CN101472892A - Organic compounds - Google Patents
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- CN101472892A CN101472892A CNA2007800215552A CN200780021555A CN101472892A CN 101472892 A CN101472892 A CN 101472892A CN A2007800215552 A CNA2007800215552 A CN A2007800215552A CN 200780021555 A CN200780021555 A CN 200780021555A CN 101472892 A CN101472892 A CN 101472892A
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Abstract
The present invention relates to compounds of the formula; and their use in therapy.
Description
Technical field
The present invention relates to compound and their purposes in treatment.
Background technology
Dipeptidyl peptidase-IV (DPP-IV) is a kind of serine protease, and it contains cracking N end dipeptides the peptide chain of proline residue usually from inferior terminal position.DPP-IV is as II type integral protein wide expression in mammalian tissues.This proteolytic enzyme is expressed on the surface of the epidermic cell of the differentiation of intestines, liver, kidney proximal tubule, prostate gland, corpus luteum, and for example expresses on lymphocyte and the scavenger cell in the white corpuscle subgroup.Find the DPP-IV of soluble form in serum, its DPP-IV with film combining form has identical 26S Proteasome Structure and Function, but lacks the hydrophobic transmembrane structural domain.
DPP-IV has the relevant substrate of many physiology, comprises chemokine (for example eotaxin and scavenger cell deutero-cytokine), neuropeptide (for example neuropeptide tyrosine and Substance P), vasoactive peptide and incretin (for example GLP-1 and GIP).GLP-1 (glucagon-like-peptide-1) responds the nutritive substance of taking in and the hormone that produces in the L of distal small bowel cell.Be combined in the expression of various structural GLP-1 receptor for stimulating insulin gene, biosynthesizing and glucose dependency insulin secretion, glucagon suppression secretion, impelling has satiety, and stomach emptying and promote the growth of pancreatic beta cell slows down.
Although the biological action of the DPP-IV in the mammlian system is also not definite fully, it is believed that it is adsorbed to endothelium and HIV at neuropeptide metabolism, T cell activation, cancer cells and enters in the lymphocyte and play an important role.Find that also DPP-IV is responsible to the inactivation of glucagon-like peptide 1 (GLP-1).As if because GLP-1 is the main stimulator of pancreas insulin secretion, and has directly useful effect to glucose disposal, DPP-IV suppresses to have described to treat for example attractive method of non-insulin-dependent diabetes mellitus (NIDDM) (NIDDM).
Shown that also DPP-IV works in immunne response.Expressed by the T-CD4+ lymphocyte, it and antigens c D26 synonym at this, DPP-IV play an important role in transplant rejection mechanism and (transplant (Transplantation) 1997,63 (10), 1495-500).With regard to more optionally suppressing immunne response, suppress the method extremely likely that DPP-IV has correspondingly represented prevention transplant rejection in the transplant patient.
The DPP-IV inhibitor especially is described among WO-A-03/000180, WO-A-000181, WO-A-004498, WO-A-03/082817, WO-A-04/032836, WO-A-04/007468, EP1679069 and the WO-A-05/121089.
Summary of the invention
A first aspect of the present invention is formula (I) compound or its pharmacy acceptable salt or prodrug:
Wherein
Asterisk * refers to (R) or (S) chiral centre of configuration;
V does not exist or ethylidene;
W is-C (O)-or-S (O)
1-;
X is the linker (linker) that contains atom in the individual chain of 1-12 (for example 1-6) and comprise one or more connectors (linkage), described connector is selected from-O-,-C (O)-,-S (O)
1-,-N (R
9)-and optional by 1,2,3,4 or 5 R
11The alkylene that replaces;
Y be selected from-O-,-N (R
9)-,-C (O)-,-C (O) O-,-C (O) N (R
9)-,-S (O)
1-and-S (O)
1N (R
9)-linker;
R
1Be selected from hydrogen;-N (R
9) (R
10); Optional by 1,2,3,4 or 5 R
11The alkyl that replaces; Optional by 1,2,3,4 or 5 R
11The-oxyl that replaces; With optional by 1,2,3,4 or 5 R
11Replace-(CH
2)
k-heterocyclic radical;
Perhaps, as Y be-N (R
9)-time, R
1And R
9Can form heterocycle with the nitrogen-atoms that they connected, wherein this heterocycle is bonded to X and optional by 1,2,3,4 or 5 R by described nitrogen-atoms
11Replace;
R
2And R
3Be selected from R independently of one another
8,-OR
8,-C (O) R
8,-C (O) OR
8With-S (O)
1R
9
R
4And R
5Be selected from hydrogen, hydroxyl, halogen and optional independently of one another by 1,2,3,4 or 5 R
11The C that replaces
1-6Alkyl;
R
6Be aryl or heteroaryl, it is optional separately by 1,2,3,4 or 5 R
11Replace;
R
8Be selected from hydrogen; Optional by 1,2,3,4 or 5 R
11The alkyl that replaces; With optional by 1,2,3,4 or 5 R
11Replace-(CH
2)
k-heterocyclic radical;
R
9And R
10Be selected from R independently of one another
8,-OR
8,-C (O) R
8,-C (O) OR
8With-S (O)
1R
8Or R
9And R
10Form optional by 1,2,3,4 or 5 R with the nitrogen-atoms that they connected
11The heterocyclic radical that replaces;
Each R
11Be independently selected from R
12Optional by 1,2,3,4 or 5 R
12The alkyl that replaces; With optional by 1,2,3,4 or 5 R
12Replace-(CH
2)
k-heterocyclic radical;
R
12Be independently selected from halogen, trifluoromethyl, cyano group, nitro, oxo ,=NR
13,-OR
13,-C (O) R
13,-C (O) N (R
13) R
14,-C (O) OR
13,-OC (O) R
13,-S (O)
1R
13,-S (O)
1N (R
13) R
14,-N (R
13) R
14,-N (R
13) N (R
13) R
14,-N (R
13) C (O) R
14With-N (R
13) S (O)
1R
13
R
13And R
14Be independently of one another hydrogen or be selected from alkyl and-(CH
2)
k-heterocyclic radical, it is optional separately by 1,2,3,4 or 5 substituting group replacement, and described substituting group is independently selected from halogen, cyano group, amino, hydroxyl, C
1-6Alkyl and C
1-6Alkoxyl group; Or
R
13And R
14Be independently of one another hydrogen or be selected from alkyl and-(CH
2)
k-heterocyclic radical, it is optional separately by 1,2,3,4 or 5 substituting group replacement, and described substituting group is independently selected from oxo, halogen, cyano group, amino, hydroxyl, C
1-6Alkyl and C
1-6Alkoxyl group;
K is 0,1,2,3,4,5 or 6; And
L is 0,1 or 2.
In some embodiments, when X be C
1-6Alkylidene group ,-O-C
1-6Alkylidene group-or-N (R
9)-C
1-6Alkylidene group-, and Y be-O-,-S-or-N (R
9)-time, the C of described X
1-6The alkylidene group connector is by 1,2,3,4 or 5 R
11Replacement, at least one described R wherein
11Not halogen or C
1-6Alkyl.
A second aspect of the present invention is the The compounds of this invention that is used for the treatment of purposes.
Another aspect of the present invention is the pharmaceutical preparation that comprises The compounds of this invention and the pharmaceutically acceptable diluent or carrier of choosing wantonly.
Another aspect of the present invention is the product that comprises The compounds of this invention and therapeutic activity agent (agent), its as in the treatment simultaneously, respectively or the combination preparation that uses successively.
Another aspect of the present invention is the purposes of The compounds of this invention in the medicine of preparation treatment or preventing disease or illness, and described disease or illness are selected from non-insulin-dependent diabetes mellitus (NIDDM), sacroiliitis, obesity, allograft transplanting, thyrocalcitonin-osteoporosis, heart failure, impaired glucose metabolism or glucose tolerance reduction, neurodegenerative disease, cardiovascular or kidney disease and neurodegenerative disorders or cognitive disorder.
The purposes that another aspect of the present invention is a The compounds of this invention in the preparation medicine, described medicine is used to produce calmness or angst resistance effect, the alienation of minimizing postoperative changes or to stress the hormone response, reduce mortality ratio after the myocardial infarction and sickness rate, adjusting hyperlipidaemia or relevant illness or reduce VLDL, LDL or Lp (a) level.
Another aspect of the present invention is the method for treatment or preventing disease or illness in the patient, and this method comprises the The compounds of this invention of drug treatment significant quantity.
The compounds of this invention can exist with multi-form, for example free acid, free alkali, ester and other prodrug, salt and tautomer, and present disclosure comprises all variant forms of described compound.
Protection domain comprises and comprises or claim personation or the duplicity product that comprises The compounds of this invention, no matter whether they contain this compound really, also no matter whether any this compounds contains with the treatment significant quantity.
Protection domain comprises the wrapped product that comprises specification sheets and product, and described specification sheets indicates this wrapped product and contains material of the present invention or pharmaceutical preparation, and described product is or comprises or claim to be or comprise this type of preparation or material.This type of wrapped product can but must not be the personation or the duplicity product.
Feature, integer, characteristic, compound, chemical part or the group of describing with regard to particular aspects of the present invention, embodiment or embodiment should be understood to be applicable to any others, embodiment or the embodiment described in the literary composition, unless they are inconsistent.
The description of various embodiments
Alkyl
As used herein, term " alkyl " is meant the group of being made up of hydrogen and carbon atom only, and this type of group can comprise aliphatics and/or aromatic group.This group can comprise 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19 or 20 carbon atom.The example of hydrocarbyl group comprises C
1-6Alkyl (C for example
1, C
2, C
3Or C
4Alkyl, for example methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl or the tertiary butyl); By the C of aryl (for example benzyl) or cycloalkyl (for example cyclopropyl methyl) replacement
1-6Alkyl; Cycloalkyl (for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl); Aryl (for example phenyl, naphthyl or fluorenyl) etc.When alkyl was cycloalkyl, it can be connected to chemical group with the form that spiral shell replaces.
Alkyl
As used herein, term " alkyl " and " C
1-6Alkyl " comprise the straight or branched alkyl group that contains 1,2,3,4,5 or 6 carbon atom.This term comprises for example group of methyl, ethyl, propyl group (n-propyl or sec.-propyl), butyl (normal-butyl, sec-butyl or the tertiary butyl), amyl group, hexyl etc.Particularly, alkyl can contain 1,2,3 or 4 carbon atoms.
Thiazolinyl
As used herein, term " thiazolinyl " and " C
2-6Thiazolinyl " comprise following straight or branched alkyl group: it contains 2,3,4,5 or 6 carbon atoms, contains at least one two key in addition, and E or Z stereochemistry can.This term comprises for example group of vinyl, 2-propenyl, 1-butylene base, crotyl, 3-butenyl, 1-pentenyl, pentenyl, 3-pentenyl, 1-hexenyl, 2-hexenyl and 3-hexenyl etc.
Alkynyl
As used herein, term " alkynyl " and " C
2-6Alkynyl " comprise following straight or branched alkyl group: it contains 2,3,4,5 or 6 carbon atoms, contains at least one triple bond in addition.This term comprises for example group of ethynyl, 1-proyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 3-butynyl, 1-pentynyl, valerylene base, 3-pentynyl, 1-hexin base, 2-hexin base and 3-hexin base etc.
Alkoxyl group
As used herein, term " alkoxyl group " and " C
1-6Alkoxyl group " be meant-the O-alkyl that wherein alkyl is a straight or branched, and comprise 1,2,3,4,5 or 6 carbon atom.In a class embodiment, alkoxyl group contains 1,2,3 or 4 carbon atom.This term comprises for example group of methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, tert.-butoxy, pentyloxy, hexyloxy etc.
Cycloalkyl
As used herein, term " cycloalkyl " comprises the alicyclic group that contains 3,4,5,6,7 or 8 carbon atoms.This group can be bridging or the polycyclic member ring systems.More generally, group of naphthene base is monocyclic.This term comprises for example group of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norcamphyl, two ring [2.2.2] octyl groups etc.
Aryl
As used herein, term " aryl " comprises the aromatic ring system that contains 6,7,8,9,10,11,12,13,14,15 or 16 ring carbon atoms.Aryl is phenyl normally, but also can be the many rings member ring systems that contains two or more rings, and wherein at least one ring is aromatic.This term comprises for example group of phenyl, naphthyl, fluorenyl, Azulene base, indenyl, anthryl etc.
Carbocylic radical
As used herein, term " carbocylic radical " comprises saturated (for example cycloalkyl) or the cyclic group of unsaturated (for example aryl) that contains 3,4,5,6,7,8,9,10,11,12,13,14,15 or 16 carboatomic ring atoms.Particularly, carbocylic radical comprises 3-to 10-unit ring or member ring systems, and particularly 5-to 6-unit encircles, and it can be saturated or unsaturated.Carbon ring group for example is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norcamphyl, two ring [2.2.2] octyl groups, phenyl, naphthyl, fluorenyl, Azulene base, indenyl, anthryl etc.
Heterocyclic radical
As used herein, term " heterocyclic radical " comprises saturated (for example Heterocyclylalkyl) or undersaturated (for example heteroaryl) heterocyclic group that contains 3,4,5,6,7,8,9,10,11,12,13,14,15 or 16 annular atomses, and at least one annular atoms is selected from nitrogen, oxygen, phosphorus, silicon and sulphur.Particularly, heterocyclic radical comprises 3-to 10-unit ring or member ring systems, and more especially 5-to 6-unit encircles, and it can be saturated or unsaturated.When heterocyclic radical was Heterocyclylalkyl, it can be connected to chemical group with the form that spiral shell replaces.
Heterocyclic group for example is selected from Oxyranyle, the azirane base, 1,2-oxygen thia cyclopentyl, imidazolyl, thienyl, furyl, tetrahydrofuran base, pyranyl, the thiapyran base, thianthrenyl, isobenzofuran-base, benzofuryl, chromenyl, the 2H-pyrryl, pyrryl, pyrrolinyl, pyrrolidyl, imidazolyl, imidazolidyl, benzimidazolyl-, pyrazolyl, pyrazinyl, pyrazolidyl, thiazolyl, isothiazolyl, dithiazole base oxazolyl isoxazolyl, pyridyl, pyrazinyl, pyrimidyl, piperidyl, piperazinyl, pyridazinyl, morpholinyl, thio-morpholinyl, especially thiomorpholine generation, the indolizine base, 1,3-dioxo-1,3-dihydro-pseudoindoyl, the 3H-indyl, indyl, benzimidazolyl-, tonka bean camphor base (Cumaryl), indazolyl, triazolyl, tetrazyl, purine radicals, the 4H-quinolizinyl, isoquinolyl, quinolyl, tetrahydric quinoline group, tetrahydro isoquinolyl, decahydroquinolyl, the octahydro isoquinolyl, benzofuryl, dibenzofuran group, benzothienyl, the dibenzothiophene base, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolyl, quinazolyl, the cinnolines base, pteridyl, carbazyl, the β-Ka Lin base, phenanthridinyl, acridyl, perimidinyl, the phenanthroline base, the furazan base, phenazinyl, phenothiazinyl phenoxazinyl, chromenyl, different chromanyl, chromanyl, 3,4-dihydro-2H-isoquinoline 99.9-1-ketone, 3,4-dihydro-2H-isoquinolyl etc.
Heterocyclylalkyl
As used herein, term " Heterocyclylalkyl " comprises and contains 3,4,5,6 or 7 ring carbon atoms and 1,2,3,4 or 5 saturated heterocyclic group that is selected from the ring hetero atom of nitrogen, oxygen, p and s.This group can be the polycyclic member ring systems, but more generally is monocyclic.This term for example comprises western pyridine base (indolizidinyl), piperazinyl, thiazolidyl, morpholinyl, thio-morpholinyl, quinolixiding base (quinolizidinyl), THP trtrahydropyranyl, tetrahydrofuran base, 1 in azetidinyl, pyrrolidyl, tetrahydrofuran base, piperidyl, Oxyranyle, pyrazolidyl, imidazolyl, the indoles, 3-dihydro-pseudoindoyl, 1,3-dioxo-1,3-dihydro-pseudoindoyl, 3,4-dihydro-2H-isoquinolyl, 3,4-dihydro-2H-isoquinolyl-1-ketone etc.
Heteroaryl
As used herein, term " heteroaryl " comprises the heteroaromatic system that contains 5,6,7,8,9,10,11,12,13,14,15 or 16 annular atomses, and at least one annular atoms is selected from nitrogen, oxygen and sulphur.This group can be the many rings member ring systems that contains two or more rings, and at least one ring is aromatic, but this group more generally is monocyclic.This term comprises for example group of pyridazinyl, pyrimidyl, furyl, benzo [b] thienyl, thienyl, pyrryl, imidazolyl, pyrrolidyl, pyridyl, benzo [b] furyl, pyrazinyl, purine radicals, indyl, benzimidazolyl-, quinolyl, phenothiazinyl, triazinyl, phthalazinyl, 2H-chromenyl, oxazolyl, isoxazolyl, thiazolyl, pseudoindoyl, indazolyl, purine radicals, isoquinolyl, quinazolyl, pteridyl etc.
Halogen
As used herein, term " halogen " comprises F, Cl, Br or I.Particularly, halogen can be F or Cl, wherein more generally is F.
Spiral shell
As used herein, term " spiral shell " comprises 3-to 6-cycloalkyl or 5-to 6-heterocycloalkyl, and it can be chosen wantonly by 1,2,3 or 4 R
13Replace.The non-limiting example of tap bolt group is:
Replace
As used herein, term " replacement " relate in the described group one or more, 5 especially at the most, more specifically 1,2 or 3 hydrogen atom is independently of one another by the described substituting group alternate group of respective number.Term " optional replacement " as used herein, refers to that replace or unsubstituted.
Of course it is to be understood that substituting group exists only in they rational positions chemically, those skilled in the art need not pay too much effort can judge promptly whether (sample plot or theoretically) concrete replacement is rational.For example, in the time of on being bonded to the carbon atom that has unsaturated (for example alkene family) key, the amino or the oh group that have free hydrogen may be unsettled.In addition, should be appreciated that certainly the substituting group described in the literary composition itself can be replaced by any substituting group, this suitable replacement that admitted by those skilled in the art noted earlier limits.
Pharmaceutically acceptable
As used herein, term " pharmaceutically acceptable " relates to those compounds, material, composition and/or formulation, they are in reliable medical judgment scope, be suitable for contacting with the tissue of the mankind or animal, and do not have overdosage toxicity, stimulation, anaphylaxis or other problem or complication, have rational benefit/risk ratio.This term comprises accepting human and purpose for animals.
Independently
When two or more groups were described to " independently of one another " and are selected from some atoms or group, this was meant that described group can be identical or different.Therefore, each group is independent of one or more other groups.
Compound
The invention provides formula (I) compound or its pharmacy acceptable salt or prodrug:
Wherein
Asterisk * refers to (R) or (S) chiral centre of configuration; And
V, W, X, Y, R
1, R
2, R
3, R
4, R
5And R
6Such as in the literary composition definition.
As mentioned above, use
*The chiral centre of indicating (is group-N (R
2) (R
3) carbon atom that connected) and three-dimensional chemical configuration can be (R) or (S).What mention especially is the The compounds of this invention of the three-dimensional chemical configuration at wherein said carbon atom place for (R), i.e. following formula: compound, perhaps its pharmacy acceptable salt or prodrug:
Compound of the present invention can exist with the pure substantially form of racemic object form or single enantiomer or diastereomer (for example have greater than 80%, particularly greater than the form of 90%, 95% or 99% purity).Therefore, one embodiment of the invention are formula (I, (R)) compounds of pure substantially form.
Embodiment of the present invention are as described below.Should be appreciated that the feature in each embodiment, described can with the characteristics combination of other description, other embodiments are provided.
V
V does not exist or ethylidene.Therefore, the present invention includes following formula compound or, in each case, its pharmacy acceptable salt or prodrug:
When V is ethylidene (being formula (III) compound), ethylene bridge and be positioned at the relative direction external form normally of hydrogen atom of contraposition of the nitrogen-atoms of piperidine ring, as shown below:
(III, external form)
In the text, term " outward " or " external form " refer to that the hydrogen atom shown in ethylene bridge and the following formula is positioned at the homonymy of piperidine ring.
The piperidine ring that the invention still further relates to wherein bridging is compound as herein described and claim as the described exo configuration of epimere.
-W-X-Y-
In formula (I), W is-C (O)-or-S (O)
1-; X is the linker that contains atom in the individual chain of 1-12 (for example 1-6) and comprise one or more connectors, described connector is selected from-O-,-C (O)-,-S (O)
1-,-N (R
9)-and optional by 1,2,3,4 or 5 R
11The alkylene that replaces; And Y be selected from-O-,-N (R
9)-,-C (O)-,-C (O) O-,-C (O) N (R
9)-,-S (O)
1-and-S (O)
1N (R
9)-linker.
W normally-C (O)-or-S (O)
2-.
When X comprised one or more alkylene connector, this connector or each connector can be aliphatic and/or isocyclic (for example cycloalkylidene).What mention especially is aliphatic, alkyls (alkylenic) for example, alkylene connector.The aliphatics connector is C normally
1-6The aliphatics connector, example comprises C
1-6The alkylidene group connector.Inferior carbocylic radical is C normally
3-7Inferior carbocylic radical comprises cycloalkylidene (C for example
3-6Cycloalkylidene, cyclopropylidene especially).In the situation of the connector that contains inferior carbocylic radical, at least one (common 1,2,3 or 4, especially 1 or 2, but in other situation 3 or 4) atom forms connector or is included in the connector in the ring.The alkylene connector is normally aliphatic, particularly C
1-
6Alkylidene group.In a compounds, X comprises the alkylene connector of Direct Bonding to W.In another kind of compound, X comprises optional by 1,2,3,4 or 5 R
11Arylidene (for example phenylene) connector that replaces.In some compound, described arylidene connector Direct Bonding is on W.What mention especially is to comprise to choose wantonly by 1,2,3,4 or 5 R
11The compound of the phenylene connector that replaces, wherein said phenylene connector Direct Bonding is to W.
