]
+
Step 5:, in methyl alcohol (1.3 milliliters) solution of 4-tetrahydroquinoline-7-methyl-formiate (156 milligrams, 0.63 mmole), add potassium hydroxide (6.3 milliliters, the 1M aqueous solution, 6.3 mmoles) at 1-butyl-1,2,3 through stirring.
Reaction mixture is at room temperature stirred 48 hours, and concentrating under reduced pressure.Wash with residue diluted with water and with ethyl acetate.With 1N hydrochloric acid water layer is acidified to pH 4, and extracts with chloroform (4 * 100 milliliters).With the organic extract drying (sodium sulfate) that merges, filter, and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 1: 9 methyl alcohol/chloroform), make 1-butyl-1,2,3,4-tetrahydroquinoline-7-formic acid (139 milligrams): ESI MS m/z234[M+H]
+
Step 6: with 1-butyl-1,2,3, (134 milligrams of 4-tetrahydroquinolines-7-formic acid, 0.57 mmole), the solution of HBTU (327 milligrams, 0.86 mmole) and diisopropylethylamine (150 microlitres, 0.86 mmole) stirred 15 minutes in methylene dichloride (3.0 milliliters).Add (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] (234 milligrams of fourths-2-alcohol (embodiment SP-272), 0.57 mmole) and diisopropylethylamine (150 microlitres, 0.86 the solution in methylene dichloride (3.0 milliliters) mmole), and reaction mixture stirred spend the night.Reaction mixture is diluted with methylene dichloride, with 1N hydrochloric acid (10 milliliters), saturated sodium bicarbonate (10 milliliters) and salt water washing.With organic layer drying (sal epsom), filter then, and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 1: 9 methyl alcohol/chloroform), make 1-butyl-N-{ (1S, 2R)-and 1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,2,3,4-tetrahydroquinoline-7-methane amide (130 milligrams): ESI MS m/z 550[M+H]
+
Embodiment SP-241
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-propyl group-1,2-benzoisoxazole-5-methane amide
The general of benzoisoxazole synthesized
Furans 1 hydrogenation is made amine 2.The Diels-Alder reaction of amine 2 and 1-hexene-3-one generates ketone 3.
1Handle ketone 3 with tosic acid then, make diketone 4.With diketone 4 virtueization again, make phenol 5 with boron trifluoride.With azanol phenol 5 is changed into oxime 6 then.Make oxime 6 cyclisation with thionyl chloride, make methyl esters 7.
2Then methyl esters 7 is saponified into acid 8.Acid 8 and amine 9 coupling under the HATU environment make benzoxazole 10.
Reaction scheme
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-propyl group-1,2-benzoisoxazole-5-methane amide
Step 1: shake 18 hours under the nitrogen atmosphere of mixture in ethanol (150 milliliters) at 40psi with 5-nitro-2-methylfuroate (13 gram, 76 mmoles) and 10%Pd/C (1.3 restrain).Reaction mixture through diatomite filtration and concentrating under reduced pressure, is made a kind of crude oil.Purify by flash column chromatography (silicon-dioxide, 2: 1 hexane/ethyl acetate), make 5-amino-2-methylfuroate (5.6 gram):
1H NMR (500MHz, CDCl
3) δ 7.11-7.10 (and m, 1H), 5.31-5.29 (m, 1H), 4.31 (br s, 2H), 3.84 (s, 3H).
Step 2: be heated to backflow 2 hours at 5-amino-2-methylfuroate through stirring (1.4 grams, 10 mmoles) and the solution of 1-hexene-3-one (7 milliliters) in benzene (50 milliliters).With the reaction mixture concentrating under reduced pressure, make a kind of crude oil.Purify by flash column chromatography (silicon-dioxide, 1: 1 hexane/ethyl acetate), make 4-amino-5-butyryl radicals-1-hydroxyl hexamethylene-2,4-diene-1-methyl-formiate (1.25 gram):
1HNMR (300MHz, CDCl
3): δ 6.26-6.23 (m, 1H), 6.09-6.05 (m, 1H), 3.80 (s, 3H), 3.02-2.96 (m, 1H), 2.89-2.84 (m, 1H), 2.42-2.37 (m, 2H), 1.64-1.57 (m, 2H), 0.96-0.88 (m, 3H).
Step 3: at 4-amino-5-butyryl-1-hydroxyl hexamethylene-2 through stirring, 4-diene-1-methyl-formiate (1.25 grams, 5.2 mmole) in the solution in 1: 1 water/tetrahydrofuran compound (10 milliliters), add a hydration tosic acid (1.1 grams, 5.8 mmoles).Reaction mixture was stirred 18 hours phase-splitting between methylene dichloride and water then.With organic layer drying (sodium sulfate), filter and concentrating under reduced pressure, obtain 5-butyryl-1-hydroxyl-4-oxo hexamethylene-2-alkene-1-methyl-formiate, it can use without further purifying or characterizing.
Step 4: in the benzole soln of 5-butyryl-1-hydroxyl-4-oxo hexamethylene-2-alkene-1-methyl-formiate, add BF through stirring
3O (Et)
2(1.3 milliliters, 10 mmoles).This mixture was stirred 0.25 hour, use the saturated sodium bicarbonate stopped reaction then, use dichloromethane extraction subsequently.With organic layer drying (sodium sulfate), filter, and concentrating under reduced pressure, making 3-butyryl-4-methyl hydroxybenzoate, it can use without further purifying or characterizing.
Step 5: ethanol (30 milliliters) vlil of 3-butyryl-4-methyl hydroxybenzoate, pyridine (3.7 milliliters, 46 mmoles) and hydroxylamine hydrochloride (3.55 restrain 51 mmoles) that will be through stirring 2 hours.With this mixture concentrating under reduced pressure and phase-splitting between water and ethyl acetate.Organic layer is washed with 1N hydrochloric acid, saturated sodium bicarbonate, and dry (sodium sulfate) filters and concentrating under reduced pressure, makes a kind of crude oil.Purify by flash column chromatography (silicon-dioxide, 10: 1 hexane/ethyl acetate), make 4-hydroxyl-3-[(1E)-N-hydroxyl fourth imidoyl] methyl benzoate (170 milligrams):
1H NMR (500MHz, CD
3OD): δ 8.30-8.28 (m, 1H), 7.85-7.82 (m, 1H), 6.92-6.89 (m, 1H), 3.88 (s, 3H), 2.87-2.84 (m, 2H), 1.67-1.60 (m, 2H), 1.05-1.00 (m, 3H).
Step 6: at ice-cold 4-hydroxyl-3-[(1E)-N-hydroxyl fourth imidoyl through stirring] (170 milligrams of methyl benzoate, 0.7 in ether mmole) (5 milliliters) solution, add thionyl chloride (60 microlitres, 0.8 mmole) and the mixture of pyridine (580 microlitres, 7.2 mmoles) in ether (5 milliliters).2.5 after hour, this mixture is poured on ice-waterborne, and with the 1N hcl acidifying to pH=1.Make the phase-splitting between water and ethyl acetate of this mixture then.Organic layer is washed with saturated sodium bicarbonate, and dry (sodium sulfate) filters and concentrating under reduced pressure, makes a kind of crude oil.Purify by flash column chromatography (silicon-dioxide, 10: 1 hexane/ethyl acetate), make 3-propyl group-1,2-benzoisoxazole-5-methyl-formiate (90 milligrams):
1H NMR (300MHz, CDCl
3): δ 8.36-8.35 (m, 1H), 8.07-8.04 (m, 1H), 7.52-7.49 (m, 1H), 3.95 (s, 3H), 2.96-2.91 (m, 2H), 2.00-1.87 (m, 2H), 1.09-1.04 (m, 3H).
Step 7: the 3-propyl group-1 in 2: 1: 1 tetrahydrofuran (THF), water and methyl alcohol, (90 milligrams of 2-benzoisoxazoles-5-methyl-formiate, 0.4 mmole) in the solution in the mixture (4 milliliters), add (50 milligrams of lithium hydroxides, 1.2 mmole), and with the reaction mixture that makes at room temperature stirred 2.5 hours.With this reaction mixture concentrating under reduced pressure, and phase-splitting between water and ether.With water layer ether washed twice, and with the 6M hcl acidifying to pH 1.With the water layer ethyl acetate extraction that makes, dry (sodium sulfate), and concentrating under reduced pressure make 3-propyl group-1,2-benzoisoxazole-5-formic acid (73 milligrams):
1H NMR (300MHz, CD
3OD): δ 8.28-8.27 (m, 1H), 8.09-8.06 (m, 1H), 7.64-7.61 (m, 1H), 2.99-2.94 (m, 2H), 1.96-1.86 (m, 2H), 1.08-1.02 (m, 3H).
Step 8: the 3-propyl group-1 through stirring adds N in methylene dichloride (5 milliliters) solution of 2-benzoisoxazole-5-formic acid (70 milligrams, 0.3 mmole) and HATU (130 milligrams, 0.3 mmole), N-diisopropylethylamine (110 microlitres, 0.6 mmole).In separating flask, (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] (140 milligrams of fourths-2-alcohol (EXA xxx), 0.3 add N in methylene dichloride mmole) (2 milliliters) solution, N-diisopropylethylamine (110 microlitres, 0.6 mmole).This solution is joined in the above-mentioned acidiferous solution, and the reaction mixture that makes was at room temperature stirred 18 hours.Make the phase-splitting between methylene dichloride and water of this reaction mixture.Organic layer is washed with water, and dry (sodium sulfate) filters and concentrating under reduced pressure, makes a kind of crude oil.By flash column chromatography (silicon-dioxide, the methylene chloride of 97: 3 to 94: 6 graded) purify, make N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-and the 3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-propyl group-1,2-benzoisoxazole-5-methane amide (30 milligrams).ESI-MS m/z 522[M+H]
+。
Embodiment SP-242
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } isoquinoline 99.9-7-methane amide dihydrochloride
Step 1: the solution reflux in acetate (20 milliliters) is 2 hours with 7-bromo-1-chlorine isoquinoline 99.9 (2.50 grams, 10.3 mmoles) and active zinc (1.40 grams, 21.65 mmoles).Reaction mixture is cooled to room temperature and concentrating under reduced pressure.The resistates that makes is divided into ethyl acetate layer and water layer.Organic layer is washed with saturated sodium-chloride, and dry (sodium sulfate) filters and concentrating under reduced pressure, makes 7-bromo-isoquinoline (1.86 gram): ESI MS m/z 208[M+H]
+
Step 2: the solution in N-Methyl pyrrolidone (17 milliliters) is heated to 200 ℃ and reaches 2 hours with 7-bromo-isoquinoline (1.80 gram, 8.65 mmoles) and cuprous cyanide (1.16 restrain 12.97 mmoles).This reaction mixture is cooled to room temperature and is divided into ethyl acetate layer and water layer.Use other ethyl acetate strip aqueous again, and the organic layer that merges is washed with saturated sodium-chloride, dry (sodium sulfate) filters and concentrating under reduced pressure, makes 7-cyano group-isoquinoline 99.9 (770 milligrams):
1H NMR (300MHz, CDCl
3) δ 9.35 (and s, 1H), 8.70 (d, J=5Hz, 1H), 8.40 (s, 1H), 7.95 (d, J=8Hz, 1H), 7.84 (d, J=8Hz, 1H), 7.73 (d, J=5Hz, 1H); ESI MS m/z 155[M+H]
+
Step 3: concentrated hydrochloric acid (25 milliliters) solution of 7-Cyanoisoquinoline (770 milligrams, 5.0 mmoles) ℃ is reached 18 hours at sealed tube internal heating to 150.Reaction mixture is cooled to room temperature and concentrating under reduced pressure.Resistates water-soluble (10 milliliters) also is neutralized to pH 7.0 with dense ammonium hydroxide.This solution for vacuum is filtered and filtrate decompression is concentrated, make isoquinoline 99.9-7-formic acid (640 milligrams): ESI MS m/z 174[M+H]
+
Step 4: at isoquinoline 99.9-7-formic acid (200 milligrams, 1.15 mmoles) and the N through stirring, (1.20 milliliters of N-diisopropylethylamine, 6.88 in methylene dichloride mmole) (14.0 milliliters) solution, add HBTU (438 milligrams, 1.15 mmoles), and reactant was stirred 0.5 hour.Disposable adding (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(3-Ethylbenzyl) amino] fourth-2-alcohol (470 milligrams, 1.15 mmoles) and reaction mixture stirred 18 hours under nitrogen.With other methylene dichloride reaction mixture is diluted then, and wash with saturated sodium bicarbonate, saturated sodium-chloride, dry (sodium sulfate) filters and concentrating under reduced pressure.By flash column chromatography (silicon-dioxide, the 0-5% ethanol/methylene) purifies, obtain N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-and the 3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } isoquinoline 99.9-7-methane amide (100 milligrams), characterize with the form of its dihydrochloride: mp 142-143 ℃; ESI MS m/z 490[M+H]
+
Embodiment SP-243
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-(third amino) isoquinoline 99.9-7-methane amide dihydrochloride
Step 1: with propylamine (15.0 milliliters) solution of 7-bromo-1-chlorine isoquinoline 99.9 in a sealed tube with 70 ℃ of heated overnight.With the reaction mixture concentrating under reduced pressure, be dissolved in chloroform then, and wash with saturated sodium bicarbonate, saturated sodium-chloride, dry (sodium sulfate) filters and concentrating under reduced pressure, makes 7-bromo-2-(N-third amino) isoquinoline 99.9 (820 milligrams): ESI MS m/z 266[M+H]
+
Step 2: anhydrous diethyl ether (1.0 milliliters) solution of 7-bromo-2-(N-third amino) isoquinoline 99.9 (200 milligrams, 0.754 mmole) is cooled to-65 ℃.In this solution, dropwise add s-butyl lithium (1.30 milliliters, the solution of 1.3M in hexanaphthene, 1.69 mmoles) and reaction mixture was stirred 10 minutes at-60 ℃.Add powdery dry ice (CO
2) make the reaction mixture stopped reaction, and reactant slowly is warmed to room temperature with 1 hour.With 1N hydrochloric acid with the solution acidifying that makes and with reaction mixture with ethyl acetate (3 * 15 milliliters) extraction.The organic phase that merges is washed with water, and dry (sodium sulfate) filters and concentrating under reduced pressure, obtains a kind of brown solid.By flash column chromatography (silicon-dioxide, 66: 20: 10: 4 ethyl acetate/chloroform/methanol/dense ammonium hydroxide) purify, obtain 1-(third amino) isoquinoline 99.9-7-formic acid (133 milligrams): ESI MS m/z 231[M+H]
+
Step 3: (81 milligrams of 1-(third amino) isoquinoline 99.9 through stirring-7-formic acid, 0.396 mmole) and N, N-diisopropylethylamine (3.75 microlitres, 2.16 mmole) in the solution in methylene dichloride (5.0 milliliters), add (152 milligrams of HBTU, 0.396 mmole), and with reactant stirred 0.5 hour.Disposable adding (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(3-Ethylbenzyl) amino] fourth-2-alcohol (150 milligrams, 0.36 mmole) and reaction mixture stirred 18 hours under nitrogen.And then with methylene dichloride reaction mixture is diluted, and with saturated sodium bicarbonate, saturated sodium-chloride washing, dry (sodium sulfate) filters and concentrating under reduced pressure.By flash column chromatography (silicon-dioxide, the 0-5% ethanol/methylene) purifies, obtain N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-and the 3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-(third amino) isoquinoline 99.9-7-methane amide (100 milligrams), characterize with the form of its dihydrochloride: mp262 ℃ of dec; ESI MS m/z 547[M+H]
+
Embodiment SP-244
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-(dipropyl amino) isoquinoline 99.9-7-methane amide
Step 1: with 7-bromo-isoquinoline-1-hydroxyl (2.5 grams, 11.1 mmoles) and POCl
3The solution of (10.4 milliliters, 111 mmoles) stirred 2.5 hours at 70 ℃.This reaction mixture is cooled to room temperature, pours in the frozen water, and this solution stirring is spent the night.This aqueous mixture is diluted with chloroform, use saturated NaHCO
3Solution, saturated NaCl washing, dry (MgSO
4), filter and concentrating under reduced pressure, make 7-bromo-1-chlorine isoquinoline 99.9 (2.3 gram):
1H NMR (300MHz, DMSO-d
6) δ 8.39-8.36 (and m, 2H), 8.09-8.02 (m, 2H), 7.95 (d, J=6Hz, 1H).
Step 2: the 7-bromo-1-chlorine isoquinoline 99.9 (500 milligrams, 2.1 mmoles) that step 1 is made and the solution of dipropyl amine (2.8 milliliters, 21 mmoles) in sealed tube with 150 ℃ of heating 2 days.With the reaction mixture cooling, solvent is removed in decompression, makes 7-bromo-N, N-dipropyl isoquinoline 99.9-1-amine (400 milligrams):
1H NMR (300MHz, DMSO-d
6) δ 8.55 (and s, 1H), 7.90 (d, J=6Hz, 1H), 7.75-7.64 (m, 2H), 6.87 (d, J=6Hz, 1H), 3.42 (q, J=7Hz, 4H), 1.65 (q, J=7Hz, 4H), 0.94 (t, J=7Hz, 6H).
Step 3: with 7-bromo-N, N-dipropyl isoquinoline 99.9-1-amine (350 milligrams, 1.1 mmoles) and CuCN (204 milligrams, 2.2 mmoles) are at N, and the solution in the dinethylformamide (2 milliliters) stirred 24 hours under refluxing.This reaction mixture is cooled to room temperature, dilute with water, and extract with ethyl acetate (3 * 50 milliliters).The organism that merges is washed with saturated sodium-chloride, and dry (sal epsom) filters, and concentrating under reduced pressure.Make 1-(dipropyl amino) isoquinoline 99.9-7-nitrile (279 milligrams), it can use without further sign.
Step 4: concentrated hydrochloric acid (4 milliliters) solution of 1-(dipropyl amino) isoquinoline 99.9-7-nitrile (279 milligrams, 1.1 mmoles) that step 3 is made in sealed tube with 150 ℃ of heating 14 hours.Reaction mixture is cooled to room temperature, and decompression removes solvent, resistates is dissolved in 25% ammonium hydroxide/water solution and stirred 1 hour.With concentrated hydrochloric acid this solution is acidified to pH 4, and extracts with chloroform (3 * 50 milliliters).With the organism drying (Na that merges
2SO
4), filter and concentrating under reduced pressure, make 1-(dipropyl amino) isoquinoline 99.9-7-formic acid (104 milligrams): ESI MS m/z 273[M+H]
+
Step 5: (103 milligrams of 1-(dipropyl amino) isoquinoline 99.9 through stirring-7-formic acid, 0.38 (2R mmole),, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] (154 milligrams of fourths-2-alcohol, 0.38 mmole), in HOBt (77 milligrams, 0.57 mmole) and the solution of DIPEA (0.2 milliliter, 1.1 mmoles) in methylene dichloride (4 milliliters), add HATU (216 milligrams, 0.57 mmole).This reaction mixture stirring is spent the night, be divided into dichloromethane layer and 1N hydrochloric acid layer then.Organic layer is washed with saturated sodium bicarbonate, saturated sodium-chloride, and dry (sodium sulfate) filters and concentrating under reduced pressure.By flash column chromatography (silicon-dioxide, 9: 1 chloroform/methanol) purify, obtain N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-(dipropyl amino) isoquinoline 99.9-7-methane amide (70 milligrams): mp142-151 ℃; APCI MS m/z 589[M+H]
+
Embodiment SP-244
1-[butyl (methyl) amino]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } isoquinoline 99.9-7-methane amide
Step 1: N-methylbutylamine (7.0 milliliters) solution of 7-bromo-1-chlorine isoquinoline 99.9 (750 milligrams, 3.09 mmoles) was heated 18 hours with 65 ℃ in sealed tube.With the reaction mixture concentrating under reduced pressure.Resistates is washed with chloroform extraction and with saturated sodium bicarbonate, and dry (sodium sulfate) filters and concentrating under reduced pressure, makes a kind of brown oil.Purify by flash column chromatography purification (silicon-dioxide, 3: 1 hexane/ether), make 7-bromo-N-butyl-N-methylisoquinolinium-1-amine (730 milligrams): ESI MS m/z 293[M+H]
+
Step 2: in the diethyl ether solution of 7-bromo-N-butyl-N-methylisoquinolinium-1-amine (230 milligrams, 0.78 mmole) of-60 ℃, add s-butyl lithium (1.00 milliliters, the solution of 1.3M in hexanaphthene, 1.30 mmoles).This solution was stirred 20 minutes at-60 ℃, add excessive dry ice (CO then
2), and reactant is warmed to room temperature.With 1N hydrochloric acid with the reaction mixture acidifying and use ethyl acetate extraction.With the water concentrating under reduced pressure, obtain a kind of yellow oil.By flash column chromatography (silicon-dioxide, 50: 33: 15: 5 ethyl acetate/chloroform/methanol/ammonium hydroxide) purify, obtain 1-[butyl (methyl) amino] isoquinoline 99.9-7-formic acid (90 milligrams): ESI MS m/z 259[M+H]
+
Step 3: at 1-[butyl (methyl) amino] (130 milligrams of isoquinoline 99.9-7-formic acid, 0.5 mmole) and N, N-diisopropylethylamine (525 microlitres, 3.0 mmole) in the solution in methylene dichloride (6.25 milliliters), add (190 milligrams of HBTU, 0.5 mmole), and with reaction mixture stirred 0.5 hour.Disposable adding (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(3-Ethylbenzyl) amino] fourth-2-alcohol (174 milligrams, 0.42 mmole) and reaction mixture at room temperature stirred 18 hours.Use the methylene dichloride diluted reaction mixture, and wash with saturated sodium bicarbonate and saturated sodium-chloride, dry (sodium sulfate) filters and concentrating under reduced pressure.By flash column chromatography (silicon-dioxide, the chloroformic solution of 1-5% methyl alcohol) purifies, obtain 1-[butyl (methyl) amino]-N-{ (1S, 2R)-and 1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } isoquinoline 99.9-7-methane amide (101 milligrams): mp120-121 ℃ of dec; ESI MS m/z 575[M+H]
+
Embodiment SP-244
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-[methyl (propyl group) amino] isoquinoline 99.9-7-methane amide
According to above-mentioned 1-[butyl (methyl) amino]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl method similar methods of isoquinoline 99.9-7-methane amide, be prepared.ESI MS m/z 561[M+H]
+。
Embodiment SP-245
1-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } isoquinoline 99.9-7-methane amide
Step 1: in ether (75 milliliters) solution of the 7-bromo-1-chlorine isoquinoline 99.9 that refluxes (4.85 grams, 23.28 mmoles), add butylmagnesium chloride (17.8 milliliters, 2.0M ether, 35.6 mmoles), and reactant is kept refluxing 2 hours.Reaction mixture is cooled to room temperature, and carefully with the dilution of equal-volume ethyl acetate, with saturated sodium bicarbonate, water and saturated sodium-chloride washing, dry (sodium sulfate) filters and concentrating under reduced pressure, makes a kind of brown oil.Purify by flash column chromatography (silicon-dioxide, 1-10% ether/hexane), obtain required 7-bromo-1-butyl isoquinoline 99.9 (1.50 gram): ESI MS m/z 264[M+H]
+
Step 2: in-60 ℃ the solution of 7-bromo-1-butyl isoquinoline 99.9 (940 milligrams, 3.55 mmoles) in ether (15 milliliters) that in step 1, makes, add s-butyl lithium (3.0 milliliters, 1.3M hexanaphthene, 3.90 mmoles), obtain a kind of dark green solution.This reaction mixture-60 ℃ of restir 15 minutes, at this moment, by the gas dispersion pipe, was fed this solution 20 minutes with carbonic acid gas.Then the solution that makes is warmed to room temperature and concentrating under reduced pressure, obtains a kind of pink solid.With the phase-splitting between ethyl acetate and the water again of this resistates, use the 1N hcl acidifying then to pH 7.Use the ethyl acetate extraction water again, and will merge organic to saturated sodium-chloride washing, dry (sodium sulfate) filters also and concentrates, and makes 1-butyl isoquinoline 99.9-7-formic acid (299 milligrams).ESI MS m/z230[M+H]
+。
Step 3: (79 milligrams of 1-butyl isoquinoline 99.9-7-formic acid, 0.26 mmole) and N, in methylene dichloride (1.8 milliliters) solution of N-diisopropylethylamine (150 microlitres, 0.86 mmole), add HBTU (100 milligrams, 0.264 mmole) and reaction mixture was stirred 0.5 hour.Contain N to wherein adding, N-diisopropylethylamine (150 microlitres, 0.86 mmole) (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] methylene dichloride (1.8 milliliters) solution of fourth-2-alcohol (107 milligrams, 0.264 mmole).Then reaction mixture is at room temperature stirred and spend the night.Reaction mixture is diluted with methylene dichloride, with saturated sodium bicarbonate and saturated sodium-chloride washing.With organic layer drying (sodium sulfate), filter then, and concentrating under reduced pressure.By flash column chromatography (silicon-dioxide, 93: 7 chloroform/methanol) purify, obtain 1-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } isoquinoline 99.9-7-methane amide (103 milligrams): mp 109-110 ℃; ESI MS m/z 546[M+H]
+
Embodiment SP-246
1-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,2,3,4-tetrahydroisoquinoline-7-methane amide
Step 1: 1-butyl isoquinoline 99.9-7-formic acid (325 milligrams, 1.41 mmoles) methyl alcohol (25 milliliters) solution that will contain the vitriol oil (800 microlitre) refluxes and spends the night.With the reaction mixture concentrating under reduced pressure, with the methylene dichloride dilution, water and saturated sodium-chloride wash then.With organic layer drying (sodium sulfate), filter and concentrate then, make 1-butyl isoquinoline 99.9-7-methyl-formiate (350 milligrams): ESI MS m/z 244[M+H]
+
Step 2: in step, add platinum oxide (IV) (35 milligrams) in methyl alcohol (6.0 milliliters) solution of the 1 1-butyl isoquinoline 99.9-7-methyl-formiate that makes (350 milligrams, 1.44 mmoles) and reaction mixture stirred under nitrogen atmosphere in room temperature and spend the night.With the reaction mixture concentrating under reduced pressure, be dissolved in methylene dichloride (15 milliliters) again.In this solution, add tert-Butyl dicarbonate (350 milligrams, 1.6 mmoles), triethylamine (500 microlitres, 3.11 mmoles), 4-Dimethylamino pyridine (20 milligrams, 0.16 mmole), and reaction mixture was at room temperature stirred 4 hours.Then reaction mixture is diluted with methylene dichloride, with saturated sodium bicarbonate, water and saturated sodium-chloride washing.With organic layer drying (sodium sulfate), filter and concentrating under reduced pressure then, obtain a kind of water white oil.Purify by flash column chromatography (silicon-dioxide, 85: 15 hexane/ethyl acetate), make 2-tertiary butyl 7-methyl 1-butyl-3,4-dihydro-isoquinoline-2,7 (1H)-dicarboxylic acid esters (347 milligrams): ESI MS m/z 248[M+H]
+
Step 3: the 2-tertiary butyl 7-methyl 1-butyl-3 that in step 2, makes, 4-dihydro-isoquinoline-2, (347 milligrams of 7 (1H)-dicarboxylic acid esters, 1.0 mmole) in the solution in 2: 1: 1 diox/methanol (6.6 milliliters), add (125 milligrams of hydronium(ion) oxidation lithiums, 3.0 mmole), and with reaction mixture at room temperature stirred 24 hours.With the reaction mixture concentrating under reduced pressure, and solid residue is divided into ethyl acetate layer and water layer.With 1N hydrochloric acid with aqueous phase as acidified to pH 1 and with 3: 1 chloroform/2-propyl alcohol extracted several times.With the organic phase water and the saturated sodium-chloride washing that merge, dry (sodium sulfate) filters and concentrating under reduced pressure, makes 2 (tert-butoxycarbonyl)-1-butyl-1,2,3,4-tetrahydroisoquinoline-7-formic acid (205 milligrams).ESI MS m/z 332[M-H]
+。
Step 4: at 2 (tert-butoxycarbonyl)-1-butyl-1,2,3, (205 milligrams of 4-tetrahydroisoquinolines-7-formic acid, 0.61 mmole) and N, in the solution of N-diisopropylethylamine (150 microlitres, 0.86 mmole) in methylene dichloride (4.0 milliliters), add HBTU (233 milligrams, 0.61 mmole) and reaction mixture was stirred 0.5 hour.Contain N to wherein adding, N-diisopropylethylamine (150 microlitres, 0.86 mmole) (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] methylene dichloride (4.0 milliliters) solution of fourth-2-alcohol (250 milligrams, 0.61 mmole).Then reaction mixture is at room temperature stirred and spend the night.Reaction mixture is diluted with methylene dichloride, with saturated sodium bicarbonate and saturated sodium-chloride washing.With organic layer drying (sodium sulfate), filter then, and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 95: 5 chloroform/methanol), obtain required amine product.Then amine is dissolved in diox (5.0 milliliters), to wherein adding hydrochloric acid (20 milliliters, 4.0M diox, 80 mmoles) and the reaction mixture stirring being spent the night.Then reaction mixture is concentrated into dry doubling by flash column chromatography (silicon-dioxide, 90: 6: 3: 1 ethyl acetate/chloroform/methanol/ammonium hydroxide) purify, obtain a kind of water white oil.Should oil phase-splitting, water and saturated sodium-chloride washing between 3: 1 chloroform/2-propyl alcohol.With organic layer drying (sodium sulfate), filter then, and concentrate, obtain a kind of white solid.There is P in this solid
20
5Situation under under high vacuum in 45 ℃ of dryings, make 1-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-and the 3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,2,3,4-tetrahydroisoquinoline-7-methane amide (140 milligrams), its mixture as diastereomer characterizes: mp121-124 ℃; ESI MS m/z 550[M+H]
+
Embodiment SP-247
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(2S)-and 2-ethyl pyrrolidine-1-yl] carbonyl }-5-toluyl amine hydrochlorate
Step 1: at 125 milliliters of ice-cold CH
2Cl
2In R-pyrrolidine carbinol (5.0 gram, 49 mmoles) and triethylamine (7.6 milliliters, 55 mmoles) solution in, add tert-Butyl dicarbonate (10.8 restrain 49 mmoles).The solution that makes is warmed to room temperature and stirs spend the night.Then reaction soln is concentrated,, use 1M KH with the EtOAc dilution
2PO
4Washing 2 * and usefulness salt water washing 2 *, through Na
2SO
4Drying is filtered and is concentrated, and makes (2R)-2-(methylol) tetramethyleneimine-1-t-butyl formate (9.9 gram).
Step 2: under nitrogen atmosphere,, oxalyl chloride (9.0 milliliters, 100 mmoles) is added 80 milliliters of CH at-78 ℃
2Cl
2In DMSO (10.5 milliliters, 150 mmoles) solution.This solution was stirred 20 minutes at-78 ℃, add (2R)-2-(methylol) tetramethyleneimine-1-t-butyl formate (9.9 grams, 49 mmoles), and the solution that makes was stirred 20 minutes at-78 ℃.In reaction soln, add triethylamine (28 milliliters, 200 mmoles), remove dry ice-propanone and bathe,, slowly be warmed to room temperature the solution stirring that makes 2 hours.Make the reaction soln stopped reaction with salt solution, separate each phase, and with organic phase 1M KH
2PO
4With saturated NaHCO
3Washing.Then with this organic solution through Na
2SO
4A kind of orange oil is filtered and be condensed into to drying.Then this oil is dissolved in heptane, filters by silica gel plug, and filtrate is concentrated, make (2R)-2-carbonyl pyrrolidine-1-t-butyl formate (7.87 gram) with the heptane wash-out.
Step 3: under nitrogen atmosphere, n-Butyl Lithium (1.6M is in hexane) (27 milliliters, 43 mmoles) is added ice-cold hexamethyldisilazane (9.2 milliliters, 44 mmoles).With this solution stirring 10 minutes, at room temperature join then in the suspension of Diethylaminoethyl (triphenyl phosphonium) (15.5 grams, 43 mmoles) in 100 milliliters of THF.Stir after 1 hour, this mixture is cooled to-78 ℃ and the solution of adding (2R)-2-carbonyl pyrrolidine-1-t-butyl formate (7.9 grams, 40 mmoles) in 50 milliliters of THF.Remove cooling bath, this mixture is at room temperature stirred spend the night.Use saturated NH then
4Cl makes the reaction mixture stopped reaction, separates each phase, and with the saturated NH of organic phase
4Cl, salt water washing are through Na
2SO
4A kind of orange oil is filtered and be condensed into to drying.Should on Biotage 40M post, purify by oil, make (2R)-2-ethenyl pyrrolidone-1-t-butyl formate (5.0 gram) with the heptane wash-out.
Step 4: in the suspension of palladium hydroxide (II)-gac (20%wt, 1.2 grams) in 10 milliliters of ethanol, add the solution of (2R)-2-ethenyl pyrrolidone-1-t-butyl formate (2.0 grams, 10 mmoles) in 15 milliliters of ethanol.And this mixture is placed the H of 12psi on the Pa Er hydrogenator
2Under spend the night.Then the mixture that makes is filtered and concentrates, make (2R)-2-ethyl pyrrolidine-1-t-butyl formate (1.5 gram)
Step 5: in the solution of (2S)-2-ethyl pyrrolidine-1-t-butyl formate (1.0 gram, 5.0 mmoles) in 10 milliliters of dioxs, add 8 milliliters of 6N HCl, and the solution that makes at room temperature stirred spend the night.Then reaction mixture is concentrated, become alkalescence with solid KOH, and extract with EtOAc.With the organic extract that merges through Na
2SO
4Drying is filtered and is concentrated, and makes (2S)-2-ethyl pyrrolidine hydrochloride (0.30 gram).
Step 6: under nitrogen atmosphere, with 3-(methoxycarbonyl)-5-tolyl acid (0.48 gram, 2.5 HATU (1.0 grams mmole),, 2.6 mmole) and the solution of HOAt (0.37 gram, 2.7 mmoles) in 10 milliliters of dry DMF stirred on ice 1 hour, add (2R then, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] fourth-2-alcohol dihydrochloride (1.0 grams, 2.5 mmoles) and DIPEA (1.8 milliliters, 10 mmoles).This solution at room temperature stirred spend the night.Make the reaction mixture stopped reaction with 1M HCl then,, and separate each phase with the EtOAc dilution.Wash organic phase with 1M HCl, and the acid elution liquid that merges is stripped, and organic phase is merged with EtOAc.With the saturated NaHCO of organic phase that merges
3, salt water washing and through Na
2SO
4Dry.This mixture is filtered and concentrates ,-make orange oily coupled product.This oil is dissolved in 35 milliliters of MeOH and adds 2 ml waters and solid LiOHH together
2O (0.6 gram, 14 mmoles).This mixture at room temperature stirred spend the night.With this solution concentration, dilute with water with 1M HCl neutralization, and concentrates.The oily resistates that makes is used the CH of 5%MeOH on Biotage 40S post
2Cl
2Eluant solution is purified, and makes a kind of water white oil.With its ethereal solution that is dissolved in 10 milliliters of MeOH and adds 3 milliliters of 1M HCl.Develop with heptane with this solution concentration and with resistates, make 3-[({ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino) carbonyl]-5-tolyl acid hydrochloride (0.65 gram).
Step 7: at 3-[({ (1S, 2R)-1-(3, the 5-difluorophenyl)-and the 3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino) carbonyl]-5-tolyl acid hydrochloride (0.50 gram, 0.94 mmole) and tert-Butyl dicarbonate (0.20 gram, 0.92 mmole) at 10 ml methanol and 10 milliliters of CH
2Cl
2In solution in, add triethylamine (0.40 milliliter, 2.9 mmoles).This solution was at room temperature stirred 2.5 hours, and concentrate it this moment, at EtOAc and 1MKH
2PO
4Between phase-splitting, and separate each phase.Use M KH
2PO
4The washing organic phase is through Na
2SO
4Drying is filtered, and concentrates and with the heptane development, makes 3-[({ (1S, 2R)-3-[(tert-butoxycarbonyl) (3-Ethylbenzyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl } amino) carbonyl]-5-tolyl acid (0.50 gram).
Step 8: under nitrogen atmosphere, with 3-[({ (1S, 2R)-and the 3-[(tert-butoxycarbonyl) (3-Ethylbenzyl) amino]-1-(3, the 5-difluorobenzyl)-and the 2-hydroxypropyl } amino) carbonyl]-5-tolyl acid (0.30 gram, 0.50 HATU (0.19 gram mmole),, 0.50 mmole) and the solution stirring of HOAt (0.07 gram, 0.51 mmole) in 5 milliliters of dry DMF 15 minutes.Add (2S)-ethyl pyrrolidine hydrochloride (0.05 gram, 0.50 mmole) and the solution of DIPEA (0.35 milliliter, 2.0 mmoles) in 5 milliliters of DMF.This solution at room temperature stirred spend the night.Make its stopped reaction with 1M HCl then,, and separate each phase with the EtOAc dilution.With 1M HCl, saturated NaHCO
3The washing organic phase is through Na
2SO
4Drying is filtered and is concentrated, and makes orange-brown oil.Should oil on Biotage 40S post with 200 milliliters of CH
2Cl
2, use the CH of 3%MeOH then
2Cl
2Eluant solution is purified.The yellow oil that makes is dissolved in 4 milliliters of CH
2Cl
2, and add 4 milliliters of TFA.After at room temperature stirring 2 hours, reaction soln is concentrated and uses 1-inch Kromasil c18 post resistates is purified by anti-phase prep hplc, make the product of formate form.The ethereal solution that adds 2 milliliters of 1M HCl then converts it into HCl salt.Concentrate and develop with heptane, acquisition N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(2S)-and 2-ethyl pyrrolidine-1-yl] carbonyl }-5-toluyl amine hydrochlorate (0.010 gram).MS m/z579.0[M+H]。
Embodiment SP-248
Following compounds is according to preparing with the foregoing description SP-247 similar methods.
3-{[(2S)-and 2-butyl pyrrolidine-1-yl] carbonyl }-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-methyl benzamide, MS m/z 606.4[M+H];
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-methyl-5-{[(2S)-2-propyl pyrrole alkane-1-yl] carbonyl } the benzamide formate, MS m/z 638.6[M+H];
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(2R)-and 2-(2-methoxy ethyl) tetramethyleneimine-1-yl] carbonyl }-the 5-methyl benzamide, MS m/z 608.6[M+H]; With
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(2S)-and 2-ethyl pyrrolidine-1-yl] carbonyl }-5-toluyl amine hydrochlorate.
Embodiment SP-249
Following compounds also is to use method preparation disclosed herein.
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-isopropyl benzyl) amino] propyl group }-3-{[(2R)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] carbonyl }-5-toluyl amine hydrochlorate, MS m/z608.3[M+H];
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-ethynyl benzyl) amino]-the 2-hydroxypropyl }-3-{[(2R)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] carbonyl }-5-toluyl amine hydrochlorate, MS m/z 590.3[M+H]; With
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-3-{[(2R)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] carbonyl }-5-toluyl amine hydrochlorate, MS m/z620.3[M+H].
Embodiment SP-250
N-[(1S, 2R)-3-{[1-(3-bromophenyl) cyclopropyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl] preparation of ethanamide:
Step 1: N-{ (1S)-2-(3, the 5-difluorophenyl)-1-[(2S)-oxyethane-2-yl that will be through stirring] ethyl } ethanamide (4.96 gram) and the solution of 1-(3-bromophenyl) cyclopropylamine (8.6 restrain) in 60 milliliters of i-PrOH is heated to 75 ℃ and reaches 3 hours.Be dissolved in ethyl acetate (200 milliliters) again with the cooled solution evaporation and with resistates.With the 10%HCl aqueous solution (25 milliliters * 2) washing organic layer.With EtOAc (75 milliliters) extraction water-washing liquid once, and with the organic layer that merges wash with saturated NaCl solution (100 milliliters).Then with organic layer through Na
2SO
4Dry and evaporation is purified the resistates that makes by column chromatography, obtain 5.0 grams (1S, 2R)-3-{[1-(3-bromophenyl) cyclopropyl] amino-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl t-butyl carbamate.
Step 2: at 23 ℃, (1S, 2R)-3-{[1-(3-bromophenyl) cyclopropyl] amino }-add 5.0 milliliters of trifluoroacetic acids in the suspension of 1-(3, the 5-difluorobenzyl)-2-hydroxypropyl t-butyl carbamate (1.3 gram) in 5.0 milliliters of methylene dichloride.Stir after 1 hour, add 10.0 milliliters of toluene also with this solution evaporation.The resistates that makes is dissolved in toluene more also with this solution evaporation.This step repeats once again.Under high vacuum, after dry 2 hours, this resistates is suspended in the methylene dichloride (10.0 milliliters), adds triethylamine (0.5 gram) and acetyl imidazole (0.3 gram).With this solution stirring 4 hours and concentrating under reduced pressure.Resistates is purified by column chromatography, make 0.90 gram title compound.ES+ measured value (M+H
+): 455.
Embodiment SP-251
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[1-(3 '-methoxyl group-1,1 '-xenyl-3-yl) cyclopropyl] amino } propyl group) preparation of ethanamide:
At N-[(1S, 2R)-3-{[1-(3-bromophenyl) cyclopropyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl] add 3-anisole ylboronic acid (0.030 gram), Cs in DMF (0.75 milliliter) solution of ethanamide (0.030 gram)
2CO
3(0.085 gram) and Pd (Ph
3P)
4This mixture was heated 12 hours at 90 ℃.Cooled solution is washed with EtOAc (15 milliliters) dilution and with salt solution (10 milliliters * 2).With organic layer through Na
2SO
4Drying is filtered and reduction vaporization.The resistates that makes is purified by column chromatography, obtain 0.010 gram title compound.ES+ measured value (M+H
+): 481.
Embodiment SP-251
N-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl-3-(1-[3 '-(methylol)-1,1 '-xenyl-3-yl] cyclopropyl } amino) propyl group] ethanamide
According to N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl-3-{[1-(3 '-methoxyl group-1,1 '-xenyl-3-yl) cyclopropyl] amino } propyl group) method of ethanamide step 1, use 3-(methylol) phenyl-boron dihydroxide (0.036 gram) to be prepared, obtain 0.008 gram title compound.ES+ measured value (M+H
+): 481.
Embodiment SP-252A
N-[(1S, 2R)-3-{[1-(2 '-ethanoyl-1,1 '-biphenyl-3-yl) cyclopropyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl] ethanamide
According to N-((1S; 2R)-and 1-(3, the 5-difluorobenzyl)-2-hydroxypropyl-3-{[1-(3 '-methoxyl group-1,1 '-xenyl-3-yl) cyclopropyl] amino } propyl group) method of ethanamide step 1; use 2-acetylbenzene ylboronic acid (0.032 gram) to be prepared, obtain 0.012 gram title compound.ES+ measured value (M+H
+): 493.
Embodiment SP-252B
N-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-(1-[3-(5-formyl radical thiophene-2-yl) phenyl] and cyclopropyl } amino)-the 2-hydroxypropyl] ethanamide
According to N-((1S; 2R)-1-(3; the 5-difluorobenzyl)-2-hydroxypropyl-3-{[1-(3 '-methoxyl group-1; 1 '-xenyl-3-yl) cyclopropyl] amino } propyl group) method of ethanamide step 1; use 5-formyl radical thiophene-2-ylboronic acid (0.030 gram) to be prepared, obtain 0.005 gram title compound.ES+ measured value (M+H
+): 484.
Embodiment 2453A to 2453D
Embodiment SP-253A
N
1-(1S, 2R)-1-(cyclopentyl-methyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine hydrochlorate;
Embodiment SP-253B
N
1-[(1S, 2R)-the 3-[(3-bromobenzyl) amino]-1-(cyclopentyl-methyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine hydrochlorate;
Embodiment SP-253C
N
1-(1S, 2R)-1-(cyclohexyl methyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine hydrochlorate;
Embodiment SP-253D
N
1-[(1S, 2R)-the 3-[(3-bromobenzyl) amino]-1-(cyclohexyl methyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine hydrochlorate;
Embodiment SP-254A
N
1-(1S, 2R)-1-(cyclopentyl-methyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine hydrochlorate (embodiment SP-254) and N
1-[(1S, 2R)-the 3-[(3-bromobenzyl) amino]-1-(cyclopentyl-methyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine hydrochlorate (embodiment SP-255) step 1: under nitrogen atmosphere, be cooled to cuprous bromide/dimethylsulphide complex compound (0.33 gram among 10 milliliters of anhydrous THF of-25 ℃, 1.6 mmole) add cyclopentyl bromination magnesium (8 milliliters, the 2M ethereal solution) in the solution.After 20 minutes, be added in (2R)-2-[(4S)-2 among 4 milliliters of anhydrous THF, 2-dimethyl-1,3-dioxolane-4-yl] aziridine-1-t-butyl formate (1.95 grams, 8 mmoles) solution.Make this mixture be warmed to ambient temperature overnight.Use saturated NH
4The Cl aqueous solution makes its stopped reaction and uses extracted with diethyl ether.Use saturated NH
4The Cl aqueous solution, 1NNaHCO
3With salt water washing organic phase.With it in anhydrous Na
2SO
4Last drying also is condensed into 2.38 gram solids.This material is dissolved in 70 ml methanol, adds 12 gram Dowex 50WX2-400, and this mixture was refluxed 2 hours.This mixture is filtered, with methyl alcohol and washed with dichloromethane.Connect the purification receiving receiver, and with this resin with 100 milliliters of 1: 1 dense NH
4OH: washing with alcohol.Filtrate is condensed into 1.16 gram brown crystal.This crystal is dissolved in 30 milliliters of anhydrous THF, and adds 1.5 gram (6.9 mmole) tert-Butyl dicarbonates.This mixture stirred under nitrogen spend the night.It is concentrated, with the ether extraction and with this ether with several parts of water and salt water washing.Through Na
2SO
4Dry and concentrate, make 1.8 grams (6.7 mmoles, 84% originates from (2R)-2-[(4S)-2,2-dimethyl-1,3-dioxolane-4-yl] aziridine-1-t-butyl formate) (1S, 2S)-the 1-[cyclopentyl-methyl]-2,3-dihydroxypropyl t-butyl carbamate:
1H NMR (CDCl
3) δ 4.5 (and d, 1H, NH), 3.7 (m, 1H), 3.6-3.49 (m, 2H), 3.36 (m, 1H), 3.26 (t, 1H, OH), 2.76 (d, 1H, OH), 1.45 (s, 9H), 1.88-1.36 (m, 9H), 1.17-1.08 (m, 2H).
Step 2: (1S, 2S)-the 1-[cyclopentyl-methyl]-2,3-dihydroxypropyl t-butyl carbamate (1.8 grams, 6.7 mmole) in the solution in 15 milliliters of anhydrous THF (under nitrogen atmosphere, in ice bath, cooling off), add tolylsulfonyl imidazoles (Ts-Im, 2.22 gram, 10 mmoles).The THF solution that wherein adds 13.4 milliliters of (13.4 mmole) 1M potassium tert.-butoxides with 8 fens clockwise.After 5 minutes, remove ice bath, and this orange mixture was stirred 3 hours.Use 1N KH
2PO
4Make its stopped reaction, and dilute with ether.Use 1N KH
2PO
4, water and salt water washing organic phase.With this solution through Na
2SO
4Drying, thus concentrate and on silica gel, carry out chromatographic separation with 5% methylene dichloride, 15% ethyl acetate and 80% heptane wash-out.Cut 4 provides 900 milligrams of (1S)-2-(cyclopentyl)-1-[(2S)-oxyethane-2-yl] 2: 1 mixtures of the ethyl carbamic acid tert-butyl ester and a kind of by product.Cut 5 provides 230 milligrams of (1S)-2-(cyclopentyl)-1-[(2S)-oxyethane-2-yl] the ethyl carbamic acid tert-butyl ester:
1HNMR (CDCl
3) δ 4.56 (and d, 1H), 3.45 (m, 1H), 2.85 (m, 1H), 2.75 (m, 2H), 1.91 (m, 1H), 1.8 (m, 2H), 1.6-1.4 (m, 6H), 1.44 (s, 9H), 1.13-1.07 (m, 2H).
Embodiment SP-254B
N
1-(1S, 2R)-1-(cyclopentyl-methyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine hydrochlorate
Step 3: at (1S)-2-(cyclopentyl)-1-[(2S)-oxyethane-2-yl] add the solution of ethyl benzyl amine in 5 milliliters of Virahols between 260 milligrams (1.9 mmoles) in the ethyl carbamic acid tert-butyl ester (230 milligrams, 0.9 mmole).This mixture refluxed under nitrogen 1.5 hours, is removed solvent in a vacuum, and resistates is dissolved in the ethyl acetate.It is washed three times with aliquot 10%HCl, and water is stripped with ethyl acetate.With the organic phase 1N NaHCO that merges
3With the salt water washing, through Na
2SO
4Dry and concentrated.By forming HCl salt,, be neutralized into free alkali (290 milligrams, 0.74 mmole) then, thereby resistates is partly purified with the pentane development.To wherein adding 2 milliliters of trifluoroacetic acids (TFA) and 2 milliliters of methylene dichloride, and this mixture was stirred 30 minutes under nitrogen.It is condensed into oil, and this oil is dissolved in 2 milliliters of anhydrous THF also with 0.2 milliliter of 4-methylmorpholine neutralization.In this mixture, add 3-[(dipropyl amino) carbonyl]-5-tolyl acid (0.2 gram, 0.76 mmole) and the solution of carbonyl dimidazoles (CDI, 0.13 gram, 0.8 mmole) in 3 milliliters of anhydrous THF, this solution has been stirred 35 minutes.This reactant stirred under nitrogen spend the night.In this mixture, add 1N KH
2PO
4And ethyl acetate.With organic phase 1N KH
2PO
4, 1N NaHCO
3(2 *) and salt water washing are through Na
2SO
4Drying, and concentrate.On silica gel, (contain 1%NH with 6% methyl alcohol
4OH) thereby dichloromethane solution wash-out carries out chromatographic separation, after ether HCl formation salt, makes 109 milligrams of (0.19 mmole) N
1-(1S, 2R)-1-(cyclopentyl-methyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine hydrochlorate (embodiment SP-254): CI MS m/z 536[M+H]
+
Embodiment SP-255
N
1-[(1S, 2R)-the 3-[(3-bromobenzyl) amino]-1-(cyclopentyl-methyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine hydrochlorate
Step 3: will be as above an embodiment is described contains (1S)-2-(cyclopentyl)-1-[(2S)-oxyethane-2-yl] cut of the ethyl carbamic acid tert-butyl ester (ca.2 mmole) and a kind of by product, an and bretylium (10 mmole) back flow reaction 3 hours in 12 milliliters of Virahols.Remove solvent and resistates is dissolved in ethyl acetate.With it with several parts of 10%HCl, 1N NaHCO
3With the salt water washing, dry (Na
2SO
4), concentrate.Use methylene dichloride on silica gel, using at the most then, 2% methyl alcohol (contains 1%NH
4OH) dichloromethane solution wash-out, thus carry out chromatographic separation, make 523 milligrams of (1.19 mmoles, 60% based on epoxide) oily affixtures.This material (0.31 gram, 0.7 mmole) is dissolved in 2 milliliters of methylene dichloride, and adds 1 milliliter of TFA.After 1 hour, it is concentrated, be dissolved in ethyl acetate, use 1N NaHCO
3Neutralization is used the salt water washing, and is condensed into free alkali.To the 3-[(dipropyl amino that wherein adds 4 milliliters of anhydrous THF and pre-mixing (2 hours)) carbonyl]-5-tolyl acid (190 milligrams, 0.72 mmole) and the solution of CDI (120 milligrams, 0.74 mmole) in 3 milliliters of anhydrous THF.After 2 days, use 1N KH
2PO
4Make the reactant stopped reaction, and be dissolved in ethyl acetate.Organic phase is used organic phase 1N KH
2PO
4, 1N NaHCO
3(2 *) and salt water washing are through Na
2SO
4Drying, and concentrate.On silica gel, (contain 1%NH with 5% methyl alcohol
4OH) thereby dichloromethane solution wash-out carries out chromatographic separation, after ether HCl formation salt, makes the N of 184 milligrams of (0.29 mmole) white solid
1-[(1S, 2R)-the 3-[(3-bromobenzyl) amino]-1-(cyclopentyl-methyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine hydrochlorate (embodiment SP-255): CI MS m/z 586[M+H]
+N
1-(1S, 2R)-1-(cyclohexyl methyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine hydrochlorate (embodiment SP-256) and N
1-[(1S, 2R)-the 3-[(3-bromobenzyl) amino]-1-(cyclohexyl methyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine hydrochlorate (embodiment SP-257)
Step 1: in anhydrous THF (20 milliliters) solution of magnesium turnings (0.97 gram, 40 mmoles), add cyclohexyl bromide (2.46 milliliters, 20 mmoles), and refluxed 1.5 hours, make cyclohexyl bromination magnesium thus.According to the step described in the last embodiment step 1, make 1.66 gram (5.8 mmoles, 70% originates from (2R)-2-[(4S)-2,2-dimethyl-1,3-dioxolane-4-yl] aziridine-1-t-butyl formate) light yellow oily (1S, 2S)-and the 1-[cyclohexyl methyl]-2, the 3-dihydroxypropyl carboxylamine S-tert-butyl ester, solidify its placement:
1H NMR (CDCl
3) δ 4.43 (and d, 1H, NH), 3.69 (m, 1H), 3.59 (m, 2H), 3.32 (m, 1H), 3.24 (t, 1H, OH), 2.70 (d, 1H, OH), 1.45 (s, 9H), 1.8-1.13 (m, 11H), 1.01 (m, 1H), 0.87 (m, 1H).
Step 2: according to the step of describing in the last embodiment step 2, with (1S, 2S)-and the 1-[cyclohexyl methyl]-2,3-dihydroxypropyl t-butyl carbamate (1.6 grams, 5.5 mmole) with Ts-Im (1.5 grams, 6.75 mmole) and potassium tert.-butoxide (11 milliliters, the solution of 1M in THF) in 20 milliliters of anhydrous THF, react.Thereby the n-heptane solution wash-out with 5% methylene dichloride and 5% to 15% ethyl acetate on silica gel carries out chromatographic separation, makes 456 milligram of 1.7 mmole (1S)-2-(cyclohexyl)-1-[(2S)-oxyethane-2-yl] the ethyl carbamic acid tert-butyl ester:
1HNMR (CDCl
3) δ 4.41 (and m, 1H), 3.55 (m, 1H), 2.84 (m, 1H), 2.75 (m, 2H), 1.8-1.6 (m, 4H), 1.45 (s, 9H), 1.4-1.1 (m, 7H), 0.98 (m, 1H), 0.86 (m, 1H).
Embodiment SP-256
N
1-(1S, 2R)-1-(cyclohexyl methyl)-34 (3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine hydrochlorate
Step 3: with (1S)-2-(cyclohexyl)-1-[(2S)-oxyethane-2-yl] (225 milligrams of the ethyl carbamic acid tert-butyl esters, 0.84 mmole) and (254 milligrams of ethyl benzyl amines, 1.9 mmole) solution in 5 milliliters of Virahols was refluxed under nitrogen 1.5 hours, remove solvent in a vacuum, and resistates is dissolved in the ethyl acetate.It is washed three times with aliquot 10%HCl, and water is stripped with ethyl acetate.With the organic phase 1N NaHCO that merges
3With the salt water washing, through Na
2SO
4Dry and concentrated.The oil (300 milligrams) that makes is dissolved in 2 milliliters of methylene dichloride and 2 milliliters of TFA, and stirred 30 minutes.It is concentrated, and mensuration contains 4 equivalent TFA by weight.It is dissolved in 2 milliliters of anhydrous THF and adds 0.4 milliliter of (3.6 mmole) 4-methylmorpholine.It is cooled to-30 ℃, and add 3-[(dipropyl amino) carbonyl]-(238 milligrams of 5-tolyl acids, 0.9 mmole) and the mixture of CDI (165 milligrams, 1 mmole) in 3 milliliters of anhydrous THF, this mixture at room temperature stirred 1 hour in advance.Make this mixture be warmed to room temperature.After 3 days, use 1N KH
2PH
4Make the reactant stopped reaction and be dissolved in ethyl acetate.With organic phase 1N KH
2PO
4, 1N NaHCO
3(2 *) and salt water washing are through Na
2SO
4Drying, and concentrate.On silica gel, (contain 1%NH with 4% to 10% methyl alcohol
4OH) thereby dichloromethane solution wash-out carries out chromatographic separation, after ether HCl formation salt, makes 124 milligrams of (0.21 mmole) white solid N
1-(1S, 2R)-1-(cyclohexyl methyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine hydrochlorate (embodiment SP-256): CI MS m/z 550[M+H]
+
Embodiment SP-257
N
1-[(1S, 2R)-the 3-[(3-bromobenzyl) amino]-1-(cyclohexyl methyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine hydrochlorate
Step 3: with (1S)-2-(cyclohexyl)-1-[(2S)-oxyethane-2-yl] (225 milligrams of the ethyl carbamic acid tert-butyl esters, 0.84 mmole) and (380 milligrams of bretyliums, 2.0 mmole) solution in 7 milliliters of Virahols was refluxed under nitrogen 2 hours, remove solvent in a vacuum, and resistates is dissolved in the ethyl acetate.It is washed three times with aliquot 10%HCl, and water is stripped with ethyl acetate.With the organic phase 1N NaHCO that merges
3With the salt water washing, through Na
2SO
4Dry and concentrated.The oil (356 milligrams) that makes is dissolved in 3 milliliters of methylene dichloride and 2 milliliters of TFA, and stirred 1.5 hours.It is concentrated, and mensuration contains 3 equivalent TFA by weight.To wherein adding 2 milliliters of anhydrous dimethyl formamides (DMF) and 0.35 milliliter of (3.2 mmole) 4-methylmorpholine.Add premixed 3-[(dipropyl amino therein) carbonyl]-(240 milligrams of 5-tolyl acids, 0.9 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC mmole),, 190 milligrams, 1 mmole) and hydroxide 1-Qiang base Ben Bing trioazole (HOBT, 135 milligrams, 1 mmole) solution in 3 milliliters of dry DMF, this solution has been stirred 1.5 hours.After 3 days, use 1N KH
2PH
4Make the reactant stopped reaction and be dissolved in ethyl acetate.With organic phase 1N KH
2PO
4, 1N NaHCO
3(2 *) and salt water washing are through Na
2SO
4Drying, and concentrate.On silica gel, (contain 1%NH with 5% methyl alcohol
4OH) thereby dichloromethane solution wash-out carries out chromatographic separation, after ether HCl formation salt, makes 208 milligrams of (0.32 mmole) N
1-[(1S, 2R)-the 3-[(3-bromobenzyl) amino]-1-(cyclohexyl methyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine hydrochlorate (embodiment SP-257): CI MS m/z 600[M+H]
+
Embodiment SP-258
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[({2-[(dimethylamino) methyl] pyridin-4-yl } methyl) amino]-the 2-hydroxypropyl }-5-(1,3-oxazole-2-yl)-N
3, N
3Synthesizing of-dipropyl isophthaloyl amine
Step 1: at 4-cyanopyridine N-oxide compound (compound 35, as above) (2.0 grams, 16.7 mmole) in the solution in methylene dichloride (260 milliliters), at room temperature dropwise add trimethylammonium oxygen a tetrafluoro borate (2.46 grams, 16.7 at room temperature stir mmole), and with this reaction mixture and to spend the night.With this reactant concentrating under reduced pressure, make required 4-cyanopyridine N-methoxyl group a tetrafluoro borate:
1H NMR (300MHz, DMSO-d
6) δ 9.80 (and d, J=6.0Hz, 2H), 8.87 (d, J=6.0Hz, 2H), 4.48 (s, 3H).Step 2: the aqueous solution of ammonium persulphate (8.3 milliliters, 8.3 mmoles) is added in the reflux solution of N-methoxypyridine salt in methyl alcohol (200 milliliters) that makes in the step 1.Stir after 0.5 hour, add 1M Sodium Persulfate (4.2 milliliters, 4.2 mmoles) again and the reaction mixture refluxed heated overnight.This reaction mixture is cooled to room temperature and concentrating under reduced pressure.Make resistates phase-splitting between methylene dichloride and saturated sodium bicarbonate.Separate organic layer and water, saturated sodium-chloride washing, dry (sodium sulfate) filters and concentrating under reduced pressure, makes a kind of white solid.Purify by flash column chromatography (silicon-dioxide, 98: 2 methylene chloride), make the 4-cyano group-2-4-hydroxymethylpiperidine (36) (670 milligrams, 30%) of white solid:
1H NMR (300MHz, CDCl
3) δ 8.75 (and d, J=5.0Hz, 1H), 7.59 (d, J=0.5Hz, 1H), 7.46 (dd, J=5.3,0.5Hz, 1H), 4.85 (d, J=5.3Hz, 2H), 3.25 (t, J=5.2Hz, 1H).
Step 3: under 0 ℃, in methylene dichloride (97 milliliters) solution of triphenyl phosphine (5.53 grams, 21.1 mmoles), slowly add bromine (1.07 milliliters, 20.8 mmoles).This solution is warmed to room temperature and observes white precipitate.Methylene dichloride (20 milliliters) solution that dropwise adds 4-cyano group-2-4-hydroxymethylpiperidine 36 (2.61 gram, 19.5 mmoles), and reaction mixture at room temperature stirred spend the night.Make reaction mixture phase-splitting between water and methylene dichloride.Organic layer is washed with saturated sodium-chloride, and dry (sodium sulfate) filters, and concentrating under reduced pressure, obtains a kind of white solid.Purify by flash column chromatography (silicon-dioxide, 99: 1 methylene chloride), make 4-cyano group-2-bromo methyl cycloheptapyridine (3.95 gram), it is directly used in next step without further purifying:
1H NMR (300MHz, CDCl
3) δ 8.76 (and d, J=5.0Hz, 1H), 7.7 (s, 1H), 7.46 (dd, J=5.0,1.3Hz, 1H), 4.58 (s, 2H).
Step 4: dimethylamine hydrochloride (4.78 grams, 58.6 mmoles) is added 4-cyano group-2-bromo methyl cycloheptapyridine (3.95 grams, 19.5 mmoles) and the solution of triethylamine (13.58 milliliters, 97.7 mmoles) in acetone (40 milliliters).Reaction mixture stirring at room temperature in sealed tube is spent the night, with the reaction mixture concentrating under reduced pressure, and phase-splitting between methylene dichloride and saturated sodium bicarbonate.Separate organic layer and water, saturated sodium-chloride washing, dry (sodium sulfate) filters, and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 99: 1 methylene chloride), make required 4-cyano group-2-(dimethylamino) picoline (2.10 gram):
1H NMR (300MHz, CDCl
3) δ 8.73 (and d, J=5.0Hz, 1H), 7.71 (s, 1H), 7.41 (dd, J=5.0,1.2Hz, 1H), 3.65 (s, 2H), 2.31 (s, 6H); ESI MS m/z 162[M+H]
+
Step 5: (80 milligrams, shake spends the night 10%Pd/C) and under the hydrogen of mixture at 60psi of concentrated hydrochloric acid (3 milliliters) in methyl alcohol (30 milliliters) with 4-cyano group-2-(dimethylamino) picoline (800 milligrams, 4.97 mmoles), palladium.With reaction mixture through diatomite filtration and water and washed with methanol filter cake.Filtrate decompression is concentrated cake with resistates phase-splitting between water and methylene dichloride.Make water layer be alkalescence and use dichloromethane extraction with 1N sodium hydroxide.Organic layer is washed with saturated sodium-chloride, and dry (sodium sulfate) filters, and concentrating under reduced pressure, makes a kind of orange oil.By flash column chromatography (97: 32-propyl alcohol/ammonium hydroxide) purify, make 4-amino methyl-2-(dimethylamino) picoline 37 (492 milligrams):
1H NMR (500MHz, CDCl
3) δ 8.50 (and d, J=5.1Hz, 1H), 7.37 (s, 1H), 7.15 (d, J=5.1Hz, 1H), 3.91 (s, 2H), 3.58 (s, 2H), 2.30 (s, 6H); ESI MS m/z 166[M+H]
+
Step 6: with 4-amino methyl-2-(dimethylamino) picoline 37 (490 milligrams, 2.98 mmole) and (1S)-2-(3, the 5-difluorophenyl)-1-[(2S)-and oxyethane-2-yl] the mixture reflux of ethyl carbamate (892 milligrams, 2.98 mmoles) in 2-propyl alcohol (20 milliliters) spend the night.This reaction mixture is cooled to room temperature and concentrating under reduced pressure.By flash column chromatography (99: 12-propyl alcohol/ammonium hydroxide) resistates is purified, obtain product (590 milligrams): ESI MS m/z 465[M+H]
+
Step 7: at room temperature, the yellow solid that in step 6, makes (590 milligrams, in 1.26 mmole) De diox (6.3 milliliters) solution, add (6.3 milliliters in hydrogenchloride, solution in the 4N Zai diox, 25 mmoles), and with reaction mixture at room temperature stirred 6 hours.Be dissolved in the reaction mixture concentrating under reduced pressure and with resistates and contain N, in the methylene dichloride of N-diisopropylethylamine (3 milliliters).With organic phase water and saturated sodium-chloride washing, dry (sal epsom) filters and concentrating under reduced pressure, obtains product (523 milligrams): ESI MS m/z 365[M+H]
+
Step 8: with 3-[(dipropyl amino) carbonyl]-5-(1,3-oxazole-2-yl) phenylformic acid 38 is (120 milligrams, 0.38 mmole) containing N, N-diisopropylethylamine (132 microlitres, 0.76 mmole) and the solution in the methylene dichloride (3.8 milliliters) of HBTU (151 milligrams, 0.40 mmole) at room temperature stirred 0.5 hour.(207 milligrams of the orange oil that adding step 7 makes in above-mentioned solution, 0.57 mmole) containing N, solution in the methylene dichloride (3.8 milliliters) of N-diisopropylethylamine (132 microlitres, 0.76 mmole), and this reaction mixture at room temperature stirred 18 hours.And then with methylene dichloride reaction mixture is diluted, with saturated sodium bicarbonate and saturated sodium-chloride washing, dry (sodium sulfate) filters and concentrating under reduced pressure, makes the oily resistates.Purify by flash column chromatography (silicon-dioxide, 90: 10 methylene chloride), make N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[({2-[(dimethylamino) methyl] pyridin-4-yl } methyl) amino]-the 2-hydroxypropyl }-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine (178 milligrams): mp63-66 ℃; ESI MS m/z 663[M+H]
+
Embodiment SP-259
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[({4-[(dimethylamino) methyl] pyridine-2-yl } methyl) amino]-the 2-hydroxypropyl }-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine, the compound 94 among following Figure 23, synthetic
Synthesizing of 2-cyano group-4-(dimethylamino) picoline (92)
Step 1: with 4-(methylol) pyridine (17.4 grams, 159 mmoles), tert-butyldimethylsilyl chloride (26.36 grams, 174.88 mmole) and imidazoles (13.31 the gram, 195.5 mmole) at N, the mixture in dinethylformamide (200 milliliters) and the methylene dichloride (20 milliliters) at room temperature stirs and spends the night.With this reaction mixture concentrating under reduced pressure, phase-splitting between the mixture of water and ethyl acetate and hexane (1: 1) then.Organic layer is washed with saturated sodium-chloride, and dry (sodium sulfate) filters and concentrating under reduced pressure, obtains a kind of oil (35.62 gram):
1H NMR (300MHz, CDCl
3) δ 8.43 (and d, J=6Hz, 2H), 7.13 (d, J=6Hz, 2H), 4.63 (s, 2H), 0.84 (s, 9H), 0.05 (s, 6H).
Step 2: in the solution of the oil that the step 1 in anhydrous methylene chloride (470 milliliters) makes (35.62 grams, 159 mmoles) through stirring, add 3-chloroperoxybenzoic acid (47.03 grams, 172.57 mmoles).Reaction mixture is at room temperature stirred the phase-splitting between water and methylene dichloride then of spending the night.With saturated sodium sulfite, saturated sodium bicarbonate, 1N sodium hydroxide and saturated sodium-chloride washing organic layer, dry (sodium sulfate) filters and concentrating under reduced pressure, makes 4-(tertiary butyl dimethyl methyl siloxy) PICOLINE N-OXIDES 91 (37.8 gram):
1H NMR (300MHz, CDCl
3) δ 8.07 (and d, J=6Hz, 2H), 7.13 (d, J=6Hz, 2H), 4.59 (s, 2H), 0.83 (s, 9H), 0.05 (s, 6H).
Step 3: the mixture backflow of 4-(tertiary butyl dimethyl methyl siloxy) PICOLINE N-OXIDES 91 (30 grams, 125 mmoles), triethylamine (40 microlitre) and cyaniding trimethyl silyl (44 milliliters, 360 mmoles) is spent the night.This dark solution is cooled to room temperature and concentrating under reduced pressure, makes the black colloid.Purify by flash column chromatography (silicon-dioxide, 10: 90 ethyl acetate/hexane), obtain a kind of oil (20.3 gram):
1H NMR (300MHz, CDCl
3) δ 8.50 (and d, J=5Hz, 1H), 7.55 (s, 1H), 7.34 (d, J=5Hz, 1H), 4.66 (s, 2H), 0.83 (s, 9H), 0.05 (s, 6H).
Step 4: under 0C, in methylene dichloride (200 milliliters) solution of triphenyl phosphine (10.29 grams, 39.28 mmoles), slowly add bromine (1.97 milliliters, 38.74 mmoles).This solution is warmed to room temperature and observes white precipitate.Be added in the brown oil that makes in the step 3 in the methylene dichloride (50 milliliters) (9.0 grams, 36.27 mmoles), and reaction mixture at room temperature stirred spend the night.Make reaction mixture phase-splitting between water and methylene dichloride.Organic layer is washed with saturated sodium-chloride, and dry (sodium sulfate) filters, and concentrating under reduced pressure, obtains a kind of brown solid.Purify by flash column chromatography (silicon-dioxide, 17: 83 ethyl acetate/hexane), make a kind of white solid (6.20 gram):
1H NMR (300MHz, CDCl
3) δ 8.71 (and d, J=3Hz, 1H), 7.73 (s, 1H), 7.55 (dd, J=6,3Hz, 1H), 4.42 (s, 2H).
Step 5: in acetone (90 milliliters) solution of the solid that in step 4, makes (9.1 grams, 46.44 mmoles), add dimethylamine hydrochloride (11.36 grams, 139.3 mmoles) and Trimethylamine 99 (38.73 milliliters, 278.6 mmoles) through stirring.Reaction mixture stirred in sealing bottles spend the night.With the reaction mixture concentrating under reduced pressure.Resistates is water-soluble, make it be alkalescence (pH 10) and use dichloromethane extraction with 1N sodium hydroxide.Organic layer is washed with saturated sodium-chloride, and dry (sodium sulfate) filters, and concentrating under reduced pressure, makes 2-cyano group-4-(dimethylamino) picoline 92 (6.2 gram): ESI MS m/z 162[M+H]
+
Embodiment SP-260
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[({4-[(dimethylamino) methyl] pyridine-2-yl } methyl) amino]-the 2-hydroxypropyl }-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine,
Step 1: will make 2-cyano group-4-(dimethylamino) picoline 92 (2.0 grams, 12.4 mmoles), 10%Pd/C (200 milligrams) and mixture under 60psi hydrogen the shake of concentrated hydrochloric acid (8 milliliters) in methyl alcohol (180 milliliters) and spend the night.With this reaction mixture through diatomite filtration and water and methanol wash repeatedly.Decompression is removed methyl alcohol and with resistates phase-splitting between water and methylene dichloride.Make water layer be alkalescence and use dichloromethane extraction with 1N sodium hydroxide.Organic layer is washed with saturated sodium-chloride, and dry (sodium sulfate) filters and concentrating under reduced pressure, obtains a kind of oil (1.07 gram):
1H NMR (300MHz, CDCl
3) δ 8.53 (and d, J=5Hz, 1H), 7.25 (s, 1H), 7.13 (d, J=5Hz, 1H), 3.98 (s, 2H), 3.42 (s, 2H), 2.26 (s, 6H); ESI MS m/z166[M+H]
+
Step 2: with (500 milligrams of the orange oil that make in the step 1,3.03 mmole) and (1S)-2-(3, the 5-difluorophenyl)-1-[(2S)-and oxyethane-2-yl] the mixture reflux of the ethyl carbamic acid tert-butyl ester (907 milligrams, 3.03 mmoles) in 2-propyl alcohol (20 milliliters) spend the night.This reaction mixture is cooled to room temperature and concentrating under reduced pressure.By flash column chromatography (1: 99 ammonium hydroxide/2-propyl alcohol) resistates is purified, obtain a kind of solid (1.13 gram): ESI MS m/z 465[M+H]
+
Step 3: the yellow solid (400 milligrams, 0.86 mmole) that makes in the step 2 is dissolved in diox (4.3 milliliters), and adds hydrogenchloride (4.3 milliliters, 4N diox, 17.22 mmoles).Reaction mixture was at room temperature stirred 6 hours.With the reaction mixture concentrating under reduced pressure and add methylene dichloride and N, N-diisopropylethylamine (3 milliliters).With organic phase water and saturated sodium-chloride washing, dry (sal epsom) filters and concentrating under reduced pressure, obtains a kind of oil (365 milligrams): ESI MS m/z 365[M+H]
+
Step 4: at 3-[(dipropyl amino) carbonyl through stirring]-5-(1,3-oxazole-2-yl) phenylformic acid 93 is (173.6 milligrams, 0.55 mmole) and N, N-diisopropylethylamine (191 microlitres, 1.10 in methylene dichloride mmole) (6.0 milliliters) solution, add HBTU (218.62 milligrams, 0.58 mmole), and reaction mixture was at room temperature stirred 0.5 hour.In above-mentioned solution, add orange oil (300 milligrams, 0.823 mmole) and N that step 3 makes, the solution of N-diisopropylethylamine (191 microlitres, 1.10 mmoles) in methylene dichloride (6.0 milliliters), and this reaction mixture stirred 18 hours under nitrogen.And then reaction mixture is diluted, and with saturated sodium bicarbonate, 0.5N hydrochloric acid and saturated sodium-chloride washing with methylene dichloride.With organic layer drying (sodium sulfate), filter and concentrating under reduced pressure then, make the oily resistates.Purify by flash column chromatography (silicon-dioxide, 10: 90 ethanol/methylene), make N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[({4-[(dimethylamino) methyl] pyridine-2-yl } methyl) amino]-the 2-hydroxypropyl }-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine (94) (233 milligrams): mp65-68 ℃; ESI MS m/z 663[M+H]
+
Embodiment SP-261
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(1-{4-[(dimethylamino) methyl] pyridine-2-yl } cyclopropyl) amino]-the 2-hydroxypropyl }-5-(1,3-oxazole-2-yl)-N
3, N
3Synthesizing of-dipropyl isophthaloyl amine
Step 1: (500 milligrams of 2-cyano group-4-(dimethylamino) picolines 92 (according to embodiment SP-259 preparation), 3.10 mmole) in the solution in tetrahydrofuran (THF) (10 milliliters), add titanium isopropylate (IV) (1.0 milliliters, 3.41 mmole) and (6.20 milliliters of ethylmagnesium bromide, 1N THF, 6.20 mmoles).Stirred disposable adding boron trifluoride diethyl etherate (786 microlitres, 6.20 mmoles) 0.5 hour.Reaction mixture at room temperature stirred 1 hour and add 1N sodium hydroxide the pH value of mixture is adjusted to 9-10.The white solid that filter to remove generates and with filtrate phase-splitting between water and methylene dichloride.Organic layer is washed with saturated sodium-chloride, and dry (sodium sulfate) filters and concentrating under reduced pressure, obtains a kind of yellow oil.Purify by flash column chromatography (silicon-dioxide, 1: 99 to 3: 97 ammonium hydroxide/2-propyl alcohol), obtain a kind of oil (360 milligrams):
1H NMR (300MHz, CDCl
3) δ 8.42 (and dd, J=6,5Hz, 1H), 3.41 (s, 2H), 7.02 (dd, J=6,5Hz, 1H), 3.98 (s, 2H), 3.42 (s, 2H), 2.25 (s, 6H), 2.08 (s, 2H), 1.31-1.27 (m, 2H), 1.15-1.11 (m, 2H); ESI MS m/z 192[M+H]
+
Step 2: with (350 milligrams of the oil that make in the step 1,1.83 mmole) and (1S)-2-(3, the 5-difluorophenyl)-1-[(2S)-and oxyethane-2-yl] mixture of the ethyl carbamic acid tert-butyl ester (496.8 milligrams, 1.66 mmoles) in 2-propyl alcohol (13 milliliters) reflux and to spend the night.This reaction mixture is cooled to room temperature and concentrating under reduced pressure.By flash column chromatography (silicon-dioxide, 1: 99 ammonium hydroxide/2-propyl alcohol) resistates is purified, obtain a kind of solid (300 milligrams): ESI MS m/z 491[M+H]
+
Step 3: in the solution of the solid (300 milligrams, 0.61 mmole) that will in the step 2 in the Zai diox (6.0 milliliters) of stirring, make, add hydrochloric acid (6.0 milliliters, 4N diox, 24.40 mmoles).Reaction mixture was at room temperature stirred 6 hours.With the reaction mixture concentrating under reduced pressure and add methylene dichloride and N, N-diisopropylethylamine (3 milliliters).With organic phase water and saturated sodium-chloride washing, dry (sal epsom) filters and concentrating under reduced pressure, obtains a kind of oil (269 milligrams): ESI MS m/z 391[M+H]
+
Step 4: at 3-[(dipropyl amino) carbonyl through stirring]-5-(1,3-oxazole-2-yl) phenylformic acid 93 is (according to embodiment S-2364, step 5 makes) (124.3 milligrams, 0.39 mmole) and N, in methylene dichloride (3.0 milliliters) solution of N-diisopropylethylamine (139 microlitres, 0.79 mmole), add (156.5 milligrams of HBTU, 0.41 mmole), and with reaction mixture stirred 0.5 hour.In above-mentioned solution, add orange oil (269.6 milligrams, 0.823 mmole) and the N in methylene dichloride (3.0 milliliters) that step 3 makes, N-diisopropylethylamine (139 microlitres, 0.79 mmole), and this reaction mixture stirred 18 hours under nitrogen.And then with methylene dichloride reaction mixture is diluted, and with saturated sodium bicarbonate and saturated sodium-chloride washing, dry (sodium sulfate) filters and concentrating under reduced pressure, makes the oily resistates.Purify by flash column chromatography (silicon-dioxide, 10: 90 ethanol/methylene), make N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(1-{4-[(dimethylamino) methyl] pyridine-2-yl } cyclopropyl) amino]-the 2-hydroxypropyl }-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine (95) (134 milligrams): mp70-72 ℃; ESI MS m/z 689[M+H]
+
Embodiment SP-262
(reorganization is from Org.Prep.﹠amp in the preparation of bromo-cyclopropyl cyanogen 2; Proc.Int., the step in 1995,27 (3), 355)
Stir 1-bromo-2-monochloroethane (BCE at 40 ℃; 120 milliliters), the mixture of 3-bromobenzylcyanide (25 gram) and benzyl-chlorination three second ammoniums (TEBAC, 1.1 grams), simultaneously with dropwise adding alkali (50%NaOH, 120 restrain) in 20 minutes.Temperature is increased to about 80 ℃ in initial 15 minutes.Continue very violent mechanical stirring, simultaneous temperature slowly falls after rise to 50 ℃ (at ensuing 3 hours).Mixture is wine-colored in this stage.After 3 hours, there are not starting material (TLC).Reaction mixture is cooled to room temperature, adds entry (100 milliliters) and stirred 5 minutes.Separate organic layer, and with methylene dichloride (3 *) aqueous phase extracted.With organic layer water and the diluted hydrochloric acid aqueous solution washing that merges.Use MgSO
4With the solution drying, filter and concentrate, produce deep yellow oil (126 grams; Still contain some BCE).Use short circuit set and single susceptor by high-vacuum fractionation with purification of products.Collect heavy oil shape liquid distillate 26.6 grams (94%) of bp108-115 ℃/0.1-0.05mmHg.After being cooled to room temperature, this liquid solidifies.
The preparation of bromamide 3
With bromine cyanogen 2 (5.9 grams; 26.6 mmole) be dissolved in methyl alcohol (150 milliliters).In this solution, add KOH (25% aqueous solution, 0.68 milliliter) and hydrogen peroxide (30%, 35 milliliter), stir simultaneously, and reaction mixture was heated 5 hours at 55 ℃.There are not starting material (TLC) this moment.With this mixture evaporation, produce solid residue (7.1 grams; Contain KOH).
The preparation of bromo-acid 4
The rough bromamide 3 that makes in the last reaction is made slurry in methyl alcohol (10 milliliters), and add NaOH (10% aqueous solution, 150 milliliters).With reaction mixture refluxed 4.5 hours (TLC control).This mixture is cooled to room temperature, with 15%HCl acidifying (to pH2) and concentrated.Filter the white solid that collecting precipitation goes out.Output 6.8 grams.
The preparation of chloride of acid 5 (to Synlett1999, the step in 11,1763 changes slightly)
Thionyl chloride (2.73 milliliters) and Ben Bing trioazole (4.47 gram) are dissolved in anhydrous methylene chloride (25 milliliters).(22.2 milliliters of the thionyl chloride solutions that rough bromo-acid 4 (6.8 gram) is dissolved in methylene dichloride (120 milliliters) and in this solution, dropwise makes above the adding with several minutes through stirring; 1.25 equivalent).Before interpolation was finished, Ben Bing trioazole hydrochloride began to separate as white solid.Again this reaction mixture was stirred 15 minutes last filtering solid.Filtrate is used anhydrous MgSO
4(2 gram) stirs to eliminate excess reagent.Filtering solid and with filtrate evaporation under high vacuum dry 1 hour, makes the viscosity amber oil.Output 6.6 grams.
The preparation of bromo-amine 6
Rough chloride of acid 5 is dissolved in anhydrous propanone (40 milliliters), is cooled to-10 ℃ and also handles with sodiumazide (4 grams, 15 ml water solution).-10 ℃ stir 1 hour after, make it be warmed to 0 ℃ and pour in the cold water (300 milliliters).Trinitride is extracted in the minimum as far as possible toluene (ca.40 milliliter).Wash toluene layer and dry with water.Filtering solid and with the solution stirring made and carefully 100 ℃ of heating 1 hour.Add dense HCl (about 25 milliliters) and mixture was refluxed 15 minutes by condenser.Be settled out white crystal during cooling and with its filtering, filtrate is slightly concentrated, cool off and regather the precipitation part.Combining solid, drying obtain the bromo-cyclopropylamine 6 of 4.1 gram hydrochloride forms.
The preparation of compound 7
With rough bromo-amine hydrochloride 6 (2 grams; 8 mmoles) be dissolved in saturated Na
2CO
3The aqueous solution (20 milliliters) is also used methylene dichloride (5 * 10 milliliters) extraction.With the extraction liquid drying that merges, evaporation is also spent the night under vacuum.Produce bromo-amine 6 (1.68 grams, 7.92 mmoles).This amine is dissolved in Virahol (20 milliliters) and adds epoxide (ii; 2.36 gram, 7.92 mmoles).With mixture in sealed tube in 80 ℃ of stirrings, do not detect epoxide raw material (2-6 hour) until TLC.With the reaction mixture cooling and with solvent evaporation, under vacuum, obtain white solid (3.9 grams, 82% purity) after the drying.
The preparation of compound 8
Rough BOC bromide 7 (3.9 grams; 7.0 mmole; 1 equivalent) is dissolved in triethylamine (20 milliliters) and add PdCl
2(PPh
3)
2(0.196 gram, 0.28 mmole; 0.04 equivalent) and CuI (0.068 the gram; 0.36 mmole; 0.05 equivalent).When adding CuI, the reaction mixture yellowing slowly becomes green then.This reaction mixture is heated to backflow, and this moment, it became orange-brown.Remove to add trimethyl silyl acetylene (0.82 gram, 1.2 milliliters, 8.2 mmoles, 1.2 equivalents) by injection.Form a kind of black precipitate immediately.Reaction mixture refluxed under nitrogen 3 hours, is cooled to room temperature with it, then then at saturated Na
2CO
3And phase-splitting between the ethyl acetate.Separate organic layer and use ethyl acetate (3 * 25 milliliters) aqueous phase extracted.With the extraction liquid salt water washing that merges, dry and evaporation.This raw product contains the acetylene impurity that is generated by bromo-amine 6.
The preparation of BOC-acetylene 8a
Protect in THF (5 milliliters) solution of acetylene 8 (from last reaction) at rough silyl-quilt, add tetrabutylammonium fluoride (1M, THF solution, 8 milliliters).This mixture was at room temperature stirred 1 hour,, resistates is dissolved in ether (30 milliliters), use the salt water washing solvent evaporation, dry and concentrated.On silica gel, use ethyl acetate/hexane (2: 3) mixture to purify raw product, obtain the BOC-acetylene 8a (1.54 grams, 43% originates from 6) of purifying by flash chromatography.
9 preparation:
1-(3, the 5-difluorobenzyl)-3-[1-(3-ethynyl phenyl) cyclopropylamino]-2-isopropanolamine dihydrochloride
With 4N HCl De diox (15.8 milliliters, 63.3 mmoles) solution-treated [1-(3, the 5-difluorobenzyl)-3-[1-(3-ethynyl phenyl) cyclopropylamino]-2-hydroxypropyl]-t-butyl carbamate (2.34 grams, 5.13 mmoles).Handle the multiphase mixture make with methyl alcohol (10 milliliters), it is with becoming homogeneous phase in 30 minutes.In a vacuum volatile matter is evaporated.Add diox (20 milliliters) and mixture is evaporated in a vacuum, make white solid (2.33 grams, 106%).
Embodiment SP-263
Ethylbenzyl amine (11) between the preparation cyclopropyl
10 preparation
With 1-(3-bromo-phenyl)-cyclopropylamine 6 (25 gram, 112 mmoles), triethylamine (21.7 grams, 2170 mmoles) at CH
2Cl
2Mix in (300 milliliters).This solution is cooled to 0 ℃ and add boc acid anhydride (25.07 gram, 115 mmoles),, added a every 15 minutes this acid anhydride quartern.(all generating gas behind each the interpolation).This mixture was stirred 30 minutes, and then add 5 gram boc acid anhydrides, finish (GC/MS) to impel reaction.This solution is handled with 1N HCl (2 * 100 milliliters), saturated sodium bicarbonate aqueous solution (2 * 100 milliliters), through dried over sodium sulfate.Decompression is removed solvent and is come separated product by crystallization in cold hexane (about 150 milliliters).Obtain 20.6 gram white solids.The hexane volume is reduced to 75 milliliters, obtain second product (9.2 gram).
11 preparation
With Boc-bretylium 10 (26.8 grams, 94.03 mmoles) and PddfPdCl
2(816 milligrams, 0.38 mmole, 0.004 equivalent) are at anhydrous THF (300 milliliters) and K
3PO
4The aqueous solution (100 milliliters mix in 2.0M).In this red solution, add boron triethyl alkane (100 milliliters, the THF solution of 1.0M, 100 mmoles).This solution blackening also refluxes them 4 hours.GC/MS shows and reacts completely.This solution is poured into separating funnel and separated water layer.Collected organic layer and to remove solvent to volume be 100 milliliters.Add ethyl acetate/hexane (300 milliliters, 1: 1), and this solution is extracted with 1N HCl (1 * 100 milliliter), sodium bicarbonate (2 * 100 milliliters) and salt solution (1 * 100 milliliter).This solution is also passed through one deck silica gel vacuum filtration (125 milliliters of silicon-dioxide) through dried over sodium sulfate.Solvent is removed in decompression, obtains the light yellow oily 11 of 20.6 grams.
Embodiment SP-264
6-methyl-pyridine-2, the preparation of 4-dioctyl phthalate 4-({ 1-(3, the 5-difluorobenzyl)-3-[1-(3-alkynyl phenyl)-cyclopropylamino]-2-hydroxypropyl }-acid amides) 2-dipropyl acidamide
CH with 50%TFA
2Cl
2Solution-treated (1 hour, room temperature) Boc is protected amine (according to embodiment SP-262 preparation) (0.912 gram, 2 mmoles).Solvent is removed in decompression, generates a kind of oil.Add toluene and evaporation; Use the toluene stripping repeatedly.After this operation, resistates is placed high vacuum following 1 hour, make pale solid (unhindered amina, the most likely form of tfa salt).This amine is dissolved in CH
2Cl
2(10 milliliters, slurry) add acid 2 (0.528 gram; 2 mmoles), HOBt (0.297 gram: 2.2 mmoles) and EDC (0.423 restrains; 2.2 mmole).When adding EDC, slurry becomes clear solution rapidly.Add excessive NET at last
3(2 milliliters) also at room temperature stir reaction mixture and to spend the night.Second day with the solvent stripping, and uses saturated Na
2CO
3The aqueous solution (3 *), salt water washing EtOAc solution, dry and concentrated.On Biotage, undertaken just purifying by flash chromatography (with 20% hexane and 80%EtOAc wash-out).Finally purify by HPLC.Add the solution of 1.25M HCl in MeOH (1.6 milliliters), thereby tfa salt is changed into the single salt of HCl.Output 0.917 gram (76%).
Embodiment SP-265
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine
On show that compound mainly is to use the step described among the embodiment SP-264 to be prepared.
M+659.3。
Carbon NMR (CDCl
3): 11.00,11.56,11.78,15.37,20.80,21.90,28.71,35.28,44.45,47.26,49.97,51.16,53.75,69.43,77.12,102.12,112.02,112.34,126.23,126.94,127.29,128.01,128.68,129.20,129.51,133.90,134.70,137.56,139.59,142.15,145.53,160.26,161.43,164.73,166.98,170.42.
Embodiment SP-266
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine
On show that compound mainly is to use the step described among the embodiment SP-264 to be prepared.
M+655.3。
Carbon NMR (CDCl
3): 11.01,11.47,11.58,11.98,20.82,21.91,35.22,43.94,47.28,50.09,51.17,53.77,69.49,77.11,78.63,82.55,102.17,112.05,113.22,126.23,126.82,128.07,128.76,129.49,130.68,133.33,134.50,137.57,139.61,142.17,160.23,161.27,164.56,167.04,170.44.
Embodiment SP-267
N
4-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-6-methyl-N
2, N
2-dipropyl pyridine-2, the 4-diformamide
P658
On show that compound mainly is to use the step described among the embodiment SP-264 to be prepared.
M+607.3。
Carbon NMR (CDCl
3): 10.96,11.06,11.53,12.09,15.43,20.73,21.90,23.96,28.75,33.93,44.32,47.82 .49.60,50.90,53.98,68.65,77.11,101.98,112.064,112.39,117.03,122.12,127.25,129.23,129.49,134.06,142.21,145.61,153.63,158.94,161.19,161.36,164.48,164.65,165.65,169.06.
Embodiment SP-268
N
4-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-6-methyl-N
2, N
2-dipropyl pyridine-2, the 4-diformamide
On show that compound mainly is to use the step described among the embodiment SP-264 to be prepared.
M+603.3。
Carbon NMR (CDCl
3): 10.99,11.58,12.29,20.75,21.92,24.03,33.98,43.91,47.91,49.83,50.96,53.95,68.74,77.13,78.72,82.57,102.08,112.08,112.41,117.63,122.16,123.32,129.51,130.66,133.37,133.55,134.63,142.28,153.56,158.96,161.20,161.37,164.66,165.80.
Embodiment SP-269
The preparation of 1-(3, the 5-difluorobenzyl)-3-(3-ethynyl) benzylamino-2-isopropanolamine dihydrochloride
Handle [1-(3, the 5-difluorobenzyl)-3-(3-ethynyl benzylamino)-2-hydroxypropyl]-t-butyl carbamate (2.73 grams, 6.33 mmoles) with the mixture in the 4N HCl Zai diox (15.8 milliliters, 63.3 mmoles).After 5 minutes, mixture becomes homogeneous phase, produces precipitation then.Add ether (15 milliliters) to help stirring and this mixture being stirred 2 hours.Volatile matter is evaporated in a vacuum.Add diox (20 milliliters) and mixture is evaporated in a vacuum, make white solid (2.67 grams, 104%).
Embodiment SP-270
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-ethynyl benzyl) amino]-the 2-hydroxypropyl }-5-ethynyl-N
3, N
3-dipropyl isophthaloyl amine
With 5-ethynyl-N, N-dipropyl-isophthalamic acid (1.73 grams, 6.32 mmoles) is dissolved in dry DMF (20 milliliters) under nitrogen.Add 1-Qiang base Ben Bing trioazole (1.28 grams, 9.48 mmoles) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (1.70 grams, 8.85 mmoles) in regular turn.This mixture is at room temperature stirred 30 minutes until homogeneous phase, disposable then amine dihydrochloride (2.67 grams that join through rapid stirring, 6.32 mmole) and (2.78 milliliters of N-methylmorpholines, 2.56 gram, 25.3 mmole) in the slurry in DMF (25 milliliters), the mixture that makes was stirred 2 hours, use saturated sodium bicarbonate aqueous solution (200 milliliters) dilution then.This mixture is washed with saturated sodium bicarbonate aqueous solution (100 milliliters), water (2 * 100 milliliters) and salt solution (100 milliliters) with ethyl acetate (3 * 100 milliliters) extraction and with the organic extract that merges, dry (sodium sulfate), filter and evaporation in a vacuum, obtain a kind of oil (3.7 gram).Use flash column chromatography (Flash 65i cylinder with 1 liter of 100% ethyl acetate, is used 4 liters of 95: 5 ethyl acetate/methanol wash-outs then) on silica gel that purification of products is made light yellow oil (2.74 grams, 74%).LC-MS(m/e)：586(M+l)；100％(254nm)。The 4N HCl that ELN 152006 free alkalis is dissolved in ethanol (25 milliliters) and is used in the diox (2.0 milliliters) handles.The mixture that makes is evaporated in a vacuum to remove volatile matter, be dissolved in the also evaporation in a vacuum of 1: 1 ethanol/water (25 milliliters) again.The solid that makes is formed slurry in ether (50 milliliters), filter and wash, make pale solid, its vacuum-drying to constant (2 days), is produced required product (2.43 gram) with ether.
Analyze: for C
35H
37F
2N
3O
3+ HCl: calculated value: C, 67.57; H, 6.16; N, 6.75; Cl, 5.50;
Measured value: C, 67.21; H, 6.04; N, 6.55; Cl, 5.71.
Embodiment SP-271
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-5-methyl-N
3, N
3The preparation of-dipropyl isophthaloyl amine
With 5-methyl-N, N-dipropyl-isophthalamic acid (1.35 grams, 5.13 mmoles) is dissolved in dry DMF (15 milliliters) under nitrogen.Add 1. Qiang base Ben Bing trioazole (1.04 grams, 7.69 mmoles) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (1.38 grams, 7.18 mmoles) in regular turn.This mixture is at room temperature stirred 30 minutes until homogeneous phase, disposable then amine dihydrochloride (2.23 grams that join through rapid stirring, 5.13 mmole) and in the slurry of N-methylmorpholine (2.25 milliliters, 2.07 grams, 20.5 mmoles) in DMF (20 milliliters).The mixture that makes was stirred 3.5 hours, use saturated sodium bicarbonate aqueous solution (150 milliliters) dilution then.This mixture is washed with saturated sodium bicarbonate aqueous solution (100 milliliters), water (2 * 100 milliliters) and salt solution (100 milliliters) with ethyl acetate (3 * 100 milliliters) extraction and with the organic extract that merges, dry (sodium sulfate), filter and evaporation in a vacuum, obtain a kind of oil (3.0 gram).Use flash column chromatography (Flash 65i cylinder with 2.8 liters of 1: 1 ethyl acetate/hexane, 2.5 liters of 2: 1 ethyl acetate/hexane, is used 2 liter of 100% eluent ethyl acetate then) on silica gel that purification of products is made clean oil (2.34 grams, 76%).LC-MS(m/e)：602(M+1)；100％(254nm)。The 4N HCl that ELN 152227 free alkalis is dissolved in ethanol (25 milliliters) and is used in the diox (2-0 milliliter) handles.The mixture that makes is evaporated in a vacuum to remove volatile matter, be dissolved in ethanol (25 milliliters) and evaporation in a vacuum again.The solid that makes is formed slurry in ether (50 milliliters), filter and make hygroscopic solid,, make ELN 152227-3 (1.93 gram) its freeze-drying.Analyze: for C
36H
41F
2N
3O
3+ HCl+0.8H
2O: calculated value: C, 66.26; H, 6.73; N, 6.44; Cl, 5.43; Measured value: C, 67.21; H, 6.40; N, 6.42; Cl, 5.34.
Embodiment SP-272
(2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(3-Ethylbenzyl) amino] preparation of fourth-2-alcohol dihydrochloride
In 250 milliliters of round-bottomed flasks that are immersed in the cooling bath, stir under nitrogen atmosphere in room temperature that [1-(3, the 5-difluorobenzyl)-3-(3-Ethylbenzyl amino)-2-hydroxypropyl]-t-butyl carbamate (5.25 grams, the 0.012m) slurry in no Shui diox (20 milliliters).Solution in the disposable adding hydrogenchloride Zai diox (4M, 32 milliliters).This reaction mixture is homogeneous at first, becomes the heavy slurry in ca.20 minute.This mixture was stirred 70 minutes, and by TLC (the silica gel sheet, is used 95: 5 mixture wash-outs of ethyl acetate-methyl alcohol by 5 * 10 centimetres) monitoring.Add ether (100 milliliters), the filtering precipitated product, and wash with ether (2 * 50 milliliters).With air-dry 1 hour of filter cake, place 35 ℃ vacuum drying oven then and baking oven found time (5torr).Product is dried to constant-quality reaches 7 hours.Output is 5.24 grams.LC-MS (m/e): 335 (M+1); Purity: 100% (254nm).
Embodiment SP-273
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-ethynyl-N
3, N
3-dipropyl isophthaloyl amine
In a round-bottomed flask (50 milliliters) of being furnished with magnetic stirring bar, with 5-ethynyl-N, (1.64 grams 0.006m) are dissolved in dry DMF (30 milliliters) to N-dipropyl-isophthalamic acid.With the purging with nitrogen gas flask and add HOBt (1.23 gram, 0.009m, 1.5 equivalents), add EDC (1.64 grams, 0.0084m, 1.4 equivalents) then.This mixture was at room temperature stirred 45 minutes, disposablely then join amine hydrochlorate (2.45 grams are 0.006m) in the solution among dry DMF (30 milliliters) and the NMO (5.0 restrain 0.05m, 8.5 equivalents) through stirring.With the homogeneous mixture that makes under nitrogen in room temperature vigorous stirring 2 hours.In this process, all solids dissolves gradually, but mixture is still muddy.By TLC (the silica gel sheet, is used 95: 5 mixture wash-outs of ethyl acetate-methyl alcohol by 5 * 10 centimetres) monitoring reaction course.Extract with the reaction mixture dilution and with ethyl acetate (3 * 150 milliliters) with saturated sodium bicarbonate aqueous solution (250 milliliters), thus separated product.With the extraction liquid usefulness salt water washing of merging and through dried over mgso.Solution is filtered and evaporation, and the output of raw product is 4.6 grams (yellow oil).Use flash column chromatography on silica gel (Flash 65i cylinder is in dichloromethane solution and with 93: 7 mixture wash-outs of ethyl acetate-methyl alcohol) with purification of products.The cut that will contain product merges and evaporation, makes light yellow oil, 2.7 grams.LC-MS(m/e)：590(M+1)；100％(254nm)。Handle purified product with ethanolic hydrogen chloride (1.05 equivalent), filter and freeze-drying.Final hydrochloride output is 2.4 grams.LC-MS (m/e): 590 (M+1); Purity: 100% (254nm), 100% (280nm).