X can comprise at least one connector, and this connector is selected from-N (R
9)-and aliphatic or cyclic alkylene (C for example
1-6Alkylidene group or cycloalkylidene), it is optional separately by 1,2,3,4 or 5 R
11Replace.Particularly, X can comprise at least one linker, and this linker is selected from-N (R
9)-and C
1-
6Alkylidene group (C for example
1, C
2Or C
3Alkylidene group), it is optional by 1,2,3,4 or 5 R11 replacement.When X comprises-N (R
9)-time, R
9Hydrogen normally, or be selected from C
1-6Alkyl (C for example
1, C
2, C
3Or C
4Alkyl) ,-(CH
2)
k-carbocylic radical and-(CH
2)
k-heterocyclic radical, it is optional separately by 1,2,3,4 or 5 R
11Replace.
What mention is following compound: wherein X is the linker that contains atom in the individual chain of 1-12 (for example 1-6) and comprise one or more connectors, described connector is selected from-O-,-C (O)-,-S (O)
1-,-N (R
9)-and optional by 1,2,3,4 or 5 R
11The C that replaces
1-6Aliphatic (C for example
1-6Alkylidene group);
In one embodiment, X is selected from one of following linker:
-X
1-；
-X
1-X
2-；
-X
1-X
2-X
3-；
-X
1-X
2-X
3-X
4-；
-X
1-X
2-X
3-X
4-X
5-；
-X
1-X
2-X
3-X
4-X
5-X
6-；
-X
1-X
2-X
3-X
4-X
5-X
6-X
7-; With
-X
1-X
2-X
3-X
4-X
5-X
6-X
7-X
8-；
X wherein
1, X
2, X
3, X
4, X
5, X
6, X
7And X
8Be selected from independently of one another-O-,-C (O)-,-S (O) 1-,-N (R
9)-and optional by 1,2,3,4 or 5 R
11The alkylene that replaces (C for example
1-6Alkylidene group).More generally, X is-X
1-or-X
1-X
2-.
What mention is following compound: X wherein
1Be optional by 1,2,3,4 or 5 R
11The alkylene that replaces (C for example
1-6Alkylidene group, C
2-6Alkenylene or inferior carbocylic radical).For example, X
1Can be optional by 1,2,3,4 or 5 R
11The C that replaces
1-6Alkylidene group.Particularly, X
1Can be methylene radical or ethylidene, it is optional separately by 1,2,3 or 4 substituting group replacement, and described substituting group independently is selected from halogen (for example fluorine or chlorine), amino and hydroxyl.Perhaps, X
1Can be optional by 1,2,3,4 or 5 R
11The arylidene that replaces is phenylene for example.
What also mention is the following compound of a class: X wherein
2Be-N (R
9)-, be R wherein
9Hydrogen or be selected from C normally
1-6Alkyl (C for example
1, C
2, C
3Or C
4Alkyl) ,-(CH
2)
k-carbocylic radical and-(CH
2)
k-heterocyclic radical, it is optional separately by 1,2,3,4 or 5 R
11Replace.Specifically ,-N (R
9)-can be-NH-or-N (CH
3)-.X therein
1Be in the compound of arylidene (for example phenylene), X
2Normally optional by 1,2,3,4 or 5 R
11The C that replaces
1-6Alkylidene group (C for example
1Or C
2Alkylidene group).
Also comprise following compound: X wherein
1By at least one R
11, for example at 1-or place, 2-position with respect to W (it is carbonyl or alkylsulfonyl normally), the C of replacement
1-6Alkylidene group.In this case, described at least one R
11Usually be selected from halogen, trifluoromethyl, cyano group, nitro, oxo ,=NR
13,-OR
13,-C (O) R
13,-C (O) N (R
13) R
14,-C (O) OR
13,-OC (O) R
13,-S (O)
1R
13,-S (O)
1N (R
13) R
14,-N (R
13) R
14,-N (R
13) N (R
13) R
14,-N (R
13) C (O) R
14,-N (R
13) S (O)
1R
13, (it is not C to alkyl
1-6Alkyl, and normally-(CH
2)
k-carbocylic radical), it is optional by 1,2,3,4 or 5 R
12Replace; With optional by 1,2,3,4 or 5 R
12Replace-(CH
2)
k-heterocyclic radical.In this case, R
13And R
14Usually be selected from hydrogen, C independently of one another
1-6Alkyl ,-(CH
2)
k-carbocylic radical (for example phenyl, cyclopropyl or benzyl) and-(CH
2)
k-heterocyclic radical.Exemplary R
11Group comprise carbamate, phenyl, benzyl ,-NH-C (O)-(C
1-6Alkyl), oxo, sulfonamido, urea, thiocarbamide and carboxyl groups.
Also comprise following compound: X wherein
1Be arylidene, it is preferably selected from:
In some compound, Y is-C (O)-,-C (O) O-,-C (O) N (R
9)-,-S (O)-,-S (O)
2-or-S (O)
1N (R
9)-.Specifically, Y normally-C (O)-,-C (O) O-,-S (O)-or-S (O)
2-.
In some embodiments, when X be C
1-6Alkylidene group ,-O-C
1-6Alkylidene group-or-N (R
9)-C
1-6Alkylidene group-time, Y is-O-,-S-or-N (R
9)-, and R
7Be hydrogen, the C of described X
1-6The alkylidene group connector is by 1,2,3,4 or 5 R
11Replace, wherein at least one described R
11Not halogen or C
1-6Alkyl.In this case, at least one R
11, this R for example
11Or each R
11Usually be independently selected from trifluoromethyl, cyano group, nitro, oxo ,=NR
13,-OR
13,-C (O) R
13,-C (O) N (R
13) R
14,-C (O) OR
13,-OC (O) R
13,-S (O)
1R
13,-S (O)
1N (R
13) R
14,-N (R
13) R
14,-N (R
13) N (R
13) R
14,-N (R
13) C (O) R
14,-N (R
13) S (O)
1R
13, (it is not C to alkyl
1-6Alkyl, and normally-(CH
2)
k-carbocylic radical), it is optional by 1,2,3,4 or 5 R
12Replace; With optional by 1,2,3,4 or 5 R
12Replace-(CH
2)
k-heterocyclic radical.In this case, R
13And R
14Usually be selected from hydrogen, C independently of one another
1-6Alkyl ,-(CH
2)
k-carbocylic radical (for example phenyl, cyclopropyl or benzyl) and-(CH
2)
k-heterocyclic radical.Exemplary R
11Group comprises carbamate, sulfonamido, urea, thiocarbamide and carboxyl groups.Carbocylic radical and heterocyclic radical can be for example 5,6 or 7-unit saturated or unsaturated ring, for example phenyl.
Atom in linker-W-X-Y-comprises 3,4 or 5 usually (especially 4 or 5) individual chain.
What mention especially is formula (IV) compound or its pharmacy acceptable salt or prodrug:
X wherein
1Be-N (R
9)-or optional by 1,2,3,4 or 5 R
11The alkylene that replaces (C for example
1-6Alkylidene group).
For formula (IV), Y normally-C (O)-,-C (O) O-,-C (O) N (R
9)-,-S (O)-,-S (O)
2-or-S (O)
1N (R
9)-.Specifically, Y normally-C (O)-,-C (O)-,-S (O)-or-S (O)
2-.
Linker-W-X
1The example of-Y-is described in the following table:
| Numbering | W | X 1 | Y |
| 1 | -C(O)- | -N(R 9)- | -C(O)- |
| 2 | -C(O)- | C 1-6Alkylidene group | -C(O)- |
| 3 | -C(O)- | -N(R 9)- | -S(O) 2- |
| 4 | -C(O)- | C 1-6Alkylidene group | -S(O) 2- |
| 5 | -S(O) 1- | -N(R 9)- | -C(O)- |
| 6 | -S(O) 1- | C 1-6Alkylidene group | -C(O)- |
| 7 | -S(O) 1- | C 1-6Alkylidene group | -S(O) 2- |
Linker-W-X
1The other example of-Y-is described in the following table:
| Numbering | W | X 1 | Y |
| 1 | -C(O)- | C 1-6Alkylidene group | -S(O) 2- |
| 2 | -S(O) 1- | C 1-6Alkylidene group | -C(O)- |
Linker-W-X
1The other example of-Y-is described in the following table:
Y is-N (R therein
9)-an embodiment of above-claimed cpd in, R
1And R
9Be joined together to form optional by 1,2,3,4 or 5 R
115 or 6 yuan of heterocyclic radicals that replace.5 or 6 yuan of heterocyclic radicals that form for example are 1-methyl-imidazolidines-2,4-diketone, imidazolidine-2,4-diketone, thiazolidine-2,4-diketone, tetramethyleneimine-2,5-diketone, isoindole-1,3-diketone or pyrrolidyl-2-oxo.
Linker-W-X
1The other example of-Y-is described in the following table:
| Numbering | W | X 1 | Y |
| 1 | -C(O)- | -CH 2- | -S(O) 2- |
| 2 | -C(O)- | -CH(CH 3)- | -S(O) 2- |
| 3 | -C(O)- | -C(CH 3) 2- | -S(O) 2- |
| 4 | -C(O)- | -CH 2CH 2- | -S(O) 2- |
| 5 | -S(O) 2- | -CH 2- | -C(O)- |
| 6 | -S(O) 2- | -CH(CH 3)- | -C(O)- |
| 7 | -S(O) 2- | -C(CH 3) 2- | -C(O)- |
| 8 | -S(O) 2- | -CH 2CH 2- | -C(O)- |
Linker-W-X
1The other example of-Y-is described in the following table:
| Numbering | W | X 1 | Y |
| 1 | -C(O)- | C 1-6Alkylidene group | -C(O)- |
| 2 | -S(O) 1- | C 1-6Alkylidene group | -S(O) 2- |
Linker-W-X
1The other example of-Y-is described in the following table:
| Numbering | W | X 1 | Y |
| 1 | -C(O)- | -CH 2- | -C(O)- |
| 2 | -C(O)- | -CH(CH 3)- | -C(O)- |
| 3 | -C(O)- | -C(CH 3) 2- | -C(O)- |
| 4 | -C(O)- | -CH 2CH 2- | -C(O)- |
Also mention wherein X especially
1Be optional by 1,2,3,4 or 5 R
11Following formula compound or its pharmacy acceptable salt or the prodrug of the inferior carbocylic radical (for example cycloalkylidene or arylidene) that replaces.
Linker-W-X
1The other example of-Y-is described in the following table:
| Numbering | W | X 1 | Y |
| 1 | -C(O)- | Cycloalkylidene | -S(O) 2- |
| 2 | -S(O) 1- | Cycloalkylidene | -C(O)- |
| 3 | -C(O)- | Cycloalkylidene | -C(O)- |
| 4 | -S(O) 1- | Cycloalkylidene | -S(O) 2- |
Linker-W-X
1The other example of-Y-is described in the following table:
| Numbering | W | X 1 | Y |
| 1 | -C(O)- | Cyclopropylidene | -S(O) 2- |
| 2 | -S(O) 1- | Cyclopropylidene | -C(O)- |
| 3 | -C(O)- | Cyclopropylidene | -C(O)- |
| 4 | -S(O) 1- | Cyclopropylidene | -S(O) 2- |
Linker-W-X
1The other example of-Y-is described in the following table:
| Numbering | W | X 1 | Y |
| 1 | -C(O)- | Arylidene | -S(O) 2- |
| 2 | -S(O) 1- | Arylidene | -C(O)- |
| 3 | -C(O)- | Arylidene | -C(O)- |
| 4 | -S(O) 1- | Arylidene | -S(O) 2- |
Linker-W-X
1The other example of-Y-is described in the following table:
| Numbering | W | X 1 | Y |
| 1 | -C(O)- | Phenylene | -S(O) 2- |
| 2 | -S(O) 1- | Phenylene | -C(O)- |
| 3 | -C(O)- | Phenylene | -C(O)- |
| 4 | -S(O) 1- | Phenylene | -S(O) 2- |
What also mention is formula V compound or its pharmacy acceptable salt or prodrug:
X wherein
1And X
2One of be-N (R
9)-; And another is optional by 1,2,3,4 or 5 R
11The C that replaces
1-6Alkylidene group.
With regard to formula V, Y normally-C (O)-,-C (O) O-,-C (O) N (R
9)-,-S (O)-,-S (O)
2-or-S (O)
1N (R
9)-.Specifically, Y normally-C (O)-,-C (O)-,-S (O)-or-S (O)
2-.
Linker-W-X
1-X
2The example of-Y-is described in the following table:
| Numbering | W | X 1 | X 2 | Y |
| 1 | -C(O)- | C 1-6Alkylidene group | -O- | -C(O)- |
| 2 | -C(O)- | C 1-6Alkylidene group | -N(R 9)- | -C(O)- |
| 3 | -C(O)- | -O- | C 1-6Alkylidene group | -C(O)- |
| 4 | -C(O)- | -N(R 9)- | C 1-6Alkylidene group | -C(O)- |
| 5 | -C(O)- | C 1-6Alkylidene group | -N(R 9)- | -S(O) 2- |
| 6 | -C(O)- | -O- | C 1-6Alkylidene group | -S(O) 2- |
| 7 | -C(O)- | -N(R 9)- | C 1-6Alkylidene group | -S(O) 2- |
| 8 | -S(O) 1- | C 1-6Alkylidene group | -O- | -C(O)- |
| 9 | -S(O) 1- | C 1-6Alkylidene group | -N(R 9)- | -C(O)- |
| 10 | -S(O) 1- | -N(R 9)- | C 1-6Alkylidene group | -C(O)- |
| 11 | -S(O) 1- | C 1-6Alkylidene group | -N(R 9)- | -S(O) 2- |
| 12 | -S(O) 1- | -N(R 9)- | C 1-6Alkylidene group | -S(O) 2- |
Linker-W-X
1-X
2The example of-Y-is described in the following table:
Linker-W-X
1-X
2The other example of-Y-is described in the following table:
| Numbering | W | X 1 | X 2 | Y |
| 1 | -C(O)- | C 1-6Alkylidene group | -N(R 9)- | -C(O)- |
| 2 | -C(O)- | C 1-6Alkylidene group | -N(R 9)- | -S(O) 2- |
| 3 | -S(O) 2- | C 1-6Alkylidene group | -N(R 9)- | -C(O)- |
| 4 | -S(O) 2- | C 1-6Alkylidene group | -N(R 9)- | -S(O) 2- |
Linker-W-X
1-X
2The other example of-Y-is described in the following table:
| Numbering | W | X 1 | X 2 | Y |
| 1 | -C(O)- | -CH 2- | -N(R 9)- | -C(O)- |
| 2 | -C(O)- | -CH 2- | -N(R 9)- | -S(O) 2- |
| 3 | -C(O)- | -CH(CH 3)- | -N(R 9)- | -C(O)- |
| 4 | -C(O)- | -CH(CH 3)- | -N(R 9)- | -S(O) 2- |
| 5 | -C(O)- | -C(CH 3) 2- | -N(R 9)- | -C(O)- |
| 6 | -C(O)- | -C(CH 3) 2- | -N(R 9)- | -S(O) 2- |
| 7 | -C(O)- | -CH 2CH 2- | -N(R 9)- | -C(O)- |
| 8 | -C(O)- | -CH 2CH 2- | -N(R 9)- | -S(O) 2- |
| 9 | -S(O) 2- | -CH 2- | -N(R 9)- | -C(O)- |
| 10 | -S(O) 2- | -CH 2- | -N(R 9)- | -S(O) 2- |
| 11 | -S(O) 2- | -CH(CH 3)- | -N(R 9)- | -C(O)- |
| 12 | -S(O) 2- | -CH(CH 3)- | -N(R 9)- | -S(O) 2- |
| 13 | -S(O) 2- | -C(CH 3) 2- | -N(R 9)- | -C(O)- |
| 14 | -S(O) 2- | -C(CH 3) 2- | -N(R 9)- | -S(O) 2- |
| 15 | -S(O) 2- | -CH 2CH 2- | -N(R 9)- | -C(O)- |
| 16 | -S(O) 2- | -CH 2CH 2- | -N(R 9)- | -S(O) 2- |
Linker-W-X
1-X
2The other example of-Y-is described in the following table:
| Numbering | W | X 1 | X 2 | Y |
| 1 | -C(O)- | -CH(CH 3)- | -NH- | -C(O)- |
In superincumbent each table, R
9Hydrogen normally, or be selected from C
1-6Alkyl (C for example
1, C
2, C
3Or C
4Alkyl) ,-(CH
2)
k-carbocylic radical and-(CH
2)
k-heterocyclic radical, it is optional separately by 1,2,3,4 or 5 R
11Replace.Specifically ,-N (R
9)-can be-NH-or-N (CH
3)-.
When mentioning C in each table in the above
1-6Alkylidene group (for example-CH
2-,-CH (CH
3)-,-C (CH
3)
2-or-CH
2CH
2-), when cycloalkylidene (for example cyclopropylidene) or arylidene (for example phenylene), they can be by 1,2,3,4 or 5 R
11Replace, more generally be unsubstituted or replaced by 1 or 2 substituting group, described substituting group is selected from: hydroxyl, amino, halogen (for example fluorine or chlorine), optional by 1,2,3,4 or 5 R
12The C that replaces
1-6Alkyl (C for example
1, C
2, C
3Or C
4Alkyl) and optional by 1,2,3,4 or 5 R
12The arylidene (for example phenylene) that replaces, wherein R
12For example be-C (O) NH
2And, when mentioning C
1-6During alkylidene group, it can be by C
3-6Inferior carbocylic radical (for example cyclopropylidene) is replaced.When mentioning cyclopropylidene, can think that it contains atom in 1 or 2 chain, be generally atom in 1 chain.
R
1
R
1Be selected from hydrogen;-N (R
9) (R
10); Optional by 1,2,3,4 or 5 R
11The alkyl that replaces; Optional by 1,2,3,4 or 5 R
11The-oxyl that replaces; With optional by 1,2,3,4 or 5 R
11Replace-(CH
2)
k-heterocyclic radical.Perhaps, as Y be-N (R
9)-time, R
1And R
9Form heterocycle with the nitrogen-atoms that they connected, wherein this heterocycle is bonded to X and optional by 1,2,3,4 or 5 R by described nitrogen-atoms
11Replace.
In one embodiment of the invention, R
1Be-N (R
9) (R
10).In this case, R
9And R
10Usually be hydrogen independently of one another or be selected from C
1-6Alkyl (C for example
1, C
2, C
3Or C
4Alkyl) ,-(CH
2)
k-carbocylic radical (for example-(CH
2)
k-cycloalkyl or-(CH
2)
k-aryl) and (CH
2)
k-heterocyclic radical, it is optional separately by 1,2,3,4 or 5 R
11Replace.For example, R
9And R
10Can be hydrogen or optional independently of one another by 1,2,3,4 or 5 R
11The C that replaces
1-6Alkyl (for example methyl or ethyl).That mention is R at least wherein
9And R
10One of by C
1-6The C that alkoxyl group replaces
1-6The compound of alkyl group.Specifically ,-N (R
9) (R
10) can be amino, methylamino, dimethylamino or (methoxymethyl) methylamino.
In another embodiment of the invention, R
1Be optional by 1,2,3,4 or 5 R
11The alkyl that replaces.In this case, R
1Usually be selected from C
1-6Alkyl (C for example
1, C
2, C
3Or C
4Alkyl) or-(CH
2)
k-carbocylic radical (for example-(CH
2)
k-cycloalkyl or-(CH
2)
k-aryl), it is optional separately by 1,2,3,4 or 5 R
11Replace.Specifically, R
1Can be C
1-6Alkyl (C for example
1, C
2, C
3Or C
4Alkyl) ,-(CH
2)
k-cycloalkyl (for example cyclopropyl, cyclobutyl or cyclopropyl methyl) or-(CH
2)
k-aryl (for example phenyl or benzyl), it is optional separately by 1,2,3,4 or 5 R
11Replace.What mention especially is methyl; Methoxymethyl; Optional by 1 or 2 R
11The cyclopropyl that replaces; With optional by 1,2,3,4 or 5 R
11The phenyl that replaces.
In another embodiment of the invention, R
1Be optional by 1,2,3,4 or 5 R
11The-oxyl that replaces.In this case, R
1Usually be selected from C
1-6Alkyl (C for example
1, C
2, C
3Or C
4Alkyl) or-O-(CH
2)
k-carbocylic radical (for example-O-(CH
2)
k-cycloalkyl or-O-(CH
2)
k-aryl), it is optional separately by 1,2,3,4 or 5 R
11Replace.Specifically, R
1Can be C
1-6Alkyl (C for example
1, C
2, C
3Or C
4Alkyl oxy) ,-O-(CH
2)
k-cycloalkyl (for example cyclopropyl oxygen base, cyclobutyl oxygen base or cyclopropyl methyl oxygen base) or-O-(CH
2)
k-aryl (for example-the O-phenyl or-the O-benzyl), it is optional separately by 1,2,3,4 or 5 R
11Replace.What mention especially is methyl; Methoxymethyl; Optional by 1 or 2 R
11The cyclopropyl that replaces; With optional by 1,2,3,4 or 5 R
11The phenyl that replaces.
In another embodiment, R
1Be optional by 1,2,3,4 or 5 R
11Replace-(CH
2)
k-heterocyclic radical.Usually, k is 0,1 or 2, more generally is 0.The heterocyclic radical group can be Heterocyclylalkyl or heteroaryl, and it is optional separately by 1,2,3,4 or 5 R
11Replace.Exemplary heterocyclic radical group comprises Oxyranyle, the azirane base, 1,2-oxygen thia cyclopentyl, imidazolyl, thienyl, furyl, tetrahydrofuran base, pyranyl, imidazolyl, the thiapyran base, thianthrenyl, isobenzofuran-base, benzofuryl, chromenyl, the 2H-pyrryl, pyrryl, pyrrolinyl, pyrrolidyl, imidazolyl, imidazolidyl, benzimidazolyl-, pyrazolyl, pyrazinyl, pyrazolidyl, thiazolyl, isothiazolyl, dithiazole base oxazolyl isoxazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridyl (piridinyl), piperidyl, piperazinyl, pyridazinyl, morpholinyl, thio-morpholinyl, especially thiomorpholine generation, the indolizine base, pseudoindoyl, the 3H-indyl, indyl, benzimidazolyl-, the tonka bean camphor base, indazolyl, triazolyl, tetrazyl, purine radicals, the 4H-quinolizinyl, isoquinolyl, quinolyl, tetrahydric quinoline group, tetrahydro isoquinolyl, 3,4-dihydro-2H-isoquinoline 99.9-1-ketone, 3,4-dihydro-2H-isoquinolyl, THP trtrahydropyranyl, 1,3-dihydro-pseudoindoyl, 1,3-dioxo-1,3-dihydro-pseudoindoyl, 3,4-dihydro-2H-isoquinolyl, 3,4-dihydro-2H-isoquinolyl-1-ketone, decahydroquinolyl, the octahydro isoquinolyl, benzofuryl, dibenzofuran group, benzothienyl, the dibenzothiophene base, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolyl, quinazolyl, the cinnolines base, pteridyl, carbazyl, the β-Ka Lin base, phenanthridinyl, acridyl, perimidinyl, the phenanthroline base, the furazan base, phenazinyl, phenothiazinyl phenoxazinyl, chromenyl, different chromanyl and chromanyl, it is optional separately by 1,2,3,4 or 5 R
11Replace.What mention especially is imidazolyl, oxazolyl, morpholinyl, 1,4-benzodioxan base, pyrimidyl and pyrazinyl, and it is optional separately by 1,2,3,4 or 5 R
11Replace.What also mention is 1,3-dioxo-pseudoindoyl, 2-oxo-pyrrolidyl and 2, and 4-dioxo-thiazolidine-3-base, it is optional separately by 1,2 or 3 R
11Replace.
Therein Y be-C (O)-compound in, R
1C normally
1-6Alkyl (C for example
1, C
2, C
3Or C
4Alkyl), cycloalkyl (for example cyclopropyl), aryl (for example phenyl) or heterocyclic radical (for example imidazolyl, oxazolyl, morpholinyl, 1,4-benzodioxan base or pyrazinyl), it is optional separately by 1,2,3,4 or 5 R
11Replace.
Y is-S (O) therein
2-or-S (O) N (R
9)-compound in, R
1Normally hydrogen, C
1-6Alkyl, cycloalkyl (for example cyclopropyl or cyclopropyl methyl), aryl (for example phenyl) or heterocyclic radical (for example imidazolyl, oxazolyl, morpholinyl, 1,4-benzodioxan base or pyrazinyl), it is optional separately by 1,2,3,4 or 5 R
11Replace.Perhaps, R
1Usually can be-N (R
9) (R
10), for example amino, C
1-6Alkylamino or two (C
1-6Alkyl) amino.
What mention especially is following compound: R wherein
1Be morpholine-4-base or cyclopropyl, it is optional separately by 1,2,3,4 or 5 R
11Replace.
In another embodiment, Y is-N (R
9)-, and-N (R
9) R
1Connecting together, it is optional by 1,2,3,4 or 5 R to form
11The nitrogen heterocyclic ring that replaces.This heterocyclic radical group can be Heterocyclylalkyl or heteroaryl, and it is optional separately by 1,2,3,4 or 5 R
11Replace.Exemplary nitrogen heterocycle group comprises the azirane base, imidazolyl, pyranyl, the 2H-pyrryl, pyrryl, pyrrolinyl, pyrrolidyl, imidazolidyl, benzimidazolyl-, pyrazolyl, pyrazinyl, pyrazolidyl, thiazolyl, isothiazolyl, dithiazole base oxazolyl isoxazolyl, pyridyl, pyrimidyl, piperidyl, piperazinyl, pyridazinyl, morpholinyl, thio-morpholinyl, pyridyl (piridinyl), the indolizine base, pseudoindoyl, the 3H-indyl, indyl, indazolyl, triazolyl, tetrazyl, purine radicals, the 4H-quinolizinyl, isoquinolyl, quinolyl, tetrahydric quinoline group, tetrahydro isoquinolyl, decahydroquinolyl, the octahydro isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolyl, quinazolyl, the cinnolines base, pteridyl, carbazyl, the β-Ka Lin base, phenanthridinyl, acridyl, perimidinyl, the phenanthroline base, the furazan base, phenazinyl, phenothiazinyl phenoxazinyl, 2,3-dihydro-benzo [1,4] dioxin, dihydro-Ben Bing dioxin, THP trtrahydropyranyl, tetrahydrofuran base, 1,3-dioxo-1,3-dihydro-pseudoindoyl, it is optional separately by 1,2,3,4 or 5 R
11Replace.What mention is indyl, pseudoindoyl, pyrrolidyl and thiazolidine-3-base, and it is optional separately by 1,2,3,4 or 5 R
11Replace.What mention especially is 1,3-dioxo-pseudoindoyl, 2-oxo-pyrrolidyl and 2, and 4-dioxo-thiazolidine-3-base, it is optional separately by 1,2 or 3 R
11Replace.
Work as R
1By R
11During replacement, be somebody's turn to do or each R
11Usually be independently selected from halogen (for example fluorine, chlorine or bromine), hydroxyl, cyano group, amino ,-C (O) OH, C
1-6Alkyl, C
1-6Alkoxyl group (C for example
1, C
2, C
3Or C
4Alkoxyl group) ,-C (O)-C
1-6Alkyl ,-C (O) O-C
1-6Alkyl ,-S (O)
1-C
1-6Alkyl ,-NH (C
1-6Alkyl) and-N (C
1-6Alkyl)
2, any C of Cun Zaiing wherein
1-6Alkyl group is optional to be replaced by 1,2,3,4 or 5 substituting group, and described substituting group is independently selected from halogen, cyano group, amino, hydroxyl and C
1-6Alkoxyl group.
Work as R
1By R
11During replacement, be somebody's turn to do or each R
11Usually be independently selected from halogen (for example fluorine, chlorine or bromine), hydroxyl, cyano group, amino, oxo ,-C (O) OH ,-C (O)-NH
2,-C (O)-NH-C
1-6Alkyl, C
1-6Alkyl, C
1-6Alkoxyl group (C for example
1, C
2, C
3Or C
4Alkoxyl group) ,-the O-aryl (for example-the O-phenyl) ,-(CH
2)
k-phenyl ,-(CH
2)
k-heterocyclic radical ,-(CH
2)
k-cycloalkyl ,-C (O)-heterocyclic radical ,-C (O)-C
1-6Alkyl ,-C (O) O-C
1-6Alkyl ,-S (O)
1-C
1-6Alkyl ,-NH (C
1-6Alkyl) ,-NH-C (O)-(C
1-6Alkyl), 6 or 5 yuan of cyclophane bases, tap bolt group (for example passing through cyclopropyl) and-N (C
1-6Alkyl)
2, any C of Cun Zaiing wherein
1-6Alkyl is optional to be replaced by 1,2,3,4 or 5 substituting group, and described substituting group is independently selected from halogen, cyano group, amino, hydroxyl and C
1-6Alkoxyl group.
R
2And R
3
R
2And R
3Be selected from R independently of one another
8,-OR
8,-C (O) R
8,-C (O) OR
8With-S (O)
1R
9
In one embodiment of the invention, R
2And R
3Be hydrogen independently of one another; Hydroxyl; Or be selected from C
1-6Alkyl, C
1-6Alkoxyl group ,-(CH
2)
k-cycloalkyl ,-(CH
2)
k-Heterocyclylalkyl ,-(CH
2)
k-aryl and-(CH
2)
k-heteroaryl, it is optional separately by 1,2,3,4,5 or 6 R
11Replace.
In another embodiment, R
2Be hydrogen; And R
3Be hydrogen, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group ,-(CH
2)
k-cycloalkyl or-(CH
2)
k-aryl, described any alkyl, alkoxyl group, cycloalkyl and aromatic yl group are optional by 1,2,3,4 or 5 R
11Replace, wherein be somebody's turn to do or each R
11For example be hydroxyl, halogen (for example chlorine or fluorine); C
1, C
2, C
3Or C
4Alkyl, for example methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl or the tertiary butyl, it is optional separately to be replaced by 1,2,3 or 4 halogen (for example fluorine or chlorine) atom, and an example is a trifluoromethyl; C
1, C
2, C
3Or C
4Alkoxyl group, for example methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy or tert.-butoxy, it is optional separately to be replaced by 1,2,3 or 4 halogen (for example fluorine or chlorine) atom, and R
3Particularly hydrogen, methyl, cyclopropyl methyl or benzyl.
In another embodiment, R
2And R
3The hydrogen of respectively doing for oneself.
R
4And R
5
R
4And R
5Be selected from hydrogen, hydroxyl, halogen and optional independently of one another by 1,2,3,4 or 5 R
11The C that replaces
1-6Alkyl.
In one embodiment, R
4And R
5Be hydrogen, hydroxyl, halogen (for example, chlorine or fluorine) independently of one another; Or C
1, C
2, C
3Or C
4Alkyl, for example methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl or the tertiary butyl, it is optional separately to be replaced by 1,2,3 or 4 halogen (for example fluorine or chlorine) atom, and an example is a trifluoromethyl.
In another embodiment, R
4Be hydrogen, hydroxyl, halogen (for example, chlorine or fluorine); Perhaps C
1, C
2, C
3Or C
4Alkyl, for example methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl or the tertiary butyl, it is optional separately to be replaced by 1,2,3 or 4 halogen (for example fluorine or chlorine) atom, and an example is a trifluoromethyl; And R
5Hydrogen normally.
In another embodiment, R
4Be hydrogen, hydroxyl, fluorine, chlorine or C
1, C
2, C
3Or C
4Alkyl; And R
5Be hydrogen.
In another embodiment, R
4Be hydrogen, hydroxyl, fluorine, chlorine or methyl; And R
5Be hydrogen.
In another embodiment, R
4And R
5Each is hydrogen naturally.
R
6
R
6Be aryl or heteroaryl, it is optional separately by 1,2,3,4 or 5 R
11Replace.
In one embodiment of the invention, R
6Be aryl, phenyl or naphthyl particularly, it is optional separately by 1,2,3,4 or 5 R
11Replace.In some embodiments, R
6Be optional by 1,2,3,4 or 5 R
11The phenyl that replaces wherein is somebody's turn to do or each R
11For example be hydroxyl, halogen (for example, chlorine or fluorine); C
1, C
2, C
3Or C
4Alkyl, for example methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl or the tertiary butyl, it is optional separately to be replaced by 1,2,3 or 4 halogen (for example fluorine or chlorine) atom, and an example is a trifluoromethyl; Perhaps C
1, C
2, C
3Or C
4Alkoxyl group, for example methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, tert.-butoxy, it is optional separately to be replaced by 1,2,3 or 4 halogen (for example fluorine or chlorine) atom.For example, R
6It can be the optional phenyl that is replaced by 1,2,3,4 or 5 halogen (for example fluorine) atom.
In another embodiment, R
6Be selected from:
In another embodiment, R
6Be 2,4, the 5-trifluorophenyl.
In another embodiment, R
6Be heteroaryl (normally monocyclic), for example thienyl or benzothienyl, and optional by 1,2,3,4 or 5 R
11Replace, wherein be somebody's turn to do or each R
11For example be hydroxyl, halogen (for example, chlorine or fluorine); C
1, C
2, C
3Or C
4Alkyl, for example methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl or the tertiary butyl, it is optional separately to be replaced by 1,2,3 or 4 halogen (for example fluorine or chlorine) atom, and an example is a trifluoromethyl; Perhaps C
1, C
2, C
3Or C
4Alkoxyl group, for example methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, tert.-butoxy, it is optional separately to be replaced by 1,2,3 or 4 halogen (for example fluorine or chlorine) atom.
R
11
Each R
11Be independently selected from R
12Optional by 1,2,3,4 or 5 R
12The alkyl that replaces (C for example
1-6Alkyl or-(CH
2)
k-aryl); With optional by 1,2,3,4 or 5 R
12Replace-(CH
2)
k-heterocyclic radical; R wherein
12Be independently selected from halogen, trifluoromethyl, cyano group, nitro, oxo ,=NR
13,-OR
13,-C (O) R
13,-C (O) N (R
13) R
14,-C (O) OR
13,-OC (O) R
13,-S (O)
1R
13,-S (O)
1N (R
13) R
14,-N (R
13) R
14,-N (R
13) N (R
13) R
14,-N (R
13) C (O) R
14With-N (R
13) S (O)
1R
13And R
13And R
14Be hydrogen independently of one another or be selected from alkyl (C for example
1-6Alkyl or-(CH
2)
k-aryl or-(CH
2)
k-cycloalkyl) and-(CH
2)
k-heterocyclic radical, it is optional separately by 1,2,3,4 or 5 substituting group replacement, and described substituting group is independently selected from halogen, cyano group, amino, hydroxyl, C
1-6Alkyl and C
1-6Alkoxyl group, or be selected from oxo, halogen, cyano group, amino, hydroxyl, C
1-6Alkyl and C
1-6Alkoxyl group.
Usually, each R
11Be independently selected from halogen (for example fluorine, chlorine or bromine), hydroxyl, cyano group, amino ,-C (O) OH, C
1-6Alkyl, C
1-6Alkoxyl group (C for example
1, C
2, C
3Or C
4Alkoxyl group) ,-C (O)-C
1-6Alkyl ,-C (O) O-C
1-6Alkyl ,-S (O)
1-C
1-6Alkyl-NH (C
1-6Alkyl) and-N (C
1-6Alkyl)
2, any C of Cun Zaiing wherein
1-6Alkyl group is optional to be replaced by 1,2,3,4 or 5 substituting group, and described substituting group independently is selected from halogen, cyano group, amino, hydroxyl and C
1-6Alkoxyl group.
Usually, each R
11Be independently selected from halogen (for example fluorine, chlorine or bromine), hydroxyl, cyano group, amino ,-C (O) OH, C
1-6Alkyl, C
1-6Alkoxyl group (C for example
1, C
2, C
3Or C
4Alkoxyl group) ,-C (O)-C
1-6Alkyl ,-C (O) O-C
1-6Alkyl ,-S (O)
1-C
1-6Alkyl ,-(CH
2)
k-cycloalkyl ,-(CH
2)
k-aryl ,-(CH
2)
k-heterocyclic radical ,-NH-(CH
2)
k-aryl ,-NH-(CH
2)
k-cycloalkyl ,-NH-C (O)-(CH
2)
k-aryl ,-NH-C (O)-(CH
2)
k-cycloalkyl ,-N (C
1-6Alkyl)-(CH
2)
k-aryl ,-N (C
1-6Alkyl)-(CH
2)
k-cycloalkyl ,-NH (C
1-6Alkyl) and-N (C
1-6Alkyl)
2, the C of any existence wherein
1-6Alkyl group or aryl (aryryl) are optional to be replaced by 1,2,3,4 or 5 substituting group, and described substituting group independently is selected from halogen, cyano group, amino, hydroxyl and C
1-6Alkoxyl group.
For fear of producing query, when group by a plurality of R
11During replacement, each R
11Be independently selected from specified substituting group.This is equally applicable to comprise a plurality of R
11Substituent The compounds of this invention; Each R
11Be independent of any other R that exists in the compound
11Substituting group is chosen.As previously mentioned, work as R
11For halogen, particularly during fluorine, the hydrogen of any number can be replaced in principle.
A specific embodiments of the present invention is formula (VI) compound or its pharmacy acceptable salt or prodrug:
Therefore, the present invention includes following formula compound or, in each case, its pharmacy acceptable salt or prodrug:
Another embodiment of the invention is formula (IX) compound or its pharmacy acceptable salt or prodrug:
X wherein
1Be selected from-O-,-C (O)-,-S (O)
1-,-N (R
9)-and optional by 1,2,3,4 or 5 R
11The alkylene that replaces (C for example
1-6Alkylidene group).
Therefore, the present invention includes following formula compound or, in each case, its pharmacy acceptable salt or prodrug:
Another embodiment of the invention is formula (XII) compound or its pharmacy acceptable salt or prodrug:
Wherein p is 0,1,2,3,4 or 5, and perhaps p is 0,1,2 or 3.
Therefore, the present invention includes following formula compound or, in each case, its pharmacy acceptable salt or prodrug:
For formula (IX) to (XIV) with (XIVb), X
1Can define suc as formula (IV) is middle, i.e. X
1Be-N (R
9)-or optional by 1,2,3,4 or 5 R
11The alkylene that replaces (C for example
1-6Alkylidene group).Y normally-C (O)-,-C (O) O-,-C (O) N (R
9)-,-S (O)-,-S (O)
2-or-S (O)
1N (R
9)-.Specifically, Y normally-C (O)-,-C (O)-,-S (O)-or-S (O)
2-.
Mention especially be wherein-W-X
1-Y-is any formula (IX) to (XIV) of one of following linker and (XIVb) compound:
| Numbering | W | X 1 | Y |
| 1 | -C(O)- | -N(R 9)- | -C(O)- |
| 2 | -C(O)- | C 1-6Alkylidene group | -C(O)- |
| 3 | -C(O)- | -N(R 9)- | -S(O) 2- |
| 4 | -C(O)- | C 1-6Alkylidene group | -S(O) 2- |
| 5 | -S(O) 1- | -N(R 9)- | -C(O)- |
| 6 | -S(O) 1- | C 1-6Alkylidene group | -C(O)- |
| 7 | -S(O) 1- | C 1-6Alkylidene group | -S(O) 2- |
Also mention be wherein-W-X
1-Y-is the compound of any above-mentioned formula of one of following linker:
| Numbering | W | X 1 | Y |
| 1 | -C(O)- | C 1-6Alkylidene group | -S(O) 2- |
| 2 | -S(O) 1- | C 1-6Alkylidene group | -C(O)- |
Also mention be wherein-W-X
1-Y-is the compound of any above-mentioned formula of one of following linker:
Y is-N (R therein
9)-an embodiment of above-claimed cpd in, R
1And R
9Connecting together, it is optional by 1,2,3,4 or 5 R to form
115 or 6 yuan of heterocyclic radicals that replace.5 or 6 yuan of heterocyclic radicals of this formation for example are 1-methyl-imidazolidines-2,4-diketone, imidazolidine-2,4-diketone, thiazolidine-2,4-diketone, tetramethyleneimine-2,5-diketone, isoindole-1,3-diketone or pyrrolidyl-2-oxo.
Also mention be wherein-W-X
1-Y-is the compound of any above-mentioned formula of one of following linker:
| Numbering | W | X 1 | Y |
| 1 | -C(O)- | -CH 2- | -S(O) 2- |
| 2 | -C(O)- | -CH(CH 3)- | -S(O) 2- |
| 3 | -C(O)- | -C(CH 3) 2- | -S(O) 2- |
| 4 | -C(O)- | -CH 2CH 2- | -S(O) 2- |
| 5 | -S(O) 2- | -CH 2- | -C(O)- |
| 6 | -S(O) 2- | -CH(CH 3)- | -C(O)- |
| 7 | -S(O) 2- | -C(CH 3) 2- | -C(O)- |
| 8 | -S(O) 2- | -CH 2CH 2- | -C(O)- |
In the situation about on the next-door neighbour, showing, R
16 yuan of heterocyclic radicals normally.It can be unsubstituted or by 1,2,3,4 or 5 R
11Replace.Next-door neighbour on the table situation in, particularly its first the row situation in, R
1Morpholinyl (for example morpholine-4-yl) normally, it can be unsubstituted or by 1,2,3,4 or 5 R
11Replace.
Also mention be wherein-W-X
1-Y-is the compound of any above-mentioned formula of one of following linker:
| Numbering | W | X 1 | Y |
| 1 | -C(O)- | C 1-6Alkylidene group | -C(O)- |
| 2 | -S(O) 1- | C 1-6Alkylidene group | -S(O) 2- |
Also mention be wherein-W-X
1-Y-is the compound of any above-mentioned formula of one of following linker:
| Numbering | W | X 1 | Y |
| 1 | -C(O)- | -CH 2- | -C(O)- |
| 2 | -C(O)- | -CH(CH 3)- | -C(O)- |
| 3 | -C(O)- | -C(CH 3) 2- | -C(O)- |
| 4 | -C(O)- | -CH 2CH 2- | -C(O)- |
That also mention especially is X wherein
1Be optional by 1,2,3,4 or 5 R
11Following formula compound or its pharmacy acceptable salt or the prodrug of the inferior carbocylic radical (for example cycloalkylidene or arylidene) that replaces.
Also mention be wherein-W-X
1-Y-is the compound of any above-mentioned formula of one of following linker:
| Numbering | W | X 1 | Y |
| 1 | -C(O)- | Cycloalkylidene | -S(O) 2- |
| 2 | -S(O) 1- | Cycloalkylidene | -C(O)- |
| 3 | -C(O)- | Cycloalkylidene | -C(O)- |
| 4 | -S(O) 1- | Cycloalkylidene | -S(O) 2- |
Also mention be wherein-W-X
1-Y-is the compound of any above-mentioned formula of one of following linker:
| Numbering | W | X 1 | Y |
| 1 | -C(O)- | Cyclopropylidene | -S(O) 2- |
| 2 | -S(O) 1- | Cyclopropylidene | -C(O)- |
| 3 | -C(O)- | Cyclopropylidene | -C(O)- |
| 4 | -S(O) 1- | Cyclopropylidene | -S(O) 2- |
Also mention be wherein-W-X
1-Y-is the compound of any above-mentioned formula of one of following linker:
| Numbering | W | X 1 | Y |
| 1 | -C(O)- | Arylidene | -S(O) 2- |
| 2 | -S(O) 1- | Arylidene | -C(O)- |
| 3 | -C(O)- | Arylidene | -C(O)- |
| 4 | -S(O) 1- | Arylidene | -S(O) 2- |
Also mention be wherein-W-X
1-Y-is the compound of any above-mentioned formula of one of following linker:
| Numbering | W | X 1 | Y |
| 1 | -C(O)- | Phenylene | -S(O) 2- |
| 2 | -S(O) 1- | Phenylene | -C(O)- |
| 3 | -C(O)- | Phenylene | -C(O)- |
| 4 | -S(O) 1- | Phenylene | -S(O) 2- |
Another embodiment of the invention is formula (XV) compound or its pharmacy acceptable salt or prodrug:
X wherein
1And X
2Be selected from independently of one another-O-,-C (O)-,-S (O)
1-,-N (R
9)-and optional by 1,2,3,4 or 5 R
11The C that replaces
1-6Alkylidene group.