1H NMR(MeOH-d
4)：δ0.70(t，3H)、1.01(t，3H)、1.23(t，3H)、1.53(m，2H)、1.73(m，2H)、2.67(q，2H)、2.87(m，1H)、3.05-3.35(m，8H)、4.00(s，1H)、4.01(m，1H)、4.25(m，3H)、4.91(s)、6.77(m，1H)、6.91(d，2H)、7.29-7.38(m，4H)、7.56(d，2H)、7.79(s，1H)。
13C NMR∶(MeOH-d
4)：δ9.73、10.17、20.17、21.33、46.51-48.32、49.27、50.71、54.04、68.75、79.79、80.94、101.17(t)、111.56(d)、123.26、124.83、127.00、128.73、129.23、130.53、130.95、132.15、134.29、137.46、142.69、142.81、145.17、161.28(d)、164.40(d)、167.13、170.28。
Analyze: for C
35H
42ClF
2N
3O
3* 0.5H
2O: calculated value: C, 66.18; H, 6.82; N, 6.62; Cl, 5.58; Measured value: C, 66.07; H, 6.85; N, 6.79; Cl, 5.17.
Embodiment SP-274
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-dipropyl-5-(1,3-thiazoles-2-yl) isophthaloyl amine
In a round-bottomed flask (50 milliliters) of being furnished with magnetic stirring bar, with N, (1.99 grams 0.006m) are dissolved in dry DMF (30 milliliters) to N-dipropyl-5-thiazol-2-yl-isophthalamic acid.With the purging with nitrogen gas flask and add HOBt (1.24 gram, 0.009m, 1.5 equivalents), add EDC (1.63 grams, 0.0084m, 1.4 equivalents) then.This mixture was at room temperature stirred 45 minutes, disposablely then join amine hydrochlorate (2.45 grams are 0.006m) in the solution among dry DMF (30 milliliters) and the NMO (5.0 restrain 0.05m, 8.5 equivalents) through stirring.With the homogeneous mixture that makes under nitrogen in room temperature vigorous stirring 2 hours.In this process, all solids dissolves gradually, but mixture slight haze still.By TLC (the silica gel sheet, is used 95: 5 mixture wash-outs of ethyl acetate-methyl alcohol by 5 * 10 centimetres) monitoring reaction process.Extract with the reaction mixture dilution and with ethyl acetate (3 * 150 milliliters) with saturated sodium bicarbonate aqueous solution (250 milliliters), thus separated product.With the extraction liquid usefulness salt water washing of merging and through dried over mgso.Solution is filtered and evaporation, and the output of raw product is 4.6 grams (light yellow oil).Use flash column chromatography on silica gel (Flash 65i cylinder is in dichloromethane solution and with 9: 1 mixture wash-outs of ethyl acetate-methyl alcohol) with purification of products.The cut that will contain product merges and evaporation, makes light yellow oil, 2.75 grams.LC-MS (m/e): 649 (M+1); Purity: 100% (254nm).Handle purified product with ethanolic hydrogen chloride (1.05 equivalent), and freeze-drying (adding ethanol before filtering to improve solubleness).Final hydrochloride output is 2.6 grams.LC-MS (m/e): 649 (M+1); Purity: 100% (254nm).
1H NMR(MeOH-d
4)：δ0.74(t，3H)、1.04(t，3H)、1.20(t，3H)、1.58(m，2H)、1.77(m，2H)、2.64(q，2H)、2.92(m，1H)、3.10-3.55(m，9H)、4.04(m，1H)、4.26(m，3H)、4.90(s)、6.77(m，1H)、6.96(d，2H)、7.23-7.38(m，4H)、7.68(t，1H)、7.73(d，1H)、7.96(d，1H)、8.11(t，1H)、8.28(t，1H)。
13C NMR∶(MeOH-d
4)：δ9.76、1O.19、14.75、20.21、21.39、28.10、35.38、46.60-48.31、50.75、54.12、68.78、101.22(t)、111.53(d)、120.48、125.65、126.12、126.97、128.70、129.218、130.56、133.96、134.97、138.00、142.84、143.53、145.16、161.31(d)、164.52(d)、165.96、167.36、170.47。
Analyze: for C
36H
43ClF
2N
4O
3S * 0.5H
2O: calculated value: C, 62.28; H, 6.39; N, 8.07; Cl, 5.11; Measured value: C, 62.42; H, 6.24; N, 8.03; Cl, 5.10.
Embodiment SP-275
2-dipropyl formamyl-6-methyl-Yi Yansuan
The 2-chloro-methyl Yi Yansuan that can buy (4.07 grams, 23.72 mmoles) is dissolved in 30%MeOH/THF solution (32 milliliters).Dropwise add (trimethyl silyl) diazomethane (the 2.0M solution in hexane).Observe the foaming phenomenon, add more reagent until stopping to bubble (15 milliliters).Reaction mixture at room temperature stirred spend the night.In reaction flask, dropwise add Glacial acetic acid to remove excess amine, then with solvent evaporation.
Embodiment SP-276
Reference: Fuqiang, J.and Confalone, N.Tet.
Lett.，41，2000，3271-3273
In being furnished with the R.B flask of stirring rod, add methylated intermediate, three (dibenzlidene acetone) two palladiums (0), 1,1-two (diphenyl phosphine), zinc metallic dust and zinc cyanide.With this flask about 5 minutes with purging with nitrogen gas.Add N,N-dimethylacetamide by syringe.In being arranged on 120 ℃ oil bath with condenser under nitrogen atmosphere with reaction mixture refluxed.Vigorous stirring.After 4 hours, make reaction mixture at ethyl acetate (50 milliliters) and 2N NH
4Phase-splitting between the OH (50 milliliters).Repeat to use 2N NH
4OH (2 * 50 milliliters) uses salt solution (50 milliliters) washing then.Collect organic phase and through Na
2SO
4Drying is filtered and evaporation.With eluting solvent (80: 20; Hexane/EtOac) carry out column chromatography to purify.
Embodiment SP-277
Nitrile intermediate (0.206 gram, 1.170 mmoles) is dissolved in methyl alcohol (5 milliliters).Add sodium hydroxide (0.267 gram, 6.675 mmoles) and at room temperature continue stirring.Add entry (5 milliliters) after 90 minutes and continue again and stirred 90 minutes.Phase-splitting between chloroform and the 2N HCl (aqueous solution) again.Add NaCl (s) so that it is saturated at aqueous phase.Continue to use Virahol: chloroform (1: 3) extraction.Collect organic phase, through NaSO
4Drying is filtered and evaporation.
Embodiment SP-278
In hydrolysis intermediate (0.136,0.697 mmole), add anhydrous methylene chloride, add the 4-methylmorpholine then.Place ice bath to cool off in flask, add HBTU and dipropyl amine then.Under nitrogen atmosphere, make this mixture be warmed to ambient temperature overnight.Make reaction mixture phase-splitting between ethyl acetate (25 milliliters) and water (25 milliliters).Water is used saturated NaHCO then
3(2 * 25 milliliters) washing.Collect organic phase, through NaSO
4Drying is filtered and evaporation.
Embodiment SP-279
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(4-methyl isophthalic acid, 3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine
Step 1: carbonyl 3-(aminocarboxyl)-5-[(dipropyl amino that will be through stirring)] the solution backflow 18 hours of methyl benzoate (200 milligrams, 0.65 mmole), monochloroacetone (10 milliliters, 93 mmoles) and salt of wormwood (90 milligrams, 0.65 mmole).Reaction mixture is cooled to room temperature, with the ethyl acetate dilution, with 2N sodium hydroxide (2 * 50 milliliters) and saturated sodium-chloride washing, dry (sal epsom), and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 1: 1 ethyl acetate/hexane), make 3-[(dipropyl amino) carbonyl]-5-(4-methyl isophthalic acid, 3-oxazole-2-yl) methyl benzoate (119 milligrams):
1H NMR (300MHz, CDCl
3) δ 8.70 (d, J=1Hz, 1H), 8.20 (d, J=1Hz, 1H), 8.09 (d, J=1Hz, 1H), 7.48 (s, 1H), 3.96 (s, 3H), 3.46 (d, J=7Hz, 2H), 3.16 (t, J=7Hz, 2H), 2.26 (s, 3H), 1.71 (d, J=7Hz, 2H), 1.54 (d, J=7Hz, 2H), 1.00 (t, J=7Hz, 3H), 0.74 (t, J=7Hz, 3H); ESI MS m/z 345[M+H]
+
Step 2: with 3-[(dipropyl amino) carbonyl]-5-(4-methyl isophthalic acid, 3-oxazole-2-yl) methyl benzoate is (118 milligrams, 0.34 mmole) solution at methyl alcohol (1 milliliter) and potassium hydroxide (1 milliliter, the 1.0M aqueous solution, 1 mmole) at room temperature stirred 45 minutes.Solvent is removed in decompression, resistates is water-soluble, use ethyl acetate extraction, with 1N hydrochloric acid water layer is acidified to pH 4, extract with chloroform (3 * 100 milliliters), and, make 3-[(dipropyl amino with the organism concentrating under reduced pressure that merges) carbonyl]-5-(4-methyl isophthalic acid, 3-oxazole-2-yl) phenylformic acid (110 milligrams):
1H NMR (300MHz, CD
3OD) δ 8.66 (d, J=1Hz, 1H), 8.17 (d, J=1Hz, 1H), 8.07 (d, J=1Hz, 1H), 7.75 (d, J=1Hz, 1H), 3.51 (t, J=7Hz, 2H), 3.25 (t, J=7Hz, 2H), 2.23 (s, 3H), 1.74 (d, J=7Hz, 2H), 1.60 (d, J=7Hz, 2H), 1.01 (t, J=7Hz, 3H), 0.76 (t, J=7Hz, 3H).
Step 3: with 3-[(dipropyl amino) carbonyl]-5-(4-methyl isophthalic acid, 3-oxazole-2-yl) phenylformic acid is (77.5 milligrams, 0.23 (2R mmole),, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] (96 milligrams of fourth-2-alcohol dihydrochlorides, 0.23 mmole), the solution of HOBt (32 milligrams, the 0-23 mmole) and N-methylmorpholine (83 microlitres, 0.75 mmole) stirred 15 minutes in dimethyl formamide (2 milliliters).Add EDC (73 milligrams, 0.42 mmole) and reaction mixture stirred and spend the night.With the reaction mixture dilute with water, and extract with ethyl acetate (3 * 25 milliliters).Organic layer is washed dry (sodium sulfate), and concentrating under reduced pressure with 1N hydrochloric acid (25 milliliters), saturated sodium bicarbonate (25 milliliters), saturated sodium-chloride.Purify by flash column chromatography (silicon-dioxide, 1: 9 methyl alcohol/chloroform), make N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(4-methyl isophthalic acid, 3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine (40 milligrams):
1H NMR (300MHz, CDCl
3) δ 8.20 (br s, 1H ,-NH), 8.17 (s, 1H), 8.05 (s, 1H), 7.52 (s, 1H), 7.38 (s, 1H), 7.24-7.08 (m, 5H), 7.02 (d, J=8Hz, 2H), 6.61 (t, J=8Hz, 1H), 4.27 (br s, 1H), 3.93 (d, J=4Hz, 1H), 3.85 (s, 2H), 3.54 (br s, 2H), 3.43 (br s, 2H), 2.84 (d, J=5Hz, 2H), 2.63 (q, J=8Hz, 2H), 2.18 (s, 3H), 1.74 (t, J=5Hz, 2H), 1.41 (d, J=7Hz, 2H), 1.22 (t, J=8Hz, 3H), 1.03 (t, J=7Hz, 3H), 0.64 (t, J=7Hz, 3H); ESI MS m/z 647[M+H]
+
Embodiment SP-280
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-dipropyl-5-(1,3-thiazoles-2-yl) isophthaloyl amine
Step 1: in THF (25 milliliters) solution of-78 ℃ thiazoles (1.2 gram), the adding n-Butyl Lithium (1.6M, in hexane, 10 milliliters).This mixture was stirred 30 minutes, in ice/water-bath, be warmed to 0 ℃ then.The adding zinc chloride (1M, in ether, 40 milliliters), and, add 3-[(dipropyl amino this moment with mixture stirring 1 hour) carbonyl]-mixture of 5-iodo-benzoic acid methyl esters (5.1 gram) in THF (20 milliliters), add Pd (PPh then
3)
4(palladium four triphenyl phosphines) (0.68 gram).Then mixture was heated 2 hours at 80 ℃, this moment is with its cooling and be divided into ethyl acetate layer and water layer.With salt water washing organic layer, dry (sal epsom) also concentrates.On silica gel, use ethyl acetate/heptane (50/50) to carry out chromatographic separation resistates, make 4.5 gram 3-[(dipropyl amino) carbonyl]-5-(1,3-thiazoles-2-yl) methyl benzoate.
Step 2: with 3-[(dipropyl amino) carbonyl]-5-(1,3-thiazoles-2-yl) methyl benzoate (4.5 gram) is dissolved in THF (20 milliliters), methyl alcohol (20 milliliters) and water (20 milliliters).Add a hydronium(ion) oxidation lithium (1.1 gram) and mixture was at room temperature stirred 1.5 hours decompression removal this moment organic solvent.Add some ethyl acetate and water and the pH value is adjusted to about 0 with the HCl aqueous solution.With this mixture of ethyl acetate extraction and with organic phase salt water washing, dry (sal epsom), and concentrate, make 3.8 gram 3-[(dipropyl amino) carbonyl]-5-(1,3-thiazoles-2-yl) phenylformic acid.
Step 3: with 3-[(dipropyl amino) carbonyl]-5-(1, the 3-thiazol-2-yl) phenylformic acid is (156 milligrams, 0.47 (2R mmole),, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] (191 milligrams of fourth-2-alcohol dihydrochlorides, 0.47 mmole), the solution of HOBt (64 milligrams, 0.47 mmole) and N-methylmorpholine (200 microlitres, 1.5 mmoles) stirred 15 minutes in dimethyl formamide (2 milliliters).Add EDC (145 milligrams, 0.84 mmole) and reaction mixture stirred and spend the night.With the reaction mixture dilute with water, and extract with ethyl acetate (3 * 25 milliliters).Organic layer is washed dry (sodium sulfate), and concentrating under reduced pressure with 1N hydrochloric acid (25 milliliters), saturated sodium bicarbonate (25 milliliters), saturated sodium-chloride.Purify by flash column chromatography (silicon-dioxide, 1: 9 methyl alcohol/chloroform), make N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-dipropyl-5-(1,3-thiazoles-2-yl) isophthaloyl amine (33 milligrams):
1H NMR (500MHz, CDCl
3) δ 8.40 (br s, 1H ,-NH), 8.15 (br s, 1H), 7.94 (br s, 1H), 7.80 (d, J=3Hz, 1H), 7.51 (br s, 1H), 7.34 (d, J=3Hz, 1H), 7.27-7.24 (m, 1H), 7.21-7.18 (m, 2H), 7.11-7.10 (m, 1H), 7.00 (br s, 1H), 6.62-6.58 (m, 1H), 4.23 (d, J=5Hz, 1H), 3.91-3.85 (m, 3H), 3.57 (br s, 2H), 3.31 (br s, 2H), 3.05 (d, J=5Hz, 4H), 2.83 (d, J=6Hz, 2H), 2.64 (q, J=8Hz, 2H), 1.75 (br s, 2H), 1.44 (t, J=7Hz, 2H), 1.22 (t, J=8Hz, 3H), 1.04 (t, J=7Hz, 3H), 0.65 (t, J=7Hz, 3H); ESI MS m/z 649[M+H]
+
Embodiment SP-281
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine
Step 1: in the solution of 3-amino-5-(methoxycarbonyl) phenylformic acid ice-cold, (5.19 grams, 26.59 mmoles) in 2N hydrochloric acid (156 milliliters), add water (10.8 milliliters) solution of Sodium Nitrite (1.84 grams, 26.67 mmoles) through stirring.Then this mixture is dropwise added in water (26.2 milliliters) solution ice-cold, the potassiumiodide through stirring (8.84 grams, 53.25 mmoles).Stir after 35 hours, with the reaction mixture dilute with water and use ethyl acetate extraction.Organic layer is washed with 5% sodium thiosulfate solution and saturated sodium-chloride, dry (sodium sulfate) and concentrating under reduced pressure, purify by flash column chromatography (silicon-dioxide, 50: 50: 2 hexane/ethyl acetate/acetate), make 3-iodo-5-(methoxycarbonyl) phenylformic acid (4.48 gram):
1H NMR (500MHz, DMSO-d
6) δ 13.49 (and br s, 1H), 8.45-8.38 (m, 3H), 3.83 (s, 3H): ESI-MS (m/z): 305[M+H]
+
Step 2: at 3-iodo-5-(methoxycarbonyl) phenylformic acid (65.8 grams, 0.215 triethylamine (52.2 grams mmole),, 0.516 mmole) and dipropyl amine (23.9 the gram, 0.237 mmole) in the mixture in methylene dichloride (950 milliliters), add iodate 2-chloro-1-picoline (65.9 grams, 0.258 mmole).Reaction mixture was at room temperature stirred 15 hours, then concentrating under reduced pressure.Purify by silica gel plug (3: 1 hexane/ethyl acetate), obtain 3-[(dipropyl amino) carbonyl]-5-iodo-benzoic acid methyl esters (66.8 gram):
1H NMR (300MHz, CDCl
3) δ 8.39 (and s, 1H), 7.98 (s, 1H), 7.88 (s, 1H), 3.93 (s, 3H), 3.45 (m, 2H), 3.14 (m, 2H), 1.69 (m, 2H), 1.54 (m, 2H), 0.98 (m, 3H), 0.77 (m, 3H).
Step 3: will be through the 2-three second first stannane Ji oxazole (Chem.Mater.1994 of stirring, 6,1023) (1.5 grams, 5.5 mmole) and 3-[(dipropyl amino) carbonyl]-5-iodo-benzoic acid methyl esters (1.8 gram, 4.6 mmoles) in dimethyl formamide (12 milliliters) the solution decompression degassing 15 minutes and use argon purge.Add palladium (O) four (triphenyl phosphines) (158 milligrams, 0.14 mmole) and, use argon purge then the reaction mixture decompression degassing 15 minutes.With reaction mixture refluxed heating 2 days, be cooled to room temperature, with the ethyl acetate dilution, water (3 * 50 milliliters) washing, dry (sodium sulfate), and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 1: 1 ethyl acetate/hexane), obtain 3-[(dipropyl amino) carbonyl]-5-(1,3-oxazole-2-yl) methyl benzoate (423 milligrams):
1HNMR (300MHz, CDCl
3) δ 8.73 (and s, 1H), 8.23 (s, 1H), 8.11 (s, 1H), 7.76 (s, 1H), 7.28 (s, 1H), 3.97 (s, 3H), 3.49 (br s, 2H), 3.18 (br s, 2H), 1.72 (d, J=7Hz, 2H), 1.55 (d, J=7Hz, 2H), 1.00 (t, J=7Hz, 3H), 0.75 (t, J=7Hz, 3H).
Step 4: with 3-[(dipropyl amino) carbonyl]-5-(1,3-oxazole-2-yl) methyl benzoate (315 milligrams, 0.95 mmole) at room temperature stirred 30 minutes at the solution of methyl alcohol (3 milliliters) and potassium hydroxide (3 milliliters, the 1.0M aqueous solution, 3 mmoles).Solvent is removed in decompression, and resistates is water-soluble, and uses ethyl acetate extraction, with 1M hydrochloric acid water layer is acidified to pH 3, with chloroform (3 * 100 milliliters) extraction, and with the organic layer concentrating under reduced pressure that merges, make 3-[(dipropyl amino) carbonyl]-5-(1,3-oxazole-2-yl) phenylformic acid (265 milligrams):
1H NMR (300MHz, CD
3OD) δ 8.71 (s, 1H), 8.08 (s, 2H), 8.05 (s, 1H), 7.34 (s, 1H), 3.52 (t, J=8Hz, 2H), 3.26 (t, J=8Hz, 2H), 1.75 (q, J=8Hz, 2H), 1.59 (q, J=8Hz, 2H), 1.02 (t, J=8Hz, 3H), 0.74 (t, J=8Hz, 3H).Step 5: with 3-[(dipropyl amino) carbonyl]-5-(1,3-oxazole-2-yl) phenylformic acid is (133 milligrams, 0.42 (2R mmole),, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] (171 milligrams of fourth-2-alcohol dihydrochlorides, 0.42 mmole), the solution of HOBt (57 milligrams, 0.42 mmole) and N-methylmorpholine (148 microlitres, 1.3 mmoles) stirred 15 minutes in dimethyl formamide (2 milliliters).Add EDC (130 milligrams, 0.75 mmole) and reaction mixture stirred and spend the night.With the reaction mixture dilute with water, and extract with ethyl acetate (3 * 25 milliliters).Organic layer is washed dry (sodium sulfate), and concentrating under reduced pressure with 1M hydrochloric acid (25 milliliters), saturated sodium bicarbonate (25 milliliters), saturated sodium-chloride.Purify by flash column chromatography (silicon-dioxide, 1: 9 methyl alcohol/chloroform), make N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine (62 milligrams): mp 65-67 ℃;
1HNMR (500MHz, CDCl
3) δ 8.21 (br s, 1H), 8.15 (s, 2H), 7.69 (s, 2H), 7.60 (s, 1H), 7.25 (t, J=8Hz, 1H), 7.19-7.17 (m, 3H), 7.10 (d, J=8Hz, 1H), 6.96 (d, J=8Hz, 2H), 6.60 (t, J=8Hz, 1H), 4.27 (d, J=8Hz, 1H), 3.88-3.80 (m, 3H), 3.53 (br s, 2H), 3.44 (br s, 2H), 3.09-3.01 (m, 4H), 2.85-2.82 (m, 2H), 2.62 (t, J=8Hz, 2H), 1.74 (br s, 2H), 1.45 (br s, 2H), 1.21 (t, J=8Hz, 3H), 1.03 (t, J=7Hz, 3H), 0.66 (t, J=7Hz, 3H); APCI MS m/z 633[M+H]
+
Embodiment SP-281
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-methyl-5-(1,3-oxazole-2-yl)-N
3-propyl group isophthaloyl amine
3-{[methyl (propyl group) amino in DMF (5 milliliters)] carbonyl }-5-(1,3-oxazole-2-yl) phenylformic acid is (350 milligrams, 1.2 mmole), add diisopropylethylamine (835 microlitres, 4.8 mmoles), HATU (554 milligrams, 1.5 mmoles), add (the 2R that makes according to embodiment SP-272 then, 3S)-and 3-amino-4-(3, the 5-difluorophenyl)-1-[(3-Ethylbenzyl) amino] fourth-2-alcohol dihydrochloride (488 milligrams, 1.2 mmoles).Reactant was at room temperature stirred 16 hours.With reactant phase-splitting between chloroform and water.Organic layer is washed with 1N hydrochloric acid, saturated sodium bicarbonate and saturated sodium-chloride, and dry (sodium sulfate) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 9% methyl alcohol/chloroform), obtain title compound.ESI MS m/z 605.3[M+H]
+。
Embodiment SP-282
Step 1
3-{[butyl (methyl) amino] carbonyl }-5-iodo-benzoic acid methyl esters
3-iodo-5-(methoxycarbonyl) phenylformic acid (1 gram, 3.3 mmoles) is dissolved in DMF (10 milliliters), and adds diisopropylethylamine (1.7 milliliters, 9.8 mmoles), HATU (1.5 grams, 3.9 mmoles) and N-methylbutylamine (581 microlitres, 4.9 mmoles).Reactant was at room temperature stirred 2 hours.Reactant is divided into ethyl acetate layer and water layer.Organic layer is washed with saturated sodium bicarbonate and saturated sodium-chloride, and dry (sodium sulfate) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 40% ethyl acetate/hexane), make title compound.ESI MS m/z 376.1[M+H]
+。
Step 2
3-{[butyl (methyl) amino] carbonyl }-5-(1,3-oxazole-2-yl) methyl benzoate
-70 ℃ through stirring in the solution of De oxazole (167 milligrams, 2.4 mmoles) in tetrahydrofuran (THF) (4 milliliters), add n-Butyl Lithium (1.6M, in hexane, 1.7 milliliters, 2.7 mmoles).After 30 minutes, add zinc chloride (1M, in ether, 7.3 milliliters, 7.3 mmoles), and reaction mixture is warmed to 0 ℃ reaches 1 hour.In this mixture, add 3-{[butyl (methyl) amino] carbonyl }-anhydrous tetrahydro furan (3 milliliters) solution of 5-iodo-benzoic acid methyl esters (864 milligrams, 2.3 mmoles), add palladium (0) four (triphenyl phosphine) (112 milligrams, 0.10 mmole) then.With reaction mixture refluxed heating 1.5 hours.With the reaction mixture cooling, with the ethyl acetate dilution, water and saturated sodium-chloride washing, dry (sodium sulfate) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 60% ethyl acetate/hexane), make title compound.ESI MS m/z 317.1[M+H]
+。
Step 3
3-{[butyl (methyl) amino] carbonyl }-5-(1,3-oxazole-2-yl) phenylformic acid
At 3-{[butyl (methyl) amino] carbonyl }-5-(1,3-oxazole-2-yl) methyl benzoate is (660 milligrams, 2.1 mmole) tetrahydrofuran (THF)/methanol (1: 1: 1,9 milliliters) in mixture in, add (175 milligrams of hydronium(ion) oxidation lithiums, 4.2 mmole), and with reactant at room temperature stirred 16 hours.This solution is diluted with chloroform and water and saturated sodium-chloride washing, and dry (sodium sulfate) filters also concentrating under reduced pressure, makes title compound.ESI MS m/z 301.1[M-H]
+。
Step 4
N
1-butyl-N
3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
1-methyl-5-(1,3-oxazole-2-yl) isophthaloyl amine
With 3-{[butyl (methyl) amino] carbonyl }-5-(1,3-oxazole-2-yl) phenylformic acid is (237 milligrams, 0.78 mmole) be dissolved in DMF (5 milliliters), and add diisopropylethylamine (546 microlitres, 3.1 mmoles), HATU (358 milligrams, 0.94 mmole), with (the 2R that makes according to the method among the embodiment SP-272,3S)-and 3-amino-4-(3, the 5-difluorophenyl)-1-[(3-Ethylbenzyl) amino] fourth-2-alcohol dihydrochloride (319 milligrams, 0.78 mmole).Reactant was at room temperature stirred 5 hours.Reactant is diluted with chloroform, water, 1N hydrochloric acid (aqueous solution), saturated sodium bicarbonate and saturated sodium-chloride washing, dry (sodium sulfate) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 9% ethanol/methylene), obtain title compound.ESI MS m/z 619.3[M+H]
+。
Embodiment SP-283
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-ethyl-5-(1,3-oxazole-2-yl)-N
3-propyl group isophthaloyl amine
Step 1
3-{[ethyl (propyl group) amino] carbonyl }-5-iodo-benzoic acid methyl esters
3-iodo-5-(methoxycarbonyl) phenylformic acid (1 gram, 3.3 mmoles) is dissolved in DMF (10 milliliters), and adds diisopropylethylamine (1.7 milliliters, 9.8 mmoles), HATU (1.5 grams, 3.9 mmoles) and N-ethyl third amino (572 microlitres, 4.9 mmoles).Reactant was at room temperature stirred 16 hours.Reactant is divided into ethyl acetate layer and water layer.Organic layer is washed with saturated sodium bicarbonate and saturated sodium-chloride, and dry (sodium sulfate) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 40% ethyl acetate/hexane), make title compound.ESI MS m/z 376.1[M+H]
+。
Step 2
3-{[ethyl (propyl group) amino] carbonyl }-5-(1,3-oxazole-2-yl) methyl benzoate
-70 ℃ through stirring in the solution of De oxazole (106 milligrams, 1.5 mmoles) in tetrahydrofuran (THF) (4 milliliters), add n-Butyl Lithium (1.6M, in hexane, 1.0 milliliters, 1.7 mmoles).After 30 minutes, add zinc chloride (1M, in ether, 4.6 milliliters, 4-6 mmole), and reaction mixture is warmed to 0 ℃ reaches 1 hour.In this mixture, add 3-{[ethyl (propyl group) amino] carbonyl }-anhydrous tetrahydro furan (1.8 milliliters) solution of 5-iodo-benzoic acid methyl esters (535 milligrams, 1.45 mmoles), add palladium (0) four (triphenyl phosphine) (120 milligrams, 0.10 mmole) then.With reaction mixture refluxed heating 2 hours.With the reaction mixture cooling, with the ethyl acetate dilution, water and saturated sodium-chloride washing, dry (sodium sulfate) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 60% ethyl acetate/hexane), make title compound.ESI MS m/z 317.1[M+H]
+。
Step 3
3-{[ethyl (propyl group) amino] carbonyl }-5-(1,3-oxazole-2-yl) phenylformic acid
At 3-{[ethyl (propyl group) amino] carbonyl }-5-(1,3-oxazole-2-yl) methyl benzoate is (375 milligrams, 1.2 mmole) tetrahydrofuran (THF)/methanol (1: 1: 1,9 milliliters) in mixture in, add (100 milligrams of hydronium(ion) oxidation lithiums, 2.4 mmole), and with reactant at room temperature stirred 16 hours.This solution is diluted with chloroform and water and saturated sodium-chloride washing, and dry (sodium sulfate) filters also concentrating under reduced pressure, makes title compound.ESI MS m/z 301.1[M-H]
-。
Step 4
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-ethyl-5-(1,3-oxazole-2-yl)-N
3-propyl group isophthaloyl amine
With 3-{[ethyl (propyl group) amino] carbonyl }-5-(1,3-oxazole-2-yl) phenylformic acid is (290 milligrams, 0.96 mmole) be dissolved in DMF (5 milliliters), and add diisopropylethylamine (668 microlitres, 3.8 mmoles), HATU (438 milligrams, 1.15 mmoles), with (the 2R that makes according to the method among the embodiment SP-272,3S)-and 3-amino-4-(3, the 5-difluorophenyl)-1-[(3-Ethylbenzyl) amino] fourth-2-alcohol dihydrochloride (319 milligrams, 0.96 mmole).Reactant was at room temperature stirred 5 hours.Reactant is diluted with chloroform, water, 1N hydrochloric acid (aqueous solution), saturated sodium bicarbonate and saturated sodium-chloride washing, dry (sodium sulfate) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 9% ethanol/methylene), obtain title compound.ESI MS m/z 619.3[M+H]
+。
Embodiment SP-284
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-N
3, N
3-dipropyl-5-(1,3-thiazoles-2-yl) isophthaloyl amine
Step 1
3-[(dipropyl amino) carbonyl]-5-(1,3-thiazoles-2-yl) methyl benzoate
In 0.5M thiazole zinc bromide (45 milliliters), add 3-[(dipropyl amino) carbonyl]-mixture of 5-iodo-benzoic acid methyl esters (8.6 grams, 21.4 mmoles) in THF (130 milliliters), add palladium (O) four (triphenyl phosphine) (2 grams, 1.7 mmoles) then.With reaction mixture refluxed heating 16 hours, be cooled to room temperature, filter then.With this solution with water, saturated sodium bicarbonate and saturated sodium-chloride washing, dry (sal epsom) filters, and concentrating under reduced pressure.Purify by flash column chromatography (35% ethyl acetate/hexane), obtain title compound.ESI MS m/z 347.1[M+H]
+。
Step 2
3-[(dipropyl amino) carbonyl]-5-(1,3-thiazoles-2-yl) phenylformic acid
With 3-[(dipropyl amino) carbonyl]-5-(1, the 3-thiazol-2-yl) methyl benzoate (4.4 grams, 12.8 mmoles) is dissolved in 1: 1: 1 tetrahydrofuran (THF)/methanol (60 milliliters), and adds a hydronium(ion) oxidation lithium (1.1 grams, 25.6 mmole), and with reactant stirred 15 minutes.This solution decompression is concentrated and dilute with chloroform.With this solution with water and saturated sodium bicarbonate washing, dry (sal epsom) filters, and concentrating under reduced pressure, obtains title compound.ESIMS m/z 333.1[M+H]
+。
Step 3
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-N
3, N
3-dipropyl-5-(1,3-thiazoles-2-yl) isophthaloyl amine
With 3-[(dipropyl amino) carbonyl]-5-(1, the 3-thiazol-2-yl) phenylformic acid is dissolved in DMF (10 milliliters), and adding diisopropylethylamine (364 microlitres, 2.1 mmole), HATU is (237 milligrams, 0.62 mmole) and according to the method among the embodiment SP-311 make (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and 1-{[3-(trifluoromethyl) benzyl] amino } fourth-2-alcohol dihydrochloride (250 milligrams, 0.52 mmole).Reactant was at room temperature stirred 4 hours.Reaction mixture is diluted with chloroform, water, saturated sodium bicarbonate and saturated sodium-chloride washing, dry (sodium sulfate) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 8% ethanol/methylene), obtain title compound as free alkali.This resistates is dissolved in ether (3 milliliters) and adds ether (2 milliliters) solution of 1N hydrochloric acid.With this mixture concentrating under reduced pressure, make title compound.ESI MS m/z689.3[M+H]
+。
Embodiment SP-285
Step 1
3-{[butyl (methyl) amino] carbonyl }-5-(1,3-thiazoles-2-yl) methyl benzoate
In 0.5M thiazole zinc bromide (4.5 milliliters), add 3-{[butyl (methyl) amino] carbonyl }-(700 milligrams of 5-iodo-benzoic acid methyl esters, 1.9 the mixture in THF (5 milliliters) mmole), add palladium (O) four (triphenyl phosphine) (175 milligrams, 0.15 mmole) then.With reaction mixture refluxed heating 16 hours, be cooled to room temperature, filter then.With this solution with water, saturated sodium bicarbonate and saturated sodium-chloride washing, dry (sal epsom) filters, and concentrating under reduced pressure.Purify by flash column chromatography (35% ethyl acetate/hexane), obtain title compound.ESI MS m/z 333.1[M+H]
+。
Step 2
3-{[butyl (methyl) amino] carbonyl }-5-(1,3-thiazoles-2-yl) phenylformic acid
With 3-{[butyl (methyl) amino] carbonyl }-5-(1, the 3-thiazol-2-yl) methyl benzoate (410 milligrams, 1.23 mmoles) is dissolved in 1: 1: 1 tetrahydrofuran (THF)/methanol (9 milliliters), and adds (103 milligrams of hydronium(ion) oxidation lithiums, 2.5 mmole), and with reactant stirred 16 hours.This solution decompression is concentrated and dilute with ethyl acetate.With this solution with water and saturated sodium bicarbonate washing, dry (sal epsom) filters, and concentrating under reduced pressure, obtains title compound.ESI MS m/z 319.1[M+H]
+。
Step 3
N
1-butyl-N
3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
1-methyl-5-(1,3-thiazoles-2-yl) isophthaloyl amine
With 3-{[butyl (methyl) amino] carbonyl }-5-(1, the 3-thiazol-2-yl) phenylformic acid is (125 milligrams, 0.39 mmole) be dissolved in DMF (3 milliliters), and add diisopropylethylamine (271 microlitres, 1.6 mmoles), HATU (178 milligrams, 0.47 mmole), (2R, 3S)-and 3-amino-4-(3, the 5-difluorophenyl)-1-{[3-(trifluoromethyl) benzyl] amino } fourth-2-alcohol dihydrochloride (176 milligrams, 0.43 mmole).Reactant was at room temperature stirred 4 hours.Reaction mixture is diluted with chloroform, water, saturated sodium bicarbonate and saturated sodium-chloride washing, dry (sodium sulfate) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 8% ethanol/methylene), obtain title compound as free alkali.This resistates is dissolved in ether (3 milliliters) and adds ether (2 milliliters) solution of 1N hydrochloric acid.With this mixture concentrating under reduced pressure, make title compound.ESI MS m/z 635.3[M+H]
+。
Embodiment SP-286
Step 1
3-{[methyl (propyl group) amino] carbonyl }-5-(1,3-thiazoles-2-yl) methyl benzoate
In 0.5M thiazole zinc bromide (4.1 milliliters), add 3-iodo-5-{[methyl (propyl group) amino] carbonyl } (616 milligrams of methyl benzoate, 1.7 the mixture in THF (5 milliliters) mmole), add palladium (0) four (triphenyl phosphine) (158 milligrams, 0.14 mmole) then.With reaction mixture refluxed heating 16 hours, be cooled to room temperature, filter then.With this solution with water, saturated sodium bicarbonate and saturated sodium-chloride washing, dry (sal epsom) filters, and concentrating under reduced pressure.Purify by flash column chromatography (35% ethyl acetate/hexane), obtain title compound.ESI MS m/z 319.1[M+H]
+。
Step 2
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-methyl-5-(1,3-thiazoles-2-yl)-N
3-propyl group isophthaloyl amine
With 3-{[methyl (propyl group) amino] carbonyl }-5-(1, the 3-thiazol-2-yl) methyl benzoate (390 milligrams, 1.22 mmoles) is dissolved in 1: 1: 1 tetrahydrofuran (THF)/methanol (9 milliliters), and adds a hydronium(ion) oxidation lithium (103 grams, 2.4 mmole), and with reactant stirred 2 hours.This solution decompression is concentrated.Resistates is dissolved in DMF (5 milliliters), and adding diisopropylethylamine (355 microlitres, 2.0 mmole), HATU is (230 milligrams, 0.61 mmole), with (the 2R that makes according to the method among the embodiment SP-272,3S)-and 3-amino-4-(3, the 5-difluorophenyl)-1-[(3-Ethylbenzyl) amino] fourth-2-alcohol dihydrochloride (206 milligrams, 0.51 mmole).Reactant was at room temperature stirred 16 hours.Reaction mixture is diluted with ethyl acetate, water, saturated sodium bicarbonate and saturated sodium-chloride washing, dry (sodium sulfate) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 9% ethanol/methylene), obtain title compound.ESI MS m/z 621.3[M+H]
+。
Embodiment SP-287
(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-dipropyl-5-pyridin-4-yl isophthaloyl amine dihydrochloride
Step 1: be dissolved in 1 through what stir, boric acid ester 3-[(dipropyl amino in the 4-diox (9.3 milliliters)) carbonyl]-5-(3,3,4,4-tetramethyl-borolan-1-yl) in the methyl benzoate solution, adds (2 milliliters in yellow soda ash, the 2M aqueous solution, 4 mmoles), 4-bromopyridine dihydrochloride (250 milligrams, 1.3 mmoles), and with the reaction mixture degassing 15 minutes.With reaction mixture argon gas purge, being heated to refluxes spends the night.Reaction mixture is cooled to room temperature, dilute with water, with ethyl acetate (3 * 50 milliliters) extraction, dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 1: 1 ethyl acetate/hexane), obtain 3-[(dipropyl amino) carbonyl]-5-pyridin-4-yl methyl benzoate (240 milligrams):
1HNMR (300MHz, CDCl
3) δ 8.46 (d, J=7Hz, 2H), 8.10 (t, J=3Hz, 1H), 8.04 (t, J=3Hz, 1H), 7.97 (t, J=3Hz, 1H), 7.48 (d, J=6Hz, 2H), 3.45 (m, 2H), 3.16 (m, 2H), 2.09 (s, 3H), 1.69 (m, 2H), 1.54 (m.2H), 094 (m, 3H), 074 (m, 3H).
Step 2: carbonyl 3-[(dipropyl amino that will be through stirring)]-(240 milligrams of 5-pyridin-4-yl phenylformic acid 1-methyl esters, 0.7 mmole) in the solution in methyl alcohol (1.5 milliliters), tetrahydrofuran (THF) (0.7 milliliter) and water (0.7 milliliter), add lithium hydroxide (58 milligrams, 1.4 mmoles).Reaction mixture was stirred 4 hours, and concentrating under reduced pressure.Resistates is water-soluble, and extract with ethyl acetate (3 * 75 milliliters).With 1N hydrochloric acid water layer is acidified to pH5 and uses chloroform (4 * 50 milliliters) extraction.With the organic extract drying (sal epsom) that merges, filter, and concentrating under reduced pressure, make pyridine (160 milligrams):
1H NMR (300MHz, CDCl
3) δ 8.79 (and d, J=5Hz, 2H), 8.45 (s, 1H), 8.19 (s, 1H), 7.89 (s, 1H), 7.69 (d, J=6Hz, 2H), 3.50 (d, J=7Hz, 2H), 1.74 (d, J=7Hz, 2H), 1.02 (m, 3H), 0.78 (m, 3H).
Step 3: (160 milligrams of the pyridines that will make through the step 3 of stirring, 0.49 mmole) in the solution in methylene dichloride (1.96 milliliters), add (190 milligrams of DIPEA, 1.47 mmole), HATU is (278 milligrams, 0.73 mmole) and (99 milligrams of HOBt, 0.73 mmole), add amine 2 (200 milligrams, 0.49 mmole) then.Reaction mixture at room temperature stirred spend the night.Make reaction mixture phase-splitting between methylene dichloride and water.Organic layer is washed with saturated sodium bicarbonate, saturated sodium-chloride, and dry (sal epsom) filters and concentrating under reduced pressure.The oil that makes is dissolved in the minimum methyl alcohol, and makes its precipitation with hydrochloric acid (10 milliliters, the 1M solution in ether, 10 mmoles).Filtering precipitate, with the ether washing, and dry under vacuum, make title compound (100 milligrams): mp 166-169 ℃; APCI MS m/z 643[M+H]
+
Embodiment SP-288
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-[(methylsulfonyl) methyl] piperidines-1-methane amide
Step 1: at sour 1-(tert-butoxycarbonyl) piperidines-4-formic acid (1.0 grams ice-cold, through stirring, 4.4 mmole) in the solution in tetrahydrofuran (THF) (11 milliliters), add borine-methyl-sulfide complex compound (3.4 milliliters, the solution of 2.0M in tetrahydrofuran (THF), 6.8 mmoles).After 2 hours, make the reaction mixture stopped reaction with methyl alcohol, and concentrating under reduced pressure, make a kind of alcohol (939 milligrams):
1H NMR (300MHz, CDCl
3) δ 4.11 (and br s, 2H), 3.50 (t, J=6Hz, 2H), 2.68 (d, J=12Hz, 2H), 1.74-1.65 (m, 3H), 1.45 (s, 9H), 1.31 (t, J=7Hz, 1H), 1.14 (dd, J=12,4Hz, 2H).
Step 2: in the alcohol (450 milligrams, 2.1 mmoles) and the ice-cold solution of triethylamine (0.32 milliliter, 2.3 mmoles) in tetrahydrofuran (THF) (6 milliliters) that make in the step 1 through stirring, add methylsulfonyl chloride (0.18 milliliter, 2.3 mmoles).Reaction mixture was stirred 5 minutes, add sodium iodide (375 milligrams, 2.3 mmoles) then.Reaction mixture is warmed to room temperature and filtration.In the filtrate of collecting, add sulfo-sodium methylate (161 milligrams, 2.3 mmoles) and with reaction mixture refluxed heating 24 hours.Reaction mixture is cooled to room temperature, with the ethyl acetate dilution, water and saturated sodium-chloride washing, dry (sodium sulfate) filters, and concentrating under reduced pressure, makes 4-[(methyl sulfo-) methyl] piperidines-1-t-butyl formate (430 milligrams):
1H NMR (300MHz, CDCl
3) δ 4.11 (and t, J=7Hz, 2H), 2.69 (t, J=12Hz, 2H), 2.42 (d, J=7Hz, 2H), 2.10 (s, 3H), 1.83-1.78 (m, 2H), 1.66-1.59 (m, 2H), 1.45 (s, 9H), 1.26-1.06 (m, 2H).
Step 3: the sulfide (420 milligrams, 1.7 mmoles) that step 2 is made, hydrogen peroxide (11 milliliters, 30% aqueous solution, 170 mmoles) and the solution stirring of sodium bicarbonate (143 milligrams, 1.7 mmoles) in acetone (10 milliliters) 18 hours.Reaction mixture is washed with 1.3N sodium hydroxide and saturated sodium-chloride, and dry (sal epsom) filters and concentrating under reduced pressure, makes sulfone (390 milligrams):
1H NMR (300MHz, CDCl
3) δ 4.11 (and t, J=7Hz, 2H), 2.94 (s, 3H), 2.81-2.73 (m, 2H), 2.35-2.20 (m, 2H), 1.96-1.91 (m, 2H), 1.45 (s, 9H), 1.38-1.23 (m, 3H).
Step 4: the sulfone (390 milligrams, 1.4 mmoles) that step 3 is made and the solution stirring of hydrochloric acid (4 milliliters, the solution in the 4M Zai diox, 14 mmoles) 18 hours.Filter and collect the precipitation that generates, obtain the 4-[(methylsulfonyl) methyl] piperidines-1-t-butyl formate (220 milligrams):
1H NMR (300MHz, DMSO-d
6) δ 8.94 (and br s, 1H), 8.70 (br s, 1H), 3.24-3.15 (m, 4H), 3.00 (s, 3H), 2.89 (q, J=7Hz, 2H), 2.29-2.18 (m, 1H), 1.97 (d, J=13Hz, 2H), 1.57-1.43 (m, 2H).
Step 5: (108 milligrams of triphosgene ice-cold, through stirring, 0.36 mmole) and (0.6 milliliter of diisopropylethylamine, 3.3 mmole) in the solution in methylene dichloride (2.0 milliliters), dropwise be added in the amino sulfone (210 milligrams, 0.98 mmole) that the step 4 in the methylene dichloride (3.5 milliliters) makes.After 5 minutes, add (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(3-Ethylbenzyl) amino] solution of fourth-2-alcohol dihydrochloride (401 milligrams, 0.98 mmole), and become homogeneous phase until solution with reaction mixture is warm.This reaction mixture is diluted with methylene dichloride, and with 1N hydrochloric acid (25 milliliters), saturated sodium bicarbonate (25 milliliters) and saturated sodium-chloride washing, dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 15: 85 methyl alcohol/chloroforms), obtain a kind of pure solid.This solid is dissolved in methyl alcohol (1 milliliter), and handles with hydrochloric acid (0.3 milliliter, the 1.0M solution in ether, 0.3 mmole).Filter and collect the precipitation that generates, obtain title compound (38 milligrams): mp 130-134 ℃; APCI MS m/z 538[M+H]
+
Embodiment SP-289
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-[(methylsulfonyl) methyl] cyclohexane carboxamide
Step 1: at hexanaphthene-1 through stirring, 4-dioctyl phthalate dimethyl ester (10.2 grams, 51 mmoles) 2: 1: 1 tetrahydrofuran (THF)/methanol (52 milliliters) solution in, add lithium hydroxide (2.13 grams, 51 mmoles).Reaction mixture was at room temperature stirred 18 hours.Decompression is removed solvent and is made resistates phase-splitting between ether and water.With 1N hydrochloric acid water layer is acidified to pH 4, and collecting precipitation, and dry under vacuum, make 4-(methoxycarbonyl) naphthenic acid (7.4 gram):
1H NMR (300MHz, CDCl
3) δ 3.68 (and s, 3H), 2.33-2.27 (m, 2H), 2.11-2.06 (m, 4H), 1.50-1.43 (m, 4H).
Step 2: in the ice-cold acid in tetrahydrofuran (THF) (40 milliliters) (3.2 grams, 17 mmoles), add borine-methyl-sulfide complex compound (12 milliliters, 22 mmoles) through stirring.Reaction mixture was heated 2 hours at 70 ℃, and add 1: 1 mixture (10 milliliters) of acetic acid/water.The mixture that makes is concentrated.Purify by flash column chromatography (silicon-dioxide, 1: 1 hexane/ethyl acetate), make 4 (methylol) naphthenic acid methyl esters (1.26 gram):
1H NMR (300MHz, CDCl
3) δ 3.67 (and s, 3H), 3.48-3.46 (m, 2H), 2.26-2.15 (m, 1H), 2.05-1.85 (m, 4H), 1.52-1.42 (m, 3H), 1.02-0.97 (m, 2H).
Step 3: in the solution in the methylene dichloride (5 milliliters) of alcohol (365 milligrams, 2.12 mmoles) ice-cold, and triethylamine (440 microlitres, 4.8 mmoles), add methylsulfonyl chloride (200 microlitres, 2.6 mmoles) through stirring.Reaction mixture was stirred 20 minutes phase-splitting between methylene dichloride and water then.Organic layer is washed with 1M hydrochloric acid and saturated sodium bicarbonate, and dry (sal epsom), and concentrating under reduced pressure make required methylsulfonyl ester, and it can use without purifying or characterizing.
Step 4: in the solution that stirred of methylsulfonyl ester (2.12 mmole) in tetrahydrofuran (THF) (5 milliliters) that step 3 makes, add sodium iodide (640 milligrams, 4.3 mmoles).This reaction mixture is heated to 60 ℃ reaches 5 hours, filter then.With the reaction mixture concentrating under reduced pressure, and can use without purifying or characterizing.Step 5: through stir at N, in the iodide (2.12 mmole) that the step 4 in the mixture of dinethylformamide (10 milliliters) and tetrahydrofuran (THF) (1 milliliter) makes, adding sulfo-sodium methylate (450 milligrams, 6.4 mmoles).Reaction mixture was heated 15 hours at 70 ℃.Make reaction mixture be cooled to room temperature, remove solvent, and make resistates phase-splitting between ether and water.With 1N hydrochloric acid water layer is acidified to pH 1, uses ethyl acetate extraction, dry (sodium sulfate) filters and concentrating under reduced pressure, makes 4-[(methyl sulfo-) methyl] naphthenic acid methyl esters (230 milligrams):
1H NMR (300MHz, CD
3OD) δ 2.40-2.37 (m, 2H), 2.22-2.05 (m, 1H), 2.05 (s, 3H), 2.02-1.93 (m, 4H), 1.48-1.38 (m, 3H), 1.03-0.95 (m, 2H).Step 6: (240 milligrams of the methyl-sulfide through stirring, 1.3 mmole) (3.5 milliliters of sodium hydroxide solutions, 0.5M in the solution solution), add (870 milligrams of sodium bicarbonates, 10.3 mmole) and acetone (1 milliliter), add the solution of oxone (1.0 grams, 1.7 mmoles) in 0.0004M EDTA (4 milliliters) subsequently.Reaction mixture was at room temperature stirred 2 hours, make its stopped reaction with sodium disulfide then.Extract with the reaction mixture acidifying and with ethyl acetate (3 * 100 milliliters) with hydrochloric acid.The organic layer that merges is washed with water, and dry (sodium sulfate) filters and concentrating under reduced pressure, makes sour 4-[(methyl sulfo-) methyl] naphthenic acid (240 milligrams):
1H NMR (300MHz, CD
3OD) δ 3.06-3.04 (m, 2H), 2.96 (s, 3H), 2.28-2.20 (m, 1H), 2.08-1.98 (m, 5H), 1.50-1.40 (m, 2H), 1.21-1.16 (m, 2H).
Step 7: (120 milligrams of the acid through stirring, 0.6 (2R mmole),, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] (230 milligrams of fourths-2-alcohol, 0.6 mmole) and the solution of HATU (210 milligrams, 0.6 mmole) in methylene dichloride (5 milliliters), add N, N-diisopropylethylamine (340 microlitres, 1.93 mmoles).Reaction mixture was at room temperature stirred 18 hours.Make reaction mixture phase-splitting between methylene dichloride and water.Organic layer is washed with water, and dry (sodium sulfate) filters and concentrating under reduced pressure, obtains raw oil.Purify by flash column chromatography (silicon-dioxide, the methylene chloride of 95: 5 to 93: 7 graded), obtain title compound (35 milligrams): mp 178-180 ℃; ESI MS m/z 537[M+H]
+
Embodiment SP-290
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl-5-piperidin-4-yl-N (u) 3 (d), N (u) 3 (d)-dipropyl isophthaloyl amine
Step 1: in-70 ℃ the solution of N-Boc-piperidone (500 milligrams, 2.5 mmoles) in tetrahydrofuran (THF) (11 milliliters), add lithium Diisopropylamine (1.37 milliliters, the solution of 2M in tetrahydrofuran (THF), 2.75 mmoles) through stirring.Reaction mixture was stirred 2 hours, be warmed to 0 ℃, and add N-phenyl triflamide (955 milligrams, 2.67 mmoles).This solution is warmed to room temperature and stirred 12 hours.With the reaction mixture concentrating under reduced pressure.Purify by flash column chromatography (3: 1 hexane/ethyl acetate), obtain the 4-{[(trifluoromethyl) alkylsulfonyl] oxygen }-3,6-dihydropyridine-1 (2H)-t-butyl formate (240 milligrams):
1H NMR (300MHz, CDCl
3) δ 5.77 (and s, 1H), 4.05 (m, 2H), 3.63 (m, 2H), 2.45 (m, 2H), 1.48 (s, 9H).
Step 2: (240 milligrams of the triflate through stirring, 0.72 mmole) and boric acid ester 3-[(dipropyl amino) carbonyl]-5-(3,3,4,4-tetramethyl-borolan-1-y1) methyl benzoate (280 milligrams in the solution in the 0.72 mmole) Zai diox (3 milliliters), add (1.2 milliliters in yellow soda ash, the 2M aqueous solution, 2.16 mmoles).With reaction mixture argon gas purge, add palladium (0) four (triphenyl phosphine) (34 milligrams, 0.03 mmole), and with reaction mixture refluxed heating hour.Reaction mixture is cooled to room temperature, and through diatomite filtration, dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (90: 10 chloroform/methanol), make acid (160 milligrams):
1HNMR (300MHz, CDCl
3) δ 8.11 (and s, 1H), 7.95 (s, 1H), 7.58 (s, 1H), 6.15 (br s, 1H), 4.10 (s, 2H), 3.65 (m, 2H), 3.48 (m, 2H), 3.16 (s, 2H), 2.54 (s, 2H), 1.70 (s, 2H), 1.50 (s, 9H), 1.25 (m, 2H), 0.99 (s, 3H), 0.76 (s, 3H).
Step 3: acid (160 milligrams, 0.37 mmole) that step 2 is made and the solution of 10%Pd/C (25 milligrams) in ethanol (10 milliliters) is with the nitrogen degassing 15 minutes, and under the nitrogen atmosphere of 50psi shake 12 hours.Through diatomite filtration, and concentrating under reduced pressure makes sour 3-[1-(tert-butoxycarbonyl) piperidin-4-yl with reaction mixture]-5-[(dipropyl amino) carbonyl] phenylformic acid (121 milligrams), it can use without further purification:
1H NMR (300MHz, CDCl
3) δ 7.94 (and d, J=12Hz, 2H), 7.44 (s, 1H), 4.27 (br s, 2H), 3.43 (m, 2H), 3.14 (m, 2H), 2.78 (m, 4H), 1.84 (m, 3H), 1.63 (m, 6H), 1.49 (s, 9H), 1.23 (m, 3H), 0.86 (m, 3H), 0.75 (m, 3H).
Step 4: (120 milligrams of the acid through stirring, 0.28 mmole) in the solution in methylene dichloride (2 milliliters), add N, (56 milligrams of N-diisopropylethylamine (0.141 milliliter, 0.84 mmole), HOBt, 0.42 mmole) and (160 milligrams of HATU, 0.42 mmole), add then (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] fourth-2-alcohol (114 milligrams, 0.28 mmole).Reaction mixture was at room temperature stirred 16 hours.Reaction mixture is diluted with methylene dichloride (25 milliliters), water, saturated sodium bicarbonate and saturated sodium-chloride washing, dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (93: 7 chloroform/methanol), make piperidines (90 milligrams):
1H NMR (300MHz, CDCl
3) δ 7.61 (and s, 1H), 7.54 (s, 1H), 7.43 (s, 1H), 7.14 (m, 4H), 6.79 (m, 2H), 6.64 (m, 1H), 4.29 (m, 3H), 3.68 (m, 4H), 3.47 (m, 2H), 3.02 (m, 4H), 2.77 (m, 5H), 2.66 (m, 2H), 1.71 (m, 8H), 1.48 (m, 9H), 1.24 (m, 5H), 0.99 (m, 3H), 0.73 (m, 3H).
Step 5: the piperidines (90 milligrams, 0.12 mmole) that step 4 is made and the solution of hydrochloric acid (0.3 milliliter, the solution in the 4.0M Zai diox, 1.2 mmoles) at room temperature stirred 30 minutes.With the reaction mixture concentrating under reduced pressure,, and filter with ether (50 milliliters) washing.Purify by flash column chromatography (89: 10: 1 chloroform/methanol/ammonium hydroxide), make title compound (35 milligrams): mp 84-87 ℃; ESI MS m/z 649[M+H]
+
Embodiment SP-291
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl-5-(1,3-oxazole-2-yl) benzamide hydrochloride salt
Step 1: at sour 3-(methoxycarbonyl)-5-nitrobenzoic acid (24.6 grams ice-cold, through stirring, 0.11 mole) in the solution in tetrahydrofuran (THF) (200 milliliters), add (82 milliliters of borines-methyl-sulfide complex compound, 2.0M the solution in tetrahydrofuran (THF), 0.16 mole), and with reaction mixture refluxed heated 24 hours.Reaction mixture is cooled to room temperature, makes its stopped reaction, and solvent is removed in decompression with methyl alcohol.Purify by flash column chromatography (silicon-dioxide, 1: 1 ethyl acetate/hexane), make a kind of alcohol (16 gram):
1H NMR (300MHz, DMSO-d
6) δ 8.51 (and d, J=1Hz, 1H), 8.42 (s, 1H), 8.32 (s, 1H), 5.69 (t, J=6Hz, 1H), 4.70 (d, J=6Hz, 2H), 3.93 (s, 3H).
Step 2: in the solution of the alcohol that makes in the step 1 ice-cold, (6.6 grams, 32 mmoles) in methylene dichloride, add phosphorus tribromide (1.5 milliliters, 16 mmoles), and reaction mixture was stirred 40 minutes through stirring.Reaction mixture is diluted with methylene dichloride, and with saturated sodium bicarbonate and saturated sodium-chloride washing, dry (sal epsom) filters and concentrating under reduced pressure, makes a kind of bromide (8.1 gram):
1H NMR (300MHz, DMSO-d
6) δ 8.79 (and t, J=2Hz, 1H), 8.45 (t, J=2Hz, 1H), 8.39 (d, J=2Hz, 1H), 4.57 (s, 2H), 4.00 (s, 3H).
Step 3: shake is 24 hours under bromide that step 2 is made (8.1 grams, 32 mmoles) and 10%Pd/C (1.0 restrain) nitrogen atmosphere of solution at 45psi in 13: 4: 1 methanol/ethyl acetate/acetate (90 milliliters).Through diatomite filtration, and concentrating under reduced pressure makes 3-amino-5-tolyl acid 1 methyl esters (2.8 gram): ESI MS m/z 166[M+H with reaction mixture]
+
Step 4: in the solution of aniline ice-cold, (2.8 grams, 17 mmoles) in 2N hydrochloric acid (48 milliliters), add water (10 milliliters) solution of Sodium Nitrite (1.2 grams, 17 mmoles), and reaction mixture was stirred 30 minutes through stirring.This reaction mixture is heated to water (10 milliliters) solution of potassiumiodide ice-cold, (5.6 grams, 34 mmoles) and cupric iodide (I) (1.6 grams, 8.6 mmoles) through stirring.Reaction mixture is warmed to room temperature with 2 hours, dilutes with ethyl acetate then.With 10% solution and the saturated sodium-chloride washing of organic layer with Sulfothiorine, dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 1: 9 ethyl acetate/hexane), obtain a kind of iodide (1.4 gram):
1H NMR (300MHz, CDCl
3) δ 8.16 (and s, 1H), 7.80 (d, J=1Hz, 1H), 7.72 (d, J=1Hz, 1H), 3.90 (s, 3H), 2.35 (s, 3H).
Step 5: in-70 ℃ tetrahydrofuran (THF) (5 milliliters) solution, add n-Butyl Lithium (1.7 milliliters, the solution of 1.6M in hexane, 2.8 mmoles) through stirring De oxazole (174 milligrams, 2.5 mmoles).After 30 minutes, add zinc chloride (7.5 milliliters, the solution of 1M in ether, 7.5 mmoles), and reaction mixture is warmed to 0 ℃ reaches 1 hour.In this mixture, add the iodide (695 milligrams, 2.5 mmoles) that step 4 makes then, add palladium (0) four (triphenyl phosphine) (145 milligrams, 0.13 mmole) subsequently.With reaction mixture refluxed heating 16 hours.With this reaction mixture cooling, with ethyl acetate (50 milliliters) dilution.With organic layer water and saturated sodium-chloride washing, dry (sal epsom), filtration and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 1: 1 ethyl acetate/hexane), obtain Yi Zhong oxazole (330 milligrams):
1H NMR (300MHz, CD
3OD) δ 8.45 (s, 1H), 8.08 (d, J=1Hz, 1H), 8.01 (s, 1H), 7.97 (d, J=1Hz, 1H), 7.32 (s, 1H), 3.95 (s, 3H), 2.48 (s, 3H); ESI MS m/z 218[M+H]
+Step 6: in the solution through stir of ester (384 milligrams, 1.7 mmoles) in methyl alcohol (5 milliliters) that step 5 makes, add potassium hydroxide (15 milliliters, the 1.0M aqueous solution, 15 mmoles).Reaction mixture was at room temperature stirred 2 hours and concentrating under reduced pressure.Wash with residue diluted with water and with ethyl acetate.With 1N hydrochloric acid water layer is acidified to pH 5 and uses chloroform (4 * 100 milliliters) extraction.With the organic extract drying (sodium sulfate) that merges, filter and concentrating under reduced pressure, make a kind of acid (358 milligrams):
1H NMR (300MHz, DMSO-d
6) δ 13.2 (and br s, 1H), 8.32 (s, 1H), 8.20 (s, 1H), 8.03 (s, 1H), 7.93 (s, 1H), 7.42 (s, 1H), 2.45 (s, 3H).
Step 7: (358 milligrams of the acid that step 6 is made, 1.8 HATU (1.0 grams mmole),, 2.6 mmole), the solution of HOBt (357 milligrams, 2.6 mmoles) and diisopropylethylamine (500 microlitres, 2.6 mmoles) stirred 15 minutes in methylene dichloride (2.0 milliliters).Add (2R, 3S)-and 3-amino-4-(3, the 5-difluorophenyl)-1-[(3-Ethylbenzyl) amino] fourth-2-alcohol (718 milligrams, 1.8 mmoles) and diisopropylethylamine (500 microlitres, 2.6 the solution in methylene dichloride (2.0 milliliters) mmole), and reaction mixture stirred spend the night.Reaction mixture is diluted with methylene dichloride, with 1N hydrochloric acid (20 milliliters), saturated sodium bicarbonate (20 milliliters) and saturated sodium-chloride washing, dry (sal epsom), filtration and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 1: 9 methyl alcohol/chloroform), make a kind of pure solid.This solid is dissolved in methyl alcohol (2 milliliters), and handles with hydrochloric acid (0.5 milliliter, the solution of 1.0M in ether, 0.5 mmole).Filter and collect the precipitation that produces, obtain title compound (250 milligrams): mp 105-107 ℃; APCI MS m/z 520[M+H]
+
Embodiment SP-292
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-[(methylsulfonyl) methyl] thiophene-2-carboxamide derivatives
Step 1: in the solution of sour 5-(methoxycarbonyl)-thiophene-2-carboxylic acid (1.00 grams, 5.37 mmoles) in tetrahydrofuran (THF) (21.5 milliliters), add borine-methyl-sulfide complex compound (3.0 milliliters, the 2.0M solution in tetrahydrofuran (THF), 6.00 mmoles).With reaction mixture refluxed heating 24 hours.Use anhydrous methanol (1.0 milliliters) to make its stopped reaction then carefully, and be cooled to room temperature.With 1N hydrochloric acid with the reaction mixture acidifying and use ethyl acetate extraction.With the organic phase water and the saturated sodium-chloride washing that merge, dry (sodium sulfate) filters and concentrates, and makes required alcohol (820 milligrams):
1H NMR (300MHz, CDCl
3) δ 7.65 (and d, J=4Hz, 1H), 6.96 (d, J=4Hz, 1H), 4.83 (s, 2H), 3.87 (s, 3H).
Step 2: (805 milligrams of the alcohol that in step 1, makes, 4.67 mmole) containing triethylamine (790 microlitres, 5.61 mmole) and in 0 ℃ the solution in the tetrahydrofuran (THF) (31 milliliters) of Dimethylamino pyridine (6 milligrams), add methylsulfonyl chloride (400 microlitres, 5.14 mmole), and with reaction mixture stirred 0.5 hour.Reaction mixture is filtered and filtrate decompression is concentrated, make rough methylsulfonyl ester, it promptly is used for next step without further purification:
1H NMR (300MHz, CDCl
3) δ 7.70 (and m, 1H), 7.18 (m, 1H), 5.39 (s, 2H), 3.99 (s, 3H), 2.97 (s, 3H).
Step 3: the methylsulfonyl ester that makes in step 2 is at N, in the mixture in the dinethylformamide (10 milliliters), adds sulfo-sodium methylate (516 milligrams, 7.0 mmoles) and reaction mixture is warmed to 50 ℃ and reach 18 hours.Extract with reactant water (200 milliliters) dilution and with chloroform (4 * 25 milliliters).The organic phase of merging is washed with 5% lithium chloride, water and saturated sodium-chloride, and dry (sodium sulfate) filters and concentrating under reduced pressure, obtains required sulfide (760 milligrams), and it can use without further purification:
1H NMR (300MHz, CDCl
3) δ 7.64 (and d, J=4Hz, 1H), 6.93 (d, J=4Hz, 1H), 3.89 (m, 5H), 2.08 (s, 3H).
Step 4: in chloroform (6.25 milliliters) solution of the sulfide (760 milligrams, 3.75 mmoles) that 0 ℃ step 3 makes, add 70%m-CPBA (2.31 grams, 9.37 mmoles) and reactant was stirred 2.5 hours at 0 ℃.Then reaction mixture is washed with the chloroform dilution and with 1N sodium hydroxide, water and saturated sodium-chloride, dry (sodium sulfate) filters, and concentrating under reduced pressure, makes required sulfone (780 milligrams), and it both can use without further purification:
1H NMR (300MHz, CDCl
3) δ 7.74 (and d, J=4Hz, 1H), 7.20 (d, J=4Hz, 1H), 4.46 (s, 2H), 3.89 (m, 3H), 2.87 (s, 3H).
Step 5: in sulfone (268 milligrams, 1.14 mmoles) that step 4 the makes solution in 2: 1: 1 diox/methanol (7.6 milliliters), add a hydronium(ion) oxidation lithium (53 milligrams, 1.14 mmoles) and reaction mixture was at room temperature stirred 24 hours.Be divided into ethyl acetate layer and water layer with the reaction mixture concentrating under reduced pressure and with solid residue.With 1N hydrochloric acid and for several times with extracted with diethyl ether with aqueous phase as acidified.With the ether extraction liquid water and the saturated sodium-chloride washing of merging, dry (sodium sulfate) filters and concentrating under reduced pressure, makes the 5-[(methylsulfonyl) methyl] thiophene-2-carboxylic acid (115 milligrams), it can use without further purification:
1H NMR (300MHz, CDCl
3) δ 7.73 (and d, J=4Hz, 1H), 7.20 (d, J=4Hz, 1H), 4.52 (s, 2H), 2.90 (s, 3H); ESI MS (negative mode) m/z 219[M-H]
-
Step 6: (115 milligrams of the acid that makes in step 5,0.52 mmole) and N, in the solution of N-diisopropylethylamine (540 microlitres, 3.12 mmoles) in methylene dichloride (6.5 milliliters), add HBTU (200 milligrams, 0.52 mmole) and reaction mixture was stirred 0.5 hour.Disposable adding (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(3-Ethylbenzyl) amino] fourth-2-alcohol (211 milligrams, 0.52 mmole), and reaction mixture at room temperature stirred 18 hours.Reaction mixture is diluted with methylene dichloride, and wash, dry (sodium sulfate), filtration and concentrating under reduced pressure with saturated sodium bicarbonate and saturated sodium-chloride.Purify by flash column chromatography (silicon-dioxide, the chloroformic solution of 1-5% methyl alcohol), make title compound (45 milligrams): mp 128-131 ℃; ESI MSm/z 537[M+H]
+
Embodiment SP-293
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl-5-(1,3-thiazoles-2-yl) benzamide hydrochloride salt
Step 1: in tetrahydrofuran (THF) (5 milliliters) solution of-70 ℃ thiazoles (214 milligrams, 2.5 mmoles), add n-Butyl Lithium (1.7 milliliters, the solution of 1.6M in hexane, 2.8 mmoles) through stirring.After 30 minutes, add zinc chloride (7.5 milliliters, the solution of 1M in ether, 7.5 mmoles), and reaction mixture is warmed to 0 ℃ reaches 1 hour.In this mixture, add above-mentioned iodide (695 milligrams, 2.5 mmoles) then, add palladium (0) four (triphenyl phosphine) (145 milligrams, 0.13 mmole) subsequently.With reaction mixture refluxed heating 16 hours.This reaction mixture is cooled off, and dilute with ethyl acetate (50 milliliters).With organic layer water and saturated sodium-chloride washing, dry (sal epsom), filtration and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 1: 1 ethyl acetate/hexane), obtain a kind of thiazole (208 milligrams):
1H NMR (300MHz, CDCl
3) δ 8.38 (and s, 1H), 8.02 (d, J=1Hz, 1H), 7.92 (s, 1H), 7.88 (d, J=3Hz, 1H), 7.37 (d, J=3Hz, 1H), 3.95 (s, 3H), 2.48 (s, 3H).
Step 2: in ester (208 milligrams, 0.89 mmole) that step 1 makes the solution in 2: 1: 1 methyl alcohol/tetrahydrofuran (THF)/water (4 milliliters), add lithium hydroxide (75 milligrams, 1.8 mmoles) through stirring.Reaction mixture was at room temperature stirred 3 hours and concentrating under reduced pressure.Wash with residue diluted with water and with ethyl acetate.With 1N hydrochloric acid water layer is acidified to pH 5 and uses chloroform (5 * 100 milliliters) extraction.With the organic extract drying (sodium sulfate) that merges, filter and concentrating under reduced pressure, make a kind of acid (146 milligrams):
1H NMR (300MHz, DMSO-d
6) δ 13.17 (and br s, 1H), 8.28 (s, 1H), 8.01 (d, J=1Hz, 1H), 7.96 (d, J=3Hz, 1H), 7.85 (d, J=3Hz, 2H), 2.45 (s, 3H).
Step 3: the solution of acid (140 milligrams, 0.64 mmole), HATU (364 milligrams, 0.96 mmole) and the diisopropylethylamine (170 microlitres, 0.96 mmole) that step 2 is made stirred 15 minutes in methylene dichloride (2.0 milliliters).Add (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] (318 milligrams of fourth-2-alcohol dihydrochlorides, 0.64 mmole) and diisopropylethylamine (170 microlitres, 0.96 the solution in methylene dichloride (2.0 milliliters) mmole), and reaction mixture stirred spend the night.Reaction mixture is diluted with methylene dichloride, with 1N hydrochloric acid (20 milliliters), saturated sodium bicarbonate (20 milliliters) and saturated sodium-chloride washing, dry (sal epsom), filtration and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 1: 9 methyl alcohol/chloroform), make a kind of pure solid.This solid is dissolved in methyl alcohol (1 milliliter), and handles with hydrochloric acid (0.5 milliliter, the 1.0M solution in ether, 0.5 mmole).Filter and collect the precipitation that produces, obtain title compound (100 milligrams): mp 178-180 ℃; APCI MS m/z 536[M+H]
+
Embodiment SP-293
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-[(methylsulfonyl) methyl] cyclohexane carboxamide
Step 1: at hexanaphthene-1 ice-cold, through stirring, in the solution of 4-dioctyl phthalate (3.0 gram, 17 mmoles) in 2: 1 tetrahydrofuran (THF)/methyl alcohol (24 milliliters), add (9 milliliters of trimethyl silyl diazomethanes, 2.0M solution in hexane, 18 mmoles).Reaction mixture was at room temperature stirred 2 hours.Add acetate (5 milliliters), and solvent is removed in decompression.Purify by flash column chromatography (silicon-dioxide, 10: 1: 0.01 hexane/ethyl acetate/acetate), make 4-(methoxycarbonyl) naphthenic acid (1.00 gram):
1H NMR (300MHz, CDCl
3) δ 3.68 (and s, 3H), 2.53-2.47 (m, 2H), 1.97-1.89 (m, 4H), 1.74-1.66 (m, 4H).
Step 2: in the solution of acid (700 milligrams, 3.8 mmoles) in tetrahydrofuran (THF) (10 milliliters) that makes in the step 1 ice-cold,, add borine-methyl-sulfide complex compound (2 milliliters, 4.1 mmoles) through stirring.Reaction mixture is warmed to room temperature 2 hours, and adds 1: 1 mixture (10 milliliters) of acetic acid/water.With the mixture concentrating under reduced pressure that makes.Purify by flash column chromatography (silicon-dioxide, 1: 1 hexane/ethyl acetate), make 4-(methylol) naphthenic acid methyl esters (560 milligrams):
1H NMR (500MHz, CDCl
3) δ 3.68 (and s, 3H), 3.51-3.46 (m, 2H), 2.59-2.57 (m, 1H), 2.05-2.00 (m, 2H), 1.65-1.55 (m, 5H), 1.31-1.27 (m, 2H).
Step 3: in the alcohol (300 milligrams, 1.8 mmoles) and the solution ice-cold, through stir of triethylamine (370 microlitres, 2.7 mmoles) in methylene dichloride (5 milliliters) that step 2 makes, add methylsulfonyl chloride (170 microlitres, 2.1 mmoles).Reaction mixture was stirred 20 minutes phase-splitting between methylene dichloride and water then.Organic layer is washed with 1M hydrochloric acid and saturated sodium bicarbonate, and dry (sal epsom), and concentrating under reduced pressure make required methylsulfonyl ester, and it can use without purifying or characterizing.
Step 4: in the solution that stirred of methylsulfonyl ester (1.8 mmole) in tetrahydrofuran (THF) (5 milliliters) that step 3 makes, add sodium iodide (530 milligrams, 3.5 mmoles).60 ℃ of heating 5 hours, cool to room temperature filtered then with this reaction mixture.With the reaction mixture concentrating under reduced pressure, and can use without purifying or characterizing.
Step 5: the iodide (1.8 mmole) that make in the step 4 through stirring are at N, in the solution in dinethylformamide (10 milliliters) and the tetrahydrofuran (THF) (1 milliliter), and adding sulfo-sodium methylate (375 milligrams, 5.3 mmoles).Reaction mixture was heated 15 hours at 70 ℃.Make reaction mixture be cooled to room temperature then, remove solvent, and make resistates phase-splitting between ether and water.With 1N hydrochloric acid water layer is acidified to pH1, uses ethyl acetate extraction, dry (sodium sulfate) filters and concentrating under reduced pressure, makes 4-[(methyl sulfo-) methyl] naphthenic acid (50 milligrams):
1H NMR (300MHz, CD
3OD) δ 2.53-2.51 (m, 1H), 2.43-2.41 (m, 3H), 2.05 (s, 3H), 2.05-1.95 (m, 2H), 1.71-1.53 (m, 4H), 1.36-1.30 (m, 2H).Step 6: (100 milligrams of the methyl-sulfide that makes in step 5,0.5 mmole) (1.5 milliliters of sodium hydroxide solutions, 0.5M in the solution the aqueous solution) through stirring, add (360 milligrams of sodium bicarbonates, 4.3 mmole) and acetone (1 milliliter), add the solution of oxone (430 milligrams, 0.7 mmole) in 0.0004M EDTA (2 milliliters) subsequently.Reaction mixture was at room temperature stirred 2 hours, make its stopped reaction with sodium disulfide then.Extract with the reaction mixture acidifying and with ethyl acetate (3 * 100 milliliters) with 1N hydrochloric acid.The organic layer that merges is washed with water, and dry (sodium sulfate) filters and concentrating under reduced pressure, makes sour 4-[(methylsulfonyl) methyl] naphthenic acid (100 milligrams):
1H NMR (300MHz, CD
3OD) δ 3.11-3.08 (m, 2H), 2.96 (s, 3H), 2.53-2.51 (m, 1H), 2.18-2.16 (m, 1H), 1-99-1.93 (m, 2H), 1.79-1.25 (m, 6H).
Step 7: (100 milligrams of the acid that makes in step 6,0.5 (2R mmole),, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] (190 milligrams of fourths-2-alcohol, 0.5 mmole) and the solution through stir of HATU (175 milligrams, 0.5 mmole) in methylene dichloride (5 milliliters), add N, N-diisopropylethylamine (280 microlitres, 1.6 mmoles).Reaction mixture was at room temperature stirred 18 hours.Make reaction mixture phase-splitting between methylene dichloride and water.Organic layer is washed with water, and dry (sodium sulfate) filters and concentrating under reduced pressure, obtains raw oil.Purify by flash column chromatography (silicon-dioxide, the methylene chloride of 95: 5 to 92: 8 graded), obtain title compound (60 milligrams): mp 45-50 ℃; ESI MS m/z 537[M+H]
+
Embodiment SP-293
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-piperidines-3-base-N, N-dipropyl isophthaloyl amine hydrochlorate
Step 1: (205 milligrams of the 3-bromo-pyridines through stirring, 1.3 mmole) and ester 3-[(dipropyl amino) carbonyl]-5-(3,3,4,4-tetramethyl-borolan-1-y1) methyl benzoate (500 milligrams in the solution in the 1.3 mmole) Zai dioxs in (9 milliliters), add (2.0 milliliters in yellow soda ash, the 2M aqueous solution, 3.9 mmoles).With reaction mixture argon gas purge, add palladium (O) four (triphenyl phosphines) (36 milligrams, 0.052 mmole), and with reaction mixture refluxed heating hour.Reaction mixture is cooled to room temperature, and through diatomite filtration, dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (3: 2 hexane/ethyl acetate), make piperidines (200 milligrams):
1H NMR (300MHz, CDCl
3) δ 8.88 (and m, 1H), 8.65 (m, 1H), 8.31 (m, 1H), 8.07 (m, 1H), 7.92 (m, 1H), 7.79 (m, 1H), 7.67 (m, 1H), 3.98 (m, 3H), 3.50 (m, 2H), 3.21 (m, 2H), 1.66 (m, 4H), 1.07 (m, 3H), 0.78 (m, 3H).
Step 2: (160 milligrams of the pyridines that step 1 is made, 0.37 mmole) and the solution of platinum oxide (15 milligrams) in ethanol (2.5 milliliters), water (0.5 milliliter) and concentrated hydrochloric acid (1.0 milliliters) with the nitrogen degassing 15 minutes, and under the nitrogen atmosphere of 50psi shake 12 hours.Through diatomite filtration, and concentrating under reduced pressure makes 3-[1-(dipropyl amino) carbonyl with reaction mixture)]-5-piperidines-3-yl benzoic acid methyl esters (204 milligrams, quantitatively), it can use without further purification:
1H NMR (300MHz, CDCl
3) δ 9.62 (and m, 3H), 8.02 (m, 3H), 4.78 (m, 2H), 3.96 (s, 3H), 3.61 (m, 5H), 2.04 (m, 5H), 1.34 (m, 3H), 0.91 (m, 6H).
Step 3: in the solution through stir of piperidines (204 milligrams, 0.59 mmole) in methylene dichloride (1.6 milliliters) that step 2 makes, add Boc acid anhydride (162 milligrams, 0.65 mmole) and triethylamine (0.122 milliliter, 0.88 mmole).This solution was at room temperature stirred 2 days.Reaction mixture is filtered and concentrating under reduced pressure.Purify by flash column chromatography, make the piperidines (100 milligrams) that Boc-is protected:
1H NMR (300MHz, CDCl
3) δ 7.93 (t, J=3Hz, 1H), 7.88 (t, J=3Hz, 1H), 7.42 (t, J=3Hz, 1H), 4.16 (m, 2H), 3.93 (s, 3H), 3.46 (m, 2H), 3.13 (m, 2H), 2.78 (m, 3H), 2.03 (d, J=10Hz, 1H), 1.70 (m, 7H), 1.48 (m, 9H), 1.00 (m, 3H), 0.75 (m, 3H).
Step 4: in piperidines (100 milligrams, 0.22 mmole) that step 3 makes the solution in methyl alcohol (2 milliliters), add potassium hydroxide (2.2 milliliters, the 1M aqueous solution, 2.2 mmoles) and reaction mixture was at room temperature stirred 2 hours through stirring.With reaction mixture phase-splitting between ethyl acetate (50 milliliters) and water (50 milliliters).With 1N hydrochloric acid water layer is acidified to pH 4-5 and uses chloroform (5 * 50 milliliters) extraction.With the organic layer drying (sal epsom) that merges, filter and concentrating under reduced pressure, make a kind of acid (90 milligrams):
1H NMR (300MHz, CDCl
3) δ 7.99 (and s, 1H), 7.94 (s, 1H), 7.47 (s, 1H), 4.12 (m, 2H), 3.47 (m, 2H), 3.14 (m, 2H), 2.77 (m, 3H), 2.03 (m, 1H), 1.67 (m, 7H), 1.48 (s, 9H), 0.98 (m, 3H), 0.77 (m, 3H).
Step 5: (90 milligrams of the piperidines that makes in step 4,0.21 mmole) in the solution in methylene dichloride (1 milliliter) through stirring, add N, (42 milligrams of N-diisopropylethylamine (0.142 milliliter, 0.84 mmole), HOBt, 0.31 mmole) and (118 milligrams of HATU, 0.31 mmole), add then (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] fourth-2-alcohol (86 milligrams, 0.21 mmole).Reaction mixture was at room temperature stirred 16 hours.Reaction mixture is diluted with methylene dichloride (25 milliliters), water, saturated sodium bicarbonate and saturated sodium-chloride washing, dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (95: 5 chloroform/methanol), make piperidines (100 milligrams), it uses without further characterizing directly.Step 6: the piperidines (100 milligrams, 0.15 mmole) that step 5 is made and the solution of hydrochloric acid (0.4 milliliter, the 4.0M solution in the Zai diox, 1.5 mmoles) at room temperature stirred 30 minutes.With the reaction mixture concentrating under reduced pressure, and wash with ether (50 milliliters).Filter and collect the precipitation that generates, obtain title compound (60 milligrams): mp 145-145 ℃; ESI MS m/z 649[M+H]
+
Embodiment SP-294
1-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl isophthalic acid H-pyrroles-2-methane amide
Step 1: in ethanol (54 milliliters) solution, add sodium metal (1.29 grams, 54.00 mmoles) through stirring.Reaction mixture was stirred 1 hour, add diethyl kharophen maloante (2.37 grams, 10.92 mmoles) then.With reaction mixture refluxed heating 1 hour and add 1,4-two chloro-2-butyne (1.14 milliliters, 11.64 mmoles).With reaction mixture refluxed 1 hour, be cooled to room temperature, and concentrating under reduced pressure.The resistates that makes is divided into ethyl acetate layer and water layer.Organic layer is washed with saturated sodium-chloride, and dry (sodium sulfate) uses activated carbon treatment, through diatomite filtration, and concentrating under reduced pressure, make 5-methyl isophthalic acid H-pyrroles-2-ethyl formate (1.26 gram):
1H NMR (300MHz, CDCl
3) δ 8.82 (and br s, 1H), 6.81 (s, 1H), 5.95 (s, 1H), 4.31 (q, J=6Hz, 2H), 2.31 (s, 3H), 1.34 (t, J=6Hz, 3H).
Step 2: pyrroles's (240 milligrams, 1.71 mmoles), salt of wormwood (306 milligrams, 2.21 mmoles) and the mixture heating up to 40 of butyl bromide (328 milligrams, 2.39 mmoles) in acetonitrile (10 milliliters) that step 1 is made ℃ reaches 2 days.Reaction mixture is cooled to room temperature, is divided into ethyl acetate layer and water layer then.With organic layer drying (sodium sulfate), filter and concentrating under reduced pressure, make a kind of brown oil.Purify by flash column chromatography (silicon-dioxide, 5.5: 1 hexane/ethyl acetate), obtain ester (232 milligrams):
1H NMR (300MHz, CDCl
3) δ 6.91 (and d, J=3Hz, 1H), 5.88 (d, J=3Hz, 1H), 4.24 (m, 4H), 2.26 (s, 3H), 1.65 (m, 2H), 1.37 (m, 5H), 0.99 (m, 3H); ESI MS m/z 210[M+H]
+
Step 3: the ester (232 milligrams, 1.11 mmoles) that step 2 is made and 3: 1: 1 methyl alcohol/tetrahydrofuran (THF)/2N sodium hydroxide (5 milliliters) mixture stir and spend the night.After 24 hours, reaction is not finished.Reaction mixture is heated to 40 ℃ reaches 4 hours, be cooled to room temperature, be divided into ethyl acetate layer and water layer then.With 1N hydrochloric acid water layer is acidified to pH 3 and uses chloroform extraction.With organic layer drying (sodium sulfate), filter and concentrating under reduced pressure, make 1-butyl-5-methyl isophthalic acid H-pyrroles-2-formic acid (110 milligrams):
1H NMR (300MHz, CDCl
3) δ 7.04 (and d, J=3Hz, 1H), 5.93 (d, J=3Hz, 1H), 4.24 (m, 4H), 2.28 (s, 3H), 1.67 (m, 2H), 1.43 (m, 2H), 0.99 (m, 3H).
Step 4: at (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] (248 milligrams of fourths-2-alcohol, 0.608 mmole), acid is (110 milligrams, 0.608 mmole), in HOBt (82 milligrams, 0.608 mmole) and N-methylmorpholine (99 milligrams, 2.43 mmoles) the solution in methylene dichloride (5 milliliters) through stirring, add EDC (210 milligrams, 1.09 mmoles).The reaction mixture stirring is spent the night, be divided into ethyl acetate layer and water layer then.Organic layer is washed with 1N hydrochloric acid, saturated sodium bicarbonate and saturated sodium-chloride, and dry (sodium sulfate) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 9: 1 methylene chloride), make title compound (100 milligrams): mp 116-121 ℃; ESI MS m/z 498[M+H]
+
Embodiment SP-295
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl-3-[(1H-pyrroles-2-ylmethyl) amino] propyl group }-5-methyl-N, N-dipropyl isophthaloyl amine
Step 1: with (1S, 2R)-3-amino-1-(3, the 5-difluorobenzyl)-(170 milligrams of 2-hydroxypropyl t-butyl carbamates, 0.538 mmole), 1H-pyrroles-2-carbaldehyde is (51 milligrams, 0.538 mmole) and the mixture of triethylamine (60 milligrams, 0.592 mmole) in the chloroform (10 milliliters) of sulfur acid magnesium, stirred 4 hours.Reaction mixture is filtered and concentrating under reduced pressure.The resistates of gained is dissolved in 2-propyl alcohol (10 milliliters) and adds sodium borohydride (26 milligrams, 0.699 mmole).The reaction mixture stirring is spent the night, handle with methyl alcohol then.With the reaction mixture concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 9: 1 chloroform/methanol), make (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(1H-pyrroles-2-ylmethyl) amino] the propyl carbamic acid tert-butyl ester (132 milligrams):
1H NMR (300MHz, CD
3OD) δ 6.82 (m, 4H), 6.21 (s, 1H), 6.09 (m, 1H), 4.09 (s, 2H), 3.66 (m, 2H), 3.19 (m, 1H), 3.13 (m, 1H), 3.03 (m, 1H), 2.88 (m, 1H), 1.31 (s, 9H).
Step 2: in pyrroles (132 milligrams in the solution through stirring in the 0.334 mmole) Zai diox (3 milliliters), add hydrochloric acid (0.33 milliliter, 4N diox, 1.34 mmoles) that step 1 makes.The reaction mixture stirring is spent the night, and concentrating under reduced pressure makes a kind of brown solid amine (134 milligrams, quantitative) then, and it is without further characterizing or purifying and can use.
Step 3: (134 milligrams of the amine that makes in step 2,0.334 carbonyl 3-[(dipropyl amino mmole))]-(88 milligrams of 5-tolyl acids, 0.334 mmole), HOBt is (45 milligrams, 0.334 mmole) and (203 milligrams of N-methylmorpholines, 2.00 mmole) in methylene dichloride (5 milliliters) in stirred mixture, add EDC (115 milligrams, 0.601 mmole).After 24 hours, make reaction mixture be divided into ethyl acetate layer and water layer.Organic layer is washed with 1N hydrochloric acid, saturated sodium bicarbonate and saturated sodium-chloride, and dry (sodium sulfate) filters and concentrating under reduced pressure, makes a kind of white solid.Purify by flash column chromatography (silicon-dioxide, 9: 1: 1 methylene chloride/ammonium hydroxide), make title compound (27 milligrams): mp 63-74 ℃; ESI MS m/z 541[M+H]
+
Embodiment SP-296
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-piperazine-1-base-N, N-dipropyl isophthaloyl amine hydrochlorate
Step 1: in sealed tube, with 5-bromo dimethyl isophthalate (5.0 grams, 18.3 mmole), N-benzyl diethylenediamine (4.0 milliliters, 23.0 mmoles) and cesium carbonate (8.4 grams, the 25.7 mmoles) solution in toluene (36 milliliters) at room temperature outgased 20 minutes with nitrogen.Under nitrogen, add acid chloride (II) (225 milligrams, 0.92 mmole) and BINAP (1.7 grams, 2.74 mmoles) rapidly and this solution is heated to 80 ℃ and spend the night, produce a kind of yellow liquid that contains the white suspension thing.Reaction mixture is cooled to room temperature, and vacuum filtration is also washed solid with fresh toluene.Then filtrate decompression is concentrated, generate a kind of yellow oil.Purify by flash chromatography (silicon-dioxide, 80: 20 hexane/ethyl acetate), obtain required 5-(4-benzyl diethylenediamine-1-yl) dimethyl isophthalate (4.40 gram): ESI MS m/z 369[M+H]
+
Step 2: in the solution of the ester that makes in step 1 (1.0 grams, 2.70 mmoles) in 2: 1: 1 diox/methanol (18 milliliters), add a hydronium(ion) oxidation lithium (100 milligrams, 2.44 mmoles) and reaction mixture was at room temperature stirred 24 hours.Be divided into ethyl acetate layer and water layer with the reaction mixture concentrating under reduced pressure and with solid residue.Organic layer put aside and with 1N hydrochloric acid with aqueous phase as acidified, and with ethyl acetate extraction three times.With the acetic acid ethyl acetate extract water and the saturated sodium-chloride washing that merge, dry (sodium sulfate) filters and concentrating under reduced pressure, makes required monoprotic acid (945 milligrams):
1H NMR (300MHz, CDCl
3) δ 10.50-10.30 (and br s, 1H), 8.19-8.12 (m, 1H), 7.80-7.60 (m, 2H), 7.35-7.26 (m, 5H), 3.91 (s, 3H), 3.73 (s, 2H), 3.36-3.33 (m, 4H), 2.77-2.71 (m, 4H); ESI MS m/z 355[M+H]
+
Step 3: the monoprotic acid that in step 2, makes (1.2 grams, 3.38 mmole) in the solution in methylene dichloride (22.5 milliliters), add triethylamine (940 microlitres, 6.76 N mmole),, N-dipropyl amine (554 microlitres, 4.0 mmole) and iodate 2-chloro-1-picoline (865 milligrams, 3.38 mmoles).Reaction mixture at room temperature stirred spend the night.Then resistates is diluted with methylene dichloride, with saturated sodium bicarbonate, water and saturated sodium-chloride washing.With organic layer drying (sodium sulfate), filter then, and concentrating under reduced pressure, make a kind of yellow oil.Purify by flash column chromatography (silicon-dioxide, 80: 20 hexane/ethyl acetate), obtain required acid amides (1.0 gram):
1H NMR (300MHz, CDCl
3) δ 7.59-7.58 (and m, 1H), 7.44-7.42 (m, 1H), 7.35-7.26 (m, 5H), 7.05-7.04 (m, 1H), 3.89 (s, 3H), 3.56 (s, 2H), 3.50-3.35 (m, 2H), 3.28-3.25 (m, 4H), 3.20-3.05 (m, 2H), 2.62-2.58 (m, 4H), 1.70-1.40 (m, 4H), 1.00-0.95 (m, 3H), 0.80-0.70 (m, 3H).
Step 4: in the solution of the acid amides that in step 3, makes (1.00 gram, 2.28 mmoles) in dehydrated alcohol (120 milliliters), add palladium hydroxide (II) (100 milligrams) and reactant is spent the night in 60 ℃ of shakes under the hydrogen of 55psi.Then reactant is cooled to room temperature,, and filter cake is washed with fresh ethanol through diatomite filtration.Filtrate decompression is concentrated, and be dissolved in anhydrous acetonitrile (15 milliliters) again.Add two dibutyl carbonates (650 milligrams, 2.96 mmoles) and N therein, N-diisopropylethylamine (450 microlitres, 2.50 mmoles), and reaction mixture at room temperature stirred spend the night.With the reaction mixture concentrating under reduced pressure, be dissolved in chloroform more then, with saturated sodium bicarbonate, water and saturated sodium-chloride washing.With organic layer drying (sodium sulfate), filter and concentrating under reduced pressure then, obtain water white oil.Purify by flash column chromatography (silicon-dioxide, 66: 33 hexane/ethyl acetate), obtain required Boc and protected amine (935 milligrams):
1H NMR (300MHz, CDCl
3) δ 7.60-7.59 (and m, 1H), 7.48-7.47 (m, 1H), 7.08-7.07 (m, 1H), 3.92 (s, 3H), 3.60-3.51 (m, 4H), 3.46-3,44 (m, 2H), 3.22-3.16 (m, 6H), 1.70-1.48 (m, 13H), 1.10-0.98 (m, 3H), 0.78-0.74 (m, 3H); ESI MS m/z 448[M+H]
+
Step 5: the Boc-that makes in step 4 is protected (953 milligrams of amine, 2.13 mmole) 2: 1: 1 diox/methanol (14.2 milliliters) solution in, add a hydronium(ion) oxidation lithium (268 milligrams, 6.39 mmoles), and reaction mixture at room temperature stirred spend the night.With the reaction mixture concentrating under reduced pressure, be divided into ethyl acetate layer and water layer then.With 1N hydrochloric acid aqueous phase as acidified is also used ethyl acetate extraction three times.With acetic acid ethyl acetate extract water and the saturated sodium-chloride washing that merges, dry (sodium sulfate), filter and concentrating under reduced pressure, make required 3-[4-(tert-butoxycarbonyl) piperazine-1-yl]-5-[(dipropyl amino) carbonyl] phenylformic acid (770 milligrams): ESI MS m/z 434[M+H]
+
Step 6: (320 milligrams of the acid that step 5 is made, 0.738 mmole) and (279 milligrams of HBTU, 0.738 mmole) containing N, the solution in the methylene dichloride (4.6 milliliters) of N-diisopropylethylamine (770 microlitres, 4.42 mmoles) at room temperature stirred 20 minutes.Add (2R therein, 3S)-and 3-amino-4-(3, the 5-difluorophenyl)-1-[(3-Ethylbenzyl) amino] fourth-2-alcohol (300 milligrams, 0.738 mmole) and N, the solution of N-diisopropylethylamine (770 microlitres, 4.42 mmoles) in methylene dichloride (4.6 milliliters).Reaction mixture at room temperature stirred spend the night.Then with the reaction mixture concentrating under reduced pressure, with the methylene dichloride dilution, with saturated sodium bicarbonate, water and saturated sodium-chloride washing.With organic layer drying (sodium sulfate), filter and concentrating under reduced pressure then, make yellow slurry.Purify by flash column chromatography (silicon-dioxide, 93: 7 chloroform/methanol), obtain required acid amides (443 milligrams): ESI MS m/z 750[M+H]
+
Step 7: the acid amides that makes in step 6 (220 milligrams, 0.293 mmole) adds hydrochloric acid (750 microlitres, 4M diox, 3.0 mmoles) 1 in the solution in the 4-diox (2.0 milliliters), and reaction mixture was at room temperature stirred 2 hours.Then with the reaction mixture concentrating under reduced pressure.Resistates is dissolved in methylene dichloride, and concentrating under reduced pressure once more.Repeat this operation until remaining solid.Do not need further purification.With the solid that reclaims under high vacuum through five phosphorus oxide with 50 ℃ of dryings 48 hours, obtain title compound (120 milligrams), characterize with the form of its dihydrochloride: mp 135-136 ℃; ESI MS m/z 650[M+H]
+
Embodiment SP-297
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(3-oxo-4-propyl group cyclohexyl) ethanamide
Step 1: with 2-propylphenol (26.83 grams, 197 mmoles), salt of wormwood (30.64 grams, 221 mmoles), methyl-iodide (50.0 milliliters, 800 mmoles) and hexaoxacyclooctadecane-6-6 (500 milligrams, the 1.9 mmoles) solution in acetone (300 milliliters) refluxed 48 hours.Reaction mixture is cooled to room temperature, filters and remove solid, and filtrate decompression is concentrated.Resistates phase-splitting between methylene dichloride and water with gained.Wash organic layer with 2N sodium hydroxide, water and saturated sodium-chloride, dry (sodium sulfate) filters and concentrating under reduced pressure, makes required oily methyl phenyl ether (23.46 gram), and it can use without further purification:
1H NMR (300MHz, CDCl
3) δ 7.16-7.11 (and m, 2H), 6.90-6.82 (m, 2H), 3.81 (s, 3H), 2.58 (m, 2H), 1.60 (tq, J=7,5Hz, 2H), 0.95 (t, J=7Hz, 3H).
Step 2: under-78 ℃, in the aaerosol solution of methyl phenyl ether (10.0 grams, 66.58 mmoles) in anhydrous ammonia (700 milliliters) that step 1 makes, add dehydrated alcohol (220 milliliters), add tetrahydrofuran (THF) (50 milliliters) again.Add the lithium metal (2.3 grams, 330 mmoles) that is divided into aliquot at-78 ℃ with 0.5 hour, generate dark blue solution.With this reactant-78 ℃ of stirrings until producing white solution.Remove cooling bath, flask is exposed under the atmosphere, under nitrogen gas stream, remove ammonia.Remaining solid residue is dissolved in minimum water, and with 10% hcl acidifying to pH 3, then for several times with extracted with diethyl ether.The ether that merges is washed with saturated sodium-chloride, and dry (sodium sulfate) filters, and carefully at 0 ℃ of following concentrating under reduced pressure, produces a kind of oil.This oil is dissolved in 10% hydrochloric acid (200 milliliters) and refluxed 3 hours.Then reaction mixture is cooled to room temperature and for several times with extracted with diethyl ether.The ether extraction liquid that merges is washed with saturated sodium-chloride, and dry (sodium sulfate) filters and concentrating under reduced pressure, produces a kind of oil.Purify by flash column chromatography (silicon-dioxide, 89: 11 hexane/ethyl acetate), obtain 2-propyl group cyclonene (4.43 gram):
1H NMR (300MHz, CDCl
3) δ 6.95-6.89 (and m, 1H), 5.97 (app dt, J=10,2Hz, 1H), 2.39-2.36 (m, 3H), 2.20-2.04 (m, 1H), 1.88-1.63 (m, 2H), 1.50-1.25 (m, 4H), 0.93 (t, J=7Hz, 3H).
Step 3: the solution of sodium metal (30 milligrams, 1.30 mmoles) in dehydrated alcohol (4.0 milliliters) was stirred 0.5 hour at-10 ℃.Add diethyl malonate (3.5 milliliters, 23 mmoles) at-10 ℃, add the solution of 2-propyl group cyclonene (3.0 grams, 21.7 mmoles) in dehydrated alcohol (3.0 milliliters) then.With reaction mixture restir 12 hours at room temperature.With 10% hydrochloric acid reaction mixture is acidified to pH 3, then for several times with extracted with diethyl ether.With the ether extraction liquid water and the saturated sodium-chloride washing that merge, dry (sodium sulfate) filters and concentrating under reduced pressure, produces a kind of yellow oil.Purify by flash column chromatography (silicon-dioxide, 83: 17 hexane/ethyl acetate), make 2-(3-oxo-4-propyl group-cyclohexyl)-diethyl malonate (5.07 gram):
1H NMR (300MHz, CDCl
3) δ 4.21 (and q, J=7Hz, 2H), 4.20 (q, J=7Hz, 2H), 3.30 (s, 0.5H), 3.28 (s, 0.5H), 2.67-1.55 (m, 8H), 1.43-1.11 (m, 10H), 0.90 (t, J=7Hz, 1.5H), 0.90 (t, J=7.0Hz, 1.5H).
Step 4: the solution of diester (2.37 grams, 7.94 mmoles) in 1N potassium hydroxide (16.27 milliliters, 16.27 mmoles) that step 2 is made refluxed 2 hours.Reaction mixture is cooled to room temperature, dilute with water, and use dichloromethane extraction.Use the 6N hcl acidifying to pH 1-2 water, refluxed then 2 hours.Reaction mixture is cooled to room temperature and with dichloromethane extraction for several times.With the organic phase water and the saturated sodium-chloride washing that merge, dry (sodium sulfate) filters and concentrating under reduced pressure, produces light yellow oil.Purify by flash column chromatography (silicon-dioxide, 66: 33 hexane/ethyl acetate contain 1% Glacial acetic acid), obtain (3-oxygen-4-propyl group-cyclohexyl)-acetate (1.42 gram):
1H NMR (300MHz, CDCl
3) δ 2.71-1.12 (and m, 14H), 1.11-0.82 (m, 3H); ESI MS m/z 197[M-H]
-
Step 5: (244 milligrams of the acid that in step 4, makes, 1.23 mmole) and N, N-diisopropylethylamine (214 microlitres, 1.23 mmole) in the solution in methylene dichloride (7.0 milliliters) through stirring, add (513 milligrams of HBTU, 1.35 mmole), and with reaction mixture stirred 0.5 hour.In above-mentioned solution, add amine (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] (500 milligrams of fourths-2-alcohol, 1.35 mmole) and N, N-one diisopropylethylamine (428 microlitres, 2.46 the solution in methylene dichloride (7.0 milliliters) mmole), and reaction mixture stirred 18 hours under nitrogen.Then reaction mixture is washed with the methylene dichloride dilution and with saturated sodium bicarbonate, 0.5N hydrochloric acid and saturated sodium-chloride again.With organic layer drying (sodium sulfate), filter and concentrating under reduced pressure then, make the oily resistates.Purify by flash column chromatography (silicon-dioxide, 7: 93 ethanol/methylene), obtain title compound (360 milligrams): mp 52-54 ℃; ESI MS m/z 515[M+H]
+
Embodiment SP-298
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(3-oxo cyclohexyl) ethanamide
Step 1: the synthetic method according to above-mentioned 2-(3-oxo-4-propyl group-cyclohexyl)-diethyl malonate prepares (3-oxo-cyclohexyl)-diethyl malonate by cyclonene, and productive rate is 88%:
1H NMR (300MHz, CDCl
3) δ 4.44-4.12 (and m, 4H), 2.88-1.22 (m, 16H).
Step 2: the synthetic method according to above-mentioned (3-oxo-4-propyl group-cyclohexyl)-acetate prepares (3-oxo-cyclohexyl)-acetate by (3-oxo-cyclohexyl)-diethyl malonate, and productive rate is 70%:
1H NMR (300MHz, CDCl
3) δ 2.58-1.92 (and m, 7H), 1.80-1.61 (m, 1H), 1.52-1.42 (m, 1H); ESI MS m/z 155[M-H]
-
Step 3: according to N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-and the 3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-synthetic method of 2-(3-oxo-4-propyl group cyclohexyl) ethanamide (embodiment SP-297) prepares N-{ (1S by (3-oxo-cyclohexyl)-acetate, 2R)-1-(3, the 5-difluorobenzyl)-and the 3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(3-oxo cyclohexyl) ethanamide, productive rate is 23%:mp 139.5-149.8 ℃; ESI MS m/z 473[M+H]
+
Embodiment SP-299
3-benzyl-4-(4-butyl phenyl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-oxo butyramide
Step 1:, phenyl aldehyde (2.81 milliliters, 27.15 mmoles) is added the solution that contains sodium hydroxide (1.39 grams, 34.75 mmoles) of 4-butyl-phenyl methyl ketone (5.26 milliliters, 27.15 mmoles) in methyl alcohol (7.8 milliliters) and water (13.0 milliliters) at 0 ℃.Reactant is warmed to room temperature and stirred 48 hours.Reaction mixture is diluted also water, saturated sodium-chloride washing with ethyl acetate, and dry (sodium sulfate) filters, and concentrated, makes a kind of light yellow slurry.Under high vacuum,, make required ketenes (6.3 gram): ESI MS m/z 265[M+H] in 120 ℃ of removal volatile impunties
+
Step 2: the solution of ketenes (2.0 grams, 7.56 mmoles) in anhydrous diethyl ether (11 milliliters) that makes in the step 1 is joined the solution of lithium metal (120 milligrams, 16.6 mmoles) in anhydrous liquid ammonia (11 milliliters) at-78 ℃.Reactant was stirred 0.5 hour at-78 ℃, and eliminate excessive lithium, produce a kind of yellow liquid with several piperylenes.Disposable adding bromoacetic acid lithium (2.75 gram, 18.9 mmoles) also stirs reactant 0.5 hour at-78 ℃, stirs 2 hours at-33 ℃ then.Use NH then
4Cl finishes reaction, and the opening reactor is warmed to room temperature.Resistates is divided into ethyl acetate layer with water layer and separate phase-splitting.With organic phase water, saturated sodium-chloride washing, dry (sodium sulfate) filters and concentrates, and produces a kind of yellow slurry.Purify by flash column chromatography (silicon-dioxide, 74: 25: 1 hexane/ethyl acetate/acetate), make 3-benzyl-4-(4-butylbenzene base)-4-ketobutyric acid (60 milligrams): ESI MS m/z 325[M+H]
+
Step 3: with (60 milligrams of 3-benzyl-4-(4-butylbenzene base)-4-ketobutyric acid, 0.185 mmole) and (70 milligrams of HBTU, 0.185 mmole) contain N in methylene dichloride (1.2 milliliters), the solution of N-diisopropylethylamine (100 microlitres, 0.55 mmole) at room temperature stirred 20 minutes.Add amine (2R therein, 3S)-and 3-amino-4-(3, the 5-difluorophenyl)-1-[(3-Ethylbenzyl) amino] fourth-2-alcohol (75 milligrams, 0.185 mmole) and N, the solution of N-diisopropylethylamine (100 microlitres, 0.55 mmole) in methylene dichloride (1.2 milliliters).Reaction mixture at room temperature stirred spend the night.With the reaction mixture concentrating under reduced pressure, wash with the methylene dichloride dilution and with saturated sodium bicarbonate, water and saturated sodium-chloride then, dry (sodium sulfate) filters and concentrating under reduced pressure, makes colourless slurry.Purify by flash column chromatography (silicon-dioxide, 93: 7 chloroform/methanol), obtain title compound (36 milligrams) (non-enantiomer mixture): mp 42-45 ℃; ESI MS m/z 641[M+H]
+
Embodiment SP-300
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(1H-indoles-6-yl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine
Step 1: in-78 ℃, the solution of 1H-indoles-6-methyl-formiate (500 milligrams, 2.85 mmoles) in methylene dichloride (11.5 milliliters), add diisobutyl aluminium hydride (5.70 milliliters, the 1.0M solution in methylene dichloride) through stirring.Reaction mixture was stirred 2 hours at-78 ℃, slowly be warmed to room temperature 10 hours.Make the reaction mixture stopped reaction with methyl alcohol, with Rochelle salt (saturated sodium tartrate aqueous solutions of potassium) washing, dry (sal epsom), and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 6: 1 ethyl acetate/hexane), obtain a kind of alcohol (100 milligrams):
1H NMR (300MHz, CDCl
3) δ 8.21 (and br s, 1H), 7.62 (d, J=9Hz, 1H), 7.39 (s, 1H), 7.20-7.22 (m, 1H), 7.10-7.13 (m, 1H), 6.54-6.56 (m, 1H), 4.77 (d, J=3Hz, 2H), 1.60 (s, 1H).
Step 2: in the solution through stir of alcohol (100 milligrams, 0.68 mmole) in methylene dichloride (3 milliliters) that step 1 makes, add magnesium oxide (590 milligrams, 6.8 mmoles), and reaction mixture was stirred 1 hour.Reaction mixture through diatomite filtration and concentrating under reduced pressure, is made the 1H-indoles-6-carbaldehyde (99 milligrams) of solid state, and it is without further purifying or characterizing promptly with continuing use.
1H NMR(300MHz，CDCl
3)δ10.03-10.88(m，1H)、8.56(br s，1H)、7.96(s，1H)、7.74(d，J＝8Hz，1H)、7.64-7.70(m，1H)、7.46(t，J＝3Hz，1H)、6.65(s，1H)。
Step 3: (99 milligrams of 1H-indoles-6-carbaldehyde, 0.68 mmole) and (1S, 2R)-3-amino-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl carbamate tert.-butyl acetate 3 (256 milligrams, 0.68 mmole) in the solution in 2-propyl alcohol (3 milliliters) through stirring, add sodium borohydride (30 milligrams, 0.82 mmole).This reaction mixture was stirred 12 hours, make its stopped reaction with methyl alcohol, and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 1: 1 ethyl acetate/hexane), make indoles (50 milligrams):
1H NMR (300MHz, CDCl
3) δ 8.41 (and br s, 1H), 7.60 (d, J=8Hz, 1H), 7.38 (s, 1H), 7.21 (t, J=3Hz, 1H), 7.04 (dd, J=8,1Hz, 1H), 6.71-6.73 (m, 3H), 6.61-6.68 (m, 1H), 6.53 (s, 1H), 5.38 (br s, 2H), 4.66 (d, J=9Hz, 1H), 3.89 (s, 2H), 3.49-3.54 (m, 1H), 2.91-2.98 (m, 1H), 2.62-2.73 (m, 3H), 1.35 (s, 9H).
Step 4: in the solution of the indoles (50 milligrams, 0.11 mmole) that the step 3 through stirring makes, add hydrochloric acid (0.27 milliliter, the solution in the 4.0M Zai diox).Reaction mixture was stirred 1 hour, with the ethyl acetate dilution, and concentrating under reduced pressure, make (2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-[(1H-indoles-6-ylmethyl) amino] fourth-2-alcohol hydrochloride 4 (70 milligrams): ESI MS m/z 346[M+H]
+
Step 5: at 3-[(dipropyl amino) carbonyl]-(29 milligrams of 5-tolyl acids (5), 0.11 mmole) in the solution in methylene dichloride (3 milliliters) through stirring, add (64 milligrams of HBTU, 0.17 mmole), HOBt is (23 milligrams, 0.17 mmole) and N, (0.075 milliliter of N-diisopropylethylamine, 0.44 mmole), add (2R then, 3S)-3-amino-4-(3, the 5-difluorophenyl)-and 1-[(1H-indoles-6-ylmethyl) amino] fourth-2-alcohol hydrochloride 4 (70 milligrams, 0.11 mmole).Reaction mixture was stirred 12 hours, with the methylene dichloride dilution, water, saturated sodium bicarbonate washing, dry (sal epsom) filters and concentrating under reduced pressure.Purify by flash column chromatography (silicon-dioxide, 89: 10: 1 chloroform/methanol/ammonium hydroxide), obtain title compound (6) (13 milligrams): mp 135-137 ℃; ESI MS m/z 591[M+H]
+
Embodiment SP-301
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,3-benzo dioxole-5-methane amide
At protocatechuic acid methylene ether (0.500 gram, 3.01 EDC (0.867 gram mmole),, 4.52 HOBT (0.611 gram mmole),, 4.52 mmole) in the solution in dry DMF (10 milliliters), add (1.67 milliliters of TEA, 12.04 mmole), 3-amino-4-(3, the 5-difluorophenyl)-1-(3-ethyl-benzyl amino)-Ding-2-alcohol (1.693 grams, 3.01 mmoles) and dry DMF (5 milliliters).Reaction mixture stirred under nitrogen spend the night.Make the reaction mixture stopped reaction with 10% sodium bicarbonate (aqueous solution), use ethyl acetate extraction then.Organic layer with 1N HCl washing, is used 10% sodium bicarbonate (aqueous solution) washing then.Through the dried over mgso organic layer, filter, concentrate in a vacuum then, make product.(ES+：483.2)
Embodiment SP-302
(1S, 2R)-1-[3-(benzyloxy)-5-luorobenzyl]-the 3-[(3-Ethylbenzyl) amino]-2-hydroxypropyl t-butyl carbamate
Will [2-(3-benzyloxy-5-fluorine-based-phenyl)-1-Oxyranyle-ethyl]-t-butyl carbamate (3.33 grams, 8.59 mmoles) and an ethyl benzyl amine (2.32 grams, 17.19 mmoles) be dissolved in Virahol (80 milliliters) and refluxed 2 hours.Then reaction mixture is concentrated in a vacuum to remove Virahol.Yellow liquid is dissolved in ethyl acetate (30 milliliters), uses 1N HCl (3 * 100 milliliters) washing then.Water layer is merged, use ethyl acetate (2 * 100 milliliters) extraction then.Organic layer with 10% sodium bicarbonate (3 * 100 ml water solution), is used the salt water washing then.Organic layer through dried over sodium sulfate, is filtered, concentrate in a vacuum then, make product (4.31 gram).(ES+：523.9)
Embodiment SP-303
5-[((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl) amino]-the 5-oxopentanoic acid
At 3-amino-4-(3, the 5-difluorophenyl)-1-[1-(3-ethyl-phenyl)-cyclopropylamino]-solution of Ding-2-alcohol (0.500 gram, 1.387 mmoles) in chloroform (7 milliliters) in, add (0.58 milliliter of TEA, 4.161 mmole), under nitrogen, stirred 30 minutes simultaneously.In this solution, add glutaric anhydride (0.158 gram, 1.387 mmoles) and reactant is spent the night 50 ℃ of stirrings.Reaction mixture is concentrated in a vacuum, make product.(ES+：475.2)
Embodiment SP-304
4-[((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl) amino]-the 4-ketobutyric acid
At 3-amino-4-(3, the 5-difluorophenyl)-1-[1-(3-ethyl-phenyl)-cyclopropylamino]-solution of Ding-2-alcohol (0.500 gram, 1.387 mmoles) in chloroform (7 milliliters) in, add (0.58 milliliter of TEA, 4.161 mmole), under nitrogen, stirred 30 minutes simultaneously.In this solution, add succinic anhydride (0.138 gram, 1.387 mmoles) and reactant is spent the night 50 ℃ of stirrings.Concentrate reaction mixture in a vacuum second day morning, makes product.(ES+：461.2)
Embodiment SP-305
Formic acid and N
1-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-N
5-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl) compound (1: 1) of glutaramide
At R-amino quinine ring (0.084 gram, 0.421 mmole), TEA is (0.294 milliliter, 2.11 mmole) and in the solution of dry DMF (2.5 milliliters), under nitrogen, add 5-[((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl) amino]-5-oxopentanoic acid (0.200 gram, 0.421 EDC (0.121 gram mmole),, 0.632 mmole), HOBT (0.085 gram, 0.632 mmole), spend the night 45 ℃ of stirrings simultaneously.Make the reaction mixture stopped reaction with 10% sodium bicarbonate (aqueous solution), use ethyl acetate extraction then, concentrate in a vacuum then, make product (0.122 gram).Prep-HPLC produces the product of formate form.(ES+：583.3)
Embodiment SP-306
Formic acid cpds and N
1-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-N
5-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl) glutaramide (1: 1)
At S-amino quinine ring (0.084 gram, 0.421 mmole), TEA is (0.294 milliliter, 2.11 mmole) and in the solution of dry DMF (2.5 milliliters), under nitrogen, add 5-[((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl) amino]-5-oxopentanoic acid (0.200 gram, 0.421 EDC (0.121 gram mmole),, 0.632 mmole), HOBT (0.085 gram, 0.632 mmole), spend the night 45 ℃ of stirrings simultaneously.Make the reaction mixture stopped reaction with 10% sodium bicarbonate (aqueous solution), use ethyl acetate extraction then, concentrate in a vacuum then, make product (0.065 gram).Prep-HPLC produces the product of formate form.(ES+：583.3)
Embodiment SP-307
Formic acid cpds and N
1-[(3S)-1-azabicyclo [2.2.2] oct-3-yl-N
4-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl) succinic diamide (1: 1)
At R-amino quinine ring (0.086 gram, 0.434 mmole), TEA is (0.302 milliliter, 2.17 mmole) and in the solution of dry DMF (2.5 milliliters), under nitrogen, add 4-[((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl) amino]-4-ketobutyric acid (0.200 gram, 0.434 EDC (0.125 gram mmole),, 0.651 mmole) and HOBT (0.088 gram, 0.651 mmole), spend the night 45 ℃ of stirrings simultaneously.Make the reaction mixture stopped reaction with 10% sodium bicarbonate (aqueous solution), use ethyl acetate extraction then, concentrate in a vacuum then, make product (0.200 gram).Prep-HPLC produces the product of formate form.(ES+：569.3)
Embodiment SP-308
Formic acid cpds and N
1-[(3R)-1-azabicyclo [2.2.2] oct-3-yl-N
4-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl) succinic diamide (1: 1)
At S-amino quinine ring (0.086 gram, 0.434 mmole), TEA is (0.302 milliliter, 2.17 mmole) and in the solution of dry DMF (2.5 milliliters), under nitrogen, add 4-[((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl) amino]-4-ketobutyric acid (0.200 gram, 0.434 EDC (0.125 gram mmole),, 0.651 mmole) and HOBT (0.088 gram, 0.651 mmole), spend the night 45 ℃ of stirrings simultaneously.Make the reaction mixture stopped reaction with 10% sodium bicarbonate (aqueous solution), use ethyl acetate extraction then, concentrate in a vacuum then, make product (0.093 gram).Prep-HPLC produces the product of formate form.(ES+：569.3)
Embodiment SP-309
MP represents macroporous resin.
2: in ice/water-bath, cool off 1 (2.50 grams; 5.75 mmole) and (1.20 milliliters of DIEA; 6.90 the solution in DCM (100 milliliters) mmole).Add (0.73 milliliter of allyl chlorocarbonate; 6.90 mmole), and with 4 hours make reactant go back up to room temperature.With reactant 10%K
2CO
3(100 milliliters), water (100 milliliters), salt solution (100 milliliters) washing, and through Na
2CO
3Dry.On 90 gram silica gel, carry out flash chromatography and separate, obtain 2.88 gram (5.55 mmoles with the 0-30%EtOAc/ heptane; 96%) white solid 2.
3: with 2 (2.88 grams; 5.55 mmole) and Dowex 50WX2 (Aldrich; 8.88 gram; About 44.4 mmoles) solution in MeOH (100 milliliters) is heated to 50 ℃ and reaches 5.25 hours.This reactant is cooled to room temperature and filtration.With MeOH this resin is thoroughly washed, and with this product with the eluant solution of about 3.5M ammonia in MeOH.After removing solvent, collect 2.11 gram (5.04 mmoles; 91%) the canescence waxy solid 3.
5: in the phial that contains 4-(chlorosulfonyl) phenylformic acid 4 (2.0 milliliters, the THF solution of 0.05M), add suitable amine (0.3 mmole), if necessary, also contain 1 normal DIEA (to discharge any amine hydrochlorate) in this phial.This phial was shaken 18 hours with room temperature/250rpm on a track wobbler.In each phial, add MP-isocyanate resin (about 0.6 mmole), be heated to 60 ℃ and reach 5 hours.Reactant is filtered,, and concentrate with the thorough washing resin of THF.
6: use HATU (1.2 equivalent) and DIEA (2.4 equivalent) in DMF, acid 5 to be protected TSI3 coupling at room temperature 18 hours with Alloc-.Add MP-isocyanic ester (3 equivalent) and MP-carbonic ether (1 equivalent) then, and reactant was at room temperature shaken 4 hours.Reactant is filtered, with 1, the thorough washing resin of 2-ethylene dichloride, and concentrate.Resistates is dissolved in 1, and 2-ethylene dichloride (1.5 milliliters) with 1M citric acid (1.5 milliliters) washing, and is placed on 3 milliliters of volume V arian ChemElut Hydromatrix cylinders.After 5 minutes, with product with 1,2-ethylene dichloride (2 * 6 milliliters) wash-out, and concentrating in a vacuum.
7: under 60 ℃, use Pd (Ph
3P)
4(0.15 equivalent) and 1,3-dimethyl barbituric acid (20 equivalent) makes Alloc intermediate 6 deprotections 3 hours in THF.Reactant is concentrated in a vacuum, and crude reaction mixture is placed on uses 5 milliliters of MeOH to carry out SCX on 1000 milligrams/3 milliliters SCX cylinders.This cylinder is thoroughly washed with MeOH, and with the MeOH eluant solution of product with about 3.5M ammonia.If desired, preparing UV HPLC by high percent of pass purifies final product.
Use the method for preparing following compounds.
Embodiment SP-310
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[methyl (methylsulfonyl) amino]-1,3-oxazole-4-methane amide
2-amino-1,3-oxazole-4-ethyl formate
Step 1. adds (20 grams, 0.3332 mole) urea, (150 milliliters) ethanol and (42.42 grams, 0.2175 mole, 0.65 equivalent) ethyl bromide acetone in 250 milliliters three neck round-bottomed flasks.Then this mixture is heated with stirring to and refluxed 16 hours.Reaction soln becomes redness from yellow.Then reaction soln is evaporated as for also handling this raw product with (50 milliliters) water and (150 milliliters) ethyl acetate.With 2N sodium hydroxide the pH value is adjusted to 10 from 1, this biphase mixture becomes garnet.Twice of ethyl acetate extraction water also used in this mixture phase-splitting.Then organic layer is merged water and salt water washing.The yellow solution that makes is concentrated into about 50 milliliters, is settled out a kind of pale solid.This solid of filtering is also used ethanol and the ether washing.Then mother liquid evaporation to dry doubling is handled the oily solid that makes with (150 milliliters) ethyl acetate, and be concentrated into about 50 milliliters.Be settled out a kind of pale solid.This mixture is cooled off in ice bath, and the filtering solid makes 2-amino-1 also with ethanol and ether washing, 3-oxazole-4-ethyl formate (14.79 gram).
The 2-[(methylsulfonyl) amino]-1,3-oxazole-4-ethyl formate
Step 2. adds (1 gram, 5.8069 mmoles) 2-amino-1,3-oxazole-4-ethyl formate, (10 milliliters) methylene dichloride and (1.39 milliliters, 7.9797 mmoles, 1.25 equivalents) N, N-diisopropylethylamine in 20 milliliters nut phial.In this reactant, add (0.545 milliliter, 7.0415 mmoles, 1.1 equivalents) methylsulfonyl chloride then, and reactant was stirred 14 hours.This reactant is evaporated to dry doubling uses the Biotage silicagel column to purify, produce (272 milligrams) 2-[(methylsulfonyl) amino]-1,3-oxazole-4-ethyl formate.
2-[methyl (methylsulfonyl) amino]-1,3-oxazole-4-ethyl formate
Step 3. adds (101.8 milligrams, 0.4346 mmole) 2-[(methylsulfonyl under nitrogen in 25 milliliters of round-bottomed flasks) amino]-1,3-oxazole-4-ethyl formate, (180.2 milligrams, 1.3038 mmoles, 3.0 equivalents) salt of wormwood and (5 milliliters) acetonitrile.At room temperature stir this mixture then, add (33.8 microlitres, 0.5429 mmole, 1.25 equivalents) methyl iodide simultaneously.Reaction was at room temperature carried out 3 hours.The electrospray mass spectrum indicates most of starting material.Remove nitrogen gas stream, add (40 microlitres, 0.6425 mmole, 1.5 equivalents) methyl iodide again.Reactant at room temperature placed spend the night.Make the reactant stopped reaction and use dichloromethane extraction with (5 milliliters) 1N HCl.Wash organic layer with water, be evaporated to dried then.By preparation HPLC gained oil is purified, generates (70 milligrams) 2-[methyl (methylsulfonyl) amino]-1,3-oxazole-4-ethyl formate.
2-[methyl (methylsulfonyl) amino]-1,3-oxazole-4-formic acid
Step 4. adds (61 milligrams in 50 milliliters of round-bottomed flasks; 0.2457 2-[methyl (methylsulfonyl) amino mmole)]-1; 3-oxazole-4-ethyl formate, (51.5 milligrams, 1.2274 mmoles, 5.0 equivalents) lithium hydroxide, (2.5 milliliters) tetrahydrofuran (THF) and (1.5 milliliters) water.With reactant stir about 2 hours at room temperature.Finish reaction by the electrospray mass spectrum.Add (5 milliliters) 1N HCl processing reaction thing, use ethyl acetate extraction then.Water and salt water washing organic layer are used dried over mgso then.Then solvent evaporation is extremely done remaining (44.6 milligrams) 2-[methyl (methylsulfonyl) amino]-1,3-oxazole-4-formic acid.
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[methyl (methylsulfonyl) amino]-1,3-oxazole-4-methane amide
Step 5. adds (20.9 milligrams in 7 milliliters of nut phials; 0.0949 2-[methyl (methylsulfonyl) amino mmole)]-1; 3-oxazole-4-formic acid, (36.7 milligrams, 0.1097 mmole, 1.15 equivalents) (2R; 3S)-3-amino-4-(3; the 5-difluorophenyl)-and the 1-[(3-Ethylbenzyl) amino] fourth-2-pure and mild (54.6 milligrams, 0.1436 mmole, 1.5 equivalents) HATU; add (1.25 milliliters) N, dinethylformamide then.Reactant is placed on the track wobbler and at room temperature placed 2 hours.With (2 milliliters) 1N HCl reaction is stopped.Clear solution with ethyl acetate extraction three times and with the organic layer saturated sodium carbonate solution that merges, is used the salt water washing then.Then with this solution with dried over mgso and flash to a kind of clean oil; HPLC purifies it by preparation; generate N-{ (1S; 2R)-1-(3; the 5-difluorobenzyl)-and the 3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[methyl (methylsulfonyl) amino]-1,3-oxazole-4-methane amide (15.7 milligrams).
Embodiment SP-311
3-cyano group-5-[(dipropyl amino) carbonyl] methyl benzoate
With 3-bromo-5-[(dipropyl amino) carbonyl] methyl benzoate (goods 3) (0.15 gram), cupric cyanide (I) and N-Methyl pyrrolidone (1 milliliter) are 150 ℃ of heated overnight, and this moment is with this mixture cooling and phase-splitting between the ethyl acetate and the HCl aqueous solution (1N).With organic layer drying (sal epsom), concentrating under reduced pressure, and on silica gel, use ethyl acetate-hexane (20/80) to carry out chromatographic separation the resistates, make the required product of 0.066 gram.ms(m+H)289.2。Preparation for acid also can be referring to goods 7.
Embodiment SP-312
(2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-{[3-(trifluoromethyl) benzyl] amino } fourth-2-alcohol dihydrochloride
Mixture in Virahol (25 milliliters) stirred 4 hours under refluxing at oxyethane (1.0 gram) and 3-(trifluoromethyl) benzylamine (1.2 gram), and remove solvent with this mixture cooling and decompression this moment.Make resistates phase-splitting between the ethyl acetate and the HCl aqueous solution (1N), and with organic layer drying (sodium sulfate), concentrate, and on silica gel, use methyl alcohol-methylene dichloride (5/95) to carry out chromatographic separation, make 1.0 gram (1S, 2R)-and 1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } the propyl carbamic acid tert-butyl ester.
Mainly use the method for describing among the embodiment SP-272 to remove carbamate groups then.
Embodiment SP-313
3-[(dipropyl amino) carbonyl]-5-acetylenylbenzene formic acid
Step 1: with 3-bromo-5-[(dipropyl amino) carbonyl] methyl benzoate (25) (200 milligrams, 0.58 mmole), PdCl
2(Ph
3P)
2(16 milligrams, 0.03 mmole) and CuI (6 milligrams, the 0.05mol%) vlil in triethylamine (1.2 milliliters).Add (trimethyl silyl) acetylene (100 microlitres, 0.7 mmole), bright yellow solution became orange in one minute rapidly, became brown then.Reaction mixture was stirred 3 hours, be cooled to room temperature, use H
2O (20 milliliters) dilution, and use CHCl
3(3 * 15 milliliters) extraction.The organism that merges is washed dry (Na with saturated NaCl (20 milliliters)
2SO
4), filter, and concentrating under reduced pressure, make 3-[(dipropyl amino) carbonyl]-the 5-[(trimethyl silyl) ethynyl] methyl benzoate 26 (185.5 milligrams):
1H NMR (300MHz, CDCl
3) δ 7.95 (and s, 1H), 7.75 (s, 1H), 7.43 (s, 1H), 3.74 (s, 3H), 3.25 (br s, 2H), 2.95 (br s, 2H), 1.49 (br s, 2H), 1.34 (br s, 2H), 0.79 (br s, 3H), 0.56 (br s, 3H), 0.06 (s, 9H).
Step 2: at 3-[(dipropyl amino) carbonyl]-the 5-[(trimethyl silyl) ethynyl] (185.3 milligrams of methyl benzoate 26,0.49 mmole) in the solution in MeOH (2.5 milliliters) through stirring, add KOH solution (2.9 milliliters, the 1M aqueous solution, 2.9 mmoles).The homogeneous phase brown solution that makes becomes white/brown suspension, becomes transparent brown solution then.Reaction mixture was stirred 4 hours, use CHCl
3(40 milliliters) dilution, phase-splitting, and, make 3-[(dipropyl amino with the organic layer concentrating under reduced pressure) carbonyl]-5-acetylenylbenzene formic acid 27 (141.8 milligrams):
1H NMR (300MHz, CDCl
3) δ 8.22 (d, J=1Hz, 1H), 8.05 (d, J=1Hz, 1H), 7.71 (d, J=1Hz, 1H), 3.48 (br s, 2H), 3.17 (s, 1H), 3.16 (br s, 2H), 1.71 (d, J=7Hz, 2H), 1.55 (d, J=7Hz, 2H), 1.00 (d, J=7Hz, 3H), 0.78 (d, J=7Hz, 3H).
Following compounds also is to use above-mentioned steps and the preparation of following chart.
* mean M/Z (EI)
* means M+H (CI)
* * means OAMS
* * * means MS Data
Figure A
Figure B
Figure C
Figure D
Figure E
Figure F
Figure G
Figure H
Figure I
Figure J
Figure K
Figure L
Figure M
Figure N
Figure O
Figure P
Figure Q
Figure R
Figure T
Figure U
Diagram U describes the preparation method of the ketone of the present invention's use in detail.Preferred halogen is a bromine or iodine.The halogenated benzoic acid ester that can obtain by commercial sources under the condition that has catalyzer (for example palladium catalyst, as dichloro two (triphenyl phosphine) palladium) with (α-vinyl ethyl ether base)-tributyl coupling, generate the benzoic ether that methyl ketone replaces after the hydrolysis treatment.In a kind of preferred implementation of the present invention, this reaction is carried out in anhydrous organic solvent.In another preferred embodiment of the present invention, this reaction is carried out in dry toluene.(Kosugi and Migita, Bull.Chem.Soc., Jpn., 1987,60,767-768).Alkyl with the stoichiometry surplus '-LG (or alkyl "-LG) carry out the nucleophilic addition of base catalysis, generate symmetric dialkyl group product, it can directly change into the equivalent benzoic ether according to the intensity of alkali.Perhaps, the benzoic ether that this methyl ketone replaces can with low excessive alkyl '-the LG reaction, generate mono-substituted derivative.By with alkyl "-LG carries out the reaction of base catalysis, thereby with the further alkylation of described derivative.Be appreciated that LG is aforesaid leavings group.Those skilled in the art understand how to carry out alkylation.In a kind of preferred implementation of the present invention, described alkylation is by sodium hydroxide or potassium hydroxide catalysed.In another preferred implementation of the present invention, this alkylation is at dipolar aprotic solvent, for example carries out in the methyl-sulphoxide.
Figure V
Scheme the synthetic of substituted ring propyl group benzylamine V.3-and relevant assorted arylamine (among the figure V Y.6).The 3-substituted benzyl oxygen nitrile that can buy and 1-bromo-2-monochloroethane react under the condition that has alkali aqueous solution and phase-transfer catalyst, generate Cyclopropanated benzyl nitrile (Y.2).This prussiate (Y.2) is changed into acid amides (Y.3), and the reactant aqueous solution of itself and alkali generates acid (Y.4) after the acidic treatment.Acid (Y.4) changes into chloride of acid (Y.5), and itself and trinitride react, and generate intermediate, with its rearrangement and decomposition, make product (Y.6).Then (Y.6) reacted formation inhibitor (X) according to figure JJ.Embodiment 2353 provides typical step.
Figure Z
Figure Z. epoxide I and aromatics hydrazine react in Virahol, make unsubstituted hydrazine nitrogen generation selective alkylation reaction, and generation hydrazine II (M.Nakakata, Tetrahedron Letters 1993,6095-6098).Use acylating agent with one in the hydrazine nitrogen; benzyloxycarbonyl acidylate for example; generate III and reduced this part reactivity further acidylate; whichever hydrazine nitrogen be first carry out acidylate (B.Gisin, Helv.Chim.Acta 1970, the volume 53; 1030-1043.S.Shinagawa; Chem.Pharm.Bull.1981, volume 29,3630-3638).Remove the tert-butoxycarbonyl protecting group of III, generate unhindered amina IV, use carbodiimide or other known coupling agent to make itself and m-phthalic acid (XIV) coupling.With hydrazine nitrogen deacylated tRNA, generated compound V.
Figure AA
Figure AA step:
At the selectively acylating (D.Butler that replaces the methyl hydrazine on the nitrogen, J.Medicinal Chemistry 1971, volume 14,1052-1054), produce acylhydrazine VI, itself and epoxide I react in Virahol, form adducts VII (S.Wang.J.Medicinal Chemistry, 1997, volume 40,937-941; G.Bold, J.MedicinalChemistry, 1998, volume 41,3387-3401).Remove the tert-butoxycarbonyl protecting group,, generate final product IX then with m-phthalic acid (XIV) coupling.
Figure BB
Figure BB step:
Epoxide X and the reaction of O-benzyl hydroxylamine, and generation adducts XI (S.Rosenberg, J.Medicinal Chemistry, 1990, volume 33,1582-1590).Remove the tert-butoxycarbonyl protecting group, use m-phthalic acid XIV acidylate then, generate target compound XIII.
Figure CC
Figure CC. uses the method that well known to a person skilled in the art, aniline XXXI with chloride of acid or anhydride acylation or with sulfonic acid halide or the sulfonation of sulphonyl acid anhydrides, is generated sulphonamide-I.Make sulphonamide-I alkylation with RX, wherein X is a leavings group, and for example there are alkali in Cl, Br, tolylsulfonyl ester or methylsulfonyl ester in this reaction, and for example trialkylamine, sodium hydride, piperidines or potassium tert.-butoxide make sulphonamide-II.
Figure DD
Figure DD. uses the method that well known to a person skilled in the art, amine-a with chloride of acid or anhydride acylation or with sulfonic acid halide or the sulfonation of sulphonyl acid anhydrides, is generated sulphonamide-I.Make sulphonamide-Ia alkylation with RX, wherein X is a leavings group, and for example there are alkali in Cl, Br, tolylsulfonyl ester or methylsulfonyl ester in this reaction, and for example trialkylamine, sodium hydride, piperidines or potassium tert.-butoxide make sulphonamide-IIa.
Figure EE
There is catalyzer (palladium (0) catalyzer for example in figure EE., as two (dibenzalacetone) palladium (0)), additive (is preferably 1,1 '-two (diphenyl phosphine) ferrocene) and under the condition of alkali (for example trialkylamine), organic solvent (for example N-Methyl pyrrolidone (NMP) or DMF) in, in room temperature to the temperature of reflux temperature, (I) is coupled to mercaptan RSH with iodoxy amine, generates sulfide (II).With hydrogen peroxide under the condition that has acid, or with a kind of peracid (for example metachloroperbenzoic acid) with sulfide (II) oxidation, generation sulfone (III).Other method for oxidation has been described, Smith and March for example, Advanced Organic Chemistry in the reference; Reactions, Mechanisms, and Structure, the 5th edition, Wiley Interscience, 2001.If sulfone (III) is a kind of ester, carry out alkaline hydrosolisis with a kind of alkali (for example lithium hydroxide, sodium hydroxide or potassium hydroxide), use acid treatment then, thus with its further hydrolysis, generate carboxylic acid (IV does not mark).With acid (IV) and amine coupling, generate the ultimate aim product then.
Figure FF
Figure FF
The halogeno-benzyl derivative of figure FF. structural formula (1).(1) with thiolate (for example mercaptan lithium, sodium mercaptides or mercaptan potassium) in organic solvent (for example THF, toluene or acetonitrile), to the temperature that refluxes, reacting the sulfanyl derivative of generating structure formula (2) from room temperature.Under the condition that has acid (for example acetate or metachloroperbenzoic acid), in organic solvent (for example methylene dichloride),, produce methylene radical sulfone (3) with a kind of oxygenant (for example hydrogen peroxide) with (2) peroxidation.Other method for oxidation has been described, Smith and March for example, Advanced Organic Chemistry in the reference; Reactions, Mechanisms, and Structure, the 5th edition, WileyInterscience, 2001.If desired,, sulfone (3) is hydrolyzed into its acid derivative, or under the situation that is carboxylic acid, directly uses by method known to those skilled in the art; Described acid and amine coupling generate target product.
Figure GG
Figure GG. isoquinoline 99.9 (1) and phosphorus oxychloride or bromine phosphorus oxide are reacted under the temperature of room temperature to 150 ℃, generate halo-isoquinoline 99.9 (2).Halo-isoquinoline 99.9 (2) and a kind of amine are reacted under the temperature of room temperature to 200 ℃, generate amino-isoquinoline 99.9 (3).This is reflected at organic solvent, for example carries out among THF, acetonitrile, DMF or the NMP.Perhaps, this amine can be used as solvent, and can use sealed reactor to hold the pyritous volatile amine.About 120 ℃ to reflux temperature, at organic solvent, the aqueous acid hydrolysis is used in for example reaction among DMF or the NMP (N-Methyl pyrrolidone) then with amino-isoquinoline 99.9 (3) and cupric cyanide (I), for example the HCl aqueous solution produces isoquinoline 99.9 formic acid (4).Other with the method that amino-isoquinoline 99.9 (3) changes into isoquinoline 99.9 formic acid (4) is
Well known by persons skilled in the art, comprise, for example, there is catalyzer (palladium catalyst for example, for example acid chloride or palladium (0) four (triphenyl phosphine)), additive (for example 1,1 '-two (diphenyl phosphine) ferrocene or 1,3-two (diphenyl phosphine) propane) under the condition, in organic solvent (for example DMF or NMP), and under the condition that has alkali (for example trialkylamine or yellow soda ash or salt of wormwood or sodium bicarbonate or potassium bicarbonate aqueous solution), about 50 under about 150 ℃,, then ester products is hydrolyzed into isoquinoline 99.9 formic acid (4) with (3) and carbon monoxide and a kind of alcohol reaction.With isoquinoline 99.9 formic acid (4) and amine coupling, generate the ultimate aim product then.
Figure HH
Figure II
Figure HH and II. figure HH disclose the synthetic of one group of racemize alpha-amino group sulfone, and figure II discloses the synthetic of active enantiomorph.Mercaptan and the Michael addition of being protected the dehydroalanine methyl esters have produced a kind of sulfanyl intermediate.A kind of according to the method described above changes into corresponding sulfone with sulfanyl derivative peroxide.The hydrolysis of this ester and protecting group can be used the aqueous solution of strong acid, and for example 6N HCl and acetate are chosen wantonly and at high temperature carried out, and make the free amine group hydrochlorate thus.Can in amine groups, add protecting group, for example Cbz or Boc.With the preferential product that contains unreacted N-Rc part that produces of unprotected diamines link coupled standard peptide, it produces the diamines of two protections subsequently by orthogonally protect.Optionally remove the Rn protecting group, produce unhindered amina.A kind of according to the method described above changes into acid amides, carbamate with this amine.Perhaps, it can with isocyanate reaction, generate urea, or with the SULPHURYL CHLORIDE reaction, generate sulphonamide.Remove the Rc protecting group, generate target compound.Figure II is with to scheme HH identical, and it also contains an isomer separation step, and this step makes by chemical action, enzymic effect or by chiral chromatography carries out, and generates single isomer acid, as mentioned above, converts it into target product.
Figure JJ
Figure KK
In closed container, pyridine 1 and amine 2 under refluxing, or react by being warmed to about 80 ℃ to about 130 ℃ in organic solvent (for example THF), make pyridine ester 3.Use method known to those skilled in the art with pyridine ester 3 hydrolysis, generate chloro-acid 4.Use aforesaid method and method known to those skilled in the art with chloro-acid 4 and amine (VIII) coupling, make final product (X).
Perhaps, as Tet.Lett.2000,41,3271 is described with 3 cyanidings of ester pyridine, generates nitrile ester 5.Other method for preparing nitrile ester 5 includes but not limited to that (N-Methyl pyrrolidone is for example handled ester pyridines 3 with about 80 ℃ to about 180 ℃ in DMF) at organic solvent with cupric cyanide.By method known to those skilled in the art 5 ester moiety is changed into acid 6.Use aforesaid method or method known to those skilled in the art with acid 5 and amine (VIII) coupling then, make final product (X).
Figure LL
With pure and mild a kind of acid catalyst or by method known to those skilled in the art with dinitrostilbene acid 1 esterification, produce dinitrobenzene ester 2.There is acid catalyst, for example under the condition of the vitriol oil or sulphosalicylic acid, dinitrobenzene ester 2 and quilt protected aldehyde (for example acetal or ketone acetal) in organic solvent (for example toluene), react generation dinitrobenzene amine 3 down in about 50 to 150 ℃.In organic solvent (for example methyl alcohol, ethanol, ethyl acetate and acetonitrile), under the condition that has acid (for example formic acid or acetate), use palladium catalyst, for example carry palladium carbon, handle dinitrobenzene amine 3, generate amino-indoles 4.With amino-indoles 4 and Sodium Nitrite and hydrochloric acid or aqueous sulfuric acid, with the potassiumiodide reaction, generate iodo-indoles 5 then.About 100 under about 200 ℃, iodo-indoles 5 and cupric cyanide are reacted generation nitrile-indoles 6 in organic solvent (for example N-Methyl pyrrolidone).There is alkali then, for example under the condition of sodium hydroxide or potassium tert.-butoxide (being preferably potassium tert.-butoxide), under the temperature of room temperature to 100 ℃, in organic solvent (for example THF, DMF or DMSO), make 6 alkylations of nitrile-indoles with alkylogen (for example propyl group or butyl iodide, bromine or chlorine), generate ester indoles 7.
Perhaps,, use alkali (for example sodium bicarbonate) neutralization then, with potassium cyanide and cupric cyanide reaction, make nitrile-indoles 6 then amino-indoles 4 and inorganic aqueous acid and Sodium Nitrite reaction.Use method known to those skilled in the art that ester indoles 7 is hydrolyzed into indolic acid 8 then.Use in method known to those skilled in the art and the preamble disclosed method with indoles 8 and amine (VIII) coupling then.
Perhaps, in room temperature to about 100 ℃ temperature, make iodine indoles 5 and alkylogen (for example propyl group or butyl iodide, bromine or chlorine) have alkali (for example sodium hydride or potassium tert.-butoxide, potassium tert.-butoxide more preferably) under the condition at organic solvent (for example THF, DMF or DMSO, be preferably DMSO) middle reaction, generate iodine alkyl 9.About 0 to about-78 ℃ following ， Jiang oxazole or thiazole in organic solvent (for example dialkyl ether or THF) with alkali (being preferably butyllithium) reaction and optional the stirring about 15 to about 60 minutes.Add zinc chloride then and mixture is warmed to 0-30 ℃, add iodine alkyl 9 this moment, adds four triphenyl phosphine palladiums then.Choose wantonly then this mixture is stirred Zhi De oxazole/thiazole indoles 10 in room temperature to about 80 ℃ temperature.By method known to those skilled in the art with 10 hydrolysis, Sheng Cheng oxazole/thiazole acid 11.By the known method of those skilled in the art Jiang acid 11 of oxazole/thiazole and amine (VIII) coupling.
Figure MM
By method known to those skilled in the art indolic acid 1 is changed into K-281 2.Then in room temperature to about 100 ℃ temperature, there are alkali (for example sodium hydride or potassium tert.-butoxide, potassium tert.-butoxide more preferably) under the condition at organic solvent (for example THF, DMF or DMSO, be preferably DMSO) in make K-281 2 alkylations with alkylogen (for example propyl group or butyl iodide, bromine or chlorine), generation alkyl indoles 3.Perhaps, in room temperature to about 100 ℃ temperature, there are alkali (for example sodium hydride or potassium tert.-butoxide, potassium tert.-butoxide more preferably) under the condition at organic solvent (for example THF, DMF or DMSO, be preferably DMSO) in alkylogen (for example propyl group or butyl iodide, bromine or chlorine) reaction, will change into alkyl indoles 3 between the indolic acid 1 thus.Then by disclosed method processing alkyl indoles 3 in Org.Lett. (2000) 1485 and wherein listed reference, Tet.Lett. (1995) 4005 and wherein listed reference and Org.Lett. (2001) 1005 and the wherein listed reference, generation acyl indol 4.Use method known to those skilled in the art that acyl indol 4 is hydrolyzed into indolic acid 5, and use method known to those skilled in the art, generate (X) indolic acid 5 and amine (VIII) coupling.
Biological Examples
Embodiment A
Enzyme inhibition is measured
Use the MBP-C125 assay method to analyze the inhibition activity of The compounds of this invention.This method has been measured with undressed contrast and has been compared, and test compound is to a kind of model APP substrate, the relative inhibition of beta-secretase cracked of MBP-125SW.In United States Patent (USP) 5,942,400 for example, can find detailed description to this location parameter.In brief, this substrate is a kind of fusogenic peptide that is made of C-terminal 125 amino acid of maltose binding protein (MBP) and APP-SW (swedish mutant body).As people such as Sinha, 1999, described in the Nature 40:537-540, beta-secretase is from human cerebral tissue, or produces as enzyme (1-501 amino acids) reorganization as total length as described in the WO00/47618, for example, made by 293 cells of express recombinant cDNA.
For example can analyze the inhibition of this enzyme by immunoassay enzymatic lysis product.A kind of typical ELISA has used the anti--MBP trapping antibody on the high board in 96 holes that is deposited on precoating and sealing, hatch with the enzyme reaction supernatant liquor of dilution subsequently, with a kind of specific report antibody, anti--the SW192 of biological example elementization reports antibody incubation, and further hatches with strepto-microbiotic/alkaline phosphatase.In this assay method, complete MBP-C125SW condenses the N-terminal segment that proteinic cracking has produced brachymemma, new SW-192 antibody-positive epitope occurs at C-terminal thus.Finish detection by the fluorogenic substrate signal that Phosphoric acid esterase produces when the cracking.ELISA only detects the APP-SW751Leu596 cracking on the mutational site afterwards of substrate.
Concrete determination step:
Compound is gone up in the row of each test-compound of 96 orifice plates (96-plate) with the dilution of 1: 1 dilution sequence (dilutionseries), forms 6 concentration curves (each concentration two hole).Every kind of test compounds is made the liquid storage of 10 mmoles with DMSO.With the serial dilution in DMSO of this liquid storage, making its compound ultimate density at the height point of 6 dilution curves is 200 micromoles.Every kind of diluent is got in two holes that C that ten (10) microlitres add corresponding V base plate lists, added 52 mmole NaOAc, the 7.9%DMSO of 190 microlitres in the plate in advance, the pH value is 4.5.The compound plate of rotation NaOAc dilution, make precipitation agent become the ball shape, then 20 microlitres/hole is transferred in the corresponding flat underside, has wherein added the ice-cold enzyme-substrate mixture of 30 microlitres (containing 2.5 microlitre MBP-C125SW substrates, 0.03 microlitre enzyme and the ice-cold 0.09%TX100 of 24.5 microlitres in per 30 microlitres).In 5%DMSO, 20 mmole NaAc, 0.06%TX100, the pH value is 4.5 at the final reacting mixture of 200 micromole's compounds of curve vertex.
Plate is heated to 37 ℃, the beginning enzyme reaction.37 ℃ keep 90 minutes after, add the cold sample diluting liquid of 200 microlitres in every hole with stopped reaction, with 20 microlitres/hole be transferred to corresponding anti--coating of MBP antibody, capturing of containing 80 microlitres/hole sample diluting liquid with in the elisa plate.Be reflected at 4 ℃ of following overnight incubation, second day, after using anti--192SW antibody, hatching 2 hours with strepto-microbiotic-AP conjugate and fluorogenic substrate then, ELISA showed gradually.On the fluorescent plate telltale, can find signal.
Calculating is compared with the enzyme reaction signal in the control wells of not adding any compound, and detected signal has reduced by 50% (IC
50) compound concentrations, thereby judge the restraint of allied compound.In this was measured, compound exhibits of the present invention went out to be less than or equal to 20 micromolar IC
50
Embodiment B
Use the acellular inhibition of synthetic APP substrate to measure
A kind of synthetic APP substrate can be by the beta-secretase cracking, and contain the terminal vitamin H of N-, and can link by the covalency of the oregon green in the Cys residue and produce fluorescence, the activity of the beta-secretase when using this APP substrate to measure to exist or do not exist inhibition compound of the present invention.Spendable substrate comprises:
Biotin-SEVNL-DAEFR[Oregon green]KK[SEQ ID NO：1]
Biotin-SEVKM-DAEFR[Oregon green]KK[SEQ ID NO：2]
Biotin-GLNIKTEEISEISY-EVEFRC[Oregon green]KK[SEQ ID NO：3]
Biotin-ADRGLTTRPGSGLTNIKTEEISEVNL-DAEF[Oregon green]KK[SEQ IDNO：4]
Biotin-FVNQHLCoxGSHLVEALY-LVCoxGERGFFYTPKA[Oregon green]KK[SEQ ID NO：5]
Enzyme (0.1 nmole) and test compounds (0.001-100 micromole) were hatched 30 minutes in (384 hole) at 37 ℃ pre-sealing, low-affinity, blackboard.The substrate that adds 150 nails (unit of length) is with initiation reaction, and the final volume until every hole is 30 microlitres.Final condition determination is: the micromolar compound inhibitor of 0.001-100; 0.1 the sodium acetate (pH4.5) of mole; The substrate of 150 nmoles; 0.1 the solubility beta-secretase of nmole; 0.001%Tween 20 and 2%DMSO.To be tried mixture and be hatched 3 hours, and be come termination reaction by the immune strepto-microbiotic that adds saturation concentration at 37 ℃.After at room temperature hatching 15 minutes with the strepto-microbiotic, for example use LJL Acqurest (Ex 485nm/Em530nm) to measure fluorescence polarization.The fluorescence polarization that takes place during by enzymatic lysis by substrate changes the activity of measuring beta-secretase.Exist or the situation of hatching when not having compound inhibitor has proved special inhibition to the enzymatic lysis of the beta-secretase of its synthetic APP substrate.In this was measured, compound exhibits of the present invention went out to be lower than 20 micromolar IC
50
Embodiment C
The beta-secretase inhibition: P26-P4 ' SW measures
The PCT that uses as announce applies for the measuring method described in the WO00/47618, measures the activity of beta-secretase with the synthetic substrate of the beta-secretase cracking position that contains APP.P26-P4 ' SW substrate is the following peptide of sequence:
(vitamin H) CGGADRGLTTRPGSGLTNIKTEEISEVNLDAEF[SEQ ID NO:6], the P26-P1 standard substance have following sequence:
(vitamin H) CGGADRGLTTRPGSGLTNIKTEEISEVNL[SEQ ID NO:7].
In brief, in this assay method, will contain the synthetic substrate of vitamin H link coupled and hatch with about 0 to about 200 micromolar concentration.If test inhibition compound, concentration preferably approximately 1.0 micromole of substrate.Add the test compounds with the DMSO dilution in reaction mixture, wherein final DMSO concentration is 5%.It is 5% DMSO that contrast also contains ultimate density.The concentration of beta-secretase is variable in the reactant, so that the production concentration that this ELISA measures after the dilution is in the linearity range of about 125 to 2000 pmols.
Reaction mixture also contains sodium acetate (pH4.5), the 0.06%Triton X100 of 20 mmoles, and reaction mixture was hatched about 1 to 3 hour at 37 ℃.Then sample (is for example being measured buffer reagent, 145.5 the bovine serum albumin of nmole sodium-chlor, 9.51 mmole sodium phosphates, 7.7 nanomole sodiumazide, 0.05%Triton X405,6 grams per liters, the pH value is 7.4) middle dilution, with termination reaction, further dilute then so that split product is carried out immunoassay.
Split product can be measured by ELISA.Scribbling trapping antibody, for example in the assay plate of SW192, dilute sample and standard substance were being hatched 24 hours at 4 ℃.Washing is hatched sample according to manufacturer's explanation then with strepto-microbiotic-AP in TTBS buffer reagent (150 micromole's sodium-chlor, 25 micromole Tris, 0.05%Tween 20, the pH value is 7.5).After at room temperature hatching 1 hour, sample floated with TTBS wash, and hatch based sols A (2-amino-2-methyl-1-propanol of 31.2 grams per liters, 30 mg/litre, pH value are 9.5) with fluorescence and hatch.Making by fluoroscopic examination with the reaction of strepto-microbiotic-alkaline phosphate becomes possibility.Compared with the control, reduced the cracking of substrate as the compound proof of the active effective inhibitor of beta-secretase.
Embodiment D
Use the mensuration of synthetic oligopeptide-substrate
The preparation synthetic oligopeptide, it comprises the cracking position and the optional detectable marker (for example fluorescence or chouromogenic part) of known beta-secretase.The example of this class peptide and their production and detection method be at United States Patent (USP) 5,942, describes to some extent in 400, is hereby incorporated by.Can use the high performance liquid chromatography or fluorescence or the color developing detection method that are applicable to tested peptide, detect split product according to known method in this technical field.
For example, a kind of such peptide has sequence SEVNL-DAEF[SEQ ID NO:8], and the cracking position is between residue 5 and 6.Another preferred substrate has sequence
ADRGLTTRPGSGLTNIKTEEISEVNL-DAEF[SEQ ID NO:9], and the cracking position is between residue 26 and 27.
Having beta-secretase and being enough to make under the substrate cracked condition of beta-secretase mediation, these synthetic APP substrate is hatched.The cracking result when having compound inhibitor and the contrast of results of comparison provide a kind of compound to suppress active measuring method.
Embodiment E
Active inhibition-the raji cell assay Raji of beta-secretase
A kind of typical measuring method that the active inhibition of beta-secretase is analyzed, as USPN 5,604,102 is described, used human embryonic kidney cells HEKp293 strain (ATCC Accession No.CRL-1573), this embryonic kidney cells strain transfection contain the APP751 (being commonly referred to as swedish mutant) of the double-mutant Lys651Met52 to Asn651Leu652 (to the numbering of APP751) of natural formation, and show and excessively produce A β (people such as Citron, 1992, Nature 360:672-674).
Exist/not existing under the condition that suppresses compound (in DMSO, diluting), hatch these cells with desired concn (usually up to 10 mcg/ml).Treating processes last for example by the analytical pyrolysis segment, analyzed the beta-secretase activity of hatching base that is conditioned.Can use special detection antibody to analyze A β by immunoassay.Enzymic activity when measuring existence and not having compound inhibitor is to prove the concrete inhibition of cracked to the APP substrate that mediates with beta-secretase.
Embodiment F
At the beta-secretase inhibition of suffering from the animal model of AD
Can use various animal models to screen to the active inhibition of beta-secretase.Can be used for the example of animal model of the present invention, include but not limited to, mouse, cavy, dog and analogue.Used animal can be a wild-type, the model of genetically modified or gene knockout (knockout).In addition, Mammals can be expressed the sudden change on the APP, APP695-SW for example as herein described and analogue.Transgene non-human mammal is at United States Patent (USP) 5,605, describes to some extent in 102,5,912,410 and 5,811,633.
People such as Games, 1995, the inhibition that when the PDAPP mouse described in the Nature 373:523-527 can be used to analyze the inhibition compound that has supposition in vivo A β is discharged.As USPN 6,191,166 is described, and four months big PDAPP mouse is formulated in compound in the carrier (for example Semen Maydis oil).Quantitatively take compound (1-30 mg/ml for mouse; Be preferably the 1-10 mg/ml).After for some time, for example put to death mouse after 3-10 hour, take out brain and analyze.
Transgenic animal are used a certain amount of compound inhibitor that preferably is formulated in the carrier that is applicable to selected administering mode.Control animal is through handling or having taken carrier or taken the compound of non-activity.Administration can be acute, takes single agent or multi-agent in promptly one day, also can be chronic, i.e. administration every day continues a couple of days.From time point 0, from selected animal, obtain cerebral tissue or brain liquid, and for example use special A β to detect the situation that exists of analyzing APP cleavage of peptide (comprising A β) with antibody by immunoassay.In test latter stage, put to death animal, analyze the situation that exists of A β in its cerebral tissue or the brain liquid and/or β starch spot.Also analyze the necrosis of cerebral tissue.
Compare with undressed contrast, the animal that compound inhibitor of the present invention has been used in expectation proves that the A β in its cerebral tissue or the brain liquid reduces, and the amyloid beta spot in the cerebral tissue also reduces.
Embodiment G
Patient is generated the inhibition of A β
Alzheimer's disease (AD) patient shows increasing of A β content in brain.AD patient is used a certain amount of intravital compound inhibitor that carries that is suitable for selected administering mode that is formulated in.In test period administration every day.From fate 0, carry out cognition and test of memory, for example, carried out once in every month.
Analyze by the variation to following one or more disease parameters, the expectation proof is compared with the patient who does not treat of control group, and the development process of the patient disease of use compound inhibitor delays or be stable.Described parameter comprises: be present in the A β in CSF or the blood plasma; The volume of brain or hippocampus; Starch spot in the brain; And to the scoring of cognitive and memory function.
Embodiment H
The patient that AD is suffered from prevention probably generates A β
By identification familial inheritance pattern, for example, there is Sweden's variation, and/or confirms easily or the loyal probably upward patient of AD by the monitoring diagnostic parameter.Use a certain amount of intravital compound inhibitor that carries that is suitable for selected administering mode that preferably is formulated in to being confirmed to be the patient who suffers from AD easily or probably.Reuse every day at test period.From fate 0, cognition and test of memory for example, carried out once in every month.
Analyze by the variation to following one or more disease parameters, show with the patient who does not treat of control group and compare, the development process of the patient disease of use compound inhibitor delays or is stable.Described parameter comprises: be present in the A β in CSF or the blood plasma; The volume of brain or hippocampus; A β deposition in the brain; Starch spot in the brain; And to the scoring of cognitive and memory function.
Although used a plurality of specific embodiments and embodiment to describe the present invention, should be understood that the present invention is not limited to foregoing, and only should annotate by the scope of claims.
Following compounds adopts aforesaid method to be prepared.
Claims (346)
1. compound that chemical formula is following,
Or it can be used for the salt of pharmacy
R wherein
1Be:
(I) C
1-C
6Alkyl, optional by one, two or three the substituting group replacement that is selected from following groups: C
1-C
3Alkyl, C
3-C
8Alkoxyl group is (optional by C
1-C
3Alkyl and C
1-C
3Alkoxyl group replaces) ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group ,-NR
1-aR
1-b, and-OC=O-NR
1-aR
1-b, the R under each situation wherein
1-aAnd R
1-bAll be independently-H or C
1-C
6Alkyl,
(II)-CH
2-S (O)
0-2-(C
1-C
6Alkyl),
(III)-CH
2-CH
2-S (O)
0-2-(C
1-C
6Alkyl),
(IV) contain the C of one or two pair key
2-C
6Alkenyl, can choose wantonly by one, two or three substituting group that is selected from following groups and replace :-F ,-Cl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group ,-NR
1-aR
1-b, R wherein
1-aAnd R
1-bBe-H or C
1-C
6Alkyl,
(V) contain one or two triple-linked C
2-C
6Alkynyl, can choose wantonly by one, two or three substituting group that is selected from following groups and replace :-F ,-Cl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group ,-NR
1-aR
1-b, R wherein
1-aAnd R
1-bBe-H or C
1-C
6Alkyl,
(VI)-(CH
2)
N1-(R
The 1-aryl), n wherein
1Be 0 or 1, and R wherein
The 1-arylBe phenyl, naphthyl, 2,3-indanyl, indenyl, dihydro naphthyl or tetrahydro naphthyl, wherein each is all chosen wantonly on aromatic ring and is replaced by one, two, three, four or five following substituting group:
(A) C
1-C
6Alkyl is chosen wantonly and is selected from C by one, two or three
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-NR
1-aR
1-b,-C ≡ N ,-CF
3And C
1-C
3The substituting group of alkoxyl group replaces,
(B) C
2-C
6Alkenyl, optional by one, two or three be selected from-F ,-Cl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bSubstituting group replace;
(C) C
2-C
6Alkynyl, optional by one, two or three be selected from-F ,-Cl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bSubstituting group replace,
(D)-F, Cl ,-Br and-I,
(E)-C
1-C
6The halogen alkoxyl group,
(F)-C
1-C
6Alkoxyl group,
(G)-NR
N-2R
N-3，
(H)-OH，
(I)-C≡N，
(J) C
3-C
7Cycloalkyl, optional by one, two or three be independently selected from-F ,-Cl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bSubstituting group replace,
(K)-CO-(C
1-C
4Alkyl),
(L)-SO
2-NR
1-aR
1-b，
(M)-CO-NR
1-aR
1-b，
(N)-SO
2-(C
1-C
4Alkyl),
(VII)-(CH
2)
N1-(R
The 1-heteroaryl), R wherein
The 1-heteroarylBe selected from pyridyl, pyrimidyl, quinoline beautiful jade base, benzothienyl, indyl, indolinyl, pyridazinyl, pyrazinyl, pseudoindoyl, different quinoline beautiful jade base, quinazolyl, quinoxalinyl, 2, the 3-phthalazinyl, imidazolyl isoxazolyl, pyrazolyl oxazolyl, thiazolyl, the indolizine base, indazolyl, benzothiazolyl, benzimidazolyl-, benzofuryl, furyl, thienyl, pyrryl oxadiazole base, thiadiazolyl group, triazolyl, tetrazyl oxazole and pyridyl, imidazopyridyl, isothiazolyl, 1, the 5-phthalazinyl, 1, the 2-phthalazinyl, carbazyl, the β-Ka Lin base, the isochroman base, chromanyl, Tetrahydroisoquinoli-beautiful jade base, dihydro-iso indolyl, different benzo tetrahydrofuran base, different benzo tetrahydro-thienyl, isobenzo-thienyl benzoxazolyl, the pyridopyridine base, the benzo tetrahydrofuran base, the benzo tetrahydro-thienyl, purine radicals, the benzodioxole base, triazinyl phenoxazinyl, phenothiazinyl, pteridyl, benzothiazolyl, imidazopyridyl, the Imidazothiazole base, dihydrobenzo Yi oxazinyl, Ben Bing Yi oxazinyl benzoxazinyl, dihydrobenzo isothiazine base, benzopyranyl, the benzo thiapyran base, the tonka bean camphor base, isocoumarinyl, the chromone base, the chromanone base, tetrahydrochysene quinoline beautiful jade base, dihydro quinoline beautiful jade base, dihydro quinoline beautiful jade ketone group, the different quinoline beautiful jade of dihydro ketone group, the melilotine base, the dihydro isocoumarinyl, the isoindoline ketone group, benzodioxan base benzoxazolinone base, pyridyl-N-oxide compound, pyrryl N-oxide compound, pyrimidyl N-oxide compound, pyridazine N-oxide compound, pyrazine N-oxide compound, quinoline beautiful jade N-oxide compound, indoles N-oxide compound, indolinyl N-oxide compound, different quinoline beautiful jade base N-oxide compound, quinazolyl N-oxide compound, quinoxalinyl N-oxide compound, 2,3-phthalazinyl N-oxide compound, imidazolyl N-oxide compound isoxazolyl N-oxide compound oxazolyl N-oxide compound, thiazolyl N-oxide compound, indolizine base N-oxide compound, indazolyl N-oxide compound, benzothiazolyl N-oxide compound, benzimidazolyl-N-oxide compound, pyrryl N-oxide compound oxadiazole base N-oxide compound, thiadiazolyl group N-oxide compound, triazolyl N-oxide compound, tetrazyl N-oxide compound, benzo thiapyran base S-oxide compound, and benzo thiapyran base S, the S-dioxide
R wherein
The 1-heteroarylBy precursor group R
The N-heteroarylAny annular atoms that is replaced by hydrogen and-(CH
2)
N1-link to each other, be connected to R like this
The 1-heteroarylOn new key substituted hydrogen atom and key thereof, wherein heteroaryl can be chosen wantonly by one, two, three, four or five following groups and replace:
(1) C
1-C
6Alkyl is chosen wantonly and is selected from C by one, two or three
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-NR
1-aR
1-b,-C ≡ N ,-CF
3And C
1-C
3The substituting group of alkoxyl group replaces,
(2) contain the C of one or two pair key
2-C
6Alkenyl, optional by one, two or three be selected from-F ,-Cl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bSubstituting group replace,
(3) contain one or two triple-linked C
2-C
6Alkynyl, optional by one, two or three be selected from-F ,-Cl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bSubstituting group replace,
(4)-F ,-Cl ,-Br and-I,
(5)-C
1-C
6The halogen alkoxyl group,
(6)-C
1-C
6Alkoxyl group,
(7)-NR
N-2R
N-3，
(8)-OH，
(9)-C≡N，
(10) C
3-C
7Cycloalkyl, optional by one, two or three be independently selected from-F ,-Cl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bSubstituting group replace,
(11)-CO-(C
1-C
4Alkyl),
(12)-SO
2-NR
1-aR
1-b，
(13)-CO-NR
1-aR
1-b，
(14)-SO
2-(C
1-C
4Alkyl), condition is to work as n
1When being zero, R
The 1-heteroarylNot to link to each other with carbochain by nitrogen-atoms,
(VIII)-(CH
2)
N1-(R
The 1-heterocycle), n wherein
1Definition as above and R
The 1-heterocycleBe selected from morpholinyl, thio-morpholinyl, thio-morpholinyl S-oxide compound, thio-morpholinyl S, the S-dioxide, piperazinyl, high piperazinyl, pyrrolidyl, pyrrolinyl, THP trtrahydropyranyl, piperidyl, tetrahydrofuran base, tetrahydro-thienyl, homopiperidinyl, high morpholinyl, high-sulfur is for morpholinyl, high-sulfur is for morpholinyl S, S-dioxide; oxazolidine ketone group, the pyrazoline base, the pyrrolin base, the dihydro pyrazinyl, the dihydropyridine base, the dihydro-pyrimidin base, the dihydrofuran base, dihydro pyranyl, tetrahydro-thienyl S-oxide compound, tetrahydro-thienyl S, the S-dioxide, high-sulfur is for morpholinyl S-oxide compound, the dithiane base, pyranyl, the dihydrofuran base, the pyrroline ketone group, the tetrahydroglyoxaline ketone group, the imidazolinedione base, wherein above-mentioned each group is all chosen wantonly and is fused to benzene, on pyridine or the pyrimidine ring, and
R
The 1-heterocycleBy precursor group R
The 1-heterocycleAny atom that is replaced by hydrogen connect, be connected to R like this
The 1-heterocycleOn new key substituted hydrogen atom and key thereof, wherein heterocycle can be chosen wantonly by one, two, three or four following groups and replace:
(1) C
1-C
6Alkyl is chosen wantonly and is independently selected from C by one, two or three
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-NR
1-aR
1-b,-C ≡ N ,-CF
3And C
1-C
3The substituting group of alkoxyl group replaces,
(2) C
2-C
6Alkenyl, optional by one, two or three be selected from-F ,-Cl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group ,-NR
1-aR
1-bSubstituting group replace,
(3) C
2-C
6Alkynyl, optional by one, two or three be independently selected from-F ,-Cl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3-alkoxyl group and-NR
1-aR
1-bSubstituting group replace,
(4)-F ,-Cl ,-Br and-I,
(5)-C
1-C
6Alkoxyl group,
(6)-C
1-C
6The halogen alkoxyl group,
(7)-NR
N-2R
N-3，
(8)-OH，
(9)-C≡N，
(10) C
3-C
7Cycloalkyl, optional by one, two or three be independently selected from-F ,-Cl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bSubstituting group replace,
(11)-CO-(C
1-C
4Alkyl),
(12)-SO
2-NR
1-aR
1-b，
(13)-CO-NR
1-aR
1-b，
(14)-SO
2-(C
1-C
4Alkyl),
(15)=and O, condition is to work as n
1When being zero, R
The 1-heterocycleNot to link to each other with carbochain by nitrogen-atoms;
R wherein
2Be selected from:
(I)-H
(II) C
1-C
6Alkyl is chosen wantonly and is independently selected from C by one, two or three
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bSubstituting group replace,
(III)-(CH
2)
0-4-R
30, R wherein
30Be R
The 1-aryl, R
The 1-hetero-aromatic ring, or R
The 1-heterocycle,
(IV) contain the C of one or two pair key
2-C
6Alkenyl, optional by one, two or three be independently selected from-F ,-Cl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bSubstituting group replace,
(V) C
2-C
6Alkynyl, optional by one, two or three be independently selected from-F ,-Cl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bSubstituting group replace,
(VI)-(CH
2)
0-4-C
3-C
7Cycloalkyl, optional by one, two or three be independently selected from-F ,-Cl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bSubstituting group replace,
R wherein
3Be selected from:
(I)-H
(II) C
1-C
6Alkyl is chosen wantonly and is selected from C by one, two or three
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bSubstituting group replace,
(III)-(CH
2)
0-4-R
30，
(IV) C
2-C
6Alkenyl,
(V) C
2-C
6Alkynyl,
(VI)-(CH
2)
0-4-C
3-C
7Cycloalkyl, optional by one, two or three be independently selected from-F ,-Cl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bSubstituting group replace,
Perhaps R
2And R
3Form the carbocyclic ring that contains three, four, five, six and seven carbon atoms with the carbon atom that links to each other with them, choose one of them carbon atom wantonly to be selected from-O-,-S-,-SO
2-,-NR
N-2-heteroatoms replace;
R
NBe:
(I) R
N-1-X
N-, X wherein
NBe selected from:
(A)-CO-
(B)-SO
2-
(C)-(CR ' R ")
1-6, wherein
R ' and R in each case " identical or different, and be-H, C
1-C
4Alkyl phenyl or pyridyl,
(D)-CO-(CR ' R ")
1-6-X
N-1, X wherein
N-1Be selected from-O-,-S-and-NR '-,
(E) singly-bound, and
(F)-CO-(CR′R″)
1-6-
R wherein
N-1Be selected from:
(A) R
The N-aryl, R wherein
The N-arylBe phenyl in each case; Naphthyl; Tetrahydro naphthyl; 2, the 3-indanyl; Indenyl; The dihydro naphthyl; Or 6,7,8,9-tetrahydrochysene-5H-benzo [a] cycloheptenyl; Wherein each group is all chosen wantonly by one, two or three group and is replaced, and described substituting group all is in each case independently:
(1) C
1-C
6Alkyl is chosen wantonly and is selected from C by one, two or three
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bSubstituting group replace R wherein
1-aAnd R
1-bBe H or C in each case
1-C
6Alkyl,
(2)-OH，
(3)-NO
2，
(4)-F、-Cl、-Br、-I，
(5)-CO
2H，
(6)-C≡N，
(7)-(CH
2)
0-4-CO-NR
N-2R
N-3, the R under every kind of situation wherein
N-2And R
N-3All identical or different, and be selected from:
(a)-H，
(b) optional by a substituting group replace-C
1-C
8Alkyl, this substituting group is selected from:
(i)-OH，
(ii)-NR’R”
(iii) phenyl,
(c) optionally be independently-F by 1,2 or 3 ,-Cl ,-Br or-the group replacement of I-C
1-C
8Alkyl,
(d)-C
3-C
8Cycloalkyl,
(e)-(C
1-C
2Alkyl)-(C
3-C
8Cycloalkyl),
(f)-(C
1-C
6Alkyl)-O-(C
1-C
3Alkyl),
(g)-C
2-C
6Alkenyl,
(h)-C
2-C
6Alkynyl,
(i) contain two keys and a triple-linked-C
1-C
6Alkyl chain,
(j)-R
The 1-aryl,
(k)-R
The 1-heteroaryl,
(l)-R
The 1-heterocycle, or
(m) R
N-2, R
N-3Form 5,6 or 7 yuan of Heterocyclylalkyls or heteroaryl with the nitrogen that links to each other with them, wherein said Heterocyclylalkyl or heteroaryl are optional to be fused on phenyl ring, pyridine ring or the pyrimidine ring, and described group is unsubstituted or all is C in each case independently by 1,2,3,4 or 5
1-C
6Alkyl, C
1-C
6Alkoxyl group, halogen, halogen C
1-C
6Alkyl, halogen C
1-C
6Alkoxyl group ,-CN ,-NO
2,-NH
2, NH (C
1-C
6Alkyl), N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-OH ,-C (O) NH
2,-C (O) NH (C
1-C
6Alkyl) ,-C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl), C
1-C
6Alkoxy C
1-C
6Alkyl, C
1-C
6Thio alkoxy and C
1-C
6Thio alkoxy C
1-C
6The group of alkyl replaces;
(8)-(CR’R”)
0-4CO-OR’
(B)-R
The N-heteroaryl, R wherein
The N-heteroarylBe selected from pyridyl, pyrimidyl, quinoline beautiful jade base, benzothienyl, indyl, indolinyl, pyridazinyl, pyrazinyl, pseudoindoyl, different quinoline beautiful jade base, quinazolyl, quinoxalinyl, 2, the 3-phthalazinyl, imidazolyl isoxazolyl, pyrazolyl oxazolyl, thiazolyl, the indolizine base, indazolyl, benzothiazolyl, benzimidazolyl-, benzofuryl, furyl, thienyl, pyrryl oxadiazole base, thiadiazolyl group, triazolyl, tetrazyl oxazole and pyridyl, imidazopyridyl, isothiazolyl, 1, the 5-phthalazinyl, 1, the 2-phthalazinyl, carbazyl, the β-Ka Lin base, different coumaran base, the coumaran base, Tetrahydroisoquinoli-beautiful jade base, dihydro-iso indolyl, different benzo tetrahydrofuran base, different benzo tetrahydro-thienyl, isobenzo-thienyl benzoxazolyl, the pyridopyridine base, the benzo tetrahydrofuran base, the benzo tetrahydro-thienyl, purine radicals, the benzodioxole base, triazinyl phenoxazinyl, phenothiazinyl, pteridyl, benzothiazolyl, the Imidazothiazole base, dihydrobenzo Yi oxazinyl, Ben Bing Yi oxazinyl benzoxazinyl, dihydrobenzo isothiazine base, benzopyranyl, the benzo thiapyran base, the tonka bean camphor base, isocoumarinyl, the chromone base, the chromanone base, tetrahydrochysene quinoline beautiful jade base, dihydro quinoline beautiful jade base, dihydro quinoline beautiful jade ketone group, the different quinoline beautiful jade of dihydro ketone group, the melilotine base, the dihydro isocoumarinyl, the isoindoline ketone group, benzodioxan base benzoxazolinone base, pyridyl-N-oxide compound, pyrryl N-oxide compound, pyrimidyl N-oxide compound, pyridazine N-oxide compound, pyrazine N-oxide compound, quinoline beautiful jade N-oxide compound, indoles N-oxide compound, indoline base N-oxide compound, different quinoline beautiful jade base N-oxide compound, quinazolyl N-oxide compound, quinoxalinyl N-oxide compound, 2,3-phthalazinyl N-oxide compound, imidazolyl N-oxide compound isoxazolyl N-oxide compound oxazolyl N-oxide compound, thiazolyl N-oxide compound, indolizine base N-oxide compound, indazolyl N-oxide compound, benzothiazolyl N-oxide compound, benzimidazolyl-N-oxide compound, pyrryl N-oxide compound oxadiazole base N-oxide compound, thiadiazolyl group N-oxide compound, triazolyl N-oxide compound, tetrazyl N-oxide compound, benzo thiapyran base S-oxide compound, benzo thiapyran base S, the S-dioxide, the imidazolopyrazole base, the quinazoline ketone group, Pyrazolopyridine base Ben Bing oxadiazole base, the dihydro-pyrimidin ketone group, with the Dihydrobenzofuranes ketone group, the optional benzene that is fused to of wherein above-mentioned each group, on pyridine or the pyrimidine ring
R wherein
The N-heteroarylBy parent R
The assorted virtue of N-Any atom that is replaced by hydrogen of group connects, and is connected to R like this
The N-heteroarylOn new key substituted hydrogen atom and key thereof, wherein heteroaryl can be chosen wantonly by one, two, three or four following groups and replace:
(1) C
1-C
6Alkyl is chosen wantonly and is independently selected from C by one, two or three
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bSubstituting group replace,
(2)-OH，
(3)-NO
2，
(4)-F、-Cl、-Br、-I，
(5)-CO
2H，
(6)-C≡N，
(7)-(CH
2)
0-4-CO-NR
N-2R
N-3，
(8)-(CH
2)
0-4-CO-(C
1-C
12Alkyl),
(9)-(CH
2)
0-4-CO-(C
2-C
12Alkenyl),
(10)-(CH
2)
0-4-CO-(C
2-C
12Alkynyl),
(11)-(CH
2)
0-4-CO-(C
3-C
8Cycloalkyl),
(12)-(CH
2)
0-4-CO-R
1 aryl,
(13)-(CH
2)
0-4-CO-R
The 1-heteroaryl,
(14)-(CH
2)
0-4-CO-R
The 1-heterocycle,
(15)-(CH
2)
0-4-CO-R
N-4，
(16)-(CH
2)
0-4-CO
2-R
N-5，
(17)-(CH
2)
0-4-SO
2-NR
N-2R
N-3，
(18)-(CH
2)
0-4-SO-(aryl C
1-C
8Alkyl),
(19)-(CH
2)
0-4-SO
2-(C
1-C
12Alkyl),
(20)-(CH
2)
0-4-SO
2-(C
3-C
8Cycloalkyl),
(21)-(CH
2)
0-4-N (H or R
N-5)-CO-O-R
N-5,
(22)-(CH
2)
0-4-N (H or R
N-5)-CO-N (R
N-2),
(23)-(CH
2)
0-4-N-CS-N(R
N-5)
2，
(24)-(CH
2)
0-4-N (H or R
N-5)-CO-R
N-2,
(25)-(CH
2)
0-4-NR
N-2R
N-3，
(26)-(CH
2)
0-4-R
N-4，
(27)-(CH
2)
0-4-O-CO-(C
1-C
6Alkyl),
(28)-(CH
2)
0-4-O-P(O)-(OR
100)
2，
(29)-(CH
2)
0-4-O-CO-N(R
N-5)
2，
(30)-(CH
2)
0-4-O-CS-N(R
N-5)
2，
(31)-(CH
2)
0-4-O-(R
N-5)，
(32)-(CH
2)
0-4-O-(R
N-5)-COOH，
(33)-(CH
2)
0-4-S-(R
N-5)，
(34)-(CH
2)
0-4-O-(the optional C that is replaced by one, two, three, four or five-F
1-C
6Alkyl),
(35) C
3-C
8Cycloalkyl,
(36) C
2-C
6Alkenyl, optional by C
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group or-NR
1-aR
1-bReplace,
(37) C
2-C
6Alkynyl, optional by C
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group or-NR
1-aR
1-bReplace,
(38)-(CH
2)
0-4-N (H or R
N-5)-SO
2-R
N-2,
(39)-(CH
2)
0-4-C
3-C
8Cycloalkyl,
(C) R
The N-aryl-W-R
The N-aryl,
(D) R
The N-aryl-W-R
The N-heteroaryl,
(E) R
The N-aryl-W-R
The 1-heterocycle,
(F) R
The N-heteroaryl-W-R
The N-aryl,
(G) R
The N-heteroaryl-W-R
The N-heteroaryl,
(H) R
The N-heteroaryl-W-R
The 1-heterocycle,
(I) R
The N-heterocycle-W-R
The N-aryl,
(J) R
The N-heterocycle-W-R
The N-heteroaryl,
(K) R
The N-heterocycle-W-R
The 1-heterocycle,
Wherein W is
(1)-(CH
2)
1-4-，
(2)-O-，
(3)-S(O)
0-2-，
(4)-N(R
N-5)-，
(5)-CO-; Or
(6) keys
(II)-CO-(C
1-C
10Alkyl), wherein alkyl is optional is replaced by one, two or three substituting group that is independently selected from following groups:
(A)-OH，
(B)-C
1-C
6Alkoxyl group,
(C)-C
1-C
6Thio alkoxy,
(D)-CO
2-R
N-8, R wherein
N-8All be independently in each case-H, C
1-C
6Alkyl or optional be halogen, C independently by 1 or 2
1-C
4Alkoxyl group, C
1-C
4Alkyl or-C (O) NH
2The phenyl that replaces of group,
(E)-CO-NR
N-2R
N-3，
(F)-CO-R
N-4，
(G)-SO
2-(C
1-C
8Alkyl),
(H)-SO
2-NR
N-2R
N-3，
(I)-NH-CO-(C
1-C
6Alkyl),
(J)-NH-CO-O-R
N-8，
(K)-NR
N-2R
N-3，
(L)-R
N-4，
(M)-O-CO-(C
1-C
6Alkyl),
(N)-O-CO-NR
N-8R
N-8，
(O)-O-(C
1-C
5Alkyl)-COOH,
(P)-O-(optional be independently-F by one, two or three ,-Cl ,-Br or-C of the group replacement of I
1-C
6Alkyl),
(Q)-NH-SO
2-(C
1-C
6Alkyl),
(R) halogen,
(S)-N (H or R
N-5)-SO
2-R
N-2,
(T)-N (H or R
N-5)-CO-(R
N-2) and
(U)-SO
2-R
N-2，
(V) R
The N-aryl
(III)-CO-(C
1-C
6Alkyl)-O-(C
1-C
6Alkyl), wherein each alkyl all is unsubstituted, or is replaced by one, two or three substituting group that is independently selected from following groups:
(A)-OH，
(B)-C
1-C
6Alkoxyl group,
(C)-C
1-C
6Thio alkoxy,
(D)-CO-O-R
N-8，
(E)-CO-NR
N-2R
N-3，
(F)-CO-R
N-4，
(G)-SO
2-(C
1-C
8Alkyl),
(H)-SO
2-NR
N-2R
N-3，
(I)-NH-CO-(C
1-C
6Alkyl),
(J)-NH-CO-O-R
N-8，
(K)-NR
N-2R
N-3，
(L)-R
N-4，
(M)-O-CO-(C
1-C
6Alkyl),
(N)-O-CO-NR
N-8R
N-8，
(O)-O-(C
1-C
5Alkyl)-CO
2H,
(P)-O-(optional be independently-F by one, two or three ,-Cl ,-Br or-C of the group replacement of I
1-C
6Alkyl),
(Q)-NH-SO
2-(C
1-C
6Alkyl),
(R) halogen,
(S)-N (H or R
N-5)-SO
2-R
N-2,
(T)-N (H or R
N-5)-CO-(R
N-2),
(U)-SO
2-R
N-2, and
(V) R
The N-aryl
(IV)-CO-(C
1-C
6Alkyl)-S-(C
1-C
6Alkyl), wherein each alkyl all is unsubstituted, or is replaced by one, two or three substituting group that is independently selected from following groups:
(A)-OH，
(B)-C
1-C
6Alkoxyl group,
(C)-C
1-C
6Thio alkoxy,
(D)-CO-O-R
N-8，
(E)-CO-NR
N-2R
N-3，
(F)-CO-R
N-4，
(G)-SO
2-(C
1-C
8Alkyl),
(H)-SO
2-NR
N-2R
N-3，
(I)-NH-CO-(C
1-C
6Alkyl),
(J)-NH-CO-O-R
N-8，
(K)-NR
N-2R
N-3，
(L)-R
N-4，
(M)-O-CO-(C
1-C
6Alkyl),
(N)-O-CO-NR
N-8R
N-8，
(O)-O-(C
1-C
5Alkyl)-CO
2H,
(P)-O-(optional by one, two or three be independently-F ,-Cl ,-Br ,-C of the group replacement of I
1-C
6Alkyl),
(Q)-NH-SO
2-(C
1-C
6Alkyl),
(R) halogen,
(S)-N (H or R
N-5)-SO
2-R
N-2,
(T)-N (H or R
N-5)-CO-(R
N-2),
(U)-SO
2-R
N-2And
(V) R
The N-aryl
(V)-CO-CH ((CH
2)
0-2-O-R
N-10)-(CH
2)
0-2-(R
The N-arylOr R
The N-heteroaryl)), wherein
R
N-10Be selected from:
(1)-H
(2) C
1-C
6Alkyl
(3) C
3-C
8Cycloalkyl
(4) C
2-C
6Alkenyl
(5) C
2-C
6Alkynyl
(6) R
The 1-aryl
(7) R
The N-heteroaryl
(8) R
The N-heterocycle
(VI)-CO-(C
3-C
8Cycloalkyl), wherein cycloalkyl is optional is replaced by one or two substituting group that is independently selected from following groups:
(A)-(CH
2)
0-4-OH，
(B)-(CH
2)
0-4-C
1-C
6Alkoxyl group,
(C)-(CH
2)
0-4-C
1-C
6Thio alkoxy,
(D)-(CH
2)
0-4-CO-O-R
N-8，
(E)-(CH
2)
0-4-CO-NR
N-2R
N-3，
(F)-(CH
2)
0-4-CO-R
N-4，
(G)-(CH
2)
0-4-SO
2-(C
1-C
8Alkyl),
(H)-(CH
2)
0-4-SO
2-NR
N-2R
N-3，
(I)-(CH
2)
0-4-NH-CO-(C
1-C
6Alkyl),
(J)-NH-CO-O-R
N-8，
(K)-(CH
2)
0-4-NR
N-2R
N-3，
(L)-(CH
2)
0-4-R
N-4，
(M)-O-CO-(C
1-C
6Alkyl),
(N)-O-CO-NR
N-8R
N-8，
(O)-O-(C
1-C
6Alkyl)-CO
2H,
(P)-O-(optional by one, two or three be independently selected from-F ,-Cl ,-Br ,-C that the group of I replaces
1-C
6Alkyl),
(Q)-NH-SO
2-(C
1-C
6Alkyl),
(R) halogen,
(S)-N (H or R
N-5)-SO
2-R
N-2,
(T)-N (H or R
N-5)-CO-(R
N-2),
(U)-SO
2-R
N-2, and
(V) R
The N-aryl
Wherein, R
CBe:
(I) optionally be selected from C by one, two or three
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
6Alkoxyl group ,-the O-phenyl ,-NR
1-aR
1-b,-OC=O-NR
1-aR
1-b,-S (=O)
0-2R
1-a,-NR
1-aC=ONR
1-aR
1-b,-C=O-NR
1-aR
1-bWith-S (=O)
2NR
1-aR
1-bSubstituting group replace-C
1-C
10Alkyl,
(II)-(CH
2)
0-3-(C
3-C
8) cycloalkyl, wherein cycloalkyl is optional is independently selected from C by one, two or three
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
6Alkoxyl group ,-the O-phenyl ,-CO
2H ,-CO
2-(C
1-C
4Alkyl) and-NR
1-aR
1-bSubstituting group replace,
(III)-(CR
C-XR
C-Y)
0-4-R
The C-aryl, all be phenyl in each case independently; Naphthyl; Tetrahydro naphthyl; 2, the 3-indanyl; Indenyl; The dihydro naphthyl; Or 6,7,8,9-tetrahydrochysene-5H-benzo [a] cycloheptenyl; Wherein each group is all chosen wantonly by 1,2 or 3 group and is replaced, and described substituting group all is in each case:
(1) C
1-C
6Alkyl is chosen wantonly and is selected from C by one, two or three
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bSubstituting group replace,
(2)-OH，
(3)-NO
2，
(4)-F、-Cl、-Br、-I，
(5)-CO
2H，
(6)-C ≡ N and
(7)-(CH
2)
0-4-CO-NR
N-2R
N-3；
R wherein
C-XAnd R
C-YBe independently
-H，
The optional C that is replaced by one or two-OH
1-C
4Alkyl,
The optional C that is replaced by 1,2 or 3-F
1-C
4Alkoxyl group,
-(CH
2)
0-4-C
3-C
8Cycloalkyl,
C
2-C
6Alkenyl,
C
2-C
6Alkynyl and
Phenyl,
Or R
C-XAnd R
C-YForm a carbocyclic ring that contains three, four, five, six and seven carbon atoms with the carbon atom that links to each other with them, choose one of them carbon atom wantonly to be selected from-O-,-S-,-SO
2-,-NR
N-2-heteroatoms replace and R
The C-arylDefinition as above;
(IV)-(CR
C-XR
C-Y)
0-4-R
The C-heteroaryl, R wherein
The C-heteroarylAll be independently selected from pyridyl in each case, pyrimidyl, quinoline beautiful jade base, benzothienyl, indyl, indolinyl, pyridazinyl, pyrazinyl, pseudoindoyl, different quinoline beautiful jade base, quinazolyl, quinoxalinyl, 2, the 3-phthalazinyl, imidazolyl isoxazolyl, pyrazolyl oxazolyl, thiazolyl, the indolizine base, indazolyl, benzothiazolyl, benzimidazolyl-, benzofuryl, furyl, thienyl, pyrryl oxadiazole base, thiadiazolyl group, triazolyl, tetrazyl oxazole and pyridyl, isothiazolyl, 1, the 5-phthalazinyl, 1, the 2-phthalazinyl, carbazyl, the β-Ka Lin base, different coumaran base, the coumaran base, Tetrahydroisoquinoli-beautiful jade base, dihydro-iso indolyl, different benzo tetrahydrofuran base, different benzo tetrahydro-thienyl, isobenzo-thienyl benzoxazolyl, the pyridopyridine base, the benzo tetrahydrofuran base, the benzo tetrahydro-thienyl, purine radicals, the benzodioxole base, triazinyl phenoxazinyl, phenothiazinyl, pteridyl, benzothiazolyl, imidazopyridyl, the Imidazothiazole base, dihydrobenzo Yi oxazinyl, Ben Bing Yi oxazinyl benzoxazinyl, dihydrobenzo isothiazine base, benzopyranyl, the benzo thiapyran base, the tonka bean camphor base, isocoumarinyl, the chromone base, the chromanone base, tetrahydrochysene quinoline beautiful jade base, dihydro quinoline beautiful jade base, dihydro quinoline beautiful jade ketone group, the different quinoline beautiful jade of dihydro ketone group, the melilotine base, the dihydro isocoumarinyl, the isoindoline ketone group, benzodioxan base benzoxazolinone base, the imidazolopyrazole base, the quinazoline ketone group, pyrazolopyridines base Ben Bing oxadiazole base, the dihydro-pyrimidin ketone group, the Dihydrobenzofuranes ketone group, pyridyl-N-oxide compound, pyrryl N-oxide compound, pyrimidyl N-oxide compound, pyridazine N-oxide compound, pyrazine N-oxide compound, quinoline beautiful jade N-oxide compound, indoles N-oxide compound, indoline base N-oxide compound, different quinoline beautiful jade base N-oxide compound, quinazolyl N-oxide compound, quinoxalinyl N-oxide compound, 2,3-phthalazinyl N-oxide compound, imidazolyl N-oxide compound isoxazolyl N-oxide compound oxazolyl N-oxide compound, thiazolyl N-oxide compound, indolizine base N-oxide compound, indazolyl N-oxide compound, benzothiazolyl N-oxide compound, benzimidazolyl-N-oxide compound, pyrryl N-oxide compound oxadiazole base N-oxide compound, thiadiazolyl group N-oxide compound, triazolyl N-oxide compound, tetrazyl N-oxide compound, benzo thiapyran base S-oxide compound, benzo thiapyran base S, the S-dioxide
R wherein
The C-heteroarylBy parent R
The assorted virtue of C-Any atom that is replaced by hydrogen of group connects, and is connected to R like this
The C-heteroarylOn new key substituted hydrogen atom and key thereof, wherein heteroaryl is optional is replaced by 1,2,3 or 4 group, described substituting group is independently:
(1) C
1-C
6Alkyl is chosen wantonly and is independently selected from C by one, two or three
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bGroup replace,
(2)-OH，
(3)-NO
2，
(4)-F、-Cl、-Br、-I，
(5)-CO-OH，
(6)-C≡N，
(7)-(CH
2)
0-4-CO-NR
N-2R
N-3，
(8)-(CH
2)
0-4-CO-(C
1-C
12Alkyl),
(9)-(CH
2)
0-4-CO-(C
2-C
12Alkenyl),
(10)-(CH
2)
0-4-CO-(C
2-C
12Alkynyl),
(11)-(CH
2)
0-4-CO-(C
3-C
7Cycloalkyl),
(12)-(CH
2)
0-4-CO-R
The 1-aryl,
(13)-(CH
2)
0-4-CO-R
The 1-heteroaryl,
(14)-(CH
2)
0-4-CO-R
The 1-heterocycle,
(15)-(CH
2)
0-4-CO-R
N-4，
(16)-(CH
2)
0-4-CO-O-R
N-5，
(17)-(CH
2)
0-4-SO
2-NR
N-2R
N-3，
(18)-(CH
2)
0-4-SO-(C
1-C
8Alkyl),
(19)-(CH
2)
0-4-SO
2-(C
1-C
12Alkyl),
(20)-(CH
2)
0-4-SO
2-(C
3-C
7Cycloalkyl),
(21)-(CH
2)
0-4-N (H or R
N-5)-CO-O-R
N-5,
(22)-(CH
2)
0-4-N (H or R
N-5)-CO-N (R
N-5)
2,
(23)-(CH
2)
0-4-N-CS-N(R
N-5)
2，
(24)-(CH
2)
0-4-N (H or R
N-5)-CO-R
N-2,
(25)-(CH
2)
0-4-NR
N-2R
N-3，
(26)-(CH
2)
0-4-R
N-4，
(27)-(CH
2)
0-4-O-CO-(C
1-C
6Alkyl),
(28)-(CH
2)
0-4-O-P(O)-(OR
100)
2，
(29)-(CH
2)
0-4-O-CO-N(R
N-5)
2，
(30)-(CH
2)
0-4-O-CS-N(R
N-5)
2，
(31)-(CH
2)
0-4-O-(R
N-5)，
(32)-(CH
2)
0-4-O-(R
N-5)-COOH，
(33)-(CH
2)
0-4-S-(R
N-5)，
(34)-(CH
2)
0-4-O-(the optional C that is replaced by one, two, three, four or five-F
1-C
6Alkyl),
(35) C
3-C
8Cycloalkyl,
(36) optional by C
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group or-NR
1-aR
1-bThe C that replaces
2-C
6Alkenyl,
(37) optional by C
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bThe C that replaces
2-C
6Alkynyl,
(38)-(CH
2)
0-4-N (H or R
N-5)-SO
2-R
N-2And
(39)-(CH
2)
0-4-(C
3-C
8Cycloalkyl),
(V)-(CR
C-XR
C-Y)
0-4-R
The C-aryl-R
The C-aryl,
(VI)-(CR
C-XR
C-Y)
0-4-R
The C-aryl-R
The C-heteroaryl,
(VII)-(CR
C-XR
C-Y)
0-4-R
The C-heteroaryl-R
The C-aryl,
(VIII)-(CR
C-XR
C-Y)
0-4-R
The C-heteroaryl-R
The C-heteroaryl,
(IX)-(CR
C-XR
C-Y)
0-4-R
The C-aryl-R
The C-heterocycle, R wherein
The C-heterocycleBe selected from morpholinyl, thio-morpholinyl, thio-morpholinyl S-oxide compound, thio-morpholinyl S, the S-dioxide, piperazinyl, high piperazinyl, pyrrolidyl, pyrrolinyl, THP trtrahydropyranyl, piperidyl, tetrahydrofuran base, tetrahydro-thienyl, homopiperidinyl, high morpholinyl, high-sulfur is for morpholinyl, high-sulfur is for morpholinyl S, S-dioxide; oxazolidine ketone group, the pyrazoline base, the pyrrolin base, the dihydro pyrazinyl, the dihydropyridine base, the dihydro-pyrimidin base, the dihydrofuran base, dihydro pyranyl, tetrahydro-thienyl S-oxide compound, tetrahydro-thienyl S, the S-dioxide, high-sulfur is for morpholinyl S-oxide compound, the dithiane base, pyranyl, the dihydrofuran base, the pyrroline ketone group, the tetrahydroglyoxaline ketone group, the imidazolinedione base, the optional benzene that is fused to of wherein above-mentioned each group, on pyridine or the pyrimidine ring, and
R wherein
The 1-heterocycleBy precursor group R
The 1-heterocycleAny atom that is replaced by hydrogen connect, be connected to R like this
The 1-heterocycleOn new key substituted hydrogen atom and key thereof, wherein heterocycle can be chosen wantonly by one, two, three or four following groups and replace:
(1) C
1-C
6Alkyl is chosen wantonly and is independently selected from C by one, two or three
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-NR
1-aR
1-b,-C ≡ N ,-CF
3And C
1-C
3The substituting group of alkoxyl group replaces,
(2) C
2-C
6Alkenyl, optional by one, two or three be selected from-F ,-Cl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group ,-NR
1-aR
1-bSubstituting group replace,
(3) C
2-C
6Alkynyl, optional by one, two or three be independently selected from-F ,-Cl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bSubstituting group replace,
(4)-F ,-Cl ,-Br and-I,
(5)-C
1-C
6Alkoxyl group,
(6)-C
1-C
6The halogen alkoxyl group,
(7)-NR
N-2R
N-3，
(8)-OH，
(9)-C≡N，
(10) C
3-
C7 cycloalkyl, optional by one, two or three be independently selected from-F ,-Cl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group and-NR
1-aR
1-bSubstituting group replace,
(11)-CO-(C
1-C
4Alkyl),
(12)-SO
2-NR
1-aR
1-b，
(13)-CO-NR
1-aR
1-b，
(14)-SO
2-(C
1-C
4Alkyl),
(15)=and O, condition is to work as n
1When being zero, R
The 1-heterocycleNot to link to each other with carbochain by nitrogen-atoms;
(X)-(CR
C-XR
C-Y)
0-4-R
The C-heteroaryl-R
The C-heterocycle,
(XI)-(CR
C-XR
C-Y)
0-4-R
The C-heterocycle-R
The C-aryl,
(XII)-(CR
C-XR
C-Y)
0-4-R
The C-heterocycle-R
The C-heteroaryl,
(XIII)-(CR
C-XR
C-Y)
0-4-R
The C-heterocycle-R
The C-heterocycle,
(XIV)-(CR
C-XR
C-Y)
0-4-R
The C-heterocycle,
(XV)-[C (R
C-1) (R
C-2)]
1-3-CO-N-(R
C-3)
2, R wherein
C-1And R
C-2Identical or different, and be selected from:
(A)-H，
(B) C
1-C
6Alkyl is chosen wantonly and is selected from C by one, two or three
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
6Alkoxyl group ,-the O-phenyl and-NR
1-aR
1-bSubstituting group replace,
(C) C
2-C
6Alkenyl is chosen wantonly and is selected from C by one, two or three
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
6Alkoxyl group ,-the O-phenyl and-NR
1-aR
1-bSubstituting group replace,
(D) C
2-C
6Alkynyl is chosen wantonly and is selected from C by one, two or three
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
6Alkoxyl group ,-the O-phenyl and-NR
1-aR
1-bSubstituting group replace,
(E)-(CH
2)
1-2-S (O)
0-2-(C
1-C
6Alkyl),
(F)-(CH
2)
0-4-C
3-C
8Cycloalkyl is chosen wantonly and is selected from C by one, two or three
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group ,-the O-phenyl and-NR
1-aR
1-bSubstituting group replace,
(G)-(C
1-C
4Alkyl)-R
The C-aryl,
(H)-(C
1-C
4Alkyl)-R
The C-heteroaryl,
(I)-(C
1-C
4Alkyl)-R
The C-heterocycle,
(J)-R
The C-heteroaryl,
(K)-R
The C-aromatic ring,
(M)-(CH
2)
1-4-R
C-4-(CH
2)
0-4-R
The C-aryl, R wherein
C-4Be-O-,-S-or-NR
C-5-, R wherein
C-5Be C
1-C
6Alkyl,
(N)-(CH
2)
1-4-R
C-4-(CH
2)
0-4-R
The C-heteroaryl,
(O)-R
The C-3 aryl,
And the R under every kind of situation wherein
C-3All identical or different, and be:
(A)-H，
(B)-C
1-C
6Alkyl is chosen wantonly and is independently selected from C by one, two or three
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group ,-the O-phenyl and-NR
1-aR
1-bSubstituting group replace,
(C) contain the C of one or two pair key
2-C
6Alkenyl is chosen wantonly and is independently selected from C by one, two or three
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
6Alkoxyl group ,-the O-phenyl and-NR
1-aR
1-bSubstituting group replace,
(D) C
2-C
6Alkynyl is chosen wantonly and is independently selected from C by one, two or three
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
6Alkoxyl group ,-the O-phenyl and-NR
1-aR
1-bSubstituting group replace,
(E)-(CH
2)
0-4-C
3-C
8Cycloalkyl is chosen wantonly and is independently selected from C by one, two or three
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
6Alkoxyl group ,-the O-phenyl ,-NR
1-aR
1-bSubstituting group replace,
(F)-R
The C-aryl,
(G)-R
The C heteroaryl,
(H)-R
The C-aromatic ring,
(I)-(C
1-C
4Alkyl)-R
The C-aryl,
(J)-(C
1-C
4Alkyl)-R
The C-heteroaryl,
(K)-(C
1-C
4Alkyl)-R
The C-heterocycle,
(XVI)-CH (R
The C-aryl)
2,
(XVII)-CH (R
The C-heteroaryl)
2,
(XVIII)-CH (R
The C-aryl) (R
The C-heteroaryl),
(XIX) be fused to R
The C-arylOr R
The assorted virtue of C-Base or R
The C-heterocycleOn-cyclopentyl ,-cyclohexyl or-the suberyl ring, wherein cyclopentyl, cyclohexyl or suberyl carbon is optional by NH, NR
N-5, O, S (=O)
0-2Replace, and wherein cyclopentyl, cyclohexyl or suberyl can be chosen wantonly by one or two-C
1-C
3Alkyl ,-F ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
6Alkoxyl group ,=O and-NR
1-aR
1-bReplace,
(XX) C
2-C
10Alkenyl is chosen wantonly and is selected from C by one, two or three
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
6Alkoxyl group ,-the O-phenyl and-NR
1-aR
1-bSubstituting group replace,
(XXI) C
2-C
10Alkynyl is chosen wantonly and is selected from C by one, two or three
1-C
3Alkyl ,-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
6Alkoxyl group ,-the O-phenyl and-NR
1-aR
1-bSubstituting group replace,
(XXI)-(CH
2)
0-1-CHR
C-6-(CH
2)
0-1-R
The C-aryl, R wherein
C-6Be-(CH
2)
0-6-OH,
(XXII)-(CH
2)
0-1-CHR
C-6-(CH
2)
0-1-R
The C-heteroaryl,
(XXIII)-CH (R
The C-arylOr R
The C-heteroaryl)-CO
2(C
1-C
4Alkyl),
(XXIV)-CH(-CH
2-OH)-CH(-OH)-NO
2，
(XXV) (C
1-C
6Alkyl)-O-(C
1-C
6Alkyl)-OH,
(XXVII)-CH
2-NH-CH
2-CH(-O-CH
2-CH
3)
2，
(XXVIII)-H，
(XXIX)-(CH
2)
0-6-C(＝NR
1-a)(NR
1-aR
1-b)；
R
25All be independently selected from hydrogen, C in each case
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
6Alkoxy C
1-C
6Alkyl, hydroxyl C
1-C
6Alkyl, halo C
1-C
6Alkyl, C
1-C
6Alkyloyl, each group all are unsubstituted or are independently selected from halogen, alkyl, hydroxyl, alkoxyl group and NH by 1,2,3 or 4
2And-R
26-R
27Group replace,, wherein
R
26Be selected from-C (O)-, SO
2-,-CO
2-,-C (O) NH-and-C (O) N (C
1-C
6Alkyl)-;
R
27Be selected from C
1-C
6Alkyl, C
1-C
6Alkoxyl group, aryl C
1-C
6Alkyl, Heterocyclylalkyl and heteroaryl, wherein above-mentioned each group all be unsubstituted or by 1,2,3,4 or 5 independently for C
1-C
4Alkyl, C
1-C
4Alkoxyl group, halogen, alkylhalide group, hydroxyalkyl ,-C (O) NH
2, NH
2, NH (C
1-C
6Alkyl), N (C
1-C
6Alkyl) (C
1-C
6Alkyl), C (O) NH (C
1-C
6Alkyl) ,-C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) group replaces.