Therefore, the present invention includes following formula compound or, in each case, its pharmacy acceptable salt or prodrug:
Another embodiment of the invention is formula (XVIII) compound or its pharmacy acceptable salt or prodrug:
Wherein p is 0,1,2,3,4 or 5.
Therefore, the present invention includes following formula compound or, in each case, its pharmacy acceptable salt or prodrug:
For formula (XV) to (XX) or formula (XXb), X
1And X
2Can such as in the formula V definition, i.e. X
1And X
2One of be-N (R
9)-; And another is optional by 1,2,3,4 or 5 R
11The C that replaces
1-6Alkylidene group.Y normally-C (O)-,-C (O) O-,-C (O) N (R
9)-,-S (O)-,-S (O)
2-or-S (O)
1N (R
9)-.Specifically, Y normally-C (O)-,-C (O)-,-S (O)-or-S (O)
2-.
Mention especially be wherein-W-X
1-X
2-Y-is the compound of any formula in the formula (XV) to (XX) of one of following linker:
| Numbering | W | X 1 | X 2 | Y |
| 1 | -C(O)- | C 1-6Alkylidene group | -O- | -C(O)- |
| 2 | -C(O)- | -O- | -N(R 9)- | -C(O)- |
| 3 | -C(O)- | C 1-6Alkylidene group | -N(R 9)- | -C(O)- |
| 4 | -C(O)- | -O- | C 1-6Alkylidene group | -C(O)- |
| Numbering | W | X 1 | X 2 | Y |
| 5 | -C(O)- | -N(R 9)- | C 1-6Alkylidene group | -C(O)- |
| 6 | -C(O)- | C 1-6Alkylidene group | -N(R 9)- | -S(O) 2- |
| 7 | -C(O)- | -O- | C 1-6Alkylidene group | -S(O) 2- |
| 8 | -C(O)- | -N(R 9)- | C 1-6Alkylidene group | -S(O) 2- |
| 9 | -S(O) 1- | C 1-6Alkylidene group | -O- | -C(O)- |
| 10 | -S(O) 1- | C 1-6Alkylidene group | -N(R 9)- | -C(O)- |
| 11 | -S(O) 1- | -N(R 9)- | C 1-6Alkylidene group | -C(O)- |
| 12 | -S(O) 1- | C 1-6Alkylidene group | -N(R 9)- | -S(O) 2- |
| 13 | -S(O) 1- | -N(R 9)- | C 1-6Alkylidene group | -S(O) 2- |
Also mention be wherein-W-X
1-X
2-Y-is the compound of any following formula of one of following linker:
Also mention be wherein-W-X
1-X
2-Y-is the compound of any following formula of one of following linker:
| Numbering | W | X 1 | X 2 | Y |
| 1 | -C(O)- | C 1-6Alkylidene group | -N(R 9)- | -C(O)- |
| 2 | -C(O)- | C 1-6Alkylidene group | -N(R 9)- | -S(O) 2- |
| 3 | -S(O) 2- | C 1-6Alkylidene group | -N(R 9)- | -C(O)- |
| 4 | -S(O) 2- | C 1-6Alkylidene group | -N(R 9)- | -S(O) 2- |
Also mention be wherein-W-X
1-X
2-Y-is the compound of any following formula of one of following linker:
| Numbering | W | X 1 | X 2 | Y |
| 1 | -C(O)- | -CH 2- | -N(R 9)- | -C(O)- |
| 2 | -C(O)- | -CH 2- | -N(R 9)- | -S(O) 2- |
| 3 | -C(O)- | -CH(CH 3)- | -N(R 9)- | -C(O)- |
| 4 | -C(O)- | -CH(CH 3)- | -N(R 9)- | -S(O) 2- |
| 5 | -C(O)- | -C(CH 3) 2- | -N(R 9)- | -C(O)- |
| 6 | -C(O)- | -C(CH 3) 2- | -N(R 9)- | -S(O) 2- |
| 7 | -C(O)- | -CH 2CH 2- | -N(R 9)- | -C(O)- |
| 8 | -C(O)- | -CH 2CH 2- | -N(R 9)- | -S(O) 2- |
| 9 | -S(O) 2- | -CH 2- | -N(R 9)- | -C(O)- |
| 10 | -S(O) 2- | -CH 2- | -N(R 9)- | -S(O) 2- |
| 11 | -S(O) 2- | -CH(CH 3)- | -N(R 9)- | -C(O)- |
| 12 | -S(O) 2- | -CH(CH 3)- | -N(R 9)- | -S(O) 2- |
| 13 | -S(O) 2- | -C(CH 3) 2- | -N(R 9)- | -C(O)- |
| 14 | -S(O) 2- | -C(CH 3) 2- | -N(R 9)- | -S(O) 2- |
| 15 | -S(O) 2- | -CH 2CH 2- | -N(R 9)- | -C(O)- |
| 16 | -S(O) 2- | -CH 2CH 2- | -N(R 9)- | -S(O) 2- |
Linker-W-X
1-X
2The other example of-Y-is described in the following table:
| Numbering | W | X 1 | X 2 | Y |
| 1 | -C(O)- | -CH(CH 3)- | -NH- | -C(O)- |
In the situation of the linker of on the next-door neighbour, describing in the table, R
1Especially cycloalkyl (for example cyclopropyl), and can be unsubstituted or by 1,2,3,4 or 5 R
11Replace.
During each is shown in the above, R
9Hydrogen or be selected from C normally
1-6Alkyl (C for example
1, C
2, C
3Or C
4Alkyl) ,-(CH
2)
k-carbocylic radical and-(CH
2)
k-heterocyclic radical, it is optional separately by 1,2,3,4 or 5 R
11Replace.Specifically ,-N (R
9)-can be-NH-or-N (CH
3)-.
When in each table, mentioning C
1-6Alkylidene group (for example-CH
2-,-CH (CH
3)-,-C (CH
3)
2-or-CH
2CH
2-), when cycloalkylidene (for example cyclopropylidene) or arylidene (for example phenylene), they can be by 1,2,3,4 or 5 R
11Replace, more generally be unsubstituted or replaced by 1 or 2 substituting group, described substituting group is selected from hydroxyl, amino, halogen (for example fluorine or chlorine), optional by 1,2,3,4 or 5 R
12The C that replaces
1-6Alkyl (C for example
1, C
2, C
3Or C
4Alkyl) and optional by 1,2,3,4 or 5 R
12The arylidene (for example phenylene) that replaces, wherein R
12For example be-C (O) NH
2And, when mentioning C
1-6During alkylidene group, it can be by C
3-6Inferior carbocylic radical (for example cyclopropylidene) is replaced.When mentioning cyclopropylidene, can think that it contains atom in 1 or 2 chain, contain atom in 1 chain usually.
Be wherein X mentioned above in one embodiment
1Or X
2Be alkylidene group or arylidene, and X wherein
1Or X
2By 1,2,3,4 or 5 R
11, preferred 1 or 2 R
11The compound that replaces.R
11Substituting group preferably is independently selected from tap bolt group, C
1-6Alkyl ,-O-C
1-6Alkyl ,-NH-C (O)-(C
1-6Alkyl), phenyl, benzyl, hydroxyl, halogen, amino, wherein alkyl group optional by amino, hydroxyl ,-C (O)-N (C
1-6Alkyl) (C
1-6Alkyl) ,-C (O)-NH (C
1-6Alkyl) ,-C (O)-NH
2, (C
1-6Alkyl) or halogen replace.
Y is-N (R therein
9)-an embodiment of above-claimed cpd in, R
1And R
9Be joined together to form optional by 1,2,3,4 or 5 R
115 or 6 yuan of heterocyclic radicals that replace.5 or 6 yuan of heterocyclic radicals of this formation for example are 1-methyl-imidazolidines-2,4-diketone, imidazolidine-2,4-diketone, thiazolidine-2,4-diketone, tetramethyleneimine-2,5-diketone or pyrrolidyl-2-oxo.
Shown in below the embodiment of The compounds of this invention comprises those.Certainly should be appreciated that in due course each compound can exist with free cpds, acid or base addition salt or prodrug forms.When showing that nitrogen-atoms only forms two keys, it represents NH usually.
Other The compounds of this invention comprises:
The compounds of this invention can exist with the form of pharmacy acceptable salt.The pharmacy acceptable salt of present disclosure can be synthetic by the conventional chemical method by the parent compound that contains alkalescence or acidic-group.Usually, the suitable alkali of compound that this type of salt can be by making free acid or alkali form and stoichiometric quantity or acid are reacted in water or organic solvent or both mixtures and are prepared; Usually, non-aqueous media such as ether, ethyl acetate, ethanol, Virahol or acetonitrile are preferred.The catalogue of suitable salt is referring to Remington ' s Pharmaceutical Sciences, and the 17th edition, Mack press (Mack Publishing Company), Easton, Pa., US, is hereby incorporated by its disclosure by 1985,1418 pages; Also referring to people such as Stahl, editor, " pharmaceutical salts character, selection and purposes handbook (Handbook of Pharmaceutical Salts Properties Selection and Use) ", Verlag Helvetica Chimica Acta and Wiley-VCH, 2002.
Therefore, present disclosure also comprises the pharmacy acceptable salt of disclosed compound, and wherein parent compound is modified to its acid or alkali salt.For example, conventional non-toxic salt or the quaternary ammonium salt that forms by inorganic or organic acid or alkali.The example of this type of acid salt comprises acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, Citrate trianion, camphorate, camsilate, cyclopentane propionate, digluconate, dodecyl sulfate, esilate, fumarate, gluceptate, glycerophosphate, Hemisulphate, enanthate, hexanoate, hydrochloride, hydrobromate, hydriodate, the 2-isethionate, lactic acid salt, maleate, mesylate, the 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectate (pectinate), persulphate, 3-phenylpropionic acid salt, picrate, Pivalate, propionic salt, succinate, tartrate, thiocyanate-, tosylate and undecane hydrochlorate.Alkali salt comprise ammonium salt, an alkali metal salt for example sodium and sylvite, alkaline earth salt for example calcium and magnesium salts, the salt that becomes with organic bases for example dicyclohexyl amine salt, N-methyl D-glucosamine with amino acid salt of becoming of arginine, Methionin etc. for example.And alkaline nitrogen-containing group can be quaternized with following material: elementary alkyl halide, for example methyl, ethyl, propyl group and butyl halogenide, bromide and iodide; Dialkylsulfates is as dimethyl, diethyl, dibutyl and diamyl sulfuric ester; Long-chain halogenide, for example decyl, lauryl, myristyl and octadecyl chlorination thing, bromide and iodide; Aralkyl halide is as benzyl and styroyl bromination thing; Or the like.
The present invention includes the prodrug of active drug substance of the present invention; protected or the derivatize of wherein one or more functional groups for example; but can be converted into this functional group in vivo; as in the situation of the ester of carboxylic acid, can being converted into free acid in vivo, or in the situation of the amine of protection, can be converted into the free amino group.As used herein, the compound of parent compound particularly represented for example to be converted into fast in vivo by hydrolysis in blood in term " prodrug ".Discuss fully and be provided at T.Higuchi and V.Stella, prodrug (Pro-drugs as Novel Delivery Systems) as new delivery system, A.C.S. academic discussion is from printing the 14th volume (Vol.14 of the A.C.S.Symposium Series), Edward B.Roche, the editor, bioreversible carrier in the medicinal design (BioreversibleCarriers in Drug Design), American Pharmaceutical Association andPergamon Press, 1987; H Bundgaard, editor, the design of prodrug (Design ofProdrugs), Elsevier, 1985; And Judkins, wait the people. synthesising communication (Synthetic Communications), 26 (23), 4351-4367 (1996) introduces above-mentioned each document in literary composition as a reference.
Therefore, prodrug comprises the medicine that contains the functional group that is changed into its reversible derivatization thing.Usually, this type of prodrug is converted into active medicine by hydrolysis.The example that can mention is as follows:
Functional group reversible derivatization thing
Carboxylicesters comprises for example acyloxy alkyl ester; Acid amides
Alcohol ester comprises for example sulfuric ester and phosphoric acid ester and carboxylic acid
Ester
Amine amide, carbamate, imines, enamine
Carbonyl (aldehyde, ketone) imines, oxime, acetal/ketal, enol ester, oxazolidine
And thiazolidine
Prodrug also comprises the compound that can change active medicine by oxidation or reduction reaction into.The example that can mention is:
Oxidized activating
● N-and O-dealkylation
● oxidative deamination
● the N-oxidation
● epoxidation
Reduction activation
● the azo reduction
● the sulfoxide reduction
● the disulphide reduction
● the biological reducing alkylation
● nitroreduction
What also can mention for the metabolism activation of prodrug is Nucleotide activation, phosphorylation activation and decarboxylation activation.For out of Memory, referring to " medicinal design and pharmaceutically-active organic chemistry (The OrganicChemistry of Drug Design and Drug Action) " R B Silverman (the 8th chapter particularly, the 497-546 page or leaf), be introduced in the literary composition as a reference.
The use of blocking group is detailed to be described in " blocking group in the organic chemistry (Protectivegroups in Organic Chemistry) ", edit by J W F McOmie, PlenumPress (1973), " blocking group in the organic synthesis (Protective groups in OrganicSynthesis); the 2nd edition, T W Greene ﹠amp; P G M Wutz, Wiley-Interscience (1991).
Therefore, may not have pharmacologically active although it will be appreciated by those skilled in the art that the derivative of protection of the compound of present disclosure, they are parenteral or oral administration for example, and metabolism generates the The compounds of this invention of pharmacologically active in vivo thereafter.Therefore, this analog derivative is the example of " prodrug ".All prodrugs of described compound are included in the scope of present disclosure.
Some groups of mentioning in the literary composition (especially contain heteroatoms and conjugated link(age) those) can exist with tautomeric form, and all these tautomers are included in the scope of present disclosure.More generally, many materials can exist with equilibrium state, for example in organic acid and their the anionic situation of pairing; Comprise its all equilibrium forms when therefore, mentioning material in the literary composition.
The compound of present disclosure can also contain one or more unsymmetrical carbons, and therefore may show optically-active and/or diastereo-isomerism.All diastereomers can adopt routine techniques (for example chromatography or fractional crystallization) to separate.Can adopt racemic mixture or other mixture of routine (for example fractional crystallization or HPLC) technology separating compound, separate obtaining various steric isomers.Perhaps, required optical isomer can followingly obtain: suitable optically active starting raw material is reacted under the condition that does not cause racemization or epimerization; Or for example use homochiral acid derivatize, use conventional means (for example HPLC, silica gel chromatography) to separate the diastereomer derivative then.All steric isomers are included in the scope of present disclosure.When disclosing single enantiomer or diastereomer, present disclosure also comprises another enantiomer or diastereomer, and racemoid; Thus, concrete appellation is at specific compound listed in the literary composition.As mentioned above, group-N (R
2) (R
3) three-dimensional chemical configuration of the carbon atom that connected can be (R) or (S), especially (R).
Can also there be geometrical isomer in the compound of present disclosure.Present disclosure relates to by the various geometrical isomers of the substituent arrangement generation that centers on carbon-to-carbon double bond and their mixture, and these isomer are appointed as Z or E configuration, wherein the homonymy of substituting group at carbon-to-carbon double bond represented in term " Z ", and term " E " expression substituting group is at the offside of carbon-to-carbon double bond.
Therefore, present disclosure comprises all variant forms of defined compound, other variant and their tautomer and the substrate of for example any tautomer or any pharmacy acceptable salt, ester, acid or the compound that defines, it can directly or indirectly provide compound as defined above once administration, the material that perhaps provides compound therewith to exist with equilibrium state.
Synthetic
By graphic extension, The compounds of this invention can be according to following flow preparation, and wherein the intermediate of flow process 1 demonstration racemic object form is synthetic; Synthesizing of the The compounds of this invention of flow process 2-4 demonstration (S) form, and the compound of flow process 5 and 6 demonstration (R) forms is synthetic.R
x, R
yAnd R
zEach can be any suitable group.For example, R
xAnd R
yCan be respectively methyl and benzyl, and-N (R
z)
2Can form the phthalimido group.
Flow process 1
Flow process 2
Flow process 3
Flow process 4
Flow process 5
Flow process 6
Should be appreciated that the method that describes in detail above only is used to illustrate the present invention, and should not be construed as limiting the invention.Utilization well known to a person skilled in the art that the method for similar or similar reagent and/or condition also can be used to obtain compound of the present invention.
The mixture of any end product that obtains or intermediate can be separated into pure end product or intermediate with known method according to the physicochemical property difference of component, for example separates by chromatography, distillation, fractional crystallization or by forming salt (if in this case for suitable or feasible).
Administration and pharmaceutical preparation
The compounds of this invention is usually by oral, intravenously, subcutaneous, cheek, rectum, skin, nose, tracheae, segmental bronchus administration, by any other parenteral approach as oral cavity or nasal mist administration or pass through inhalation.Compound can be with the pharmaceutical dosage forms administration in pharmaceutically acceptable formulation, and described pharmaceutical preparation comprises prodrug or is the active compound of free cpds or acid of for example pharmaceutically acceptable non-toxicity organic or inorganic or base addition salt.According to illness to be treated and patient and route of administration, composition can be with the various dose administration.
Therefore, usually, medical compounds of the present invention can be oral or parenteral (" parenteral " refers to comprise intravenously, intramuscular, intraperitoneal as used herein, breastbone is interior, subcutaneous and the administering mode of intra-articular injection and infusion) be administered to the host, to obtain the proteolytic enzyme restraining effect.Than large animal for example under people's the situation, compound can be individually dosed or with pharmaceutically acceptable thinner, vehicle or carrier as the composition administration.
The actual dose level of the activeconstituents in the pharmaceutical composition of the present invention can change, to obtain concrete patient, composition and administering mode are reached the amount of the active compound of expection treatment response.The dosage level of choosing will depend on severity and the patient's to be treated situation and the previous medical history of the activity, route of administration of particular compound, illness to be treated.But, expect that to be lower than to reach the required level of curative effect begins to give compound, and increase dosage gradually that this is in the scope that those skilled in the art understand up to reaching desired effects.
In treatment, prevention, control, improve or reduce in the risk of the illness that needs to suppress the DPP-IV enzymic activity, suitable dosage level is generally the about 0.01-500mg of every kg weight in patients every day, it can be with single dose or multiple dose administration.Preferably, dosage level is that every day about 0.1 is to about 250mg/kg; More preferably every day about 0.5 is to about 100mg/kg.Suitable dosage level can be every day about 0.01 to 250mg/kg, every day about 0.05 to 100mg/kg or every day about 0.1 to 50mg/kg.In this scope, dosage can be every day 0.05-0.5,0.5-5 or 5-50mg/kg.For oral administration, composition preferably offers patient to be treated with tablet form, described tablet contains 1.0 to the 1000mg activeconstituentss that are useful on the dosage of regulating symptom, and particularly 1.0,5.0,10.0,15.0,20.0,25.0,50.0,75.0,100.0,150.0,200.0,250.0,300.0,400.0,500.0,600.0,750.0,800.0,900.0 and the 1000.0mg activeconstituents.Compound can be with the scheme administration of every day 1-4 time, preferred every day 1 or 2 times.Dosage can be adjusted so that the optimal treatment response to be provided.
Another aspect of the present invention provides the pharmaceutical composition that comprises The compounds of this invention and pharmaceutically acceptable auxiliary, diluent or carrier.
The pharmaceutical composition of the present invention that is used for parenteral injection suitably comprises pharmaceutically acceptable aseptic moisture or non-aqueous solution agent, dispersion agent, suspensoid or emulsion and is used for before being about to use reconstruct in the sterilized powder of aseptic parenteral solution or dispersion.Suitable water-based and nonaqueous carrier, thinner, solvent or solvent comprise for example ethyl oleate of water, ethanol, polyvalent alcohol (for example glycerine, propylene glycol, polyoxyethylene glycol etc.) and their suitable mixture, vegetables oil (for example sweet oil) and injectable organosilane ester.Suitable flowability can be for example by use coating material for example Yelkin TTS, in the situation of dispersion agent by keeping required granular size and by using tensio-active agent to be maintained.
These compositions can also contain auxiliary for example sanitas, wetting agent, emulsifying agent and dispersion agent.Can for example p-Hydroxybenzoate, butylene-chlorohydrin or phenol Sorbic Acid be guaranteed the effect of prophylaxis of microbial by introducing various antiseptic-germicides and anti-mycotic agent.Also may need to comprise isotonic agent for example sugar or sodium-chlor.Prolonging the injectable drug form that absorbs can be by introducing material (for example aluminum monostearate and the gelatin) preparation that delay absorbs.
In some cases, for the effect of prolong drug, the absorption of the medicine of need slow down subcutaneous or intramuscularly.This can have the liquid suspension realization of the crystal or the amorphous substance of poorly water soluble by use.Thereby the speed of drug absorption depends on its dissolution rate, so it may depend on crystallographic dimension and crystal formation.Perhaps, the medicament forms of the parenteral admin that postpone to absorb is by with medicine dissolution or be suspended in the oiliness solvent and realize.
The injectable long-acting dosage form by form medicine biodegradable polymer for example the micro-capsule matrix in the polylactic acid-polyglycolic acid lactide suitably prepare.According to the character of the ratio of medicine and polymkeric substance and used particular polymers, speed that can control drug release.The example of other biodegradable polymer comprises poly-(ortho ester) and poly-(acid anhydrides).The long-acting injectable preparation can also prepare by medicine being wrapped in liposome compatible with bodily tissue or the micro emulsion.Described injectable formulation can be sterilized: for example keep somewhere strainer by bacterium and filter, or disinfectant sneaked in the sterile solid form composition, described sterile solid form composition can dissolve before being about to use or be dispersed in sterilized water or other sterile injectable medium.