2. compound that chemical formula is following
And can be used for the salt of pharmacy, wherein
M is 0-5;
B chooses wantonly to be independently selected from R by one or two
6, R '
6, R "
6And R_
6The group aryl or the heteroaryl that replace, or
B chooses wantonly to be independently selected from R by one, two, three, four, five, six, seven or eight
6a, R
6b, R '
6a, R '
6b, R "
6a, R "
6b, R_
6a, R_
6bThe group cycloalkyl or the Heterocyclylalkyl that replace;
Each optional by one, two or three are selected from-NRR ' ,-SR ,-CN ,-OCF
3,-CF
3,-CONRR ' ,-CO
2R ,-SO
2NRR ' ,-O-P (=O) (OR) (OR ') ,-N (R)-C (=O) (R ') ,-N (R) (SO
2R ') ,-SO
2R ,-C (=O) R ,-NO
2, halogen ,-(CH
2)
0-4-aryl or-(CH
2)
0-4The C that the group of-heteroaryl replaces
1-C
8Alkyl, C
2-C
7Alkenyl or C
2-C
7Alkynyl, or
R and R ' be independently-H ,-(C
1-C
10)Alkyl ,-(CH
2)
0-4-R
Aryl,-(CH
2)
0-4-R
Heteroaryl,-(CH
2)
0-4-R
Heterocycle, or
Each optional by one, two or three be selected from halogen ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group, amino, list or dialkyl amido and C
1-C
6The C that the substituting group of alkyl replaces
2-C
7Alkenyl or C
2-C
7Alkynyl or
Optional by one, two or three be selected from halogen ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3Alkoxyl group, amino, list or dialkyl amido and C
1-C
6The substituting group of alkyl replaces-(CH
2)
0-4-C
3-C
7Cycloalkyl;
Benzyl, wherein benzyl ring optional by 1-3 be independently selected from halogen ,-OH ,-SH ,-C ≡ N, list or dialkyl amido, C
1-C
6The group of alkyl or trifluoromethyl replaces;
R
6, R '
6, R "
6, R_
6, R
6a, R
6b, R '
6a, R '
6b, R "
6a, R "
6b, R_
6aAnd R_
6bBe independently-OR ,-NO
2, halogen ,-CO
2R ,-C ≡ N ,-NRR ' ,-SR ,-SO
2R ,-C (=O) R ,-OCF
3,-CF
3,-CONRR ' ,-SO
2NRR ' ,-O-P (=O) (OR) (OR ') ,-N (R) (COR ') ,-N (R) (SO
2R ') ,-(CH
2)
0-4-CO-NR
7R '
7,-(CH
2)
0-4-O-(CH
2)
0-4-CONRR ' ,-(CH
2)
0-4-CO-(C
1-C
12Alkyl) ,-(CH
2)
0-4-CO-(C
2-C
12Alkenyl) ,-(CH
2)
0-4-CO-(C
2-C
12Alkynyl) ,-(CH
2)
0-4-CO-(C
3-C
7Cycloalkyl) ,-(CH
2)
0-4-R
Aryl,-(CH
2)
0-4-R
Heteroaryl,-(CH
2)
0-4-R
Heterocycle,-(CH
2)
0-4-CO-R
Aryl,-(CH
2)
0-4-CO-R
Heteroaryl,-(CH
2)
0-4-CO-R
Heterocycle,-(CH
2)
0-4-CO-R
10,-(CH
2)
0-4-CO-O-R
11,-(CH
2)
0-4-SO
2-NR
7R '
7,-(CH
2)
0-4-SO-(C
1-C
8Alkyl) ,-(CH
2)
0-4-SO
2-(C
1-C
12Alkyl) ,-(CH
2)
0-4-SO
2-(C
3-C
7Cycloalkyl) ,-(CH
2)
0-4-N (H or R
11)-CO-O-R
11,-(CH
2)
0-4-N (H or R
11)-CO-N (R
11)
2,-(CH
2)
0-4-N (H or R
11)-CS-N (R
11)
2,-(CH
2)
0-4-N (H or R
11)-CO-R
7,-(CH
2)
0-4-NR
7R '
7,-(CH
2)
0-4-R
10,-(CH
2)
0-4-O-CO-(C
1-C
6Alkyl) ,-(CH
2)
0-4-O-P (O)-(O-R
Aryl)
2,-(CH
2)
0-4-O-CO-N (R
11)
2,-(CH
2)
0-4-O-CS-N (R
11)
2,-(CH
2)
0-4-O-(R
11) ,-(CH
2)
0-4-O-(R
11)-COOH ,-(CH
2)
0-4-S-(R
11), C
3-C
7Cycloalkyl ,-(CH
2)
0-4-N (H or R
11)-SO
2-R
7, or-(CH
2)
0-4-C
3-C
7Cycloalkyl,
Or optional by one, two or three are independently selected from the C that the substituting group of following groups replaces
1-C
8Alkyl: C
1-C
6Alkyl ,-F ,-Cl ,-Br ,-I ,-OR ,-NO
2,-F ,-Cl ,-Br ,-I ,-CO
2R ,-C ≡ N ,-NRR ' ,-SR ,-SO
2R ,-C (=O) R ,-OCF
3,-CF
3,-CONRR ' ,-SO
2NRR ' ,-O-P (=O) (OR) (OR ') ,-N (R) (COR ') ,-N (R) (SO
2R ') ,-(CH
2)
0-4-CO-NR
7R '
7,-(CH
2)
0-4-CO-(C
1-C
12Alkyl) ,-(CH
2)
0-4-CO-(C
2-C
12Alkenyl) ,-(CH
2)
0-4-CO-(C
2-C
12Alkynyl) ,-(CH
2)
0-4-CO-(C
3-C
7Cycloalkyl) ,-(CH
2)
0-4-R
Aryl,-(CH
2)
0-4-R
Heteroaryl,-(CH
2)
0-4-R
Heterocycle,-(CH
2)
0-4-CO-R
Aryl,-(CH
2)
0-4-CO-R
Heteroaryl,-(CH
2)
0-4-CO-R
Heterocycle,-(CH
2)
0-4-CO-R
10,-(CH
2)
0-4-CO-O-R
11,-(CH
2)
0-4-SO
2-NR
7R '
7,-(CH
2)
0-4-SO-(C
1-C
8Alkyl) ,-(CH
2)
0-4-SO
2-(C
1-C
12Alkyl) ,-(CH
2)
0-4-SO
2-(C
3-C
7Cycloalkyl) ,-(CH
2)
0-4-N (H or R
11)-CO-O-R
11,-(CH
2)
0-4-N (H or R
11)-CO-N (R
11)
2,-(CH
2)
0-4-N (H or R
11)-CS-N (R
11)
2,-(CH
2)
0-4-N (H or R
11)-CO-R
7,-(CH
2)
0-4-NR
7R '
7,-(CH
2)
0-4-R
10,-(CH
2)
0-4-O-CO-(C
1-C
6Alkyl) ,-(CH
2)
0-4-O-P (O)-(O-R
Aryl)
2,-(CH
2)
0-4-O-CO-N (R
11)
2,-(CH
2)
0-
4-O-CS-N (R
11)
2,-(CH
2)
0-4-O-(R
11) ,-(CH
2)
0-4-O-(R
11)-COOH ,-(CH
2)
0-4-S-(R
11), C
3-C
7Cycloalkyl ,-(CH
2)
0-4-N (H or R
11)-SO
2-R
7, or-(CH
2)
0-4-C
3-C
7Cycloalkyl or all choose wantonly by one, two or three be independently selected from halogen or-C that the group of OH replaces
2-C
7Alkenyl or C
2-C
7Alkynyl,
Or each optional by one, two or three are independently selected from halogen, C
1-C
3Alkyl ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3The C that the group of alkoxyl group, amino and list or dialkyl amido replaces
2-C
7Alkenyl or C
2-C
7Alkynyl or
-(CH
2)
0-4-O-(C
1-C
6Alkyl), wherein moieties is optional by one, two, three, four or five halogens replacements, or
R
6a, R
6b, R '
6a, R '
6b, R "
6a, R "
6b, R_
6aAnd R_
6bIn any two be oxo altogether;
R
7And R '
7Can be identical or different, and representative-H ,-C
3-C
7Cycloalkyl ,-(C
1-C
2Alkyl)-(C
3-C
7Cycloalkyl) ,-(C
1-C
6Alkyl)-O-(C
1-C
3Alkyl) ,-C
2-C
6Alkenyl ,-C
2-C
6Alkynyl, contain two keys and a triple-linked-C
1-C
6Alkyl or optional quilt-OH or-NH
2Replace-C
1-C
6Alkyl; Or optional by one, two or three are independently selected from that the group of halogen replaces-C
1-C
6Alkyl; Or
The optional heterocycle that is replaced by following group: halogen, amino, list or dialkyl amido ,-OH ,-C ≡ N ,-SO
2-NH
2,-SO
2-NH-C
1-C
6Alkyl ,-SO
2-N (C
1-C
6Alkyl)
2,-SO
2-(C
1-C
4Alkyl) ,-CO-NH
2,-CO-NH-C
1-C
6Alkyl, oxo and-CO-N (C
1-C
6Alkyl)
2Or optional by one, two or three are independently selected from C
1-C
3Alkyl, halogen ,-OH ,-SH ,-C ≡ N ,-CF
3,-C
1-C
3The C that the group of alkoxyl group, amino and list or dialkyl amido replaces
1-C
6Alkyl; Or each optional by one, two or three are independently selected from C
1-C
3Alkyl, halogen ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3The C that the group of alkoxyl group, amino and list or dialkyl amido replaces
2-C
6Alkenyl or C
2-C
6Alkynyl; Or the optional C that is replaced by, two or three halogens
1-C
6Alkoxyl group;
Aryl or heteroaryl, each each optionally replaced by following group: halogen, amino, list or dialkyl amido ,-OH ,-C ≡ N ,-SO
2-NH
2,-SO
2-NH-C
1-C
6Alkyl ,-SO
2-N (C
1-C
6Alkyl)
2,-SO
2-(C
1-C
4Alkyl) ,-CO-NH
2,-CO-NH-C
1-C
6Alkyl and-CO-N (C
1-C
6Alkyl)
2Or optional by one, two or three are independently selected from C
1-C
3Alkyl, halogen ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3The C that the group of alkoxyl group, amino and list or dialkyl amido replaces
1-C
6Alkyl; Or each optional by one, two or three are independently selected from C
1-C
3Alkyl, halogen ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3The C that the group of alkoxyl group, amino and list or dialkyl amido replaces
2-C
6Alkenyl or C
2-C
6Alkynyl; Or the optional C that is replaced by, two or three halogens
1-C
6Alkoxyl group;
R
10Be to choose wantonly to be independently selected from C by one, two, three or four
1-C
6The heterocycle that the group of alkyl replaces;
R
11Be C
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
3-C
7Cycloalkyl ,-(CH
2)
0-2-R
ArylOr-(CH
2)
0-2-R
Heteroaryl
R
ArylBe the optional aryl that is replaced by following group: halogen, amino, list or dialkyl amido ,-OH ,-C ≡ N ,-SO
2-NH
2,-SO
2-NH-C
1-C
6Alkyl ,-SO
2-N (C
1-C
6Alkyl)
2,-SO
2-(C
1-C
4Alkyl) ,-CO-NH
2,-CO-NH-C
1-C
6Alkyl or-CO-N (C
1-C
6Alkyl)
2Or
Optional by one, two or three are independently selected from C
1-C
3Alkyl, halogen ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3The C that the group of alkoxyl group, amino and list or dialkyl amido replaces
1-C
6Alkyl; Or
Each optional by one, two or three are independently selected from C
1-C
3Alkyl, halogen ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3The C that the group of alkoxyl group, amino and list or dialkyl amido replaces
2-C
6Alkenyl or C
2-C
6Alkynyl; Or
The optional C that is replaced by, two or three halogens
1-C
6Alkoxyl group;
R
HeteroarylBe the optional heteroaryl that is replaced by following group: halogen, amino, list or dialkyl amido ,-OH ,-C ≡ N ,-SO
2-NH
2,-SO
2-NH-C
1-C
6Alkyl ,-SO
2-N (C
1-C
6Alkyl)
2,-SO
2-(C
1-C
4Alkyl) ,-CO-NH
2,-CO-NH-C
1-C
6Alkyl or-CO-N (C
1-C
6Alkyl)
2Or optional by one, two or three are independently selected from C
1-C
3Alkyl, halogen ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3The C that the group of alkoxyl group, amino and list or dialkyl amido replaces
1-C
6Alkyl; Or each optional by one, two or three are independently selected from C
1-C
3Alkyl, halogen ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3The C that the group of alkoxyl group, amino and list or dialkyl amido replaces
2-C
6Alkenyl or C
2-C
6Alkynyl; Or the optional C that is replaced by, two or three halogens
1-C
6Alkoxyl group;
R
HeterocycleBe the optional heterocycle that is replaced by following group: halogen, amino, list or dialkyl amido ,-OH ,-C ≡ N ,-SO
2-NH
2,-SO
2-NH-C
1-C
6Alkyl ,-SO
2-N (C
1-C
6Alkyl)
2,-SO
2-(C
1-C
4Alkyl) ,-CO-NH
2,-CO-NH-C
1-C
6Alkyl ,=O or-CO-N (C
1-C
6Alkyl)
2Or optional by one, two or three are independently selected from C
1-C
3Alkyl, halogen ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3The C that the group of alkoxyl group, amino and list or dialkyl amido replaces
1-C
6Alkyl; Or each optional by one, two or three are independently selected from C
1-C
3Alkyl, halogen ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
3The C that the group of alkoxyl group, amino and list or dialkyl amido replaces
2-C
6Alkenyl or C
2-C
6Alkynyl; Or the optional C that is replaced by, two or three halogens
1-C
6Alkoxyl group;
R
2And R
3Be hydrogen or C independently
1-C
6Alkyl; Or
R
2, R
3Form 3 or 4 yuan of rings with the carbon atom that links to each other with them;
R
CBe hydrogen or optional by C
1-C
3Alkyl, C
2-C
4Alkynyl, trifluoromethyl or C
1-C
2The phenyl that alkoxyl group replaces.
3. compound that chemical formula is following
Or it can be used for the salt of pharmacy, wherein
R
30Be selected from phenyl; the pyrazolopyrimidine base; oxa--azepine-benzo Azulene base isoxazolyl; the Triazolopyridine base; pyrrolidone-base; tetrahydrochysene sulfo--azepine-fluorenyl; pyridyl; piperidyl; dihydro ring penta quinolyl; furyl; the naphthalene thienyl; 2; 3-naphthyridine ketone group; thiadiazolyl group; the Thienopyrimidine ketone group; oxa--diaza-ring penta naphthyl; dihydrobenzo dioxepinyl; the chromanone base; the chromene ketone group; oxazolidinyl; benzophenone; pyrazinyl list N-oxide compound; cumarone; pyrazolyl;-isoxazolyls-phenyl; phenyl-triazolyl; benzimidazolyl-; indyl; phenyl-pyrryl; chromanyl; isoquinolyl;-thienyl-thienyl; benzothienyl;-phenyl-thiadiazolyl group; the chromanone base; quinolyl;-pyrryl-C (O)-phenyl;-phenyl-O-phenyl;-phenyl-oxazolyls;-pyrrolidone-base-phenyl;-phenyl-pyrimidine base;-phenyl-oxadiazole bases; two ring [2.2.1] heptenyls; cyclopentyl; thieno-[2; 3-b] thiophene; cyclohexyl;-phenyl-imidazolyl benzoxazole; dihydro-1H-indyl; 2; 3-dihydro-benzo [b] thiophene 1; the 1-dioxide; benzo [b] thiophene 1; the 1-dioxide; 2; 3-dihydro-benzo [d] isothiazole 1; the 1-dioxide;-phenyl-thiazolyl;-phenyl-pyrazole base;-phenyl-C (O)-piperidyl;-phenyl-C (O)-pyrrolidyl;-phenyl-isoxazolyls; pseudoindoyl; purine radicals; oxaxolyl; thiazolyl; the pyridazine ketone group; thiazolyl; pyranyl; dihydropyrane and pyridyl; the tall and erect yl of di nitrogen; the tall and erect yl of nitrogen; cyclopropyl; the dihydro-naphtho isoxazolyl; the benzo indazolyl; dihydro ring penta chromene ketone group; the imidazolopyrazole base; tetrahydro cyclopentyl chromene ketone group; the dihydroquinoline ketone group; pyridyl N-oxide compound; the isochroman base; the quinazoline ketone group; the Pyrazolopyridine base; titanium dioxide dihydrobenzo thiophene; dihydro furan benzoisoxazole base; the dihydro-pyrimidin diketo; thieno-pyrazolyl oxazolyl; the tetrahydro cyclopentyl pyrazolyl; dihydro naphthalenonyl; the Dihydrobenzofuranes ketone group; dihydro monodral base; the tetrahydro cyclopentyl pyrazolyl; tetrahydro-pyrazole and azepine base; indazolyl; the tetrahydro cyclopentyl isoxazolyl; the tetrahydro indole base; pyrrolidyl; the thienopyridine base; dioxy dihydrobenzo isothiazole ketone group; triazolopyrimidinyl; thienyl; dihydrothieno pyrimidines ketone group Ben Bing oxadiazole base; carbazyl; chromene also [3,4-d] isoxazole; the chroman acyl group; Triazolopyridazines base oxazolidinyl;-pyrryl-(C
1-C
6Alkyl)-pyridyl;-pyrryl-cyclohexyl; pyrrolidyl; pyrazoline base Ben Bing oxadiazole base list N-oxide compound; 1-H-pyridazine acyl group;-phenyl-dihydro-1-H-pyrazolidine acyl group;-phenyl-pyrrolidyl-diketone; the thieno-indyl; the thio phenyl benzothiazolyl; the Pyrazolopyridine base; thio-morpholinyl S-oxide compound; dihydrofuran base benzoisoxazole base; benzisothiazole alkyloyl 1; the 1-dioxide; tetrahydro-pyrimidine base-diketone; tetrahydrochysene sulfo-pyranyl indyl; benzo two oxepinyl;-phenyl-pyrrazolidinonyl; the dihydro naphthyl; tetralyl; iso-dihydro-indole-group-diketone;-imidazoles-benzyl;-thiophene-dihydro-oxazole bases; thieno-quinoline beautiful jade base;-tetramethyleneimine-phenyl benzoxazole alkyl; thieno-quinoline beautiful jade base;-tetramethyleneimine-phenyl; benzo oxazolidinonyl; pyrrolopyridine; the indone base; 1-H-imidazo [1; 2-b] pyrazolyl; dihydro ring penta [b] thienyl; the dihydro-indazol ketone group; tetrahydrochysene pyrazoloazepinyl; the tetrahydrochysene benzfuran ketone group; the thieno-pyrazolyl; ring penta [c] pyrazolyl; tetrahydro cyclopentyl [c] pyrazolyl; tetrahydroquinoxaline base diketone; the tetrahydrochysene indazole base; the imidazo benzoxazinyl;-phenyl-pyrrolin base diketone;-phenyl-O-benzyl;-phenyl-benzyl; 3 '; 4 ';-dihydro-1 ' H-spiral shell [1; 3] dioxolane-2; 2 '-naphthyl, wherein above-mentioned each group respectively is unsubstituted or by 1; 2; 3; 4 or 5 substituting groups that are independently selected from following groups replace:
Optional by 1 phenyl or 1 C that CN replaces1-C
10Alkyl; OH, optional by phenyl or (C1-C
4Alkyl) the hydroxyl C of phenyl substituted1-C
10Alkyl; Optional is the C of the group replacement of hydroxyl or phenyl by 1 or 2 independently1-C
6Alkoxyl; Alkylhalide group, halogen alkoxyl, (CH2)
0-4C(O)NR
31R
32；NR
31-SO
2-(C
1-C
6Alkyl), wherein alkyl is optional is halogen or R by 1,2 or 3 independently33Group replace;-SO2-NH(C
1-C
6Alkyl), wherein alkyl is optional is halogen, OH, alkoxyl or R by 1 or 2 independently33Group replace;-(C1-C
6Alkyl)-SO2-(C
1-C
6Alkyl), wherein alkyl is optional is halogen, OH, C by 1 or 2 independently1-C
4Alkoxyl or R33Group replace;-SO2-(C
1-C
6Alkyl), wherein alkyl is optional is OH or C by 1 or 2 independently1-C
4The group of alkoxyl replaces;-SO2-N(C
1-C
6Alkyl) (C1-C
6Alkyl), wherein each alkyl each optional be halogen, OH or R independently by 1 or 233Group replace;-SO2-NH(C
1-C
6Alkyl)-phenyl, wherein phenyl is optional is C by 1 or 2 independently1-C
4The group of alkoxy or halogen replaces;-(C1-C
6Alkyl)-O-phenyl ,-(C1-C
6Alkyl)-O-(C1-C
6Alkyl)-phenyl, triazolidine-3,5-diketone, halogen ,-NHC (O) NH2、-NHC(O)NH(C
1-C
6Alkyl) ,-NHC (O) N (C1-C
6Alkyl) (C1-C
6Alkyl) ,-N (C1-C
6Alkyl) C (O) NH2、-N(C
1-C
6Alkyl) C (O) NH (C1-C
6Alkyl) ,-N (C1-C
6Alkyl) C (O) N (C1-C
6Alkyl) (C1-C
6Alkyl) ,-(C1-C
6Alkyl) thienyl ,-(C1-C
6Alkyl) furyl ,-S-(C1-C
6Alkyl) phenyl ,-SO2NR
31R
32、-C(O)-NR
31R
32、-NR
31R
32, dithiane ,-NHC (S) NH2、-NHC(S)NH
(C
1-C
6Alkyl) ,-NHC (S) N (C1-C
6Alkyl) (C1-C
6Alkyl) ,-CO2(C
1-C
6Alkyl), oxinane, optional be the phenyl of F, Cl or Br replacement independently by 1 or 2; Pyridine ,-C2-C
4Alkynyl-phenyl ,-O-C3-C
8Cycloalkyl ,-O-(C1-C
6Alkyl)-R33 Optional by one or two methyl substituted pyrroles; 2,3-dihydro-benzofuran, benzo [1,2,5] oxadiazoles;-C (O)-(C1-C
10Alkyl), wherein alkyl is optional by NH2、N(C
1-C
6Alkyl) or N (C1-C
6Alkyl) (C1-C
6Alkyl) replace;-C (O) NH-phenyl ,-C (O) N (C1-C
6Alkyl)-phenyl, 4,4-dimethyl-4,5-dihydro-oxazoles ,-(C1-C
6Alkyl)-S-pyridine ,-(C1-C
6Alkyl)-SO2-pyridine ,-(C1-C
6Thio alkoxy)-pyridine, optional by 1 or 2 methyl substituted thiazole; Pyrazoles ,-S-(C1-C
6Alkyl), wherein alkyl is optional is the group replacement of CN or OH by 1 or 2 independently; Indoles, (C1-C
6Thio alkoxy)-(C1-C
6Alkyl), C2-C
8Alkynyl ,-(CH2)
0-4-SO
2-(C
1-C
10Alkyl), wherein alkyl is optional is replaced by OH;-NHC (O) NH (C3-C
8Cycloalkyl) ,-N (C1-C
6Alkyl) C (O) NH (C3-C
8Cycloalkyl) ,-N (C1-C
6Alkyl) C (O) N (C1-C
6Alkyl) (C3-C
8Cycloalkyl) ,-NHC (O) N (C1-C
6Alkyl) (C3-C
8Cycloalkyl) ,-(C1-C
6Alkoxyl)-(C1-C
6Thio alkoxy);-CO2-(C
1-C
6Alkyl), wherein alkyl is optional by phenyl substituted;-C (O)-furans; And imidazole radicals;
R wherein
31And R
32Respectively be independently selected from hydrogen, C in each case
1-C
8Alkyl, C
2-C
8Alkenyl, hydroxyl C
1-C
6Alkyl, C
1-C
6Alkylhalide group, C
1-C
6Alkoxy C
1-C
6Alkyl;-(CH
2)
0-4-SO
2-(C
1-C
6Alkyl), wherein alkyl is optional is replaced by the group of 1,2,3 or 4 independently selected from halogen atoms;-(CH
2)
0-4-SO
2-imidazolyl ,-(C
1-C
6Alkyl)-C (O) NH
2,-(C
1-C
6Alkyl)-C (O) NH (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-NH
2,-(C
1-C
6Alkyl)-NH (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl) phenyl ,-(C
1-C
6Alkyl) pyridyl ,-C (O) furyl, (C
1-C
6Alkyl)-tetrahydrofuran (THF), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl ,-CO
2-(C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-furyl ,-(CH
2)
0-4-SO
2-thienyl ,-pyrrolidyl-benzyl ,-(C
1-C
6Thio alkoxy)-(C
1-C
6Alkyl) ,-C (O)-(C
1-C
6Alkyl), (C
1-C
6Alkoxyl group) ,-(C
2-C
6Alkenyloxy) ,-(C
1-C
6Alkyl)-CO
2-(C
1-C
6Alkyl) and optional by C
1-C
6Alkyl replaces-C (O)-piperidyl; Wherein phenyl and pyridyl be unsubstituted or by 1,2,3,4 or 5 independently for C
1-C
4Alkyl, hydroxyl, C
1-C
4The group of alkoxyl group, halogen replaces, or
R
31, R
32Form 5,6 or 7 yuan of Heterocyclylalkyls or 6 yuan of hetero-aromatic rings with the nitrogen that links to each other with them, each each optional being fused on benzene, pyridine or the pyrimidine ring wherein, and each each optional by C
1-C
6Alkoxyl group, hydroxyl, hydroxyl C
1-C
6Alkyl, C
1-C
4Alkoxy C
1-C
6Alkyl ,-C (O) NH
2,-C (O) NH (C
1-C
6Alkyl)-the phenyl replacement;
R
33Each is H, NH independently in each case
2, NH (C
1-C
6Alkyl), N (C
1-C
6Alkyl) (C
1-C
6Alkyl), N (C
1-C
6Alkyl) (phenyl), N (C
1-C
6Alkyl) (benzyl);
R
35Be phenyl, C
3-C
8Cycloalkyl ,-the S-phenyl ,-benzo dioxole, thienyl, C
1-C
6Alkyl, furyl, imidazolyl, wherein each group respectively be unsubstituted or by 1,2,3,4 or 5 independently for C
1-C
4Alkyl, C
1-C
4Alkoxyl group, OH, hydroxyl C
1-C
6Alkyl, halogen, halogen C
1-C
6Alkyl, halogen C
1-C
6Alkoxyl group ,-O-(C
1-C
6Alkyl)-phenyl ,-CO
2-(C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-(C
5-C
6Cycloalkyl) or (CH
2)
0-4The group of CN replaces;
R
40Be phenyl ,-phenyl-pyridyl, xenyl ,-phenyl-benzothienyl ,-phenyl-thienyl ,-phenyl-furyl ,-the phenyl-pyrimidine base ,-phenyl-isoxazolyls ,-C (O)-pyridyl;-(C
1-C
4Alkyl)-and O-C (O) NH-phenyl, wherein phenyl is optional is replaced by 1,2 or 3 halogen atom;-(C
1-C
4Alkyl)-O-C (O) N (C
1-C
6Alkyl)-phenyl ,-(C
1-C
6Alkyl)-phenyl ,-(C
1-C
4Alkyl)-SO
2NH
2,-(C
1-C
4Alkyl)-SO
2NH (C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-SO
2N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-SO
2NH
2,-SO
2NH (C
1-C
6Alkyl) ,-SO
2N (C
1-C
6Alkyl) (C
1-C
6Alkyl), CN ,-(CH
2)
0-4-(C
3-C
8Cycloalkyl) ,-(C
1-C
4Alkyl)-C (O) O-(C
1-C
4Alkyl) ,-(C
1-C
4Alkyl)-R
33, C
1-C
10Alkyl, C
2-C
8Alkenyl ,-(C
1-C
4Alkyl)-NHC (O)-(C
1-C
4Alkyl) ,-(CH
2)
0-4-C (O) NH
2,-(CH
2)
0-4-C (O) NH (C
1-C
6Alkyl) ,-(CH
2)
0-4-C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl), naphthyl, tetralyl, dihydro naphthyl ,-(CH
2)
0-4-imidazolyl ,-(CH
2)
0-4-pyrrolidyl, oxazolidone 3,4-dihydro-benzo [e] [1,2] oxathiin 2,2-dioxide, pyrimidyl, 3,4-dihydro-2H-benzo [e] [1,2] thiazine 1,1-dioxide, pyridyl; Or pyrimidyl, alkoxyalkyl ,-phenyl-benzothienyl ,-phenyl-cyclohexyl ,-phenyl-cyclopentyl ,-phenyl-(C
1-C
6Alkyl)-cyclopentyl ,-phenyl-(C
1-C
6Alkyl)-cyclohexyl ,-phenyl-oxazolyls, furyl, tetrahydrofuran base, 7-oxa--two ring [2.2.1] heptyl;-dihydro-1-H-pyrazolidone-phenyl;-phenyl-two ring [2.2.1] heptyl; Imidazoles [2,1-b] [1,3] thiazolyl; The tall and erect onyl of nitrogen; Piperidyl;-(C
1-C
6Alkyl)-piperidyl; Two ring [2.2.1] heptyl; The benzodihydropyrone base;-(C
1-C
6)-morpholinyl;-phenyl-C (O)-piperidyl; Thiazolidine and pyridyl ,-pyrrolo--C (O)-pyrrolidyl;-phenyl-C (O)-phenyl;-phenyl-O-phenyl;-phenyl-O-benzyl;-phenyl-tetrahydro pyridazine ketone group and-phenyl-dihydrogen dazin ketone group;
Wherein above-mentioned each group respectively is unsubstituted or is replaced for the substituting group of following groups independently by 1,2,3,4 or 5: halogen, optional by 1 or 2 C that replaces for the group of CN or OH independently
1-C
8Alkyl; C
1-C
6Alkoxyl group, halogen (C
1-C
8Alkyl), halogen (C
1-C
4Alkoxyl group), wherein phenyl optional by 1 or 2 halogen replace-O-(C
1-C
4Alkyl)-phenyl, CN ,-CHO, C
1-C
4Thio alkoxy ,-NHSO
2-(C
1-C
6Alkyl), alkyl wherein optional by 1,2 or 3 halogen replace-N (C
1-C
4Alkyl) SO
2-(C
1-C
4Alkyl); OH;-SO
2R
33R
33C
2-C
8Alkynyl; C
2-C
8Alkenyl; The thio alkoxy alkyl;-SO
2-(C
1-C
10Alkyl); NR
31R
32-C (O)-NR
31R
32-OC (O) R
33C
1-C
8Alkyloyl; With-(C
1-C
6Alkyl)-C (O)-(C
1-C
6Alkoxyl group) ,-C (O)-(C
1-C
6Alkoxyl group) ,-O-(C
1-C
6Alkyl)-C (O) NR
31R
32-CO
2-(C
1-C
6Alkyl);
R
41A and R
41Be H, cyclohexyl, phenyl or optional independently by 1 or 2 phenyl, hydroxyl, C
1-C
4Thio alkoxy, C
1-C
4Thio alkoxy C
1-C
6The C that alkyl replaces
1-C
6Alkyl; Or-C
1-C
6Alkyl-SO
2-C
1-C
6Alkyl;
R
40, R
41Forming one with the atom that links to each other with them chooses wantonly by C
1-C
4Alkyl ring, C
1-C
4Alkoxyl group, halogen ,-CO
2NH
2,-CO
2NH (C
1-C
6Alkyl) or-CO
2N (C
1-C
6Alkyl) (C
1-C
6Alkyl) C of Qu Daiing
3-C
8Cycloalkyl ring; One optional by C
1-C
6The thiazole basic ring that alkyl replaces; Optional by C
1-C
6The isoxazole basic ring that alkyl replaces; Optional is halogen or C by 1,2 or 3 independently
1-C
6The phenyl that the group of alkyl replaces;-pyrrolidyl-benzyl; Choose wantonly and by 1 or 2 be independently-CO
2-(C
1-C
6Alkyl) or-C (O)-(C
1-C
6Alkyl) piperidyl of Qu Daiing;
And
R
42Be H, the optional C that is replaced by OH
1-C
6Alkyl; Benzyl;-NHC (O)-(C
1-C
6Alkyl);-NHC (O)-phenyl, wherein phenyl is optional is replaced by 1 and 2 alkyl;-CO
2-(C
1-C
6Alkyl);-CO
2(benzyl); Or-C (O)-(C
1-C
6Alkyl).
4. compound as claimed in claim 3, its chemical formula is as follows
Or it can be used for the salt of pharmacy, wherein
R
51Each is C independently in each case
1-C
6Alkyl, C
1-C
6Alkoxyl group, NHSO
2-(C
1-C
4Alkyl), wherein alkyl is optional is replaced by 1,2 or 3 halogen;-SO
2-NH-(C
1-C
6Alkyl)-NH
2,-SO
2-NH-(C
1-C
6Alkyl)-NH (C
1-C
4Alkyl) ,-SO
2-NH-(C
1-C
6Alkyl)-N (C
1-C
4Alkyl) (C
1-C
4Alkyl), [1,2,4] triazolidine-3, the 5-diketone ,-NHC (O) NH
2,-NHC (O) NH (C
1-C
6Alkyl) ,-NHC (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl) C (O) NH
2,-N (C
1-C
6Alkyl) C (O) NH (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl) C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl), halogen ,-CF
3, OH ,-SO
2NR
31R
32,-C (O)-NR
31R
32,-NR
31R
32, optional by phenyl or (C
1-C
4Alkyl) the hydroxyl C of phenyl replacement
1-C
10Alkyl ,-O-(C
1-C
4Alkyl)-phenyl ,-NHC (S) NH
2,-NHC (S) NH (C
1-C
6Alkyl) ,-NHC (S) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-the O-phenyl;-C (O)-(C
1-C
6Alkyl), wherein alkyl is optional by NH
2, N (C
1-C
6Alkyl) or N (C
1-C
6Alkyl) (C
1-C
6Alkyl) replaces;-O-C
3-C
6Cycloalkyl, optional be C independently by 1 or 2
1-C
4The group of alkyl or phenyl replaces the De oxazole; Hydroxyl C
1-C
4Alkoxyl group, aminoalkoxy, NH (C
1-C
6Alkyl)-alkoxyl group, N (C
1-C
6Alkyl) (C
1-C
6Alkyl)-alkoxyl group,
R wherein
31And R
32Respectively be independently selected from hydrogen, C in each case
1-C
6Alkyl, hydroxyl C
1-C
6Alkyl, C
1-C
6Alkylhalide group, (C
1-C
6Alkyl) C (O) NH
2,-(C
1-C
6Alkyl) C (O) NH (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl) C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-NH
2,-(C
1-C
6Alkyl)-NH (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl) phenyl ,-(C
1-C
6Alkyl) pyridyl ,-C (O) furyl, (C
1-C
6Alkyl)-tetrahydrofuran (THF), wherein phenyl and pyridyl be unsubstituted or by 1,2,3,4 or 5 independently for C
1-C
4Alkyl, hydroxyl, C
1-C
4The group of alkoxyl group, halogen replaces, or
Wherein in each case, R
31, R
32Each forms the tall and erect yl of a pyrrolidyl, piperazinyl, piperidyl, nitrogen, pyridyl or pyrimidine-ring independently with the nitrogen that links to each other with them, each each optional being fused on benzene, pyridine or the pyrimidine ring wherein, and each each choose wantonly by C
1-C
6Alkoxyl group, C
1-C
6Alkyl, hydroxyl, hydroxyl C
1-C
6Alkyl, C
1-C
4Alkoxy C
1-C
6Alkyl ,-C (O) NH
2, or-C (O) NH-(C
1-C
6Alkyl)-the phenyl replacement.
5. compound as claimed in claim 4, wherein R
41And R
42It respectively is the compound of hydrogen.
6. compound as claimed in claim 4, wherein
R
35Be phenyl, cyclohexyl ,-S-phenyl, benzo dioxole, thienyl, C
3-C
6Alkyl, furyl, wherein each group respectively be unsubstituted or by 1,2,3,4 or 5 independently for C
1-C
4Alkyl, C
1-C
4Alkoxyl group, OH, hydroxyl C
1-C
6Alkyl, halogen, halogen C
1-C
6Alkyl, halogen C
1-C
6Alkoxyl group ,-O-(C
1-C
6Alkyl)-phenyl ,-CO
2-(C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-(C
5-C
6Cycloalkyl) group replaces.
7. compound as claimed in claim 3, wherein
R
35Be phenyl, cyclohexyl ,-S-phenyl, benzo dioxole, thienyl, C
3-C
6Alkyl, furyl, wherein each group all be unsubstituted or by 1,2,3,4 or 5 independently for C
1-C
4Alkyl, C
1-C
4Alkoxyl group, OH, hydroxyl C
1-C
6Alkyl, halogen, halogen C
1-C
6Alkyl, halogen C
1-C
6Alkoxyl group ,-O-(C
1-C
6Alkyl)-phenyl ,-CO
2-(C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-(C
5-C
6Cycloalkyl) group replaces;
R
40Be phenyl ,-phenyl-pyridyl, xenyl ,-phenyl-benzothienyl ,-phenyl-thienyl ,-phenyl-furyl ,-the phenyl-pyrimidine base ,-phenyl-isoxazolyls ,-C (O)-pyridyl ,-(C
1-C
4Alkyl)-O-C (O) NH-phenyl ,-(C
1-C
4Alkyl)-O-C (O) N (C
1-C
6Alkyl)-phenyl ,-(C
1-C
4Alkyl)-phenyl ,-(C
1-C
4Alkyl)-SO
2NH
2,-(C
1-C
4Alkyl)-SO
2NH (C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-SO
2N (C
1-C
6Alkyl) (C
1-C
6Alkyl), CN ,-(CH
2)
0-4-(C
3-C
8Cycloalkyl) ,-(C
1-C
4Alkyl)-C (O) O-(C
1-C
4Alkyl) ,-(C
1-C
4Alkyl)-R
33, C
1-C
8Alkyl ,-(C
1-C
4Alkyl)-NHC (O)-(C
1-C
4Alkyl) ,-(CH
2)
0-4-C (O) NH
2,-(CH
2)
0-4-C (O) NH (C
1-C
6Alkyl) ,-(CH
2)
0-4-C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl), tetralyl, dihydro naphthyl, above-mentioned each group all is unsubstituted or is replaced for the substituting group of following groups independently by 1,2,3,4 or 5: halogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, halogen (C
1-C
4Alkyl), wherein phenyl optional by 1 or 2 halogen replace-O-(C
1-C
4Alkyl)-phenyl ,-CHO, C
1-C
4Thio alkoxy ,-NHSO
2-(C
1-C
4Alkyl), alkyl wherein optional by 1,2 or 3 halogen replace-N (C
1-C
4Alkyl) SO
2-(C
1-C
4Alkyl), OH ,-SO
2R
33, R
33
R
41Be H, cyclohexyl, phenyl or optional by 1 or 2 phenyl, hydroxyl or C
1-C
4The C that thio alkoxy replaces
1-C
6Alkyl; And
R
42Be hydrogen or CH
2CN.
8. compound as claimed in claim 6, wherein
R
35Be phenyl, C
3-C
8Cycloalkyl ,-S-phenyl, benzo dioxole, thienyl, C
3-C
6Alkyl, furyl, wherein each group respectively be unsubstituted or by 1,2,3,4 or 5 independently for C
1-C
4Alkyl, C
1-C
4Alkoxyl group, OH, hydroxyl C
1-C
6Alkyl, halogen, CF
3, OCF
3,-O benzyl ,-CO
2-(C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-(C
5-C
6Cycloalkyl) group replaces.
R
40Be phenyl ,-phenyl-pyridyl, xenyl ,-phenyl-benzothienyl ,-phenyl-thienyl ,-phenyl-furyl ,-the phenyl-pyrimidine base ,-phenyl-isoxazolyls ,-C (O)-pyridyl ,-(C
1-C
4Alkyl)-O-C (O) NH-phenyl ,-(C
1-C
4Alkyl)-O-C (O) N (C
1-C
6Alkyl)-phenyl ,-(C
1-C
4Alkyl)-phenyl ,-(C
1-C
4Alkyl)-SO
2NH
2,-(C
1-C
4Alkyl)-SO
2NH (C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-SO
2N (C
1-C
6Alkyl) (C
1-C
6Alkyl), CN ,-(C
1-C
4Alkyl)-(C
3-C
6Cycloalkyl) ,-(C
1-C
4Alkyl)-C (O) O-(C
1-C
4Alkyl) ,-(C
1-C
4Alkyl)-R
33, C
1-C
8Alkyl ,-(C
1-C
4Alkyl)-NHC (O)-(C
1-C
4Alkyl) ,-C (O) NH
2, above-mentioned each ring is unsubstituted or is replaced for the substituting group of following groups independently by 1,2 or 3: halogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, CF
3, wherein phenyl optional by 1 or 2 halogen replace-O-(C
1-C
4Alkyl)-phenyl ,-CHO ,-NHSO
2-(C
1-C
4Alkyl), alkyl wherein optional by 1,2 or 3 halogen replace-N (C
1-C
4Alkyl) SO
2-(C
1-C
4Alkyl);
R
41Be H, cyclohexyl, phenyl or optional by 1 or 2 phenyl, hydroxyl or C
1-C
4The C that thio alkoxy replaces
1-C
6Alkyl; And
R
42Be hydrogen or-CH
2CN;
R
51Be C in each case independently
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NHSO
2-(C
1-C
4Alkyl), wherein alkyl optional by 1,2 or 3 halogen replace ,-SO
2-NH-(C
1-C
6Alkyl)-NH
2,-SO
2-NH-(C
1-C
6Alkyl)-NH (C
1-C
4Alkyl) ,-SO
2-NH-(C
1-C
6Alkyl)-N (C
1-C
4Alkyl) (C
1-C
4Alkyl), [1,2,4] triazolidine-3, the 5-diketone ,-NHC (O) NH
2,-NHC (O) NH (C
1-C
6Alkyl) ,-NHC (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl) C (O) NH
2,-N (C
1-C
6Alkyl) C (O) NH (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl) C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl), halogen ,-CF
3, OH ,-SO
2NR
31R
32,-C (O)-NR
31R
32,-NR
31R
32, the optional hydroxyl C that is replaced by phenyl or 2-aminomethyl phenyl
1-C
10Alkyl ,-O-(C
1-C
4Alkyl)-phenyl ,-NHC (S) NH
2,-NHC (S) NH (C
1-C
6Alkyl) ,-NHC (S) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-the O-phenyl ,-C (O)-(C
1-C
6Alkyl), wherein alkyl is optional by NH
2, N (C
1-C
6Alkyl) or N (C
1-C
6Alkyl) (C
1-C
6Alkyl) replace ,-O-C
3-C
6Cycloalkyl, optional be C independently by 1 or 2
1-C
4The group of alkyl or phenyl replaces the De oxazole; Hydroxyl C
1-C
4Alkoxyl group, aminoalkoxide, NH (C
1-C
6Alkyl)-alkoxyl group, N (C
1-C
6Alkyl) (C
1-C
6Alkyl)-alkoxyl group,
R wherein
31And R
32All be independently selected from hydrogen, C in each case
1-C
6Alkyl, hydroxyl C
1-C
6Alkyl ,-(C
1-C
6Alkyl) C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-NH (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl) phenyl ,-(C
1-C
6Alkyl) pyridyl ,-C (O) furyl, (C
1-C
6Alkyl)-tetrahydrofuran (THF), wherein phenyl be unsubstituted or by 1,2 or 3 independently for C
1-C
4The group of alkoxy or halogen replaces, or
R in each case wherein
31, R
32All form the tall and erect yl of a pyrrolidyl, piperazinyl, piperidyl or nitrogen independently with the nitrogen that links to each other with them, wherein each is chosen wantonly and is fused on benzene, pyridine or the pyrimidine ring, and each is optional by hydroxyl, C
1-C
6Alkyl, hydroxyl C
1-C
6Alkyl, C
1-C
4Alkoxy C
1-C
6Alkyl ,-C (O) NH
2, or-C (O) NH-benzyl replaces.
9. compound as claimed in claim 8, wherein
R
35Be phenyl, halogenation phenyl, dihalide phenyl, three halogenation phenyl, four halogenation phenyl, five halogenation phenyl, halogen, benzyl oxy phenyl, halogen, alkyl phenyl, benzyl oxy phenyl, cyclohexyl, (C
1-C
4Alkoxyl group) carbonyl phenyl, (C
1-C
4Alkoxyl group) phenyl ,-S-phenyl or benzo dioxole;
R
41Be H, cyclohexyl, phenyl or optional by 1 or 2 phenyl, hydroxyl or C
1-C
4The C that thio alkoxy replaces
1-C
6Alkyl; And
R
42Be hydrogen or-CH
2CN.
10. compound as claimed in claim 9, wherein
R
35Be 3,5-dihalide phenyl;
R
40Be phenyl ,-phenyl-pyridyl, xenyl ,-phenyl-benzothienyl ,-phenyl-thienyl ,-phenyl-furyl ,-the phenyl-pyrimidine base ,-phenyl-isoxazolyls ,-(C
1-C
4Alkyl)-O-C (O) NH-phenyl ,-(C
1-C
4Alkyl)-O-C (O) N (C
1-C
6Alkyl)-phenyl ,-(C
1-C
4Alkyl)-SO
2NH
2, CN ,-(C
1-C
4Alkyl)-(C
3-C
6Cycloalkyl) ,-(C
1-C
4Alkyl)-C (O) O-(C
1-C
4Alkyl) ,-(C
1-C
4Alkyl)-R
33Or C
1-C
8Alkyl, above-mentioned each be unsubstituted or replaced for the group of following groups independently by 1,2 or 3: halogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, CF
3, wherein phenyl optional by 1 or 2 halogen replace-O-(C
1-C
4Alkyl)-phenyl ,-CHO or-NHSO
2-(C
1-C
4Alkyl).
11. compound as claimed in claim 10, wherein
R
35Be 3, the 5-difluorophenyl; 3, the 5-dichlorophenyl; Or 3-chlorine, the 5-fluorophenyl; And
R
40Be unsubstituted or be fluorine-based, chloro, bromo, iodo, methyl, ethyl, methoxyl group, oxyethyl group, CF independently by 1,2 or 3
3Or-phenyl that the group of O benzyl replaces, the phenyl in-O benzyl optional by 1 or 2 be independently halogen or-NHSO
2CH
3Group replace.
12. compound as claimed in claim 11, wherein
R
51Be C in each case independently
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NHSO
2CH
3,-SO
2-NH-(ethyl)-NH (CH
3), [1,2,4] triazolidine-3, the 5-diketone ,-NHC (O) NH
2,-CF
3, OH ,-SO
2NR
31R
32,-C (O)-NR
31R
32, the hydroxyl octyl group ,-CH (OH)-2-aminomethyl phenyl ,-the O benzyl or-NHC (S) NH (CH
3);
R wherein
31And R
32Be independently selected from hydrogen in each case; C
1-C
6Alkyl; Hydroxyl C
1-C
6Alkyl;-(CH
2) C (O) N (CH
3)
2-CH
2CH
2N (CH
3)
2Optional is C by 1 or 2 independently
1-C
4Alkyl, C
1-C
4The benzyl that the group of alkoxy or halogen replaces; Styroyl;-CH
2CH
2Pyridyl;-C (O) furyl; Or
R in each case
31, R
32Form a pyrrolidyl, piperazinyl, piperidyl or the tall and erect yl of nitrogen independently with the nitrogen that links to each other with them, wherein each each optional by methylol, hydroxyethyl, methoxymethyl or-C (O) NH
2Replace.
13. compound as claimed in claim 12, wherein
R
40Be 3-ethylphenyl or 3-p-methoxy-phenyl; And
R
42Be hydrogen.
14. compound as claimed in claim 12, wherein
R
51In each case each be independently H ,-SO
2NH-propyl group-OH ,-SO
2NH-ethyl-OH ,-SO
2NH-ethyl-OCH
3,-SO
2NH-CH (CH
3)
2-CH
2OH ,-SO
2NH-(CH
2CH (OH) CH
3) ,-SO
2NH-ethyl-NH (CH
3) ,-SO
2NH-(CH
2CH
2OH)
2,-SO
2NHCH (CH
3) CH
2OH ,-SO
2N (CH
3)
2,-SO
2NH (CH
2CH (OH) CH
3) ,-SO
2-tetramethyleneimine ,-SO
2-(lupetidine) ,-SO
2-(2-propyl group piperidines) ,-SO
2-(hydroxypropyl),-C (O)-(2-methoxymethyl tetramethyleneimine),-C (O)-(2-crassitude),-C (O)-(2, the 6-dimethyl pyrrolidine),-C (O)-(2-hydroxymethyl pyrrolidine),-C (O) N (methyl) (ethyl),-C (O) N (methyl) (propyl group),-C (O) N (methyl) (butyl),-C (O) N (propyl group) (butyl),-C (O) N (allyl group) (cyclopentyl),-C (O) N (allyl group) (cyclohexyl),-C (O) N (methyl) (methyl),-C (O) N (ethyl) (ethyl),-C (O) N (butyl) (butyl),-C (O) N (sec.-propyl) (sec.-propyl),-C (O) N (propyl group) (propyl group),-C (O) N (methyl) (cyclohexyl),-C (O) N (ethyl) (cyclohexyl),-C (O) NH (cyclobutyl),-C (O) NH (cyclopentyl),-C (O) N (CH
3) (cyclopentyl) ,-C (O) NH (2-methylcyclohexyl) ,-C (O) NH (amyl group) ,-C (O) N (amyl group) (amyl group) ,-C (O) NH (isopentyl) ,-C (O) NH (ethoxyethyl group) ,-C (O) N (CH
3) (methoxy ethyl) ,-C (O) N (propyl group) (methoxy ethyl) ,-C (O) N (methoxy ethyl) (methoxy ethyl) ,-C (O) N (ethoxyethyl group) (ethoxyethyl group) ,-C (O) N (ethyl) (methoxy ethyl) ,-C (O) N (propyl group) (hydroxyethyl) ,-C (O) N (hydroxyethyl) (ethyl), ethynyl, methyl, bromo ,-N (CH
3) SO
2(CH
3) ,-N (CH
3) SO
2-thienyl ,-N (hydroxypropyl) SO
2CH
3,-(CH
2)-SO
2-(CH
3) or-C (O)-CH (CH
3) CH
2CH
2CH
3
15. compound as claimed in claim 14 wherein has two R
51Group.
16. compound as claimed in claim 15, wherein R
51Group is at 3 and 5 of phenyl.
17. compound as claimed in claim 11, wherein
R
51Be C in each case independently
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-C (O)-NR
31R
32,-C (O) CH
2NH
2, cyclopentyloxy ,-NHC (O) NH (ethyl), optional be C independently by 1 or 2
1-C
4Alkyl or phenyl replaces De oxazole, hydroxy ethoxy, diethylamino oxyethyl group,
R wherein
31And R
32Be independently selected from hydrogen, C in each case
1-C
6Alkyl, hydroxyl C
1-C
6Alkyl ,-CH
2Tetrahydrofuran (THF).
18. compound as claimed in claim 9, wherein R
35It is cyclohexyl.
19. compound as claimed in claim 15, wherein
R
40Be phenyl or C
1-C
8Alkyl, wherein each is unsubstituted or is halogen, C independently by 1,2,3,4 or 5
1-C
4Alkyl, C
1-C
4Alkoxyl group, halogen (C
1-C
4Alkyl) group replaces; And
R
42And R
41Be hydrogen.
20. compound as claimed in claim 16, wherein
R
40Be phenyl, 3-p-methoxy-phenyl, 4-p-methoxy-phenyl, 3-ethoxyl phenenyl, 4-ethoxyl phenenyl, 3-trifluoromethyl, 4-trifluoromethyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 2-ethylphenyl, 3-ethylphenyl or C
3-C
6Alkyl; And
R
51Be C in each case independently
1-C
6Alkyl, C
1-C
6Alkoxy or halogen,
R wherein
31And R
32Be independently selected from hydrogen, C in each case
1-C
6Alkyl, hydroxyl C
1-C
6Alkyl and-(C
1-C
6Alkyl) phenyl, wherein phenyl be unsubstituted or by 1,2 or 3 independently for C
1-C
4The group of alkoxy or halogen replaces,
R in each case wherein
31, R
32Form the tall and erect yl of a pyrrolidyl, piperazinyl, piperidyl or nitrogen independently with the nitrogen that links to each other with them, wherein each is chosen wantonly and is fused on benzene, pyridine or the pyrimidine ring, and each is optional by hydroxyl, hydroxyl C
1-C
6Alkyl, C
1-C
4Alkoxy C
1-C
6Alkyl ,-C (O) NH
2, or-C (O) NH-benzyl replaces.
21. compound as claimed in claim 9, wherein
R
35Be 3-halogen, 5-benzyloxy phenyl; 3-benzyloxy phenyl; Or 4-benzyloxy phenyl;
R
41Be H, cyclohexyl, phenyl or optional by 1 or 2 phenyl, hydroxyl or C
1-C
4The C that thio alkoxy replaces
1-C
6Alkyl; And
R
42Be hydrogen or-CH
2CN.
22. compound as claimed in claim 21, wherein
R
40Be phenyl ,-phenyl-pyridyl, xenyl ,-(C
1-C
4Alkyl)-O-C (O) NH-phenyl ,-(C
1-C
4Alkyl)-O-C (O) N (C
1-C
6Alkyl)-phenyl ,-(C
1-C
4Alkyl)-SO
2NH
2,-(C
1-C
4Alkyl)-(C
3-C
6Cycloalkyl) ,-(C
1-C
4Alkyl)-C (O) O-(C
1-C
4Alkyl) ,-(C
1-C
4Alkyl)-R
33Or C
1-C
8Alkyl, above-mentioned each be unsubstituted or be halogen, C independently by 1,2 or 3
1-C
4Alkyl, C
1-C
4Alkoxyl group, CF
3, in the base phenyl optional by 1 or 2 halogen replace-the O benzyl ,-CHO or-NHSO
2-(C
1-C
4Alkyl) group replaces.
23. compound as claimed in claim 22, wherein
R
40Be phenyl or C
1-C
8Alkyl, wherein above-mentioned each be unsubstituted or be halogen, C independently by 1,2 or 3
1-C
4Alkyl, C
1-C
4Alkoxyl group, CF
3, in the base phenyl optional by 1 or 2 halogen replace-the O benzyl ,-CHO or-NHSO
2-(C
1-C
4Alkyl) group replaces; And
R
41Be hydrogen or optional by 1 or 2 phenyl, hydroxyl or C
1-C
4The C that thio alkoxy replaces
1-C
6Alkyl;
R
42Be hydrogen; And
R
51Be C in each case independently
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NHSO
2-(C
1-C
4Alkyl), wherein alkyl optional by 1,2 or 3 halogen replace ,-SO
2-NH-(C
1-C
6Alkyl)-NH
2,-SO
2-NH-(C
1-C
6Alkyl)-NH (C
1-C
4Alkyl) ,-SO
2-NH-(C
1-C
6Alkyl)-N (C
1-C
4Alkyl) (C
1-C
4Alkyl) ,-NHC (O) NH
2,-NHC (O) NH (C
1-C
6Alkyl) ,-NHC (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl) C (O) NH
2,-N (C
1-C
6Alkyl) C (O) NH (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl) C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl), halogen ,-CF
3, OH ,-SO
2NR
31R
32,-C (O)-NR
31R
32,-NR
31R
32, hydroxyl C
1-C
10Alkyl;-O benzyl ,-NHC (S) NH
2,-NHC (S) NH (C
1-C
6Alkyl) ,-NHC (S) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-the O-phenyl;-C (O)-(C
1-C
6Alkyl) ,-the O-cyclopentyl ,-O-cyclohexyl, hydroxyl C
1-C
4Alkoxyl group, aminoalkoxide, NH (C
1-C
6Alkyl)-alkoxyl group, N (C
1-C
6Alkyl) (C
1-C
6Alkyl)-alkoxyl group,
R wherein
31And R
32Be independently selected from hydrogen, C in each case
1-C
6Alkyl, hydroxyl C
1-C
6Alkyl ,-(C
1-C
6Alkyl)-NH (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-N (C
1-C
6Alkyl) (C
1-C
6Alkyl) and benzyl, the phenyl in the benzyl is unsubstituted or is C independently by 1 or 2
1-C
4The group of alkoxy or halogen replaces,
R in each case wherein
31, R
32Form pyrrolidyl, piperazinyl or a piperidyl independently with the nitrogen that links to each other with them, wherein each is optional by hydroxyl, hydroxyl C
1-C
6Alkyl, C
1-C
4Alkoxy C
1-C
6Alkyl ,-C (O) NH
2, or-C (O) NH-benzyl replaces.
24. compound as claimed in claim 23, wherein
R
40Be phenyl or C
1-C
8Alkyl, wherein above-mentioned each be unsubstituted or be halogen, C independently by 1,2 or 3
1-C
4Alkyl, C
1-C
4Alkoxyl group or CF
3Group replace; And
R
51Be C in each case independently
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NHSO
2CH
3,-NHSO
2CF
3, halogen ,-CF
3, OH ,-SO
2NR
31R
32,-C (O)-NR
31R
32,-NR
31R
32, hydroxyl C
1-C
10Alkyl, hydroxyl C
1-C
4Alkoxyl group, aminoalkoxide, NH (C
1-C
6Alkyl)-alkoxyl group, N (C
1-C
6Alkyl) (C
1-C
6Alkyl)-alkoxyl group,
R wherein
31And R
32Be independently selected from hydrogen, C in each case
1-C
6Alkyl, hydroxyl C
1-C
6Alkyl and benzyl, the phenyl in the benzyl be unsubstituted or by 1 or 2 independently for the group of methoxyl group, oxyethyl group or halogen replaces,
R in each case wherein
31, R
32Form a pyrrolidyl, piperazinyl or piperidines basic ring independently with the nitrogen that links to each other with them, wherein each is optional by hydroxyl, hydroxyl C
1-C
6Alkyl, C
1-C
4Alkoxy C
1-C
6Alkyl or-C (O) NH
2Replace.
25. compound as claimed in claim 24, wherein R
35Be that 3-is fluorine-based, 5-benzyloxy phenyl or 3-chloro, 5-benzyloxy phenyl.
26. compound as claimed in claim 9, wherein
R
35Be-the S-phenyl, benzo [1,3] dioxole, furyl or thienyl;
R
41Be H, cyclohexyl, phenyl or optional by 1 or 2 phenyl, hydroxyl or C
1-C
4The C that thio alkoxy replaces
1-C
6Alkyl; And
R
42Be hydrogen or-CH
2CN.
27. compound as claimed in claim 26, wherein
R
40Be phenyl ,-phenyl-pyridyl, xenyl ,-the phenyl-pyrimidine base ,-(C
1-C
4Alkyl)-O-C (O) NH-phenyl ,-(C
1-C
4Alkyl)-O-C (O) N (C
1-C
6Alkyl)-phenyl ,-(C
1-C
4Alkyl)-SO
2NH
2,-(C
1-C
4Alkyl)-(C
3-C
6Cycloalkyl) ,-(C
1-C
4Alkyl)-C (O) O-(C
1-C
4Alkyl) ,-(C
1-C
4Alkyl)-R
33Or C
1-C
8Alkyl, wherein above-mentioned each be unsubstituted or be halogen, C independently by 1,2 or 3
1-C
4Alkyl, C
1-C
4Alkoxyl group, CF
3, in the base phenyl optional by 1 or 2 halogen replace-the O benzyl ,-CHO or-NHSO
2-(C
1-C
4Alkyl) ,-NHSO
2CF
3Group replace.
28. compound as claimed in claim 27, wherein
R
51Be independently selected from each case:
C
1-C
4Alkyl ,-C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-C (O) NH
2,-C (O) N (C
2-C
6Alkenyl) (C
3-C
8Cycloalkyl) ,-C (O) NH (C
3-C
8Cycloalkyl) ,-C (O) NH (C
1-C
6Alkyl), optional by 1 and 2 be independently the group replacement of alkoxyalkyl or hydroxyl C (O)-(tetramethyleneimine), halogen ,-C (O) N (C
1-C
6Hydroxyalkyl) (C
1-C
6Alkyl) ,-C (O) NH (alkoxyalkyl) ,-C (O) N (alkoxyalkyl) (alkoxyalkyl) ,-C (O) N (C
1-C
6Alkyl) (alkoxyalkyl) ,-C (O) N (C
1-C
6Hydroxyalkyl) (alkyl) ,-NHSO
2CF
3,-N (C
1-C
6Alkyl)-SO
2-thienyl ,-N (C
1-C
6Hydroxyalkyl) SO
2-(C
1-C
6Alkyl) ,-NHC (O) C
1-C
4Alkyl, optional by 1 or 2 methyl substituted De oxazolyl, optional by 1 or 2 methyl substituted thiazolyl, optional by 1 or 2 methyl substituted pyrazolyl, optional by 1 or 2 methyl substituted imidazolyl, optional by 1 or 2 methyl substituted isoxazolyl, the optional pyrimidyl that is replaced by 1 or 2 methyl or halogen group ,-NHSO
2CH
3, wherein imidazole ring is optional by 1 or 2 methyl substituted-NHSO
2-imidazolyl ,-N (C
1-C
6Alkyl) SO
2(C
1-C
6Alkyl) ,-SO
2NH-C
1-C
6Hydroxyalkyl ,-SO
2NH-C
1-C
6Alkyl-NH (C
1-C
4Alkyl), optional by 1 or 2 methyl substituted-SO
2-piperazinyl, optional by 1 or 2 methyl substituted-SO
2-tetramethyleneimine, optional by 1 or 2 C
1-C
4Alkyl replaces-SO
2-piperidines ,-SO
2N (C
1-C
4Hydroxyalkyl) (C
1-C
4Hydroxyalkyl) ,-SO
2NH
2,-SO
2N (C
1-C
6Alkyl) (C
1-C
6Alkyl), C
2-C
6Alkynyl ,-SO
2-(C
1-C
6Hydroxyalkyl) ,-SO
2NH (C
1-C
6Hydroxyalkyl) ,-SO
2N (C
1-C
6Alkyl) (C
1-C
6Hydroxyalkyl) ,-(C
1-C
4Alkyl) SO
2-(C
1-C
4Alkyl) or-C (O)-(C
1-C
10Alkyl).
29. compound as claimed in claim 28, wherein
R
51Be independently selected from each case-SO
2NH-propyl group-OH ,-SO
2NH-ethyl-OH ,-SO
2NH-ethyl-OCH
3,-SO
2NH-CH (CH
3)
2-CH
2OH ,-SO
2NH-(CH
2CH (OH) CH
3) ,-SO
2NH-ethyl-NH (CH
3) ,-SO
2NH-(CH
2CH
2OH)
2,-SO
2NHCH (CH
3) CH
2OH ,-SO
2N (CH
3)
2,-SO
2NH (CH
2CH (OH) CH
3) ,-SO
2-tetramethyleneimine ,-SO
2-(lupetidine) ,-SO
2-(2-propyl group piperidines) ,-SO
2-(hydroxypropyl),-C (O)-(2-methoxymethyl tetramethyleneimine),-C (O)-(2-crassitude),-C (O)-(2, the 6-dimethyl pyrrolidine),-C (O)-(2-hydroxymethyl pyrrolidine),-C (O) N (methyl) (ethyl),-C (O) N (methyl) (propyl group),-C (O) N (methyl) (butyl),-C (O) N (propyl group) (butyl),-C (O) N (allyl group) (cyclopentyl),-C (O) N (allyl group) (cyclohexyl),-C (O) N (methyl) (methyl),-C (O) N (ethyl) (ethyl),-C (O) N (butyl) (butyl),-C (O) N (sec.-propyl) (sec.-propyl),-C (O) N (propyl group) (propyl group),-C (O) N (methyl) (cyclohexyl),-C (O) N (ethyl) (cyclohexyl),-C (O) NH (cyclobutyl),-C (O) NH (cyclopentyl),-C (O) N (CH
3) (cyclopentyl) ,-C (O) NH (2-methylcyclohexyl) ,-C (O) NH (amyl group) ,-C (O) N (amyl group) (amyl group) ,-C (O) NH (isopentyl) ,-C (O) NH (ethoxyethyl group) ,-C (O) N (methoxy ethyl) (methoxy ethyl) ,-C (O) N (CH
3) (methoxy ethyl) ,-C (O) N (propyl group) (methoxy ethyl) ,-C (O) N (ethoxyethyl group) (ethoxyethyl group) ,-C (O) N (ethyl) (methoxy ethyl) ,-C (O) N (propyl group) (hydroxyethyl) ,-C (O) N (hydroxyethyl) (ethyl), ethynyl, methyl, bromo ,-N (CH
3) SO
2(CH
3) ,-N (CH
3) SO
2-thienyl ,-N (hydroxypropyl) SO
2CH
3,-(CH
2)-SO
2-(CH
3) or-C (O)-CH (CH
3) CH
2CH
2CH
3
30. compound as claimed in claim 27, wherein
R
40Be phenyl or C
1-C
8Alkyl, wherein above-mentioned each be unsubstituted or be halogen, C independently by 1,2 or 3
1-C
4Alkyl, C
1-C
4Alkoxyl group, CF
3, in the base phenyl optional by 1 or 2 halogen replace-the O benzyl ,-CHO or-NHSO
2-(C
1-C
4Alkyl) group replaces; And
R
41Be hydrogen or optional by 1 or 2 phenyl, hydroxyl or C
1-C
4The C that thio alkoxy replaces
1-C
6Alkyl; And
R
42Be hydrogen; And
R
51Be C in each case independently
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NHSO
2-(C
1-C
4Alkyl), wherein alkyl optional by 1,2 or 3 halogen replace ,-SO
2-NH-(C
1-C
6Alkyl)-NH
2,-SO
2-NH-(C
1-C
6Alkyl)-NH (C
1-C
4Alkyl) ,-SO
2-NH-(C
1-C
6Alkyl)-N (C
1-C
4Alkyl) (C
1-C
4Alkyl) ,-NHC (O) NH
2,-NHC (O) NH (C
1-C
6Alkyl) ,-NHC (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl) C (O) NH
2,-N (C
1-C
6Alkyl) C (O) NH (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl) C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl), halogen ,-CF
3, OH ,-SO
2NR
31R
32,-C (O)-NR
31R
32,-NR
31R
32, hydroxyl C
1-C
10Alkyl;-O benzyl ,-NHC (S) NH
2,-NHC (S) NH (C
1-C
6Alkyl) ,-NHC (S) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-the O-phenyl ,-C (O)-(C
1-C
6Alkyl) ,-the O-cyclopentyl ,-O-cyclohexyl, hydroxyl C
1-C
4Alkoxyl group, aminoalkoxide, NH (C
1-C
6Alkyl)-alkoxyl group, N (C
1-C
6Alkyl) (C
1-C
6Alkyl)-alkoxyl group,
R wherein
31And R
32Be independently selected from hydrogen, C in each case
1-C
6Alkyl, hydroxyl C
1-C
6Alkyl ,-(C
1-C
6Alkyl)-NH (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-N (C
1-C
6Alkyl) (C
1-C
6Alkyl) and benzyl, the phenyl in the benzyl is unsubstituted or is C independently by 1 or 2
1-C
4The group of alkoxy or halogen replaces,
R in each case wherein
31, R
32Form pyrrolidyl, piperazinyl or a piperidyl independently with the nitrogen that links to each other with them, wherein each is optional by hydroxyl, hydroxyl C
1-C
6Alkyl, C
1-C
4Alkoxy C
1-C
6Alkyl ,-C (O) NH
2, or-C (O) NH-benzyl replaces.
31. compound as claimed in claim 30, wherein
R
40Be phenyl or C
1-C
8Alkyl, wherein above-mentioned each be unsubstituted or be halogen, C independently by 1,2 or 3
1-C
4Alkyl, C
1-C
4Alkoxyl group or CF
3Group replace; And
R
51Be C in each case independently
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NHSO
2CH
3,-NHSO
2CF
3, halogen ,-CF
3, OH ,-SO
2NR
31R
32,-C (O)-NR
31R
32,-NR
31R
32, hydroxyl C
1-C
10Alkyl, hydroxyl C
1-C
4Alkoxyl group, aminoalkoxide, NH (C
1-C
6Alkyl)-alkoxyl group, N (C
1-C
6Alkyl) (C
1-C
6Alkyl)-alkoxyl group,
R wherein
31And R
32Be independently selected from hydrogen, C in each case
1-C
6Alkyl, hydroxyl C
1-C
6Alkyl and benzyl, the phenyl in the benzyl be unsubstituted or by 1 or 2 independently for the group of methoxyl group, oxyethyl group or halogen replaces,
R in each case wherein
31, R
32Form a pyrrolidyl, piperazinyl or piperidines basic ring independently with the nitrogen that links to each other with them, wherein each is optional by hydroxyl, hydroxyl C
1-C
6Alkyl, C
1-C
4Alkoxy C
1-C
6Alkyl or-C (O) NH
2Replace.
32. compound that chemical formula is following:
Or it can be used for the salt of pharmacy, wherein
R
30Be selected from phenyl, the pyrazolopyrimidine base, oxa--azepine-benzo Azulene base isoxazolyl, the Triazolopyridine base, pyrrolidone-base, tetrahydrochysene sulfo--azepine-fluorenyl, pyridyl, piperidyl, dihydro ring penta quinolyl, furyl, the naphthalene thienyl, 2,3-naphthyridine ketone group, thiadiazolyl group, the Thienopyrimidine ketone group, oxa--diaza-ring penta naphthyl, dihydrobenzo dioxepinyl, the chromanone base, the chromene ketone group, oxazolidinyl, purine radicals, oxaxolyl, thiazolyl, the pyridazine ketone group, thiazolyl, pyranyl, dihydropyrane and pyridyl, the tall and erect yl of di nitrogen, cyclopropyl, the dihydro-naphtho isoxazolyl, the benzo indazolyl, dihydro ring penta chromene ketone group, the imidazolopyrazole base, tetrahydro cyclopentyl chromene ketone group, the dihydroquinoline ketone group, pyridyl, the isochroman base, the quinazoline ketone group, the Pyrazolopyridine base, titanium dioxide dihydrobenzo thiophene, dihydro furan benzoisoxazole base, the dihydro-pyrimidin diketo, thieno-pyrazolyl oxazolyl, the tetrahydro cyclopentyl pyrazolyl, dihydro naphthalenonyl, the Dihydrobenzofuranes ketone group, dihydro monodral base, the tetrahydro cyclopentyl pyrazolyl, tetrahydro-pyrazole and azepine base, indazolyl, the tetrahydro cyclopentyl isoxazolyl, the tetrahydro indole base, pyrrolidyl, the thienopyridine base, dioxy dihydrobenzo isothiazole ketone group, triazolopyrimidinyl, thienyl, the dihydrothieno pyrimidines ketone group, with Ben Bing oxadiazole base, wherein above-mentioned each group is unsubstituted or by 1,2,3,4 or 5 groups replace, and described substituting group is independently selected from:
The optional C that is replaced by phenyl
1-C
10Alkyl, hydroxyl, optional by phenyl or (C
1-C
4Alkyl) the hydroxyl C of phenyl replacement
1-C
10Alkyl, the optional C that is replaced by 1 or 2 hydroxyl
1-C
6Alkoxyl group ,-C (O) NR
31R
32, NR
31-SO
2-(C
1-C
6Alkyl), wherein alkyl is optional is halogen or R by 1,2 or 3 independently
33Group replace ,-SO
2-NH (C
1-C
6Alkyl), wherein alkyl is optional by 1 or 2 R
33The group replacement ,-SO
2-N (C
1-C
6Alkyl) (C
1-C
6Alkyl), wherein each alkyl is optional by 1 or 2 R
33The group replacement ,-SO
2-NH (C
1-C
6Alkyl)-and phenyl, wherein phenyl is optional is C by 1 or 2 independently
1-C
4The group replacement of alkoxy or halogen ,-O-(C
1-C
6Alkyl)-phenyl ,-(C
1-C
6Alkyl)-the O-phenyl ,-(C
1-C
6Alkyl)-O-(C
1-C
6Alkyl)-phenyl, triazolidine-3,5-diketone, halogen ,-NHC (O) NH
2,-N (C
1-C
6Alkyl) C (O) NH
2,-N (C
1-C
6Alkyl) C (O) NH (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl) C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl) thienyl ,-(C
1-C
6Alkyl) furyl ,-S-(C
1-C
6Alkyl) phenyl ,-SO
2NR
31R
32,-C (O)-NR
31R
32,-NR
31R
32, dithiane ,-NHC (S) NH
2,-NHC (S) NH (C
1-C
6Alkyl) ,-NHC (S) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-CO
2(C
1-C
6Alkyl), tetrahydropyrans, optional by 1 or 2 be independently F, Cl or Br replacement phenyl, pyridine ,-C
2-C
4Alkynyl-phenyl ,-O-C
3-C
8Cycloalkyl ,-O-(C
1-C
6Alkyl)-R
33, benzo [1,2,5] oxadiazoles ,-C (O)-(C
1-C
10Alkyl), wherein alkyl is optional by NH
2, N (C
1-C
6Alkyl) or N (C
1-C
6Alkyl) (C
1-C
6Alkyl) replace ,-C (O) NH-phenyl ,-C (O) N (C
1-C
6Alkyl)-and phenyl, 4,4-dimethyl-4,5-dihydro-oxazole azoles ,-(C
1-C
6Alkyl)-the S-pyridine ,-(C
1-C
6Alkyl)-SO
2-pyridine ,-(C
1-C
6Thio alkoxy)-pyridine,
R wherein
31And R
32Be independently selected from hydrogen, C in each case
1-C
6Alkyl, hydroxyl C
1-C
6Alkyl, C
1-C
6Alkylhalide group ,-(C
1-C
6Alkyl)-C (O) NH
2,-(C
1-C
6Alkyl)-C (O) NH (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-NH
2,-(C
1-C
6Alkyl)-NH (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl) phenyl ,-(C
1-C
6Alkyl) pyridyl ,-C (O) furyl, (C
1-C
6Alkyl)-tetrahydrofuran (THF), wherein phenyl and pyridyl be unsubstituted or by 1,2,3,4 or 5 independently for C
1-C
4Alkyl, hydroxyl, C
1-C
4The group of alkoxyl group, halogen replaces, or
R
31, R
32Form 5,6 or 7 yuan of Heterocyclylalkyls or 6 yuan of hetero-aromatic rings with the nitrogen that links to each other with them, wherein each is chosen wantonly and is fused on benzene, pyridine or the pyrimidine ring, and each is optional by C
1-C
6Alkoxyl group, hydroxyl, hydroxyl C
1-C
6Alkyl, C
1-C
4Alkoxy C
1-C
6Alkyl ,-C (O) NH
2,-C (O) NH (C
1-C
6Alkyl)-the phenyl replacement;
R
33Be H, NH in each case independently
2, NH (C
1-C
6Alkyl), N (C
1-C
6Alkyl) (C
1-C
6Alkyl), N (C
1-C
6Alkyl) (phenyl);
R
35Be phenyl, C
3-C
8Cycloalkyl ,-the S-phenyl ,-benzo dioxole, thienyl, C
1-C
6Alkyl, furyl, wherein each group be unsubstituted or by 1,2,3,4 or 5 independently for C
1-C
4Alkyl, C
1-C
4Alkoxyl group, OH, hydroxyl C
1-C
6Alkyl, halogen, halogen C
1-C
6Alkyl, halogen C
1-C
6Alkoxyl group ,-O-(C
1-C
6Alkyl)-phenyl ,-CO
2-(C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-(C
5-C
6Cycloalkyl) group replaces;
R
42Be H, C
1-C
6Alkyl; Benzyl ,-NHC (O)-(C
1-C
6Alkyl) or-NHC (O)-phenyl, wherein phenyl is optional is replaced by 1 and 2 alkyl;
R
55It is cyclohexyl; Cyclopentyl; The tall and erect one of nitrogen; Phenyl; Piperidyl;-SO
2-phenyl, pyrrolidyl; Or 4,5,6,7-tetrahydrochysene-thiazole [5,4-c] pyridine; Wherein each chooses quilt-C (O) NH wantonly
2Replace;-C (O) NH (C
1-C
6Alkyl);-C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl); C
1-C
6Alkoxy carbonyl;-O-(C
1-C
6Alkyl)-C (O)-NR
31R
32-(C
1-C
6Alkyl)-phenyl; 4,5-dihydro-2H-pyridazin-3-one; The optional C that is replaced by a CN group
5-C
6Cycloalkyl; Wherein phenyl is chosen quilt-NHC (O) C wantonly
1-C
6The phenoxy group that alkyl replaces ,-N (C
1-C
6Alkyl)-C (O) C
1-C
6Alkyl, wherein
R
31, R
32Form tetramethyleneimine, piperidines, piperazine, morpholine or a thiomorpholine ring with the nitrogen that links to each other with them, wherein each ring is unsubstituted or is OH, C independently by 1,2 or 3
1-C
6Alkyl, C
1-C
6Alkoxyl group, wherein imidazoles is optional by 1 or 2 C
1-C
4Alkyl replaces-(C
1-C
6Alkyl)-imidazoles or the optional hydroxyl (C that is replaced by 1 phenyl ring of alkyl wherein
1-C
6Alkyl) group replaces;
Or
R
42, R
55Forming a tetrahydro isoquinolyl, dihydro-isoquinoline base or choose wantonly by 1,2,3 or 4 with the nitrogen that links to each other with them is halogen, C independently
1-C
4Alkyl, C
1-C
4The isoquinolyl that alkoxyl group, CN, OH and phenyl groups replace, wherein phenyl is optional by halogen, hydroxyl, C
1-C
4Alkoxyl group and C
1-C
4Alkyl replaces.
33. compound as claimed in claim 32, wherein
R
30Be selected from phenyl, pyrrolidone-base, pyridyl, piperidyl, furyl, cyclopropyl and thienyl, wherein above-mentioned each group is unsubstituted or is replaced by 1,2,3,4 or 5 substituting group that is independently selected from following groups:
C
1-C
10Alkyl, hydroxyl, hydroxyl C
1-C
10Alkyl C
1-C
6Alkoxyl group ,-NR
31-SO
2-(C
1-C
6Alkyl) ,-SO
2-NH (C
1-C
6Alkyl) ,-SO
2-N (C
1-C
6Alkyl) (C
1-C
6Alkyl), halogen ,-NHC (O) NH
2,-N (C
1-C
6Alkyl) C (O) NH
2,-N (C
1-C
6Alkyl) C (O) NH (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl) C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-SO
2NR
31R
32,-C (O)-NR
31R
32,-NR
31R
32,-C
2-C
4Alkynyl-phenyl ,-O-C
3-C
8Cycloalkyl ,-O-(C
1-C
6Alkyl)-R
33, benzo [1,2,5] oxadiazoles;-C (O)-(C
1-C
10Alkyl);
R wherein
31And R
32Be independently selected from hydrogen, C in each case
1-C
6Alkyl, hydroxyl C
1-C
6Alkyl, C
1-C
6Alkylhalide group ,-(C
1-C
6Alkyl)-C (O) NH
2,-(C
1-C
6Alkyl)-C (O) NH (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-NH
2,-(C
1-C
6Alkyl)-NH (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-N (C
1-C
6Alkyl) (C
1-C
6Alkyl), benzyl and-C (O) furyl, wherein phenyl and pyridyl be unsubstituted or by 1,2 or 3 independently for C
1-C
4Alkyl, hydroxyl, C
1-C
4The group of alkoxyl group, halogen replaces, or
R
31, R
32Form 5,6 or 7 yuan of Heterocyclylalkyls or 6 yuan of hetero-aromatic rings with the nitrogen that links to each other with them, wherein each is optional by C
1-C
6Alkoxyl group, hydroxyl, hydroxyl C
1-C
6Alkyl, C
1-C
4Alkoxy C
1-C
6Alkyl or-C (O) NH
2Replace;
R
35Be phenyl, C
3-C
6Cycloalkyl or-the S-phenyl, wherein each group be unsubstituted or by 1,2 or 3 independently for C
1-C
4Alkyl, C
1-C
4Alkoxyl group, CF
3, OCF
3, halogen ,-the O benzyl ,-CO
2-(C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-(C
5-C
6Cycloalkyl) group replaces;
R
42Be H, C
1-C
6Alkyl; Benzyl ,-NHC (O)-(C
1-C
6Alkyl) or-NHC (O)-phenyl, wherein phenyl is optional is replaced by 1 or 2 alkyl;
R
55It is cyclohexyl; The tall and erect one of nitrogen; Phenyl; Piperidyl;-SO
2-phenyl, pyrrolidyl; Or 4,5,6,7-tetrahydrochysene-thiazole [5,4-c] pyridine; Wherein each chooses quilt-C (O) NH wantonly
2Replace; C
1-C
6Alkoxy carbonyl;-O-(C
1-C
6Alkyl)-C (O)-NR
31R
32-(C
1-C
6Alkyl)-phenyl; 4,5-dihydro-2H-pyridazin-3-one; The optional cyclopentyl that is replaced by a CN; Wherein phenyl is chosen quilt-NHC (O) C wantonly
1-C
6The phenoxy group that alkyl replaces, wherein
R
31, R
32Form tetramethyleneimine, piperidines, piperazine or a morpholine ring with the nitrogen that links to each other with them, wherein each ring be unsubstituted or by 1,2 or 3 independently for OH, wherein imidazoles is optional by 1 or 2 C
1-C
4Alkyl replaces-(C
1-C
6Alkyl)-imidazoles or the optional hydroxyl (C that is replaced by 1 phenyl ring of alkyl wherein
1-C
6Alkyl) group replaces; Or
R
42, R
55Forming a tetrahydro isoquinolyl with the nitrogen that links to each other with them, choosing wantonly by 1,2,3 or 4 is halogen, C independently
1-C
4Alkyl, C
1-C
4The group that alkoxyl group, CN, OH and phenyl groups replace, wherein phenyl is optional by halogen, hydroxyl, C
1-C
4Alkoxyl group and C
1-C
4Alkyl replaces.
34. compound as claimed in claim 33, wherein
R
30Be selected from phenyl, pyridyl or piperidyl, above-mentioned each group is unsubstituted or is independently selected from C by 1,2,3,4 or 5
1-C
10Alkyl, hydroxyl, hydroxyl C
1-C
10Alkyl C
1-C
6Alkoxyl group, halogen ,-SO
2NR
31R
32,-C (O)-NR
31R
32,-NR
31R
32,-O-C
3-C
6Cycloalkyl ,-C (O)-(C
1-C
6Alkyl) group replaces;
R wherein
31And R
32Be independently selected from hydrogen, C in each case
1-C
6Alkyl, hydroxyl C
1-C
6Alkyl ,-(C
1-C
6Alkyl)-NH
2,-(C
1-C
6Alkyl)-NH (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-N (C
1-C
6Alkyl) (C
1-C
6Alkyl), benzyl and-C (O) furyl, wherein phenyl be unsubstituted or by 1,2 or 3 independently for C
1-C
4Alkyl, hydroxyl, C
1-C
4The group of alkoxy or halogen replaces, or
R
31, R
32Form tetramethyleneimine, piperidines, morpholine, pyridine or a pyrimidine ring with the nitrogen that links to each other with them, wherein each is optional by C
1-C
6Alkoxyl group, hydroxyl, hydroxyl C
1-C
6Alkyl, C
1-C
4Alkoxy C
1-C
6Alkyl or-C (O) NH
2Replace;
R
35Be phenyl, cyclohexyl, cyclopentyl or-the S-phenyl, wherein each group is unsubstituted or is C independently by 1,2 or 3
1-C
4Alkyl, C
1-C
4Alkoxyl group, CF
3, OCF
3, halogen ,-the O benzyl ,-CO
2-(C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-(C
5-C
6Cycloalkyl) group replaces.
35. compound that chemical formula is following
Or it can be used for the salt of pharmacy, wherein
R
35Be phenyl, C
3-C
8Cycloalkyl ,-S-phenyl, benzo dioxole, thienyl, C
1-C
6Alkyl, furyl, wherein each group be unsubstituted or by 1,2,3,4 or 5 independently for C
1-C
4Alkyl, C
1-C
4Alkoxyl group, OH, hydroxyl C
1-C
6Alkyl, halogen, halogen C
1-C
6Alkyl, halogen C
1-C
6Alkoxyl group ,-O-(C
1-C
6Alkyl)-phenyl ,-CO
2-(C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-(C
5-C
6Cycloalkyl) group replaces.
R
40Be phenyl ,-phenyl-pyridyl, xenyl ,-phenyl-benzothienyl ,-phenyl-thienyl ,-phenyl-furyl ,-the phenyl-pyrimidine base ,-phenyl-isoxazolyls ,-C (O)-pyridyl ,-(C
1-C
4Alkyl)-O-C (O) NH-phenyl ,-(C
1-C
4Alkyl)-O-C (O) N (C
1-C
6Alkyl)-phenyl ,-(C
1-C
4Alkyl)-phenyl ,-(C
1-C
4Alkyl)-SO
2NH
2,-(C
1-C
4Alkyl)-SO
2NH (C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-SO
2N (C
1-C
6Alkyl) (C
1-C
6Alkyl), CN ,-(C
1-C
4Alkyl)-(C
3-C
7Cycloalkyl) ,-(C
1-C
4Alkyl)-C (O) O-(C
1-C
4Alkyl) ,-(C
1-C
4Alkyl)-R
33, C
1-C
8Alkyl ,-(C
1-C
4Alkyl)-NHC (O)-(C
1-C
4Alkyl) ,-C (O) NH
2, wherein above-mentioned each ring is unsubstituted or is replaced for the substituting group of following groups independently by 1,2,3,4 or 5: halogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, halogen C
1-C
4Alkyl, wherein phenyl optional by 1 or 2 halogen replace-O-(C
1-C
4Alkyl)-phenyl ,-CHO ,-NHSO
2-(C
1-C
4Alkyl), alkyl wherein optional by 1,2 or 3 halogen replace-N (C
1-C
4Alkyl) SO
2-(C
1-C
4Alkyl);
R
42Be H, the optional C that is replaced by OH
1-C
6Alkyl; Benzyl;-NHC (O)-(C
1-C
6Alkyl);-NHC (O)-phenyl, wherein phenyl is optional is replaced by 1 or 2 alkyl;-CO
2-(C
1-C
6Alkyl);-CO
2-(benzyl); Or-C (O)-(C
1-C
6Alkyl);
R
52Be H, phenyl ,-NHC (O)-(C
1-C
6Alkyl)-(C
1-C
6Thio alkoxy) ,-N (C
1-C
6Alkyl) C (O)-(C
1-C
6Alkyl)-(C
1-C
6Thio alkoxy), OH, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, list or two (C
1-C
6Alkyl) amino, wherein alkyl optional by phenyl replace-NHC (O)-(C
1-C
6Alkyl), wherein each alkyl optional by phenyl replace-N (C
1-C
6Alkyl) C (O)-(C
1-C
6Alkyl) ,-(CH
2)
0-4-SO
2-(C
1-C
10Alkyl) ,-NHCO
2-benzyl or NH
2, and
R
60Be-L-V-R
65, C
1-C
8Alkyl or hydroxyl C
1-C
8Alkyl, wherein alkyl or hydroxyalkyl are optional by 1 or 2 L-V-R
65Group replaces, wherein
L can be do not exist or-C (O)-,-CO
2-,-C (O) NH-,-C (O) N (C
1-C
6Alkyl)-,-NHC (O)-,-N (C
1-C
6Alkyl)-C (O)-,-(CH
2)
0-4-SO
2-(CH
2)
0-4-,-(CH
2)
0-4-O-(CH
2)
0-4-,-(CH
2)
0-4-S-(CH
2)
0-4-,-NHC (O) NH-,-N (C
1-C
6Alkyl) C (O) NH-,-N (C
1-C
6Alkyl) C (O) N (C
1-C
6Alkyl) ,-NHC (O) N (C
1-C
6Alkyl)-,-NH-,-N (benzyl)-,-N (phenyl)-,-(CH
2)
0-4-NHSO
2-(CH
2)
0-4-,-N (C
1-C
6Alkyl) SO
2-,-SO
2NH-,-SO
2N (C
1-C
6Alkyl)-or C
2-C
6Alkenyl; Or
V can not exist or-(CH
2)
0-4-C (O) NH-,-(CH
2)
0-4-C (O) N (C
1-C
6Alkyl)-, optional by 1 or 2 C
1-C
4The cyclopropyl that alkyl replaces ,=NH ,=NOH ,=N-alkoxyl group, optional by the C of 1 or 2 OH replacement
1-C
8Alkyl; Or-CH (phenyl)-, wherein phenyl optional by 1,2,3,4 or 5 be independently halogen or OH group replacement, cyclopentyl, cyclohexyl or-CH (phenyl)-;
R
65It is cyclohexyl; Cyclopentyl; Phenyl;-(C
1-C
6Alkyl)-phenyl; NH
2List or two (C
1-C
10Alkyl) amino, wherein alkyl is optional is the group replacement of cyclopropyl, phenyl or OH by 1 or 2 independently; The oxadiazole base; Triazolopyrimidinyl; Triazolyl; Thiadiazolyl group; 3H-quinazoline-2-ketone group; Pyrimidyl, pyridyl; Pyridine N-oxides;-(C
1-C
6Alkyl)-pyridyl; Piperazinyl; The 2 base; Tetrahydrochysene-thiophene 1, the 1-dioxide; Tetrazyl; C
3-C
6Cycloalkyl-C
1-C
6Alkyl;-(C
1-C
4Alkyl)-SO
2-(C
1-C
4Alkyl);-SO
2-(C
1-C
6Alkyl); Benzothiazolyl; Six hydrogen-isoindole-1, the 3-diketo; Benzimidazolyl-; Benzoxazolyl; [1,2,4] triazole [1,5-a] pyrimidyl; [1,2,4] triazole [4,3-a] pyrimidyl; Thiazolyl; Thiadiazolyl group; Imidazo [1,2-a] pyridine; 3-aza-bicyclo [3.2.2] nonane; Pyrrolidone-base; The tall and erect yl of di nitrogen; Benzo [1,2,5] thiadiazolyl group;-NHSO
2-(4-tolyl); [1,2,4] triazolo [4,3-b] pyridazinyl, benzopyrrole alkane ketone group; Morpholinyl; Thio-morpholinyl; Thio-morpholinyl S-oxide compound; Thio-morpholinyl S, the S-dioxide; 2,3-dihydro-benzo [b] thiophene 1,1-dioxide; Pyrrolidyl; [1,2,4] oxadiazoles; C
1-C
10Alkyl; Isoxazolyl; 2,3-dihydro-1H-indyl; The quinazoline ketone group; Quinazolyl; Piperidyl;-CO
2-(C
1-C
6Alkyl); Dibenzofuran group; The indoline ketone group; The triazolo benzimidazolyl-; The benzotriazole base; The tetrahydrochysene benzfuran ketone group; Benzofuryl; Dihydro benzo furyl; Tetrahydrofuran base; Furyl; Oxazole and pyridyl; The tetrahydro benzo thienyl; The yellow fast quinoline base of dihydro; Indyl; Thienyl; Imidazolyl; The hexamethylene ketone group; Naphthyl; Tetrahydro-thienyl S, the S-dioxide; Chromanyl; The isoindole ketone group; [1,2,4] triazole [4,3-a] pyrimidyl;-phenyl-oxazolidine ketone group; 3-oxygen-2,3-glyoxalidine [2,1-b] [1,3] thiazolyl; Dihydro-thiazolyl; Ben Bing dioxine base; 2,3-dihydrobenzo tetrahydroglyoxaline ketone group; Tetrahydro cyclopentyl [b] chromene ketone group; 1-H-benzo [g] indazolyl; 4, and the 5-dihydro-naphtho [2,1-d] isoxazolyl; Tetrazolo [1,5-b] pyridazinyl; Pyrryl; Pyrazoline alkane ketone;-NHSO
2NH
2-N (C
1-C
6Alkyl) SO
2NH
2-N (C
1-C
6Alkyl) SO
2NH (C
1-C
6Alkyl);-N (C
1-C
6Alkyl) SO
2N (C
1-C
6Alkyl) (C
1-C
6Alkyl);-NHSO
2NH (C
1-C
6Alkyl);-NHSO
2N (C
1-C
6Alkyl) (C
1-C
6Alkyl); The tetrahydro benzo thienyl; Imidazolidimedione; The tall and erect onyl of di nitrogen; Or dihydroanthracene diketone; Wherein above-mentioned each optional be C independently by 1,2,3,4 or 5
1-C
6Alkyl, CF
3, halogen, phenyl ,-(C
1-C
4Alkyl)-phenyl ,-C (O) phenyl, pyrrolidine-2,4-diketo, C
1-C
6Alkoxyl group ,-C (O)-furans ,-C (O)-NH
2,-C (O) NH (C
1-C
6Alkyl) ,-C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl), cyclopropyl ,-(CH
2)
0-4-cyclopentyl, benzoxazolyl, pyridine ,-NHC (O)-(C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl) C (O)-(C
1-C
6Alkyl) ,-C (O) C
1-C
6Alkyl ,-CO
2H ,-NHSO
2-(C
1-C
8Alkyl) ,-N (C
1-C
6Alkyl) SO
2-(C
1-C
8Alkyl), (C
1-C
6Alkoxyl group), OH, oxazolyl, (C
1-C
6Alkylthio) or the group of CN replace.
36. compound as claimed in claim 35, wherein
R
35Be phenyl, cyclohexyl ,-S-phenyl or benzo dioxole, wherein each group is unsubstituted or is methyl, ethyl, methoxyl group, oxyethyl group, OH, halogen, CF independently by 1,2,3,4 or 5
3, OCF
3,-O benzyl ,-CO
2-(C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-(C
5-C
6Cycloalkyl) group replaces;
R
40Be phenyl ,-phenyl-pyridyl, xenyl ,-(C
1-C
4Alkyl)-SO
2NH
2,-(C
1-C
4Alkyl)-SO
2NH (C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-SO
2N (C
1-C
6Alkyl) (C
1-C
6Alkyl)-(C
1-C
4Alkyl)-(cyclopentyl) ,-(C
1-C
4Alkyl)-C (O) O-(C
1-C
4Alkyl), C
1-C
8Alkyl ,-(C
1-C
4Alkyl)-NHC (O)-(C
1-C
4Alkyl) ,-C (O) NH
2, wherein above-mentioned each ring is unsubstituted or is halogen, C independently by 1,2,3,4 or 5
1-C
4Alkyl, C
1-C
4Alkoxyl group, halogen (C
1-C
4Alkyl) ,-group of O benzyl replaces, and the phenyl the in-O benzyl is optional to be replaced by 1 or 2 halogen;
R
42Be H, C
1-C
6Alkyl or benzyl;
R
52Be H ,-NHC (O)-(C
1-C
6Alkyl)-(C
1-C
6Thio alkoxy) ,-N (C
1-C
6Alkyl) C (O)-(C
1-C
6Alkyl)-(C
1-C
6Thio alkoxy), OH, C
1-C
4Alkyl, and
R
60Be-L-V-R
65, C
1-C
8Alkyl or hydroxyl C
1-C
8Alkyl, wherein alkyl or hydroxyalkyl are optional by 1 or 2 L-V-R
65Group replaces, wherein
L can not exist or-C (O)-,-CO
2-,-C (O) NH-,-C (O) N (C
1-C
6Alkyl)-,-NHC (O)-,-N (C
1-C
6Alkyl)-C (O)-,-SO
2-,-(CH
2)
0-4-O-(CH
2)
0-4-,-(CH
2)
0-4-S-(CH
2)
0-4-,-NHC (O) NH-,-N (C
1-C
6Alkyl) C (O) NH-,-N (C
1-C
6Alkyl) C (O) N (C
1-C
6Alkyl) ,-NHC (O) N (C
1-C
6Alkyl)-,-NH-,-N (benzyl)-,-(CH
2)
0-4-NHSO
2-(CH
2)
0-4-,-N (C
1-C
6Alkyl) SO
2-,-SO
2NH-,-SO
2N (C
1-C
6Alkyl)-, and
V can not exist or-C (O) NH-,-C (O) N (C
1-C
6Alkyl)-, cyclopropyl,
R
65It is cyclohexyl; Cyclopentyl; Phenyl;-(C
1-C
6Alkyl)-phenyl; NH
2List or two (C
1-C
10Alkyl) amino, wherein alkyl is optional is the group replacement of cyclopropyl, phenyl or OH by 1 or 2 independently; The oxadiazole base; Triazolopyrimidinyl; Triazolyl; Thiadiazolyl group; 3H-quinazoline-2-ketone group; Pyrimidyl, pyridyl; Pyridine N-oxides;-(C
1-C
6Alkyl)-pyridyl; Piperazinyl; The 2 base; Tetrahydrochysene-thiophene 1, the 1-dioxide; Tetrazyl; C
3-C
6Cycloalkyl-C
1-C
6Alkyl;-(C
1-C
4Alkyl)-SO
2-(C
1-C
4Alkyl); Benzothiazolyl; Six hydrogen-isoindole-1, the 3-diketo; Benzimidazolyl-; Benzoxazolyl; [1,2,4] triazole [1,5-a] pyrimidyl; Thiazolyl; Thiadiazolyl group; Imidazo [1,2-a] pyridine; C
1-C
6Alkyl; 3-aza-bicyclo [3.2.2] nonane; Pyrrolidone-base; The tall and erect yl of di nitrogen; Benzo [1,2,5] thiadiazolyl group;-NHSO
2-(4-tolyl); [1,2,4] triazolo [4,3-b] pyridazinyl, benzopyrrole alkane ketone group; Thio-morpholinyl S-oxide compound; 2,3-dihydro-benzo [b] thiophene 1,1-dioxide; Pyrrolidyl; [1,2,4] oxadiazoles; C
1-C
10Alkyl; Isoxazolyl; 2,3-dihydro-1H-indyl; Wherein above-mentioned each optional be C independently by 1,2,3,4 or 5
1-C
6Alkyl, CF
3, halogen, phenyl ,-(C
1-C
4Alkyl)-phenyl ,-C (O) phenyl, pyrrolidine-2,4-diketo, C
1-C
6Alkoxyl group ,-C (O)-furans ,-C (O)-NH
2,-C (O) NH (C
1-C
6Alkyl) ,-C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl), cyclopropyl, benzoxazolyl, pyridine ,-NHC (O)-(C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl) C (O)-(C
1-C
6Alkyl) ,-C (O) C
1-C
6The group of alkyl replaces.
37. compound as claimed in claim 36, wherein
R
35Be phenyl, cyclohexyl ,-S-phenyl or benzo dioxole, furyl or thienyl, wherein each group is unsubstituted or is methyl, ethyl, methoxyl group, oxyethyl group, OH, halogen, CF independently by 1,2,3,4 or 5
3, OCF
3,-O benzyl ,-CO
2-(C
1-C
4Alkyl) ,-(C
1-C
2Alkyl)-(C
5-C
6Cycloalkyl) group replaces;
R
40Be phenyl ,-(C
1-C
4Alkyl)-SO
2NH
2,-(C
1-C
4Alkyl)-SO
2NH (C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-SO
2N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-(cyclopentyl) C,
1-C
8Alkyl ,-(C
1-C
4Alkyl)-NHC (O)-(C
1-C
4Alkyl) ,-C (O) NH
2, wherein above-mentioned each ring is unsubstituted or is halogen, C independently by 1,2,3,4 or 5
1-C
4Alkyl, halogen (C
1-C
4Alkyl) ,-group of O benzyl replaces, and the phenyl the in-O benzyl is optional to be replaced by 1 or 2 halogen;
R
42Be H, C
1-C
6Alkyl or benzyl;
R
52Be H ,-NHC (O)-(C
1-C
6Alkyl)-(C
1-C
6Thio alkoxy) ,-N (C
1-C
6Alkyl) C (O)-(C
1-C
6Alkyl)-(C
1-C
6Thio alkoxy), OH, C
1-C
4Alkyl, and
R
60Be-L-V-R
65Or it is optional by 1 or 2 L-R
65The C that group replaces
1-C
6Alkyl, wherein
L can not exist or-C (O)-,-C (O) NH-,-C (O) N (C
1-C
6Alkyl)-,-NHC (O)-,-N (C
1-C
6Alkyl)-C (O)-,-SO
2-,-(CH
2)
0-4-O-(CH
2)
0-4-,-S-,-NHC (O) NH-,-NH-,-N (benzyl)-,-(CH
2)
0-4-NHSO
2-(CH
2)
0-4-,-N (C
1-C
6Alkyl) SO
2-,-SO
2NH-,-SO
2N (C
1-C
6Alkyl)-.
38. compound as claimed in claim 32, wherein R
35It is phenyl; The halobenzene base; The dihalo-phenyl; The trihalogenated benzene base; Four halobenzene bases; The phenyl-pentahalide base; By a halogen and the phenyl that benzyloxy replaces; By a halogen and the phenyl that alkyl replaces; The benzyloxy phenyl; Cyclohexyl; (C
1-C
4Alkoxyl group) carbonyl phenyl; (C
1-C
4Alkoxyl group) phenyl;-S-phenyl or benzo dioxole;
R
40Be phenyl or-(C
1-C
4Alkyl)-SO
2NH
2, wherein above-mentioned each be unsubstituted or by 1,2,3,4 or 5 independently for halogen, methyl, ethyl, methoxyl group, oxyethyl group or-group of O benzyl replaces, the phenyl the in-O benzyl is optional to be replaced by 1 or 2 halogen;
R
42Be H.
39. compound as claimed in claim 38, wherein
R
35It is the halobenzene base; The dihalo-phenyl; The trihalogenated benzene base; By a halogen and the phenyl that benzyloxy replaces; By a halogen and the phenyl that alkyl replaces; The benzyloxy phenyl; Or (C
1-C
4Alkoxyl group) phenyl.
40. compound as claimed in claim 3, wherein
R
30Be pyridine or pyrimidyl, wherein each group is unsubstituted or is replaced by 1,2,3,4 or 5 group, and described substituting group is independently selected from:
Optional by 1 phenyl or 1 C that CN replaces1-C
10Alkyl; OH, optional by phenyl or (C1-C
4Alkyl) the hydroxyl C of phenyl substituted1-C
10Alkyl; Optional is the C of the group replacement of hydroxyl or phenyl by 1 or 2 independently1-C
6Alkoxyl; Alkylhalide group; The halogen alkoxyl; (CH2)
0-4C(O)NR
31R
32；NR
31-SO
2-(C
1-C
6Alkyl), wherein alkyl is optional by 1; 2 or 3 is halogen or R independently33Group replace;-SO2-NH(C
1-C
6Alkyl), wherein alkyl is optional is halogen by 1 or 2 independently; OH; Alkoxyl or R33Group replace;-(C1-C
6Alkyl)-SO2-(C
1-C
6Alkyl), wherein alkyl is optional is halogen by 1 or 2 independently; OH; C1-C
4Alkoxyl or R33Group replace;-SO2-(C
1-C
6Alkyl), wherein alkyl is optional is OH or C by 1 or 2 independently1-C
4The group of alkoxyl replaces;-SO2-N(C
1-C
6Alkyl) (C1-C
6Alkyl), wherein each alkyl is optional is halogen by 1 or 2 independently; OH or R33Group replace;-SO2-NH(C
1-C
6Alkyl)-phenyl, wherein phenyl is optional is C by 1 or 2 independently1-C
4The group of alkoxy or halogen replaces;-(C1-C
6Alkyl)-O-phenyl;-(C1-C
6Alkyl)-O-(C1-C
6Alkyl)-phenyl; Triazolidine-3, the 5-diketone; Halogen;-NHC (O) NH2；
-NHC(O)NH(C
1-C
6Alkyl);-NHC (O) N (C1-C
6Alkyl) (C1-C
6Alkyl);-N (C1-C
6Alkyl) C (O) NH2；-N(C
1-C
6Alkyl) C (O) NH (C1-C
6Alkyl);-N (C1-C
6Alkyl) C (O) N (C1-C
6Alkyl) (C1-C
6Alkyl);-(C1-C
6Alkyl) thienyl;-(C1-C
6Alkyl) furyl;-S-(C1-C
6Alkyl) phenyl;-SO2NR
31R
32；-C(O)-NR
31R
32；-NR
31R
32 Dithiane;-NHC (S) NH2；-NHC(S)NH(C
1-C
6Alkyl);-NHC (S) N (C1-C
6Alkyl) (C1-C
6Alkyl);-CO2(C
1-C
6Alkyl); Oxinane; Optional is F by 1 or 2 independently; The phenyl that Cl or Br replace; Pyridine;-C2-C
4Alkynyl-phenyl;-O-C3-C
8Cycloalkyl;-O-(C1-C
6Alkyl)-R33 Optional by one or two methyl substituted pyrroles; 2,3-dihydro-benzofuran; Benzo [1,2,5] oxadiazoles;-C (O)-(C1-C
10Alkyl), wherein alkyl is optional by NH2；N(C
1-C
6Alkyl) or N (C1-C
6Alkyl) (C1-C
6Alkyl) replace;-C (O) NH-phenyl;-C (O) N (C1-C
6Alkyl)-phenyl; 4,4-dimethyl-4,5-dihydro-azoles;-(C1-C
6Alkyl)-S-pyridine;-(C1-C
6Alkyl)-SO2-pyridine;-(C1-C
6Thio alkoxy)-pyridine; Optional by 1 or 2 methyl substituted thiazole; Pyrazoles;-S-(C1-C
6Alkyl), wherein alkyl is optional is the group replacement of CN or OH by 1 or 2 independently; Indoles; (C1-C
6Thio alkoxy)-(C1-C
6Alkyl); C2-C
8Alkynyl;-(CH2)
0-4-SO
2-(C
1-C
10Alkyl), wherein alkyl is optional is replaced by OH;-NHC (O) NH (C3-C
8Cycloalkyl);-N (C1-C
6Alkyl) C (O) NH (C3-C
8Cycloalkyl);-N (C1-C
6Alkyl) C (O) N (C1-C
6Alkyl) (C3-C
8Cycloalkyl);-NHC (O) N (C1-C
6Alkyl) (C3-C
8Cycloalkyl);-(C1-C
6Alkoxyl)-(C1-C
6Thio alkoxy);-CO2-(C
1-C
6Alkyl), wherein alkyl is optional by phenyl substituted;-C (O)-furans; And imidazole radicals;
R wherein
31And R
32Be independently selected from hydrogen, C in each case
1-C
8Alkyl, C
2-C
8Alkenyl, hydroxyl C
1-C
6Alkyl, C
1-C
6Alkylhalide group, C
1-C
6Alkoxy C
1-C
6Alkyl ,-(CH
2)
0-4-SO
2-(C
1-C
6Alkyl), wherein alkyl optional by the group of 1,2,3 or 4 independently selected from halogen atoms replace ,-(CH
2)
0-4-SO
2-imidazolyl ,-(C
1-C
6Alkyl)-C (O) NH
2,-(C
1-C
6Alkyl)-C (O) NH (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-NH
2,-(C
1-C
6Alkyl)-NH (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl) phenyl ,-(C
1-C
6Alkyl) pyridyl ,-C (O) furyl, (C
1-C
6Alkyl)-tetrahydrofuran (THF), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl ,-CO
2-(C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-furyl ,-(CH
2)
0-4-SO
2-thienyl ,-pyrrolidyl-benzyl ,-(C
1-C
6Thio alkoxy)-(C
1-C
6Alkyl) ,-C (O)-(C
1-C
6Alkyl), (C
1-C
6Alkoxyl group) ,-(C
2-C
6Alkenyloxy) ,-(C
1-C
6Alkyl)-CO
2-(C
1-C
6Alkyl) and optional by C
1-C
6Alkyl replaces-C (O)-piperidyl; Wherein phenyl and pyridyl be unsubstituted or by 1,2,3,4 or 5 independently for C
1-C
4Alkyl, hydroxyl, C
1-C
4The group of alkoxyl group, halogen replaces, or
R
31, R
32Form 5,6 or 7 yuan of Heterocyclylalkyls or 6 yuan of hetero-aromatic rings with the nitrogen that links to each other with them, wherein each is chosen wantonly and is fused on benzene, pyridine or the pyrimidine ring, and each is optional by C
1-C
6Alkoxyl group, hydroxyl, hydroxyl C
1-C
6Alkyl, C
1-C
4Alkoxy C
1-C
6Alkyl ,-C (O) NH
2,-C (O) NH (C
1-C
6Alkyl)-the phenyl replacement;
R
33Be H, NH in each case independently
2, NH (C
1-C
6Alkyl), N (C
1-C
6Alkyl) (C
1-C
6Alkyl), N (C
1-C
6Alkyl) (phenyl), N (C
1-C
6Alkyl) (benzyl).
41. compound as claimed in claim 40, wherein
R
35It is phenyl; The halobenzene base; The dihalo-phenyl; The trihalogenated benzene base; Four halobenzene bases; The phenyl-pentahalide base; By a halogen and the phenyl that benzyloxy replaces; By a halogen and the phenyl that alkyl replaces; The benzyloxy phenyl; Cyclohexyl; (C
1-C
4Alkoxyl group) carbonyl phenyl; (C
1-C
4Alkoxyl group) phenyl;-S-phenyl or benzo dioxole.
42. compound as claimed in claim 41, wherein
R
40Be phenyl ,-phenyl-pyridyl, xenyl ,-phenyl-benzothienyl ,-phenyl-thienyl ,-phenyl-furyl ,-the phenyl-pyrimidine base ,-phenyl-isoxazolyls ,-(C
1-C
4Alkyl)-O-C (O) NH-phenyl ,-(C
1-C
4Alkyl)-O-C (O) N (C
1-C
6Alkyl)-phenyl ,-(C
1-C
4Alkyl)-SO
2NH
2, CN ,-(C
1-C
4Alkyl)-(C
3-C
6Cycloalkyl) ,-(C
1-C
4Alkyl)-C (O) O-(C
1-C
4Alkyl) ,-(C
1-C
4Alkyl)-R
33, C
1-C
8Alkyl, pyridyl or pyrimidyl, wherein above-mentioned each be unsubstituted or be halogen, C independently by 1,2 or 3
1-C
4Alkyl, C
1-C
4Alkoxyl group, CF
3, wherein phenyl optional by 1 or 2 halogen replace-O-(C
1-C
4Alkyl)-phenyl ,-CHO or-NHSO
2-(C
1-C
4Alkyl) group replaces.
43. compound as claimed in claim 42, wherein
R
30Be pyridine or pyrimidyl, wherein each group is unsubstituted or is independently selected from-SO by 1,2 or 3
2NR
31R
32,-C (O)-NR
31R
32,-NR
31R
32, C
1-C
4Alkyl, halogen, C
1-C
4Alkoxyl group, C
6Alkyl) ,-(C
1-C
6Alkyl)-NH
2,-(C
1-C
6Alkyl)-NH (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl) phenyl and-(C
1-C
6Alkyl) group of pyridyl replaces,
R wherein
31And R
32Be independently selected from hydrogen, C in each case
1-C
6Alkyl, C
2-C
6Alkenyl, hydroxyl C
1-C
6Alkyl, C
1-C
6Alkylhalide group, C
1-C
6Alkoxy C
1-C
6Alkyl ,-(CH
2)
0-4-SO
2-(C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-C (O) NH
2,-(C
1-C
6Alkyl)-C (O) NH (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-NH
2,-(C
1-C
6Alkyl)-NH (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl) phenyl ,-(C
1-C
6Alkyl) pyridyl ,-C (O) furyl, (C
1-C
6Alkyl)-tetrahydrofuran (THF), or
R
31, R
32Form pyrrolidyl, piperidyl, piperazinyl, pyridyl or a pyrimidine-ring with the nitrogen that links to each other with them, wherein each is chosen wantonly and is fused on benzene, pyridine or the pyrimidine ring, and each is optional by C
1-C
6Alkoxyl group, hydroxyl, hydroxyl C
1-C
6Alkyl, C
1-C
4Alkoxy C
1-C
6Alkyl ,-C (O) NH
2,-C (O) NH (C
1-C
6Alkyl)-the phenyl replacement.
44. compound as claimed in claim 43, wherein
R
40Be phenyl, pyridyl or pyrimidyl, wherein above-mentioned each be unsubstituted or be halogen, C independently by 1,2 or 3
1-C
4Alkyl, C
1-C
4Alkoxyl group, CF
3, wherein phenyl optional by 1 or 2 halogen replace-O-(C
1-C
4Alkyl)-phenyl ,-CHO or-NHSO
2-(C
1-C
4Alkyl) group replaces.
45. compound as claimed in claim 44, wherein R
35It is phenyl; Halobenzene base or dihalo-phenyl.
46. compound as claimed in claim 45, wherein
R
30Be pyridyl, it is unsubstituted or is replaced by 1 or 2 substituting group that is independently selected from following radicals: C
1-C
4Alkyl ,-C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-C (O) NH
2,-C (O) N (C
2-C
6Alkenyl) (C
3-C
8Cycloalkyl) ,-C (O) NH (C
3-C
8Cycloalkyl) ,-C (O) NH (C
1-C
6Alkyl), optional by 1 and 2 be independently the group replacement of alkoxyalkyl or hydroxyl C (O)-(tetramethyleneimine), halogen ,-C (O) N (C
1-C
6Hydroxyalkyl) (C
1-C
6Alkyl) ,-C (O) NH (alkoxyalkyl) ,-C (O) N (alkoxyalkyl) (alkoxyalkyl) ,-C (O) N (C
1-C
6Alkyl) (alkoxyalkyl) ,-C (O) N (C
1-C
6Hydroxyalkyl) (alkyl) ,-NHSO
2CF
3,-N (C
1-C
6Alkyl)-SO
2-thienyl ,-N (C
1-C
6Hydroxyalkyl) SO
2-(C
1-C
6Alkyl) ,-NHC (O) C
1-C
4Alkyl, optional by 1 or 2 methyl substituted De oxazolyl, optional by 1 or 2 methyl substituted thiazolyl, optional by 1 or 2 methyl substituted pyrazolyl, optional by 1 or 2 methyl substituted imidazolyl, optional by 1 or 2 methyl substituted isoxazolyl, the optional pyrimidyl that is replaced by 1 or 2 methyl or halogen group ,-NHSO
2CH
3, wherein imidazole ring is optional by 1 or 2 methyl substituted-NHSO
2-imidazolyl ,-N (C
1-C
6Alkyl) SO
2(C
1-C
6Alkyl) ,-SO
2NH-C
1-C
6Hydroxyalkyl ,-SO
2NH-C
1-C
6Alkyl-NH (C
1-C
4Alkyl), optional by 1 or 2 methyl substituted-SO
2-piperazinyl, optional by 1 or 2 methyl substituted-SO
2-tetramethyleneimine, optional by 1 or 2 C
1-C
4Alkyl replaces-SO
2-piperidines ,-SO
2N (C
1-C
4Hydroxyalkyl) (C
1-C
4Hydroxyalkyl) ,-SO
2NH
2,-SO
2N (C
1-C
6Alkyl) (C
1-C
6Alkyl), C
2-C
6Alkynyl ,-SO
2-(C
1-C
6Hydroxyalkyl) ,-SO
2NH (C
1-C
6Hydroxyalkyl) ,-SO
2N (C
1-C
6Alkyl) (C
1-C
6Hydroxyalkyl) ,-(C
1-C
4Alkyl) SO
2-(C
1-C
4Alkyl) or-C (O)-(C
1-C
10Alkyl).
47. compound as claimed in claim 46, wherein
R
30Be pyridyl, it is unsubstituted or is replaced by at least one following groups :-SO
2NH-propyl group-OH ,-SO
2NH-ethyl-OH ,-SO
2NH-ethyl-OCH
3,-SO
2NH-CH (CH
3)
2-CH
2OH ,-SO
2NH-(CH
2CH (OH) CH
3) ,-SO
2NH-ethyl-NH (CH
3) ,-SO
2NH-(CH
2CH
2OH)
2,-SO
2NHCH (CH
3) CH
2OH ,-SO
2N (CH
3)
2,-SO
2NH (CH
2CH (OH) CH
3) ,-SO
2-tetramethyleneimine ,-SO
2-(lupetidine) ,-SO
2-(2-propyl group piperidines) ,-SO
2-(hydroxypropyl),-C (O)-(2-methoxymethyl tetramethyleneimine),-C (O)-(2-crassitude),-C (O)-(2, the 6-dimethyl pyrrolidine),-C (O)-(2-hydroxymethyl pyrrolidine),-C (O) N (methyl) (ethyl),-C (O) N (methyl) (propyl group),-C (O) N (methyl) (butyl),-C (O) N (propyl group) (butyl),-C (O) N (allyl group) (cyclopentyl),-C (O) N (allyl group) (cyclohexyl),-C (O) N (methyl) (methyl),-C (O) N (ethyl) (ethyl),-C (O) N (butyl) (butyl),-C (O) N (sec.-propyl) (sec.-propyl),-C (O) N (propyl group) (propyl group),-C (O) N (methyl) (cyclohexyl),-C (O) N (ethyl) (cyclohexyl),-C (O) NH (cyclobutyl),-C (O) NH (cyclopentyl),-C (O) N (CH
3) (cyclopentyl) ,-C (O) NH (2-methylcyclohexyl) ,-C (O) NH (amyl group) ,-C (O) N (amyl group) (amyl group) ,-C (O) NH (isopentyl) ,-C (O) NH (ethoxyethyl group) ,-C (O) N (CH
3) (methoxy ethyl) ,-C (O) N (propyl group) (methoxy ethyl) ,-C (O) N (methoxy ethyl) (methoxy ethyl) ,-C (O) N (ethoxyethyl group) (ethoxyethyl group) ,-C (O) N (ethyl) (methoxy ethyl) ,-C (O) N (propyl group) (hydroxyethyl) ,-C (O) N (hydroxyethyl) (ethyl), ethynyl, methyl, bromo ,-N (CH
3) SO
2(CH
3) ,-N (CH
3) SO
2-thienyl ,-N (hydroxypropyl) SO
2CH
3,-(CH
2)-SO
2-(CH
3) or-C (O)-CH (CH
3) CH
2CH
2CH
3
48. the compound that chemical formula is following, wherein
Or it can be used for the salt of pharmacy, wherein
X
10Be-O-,-S-,-NH-,-N (C
1-C
6Alkyl)-,-N (phenyl)-,-N (benzyl)-,-N (CO
2-C
1-C
6Alkyl)-;-N (CO
2-C
1-C
6Alkyl-phenyl)-or alkylhalide group;
R
35Be phenyl, C
3-C
8Cycloalkyl ,-S-phenyl, benzo dioxole, thienyl, C
1-C
6Alkyl, furyl, wherein each group be unsubstituted or by 1,2,3,4 or 5 independently for C
1-C
4Alkyl, C
1-C
4Alkoxyl group, OH, hydroxyl C
1-C
6Alkyl, halogen, halogen C
1-C
6Alkyl, halogen C
1-C
6Alkoxyl group ,-CO
2-(C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-(C
5-C
6Cycloalkyl) group replaces;
R
40Be phenyl ,-phenyl-pyridyl, xenyl ,-phenyl-benzothienyl ,-phenyl-thienyl ,-phenyl-furyl ,-the phenyl-pyrimidine base ,-phenyl-isoxazolyls ,-C (O)-pyridyl ,-(C
1-C
4Alkyl)-O-C (O) NH-phenyl ,-(C
1-C
4Alkyl)-O-C (O) N (C
1-C
6Alkyl)-phenyl ,-(C
1-C
4Alkyl)-phenyl ,-(C
1-C
4Alkyl)-SO
2NH
2,-(C
1-C
4Alkyl)-SO
2NH (C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-SO
2N (C
1-C
6Alkyl) (C
1-C
6Alkyl), CN ,-(C
1-C
4Alkyl)-(C
3-C
7Cycloalkyl) ,-(C
1-C
4Alkyl)-C (O) O-(C
1-C
4Alkyl) ,-(C
1-C
4Alkyl)-R
33, C
1-C
8Alkyl ,-(C
1-C
4Alkyl)-NHC (O)-(C
1-C
4Alkyl) ,-C (O) NH
2, wherein above-mentioned each ring is unsubstituted or is replaced for the substituting group of following groups independently by 1,2,3,4 or 5: halogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, halogen C
1-C
4Alkyl, wherein phenyl optional by 1 or 2 halogen replace-O-(C
1-C
4Alkyl)-phenyl ,-CHO ,-NHSO
2-(C
1-C
4Alkyl), alkyl wherein optional by 1,2 or 3 halogen replace-N (C
1-C
4Alkyl) SO
2-(C
1-C
4Alkyl);
R
42Be H, C
1-C
6Alkyl, benzyl ,-NHC (O)-(C
1-C
6Alkyl) or-NHC (O)-phenyl, wherein phenyl is optional is replaced by 1 or 2 alkyl;
R
52Be H, phenyl ,-NHC (O)-(C
1-C
6Alkyl)-(C
1-C
6Thio alkoxy) ,-N (C
1-C
6Alkyl) C (O)-(C
1-C
6Alkyl)-(C
1-C
6Thio alkoxy), OH, C
1-C
6Alkyl, list or two (C
1-C
6Alkyl) amino, wherein alkyl optional by phenyl replace-NHC (O)-(C
1-C
6Alkyl), wherein each alkyl optional by phenyl replace-N (C
1-C
6Alkyl) C (O)-(C
1-C
6Alkyl) ,-(CH
2)
0-4-SO
2-(C
1-C
10Alkyl) ,-NHCO
2-benzyl or-NH
2, and
R
60Be-L-V-R
65, C
1-C
8Alkyl or hydroxyl C
1-C
8Alkyl, wherein alkyl or hydroxyalkyl are optional by 1 or 2 L-V-R
65Group replaces, wherein
L can not exist or-C (O)-,-CO
2-,-C (O) NH-,-C (O) N (C
1-C
6Alkyl)-,-NHC (O)-,-N (C
1-C
6Alkyl)-C (O)-,-(CH
2)
0-4-SO
2-(CH
2)
0-4-,-(CH
2)
0-4-O-(CH
2)
0-4-,-(CH
2)
0-4-S-(CH
2)
0-4-,-NHC (O) NH-,-N (C
1-C
6Alkyl) C (O) NH-,-N (C
1-C
6Alkyl) C (O) N (C
1-C
6Alkyl) ,-NHC (O) N (C
1-C
6Alkyl)-,-NH-,-N (benzyl)-,-N (phenyl)-,-(CH
2)
0-4-NHSO
2-(CH
2)
0-4-,-N (C
1-C
6Alkyl) SO
2-,-SO
2NH-,-SO
2N (C
1-C
6Alkyl)-, or
V can not exist or-(CH
2)
0-4-C (O) NH-,-(CH
2)
0-4-C (O) N (C
1-C
6Alkyl)-, optional by 1 or 2 C
1-C
4The cyclopropyl of alkyl ,=NH ,=NOH ,=N-alkoxyl group, optional by the C of 1 or 2 OH replacement
1-C
8Alkyl or-CH (phenyl)-, wherein phenyl is optional be the group replacement of halogen or OH by 1,2,3,4 or 5 independently;
R
65It is cyclohexyl; Cyclopentyl; Phenyl;-(C
1-C
6Alkyl)-phenyl; NH
2List or two (C
1-C
10Alkyl) amino, wherein alkyl is optional is the group replacement of cyclopropyl, phenyl or OH by 1 or 2 independently; The oxadiazole base; Triazolopyrimidinyl; Triazolyl; Thiadiazolyl group; 3H-quinazoline-2-ketone group; Pyrimidyl, pyridyl; Pyridine N-oxides;-(C
1-C
6Alkyl)-pyridyl; Piperazinyl; The 2 base; Tetrahydrochysene-thiophene 1, the 1-dioxide; Tetrazyl; C
3-C
6Cycloalkyl-C
1-C
6Alkyl;-(C
1-C
4Alkyl)-SO
2-(C
1-C
4Alkyl); Benzothiazole; Six hydrogen-isoindole-1, the 3-diketo; Benzimidazolyl-; Benzoxazolyl; [1,2,4] triazole [1,5-a] pyrimidyl; Thiazolyl; Thiadiazolyl group; Imidazo [1,2-a] pyridine; C
1-C
6Alkyl; 3-aza-bicyclo [3.2.2] nonane; Pyrrolidone-base; The tall and erect yl of di nitrogen; Benzo [1,2,5] thiadiazolyl group;-NHSO
2-(4-tolyl); [1,2,4] triazolo [4,3-b] pyridazinyl, benzopyrrole alkane ketone group; Morpholinyl; Thio-morpholinyl; Thio-morpholinyl S-oxide compound; Thio-morpholinyl S, the S-dioxide; 2,3-dihydro-benzo [b] thiophene 1,1-dioxide; Pyrrolidyl; [1,2,4] oxadiazoles; C
1-C
10Alkyl; Isoxazolyl; 2,3-dihydro-1H-indyl; Quinazoline ketone group, quinazolyl, piperidyl, C
1-C
6Alkoxyl group ,-O-(C
1-C
6Alkyl)-phenyl or C
2-C
6Alkynyl;
Wherein above-mentioned each optional be C independently by 1,2,3,4 or 5
1-C
6Alkyl, CF
3, halogen, phenyl ,-(C
1-C
4Alkyl)-phenyl ,-C (O) phenyl, pyrrolidine-2,4-diketo, C
1-C
6Alkoxyl group ,-C (O)-furans ,-C (O)-NH
2,-C (O) NH (C
1-C
6Alkyl) ,-C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl), cyclopropyl ,-(CH
2)
0-4-cyclopentyl, benzoxazolyl, pyridine ,-NHC (O)-(C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl) C (O)-(C
1-C
6Alkyl) ,-C (O) C
1-C
6Alkyl ,-CO
2H ,-NHSO
2-(C
1-C
8Alkyl) ,-N (C
1-C
6Alkyl) SO
2-(C
1-C
8Alkyl) ,-CO
2-(C
1-C
6Alkyl) group replaces.
49. the compound that chemical formula is following, wherein
Or it can be used for the salt of pharmacy, wherein
X
10Be-O-,-S-,-NH-,-N (C
1-C
6Alkyl);
R
35Be phenyl, C
3-C
8Cycloalkyl ,-S-phenyl, benzo dioxole, thienyl, C
1-C
6Alkyl, furyl, wherein each group be unsubstituted or by 1,2,3,4 or 5 independently for C
1-C
4Alkyl, C
1-C
4Alkoxyl group, OH, hydroxyl C
1-C
6Alkyl, halogen, halogen C
1-C
6Alkyl, halogen C
1-C
6Alkoxyl group ,-O-(C
1-C
6Alkyl)-phenyl ,-CO
2-(C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-(C
5-C
6Cycloalkyl) group replaces;
R
40Be phenyl ,-phenyl-pyridyl, xenyl ,-phenyl-benzothienyl ,-phenyl-thienyl ,-phenyl-furyl ,-the phenyl-pyrimidine base ,-phenyl-isoxazolyls ,-C (O)-pyridyl ,-(C
1-C
4Alkyl)-O-C (O) NH-phenyl ,-(C
1-C
4Alkyl)-O-C (O) N (C
1-C
6Alkyl)-phenyl ,-(C
1-C
4Alkyl)-phenyl ,-(C
1-C
4Alkyl)-SO
2NH
2,-(C
1-C
4Alkyl)-SO
2NH (C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-SO
2N (C
1-C
6Alkyl) (C
1-C
6Alkyl), CN ,-(C
1-C
4Alkyl)-(C
3-C
7Cycloalkyl) ,-(C
1-C
4Alkyl)-C (O) O-(C
1-C
4Alkyl) ,-(C
1-C
4Alkyl)-R
33, C
1-C
8Alkyl ,-(C
1-C
4Alkyl)-NHC (O)-(C
1-C
4Alkyl) ,-C (O) NH
2, above-mentioned each ring is unsubstituted or is replaced for the substituting group of following groups independently by 1,2,3,4 or 5: halogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, halogen C
1-C
4Alkyl, wherein phenyl optional by 1 or 2 halogen replace-O-(C
1-C
4Alkyl)-phenyl ,-CHO ,-NHSO
2-(C
1-C
4Alkyl), wherein alkyl optional by 1,2 or 3 halogen replace-N (C
1-C
4Alkyl) SO
2-(C
1-C
4Alkyl);
R
42Be H, C
1-C
6Alkyl, benzyl ,-NHC (O)-(C
1-C
6Alkyl) ,-NHC (O)-phenyl, wherein phenyl is optional is replaced by 1 or 2 alkyl;
R
52Be H, phenyl ,-NHC (O)-(C
1-C
6Alkyl)-(C
1-C
6Thio alkoxy) ,-N (C
1-C
6Alkyl) C (O)-(C
1-C
6Alkyl)-(C
1-C
6Thio alkoxy), OH, C
1-C
6Alkyl, list or two (C
1-C
6Alkyl) amino, wherein alkyl optional by phenyl replace-NHC (O)-(C
1-C
6Alkyl), wherein each alkyl optional by phenyl replace-N (C
1-C
6Alkyl) C (O)-(C
1-C
6Alkyl) ,-(CH
2)
0-4-SO
2-(C
1-C
10Alkyl) ,-NHCO
2-benzyl or-NH
2, and
R
60Be-L-V-R
65, C
1-C
8Alkyl or hydroxyl C
1-C
8Alkyl, wherein alkyl or hydroxyalkyl are optional by 1 or 2 L-V-R
65Group replaces, wherein
L can not exist or-C (O)-,-CO
2-,-C (O) NH-,-C (O) N (C
1-C
6Alkyl)-,-NHC (O)-,-N (C
1-C
6Alkyl)-C (O)-,-(CH
2)
0-4-SO
2-(CH
2)
0-4-,-(CH
2)
0-4-O-(CH
2)
0-4-,-(CH
2)
0-4-S-(CH
2)
0-4-,-NHC (O) NH-,-N (C
1-C
6Alkyl) C (O) NH-,-N (C
1-C
6Alkyl) C (O) N (C
1-C
6Alkyl) ,-NHC (O) N (C
1-C
6Alkyl)-,-NH-,-N (benzyl)-,-N (phenyl)-,-(CH
2)
0-4-NHSO
2-(CH
2)
0-4-,-N (C
1-C
6Alkyl) SO
2-,-SO
2NH-,-SO
2N (C
1-C
6Alkyl)-, or
V can not exist or-(CH
2)
0-4-C (O) NH-,-(CH
2)
0-4-C (O) N (C
1-C
6Alkyl)-, optional by 1 or 2 C
1-C
4The cyclopropyl of alkyl ,=NH ,=NOH ,=N-alkoxyl group, optional by the C of 1 or 2 OH replacement
1-C
8Alkyl or-CH (phenyl)-, wherein phenyl is optional be the group replacement of halogen or OH by 1,2,3,4 or 5 independently;
R
65It is cyclohexyl; Cyclopentyl; Phenyl;-(C
1-C
6Alkyl)-phenyl; NH
2List or two (C
1-C
10Alkyl) amino, wherein alkyl is optional is the group replacement of cyclopropyl, phenyl or OH by 1 or 2 independently; The oxadiazole base; Triazolopyrimidinyl; Triazolyl; Thiadiazolyl group; 3H-quinazoline-2-ketone group; Pyrimidyl, pyridyl; Pyridine N-oxides;-(C
1-C
6Alkyl)-pyridyl; Piperazinyl; The 2 base; Tetrahydrochysene-thiophene 1, the 1-dioxide; Tetrazyl; C
3-C
6Cycloalkyl-C
1-C
6Alkyl;-(C
1-C
4Alkyl)-SO
2-(C
1-C
4Alkyl); Benzothiazole; Six hydrogen-isoindole-1, the 3-diketo; Benzimidazolyl-; Benzoxazolyl; [1,2,4] triazole [1,5-a] pyrimidyl; Thiazolyl; Thiadiazolyl group; Imidazo [1,2-a] pyridine; C
1-C
6Alkyl; 3-aza-bicyclo [3.2.2] nonane; Pyrrolidone-base; The tall and erect yl of di nitrogen; Benzo [1,2,5] thiadiazolyl group;-NHSO
2-(4-tolyl); [1,2,4] triazolo [4,3-b] pyridazinyl, benzopyrrole alkane ketone group; Morpholinyl; Thio-morpholinyl; Thio-morpholinyl S-oxide compound; Thio-morpholinyl S, the S-dioxide; 2,3-dihydro-benzo [b] thiophene 1,1-dioxide; Pyrrolidyl; [1,2,4] oxadiazoles; C
1-C
10Alkyl; Isoxazolyl; 2,3-dihydro-1H-indyl; Quinazoline ketone group, quinazolyl, piperidyl, wherein above-mentioned each optional be C independently by 1,2,3,4 or 5
1-C
6Alkyl, CF
3, halogen, phenyl ,-(C
1-C
4Alkyl)-phenyl ,-C (O) phenyl, pyrrolidine-2,4-diketo, C
1-C
6Alkoxyl group ,-C (O)-furans ,-C (O)-NH
2,-C (O) NH (C
1-C
6Alkyl) ,-C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl), cyclopropyl ,-(CH
2)
0-4-cyclopentyl, benzoxazolyl, pyridine ,-NHC (O)-(C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl) C (O)-(
C1-C
6Alkyl) ,-C (O) C
1-C
6Alkyl ,-CO
2H ,-NHSO
2-(C
1-C
8Alkyl) ,-N (C
1-C
6Alkyl) SO
2-(C
1-C
8Alkyl) group replaces.
50. compound that chemical formula is following
R
30Be selected from phenyl, the pyrazolopyrimidine base, oxa--azepine-benzo Azulene base isoxazolyl, the Triazolopyridine base, pyrrolidone-base, tetrahydrochysene sulfo--azepine-fluorenyl, pyridyl, piperidyl, dihydro ring penta quinolyl, furyl, the naphthalene thienyl, 2,3-naphthyridine ketone group, thiadiazolyl group, the Thienopyrimidine ketone group, oxa--diaza-ring penta naphthyl, dihydrobenzo dioxepinyl, the chromanone base, chromene ketone group; oxazolidinyl, benzophenone, pyrazinyl list N-oxide compound, cumarone, pyrazolyl,-isoxazolyls-phenyl, phenyl-triazolyl, benzimidazolyl-, indyl, phenyl-pyrryl, chromanyl, isoquinolyl,-thienyl-thienyl, benzothienyl,-phenyl-thiadiazolyl group, the chromanone base, quinolyl,-pyrryl-C (O)-phenyl,-phenyl-O-phenyl,-phenyl-oxazolyls,-pyrrolidone-base-phenyl,-phenyl-pyrimidine base,-phenyl-oxadiazole bases, two ring [2.2.1] heptenyls, cyclopentyl, thieno-[2,3-b] thiophene, cyclohexyl,-phenyl-imidazolyl benzoxazole, dihydro-1H-indyl, 2,3-dihydro-benzo [b] thiophene 1, the 1-dioxide, benzo [b] thiophene 1, the 1-dioxide, 2,3-dihydro-benzo [d] isothiazole 1, the 1-dioxide,-phenyl-thiazolyl,-phenyl-pyrazole base,-phenyl-C (O)-piperidyl,-phenyl-C (O)-pyrrolidyl,-phenyl-isoxazolyls, pseudoindoyl, purine radicals, oxaxolyl, thiazolyl, the pyridazine ketone group, thiazolyl, pyranyl, dihydropyrane and pyridyl, the tall and erect yl of di nitrogen, cyclopropyl, the dihydro-naphtho isoxazolyl, the benzo indazolyl, dihydro ring penta chromene ketone group, the imidazolopyrazole base, tetrahydro cyclopentyl chromene ketone group, the dihydroquinoline ketone group, pyridyl N-oxide compound, the isochroman base, the quinazoline ketone group, the Pyrazolopyridine base, dihydrobenzo thiophene dioxide, dihydro furan benzoisoxazole base, the dihydro-pyrimidin diketo, thieno-pyrazolyl oxazolyl, the tetrahydro cyclopentyl pyrazolyl, dihydro naphthalenonyl, the Dihydrobenzofuranes ketone group, dihydro monodral base, the tetrahydro cyclopentyl pyrazolyl, tetrahydro-pyrazole and azepine base, indazolyl, the tetrahydro cyclopentyl isoxazolyl, the tetrahydro indole base, pyrrolidyl, the thienopyridine base, dioxy dihydrobenzo isothiazole ketone group, triazolopyrimidinyl, thienyl, dihydrothieno pyrimidines ketone group and Ben Bing oxadiazole base, wherein above-mentioned each group are unsubstituted or by 1,2,3,4 or 5 substituting groups that are independently selected from following groups replace:
Optional by 1 phenyl or 1 C that CN replaces
1-C
10Alkyl; OH; Optional by phenyl or (C
1-C
4Alkyl) the hydroxyl C of phenyl replacement
1-C
10Alkyl; Optional is the C that hydroxyl or phenyl groups replace by 1 or 2 independently
1-C
6Alkoxyl group; Alkylhalide group; The halogen alkoxyl group; (CH
2)
0-4C (O) NR
31R
32NR
31-SO
2-(C
1-C
6Alkyl), wherein alkyl is optional is halogen or R by 1,2 or 3 independently
33Group replace;-SO
2-NH (C
1-C
6Alkyl), wherein alkyl is optional is halogen, OH, alkoxyl group or R by 1 or 2 independently
33Group replace;-(C
1-C
6Alkyl)-SO
2-(C
1-C
6Alkyl), wherein alkyl is optional is halogen, OH, C by 1 or 2 independently
1-C
4Alkoxyl group or R
33Group replace;-SO
2-(C
1-C
6Alkyl), wherein alkyl is optional is OH or C by 1 or 2 independently
1-C
4The group of alkoxyl group replaces;-SO
2-N (C
1-C
6Alkyl) (C
1-C
6Alkyl), wherein each alkyl is optional is halogen, OH or R by 1 or 2 independently
33Group replace;-SO
2-NH (C
1-C
6Alkyl)-and phenyl, wherein phenyl is optional is C by 1 or 2 independently
1-C
4The group of alkoxy or halogen replaces;-O-(C
1-C
6Alkyl)-phenyl;-(C
1-C
6Alkyl)-the O-phenyl;-(C
1-C
6Alkyl)-O-(C
1-C
6Alkyl)-phenyl; Triazolidine-3, the 5-diketone; Halogen;-NHC (O) NH
2-NHC (O) NH (C
1-C
6Alkyl);-NHC (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl);-N (C
1-C
6Alkyl) C (O) NH
2-N (C
1-C
6Alkyl) C (O) NH (C
1-C
6Alkyl);-N (C
1-C
6Alkyl) C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl);-(C
1-C
6Alkyl) thienyl;-(C
1-C
6Alkyl) furyl;-S-(C
1-C
6Alkyl) phenyl;-SO
2NR
31R
32-C (O)-NR
31R
32-NR
31R
32Dithiane;-NHC (S) NH
2-NHC (S) NH (C
1-C
6Alkyl);-NHC (S) N (C
1-C
6Alkyl) (C
1-C
6Alkyl);-CO
2(C
1-C
6Alkyl); Tetrahydropyrans; Optional is the phenyl that F, Cl or Br replace by 1 or 2 independently; Pyridine ,-C
2-C
4Alkynyl-phenyl;-O-C
3-C
8Cycloalkyl;-O-(C
1-C
6Alkyl)-R
33Optional by one or two methyl substituted pyrroles; 2,3-dihydro-cumarone; Benzo [1,2,5] oxadiazoles;-C (O)-(C
1-C
10Alkyl), wherein alkyl is optional by NH
2, N (C
1-C
6Alkyl) or N (C
1-C
6Alkyl) (C
1-C
6Alkyl) replaces;-C (O) NH-phenyl;-C (O) N (C
1-C
6Alkyl)-phenyl; 4,4-dimethyl-4,5-dihydro-oxazoles;-(C
1-C
6Alkyl)-the S-pyridine;-(C
1-C
6Alkyl)-SO
2-pyridine;-(C
1-C
6Thio alkoxy)-pyridine; Optional by 1 or 2 methyl substituted thiazole; Pyrazoles;-S-(C
1-C
6Alkyl); Indoles; (C
1-C
6Thio alkoxy)-(C
1-C
6Alkyl); C
2-C
8Alkynyl;-CO
2-(C
1-C
6Alkyl);-C
1-C
10Alkyloyl ,-(CH
2)
0-4-SO
2-(C
1-C
10Alkyl), wherein alkyl is optional is replaced by OH;
R wherein
31And R
32Be independently selected from hydrogen in each case; C
1-C
8Alkyl; C
2-C
8Alkenyl; Hydroxyl C
1-C
6Alkyl; C
1-C
6Alkylhalide group; C
1-C
6Alkoxy C
1-C
6Alkyl;-(CH
2)
0-4-SO
2-(C
1-C
6Alkyl), wherein alkyl is optional is replaced by the group of 1,2,3 or 4 independently selected from halogen atoms;-(CH
2)
0-4-SO
2-imidazolyl;-(C
1-C
6Alkyl)-C (O) NH
2-(C
1-C
6Alkyl)-C (O) NH (C
1-C
6Alkyl);-(C
1-C
6Alkyl)-C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl);-(C
1-C
6Alkyl)-NH
2-(C
1-C
6Alkyl)-NH (C
1-C
6Alkyl);-(C
1-C
6Alkyl)-N (C
1-C
6Alkyl) (C
1-C
6Alkyl);-(C
1-C
6Alkyl) phenyl;-(C
1-C
6Alkyl) pyridyl;-C (O) furyl; (C
1-C
6Alkyl)-tetrahydrofuran (THF); Cyclopropyl; Cyclobutyl; Cyclopentyl; Cyclohexyl;-CO
2-(C
1-C
6Alkyl);-(C
1-C
6Alkyl)-furyl;-(CH
2)
0-4-SO
2-thienyl, wherein phenyl and pyridyl be unsubstituted or by 1,2,3,4 or 5 independently for C
1-C
4Alkyl, hydroxyl, C
1-C
4The group of alkoxyl group, halogen replaces, or
R
31, R
32Form 5,6 or 7 yuan of Heterocyclylalkyls or 6 yuan of hetero-aromatic rings with the nitrogen that links to each other with them, wherein each is chosen wantonly and is fused on benzene, pyridine or the pyrimidine ring, and each is optional by C
1-C
6Alkoxyl group, hydroxyl, hydroxyl C
1-C
6Alkyl, C
1-C
4Alkoxy C
1-C
6Alkyl ,-C (O) NH
2,-C (O) NH (C
1-C
6Alkyl)-the phenyl replacement;
R
33Be H, NH in each case independently
2, NH (C
1-C
6Alkyl), N (C
1-C
6Alkyl) (C
1-C
6Alkyl), N (C
1-
6Alkyl) (phenyl), N (C
1-C
6Alkyl) (benzyl);
R
35Be phenyl, C
3-C
8Cycloalkyl ,-the S-phenyl ,-benzo dioxole, thienyl, C
1-C
6Alkyl, furyl, imidazolyl, wherein each group be unsubstituted or by 1,2,3,4 or 5 independently for C
1-C
4Alkyl, C
1-C
4Alkoxyl group, OH, hydroxyl C
1-C
6Alkyl, halogen, halogen C
1-C
6Alkyl, halogen C
1-C
6Alkoxyl group ,-O-(C
1-C
6Alkyl)-phenyl ,-CO
2-(C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-(C
5-C
6Cycloalkyl) or (CH
2)
0-4The group of CN replaces;
R
40Be phenyl ,-phenyl-pyridyl, xenyl ,-phenyl-benzothienyl ,-phenyl-thienyl ,-phenyl-furyl ,-the phenyl-pyrimidine base ,-phenyl-isoxazolyls ,-C (O)-pyridyl ,-(C
1-C
4Alkyl)-O-C (O) NH-phenyl, wherein phenyl optional by 1,2 or 3 halogen atom replace ,-(C
1-C
4Alkyl)-O-C (O) N (C
1-C
6Alkyl)-phenyl ,-(C
1-C
6Alkyl)-phenyl ,-(C
1-C
4Alkyl)-SO
2NH
2,-(C
1-C
4Alkyl)-SO
2NH (C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-SO
2N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-SO
2NH
2,-SO
2NH (C
1-C
6Alkyl) ,-SO
2N (C
1-C
6Alkyl) (C
1-C
6Alkyl), CN ,-(CH
2)
0-4-(C
3-C
8Cycloalkyl) ,-(C
1-C
4Alkyl)-C (O) O-(C
1-C
4Alkyl) ,-(C
1-C
4Alkyl)-R
33, C
1-C
10Alkyl, C
2-C
8Alkenyl ,-(C
1-C
4Alkyl)-NHC (O)-(C
1-C
4Alkyl) ,-(CH
2)
0-4-C (O) NH
2,-(CH
2)
0-4-C (O) NH (C
1-C
6Alkyl) ,-(CH
2)
0-4-C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl), naphthyl, tetralyl, dihydro naphthyl ,-(CH
2)
0-4-imidazolyl ,-(CH
2)
0-4-pyrrolidyl, oxazolidone 3,4-dihydro-benzo [e] [1,2] oxathiin 2,2-dioxide, pyrimidyl, 3,4-dihydro-2H-benzo [e] [1,2] thiazine 1,1-dioxide, pyridyl; Or pyrimidyl, alkoxyalkyl ,-phenyl-benzothienyl ,-phenyl-cyclohexyl ,-phenyl-cyclopentyl ,-phenyl-(C
1-C
6Alkyl)-cyclopentyl ,-phenyl-(C
1-C
6Alkyl)-cyclohexyl ,-phenyl-oxazolyls, furyl, tetrahydrofuran base, wherein above-mentioned each group is unsubstituted or is replaced for the substituting group of following groups independently by 1,2,3,4 or 5: halogen, optional by 1 or 2 C that replaces for the group of CN or OH independently
1-C
8Alkyl; C
1-C
6Alkoxyl group, halogen (C
1-C
8Alkyl), halogen (C
1-C
4Alkoxyl group); Wherein phenyl optional by 1 or 2 halogen replace-O-(C
1-C
4Alkyl)-phenyl, CN ,-CHO, C
1-C
4Thio alkoxy ,-NHSO
2-(C
1-C
6Alkyl), alkyl wherein optional by 1,2 or 3 halogen replace-N (C
1-C
4Alkyl) SO
2-(C
1-C
4Alkyl), OH ,-SO
2R
33, R
33, C
2-C
8Alkynyl, C
2-C
8Alkenyl, thio alkoxy alkyl ,-SO
2-(C
1-C
10Alkyl); , NR
31R
32,-C (O)-NR
31R
32,-OC (O) R
33, C
1-C
8Alkyloyl and-(C
1-C
6Alkyl)-C (O)-(C
1-C
6Alkoxyl group);
R
41aAnd R
41Be H, cyclohexyl, phenyl or optional independently by 1 or 2 phenyl, hydroxyl, C
1-C
4Thio alkoxy, C
1-C
4Thio alkoxy C
1-C
6The C that alkyl replaces
1-C
6Alkyl; Or-C
1-C
6Alkyl-SO
2-C
1-C
6Alkyl;
R
40, R
41Forming one with the atom that links to each other with them chooses wantonly by C
1-C
4Alkyl ring, C
1-C
4Alkoxyl group, halogen ,-CO
2NH
2,-CO
2NH (C
1-C
6Alkyl) or-CO
2N (C
1-C
6Alkyl) (C
1-C
6Alkyl) C of Qu Daiing
3-C
8Cycloalkyl ring; One optional by C
1-C
6The thiazolyl that alkyl replaces; Optional by C
1-C
6Alkyl replaces the De isoxazolyl; Optional is halogen or C by 1,2 or 3 independently
1-C
6The phenyl that the group of alkyl replaces;
And
R
42Be H, the optional C that is replaced by OH
1-C
6Alkyl; Benzyl;-NHC (O)-(C
1-C
6Alkyl);-NHC (O)-phenyl, wherein phenyl is optional is replaced by 1 and 2 alkyl.
51. compound as claimed in claim 50, wherein
R
30Be selected from pyrazolopyrimidine base, oxa--azepine-benzo Azulene base, isoxazolyl, Triazolopyridine base, pyrrolidone-base, tetrahydrochysene sulfo--azepine-fluorenyl, pyridyl, piperidyl, thiazolyl, thiadiazolyl group or thienyl, wherein each is unsubstituted or is replaced by 1,2,3,4 or 5 substituting group that is independently selected from following groups:
C
1-C
4Alkyl ,-C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-C (O) NH
2,-C (O) N (C
2-C
6Alkenyl) (C
3-C
8Cycloalkyl) ,-C (O) NH (C
3-C
8Alkyl) ,-C (O) NH (C
1-C
6Alkyl), optional by 1 or two be independently the group replacement of alkoxyalkyl or hydroxyl C (O)-(tetramethyleneimine), halogen ,-C (O) N (C
1-C
6Hydroxyalkyl) (C
1-C
6Alkyl) ,-C (O) NH (C
1-C
6Hydroxyalkyl) ,-C (O) N (alkoxyalkyl) (alkoxyalkyl) ,-C (O) N (C
1-C
6Alkyl) (alkoxyalkyl) ,-C (O) N (C
1-C
6Hydroxyalkyl) (alkyl) ,-NHSO
2CF
3,-N (C
1-C
6Alkyl)-SO
2-thiophene ,-N (C
1-C
6Hydroxyalkyl) SO
2-(C
1-C
6Alkyl) ,-NHC (O) C
1-C
4Alkyl, optional by 1 or 2 methyl substituted De oxazolyl, optional by 1 or 2 methyl substituted thiazolyl, optional by 1 or 2 methyl substituted pyrazolyl, optional by 1 or 2 methyl substituted imidazolyl, optional by 1 or 2 methyl substituted isoxazolyl, the optional pyrimidyl that is replaced by 1 or 2 methyl or halogen group ,-NHSO
2CH
3, wherein imidazole ring is optional by 1 or 2 methyl substituted-NHSO
2-imidazolyl ,-N (C
1-C
6Alkyl) SO
2(C
1-C
6Alkyl) ,-SO
2NH-C
1-C
6Hydroxyalkyl ,-SO
2NH-C
1-C
6Alkyl-NH (C
1-C
4Alkyl), optional by 1 or 2 methyl substituted-SO
2-piperazinyl, optional by 1 or 2 methyl substituted-SO
2-tetramethyleneimine, optional by 1 or 2 C
1-C
4Alkyl replaces-SO
2-piperidines ,-SO
2N (C
1-C
4Hydroxyalkyl) (C
1-C
4Hydroxyalkyl) ,-SO
2NH
2,-SO
2N (C
1-C
6Alkyl) (C
1-C
6Alkyl), C
2-C
6Alkynyl ,-SO
2-(C
1-C
6Hydroxyalkyl) ,-SO
2NH (C
1-C
6Hydroxyalkyl) ,-SO
2N (C
1-C
6Alkyl) (C
1-C
6Hydroxyalkyl) ,-(C
1-C
4Alkyl) SO
2-(C
1-C
4Alkyl) or-C (O)-(C
1-C
10Alkyl).
52. compound as claimed in claim 51, wherein
R
30Be pyridyl, it is unsubstituted or is replaced by at least one following groups :-SO
2NH-propyl group-OH ,-SO
2NH-ethyl-OH ,-SO
2NH-ethyl-OCH
3,-SO
2NH-CH (CH
3)
2-CH
2OH ,-SO
2NH-(CH
2CH (OH) CH
3) ,-SO
2NH-ethyl-NH (CH
3) ,-SO
2NH-(CH
2CH
2OH)
2,-SO
2NHCH (CH
3) CH
2OH ,-SO
2N (CH
3)
2,-SO
2NH (CH
2CH (OH) CH
3) ,-SO
2-tetramethyleneimine ,-SO
2-(lupetidine) ,-SO
2-(2-propyl group piperidines) ,-SO
2-(hydroxypropyl),-C (O)-(2-methoxymethyl tetramethyleneimine),-C (O)-(2-crassitude),-C (O)-(2, the 6-dimethyl pyrrolidine),-C (O)-(2-hydroxymethyl pyrrolidine),-C (O) N (methyl) (ethyl),-C (O) N (methyl) (propyl group),-C (O) N (methyl) (butyl),-C (O) N (propyl group) (butyl),-C (O) N (allyl group) (cyclopentyl),-C (O) N (allyl group) (cyclohexyl),-C (O) N (methyl) (methyl),-C (O) N (ethyl) (ethyl),-C (O) N (butyl) (butyl),-C (O) N (sec.-propyl) (sec.-propyl),-C (O) N (propyl group) (propyl group),-C (O) N (methyl) (cyclohexyl),-C (O) N (ethyl) (cyclohexyl),-C (O) NH (cyclobutyl),-C (O) NH (cyclopentyl),-C (O) N (CH
3) (cyclopentyl) ,-C (O) NH (2-methylcyclohexyl) ,-C (O) NH (amyl group) ,-C (O) N (amyl group) (amyl group) ,-C (O) NH (isopentyl) ,-C (O) NH (ethoxyethyl group) ,-C (O) N (CH
3) (methoxy ethyl) ,-C (O) N (propyl group) (methoxy ethyl) ,-C (O) N (methoxy ethyl) (methoxy ethyl) ,-C (O) N (ethoxyethyl group) (ethoxyethyl group) ,-C (O) N (ethyl) (methoxy ethyl) ,-C (O) N (propyl group) (hydroxyethyl) ,-C (O) N (hydroxyethyl) (ethyl), ethynyl, methyl, bromo ,-N (CH
3) SO
2(CH
3) ,-N (CH
3) SO
2-thienyl ,-N (hydroxypropyl) SO
2CH
3,-(CH
2)-SO
2-(CH
3) or-C (O)-CH (CH
3) CH
2CH
2CH
3
53. the compound that chemical formula is following,
Or it can be used for the salt of pharmacy, wherein
R
30Be selected from phenyl, the pyrazolopyrimidine base, oxa--azepine-benzo Azulene base isoxazolyl, the Triazolopyridine base, pyrrolidone-base, tetrahydrochysene sulfo--azepine-fluorenyl, pyridyl, piperidyl, dihydro ring penta quinolyl, furyl, the naphthalene thienyl, 2,3-naphthyridine ketone group, thiadiazolyl group, the Thienopyrimidine ketone group, oxa--diaza-ring penta naphthyl, dihydrobenzo dioxepinyl, the chromanone base, the chromene ketone group, oxazolidinyl, benzophenone, pyrazinyl list N-oxide compound, cumarone, pyrazolyl,-isoxazolyls-phenyl, phenyl-triazolyl, benzimidazolyl-, indyl, phenyl-pyrryl, chromanyl, isoquinolyl,-thienyl-thienyl, benzothienyl,-phenyl-thiadiazolyl group, the chromanone base, quinolyl,-pyrryl-C (O)-phenyl,-phenyl-O-phenyl,-phenyl-oxazolyls,-pyrrolidone-base-phenyl,-phenyl-pyrimidine base,-phenyl-oxadiazole bases, two ring [2.2.1] heptenyls, cyclopentyl, thieno-[2,3-b] thiophene, cyclohexyl,-phenyl-imidazolyl benzoxazole, dihydro-1H-indyl, 2,3-dihydro-benzo [b] thiophene 1, the 1-dioxide, benzo [b] thiophene 1, the 1-dioxide, 2,3-dihydro-benzo [d] isothiazole 1, the 1-dioxide,-phenyl-thiazolyl,-phenyl-pyrazole base,-phenyl-C (O)-piperidyl,-phenyl-C (O)-pyrrolidyl,-phenyl-isoxazolyls, pseudoindoyl, purine radicals, oxaxolyl, thiazolyl, the pyridazine ketone group, thiazolyl, pyranyl, dihydropyrane and pyridyl, the tall and erect yl of di nitrogen, cyclopropyl, the dihydro-naphtho isoxazolyl, the benzo indazolyl, dihydro ring penta chromene ketone group, the imidazolopyrazole base, tetrahydro cyclopentyl chromene ketone group, the dihydroquinoline ketone group, pyridyl N-oxide compound, the isochroman base, the quinazoline ketone group, the Pyrazolopyridine base, dihydrobenzo thiophene dioxide, dihydro furan benzoisoxazole base, the dihydro-pyrimidin diketo, thieno-pyrazolyl oxazolyl, the tetrahydro cyclopentyl pyrazolyl, dihydro naphthalenonyl, the Dihydrobenzofuranes ketone group, dihydro monodral base, the tetrahydro cyclopentyl pyrazolyl, tetrahydro-pyrazole and azepine base, indazolyl, the tetrahydro cyclopentyl isoxazolyl, the tetrahydro indole base, pyrrolidyl, the thienopyridine base, dioxy dihydrobenzo isothiazole ketone group, triazolopyrimidinyl, thienyl, dihydrothieno pyrimidines ketone group and Ben Bing oxadiazole base, wherein above-mentioned each group are unsubstituted or by 1,2,3,4 or 5 substituting groups that are independently selected from following groups replace:
Optional by 1 phenyl or 1 C that CN replaces
1-C
10Alkyl; OH; Optional by phenyl or (C
1-C
4Alkyl) the hydroxyl C of phenyl replacement
1-C
10Alkyl; Optional is the C that hydroxyl or phenyl groups replace by 1 or 2 independently
1-C
6Alkoxyl group; Alkylhalide group; The halogen alkoxyl group; (CH
2)
0-4C (O) NR
31R
32NR
31-SO
2-(C
1-C
6Alkyl), wherein alkyl is optional is halogen or R by 1,2 or 3 independently
33Group replace;-SO
2-NH (C
1-C
6Alkyl), wherein alkyl is optional is halogen, OH, alkoxyl group or R by 1 or 2 independently
33Group replace;-(C
1-C
6Alkyl)-SO
2-(C
1-C
6Alkyl), wherein alkyl is optional is halogen, OH, C by 1 or 2 independently
1-C
4Alkoxyl group or R
33Group replace;-SO
2-(C
1-C
6Alkyl), wherein alkyl is optional is OH or C by 1 or 2 independently
1-C
4The group of alkoxyl group replaces;-SO
2-N (C
1-C
6Alkyl) (C
1-C
6Alkyl), wherein each alkyl is optional is halogen, OH or R by 1 or 2 independently
33Group replace;-SO
2-NH (C
1-C
6Alkyl)-and phenyl, wherein phenyl is optional is C by 1 or 2 independently
1-C
4The group of alkoxy or halogen replaces;-O-(C
1-C
6Alkyl)-phenyl;-(C
1-C
6Alkyl)-the O-phenyl;-(C
1-C
6Alkyl)-O-(C
1-C
6Alkyl)-phenyl; Triazolidine-3, the 5-diketone; Halogen;-NHC (O) NH
2-NHC (O) NH (C
1-C
6Alkyl);-NHC (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl);-N (C
1-C
6Alkyl) C (O) NH
2-N (C
1-C
6Alkyl) C (O) NH (C
1-C
6Alkyl);-N (C
1-C
6Alkyl) C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl);-(C
1-C
6Alkyl) thienyl;-(C
1-C
6Alkyl) furyl;-S-(C
1-C
6Alkyl) phenyl;-SO
2NR
31R
32-C (O)-NR
31R
32-NR
31R
32Dithiane;-NHC (S) NH
2-NHC (S) NH (C
1-C
6Alkyl);-NHC (S) N (C
1-C
6Alkyl) (C
1-C
6Alkyl);-CO
2(C
1-C
6Alkyl); Tetrahydropyrans; Optional is the phenyl that F, Cl or Br replace by 1 or 2 independently; Pyridine;-C
2-C
4Alkynyl-phenyl;-O-C
3-C
8Cycloalkyl;-O-(C
1-C
6Alkyl)-R
33Optional by one or two methyl substituted pyrroles; 2,3-dihydro-cumarone; Benzo [1,2,5] oxadiazoles;-C (O)-(C
1-C
10Alkyl), wherein alkyl is optional by NH
2, N (C
1-C
6Alkyl) or N (C
1-C
6Alkyl) (C
1-C
6Alkyl) replaces;-C (O) NH-phenyl;-C (O) N (C
1-C
6Alkyl)-phenyl; 4,4-dimethyl-4,5-dihydro-oxazoles;-(C
1-C
6Alkyl)-the S-pyridine;-(C
1-C
6Alkyl)-SO
2-pyridine;-(C
1-C
6Thio alkoxy)-pyridine; Optional by 1 or 2 methyl substituted thiazole; Pyrazoles;-S-(C
1-C
6Alkyl); Indoles; (C
1-C
6Thio alkoxy)-(C
1-C
6Alkyl); C
2-C
8Alkynyl;-CO
2-(C
1-C
6Alkyl);-C
1-C
10Alkyloyl;-(CH
2)
0-4-SO
2-(C
1-C
10Alkyl), wherein alkyl is optional is replaced by OH;
R wherein
31And R
32Be independently selected from hydrogen, C in each case
1-C
8Alkyl, C
2-C
8Alkenyl, hydroxyl C
1-C
6Alkyl, C
1-C
6Alkylhalide group, C
1-C
6Alkoxy C
1-C
6Alkyl ,-(CH
2)
0-4-SO
2-(C
1-C
6Alkyl), wherein alkyl is optional is replaced by the group of 1,2,3 or 4 independently selected from halogen atoms;-(CH
2)
0-4-SO
2-imidazolyl ,-(C
1-C
6Alkyl)-C (O) NH
2,-(C
1-C
6Alkyl)-C (O) NH (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-NH
2,-(C
1-C
6Alkyl)-NH (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-N (C
1-C
6Alkyl) (C
1-C
6Alkyl) ,-(C
1-C
6Alkyl) phenyl ,-(C
1-C
6Alkyl) pyridyl ,-C (O) furyl, (C
1-C
6Alkyl)-tetrahydrofuran (THF), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl ,-CO
2-(C
1-C
6Alkyl) ,-(C
1-C
6Alkyl)-furyl ,-(CH
2)
0-4-SO
2-thienyl, wherein phenyl and pyridyl be unsubstituted or by 1,2,3,4 or 5 independently for C
1-C
4Alkyl, hydroxyl, C
1-C
4The group of alkoxyl group, halogen replaces, or
R
31, R
32Form 5,6 or 7 yuan of Heterocyclylalkyls or 6 yuan of hetero-aromatic rings with the nitrogen that links to each other with them, wherein each is chosen wantonly and is fused on benzene, pyridine or the pyrimidine ring, and each is optional by C
1-C
6Alkoxyl group, hydroxyl, hydroxyl C
1-C
6Alkyl, C
1-C
4Alkoxy C
1-C
6Alkyl ,-C (O) NH
2,-C (O) NH (C
1-C
6Alkyl)-the phenyl replacement;
R
33Be H, NH in each case independently
2, NH (C
1-C
6Alkyl), N (C
1-C
6Alkyl) (C
1-C
6Alkyl), N (C
1-C
6Alkyl) (phenyl), N (C
1-C
6Alkyl) (benzyl);
R
35Be phenyl, C
3-C
8Cycloalkyl ,-the S-phenyl ,-benzo dioxole, thienyl, C
1-C
6Alkyl, furyl, imidazolyl, wherein each group be unsubstituted or by 1,2,3,4 or 5 independently for C
1-C
4Alkyl, C
1-C
4Alkoxyl group, OH, hydroxyl C
1-C
6Alkyl, halogen, halogen C
1-C
6Alkyl, halogen C
1-C
6Alkoxyl group ,-O-(C
1-C
6Alkyl)-phenyl ,-CO
2-(C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-(C
5-C
6Cycloalkyl) or (CH
2)
0-4The group of CN replaces;
R
42Be H, the optional C that is replaced by OH
1-C
6Alkyl; Benzyl;-NHC (O)-(C
1-C
6Alkyl);-NHC (O)-phenyl, wherein phenyl is optional is replaced by 1 or 2 alkyl.
R
48Be-C (O) R
49,
R wherein
49Be phenyl or C
1-C
8Alkyl, wherein each is optional by halogen, C
1-C
4Alkoxyl group, C
1-C
4Alkyl or R
33Replace.
54. compound that chemical formula is following:
Or it can be used for the salt of pharmacy, wherein
R
35Be phenyl, C
3-C
8Cycloalkyl ,-S-phenyl, benzo dioxole, thienyl, C
1-C
6Alkyl, furyl, imidazolyl, wherein each group be unsubstituted or by 1,2,3,4 or 5 independently for C
1-C
4Alkyl, C
1-C
4Alkoxyl group, OH, hydroxyl C
1-C
6Alkyl, halogen, halogen C
1-C
6Alkyl, halogen C
1-C
6Alkoxyl group ,-O-(C
1-C
6Alkyl)-phenyl ,-CO
2-(C
1-C
6Alkyl) ,-(C
1-C
4Alkyl)-(C
5-C
6Cycloalkyl) or (CH
2)
0-4The group of-CN replaces.
R
42Be H, the optional C that is replaced by OH
1-C
6Alkyl; Benzyl;-NHC (O)-(C
1-C
6Alkyl);-NHC (O)-phenyl, wherein phenyl is optional is replaced by 1 or 2 alkyl; And
R
48Be-C (O) R
49,
R wherein
49Be phenyl or C
1-C
8Alkyl, wherein each is optional by halogen, C
1-C
4Alkoxyl group, C
1-C
4Alkyl or R
33Replace;
R
52Be H, phenyl ,-NHC (O)-(C
1-C
6Alkyl)-(C
1-C
6Thio alkoxy) ,-N (C
1-C
6Alkyl) C (O)-(C
1-C
6Alkyl)-(C
1-C
6Thio alkoxy), OH, C
1-C
6Alkyl, list or two (C
1-C
6Alkyl) amino, wherein alkyl optional by phenyl replace-NHC (O)-(C
1-C
6Alkyl), wherein each alkyl optional by phenyl-N (C
1-C
6Alkyl) C (O)-(C
1-C
6Alkyl) ,-(CH
2)
0-4-SO
2-(C
1-C
10Alkyl) ,-NHCO
2-benzyl or NH
2, and
R
60Be-L-V-R
65, C
1-C
8Alkyl or hydroxyl C
1-C
8Alkyl, wherein alkyl or hydroxyalkyl are optional by 1 or 2 L-V-R
65Group replaces, wherein
L can not exist or-C (O)-,-CO
2-,-C (O) NH-,-C (O) N (C
1-C
6Alkyl)-,-NHC (O)-,-N (C
1-C
6Alkyl)-C (O)-,-(CH
2)
0-4-SO
2-(CH
2)
0-4-,-(CH
2)
0-4-O-(CH
2)
0-4-,-(CH
2)
0-4-S-(CH
2)
0-4-,-NHC (O) NH-,-N (C
1-C
6Alkyl) C (O) NH-,-N (C
1-C
6Alkyl) C (O) N (C
1-C
6Alkyl) ,-NHC (O) N (C
1-C
6Alkyl)-,-NH-,-N (benzyl)-,-N (phenyl)-,-(CH
2)
0-4-NHSO
2-(CH
2)
0-4-,-N (C
1-C
6Alkyl) SO
2-,-SO
2NH-,-SO
2N (C
1-C
6Alkyl)-, or
V can not exist or-(CH
2)
0-4-C (O) NH-,-(CH
2)
0-4-C (O) N (C
1-C
6Alkyl)-, optional by 1 or 2 C
1-C
4The cyclopropyl of alkyl ,=NH ,=NOH ,=N-alkoxyl group, optional by the C of 1 or 2 OH replacement
1-C
8Alkyl or-CH (phenyl)-, wherein phenyl is optional be the group replacement of halogen or OH by 1,2,3,4 or 5;
R
65It is cyclohexyl; Cyclopentyl; Phenyl;-(C
1-C
6Alkyl)-phenyl; NH
2List or two (C
1-C
10Alkyl) amino, wherein alkyl is optional is the group replacement of cyclopropyl, phenyl or OH by 1 or 2 independently; The oxadiazole base; Triazolopyrimidinyl; Triazolyl; Thiadiazolyl group; 3H-quinazoline-2-ketone group; Pyrimidyl, pyridyl; Pyridine N-oxides;-(C
1-C
6Alkyl)-pyridyl; Piperazinyl; The 2 base; Tetrahydrochysene-thiophene 1, the 1-dioxide; Tetrazyl; C
3-C
6Cycloalkyl-C
1-C
6Alkyl;-(C
1-C
4Alkyl)-SO
2-(C
1-C
4Alkyl);-SO
2-(C
1-C
6Alkyl); Benzothiazolyl; Six hydrogen-isoindole-1, the 3-diketo; Benzimidazolyl-; Benzoxazolyl; [1,2,4] triazole [1,5-a] pyrimidyl; [1,2,4] triazole [4,3-a] pyrimidyl; Thiazolyl; Thiadiazolyl group; Imidazo [1,2-a] pyridine; C
1-C
6Alkyl; 3-aza-bicyclo [3.2.2] nonane; Pyrrolidone-base; The tall and erect yl of di nitrogen; Benzo [1,2,5] thiadiazolyl group;-NHSO
2-(4-tolyl); [1,2,4] triazolo [4,3-b] pyridazinyl; Benzopyrrole alkane ketone group; Morpholinyl; Thio-morpholinyl; Thio-morpholinyl S-oxide compound; Thio-morpholinyl S, the S-oxide compound; 2,3-dihydro-benzo [b] thiophene 1,1-dioxide; Pyrrolidyl; [1,2,4] oxadiazoles; C
1-C
10Alkyl; Isoxazolyl; 2,3-dihydro-1H-indyl; The quinazoline ketone group; Quinazolyl; Piperidyl, wherein above-mentioned each optional replaced by 1,2,3,4 or 5 following groups, described group is C independently
1-C
6Alkyl, CF
3, halogen, phenyl ,-(C
1-C
4Alkyl)-phenyl ,-C (O) phenyl, pyrrolidine-2,4-diketo, C
1-C
6Alkoxyl group ,-C (O)-furans ,-C (O)-NH
2,-C (O) NH (C
1-C
6Alkyl) ,-C (O) N (C
1-C
6Alkyl) (C
1-C
6Alkyl), cyclopropyl ,-(CH
2)
0-4-cyclopentyl, benzoxazolyl, pyridine ,-NHC (O)-(C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl) C (O)-(C
1-C
6Alkyl) ,-C (O) C
1-C
6Alkyl ,-CO
2H ,-NHSO
2-(C
1-C
8Alkyl) ,-N (C
1-C
6Alkyl) SO
2-(C
1-C
8Alkyl).
55. compound that chemical formula is following
Or it can be used for the salt of pharmacy, wherein
N, p and q are O, 1 or 2 independently;
Dotted line is represented a singly-bound or two key;
R
1, R
2, R
3And R
4Be independently selected from
Hydrogen, halogen, C
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl group, halogen (C
1-C
6) alkyl, hydroxyl (C
1-C
6) alkyl, halogen (C
1-C
6) alkoxyl group, sulfenyl (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group (C
1-C
6) alkyl, amino (C
1-C
6) alkyl, list (C
1-C
6) alkylamino (C
1-C
6) alkyl, two (C
1-C
6) alkylamino (C
1-C
6) alkyl,
-(CH
2)
0-4-aryl or-(CH
2)
0-4-heteroaryl,
C
2-C
6Alkenyl or C
2-C
6Alkynyl, wherein each group optional by one, two or three be independently selected from halogen, hydroxyl ,-SH, cyano group ,-CF
3, C
1-C
3Alkoxyl group, amino, list (C
1-C
6) alkylamino and two (C
1-C
6) substituting group of alkylamino replaces,
-(CH
2)
0-4-C
3-C
7Cycloalkyl, wherein cycloalkyl optional by one, two or three be independently selected from halogen, hydroxyl ,-SH, cyano group ,-CF
3, C
1-C
3Alkoxyl group, amino, list (C
1-C
6) alkylamino and two (C
1-C
6) substituting group of alkylamino replaces;
R
z, R
z', R
z" and R
z_ representative independently
C
1-C
6Alkyl, optional by one, two or three are independently selected from C
1-C
3Alkyl, halogen ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
6Alkoxyl group, amino, list (C
1-C
6) alkylamino and two (C
1-C
6) substituting group of alkylamino replaces,
Hydroxyl, nitro, halogen ,-CO
2H, cyano group,
-(CH
2)
0-4-CO-NR
142R
144, R wherein
142And R
144Represent hydrogen, C independently
1-C
6Alkyl, hydroxyl (C
1-C
6) alkyl, amino (C
1-C
6) alkyl, alkylhalide group, C
3-C
7Cycloalkyl ,-(C
1-C
2Alkyl)-(C
3-C
7Cycloalkyl) ,-(C
1-C
6Alkyl)-O-(C
1-C
3Alkyl), contain one or two pair key-C
2-C
6Alkenyl, contain one or two triple-linked C
2-C
6Alkynyl, contain two keys and a triple-linked-C
1-C
6Alkyl chain ,-R
The 1-aryl, R wherein
The 1-arylDefinition as above; Or R
The 1-heteroaryl, R wherein
The 1-heteroarylDefinition as above,
-(CH
2)
0-4-CO-(C
1-C
12Alkyl) ,-(CH
2)
0-4-CO-(C
2-C
12Alkenyl) ,-(CH
2)
0-4-CO-(C
2-C
12Alkynyl) ,-(CH
2)
0-4-CO-(C
3-C
7Cycloalkyl) ,-(CH
2)
0-4-CO-R
The 1-aryl, R wherein
1 arylDefinition as above;-(CH
2)
0-4-CO-R
The 1-heteroaryl, R wherein
The 1-heteroarylDefinition as above;-(CH
2)
0-4-CO-R
The 1-heterocycle-(CH
2)
0-4-CO-R
146, R wherein
146Be Heterocyclylalkyl, wherein Heterocyclylalkyl is optional by 1-4 C
1-C
6Alkyl replaces;
-(CH
2)
0-4-CO-O-R
148, R wherein
148Be selected from: C
1-C
6Alkyl ,-(CH
2)
0-2-(R
The 1-aryl), C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
3-C
7Cycloalkyl and-(CH
2)
0-2-(R
The 1-heteroaryl);
-(CH
2)
0-4-SO
2-NR
142R
144,-(CH
2)
0-4-SO-(C
1-C
8Alkyl) ,-(CH
2)
0-4-SO
2-(C
1-C
12Alkyl) ,-(CH
2)
0-4-SO
2-(C
3-C
7Cycloalkyl) ,-(CH
2)
0-4-N (H or R
148)-CO-O-R
148,-(CH
2)
0-4-N (H or R
148)-CO-N (R
148)
2,-(CH
2)
0-4-N-CS-N (R
148)
2,-(CH
2)
0-4-N (H or R
148)-CO-R
142,-(CH
2)
0-4-NR
142R
144,-(CH
2)
0-4-R
146, R wherein
N-4Definition as above;
-(CH
2)
0-4-O-CO-(C
1-C
6Alkyl) ,-(CH
2)
0-4-O-P (O)-(OR
150)
2, each R wherein
150Be hydrogen or C independently
1-C
4Alkyl ,-(CH
2)
0-4-O-CO-N (R
148)
2,-(CH
2)
0-4-O-CS-N (R
148)
2,-(CH
2)
0-4-O-(R
148)
2,-(CH
2)
0-4-O-(R
148)
2-CO
2H ,-(CH
2)
0-4-S-(R
148)
2,-(CH
2)
0-4-O-halogen (C
1-C
6) alkyl ,-(CH
2)
0-4-O-(C
1-C
6) alkyl, C
3-C
7Cycloalkyl,
C
2-C
6Alkenyl or C
2-C
6Alkynyl, each is optional by C
1-C
3Alkyl, halogen, hydroxyl ,-SH, cyano group ,-CF
3, C
1-C
3Alkoxyl group, amino, list (C
1-C
6) alkylamino and two (C
1-C
6) the alkylamino replacement;
-(CH
2)
0-4-N (H or R
148)-SO
2-R
142, or-(CH
2)
0-4-C
3-C
7Cycloalkyl;
R
35Be phenyl, cyclohexyl ,-S-phenyl, benzo dioxole, thienyl, C
3-C
6Alkyl, furyl, wherein each group be unsubstituted or by 1,2,3,4 or 5 independently for C
1-C
4Alkyl, C
1-C
4Alkoxyl group, OH, hydroxyl C
1-C
6Alkyl, halogen, halogen C
1-C
6Alkyl, halogen C
1-C
6Alkoxyl group ,-O-(C
1-C
6Alkyl)-phenyl ,-CO
2-(C
1-C
6Alkyl) or-(C
1-C
4Alkyl)-(C
5-C
6Cycloalkyl) group replaces;
X and Y are independently selected from O, NR
5, C (O), CR
1R
2, SO
2And S,
R wherein
5Be hydrogen, C
1-C
6Alkyl, SO
2R
5'; C (O) R
5', R wherein
5' be hydrogen, halogen, C
1-C
6Alkyl, hydroxyl C
1-C
6Alkoxyl group, halogen (C
1-C
6) alkyl, halogen (C
1-C
6) alkoxyl group, sulfo-(C
1-C
6) alkyl, (C
1-C
6) alkoxyl group (C
1-C
6) alkyl, amino (C
1-C
6) alkyl, list (C
1-C
6) alkylamino (C
1-C
6) alkyl, two (C
1-C
6) alkylamino (C
1-C
6) alkyl;
-(CH
2)
0-4-aryl or-(CH
2)
0-4-heteroaryl,
C
2-C
6Alkenyl or C
2-C
6Alkynyl, each optional by one, two or three be independently selected from halogen, hydroxyl ,-SH, cyano group ,-CF
3, C
1-C
3Alkoxyl group, amino, list (C
1-C
6) alkylamino and two (C
1-C
6) substituting group of alkylamino replaces,
-(CH
2)
0-4-C
3-C
7Cycloalkyl, wherein cycloalkyl optional by one, two or three be independently selected from halogen, hydroxyl ,-SH, cyano group ,-CF
3, C
1-C
3Alkoxyl group, amino, list (C
1-C
6) alkylamino and two (C
1-C
6) substituting group of alkylamino replaces;
R
140Represent phenyl or naphthyl, wherein each is optional by 1-5 substituting group replacement that is independently selected from following groups:
C
1-C
6Alkyl, optional by one, two or three are selected from C
1-C
3Alkyl ,-halogen, hydroxyl ,-SH, cyano group ,-CF
3, C
1-C
3Alkoxyl group, amino, list (C
1-C
6) alkylamino and two (C
1-C
6) substituting group of alkylamino replaces,
Hydroxyl, nitro, halogen ,-CO
2H, cyano group,
-(CH
2)
0-4-CO-NR
142R
144, R wherein
142And R
144Represent hydrogen, C independently
1-C
6Alkyl, hydroxyl (C
1-C
6) alkyl, amino (C
1-C
6) alkyl, alkylhalide group, C
3-C
7Cycloalkyl ,-(C
1-C
2Alkyl)-(C
3-C
7Cycloalkyl) ,-(C
1-C
6Alkyl)-O-(C
1-C
3Alkyl), contain one or two pair key-C
2-C
6Alkenyl, contain one or two triple-linked C
2-C
6Alkynyl, contain two keys and a triple-linked-C
1-C
6Alkyl chain ,-R
The 1-arylOr R
The 1-heteroaryl,
-(CH
2)
0-4-CO-(C
1-C
12Alkyl) ,-(CH
2)
0-4-CO-(C
2-C
12Alkenyl) ,-(CH
2)
0-4-CO-(C
2-C
12Alkynyl) ,-(CH
2)
0-4-CO-(C
3-C
7Cycloalkyl) ,-(CH
2)
0-4-CO-R
The 1-aryl, R wherein
The 1-arylDefinition as above;-(CH
2)
0-4-CO-R
The 1-heteroaryl, R wherein
The 1-heteroarylDefinition as above;-(CH
2)
0-4-CO-R
The 1-heterocycle-(CH
2)
0-4-CO-R
146, R wherein
146Be Heterocyclylalkyl, wherein Heterocyclylalkyl is optional by 1-4 C
1-C
6Alkyl replaces;
-(CH
2)
0-4-CO-O-R
148, R wherein
148Be selected from: C
1-C
6Alkyl ,-(CH
2)
0-2-(R
The 1-aryl), C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
3-C
7Cycloalkyl and-(CH
2)
0-2-(R
The 1-heteroaryl);
-(CH
2)
0-4-SO
2-NR
142R
144,-(CH
2)
0-4-SO-(C
1-C
8Alkyl) ,-(CH
2)
0-4-SO
2-(C
1-C
12Alkyl) ,-(CH
2)
0-4-SO
2-(C
3-C
7Cycloalkyl) ,-(CH
2)
0-4-N (H or R
148)-CO-O-R
148,-(CH
2)
0-4-N (H or R
148)-CO-N (R
148)
2,-(CH
2)
0-4-N-CS-N (R
148)
2,-(CH
2)
0-4-N (H or R
148)-CO-R
142,-(CH
2)
0-4-NR
142R
144-(CH
2)
0-4-R
146, R wherein
N-4Definition as above;
-(CH
2)
0-4-O-CO-(C
1-C
6Alkyl);-(CH
2)
0-4-O-P (O)-(OR
150)
2, each R wherein
150Be hydrogen or C independently
1-C
4Alkyl;-(CH
2)
0-4-O-CO-N (R
148)
2,-(CH
2)
0-4-O-CS-N (R
148)
2,-(CH
2)
0-4-O-(R
148)
2,-(CH
2)
0-4-O-(R
148)
2-CO
2H ,-(CH
2)
0-4-S-(R
148)
2,-(CH
2)
0-4-O-halogen (C
1-C
6) alkyl ,-(CH
2)
0-4-O-(C
1-C
6) alkyl, C
3-C
7Cycloalkyl,
C
2-C
6Alkenyl or C
2-C
6Alkynyl, each is optional by C
1-C
3Alkyl, halogen, hydroxyl ,-SH, cyano group ,-CF
3, C
1-C
3Alkoxyl group, amino, list (C
1-C
6) alkylamino and two (C
1-C
6) the alkylamino replacement;
-(CH
2)
0-4-N (H or R
148)-SO
2-R
142, or-(CH
2)
0-4-C
3-C
7Cycloalkyl.
56. compound as claimed in claim 55, wherein q is 1.
57. compound as claimed in claim 56, wherein R
z, R
z', R
z" and R
z_ in two or three be hydrogen, and
R
z, R
z', R
z" and R
z_ middle another one or two be hydroxyl, nitro, halogen ,-CO
2H, cyano group or C
1-C
6Alkyl, wherein alkyl optional by one, two or three are independently selected from C
1-C
3Alkyl, halogen ,-OH ,-SH ,-C ≡ N ,-CF
3, C
1-C
6Alkoxyl group, amino, list (C
1-C
6) alkylamino and two (C
1-C
6) substituting group of alkylamino replaces.
58. compound as claimed in claim 57, wherein R
z, R
z', R
z" and R
z_ in three be that hydrogen and another are (C
1-C
6) alkyl, halogen or (C
1-C
6) alkoxyl group.
59. compound as claimed in claim 58, wherein R
140The phenyl that is replaced by 1,2 or 3 substituting group that is independently selected from following groups:
Optional by one, two or three are independently selected from C
1-C
3Alkyl ,-halogen, hydroxyl ,-SH, cyano group ,-CF
3, C
1-C
3Alkoxyl group, amino, list (C
1-C
6) alkylamino and two (C
1-C
6) C that replaces of the group of alkylamino
1-C
6Alkyl,
Hydroxyl, nitro, halogen ,-CO
2H, cyano group,
-(CH
2)
0-4-CO-NR
142R
144, R wherein
142And R
144Represent hydrogen, C independently
1-C
6Alkyl, hydroxyl (C
1-C
6) alkyl, amino (C
1-C
6) alkyl and C
3-C
7Cycloalkyl.
60. compound as claimed in claim 59, wherein R
140By hydroxyl, nitro, halogen ,-CO
2H, cyano group or C
1-C
6In the alkyl one; With-(CH
2)
0-4-CO-NR
142R
144In the phenyl of a replacement, wherein alkyl optional by one, two or three are independently selected from C
1-C
3Alkyl ,-halogen, hydroxyl ,-SH, cyano group ,-CF
3, C
1-C
3Alkoxyl group, amino, list (C
1-C
6) alkylamino and two (C
1-C
6) group of alkylamino replaces.
61. compound as claimed in claim 60, wherein R
140By-CONR
142R
144Monobasic phenyl, and R
142And R
144Be hydrogen or C independently
1-C
6Alkyl.
62. compound as claimed in claim 61, wherein R
142And R
144Identical and be propyl group.
63. compound as claimed in claim 60, wherein R
140By (a C
1-C
6) alkyl and one-CONR
142R
144The phenyl that replaces, and R
142And R
144Be hydrogen or C independently
1-C
6Alkyl.
64. compound as claimed in claim 61, wherein R
142And R
144Identical and be propyl group.
65. compound as claimed in claim 57, wherein R
35Be independently selected from (C by the phenyl of 1-5 halogen replacement or by 1,2 or 3
1-C
6) alkyl, hydroxyl, halogen, (C
1-C
6) alkoxyl group, amino, list (C
1-C
6) alkylamino and two (C
1-C
6) phenyl that replaces of the group of alkylamino.
66. as the described compound of claim 65, wherein R
35By the phenyl of 2 halogens replacements.
67. as the described compound of claim 66, wherein R
35Be 3, the 5-difluorophenyl.
68. as the described compound of claim 65, wherein R
140By hydroxyl, nitro, halogen ,-CO
2H, cyano group or C
1-C
6In the alkyl one and-(CH
2)
0-4-CO-NR
142R
144In the phenyl of a replacement, alkyl optional by one, two or three are independently selected from C
1-C
3Alkyl ,-halogen, hydroxyl ,-SH, cyano group ,-CF
3, C
1-C
3Alkoxyl group, amino, list (C
1-C
6) alkylamino and two (C
1-C
6) group of alkylamino replaces.
69. as the described compound of claim 68, wherein R
140By-CONR
142R
144Monobasic phenyl, and R
142And R
144Be hydrogen or C independently
1-C
6Alkyl.
70. as the described compound of claim 69, wherein R
142And R
144Identical and be propyl group.
71. as any one described compound among the claim 55-70, wherein n be 1 and p be 0.
72. as the described compound of claim 71, wherein dotted line is represented singly-bound.
73. as the described compound of claim 72, wherein R
1Be that hydrogen and X are SO
2
74. as the described compound of claim 73, wherein Y is a methylene radical.
75. as the described compound of claim 74, wherein Z ' is the 2-propyl group.
76. as the described compound of claim 74, wherein R
2Be hydrogen, hydroxyl (C
1-C
3) alkyl or (C
1-C
3) alkyl.
77. as the described compound of claim 75, wherein R
2It is methyl.
78. as the described compound of claim 72, wherein R
1Be hydrogen;
X is SO
2And Y is NR
5, or X is NR
5And Y is SO
2, each R wherein
5Be hydrogen, (C
1-C
6) alkyl or hydroxyl (C
1-C
6) alkyl.
79. as the described compound of claim 72, wherein
R
1Be hydrogen;
X is that C (O) and Y are NR
5, or X is NR
5And Y is C (O), wherein each R
5Be hydrogen, (C
1-C
6) alkyl or hydroxyl (C
1-C
6) alkyl.
80. compound as claimed in claim 55, its chemical formula is as follows
81. compound as claimed in claim 55, its chemical formula is as follows
82. as the described compound of claim 69, its chemical formula is as follows
83. as the described compound of claim 69, its chemical formula is as follows
84. as the described compound of claim 82, wherein R
2Be (C
1-C
3) alkyl.
85. as the described compound of claim 82, wherein R
2It is methyl.
86. as the described compound of claim 82, wherein R
2Be hydroxyl (C
1-C
3) alkyl.
87. as the described compound of claim 83, wherein R
2Be (C
1-C
3) alkyl.
88. as the described compound of claim 83, wherein R
2It is methyl.
89. as the described compound of claim 83, wherein R
2Be hydroxyl (C
1-C
3) alkyl.
90. compound as claimed in claim 53, it is
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(4S)-6-sec.-propyl-2,2-titanium dioxide-3, the different benzothiopyran of 4-dihydro-1H--4-yl] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine;
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(3R, 4S)-3-(methylol)-6-sec.-propyl-2,2-titanium dioxide-3, the different benzothiopyran of 4-dihydro-1H--4-yl] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine;
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(3R, 4S)-6-sec.-propyl-3-methyl-2,2-titanium dioxide-3, the different benzothiopyran of 4-dihydro-1H--4-yl] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine;
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(3R, 4S)-6-sec.-propyl-2,2-titanium dioxide-3-propyl group-3, the different benzothiopyran of 4-dihydro-1H--4-yl] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine;
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(3S, 4R)-3-(methylol)-6-sec.-propyl-2,2-titanium dioxide-3, the different benzothiopyran of 4-dihydro-1H--4-yl] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine;
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(3R, 4S)-3-(2-hydroxyethyl)-6-sec.-propyl-2,2-titanium dioxide-3, the different benzothiopyran of 4-dihydro-1H--4-yl] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine;
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(3S, 4S)-3-(2-hydroxyethyl)-6-sec.-propyl-2,2-titanium dioxide-3, the different benzothiopyran of 4-dihydro-1H--4-yl] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine;
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(3S, 4S)-6-sec.-propyl-2,2-titanium dioxide-3-propyl group-3, the different benzothiopyran of 4-dihydro-1H--4-yl] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine;
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(3S, 4S)-6-sec.-propyl-3-methyl-2,2-titanium dioxide-3, the different benzothiopyran of 4-dihydro-1H--4-yl] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine;
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(4R)-6-sec.-propyl-2,2-titanium dioxide-3, the different benzothiopyran of 4-dihydro-1H--4-yl] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine; Or they can be used for the salt of pharmacy.
91. compound that chemical formula is following:
Wherein
R
100Be H, C
1-C
8Alkoxy carbonyl, phenyl C
1-C
6Alkyl or phenyl C
1-C
6Alkoxy carbonyl;
R
110Be phenyl C
1-C
6Alkyl, thienyl ,-S-phenyl, furyl or benzo dioxolyl, wherein each optional be halogen, C independently by 1,2,3,4 or 5
1-C
4Alkyl, C
1-C
4Alkoxyl group or phenyl C
1-C
6The group of alkoxyl group replaces; And
R
120Be H, phenyl C
1-C
6Alkyl, optional by C
1-C
6The C that alkyl or phenyl replaces
3-C
8Cycloalkyl, C
3-C
8Cycloalkyl C
1-C
4Alkyl or optional quilt-C (O) NR
121R
122The C that replaces
1-C
6Alkyl, wherein above-mentioned each optional be C independently by 1,2 or 3
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, halogen or C
1-C
6The group of alkoxyl group replaces; Wherein
R
121And R
122Be H or C independently
1-C
6Alkyl.
92. as the described compound of claim 91, wherein R
100It is tert-butoxycarbonyl.
93. as the described compound of claim 91, wherein
R
110Be to choose wantonly by 1,2,3,4 or 5 to be halogen, C independently
1-C
4Alkyl, C
1-C
4Alkoxyl group or phenyl C
1-C
6The phenyl C that the group of alkoxyl group replaces
1-C
6Alkyl.
94. as the described compound of claim 91, wherein
R
110Be phenyl-monohalide base, dihalogenated phenyl or trihalogenated benzene base.
95. as the described compound of claim 91, wherein
R
110Be to choose wantonly by 1,2,3,4 or 5 to be halogen, C independently
1-C
4Alkyl, C
1-C
4The thienyl that the group of alkoxyl group, benzyloxy replaces or-the S-phenyl.
96. as the described compound of claim 91, wherein
R
110Be that each optional is halogen, C independently by 1,2,3,4 or 5
1-C
4Alkyl, C
1-C
4Furyl or benzo dioxolyl that the group of alkoxyl group, benzyloxy replaces.
97. as the described compound of claim 91, wherein
R
120Be to choose wantonly by 1,2 or 3 to be C independently
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, halogen or C
1-C
6The benzyl that the group of alkoxyl group replaces.
98. as the described compound of claim 91, wherein
R
120Be optional by C
1-C
6The cyclopropyl that alkyl or phenyl replaces; Or cyclopropyl C
1-C
4Alkyl, wherein above-mentioned each optional be C independently by 1,2 or 3
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, halogen or C
1-C
6The group of alkoxyl group replaces.
99. as the described compound of claim 92, wherein
R
110Be to choose wantonly by 1,2,3,4 or 5 to be halogen, C independently
1-C
4Alkyl, C
1-C
4Alkoxyl group or phenyl C
1-C
6The phenyl C that the group of alkoxyl group replaces
1-C
6Alkyl; And
R
120Be H or optional be C independently by 1,2 or 3
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, halogen or C
1-C
6The benzyl that the group of alkoxyl group replaces.