The solid dosage of oral administration comprises capsule, tablet, pill, powder and granule.In this type of solid dosage, active compound usually with at least a inertia, pharmaceutically acceptable vehicle or carrier for example Trisodium Citrate or Lin Suanergai, and/or one or more following materials mix: a) weighting agent or supplement, for example starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid; B) tackiness agent, for example carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; C) wetting agent, for example glycerine; D) disintegrating agent, for example agar, lime carbonate, potato or tapioca (flour), Lalgine, some silicate and yellow soda ash; E) solution retarding agent, for example paraffin; F) absorption enhancer, for example quaternary ammonium compound; G) wetting agent, for example hexadecanol and glyceryl monostearate; H) absorption agent, for example kaolin and soap clay; And i) lubricant, for example talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate and their mixture.In capsule, tablet and pill situation, described formulation can also comprise buffer reagent.The solids composition of similar type can also be as the weighting agent of soft hard-filled gelatin capsule, and it for example adopts the vehicle as lactose and high molecular weight polyethylene glycol.
Suitably, oral preparations contains the stripping auxiliary agent.The stripping auxiliary agent is not limited by its kind, as long as it is pharmaceutically acceptable.Example comprises nonionogenic tenside, for example the sucrose fatty ester class, the glycerol fatty acid ester class, sorbitan fatty acid esters class (for example sorbitan trioleate), polyoxyethylene glycol, polyoxyethylene hydrogenated castor oil, the polyoxyethylene sorbitan fatty acid esters class, the Voranol EP 2001 class, the methoxy polyoxyethylene alkyl ether, the polyoxyethylene alkyl phenyl ether class, the cithrol class, the polyoxyethylene alkyl amine class, the polyoxyethylene alkyl thioether class, poloxalkol, polyoxyethylene glycerol fatty acid ester class, the pentaerythritol fatty ester class, the propylene glycol fatty acid monoester, polyoxyethylene propylene glycol fatty acid monoester, the Polyoxyethylene Sorbitol Fatty Acid Esters class, fatty acid alkyl oleoyl amine and alkyl amine oxide; Cholic acid and its salt (for example Chenodiol, cholic acid, Deoxycholic Acid, dehydrocholic acid and its salt and glycine thereof or taurine conjugate); Ionogenic surfactant, for example soap of sodium lauryl sulphate, fatty acid soaps, alkylsulfonate, alkylphosphonic, ether phosphate, basic aminoacids, trolamine soap and alkyl quaternary ammonium salts; And amphoterics, for example trimethyl-glycine and aminocarboxylate.
Tablet, sugar-coat agent, capsule, pill and granule can for example enteric coating and known other dressing of field of pharmaceutical preparations be prepared with dressing and shell.They can be chosen wantonly and contain opalizer, and can also be only or preferably in a part of enteron aisle and/or with the composition of delayed mode release of active ingredients.The example of embedding component comprises polymeric material and wax.
Active compound is all right, if suitably, be present in the microencapsulation form with one or more above-mentioned vehicle.
Active compound can be the micronization form, and for example it can be micronized.
The liquid dosage form of oral administration comprises pharmaceutically acceptable emulsion, solution, suspensoid, syrup and elixir.Remove sub-active ingredient beyond the region of objective existence, liquid dosage form can contain the normally used inert diluent in this area for example water or other solvent; Solubilizing agent and emulsifying agent, for example ethanol, Virahol, ethyl-carbonate, ethyl acetate, benzylalcohol, peruscabin, propylene glycol, 1,3 butylene glycol, dimethyl formamide, oils (particularly Oleum Gossypii semen, Peanut oil, Semen Maydis oil, embryo oil, sweet oil, Viscotrol C and sesame oil), glycerine, tetrahydrofurfuryl alcohol, polyethylene glycols and the fatty acid ester of sorbitan and their mixture.Except inert diluent, above-mentioned oral compositions can also comprise auxiliary, for example wetting agent, emulsifying agent and suspending agent, sweeting agent, correctives and perfume compound.Except the active ingredient beyond the region of objective existence, suspensoid can contain suspending agent for example isooctadecanol class, polyoxyethylene sorbitol and sorbitan ester class, Microcrystalline Cellulose, inclined to one side aluminium hydroxide (aluminum metahydroxide), soap clay, agar and the tragacanth gum and their mixture of ethoxylation.
The composition that is used for rectum or vagina administration is suppository preferably, it can be by for example theobroma oil, polyoxyethylene glycol or suppository wax are mixed and prepared with The compounds of this invention and suitable non-irritating excipient or carrier, it at room temperature is a solid, but be liquid under body temperature, so it melt in rectum or vaginal canal and release of active compounds.
The compounds of this invention can also be with the liposome form administration.As well known in the art, liposome is usually derived from phospholipid or other liquid substance.Liposome forms by the aqua liquid that is dispersed in the single or multiple lift in the water-bearing media is brilliant.Can form any non-toxicity of liposome, physiologically acceptable and metabolizable lipid can use.Except The compounds of this invention, the present composition of liposome form can comprise stablizer, sanitas, vehicle etc.Preferred lipid is natural and synthetic phospholipid and phosphatidylcholine class (Yelkin TTS class).The method that forms liposome is well known in the art, for example sees Prescott, editor, the method in the cytobiology (Methods in Cell Biology), XIV volume, academic press (Academic Press), New York, N.Y. (1976), 33 pages.
The formulation of the topical of The compounds of this invention comprises powder, sprays, ointment and inhalation.Active compound is mixed with the sanitas of pharmaceutically acceptable carrier and any needs, the propellent that buffer reagent maybe may need under aseptic condition.Ophthalmic preparation, Eye ointments, powder and solution are also thought within the scope of the invention.
The compounds of this invention can be activity and hypotoxicity Orally active, that have quick acting, and this is favourable.
The compounds of this invention may have following advantage: compare with the prior art compound known, they have stronger effectiveness, lower toxicity, the effect of longer time, wideer field of activity, higher tiring, produce side effect still less, easier absorption, or have other useful pharmacological properties.
Combination therapy
The compounds of this invention can with one or more other therapeutic activity agent Combined Preparation.Therefore, the invention provides the pharmaceutical composition that comprises other promoting agent.The present invention also provides the product that comprises The compounds of this invention and promoting agent, its be in treatment simultaneously, respectively or the combination preparation that uses successively.
Particularly, composition of the present invention or product can also comprise the therapeutic activity agent, and it is selected from antidiabetic, hypolipidemic, anti-obesity or appetite stimulator, antihypertensive drug, HDL-dose, cholesterol absorption conditioning agent, Apo-A1 analogue and stand-in, thrombin inhibitors, aldosterone inhibitor, anticoagulant, oestrogenic hormon, testosterone, selective estrogen receptor modulators, SARM, chemotherapeutics and 5-HT
3Or 5-HT
4Receptor modulators; Or its pharmacy acceptable salt or prodrug.
The example of antidiabetic comprises Regular Insulin, insulin derivates and stand-in; Regular Insulin succagoga, for example sulfonylurea (for example Glipizide, Glyburide or or Ya Moli); Pancreotropic hormone sulfonylurea receptors ligand, for example meglitinides (for example nateglinide or repaglinide); Insulin sensitizer, for example Protein-tyrosine-phosphatase-1B (PTP-1B) inhibitor (for example PTP-112); GSK3 (glycogen synthase kinase-3) inhibitor, for example SB-517955, SB-4195052, SB-216763, NN-57-05441 or NN-57-05445; RXR part, for example GW-0791 or AGN-194204; Sodium dependent glucose cotransporter inhibitor, for example T-1095; Glycogen phosphorylase A inhibitor, for example BAY R3401; Biguanides, for example N1,N1-Dimethylbiguanide; Alpha-glucosidase inhibitor, for example acarbose; GLP-1 (glucagon-like-peptide-1), GLP-1 analogue and stand-in, for example exendin-4; DPPIV (DPP IV) inhibitor, for example DPP728, LAF237 (Vildagliptin), MK-0431, Sha Gelieting or GSK23A; The AGE clastogen; With the thiazolidone analog derivative, lattice row ketone for example, pioglitazone, rosiglitazone or (R)-1-{4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole-4-ylmethoxy]-benzenesulfonyl }-2,3-dihydro-1H-indole-2-carboxylic acid (compound 4 of WO03/043985 embodiment 19) or Fei Gelie ketone type ppar agonist (for example GI-262570); Or its pharmacy acceptable salt or prodrug.
The example of hypolipidemic comprises 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor, for example lovastatin, pitavastatin, Simvastatin, Pravastatin, Cerivastatin, mevastatin, Wei Luotating (velostatin), fluvastatin, Dalvastatin, atorvastatin, superstatin or rivastatin (rivastatin); Squalene synthase inhibitor; FXR (farnesol X acceptor) part; LXR (liver X receptor) part; Colestyramine; The special class of shellfish; Nicotinic acid; And acetylsalicylic acid; Or its pharmacy acceptable salt or prodrug.
The example of anti-obesity/appetite stimulator comprises phentermine, Leptin, bromocriptine, dexamphetamine, Amphetamine, Phenfluoramine, dexfenfluramine, sibutramine, orlistat, dexfenfluramine, Mazindol, phentermine, phendimetrazine, Diethylpropion, fluoxetine, Bupropion, topiramate, Diethylpropion, Benzphetamine, Phenylpropanolamine or ecopipam, ephedrine, pseudoephedrine and cannabinoid receptor antagonists, or its pharmacy acceptable salt or prodrug.
The example of antihypertensive drug comprises loop diuretic, for example Ethacrynic Acid, Furosemide or torsemide; Hydragog(ue), thiazides derivative for example, chlorothiazide (chlorithiazide), hydrochlorothiazide or guanamprazine; Angiotensin-converting enzyme (ACE) inhibitor, for example benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril (perinodopril), quinapril, Ramipril or Trolapril; Na-K-ATP enzyme membrane pump inhibitor, for example digoxin; Neutral endopeptidase (NEP) inhibitor; For example thiorphan, terteo-thiorphan or SQ29072; ECE inhibitor, for example SLV306; ACE/NEP double inhibitor, for example omapatrilat, Sampatrilat or Fasidotril; Angiotensin II antagonist, for example Candesartan, Eprosartan, irbesartan, losartan, telmisartan or valsartan; Renin inhibitor, for example aliskiren, terlakiren, ditekiren, RO-66-1132 or RO-66-1168; B-adrenergic receptor retarding agent, for example acebutolol, atenolol USP 23, betaxolol, bisoprolol, metoprolol, nadolol, Proprasylyte, sotalol or timolol; Inotropic agent, for example digoxin, dobutamine or milrinone; Calcium channel blocker, for example amlodipine, Bepridil, diltiazem
, felodipine, nicardipine, nimodipine, nifedipine, nisoldipine or verapamil; The aldosterone receptor antagonist; With the aldosterone synthase inhibitor; Or its pharmacy acceptable salt or prodrug.
The example of cholesterol absorption conditioning agent comprises
And KT6-971, or its pharmacy acceptable salt or prodrug.
The example of aldosterone inhibitor comprises Anastrozole (anastrazole), fadrozole (fadrazole) and eplerenone, or its pharmacy acceptable salt or prodrug.
The example of anticoagulant comprises acetylsalicylic acid or SR-25990C, or its pharmacy acceptable salt or prodrug.
The example of chemotherapeutics comprises the compound that reduces protease activity, pdgf receptor tyrosine kinase inhibitor (for example imatinib or 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide) for example, or its pharmacy acceptable salt or prodrug.
5-HT
3Or 5-HT
4The example of receptor modulators comprises Tegaserod, Tegaserod dimaleate, cisapride or cilansetron, or its pharmacy acceptable salt or prodrug.
The weight ratio of The compounds of this invention and other activeconstituents can change, and depends on the effective dose of each composition.Usually, can use separately effective dose.Therefore, for example, fashionable when The compounds of this invention and another active groups, the weight ratio of The compounds of this invention and another promoting agent is generally about 1000:1 to about 1:1000, preferred about 200:1 about 1:200 extremely.
The combined prod of The compounds of this invention and other activeconstituents but in each situation, should use each activeconstituents of effective dose usually also in above-mentioned scope.
In this type of combined prod, The compounds of this invention and other promoting agent can be distinguished or administration simultaneously.In addition, a kind of administration of composition can be before other promoting agent of administration, simultaneously or carry out afterwards.
Purposes
The compounds of this invention can be used for the treatment of numerous disease and illness.
Particularly, The compounds of this invention can be used for the treatment of or preventing disease or illness, and described disease or illness are selected from non-insulin-dependent diabetes mellitus (NIDDM), sacroiliitis, fat, allograft is transplanted, osteoporosis, in heart failure, impaired glucose metabolism or glucose tolerance reduce, neurodegenerative disease (for example Alzheimer or Parkinson's disease), cardiovascular or kidney disease (diabetic cardiomyopathy for example, a left side or right ventricular hypertrophy, the hypertrophy medial thickness of artery and/or great vessels, mesentery vascular system hypertrophy or glomerular mesangium (mesanglial) hypertrophy), neurodegenerative disorders or cognitive disorder, hyperglycemia, insulin resistant, lipid disorders (lipid disorders), hyperlipemia, hyperlipidaemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL level, atherosclerosis, vascular restenosis, irritable bowel syndrome, inflammatory bowel disease (for example Crohn disease or ulcerative colitis), pancreatitis, retinopathy, ephrosis, neuropathy, X syndrome, ovarian androgens increase disease (polycystic ovarian syndrome), diabetes B, growth hormone deficiency, neutrophilic granulocytopenia, the neurone illness, metastases, benign prostatauxe, gingivitis, hypertension and osteoporosis.
Described compound can also be used to produce calmness or angst resistance effect, the alienation of minimizing postoperative changes or to stress the hormone response, reduce mortality ratio and sickness rate, adjusting hyperlipidaemia or associated conditions after the myocardial infarction; With reduction VLDL, LDL or Lp (a) level.
Embodiment
Following examples are used to illustrate the present invention.
The term that uses among the embodiment:
ACN: acetonitrile
HPLC: high performance liquid chromatography
Cbz: carbobenzoxy-(Cbz)
Min: minute
H: hour
Intermediate A 1 and A2
Intermediate A 1 and A2 prepare according to flow process A:
Flow process A
A) 3-oxo-8-aza-bicyclo [3.2.1] octane-8-benzyl formate
To tropinone (20g, in toluene 142mmol) (600mL) solution, add chloroformic acid benzyl ester (42.2 mL, 284mmol) and K
2CO
3(118mg, 0.853mmol), and with the solution backflow stirring 16h that obtains.Behind the evaporating solvent, with residue methylene dichloride/saturated NaHCO
3The aqueous solution is handled, and with the organic phase drying, filters and evaporation, obtains yellow oil.
MS：260[M+H]
+
TLC, Rf (cyclohexane/ethyl acetate 1/1)=0.7.
B) 3-[1-methoxyl group-methylene radical]-8-aza-bicyclo [3.2.1] octane-8-benzyl formate
Under-40 ℃, to chlorination methoxymethyl triphenyl phosphonium (46.6g, in tetrahydrofuran (THF) 133mmol) (900mL) solution, drip the tetrahydrofuran (THF) (2M that adds two (trimethyl silicon based) sodium amides, 67mL, 130mmol) solution stirs 1h with the red solution that obtains down at-40 ℃ then, and stirred 30 minutes down at 0 ℃.After being cooled to-40 ℃, oxo-(27g, tetrahydrofuran (THF) 83mmol) (100mL) solution rises to 0 ℃ with the mixture that obtains to 8-aza-bicyclo [3.2.1] octane-8-benzyl formate, and stirs 30 minutes to add 3-.It is used saturated NH
4The cancellation of the Cl aqueous solution is also used saturated NaHCO with dichloromethane extraction
3Solution washing.With the organic phase drying, filtration and evaporation obtain residue, and (eluent: cyclohexane/ethyl acetate 100/0 to 7/3) purifying obtains yellow oil by flash chromatography on silica gel with it.
MS：288[M+H]
+
TLC, Rf (cyclohexane/ethyl acetate 1/1)=0.75.
C) 3-outer-formyl radical-8-aza-bicyclo [3.2.1] octane-8-benzyl formate
To 3-[1-methoxyl group-methylene radical]-8-aza-bicyclo [3.2.1] octane-8-benzyl formate (13g, in acetone 40.7mmol) (450mL) and water (50mL) solution, add 37% dense HCl the aqueous solution (0.920mL, 9.4mmol).The mixture that obtains is stirred 24h down at 50 ℃.Behind the evaporating solvent, with residue methylene dichloride/saturated NaHCO
3The aqueous solution is handled, and with the organic phase drying, filtration and evaporation obtain residue, and (eluent: cyclohexane/ethyl acetate 100/0 to 7/3) purifying obtains yellow oil by flash chromatography on silica gel with it.
MS：274[M+H]
+
TLC, Rf (cyclohexane/ethyl acetate 1/1)=0.42.
D) 3-outer-{ [(S)-2-methyl-propane-2-sulfinyl imino-]-methyl }-8-aza-bicyclo [3.2.1] octane-8-benzyl formate
With (S)-2-methyl-2-propane sulfinyl amine (543mg, 4.39mmol), the toluene-4-sulfonic acid pyridine (46mg, 0.183mmol) and MgSO
4(2.21g 18.3mmol) stirs 1h in ethylene dichloride (15mL), and then outside the adding 3--formyl radical-8-aza-bicyclo [3.2.1] octane-8-benzyl formate (1g, ethylene dichloride 3.66mmol) (5mL) solution.The mixture that obtains is stirred 16h down at 50 ℃, its filtration and evaporation are obtained residue, (eluent: cyclohexane/ethyl acetate 100/0 to 50/50) purifying obtains yellow oil by flash chromatography on silica gel with residue.
MS：377[M+H]
+
TLC, Rf (cyclohexane/ethyl acetate 1/1)=0.37.
E) 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-benzyl formate (intermediate A 1); With 3-outer-[(S)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-benzyl formate (intermediate A 2)
(18mg 0.75mmol), adds 2,4,5-trifluoro-benzyl bromine (112mg, ether 0.499mmol) (0.5mL) solution to magnesium chips in the ether that is stirring (0.5mL).After at room temperature stirring 30 minutes; under 0 ℃; with the suspension that obtains join 3-outer-{ [(S)-2-methyl-propane-2-sulfinyl imino-]-methyl }-(179mg is in methylene dichloride 0.333mmol) (1mL) solution for 8-aza-bicyclo [3.2.1] octane-8-benzyl formate.The mixture that obtains is at room temperature stirred 4h, use saturated NH at 0 ℃ then
4The cancellation of the Cl aqueous solution, and use dichloromethane extraction.With the organic phase drying, filtration and evaporation obtain residue, and it is passed through flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate) purifying.
Intermediate A 1:MS:523[M+H]
+
TLC, Rf (cyclohexane/ethyl acetate 1/1)=0.17
Intermediate A 2:MS:523[M+H]
+
TLC, Rf (cyclohexane/ethyl acetate 1/1)=0.12
Intermediate A ' 1 and A ' 2
Intermediate A ' 1 and A ' 2 prepare according to flow process A:
Flow process A '
4-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-benzyl formate (intermediate A 1); And 4-[(S)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-benzyl formate (intermediate A 2)
Title compound is with being similar to the preparation of the described method of flow process A, but with 4-formyl radical-piperidines-1-benzyl formate replace 3-outward-formyl radical-8-aza-bicyclo [3.2.1] octane-8-benzyl formate.
Intermediate A ' 1:MS:497.1[M+H]
+
TLC, Rf (cyclohexane/ethyl acetate 1/1)=0.23
Intermediate A ' 2:MS:497.1[M+H]
+
TLC, Rf (cyclohexane/ethyl acetate 1/1)=0.10
Embodiment B 1:N-(outside the 2-{3--[and (S)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-ethanamide
This compound prepares according to flow process B:
Flow process B
A) 3-outer-[(S)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane
Outside 3--[(S)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-benzyl formate (intermediate A 2; 300mg, in ethyl acetate 0.574mmol) (10mL) solution, adding 10%Pd/C (610mg, 0.57mmol).The mixture that obtains is stirred, and place H
2Under the atmosphere.After stirring 1h, suspension is also evaporated by diatomite filtration, obtain residue, it is passed through preparation HPLC (Column Interchrom C18 ODB10 μ m 28 * 250, gradient: 0-2.5min 5%ACN, 2.5-25.5min5-100% ACN, 25.5-30min 100% CAN) purifying, obtain title compound.
MS：389[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.06 min.
B) N-(2-{3-is outer-[(S)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl-ethyl)-phthalic imidine
Outside 3--[(S)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane (540mg; 1.2mmol) methylene dichloride/1M NaOH (1/1; 5mL) in the mixture; (1.101g 3.59mmol), stirs 16h with the mixture that obtains down at 50 ℃ then to add 2-phthaloyl imino ethyl sulfonyl chloride.It is used dichloromethane extraction, and dry and evaporation obtains white solid with organic phase.
MS：626[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.44min.
C) 2-{3-outer-[(S)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl-ethylamine
To N-(outside the 2-{3--[(S)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-phthalic imidine (100mg; 0.160mmol) ethanol (2mL) mixture in; add hydrazine monohydrate (0.396mL; 8mmol), and with the solution that obtains at room temperature stir 12h.With methylene dichloride and saturated NaHCO
3Behind the aqueous solution extraction, the dry also evaporate to dryness of organic phase is obtained residue, it is passed through preparation HPLC (Column Waters C18 ODB 5 μ m 19 * 50, gradient: 0-2.5min 5% ACN, 2.5-12.5min 5-100% ACN, 12.5-15min 100% ACN) purifying obtains white solid.
MS 496[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.05min.
D) N-(2-{3-is outer-[(S)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl-ethyl)-ethanamide
Outside 2-{3--[(S)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethylamine (27mg; 0.054mmol) acetate (1mL) mixture in; add aceticanhydride (7.86 μ L; 0.081mmol), and the solution that obtains at room temperature stirred 3h.With methylene dichloride and saturated NaHCO
3Behind the aqueous solution extraction, dry and evaporate to dryness obtains colourless jelly with organic phase.
MS 538[M+H]+
E) N-(2-{3-is outer-[(S)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl-ethyl)-ethanamide
To N-(outside the 2-{3--[(S)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-ethanamide (29.3 mg; 0.545 in dioxane mmol) (3 mL) mixture, add the dioxane solution (2 mL) of 4N HCl.The mixture that obtains is at room temperature stirred 1h.Freezing and freeze-drying obtains white solid with solution.
MS：435[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 0.95min.
Embodiment C 1:N-(outside the 2-{3--[and (S)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-ethanamide
This compound prepares according to flow process C:
Flow process C
A) N-(2-{3-is outer-[(S)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl-2-oxo-ethyl)-phthalic imidine
To N-phthaloyl glycine (291mg; 1.41mmol) acetonitrile (7mL) solution in; add benzotriazole-1-base oxygen base tripyrrole Wan Ji Phosphonium hexafluorophosphate (805mg; 1.54mmol); and the mixture that obtains at room temperature stirred 1h; add then 3-outer-[(S)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane (500mg; 1.29mmol) and triethylamine (720 μ L, acetonitrile 5.16mmol) (5mL) solution.The solution that obtains is at room temperature stirred 16h, and evaporate to dryness, then by preparation HPLC (Column InterchromC18 ODB 10 μ m 28 * 250, gradient: 0-2.5min 5% ACN, 2.5-25.5min 5-100%ACN, 25.5-30min 100% ACN) purifying obtains yellow solid.
MS：576[M+H]+
B) N-(2-{3-is outer-[(S)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl-2-oxo-ethyl)-ethanamide
Title compound is with being similar to Embodiment B 1 described method preparation; but with N-(2-{3-is outer-[(S)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-phthalic imidine replacement N-(outside the 2-{3--[and (S)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-phthalic imidine.
MS：384[M+H]
HPLC (Nucleosil 100-5 C18, and the 10min method (0-1min 10%ACN, 1-6min10-100%ACN, 6-8.5min 100%ACN, 8.5-9min 100-10%ACN, 9-10min10%ACN): 3.28min.
Embodiment C 2: cyclopropane sulfonic acid (outside the 2-{3--[and (S)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-acid amides
This compound also prepares according to flow process C
A) cyclopropane sulfonic acid (2-{3-is outer-[(S)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl-2-oxo-ethyl)-acid amides
Outside 2-{3--[(S)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethylamine (50mg; 0.112mmol) methylene dichloride (1mL) solution in add triethylamine (32 μ L; 0.224mmol) and the cyclopropane SULPHURYL CHLORIDE (14 μ L, 0.134mmol).The solution that obtains is at room temperature stirred 16h, evaporate to dryness then, and by preparation HPLC (Column Waters C18 ODB 5 μ m 19 * 50, gradient: 0-2.5min 5%ACN, 2.5-12.5min 5-100% ACN, 12.5-15min 100% ACN) purifying, obtain colourless jelly.
MS 550[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.17 min.
B) cyclopropane sulfonic acid (2-{3-is outer-[(S)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl-2-oxo-ethyl)-acid amides
To cyclopropane sulfonic acid (outside the 2-{3--[(S)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-acid amides (27mg; 0.049mmol) dioxane (0.5mL) mixture in, add the dioxane solution (0.5mL) of 4N HCl.The mixture that obtains is at room temperature stirred 1h.Freezing and freeze-drying obtains white solid with solution, then by preparation HPLC (Column Waters C18 ODB 5 μ m19 * 50, gradient: 0-2.5min 5%ACN, 2.5-12.5min 5-100%ACN, 12.5-15min100% ACN) purifying, obtain colourless jelly.
MS 446[M+H]+
HPLC (Nucleosil 100-5 C18, and the 10min method (0-1min 10%ACN, 1-6min10-100%ACN, 6-8.5min 100%ACN, 8.5-9min 100-10%ACN, 9-10min10%ACN): 3.5min.
Embodiment D1:5-methyl-pyrazine-2-formic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides
This compound prepares according to flow process D:
Flow process D
A) 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane
Outside 3--[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-benzyl formate (intermediate A 1; 7.74g in ethanol 14.8mmol) (200mL) mixture, (16g 15mmol), stirs the mixture that obtains, and places H to add 10%Pd/C
2Under the atmosphere.After stirring 1h, suspension by diatomite filtration and evaporation, is obtained title compound.
MS：389[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 0.91min.
B) N-(2-{3-is outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl-ethyl)-phthalic imidine
Outside 3--[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane (265mg; 0.68mmol) methylene dichloride/1MNaOH (1/1; 5mL) in the mixture; (577mg 2.05mmol), stirs 16h with the mixture that obtains down at 50 ℃ then to add 2-phthaloyl imino ethyl sulfonyl chloride.It is used dichloromethane extraction, and dry and evaporate to dryness obtains white solid with organic phase.
MS：626[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.25min.
C) 2-{3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl-ethylamine
To N-(outside the 2-{3--[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-phthalic imidine (256mg; 0.409mmol) ethanol (3mL) mixture in; add hydrazine monohydrate (1.01mL; 20.5mmol), and the solution that obtains at room temperature stirred 12h.With methylene dichloride and saturated NaHCO
3Behind the aqueous solution extraction, dry and evaporation obtains colorless oil with organic phase.
MS：496[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 0.95min.
D) 5-methyl-pyrazine-2-formic acid (2-{3-is outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl-ethyl)-acid amides
(18.8mg, in acetonitrile 0.133mmol) (2mL) solution, (75.6mg 0.145mmol), and at room temperature stirs 1h with the mixture that obtains to add benzotriazole-1-base oxygen base tripyrrole Wan Ji Phosphonium hexafluorophosphate to 5-methylpyrazine formic acid.Afterwards; outside the adding 2-{3--[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethylamine (60mg; 0.121) and triethylamine (50.5 μ L; 0.363mmol) acetonitrile solution, and with solution jolting 16h at room temperature.Solution by preparation HPLC (Column Waters C18ODB 5 μ m 19 * 50, gradient: 0-2.5min 5% ACN, 2.5-12.5min 5-100% ACN, 12.5-15min 100%C AN) purifying, is obtained white solid.
MS：616[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.18min.
E) 5-methyl-pyrazine-2-formic acid (2-{3-is outer-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl-ethyl)-acid amides
To 5-methyl-pyrazine-2-formic acid (outside the 2-{3--[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides (48.5mg; 0.0788mmol) dioxane (3mL) mixture in, add the dioxane solution (1mL) of 4N HCl.The mixture that obtains is at room temperature stirred 1h, then by preparation HPLC (Column Waters C18 ODB 5 μ m 19 * 50, gradient: 0-2.5min 5% ACN, 2.5-12.5min 5-100% ACN, 12.5-15min 100%C AN) purifying obtains white solid.MS 513[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 0.95min.
Embodiment D2: cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides
This compound prepares according to flow process D.
A) cyclopropane sulfonic acid (2-{3-is outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl-ethyl)-acid amides
Outside 2-{3--[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethylamine (40mg; 0.078mmol) ethylene dichloride (2mL) solution in; add triethylamine (32.7 μ L; 0.235mmol), 4-dimethylaminopyridine (0.95mg, 0.007mmol) and the cyclopropane SULPHURYL CHLORIDE (16.8 μ L, 0.157mmol).The solution that obtains is at room temperature stirred 2h, and evaporate to dryness obtains title compound then.
MS：600[M+H]+
HPLC (Waters Symmetry C18 3.5 μ m 2.1 * 50mm, and the 6min method (0-3min20-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min20%ACN): 3.28min.
B) cyclopropane sulfonic acid (2-{3-is outer-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl-ethyl)-acid amides
To cyclopropane sulfonic acid (outside the 2-{3--[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides (63mg; 0.102mmol) dioxane (2mL) mixture in, add the dioxane solution (3mL) of 4N HCl.The mixture that obtains is at room temperature stirred 1h.Freezing and freeze-drying obtains white solid with solution, then by preparation HPLC (Column Waters C18 ODB 5 μ m 19 * 50, gradient: 0-2.5min 5% ACN, 2.5-12.5min 5-100% ACN, 12.5-15min 100%ACN) purifying, obtain title compound.
MS：496[M+H]+
HPLC (Waters Symmetry C18 3.5 μ m 2.1 * 50mm, and the 6min method (0-3min5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min5%ACN): 2.56min.
Embodiment D2a: cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-the acid amides maleate
This compound prepares according to flow process Da:
Flow process Da
Under agitation, to ethyl acetate solution (1 molar equivalent of toxilic acid; 0.1M) in, add cyclopropane sulfonic acid (2-{3-is outer-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl-ethyl)-ethyl acetate (1mL) solution of acid amides free alkali (20mg).The mixture that obtains was placed precipitation 1 hour, then its stirring is spent the night.The white suspension that obtains is filtered, and, obtain title compound the solid drying that obtains.
Embodiment D2b: cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides toluene-4-sulfonic acid salt
This compound prepares according to flow process Db:
Flow process Db
Under agitation, to ethyl acetate solution (1 molar equivalent of toluene-4-sulfonic acid; 0.1M) in, add cyclopropane sulfonic acid (2-{3-is outer-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl-ethyl)-ethyl acetate (1mL) solution of acid amides free alkali (50mg).The mixture that obtains was placed precipitation 2 hours, then its stirring is spent the night.The white suspension that obtains is filtered, and, obtain title compound the solid drying that obtains.
Embodiment D3:N-(outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-ethanamide
This compound prepares according to flow process D:
A) N-(2-{3-is outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl-ethyl)-ethanamide
Outside 2-{3--[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethylamine (100mg; 0.202mmol) acetate (2mL) mixture in; add aceticanhydride (29.1 μ L; 0.303mmol), and the solution that obtains at room temperature stirred 3h.With methylene dichloride and saturated NaHCO
3Behind the aqueous solution extraction, dry and evaporate to dryness obtains title compound with organic phase.
MS：538[M+H]+
B) N-(2-{3-is outer-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl-ethyl)-ethanamide
To N-(outside the 2-{3--[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-ethanamide (108mg; 0.199mmol) dioxane (2mL) mixture in, add the dioxane solution (3mL) of 4N HCl.The mixture that obtains is at room temperature stirred 1h.Freezing and freeze-drying obtains white solid with solution, then by preparation HPLC (Column Waters C18 ODB 5 μ m 19 * 50, gradient: 0-2.5min 5% ACN, 2.5-12.5min 5-100% ACN, 12.5-15min 100% ACN) purifying, obtain title compound.
MS：434[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 0.84 min.
Embodiment D3a:N-(outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-the ethanamide maleate
Title compound is with being similar to the described method preparation of embodiment D2a; but with N-(2-{3-is outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-ethanamide replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment D3b:N-(outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-ethanamide toluene-4-sulfonic acid salt
Title compound is with being similar to the described method preparation of embodiment D2b; but with N-(2-{3-is outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-ethanamide replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment D4: dimethylamino sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides
Title compound prepares with being similar to the described method of embodiment D2, but replaces the cyclopropane SULPHURYL CHLORIDE with the dimethylamino SULPHURYL CHLORIDE.
MS：499[M+H]
HPLC (Waters Symmetry C183.5 μ m 2.1 * 50mm, and the 6min method (0-3min20-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min20%ACN): 0.94min.
Embodiment D4a: dimethylamino sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-the acid amides maleate
Title compound is with being similar to the described method preparation of embodiment D2a; but with dimethylamino sulfonic acid (2-{3-is outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment D4b: dimethylamino sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides toluene-4-sulfonic acid salt
Title compound is with being similar to the described method preparation of embodiment D2b; but with dimethylamino sulfonic acid (2-{3-is outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment D5:N-(outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-4-methoxyl group-benzsulfamide
Title compound prepares with being similar to the described method of embodiment D2, but replaces the cyclopropane SULPHURYL CHLORIDE with 4-p-methoxy-phenyl SULPHURYL CHLORIDE.
MS：562[M+H]
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.0min.
Embodiment D5a:N-(outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-4-methoxyl group-benzsulfamide maleate
Title compound is with being similar to the described method preparation of embodiment D2a; but with N-(2-{3-is outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-4-methoxyl group-benzsulfamide replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment D5b:N-(outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-4-methoxyl group-benzsulfamide toluene-4-sulfonic acid salt
Title compound is with being similar to the described method preparation of embodiment D2b; but with N-(2-{3-is outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-4-methoxyl group-benzsulfamide replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment D6: tetrahydropyrans-4-formic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides
Title compound prepares with being similar to the described method of embodiment D1, but replaces 5-methylpyrazine formic acid with tetrahydrochysene-2H-pyrans-4-formic acid.
MS：505[M+H]
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 0.92 min.
Embodiment D7: morpholine-4-sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides
Title compound prepares with being similar to the described method of embodiment D2, but replaces the cyclopropane SULPHURYL CHLORIDE with 4-morpholine SULPHURYL CHLORIDE.
MS：541[M+H]
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.13 min.
Embodiment D8:2-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-ethyl sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides
A) 2-(1; 3-dioxo-1; 3-dihydro-isoindole-2-yl)-ethyl sulfonic acid (outside the 2-{3--[and (R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides
Outside 2-{3--[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethylamine (100mg; 0.202mmol) methylene dichloride/2N NaOH (2mL; 1/1) in the solution; adding 2-phthaloyl imino ethyl sulfonyl chloride (167mg, 0.605mmol).The solution that obtains is stirred 2h down at 50 ℃, and extraction and with the organic phase evaporate to dryness then obtains the crude product compound.It by preparation HPLC (Column Waters C18ODB 5 μ m 19 * 50, gradient: 0-2.5min 5%ACN, 2.5-12.5min 5-100% ACN, 12.5-15min 100% ACN) purifying, is obtained title compound.
MS：734[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.43min.
B) 2-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-ethyl sulfonic acid (2-{3-is outer-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl-ethyl)-acid amides
To 2-(1; 3-dioxo-1; 3-dihydro-isoindole-2-yl)-ethyl sulfonic acid (outside the 2-{3--[and (R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides (49mg; 0.057mmol) dioxane (3mL) solution in, add the dioxane solution (3mL) of 4N HCl.The mixture that obtains is at room temperature stirred 1h.Freezing and freeze-drying obtains white solid with solution, then by preparation HPLC (Column WatersC18 ODB 5 μ m 19 * 50, gradient: 0-2.5min 5%ACN, 2.5-12.5min 5-100%ACN, 12.5-15min 100%ACN) purifying, obtain title compound.
MS：629[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.22min.
Embodiment D9:N-(outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-3-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-propionic acid amide
Title compound prepares with being similar to the described method of embodiment D1, but replaces 5-methylpyrazine formic acid with 2-phthaloyl sub-aminoethyl formic acid.
MS：593[M+H]
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.8min.
Outside the embodiment D10:(2-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-carboxylamine 2-methoxyl group-ethyl ester
Title compound prepares with being similar to the described method of embodiment D8, but replaces 2-phthaloyl imino ethyl sulfonyl chloride with chloroformic acid 2-methoxy ethyl ester.
MS：494[M+H]
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.14 min.
Outside the embodiment D10a:(2-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-carboxylamine 2-methoxyl group-ethyl ester maleate
Title compound is with being similar to the described method preparation of embodiment D2a; but with (outside the 2-{3--[and (R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-carboxylamine 2-methoxyl group-ethyl ester replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Outside the embodiment D10b:(2-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-carboxylamine 2-methoxyl group-ethyl ester toluene-4-sulfonic acid salt
Title compound is with being similar to the described method preparation of embodiment D2b; but with (outside the 2-{3--[and (R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-carboxylamine 2-methoxyl group-ethyl ester replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment D11:N-(outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-4-methoxyl group-benzamide
Title compound prepares with being similar to the described method of embodiment D1, but replaces 5-methylpyrazine formic acid with anisic acid.
MS：526[M+H]
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.18min.
Outside the embodiment D12:(2-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-carboxylamine 1,1-dioxo-thionaphthene-2-base-methyl ester
Title compound is with being similar to the preparation of the described method of embodiment D8, but with chloroformic acid 1,1-dioxo thionaphthene-2-base-methyl ester replacement 2-phthaloyl imino ethyl sulfonyl chloride.
MS：614[M+H]
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.21min.
Outside the embodiment D13:(2-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-carboxylamine ethyl ester
Title compound prepares with being similar to the described method of embodiment D2, but replaces the cyclopropane SULPHURYL CHLORIDE with Vinyl chloroformate.
MS：464[M+H]
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 0.96 min.
Embodiment D14: tetramethyleneimine-1-formic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides
Title compound prepares with being similar to the described method of embodiment D2, but replaces the cyclopropane SULPHURYL CHLORIDE with 1-tetramethyleneimine carbonyl chloro.
MS：489[M+H]
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 0.97min.
Embodiment D15: morpholine-4-formic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides
Title compound prepares with being similar to the described method of embodiment D2, but replaces the cyclopropane SULPHURYL CHLORIDE with 4-morpholine carbonyl chloro.
MS：505[M+H]
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 0.92min.
Embodiment D15a: morpholine-4-formic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-the acid amides maleate
Title compound is with being similar to the described method preparation of embodiment D2a; but with morpholine-4-formic acid (2-{3-is outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment D15b: morpholine-4-formic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides toluene-4-sulfonic acid salt
Title compound is with being similar to the described method preparation of embodiment D2b; but with morpholine-4-formic acid (2-{3-is outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment D16:1-(outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-3-(2-methoxyl group-ethyl)-urea
A) (S)-2-methyl-propane-2--sulfinic acid [(R)-1-(outside the 3--8-{2-[3-(2-methoxyl group-ethyl)-urea groups]-the ethane alkylsulfonyl }-8-aza-bicyclo [3.2.1] oct-3-yl)-2-(2,4,5-three fluoro-phenyl)-ethyl]-acid amides
(29.8 μ L in dimethyl formamide 0.344mmol) (2mL) solution, add 1,1 '-carbonyl dimidazoles (58.6mg) to the 2-methoxyethyl amine.After the stirring at room, outside the adding 2-{3--[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethylamine (180mg, 0.312mmol).The solution that obtains is stirred 3h down at 80 ℃, then by preparation HPLC (Column Waters C18 ODB 5 μ m 19 * 50, gradient: 0-2.5min 5%A CN, 2.5-12.5min 5-100% ACN, 12.5-15min 100% ACN) purifying obtains title compound.
MS：597[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.32min.
B) 1-(2-{3-is outer-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl-ethyl)-3-(2-methoxyl group-ethyl)-urea
To (S)-2-methyl-propane-2--sulfinic acid [(R)-1-(outside the 3--8-{2-[3-(2-methoxyl group-ethyl)-urea groups]-the ethane alkylsulfonyl-8-aza-bicyclo [3.2.1] oct-3-yl)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-acid amides (143mg; 0.206mmol) dioxane (3mL) mixture in, add the dioxane solution (3mL) of 4N HCl.The mixture that obtains is at room temperature stirred 1h.Freezing and freeze-drying obtains white solid with solution, then by preparation HPLC (Column Waters C18 ODB 5 μ m19 * 50, gradient: 0-2.5min 5% ACN, 2.5-12.5min 5-100% ACN, 12.5-15min100% ACN) purifying, obtain title compound.
MS：493[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.12min.
Embodiment D17:2-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-ethyl sulfonic acid (2-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-alkylsulfonyl }-ethyl)-acid amides
Title compound is with being similar to the described method preparation of embodiment D8; but with (S)-2-methyl-propane-2--sulfinic acid [(R)-1-piperidin-4-yl-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-acid amides replace 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane.
MS：603[M+H]
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.17min.
Embodiment D18:N-[2-(outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-the ethyl sulfamyl)-ethyl]-benzamide
A) 2-amino-ethyl sulfonic acid (2-{3-is outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl-ethyl)-acid amides
Title compound is with being similar to the described method preparation of embodiment D1; but with 2-(1; 3-dioxo-1; 3-dihydro-isoindole-2-yl)-ethyl sulfonic acid (outside the 2-{3--[and (R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides replacement N-(outside the 2-{3--[and (R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-phthalic imidine.
MS：603[M+H]
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.22min.
B) N-[2-(2-{3-is outer-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo
[3.2.1] octane-8-alkylsulfonyl }-the ethyl sulfamyl)-ethyl]-benzamide
Title compound is with being similar to the described method preparation of embodiment D1; but with 2-amino-ethyl sulfonic acid (2-{3-is outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl-ethyl)-acid amides replace 2-{3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethylamine, and replace 5-methyl-pyrazine-2-formic acid with phenylformic acid.
MS：601[M+H]
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.16min.
Embodiment D19: oxazole-5-formic acid [2-(outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-the ethyl sulfamyl)-ethyl]-acid amides
Title compound is with being similar to the described method preparation of embodiment D1, and Dan Yong oxazole-5-formic acid replaces 5-methylpyrazine formic acid.
MS：488[M+H]
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.17min.
Embodiment E 1: cyclopropane-carboxylic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-acid amides
This compound prepares according to flow process E:
Flow process E
A) (S)-2-methyl-propane-2--sulfinic acid [(R)-and 1-{3-is outer-8-[2-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-ethanoyl]-8-aza-bicyclo [3.2.1] oct-3-yl }-2-(2,4,5-three fluoro-phenyl)-ethyl]-acid amides
To N-phthaloyl glycine (291mg; 1.41mmol) acetonitrile (7mL) solution in; add benzotriazole-1-base oxygen base tripyrrole Wan Ji Phosphonium hexafluorophosphate (805mg; 1.54mmol); and the mixture that obtains at room temperature stirred 1h; add then 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane (500mg; 1.29mmol) and triethylamine (720 μ L, acetonitrile 5.16mmol) (5mL) solution.The solution that obtains is at room temperature stirred 16h, and evaporate to dryness, then by preparation HPLC (Column InterchromC18 ODB 10 μ m 28 * 250, gradient: 0-2.5min 5% ACN, 2.5-25.5min5-100%ACN, 25.5-30min 100%ACN) purifying, obtain yellow solid.
MS：576[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.22min.