100. as the described compound of claim 92, wherein
R
110Be to choose wantonly by 1,2,3,4 or 5 to be halogen, C independently
1-C
4Alkyl, C
1-C
4Alkoxyl group or phenyl C
1-C
6The phenyl C that the group of alkoxyl group replaces
1-C
6Alkyl; And
R
120Be optional by C
1-C
6The cyclopropyl that alkyl or phenyl replaces; Or cyclopropyl C
1-C
4Alkyl, wherein above-mentioned each optional be C independently by 1,2 or 3
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, halogen or C
1-C
6The group of alkoxyl group replaces.
101. as the described compound of claim 92, wherein
R
110Be to choose wantonly by 1,2,3,4 or 5 to be halogen, C independently
1-C
4Alkyl, C
1-C
4The thienyl that the group of alkoxyl group, benzyloxy replaces or-the S-phenyl; And
R
120Be H or optional be C independently by 1,2 or 3
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, halogen or C
1-C
6The benzyl that the group of alkoxyl group replaces.
102. as the described compound of claim 92, wherein
R
110Be to choose wantonly by 1,2,3,4 or 5 to be halogen, C independently
1-C
4Alkyl, C
1-C
4The thienyl that the group of alkoxyl group, benzyloxy replaces or-the S-phenyl; And
R
120Be optional by C
1-C
6The cyclopropyl that alkyl or phenyl replaces; Or cyclopropyl C
1-C
4Alkyl, wherein above-mentioned each optional be C independently by 1,2 or 3
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, halogen or C
1-C
6The group of alkoxyl group replaces.
103. as the described compound of claim 92, wherein
R
110Be to choose wantonly by 1,2,3,4 or 5 to be halogen, C independently
1-C
4Alkyl, C
1-C
4Furyl or benzo dioxolyl that the group of alkoxyl group, benzyloxy replaces.
R
120Be H or optional be C independently by 1,2 or 3
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, halogen or C
1-C
6The benzyl that the group of alkoxyl group replaces.
104. as the described compound of claim 92, wherein
R
110Be to choose wantonly by 1,2,3,4 or 5 to be halogen, C independently
1-C
4Alkyl, C
1-C
4Furyl or benzo dioxolyl that the group of alkoxyl group, benzyloxy replaces;
R
120Be optional by C
1-C
6The cyclopropyl that alkyl or phenyl replaces; Or cyclopropyl C
1-C
4Alkyl, wherein above-mentioned each optional be C independently by 1,2 or 3
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, halogen or C
1-C
6The group of alkoxyl group replaces.
105. compound that chemical formula is following
Or it can be used for the salt of pharmacy, wherein
R
1Be C
1-C
4Alkyl, C
2-C
4Alkynyl or CF
3
R
2And R
3All be hydrogen; Or
R
2And R
3Form a cyclopropyl rings with the carbon that links to each other with them;
R
4Be optional by methyl, thiazolyl, C
2-C
4Alkynyl or C
1-C
4Alkyl replaces the De oxazolyl;
R
5Be C
1-C
4Alkyl;
R
6Be C
1-C
4Alkyl;
X and Y are halogen independently;
Z is CH or N.
106. as the described compound of claim 105, wherein Z is CH.
107. as the described compound of claim 106, wherein R
2And R
3Be H.
108. one kind as the described compound of claim 107, its chemical formula is:
109. as the described compound of claim 108, wherein
R
1Be ethyl, ethynyl or CF
3And
R
4Be optional by methyl, 2-thiazolyl, ethynyl or methyl substituted 2-oxazolyl.
110. as the described compound of claim 109, wherein R
5It is propyl group; And R
6It is propyl group.
111. as the compound of claim 110, wherein
R
1It is ethyl;
R
4Be optional by methyl substituted 2-oxazolyl; And
X and Y are F.
112. as the described compound of claim 109, wherein
R
1Be ethyl or CF
3And R
4It is the 2-thiazolyl.
113. as the described compound of claim 112, wherein
R
5It is propyl group; And R
6It is propyl group;
Or R
5It is methyl; And R
6Be propyl group or butyl; And
X and Y are F.
114. as the described compound of claim 113, wherein R
1It is ethyl.
115. as the described compound of claim 112, wherein R
1Be CF
3R
5It is propyl group; And R
6It is propyl group.
116. as the described compound of claim 109, wherein R
1Be ethynyl and R
4Be ethynyl, methyl and 2-oxazolyl.
117. as the described compound of claim 116, wherein R
5It is propyl group; And R
6It is propyl group; And X and Y are F.
118. as the described compound of claim 117, wherein R
4Be ethynyl or methyl.
119. one kind as the described compound of claim 106, its chemical formula is as follows:
120. as the described compound of claim 119, wherein R
1Be ethyl or ethynyl; R
4Be methyl or 2-oxazolyl.
121. as the described compound of claim 120, wherein R
5And R
6It is propyl group; And X and Y are F.
122. as the described compound of claim 121, wherein Z is N; And R
4It is methyl.
123. as the described compound of claim 121, wherein Z is CH; And R
4Be methyl or 2-oxazolyl.
124. as the described compound of claim 105, wherein R
4It is the 2-oxazolyl.
125. compound that chemical formula is following
Or it can be used for the salt of pharmacy, wherein
R
1Be C
2-C
3Alkyl;
R
2And R
3Be hydrogen; Or
R
fAnd R
gBe halogen independently;
R
5Be C
1-C
2Alkyl sulphonyl;
R
6Be hydroxyethyl or methylol.
126. compound that chemical formula is following
Or it can be used for the salt of pharmacy, wherein
R
1Be C
2-C
3Alkyl;
R
2And R
3Be hydrogen; Or
R
fAnd R
gBe halogen independently;
R
5And R
6Be C independently
3-C
4Alkyl; Or
R
5Be H and R
6Be C
3Alkyl; Or
R
5, R
6Form an optional pyrrolidine ring that is replaced by methoxymethyl with the nitrogen that links to each other with them; And R
sBe C
1-C
2Alkyl, hydroxyl (C
2-C
4Alkyl), N-[hydroxyl (C
2-C
4Alkyl)]-N-(C
1-C
2) alkylamino, N-methyl-N-(C
4(tertiary butyl) alkyl) amino ,-NH (C
1-C
4Hydroxyalkyl) ,-N (C
1-C
3Hydroxyalkyl) (C
1-C
3Hydroxyalkyl) ,-N (C
1-C
2Alkyl) (C
1-C
2Alkyl), optional by tetramethyleneimine-1-base, the C of methylol or methoxymethyl replacement
1-C
2Alkoxy C
2-C
3Alkyl, 1-piperazinyl ,-NH
2,-NH (C
2-C
3Alkyl-NH (C
1-C
2Or C alkyl))
1-C
4(C
2) alkylamino.
127. as the described compound of claim 126, wherein R
sBe N-[hydroxyl (C
4-alkyl)]-the N-methylamino-,-N (C
1-C
3Hydroxyalkyl) (C
1-C
3Hydroxyalkyl) or-NH (C
1-C
4Hydroxyalkyl).
128. as the described compound of claim 127, wherein hydroxyalkyl is a 2-hydroxyl-1, the 1-dimethyl ethyl; The 2-hydroxyethyl; The 3-hydroxypropyl; 1 (R)-2-hydroxyl-1-methylethyl; 1 (S)-2-hydroxyl-1-methylethyl; 1 (S)-2-hydroxyl-1-methylethyl; 2 (R)-2-hydroxypropyls; Or 2 (S)-2-hydroxypropyl.
129. as the described compound of claim 126, wherein R
sBe 3-hydroxypropyl or 4-hydroxyl butyl.
130. as the described compound of claim 126, wherein R
sBe 2 (R)-2-methoxymethyl tetramethyleneimine-1-base, 2 (R)-2-hydroxymethyl pyrrolidine-1-base, 2 (S)-2-hydroxymethyl pyrrolidine-1-bases, tetramethyleneimine-1-base or 1-piperazinyl.
131. as the described compound of claim 126, wherein R
5, R
6Form one 2 (S)-2-methoxymethyl tetramethyleneimine-1-base with the nitrogen that links to each other with them.
132. as the described compound of claim 131, wherein R
sBe-NH (tertiary butyl) ,-N (CH
3) (CH
2CH
3) or 2 (S)-2-methoxymethyl tetramethyleneimine-1-bases.
Or it can be used for the salt of pharmacy, wherein
R
1Be C
2-C
3Alkyl;
R
2And R
3All be hydrogen; Or
R
fAnd R
gBe halogen independently;
R
5And R
6Be C independently
1-C
4Alkyl; And
R
dBe C
1-C
2Alkyl, N-hydroxyl (C
2-C
3Alkyl)-N-(C
1-C
2) alkylamino or C
1-C
2Alkylamino.
134. compound that chemical formula is following
Or it can be used for the salt of pharmacy, wherein
X is nitrogen or CH;
R
1Be C
2-C
3Alkyl, amino, list (C
1-C
3) alkylamino, two (C
1-C
3) alkylamino, amino (C
1-C
3) alkyl, list (C
1-C
3) alkylamino (C
1-C
2) alkyl or two (C
1-C
3) alkylamino (C
1-C
2) alkyl;
R
2And R
3All be hydrogen; Or
R
fAnd R
gAll be hydrogen or independently for halogen;
R
5And R
6Be methyl or C independently
2-C
3-C
4Alkyl, wherein R
5And R
6In at least one is not a methyl.
135. as the described compound of claim 134, wherein X is CH.
136. as the described compound of claim 135, wherein R
1Be two (C
1-C
2) alkylamino.
137. as the described compound of claim 136, wherein R
5And R
6In at least one is a propyl group.
138. as the described compound of claim 134, wherein X is a nitrogen.
139., as the described compound of claim 138, wherein R
5And R
6It not methyl.
140. as the described compound of claim 135, wherein R
1Be two (C
1-C
2) alkylamino (C
1-C
2) alkyl.
141. compound that chemical formula is following
Or it can be used for the salt of pharmacy, wherein
R
1Be C
2-C
3Alkyl;
R
2And R
3All be hydrogen; Or
R
fAnd R
gBe halogen independently;
R
5And R
6Be C independently
3-C
4Alkyl; And
R
jBe hydrogen or C
1-C
2Alkoxy methyl.
142. compound that chemical formula is following
Or it can be used for the salt of pharmacy, wherein
R
1Be C
2-C
4Alkynyl, C
2-C
4Alkyl or trifluoromethyl;
R
2And R
3All be hydrogen; Or
R
2, R
3Form a triatomic ring with the carbon atom that links to each other with them;
R
fAnd R
gBe halogen independently;
R
5And R
6Be C independently
3-C
4Alkyl; Or
R
5And R
6In one be methyl or ethyl, and another is C
3-C
4Alkyl.
143. as the described compound of claim 142, wherein R
1Be ethyl, n-propyl, sec.-propyl or trifluoromethyl.
144. as the described compound of claim 143, wherein R
5Be methyl or ethyl and R
6Be C
3-C
4Alkyl
145. as the described compound of claim 142, wherein R
5Be methyl or propyl group.
146. as the described compound of claim 145, wherein R
fAnd R
gIt all is chloro or fluorine-based.
147. as the described compound of claim 146, wherein R
2And R
3All be hydrogen; And R
1Be C
2-C
3Alkynyl.
148. as the described compound of claim 1151, wherein R
5And R
6Be propyl group or butyl independently.
149. as the described compound of claim 1156, wherein R
2And R
3All be hydrogen.
150. as the described compound of claim 1157, wherein R
fAnd R
gIt all is chloro or fluorine-based.
151. as the described compound of claim 1157, wherein
R
2, R
3Form a triatomic ring with the carbon atom that links to each other with them.
152. compound that chemical formula is following
And can be used for the salt of pharmacy, wherein
X or X
1In one be nitrogen or N
+-O
-, and another is CH;
R
1Be C
2-C
4Alkynyl, cyano group or C
1-C
3Alkyl;
R
2And R
3All be hydrogen; Or
R
2, R
3Form a triatomic ring with the carbon atom that links to each other with them;
R
fAnd R
gBe halogen independently;
R
pBe hydrogen, C
1-C
2Wan Ji Huo oxazolyl; And
R
5And R
6Be C independently
3-C
4Alkyl.
153. as the described compound of claim 152, wherein X is a nitrogen; R
1Be C
2-C
3Alkynyl; R
2And R
3Form a triatomic ring with the carbon atom that links to each other with them; And R
pBe C
1-C
2Alkyl.
154. as the described compound of claim 152, wherein X is a nitrogen; And R
1Be C
2Alkynyl.
155. as the described compound of claim 152, wherein X is a nitrogen; R
1Be C
1-C
2Alkyl; R
2And R
3Be hydrogen; And R
pBe hydrogen, C
1-C
2Wan Ji Huo oxazole-2-base.
156. as the described compound of claim 152, wherein X is a nitrogen; R
1Be C
1-C
2Alkyl; R
2And R
3Be hydrogen; And R
pBe cyano group.
157. as the described compound of claim 152, wherein X is a nitrogen; R
1Be C
2-C
3Alkyl; R
2And R
3Form a triatomic ring with the carbon atom that links to each other with them; And R
pBe C
1-C
2Alkyl.
158. as any one described compound, wherein R among the claim 153-157
fAnd R
gIt all is chloro or fluorine-based.
159. as any one described compound, wherein R among the claim 153-157
5And R
6Be propyl group or butyl independently.
160. compound that chemical formula is following
Or it can be used for the salt of pharmacy, wherein
R
cIt is the following group of chemical formula
Wherein among X and the X ' one be nitrogen, and another is CH, and R
1Be C
2-C
4Alkyl or-(C
1-C
2Alkyl)-N (C
1-C
2Alkyl) (C
1-C
2Alkyl);
R
fAnd R
gBe halogen independently;
R
pBe C
1-C
2Alkyl; And
R
5And R
6Be hydrogen or C independently
3-C
4(sec-butyl) alkyl.
161. as the described compound of claim 160, wherein X is a nitrogen; X ' is CH; And R
5And R
6Be propyl group or butyl independently.
162. as the described compound of claim 160, wherein X is CH; X ' is a nitrogen; And R
5And R
6Be propyl group or butyl independently.
163. as the described compound of claim 162, wherein R
1Be-CH
2N (CH
3) CH
3
164. compound that chemical formula is following
Or it can be used for the salt of pharmacy, wherein
R
sBe methylamino-, ethylamino, C
3Alkylamino, two (C
3-alkyl) the amino or following group of chemical formula
R wherein
qBe C
1-C
2Alkoxyl group (C
1-C
2) alkyl;
R
1Be C
2-C
3Alkyl;
R
2And R
3Be hydrogen; And
R
fAnd R
gBe halogen independently.
165. compound that chemical formula is following
Or it can be used for the salt of pharmacy, wherein
When dotted line was represented a singly-bound, Z was CH, or when dotted line was represented one pair of key, Z was a carbon atom or a nitrogen-atoms;
R
1Be C
2-C
3Alkyl;
R
2And R
3All be hydrogen;
R
fAnd R
gBe halogen independently;
R
pBe hydrogen, cyano group, C
1-C
3Alkyl, amino, N-(C
1-C
3Alkyl sulphonyl)-N-((C
1-C
3) alkyl) amino, 2-oxazolyl or choose wantonly on 2 and 5 by C
1-C
2The 1-pyrryl that alkyl replaces; And
R
iBe C
1-C
5Alkyl.
166. as the described compound of claim 165, wherein R
jBe methyl, and Z
1Be hydrogen.
167. as the described compound of claim 165, wherein Z is CH, and R
pBe N-(C
1-C
2Alkyl sulphonyl)-N-((C
1-C
2) alkyl) amino; And R
jBe C
3-C
4Alkyl.
168. as the described compound of claim 165, wherein R
pBe that 2-oxazolyl and Z are CH.
169. as the described compound of claim 165, wherein R
pBe cyano group; Z is CH; And R
jBe C
1-C
3(butyl) alkyl.
170. as the described compound of claim 167, wherein R
pBe-N-(CH
3) SO
2(C
1-C
2Alkyl); And R
1It is ethyl.
171. compound that chemical formula is following
Or it can be used for the salt of pharmacy, wherein
X and X ' all be among CH or X and the X ' one be nitrogen and another is CH;
R
1Be C
2-C
3Alkynyl, C
1,2-C
3Alkyl, amino, list (C
1-C
3) alkylamino or two (C
1-C
3) alkylamino, aminoalkyl group, list (C
1-C
3) alkylamino (C
1-C
2) alkyl, two (C
1-C
3) alkylamino (C
1-C
2) alkyl, CF
3, C
1-C
2Alkoxyl group, halogen ,-NHSO
2(C
1-C
2Alkyl);
R
2And R
3All be hydrogen; Or
R
2, R
3Form a triatomic ring with the carbon atom that links to each other with them;
R
fAnd R
gBe hydrogen or independently for halogen;
R
5And R
6Be C independently
1-C
4Alkyl; Or
R
5And R
6In one be methyl or ethyl, and another is C
3Or C
4Alkyl.
172. as the described compound of claim 171, wherein R
1Be C
2-C
3Alkyl.
173. as the described compound of claim 171, wherein R
1Be two (C
1-C
3) alkylamino and R
fAnd R
gIt all is chloro or fluorine-based.
174. as the described compound of claim 171, wherein R
1Be two (C
1-C
3) alkylamino (C
1-C
2) alkyl and R
fAnd R
gIt all is chloro or fluorine-based.
175. as the described compound of claim 171, wherein X is a nitrogen; R
fAnd R
gAll be fluorine-based; R
1Be C
1-C
3Alkyl; And R
2, R
3Form a triatomic ring with the carbon atom that links to each other with them.
176. as the described compound of claim 172, wherein X and X ' are CH; And R
fAnd R
gIt all is chloro or fluorine-based.
177. as the described compound of claim 176, wherein R
5And R
6In one be methyl or ethyl, and another is C
3Or C
4Alkyl.
178. as the described compound of claim 176, wherein R
5And R
6Be C independently
2,3-C
4Alkyl.
179. as the described compound of claim 178, wherein R
5Be C
2-C
4Alkyl and R
6Be ethyl.
180. as the described compound of claim 176, wherein R
5And R
6In one be methyl, and another is C
3Or C
4Alkyl
181. as the described compound of claim 176, wherein R
5And R
6Be propyl group or butyl independently.
182. as the described compound of claim 171, wherein R
1Be C
2Alkynyl.
183. as the described compound of claim 82, wherein
X is that nitrogen and X ' are CH; And
R
2, R
3Form a triatomic ring with the carbon atom that links to each other with them.
184. as the described compound of claim 182, wherein X and X ' are CH and R
fAnd R
gIt all is chloro or fluorine-based.
185. as the described compound of claim 176, wherein R
5And R
6Be propyl group or butyl independently.
186. any one described compound, wherein R as claim 176-185
2, R
3Form a triatomic ring with the carbon atom that links to each other with them.
187. as the described compound of claim 171, wherein
R
1Be CF
3Or-NHSO
2CH
3
R
2And R
3All be H;
R
5And R
6Be C independently
3Or C
4Alkyl.
188. as the described compound of claim 172, wherein
X is that CH and X ' are nitrogen.
189. as the described compound of claim 88, wherein R
2, R
3Form a cyclopropyl rings with the carbon atom that links to each other with them.
190. as the described compound of claim 186, wherein R
1Be bromo or chloro.
191. compound that chemical formula is following
Or it can be used for the salt of pharmacy, wherein
R
1Be C
2-C
3Alkyl;
R
2And R
3All be hydrogen;
R
fAnd R
gBe halogen independently;
R
sBe C
3-C
4Alkyl, thiazolinyl or thiazolidyl.
192. as the described compound of claim 191, wherein, R
sBe 2-thiazolidyl or 2-thiazolinyl.
193. compound that chemical formula is following
Or it can be used for the salt of pharmacy, wherein
R
1Be C
2-C
3Alkyl, CF
3, or-NH (C
3-C
6Cycloalkyl);
R
2And R
3All be hydrogen; Or
R
2, R
3Form a triatomic ring with the carbon atom that links to each other with them;
R
pBe pyridyl, piperazinyl, amino, amino (C
1-C
5) alkyl, list (C
1-C
2) alkylamino (C
1-C
5) alkyl, two (C
1-C
2) alkylamino (C
1-C
5) alkyl, list (C
1-C
3) alkylamino, two (C
1-C
3) alkylamino, amino (C
3-C
4) alkynyl, list (C
1-C
2) alkylamino (C
3-C
4) alkynyl, two (C
1-C
2) alkylamino (C
3-C
5) alkynyl ,-N (C
1-C
2Alkyl)-SO
2(C
1-C
2Alkyl) ,-NH-SO
2(C
1-C
2Alkyl) ,-N (C
1-C
2Alkyl)-SO
2-thienyl ,-N (C
1-C
2Alkyl)-SO
2(C
1-C
2Alkylhalide group), two (C
1-C
2) alkylamino (C
3-C
4) alkynyl, pyrimidyl, pyrazolyl, imidazolyl or C
2-C
4Alkynyl;
R
fAnd R
gBe halogen independently;
R
5And R
6Be C independently
3-C
4Alkyl.
194. as the described compound of claim 193, wherein R
pBe 4-pyridyl, 2-pyrimidyl, 4-pyrazolyl or 4-imidazolyl.
195. as the described compound of claim 193, wherein R
pBe diethylin or dimethylamino.
196. as the described compound of claim 193, wherein R
pBe amino or C
1-C
6Alkylamino.
197. as the described compound of claim 193, wherein R
pIt is the 1-piperazinyl.
198. as the described compound of claim 193, wherein R
pBe amino (C
2-C
4) alkyl, wherein amino optional by C
1-C
2The alkyl monosubstitution; Or R
pBe-N (CH
3)-SO
2CH
3,-NH-SO
2CH
3,-N (CH
3)-SO
2-thiophene-2-base or-N (CH
3)-SO
2CF
3
199. as the described compound of claim 193, wherein R
pBe 3-(single (C
1-C
2) alkylamino) propine-1-base, 3-(two (C
1-C
2) alkylamino) propine-1-base or 4-(two (C
1-C
2) alkylamino) propine-1-base.
200. any one described compound, wherein R as claim 194 to 199
5And R
6Be C
3Alkyl.
201. any one described compound, wherein R as claim 194 to 199
2And R
3Be hydrogen.
202. any one described compound, wherein R as claim 194 to 199
2, R
3Form a triatomic ring with the carbon atom that links to each other with them.
203. as the described compound of claim 193, wherein R
pBe two (C
1-C
2) alkylamino (C
3-C
5) alkyl; And R
5And R
6All be C
3Alkyl.
204. as the described compound of claim 193, wherein
R
pBe C
2-C
3Alkynyl, C
1-C
2Alkyl or-NH (cyclopropyl); And R
2And R
3All be H.
205. as the described compound of claim 193, wherein
R
pBe C
2-C
3Alkynyl, C
1-C
2Alkyl or-NH (cyclopropyl); And
R
2, R
3Form a triatomic ring with the carbon atom that links to each other with them.
206. compound that chemical formula is following
Or it can be used for the salt of pharmacy, wherein
R
1Be C
2-C
3Alkynyl;
R
2And R
3All be hydrogen;
R
pBe C
1-C
3Alkyl;
R
fAnd R
gBe halogen independently;
R
5And R
6Be C independently
3-C
4Alkyl; Or
R
5And R
6In one be methyl, and another is C
3Or C
4Alkyl.
207. as the described compound of claim 206, wherein middle R
pIt is methyl.
208. compound that chemical formula is following
Or it can be used for the salt of pharmacy, wherein
R
1Be C
1-C
2Alkyl, C
2-C
4Alkynyl or C
3-C
4Alkyl;
R
2And R
3All be hydrogen; Or
R
2, R
3Form a triatomic ring with the carbon atom that links to each other with them;
R
fAnd R
gBe halogen independently;
R
pBe C
1-C
3Alkyl or chemical formula are R
sSO
2-group, R wherein
sBe R
51R
61N-, and R
51And R
61Represent hydrogen or C independently
1-C
4Alkyl; Or
R
sBe the following group of chemical formula:
R wherein
tBe C
1-C
2Alkoxyl group (C
1-C
2) alkyl; And
R
qBe C
1-C
3Alkoxyl group (C
1-C
2) alkyl, C
1-C
4Alkyl ,-C (O) NH
2, or H.
209. as the described compound of claim 1240, wherein R
1Be C
2Alkynyl; R
2, R
3Form a triatomic ring with the carbon atom that links to each other with them; And R
pBe R
sSO
2-, R wherein
sBe
210. as the described compound of claim 208, wherein R
1Be C
1-C
2Alkyl; R
2And R
3Be hydrogen; And R
pBe R
sSO
2-, R wherein
sBe C
3-C
4Tertiary butyl amino.
211. as the described compound of claim 208, wherein R
1Be C
1-C
2Alkyl; R
2And R
3Be hydrogen; R
pBe C
1-C
2Alkyl; And R
qBe C
2-C
4Alkyl.
212. as the described compound of claim 208, wherein R
1Be C
1-C
2Alkyl; R
2And R
3Be hydrogen; R
pBe C
1-C
2Alkyl; And R
qBe propoxy-(C
1-C
2) alkyl.
213. as the described compound of claim 208, wherein R
1Be C
1-C
2Alkyl; R
2And R
3Be hydrogen; R
pBe C
1-C
2Alkyl; And R
qBe methoxyl group (C
1-C
2) alkyl.
214. as the described compound of claim 208, wherein R
1Be C
1-C
2Alkyl; R
2, R
3Form a triatomic ring with the carbon atom that links to each other with them; R
pBe C
1-C
2Alkyl; And R
qBe C
1-C
2Alkyl.
215. as the described compound of claim 208, wherein R
1Be C
1-C
2Alkyl; R
2And R
3Be hydrogen; R
pBe C
1-C
2Alkyl; And R
qBe C
1-C
2Alkyl.
216. as the described compound of claim 208, wherein R
qIt is (R)-methoxymethyl, methyl, propyl group, (S)-propyl group, (R)-propyl group, butyl, (R)-butyl, (S)-butyl, (R)-2-methoxymethyl or (R)-2-methoxy ethyl.
217. compound that chemical formula is following
Or it can be used for the salt of pharmacy, wherein
Z is oxygen, nitrogen or sulphur;
R
1Be chloro, bromo, hydrogen or C
1-C
2Alkyl;
R
fAnd R
gBe halogen independently; And
R
5And R
6Be C independently
3-C
4Alkyl; Or
R
5And R
6In one be methyl, and another is C
3Or C
4Alkyl.
218. as the described compound of claim 217, wherein R
1Be that bromo and Z are oxygen.
219. as the described compound of claim 217, wherein Z is a nitrogen; And R
1Be C
1-C
3Alkyl.
220. as the described compound of claim 217, wherein Z is a sulphur; And R
1Be C
1-C
3Alkyl.
221. compound that chemical formula is following
Or it can be used for the salt of pharmacy, wherein
R
1Be C
1-C
2-C
3Alkyl;
R
2And R
3All be hydrogen; Or
R
pBe C
1-C
2Alkyl;
R
fAnd R
gAll be hydrogen or independently for halogen; And
R
5And R
6Be C independently
3-C
4Alkyl.
222. as the described compound of claim 221, wherein R
1It is ethyl.
223. compound that chemical formula is following
Or it can be used for the salt of pharmacy, wherein
One is that nitrogen and another are CH or CR among X and the X '
1
R
1Be C
1-C
2-C
3Alkyl;
R
2And R
3Be hydrogen; Or
R
pBe C
1-C
2Alkyl;
R
fAnd R
gBe halogen independently; And
R
5And R
6Be C independently
3-C
4Alkyl.
224. as the described compound of claim 223, wherein X is that CH and X ' are nitrogen.
225. compound that chemical formula is following
Or it can be used for the salt of pharmacy, wherein
R
1Be the following group of chemical formula:
Wherein
R
S11And R '
S11In one be that hydrogen and another are C
1-C
3Acyl group, C
1-C
2Alkyl or CHO; Or
R
S11And R '
S11In one be that methyl and another are CHO or methyl,
Each R
S21Be C
1-C
3Alkoxyl group, halogen, H, C
1-C
2Alkyl or cyano group; Or
R
1Be cyclopentyl, cyclohexyl, oxazolyl, optional by one or two C
1-C
2Alkyl replaces De isoxazolyl, phenyl, optional thiophene-2-base, the unsubstituted thiene-3-yl-that is replaced by CHO;
R
2And R
3All be hydrogen;
R
pBe C
1-C
2Alkyl;
R
fAnd R
gBe halogen independently; And
R
5And R
6Be C independently
3-C
4Alkyl.
226. as the described compound of claim 226, wherein R
1Be 6-(C
1-C
2) alkoxy pyridines-2-base.
227. as the described compound of claim 225, wherein R
1It is 2-formyl thiene-3-yl-.
228. as the described compound of claim 225, wherein R
1It is 5-formyl thiene-3-yl-.
229. as the described compound of claim 225, wherein R
S21Be cyano group.
230. as the described compound of claim 225, wherein R
1It is 5-cyanopyridine-3-base.
231. as the described compound of claim 225, wherein R
1It is 6-haloperidid-3-base.
232. as any one described compound among the claim 226-1285, wherein halogen is fluorine-based or chloro.
233. as the described compound of claim 225, wherein R
1Be to replace or unsubstituted thienyl.
234. compound that chemical formula is following
Or it can be used for the salt of pharmacy, wherein
Z is
Or
R
1Be C
1-C
3Alkyl or halogen;
R
2And R
3Be hydrogen;
R
sBe C
1-C
3Alkyl sulphonyl, C
1-C
3Alkyl sulphonyl (C
1-C
3) alkyl ,-NHSO
2(C
1-C
2Alkyl) or-N (C
1-C
2Alkyl) SO
2(C
1-C
2Alkyl); And
R
fAnd R
gBe halogen independently.
235. as the described compound of claim 234, wherein
R
1It is ethyl; And
Z is
236. compound that chemical formula is following
Or it can be used for the salt of pharmacy, wherein
R
1Be C
2-C
3Alkyl;
R
2And R
3All be hydrogen;
R
5And R
6The C that is replaced by phenyl is chosen in representative (a) wantonly independently
1-C
3Alkyl and (b) the optional phenyl that is replaced by halogen; And
R
fAnd R
gBe halogen independently.
237. as the described compound of claim 236, wherein R
5Be optional methyl and the R that is replaced by phenyl
6Be phenyl.
238. as the described compound of claim 236, wherein R
5Be C
1-C
2Alkyl and R
6Be 4-halobenzene base.
239. compound that chemical formula is following
Or it can be used for the salt of pharmacy, wherein
X is nitrogen or N
+-O
-
R
1Be C
2-C
4Alkynyl or C
1-C
3Alkyl;
R
2And R
3Be hydrogen; Or
R
2, R
3Form a triatomic ring with the carbon atom that links to each other with them;
R
fAnd R
gBe halogen independently;
R
pBe hydrogen or C
1-C
2Alkyl; And
R
5And R
6Be C independently
3-C
4Alkyl.
240. as the described compound of claim 239, wherein X is a nitrogen; R
pBe C
1-C
2Alkyl and R
1It is ethyl.
241. compound that chemical formula is following
Or it can be used for the salt of pharmacy, wherein
R
1Be hydrogen or C
1-C
3Alkyl;
R
2And R
3All be hydrogen;
R
pBe C
1-C
2Alkyl;
R
fAnd R
gBe halogen independently; And
R
5And R
6Be C independently
3-C
4Alkyl.
242. compound that chemical formula is following
Or it can be used for the salt of pharmacy, wherein
R
sBe NR
S31R
S41, wherein
R
S31Be C
1-C
2Alkyl; And
R
S41Be C
1-C
6Alkyl, allyl group, cyano group (C
1-C
3) alkyl, (C
4-C
7) cycloalkyl, pyridine (C
1-C
3) alkyl, phenyl, phenyl (C
1-C
3) alkyl, amino (C
1-C
3) alkyl, list (C
1-C
3) alkylamino (C
1-C
2) alkyl or two (C
1-C
3) alkylamino (C
1-C
2) alkyl; Or
R
sBe CH
3,-N (C
1-C
2Alkyl) phenyl or-N (C
2-C
3Alkyl) (C
3-C
4Alkyl);
R
1Be C
2-C
3Alkyl;
R
2And R
3All be hydrogen; And
R
fAnd R
gBe halogen independently;
243. as the described compound of claim 242, wherein R
sBe (2-cyanoethyl) (methyl) amino.
244. as the described compound of claim 242, wherein R
sBe (cyclohexyl) (methyl) amino.
245. as the described compound of claim 242, wherein R
S41Be C
1-C
6Alkyl, allyl group, cyano group (C
1-C
3) alkyl, (C
4-C
7) cycloalkyl, pyridine (C
1-C
3) alkyl, phenyl or phenyl (C
1-C
3) alkyl.
246. as the described compound of claim 242, wherein R
S41Be phenyl or cyclohexyl.
247. as the described compound of claim 242, wherein R
sBe-N (CH
3) phenyl or-N (ethyl) (C
3-C
4Alkyl).
248. compound that chemical formula is following
Or it can be used for the salt of pharmacy, wherein
R
1Be C
2-C
3Alkynyl or C
1-C
3Alkyl;
R
fAnd R
gBe halogen independently;
R
5And R
6Be C independently
1-C
4Alkyl.
249. as the described compound of claim 248, wherein R
5And R
6Be C
3Alkyl.
250. as the described compound of claim 248, wherein middle R
5Be methyl and R
6Be C
3Alkyl.
251. compound that chemical formula is following
Or it can be used for the salt of pharmacy, wherein
R
sBe C
1-C
4Alkyl;
R
mBe C
1-C
4Alkyl;
R
1Be C
2-C
3Alkyl;
R
2And R
3All be hydrogen; And
R
fAnd R
gBe halogen independently.
252. compound that chemical formula is following
Or it can be used for the salt of pharmacy, wherein
R
mBe C
1-C
4Alkyl;
R
1Be C
2-C
3Alkyl;
R
2And R
3All be hydrogen; And
R
fAnd R
gBe halogen independently;
Z is S, S (O), S (O)
2Or O.
253. as the described compound of claim 252, wherein Z is S or S (O).
254. compound that chemical formula is following
Or it can be used for the salt of pharmacy, wherein
One is that CH and another are N among X and the X ';
R
1Be C
2-C
4Alkynyl; Amino (C
1-C
3) alkyl, list (C
1-C
3) alkylamino (C
1-C
2) alkyl or two (C
1-C
3) alkylamino (C
1-C
2) alkyl;
R
2And R
3All be hydrogen; Or
R
2, R
3Form a triatomic ring with the carbon atom that links to each other with them;
R
fAnd R
gBe halogen independently;
R
5And R
6Be C independently
1-C
3-C
4Alkyl.
255. as the described compound of claim 254, wherein R
2, R
3Form a triatomic ring with the carbon atom that links to each other with them; X is N; And X ' is CH.
256. as the described compound of claim 254, wherein R
2And R
3Be hydrogen; X ' is N; And X is CH.
257. as the described compound of claim 255, wherein R
1Be C
2Alkynyl.
258. as claim 256 or 257 described compound, wherein R
1Be two (C
1-C
3) alkylamino (C
1-C
3) alkyl.
259. as claim 256 or 257 described compound, wherein R
1Be dimethylamino (C
1-C
2) alkyl.
260. compound that chemical formula is following
Or it can be used for the salt of pharmacy, wherein
R
1Be C
2-C
3Alkyl;
R
2And R
3All be hydrogen;
R
fAnd R
gBe halogen independently;
R
pBe hydrogen, cyano group, C
1-C
3Alkyl, amino, N-(C
1-C
3Alkyl sulphonyl)-N-((C
1-C
3) alkyl) amino, 2-oxazolyl or choose wantonly at 2 and 5 by C
1-C
2The pyrryl that alkyl replaces;
R
aBe C
1-C
3Alkyl, H or trifluoromethyl; And
R
jBe C
1-C
5Alkyl.
261. as the described compound of claim 260, wherein R
jBe methyl or ethyl and R
pBe hydrogen, methyl or ethyl.
262. as the described compound of claim 260, wherein R
jBe methyl or butyl; And R
pBe hydrogen.
263. compound that chemical formula is following
Or it can be used for the salt of pharmacy, wherein
X is nitrogen or N
+-O
-
R
1Be C
2-C
4Alkynyl, cyano group, C
1-C
3Alkyl or CF
3
R
2And R
3All be hydrogen; Or
R
2, R
3Form a triatomic ring with the carbon atom that links to each other with them;
R
fAnd R
gBe halogen independently;
R
pBe hydrogen, cyano group or C
1-C
2Alkyl; And
R
5And R
6Be C independently
1-C
4Alkyl.
264. as the described compound of claim 263, wherein X is N.
265. as the described compound of claim 264, wherein R
pBe cyano group.
266. as the described compound of claim 265, wherein R
5Be methyl and R
6Be C
2-C
4Alkyl.
267. as the described compound of claim 266, wherein R
6It is propyl group.
268. as the described compound of claim 264, wherein
R
1Be C
2-C
3Alkyl;
R
pIt is methyl;
And R
5And R
6Be C independently
3-C
4Alkyl.
269. as the described compound of claim 268, wherein R
2And R
3All be hydrogen.
270. as the described compound of claim 264, wherein
R
1Be C
2-C
3Alkynyl or C
2Alkyl; And
R
pIt is methyl.
271. as the described compound of claim 263, wherein R
1Be CF
3
272. compound that chemical formula is following
Or it can be used for the salt of pharmacy, wherein
R
1Be hydrogen or methyl;
R
2And R
3All be hydrogen; Or
R
2, R
3Form a triatomic ring with the carbon atom that links to each other with them;
R
pBe C
2-C
3Alkynyl or C
1-C
3Alkyl;
R
fAnd R
gBe halogen independently;
R
5And R
6Be C independently
3-C
4Alkyl, or
R
5Be methyl and R
6Be C
3-C
4Alkyl.
273. as the described compound of claim 272, wherein R
1Be hydrogen and R
2And R
3All be hydrogen.
274. as the described compound of claim 272, wherein R
1Be hydrogen and R
2And R
3Form a triatomic ring with the carbon atom that links to each other with them.
275. as claim 273 or 274 described compound, wherein R
fAnd R
gIt all is chloro or fluorine-based.
276. as claim 273 or 274 described compound, wherein R
fAnd R
gAll be that position fluorine-based and that link to each other with phenyl is at 3 and 5.
277. compound that chemical formula is following
Wherein
R
1Be C
2-C
3Alkyl;
R
2And R
3It all is methyl; Or
R
2, R
3Form a cyclopropyl rings with the carbon that links to each other with them;
R
fAnd R
gBe halogen independently;
R
5And R
6Be C independently
3-C
4Alkyl; And
R
sBe-NH (C
1-C
4Hydroxyalkyl).
278. as the described compound of claim 277, wherein hydroxyalkyl is a 2-hydroxyl-1,1, dimethyl ethyl.
279. compound that chemical formula is following
Wherein
R
1Be C
2-C
3Alkynyl;
R
2And R
3All be hydrogen; Or
R
fAnd R
gBe halogen independently;
R
5And R
6Be C independently
3-C
4Alkyl; And
R
sBe-NH (C
2-C
4Hydroxyalkyl).
280. as the described compound of claim 279, wherein hydroxyalkyl is a 2-hydroxyl-1,1, dimethyl ethyl; Or 2-hydroxyethyl.
281. compound that chemical formula is following
Wherein
R
cBe C
4-C
5Alkyl; Cyclopropyl; The tetrahydrochysene naphthylidene;-CH (C
2Alkyl-S-(C
1-C
2) alkyl) C (O) NH (C
4Alkyl);-CH (C
2Alkyl-SO
2-(C
1-C
2) alkyl) C (O) NH (C
4Alkyl); Optional by C
3-C
4The pyrimidyl that alkyl replaces; Thiochroman 1, the 1-dioxide; Optional by C
3-C
4Alkyl replaces-CH
2-thiazolyl;
R
fAnd R
gBe halogen independently;
R
pBe-NHSO
2CF
3,-SO
2NH (C
3-C
4Hydroxyalkyl) ,-NHSO
2CH
3, oxazole-2-base; And
R
5And R
6Be C independently
3-C
4Alkyl.
282. as the described compound of claim 281, wherein
R
cIt is isobutyl-; Or 1,2,3, the inferior naphthalene of 4-tetrahydrochysene-1-base;-CH (CH
2CH
2-S-CH
3) C (O) NH (isobutyl-) or 2-tertiary butyl pyrimidine-4-base.
283. as the described compound of claim 281, wherein R
pBe-SO
2NH (2-hydroxyl-1,1-dimethyl ethyl).
284. as claim 282 or 283 described compound, wherein R
5And R
6All be C
3Alkyl.
285. as the described compound of claim 281, wherein
R
pShi oxazole-2-base; And
R
cBe-CH
2-(2-isobutyl thiazole-5-yl).
286. compound that chemical formula is following
Wherein
R
1Be C
2-C
3Alkyl or halogen;
R
2And R
3All be hydrogen; Or
R
fAnd R
gBe halogen independently; And
R
mBe-NH-SO
2CF
3, oxazole-2-base ,-N (CH
3) SO
2CH
3,-N (C
3-C
4Hydroxyalkyl) SO
2(C
1-C
2And R alkyl),
pBe H; Or
R
mBe H and R
pBe-NH-SO
2CF
3,-NH
2SO
2(C
1-C
2Alkyl); Or
R
mBe-C (O) pyrrolidyl and R
pBe OH.
287. compound that chemical formula is following
Wherein
R
1Be C
2-C
5Alkyl, C
3-C
6Qing Wanji, C
3-C
6Alkenyl ,-NHSO
2(C
1-C
2Alkyl), C
4-C
5Alkylhalide group ,-C
3Alkyl-CO
2-(C
1-C
2Alkyl), CN ,-N (C
1-C
2Alkyl) SO
2(C
1-C
2Alkyl) ,-SO
2(C
1-C
2Alkyl) ,-NH-(C
3-C
6Cycloalkyl) or-OC (O) N (C
1-C
2Alkyl) (C
1-C
2Alkyl),
R
2And R
3All be hydrogen;
R
fAnd R
gBe halogen independently;
R
pBe C
1-C
2Alkyl;
R
5And R
6Be C independently
3-C
5Alkyl, C
1-C
2Alkoxy C
1-C
2,3Alkyl, or
R
5Be hydrogen and R
6Be C
4,5-C
6Alkyl or (C
1-C
2Alkoxyl group)-(C
2-C
3Alkyl);
R
5Be ethyl and R
6Be C
2-C
3Hydroxyalkyl or-(C
1-C
2Alkyl)-N (C
1-C
2Alkyl) (C
1-C
2Alkyl); Or
R
5Be CH
3And R
6Be C
4-C
5Alkyl, cyclohexyl ,-(C
1-C
2Alkyl)-phenyl ,-(C
1-C
2Alkyl)-pyridyl or-CH
2-furyl; Or
R
5Be methyl or ethyl and R
6Be (C
1-C
2Alkoxyl group)-(C
2-C
3Alkyl),
R
5, R
6Forming one with the nitrogen that links to each other with them chooses wantonly by C
3-C
4The piperidines basic ring that alkyl or OH replace, the tall and erect yl of nitrogen, tetramethyleneimine-2-first benzoic acid amides, 3-hydroxy piperidine-1-base.
288. as the described compound of claim 287, wherein R
1Be C
2-C
3Alkyl.
289. as the described compound of claim 288, wherein
R
5And R
6Be simultaneously ethoxyethyl group or
R
5Be propyl group and R
6Be butyl.
290. as the described compound of claim 288, wherein
R
5, R
6Form a 2-propyl group piperidines-1-basic ring with the nitrogen that links to each other with them.
291. as the described compound of claim 287, wherein
R
1Be cyclopentyl, cyclohexyl, propylene thiazolinyl, allyl group or-(C
3-C
6Alkyl)-CN, C
2-C
5Alkyl, 4-chlorobutyl, 3-pyridyl, 2 Methylpropionic acid methyl esters, oneself-5-thiazolinyl, CN ,-N (CH
3) SO
2CH
3,-SO
2CH
2CH
3, 3-picoline-2-Ji, oxazole-2-base, 3,5-dimethyl isoxazole-4-base, 3 methyl thiophene-2-base, 2-pyridyl, 4-carbonyl aldehyde furans-5-base and 2-carbonyl aldehyde thiophene-5-base, 2-carbonyl aldehyde-3 methyl thiophene-5-base, 2-methoxypyridine-4-base ,-the NH-cyclopropyl ,-NHSO
2CH
3And R
pIt is methyl.
292. as the described compound of claim 291, wherein
R
5And R
6All be C
3Alkyl.
293. compound that chemical formula is following
Wherein
R
1Be C
2-C
3Alkyl, halogen ,-NH (cycloalkyl),
R
fAnd R
gBe halogen independently;
R
pBe C
1-C
2Alkyl, oxazolyl, thiazolyl or C
2-C
3Alkynyl;
R
2, R
3Form a cyclopropyl rings with the carbon that links to each other with them; Or
R
2And R
3It all is methyl;
R
5And R
6Be C independently
3-C
4Alkyl; Or
R
5Be methyl and R
6Be C
3-C
5Alkyl.
294. as the described compound of claim 293, wherein
R
2And R
3It all is methyl; And
R
5And R
6Be C independently
3-C
4Alkyl.
295. as the described compound of claim 294, wherein
R
pShi oxazole-2-base or thiazol-2-yl.
296. as the described compound of claim 294, wherein
R
pBe C
2-C
3Alkynyl; And
R
5And R
6Be C independently
3-C
4Alkyl
297. compound that chemical formula is following
Wherein
R
cBe optional by C
3-C
5Alkyl replaces De isoxazolyl, optional by C
3-C
4The thiazolyl that alkyl replaces or-C
1-C
3Alkyl-C (O) NH (C
1-C
3Alkyl);
R
fAnd R
gBe halogen independently;
R
pBe C
1-C
2Alkyl, oxazolyl, thiazolyl or C
2-C
4Alkynyl;
R
5And R
6Be C independently
3-C
4Alkyl.
298. as the described compound of claim 297, wherein R
pShi oxazole-2-base or thiazol-2-yl.
299. as the described compound of claim 298, wherein R
cIt is 3-isobutyl-isoxazole-5-base or N-isobutyl--2 Methylpropionic acid-2-base acid amides; And
R
fAnd R
gBe Cl or F independently.
300. as the described compound of claim 298, wherein
R
cIt is 2-isobutyl thiazole-2-base; And
R
fAnd R
gBe Cl or F independently.
301. as the described compound of claim 297, wherein
R
cBe 3-isobutyl-isoxazole-5-base or N-isobutyl--2 Methylpropionic acid--2-base acid amides;
R
fAnd R
gBe Cl or F independently; And
R
pBe C
2-C
3Alkynyl.
302. compound that chemical formula is following
Wherein
Hal is a halogen;
R
1Be C
1-C
2Alkyl or halogen;
R
2And R
3All be hydrogen;
R
fAnd R
gBe halogen independently;
R
zBe C
1-C
2Alkyl;
R
5And R
6Be C independently
3-C
4Alkyl.
303. as the described compound of claim 302, wherein Hal is bromo or chloro.
304. as the described compound of claim 303, wherein R
1Be methyl, ethyl, bromo or iodo.
305. compound that chemical formula is following
N is 0 or 1;
R
1Be C
1-C
2Alkyl;
R
2And R
3All be hydrogen;
R
fAnd R
gBe halogen independently;
R
sBe (C
1-C
2Alkoxyl group) (C
1-C
2Alkyl).
306. as the described compound of claim 305, wherein R
2It is methoxymethyl.
307. compound that chemical formula is following
Wherein
R
1Be C
1-C
2Alkyl;
R
2And R
3All be hydrogen;
R
fAnd R
gBe halogen independently;
R
pBe optional by C
1-C
2Alkyl replaces the De isoxazole;
R
5And R
6Be C independently
3-C
4Alkyl.
308. as the described compound of claim 307, wherein R
pBe 3-methyl-isoxazole-4-base, 5-oxazolyl, 3-oxazolyl, 3-Jia Ji oxazole-2-base, 3-Yi Ji oxazole-2-base.
309. a compound, or it can be used for the salt of pharmacy, and this compound is
N-[1-(3,5-two fluoro-benzyls)-2-hydroxyl-3-(1-isobutylamino formyl radical-3-methyl sulfane base-third amino)-propyl group]-5-methyl-N ', N '-dipropyl-isophthaloyl amine;
N
4-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-6-methyl-N
2, N
2-dipropyl pyridine-2, the 4-diformamide;
N
1-butyl-N
3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
1-methyl-5-(1,3-thiazoles-2-yl) isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-methyl-N
3-propyl group-5-(1,3-thiazoles-2-yl) isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-methyl-5-(1,3-oxazole-2-yl)-N
3-propyl group isophthaloyl amine;
N
1-butyl-N
3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
1-methyl-5-(1,3-oxazole-2-yl) isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-ethyl-5-(1,3-oxazole-2-yl)-N
3-propyl group isophthaloyl amine;
N-[1-(3,5-two fluoro-benzyls)-3-(1-ethylamino formyl radical-ethylamino)-2-hydroxyl-propyl group]-5-methyl-N ', N '-dipropyl-isophthaloyl amine;
N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-N '-formyl-dimethylamino methyl-5, N '-two bases-isophthaloyl amine;
N-[1-(3,5-two fluoro-benzyls)-2-hydroxyl-3-(1-methylamino formyl radical-3-methyl sulfane base-propyl group amino)-propyl group]-5-methyl-N ', N '-dipropyl-isophthaloyl amine;
N-[3-(1-benzylamino formyl radical-ethylamino)-1-(3,5-two fluoro-benzyls)-2-hydroxyl-propyl group]-5-methyl-N ', N '-dipropyl-isophthaloyl amine;
N-{[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group formamyl]-methyl }-3-trifluoromethyl-benzamide;
N-{[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group formamyl]-methyl }-4-trifluoromethyl-benzamide;
3,4-two chloro-N-{[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group formamyl]-methyl }-benzamide;
N-[3-(1-formamyl-3-methyl-Ding amino)-1-(3,5-two fluoro-benzyls)-2-hydroxyl-propyl group]-5-methyl-N ', N '-dipropyl-isophthaloyl amine;
N-{[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group formamyl]-methyl }-4-methoxyl group-benzamide;
N-{[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group formamyl]-methyl }-2,6-two fluoro-benzamide;
N-[3-(1-formamyl-ethylamino)-1-(3,5-two fluoro-benzyls)-2-hydroxyl-propyl group]-5-methyl-N ', N '-dipropyl-isophthaloyl amine;
N-{[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group formamyl]-methyl }-2,6-dimethoxy-benzamide;
2-{[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group formamyl]-methyl sulfane base }-N-(4-oxazole-5-base-phenyl)-ethanamide;
2-{[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group formamyl]-methyl sulfane base }-N-(5-methyl-isoxazole-3-base)-ethanamide;
N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-4-methane sulfonyl-benzsulfamide;
2-cyano group-N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-benzsulfamide;
2-chloro-N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-4-trifluoromethoxy-benzsulfamide;
2-chloro-N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-6-methyl-benzsulfamide;
5-chloro-N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-2-methoxyl group-benzsulfamide;
2-chloro-4-cyano group-N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-benzsulfamide;
N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-2-trifluoromethyl-benzsulfamide;
4-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group sulphonamide]-phenylformic acid;
6-chloro-pyridine-3-sulphonic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-amine;
N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-2,5-pair-(2,2,2-three fluoro-oxyethyl groups)-benzsulfamide;
Pyridine-3-sulphonic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
N-{2-chloro-4-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group sulphonamide]-phenyl }-ethanamide;
N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-2-trifluoromethoxy-benzsulfamide;
N-{5-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propylthio alkyl]-thiophene-2-ylmethyl }-benzamide;
5-chloro-3-methyl-benzo [b] thiophene-2-sulfonic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-amine;
N-{5-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propylthio alkyl]-4-methyl-thiazol-2-yl }-ethanamide;
4-chloro-N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-benzamide;
3-chloro-N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-benzamide;
N-[1-(3,5-two fluoro-benzyls)-2-hydroxyl-3-(3-methoxyl group-benzyl amino)-propyl group]-2-trifluoromethyl-benzamide;
6-chloro-pyridine-3-sulphonic acid [1-(3,5-two fluoro-benzyls)-2-hydroxyl-3-(3-methoxyl group-benzyl amino)-propyl group]-amine;
Pyridine-3-sulphonic acid [1-(3,5-two fluoro-benzyls)-2-hydroxyl-3-(3-methoxyl group-benzyl amino)-propyl group]-amine;
N-[1-(3,5-two fluoro-benzyls)-2-hydroxyl-3-(3-methoxyl group-benzyl amino)-propyl group]-2-methane sulfonyl-benzsulfamide;
3,5-two chloro-N-[1-(3,5-two fluoro-benzyls)-2-hydroxyl-3-(3-methoxyl group-benzyl amino)-propyl group]-benzsulfamide;
1,2-dimethyl-1H-imidazoles-4-sulfonic acid [1-(3,5-two fluoro-benzyls)-2-hydroxyl-3-(3-methoxyl group-benzyl amino)-propyl group]-acid amides;
N-[1-(3,5-two fluoro-benzyls)-2-hydroxyl-3-(3-methoxyl group-benzyl amino)-propyl group]-3,4-dimethoxy-benzsulfamide;
2-(2,2,2-three fluoro-ethanoyl)-1,2,3,4-tetrahydrochysene-different quinoline beautiful jade-7-sulfonic acid [1-(3,5-two fluoro-benzyls)-2-hydroxyl-3-(3-methoxyl group-benzyl amino)-propyl group]-acid amides;
5-chloro-3-methyl-benzo [b] thiophene-2-sulfonic acid [1-(3,5-two fluoro-benzyls)-2-hydroxyl-3-(3-methoxyl group-benzyl amino)-propyl group]-acid amides;
3-{4-[1-(3,5-two fluoro-benzyls)-2-hydroxyl-3-(3-methoxyl group-benzyl amino)-propyl group sulphonamide]-phenyl }-methyl propionate;
3-chloro-N-[1-(3,5-two fluoro-benzyls)-2-hydroxyl-3-(3-methoxyl group-benzyl amino)-propyl group]-benzsulfamide;
3-cyano group-N-[1-(3,5-two fluoro-benzyls)-2-hydroxyl-3-(3-methoxyl group-benzyl amino)-propyl group]-benzsulfamide;
Butane-1-sulfonic acid [1-(3,5-two fluoro-benzyls)-2-hydroxyl-3-(3-methoxyl group-benzyl amino)-propyl group]-acid amides;
N-{1-(3,5-two fluoro-benzyls)-2-hydroxyl-3-[1-methane sulfonyl-piperidin-4-yl methyl)-amino]-propyl group }-5-methyl-N ', N '-dipropyl-isophthaloyl amine;
N-[3-benzenesulfonyl amino-1-(3,5-two fluoro-benzyls)-2-hydroxyl-propyl group]-5-methyl-N ', N '-dipropyl-isophthaloyl amine;
N-[1-(3,5-two fluoro-benzyls)-2-hydroxyl-3-(3-methoxyl group-benzoyl-amido)-propyl group]-5-methyl-N ', N '-dipropyl-isophthaloyl amine;
4-(3,5-two fluoro-phenyl)-3-(2,5-dimethyl-4-nitro-2H-pyrazole-3-yl amino)-1-(3-methoxyl group-benzyl amino)-Ding-2-alcohol;
3-(2-amino-7H-purine-6-base is amino)-4-(3,5-two fluoro-phenyl)-1-(3-methoxyl group-benzyl amino)-Ding-2-alcohol;
3-(4-chloro-pyrimidine-2--amino)-4-(3,5-two fluoro-phenyl)-1-(3-methoxyl group-benzyl amino)-Ding-2-alcohol;
3-(2-amino-6-methyl-pyrimidine-4-base is amino)-4-(3,5-two fluoro-phenyl)-1-(3-methoxyl group-benzyl amino)-Ding-2-alcohol;
3-(2-chloro-6-methyl-pyrimidine-4-base is amino)-4-(3,5-two fluoro-phenyl)-1-(3-methoxyl group-benzyl amino)-Ding-2-alcohol;
3-(2-amino-6-chloro-pyrimidine-4-base is amino)-4-(3,5-two fluoro-phenyl)-1-(3-methoxyl group-benzyl amino)-Ding-2-alcohol;
4-(3,5-two fluoro-phenyl)-1-(3-methoxyl group-benzyl amino)-3-(1-phenyl-tetrazolium-5-base is amino)-Ding-2-alcohol;
3-(2-chloro-7H-purine-6-base is amino)-4-{3,5-two fluoro-phenyl }-1{3-methoxyl group-benzyl amino)-Ding-2-alcohol;
4-(3,5-two fluoro-phenyl)-1-(3-methoxyl group-benzyl amino)-3-[9-(tetrahydrochysene-pyrans-2-yl)-9H-purine-6-base is amino]-Ding-2-alcohol;
3-[1-(3,5-two fluoro-benzyls)-2-hydroxyl-3-(3-methoxyl group-benzyl amino)-third amino]-pyrazine-2-nitrile;
4-(3,5-two fluoro-phenyl)-3-(4,6-dimethoxy-[1,3,5] triazine-2-base is amino)-1-(3-methoxyl group-benzyl amino)-Ding-2-alcohol;
2-[1-(3,5-two fluoro-benzyls)-2-hydroxyl-3-(3-methoxyl group-benzyl amino)-propyl group amino]-the nicotinoyl nitrile;
4-(3,5-two fluoro-phenyl)-1-(3-methoxyl group-benzyl amino)-3-(7H-purine-6-base is amino)-Ding-2-alcohol;
3-(benzothiazole-2-base is amino)-4-(3,5-two fluoro-phenyl)-1-(3-methoxyl group-benzyl amino)-Ding-2-alcohol;
4-(3,5-two fluoro-phenyl)-1-(3-methoxyl group-benzyl amino)-3-(2-phenyl-quinoline beautiful jade-4-base is amino)-Ding-2-alcohol;
6-[1-(3,5-two fluoro-benzyls)-2-hydroxyl-3-(3-methoxyl group-benzyl amino)-propyl group amino]-the nicotinoyl nitrile;
6-[1-(3,5-two fluoro-benzyls)-2-hydroxyl-3-(3-methoxyl group-benzyl amino)-propyl group amino]-Nikithan;
4-(3,5-two fluoro-phenyl)-1-(3-methoxyl group-benzyl amino)-3-(3-methyl-5-nitro-3H-imidazol-4 yl amino)-Ding-2-alcohol;
3-(benzoxazole-2-base is amino)-4-(3,5-two fluoro-phenyl)-1-(3-methoxyl group-benzyl amino)-Ding-2-alcohol;
4-(3,5-two fluoro-phenyl)-1-(3-methoxyl group-benzyl amino)-3-(quinoline beautiful jade-4-base is amino)-Ding-2-alcohol;
4-(3,5-two fluoro-phenyl)-3-(5-ethyl-pyrimidine-2--amino)-1-(3-methoxyl group-benzyl amino)-Ding-2-alcohol;
4-(3,5-two fluoro-phenyl)-1-(3-methoxyl group-benzyl amino)-3-(4-trifluoromethyl-pyrimidine-2--amino)-Ding-2-alcohol;
3-(6-chloro-2-methyl sulfane base-5-phenyl-pyrimidine-4-base is amino)-4-(3,5-two fluoro-phenyl)-1-(3-methoxyl group-benzyl amino)-Ding-2-alcohol;
3-(3-chloro-quinoxaline-2-base is amino)-4-(3,5-two fluoro-phenyl)-1-(3-methoxyl group-benzyl amino)-Ding-2-alcohol;
4-(3,5-two fluoro-phenyl)-1-(3-methoxyl group-benzyl amino)-3-(8-trifluoromethyl-quinoline beautiful jade-4-base is amino)-Ding-2-alcohol;
3-(6-chloro-2,5-phenylbenzene-pyrimidine-4-base is amino)-4-(3,5-two fluoro-phenyl)-1-(3-methoxyl group-benzyl amino)-Ding-2-alcohol;
3-(3-chloro-pyrazine-2-base is amino)-4-(3,5-two fluoro-phenyl)-1-(3-methoxyl group-benzyl amino)-Ding-2-alcohol;
4-(3,5-two fluoro-phenyl)-1-(3-methoxyl group-benzyl amino)-3-(5-trifluoromethyl-pyridine-2-base is amino)-Ding-2-alcohol;
4-(3,5-two fluoro-phenyl)-1-(3-methoxyl group-benzyl amino)-3-(quinoline beautiful jade-2-base is amino)-Ding-2-alcohol;
3-(6-chloro-pyrazine-2-base is amino)-4-(3,5-two fluoro-phenyl)-1-(3-methoxyl group-benzyl amino)-Ding-2-alcohol;
4-(3,5-two fluoro-phenyl)-1-(3-methoxyl group-benzyl amino)-3-(3-nitro-pyridine-2-base is amino)-Ding-2-alcohol;
4-(3,5-two fluoro-phenyl)-1-(3-methoxyl group-benzyl amino)-3-(pyrimidine-2--amino)-Ding-2-alcohol;
4-(3,5-two fluoro-phenyl)-1-(3-methoxyl group-benzyl amino)-3-(2-phenyl-quinazoline-4-base is amino)-Ding-2-alcohol;
N-[3-(N '-ethanoyl-N-ethyl-diazanyl)-1-benzyl-2-hydroxyl-propyl group]-3-hydroxyl-4-(tetramethyleneimine-1-carbonyl)-benzamide;
3-(4,6-diamino-[1,3,5] triazine-2-base is amino)-4-(3,5-two fluoro-phenyl)-1-(3-methoxyl group-benzyl amino)-Ding-2-alcohol;
5-acetylaminohydroxyphenylarsonic acid N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzylamino)-2-hydroxyl-propyl group]-2-hydroxyl-benzamide;
2-(2,5-dimethyl-pyrroles-1-yl)-thiophene-3-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
N-{1-(3,5-two fluoro-benzyls)-2-hydroxyl-3-[3-(3-hydroxymethyl-piperidines-1-carbonyl)-phenyl amino]-propyl group }-5-methyl-N ', N '-isophthaloyl amine;
4-phenyl-[1,2,3] thiadiazoles-5-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
N-[3-(3-cyclohexyl-1-phenyl-third amino)-1-(3,5-two fluoro-benzyls)-2-hydroxyl-propyl group]-5-methyl-N ', N '-dipropyl-isophthaloyl amine;
Amino-oxazoles of 2-methane sulfonyl-4-formic acid 1-benzyl-3-[N-ethyl-N '-(3-ethyl-benzoyl)-diazanyl]-2-hydroxyl-propyl group }-acid amides;
N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-2-(2,6-dimethyl-phenoxy group)-propionic acid amide;
Amino-oxazoles of 2-methane sulfonyl-4-formic acid 1-benzyl-3-[N-ethyl-N '-(4-methyl-pentanoyl)-diazanyl]-2-hydroxyl-propyl group }-acid amides;
4-acetylaminohydroxyphenylarsonic acid 1-methyl isophthalic acid H-pyrroles-2-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
2-ethyl-5-thiophene-2-base-2H-pyrroles-3-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
Amino-oxazoles of 2-methane sulfonyl-4-formic acid [3-(N '-ethanoyl-N-ethyl-diazanyl)-1-benzyl-2-hydroxyl-propyl group]-acid amides;
Amino-oxazoles of 2-methane sulfonyl-4-formic acid [3-(N '-benzoyl-N-ethyl-diazanyl)-1-benzyl-2-hydroxyl-propyl group]-acid amides;
6-methyl-4-oxo-1-phenyl-1,4-dihydro-pyridazine-3-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
2-methane sulfonyl amino-thiazolyl--4-formic acid 1-benzyl-3-[N-ethyl-N '-(3-ethyl-benzoyl)-diazanyl]-2-hydroxyl-propyl group }-acid amides;
4-methyl-2-phenyl-oxazole-5-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
2-methane sulfonyl amino-thiazolyl--4-formic acid [3-(N '-ethanoyl-N-ethyl-diazanyl)-1-benzyl-2-hydroxyl-propyl group]-acid amides;
N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-2-pyridin-3-yl-benzamide;
2-p-methylphenyl-thiazole-4-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
N-{1-benzyl-3-[N-ethyl-N '-(3-ethyl-benzoyl)-diazanyl]-2-hydroxyl-propyl group }-2-[4-(2-oxo-tetramethyleneimine-1-yl)-phenyl]-ethanamide;
2-phenoxymethyl-thiazole-4-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
N-{1-benzyl-3-[N-ethyl-N '-(4-methyl-pentanoyl)-diazanyl]-2-hydroxyl-propyl group }-2-[4-(2-oxo-tetramethyleneimine-1-yl)-phenyl]-ethanamide;
[1,2,5] thiadiazoles-3-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
N-[3-(N '-ethanoyl-N-ethyl-diazanyl)-1-benzyl-2-hydroxyl-propyl group]-2-[4-(2-oxo-pyrroline-1-yl)-phenyl]-ethanamide;
Tolyl-thiazole between 2--4-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
N-[3-(N '-benzoyl-N-ethyl-diazanyl)-1-benzyl-2-hydroxyl-propyl group]-2-[4-(2-oxo-pyrroline-1-yl)-phenyl]-ethanamide;
2-(2-chloro-phenyl)-thiazole-4-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
N-{1-benzyl-3-[N-ethyl-N '-(3-ethyl-benzoyl)-diazanyl]-2-hydroxyl-propyl group }-3-hydroxyl-4-(tetramethyleneimine-1-carbonyl)-benzamide;
N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-3-phenyl-2-tetrazolium-1-base-propionic acid amide;
N-{1-benzyl-3-[N-ethyl-N '-(4-methyl-pentanoyl)-diazanyl]-2-hydroxyl-propyl group }-3-hydroxyl-4-(tetramethyleneimine-1-carbonyl)-benzamide;
4-chloro-7,7-dimethyl-7,8-dihydro-5H-pyrans be [4,3-b] pyridine-2-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides also;
2-propyl group-tetrahydropyrans-4-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
5-p-methylphenyl-3,4-dihydro-2H-pyrazoles-3-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
2-acetylaminohydroxyphenylarsonic acid 5-chloro-thiophene-3-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
4-(4-methoxyl group-phenyl)-thiophene-2-carboxylic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-N '-(2-fluoro-5-methane sulfonyl-phenyl)-succinic diamide;
1-(4-fluoro-phenyl)-5-methyl isophthalic acid H-[1,2,4] triazole-3-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
N-(2-ethanoyl-thiene-3-yl-)-N '-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-succinic diamide;
6-chloro-4-trifluoromethyl-pyridine-2-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-2-(5,7-dimethyl-[1,2,4] triazolo [1,5-a] pyrimidine-2-base)-ethanamide;
N-(1-cyclopropyl-ethyl)-N '-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-N-phenyl-succinic diamide;
N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-2-(3,4-dimethoxy-phenyl sulfane base)-ethanamide;
1-methyl-5-oxo-2-pyridin-3-yl-tetramethyleneimine-3-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
4-methoxyl group-thiophene-3-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
2,5-dimethyl-1-pyridin-4-yl methyl isophthalic acid H-pyrroles-3-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
2-methyl-5-thiophene-2-base-furans-3-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
4-(4-benzyl-[1,4] diaza ring-1-in heptan yl)-N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-4-oxo-butyramide;
2-(benzo [1,2,5] thiadiazoles-4-base oxygen base)-N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-ethanamide;
3-chloro-5-phenyl-isothiazole-4-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-5-phenylacetylene base-niacinamide;
4,7-dimethoxy-cumarone-5-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-3-morpholine-4-ylmethyl-benzamide;
2,2-dimethyl-4-oxo-chroman-6-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
[1,6] naphthyridine-2-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
8-cyano group-4-hydroxyl-quinoline beautiful jade-3-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
3-pyridin-3-yl-thiazole-4-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
5-chloro-coumarilic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
4-dibenzofuran-2-base-N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-4-oxo-butyramide;
N-{[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group formamyl]-methyl }-niacinamide;
The 4-tertiary butyl-N-{[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group formamyl]-methyl }-benzamide;
4-chloro-N-{[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group formamyl]-methyl }-benzamide;
4-chloro-6-methyl-quinoline beautiful jade-2-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-2-(2,4-dihydroxyl-thiazole-5-yl)-ethanamide;
2-methyl-pyrimidine-5-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-4-piperidines-1-base-benzamide;
4-acetylamino-N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-benzamide;
N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-4-methoxyl group-benzamide;
4-methyl-oxazole-5-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
1H-indole-5-carboxylic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
6-chloro-1H-indole-2-carboxylic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
2-(4-chloro-2-oxo-benzothiazole-3-yl)-N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-ethanamide;
Thiophene-3-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
2-methyl-oxazole-4-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-2-(1-oxo-pyridin-3-yl)-ethanamide;
N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-2-hydroxyl-2-phenyl-2-thiophene-2-base-ethanamide;
6-hydroxy-2-methyl sulfane base-pyrimidine-4-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
2,5-dimethyl-furans-3-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-niacinamide;
N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-4-(3-methoxyl group-phenyl)-4-oxo-butyramide;
4-ethanoyl-N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-benzamide;
N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-4-hydroxyl-3,5-dimethoxy-benzamide;
Furans-2-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydrochysene-purine-7-yl)-ethanamide;
4-acetylamino-N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-2,6-dimethyl-benzamide;
N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-2-thiophene-2-base-ethanamide;
N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-4-oxo-4-phenyl-butyramide;
1H-indole-3-carboxylic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-3-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-propionic acid amide;
3-benzo [1.3] dioxole-5-base-N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-propionic acid amide;
N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-4-morpholine-4-base-4-oxo-butyramide;
[2,3 '] thiophthene base-5-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
5-methoxyl group-thiophene-2-carboxylic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
4-phenyl-thiophene-2-carboxylic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
2-(5-benzo [1,3] dioxole-5-base-tetrazolium-2-yl)-N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-ethanamide;
2-(benzothiazole-2-ylmethoxy)-N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-ethanamide;
Tetramethyleneimine-1,2-dioctyl phthalate 1-{[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides } the 2-phenyl amide;
N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-3-(6-oxyethyl group-1H-benzimidazolyl-2 radicals-yl)-propionic acid amide;
N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-2-(3-methyl-2-oxo-2,3-dihydro-benzoglyoxaline-1-yl)-ethanamide;
2-oxo-2,3-dihydro-benzoxazole-6-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
Thieno-[3,2-c] pyridine-2-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
1-Methyl-1H-indole-3-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
Benzo [b] thiophene-3-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
4-oxygen-3-propyl group-pyrazine-2-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
1,1,3-trioxy--2,3-dihydro-1H-116-benzo [d] isothiazole-6-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-2-(7-hydroxy-5-methyl base-[1,2,4] triazolo [1,5-a] pyrimidine-2-base sulfane base)-ethanamide;
2-hydroxyl-6-methyl-quinoline beautiful jade-4-formic acid [1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-acid amides;
N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-2-(2-methyl-2,3-dihydro-cumarone-5-yl)-propionic acid amide;
3-(benzoxazole-2-base sulfane base)-N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-propionic acid amide;
N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-2-(5-o-tolyl-tetrazolium-2-yl)-ethanamide;
2-chloro-N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-4-tetrazolium-1-base-benzamide;
N-(the 4-tertiary butyl-thiazol-2-yl)-N '-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-succinic diamide;
N-(5-cyclopropyl-[1,3,4] thiadiazoles-2-yl)-N '-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-succinic diamide;
2-(3-chloro-phenoxy group)-N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-propionic acid amide;
N-[1-(3,5-two fluoro-benzyls)-3-(3-ethyl-benzyl amino)-2-hydroxyl-propyl group]-3-(pyridin-4-yl methyl sulfane base)-benzamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-{[(2-hydroxyethyl) amino] sulphonyl }-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(2-isobutyl--1,3-thiazoles-5-yl) methyl] amino } propyl group)-5-ethynyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-isopropyl benzyl) amino] propyl group }-5-ethynyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-isopropyl benzyl) amino] propyl group }-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-{[(2-hydroxyl-1, the 1-dimethyl ethyl) amino] alkylsulfonyl }-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(4-methyl isophthalic acid, 3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(2-isobutyl--1,3-thiazoles-5-yl) methyl] amino } propyl group)-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-{[(3-hydroxypropyl) amino] alkylsulfonyl }-N
3, N
3-dipropyl isophthaloyl amine;
3-([(2R, 3S)-4-(3, the 5-difluorophenyl)-3-(3-[(dipropyl amino) carbonyl]-the 5-methyl benzoyl } amino)-2-hydroxyl butyl] amino } methyl) phenyl (methyl) Urethylane;
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(4R)-2,2-titanium dioxide-3,4-dihydro-1H-2,1-benzothiazine-4-yl] amino }-the 2-hydroxypropyl)-5-methyl-N, N-dipropyl isophthaloyl amine;
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(4S)-2,2-titanium dioxide-3,4-dihydro-1H-2,1-benzothiazine-4-yl] amino }-the 2-hydroxypropyl)-5-methyl-N, N-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3,3-dimethyl-N
2, N
2-dipropyl cyclopropane-1, the 2-diformamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-(2,2-dimethyl propylene acyl group)-3-[(1-propyl group butyl) alkylsulfonyl]-the amino propionic acid amide of right type;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-dipropyl-5-pyrimidine-2-base isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-propyl group benzyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-ethynyl benzyl) amino]-the 2-hydroxypropyl }-5-ethynyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(3-isobutyl-isoxazole-5-base) methyl] amino } propyl group)-
5-ethynyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-[(dimethylamino) alkylsulfonyl]-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[3-(5-formyl radical thiophene-2-yl) benzyl] amino }-the 2-hydroxypropyl)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
5-bromo-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-benzyl iodide) amino] propyl group }-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-([(1R)-and 2-hydroxyl-1-methylethyl] amino } alkylsulfonyl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-isobutyl-benzyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-5-ethynyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(2R)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] carbonyl }-the 5-methyl benzamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-([(1S)-and 2-hydroxyl-1-methylethyl] amino } alkylsulfonyl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-butyl-N
3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-N
1-propyl group isophthaloyl amine;
N
1, N
1-dibutyl-N
3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the oreinol diformamide;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(3-hydroxyl third-1-alkynyl) benzyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-{[(2S)-and 2-(methylol) tetramethyleneimine-1-yl] alkylsulfonyl }-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-{[3-(cyclopropyl amino) benzyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-ethynyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-thiene-3-yl-benzyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(piperazine-1-base alkylsulfonyl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[1-(3-iodophenyl) cyclopropyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-the 3-[(3-sec-butyl) benzyl]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(3-methyl-isoxazole-4-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[1-(3-isobutyl-isoxazole-5-base) cyclopropyl] amino } propyl group)-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylbenzene base) cyclopropyl] amino }-the 2-hydroxypropyl)-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N
4-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-6-methyl-N
2, N
2-dipropyl pyridine-2, the 4-diformamide;
N
1-(cyclopropyl methyl)-N
3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-N
1-propyl group isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
5-(amino-sulfonyl)-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(3-[(1Z)-third-1-thiazolinyl] benzyl } amino) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-dipropyl-5-(1H-pyrazoles-4-yl) isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylbenzene base)-1-methylethyl] amino }-the 2-hydroxypropyl)-5-ethynyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-[(3-allyl group benzyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylbenzene base) cyclopropyl] amino }-the 2-hydroxypropyl)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-Ethylbenzyl)-1-methylethyl] amino }-the 2-hydroxypropyl)-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-ethyl-5-methyl-N
3-propyl group isophthaloyl amine;
N
1-[(1S, 2R)-3-{[3-(cyclopropyl amino) benzyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-5-ethynyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[1-(3-isobutyl-isoxazole-5-base) cyclopropyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[3-(5-formyl radical-4-thiotolene-2-yl) benzyl] amino }-the 2-hydroxypropyl)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(the 3-[(methyl sulphonyl) and amino] benzyl } amino) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-isopentyl benzyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-[(1,1 '-phenylbenzene-3-ylmethyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-({ [2-(methylamino-) ethyl] amino } alkylsulfonyl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[1-(3-isobutyl-isoxazole-5-base) cyclopropyl] amino } propyl group)-5-ethynyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1, N
1-diallyl-N
3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the oreinol diformamide;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[1-(2-isobutyl--1,3-thiazoles-5-yl) cyclopropyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylbenzene base)-1-methylethyl] amino }-the 2-hydroxypropyl)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-{[(2-hydroxyethyl) amino] alkylsulfonyl }-N
3-propyl group isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, 5-dimethyl-N
3-propyl group isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-(phenyl sulfonyl)-3-[(1-propyl group butyl) alkylsulfonyl] amino propionic acid amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-diethyl-5-(1,3-oxazole-2-yl) isophthaloyl amine;
N
2-[(benzylamino) carbonyl]-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(1-propyl group butyl) alkylsulfonyl] amino propionic acid amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-pyridin-3-yl benzyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[3-(3-formyl radical-2-furyl) benzyl] amino }-the 2-hydroxypropyl)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1-methyl isophthalic acid H-imidazoles-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-diethyl-oreinol diformamide;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[3-(ethyl sulfinyl) benzyl] amino }-the 2-hydroxypropyl)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
3-{[butyl (ethyl) amino] alkylsulfonyl }-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } propionic acid amide;
N
1-[(1S, 2R)-3-[(3-cyano group benzyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(1-propyl group butyl) alkylsulfonyl] propionic acid amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-isobutyl--N
3, 5-dimethyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-pyridine-2-base benzyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(3-[methyl (methyl sulphonyl) amino] and benzyl } amino) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-(3-phenyl propanol base)-3-[(1 propyl group butyl) alkylsulfonyl] amino propionic acid amide trifluoroacetate;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[3-(ethylsulfonyl) benzyl] amino }-the 2-hydroxypropyl)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
2-[(5-chlorothiophene-2-yl) alkylsulfonyl]-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(1-propyl group butyl) alkylsulfonyl] amino propionic acid amide;
N
1-[(1S, 2R)-3-{[3-(5-acetyl thiophene-2-yl) benzyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(sec-butyl)-N
3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the oreinol diformamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(1,3-oxazole-2-yl) benzamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, 5-dimethyl-N
3-(2-styroyl) isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[3-(3,5-dimethyl isoxazole-4-yl) benzyl] amino }-the 2-hydroxypropyl)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, 5-dimethyl-N
3-Propargyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-ethyl-N
3, 5-dimethyl isophthaloyl amine;
3-([(2R, 3S)-4-(3, the 5-difluorophenyl)-3-(3-[(dipropyl amino) carbonyl]-the 5-methyl benzoyl } amino)-2-hydroxyl butyl] amino } methyl) the phenyl dimethylcarbamate;
N
1-benzyl-N
3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
1, 5-dimethyl isophthaloyl amine;
N
1-(sec-butyl)-N
3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-N
1-propyl group isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(4-thiotolene-2-yl) benzyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
3-([(2R, 3S)-4-(3, the 5-difluorophenyl)-3-(3-[(dipropyl amino) carbonyl]-the 5-methyl benzoyl } amino)-2-hydroxyl butyl] amino } methyl) phenyl (methyl) Urethylane;
N
1-((1S, 2R)-2-hydroxyl-1-(2,3, the 5-trifluoro-benzyl)-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-diisobutyl-oreinol diformamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, 5-dimethyl-N
3-(2-pyridine-2-base ethyl) isophthaloyl amine;
N
1-(1S, 2R)-1-(3-fluoro-5-hydroxybenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3-chloro-5-luorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-4-hydroxyl-3-(tetramethyleneimine-1-base carbonyl) benzamide;
5-oxo-right type prolyl-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(1-propyl group butyl) alkylsulfonyl] amino propionic acid amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-{[(trifluoromethyl) alkylsulfonyl] amino } benzamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[3-pyridine-(4-base benzyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-(the 3-[(dimethylamino) and alkylsulfonyl] benzyl } amino)-the 2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(6-methoxyl group-1,2,3,4-tetralin-1-yl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-(phenyl acetyl)-3-[(1-propyl group butyl) alkylsulfonyl] amino propionic acid amide;
3-([(2R, 3S)-4-(3, the 5-difluorophenyl)-3-(3-[(dipropyl amino) carbonyl]-the 5-methyl benzoyl } amino)-2-hydroxyl butyl] amino } methyl) the phenylcarbamic acid methyl esters;
5-oxo-levorotation prolyl-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(1-propyl group butyl) alkylsulfonyl] amino propionic acid amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-isobutyl--oreinol diformamide;
4-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino)-4-oxo-3-{[(1-propyl group butyl) alkylsulfonyl] amino } the butyric acid trifluoroacetate;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[methyl (methyl sulphonyl) amino] benzamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-ethyl-N
3-sec.-propyl-oreinol diformamide;
N
1-[(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(thiophene-2-ylmethyl) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-{[(2-hydroxyethyl) (propyl group) amino] alkylsulfonyl } propionic acid amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-sec.-propyl-N
3, 5-dimethyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-[(methyl sulphonyl) amino]-1,3-thiazoles-4-methane amide;
N
1-allyl group-N
1-cyclopentyl-N
3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the oreinol diformamide;
N-(3-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino-3-oxo-2-{[(1-propyl group butyl) alkylsulfonyl] methyl } propyl group) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(isopentyl alkylsulfonyl) propionic acid amide;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(5-thiotolene-2-yl) benzyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(1-methyl hexyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-{[1-(aminocarboxyl) cyclohexyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(2E)-oneself-the 2-alkenyl amino]-the 2-hydroxypropyl }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-hydoxyisoxazole-5-methane amide;
N
1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-(3-[(1E)-oneself-the 1-thiazolinyl] benzyl } amino)-the 2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-sec.-propyl-oreinol diformamide;
N
1-[(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(thiophene-2-ylmethyl) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
2-[3-(2-amino-2-oxo oxyethyl group) phenyl]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-benzyl iodide) amino] propyl group } ethanamide;
N
1-(1S, 2R)-1-(3-bromobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(2-ethylhexyl) amino]-the 2-hydroxypropyl }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(6-methoxypyridine-3-yl) benzyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[3-(2,4-dimethoxypyridin-5-yl) benzyl] amino }-the 2-hydroxypropyl)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(2-ethyl butyryl radicals) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(4-hydroxy piperidine-1-yl) carbonyl]-the 5-methyl benzamide;
N
1-(1S, 2R)-1-(3-bromobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
4 '-[4-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-benzyl iodide) amino] propyl group } amino)-the 4-oxobutanoyl]-1,1 '-phenylbenzene-2-methane amide;
1-{3-[({ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino) carbonyl]-the 5-methyl benzoyl }-levorotation-prolineamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(3-hydroxy piperidine-1-yl) carbonyl]-the 5-methyl benzamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-hydroxyl-1-phenyl propyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-[2-(dimethylamino) ethyl]-N
3-ethyl-oreinol diformamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-methyl-4H, 6H-pyrrolo-[1,2-a] [4,1] benzoxazine-4-methane amide;
2-(5-acetyl thiophene-2-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-di-isopropyl-oreinol diformamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-[(methyl sulphonyl) amino] benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-benzyl iodide) amino] propyl group }-2-[4-(2-oxo-pyrrolidine-1-yl) phenyl] ethanamide;
N-{ (1S, 2R)-1-(3-chloro-5-luorobenzyl)-2-hydroxyl-3-[(3-methyl-benzyl) amino] propyl group }-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N
1-[(1S, 2R)-1-(3-chloro-5-luorobenzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(1-methyl isophthalic acid H-imidazol-4 yl) alkylsulfonyl] amino } benzamide three;
N
1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(penta amino) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(4-luorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-[(1S, 2R)-3-(benzylamino)-1-(3-chloro-5-luorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-cyclohexyl-N
3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
1-ethyl-oreinol diformamide;
2-{[(2R, 3S)-4-(3, the 5-difluorobenzyl)-3-(3-[(dipropyl amino) carbonyl]-the 5-methyl benzoyl } amino)-2-hydroxyl butyl] amino } butyl 2,4 difluorobenzene aminocarbamic acid ester;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(2S)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] carbonyl }-the 5-methyl benzamide;
N
1-[(1S, 2R)-1-(3-bromobenzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,8-dimethyl quinoline beautiful jade-3-methane amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(6-hydroxyl hexyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(2R)-the 2-hydroxypropyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-[(1-propyl group butyl) alkylsulfonyl] propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(2-hydroxyl-1, the 1-dimethyl ethyl) amino] alkylsulfonyl } benzamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(4-phenyl butyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-benzyl iodide) amino] propyl group }-7-(1H-imidazoles-1-yl)-5,6-dialin-2-methane amide;
3-(kharophen)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-methyl benzamide;
N
1-[(1S, 2R)-3-{[2-(amino-sulfonyl) ethyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[2-(ethylmercapto group) ethyl] amino }-the 2-hydroxypropyl)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-[benzyl (cyano methyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-hydroxypropyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-[(3-butoxy propyl group) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[2-(2-hydroxyethyl) piperidines-1-yl] carbonyl }-the 5-methyl benzamide;
N-[(2S, 3R)-4-(3, the 5-difluorophenyl)-3-(3-[(dipropyl amino) carbonyl]-the 5-methyl benzoyl } amino)-2-hydroxyl butyl]-the β-An Jibingsuan methyl esters;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(1-hydroxyl-2-propyl group amyl group) benzamide;
N
1-[(1S, 2R)-3-(benzyl amino)-1-(3-chloro-5-luorobenzyl)-2-hydroxypropyl]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-[(methyl sulphonyl) amino] butyramide;
N
1-[(1S, 2R)-3-{[3-(1-thionaphthene-2-yl) benzyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
3-(benzyloxy)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-2-hydroxypropyl } isoxazole-5-methane amide;
The 2-{[(benzyloxy) carbonyl] amino }-7-[(cyclopropyl methyl) amino]-1,2,4,5,7-pentadecyl oxygen-5-(3, the 5-difluorobenzyl)-1-[(1-propyl group butyl) alkylsulfonyl]-right type-threo form ketoheptose trifluoro-acetate;
1-{3-[({ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino) carbonyl]-the 5-methyl benzoyl }-right type-prolineamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1H-pyrazol-1-yl) valeramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-(2-furyl methyl)-5-oxo-pyrrolidine-3-methane amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(5-hydroxyl amyl group) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
3-[({ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(1-methyl)-the 1-styroyl] amino } propyl group } amino) alkylsulfonyl]-N, N-dipropyl benzamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
3, N
3-dipropyl piperidines-1, the 3-diformamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
3, N
3-diethyl piperidines-1, the 3-diformamide;
5-bromo-N
1-((1S, 2R)-2-hydroxyl-1-(PFBBR)-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-[(methyl sulphonyl) amino] benzamide;
N-{ (1S, 2R)-1-(3-bromobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
3-[(dipropyl amino) alkylsulfonyl]-N-[(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(thiophene-2-ylmethyl) propyl group } propionic acid amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-ethoxycarbonyl propyl) amino]-the 2-hydroxypropyl }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(thiophene-2-ylmethyl) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl-4-(phenyl sulfonyl) butyramide;
N
1-[(1S, 2R)-1-(3, the 5-dichloro benzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3, the 3-dimethylbutyl) amino]-the 2-hydroxypropyl }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-(benzyl amino)-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-[(1S, 2R)-1-(3-chloro-5-luorobenzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(1, the 3-diphenyl propyl) amino]-the 2-hydroxypropyl }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1S)-1-(methylol) propyl group] amino } propyl group)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(3S)-the tall and erect oxo nitrogen of 2-nitrogen Zhuo-3-yl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-cyclohexyl-N
5-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } valeramide;
N
1-[(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(3-methyl-benzyl) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-[(2-propyl group amyl group) alkylsulfonyl]-beta-amino propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(1,3-thiazoles-2-yl) benzamide;
N
1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(3-[methyl (phenyl) amino] and propyl group } amino) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(4-methyl-benzyl) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-oxo-1-(thiophene-2-ylmethyl) tetramethyleneimine-3-methane amide;
The 4-[(butylthio) methyl]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-2-furoamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-{[(2-hydroxyethyl) amino] alkylsulfonyl } benzamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methylcyclohexyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2-oxo-1,3-oxazolidine-3-yl) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(1H-pyrroles-1-yl) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,3,4,5-tetrahydro-thiapyran is [4,3-b] indoles-8-methane amide also;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
4-[2-(trifluoromethyl) phenyl] succinic diamide;
N
1-[(1S, 2R)-1-(3-bromobenzyl)-2-hydroxyl-3-(isoamylamino) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4,5-dimethyl-2-(1H-pyrroles-1-yl) thiophene-3-methane amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(2, the 3-dihydroxypropyl) amino]-the 2-hydroxypropyl }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(2S)-the 2-hydroxypropyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1R)-the 1-methyl-propyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
2-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(methyl sulphonyl) benzamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(2-hydroxyethyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S, 2R)-2-hydroxyl-1-(3-methoxy-benzyl)-3-[(3-methoxy-benzyl) amino] propyl group } propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{ methyl [(trifluoromethyl) alkylsulfonyl] amino } benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-hydroxyl-6-(1-hydroxyl-2,2-dimethyl propyl) pyridine-2-carboxamide;
N
1-[(1S, 2R)-3-[(1,3-dicyclohexyl propyl group) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,2 '-two thiophene-5-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(1H-imidazoles-1-yl) butyramide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,3-dihydroxyl-N
4-(4-p-methoxy-phenyl) succinic diamide;
N
1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(4-hydroxybenzyl) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-[3-(trifluoromethyl) benzyl] propyl group }-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(thiophene-2-ylmethyl) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-[(1S, 2R)-3-{[2-(aminocarboxyl)-1H-indoles-6-yl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-(benzyl amino)-1-(3-bromobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(1-oxo-1,3-dihydro-H-isoindole-2-yl) butyramide;
3-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(methyl sulphonyl) thiophene-2-carboxamide derivatives;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(1-ethyl propyl) amino]-the 2-hydroxypropyl }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-([(5R)-and 3-ethyl-2-oxo-1,3-oxazolidine-5-yl] methyl } amino)-the 2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-7-(trifluoromethyl) pyrazolo [1,5-a] pyrimidine-2-methane amide;
N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
2-[(methylthio group) ethanoyl]-3-[(1-propyl group butyl) alkylsulfonyl] amino propionic acid amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(2, the 3-Dimethylcyclohexyl) amino]-the 2-hydroxypropyl }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4,5-dimethoxy-1-thionaphthene-2-methane amide;
N
1-[(1S, 2R)-1-[3-fluoro-5-(trifluoromethyl) benzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-([(5S)-and 3-ethyl-2-oxo-1,3-oxazolidine-5-yl] methyl } amino)-the 2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(1,3-benzo dioxole-5-ylmethyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3,5-dioxo-1,2,4-triazolidine-4-yl) benzamide;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) aminopropyl }-2-hydroxyl-3-[(3-p-methoxy-phenyl) alkylsulfonyl] propionic acid amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(2-methylcyclohexyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-3-[(2-{4-[(3-benzyl chloride base) oxygen] phenyl } ethyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-2-hydroxypropyl-2-hydroxyl-4-oxo-4-thiene-3-yl-butyramide;
N
1-(1S, 2R)-1-[3-(benzyloxy)-5-luorobenzyl]-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl-4-oxo-4-[3-(trifluoromethyl) phenyl] butyramide;
N
1-(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-[3-(trifluoromethoxy) benzyl] propyl group }-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[1-(methylol)-3-(methylthio group) propyl group] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
2-(1H-1,2,3-benzotriazole-1-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } hexanamide;
N
1-[(1S, 2R)-1-(3-fluoro-4-methyl-benzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl)-2-{[(1-propyl group butyl) alkylsulfonyl] methyl } propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-{[(trifluoromethyl) alkylsulfonyl] amino } butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(5-methyl isophthalic acid, 3-dioxo-1,3-dihydro-2H-isoindole-2-yl) ethanamide;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[1-(methylol) propyl group] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-(benzylamino)-1-(3, the 5-dichloro benzyl)-2-hydroxypropyl]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-the 3-{[(2-hydroxyethyl) (propyl group) amino] alkylsulfonyl } propionic acid amide;
5-(benzylthio)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } niacinamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-pyrazoles-5-methane amide;
6-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazole-5-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-benzimidazolyl-2 radicals-methane amide;
N
1-(1S, 2R)-1-(cyclohexyl methyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-6-hydroxyl-4,7-dimethoxy-1-cumarone-5-methane amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(4-methylcyclohexyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } [1,2,4] triazolo [4,3-a] pyridine-6-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl-4-oxo-4-thiophene-2-base butyramide;
N
1-[(1S, 2R)-3-(benzyl amino)-1-(3, the 5-dichloro benzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2-hydroxy-5-methyl base phenyl)-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-phenoxy benzamide;
The 4-[(aminocarboxyl) amino]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1S)-1-(methylol)-3-(methylthio group) propyl group] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-7-hydroxyl-4-oxo look alkane-2-methane amide;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1S)-1-(methylol)-3-methyl butyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1R)-1-(methylol) propyl group] amino } propyl group)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(1-methyl-3-phenyl propyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2,3-dihydro-1-cumarone-5-yl)-1,3-thiazoles-4-methane amide;
N
1-(1S, 2R)-1-[3-(benzyloxy) benzyl]-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(4-benzyl chloride base)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-amyl group Malonamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(trifluoromethoxy) benzamide;
3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S, 2R)-1-(3-fluoro-4-methyl-benzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } propionic acid amide;
N-[(1S, 2R)-1-(3-chloro-5-luorobenzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-3-[(3-dipropyl amino) alkylsulfonyl] propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl)-2-{[(1-propyl group butyl) alkylsulfonyl] methyl } propionic acid amide;
N
1-[4-(acetylamino) phenyl]-N
4-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } succinic diamide;
3-(1-cyanoethyl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
4-(5-phenyl-1,3,4-thiadiazoles-2-yl) succinic diamide;
N
1-(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-[3-(trifluoromethoxy) benzyl] propyl group }-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[2-(2-oxo-2-tetramethyleneimine-1-base oxethyl) phenyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-1-(4-benzyl chloride base)-2-hydroxyl-3-(isopentyl amino) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(1,1-titanium dioxide tetramethylene sulfide-2-yl) ethanamide;
N
1-[(1S, 2R)-3-(benzyl amino)-1-(4-benzyl chloride base)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl-5-oneself-1-alkynyl niacinamide;
N-[(1S, 2R)-1-(3-bromobenzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-first oxygen isoxazole-5-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,3-dimethyl-1H-indoles-7-methane amide;
4-(3-chloro-phenyl-)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(1-Methyl-1H-indole-3-yl)-2-oxo ethanamide;
N
1-[(1S, 2R)-1-(3-fluoro-4-methyl-benzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
3-[(dipropyl amino) alkylsulfonyl]-N-[(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(4-methyl-benzyl) propyl group] propionic acid amide;
N
1-[(1S, 2R)-3-(benzyl amino)-1-(3-fluoro-4-methyl-benzyl)-2-hydroxypropyl]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[5-(4-aminomethyl phenyl)-2H-tetrapyrrole-2-yl] ethanamide;
N-{ (1S, 2R)-1-(3, the 5-dichloro benzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N
1-(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(thiophene-2-ylmethyl) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-3-phenyl-isoxazole azoles-4-methane amide;
N
1-[(1S, 2R)-3-(benzyl amino)-1-(4-luorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-[(methyl sulphonyl) ethanoyl]-N
2-amyl group G-NH2;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(1H-indol-3-yl)-4-oxo butyramide;
N
1-(5-benzyl-1,3,4-thiadiazoles-2-yl)-N
4-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } succinic diamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3-fluoro-4-p-methoxy-phenyl)-4-oxo butyramide;
4-{[(2R, 3S)-4-(3, the 5-difluorophenyl)-3-(3-[(dipropyl amino) carbonyl]-the 5-methyl benzoyl } amino)-2-hydroxyl butyl] amino } piperidines-1-ethyl formate;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2-fluoro benzoyl)-1H-pyrroles-2-methane amide;
N
1-[(1S, 2R)-3-(benzyl amino)-1-(4-benzyl chloride base)-2-hydroxypropyl]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-[3-(trifluoromethyl) benzyl] propyl group }-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-[(1S, 2R)-2-hydroxyl-1-(4-hydroxybenzyl)-3-(isopentyl amino) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(4-morpholine-4-base phenyl) ethanamide;
3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-[3-(trifluoromethoxy) benzyl] propyl group } propionic acid amide;
N
1-benzyl-N
1-(1-cyclopropyl ethyl)-N
4-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } succinic diamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-(2, the 5-dimethylbenzoyl)-5-methyl benzamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
4-(2-methoxyl group-5-aminomethyl phenyl) succinic diamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(3-hydroxy phenyl) ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-[hydroxyl (2-aminomethyl phenyl) methyl]-the 5-methyl benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(ethylmercapto group) niacinamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-[4-(2-furoyl base) piperazine-1-yl]-4-oxo butyramide;
N
1-[(1S, 2R)-3-(benzyl amino)-1-(3-fluoro-4-methyl-benzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-oxoisoindoline diindyl-1-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(ethylmercapto group) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } thieno-[2,3-b] quinoline-2-formamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(4-methyl isophthalic acid, 3-oxazole-2-yl) benzamide;
N
1-[(1S, 2R)-3-(benzyl amino)-1-(4-luorobenzyl)-2-hydroxypropyl]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N-{2-[({ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino) carbonyl] phenyl }-N-methyl-2-furoamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl-4-(3-p-methoxy-phenyl)-4-oxo butyramide;
N
1-[(1S, 2R)-3-(suberyl amino)-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(4-methyl-benzyl) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
1,3-[(dipropyl amino) alkylsulfonyl] N-{ (1S, 2R)-1-(3-fluoro-5-hydroxybenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } propionic acid amide;
3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S, 2R)-1-(3-fluoro-5-hydroxybenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-hydroxyl-1H-indoles-2-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,2-diformazan primary colours alkane-8-methane amide;
6-benzyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } piperazine-2-methane amide-4-oxide compound;
2-{[({ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } amino) carbonyl] amino }-N, N-dipropyl ethane sulphonamide;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1R)-1-(methylol)-2-methyl-propyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-[(1S, 2R)-3-(benzyl amino)-1-(3-chloro-5-luorobenzyl)-2-hydroxypropyl]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(4-p-methoxy-phenyl)-4-oxo butyramide;
N
1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(4-hydroxybenzyl) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl 4-oxo-3,4-dihydro naphthyridine-1-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3,4-dihydro-2H-1,5-benzo dioxepine-7-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[4-(2,5-dioxo tetramethyleneimine-1-yl) phenoxy group] ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-4-oxo-3, the 4-dihydro-thiophene is [2,3-d] pyrimidine-6-methane amide also;
N
1-[(1S, 2R)-1-(1,3-benzo dioxole-5-ylmethyl)-2-hydroxyl-3-(3-isopentyl amino) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-(1S, 2R)-1-(3-chloro-5-luorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
5, N
5-dipropyl glutaramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-6-fluoro-2-hydroxyl quinoline beautiful jade-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-oxo-4-thiophene-2-base butyramide;
N
3-[((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } amino) carbonyl]-N
1, N
1-dipropyl-beta-amino propionic acid amide;
N
1-(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-the 1-[(thiophenyl) methyl] propyl group }-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1R, 2S)-1-(methylol)-2-methyl butyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(phenoxymethyl) benzamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
5-(2,4 difluorobenzene base) glutaramide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
5-(4.6-dimethyl pyrimidine-2-yl) glutaramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-(3-anisoyl)-5-methyl benzamide;
N
1-(1S, 2R)-1-[3-(benzyloxy) benzyl]-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
4-(3, the 4-dichlorophenyl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-oxo butyramide;
4-{ (2R, 3R)-2-(3-[(dipropyl amino) carbonyl]-the 5-methyl benzoyl } amino)-3-hydroxyl-4-[(3-methoxy-benzyl) amino] butyl } methyl benzoate;
N
1-(4-acetylphenyl)-N
5-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } glutaramide;
N
1-(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-the 1-[(thiophenyl) methyl] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
2-{[3-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino)-the 3-oxopropyl] sulfenyl }-N-methyl-benzamide;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-[(1-propyl group butyl) sulfenyl] propionic acid amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
4-(4-ethoxyl phenenyl) succinic diamide;
N
1-[(1S, 2R)-1-[3-(benzyloxy)-5-luorobenzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
2-{[(2R, 3S)-4-(3, the 5-difluorophenyl)-3-(3-[(dipropyl amino) carbonyl]-the 5-methyl benzoyl } amino)-2-hydroxyl butyl]-amino } ethyl 3-p-methoxy-phenyl carbamate;
3-(benzyloxy)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1S)-2-hydroxyl-1-methylethyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-2-hydroxyl-1-(PFBBR)-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(4-hydroxy phenyl)-4-oxo butyramide;
3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-[3-(trifluoromethyl) benzyl] propyl group } propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(piperidines-3-base alkylsulfonyl) benzamide;
6-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-hydroxyl quinoline beautiful jade-2-methane amide;
N
1-[(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(thiophene-2-ylmethyl) propyl group]-N
5, N
5-dipropyl glutaramide;
N
1-((1S)-1-{ (1R)-1-hydroxyl-2-[(3-methoxy-benzyl) amino] ethyl }-the 3-methyl butyl)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(6-oxo-3-phenylpiperazine-1 (6H)-yl) ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-{4-[(methyl sulphonyl) amino] phenyl } propionic acid amide;
N
1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(4-methyl-benzyl) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
3-(2-chlorophenoxy)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group } propionic acid amide;
N
1-[(1S, 2R)-1-(4-luorobenzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
May contain unsupported peptide in the existing version in the structure;
1N-{ (1S, 2R)-1-[3-(benzyloxy)-5-luorobenzyl]-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(4-aminomethyl phenyl)-4-oxo butyramide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
4-[3-(trifluoromethyl) phenyl] succinic diamide;
N
1-(1S, 2R)-1-(1,3-benzo dioxole-5-ylmethyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(5-piperidines-2-base-2H-tetrapyrrole-2-yl) ethanamide;
May contain unsupported peptide in the existing version in the structure;
3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(3-methyl-benzyl) propyl group] propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-2-hydroxypropyl } isoxazole-5-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(3,5-dimethoxy phenoxy group) ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2,5-dimethyl-1H-pyrroles-1-yl)-3-hydroxybenzamide;
N
1-(1S, 2R)-1-(3-bromobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
5, N
5-dipropyl glutaramide;
N1-[5-(cyclopentyl-methyl)-1,3,4-thiadiazoles-2-yl]-N
4-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } succinic diamide;
N
1-(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-[3-(trifluoro-benzyl) benzyl] propyl group }-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(3-oxo-1,2-benzisothiazole-2 (3H)-yl) ethanamide;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[1-methyl-5-(tetramethyleneimine-1-base carbonyl)-1H-pyrroles-3-yl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3, the 4-difluorophenyl)-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2-naphthyl)-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4,6-diethoxy pyridine-2-carboxamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(5-methyl isophthalic acid H-pyrroles-2-yl)-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-({ [2-(methylamino) ethyl] amino } alkylsulfonyl) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-dipropyl isophthaloyl amine;
N-[(1S, 2R)-1-(1,3-benzo dioxole-5-ylmethyl)-3-(benzylamino)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(piperazine-1-base alkylsulfonyl) benzamide;
N
1-[(1S, 2R)-3-(2-[4-(amino-sulfonyl) phenyl] and ethyl } amino)-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[2-hydroxyl]-1-(methylol) ethyl } amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-1-(4-fluoro-3-methyl-benzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(3-oxo-2,1-benzisothiazole-1 (3H)-yl) propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2,6-dihydroxy-pyrimidine-4-yl) ethanamide;
N
1-(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-[3-(trifluoromethyl) benzyl] propyl group }-N
5, N
5-dipropyl glutaramide;
N-{ (1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(4-hydroxybenzyl) propyl group]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3, the 4-difluorophenyl)-2-methyl-4-oxo butyramide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
5-(2-pyridine-2-base ethyl) glutaramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[2-(4-fluorophenyl)-1,3-benzoxazole-5-yl] ethanamide;
N
2-(anilino carbonyl)-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } G-NH2;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(1,3-dithiane-2-yl)-3-furoamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[2-oxo-2-(propyl group amino) ethyl] benzamide;
N-[(1S, 2R)-3-(benzylamino)-1-(3-bromobenzyl)-2-hydroxypropyl]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-3-(2-fluorophenyl) propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-thiotolene-2-methane amide;
2-[4-(benzyloxy) phenyl]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group } ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[(5,7-dimethyl [1,2,4] triazolo [4,3-a] pyrimidin-3-yl) sulfenyl] ethanamide;
N
1-(1-ethanoyl-2,3-dihydro-1H-indoles-7-yl)-N
4-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } succinic diamide;
N
1-(3-acetylphenyl)-N
5-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } glutaramide;
3-(4-chlorophenoxy)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl propionic acid amide;
N
1-[(1S, 2R)-3-(benzyl amino)-1-(3-fluoro-4-methoxy-benzyl)-2-hydroxypropyl]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(3-methyl-benzyl) propyl group]--N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-indoles-7-methane amide;
N
1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(3-methyl-benzyl) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(1,2,3-thiadiazoles-4-yl) benzamide;
N-{ (1S, 2R)-1-[3-(benzyloxy)-5-luorobenzyl]-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl)-2-{[(1-propyl group butyl) alkylsulfonyl] methyl } propionic acid amide;
N
1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(4-methyl-benzyl) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-3-(benzylamino)-1-[3-fluoro-5-(trifluoromethyl) benzyl]-the 2-hydroxypropyl }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[1-methyl-3-(methylthio group)-1H-indoles-2-yl] ethanamide;
N
1-[(1S, 2R)-1-(3, the 5-dichloro benzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2-furyl)-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(3-pyridine-2-base-1,2,4-oxadiazole-5-yl) propionic acid amide;
2-[2-(acetylamino)-1,3-thiazoles-4-yl]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[(4-methyl-4H-1,2,4-triazole-3-yl) sulfenyl]-the 2-phenyl-acetamides;
N
1-[(1S, 2R)-1-(4-benzyl chloride base)-2-hydroxyl-3-(isopentyl amino) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
4-(1,3-benzothiazole-2-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } butyramide;
N
1-(3-chloro-4-fluorophenyl)-N
4-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } succinic diamide;
N
1-[(1S, 2R)-1-[3-(benzyloxy)-5-luorobenzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[(2-oxo-2,3-dihydro quinoline beautiful jade-4-yl) sulfenyl] ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-methyl-5-(2-methyl benzoyl) benzamide;
N
1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(4-methyl-benzyl) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-propoxy-benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-Methyl-1H-indole-2-methane amide;
5-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(3-methyl-4H-1,2,4-triazole-4-yl) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3, the 4-difluorophenyl)-2-methoxyl group-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(3-thiophene-2-base-1H-pyrazol-1-yl) ethanamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
5-phenyl glutaramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2-sulfo--1,3-benzothiazole-3 (2H)-yl) ethanamide;
N
1-[(1S, 2R)-3-(benzyl amino)-1-(cyclohexyl methyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-2-hydroxypropyl-1-(4-methoxy-benzyl)-3-[(3-methoxy-benzyl) amino] propyl group }-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(3-hydroxy-4-methyl phenyl) ethanamide;
N
1-[(1S, 2R)-1-[3-fluoro-5-(trifluoromethyl) benzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-7-fluoro-4H-imidazo [5,1-c] [1,4] benzoxazine-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3,4-dihydro-2H-1,5-benzo dioxepin-7-yl)-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-cumarone-3-methane amide;
N
1-(3, the 4-dichlorophenyl)-N
3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } Malonamide;
N
1-(1S, 2R)-3-(benzyl amino)-1-[3-fluoro-5-(trifluoromethyl) benzyl]-the 2-hydroxypropyl }-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1R)-2-hydroxyl-1-methylethyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(3-methyl-benzyl) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
5-pyridin-3-yl glutaramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-methyl-4-oxo-4H-chromene-6-methane amide;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(1H-imidazoles-1-yl) propyl group] amino } propyl group)-5-methyl-N
3N
3-dipropyl isophthaloyl amine;
3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S, 2R)-1-[3-fluoro-5-(trifluoromethyl) benzyl]-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } propionic acid amide;
3-[(dipropyl amino) alkylsulfonyl]-N-[(1S, 2R)-2-hydroxyl-1-(4-hydroxybenzyl)-3-(isopentyl amino) propyl group] propionic acid amide;
N
1-[(1S, 2R)-1-(1,3-benzo dioxole-5-ylmethyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
3-[(dipropyl amino) alkylsulfonyl]-N-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(thiophene-2-ylmethyl) propyl group] propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-[(2,2-dimethyl propylene acyl group) amino]-the 2-hydroxybenzamide;
N
1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(3-methoxy-benzyl) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-((1S, 2R)-1-(4-luorobenzyl)-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-the 3-{[(3-methoxy-benzyl) amino] alkylsulfonyl } benzamide;
N
1-(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-[3-(trifluoromethyl) benzyl] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-[6-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino)-the 6-oxo-hexyl]-the 2-furoamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[(1-phenyl-4,5-dihydro-1H-tetrapyrrole-5-yl) sulfenyl] ethanamide;
4-ethanoyl-4-amino-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } hexamethylene-1,5-diene-1-sulphonamide;
N-((1S, 2S)-1-benzyl-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-the 3-{[(3-methoxy-benzyl) amino] alkylsulfonyl } benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3,4-dihydro-2H-chromene-6-yl)-4-oxo butyramide;
N
1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(3-methoxy-benzyl) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-(1S, 2R)-1-(3-fluoro-4-methyl-benzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
5, N
5-dipropyl glutaramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } indolizine-2-methane amide;
N
1-(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-[3-(trifluoromethoxy) benzyl] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } niacinamide 1-oxide compound;