B) (S)-2-methyl-propane-2--sulfinic acid [(R)-and 1-[3-is outer-8-(2-amino-ethanoyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-2-(2,4,5-three fluoro-phenyl)-ethyl]-acid amides
To (S)-2-methyl-propane-2--sulfinic acid [(R)-1-{3-outside-8-[2-(1; 3-dioxo-1; 3-dihydro-isoindole-2-yl)-ethanoyl]-8-aza-bicyclo [3.2.1] oct-3-yl }-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-(300mg in ethanol 0.521mmol) (3.5mL) mixture, adds hydrazine monohydrate (1.3mL to acid amides; 26.05mmol), and the solution that obtains at room temperature stirred 16h.With methylene dichloride and saturated NaHCO
3Behind the aqueous solution extraction, dry and evaporate to dryness obtains white solid with organic phase.
MS：446[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 0.96min.
C) cyclopropane-carboxylic acid (2-{3-is outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl-2-oxo-ethyl)-acid amides
To (S)-2-methyl-propane-2--sulfinic acid [(R)-1-[3-outside-8-(2-amino-ethanoyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-acid amides (50mg; 0.112mmol) methylene dichloride (1mL) solution in; add triethylamine (32 μ L; 0.224mmol) and cyclopropane carbonyl chlorine (14 μ L, 0.134mmol).The solution that obtains is at room temperature stirred 2h, evaporate to dryness then, and by preparation HPLC (Column Waters C18 ODB 5 μ m 19 * 50, gradient: 0-2.5min 5%ACN, 2.5-12.5min 5-100% ACN, 12.5-15min 100% ACN) purifying, obtain white solid.
MS：514[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 2.87min.
D) cyclopropane-carboxylic acid (2-{3-is outer-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl-2-oxo-ethyl)-acid amides
To cyclopropane-carboxylic acid (outside the 2-{3--[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-acid amides (26.4mg; 0.052mmol) dioxane (0.5mL) mixture in, add the dioxane solution (0.5mL) of 4N HCl.The mixture that obtains is at room temperature stirred 1h.Freezing and freeze-drying obtains white solid with solution.
MS：410[M+H]+
HPLC (Nucleosil 100-5 C18, and the 10min method (0-1min 10%ACN, 1-6min10-100%ACN, 6-8.5min 100%ACN, 8.5-9min 100-10%ACN, 9-10min10%ACN): 3.55min.
Embodiment E 1a: cyclopropane-carboxylic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-the acid amides maleate
Title compound is with being similar to the described method preparation of embodiment D2a; but with cyclopropane-carboxylic acid (2-{3-is outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-acid amides replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment E 1b: cyclopropane-carboxylic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-acid amides toluene-4-sulfonic acid salt
Title compound is with being similar to the described method preparation of embodiment D2b; but with cyclopropane-carboxylic acid (2-{3-is outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-acid amides replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment E 2:5-methyl-pyrazine-2-formic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-acid amides
This compound also prepares according to flow process E and with the method that is similar to embodiment D1; but with 2-{3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl-2-oxo-ethylamine replace 2-{3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethylamine.
MS：462[M+H]
HPLC (Nucleosil 100-5 C18, and the 10min method (0-1min 10%ACN, 1-6min10-100%ACN, 6-8.5min 100%ACN, 8.5-9min 100-10%ACN, 9-10min10%ACN): 3.59min.
Embodiment E 3: cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-acid amides
This compound prepares with the method that is similar to embodiment E 1, but replaces cyclopropane carbonyl chlorine with the cyclopropane SULPHURYL CHLORIDE.
MS：446[M+H]
HPLC (Nucleosil 100-5 C18, and the 10min method (0-1min 10%ACN, 1-6min10-100%ACN, 6-8.5min 100%ACN, 8.5-9min 100-10%ACN, 9-10min10%ACN): 3.56min.
Embodiment E 3a: cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-the acid amides maleate
Title compound is with being similar to the described method preparation of embodiment D2a; but with cyclopropane sulfonic acid (2-{3-is outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-acid amides replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment E 3b: cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-acid amides toluene-4-sulfonic acid salt
Title compound is with being similar to the described method preparation of embodiment D2b; but with cyclopropane sulfonic acid (2-{3-is outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-acid amides replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment E 4:N-(outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-ethanamide
A) N-(2-{3-is outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl-2-oxo-ethyl)-ethanamide
Outside 2-{3--[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethylamine (50mg; 0.112mmol) acetate (2mL) mixture in; the adding aceticanhydride (16 μ L, 0.168mmol).And the solution that obtains at room temperature stirred 3h.With methylene dichloride and saturated NaHCO
3Behind the aqueous solution extraction, dry and the evaporate to dryness with organic phase, obtain residue, by preparation HPLC (Column Interchrom C18 ODB 10 μ m28 * 250, gradient: 0-2.5min 5% ACN, 2.5-25.5 min 5-100% ACN, 25.5-30min100% ACN) purifying, obtain colourless jelly.
MS：488[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.09min.
B) N-(2-{3-is outer-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl-2-oxo-ethyl)-ethanamide
To N-(outside the 2-{3--[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-ethanamide (38mg; 0.078mmol) dioxane (0.5mL) mixture in, add the dioxane solution (0.5mL) of 4N HCl.The mixture that obtains is at room temperature stirred 1h.Freezing and freeze-drying obtains white solid with solution, then by preparation HPLC (Column Waters C18 ODB 5 μ m 19 * 50, gradient: 0-2.5min 5%ACN, 2.5-12.5min 5-100%ACN, 12.5-15min 100%ACN) purifying, obtain light yellow solid.
MS 384[M+H]+
HPLC (Nucleosil 100-5 C18, and the 10min method (0-1min 10%ACN, 1-6min10-100%ACN, 6-8.5min 100%ACN, 8.5-9min 100-10%ACN, 9-10min10%ACN): 3.28min.
Embodiment E 5: morpholine-4-sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-acid amides
Title compound prepares with being similar to embodiment E 1 described method, but replaces cyclopropane carbonyl chlorine with the morpholine SULPHURYL CHLORIDE.
MS：491[M+H]
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 0.92 min.
Embodiment E 6: morpholine-4-formic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-acid amides
Title compound prepares with being similar to embodiment E 1 described method, but replaces cyclopropane carbonyl chlorine with morpholine carbonyl chloro.
MS：455[M+H]
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 0.87min.
Embodiment E 6a: morpholine-4-formic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-the acid amides maleate
Title compound is with being similar to the described method preparation of embodiment D2a; but with morpholine-4-formic acid (2-{3-is outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-acid amides replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment E 6b: morpholine-4-formic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-acid amides toluene-4-sulfonic acid salt
Title compound is with being similar to the described method preparation of embodiment D2b; but with morpholine-4-formic acid (2-{3-is outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-acid amides replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment E 7:1-hydroxyl-cyclopropane-carboxylic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-acid amides
Title compound prepares with being similar to embodiment E 2 described methods, but replaces 4-methylpyrazine formic acid with 1-hydroxyl cyclopropane-1-formic acid.
MS：426[M+H]
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 0.87min.
Embodiment E 8: tetrahydropyrans-4-formic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-acid amides
Title compound prepares with being similar to embodiment E 2 described methods, but replaces 4-methylpyrazine formic acid with tetrahydropyrans-4-formic acid.
MS：454[M+H]
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.18min.
Embodiment E 9: cyclobutane formate (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-acid amides
Title compound prepares with being similar to embodiment E 2 described methods, but replaces 4-methylpyrazine formic acid with cyclobutane formate.
MS：424[M+H]
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.22min.
Embodiment E 10:3-methyl-3H-imidazoles-4-formic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-acid amides
Title compound prepares with being similar to embodiment E 2 described methods, but replaces 4-methylpyrazine formic acid with 3-methyl-3H-imidazoles-4-formic acid.
MS：449[M-H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 0.76min.
Embodiment E 11:N-(outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-4-fluoro-benzamide
This compound prepares with the method that is similar to embodiment E 1, but replaces cyclopropane carbonyl chlorine with the 4-fluorobenzoyl chloride.
MS：464[M-H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.13min.
Embodiment E 11a:N-(outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-4-fluoro-benzamide maleate
Title compound is with being similar to the described method preparation of embodiment D2a; but with N-(2-{3-is outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-4-fluoro-benzamide replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment E 11b:N-(outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-4-fluoro-benzamide toluene-4-sulfonic acid salt
Title compound is with being similar to the described method preparation of embodiment D2b; but with N-(2-{3-is outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-4-fluoro-benzamide replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment E 12:3H-imidazoles-4-formic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-acid amides
This compound prepares with the method that is similar to embodiment E 2, but replaces 4-methylpyrazine formic acid with N-boc-3H-imidazoles-4-formic acid.
MS：436[M-H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 0.81min.
Embodiment E 13: pyrazine-2-formic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-acid amides
This compound prepares with the method that is similar to embodiment E 2, but replaces 4-methylpyrazine formic acid with pyrazine-2-formic acid.
MS：448[M-H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.2min.
Embodiment E 14:4-methyl-oxazoles-5-formic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-the method preparation that is similar to embodiment E 2 of this compound of acid amides, but replace 4-methylpyrazine formic acid with 4-methyl-oxazole-5-formic acid.
MS：451[M-H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 0.9min.
Embodiment E 15:2-amino-pyrimidine-5-formic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-acid amides
This compound prepares with the method that is similar to embodiment E 2, but replaces 4-methylpyrazine formic acid with 2-amino-pyrimidine-5-formic acid.
MS：463[M-H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.11min.
Embodiment E 16:N-(outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-2-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-ethanamide
This compound prepares with the method that is similar to embodiment E 2, but replaces 4-methylpyrazine formic acid with N-phthaloyl glycine.
MS：530 [M-H]+
HPLC (waters symmetry C18,6min method (0-3.5min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 5%ACN): 2.87min.
Embodiment E 17:N-(outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-4-fluoro-benzsulfamide
This compound prepares with the method that is similar to embodiment E 1, but replaces cyclopropane carbonyl chlorine with 4-fluorophenyl SULPHURYL CHLORIDE.
MS：500[M-H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.14min.
Embodiment E 18:N-(outside the 3-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-oxo-propyl group)-3-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-propionic acid amide
A) (S)-2-methyl-propane-2--sulfinic acid [(R)-and 1-[3-is outer-8-(3-amino-propionyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-2-(2,4,5-three fluoro-phenyl)-ethyl]-acid amides
This compound prepares with the method that is similar to embodiment E 1, but replaces N-phthaloyl glycine with N-phthaloyl-β-glycine.
MS：460[M-H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.17min.
B) N-(3-{3-is outer-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl-3-oxo-propyl group)-3-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-propionic acid amide
This compound prepares with the method that is similar to embodiment E 2, but replaces 4-methylpyrazine formic acid with N-phthaloyl-β-glycine.
MS：557[M-H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.17min.
Embodiment E 19: cyclopropane sulfonic acid (outside the 3-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-oxo-propyl group)-acid amides
This compound prepares with the method that is similar to embodiment E 3; but with (S)-2-methyl-propane-2--sulfinic acid [(R)-1-[3-is outer-8-(3-amino-propionyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-acid amides replaces (S)-2-methyl-propane-2--sulfinic acid [(R)-1-[3-is outer-8-(2-amino-ethanoyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-2-(2; 4,5-three fluoro-phenyl)-ethyl]-acid amides.
MS：460[M-H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.11min.
Embodiment E 20:N-(outside the 3-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-oxo-propyl group)-ethanamide
This compound prepares with the method that is similar to embodiment E 4; but with (S)-2-methyl-propane-2--sulfinic acid [(R)-1-[3-is outer-8-(3-amino-propionyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-acid amides replaces (S)-2-methyl-propane-2--sulfinic acid [(R)-1-[3-is outer-8-(2-amino-ethanoyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-2-(2; 4,5-three fluoro-phenyl)-ethyl]-acid amides.
MS：398[M-H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.07min.
Embodiment E 20a:N-(outside the 3-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-oxo-propyl group)-the ethanamide maleate
Title compound is with being similar to the described method preparation of embodiment D2a; but with N-(3-{3-is outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-oxo-propyl group)-ethanamide replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment E 20b:N-(outside the 3-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-oxo-propyl group)-ethanamide toluene-4-sulfonic acid salt
Title compound is with being similar to the described method preparation of embodiment D2b; but with N-(3-{3-is outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-oxo-propyl group)-ethanamide replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment E 21:N-(outside the 3-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-oxo-propyl group)-benzamide
This compound prepares with the method that is similar to embodiment E 19, but replaces the cyclopropane SULPHURYL CHLORIDE with Benzoyl chloride.
MS：460[M-H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.12min.
Embodiment E 22: cyclopropane-carboxylic acid (2-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-2-oxo-ethyl)-acid amides
Title compound is with being similar to embodiment E 1 described method preparation; but with (S)-2-methyl-propane-2--sulfinic acid [(R)-1-piperidin-4-yl-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-acid amides replace 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane.
MS：384[M+H]
HPLC (YMC Pack ODS-AQ 3 μ m 2.1 * 50mm, and the 6min method (0-3.5min5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min5%ACN): 2.6min.
Embodiment E 23:N-(2-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-2-oxo-ethyl)-benzamide
This compound prepares with the method that is similar to embodiment E 22, but replaces cyclopropane carbonyl chlorine with Benzoyl chloride.
MS：420[M+H]
HPLC (YMC Pack ODS-AQ 3 μ m 2.1 * 50mm, and the 6min method (0-3.5min5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min5%ACN): 2.83min.
Embodiment E 24: cyclopropane-carboxylic acid (2-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-sec.-propyl-acid amides
A) (S)-2-methyl-propane-2--sulfinic acid [(R)-1-[(1S, 5R)-8-(2-sec.-propyl amino-ethanoyl)-two ring [3.2.1] oct-3-yls]-2-(2,4,5-three fluoro-phenyl)-ethyl]-acid amides
To (S)-2-methyl-propane-2--sulfinic acid [(R)-1-[(1S; 5R)-8-(2-amino-ethanoyl)-two ring [3.2.1] oct-3-yls]-2-(2,4,5-three fluoro-phenyl)-ethyl]-acid amides (150mg; 0.33mmol) methyl alcohol (3mL) solution in, add acetate until pH5-5.5.Add acetone (124 μ L, 1.68mmol) after, reactant is at room temperature stirred 1h, and (43mg 0.67mmol), at room temperature stirs 16h then to add sodium cyanoborohydride.To react with ethyl acetate and saturated NaHCO
3Aqueous solution cancellation, dry and evaporate to dryness obtains the crude product compound with organic phase, then by SCX-2 post (5g, DCM/MeOH1:1,2N NH then
3MeOH solution) purifying, obtain title compound.
MS：488[M+H]
HPLC (3 microns C18 (2) 30 * 4.6mm of Luna, 6min method, 0-0.5min 5% ACN, 0.5-5.5min 5-95% ACN, 5.5-6min 5% ACN): 2.17min.
B) cyclopropane-carboxylic acid (2-{ (and 1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl-2-oxo-ethyl)-sec.-propyl-acid amides
This compound prepares with the method that is similar to embodiment E 1; but with (S)-2-methyl-propane-2--sulfinic acid [(R)-1-[(1S; 5R)-8-(2-sec.-propyl amino-ethanoyl)-two ring [3.2.1] oct-3-yls]-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-acid amides replaces (S)-2-methyl-propane-2--sulfinic acid [(R)-1-[3-is outer-8-(2-amino-ethanoyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-2-(2; 4,5-three fluoro-phenyl)-ethyl]-acid amides.
MS：452[M+H]
HPLC (5 microns C18 (2) 100 * 3mm of Higgins Clipeus, 25min method, 0-1min 5% ACN, 1-15min 5-95% ACN, 15-20 95% CAN, 20-22min 95-5%CAN, 22-25min 5% ACN): 6.39min.
Embodiment E 25:N-(2-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-3-phenyl-propionic acid amide
Title compound prepares with being similar to embodiment E 2 described methods, but replaces 4-methylpyrazine formic acid with the 3-phenylpropionic acid.
MS：474[M+H]
HPLC (5 microns C18 (2) 100 * 3mm of Higgins Clipeus, 25min method, 0-1min5% ACN, 1-15min 5-95% ACN, 15-20 95% CAN, 20-22min 95-5% CAN, 22-25min 5% ACN): 6.74min.
Embodiment E 25a:N-(2-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-3-phenyl-propionic acid amide maleate
Title compound is with being similar to the described method preparation of embodiment D2a; but with N-(2-{ (1S; 3S; 5R)-3-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-3-phenyl-propionic acid amide replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment E 25b:N-(2-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-3-phenyl-propionic acid amide toluene-4-sulfonic acid salt
Title compound is with being similar to the described method preparation of embodiment D2b; but with N-(2-{ (1S; 3S; 5R)-3-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-3-phenyl-propionic acid amide replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment E 26:N-(2-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-2-phenoxy group-ethanamide
Title compound prepares with being similar to embodiment E 2 described methods, but replaces 4-methylpyrazine formic acid with the 2-phenylium.
MS：476[M+H]
HPLC (5 microns C18 (2) 100 * 3mm of Higgins Clipeus, 25min method, 0-1min5% ACN, 1-15min 5-95% ACN, 15-20 95% CAN, 20-22min 95-5% CAN, 22-25min 5% ACN): 6.67min.
Embodiment E 27:N-(2-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-2-(3-methyl-isoxazole-5-base)-ethanamide
Title compound prepares with being similar to embodiment E 2 described methods, but replaces 4-methylpyrazine formic acid with (3-methyl-isoxazole-5-bases)-acetate.
MS：465[M+H]
HPLC (5 microns C18 (2) 100 * 3mm of Higgins Clipeus, 25min method, 0-1min5% ACN, 1-15min 5-95% ACN, 15-20 95% CAN, 20-22min 95-5% CAN, 22-25min 5% ACN): 5.76min.
Embodiment E 28:N-(2-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-2-morpholine-4-base-ethanamide
Title compound prepares with being similar to embodiment E 2 described methods, but replaces 4-methylpyrazine formic acid with morpholine-4-base-acetate.
MS：469[M+H]
HPLC (5 microns C18 (2) 100 * 3mm of Higgins Clipeus, 25min method, 0-1min5% ACN, 1-15min 5-95% ACN, 15-20 95% CAN, 20-22min 95-5% CAN, 22-25min 5% ACN): 4.09min.
Embodiment E 29:N-(2-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-2-phenyl-ethanamide
Title compound prepares with being similar to embodiment E 2 described methods, but replaces 4-methylpyrazine formic acid with phenylacetic acid.
MS：460[M+H]
HPLC (5 microns C18 (2) 100 * 3mm of Higgins Clipeus, 25min method, 0-1min5% ACN, 1-15min 5-95% ACN, 15-20 95% CAN, 20-22min 95-5% CAN, 22-25min 5% ACN): 6.38min.
Embodiment E 30:N-(2-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-C-phenyl-Toluidrin
Title compound prepares with being similar to embodiment E 1 described method, but replaces cyclopropane carbonyl chlorine with the phenyl methanesulfonamide acyl chlorides.
MS：496[M+H]
HPLC (5 microns C18 (2) 100 * 3mm of Higgins Clipeus, 25min method, 0-1min5%ACN, 1-15min 5-95% ACN, 15-20 95% CAN, 20-22min 95-5% CAN, 22-25min 5% ACN): 6.76min.
Embodiment E 30a:N-(2-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-C-phenyl-Toluidrin maleate
Title compound is with being similar to the described method preparation of embodiment D2a; but with N-(2-{ (1S; 3S; 5R)-3-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-C-phenyl-Toluidrin replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment E 30b:N-(2-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-C-phenyl-Toluidrin toluene-4-sulfonic acid salt
Title compound is with being similar to the described method preparation of embodiment D2b; but with N-(2-{ (1S; 3S; 5R)-3-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-C-phenyl-Toluidrin replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment E 31:N-(2-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-2-[1,2,4] triazol-1-yl-isobutyramide
Title compound is with being similar to the described methods preparation of embodiment E 2, but with 2-methyl-2-[1,2,4] triazol-1-yl-propionic acid replacement 4-methylpyrazine formic acid.
MS：479[M+H]
HPLC (5 microns C18 (2) 100 * 3mm of Higgins Clipeus, 25min method, 0-1min5% ACN, 1-15min 5-95% ACN, 15-20 95% CAN, 20-22min 95-5% CAN, 22-25min 5% ACN): 5.53min.
Embodiment E 32:N-(2-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-2-(tetrahydrochysene-pyrans-4-yl)-ethanamide
Title compound prepares with being similar to embodiment E 2 described methods, but replaces 4-methylpyrazine formic acid with (tetrahydrochysene-pyrans-4-yl)-acetate.
MS：468[M+H]
HPLC (5 microns C18 (2) 100 * 3mm of Higgins Clipeus, 25min method, 0-1min5%ACN, 1-15min5-95%ACN, 15-20 95%CAN, 20-22 min95-5%CAN, 22-25min 5% ACN): 5.56min.
Embodiment E 33:N-(2-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-2-methoxyl group-benzamide
Title compound prepares with being similar to embodiment E 2 described methods, but replaces 4-methylpyrazine formic acid with O-Anisic Acid.
MS：476[M+H]
HPLC (5 microns C18 (2) 100 * 3mm of Higgins Clipeus, 25min method, 0-1min5% ACN, 1-15min 5-95% ACN, 15-20 95% CAN, 20-22min 95-5% CAN, 22-25min 5% ACN): 6.62min.
Embodiment E 34:2,3-dihydro-benzo [1,4] dioxin-5-formic acid (2-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-acid amides
Title compound prepares with being similar to embodiment E 2 described methods, but with 2, [1,4] dioxin-5-formic acid replaces 4-methylpyrazine formic acid to 3-dihydro-benzo.
MS：504[M+H]
HPLC (5 microns C18 (2) 100 * 3mm of Higgins Clipeus, 25min method, 0-1min5% ACN, 1-15min 5-95% ACN, 15-20 95% CAN, 20-22min 95-5% CAN, 22-25min 5% ACN): 6.43min.
Embodiment E 35: pyridazine-3-formic acid (2-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-acid amides
Title compound prepares with being similar to embodiment E 2 described methods, but replaces 4-methylpyrazine formic acid with pyridazine-3-formic acid.
MS：448[M+H]
HPLC (5 microns C18 (2) 100 * 3mm of Higgins Clipeus, 25min method, 0-1min5% ACN, 1-15min 5-95% ACN, 15-20 95% CAN, 20-22min 95-5% CAN, 22-25min 5% ACN): 5.56min.