N-[(1S, 2R)-1-[3-(benzyloxy)-5-luorobenzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
2-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group } amino)-2-oxoethyl carbamate;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,3-dihydro-1H-cyclopenta [b] quinoline beautiful jade-9-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl isophthalic acid H-pyrazoles-5-methane amide;
N-[5-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino)-5-oxo amyl group] benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-[(methoxymethyl) sulfenyl] benzamide;
3-(1,3-benzothiazole-2-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methoxy propyl acid amides;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-{[(methylamino-) carbonyl] amino }-3-thiene-3-yl-propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-pyridine-2-base thiophene-2-carboxamide derivatives;
N
1-(1S, 2R)-3-(benzyl amino)-1-[3-(benzyloxy)-5-luorobenzyl]-the 2-hydroxypropyl }-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(5,6-dimethyl-2,4-dioxy-1,2,3,4-tetrahydropyridine-3-yl) ethanamide;
N
1-[(1S, 2R)-1-(3-fluoro-4-methoxy-benzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-isobutyl--1,3-dioxoisoindolin-5-methane amide;
3-[({ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino) alkylsulfonyl] phenylformic acid;
5-(acetylamino)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-furoamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-[(4-p-methoxy-phenyl) ethanoyl] G-NH2;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } different quinoline beautiful jade-4-methane amide;
N
1-[(1S, 2R)-1-[3-(benzyloxy) benzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(4-hydroxy 3-methoxybenzene base) ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[(4-phenyl-4H-1,2,4-triazole-3-yl) sulfenyl] ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(3, the 5-Dimethoxyphenyl) ethanamide;
N
1-[(1S, 2R)-3-(benzylamino)-2-hydroxyl-1-(3-methoxy-benzyl) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2-ethyl-4H-[1,2,4] triazolo [1,5-a] benzoglyoxaline-4-yl) ethanamide;
N
1-[(1S, 2R)-3-(benzylamino)-1-(2-furyl methyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
7-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 1-benzofuran-2-carboxamides;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl) propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(2-oxo-2H-1,3-benzoxazine-3 (4H)-yl) propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(pyrimidine-2-base sulfenyl) ethanamide;
N
1-[3-(aminocarboxyl)-4,5,6,7-tetrahydrochysene-1-thionaphthene-2-yl]-N
4-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } succinic diamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[(5-phenyl-1,3,4-oxadiazole-2-yl) sulfenyl] ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } quinoline beautiful jade-6-methane amide;
N
1-[(1S, 2R)-3-(benzyl amino)-1-(2-furyl methyl)-2-hydroxypropyl]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2,3-dihydro-1,4-benzo dioxin-6-yl)-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(1H-indol-3-yl)-1H-pyrazoles-5-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl-4-{[(methylamino-) the carbonyl sulfenyl] amino } benzamide;
6-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } niacinamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3-hydroxy phenyl)-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2-2-base sulfenyl) ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[(1-pyridine oxide-2-yl) sulfenyl 1 ethanamide;
3-(acetylamino)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-fluoro-1H-indoles-2-methane amide;
N-((1S, 2R)-1-benzyl-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-3-{[(3-benzyl chloride base) amino] alkylsulfonyl } benzamide;
N
1-[(1S, 2R)-1-(1,3-benzo dioxole-5-ylmethyl)-3-(benzylamino)-2-hydroxypropyl]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
4-(3, the 4-dichlorophenyl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxy-3-methyl-4-oxo butyramide;
3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-[3-(trifluoromethoxy) benzyl] propyl group } propionic acid amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
4-(5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl) succinic diamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2-ethyl-1H-benzoglyoxaline-1-yl) ethanamide;
N-{ (1S, 2R)-1-(1,3-benzodioxole-5-ylmethyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(2-oxo-1,3-benzoxazole-3 (2H)-yl) propionic acid amide;
N-[(1S, 2R)-1-(3, the 5-dichloro benzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
4-(6-picoline-2-yl) succinic diamide;
(4R)-4-[({ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino) carbonyl]-1,3-oxazolidine-3-ethyl formate;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-glycyl benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(1-methyl isophthalic acid H-imidazoles-2-yl) benzamide;
4-(acetylamino)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } the butyramide trifluoroacetate;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-[(3S)-and tetrahydrofuran (THF)-3-base oxo] carbonyl }-right type-leucyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(tetramethyleneimine-3-base alkylsulfonyl) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-[(dipropyl amino) methyl] benzamide;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1R)-1-(methylol)-3-methyl butyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-the 3-[tertiary butyl (cyclohexyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1S)-1-(methylol)-2, the 2-dimethyl propyl] amino } propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-([(2R)-and 1-ethyl pyrrolidine-2-yl] methyl } amino)-the 2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[3-(dimethylamino)-2, the 2-dimethyl propyl] amino }-the 2-hydroxypropyl)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[2-(diisopropylaminoethyl) ethyl] amino }-the 2-hydroxypropyl)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(1-ethyl pyrrolidine-2-yl) methyl] amino }-the 2-hydroxypropyl)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-[(1-benzyl-pyrrole alkane-3-yl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-tetramethyleneimine-1-base propyl group) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[3-(dimethylamino) propyl group] amino }-the 2-hydroxypropyl)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-{[2-(acetylamino) ethyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[2-(6-oxo-1,4,5,6-tetrahydro pyridazine-3-yl) phenyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-[7-chloro-1-(2-hydroxy 3-methoxybenzene base)-3, the different quinoline beautiful jade-2 of 4-dihydro (1H)-yl]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-{[4-(1-cyano group cyclopentyl) phenyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-(4-[4-(acetylamino) phenoxy group] and phenyl } amino)-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-[(4-benzoyl-2, the 3-3,5-dimethylphenyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-[(2-amino-2-oxo-1-styroyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{4-[(1-methyl isophthalic acid H-imidazoles-2-yl) methyl] piperazine-1-yl } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-[3, two (trifluoromethyl) benzyls of 5-]-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
(1S, 2R)-N
1-[2-(tertiary butyl sulfenyl) ethyl]-N
2-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } cyclopropane-1, the 2-diformamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4, the 5-dihydro-naphtho [2,1-d] isoxazole-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-methyl isophthalic acid H-benzo [g] indazole-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-methyl isophthalic acid, the 3-thiazole-4-carboxamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-methoxyl group-1H-pyrrole-3-carboxamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-9-oxo-1,2,3,9-tetrahydro cyclopentyl diene is [b] chromene-7-methane amide also;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2-oxo-2,3-dihydro-1H-benzoglyoxaline-5-yl) ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2-oxo-2,3-dihydro-1,3-benzoxazole-5-yl) ethanamide;
2-[2-(1,3-benzoxazole-2-yl) phenoxy group]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide;
5-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-morpholine-4-yl-benzamide;
3-(3-Lv isoxazole-5-base)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(6-methoxyl group-1,1 '-phenylbenzene-3-yl)-4-oxo butyramide;
4-(1-cumarone-2-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-oxo-1,2,3,4-tetrahydrochysene quinoline beautiful jade-3-methane amide;
2-(1-cumarone-2-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-methyl propanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-6-methoxyl group-1-benzofuran-2-carboxamides;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[4-(1H-pyrroles-1-yl) phenyl] propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-imidazo [1,2-b] pyrazoles-6-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-[(4-methyl isophthalic acid, the 3-thiazol-2-yl) sulfenyl] ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-methoxyl group-4-(methylthio group) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl-4-(propionamido) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 6-{[(4-aminomethyl phenyl) alkylsulfonyl] amino }-4-oxo hexanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-benzoglyoxaline-5-formyl ammonia;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-methyl-2-(1-oxo-1,3-dihydro-2H-isoindole-2-yl) propionic acid amide;
7-(acetylamino)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-methyl quinoline beautiful jade-5-methane amide;
N
3-(tert-butoxycarbonyl)-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the amino propionic acid amide of b-;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-hydroxyl-3-propyl group hexanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-phenyl-2-(1H-pyrroles-1-yl) ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-methyl-5-phenyl-1H-pyrazole-3-formamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(3-oxo-2,3-dihydro-1H-isoindole-1-yl) ethanamide;
4-[2-(acetylamino)-4, the 5-3,5-dimethylphenyl]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-oxo butyramide;
6-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } pyrazine-2-methane amide 4-oxide compound;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } methoxypyrazine-2-methane amide 4-oxide compound;
2-(1H, 1 ' H-2,2-diimidazole-1-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide;
5-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,3-dihydro-1-cumarone-7-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-([1,2,4] triazolo [4,3-b] pyrazine-6-base sulfenyl) ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl isophthalic acid-pyridin-4-yl-1H-1,2,3-triazole-4-methane amide;
2-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-oxo-3,4-dihydroquinazoline-6-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(7-methoxyl group-1-cumarone-2-yl)-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[(2-ethyl-1-oxo-2,3-dihydro-1H-isoindole-5-yl) oxo] propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } pyrazine-2-methane amide 4-oxide compound;
7-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } quinoline beautiful jade-2-methane amide;
2-cyano group-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(3, the 4-Dimethoxyphenyl)-2-methyl propanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl-5-(propionyl amino) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[2-oxo-5-(trifluoromethyl) pyridine-1 (2H)-yl] propionic acid amide;
5-(4-chloro-phenyl-)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-furoamide;
4-cyano group-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(1H-pyrroles-1-yl) thiophene-2-carboxamide derivatives;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3, two (methylthio group) isothiazole of 5--4-methane amide;
2-chloro-4-cyano group-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(methoxyl group ethanoyl) amino]-the 3-Phenylpropionamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-fluoro-4-morpholine-4-yl-benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(1-epoxy thiomorpholine-4-yl) butyramide;
4-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide;
N-{2-[({ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino) carbonyl] phenyl }-5-methyl-2-furoamide;
1-(cyano methyl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-pyrroles-2-methane amide;
N
1-(2-chloropyridine-3-yl)-N
4-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } succinic diamide;
3-(cyclopentyloxy)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-methoxy benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(5-tetramethyleneimine-1-base-2H-tetrazolium-2-yl) ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,5-dimethyl-1-phenyl-1H-pyrrole-3-carboxamide;
1-(4-acetylphenyl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } piperidines-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-methyl-2-(1H-1,2,4-triazol-1-yl) propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(piperidines-1-ylmethyl)-2-furoamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-methyl-2,3-dihydro-1-thionaphthene-2-methane amide-1,1-dioxide;
2-(2,1,3-Ben Bing oxadiazole-5-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,3-thiazoles-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4, the 5-dihydrofuran is [2,3-g] [2,1] benzoisoxazole-8-methane amide also;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-[(4-methyl isophthalic acid, 2,3-thiadiazoles-5-yl) sulfenyl] ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-(2-furoyl base)-4-hydroxyl prolineamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-oxo-4,5,6,7-tetrahydrochysene-1-cumarone-3-methane amide;
4,5-two chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } isothiazole-3-methane amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
5-(1,3-thiazoles-2-yl) glutaramide;
N-ethanoyl-4-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } the phenyl amino propionic acid amide;
8-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-hydroxyl cinnolines-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,6-dioxo pentahydro-pyrimidine-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(5-methyl-4-phenyl-1,3-oxazole-2-yl) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-phenylimidazole [1,2-a] pyridine-6-methane amide also;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[3-(4-p-methoxy-phenyl)-1,2,4-oxadiazole-5-yl] propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-yl)-1,3-thiazoles-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-2-phenyl-2H-1,2,3-triazole-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3-pyridine-2-base-1,2,4-oxadiazole-5-yl) butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,3-dimethyl-1H-thieno-[2,3-c] pyrazoles-5-methane amide;
4-(1,3-benzo dioxole-5-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl-5-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base) isoxazole-4-methane amide;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[2-(dimethylamino)-1-methylethyl] amino }-the 2-hydroxypropyl)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(2-methylmorpholine-4-yl) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{2-[hydroxyl (phenyl) methyl]-4-methylpiperazine-1-yl } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(2R)-the 2-methyl butyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-{[4-(diethylamino)-1-methyl butyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(2-hydroxyl-1, the 1-dimethyl ethyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(pipecoline-1-yl) propyl group] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[5-(trifluoromethyl)-1,3,4-thiadiazoles-2-yl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methyl-4,5,6,7-tetrahydrochysene-3H-3 λ 4-[1,3] thiazole also [5,4-c] pyridine-2-yl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-the 3-[(3-Ethylbenzyl) amino]-2-hydroxyl-1-(1H-pyrazol-1-yl methyl) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
3, two (the kharophen)-N-{ of 5-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide;
N
1-[4-(amino-sulfonyl) phenyl]-N
4-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } succinic diamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-[methyl (methyl sulphonyl) amino] benzamide;
1-ethanoyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-piperidines-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(4-methoxyl group phenoxy group) propionic acid amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
4-methyl succinic diamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
4-(2, the 6-3,5-dimethylphenyl) succinic diamide;
N-ethanoyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-right type-phenyl amino propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-[(4-aminomethyl phenyl) alkylsulfonyl] ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-{[(ethylamino) carbonyl] amino } benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-phenyl-1,4,5,6-tetrahydro cyclopentyl diene is [c] pyrazole-3-formamide also;
4-(cyclopentyloxy)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
4-pyridin-3-yl succinic diamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
4-phenyl succinic diamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3, the 4-dihydroxy benzoyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1H-1,2,4-triazol-1-yl) valeramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-phenyl-1,3-oxazole-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-7-methoxyl group-4-oxo-1,2,3,4-tetralin-2-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-{4-[(methyl sulphonyl) amino] phenyl }-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-hydroxyl-7-methoxyl group-1-cumarone-5-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-hydroxyl-7-methoxyl group-1-thionaphthene-5-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3,6,6-trimethylammonium-4-oxo-4,5,6,7-tetrahydrochysene-1-benzofuran-2-carboxamides;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5,6-dihydro-4H-cyclopenta [b] thiophene-2-carboxamide derivatives;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,3-thiazoles-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2-pyridine-2-base-1,3-thiazoles-4-yl) ethanamide;
N
1-[5-(amino-sulfonyl)-1,3,4-thiadiazoles-2-yl]-N
4-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } succinic diamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-hydroxyl-6-neo-pentyl pyridine-2-carboxamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-(4-fluorophenyl)-1,4,5,6-tetrahydro cyclopentyl diene is [c] pyrazole-3-formamide also;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-methyl-5,6,7,8-tetrahydrochysene-4H-pyrazolo [1,5-a] azepine-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-methyl-3-furoamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-furoamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2-hydroxyl-oxethyl) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } thiophene-2-carboxamide derivatives;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2, N
2-dimethyl phthalamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-2-phenyl-1,3-oxazole-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)-2-maloyl group amine;
2-(2H-1,2,3-benzotriazole-2-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-indazole-3-formyl radical;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-hydroxy quinoxaline-2-methane amide;
2-(kharophen)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4,5-thioxene-3-methane amide;
N
1-(2-cyano-phenyl)-N
4-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } succinic diamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-ethyl-1H-indoles-2-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 1-benzofuran-2-carboxamides;
1-benzyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3,5-dimethyl-1H-pyrazole-4-carboxamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-[(4-aminomethyl phenyl) alkylsulfonyl] G-NH2;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4,8-dihydroxyl quinoline beautiful jade-2-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(1,1-titanium dioxide tetramethylene sulfide-3-yl) ethanamide;
5-[({ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino) carbonyl]-1H-benzimidazolyl-2 radicals-aminocarbamic acid methyl esters;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2-methyl isophthalic acid, 3-benzoxazole-5-yl) ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[ethyl (methyl) amino]-4-hydroxy pyrimidine-5-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2-pyridin-4-yl-1,3-benzoxazole-5-yl) ethanamide;
4-[2-(diethylamino) oxyethyl group]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide;
3-(amino-sulfonyl)-4-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide;
2-(diethylamino)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-hydroxy pyrimidine-5-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5,6,7,8-tetrahydrochysene-4H-cyclopenta [c] isoxazole-3-methane amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
4, N
4-phenylbenzene succinic diamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-6-hydroxy-4-methyl pyridine-2-carboxamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-phenylimidazole [1,2-a] pyridine-7-methane amide also;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } quinoline beautiful jade-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydrochysene-9H-purine-9-yl) ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methoxyl group-1H-indoles-2-formyl radical;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3,5-dimethyl-1H-pyrazol-1-yl) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-isoxazole-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl-isoxazole-5-methane amide;
2-(1-thionaphthene-4-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-2-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-thionaphthene-2-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 6-hydroxy nicotinoyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-[(4-aminomethyl phenyl) alkylsulfonyl]-beta-amino propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl quinoline beautiful jade-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(5-phenyl-1H-tetrapyrrole-1-yl) ethanamide;
The 4-{[(cyclobutyl carbonyl) amino] methyl }-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2-oxo-1,3-benzoxazole-3 (2H)-yl) butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(1,3-dioxo octahydro-2H-isoindole-2-yl) butyramide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-(tetrahydrofuran (THF)-2-ylmethyl) phthalamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2,3-dihydro-1H-indoles-1-yl)-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } thieno-[3,2-b] pyridine-6-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-sulfenyl of 2-[(6-methoxyl group-1H-benzimidazolyl-2 radicals-yl)] ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } thieno-[2,3-c] pyridine-2-carboxamide;
2-(1H-benzimidazolyl-2 radicals-Ji sulfenyl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(2, the 4-difluorobenzyl) the oxygen base] propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5,6-dimethyl-4-oxo-3,4-dihydro-thiophene be [2,3-d] pyrimidine-2-methane amide also;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-(2-fluorophenyl)-5-oxo-pyrrolidine-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(5-methyl isophthalic acid H-tetrapyrrole-1-yl) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(4,4-dimethyl-4,5-dihydro-1,3-oxazole-2-yl) thiophene-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(trifluoromethoxy)-1H-indoles-2-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-phenyl-5-propyl group-1H-pyrazole-4-carboxamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-[(pyridine-2-base sulfenyl) methyl]-the 2-furoamide;
5-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-morpholine-4-yl pyrimidines-4-methane amide;
5-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl isophthalic acid-phenyl-1H-pyrazole-4-carboxamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-methyl isophthalic acid, 2,3-thiadiazoles-5-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,1,3-Ben Bing oxadiazole-5-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[(imidazo [1,2-a] pyridine-2-ylmethyl) sulfenyl] ethanamide;
2-(kharophen)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-1,3-oxazole-4-methane amide '
N-{ (1S, 2R)-1-[3-(cyclohexyl methyl) benzyl]-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } ethanamide;
12-{[({ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } amino) carbonyl] amino }-N, N-dipropyl ethane sulphonamide;
2-(3-azabicyclo [3,2,2] non-3-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group } ethanamide;
2-(4-benzoyl phenoxy group)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group } propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-4-(7-methoxyl group-2,3-dihydro-1-cumarone-4-yl)-4-oxo butyramide;
N-{ (1S, 2R)-1-[3-(cyclohexyl methyl) benzyl]-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-the 3-{[(trifluoromethyl) alkylsulfonyl] amino } benzamide;
N
1-(1S, 2R)-1-[3-(cyclohexyl methyl) benzyl]-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
3-chloro-N-((1S, 2R)-1-(4-luorobenzyl)-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group) benzamide;
3-chloro-N-{ (1S, 2R)-1-(4-luorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } benzamide;
3-chloro-N-((1S, 2R)-1-(cyclohexyl methyl)-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group) benzamide;
3-chloro-N-{ (1S, 2R)-1-(cyclohexyl methyl)-2-hydroxyl-3-[(3-second methoxy-benzyl) amino] propyl group } benzamide;
N-((1S, 2R)-1-benzyl-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-the 3-chlorobenzamide;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-the 3-chlorobenzamide;
3-{[(3-benzyl chloride base) amino] alkylsulfonyl }-N-((1S, 2R)-1-(4-luorobenzyl)-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group) benzamide;
3-{[(3-benzyl chloride base) amino] alkylsulfonyl }-N-{ (1S, 2R)-1-(4-luorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } benzamide;
3-{[(3-benzyl chloride base) amino] alkylsulfonyl }-N-((1S, 2R)-1-(cyclohexyl methyl)-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group) benzamide;
3-{[(3-benzyl chloride base) amino] alkylsulfonyl }-N-{ (1S, 2R)-1-(cyclohexyl methyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } benzamide;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-{[(3-benzyl chloride base) amino] alkylsulfonyl } benzamide;
N-{ (1S, 2R)-1-(4-luorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-the 3-{[(3-methoxy-benzyl) amino] alkylsulfonyl } benzamide;
N-((1S, 2R)-1-(cyclohexyl methyl)-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-the 3-{[(3-methoxy-benzyl) amino] alkylsulfonyl } benzamide;
N-{ (1S, 2R)-1-(cyclohexyl methyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-the 3-{[(3-methoxy-benzyl) amino] alkylsulfonyl } benzamide;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-the 3-{[(3-methoxy-benzyl) amino] alkylsulfonyl } benzamide;
N
1-[(1R, 2S)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(4-methyl-benzyl) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-[(1R, 2S)-2-hydroxyl-3-(isopentyl amino)-1-(4-methyl-benzyl) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-[(1R, 2S)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(4-methyl-benzyl) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1R, 2S)-2-hydroxyl-3-(isopentyl amino)-1-(4-methyl-benzyl) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1R, 2S)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(4-methyl-benzyl) propyl group]-N
5, N
5-dipropyl glutaramide;
N
1-[(1R, 2S)-2-hydroxyl-3-(isopentyl amino)-1-(4-methyl-benzyl) propyl group]-N
5, N
5-dipropyl glutaramide;
3-[(dipropyl amino) alkylsulfonyl]-N-[(1R, 2S)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(4-methyl-benzyl) propyl group] propionic acid amide;
3-[(dipropyl amino) alkylsulfonyl]-N-[(1R, 2S)-2-hydroxyl-3-(isopentyl amino)-1-(4-methyl-benzyl) propyl group] propionic acid amide;
N
1-[(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(4-methyl-benzyl) propyl group]-N
5, N
5-dipropyl glutaramide;
N
1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(4-methyl-benzyl) propyl group]-N
5, N
5-dipropyl glutaramide;
N
1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(4-methyl-benzyl) propyl group]-N
5, N
5-dipropyl glutaramide;
N-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(4-methyl-benzyl) propyl group]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
3-[(dipropyl amino) alkylsulfonyl]-N-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(4-methyl-benzyl) amino] propionic acid amide;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-(4,5-dimethyl-2-furoyl base)-5-methyl benzamide;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-2-hydroxyl-3-(isopentyl alkylsulfonyl) propionic acid amide;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-the 3-{[(2-methoxy ethyl) (propyl group) amino] alkylsulfonyl } propionic acid amide;
N
1-(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-[(phenyl sulfenyl) methyl] propyl group }-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-[(phenyl sulfenyl) methyl] propyl group }-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-(1S, 2R)-3-(benzyl amino)-1-[4-(benzyloxy) benzyl]-the 2-hydroxypropyl }-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-[(1S, 2R)-1-[4-(benzyloxy) benzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-[(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(1-naphthyl methyl) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(1-naphthyl methyl) propyl group]--N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(1-naphthyl methyl) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-[(1S, 2R)-1-(2-furyl methyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-(1S, 2R)-3-(benzyl amino)-1-[3-(benzyloxy) benzyl]-the 2-hydroxypropyl }-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-[(1S, 2R)-2-hydroxyl-1-(4-hydroxybenzyl)-3-(isopentyl amino) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-((1S)-1-{ (1R)-1-hydroxyl-2-[(3-methoxy-benzyl) amino] ethyl } fourth-3-alkynyl)-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-(1S)-1-[(1R)-and 2-(benzyl amino)-1-hydroxyethyl] fourth-3-alkynyl }-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-(1S)-1-[(1R)-and 1-hydroxyl-2-(isopentyl amino) ethyl] fourth-3-alkynyl }-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-[(1S, 2R)-3-(benzyl amino)-1-(cyclohexyl methyl)-2-hydroxypropyl]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-[(1S, 2R)-1-(cyclohexyl methyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-((1S)-1-{ (1R)-1-hydroxyl-2-[(3-methoxy-benzyl) amino] ethyl }-the 3-methyl butyl)-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-(1S)-1-[(1R)-1-hydroxyl-2-(isopentyl amino) ethyl]-the 3-methyl butyl }-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-(1R, 2R)-3-(benzyl amino)-2-hydroxyl-1-[(phenyl sulfenyl) methyl] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1R, 2R)-2-hydroxyl-3-(isopentyl amino)-1-[(phenyl sulfenyl) methyl] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-3-(benzyl amino)-1-[4-(benzyloxy) benzyl]-the 2-hydroxypropyl }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-1-[4-(benzyloxy) benzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(1-naphthyl methyl) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-(benzylamino)-2-hydroxyl-1-(1-naphthyl methyl) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-(isopentyl amino)-1-(1-naphthyl methyl) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-1-(2-furyl methyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-3-(benzyl amino)-1-[3-(benzyloxy) benzyl]-the 2-hydroxypropyl }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-1-[3-(benzyloxy) benzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-1-(4-luorobenzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(thiophene-2-ylmethyl) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S)-1-{ (1R)-1-hydroxyl-2-[(3-methoxy-benzyl) amino] ethyl } fourth-3-alkynyl)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S)-1-[(1R)-and 2-(benzyl amino)-1-hydroxyethyl] fourth-3-alkynyl }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S)-1-[(1R)-and 1-hydroxyl-2-(isopentyl amino) ethyl] fourth-3-alkynyl }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-1-(cyclohexyl methyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S)-1-[(1R)-1-hydroxyl-2-(isopentyl amino) ethyl]-the 3-methyl butyl }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-{ (phenyl sulfenyl) methyl } propyl group }-N
5, N
5-dipropyl glutaramide;
N
1-(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-[(phenyl sulfenyl) methyl] propyl group }-N
5, N
5-dipropyl glutaramide;
N
1-(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-[(phenyl sulfenyl) methyl] propyl group }-N
5, N
5-dipropyl glutaramide;
N
1-(1S, 2R)-3-(benzyl amino)-1-[4-(benzyloxy) benzyl]-the 2-hydroxypropyl }-N
5, N
5-dipropyl glutaramide;
N
1-[(1S, 2R)-1-[4-(benzyloxy) benzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-N
5, N
5-dipropyl glutaramide;
N
1-[(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(1-naphthyl methyl) propyl group]-N
5, N
5-dipropyl glutaramide;
N
1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(1-naphthyl methyl) propyl group]-N
5, N
5-dipropyl glutaramide;
N
1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(1-naphthyl methyl) propyl group]-N
5, N
5-dipropyl glutaramide;
N
1-[(1S, 2R)-3-(benzyl amino)-1-(2-furyl methyl)-2-hydroxypropyl]-N
5, N
5-dipropyl glutaramide;
N
1-[(1S, 2R)-1-(2-furyl methyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N
5, N
5-dipropyl glutaramide;
N
1-(1S, 2R)-1-[3-(benzyloxy) benzyl]-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
5, N
5-dipropyl glutaramide;
N
1-(1S, 2R)-3-(benzyl amino)-1-[3-(benzyloxy) benzyl]-the 2-hydroxypropyl }-N
5, N
5-dipropyl glutaramide;
N
1-[(1S, 2R)-1-[3-(benzyloxy) benzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-N
5, N
5-dipropyl glutaramide;
N
1-[(1S, 2R)-3-(benzyl amino)-1-(4-luorobenzyl)-2-hydroxypropyl]-N
5, N
5-dipropyl glutaramide;
N
1-[(1S, 2R)-1-(4-luorobenzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N
5, N
5-dipropyl glutaramide;
N
1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(thiophene-2-ylmethyl) propyl group]-N
5, N
5-dipropyl glutaramide;
N
1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(thiophene-2-ylmethyl) propyl group]-N
5, N
5-dipropyl glutaramide;
N
1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(4-hydroxybenzyl) propyl group]-N
5, N
5-dipropyl glutaramide;
N
1-[(1S, 2R)-2-hydroxyl-1-(4-hydroxybenzyl)-3-(isopentyl amino) propyl group]-N
5, N
5-dipropyl glutaramide;
N
1-((1S)-1-{ (1R)-1-hydroxyl-2-[(3-methoxy-benzyl) amino] ethyl } fourth-3-alkynyl)-N
5, N
5-dipropyl glutaramide;
N
1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(4-isopropyl benzyl) propyl group]-N
5, N
5-dipropyl glutaramide;
N
1-(1S)-1-[(1R)-and 2-(benzyl amino)-1-hydroxyethyl] fourth-3-alkynyl }-N
5, N
5-dipropyl glutaramide;
N
1-[(1S, 2R)-2-hydroxyl-3-(sec.-propyl amino)-1-(4-isopropyl benzyl) propyl group]-N
5, N
5-dipropyl glutaramide;
N
1-(1S)-1-[(1R)-and 1-hydroxyl-2-(isopentyl amino) ethyl] fourth-3-alkynyl }-N
5, N
5-dipropyl glutaramide;
N
1-(1S, 2R)-1-(cyclohexyl methyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
5, N
5-dipropyl glutaramide;
N
1-(1S, 2R)-1-[3-fluoro-5-(trifluoromethyl) benzyl]-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
5, N
5-dipropyl glutaramide;
N-[(1S, 2R)-1-(4-benzyl chloride base)-2-hydroxyl-3-(isopentyl amino) propyl group]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N
1-[(1S, 2R)-3-(benzyl amino)-1-(cyclohexyl methyl)-2-hydroxypropyl]-N
5, N
5-dipropyl glutaramide;
N
1-(1S, 2R)-3-(benzyl amino)-1-[3-fluoro-5-(trifluoromethyl) benzyl]-the 2-hydroxypropyl }-N
5, N
5-dipropyl glutaramide;
N-[(1S, 2R)-1-(1,3-benzo dioxole-5-ylmethyl)-3-(benzyl amino)-2-hydroxypropyl]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N
1-[(1S, 2R)-1-(cyclohexyl methyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N
5, N
5-dipropyl glutaramide;
N
1-[(1S, 2R)-1-[3-fluoro-5-(trifluoromethyl) benzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-N
5, N
5-dipropyl glutaramide;
N-[(1S, 2R)-1-(1,3-benzo dioxole-5-ylmethyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N
1-((1S)-1-{ (1R)-1-hydroxyl-2-[(3-methoxy-benzyl) amino] ethyl }-the 3-methyl butyl)-N
5, N
5-dipropyl glutaramide;
N
1-(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-[3-(trifluoromethoxy) benzyl] propyl group }-N
5, N
5-dipropyl glutaramide;
3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S, 2R)-1-(4-fluoro-3-methyl-benzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } propionic acid amide;
N
1-(1S)-1-[(1R)-2-(benzyl amino)-1-hydroxyethyl]-the 3-methyl butyl }-N
5, N
5-dipropyl glutaramide;
N
1-(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-[3-(trifluoromethoxy) benzyl] propyl group }-N
5, N
5-dipropyl glutaramide;
N-[(1S, 2R)-3-(benzyl amino)-1-(4-fluoro-3-methyl-benzyl)-2-hydroxypropyl]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N
1-(1S)-1-[(1R)-1-hydroxyl-2-(isopentyl amino) ethyl]-the 3-methyl butyl }-N
5, N
5-dipropyl glutaramide;
N
1-(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-[3-(trifluoromethoxy) benzyl] propyl group }-N
5, N
5-dipropyl glutaramide;
3-[(dipropyl amino) alkylsulfonyl]-N-[(1S, 2R)-1-(4-fluoro-3-methyl-benzyl)-2-hydroxyl-3-(isopentyl amino) propyl group] propionic acid amide;
3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-[(phenyl sulfenyl) methyl] propyl group } propionic acid amide;
N
1-[(1S, 2R)-3-(benzyl amino)-1-(3-fluoro-4-methyl-benzyl)-2-hydroxypropyl]-N
5, N
5-dipropyl glutaramide;
N-{ (1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-[(phenyl sulfenyl) methyl] propyl group }-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N-{ (1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-[3-(trifluoromethyl) benzyl] propyl group }-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N
1-[(1S, 2R)-1-(3-fluoro-4-methyl-benzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N
5, N
5-dipropyl glutaramide;
3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-[3-(trifluoromethyl) benzyl] propyl group } propionic acid amide;
3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-[(phenyl sulfenyl) methyl] propyl group } propionic acid amide;
N
1-(1S, 2R)-2-hydroxyl-1-(4-methoxy-benzyl)-3-[(3-methoxy-benzyl) amino] propyl group }-N
5, N
5-dipropyl glutaramide;
N-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(3-methyl-benzyl) propyl group]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N-{ (1S, 2R)-3-(benzyl amino)-1-[4-(benzyloxy) benzyl]-the 2-hydroxypropyl }-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N
1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(4-methoxy-benzyl) propyl group]-N
5, N
5-dipropyl glutaramide;
3-[(dipropyl amino) alkylsulfonyl]-N-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(3-methyl-benzyl) propyl group] propionic acid amide;
N-[(1S, 2R)-1-[4-(benzyloxy) benzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N
1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(4-methoxy-benzyl) propyl group]-N
5, N
5-dipropyl glutaramide;
N-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(1-naphthyl methyl) propyl group]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N-{ (1S, 2R)-3-(benzyl amino)-1-[3-(benzyloxy)-5-luorobenzyl]-the 2-hydroxypropyl }-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N
1-(1S, 2R)-1-(4-benzyl chloride base)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
5, N
5-dipropyl glutaramide;
3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S, 2R)-1-(3-fluoro-4-methoxy-benzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } propionic acid amide;
3-[(dipropyl amino) alkylsulfonyl]-N-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(1-naphthyl methyl) propyl group] propionic acid amide;
N
1-[(1S, 2R)-3-(benzyl amino)-1-(4-benzyl chloride base)-2-hydroxypropyl]-N
5, N
5-dipropyl glutaramide;
N-[(1S, 2R)-3-(benzyl amino)-1-(2-furyl methyl)-2-hydroxypropyl]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N-[(1S, 2R)-3-(benzyl amino)-1-(3-fluoro-4-methoxy-benzyl)-2-hydroxypropyl]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N
1-[(1S, 2R)-1-(4-benzyl chloride base)-2-hydroxyl-3-(isopentyl amino) propyl group]-N
5, N
5-dipropyl glutaramide;
3-[(dipropyl amino) alkylsulfonyl]-N-[(1S, 2R)-1-(2-furyl methyl)-2-hydroxyl-3-(isopentyl amino) propyl group] propionic acid amide;
3-[(dipropyl amino) alkylsulfonyl]-N-[(1S, 2R)-1-(3-fluoro-4-methoxy-benzyl)-2-hydroxyl-3-(isopentyl amino) propyl group] propionic acid amide;
N
1-(1S, 2R)-1-(1,3-benzo dioxole-5-ylmethyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
5, N
5-dipropyl glutaramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-phenyl-2-(4H-1,2,4-triazole-3-base sulfenyl) ethanamide;
N
1-[(1S, 2R)-1-(1,3-benzo dioxole-5-ylmethyl)-3-(benzyl amino)-2-hydroxypropyl]-N
5, N
5-dipropyl glutaramide;
1-ethanoyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-phenyl prolineamide;
N-{ (1S, 2R)-3-(benzyl amino)-1-[3-(benzyloxy) benzyl]-the 2-hydroxypropyl }-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N
1-[(1S, 2R)-1-(1,3-benzo dioxole-5-ylmethyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N
3, N
3-dipropyl glutaramide;
N-[(1S, 2R)-1-[3-(benzyloxy) benzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N
1-(1S, 2R)-1-(4-fluoro-3-methyl-benzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
5, N
5-dipropyl glutaramide;
N-[(1S, 2R)-3-(benzyl amino)-1-(4-luorobenzyl)-2-hydroxypropyl]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N
1-[(1S, 2R)-3-(benzyl amino)-1-(4-fluoro-3-methyl-benzyl)-2-hydroxypropyl]-N
5, N
5-dipropyl glutaramide;
3-[(dipropyl amino) alkylsulfonyl]-N-[(1S, 2R)-1-(4-luorobenzyl)-2-hydroxyl-3-(isopentyl amino) propyl group] propionic acid amide;
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(3R, 4S)-3-(methylol)-6-sec.-propyl-2,2-titanium dioxide-3, the different sulfenyl chromene of 4-dihydro-1H--4-yl] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-1-(4-fluoro-3-methyl-benzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N
5, N
5-dipropyl glutaramide;
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(3R, 4S)-6-sec.-propyl-3-methyl-2,2-titanium dioxide-3, the different sulfenyl chromene of 4-dihydro-1H--4-yl] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine;
N-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(thiophene-2-ylmethyl) propyl group]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N
1-(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-[3-(trifluoromethyl) benzyl] propyl group }-N
5, N
5-dipropyl glutaramide;
3-[(dipropyl amino) alkylsulfonyl]-N-((1S)-1-{ (1R)-1-hydroxyl-2-[(3-methoxy-benzyl) amino] ethyl } fourth-3-alkynyl) propionic acid amide;
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(3R, 4S)-6-sec.-propyl-2,2-titanium dioxide-3-propyl group-3, the different sulfenyl chromene of 4-dihydro-1H--4-yl] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-2-hydroxyl-3-(isopentyl) amino]-1-[3-(trifluoromethyl) benzyl] propyl group }-N
5, N
5-dipropyl glutaramide;
N-{ (1S)-1-[(1R)-2-(benzyl amino)-1-hydroxyethyl] fourth-3-alkynyl }-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N
1-[(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(3-methyl-benzyl) propyl group-N
5, N
5-dipropyl glutaramide;
3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S)-1-[(1R)-1-hydroxyl-2-(isopentyl amino) ethyl] fourth-3-alkynyl } propionic acid amide;
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(3S, 4R)-3-(methylol)-6-sec.-propyl-2,2-titanium dioxide-3, the different sulfenyl chromene of 4-dihydro-1H--4-yl] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(3-xylyl) propyl group]-N
5, N
5-dipropyl glutaramide;
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(3S, 4R)-3-(2-hydroxyethyl)-6-sec.-propyl-2,2-titanium dioxide-3, the different sulfenyl chromene of 4-dihydro-1H--4-yl] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(cyclohexyl methyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N
1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(3-methyl-benzyl) propyl group]-N
5, N
5-dipropyl glutaramide;
N-[(1S, 2R)-3-(benzyl amino)-1-(cyclohexyl methyl)-2-hydroxypropyl]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N
1-(1S, 2R)-1-[3-(benzyloxy)-5-luorobenzyl]-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
5, N
5-dipropyl glutaramide;
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(3S, 4S)-6-sec.-propyl-2,2-titanium dioxide-3-propyl group-3, the different sulfenyl chromene of 4-dihydro-1H--4-yl] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine;
N-[(1S, 2R)-1-(cyclohexyl methyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N
1-(1S, 2R)-3-(benzyl amino)-1-[3-(benzyloxy)-5-luorobenzyl)]-the 2-hydroxypropyl }-N
5, N
5-dipropyl glutaramide;
3-[(dipropyl amino) alkylsulfonyl]-N-((1S)-1-{ (1R)-1-hydroxyl-2-[(3-methoxy-benzyl) amino] ethyl }-the 3-methyl butyl) propionic acid amide;
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(3S, 4S)-6-sec.-propyl-3-methyl-2,2-titanium dioxide-3, the different sulfenyl chromene of 4-dihydro-1H--4-yl] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-1-[3-(benzyloxy)-5-luorobenzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-N
5, N
5-dipropyl glutaramide;
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(4R)-6-sec.-propyl-2,2-titanium dioxide-3, the different sulfenyl chromene of 4-dihydro-1H--4-yl] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine;
N-{ (1S)-1-[(1R)-2-(benzyl amino)-1-hydroxyethyl]-the 3-methyl butyl }-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N
1-(1S, 2R)-1-(3-fluoro-4-methoxy-benzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
5, N
5-dipropyl glutaramide;
3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S)-1-[(1R)-1-hydroxyl-2-(isopentyl amino) ethyl]-the 3-methyl butyl } propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-[(3-methoxy-propyl) (methyl sulphonyl) amino] benzamide;
N
1-[(1S, 2R)-3-(benzyl amino)-1-(3-fluoro-4-methoxy-benzyl)-2-hydroxypropyl]-N
5, N
5-dipropyl glutaramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-[(3-methoxy-propyl) (methyl sulphonyl) amino] benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 1-methyl isophthalic acid, 3-dihydro-2,1-benzisothiazole-5-methane amide 2,2-dioxide;
N
1-[(1S, 2R)-1-(3-fluoro-4-methoxy-benzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N
5, N
5-dipropyl glutaramide;
N
1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(3-methoxy-benzyl) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-[(2-methoxy ethyl) (methyl sulphonyl) amino] benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,2-dimethylbiphenyl dihydropyrane-6-methane amide;
N
1-[(1S, 2R)-3-(benzyl amino)-1-(3-bromobenzyl)-2-hydroxypropyl]-N
5, N
5-dipropyl glutaramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 6-[(2-methoxy ethyl) (methyl sulphonyl) amino] niacinamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,2-dimethylbiphenyl dioxy pyrans-6-methane amide;
N
1-[(1S, 2R)-1-(3-bromobenzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N
5, N
5-dipropyl glutaramide;
N
1-[(1S, 2R)-3-(benzylamino)-2-hydroxyl-1-(4-sec.-propyl amino) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
(3R)-4-((1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } amino)-2,2,3-trimethylammonium-4-ketobutyric acid benzyl ester;
N-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(3-methoxy-benzyl) propyl group]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 6-[(3-hydroxypropyl) (methyl sulphonyl) amino] niacinamide;
N
1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(4-isopropyl benzyl) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-[(3-methoxy-benzyl) propyl group] propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 6-[(2-hydroxyethyl) (methyl sulphonyl) amino] niacinamide;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-4-(phenyl sulfonyl) butyramide;
(3S)-and tetrahydrofuran (THF)-3-base (1S, 2R)-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl carbamate;
N-[(1S, 2R)-3-(benzyl amino)-1-(3, the 5-dichloro benzyl)-2-hydroxypropyl]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 6-[(2-methoxy ethyl) (methyl sulphonyl) amino] niacinamide;
N
1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(4-methoxy-benzyl) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
3-[(dipropyl amino) alkylsulfonyl]-N-[(1S, 2R)-2-hydroxyl-1-(4-isopropyl benzyl)-3-(3-methoxy-benzyl) amino] propyl group } propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-[(2-methoxy ethyl) (methyl sulphonyl) amino] Isonicotinamide;
N
1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(4-methoxy-benzyl) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
3-(phenyl sulfonyl)-beta-amino propionic acid amide;
N-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(4-isopropyl benzyl) propyl group]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-[(2-methoxy ethyl) (methyl sulphonyl) amino] niacinamide;
N
1-[(1S, 2R)-3-(benzyl amino)-1-(4-fluoro-3-methyl-benzyl)-2-hydroxypropyl]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
3-[(4-aminomethyl phenyl) alkylsulfonyl]-beta-amino propionic acid amide;
3-[(dipropyl amino) alkylsulfonyl]-N-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(4-isopropyl benzyl) propyl group] propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-[(3-hydroxypropyl) (methyl sulphonyl) amino] Isonicotinamide;
N
1-[(1S, 2R)-1-(3-fluoro-4-methoxy-benzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
3-[(4-fluorophenyl) alkylsulfonyl]-beta-amino propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-[(2-hydroxyethyl) (methyl sulphonyl) amino] Isonicotinamide;
N-{ (1S, 2R)-3-(benzyl amino)-1-[3-fluoro-5-(trifluoromethyl) benzyl]-the 2-hydroxypropyl }-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N
1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(4-isopropyl benzyl) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
3-[(4-p-methoxy-phenyl) alkylsulfonyl]-beta-amino propionic acid amide;
3-[(dipropyl amino) alkylsulfonyl]-N-[(1S, 2R)-1-[3-fluoro-5-(trifluoromethyl) benzyl]-2-hydroxyl-3-(isopentyl amino) propyl group] propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-[(2-hydroxyethyl) (methyl sulphonyl) amino] niacinamide;
N
1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(4-isopropyl benzyl) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
2-[(4-aminomethyl phenyl) alkylsulfonyl] G-NH2;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-[(3-hydroxypropyl) (methyl sulphonyl) amino] niacinamide;
N-{ (1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-[3-(trifluoromethoxy) benzyl] propyl group }-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
2-[(4-fluorophenyl) alkylsulfonyl] G-NH2;
N
1-(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-[3-(trifluoromethoxy) benzyl] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-[(1S, 2R)-3-(benzyl amino)-1-(3-fluoro-4-methyl-benzyl)-2-hydroxypropyl]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-[(3-methoxy-propyl) (methyl sulphonyl) amino] Isonicotinamide;
N
1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(4-methoxy-benzyl) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
2-[(4-p-methoxy-phenyl) alkylsulfonyl] G-NH2;
3-[(dipropyl amino) alkylsulfonyl]-N-[(1S, 2R)-1-(3-fluoro-4-methyl-benzyl)-2-hydroxyl-3-(isopentyl amino) propyl group] propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-[(3-methoxy-propyl) (methyl sulphonyl) amino] niacinamide;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-the 3-[(4-chloro-phenyl-) alkylsulfonyl] propionic acid amide;
N
1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(4-methoxy-benzyl) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S, 2R)-2-hydroxyl-1-(4-methoxy-benzyl)-3-[(3-methoxy-benzyl) amino] propyl group } propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-(methyl sulphonyl)-1H-indoles-5-methane amide;
N
1-[(1S, 2R)-3-(benzyl amino)-1-(4-fluoro-3-methyl-benzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
2-(benzyl alkylsulfonyl) G-NH2;
N-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(4-methoxy-benzyl) propyl group]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-(methyl sulphonyl) indoline-5-methane amide;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-the 3-[(4-fluorophenyl) alkylsulfonyl] propionic acid amide;
N
1-[(1S, 2R)-1-4-fluoro-3-xylyl-2-hydroxyl-3-(isopentyl amino) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
3-[(dipropyl amino) alkylsulfonyl]-N-{ (1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(4-methoxy-benzyl) propyl group] propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-(methyl sulphonyl) indoline-4-methane amide;
N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
3-[(4-chloro-phenyl-) alkylsulfonyl]-beta-amino propionic acid amide;
N
1-(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-[3-(trifluoromethyl) benzyl] amino }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-[(1S, 2R)-3-(benzyl amino)-1-(4-benzyl chloride base)-2-hydroxypropyl]-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-(methyl sulphonyl) indoline-6-methane amide;
N
1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(3-methyl-benzyl) propyl group]-5-methyl--N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
3-(benzyl alkylsulfonyl)-beta-amino propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-(methyl sulphonyl)-1H-indoles-4-methane amide;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-the 3-[(4-p-methoxy-phenyl) alkylsulfonyl] propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[1-methyl isophthalic acid-(methyl sulphonyl) ethyl] benzamide;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-the 3-[(4-aminomethyl phenyl) alkylsulfonyl] propionic acid amide;
N
1-[(1S, 2R)-3-(benzyl amino)-1-(3-fluoro-4-methoxy-benzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-[1-methyl isophthalic acid-(methyl sulphonyl) ethyl] benzamide;
N
1-(1S, 2R)-2-hydroxyl-1-(3-methoxy-benzyl)-3-[(3-methoxy-benzyl) amino] propyl group }-N
5, N
5-dipropyl glutaramide;
N
1-benzyl-N
4-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-2,2-dimethyl succinic diamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(ethylsulfonyl) benzamide;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-(1,1-titanium dioxide-3-oxo-1,2-benzisothiazole-2 (3H)-yl) propionic acid amide;
N
1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(3-methoxy-benzyl) propyl group]-N
5, N
5-dipropyl glutaramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(sulfonyl propyl base) benzamide;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl) propionic acid amide;
N
1-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(3-methoxy-benzyl) propyl group]-N
5, N
5-dipropyl glutaramide;
(2R)-N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-2-methyl-3-(phenyl sulfonyl) propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(amyl group alkylsulfonyl) benzamide;
N
1-[(1S, 2R)-3-(benzyl amino)-1-(3-chloro-5-luorobenzyl)-2-hydroxypropyl]-N
5, N
5-dipropyl glutaramide;
(2S)-N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-2-methyl-3-(phenyl sulfonyl) propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-[(2-hydroxyethyl) alkylsulfonyl] benzamide;
N
1-[(1S, 2R)-1-(3-chloro-5-luorobenzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N
5, N
5-dipropyl glutaramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-[(2-methoxy ethyl) alkylsulfonyl] benzamide;
N
1-(1S, 2R)-1-(3, the 5-dichloro benzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
5, N
5-dipropyl glutaramide;
N
1-benzyl-N
5-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } glutaramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-[(2-ethoxyethyl group) alkylsulfonyl] benzamide;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-the 2-[(phenyl sulfonyl) methyl] acrylamide;
N
1-[(1S, 2R)-3-(benzyl amino)-1-(3, the 5-dichloro benzyl)-2-hydroxypropyl]-N
5, N
5-dipropyl glutaramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-[(3-hydroxypropyl) alkylsulfonyl] benzamide;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-2-[(isopentyl alkylsulfonyl) methyl] acrylamide;
N
1-[(1S, 2R)-1-(3, the 5-dichloro benzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N
5, N
5-dipropyl glutaramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,3-dihydro-1-thionaphthene-5-methane amide 1,1-dioxide;
N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
3-[(dipropyl amino) carbonyl]-beta-amino propionic acid amide;
N
1-(1S, 2R)-2-hydroxyl-1-(4-isopropyl benzyl)-3-[(3-methoxy-benzyl) amino] propyl group }-N
5, N
5-dipropyl glutaramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-thionaphthene-5-methane amide 1, the 1-dioxide;
N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
2-[(dipropyl amino) carbonyl] G-NH2;
(4R)-4-{[((1S, 2R)-1-benzyl-3-{[3-(dimethylamino)-2, the 2-dimethyl propyl] amino }-the 2-hydroxypropyl) amino] carbonyl }-1,3-oxazolidine-3-benzyl formate compound and methyl hydroperoxide (1: 2);
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,3-dihydro-1-thionaphthene-6-methane amide 1,1-dioxide;
(2R, 3S)-2-hydroxyl-3-(2-hydroxyl-3-[(3-p-methoxy-phenyl) and alkylsulfonyl] propionyl } amino)-4-phenyl butyl (3-methoxy-benzyl) t-butyl carbamate;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-thionaphthene-6-methane amide 1, the 1-dioxide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-methyl-2,3-dihydro-1,2-benzisothiazole-6-methane amide 1,1-dioxide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-methyl-2,3-dihydro-1,2-benzisothiazole-5-methane amide 1,1-dioxide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 1-methyl isophthalic acid, 3-dihydro-2,1-benzisothiazole-6-methane amide 2,2-dioxide;
N
1-[(1S, 2R)-1-[3-(benzyloxy)-5-luorobenzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-3-(benzyl amino)-1-[3-(benzyloxy)-5-luorobenzyl]-the 2-hydroxypropyl }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-1-[3-(benzyloxy)-5-luorobenzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N-{ (1S, 2R)-1-[3-(benzyloxy) benzyl]-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-[(dipropyl amino) alkylsulfonyl] propionic acid amide;
N
1-[(1S, 2R)-1-(cyclohexyl methyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-1-[4-(benzyloxy) benzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-1-(cyclohexyl methyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-[(1S, 2R)-3-(benzyl amino)-1-(cyclohexyl methyl)-2-hydroxypropyl]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-(1S, 2R)-3-(benzyl amino)-1-[3-(benzyloxy) benzyl]-the 2-hydroxypropyl }-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-[(1S, 2R)-1-[4-(benzyloxy) benzyl]-2-hydroxyl-3-(isopentyl amino) propyl group]-N, N-dipropyl benzene-1,3,5-trimethamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-[hydroxyl (2-aminomethyl phenyl) methyl]-the 5-methyl benzamide;
N
1-[(1R, 2S)-2-hydroxyl-3-(isopentyl amino)-1-(4-methyl-benzyl) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1R, 2S)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(4-methyl-benzyl) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1R, 2S)-2-hydroxyl-3-(isopentyl amino)-1-(4-methyl-benzyl) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-[(1R, 2S)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(4-methyl-benzyl) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
3-chloro-N-{ (1S, 2R)-1-(cyclohexyl methyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } benzamide;
3-chloro-N-((1S, 2R)-1-(cyclohexyl methyl)-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group) benzamide;
(2R, 3S)-4-(3, the 5-difluorophenyl)-3-[(3-(4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl)-2-{[(1-propyl group butyl) alkylsulfonyl] methyl } the propyl alcohol base) amino]-2-hydroxyl butyl (3-Ethylbenzyl) benzyl carbamate;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-7-(1H-imidazoles-1-yl)-5,6-dihydronaphthalene-2-methane amide;
2-{[({ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } amino) carbonyl] amino }-N, N-dipropyl ethane sulphonamide;
(2R, 3S)-4-(3, the 5-difluorophenyl)-2-hydroxyl-3-(N-(3-phenyl propionyl)-3-[(1-propyl group butyl) and alkylsulfonyl] alanyl } amino) butyl (3-Ethylbenzyl) benzyl carbamate;
N
1-[(1S, 2R)-the 3-[[(benzyloxy) carbonyl] (3-Ethylbenzyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-N
2-[(3S)-and tetrahydrofuran (THF)-3-base oxygen base] carbonyl }-right type-leucyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-([1,3] oxazole is [4,5-b] pyridine-2-base sulfenyl also) ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[(imidazo [1,2-a] pyridine-2-ylmethyl) sulfenyl] ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[(5,7-dimethyl [1,2,4] triazolo [4,3-a] pyrimidin-3-yl) sulfenyl] ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,3-dihydro-1H-ring five [b] quinoline beautiful jade-9-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-hydroxyl-6-oxygen-1-phenyl-1,6-dihydrogen dazin-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,3-dioxy isoindoline-5-methane amide;
1-benzyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-imidazoles-2-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(4,4-dimethyl-4,5-dihydro-1,3-oxazole-2-yl) thiophene-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-isobutyl--1,3-dioxy isoindoline-5-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-oxygen-2-phenylpyrazole alkane-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5,6-dimethyl-4-oxygen-3,4-dihydro-thiophene be [2,3-d] pyrimidine-2-methane amide also;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(2, the 4-difluorobenzyl) the oxygen base] propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } thieno-[2,3-c] pyridine-2-carboxamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2-methyl isophthalic acid H-benzoglyoxaline-1-yl)-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(2,5-dioxo tetramethyleneimine-1-yl)-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } thieno-[3,2-b] pyridine-6-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2,3-dihydro-1H-indoles-1-yl)-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(1,3-dioxo octahydro-2H-isoindole-2-yl) butyramide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-[(4-aminomethyl phenyl) alkylsulfonyl]-beta-amino propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(1H-indol-3-yl)-4-oxo butyramide;
N
2-(anilino carbonyl sulfenyl)-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } G-NH2;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl-4-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-2-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5,6,7,8-tetrahydrochysene-4H-encircles seven [c] isoxazoles-3-methane amide;
4-[2-(diethylamino) oxyethyl group]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-[(4-aminomethyl phenyl) alkylsulfonyl] G-NH2;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3,5-dioxy-1,2,4-triazolidine-4-yl) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2-hydroxyl-oxethyl) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(1,3-dithiane-2-yl)-3-furoamide;
4-(3-chloro-phenyl-)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl-4-oxo butyramide; Or 2479
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-methyl-5,6,7,8-tetrahydrochysene-pyrazolo [1,5-a] azepine-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-(4-fluorophenyl)-1,4,5,6-tetrahydrochysene ring five [c] pyrazole-3-formamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5,6-dihydro-4H-encircles five [b] thiophene-2-carboxamide derivatives;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3,6,6-trimethylammonium-4-oxo-4,5,6,7-tetrahydrochysene-1-benzofuran-2-carboxamides;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-7-methoxyl group-4-oxo-1,2,3,4-naphthane-2-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4,5,6,7-tetrahydrochysene-2H-indazole-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-4-oxo-3, the 4-dihydro-thiophene is [2,3-d] pyrimidine-6-methane amide also;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-7-fluoro-4H-imidazo [5,1-c] [1,4] benzoxazine-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3-fluoro-4-p-methoxy-phenyl)-4-oxo butyramide;
4-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino)-4-oxo butyl-(dithiocarbamic acid methyl esters);
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } [1,2,4] triazolo [4,3-a] pyridine-6-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-(3-Ethylbenzyl) amino-2-hydroxypropyl } 1 base-1,4,5,6-tetrahydro cyclopentyl base [c] pyrazole-3-formamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-[(4-aminomethyl phenyl) alkylsulfonyl] ethanamide;
3-(2-chloro-phenyl-)-2-cyano group-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(4-aminomethyl phenyl)-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2-hydroxy-5-methyl base phenyl)-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(2,5-dioxo-2,5-dihydro-1H-pyrroles-1-yl) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-oxo-4-thiophene-2-base butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2,5-dioxo-2,5-dihydro-1H-pyrroles-1-yl)-2-hydroxybenzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2,5-dioxo tetramethyleneimine-1-yl) benzamide;
The 4-[(aminocarboxyl) amino]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-[(trifluoroacetyl group) amino] butyramide;
5-bromo-N
1-((1S, 2R)-2-hydroxyl-1-(PFBBR)-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[(1-hydroxycyclopent base) sulfenyl] ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(2-oxo cyclohexyl) propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2-naphthyl)-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-oxo-2,3-dihydro-1H-indazole-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,3-dimethyl-1H-thieno-[2,3-c] pyrazoles-5-methane amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-[(dimethylamino) alkylsulfonyl] valine amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2-furyl)-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(5-methyl-4-phenyl-1,3-oxazole-2-yl) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,6-dioxo hexahydropyrimidine-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5,7-dimethoxy-1-oxo-dihydro indenes-2-methane amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
5-(2-pyridine-2-base ethyl) glutaramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-[4-(2-furoyl) piperazine-1-yl]-4-oxo butyramide;
N '-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(3-[(1Z)-third-1-alkene-1-yl] benzyl } amino) propyl group]-5-methyl-N, N-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-oxo-4,5,6,7-tetrahydrochysene-1-cumarone-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-oxo-1-(thiophene-2-ylmethyl) tetramethyleneimine-3-methane amide;
The 2-[(cyano methyl) sulfenyl]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } niacinamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-(2-furoyl)-4-hydroxyl prolineamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4,5-dihydrofuran [2,3-g] [2,1] benzoisoxazole-8-methane amide;
3-[({ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino) carbonyl]-5 thiotolenes-2--sulfinic acid methyl esters;
2-(acetylamino)-2-(1H-1,2,3-benzotriazole-1-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide;
1-{[(cyclohexyl amino) carbonyl] amino }-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } cyclopropane carboxamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2-ethyl-4H-[1,2,4] triazolo [1,5-a] benzoglyoxaline-4-yl) ethanamide;
(2E)-N
1-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
4-[4-(1,3-oxazole-5-yl) phenyl] but-2-ene diamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,3,4,5-tetrahydrochysene sulfenyl pyrans is [4,3-b] indoles-8-methane amide also;
4-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3,4-dihydro-2H-1,5-benzo dioxepin-7-yl)-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(1-oxidation sulfenyl morpholine-4-yl) butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-oxo-4-(2-sulfenyl oxygen-1,3-benzothiazole-3 (2H)-yl) butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-8H-thieno-[2,3-b] indoles-2-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3,4-dihydro-2H-1,5-benzo dioxepine-7-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl-the 4H-chromene also [3,4-d] isoxazole-4-methane amide;
4-(3, the 4-dichlorophenyl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3, the 4-difluorophenyl)-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3, the 4-difluorophenyl)-2-methyl-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3, the 4-difluorophenyl)-2-methoxyl group-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl-4-oxo-4-[3-(trifluoromethyl) phenyl] butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl-4-oxo-4-thiophene-2-base butyramide;
4-(3, the 4-dichlorophenyl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxy-3-methyl-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[(2-ethyl-1-oxo-2,3-dihydro-1H-isoindole-5-yl) oxo] propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-oxoisoindoline diindyl-1-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(7-methoxyl group-1-cumarone-2-yl)-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl-the 4H-chromene also [3,4-d] isoxazole-8-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-methyl-4-oxo-4H-chromene-6-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-([1,2,4] triazolo [4,3-b] pyridazine-6-base sulfo-) ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(1,1-titanium dioxide tetramethylene sulfide-2-yl) ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3,4-dihydro-2H-chromene-6-yl)-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-ethyl-3-oxoisoindoline diindyl-1-methane amide;
4-[2-(acetylamino)-4, the 5-3,5-dimethylphenyl]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(4-hydroxy phenyl)-4-oxo butyramide;
2-[(6-chlorine [1,2,4] triazolo [4,3-b] pyridazine-3-yl) oxo]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl-4-(3-p-methoxy-phenyl)-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl-4-oxo-4-thiene-3-yl-butyramide;
4-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino)-4-ketobutyric acid-3-chlorobenzene ester;
4-(4-chloro-2-hydroxyphenyl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 6-{[(4-aminomethyl phenyl) alkylsulfonyl] amino }-4-oxo hexanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(6-hydroxyl-3-oxo-2,3-glyoxalidine be [2,1-b] [1,3] thiazol-2-yl also) ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(4,5-dihydro-1,3-thiazoles-2-base sulfo-) ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-imidazo [1,2-b] pyrazoles-6-methane amide;
4-(1-cumarone-2-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(6-methoxyl group-1,1 '-phenylbenzene-3-yl)-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(4-p-methoxy-phenyl)-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2,3-dihydro-1,4-benzo dioxine-6-yl)-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2-oxo-2,3-dihydro-1,3-benzoxazole-5-yl) ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2-oxo-2,3-dihydro-1H-benzoglyoxaline-5-yl) ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-9-oxo-1,2,3,9-tetrahydrochysene ring five [b] chromene-7-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-methyl isophthalic acid H-benzo [g] indazole-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4, the 5-dihydro-naphtho [2,1-d] isoxazole-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(tetrazolium [1,5-b] pyridazine-6-base sulfo-) ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(5-methyl isophthalic acid H-pyrroles-2-yl)-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-{[(trifluoromethyl) alkylsulfonyl] amino } butyramide;
N-[(1S, 2R)-3-(2-ethanoyl-1-ethyl diazanyl)-1-benzyl-2-hydroxypropyl]-the 2-[(methyl sulphonyl) amino]-1,3-thiazoles-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(1-hydroxyl-2-propyl group phenyl) benzamide;
N
1-[(1S, 2R)-3-[(2-{4-[(3-benzyl chloride base) oxo] phenyl } ethyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-morpholine-4-base propyl group) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
4-{[(2R, 3S)-4-(3, the 5-difluorophenyl)-3-(3-[(dipropyl amino) carbonyl]-the 5-methyl benzoyl } amino)-2-hydroxyl butyl] amino } piperidines-1-ethyl formate;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-[(methyl sulphonyl) ethanoyl]-N
2-amyl group G-NH2;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(2R)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] alkylsulfonyl } propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(2S)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] alkylsulfonyl } propionic acid amide;
4-{ (1S, 2R)-3-(3-[(dipropyl amino) and carbonyl] benzoyl } amino)-2-hydroxy-4-phenyl butyl] amino } piperidines-1-ethyl formate;
N
1-((1S, 2R)-the 1-benzyl-3-{[(3R)-1-benzyl-pyrrole alkane-3-yl] amino }-the 2-hydroxypropyl)-N
3, N
3-dipropyl isophthaloyl amine;
(2E)-2-[2-((1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } amino)-2-oxygen ethyl]-4-methylpent-2-olefin(e) acid methyl esters;
N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
4-(4-methoxy-benzyl) succinic diamide;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-the 3-{[(4-fluorophenyl) alkylsulfonyl] amino }-3-methylbutyryl amine;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-9,10-dioxo-9,10-dihydroanthracene-2-methane amide;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-4-(phenoxy group) benzamide;
N '-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N-methyl-N-phenylurea;
N '-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N, N-diisopropyl urea;
N '-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N, the N-sym-diphenylurea;
N '-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N, the N-Dimethylurea;
2-{[({ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } amino) carbonyl] amino } methyl benzoate;
(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] the propyl carbamic acid phenyl ester;
(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl carbamic acid-2-methoxyl group ethyl ester;
(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl carbamic acid-2-(benzyloxy) ethyl ester;
(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl carbamic acid Propargyl ester;
(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl carbamic acid-(1R, 2S, 5R)-2-sec.-propyl-5-methylcyclohexyl ester;
(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] the propyl carbamic acid pentyl ester;
(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] the propyl carbamic acid peopentyl ester;
N
1-[(1S, 2R)-3-{[(6-chlorine imidazo [2,1-b] [1,3] thiazole-5-yl) methyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(4-oxo-4H-chromene-3-yl) methyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(1,7,7-trimethylammonium two rings [2.2.1] heptan-2-yl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-4-(3-methyl-5-oxo-4,5-dihydro-1 h-pyrazole-1-yl) benzamide;
N
1-[(1S, 2R)-3-[(1-ethanoyl piperidines-3-yl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-oxyethyl group-oreinol diformamide;
N
1-(allyloxy)-N
3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the oreinol diformamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-isobutoxy-oreinol diformamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-N
3-(2,2,3,3,3-five fluoropropyls) isophthaloyl amine;
4-(3-[({ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino) carbonyl]-the 5-methyl benzoyl } amino) ethyl butyrate;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-N
3, N
3-two (2,2, the 2-trifluoroethyl) isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-ethyl-N
3-[(1-ethyl piperidine-4-yl) carbonyl]-oreinol diformamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-(2,2,3,3,4,4,4-seven fluorine butyl)-oreinol diformamide;
N
1-(1-benzyl-pyrrole alkane-3-yl)-N
3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
1-ethyl-oreinol diformamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-N
3-(tetrahydrofuran (THF)-2-ylmethyl) isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(3R)-2-oxo nitrogen Zhuo-3-yl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(1,1-titanium dioxide-3,4-dihydro-2H-1,2-benzothiazine-4-yl) amino]-the 2-hydroxypropyl }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[2-(4-methylpent acyl group) diazanyl] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-[(3-ethylphenyl) alkylsulfonyl] propionic acid amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,2,3,3,4,4-hexafluoro-N
3, N
3-dipropyl isophthaloyl amine;
N
5-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-phenyl-N
1, N
1-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-[(3-hydroxypropyl) (methyl sulphonyl) amino] benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-[(2-hydroxyethyl) (methyl sulphonyl) amino] benzamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-{[(2R)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] alkylsulfonyl }-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-[(3-hydroxypropyl) (methyl sulphonyl) amino] benzamide;
5-bromo-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-{[(trifluoromethyl) alkylsulfonyl] amino } benzamide;
N
1-[(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(thiophene-2-ylmethyl) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(4-methyl isophthalic acid, 3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-dipropyl-5-(1,3-thiazoles-2-yl) isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-[(methyl sulphonyl) amino] benzamide;
4-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino)-4-oxygen-3-{[(1-propyl group butyl) alkylsulfonyl] methyl } the butyric acid trifluoroacetate;
N
1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-the 5-[(methyl sulphonyl) amino]-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(1-propyl group butyl) alkylsulfonyl] propionic acid amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-the 2-[(methyl sulphonyl) amino]-1,3-thiazoles-4-methane amide;
N
1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N
3, N
3-dipropyl-5-{[(trifluoromethyl) alkylsulfonyl] amino } isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(isopentyl alkylsulfonyl) propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(1-methyl isophthalic acid H-imidazol-4 yl) alkylsulfonyl] amino } benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-{[(trifluoromethyl) alkylsulfonyl] amino } benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-{[(2-hydroxyethyl) (propyl group) amino] alkylsulfonyl } propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(1,3-oxazole-2-yl) benzamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-{[(2-hydroxyl-1, the 1-dimethyl ethyl) amino] alkylsulfonyl }-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(2-hydroxyl-1, the 1-dimethyl ethyl) amino] alkylsulfonyl } benzamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-{[(3-hydroxypropyl) amino] alkylsulfonyl }-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-[(methyl sulphonyl) amino]-1,3-thiazoles-4-methane amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-(phenyl formyl radical)-3-[(1-propyl group butyl) alkylsulfonyl] amino propionic acid amide;
N
1-(1R, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-benzyloxycarbonyl-3-[(1-propyl group butyl) alkylsulfonyl] amino propionic acid amide trifluoroacetate;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(3-methyl-isoxazole-4-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-({ [2-(methylamino) ethyl] amino } alkylsulfonyl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-{[(2-hydroxyethyl) amino] alkylsulfonyl }-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-[(methyl sulphonyl) amino] butyramide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(piperazine-1-base alkylsulfonyl)-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[methyl (methyl sulphonyl) amino] benzamide;
Two (2-hydroxyethyl) amino of 5-{[] alkylsulfonyl }-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,8-dimethyl quinoline beautiful jade-3-methane amide;
2,4 difluorobenzene aminocarbamic acid-2-{[(2R, 3S)-4-(3, the 5-difluorophenyl)-3-(3-[(dipropyl amino) carbonyl]-the 5-methyl benzoyl } amino)-2-hydroxyl butyl] amino } ethyl ester;
5-(amino-sulfonyl)-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-dipropyl-5-(1H-pyrazoles-4-yl) isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-hydoxyisoxazole-5-methane amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1-methyl isophthalic acid H-imidazoles-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(2R)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] carbonyl }-the 5-methyl benzamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-{[(2-hydroxyethyl) amino] alkylsulfonyl }-N
3-propyl group isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-([(1S)-and 2-hydroxyl-1-methylethyl] amino } alkylsulfonyl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-diethyl-5-(1,3-oxazole-2-yl) isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(2S)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] carbonyl }-the 5-methyl benzamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-{[(2S)-and 2-(methylol) tetramethyleneimine-1-yl] alkylsulfonyl }-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-([(1R)-and 2-hydroxyl-1-methylethyl] amino } alkylsulfonyl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-2-hydroxyl-1-(2,3, the 5-trifluoro-benzyl)-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(2-ethyl-1-hydroxyl butyl) benzamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-[(dimethylamino) alkylsulfonyl]-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-{[1-(aminocarboxyl) cyclohexyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-{[2-(amino-sulfonyl) ethyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(1-methyl hexyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(2-hydroxypropyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(2-ethylhexyl) amino]-the 2-hydroxypropyl }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(4-phenyl butyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(penta amino) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(5-hydroxyl amyl group) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(6-hydroxyl hexyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-[(3-butoxy propyl group) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(2R)-the 2-hydroxypropyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-methyl-5-(1,3-oxazole-2-yl)-N
3-propyl group isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-methyl-5-(1, the 3-oxazole-
2-yl)-N
3-propyl group isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, NA-dipropyl-5-(tetramethyleneimine-1-base alkylsulfonyl) isophthaloyl amine;
N
1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-5-{[(2-hydroxyl-1, the 1-dimethyl ethyl) amino] alkylsulfonyl }-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1,3-oxazole-5-yl)-N
3, N
3-dipropyl isophthaloyl amine hydrogen chloro-acid amide (hydrochlormide);
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine hydrogen chloro-acid amide;
N
1-butyl-N
3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
1-methyl-5-(1,3-oxazole-2-yl) isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-dimethyl-5-(1,3-oxazole-2-yl) isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-ethyl-5-(1, the 3-oxazole-
2-yl)-N
3-propyl group isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-dipropyl-5-(1,3-thiazoles-2-yl) isophthaloyl amine hydrogen chloro-acid amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(1-propyl group butyl) amino] alkylsulfonyl } propionic acid amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-{[(2R)-and 2-(methylol) tetramethyleneimine-1-yl] alkylsulfonyl }-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-{[(2-hydroxyl-1, the 1-dimethyl ethyl) amino] alkylsulfonyl }-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(isobutylamino) propyl group]-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine hydrogen chloro-acid amide;
5-bromo-N
1-((1S, 2R)-1-[3-fluoro-4-(trifluoromethyl) benzyl]-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-N
3, N
3-dipropyl isophthaloyl amine;
5-bromo-N
1-((1S, 2R)-2-hydroxyl-1-(2,3, the 4-trifluoro-benzyl)-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(2-ethyl butyryl radicals)-5-methyl benzamide hydrogen chloro-acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl-5-[(2-propyl group piperidines-1-yl) carbonyl] benzamide hydrogen chloro-acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl-5-[(2-methylpyrrolidin-1-yl) carbonyl] benzamide hydrogen chloro-acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(2,6-lutidine-1-yl) carbonyl]-5-methyl benzamide hydrogen chloro-acid amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-{[(2-methoxy ethyl) amino] alkylsulfonyl }-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group }-N
3, N
3-dipropyl-5-(1,3-thiazoles-2-yl) isophthaloyl amine hydrogen chloro-acid amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-{[(2-hydroxyethyl) amino] alkylsulfonyl }-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl-5-(2-propyl group pentanoyl) benzamide hydrogen chloro-acid amide;
N
1-(sec-butyl)-N
3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-N
1-propyl group isophthaloyl amine;
N
1-butyl-N
3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-N
1-propyl group isophthaloyl amine;
N
1-allyl group-N
1-cyclopentyl-N
3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the oreinol diformamide;
N
1, N
1-dibutyl-N
3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the oreinol diformamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-diisobutyl-oreinol diformamide;
N
1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(3-[(1Z)-third-1-thiazolinyl] benzyl } amino) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[3-(ethylsulfonyl) benzyl] amino }-the 2-hydroxypropyl)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[1-(3-iodophenyl) cyclopropyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N '-(1-(3, the 5-difluorobenzyl)-3-{[2-(ethylamino)-1-methyl-2-oxygen ethyl] amino }-the 2-hydroxypropyl)-5-methyl-N, N-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-[(1,1 '-phenylbenzene-3-ylmethyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-hydroxyl-1-phenyl propyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-cyclohexyl-N
3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
1, 5-dimethyl isophthaloyl amine;
N
1-cyclohexyl-N
3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
1-ethyl-oreinol diformamide;
N
1-[(1S, 2R)-3-{[3-(1-thionaphthene-2-yl) benzyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-5-ethynyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-thiene-3-yl-benzyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(5-thiotolene-2-yl) benzyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-pyridin-4-yl benzyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(4-thiotolene-2-yl) benzyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[3-(2,4-dimethoxypyridin-5-yl) benzyl] amino }-the 2-hydroxypropyl)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[3-(3,5-dimethyl isoxazole-4-yl) benzyl] amino }-the 2-hydroxypropyl)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
4-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-6-methyl-N
2, N
2-dipropyl pyridine-2, the 4-diformamide;
N
1-[(1S, 2R)-3-{[3-(cyclopropyl amino) benzyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-{[3-(cyclopropyl amino) benzyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-ethynyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[1-(2-isobutyl--1,3-thiazoles-5-yl) cyclopropyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
3-([(2R, 3S)-4-(3, the 5-difluorophenyl)-3-(3-[(dipropyl amino) carbonyl]-the 5-methyl benzoyl } amino)-2-hydroxyl butyl] amino } methyl) phenyl (methyl) Urethylane;
N
1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(3-[methyl (methyl sulphonyl) amino] and benzyl } amino) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-(the 3-[(dimethylamino) and alkylsulfonyl] benzyl } amino)-the 2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(2-isobutyl--1,3-thiazoles-5-yl) methyl] amino } propyl group)-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl)-1-methylethyl] amino }-the 2-hydroxypropyl)-5-ethynyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl)-1-methylethyl] amino }-the 2-hydroxypropyl)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-isopropyl benzyl) amino] propyl group }-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl)-1-methylethyl] amino }-the 2-hydroxypropyl)-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[1-(3-isobutyl-isoxazole-5-base) cyclopropyl] amino } propyl group)-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[1-(3-isobutyl-isoxazole-5-base) cyclopropyl] amino } propyl group)-5-ethynyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(the 3-[(methyl sulphonyl) and amino] benzyl } amino) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[1-(3-isobutyl-isoxazole-5-base) cyclopropyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-ethynyl benzyl) amino]-the 2-hydroxypropyl }-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-[(3-cyano group benzyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1S)-the 1-[(isobutylamino) (oxygen) methyl]-3-(methyl sulfenyl) propyl group] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-(3-[(1E)-oneself-the 1-thiazolinyl] benzyl } amino)-the 2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-{[3-(5-acetyl thiophene-2-yl) benzyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-[(3-allyl group benzyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(6-methoxypyridine-3-yl) benzyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-{[(2-tertiary butyl pyrimidine-4-yl) methyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
4-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-isopropyl benzyl) amino] propyl group }-6-methyl-N
2, N
2-dipropyl pyridine-2, the 4-diformamide;
N
1-[(1S, 2R)-the 3-[(3-butyl benzyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-amyl group benzyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-penta-4-thiazolinyl benzyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-[(3-cyclopentyl benzyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-the 3-[(3-cyclohexyl benzyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-{[3-(cyclohexyl methyl) benzyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-oneself-5-thiazolinyl benzyl) amino]-the 2-hydroxypropyl-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
(2S)-3-[3-([(2R, 3S)-4-(3, the 5-difluorophenyl)-3-(3-[(dipropyl amino) carbonyl]-the 5-methyl benzoyl } amino)-2-hydroxyl butyl] amino } methyl) phenyl]-the 2 Methylpropionic acid methyl esters;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(3 methyl thiophene-2-yl) benzyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2 hydroxyls-3-{[3-(3-picoline-2-yl) benzyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(4-picoline-2-yl) benzyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(5-picoline-2-yl) benzyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-{[3-(4-chlorobutyl) benzyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-{[3-(3-cyano group butyl) benzyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-{[3-(4-cyano group butyl) benzyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-{[3-(6-cyano group hexyl) benzyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(6-picoline-2-yl) benzyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(1,3-oxazole-2-yl) benzyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
3-{[((2R, 3S)-4-(3, the 5-difluorophenyl)-3-{[3-[(dipropyl amino) carbonyl]-5-(1,3-oxazole-2-yl) benzoyl] amino }-2-hydroxyl butyl) amino] methyl } phenyl (methyl) Urethylane;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1S)-the 1-[(isobutylamino) carbonyl]-3-(methyl sulphonyl) propyl group] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-butyl-N
3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-isopropyl benzyl) amino] propyl group }-N
1, 5-dimethyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl)-1-methylethyl] amino }-the 2-hydroxypropyl)-5{[(2-hydroxyl-1, the 1-dimethyl ethyl) amino] alkylsulfonyl }-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-{ methyl [(trifluoromethyl) alkylsulfonyl] amino }-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-(cyclopropyl amino)-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-{[(2-hydroxyl-1, the 1-dimethyl ethyl) amino] alkylsulfonyl }-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl)-1-methylethyl] amino }-the 2-hydroxypropyl)-N
3, N
3-dipropyl-5-(1,3-thiazoles-2-yl) isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-[methyl (methyl sulphonyl) amino]-N
3, N
3-dipropyl isophthaloyl amine;
N
1-butyl-N
3-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl)-1-methylethyl] amino }-the 2-hydroxypropyl)-N
1, 5-dimethyl isophthaloyl amine;
N
1-((1S, 2R)-1-(2, the 4-difluorobenzyl)-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
5-bromo-N
1-((1S, 2R)-1-(2, the 4-difluorobenzyl)-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(2-ethyl piperidine-1-yl) alkylsulfonyl] propionic acid amide;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-5-ethynyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-cyclobutyl-N
3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the oreinol diformamide;
N
1-cyclopentyl-N
3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the oreinol diformamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-N
3-amyl group isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-isopentyl-oreinol diformamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-ethyl-N
3-(2-hydroxyethyl)-oreinol diformamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-(2-ethoxyethyl group)-oreinol diformamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-(2-methoxy ethyl)-N
3, 5-dimethyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-(2-furyl methyl)-N
3, 5-dimethyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(2R, 5R)-2,5-dimethyl pyrrolidine-1-yl] carbonyl }-the 5-methyl benzamide;
N
1-cyclopentyl-N
3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
1, 5-dimethyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, 5-dimethyl-N
3-amyl group isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-(2-hydroxyethyl)-5-methyl-N
3-propyl group isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-ethyl-N
3-(2-methoxy ethyl)-oreinol diformamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-N
3-(2-methylcyclohexyl) isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-(2-methoxy ethyl)-5-methyl-N
3-propyl group isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-two (2-methoxy ethyl)-oreinol diformamides;
N
1-allyl group-N
1-cyclohexyl-N
3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the oreinol diformamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-N
3, N
3-diamyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-two (2-ethoxyethyl group)-oreinol diformamides;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(2-naphthyl methyl) amino] propyl group }-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-butyl-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-2-hydroxypropyl-N, 5-dimethyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-5-{[(2-hydroxyl-1, the 1-dimethyl ethyl) amino] alkylsulfonyl }-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(1S)-1,2,3,4-naphthane-1-base is amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(2S)-tetrahydrofuran (THF)-2-ylmethyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-[(3-hydroxypropyl) alkylsulfonyl]-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1H-imidazol-4 yl)-N
3, N
3-dipropyl isophthaloyl amine trifluoro-acetate;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-isoxazole-3-base-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(2R)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] carbonyl }-5-(1,3-oxazole-2-yl) benzamide;
N
4-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-6-methyl-N
2, N
2-dipropyl pyridine-2, the 4-diformamide;
N
4-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-6-methyl-N
2, N
2-dipropyl pyridine-2, the 4-diformamide;
N
4-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-6-methyl-N
2, N
2-dipropyl pyridine-2, the 4-diformamide;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl }-N
3, N
3-dipropyl-5-(1,3-thiazoles-2-yl) isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-[methyl (thiophene-2-base alkylsulfonyl) amino]-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-([(2R)-and the 2-hydroxypropyl] amino } alkylsulfonyl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[1-(2-isobutyl--1-, 3-thiazole-5-yl) cyclopropyl] amino } propyl group)-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-hydroxy-n
5, N
5-dipropyl glutaramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2-dipropylamine-2-oxo oxyethyl group) ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[(2-dipropylamine-2-oxygen ethyl) sulfenyl] ethanamide;
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[2-(isobutylamino)-1,1-dimethyl-2-oxygen ethyl] aminopropyl }-5-(1,3-oxazole-2-yl)-N, N-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-[(methyl sulphonyl) methyl] benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl-5-(2-methylpent acyl group) benzamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl-5-[(methyl sulphonyl) amino]-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(1-propyl group butyl) alkylsulfonyl]-the amino propionic acid amide of right type;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-propionyl-3-[(1-propyl group butyl) alkylsulfonyl]-the amino propionic acid amide of right type;
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1S)-2-(isobutylamino)-1-methyl-2-oxygen ethyl] amino } propyl group)-N, N-dipropyl-5-(1,3-thiazoles-2-yl) isophthaloyl amine;
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1S)-2-(isobutylamino)-1-methyl-2-oxygen ethyl] amino } propyl group)-N-methyl-N-propyl group-5-(1,3-thiazoles-2-yl) isophthaloyl amine;
N
1-butyl-N
3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
1-methyl-5-(1,3-thiazoles-2-yl) isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-[(3-hydroxypropyl) (methyl sulphonyl) amino] benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(methyl sulphonyl) benzamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-(1-oxygen-butyl)-3-[(1-propyl group butyl) alkylsulfonyl]-the amino propionic acid amide of right type;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-dipropyl-5-pyrimidine-2-base isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-([(2S)-and the 2-hydroxypropyl] amino } alkylsulfonyl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-methyl-N
3-propyl group-5-(1,3-thiazoles-2-yl) isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(2-methylpent acyl group)-5-(1,3-oxazole-2-yl) benzamide;
N
1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(the 3-[(methyl sulphonyl) and amino] benzyl } amino) propyl group]-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-(2,2-dimethyl propylene acyl group)-3-[(1-propyl group butyl) alkylsulfonyl]-the amino propionic acid amide of right type;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-{[(2R)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] alkylsulfonyl }-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-[(3-hydroxypropyl) (methyl sulphonyl) amino] benzamide;
N
2-ethanoyl-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(1-propyl group butyl) alkylsulfonyl]-the amino propionic acid amide of right type;
2-[allyl group (methyl sulphonyl) amino]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,3-thiazoles-5-methane amide;
3-(butyl alkylsulfonyl)-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the amino propionic acid amide of right type two (trifluoroacetate);
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-3-[(1-propyl group butyl) alkylsulfonyl]-the amino propionic acid amide of right type two (trifluoroacetate);
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-isobutyryl-3-[(1-propyl group butyl) alkylsulfonyl]-the amino propionic acid amide of right type;
N-[(1S, 2R)-3-(fourth amino)-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-4-(ethylenebis dithiocarbamate) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-(2-fluorophenyl)-5-oxo-pyrrolidine-3-methane amide;
N
1-(the 4-tertiary butyl-1,3-thiazoles-2-yl)-N
4-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } succinic diamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-hydroxyl-6-(1-hydroxyl-2,2-dimethyl propyl) pyridine-2-carboxamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-{[(ethylamino) carbonyl] amino } benzamide;
3-(1-cyano ethyl)-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl) benzamide;
1-(cyano methyl)-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl)-1H-pyrroles-2-methane amide;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(1H-imidazoles-1-yl) propyl group] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-([(2R)-and 1-ethyl pyrrolidine-2-yl] methyl } amino)-the 2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
3-ethanoyl-N-[(1S, 2R)-3-(benzylamino)-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl] benzamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(7-methoxyl group-1,2,3,4-naphthane-1-yl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(2E)-oneself-the 2-alkenyl amino]-the 2-hydroxypropyl }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-([(5R)-and 3-ethyl-2-oxygen-1,3-oxazolidine-5-yl] methyl } amino)-the 2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-([(5S)-and 3-ethyl-2-oxygen-1,3-oxazolidine-5-yl] methyl } amino)-the 2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(2,2-titanium dioxide-3,4-dihydro-1,2-benzo oxathiin-4-yl) amino]-the 2-hydroxypropyl }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(1,1-titanium dioxide-3,4-dihydro-1,2-benzo oxathiin-4-yl) amino]-the 2-hydroxypropyl }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
5-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-phenyl-N
1, N
1-dipropyl glutaramide;
N
1-(1S, 2R)-1-{[5-(cyano methyl)-1H-imidazoles-1-yl] methyl }-the 3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-dipropyl-5-pyrimidine-2-base isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(2-ethyl-pyrimidine-4-yl) methyl] amino }-the 2-hydroxypropyl)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-(2,2-dimethyl propylene acyl group)-3-[(1-propyl group butyl) alkylsulfonyl]-right type-amino propionic acid amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-{[ethyl (methyl) amino] alkylsulfonyl }-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-[(2-hydroxyethyl) (methyl sulphonyl) amino] benzamide;
5-bromo-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(2-first and second bases) (methyl sulphonyl) amino] the hydrogen chloro-acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-[(methyl sulphonyl) methyl] benzamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-[(4-hydroxyl butyl) alkylsulfonyl]-N
3, N
3-dipropyl isophthaloyl amine hydrogen chloro-acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the different quinoline beautiful jade of 1-(dipropyl amino)-7-methane amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-{[(2-hydroxyethyl) (methyl) amino] alkylsulfonyl }-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-[(ethylamino) alkylsulfonyl]-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[methyl (methyl sulphonyl) amino]-1,3-oxazole-4-methane amide;
3-(butyl alkylsulfonyl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } propionic acid amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-dipropyl Malonamide;
N
2-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-2-hydroxypropyl }-N, N-dipropyl two rings [2.2.1] heptan-5-alkene-2,3-diformamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-dipropyl pentamethylene-1, the 3-diformamide;
N
2-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3,4-dimethyl-N
5, N
5-dipropyl thieno-[2,3-b] thiophene-2, the 5-diformamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-phenyl-N
5, N
5-dipropyl glutaramide;
N
2-benzyl-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-[2-(dipropyl amino)-2-oxygen ethyl] G-NH2;
3-(4-chloro-phenyl-)-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
5, N
5-dipropyl glutaramide;
(2E)-N
5-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(methoxyimino)-N
1, N
1-dipropyl glutaramide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-[2-(dipropyl amino)-2-oxygen ethyl]-N
2-phenylglycinamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2, N
2-dipropyl hexanaphthene-1, the 2-diformamide;
N
1-[(1S, 2R)-the 3-[(benzyloxy) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl Malonamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-Phenylpropionamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(1,1-Er oxazole-3,4 dihydros-2H-1,2-benzothiazine-4-yl) amino]-the 2-hydroxypropyl }-5-methyl-N
3, N
3-dipropyl Malonamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1H-imidazoles-2-yl)-N
3, N
3-dipropyl Malonamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(1-hydroxyl-2-propyl group phenyl) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-phenyl isopropyl ketone methane amide;
The hydrogen chloro-acid amide
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(2-propyl group pentanoyl) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(2-ethyl butyryl radicals) benzamide hydrogen chloro-acid amide;
N
3-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(1,2,3,4-naphthane-1-yl) propyl group]-N
5, N
5-di-isopropyl pyridine-3, the 5-diformamide;
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(1S)-2-(ethylamino)-1-methyl-2-oxygen ethyl] amino }-the 2-hydroxypropyl)-5-methyl-N, N-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-hydroxyl-1-amyl group propyl group) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N '-[(1S, 2R)-3-{[(1S)-2-(benzylamino)-1-methyl-2-oxygen ethyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N, N-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3,3-dimethyl-N
2, N
2-dipropyl basic ring and alkane-1, the 2-diformamide;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3,3-dimethyl-N
2, N
2-dipropyl cyclopropane-1, the 2-diformamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl-N
5, N-dipropyl glutaramide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3,3-dimethyl-N
5, N
5-dipropyl glutaramide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-ethyl-3-methyl-N
5, N
5-dipropyl glutaramide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-hydroxy-3-methyl-N
5, N
5-dipropyl glutaramide;
2-[allyl group (methyl sulphonyl) amino]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,3-oxazole-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(2-dimethylamino) ethyl] amino }-the 2-hydroxypropyl }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-(two (2-hydroxyethyl) amino of 2-[] and ethyl } amino)-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-(cyclopropylamino)-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-3-[(1-propyl group butyl) alkylsulfonyl]-the amino propionic acid amide of right type;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[4-(methylol)-1,3-oxazole-2-yl] benzamide hydrogen chloro-acid amide.
310. compound that chemical formula is following:
Wherein
R
aAnd R
bBe C independently
1-C
6Alkyl;
X is O or S;
R
bAnd R
cBe hydrogen or halogen independently;
R
eBe C
1-C
6Alkyl or the phenyl that is optionally substituted.
311. as the described compound of claim 310, wherein R
aBe methyl and R
dIt is ethyl.
312. as the described compound of claim 311, wherein X is O.
313. as the described compound of claim 312, wherein R
bAnd R
cBe F.
314. as the described compound of claim 312, wherein R
bAnd R
cBe hydrogen.
315. as the described compound of claim 314, wherein R
eThe ethylphenyl that the position replaces between being.
316. as the described compound of claim 314, wherein R
eBe-CH
2CH
2CH (CH
3)
2
317. as the described compound of claim 314, wherein R
eIt is methyl.
318. as the described compound of claim 314, wherein R
eIt is phenyl.
319. as the described compound of claim 311, wherein X is S.
320. as the described compound of claim 319, wherein R
bAnd R
cBe F.
321. as the described compound of claim 319, wherein R
bAnd R
cBe hydrogen.
322. as the described compound of claim 321, wherein R
eThe ethylphenyl that the position replaces between being.
323. as the described compound of claim 321, wherein R
eIt is methyl.
324. compound that chemical formula is following:
Wherein
Ya is
Or-N (CH
2CH
2CH
3)
2
R
fAnd R
gAll be hydrogen or form a carbonyl with the carbon that links to each other with them;
X
aBe two valence links and carbonyl;
R
nBe hydrogen or hydroxyl;
R
iAnd R
jBe hydrogen or halogen independently;
R
kBe C
1-C
6Alkyl;
R
lBe C
1-C
6Alkyl or the phenyl that is optionally substituted; And
M is 0 or 1.
325. as the described compound of claim 324, wherein R
fAnd R
gForm a carbonyl with the carbon that links to each other with them.
326. as the described compound of claim 325, wherein X
aIt is covalent linkage.
327. as the described compound of claim 326, wherein R
hBe hydrogen.
328. as the described compound of claim 327, wherein m is 1.
329. as the described compound of claim 328, wherein R
iAnd R
jBe F.
330. as the described compound of claim 328, wherein R
iAnd R
jBe hydrogen.
331. as the described compound of claim 330, wherein R
kIt is ethyl.
332. as the described compound of claim 330, wherein R
eThe ethylphenyl that the position replaces between being.
333. as the described compound of claim 330, wherein R
eBe-CH
2CH
2CH (CH
3)
2
334. as the described compound of claim 330, wherein R
eIt is methyl.
335. as the described compound of claim 330, wherein R
eIt is phenyl.
336. as the described compound of claim 324, wherein R
fAnd R
gBe hydrogen.
337. as the described compound of claim 336, wherein X
aIt is carbonyl.
338. as the described compound of claim 337, wherein R
hIt is hydroxyl.
339. as the described compound of claim 338, wherein R
iAnd R
jBe F.
340. as the described compound of claim 328, wherein R
iAnd R
jBe hydrogen.
341. as the described compound of claim 338, wherein R
kIt is ethyl.
342. as the described compound of claim 338, wherein R
eThe ethylphenyl that the position replaces between being.
343. as the described compound of claim 338, wherein R
eBe-CH
2CH
2CH (CH
3)
2
344. as the described compound of claim 338, wherein R
eIt is methyl.
345. a compound, or it can be used for the salt of pharmacy, and this compound is:
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-[(2-hydroxyethyl) (methyl sulphonyl) amino] benzamide;
5-bromo-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-[(2-methoxy ethyl) (methyl sulphonyl) amino] benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-[(methyl sulphonyl) methyl] benzamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-[(4-hydroxyl butyl) alkylsulfonyl]-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the different quinoline beautiful jade of 1-(dipropyl amino)-7-methane amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-{[(2-hydroxyethyl) (methyl) amino] alkylsulfonyl }-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-[(ethylamino) alkylsulfonyl]-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[methyl (methyl sulphonyl) amino]-1,3-oxazole-4-methane amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-dipropyl Malonamide;
N
2-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-dipropyl dicyclo [2.2.1] heptan-5-alkene-2, the 3-diformamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-dipropyl cyclopentenes-1, the 3-diformamide;
N
2-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3,4-dimethyl-N
5, N
5-dipropyl thieno-[2,3-b] thiophene-2, the 5-diformamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-phenyl-N
5, N
5-dipropyl glutaramide;
N
2-benzyl-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-[2-(dipropyl amino)-2-oxygen ethyl] G-NH2;
3-(4-chloro-phenyl-)-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
5, N
5-dipropyl glutaramide;
(2E)-N
5-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(methoxyimino)-N
1, N
1-dipropyl glutaramide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-[2-(dipropyl amino)-2-oxygen ethyl]-N
2-phenylglycinamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2, N
2-dipropyl hexanaphthene-1, the 2-diformamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-Phenylpropionamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(2,2-titanium dioxide-3,4-dihydro-1,2-benzo oxathiin-4-yl) amino]-the 2-hydroxypropyl }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(2,2-titanium dioxide-3,4-dihydro-1,2-benzo oxathiin-4-yl) amino]-the 2-hydroxypropyl }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(7-methoxyl group-1,2,3,4-naphthane-1-yl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(7-methoxyl group-1,2,3,4-naphthane-1-yl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1H-imidazoles-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-propyl group-1,3-benzoxazole-6-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-methyl isophthalic acid, 3-benzoxazole-6-methane amide;
5-[(tertiary butyl amino) alkylsulfonyl]-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N
4-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-6-methyl-N
2, N
2-dipropyl pyridine-2, the 4-diformamide;
N
4-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-5-ethynyl-N
2, N
2-dipropyl pyridine-2, the 4-diformamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-ethynyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-ethynyl benzyl) amino]-the 2-hydroxypropyl }-5-ethynyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-N
3, N
3-dipropyl-5-(1,3-thiazoles-2-yl) isophthaloyl amine;
N
1-butyl-N
3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
1-methyl-5-(1,3-thiazoles-2-yl) isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-methyl-N
3-propyl group-(1,3-thiazoles-2-yl) isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(4-methyl isophthalic acid, 3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-methyl-5-(1,3-oxazole-2-yl)-N
3-propyl group isophthaloyl amine;
N
1-butyl-N
3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
1-methyl-5-(1,3-thiazoles-2-yl) isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-ethyl-5-(1,3-oxazole-2-yl)-N
3-propyl group isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-N
3, N
3-dipropyl-5-(1,3-thiazoles-2-yl) isophthaloyl amine; With
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
The 5-{[tertiary butyl (methyl) amino] alkylsulfonyl }-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-sec.-propyl-1,3-benzoxazole-6-methane amide;
(2S)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl-2-(1-naphthyl) ethanamide;
(2R)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl-2-(1-naphthyl) ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } Isonicotinamide;
N
1-(1S, 2R)-1-benzyl-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-methyl-5-(1,3-oxazole-2-yl)-N
3-propyl group isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-[1-(ethoxyl methyl)-1H-imidazoles-2-yl]-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-propyl group-1,3-benzoxazole-5-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-sec.-propyl-1,3-benzoxazole-5-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[ethyl (methyl) amino] alkylsulfonyl } benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-methyl isophthalic acid, 3-benzoxazole-5-methane amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(methyl sulphonyl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(methyl sulphonyl)-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-methyl isophthalic acid, 3-benzoxazole-7-methane amide;
3-[({ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino) carbonyl] methyl benzoate;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(5-methoxyl group-1,2,3,4-naphthane-1-yl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(5-methoxyl group-1,2,3,4-naphthane-1-yl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(1S)-2,3-dihydro-1H-indenes-1-base is amino]-the 2-hydroxypropyl }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2, N
2-dipropyl hexanaphthene-1, the 2-diformamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(2R)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] alkylsulfonyl } benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-{[ethyl (methyl) amino] alkylsulfonyl } benzamide;
Formic acid cpds and N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-{[ethyl (methyl) amino] alkylsulfonyl } benzamide (1: 1);
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3, the 5-dimethyl benzamide;
N
1-butyl-N
3-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-N
1-methyl-5-(1,3-thiazoles-2-yl) isophthaloyl amine;
N
1-butyl-N
5-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
1-methyl glutaryl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
5, N
5-dipropyl glutaramide;
(2R)-N
5-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-methyl-N
1, N
1-dipropyl glutaramide;
(2S)-
N5-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-methyl-N
1, N
1-dipropyl glutaramide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
4, N
4-dipropyl succinic diamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-[2-(dipropyl amino)-2-oxygen ethyl]-N
2-methyl G-NH2;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-[2-(dipropyl amino)-2-oxygen ethyl] G-NH2;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-[2-(methoxymethyl) tetramethyleneimine-1-yl]-5-oxo valeramide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
5-(2-furyl methyl)-N
5-methyl glutaryl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(4-ethylpyridine-2-yl) methyl] amino }-the 2-hydroxypropyl)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
4-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-6-methyl-N
2, N
2-dipropyl pyridine-2, the 4-diformamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,2-diformazan primary colours alkane-7-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,2-diformazan primary colours alkane-6-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-methyl isophthalic acid, 3-benzoxazole-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-propyl group-1,3-benzoxazole-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-{[(2R)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] alkylsulfonyl } benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-{ dihydroxyl [(2S)-2-(methylol) tetramethyleneimine-1-yl]-λ
4-sulfane base } benzamide;
1-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-indoles-6-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-propyl group-1H-indoles-6-methane amide;
1-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-indoles-5-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[4-(2-hydroxyethyl)-1,3-oxazole-2-yl] benzamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-isopropyl benzyl) amino] propyl group }-N
3, N
3-dipropyl-5-(1,3-thiazoles-2-yl) isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-isopropyl benzyl) amino] propyl group }-N
3, N
3-dipropyl-5-(1,3-thiazoles-2-yl) isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(4-ethylpyridine-2-yl) methyl] amino }-the 2-hydroxypropyl)-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-4-(ethoxyl methyl) benzamide;
1-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } indoline-6-methane amide;
3-[(tertiary butyl amino) alkylsulfonyl]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,3-dihydro-1,4-Ben Bing dioxine-6-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(2R)-and 2-(methylol) tetramethyleneimine-1-yl] alkylsulfonyl } benzamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-dipropyl-5-pyridin-4-yl isophthaloyl amine;
N
1-butyl-N
3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-ethynyl benzyl) amino]-the 2-hydroxypropyl }-N
1, 5-dimethyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-isopropyl benzyl) amino] propyl group }-3-{[(2R)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] carbonyl }-the 5-methyl benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(2R)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] carbonyl }-the 5-methyl benzamide;
3-(1-butyl-1H-pyrazoles-4-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } propionic acid amide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl }-3-{[(2R)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] carbonyl }-the 5-methyl benzamide;
1-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-indazole-6-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-thiophene-2-base-1,3-thiazoles-4-methane amide;
5-(amino-sulfonyl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-methyl isophthalic acid H-pyrroles-2-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-{[(2-furyl methyl) alkylsulfonyl] methyl }-1,3-thiazoles-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-{[(4-luorobenzyl) alkylsulfonyl] methyl }-1,3-thiazoles-4-methane amide;
1-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-[methyl (methyl sulphonyl) amino]-1H-indoles-6-methane amide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-4-(2-methoxy ethyl) benzamide;
N
1-butyl-N
3-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(1-phenycyclopropyl) amino] propyl group }-N
1-methyl-5-(1,3-thiazoles-2-yl) isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(1-phenycyclopropyl) amino] propyl group }-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-[(ethylamino) alkylsulfonyl] benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-[(methylamino-) alkylsulfonyl] benzamide;
(2E)-3-(1-butyl-1H-pyrazoles-4-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-and the 3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } third-2-alkene acid amides or (2E)-3-(1-butyl-1H-pyrazoles-4-yl)-N-{ (1S, 2R)-and 1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } third-2-alkene acid amides;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } different quinoline beautiful jade-7-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-and the 3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the different quinoline beautiful jade of 1-(third amino)-7-methane amide dihydrochloride or N-{ (1S, 2R)-and 1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the different quinoline beautiful jade of 1-(third amino)-7-methane amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-isopropyl benzyl) amino] propyl group }-5-{[(2-hydroxyl-1, the 1-dimethyl ethyl) amino] alkylsulfonyl }-N
3, N
3-dipropyl isophthaloyl amine;
3-(2-{3-[({ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino) carbonyl] phenyl }-1,3-oxazole-5-yl) methyl propionate;
3-(2-{3-[({ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino) carbonyl] phenyl }-1,3-oxazole-5-yl) propionic acid;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-(3-hydroxypropyl)-1H-indoles-6-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-ethoxy benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-methyl-6-(tetramethyleneimine-1-base carbonyl) Isonicotinamide;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(6-ethylpyridine-2-yl) methyl] amino }-the 2-hydroxypropyl)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(dipropyl amino) alkylsulfonyl] benzamide;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(6-ethylpyridine-2-yl) methyl] amino }-the 2-hydroxypropyl)-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
(1R)-1-[({ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino) carbonyl]-3-(methylsulfinyl) the propyl carbamic acid tert-butyl ester;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(dipropyl amino) Isonicotinamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(dipropyl amino) Isonicotinamide;
(2R)-2-amino-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(methylsulfinyl) butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[ethyl (methyl) amino] alkylsulfonyl }-5-{[(2S)-and 2-(methoxymethyl) pyrroline-1-yl] carbonyl } benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-and the 3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-[methyl (propyl group) amino] different quinoline beautiful jade-7-methane amide or N-{ (1S, 2R)-and 1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-[methyl (propyl group) amino] different quinoline beautiful jade-7-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(1,3-oxazole-2-yl) benzamide;
N
1-[(1S, 2R)-3-{[1-(3-bromophenyl) cyclopropyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-{[1-(3-bromophenyl) cyclopropyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N
5-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-dipropyl-1H-pyrazoles-3, the 5-diformamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2, N
2-dipropyl tetramethylene-1, the 2-diformamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(dipropyl amino) the carbonyl sulfenyl] benzamide;
3-[(E)-(cyanoimino) (dipropyl amino) methyl]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(6-sec.-propyl-2,2-titanium dioxide-3, the different benzothiopyran of 4-dihydro-1H--4-yl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(1-propyl group butoxy) benzamide;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(5-ethylpyridine-3-yl) methyl] amino }-the 2-hydroxypropyl)-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(6-sec.-propyl-2,2-titanium dioxide-3, the different benzothiopyran of 4-dihydro-1H--4-yl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-(2-methoxy ethyl)-1H-indoles-6-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3,4-dihydro-2H-1,4-benzoxazine-6-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(2R)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] carbonyl }-5-{[(2R)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] alkylsulfonyl } benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(1,3-thiazoles-2-yl) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4,8-diethoxy quinoline beautiful jade-2-methane amide;
2-(4-butyl-3-oxo piperazine-1-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-[2-(dimethylamino) ethyl]-N
3, 5-dimethyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methylbutyryl base) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(4-methylpent acyl group) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
(2R, 3S)-4-(3, the 5-difluorophenyl)-3-(3-[(dipropyl amino) carbonyl]-the 5-methyl benzoyl } amino)-2-hydroxybutyl isobutyl carbamate;
(2R, 3S)-4-(3, the 5-difluorophenyl)-3-(3-[(dipropyl amino) carbonyl]-the 5-methyl benzoyl } amino)-2-hydroxybutyl urethanum;
N
1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(pyrimidine-2--amino) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-N
3-[(1S)-and the 1-methyl-propyl] isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-N
3-[(1R)-and the 1-methyl-propyl] isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(dipropyl amino)-6-methylpyrimidine-4-methane amide;
1-[butyl (methyl) amino]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-and the 3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } different quinoline beautiful jade-7-methane amide or 1-[butyl (methyl) amino]-N-{ (1S, 2R)-and 1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } different quinoline beautiful jade-7-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,3-dihydro-2-thionaphthene-5-methane amide 2,2-dioxide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(2R)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] carbonyl }-the 5-methyl benzamide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-3-{[(2R)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] carbonyl }-5-methyl benzamide trifluoroacetate;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-isobutyl--1H-indoles-6-methane amide;
1-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2,5-dimethyl-1H-pyrroles-1-yl)-1H-indoles-6-methane amide;
1-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-Methyl-1H-indole-6-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-oxo-2-propyl group-2,3-dihydro-1,2-benzisothiazole-6-methane amide 1,1-dioxide;
1-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(1,3-oxazole-2-yl)-1H-indoles-6-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(dipropyl amino)-6-methyl Isonicotinamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-[(methyl sulphonyl) methyl]-1,3-thiazoles-4-methane amide;
4-amino-1-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-indoles-6-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-ethyl-3-oxo-2,3-dihydro-1,2-benzisothiazole-6-methane amide 1,1-dioxide;
3-[(tertiary butyl amino) alkylsulfonyl]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-{[(2S)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] carbonyl } benzamide;
3-{[(2S)-and 2-butyl pyrrolidine-1-yl] carbonyl }-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-methyl benzamide;
4-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3,4-dihydro-2H-1,4-benzoxazine-6-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-methyl-5-{[(2R)-2-(propoxy-methyl) tetramethyleneimine-1-yl] carbonyl } benzamide;
2-(1-butyl-2-oxo-piperidine-4-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-amylbenzene methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(2-ethylhexyl) benzamide;
Methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(6-methoxypyridine-2-yl) benzyl] amino } propyl group)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-{[3-(5-cyanopyridine-3-yl) benzyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[3-(6-fluorine pyridin-3-yl) benzyl] amino }-the 2-hydroxypropyl)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-pyrimidine-4-base benzyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[3-(5-ethyl-pyrimidine-2-yl) benzyl] amino }-the 2-hydroxypropyl)-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-pyrimidine-2-base benzyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
2-[({ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino) carbonyl]-6-methyl iso methyl nicotinate;
N
4-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-6-methyl-N
2, N
2-dipropyl pyridine-2,4-diformamide 1-oxide compound;
1-butyl-4-cyano group-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-indoles-6-methane amide;
1-butyl-4-cyano group-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-indoles-6-methane amide;
5-(diethylamino)-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-{[3-(diethylamino) benzyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(dimethylamino)-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(2-ethylpyridine-4-yl) methyl] amino }-the 2-hydroxypropyl)-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N
2-(tert-butoxycarbonyl)-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-levorotation norleucyl-amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(3H-[1,2,3] triazole [4,5-b] pyridin-3-yl oxygen base) methyl] benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-indoles benzyl) amino] propyl group }-the 3-{[(2-hydroxyethyl) (propyl group) amino] methyl }-the 5-methyl benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-indoles benzyl) amino] propyl group }-3-{[ethyl (propyl group)
5-{3-[({ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino) carbonyl] phenyl }-the 2-ethyl furoate;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,1 '-biphenyl-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2 '-(methyl sulfenyl)-1,1 '-biphenyl-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(2-luorobenzyl) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(4-luorobenzyl) benzamide;
3 '-[((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino) carbonyl]-1,1 '-biphenyl-2-ethyl formate;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3 ', 5 '-two fluoro-1,1 '-biphenyl-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-phenyl-acetamides;
4-[({ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino) carbonyl] the benzylamino t-butyl formate;
(2R)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl-2-phenyl-acetamides;
(2S)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl-2-phenyl-acetamides;
3-(5-chloro-phenyl-)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(1-styroyl) benzamide trifluoroacetate;
3-(cyclohexyl methyl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide;
3-cyclopentyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl-3-oneself-5-alkenyl benzene methane amide;
3-(6-cyano group hexyl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[3-(2-formyl thiene-3-yl-) benzyl] amino }-the 2-hydroxypropyl }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[3-(5-formyl thiene-3-yl-) benzyl] amino }-the 2-hydroxypropyl }-5-amino] methyl }-the 5-methyl benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 1-methyl isophthalic acid, 3-dihydro-2,1-benzisothiazole-5-methane amide 2,2-dioxide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-levorotation norleucyl-amine;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[3-(dimethylamino) benzyl] amino }-the 2-hydroxypropyl)-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
2-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-6-methyl Isonicotinamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-the 3-{[(2-hydroxyethyl) (propyl group) amino] methyl } benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(3-fluoro-4-propoxy-phenyl) ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(3-methoxyl group-4-propoxy-phenyl) ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-3-methyl-5-{[methyl (propyl group) amino] methyl } benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-3-[(dipropyl amino) methyl]-the 5-methyl benzamide;
3-{[butyl (methyl) amino] methyl }-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-the 5-methyl benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(piperidines-1-base alkylsulfonyl) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(6-sec.-propyl-2,2-titanium dioxide-3, the different benzothiopyran of 4-dihydro-1H--4-yl) amino] propyl group }-the 3-methyl benzamide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-4-(3-methoxy-propyl) benzamide;
5-amino-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-(the 3-[(dimethylamino) and methyl] benzyl } amino)-the 2-hydroxypropyl]-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N-(tert-butoxycarbonyl)-3-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-levorotation histidyl-amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-isopentyl-1H-indoles-6-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-propyl group-2,3-dihydro-1,2-benzisothiazole-6-methane amide 1,1-dioxide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-ethyl-2,3-dihydro-1,2-benzisothiazole-6-methane amide 1,1-dioxide;
6-bromo-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,2-dimethylbiphenyl pyrans-8-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-[(methyl sulphonyl) methyl] cyclohexane carboxamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-piperidin-4-yl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl-5-(1,3-oxazole-2-yl) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-[(methyl sulphonyl) methyl] thiophene-2-carboxamide derivatives;
3-[(cyclohexyl amino) methyl]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-the 5-methyl benzamide;
2-(2-chlorophenoxy)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } piperazine-2-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(phenyl sulfonyl) propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[(2S)-2-(methoxymethyl) tetramethyleneimine-1-yl]-6-methyl Isonicotinamide;
3-[({ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino) carbonyl]-the 5-tolyl acid;
6-cyano group-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,2-dimethylbiphenyl pyrans-8-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl-5-(1,3-thiazoles-2-yl) benzamide;
Formic acid cpds and N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(4-ethoxyl phenenyl) ethanamide (1: 1);
Formic acid cpds and N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-methyl-5-{[(2S)-2-propyl pyrrole alkane-1-yl] carbonyl } benzamide (1: 1);
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(2R)-and 2-(2-methoxy ethyl) tetramethyleneimine-1-yl] carbonyl }-the 5-methyl benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-[(methyl sulphonyl) methyl] cyclohexane carboxamide;
3-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-Methyl-1H-indole-5-methane amide;
Formic acid cpds and 2-(1-butyl-2-oxo-1,2-dihydropyridine-4-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide (1: 1);
3-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-levorotation histidyl-amine;
The 5-[(diethylamino) methyl]-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-[(dimethylamino) methyl]-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-the 3-[(3-Ethylbenzyl) amino]-1-[3-(hexyloxy) benzyl]-the 2-hydroxypropyl }-3-(1,3-oxazole-2-yl) benzamide;
Formic acid cpds and N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(3-hydroxyl-4-p-methoxy-phenyl) ethanamide (1: 1);
Formic acid cpds and N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(1,3-thiazoles alkane-3-base alkylsulfonyl) benzamide (1: 1);
Formic acid cpds and N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3, the different quinoline beautiful jade-2 of 4-dihydro (1H)-Ji alkylsulfonyl) benzamide (1: 1);
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-[(4-phenylpiperazine-1-yl) alkylsulfonyl] benzoyl;
3-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-indoles-5-methane amide;
N-(1S, 2R)-the 3-[(3-Ethylbenzyl) amino]-1-[3-(hexyloxy) amino]-the 2-hydroxypropyl } ethanamide;
1-butyl-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-1H-benzoglyoxaline-6-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-[(methyl sulphonyl) methyl] niacinamide;
N
1-[(1S, 2R)-3-(the 3-[(diethylin) and methyl] benzyl } amino)-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[1-methyl-5-(4-methyl benzoyl)-1H-pyrroles-2-yl] ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(dipropyl amino)-6-(1,3-oxazole-2-yl) Isonicotinamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-methyl-6-(1,3-oxazole-2-yl) Isonicotinamide;
1-butyl-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl }-1H-benzoglyoxaline-5-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(6-sec.-propyl-2,2-titanium dioxide-3, the different benzothiopyran of 4-dihydro-1H--4-yl) amino] propyl group }-the 3-methyl benzamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-piperidines-3-base-N
3, N
3-dipropyl isophthaloyl amine;
3-{[benzyl (methyl) amino] methyl }-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-the 5-methyl benzamide;
Formic acid cpds and N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-{[4-(4-fluorophenyl) piperazine-1-yl] alkylsulfonyl } benzamide (2: 1);
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(tetramethyleneimine-1-base alkylsulfonyl) benzamide;
Formic acid cpds and N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(tetramethyleneimine-1-base alkylsulfonyl) benzamide (1: 1);
Formic acid cpds and N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(4-[3-(trifluoromethyl) phenyl] and piperazine-1-yl } alkylsulfonyl) benzamide (2: 1);
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-[(dimethylamino) alkylsulfonyl] benzamide;
Formic acid cpds and N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-[(dimethylamino) alkylsulfonyl] benzamide (1: 1);
N-{ (1S, 2R)-the 3-[(3-Ethylbenzyl) amino]-1-[3-(hexyloxy) benzyl]-the 2-hydroxypropyl }-the 2-[(methyl sulphonyl) amino]-1,3-oxazole-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 6-[(methyl sulphonyl) methyl] niacinamide;
N-[(1S, 2R)-the 3-[(3-bromobenzyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-4-methylpent acid amides;
1-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl isophthalic acid H-pyrroles-2-methane amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(1H-pyrroles-2-ylmethyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-piperazine-1-base-N
3, N
3-dipropyl isophthaloyl amine;
N-[(1S, 2R)-the 3-[(3-bromobenzyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl] ethanamide;
N
2-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-6-methyl-N
4, N
4-dipropyl pyridine-2, the 4-diformamide;
N
2-(tert-butoxycarbonyl)-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-right type norleucyl-amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-right type norleucyl-amine;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(4R)-6-sec.-propyl-2,2-titanium dioxide-3, the different sulfo-cumarone of 4-dihydro-1H--4-yl] propyl group } ethanamide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(4S)-6-sec.-propyl-2,2-titanium dioxide-3, the different sulfo-cumarone of 4-dihydro-1H--4-yl] propyl group } ethanamide;
Formic acid cpds and 4-{[(4-chloro-phenyl-) (methyl) amino] alkylsulfonyl }-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide (1: 1);
Formic acid cpds and 4-{[benzyl (phenyl) amino] alkylsulfonyl }-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide (1: 1);
Formic acid cpds and N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(morpholine-4-base alkylsulfonyl) benzamide (1: 1);
N-[(1S, 2R)-the 3-[(3-bromobenzyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl] propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(3-oxo-4-propyl group cyclohexyl) ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(3-oxo cyclohexyl) ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,1-biphenyl-3, the different chromene of 4-dihydro-1H--7-methane amide;
Formic acid cpds and 4-{[(2-cyano ethyl) (methyl) amino] alkylsulfonyl }-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide (1: 1);
Formic acid cpds and 4-{[cyclohexyl (methyl) amino] alkylsulfonyl }-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide (1: 1);
Formic acid cpds and N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-{[methyl (2-pyridine-2-base ethyl) amino] alkylsulfonyl } benzamide (2: 1);
Formic acid cpds and N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-{[methyl (phenyl) amino] alkylsulfonyl } benzamide (1: 1);
Formic acid cpds and 4-{[benzyl (methyl) amino] alkylsulfonyl }-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide (1: 1);
Formic acid cpds and N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-{[methyl (2-styroyl) amino] alkylsulfonyl } benzamide (1: 1);
Formic acid cpds and 4-{[allyl group (methyl) amino] alkylsulfonyl }-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide (1: 1);
Formic acid cpds and 4-{[[2-(diethylamino) ethyl] (methyl) amino] alkylsulfonyl }-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide (2: 1);
Formic acid cpds and N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-{[methyl (propyl group) amino] alkylsulfonyl } benzamide (1: 1);
Formic acid cpds and 4-{[butyl (methyl) amino] alkylsulfonyl }-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide (1: 1);
Formic acid cpds and N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-{[methyl (amyl group) amino] alkylsulfonyl } benzamide (1: 1);
Formic acid cpds and N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-{[isopentyl (methyl) amino] alkylsulfonyl } benzamide (1: 1);
2-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,2,3,4-Tetrahydroisoquinoli-beautiful jade-7-methane amide;
Formic acid cpds and N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-{[methyl (1-methylpyrrolidin-3-yl) amino] alkylsulfonyl } benzamide (2: 1);
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(4-ethylpyridine-2-yl) cyclopropyl] amino }-the 2-hydroxypropyl)-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(2-methoxy ethyl) benzamide;
1-butyl-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-2-(2-methoxy ethyl)-1H-benzoglyoxaline-6-methane amide;
Levorotation-α-Gu Anxianji-levorotation-valyl-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-levorotation-methionyl amine;
3-{[cyclohexyl (methyl) amino] methyl }-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-the 5-methyl benzamide;
N-{ (1S, 2R)-1-(3-butoxy benzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide;
Formic acid cpds and 2-(4-butyl-2,5-dioxo piperazine-1-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide (1: 1);
3-dicyclo [2.2.1] heptan-2-base-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide;
3-(butyl amino)-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-4-(2-methoxy ethyl) benzamide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-2-(dipropyl amino)-6-(1,3-oxazole-2-yl) Isonicotinamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(1S)-1,2,3,4-naphthane-1-base is amino] propyl group }-the 3-methyl benzamide;
Formic acid cpds and N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-[(dipropyl amino) alkylsulfonyl] benzamide (1: 1);
Formic acid cpds and 4-[(diethylamino) alkylsulfonyl]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide (1: 1);
4-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-(methyl sulphonyl)-1,2,3,4-tetrahydroquinoxaline-6-methane amide;
1-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } different quinoline beautiful jade-7-methane amide;
5-{[butyl (methyl) amino] methyl }-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } thiophene-2-carboxamide derivatives;
3-{[butyl (methyl) amino] methyl }-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-the 5-methyl benzamide;
3-{[butyl (methyl) amino] methyl }-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(trifluoromethyl) benzyl] amino } propyl group)-the 5-methyl benzamide;
3-bromo-5-{[butyl (methyl) amino] methyl }-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl) benzamide;
3-{[butyl (methyl) amino] methyl }-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-the 5-methyl benzamide;
(2R)-2-(4-butyl-3-oxo piperazine-1-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } propionic acid amide;
3-{[butyl (methyl) amino] methyl }-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-methyl benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(dipropyl amino)-6-(1,3-thiazoles-2-yl) Isonicotinamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-3-{[isopentyl (methyl) amino] methyl }-the 5-methyl benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-[(methyl sulphonyl) amino]-1,3-oxazole-4-formyl radical;
3-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } imidazo [1,2-a] pyridine-6-methane amide;
2-[butyl (methyl) amino]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-6-(1,3-oxazole-2-yl) Isonicotinamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,3-benzo dioxole-5-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(6-ethyl-2,2-titanium dioxide-3, the different sulfo-chromene of 4-dihydro-1H--4-yl) amino]-the 2-hydroxypropyl } ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(6-ethyl-2,2-titanium dioxide-3, the different sulfo-chromene of 4-dihydro-1H--4-yl) amino]-the 2-hydroxypropyl } ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[methyl (propyl group) amino]-6-(1,3-oxazole-2-yl) Isonicotinamide;
3-{[butyl (methyl) amino] methyl }-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(1-benzyl ring alkyl) amino] propyl group }-the 5-methyl benzamide;
3-{[butyl (methyl) amino] methyl }-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-isopropyl benzyl) amino] propyl group }-the 5-methyl benzamide;
N-[(1S, 2R)-3-{[1-(3-bromophenyl) cyclopropyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl] ethanamide;
3-{[butyl (methyl) amino] methyl }-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-5-(1,3-oxazole-2-yl) benzamide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[2-methyl sulphonyl]-the 1-phenylethyl] amino } propyl group) ethanamide;
3-{[butyl (methyl) amino] methyl }-5-cyano group-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide;
N-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(the 2-[(methyl sulphonyl) and methyl] benzyl } amino) propyl group] ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-{[(2-furyl methyl) (methyl) amino] methyl }-the 5-methyl benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-{[(2-methoxy ethyl) (methyl) amino] methyl }-the 5-methyl benzamide;
3-{[[2-(diethylamino) ethyl] (methyl) amino] methyl }-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-methyl benzamide;
N-[(1S, 2R)-the 3-[(3-bromobenzyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-2-methoxyl group ethanamide;
Formic acid cpds and N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[4-(ethoxyl methyl) piperidines-1-yl] valeramide (2: 1);
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-oxo indenes-5-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-hydroxyl indenes-5-methane amide;
Formic acid cpds and N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(4-propoxy-piperidines-1-yl) ethanamide (2: 1);
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[sec.-propyl (methyl) amino] methyl }-the 5-methyl benzamide;
Formic acid cpds and 2-(1-butyl-2-oxo-piperidine-4-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide (1: 1);
Formic acid cpds and 2-(4-butyl piperazine-1-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide (3: 1);
4-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3,4-dihydro-2H-1,4-benzothiazine-6-methane amide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1R, 2S)-2-hydroxyl-2,3-dihydro-1H-indenes-1-yl] amino } propyl group) ethanamide;
2-[(2S)-4-butyl-2-methyl-3-oxo piperazine-1-yl]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide;
2-[(2R)-4-butyl-2-methyl-3-oxo piperazine-1-yl]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2,3-dioxo-4-propyl group piperazine-1-yl) ethanamide;
4-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,2,3,4-tetrahydroquinoxaline-6-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl-5-{[methyl (amyl group) amino] methyl } benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(2R)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] methyl }-the 5-methyl benzamide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-2-(dipropyl amino) Isonicotinamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(1-{4-[(dimethylamino) amino] pyridine-2-yl } cyclopropyl) amino]-the 2-hydroxypropyl }-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(dipropyl amino)-4-methyl isophthalic acid, 3-thiazole-5-methane amide;
N-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-(the 2-[(4-Ethylbenzyl) and alkylsulfonyl] ethyl } amino)-the 2-hydroxypropyl] ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-methyl-3-phenyl-1H-thieno-[2,3-c] pyrazoles-5-methane amide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-titanium dioxide-3, the different sulfenyl chromene of 4-dihydro-1H--4-yl] amino }-the 2-hydroxypropyl)-3, the 5-dimethyl benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(1S)-1,2,3,4-naphthane-1-base is amino] propyl group } ethanamide;
3-bromo-5-{[butyl (methyl) amino] methyl }-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide;
1-butyl-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl }-1H-indoles-6-methane amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[({4-[(dimethylamino) methyl] pyridine-2-yl } methyl) amino]-the 2-hydroxypropyl }-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
3-[(butyl amino) methyl]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 5-methyl benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(2S)-and 2-(methoxymethyl) tetramethyleneimine-1-yl] methyl }-the 5-methyl benzamide;
Formic acid cpds and N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[4-(2-methoxy ethyl) piperidines-1-yl] ethanamide (2: 1);
1-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,2,3,4-Tetrahydroisoquinoli-beautiful jade-7-methane amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
1, 5-dimethyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-[3-(dimethylamino) third-1-alkynyl]-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2-Phenoxyphenyl) ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2, the 5-3,5-dimethylphenyl) ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[2-(trifluoromethoxy) phenyl] ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2-ethoxyl phenenyl) ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[2-(trifluoromethyl) phenyl] ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2-p-methoxy-phenyl) ethanamide;
2-[2-(benzyloxy) phenyl]-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-phenylbutanamides;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-phenyl-acetamides;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2, the 4-dimethoxy phenyl) ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2, the 4-Dimethoxyphenyl) ethanamide;
2-(2-chloro-phenyl-)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide;
2-cyclohexyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide;
2-ring penta-2-alkene-1-base-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(1-methyl-5-oxo-2-sulfo-oxo-imidazole alkane-4-yl) ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2-fluorophenyl) ethanamide;
2-cyclopropyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide;
2-hexamethylene-1-alkene-1-base-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide;
2-(1-adamantyl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide;
(2S)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-Phenylpropionamide;
(2R)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-Phenylpropionamide;
2-(2,4 dichloro benzene base)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2, the 3-Dimethoxyphenyl) ethanamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-[3-(dimethylamino) propyl group]-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(2,2-titanium dioxide-3, the different sulfo-chromene of 4-dihydro-1H--4-yl) amino]-the 2-hydroxypropyl } ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(2,3-titanium dioxide-3, the different sulfo-chromene of 4-dihydro-1H--4-yl) amino]-the 2-hydroxypropyl } ethanamide;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(4-ethynyl pyridine-2j yl) cyclopropyl] amino }-the 2-hydroxypropyl)-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
4-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3,4-dihydro-2H-1,4-benzothiazine-6-methane amide 1-oxide compound;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-heptyl-4-hydroxyl-levorotation-prolineamide;
2-[butyl (methyl) amino]-6-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } Isonicotinamide;
2-[butyl (methyl) amino]-6-cyano group-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } Isonicotinamide;
N '-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[({2-[(dimethylamino) methyl] pyridin-4-yl } methyl) amino]-the 2-hydroxypropyl }-5-(1,3-oxazole-2-yl)-N, N-dipropyl isophthaloyl amine;
4-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl-8-(1,3-oxazole-2-yl)-3,4-dihydro-2H-1,4-benzoxazine-6-methane amide or
4-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-8-(1,3-oxazole-2-yl)-3,4-dihydro-2H-1,4-benzoxazine-6-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(4-ethyl-1,3-oxazole-2-yl)-5-(1,3-oxazole-2-yl) benzamide;
3-benzyl-4-(4-butyl phenyl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-oxo butyramide;
2-(4-butyl-2-oxo piperazine-1-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[4-(ethoxyl methyl) piperidines-1-yl] ethanamide;
2-(4-butyl-2,3-dioxo piperazine-1-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } hexanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group } ethanamide;
N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(4-ethynyl pyridine-2-yl) cyclopropyl] amino }-the 2-hydroxypropyl)-5-(1,3-oxazole-2-yl)-N
3, N
3-dipropyl isophthaloyl amine;
5-[((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl) amino]-the 5-oxopentanoic acid;
1-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-and the 3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,2,3,4-tetrahydrochysene quinoline beautiful jade-7-methane amide or 1-butyl-N-{ (1S, 2R)-and 1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,2,3,4-tetrahydrochysene quinoline beautiful jade-7-methane amide;
4-[((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-(ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl) amino]-the 4-ketobutyric acid;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-propyl group-1,2-benzoisoxazole-5-methane amide;
2-[allyl group (methyl) amino]-N-{ (1S, 2R)-1-[3-(allyloxy)-5-luorobenzyl]-the 3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } Isonicotinamide;
1-allyl group-N-{ (1S, 2R)-1-[4-(allyloxy)-3-luorobenzyl]-the 3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-indoles-6-methane amide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-4-phenyl-2-(1H-pyrroles-1-yl)-1,3-thiazoles-5-methane amide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-2-(dipropyl amino)-4-(trifluoromethyl)-1,3-thiazoles-5-methane amide;
(2S)-2-{[(2R, 3S)-3-(acetylamino)-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl] amino }-N-isobutyl--4-(methyl sulphonyl) butyramide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(3-hydroxyl third-1-alkynyl) benzyl] amino } propyl group) ethanamide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-2,6-dimorpholine-4-yl pyrimidines-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[(2S)-and 2-ethyl pyrrolidine-1-yl] carbonyl }-the 5-methyl benzamide;
(2S)-2-(4-butyl-3-oxo piperazine-1-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } propionic acid amide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-titanium dioxide-3, the different sulfenyl chromene of 4-dihydro-1H--4-yl] amino }-the 2-hydroxypropyl) tetrahydrofuran (THF)-3-methane amide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-titanium dioxide-3, the different sulfenyl chromene of 4-dihydro-1H--4-yl] amino }-the 2-hydroxypropyl) propionic acid amide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-titanium dioxide-3, the different sulfenyl chromene of 4-dihydro-1H--4-yl] amino }-the 2-hydroxypropyl)-2-(1H-imidazol-4 yl) ethanamide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-titanium dioxide-3, the different sulfenyl chromene of 4-dihydro-1H--4-yl] amino }-the 2-hydroxypropyl)-N
2, 2-dimethylamino propionic acid amide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-titanium dioxide-3, the different sulfenyl chromene of 4-dihydro-1H--4-yl] amino }-the 2-hydroxypropyl) cyclopentane formamide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-titanium dioxide-3, the different sulfenyl chromene of 4-dihydro-1H--4-yl] amino }-the 2-hydroxypropyl) cyclopropane carboxamide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-titanium dioxide-3, the different sulfenyl chromene of 4-dihydro-1H--4-yl] amino }-the 2-hydroxypropyl)-the 2-phenyl-acetamides;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-titanium dioxide-3, the different sulfenyl chromene of 4-dihydro-1H--4-yl] amino }-the 2-hydroxypropyl) tetrahydrofuran (THF)-2-methane amide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-titanium dioxide-3, the different sulfenyl chromene of 4-dihydro-1H--4-yl] amino }-the 2-hydroxypropyl)-1,3-thiazoles alkane-4-methane amide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-titanium dioxide-3, the different sulfenyl chromene of 4-dihydro-1H--4-yl] amino }-the 2-hydroxypropyl)-3-maloyl group amine;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-titanium dioxide-3, the different sulfenyl chromene of 4-dihydro-1H--4-yl] amino }-the 2-hydroxypropyl)-3-hydroxyl propionic acid amide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-titanium dioxide-3, the different sulfenyl chromene of 4-dihydro-1H--4-yl] amino }-the 2-hydroxypropyl)-3-hydroxyl-2,2-dimethyl propylene acid amides;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-titanium dioxide-3, the different sulfenyl chromene of 4-dihydro-1H--4-yl] amino }-the 2-hydroxypropyl)-3-methylbutyryl amine;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-titanium dioxide-3, the different sulfenyl chromene of 4-dihydro-1H--4-yl] amino }-the 2-hydroxypropyl) G-NH2;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-titanium dioxide-3, the different sulfenyl chromene of 4-dihydro-1H--4-yl] amino }-the 2-hydroxypropyl)-N
2-methyl G-NH2;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-1-methyl-3-(trifluoromethyl)-1H-thieno-[2,3-c] pyrazoles-5-methane amide;
2-[allyl group (methyl) amino]-N-{ (1S, 2R)-1-[4-(allyloxy)-3-luorobenzyl]-the 3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } Isonicotinamide;
3-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,2-benzoisoxazole-5-methane amide;
5-(3-aminopropyl)-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-[3-(methylamino) propyl group]-N
3, N
3-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-[3-(methylamino) third-1-alkynyl]-N
3, N
3-dipropyl isophthaloyl amine;
5-(3-amino third-1-alkynyl)-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-dipropyl isophthaloyl amine;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl }-5-tetramethyleneimine-1-base piperazine-2-methane amide;
4-butoxy-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } quinoline beautiful jade-2-methane amide;
2-cyano group-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-6-[methyl (propyl group) amino] Isonicotinamide;
3-ethanoyl-1-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-indoles-6-methane amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(1H-indoles-6-ylmethyl) amino] propyl group }-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-isobutyl--1,2-benzoisoxazole-5-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[(2S)-and tetramethyleneimine-2-yl] ethanamide;
2-[2-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino)-2-oxygen ethyl]-N-(6-methoxypyridine-3-yl) benzamide;
2-[2-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino)-2-oxygen ethyl]-N-(2,4 difluorobenzene base) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-piperidines-3-yl acetamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(1H-imidazoles-5-yl) ethanamide;
2-cyclopentyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2-hydroxyphenyl) ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2-aminomethyl phenyl) ethanoyl;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(iodophenyl) ethanamide;
1-(4-chloro-phenyl-)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-oxo-pyrrolidine-3-methane amide;
4-(2,4 dichloro benzene oxygen base)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } butyramide;
4,5-two bromo-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } thiophene-2-carboxamide derivatives;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) ethanamide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-2, two (dimethylamino) pyrimidines of 6--4-methane amide;
4-butyl-8-cyano group-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3,4-dihydro-2H-1,4-benzoxazine-6-methane amide;
3-(allyl group alkylsulfonyl)-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl) benzamide;
3-(allyl group sulfenyl)-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(7-methoxyl group-1,2,3,4-naphthane-1-yl) amino] propyl group } ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(7-methoxyl group-1,2,3,4-naphthane-1-yl) amino] propyl group } ethanamide;
Formic acid cpds and N
1-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-N
5-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl) glutaramide (1: 1);
Formic acid cpds and N
1-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-N
5-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl) glutaramide (1: 1);
Formic acid cpds and N
1-[(3S)-1-azabicyclo [2.2.2] oct-3-yl]-N
4-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl) succinic diamide (1: 1);
Formic acid cpds and N
1-[(3R)-1-azabicyclo [2.2.2] oct-3-yl]-N
4-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl) succinic diamide (1: 1);
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-titanium dioxide-3, the different sulfo-chromene of 4-dihydro-1H--4-yl] amino }-the 2-hydroxypropyl) valeramide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-titanium dioxide-3, the different sulfo-chromene of 4-dihydro-1H--4-yl] amino }-the 2-hydroxypropyl)-the 3-Phenylpropionamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-[4-(dimethylamino) fourth-1-alkynyl]-N
3, N
3-dipropyl isophthaloyl amine;
1-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(trifluoroacetyl group)-1H-indoles-6-methane amide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-3-{[isopentyl (methyl) amino] methyl }-the 5-methyl benzamide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-3-{[isopentyl (methyl) amino] methyl }-the 5-methyl benzamide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-4-(dipropyl amino)-1-methyl isophthalic acid H-pyrroles-2-methane amide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-titanium dioxide-3, the different benzothiopyran of 4-dihydro-1H--4-yl] amino }-the 2-hydroxypropyl)-4-(2-methoxy ethyl) benzamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-[4-(dimethylamino) butyl]-N
3, N
3-dipropyl isophthaloyl amine;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[6-ethyl-2-(methyl sulphonyl)-1,2,3,4-Tetrahydroisoquinoli-beautiful jade-4-yl] amino }-the 2-hydroxypropyl) ethanamide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[6-ethyl-2-(methyl sulphonyl)-1,2,3,4-Tetrahydroisoquinoli-beautiful jade-4-yl] amino }-the 2-hydroxypropyl) ethanamide;
2,6-two chloro-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl) pyrimidine-4-methane amide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(1S)-7-ethyl-1,2,3,4-naphthane-1-yl] amino }-the 2-hydroxypropyl) ethanamide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(1R)-7-ethyl-1,2,3,4-naphthane-1-yl] amino }-the 2-hydroxypropyl) ethanamide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl }-2-morpholine-4-base-4-(trifluoromethyl)-1,3-thiazoles-5-methane amide;
N-{ (1S, 2R)-1-benzyl-3-[(6-ethyl-2,2-titanium dioxide-3, the different sulfo-chromene of 4-dihydro-1H--4-yl) amino]-the 2-hydroxypropyl } ethanamide;
N-[(1S, 2R)-3-{[1-(3-bromophenyl) cyclopropyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl] ethanamide;
N
1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-({ [1-(3-ethylphenyl)-1H-tetrazolium-5-yl] methyl } amino)-2-hydroxypropyl]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
3-(allyl group sulfinyl)-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl) benzamide;
3-[3 '-(acetylamino)-1,1 '-phenylbenzene-3-yl]-3-{[(2R, 3S)-3-(acetylamino)-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl] amino } methyl propionate;
3-[3 '-(acetylamino)-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl] amino }-3-[3-(5-furoyl base thiophene-2-yl) phenyl] methyl propionate;
3-{[(2R, 3S)-3-(acetylamino)-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl] amino }-3-(2 '-ethanoyl-1,1 '-phenylbenzene-3-yl) methyl propionate;
3-{[(2R, 3S)-3-(acetylamino)-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl] amino }-3-[3 '-(methylol)-1,1 '-phenylbenzene-3-yl] methyl propionate;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[1-(3 '-methoxyl group-1,1 '-phenylbenzene-3-yl) cyclopropyl] amino } propyl group) ethanamide;
N-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(1-[3 '-(methylol)-1,1 '-phenylbenzene-3-yl] cyclopropyl } amino) propyl group] ethanamide;
N-[(1S, 2R)-3-{[1-(2 '-ethanoyl-1,1 '-phenylbenzene-3-yl) cyclopropyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl] ethanamide;
N-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-(1-[3-(5-furoyl base thiophene-2-yl) phenyl] and cyclopropyl } amino)-the 2-hydroxypropyl] ethanamide;
N-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-(9H-fluorenes-9-base is amino)-2-hydroxypropyl] ethanamide;
3-{[92R, 3S)-3-(acetylamino)-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl] amino }-3-[3-(trifluoromethyl) phenyl] methyl propionate;
3-{[(2R, 3S)-3-(acetylamino)-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl] amino }-3-(3-cyano-phenyl) methyl propionate;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-[3-(dimethylamino) propyl group]-N
3, N
3-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3 '-(methylol)-5-(1,3-thiazoles-2-yl)-1,1 '-biphenyl-3-methane amide;
3 '-cyano group-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1,3-thiazoles-2-yl)-1,1 '-biphenyl-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2 '-oxyethyl group-5-(1,3-thiazoles-2-yl)-1,1 '-biphenyl-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1,3-thiazoles-2-yl)-3 '-(trifluoromethoxy)-1,1 '-biphenyl-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4 '-propoxy--5-(1,3-thiazoles-2-yl)-1,1 '-biphenyl-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4 '-(dimethylamino)-5-(1,3-thiazoles-2-yl)-1,1 '-biphenyl-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2 '-propoxy--5-(1,3-thiazoles-2-yl)-1,1 '-biphenyl-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3 '-propoxy--5-(1,3-thiazoles-2-yl)-1,1 '-biphenyl-2-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3 '-oxyethyl group-5-(1,3-thiazoles-2-yl)-1,1 '-biphenyl-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4 '-oxyethyl group-5-(1,3-thiazoles-2-yl)-1,1 '-biphenyl-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4 '-isopropoxy-5-(1,3-thiazoles-2-yl)-1,1 '-biphenyl-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4 '-(methylol)-5-(1,3-thiazoles-2-yl)-1,1 '-biphenyl-3-methane amide;
4-butoxy-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1,3-thiazoles-2-yl)-1,1 '-biphenyl-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4 '-methoxyl group-5-(1,3-thiazoles-2-yl)-1,1 '-biphenyl-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1,3-thiazoles-2-yl)-4 '-(trifluoromethoxy)-1,1 '-biphenyl-3-methane amide;
4 '-butyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1,3-thiazoles-2-yl)-1,1 '-biphenyl-3-methane amide;
3 '-butoxy-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1,3-thiazoles-2-yl)-1,1 '-biphenyl-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3 '-sec.-propyl-5-(1,3-thiazoles-2-yl)-1,1 '-biphenyl-3-methane amide;
3-(acetylamino)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1,3-thiazoles-2-yl)-1,1 '-biphenyl-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2 '-methyl-5-(1,3-thiazoles-2-yl)-1,1 '-biphenyl-3-methane amide;
2 '-ethanoyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1,3-thiazoles-2-yl)-1,1 '-biphenyl-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4 '-hydroxyl-5-(1,3-thiazoles-2-yl)-1,1 '-biphenyl-3-methane amide;
4 '-(acetylamino)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(1,3-thiazoles-2-yl)-1,1 '-biphenyl-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(1H-pyrroles-2-yl)-5-(1,3-thiazoles-2-yl) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(E)-2-(4-fluorophenyl) vinyl]-5-(1,3-thiazoles-2-yl) benzamide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl) pyrimidine-4-methane amide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl) ethanamide;
3-{[(2R, 3S)-3-(acetylamino)-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl] amino }-3-(3-bromophenyl) methyl propionate;
2-chloro-N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-6-morpholine-4-yl pyrimidines-4-methane amide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl)-2-(dipropyl amino)-6-morpholine-4-yl pyrimidines-4-methane amide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl }-2, two (dipropyl amino) pyrimidines of 6--4-methane amide;
3-{[(2R, 3S)-3-(acetylamino)-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl] amino }-3-(3-bromophenyl) methyl propionate;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl) ethanamide.
346. a compound, or it can be used for the salt of pharmacy, and this compound is:
N '-[(1S, 2S)-3-(benzyl amino)-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N, N-dipropyl isophthaloyl amine;
N '-(1S, 2S)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-ethynyl-N, N-dipropyl isophthaloyl amine;
N-(1-cyclopropyl ethyl)-N '-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N-phenyl succinic diamide;
N '-[(1S, 2S)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(3-[(1E)-third-1-thiazolinyl] benzyl } amino) propyl group]-5-methyl-N, N-dipropyl isophthaloyl amine;
N '-[(1S, 2S)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-isopropyl benzyl) amino] propyl group }-5-(1,3-oxazole-2-yl)-N, N-dipropyl isophthaloyl amine;
(3-{[((2R, 3S)-4-(3, the 5-difluorophenyl)-3-{[3-[(dipropyl amino) carbonyl]-5-(1,3-oxazole-2-yl) benzoyl] amino }-2-hydroxyl butyl) amino] methyl } phenyl) methylene dicarbamate;
N '-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(the 3-[(methyl sulphonyl) and amino] benzyl } amino) propyl group]-5-(1,3-oxazole-2-yl)-N, N-dipropyl isophthaloyl amine;
N '-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-isopropyl benzyl) amino] propyl group }-N, N-dipropyl pyridine-3,5-diformamide;
N '-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N, N-dipropyl pyridine-3,5-diformamide 1-oxide compound;
N '-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-ethynyl benzyl) amino]-the 2-hydroxypropyl }-5-ethynyl-N, N-dipropyl isophthaloyl amine;
N
4-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-isopropyl benzyl) amino] propyl group }-6-methyl-N
2, N
2-dipropyl pyridine-2, the 4-diformamide;
N '-[(1S, 2R)-3-{[(2-tertiary butyl pyrimidine-4-yl) methyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N, N-dipropyl isophthaloyl amine;
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[(2-ethyl-pyrimidine-4-yl) methyl] amino }-the 2-hydroxypropyl)-5-methyl-N, N-dipropyl isophthaloyl amine;
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1S)-the 1-[(isobutylamino) carbonyl]-3-(methyl sulphonyl) propyl group] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine;
N '-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-hydroxyl-1-phenyl propyl) amino] propyl group }-5-methyl-N, N-dipropyl isophthaloyl amine;
N '-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(6,7,8,9-tetrahydrochysene-5H-benzo [7] annulene-5-base is amino) propyl group]-5-methyl-N, N-dipropyl isophthaloyl amine;
N '-((1S, 2S)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1R)-6-methoxyl group-1,2,3,4-naphthane-1-yl] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine;
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1R)-6-methoxyl group-1,2,3,4-naphthane-1-yl] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine;
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1S)-2-oxo-1-methyl-2-(methylamino) ethyl] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine;
N '-[(1S, 2R)-3-{[(1S)-1-benzyl-2-oxo-2-(methylamino) ethyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N, N-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-{ oxo [3-trifluoromethyl] phenyl } methyl } G-NH2;
2-{[2-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-2-oxygen ethyl] sulfenyl }-N-(5-methyl-isoxazole-3-yl) ethanamide;
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1S)-1-[oxo (methylamino) methyl]-3-(methylthio group) propyl group] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine;
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1R)-1-(methylol)-2-oxygen-2-(methylamino) ethyl] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine;
N '-[(1S, 2R)-3-((1S)-1-[amino (oxygen) methyl]-the 3-methyl butyl } amino)-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N, N-dipropyl isophthaloyl amine;
N '-[(1S, 2R)-3-[(2-amino-2-oxygen-1-methylethyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N, N-dipropyl isophthaloyl amine;
(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-2-hydroxypropyl t-butyl carbamate;
(1S, 2R)-3-(cyclopropyl amino)-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl t-butyl carbamate;
(1S, 2R)-3-[(cyclopropyl methyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl t-butyl carbamate;
((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[2-oxygen-2-(isobutylamino)-1-methylethyl] amino } propyl group) t-butyl carbamate;
(1S, 2R)-1-benzyl-3-[(3-Ethylbenzyl) amino]-2-hydroxypropyl benzyl carbamate;
(2R, 3S)-3-amino-4-(3, the 5-difluorobenzyl)-1-{[1-(3-ethynyl phenyl) cyclopropyl] amino } fourth-2-alcohol;
[(1S, 2R)-3-{[(1S)-2-(benzyl amino)-2-oxo-1-methylethyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl] t-butyl carbamate;
N
2-[(2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl]-N
1Two (trifluoro-acetate) (salt) of-benzyl-levorotation-amino propionic acid amide;
((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[1-(2-isobutyl--1,3-thiazoles-5-yl) cyclopropyl] amino } propyl group) t-butyl carbamate;
(2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-{[1-(2-isobutyl--1,3-thiazoles-5-yl) cyclopropyl] amino } fourth-two (trifluoro-acetate) (salt) of 2-alcohol;
((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[1-(3-isobutyl-isoxazole-5-base) cyclopropyl] amino } propyl group) t-butyl carbamate;
(2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-{[1-(3-isobutyl-isoxazole-5-base) cyclopropyl] amino } fourth-two (trifluoro-acetate) (salt) of 2-alcohol;
((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[2-ethyl-pyrimidine-4-yl] methyl } amino-2-hydroxypropyl) t-butyl carbamate;
(2R, 3S)-3-amino-4-(3, the 5-difluorophenyl)-1-{[(2-ethyl-pyrimidine-4-yl) methyl] amino } fourth-two (trifluoroacetic acid) (salt) of 2-alcohol;
(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(7-methoxyl group-1,2,3,4-naphthane-1-yl) amino] propyl group } t-butyl carbamate;
[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(6,7,8,9-tetrahydrochysene-5H-benzo [7] annulene-5-base is amino) propyl group] t-butyl carbamate;
(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-hydroxyl-1-phenyl propyl) amino] propyl group } t-butyl carbamate;
((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1S)-1-[oxo (isobutylamino) methyl]-3-(methylthio group) propyl group] amino } propyl group) t-butyl carbamate;
((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1S)-the 1-[(isobutylamino) carbonyl]-3-(methyl sulphonyl) propyl group] amino } propyl group) t-butyl carbamate;
(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(2,2-dioxo-3,4-dihydro-1,2-benzo oxathiin-4-yl) amino]-the 2-hydroxypropyl } t-butyl carbamate;
(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(2,2-titanium dioxide-3,4-dihydro-1H-2,1-benzothiazine-4-yl) amino]-the 2-hydroxypropyl } t-butyl carbamate;
((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl) cyclopropyl] amino }-the 2-hydroxypropyl) t-butyl carbamate;
((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethynyl phenyl) cyclopropyl] amino }-the 2-hydroxypropyl) t-butyl carbamate;
((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[1-(3-aminomethyl phenyl) cyclopropyl] amino } propyl group) t-butyl carbamate;
((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[1-(3-iodophenyl) cyclopropyl] amino } propyl group) t-butyl carbamate;
[(1S, 2R)-3-{[3-(cyclopropyl amino) benzyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl] t-butyl carbamate;
3-([(2R, 3S)-the 3-[(tert-butoxycarbonyl) amino]-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl] amino } methyl) methyl benzoate;
[3-([(2R, 3S)-the 3-[(tert-butoxycarbonyl) amino]-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl] amino } methyl) phenyl] Urethylane;
[3-([(2R, 3S)-the 3-[(tert-butoxycarbonyl) amino]-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl] amino } methyl) phenyl] methylene dicarbamate;
[(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-(the 3-[(dimethylamino) and alkylsulfonyl] benzyl } amino)-the 2-hydroxypropyl] t-butyl carbamate;
[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(the 3-[(methyl sulphonyl) and amino] benzyl } amino) propyl group] t-butyl carbamate;
[(1S, 2R)-3-[(3-cyano group benzyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl] t-butyl carbamate;
3-([(2R, 3S)-the 3-[(tert-butoxycarbonyl) amino]-4-(3, the 5-difluorophenyl)-2-hydroxyl butyl] amino } methyl) the phenyl dimethylcarbamate;
[(2R, 3S)-4-(3, the 5-difluorophenyl)-3-(3-[(dipropyl amino) carbonyl]-the 5-methyl benzoyl } amino)-2-hydroxyl butyl] [3-(ethyl sulfenyl) benzyl] t-butyl carbamate;
(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(1R)-2,3-dihydro-1H-indenes-1-base is amino]-the 2-hydroxypropyl } t-butyl carbamate;
(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(1S)-2,3-dihydro-1H-indenes-1-base is amino]-the 2-hydroxypropyl } t-butyl carbamate;
((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1S, 2R)-2-hydroxyl-2,3-dihydro-1H-indenes-1-yl] amino } propyl group) t-butyl carbamate;
((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(1R, 2S)-2-hydroxyl-2,3-dihydro-1H-indenes-1-yl] amino } propyl group) t-butyl carbamate;
((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(3S)-2-oxo nitrogen Zhuo-3-yl] amino } propyl group) t-butyl carbamate;
((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(3R)-2-oxo nitrogen Zhuo-3-yl] amino } propyl group) t-butyl carbamate;
[(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-([(5S)-and 3-ethyl-2-oxygen-1,3-oxazolidine-5-yl] methyl } amino)-the 2-hydroxypropyl] t-butyl carbamate;
[(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-([(5R)-and 3-ethyl-2-oxygen-1,3-oxazolidine-5-yl] methyl } amino)-the 2-hydroxypropyl] t-butyl carbamate;
((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[1-(3-ethylphenyl)-1-methylethyl] amino }-the 2-hydroxypropyl) t-butyl carbamate;
(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(2-naphthyl methyl) amino] propyl group } t-butyl carbamate;
((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[2-oxo-2-(isobutylamino)-1, the 1-dimethyl ethyl] amino } propyl group) t-butyl carbamate;
[(1S, 2R) 3-[(benzyloxy) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl] t-butyl carbamate;
4-[({ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino) carbonyl] piperidines-1-t-butyl formate trifluoroacetate;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-fluoro-1-naphthoamide;
N-[(1S, 2R)-1-benzyl-3-(2-butyryl radicals-1-ethyl diazanyl)-2-hydroxypropyl]-2-(3-methyl-isoxazole-5-yl) ethanamide;
N '-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N-hexyl-N, 5-dimethyl isophthaloyl amine;
N '-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-anisoyl) amino] propyl group }-5-methyl-N, N-dipropyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-methyl isophthalic acid H-imidazoles-2-methane amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3,3-dimethyl-N
2, N
2-dipropyl cyclopropane-1, the 2-diformamide;
2-[({ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino) carbonyl]-1-methyl isophthalic acid H-imidazol-4 yl t-butyl carbamate;
N
5-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,2-dimethyl-N
1, N
1-dipropyl glutaramide;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(2-morpholine-4-base ethyl) amino] propyl group }-2-(4-chlorophenoxy)-2-methyl propanamide compound and methyl hydroperoxide (1: 2);
N-[(1S, 2R)-3-(benzyl amino)-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-4-fluoro-1-naphthoamide;
3-[(dipropyl amino) alkylsulfonyl]-N-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(4-isopropyl benzyl) propyl group] propionic acid amide;
3-[(dipropyl amino) alkylsulfonyl]-N-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(3-methoxy-benzyl) propyl group] propionic acid amide;
N
1-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N
5, N
5-dipropyl glutaramide;
N
1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(4-methoxy-benzyl) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-3-(benzyl amino)-2-hydroxyl-1-(4-methoxy-benzyl) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-(1S, 2R)-2-hydroxyl-1-(4-isopropyl benzyl)-3-[(3-methoxy-benzyl) amino] propyl group }-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
3-[(dipropyl amino) alkylsulfonyl]-N-((1S)-1-{ (1R)-1-hydroxyl-2-[(3-methoxy-benzyl) amino] ethyl } fourth-3-alkynyl) propionic acid amide;
N
1-[(1S, 2R)-1-(furfuryl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N
5, N
5-dipropyl glutaramide;
N
1-[(1S, 2R)-1-(furfuryl)-2-hydroxyl-3-(isopentyl amino) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-[(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(1-naphthyl methyl) propyl group]-5-methyl-N
3, N
3-dipropyl isophthaloyl amine;
N
1-((1S)-1-{ (1R)-1-hydroxyl-2-[(3-methoxy-benzyl) amino] ethyl }-the 3-methyl butyl)-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-[(1S, 2R)-1-(2-furyl methyl)-2-hydroxyl-3-(isopentyl amino) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N
1-[(1S, 2R)-2-hydroxyl-3-[(3-methoxy-benzyl) amino]-1-(1-naphthyl methyl) propyl group]-N
3, N
3-dipropyl benzene-1,3, the 5-trimethamide;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-the 3-{[(2-methoxy ethyl) (propyl group) amino] alkylsulfonyl } propionic acid amide;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-(4,5-dimethyl-2-furoyl base)-5-methyl benzamide;
3-[(dipropyl amino) alkylsulfonyl]-N-[(1S, 2R)-2-hydroxyl-3-(isopentyl amino)-1-(4-methyl-benzyl) propyl group] propionic acid amide;
13-[(dipropyl amino) alkylsulfonyl]-N-{ (1S, 2R)-1-(3-fluoro-5-hydroxybenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-1,3-benzothiazole-2-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group }-5-(2, the 5-dimethyl phenoxy)-2,2-dimethyl-penten acid amides;
N-[(1S, 2R)-3-amino-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-3-(isopentyl alkylsulfonyl) propionic acid amide trifluoroacetate;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-2-hydroxy-5-methyl yl-benzamide;
4-amino-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } butyramide two (trifluoroacetate);
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(pyridin-4-yl methyl) sulfenyl] benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,1,3-Ben Bing oxadiazole-5-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-methyl isophthalic acid, 2,3-thiadiazoles-5-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-[(pyridine-2-base sulfenyl) methyl]-the 2-furoamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-phenyl-5-propyl group-1H-pyrazole-4-carboxamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(trifluoromethoxy)-1H-indoles-2-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(5-methyl isophthalic acid H-tetrazolium-1-yl) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,8-dimethyl quinoline beautiful jade-3-methane amide;
2-(3-chlorophenoxy)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } propionic acid amide;
2-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(1H-tetrazolium-1-yl) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[5-(2-aminomethyl phenyl)-2H-tetrazolium-2-yl] ethanamide;
3-(1,3-benzoxazole-2-base sulfenyl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[] (3-Ethylbenzyl) amino }-the 2-hydroxypropyl }-2-hydroxyl-6-methyl quinoline beautiful jade-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-propyl group pyrazine-2-methane amide 4-oxide compound;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-thionaphthene-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-Methyl-1H-indole-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-6-methoxyl group-1,3-benzothiazole-2-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-sulfenyl of 2-[(6-methoxyl group-1H-benzimidazolyl-2 radicals-yl)] ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-phenyl thiophene-2-carboxamide derivatives;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methoxythiophene-2-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,3 '-two thiophene-5-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-morpholine-4-base-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-indoles-3-methane amide;
4-(acetylamino)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2, the 6-dimethyl benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-furoamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-hydroxyl-3,5-dimethoxy benzamide;
4-ethanoyl-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } niacinamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl quinoline beautiful jade-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 6-hydroxy nicotinoyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-thionaphthene-2-methane amide;
7-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-hydroxyl quinoline beautiful jade-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl-isoxazole-5-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-isoxazole-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3,5-dimethyl-1H-pyrazol-1-yl) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methoxyl group-1H-indoles-2-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,5-dimethyl-3-furoamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-6-hydroxyl-2-(methylthio group) pyrimidine-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-methyl isophthalic acid, 3-oxazole-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl isophthalic acid H-pyrazoles-5-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } thiophene-3-methane amide;
6-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-indoles-2-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-indoles-5-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-methyl isophthalic acid, 3-oxazole-5-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-methoxy benzamide;
4-(acetylamino)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-piperidines-1-yl-benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-methylpyrimidine-5-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } quinoline beautiful jade-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-phenylimidazole [1,2-a] pyridine-7-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-6-hydroxy-4-methyl pyridine-2-carboxamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
4, N
4-phenylbenzene succinic diamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[ethyl (methyl) amino]-4-hydroxy pyrimidine-5-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4,8-dihydroxyl quinoline beautiful jade-2-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 1-benzofuran-2-carboxamides;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-ethyl-1H-indoles-2-methane amide;
2-(acetylamino)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4,5-thioxene-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-hydroxy quinoxaline-2-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-indazole-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-2-phenyl-1,3-oxazole-4-methane amide;
4-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-6-methyl quinoline beautiful jade-2-methane amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2, N
2-dimethyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } thiophene-2-carboxamide derivatives;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-furoamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-methyl-3-furoamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-hydroxyl-6-neo-pentyl pyridine-2-carboxamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,3-thiazoles-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-hydroxyl-7-methoxyl group-1-thionaphthene-5-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-hydroxyl-7-methoxyl group-1-cumarone-5-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-phenyl-1,3-oxazole-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3, the 4-dihydroxy benzoyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
4-phenyl succinic diamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
4-pyridin-3-yl succinic diamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
4-(2, the 6-3,5-dimethylphenyl) succinic diamide;
N
1-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
4-methyl succinic diamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(4-methoxyl group phenoxy group) propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-hydroxyl-7-methoxyl group quinoline beautiful jade-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-[methyl (methyl sulphonyl) amino] benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(tetramethyleneimine-3-base alkylsulfonyl) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl-5-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base) isoxazole-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-2-phenyl-2H-1,2,3-triazole-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-yl)-1,3-thiazoles-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-phenylimidazole third [1,2-a] pyridine-6-methane amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
5-(1,3-thiazoles-2-yl) glutaramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-[(4-methyl isophthalic acid, 2,3-thiadiazoles-5-yl) sulfenyl] ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(piperidines-1-ylmethyl)-2-furoamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,5-dimethyl-1-phenyl-1H-pyrrole-3-carboxamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl isophthalic acid-phenyl-1H-pyrazole-3-formamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-fluoro-4-morpholine-4-yl-benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3, two (methyl sulfenyl) isothiazole of 5--4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl-5-(trifluoromethyl) isoxazole-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl-5-(propionamido) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-phenyl-1H-pyrroles-2-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } pyrazine-2-methane amide 4-oxide compound;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl isophthalic acid-pyridin-4-yl-1H-1,2,3-triazole-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-6-methoxypyrazine-2-methane amide 4-oxide compound;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-methyl-5-phenyl-1H-pyrazole-3-formamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-hydroxyl-3-propyl group hexanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1H-benzoglyoxaline-5-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl-4-(propionyl amino) benzamide;
5-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 1-benzofuran-2-carboxamides;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-pyridin-3-yl-1,3-thiazoles-4-methane amide;
8-cyano group-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-hydroxyquinoline-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,6-naphthyridine-2-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,2-dimethyl-4-oxo look alkane-6-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(morpholine-4-ylmethyl) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4,7-dimethoxy-1-cumarone-5-methane amide;
3-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-phenyl isothiazole-4-methane amide;
2-(2,1,3-diazosulfide-4-base oxygen base)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-methoxyl group-4-(methyl sulfenyl) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-[(4-methyl isophthalic acid, the 3-thiazol-2-yl) sulfenyl] ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-6-methoxyl group-1-benzofuran-2-carboxamides;
5-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-morpholine-4-yl-benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-methoxyl group-1H-pyrrole-3-carboxamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-methyl isophthalic acid, the 3-thiazole-4-carboxamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-methyl-5-(2-thienyl)-3-furoamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-methoxythiophene-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N '-(3,5-dimethylpyrazine-2-yl) succinic diamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[(3, the 4-Dimethoxyphenyl) sulfenyl] ethanamide;
6-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(trifluoromethyl) pyridine-2-carboxamide;
N-(2-ethanoyl-3-thienyl)-N '-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } succinic diamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-(4-fluorophenyl)-5-methyl isophthalic acid H-1,2,4-triazole-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N '-[2-fluoro-5-(methyl sulphonyl) phenyl] succinic diamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(4-p-methoxy-phenyl) thiophene-2-carboxamide derivatives;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-[5-(methylsulfinyl)-2,3-dihydro-1H-indoles-1-yl]-4-oxo butyramide;
2-(acetylamino)-5-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } thiophene-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-propyl group tetrahydrochysene-2H-pyrans-4-methane amide;
4-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-7,7-dimethyl-7,8-dihydro-5H-pyrans be [4,3-b] pyridine-2-carboxamide also;
2-(2-chloro-phenyl-)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,3-thiazoles-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(3-aminomethyl phenyl)-1,3-thiazoles-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1,2,5-thiadiazoles-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(phenoxymethyl)-1,3-thiazoles-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(4-aminomethyl phenyl)-1,3-thiazoles-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-pyridin-3-yl benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-methyl-2-phenyl-1,3-oxazole-5-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-ethyl-3-(2-thienyl)-1H-pyrazoles-5-methane amide;
4-(acetylamino)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-methyl isophthalic acid H-pyrroles-2-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2, the 6-dimethyl phenoxy) propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-phenyl-1,2,3-thiadiazoles-5-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2,5-dimethyl-1H-pyrroles-1-yl) thiophene-3-methane amide;
5-(acetylamino)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 2-hydroxybenzamide;
4-(acetylamino)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } the butyramide trifluoroacetate;
N-{ (1S, 2R)-1-benzyl-3-[1-ethyl-2-(4-methylpent acyl group) diazanyl]-the 2-hydroxypropyl }-the 2-[(methyl sulphonyl) amino]-1,3-oxazole-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(1-methyl isophthalic acid H-imidazoles-2-yl) benzamide;
N '-[(1S, 2R)-3-{[(1R)-3-cyclohexyl-1-phenyl propyl] amino }-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N, N-dipropyl isophthaloyl amine;
N '-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3, N
3-dipropyl-5-pyridin-3-yl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-fluoro-1-naphthoamide;
N-cyclohexyl-N '-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N, 5-dimethyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3[((3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-methyl isophthalic acid H-imidazoles-2-methane amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-[oxo (phenyl) methyl]-beta-amino propionic acid amide;
N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
2-[imidazo (phenyl) methyl] G-NH2;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-(2-propyl group penta inferior amide group)-beta-amino propionic acid amide;
6-(4-benzyl diethylenediamine-1-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-iodine benzyl) amino] propyl group } niacinamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 3-[(3-p-methoxy-phenyl) alkylsulfonyl] propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-methyl-7-(trifluoromethyl) pyrazolo [1,5-a] pyrimidine-2-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N '-(5-phenyl-1,3,4-thiadiazoles-2-yl) succinic diamide;
N-(5-cyclopropyl-1,3,4-thiadiazoles-2-yl)-N '-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } succinic diamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(3-methyl-5-oxo-4,5-dihydro-1 h-pyrazole-1-yl) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } thieno-[2,3-b] quinoline beautiful jade-2-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-methyl-5-oxo-2-phenyl prolineamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-methyl-4H, 6H-pyrrolo-[1,2-a] [4,1] benzo xazepine-4-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[(7-hydroxy-5-methyl base [1,2,4] triazolo [1,5-a] pyrimidine-2-base) sulfenyl] ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-oxo-2,3-dihydro-1,2-benzisothiazole-6-methane amide 1,1-dioxide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } thieno-[3,2-c] pyridine-2-carboxamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-oxo-2,3-dihydro-1,3-benzoxazole-6-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-[oxo (phenoxy group) methyl] prolineamide;
6-chloro-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazole-5-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-[4-(2,5-dioxy tetramethyleneimine-1-yl) phenoxy group] ethanamide;
N
2-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
1-Phenylpyrrolidine-1, the 2-diformamide;
2-(1,3-benzothiazole-2-ylmethoxy)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-methyl-4-oxo-3,4-dihydro (2)-1-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } indolizine-2-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-oxygen-4-phenylbutanamides;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydrochysene-7H-purine-7-yl) ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3-hydroxyphenyl)-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(3-p-methoxy-phenyl)-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3 ', 4 '-dihydro-1 ' H-spiral shell [1,3-dioxolane-2,2 '-naphthalene]-8 '-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3 ', 4 '-dihydro-1 ' H-spiral shell [1,3-dioxolane-2,2 '-naphthalene]-7 '-methane amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-[sulfydryl (methylthio group) methyl]-right type-amino propionic acid amide;
N
2-[(4-chloro-phenyl-) (oxygen) methyl]-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } G-NH2;
N
2-[(4-tert-butyl-phenyl) (oxo) methyl]-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } G-NH2;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-[oxo (pyridin-3-yl) methyl] G-NH2;
2-{[2-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino)-2-oxygen ethyl] sulfenyl }-N-[4-(1,3-oxazole-5-yl) phenyl] ethanamide;
N
2-[(4-chloro-phenyl-) (oxygen) methyl]-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-right type-amino propionic acid amide;
N
2-[(3, the 4-dichlorophenyl) (oxo) methyl]-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } G-NH2;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(5a, 9a-dihydro-dibenzo [b, d] furans-2-yl)-4-oxo butyramide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-{ oxo [4-(trifluoromethyl) phenyl] methyl } G-NH2;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-[(2, the 6-difluorophenyl) (oxo) methyl] G-NH2;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-[oxo (4-p-methoxy-phenyl) methyl] G-NH2;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(2-oxygen-1,3-oxazolidine-3-yl) benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-5-(phenylacetylene base) niacinamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
3-[oxo (1H-1,2,4-triazole-5-yl) methyl]-beta-amino propionic acid amide;
2-{[2-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino)-the 2-oxoethyl] sulfenyl }-N-(pyridin-4-yl methyl) ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-the 4-[(methoxymethyl) sulfenyl] benzamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-(1,5-dimethyl-3-oxygen-2-phenyl-2,3-dihydro-1 h-pyrazole-4-yl)-4-oxo butyramide;
4-(4-benzyl-1,4-phenodiazine Zhuo-1-yl)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-oxo butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,5-dimethyl-1-(pyridin-4-yl methyl)-1H-pyrrole-3-carboxamide;
The N-[(dimethylamino) alkylsulfonyl] glycyl-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } G-NH2;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-hydroxyl-1-[(1R, 2R)-the 2-hydroxy-cyclohexyl] prolineamide;
(2S, 3S)-N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-methyl-5-oxo-2-pyridin-3-yl tetramethyleneimine-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(2,5-dioxo tetramethyleneimine-1-yl) benzamide;
N-(2-cyano group-4,5,6,7-tetrahydrochysene-1-thionaphthene-3-yl)-N '-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } succinic diamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(2,5-dioxo alkyl imidazole-4-yl) ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-(5,7-dimethyl [1,2,4] triazole [1,5-a] pyrimidine-2-base) ethanamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-1-(2-furyl methyl)-5-oxo-pyrrolidine-3-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } 4-oxo-4-(5-oxo-1,4-phenodiazine Zhuo-1-yl) butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(4-aminomethyl phenyl)-4,5-dihydro-1 h-pyrazole-5-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2,1,3-Ben Bing oxadiazole-5-methane amide 1-oxide compound;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(2-pyridin-3-yl piperidines-1-yl) propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4-oxygen-4-(2-propyl group-1H-imidazoles-1-yl) butyramide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-4a, 9a-dihydro-9H-carbazole-9-methane amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-6-methyl-4-oxygen-1-phenyl-1,4-dihydrogen dazin-3-methane amide;
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[1-methyl-5-(tetramethyleneimine-1-base carbonyl)-1H-pyrroles-3-yl] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine;
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[2-(2-oxo-2-tetramethyleneimine-1-base oxethyl) phenyl] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine;
N '-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-{[3-(methylol) piperidines-1-yl] carbonyl } phenyl) amino] propyl group }-5-methyl-N, N-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } N
2-[3-(methyl sulfenyl)-1-oxopropyl]-N
2-amyl group G-NH2;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-[3-(methyl sulphonyl)-1-oxygen propyl group]-N
2-amyl group G-NH2;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-(phenyl sulfonyl) propionic acid amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(7-oxabicyclo [2.2.1] heptan-2-ylmethyl) amino] propyl group }-5-methyl-N, N-dipropyl isophthaloyl amine;
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[(3R)-2-oxygen-1-propyl group nitrogen Zhuo-3-yl] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine;
N '-[(1S, 2R)-3-[(1-ethanoyl piperidin-4-yl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N, N-dipropyl isophthaloyl amine;
N '-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N-[2-(dimethylamino)-2-oxygen ethyl]-N, 5-dimethyl isophthaloyl amine;
N '-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N-[2-(dimethylamino) ethyl]-N-ethyl-oreinol diformamide;
N-benzyl-N '-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N, 5-dimethyl isophthaloyl amine;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-{[2-(2-hydroxyethyl) piperidines-1-yl] carbonyl }-the 5-methyl benzamide;
N '-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N, 5-dimethyl-N-(2-styroyl) isophthaloyl amine;
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[3-(3-formyloxy-2-furyl) benzyl] amino }-the 2-hydroxypropyl)-5-methyl-N, N-dipropyl isophthaloyl amine;
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[3-(5-formyloxy-2-thienyl) benzyl] amino }-the 2-hydroxypropyl)-5-methyl-N, N-dipropyl isophthaloyl amine;
N '-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N, 5-dimethyl-N-(2-pyridine-2-base ethyl) isophthaloyl amine;
N '-[(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-({ [1-(methyl sulphonyl) piperidin-4-yl] methyl } amino) propyl group]-5-methyl-N, N-dipropyl isophthaloyl amine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
3, N
3-diethyl piperidines-1, the 3-diformamide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
3, N
3-dipropyl piperidines-1, the 3-diformamide;
N-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[3-(5-formyloxy-4-methyl-2-thienyl) benzyl] amino }-the 2-hydroxypropyl)-5-methyl-N, N-dipropyl isophthaloyl amine;
N '-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[3-(1-phenyl vinyl) benzyl] amino } propyl group)-5-methyl-N, N-dipropyl isophthaloyl amine;
N '-[(1S, 2R)-3-[(3-dicyclo [2.2.1] heptan-2-base benzyl) amino]-1-(3, the 5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N, N-dipropyl isophthaloyl amine;
3-[3-((2R, 3S)-4-(3, the 5-difluorophenyl)-3-(3-[(dipropyl amino) carbonyl]-the 5-methyl benzoyl } amino)-2-hydroxyl butyl] amino } methyl) phenyl] ethyl propionate;
4-[3-([(2R, 3S)-4-(3, the 5-difluorophenyl)-3-(3-[(dipropyl amino) carbonyl]-the 5-methyl benzoyl } amino)-2-hydroxyl butyl] amino } methyl) phenyl] ethyl butyrate;
(2R)-3-[3-([(2R, 3S)-4-(3, the 5-difluorophenyl)-3-(3-[(dipropyl amino) carbonyl]-the 5-methyl benzoyl } amino)-the 2-hydroxybutyl] amino } methyl) phenyl]-the 2 Methylpropionic acid methyl esters;
3 '-([(2R, 3S)-4-(3, the 5-difluorophenyl)-3-({ 3-[{ dipropyl amino } carbonyl]-the 5-methyl benzamide } amino)-2-hydroxyl butyl] amino } methyl) phenylbenzene-2-ethyl formate;
2-{1-[2-((1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl } amino)-2-oxygen ethyl] cyclopentyl }-N, the N-Valpromide;
N
2-[(benzyloxy) carbonyl]-N
1-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-2-hydroxypropyl }-3-[(1-propyl group butyl) alkylsulfonyl]-right type, levorotation-amino propionic acid amide trifluoroacetate;
N
2-[(benzyloxy) carbonyl]-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-methyl butyl) amino]-the 2-hydroxypropyl }-3-[(1-propyl group butyl) alkylsulfonyl]-right type, levorotation-amino propionic acid amide;
N
2-[(benzyloxy) carbonyl]-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-(3-cyclopropyl amino)-2-hydroxypropyl }-3-[(1-propyl group butyl) alkylsulfonyl]-right type, levorotation-amino propionic acid amide trifluoroacetate;
N
2-[(benzyloxy) carbonyl]-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-cyclopropyl methyl) amino]-the 2-hydroxypropyl }-3-[(1-propyl group butyl) alkylsulfonyl]-right type, levorotation-amino propionic acid amide trifluoroacetate;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-[(3S)-and tetrahydrofuran (THF)-3-base oxygen base] carbonyl }-3-[(1-propyl group butyl) alkylsulfonyl]-levorotation-amino propionic acid amide trifluoroacetate;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-[(3S)-and tetrahydrofuran (THF)-3-base oxygen base] carbonyl }-3-[(1-propyl group butyl) alkylsulfonyl]-right type-amino propionic acid amide trifluoroacetate;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-[(3S)-and tetrahydrofuran (THF)-3-base oxygen base] carbonyl }-3-[(1-propyl group butyl) alkylsulfonyl]-right type, levorotation-amino propionic acid amide trifluoroacetate;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-[(3R)-and tetrahydrofuran (THF)-3-base oxygen base] carbonyl }-3-[(1-propyl group butyl) alkylsulfonyl]-right type, levorotation-amino propionic acid amide trifluoroacetate;
N
1-(1S, 2R)-1-benzyl-3-[(3-methoxy-benzyl) amino]-the 2-hydroxypropyl }-N
2-[(3S)-and tetrahydrofuran (THF)-3-base oxygen base] carbonyl }-3-[(1-propyl group butyl) alkylsulfonyl]-right type, levorotation-amino propionic acid amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-{[3-Ethylbenzyl] amino-2-hydroxypropyl }-N
2-{ [(3S)-1,1-titanium dioxide tetramethylene sulfide-3-base oxygen base] carbonyl }-3-[(1-propyl group butyl) alkylsulfonyl]-right type, levorotation-amino propionic acid amide trifluoroacetate;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-methoxy-benzyl) amino]-the 2-hydroxypropyl }-N
2-[(3S)-and tetramethylene sulfide-3-base oxygen base] carbonyl }-3-[(1-propyl group butyl) alkylsulfonyl]-right type, levorotation-amino propionic acid amide trifluoroacetate;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-{ [tetrahydropyran-4-base oxygen base] carbonyl }-3-[(1-propyl group butyl) alkylsulfonyl]-right type, levorotation-amino propionic acid amide trifluoroacetate;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-{ [1-(methyl sulphonyl) piperidin-4-yl oxygen base] carbonyl }-3-[(1-propyl group butyl) alkylsulfonyl]-right type, levorotation-amino propionic acid amide trifluoroacetate;
N
2-{ [1-ethanoyl piperidin-4-yl oxygen base] carbonyl }-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(1-propyl group butyl) alkylsulfonyl]-right type, levorotation-amino propionic acid amide trifluoroacetate;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-[[(3R)-and 5-oxo-pyrrolidine-3-yl] methyl] carbonyl }-3-[(1-propyl group butyl) alkylsulfonyl]-right type, levorotation-amino propionic acid amide trifluoroacetate;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-[(benzyloxy) carbonyl]-3-[(1-propyl group butyl) alkylsulfonyl]-right type, levorotation-amino propionic acid amide;
N
2-[(benzyloxy) carbonyl]-N
1-((1S, 2R)-1-(3, the 5-difluorobenzyl)-2-hydroxyl-3-{[2-(3-p-methoxy-phenyl) ethyl] amino } propyl group)-3-[(1-propyl group butyl) alkylsulfonyl]-right type, levorotation-amino propionic acid amide trifluoroacetate;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-[(3S)-and tetrahydrofuran (THF)-3-base oxygen base] carbonyl }-right type-leucyl amine trifluoroacetate;
N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
2-[(benzyloxy) carbonyl]-levorotation-leucyl amine;
N
2-[(benzyloxy) carbonyl]-N
1-((1S)-1-{ (1R)-2-[ethyl (isobutyl-alkylsulfonyl) amino]-the 1-hydroxyethyl }-the 3-methyl butyl)-3-[(1-propyl group butyl) alkylsulfonyl]-right type, levorotation-amino propionic acid amide;
N
2-[(benzyloxy) carbonyl]-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
5, N
5-dipropyl-levorotation-glutamine trifluoroacetate;
N
2-[(benzyloxy) carbonyl]-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
5, N
5-dipropyl-right type-glutamine;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-[(1H-pyrazoles-4-yl) carbonyl]-3-[(1-propyl group butyl) alkylsulfonyl]-right type, levorotation-amino propionic acid amide;
N
2-[(6-chloropyridine-3-yl) carbonyl]-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(1-propyl group butyl) alkylsulfonyl]-right type, levorotation-amino propionic acid amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-[(pyridine-2-yl) carbonyl]-3-[(1-propyl group butyl) alkylsulfonyl]-right type, levorotation-amino propionic acid amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-(2-methyl benzoyl)-3-[(1-propyl group butyl) alkylsulfonyl]-right type, levorotation-amino propionic acid amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-(3-methyl benzoyl)-3-[(1-propyl group butyl) alkylsulfonyl]-right type, levorotation-amino propionic acid amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-(4-methyl benzoyl)-3-[(1-propyl group butyl) alkylsulfonyl]-right type, levorotation-amino propionic acid amide;
N
2-(3-chlorobenzene formacyl)-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(1-propyl group butyl) alkylsulfonyl]-right type, levorotation-amino propionic acid amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-(4-anisoyl)-3-[(1-propyl group butyl) alkylsulfonyl]-right type, levorotation-amino propionic acid amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-(4-trifluoromethyl benzoyl)-3-[(1-propyl group butyl) alkylsulfonyl]-right type, levorotation-amino propionic acid amide;
N
2-(cyclohexyl-carbonyl)-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(1-propyl group butyl) alkylsulfonyl]-right type, levorotation-amino propionic acid amide;
N
2-(benzoyl)-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(1-propyl group butyl) alkylsulfonyl]-right type, levorotation-amino propionic acid amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-(phenyl acetyl)-3-[(1-propyl group butyl) alkylsulfonyl]-right type, levorotation-amino propionic acid amide;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-(3-Phenylpropionamide)-3-[(1-propyl group butyl) alkylsulfonyl]-right type, levorotation-amino propionic acid amide trifluoroacetate;
N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group)-N
2-(cyclopropyl ethanoyl)-3-[(1-propyl group butyl) alkylsulfonyl]-right type, levorotation-amino propionic acid amide;
N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
2-[(methyl sulphonyl) ethanoyl]-3-[(1-propyl group butyl) alkylsulfonyl]-right type, levorotation-amino propionic acid amide trifluoroacetate;
N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
2-[(methyl sulfenyl) ethanoyl]-3-[(1-propyl group butyl) alkylsulfonyl]-right type, levorotation-amino propionic acid amide;
N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
2-(4-hydroxyl-4-oxobutanoyl)-3-[(1-propyl group butyl) alkylsulfonyl]-right type, levorotation-amino propionic acid amide;
N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
2-[4-(methylamino)-4-oxobutanoyl]-3-[(1-propyl group butyl) alkylsulfonyl]-right type, levorotation-amino propionic acid amide;
N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
2-(4-methoxyl group-4-oxobutanoyl)-3-[(1-propyl group butyl) alkylsulfonyl]-right type, levorotation-amino propionic acid amide;
N-(methyl sulphonyl) glycyl-N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-[(1-propyl group butyl) alkylsulfonyl]-right type, levorotation-amino propionic acid amide;
N
2-ethanoyl-N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-(phenyl sulfonyl)-right type, levorotation-amino propionic acid amide;
(2S)-2-(4-methoxyl group-4-oxobutanoyl) amino-N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-5-oxo-5-piperidines-1-base valeramide;
(2R)-and the 2-{[(benzyloxy) carbonyl] amino }-N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-5-oxo-5-piperidines-1-base valeramide;
(2R)-2-(3-oxyethyl group-3-oxo propionyl) amino-N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-5-oxo-5-piperidines-1-base valeramide;
N
1-(1S, 2R)-1-benzyl-3-[(3-methoxy-benzyl) amino]-the 2-hydroxypropyl }-N
2-(4-methoxyl group-4-oxobutanoyl)-N
5, N
5-dipropyl-right type-glutamine;
(2R)-2-(4-methoxyl group-4-oxobutanoyl) amino-N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-5-oxo-5-piperidines-1-base valeramide;
(2R)-2-(5-methoxyl group-5-oxo pentanoyl) amino-N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-5-oxo-5-piperidines-1-base valeramide;
N
2-[(5-chlorothiophene-2-yl) alkylsulfonyl]-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(1-propyl group butyl) alkylsulfonyl]-right type, the amino propionic acid amide of levorotation;
N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-N
2-(phenyl sulfonyl)-3-[(1-propyl group butyl) alkylsulfonyl]-right type, the amino propionic acid amide of levorotation;
N
2-[(benzylamino) carbonyl]-N
1-(1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-[(1-propyl group butyl) alkylsulfonyl]-right type, the amino propionic acid amide of levorotation;
4-((1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } amino)-3-[(isopentyl alkylsulfonyl) methyl]-the 4-ketobutyric acid;
4-((1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } amino)-3-[(isopentyl alkylsulfonyl) methyl]-4-ketobutyric acid methyl esters;
N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-2-[(isopentyl alkylsulfonyl) methyl] succinic diamide;
N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-2-[(isopentyl alkylsulfonyl) methyl]-N
4-methyl succinic diamide;
N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-2-[(isopentyl alkylsulfonyl) methyl]-N
4, N
4-dimethyl succinic diamide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-3-(4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl)-2-{[(1-propyl group butyl) alkylsulfonyl] methyl } propionic acid amide;
N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-(ethylsulfonyl)-2-([(isobutyl-alkylsulfonyl) amino] methyl) propionic acid amide;
N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-3-(ethylmercapto group)-2-{[(isobutyl-alkylsulfonyl) amino] methyl } propionic acid amide;
(2S)-N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-2-[(isopentyl alkylsulfonyl) amino]-4-(methyl sulphonyl) butyramide;
N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
2-(isopentyl alkylsulfonyl)-levorotation-methinyl amine;
S-{3-((1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } amino)-2-[(isopentyl alkylsulfonyl) methyl]-the 3-oxopropyl } thioacetate;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-2-hydroxyl-3-[(1-propyl group butyl) alkylsulfonyl] propionic acid amide;
N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-hydroxyl-4-(phenyl sulfonyl) butyramide;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-2-hydroxyl-4-(isopentyl alkylsulfonyl) butyramide;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-4-(isopentyl alkylsulfonyl)-2-phenoxy group butyramide;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-4-(isopentyl alkylsulfonyl)-2-(3-methoxyl group phenoxy group) butyramide;
3-[1-[({ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } amino) carbonyl]-3-(isopentyl alkylsulfonyl) propoxy-] the phenylformic acid trifluoroacetate;
3-[1-[({ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group } amino) carbonyl]-3-(isopentyl alkylsulfonyl) propoxy-] methyl benzoate;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-2-hydroxyl-4-(phenyl sulfonyl) butyramide;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-2-hydroxyl-4-(phenyl sulfo-) butyramide;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-2-methoxyl group-4-(phenyl sulfonyl) butyramide;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-2-methoxyl group-4-(phenyl sulfenyl) butyramide;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-4-(phenyl sulfonyl)-2-propoxy-butyramide;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-2-(benzyloxy)-4-(phenyl sulfonyl) butyramide;
N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
2-[(benzyloxy) carbonyl]-right type, levorotation-methinyl amine;
(2S)-2-amino-N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-5-oxo-5-piperidines-1-base valeramide;
(2S)-2-(2-oxyethyl group-2-oxo ethyl group) amino-N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-5-oxo-5-piperidines-1-base valeramide;
(2R)-2-amino-N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-5-oxo-5-piperidines-1-base valeramide;
(2R)-2-(2-oxyethyl group-2-oxo ethyl group) amino-N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-5-oxo-5-piperidines-1-base valeramide;
(2R)-2-(4-oxyethyl group-4-oxygen base butane group) ammonia-N-{ (1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-5-oxo-5-piperidines-1-base valeramide two trifluoroacetates
N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
2-[(benzyloxy) carbonyl]-levorotation-l-asparagine;
N
1-(1S, 2R)-1-benzyl-2-hydroxyl-3-[(3-methoxy-benzyl) amino] propyl group }-N
2-[(tert.-butoxy) carbonyl]-levorotation-l-asparagine.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US33712201P | 2001-11-08 | 2001-11-08 | |
| US60/337,122 | 2001-11-08 | ||
| US60/344,086 | 2001-12-28 | ||
| US60/345,635 | 2002-01-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1759095A true CN1759095A (en) | 2006-04-12 |
Family
ID=35976924
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 02826786 Pending CN1759095A (en) | 2001-11-08 | 2002-11-08 | N,N'-substituted-1,3-diamino-2-hydroxypropane derivatives |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN1759095A (en) |
| UA (1) | UA85994C2 (en) |
| ZA (1) | ZA200403578B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012013012A1 (en) * | 2010-07-30 | 2012-02-02 | 中国人民解放军军事医学科学院毒物药物研究所 | Benzo-azacyclic hydroxyethylamine compound, preparation method and uses thereof |
| CN104326952A (en) * | 2010-09-08 | 2015-02-04 | 住友化学株式会社 | Method for producing pyridazinone compounds and intermediate thereof |
| CN110407763A (en) * | 2019-08-08 | 2019-11-05 | 苏州汉德创宏生化科技有限公司 | A kind of 4-(oxazole -2- base) benzoic acid synthetic method |
| WO2022022677A1 (en) * | 2020-07-31 | 2022-02-03 | 深圳市橄榄生物医药科技有限公司 | Multi-efficacy pyrazine compound, preparation method therefor, and application thereof |
-
2002
- 2002-11-08 UA UA20040604411A patent/UA85994C2/en unknown
- 2002-11-08 CN CN 02826786 patent/CN1759095A/en active Pending
-
2004
- 2004-05-11 ZA ZA200403578A patent/ZA200403578B/en unknown
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012013012A1 (en) * | 2010-07-30 | 2012-02-02 | 中国人民解放军军事医学科学院毒物药物研究所 | Benzo-azacyclic hydroxyethylamine compound, preparation method and uses thereof |
| CN102344402A (en) * | 2010-07-30 | 2012-02-08 | 中国人民解放军军事医学科学院毒物药物研究所 | Benzoazacyclo hydroxyethylamine compounds, preparation method thereof and purposes thereof |
| CN104326952A (en) * | 2010-09-08 | 2015-02-04 | 住友化学株式会社 | Method for producing pyridazinone compounds and intermediate thereof |
| CN104326952B (en) * | 2010-09-08 | 2016-08-24 | 住友化学株式会社 | Prepare method and its intermediate of pyridazinone compound |
| CN110407763A (en) * | 2019-08-08 | 2019-11-05 | 苏州汉德创宏生化科技有限公司 | A kind of 4-(oxazole -2- base) benzoic acid synthetic method |
| CN110407763B (en) * | 2019-08-08 | 2022-10-14 | 苏州汉德创宏生化科技有限公司 | Synthesis method of 4- (oxazole-2-yl) benzoic acid |
| WO2022022677A1 (en) * | 2020-07-31 | 2022-02-03 | 深圳市橄榄生物医药科技有限公司 | Multi-efficacy pyrazine compound, preparation method therefor, and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| UA85994C2 (en) | 2009-03-25 |
| ZA200403578B (en) | 2005-10-10 |
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