Embodiment E 36:N-(2-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-2-(3H-imidazol-4 yl)-ethanamide
Title compound prepares with being similar to embodiment E 2 described methods, but replaces 4-methylpyrazine formic acid with (3H-imidazol-4 yl)-acetate.
MS：450[M+H]
HPLC (5 microns C18 (2) 100 * 3mm of Higgins Clipeus, 25min method, 0-1min5% ACN, 1-15min 5-95% ACN, 15-20 95% CAN, 20-22min 95-5% CAN, 22-25min 5% ACN): 0.84-3.14min.
Embodiment E 37:2-phenyl-ethyl sulfonic acid (2-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-acid amides
Title compound prepares with being similar to embodiment E 1 described method, but replaces cyclopropane carbonyl chlorine with the phenyl ethyl sulfonyl chloride.
MS：510[M+H]
HPLC (5 microns C18 (2) 100 * 3mm of Higgins Clipeus, 25min method, 0-1min5% ACN, 1-15min 5-95% ACN, 15-20 95% CAN, 20-22min 95-5% CAN, 22-25min 5% ACN): 6.35min.
Embodiment E 38:N-(2-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-4-methyl-benzsulfamide
Title compound prepares with being similar to embodiment E 1 described method, but replaces cyclopropane carbonyl chlorine with toluene sulfonyl chloride.
MS：496[M+H]
HPLC (5 microns C18 (2) 100 * 3mm of Higgins Clipeus, 25min method, 0-1min5% ACN, 1-15min 5-95% ACN, 15-20 95%CAN, 20-22min 95-5% CAN, 22-25min 5% ACN): 6.11min.
Embodiment E 39:2,3-dihydro-benzo [1,4] dioxin-6-sulfonic acid (2-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-acid amides
Title compound prepares with being similar to embodiment E 1 described method, but with 2, [1,4] dioxin-6-SULPHURYL CHLORIDE replaces cyclopropane carbonyl chlorine to 3-dihydro-benzo.
MS：540[M+H]
HPLC (5 microns C18 (2) 100 * 3mm of Higgins Clipeus, 25min method, 0-1min5% ACN, 1-15min 5-95% ACN, 15-20 95% CAN, 20-22min 95-5% CAN, 22-25min 5% ACN): 5.87min.
Embodiment E 40:N-(2-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-2-methoxyl group-benzsulfamide
Title compound prepares with being similar to embodiment E 1 described method, but replaces cyclopropane carbonyl chlorine with 2-anisole SULPHURYL CHLORIDE.
MS：512[M+H]
HPLC (5 microns C18 (2) 100 * 3mm of Higgins Clipeus, 25min method, 0-1min5% ACN, 1-15min 5-95% ACN, 15-20 95% CAN, 20-22min 95-5% CAN, 22-25min 5% ACN): 5.74min.
Embodiment E 40a:N-(2-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-2-methoxyl group-benzsulfamide maleate
Title compound is with being similar to the described method preparation of embodiment D2a; but with N-(2-{ (1S; 3S; 5R)-3-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-2-methoxyl group-benzsulfamide replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment E 40b:N-(2-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-2-methoxyl group-benzsulfamide toluene-4-sulfonic acid salt
Title compound is with being similar to the described method preparation of embodiment D2b; but with N-(2-{ (1S; 3S; 5R)-3-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-2-methoxyl group-benzsulfamide replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment E 41:3,5-dimethyl-isoxazole-4-sulfonic acid (2-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-acid amides
Title compound prepares with being similar to embodiment E 1 described method, but with 3,5-dimethyl-isoxazoles-4-SULPHURYL CHLORIDE replaces cyclopropane carbonyl chlorine.
MS：501[M+H]
HPLC (5 microns C18 (2) 100 * 3mm of Higgins Clipeus, 25min method, 0-1min5% ACN, 1-15min 5-95% ACN, 15-20 95% CAN, 20-22min 95-5% CAN, 22-25min 5% ACN): 5.55min.
Embodiment E 42:1,3,5-trimethylammonium-1H-pyrazoles-4-sulfonic acid (2-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-acid amides
Title compound prepares with being similar to embodiment E 1 described method, but with 1,3,5-trimethylammonium-1H-pyrazoles-4-SULPHURYL CHLORIDE replaces cyclopropane carbonyl chlorine.
MS：514[M+H]
HPLC (5 microns C18 (2) 100 * 3mm of Higgins Clipeus, 25min method, 0-1min5% ACN, 1-15min 5-95% ACN, 15-20 95% CAN, 20-22min 95-5% CAN, 22-25min 5% ACN): 5.15min.
Embodiment F 1: cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-methyl-acid amides
This compound is according to flow process F preparation, and wherein " Cbz " is carbobenzoxy-(Cbz):
Flow process F
A) methyl-(2-{3-is outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl-2-oxo-ethyl)-benzyl carbamate
Title compound prepares with being similar to embodiment E 1 described method, but replaces N-phthaloyl glycine with N-methyl-N-Cbz-glycine.
MS：594[M+H]
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.25min.
B) methyl-2-{3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl-2-oxo-ethylamine
To methyl-(outside the 2-{3--[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-benzyl carbamate (340mg; 0.573mmol) ethanol (5mL) solution in; add palladium charcoal (122mg; 0.114mmol), and at H
2Under the atmosphere, the mixture that obtains is at room temperature stirred 4h.Suspension is passed through diatomite filtration, and, obtain gray solid the filtrate evaporate to dryness.
MS：460[M+H]
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 0.97min.
C) the cyclopropane sulfonic acid methyl-(2-{3-is outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl-2-oxo-ethyl)-acid amides
Outside methyl-2-{3--[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethylamine (100mg; 0.217mmol) methylene dichloride (2mL) solution in; add triethylamine (91 μ L; 0.651mmol) and the cyclopropane SULPHURYL CHLORIDE (33 μ L, 0.326mmol).The solution that obtains is at room temperature stirred 3h, evaporate to dryness then, and by preparation HPLC (Column Waters C18 ODB 5 μ m 19 * 50, gradient: 0-2.5min 5% ACN, 2.5-12.5min 5-100% ACN, 12.5-15min 100% ACN) purifying, obtain white solid.
MS：564[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.18min.
D) cyclopropane sulfonic acid (2-{3-is outer-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl-2-oxo-ethyl)-methyl-acid amides
To the cyclopropane sulfonic acid methyl-(outside the 2-{3--[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-acid amides (62mg; 0.11mmol) dioxane (1mL) solution in, add the dioxane solution (1mL) of 4N HCl.The mixture that obtains is at room temperature stirred 1h.Freezing and freeze-drying obtains white solid with solution.
MS 460[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 0.95min.
Embodiment F 1a: cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-methyl-acid amides maleate
Title compound is with being similar to the described method preparation of embodiment D2a; but with cyclopropane sulfonic acid (2-{3-is outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-methyl-acid amides replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment F 1b: cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-methyl-acid amides toluene-4-sulfonic acid salt
Title compound is with being similar to the described method preparation of embodiment D2b; but with cyclopropane sulfonic acid (2-{3-is outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-methyl-acid amides replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment F 2: cyclopropane sulfonic acid (outside (S)-2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-1-hydroxymethyl-2-oxo-ethyl)-acid amides
Title compound prepares with being similar to embodiment F 1 described method, but replaces N-methyl-N-Cbz-glycine with N-Cbz-Serine (tBu)-OH.
MS：476[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 0.88min.
Embodiment F 3:N-(outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-N-methyl-ethanamide
Title compound is with being similar to embodiment E 4 described method preparations; but with (S)-2-methyl-propane-2--sulfinic acid [(R)-1-[3-is outer-8-(2-methylamino-ethanoyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-acid amides replaces (S)-2-methyl-propane-2--sulfinic acid [(R)-1-[3-is outer-8-(2-amino-ethanoyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-2-(2; 4,5-three fluoro-phenyl)-ethyl]-acid amides.
MS：398[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 0.86min.
Embodiment F 3a:N-(outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-N-methyl-ethanamide maleate
Title compound is with being similar to the described method preparation of embodiment D2a; but with N-(2-{3-is outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-N-methyl-ethanamide replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment F 3b:N-(outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-N-methyl-ethanamide toluene-4-sulfonic acid salt
Title compound is with being similar to the described method preparation of embodiment D2b; but with N-(2-{3-is outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-N-methyl-ethanamide replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment F 4: cyclopropane-carboxylic acid (outside (S)-2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-1-hydroxymethyl-2-oxo-ethyl)-acid amides
Title compound prepares with being similar to embodiment F 1 described method, but replaces the cyclopropane SULPHURYL CHLORIDE with the cyclopropane carbonyl chloro.
MS：424[M+H]+
HPLC (Waters Symmetry C18 3.5 μ m 2.1 * 50mm, and the 6min method (0-3min20-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min20%ACN): 2.74 min.
Embodiment F 5: cyclopropane-carboxylic acid (outside (S)-2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-1-methyl-2-oxo-ethyl)-acid amides
Title compound prepares with being similar to embodiment F 4 described methods, but replaces N-methyl-N-Cbz-glycine with N-Cbz-(S)-L-Ala.
MS：460[M+H]+
HPLC (Waters Symmetry C18 3.5 μ m 2.1 * 50mm, and the 6min method (0-3min20-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min20%ACN): 2.80min.
Embodiment F 5a: cyclopropane-carboxylic acid (outside (S)-2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-1-methyl-2-oxo-ethyl)-the acid amides maleate
Title compound is with being similar to the described method preparation of embodiment D2a; but with cyclopropane-carboxylic acid ((S)-2-{3-is outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-1-methyl-2-oxo-ethyl)-acid amides replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment F 5b: cyclopropane-carboxylic acid (outside (S)-2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-1-methyl-2-oxo-ethyl)-acid amides toluene-4-sulfonic acid salt
Title compound is with being similar to the described method preparation of embodiment D2b; but with cyclopropane-carboxylic acid ((S)-2-{3-is outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-1-methyl-2-oxo-ethyl)-acid amides replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment F 6:N-(outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-4-fluoro-N-methyl-benzsulfamide
Title compound prepares with being similar to embodiment F 1 described method, but replaces the cyclopropane SULPHURYL CHLORIDE with 4-fluorophenyl SULPHURYL CHLORIDE.
MS：514[M+H]+
HPLC (Waters Symmetry C18 3.5 μ m 2.1 * 50mm, and the 6min method (0-3min20-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min20%ACN): 3.13min.
Embodiment F 7: cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-1,1-dimethyl-2-oxo-ethyl)-acid amides
Title compound prepares with being similar to embodiment F 4 described methods, but replaces N-methyl-N-Cbz-glycine with N-Cbz-methyl-L-Ala.
MS：474[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 0.93min.
Embodiment F 7a: cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-1,1-dimethyl-2-oxo-ethyl)-the acid amides maleate
Title compound is with being similar to the described method preparation of embodiment D2a; but with cyclopropane sulfonic acid (2-{3-is outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-1; 1-dimethyl-2-oxo-ethyl)-acid amides replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment F 7b: cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-1,1-dimethyl-2-oxo-ethyl)-acid amides toluene-4-sulfonic acid salt
Title compound is with being similar to the described method preparation of embodiment D2b; but with cyclopropane sulfonic acid (2-{3-is outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-1; 1-dimethyl-2-oxo-ethyl)-acid amides replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment F 8:N-(outside the 3-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-oxo-propyl group)-N-methyl-ethanamide
Title compound is with being similar to embodiment F 3 described method preparations; but with (S)-2-methyl-propane-2--sulfinic acid [(R)-1-[3-is outer-8-(3-methylamino-propionyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-acid amides replaces (S)-2-methyl-propane-2--sulfinic acid [(R)-1-[3-is outer-8-(2-methylamino-ethanoyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-2-(2; 4,5-three fluoro-phenyl)-ethyl]-acid amides.
MS：412[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.09min.
Embodiment F 9: cyclopropane-carboxylic acid (outside (R)-2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-1-hydroxymethyl-2-oxo-ethyl)-acid amides
A) (R)-2-benzyloxycarbonyl amino-3-(tertiary butyl-dimethyl-silanyloxy base)-methyl propionate
To (R)-2-benzyloxycarbonyl amino-3-hydroxyl-methyl propionate (1g, in dimethyl formamide solution 4mmol), add triethylamine (1.2mL, 8mmol), the silica-based chlorine (895mg of tertiary butyl dimethyl, 6mmol) and 4-dimethylaminopyridine (50mg, 0.4mmol).After stirring 16h under the room temperature, will react water and the cancellation of the 1N HCl aqueous solution, and use ethyl acetate extraction.Dry and evaporate to dryness obtains residue with organic phase, and it by flash chromatography (silica gel, ethyl acetate/hexanaphthene 1/9 to 1/4) purifying, is obtained light yellow gluey thing.
MS：368[M+H]+
HPLC (waters symmetry C18,6min method (0-3.5min 20-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min 20%ACN): 4.63min.
B) (R)-2-benzyloxycarbonyl amino-3-(tertiary butyl-dimethyl-silanyloxy base)-propionic acid
To (R)-2-benzyloxycarbonyl amino-3-(tertiary butyl-dimethyl-silanyloxy base)-methyl propionate (1.450g, add in tetrahydrofuran (THF)/water 3.95mmol) (2/1) solution lithium hydroxide (250mg, 5.92mmol).After stirring 16h under the room temperature, solution is handled with ethyl acetate, and made pH reduce to 2 with the 1N HCl aqueous solution.Dry and evaporate to dryness obtains title compound with organic phase.
MS：354[M+H]+
HPLC (waters symmetry C18,6min method (0-3.5min 20-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min 20%ACN): 4.25min.
C) cyclopropane-carboxylic acid ((R)-2-{3-is outer-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl-1-hydroxymethyl-2-oxo-ethyl)-acid amides
Title compound prepares with being similar to embodiment F 2 described methods, but replaces N-Cbz-Serine (tBu)-OH with (R)-2-benzyloxycarbonyl amino-3-(tertiary butyl-dimethyl-silanyloxy base)-propionic acid, and replaces the cyclopropyl SULPHURYL CHLORIDE with ethylene-acetic acid.
MS：440[M+H]+
HPLC (waters symmetry C18,6min method (0-3.5min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 5%ACN): 2.65min.
Embodiment F 10:N-((S)-2-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-1-methyl-2-oxo-ethyl)-isobutyramide
Title compound prepares with being similar to embodiment F 5 described methods, but replaces cyclopropane carbonyl chlorine with isobutyryl chloride.
MS：426[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.239min.
Embodiment F 11:N-((R)-2-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-1-methyl-2-oxo-ethyl)-isobutyramide
Title compound prepares with being similar to embodiment F 10 described methods, but replaces N-Cbz-(S)-L-Ala with N-Cbz-(R)-L-Ala.
MS：426[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.236min.
Embodiment F 12: cyclopropane-carboxylic acid (outside (R)-2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-1-methyl-2-oxo-ethyl)-acid amides
Title compound prepares with being similar to embodiment F 5 described methods, but replaces N-Cbz-(S)-L-Ala with N-Cbz-(R)-L-Ala.
MS：424[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.224min.
Embodiment F 12a: cyclopropane-carboxylic acid (outside (R)-2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-1-methyl-2-oxo-ethyl)-the acid amides maleate
Title compound is with being similar to the described method preparation of embodiment D2a; but with cyclopropane-carboxylic acid ((R)-2-{3-is outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-1-methyl-2-oxo-ethyl)-acid amides replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment F 12b: cyclopropane-carboxylic acid (outside (R)-2-{3--[and (R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-1-methyl-2-oxo-ethyl)-acid amides toluene-4-sulfonic acid salt title compound is with being similar to the preparation of the described method of embodiment D2b; but with cyclopropane-carboxylic acid ((R)-2-{3-is outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-1-methyl-2-oxo-ethyl)-acid amides replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment G1:N-(outside (S)-2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-1-methyl-2-oxo-ethyl)-ethanamide
This compound prepares according to flow process G:
Flow process G
A) N-((S)-1-methyl-2-{3-is outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl-2-oxo-ethyl)-ethanamide
Title compound prepares with being similar to embodiment E 1 described method, but replaces N-phthaloyl glycine with N-ethanoyl-L-L-Ala.
MS：502[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.11min.
B) N-((S)-2-{3-is outer-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl-1-methyl-2-oxo-ethyl)-ethanamide
To N-(outside (S)-1-methyl-2-{3--[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-ethanamide (60mg; 0.120mmol) dioxane (1mL) solution in, add the dioxane solution (1mL) of 4N HCl.The mixture that obtains is at room temperature stirred 1h.Freezing and freeze-drying obtains white solid with solution, then by preparation HPLC (Column Waters C18 ODB 5 μ m 19 * 50, gradient: 0-2.5min 5% ACN, 2.5-12.5min 5-100% ACN, 12.5-15min 100%ACN) purifying, obtain title compound.
MS：398[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 0.91min.
Embodiment G1a:N-(outside (S)-2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-1-methyl-2-oxo-ethyl)-the ethanamide maleate
Title compound is with being similar to the described method preparation of embodiment D2a; but with N-((S)-2-{3-is outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-1-methyl-2-oxo-ethyl)-ethanamide replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment G1b:N-(outside (S)-2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-1-methyl-2-oxo-ethyl)-ethanamide toluene-4-sulfonic acid salt
Title compound is with being similar to the described method preparation of embodiment D2b; but with N-((S)-2-{3-is outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-1-methyl-2-oxo-ethyl)-ethanamide replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment G2:N-(outside (R)-2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-1-methyl-2-oxo-ethyl)-ethanamide
Title compound prepares with being similar to the described method of embodiment G1, but replaces N-ethanoyl-L-L-Ala with N-ethanoyl-D-L-Ala.
MS：398[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 0.88min.
Embodiment G3:N-(outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-benzamide
Title compound prepares with being similar to the described method of embodiment G1, but replaces N-ethanoyl-L-L-Ala with the N-benzoylglycine.
MS：446[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 0.94min.
Embodiment G4:(R)-1-{3-is outer-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-hydroxyl-2-phenyl-third-1-ketone
Title compound prepares with being similar to the described method of embodiment G1, but replaces N-ethanoyl-L-L-Ala with (R)-2-hydroxyl-2-phenyl-propionic acid.
MS：433[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.00min.
Embodiment G5:N-(outside (S)-5-acetylamino-1-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-carbonyl }-amyl group)-ethanamide
Title compound is with being similar to the preparation of the described method of embodiment G1, but with (S)-2, and 6-is two-acetylamino-caproic acid replacement N-ethanoyl-L-L-Ala.
MS：497[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.10min.
Embodiment G6:((S)-2-{3-is outer-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-1-phenyl-ethyl)-urethanum
Title compound prepares with being similar to the described method of embodiment G1, but replaces N-ethanoyl-L-L-Ala with (S)-ethoxy carbonyl amino-phenyl-acetic acid.
MS：490[M+H]+
HPLC (waters symmetry C18,6min method (0-3.5min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 5%ACN): 3.14min.
Embodiment G7:((R)-2-{3-is outer-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-1-phenyl-ethyl)-urethanum
Title compound prepares with being similar to the described method of embodiment G1, but replaces N-ethanoyl-L-L-Ala with (R)-ethoxy carbonyl amino-phenyl-acetic acid.
MS：490[M+H]+
HPLC (waters symmetry C18,6min method (0-3.5min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 5%ACN): 3.14min.
Embodiment G8:(S)-1-{3-is outer-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-methoxyl group-2-phenyl-ethyl ketone
Title compound prepares with being similar to the described method of embodiment G1, but replaces N-ethanoyl-L-L-Ala with (S)-p-methoxy-phenyl-acetate.
MS：433[M+H]+
HPLC (Waters Symmetry C183.5 μ m 2.1 * 50mm, and the 6min method (0-3min20-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min20%ACN): 2.49min.
Embodiment G9:(R)-1-{3-is outer-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-methoxyl group-2-phenyl-ethyl ketone
Title compound prepares with being similar to the described method of embodiment G1, but replaces N-ethanoyl-L-L-Ala with (R)-p-methoxy-phenyl-acetate.
MS：433[M+H]+
HPLC (Waters Symmetry C183.5 μ m 2.1 * 50mm, and the 6min method (0-3min20-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min20%ACN): 2.47min.
Embodiment G10:N-(outside the 3-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-oxo-propyl group)-benzsulfamide
Title compound prepares with being similar to the described method of embodiment G1, but replaces N-ethanoyl-L-L-Ala with 3-benzenesulfonyl amino-propionic acid.
MS：496[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.17min.
Embodiment G10a:N-(outside the 3-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-oxo-propyl group)-the benzsulfamide maleate
Title compound is with being similar to the described method preparation of embodiment D2a; but with N-(3-{3-is outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-oxo-propyl group)-benzsulfamide replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment G10b:N-(outside the 3-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-oxo-propyl group)-benzsulfamide toluene-4-sulfonic acid salt
Title compound is with being similar to the described method preparation of embodiment D2b; but with N-(3-{3-is outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-oxo-propyl group)-benzsulfamide replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment G11:2,3-dihydro-benzo [1,4] dioxin-6-sulfonic acid (outside the 3-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-oxo-propyl group)-acid amides
Title compound is with being similar to the preparation of the described method of embodiment G1, but with 3-(2,3-dihydro-benzo [1,4] dioxin-6-sulfuryl amino)-propionic acid replacement N-ethanoyl-L-L-Ala.
MS：554[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.18min.
Outside the embodiment G12:1-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-(2,3-dihydro-benzo [1,4] dioxin-6-alkylsulfonyl)-third-1-ketone
Title compound is with being similar to the preparation of the described method of embodiment G1, but with 3-(2,3-dihydro-benzo [1,4] dioxin-6-alkylsulfonyl)-propionic acid replacement N-ethanoyl-L-L-Ala.
MS：539[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 0.97min.
Embodiment G13:N-[4-(outside the 3-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-oxo-propane-1-alkylsulfonyl)-phenyl]-ethanamide
Title compound prepares with being similar to the described method of embodiment G1, but replaces N-ethanoyl-L-L-Ala with 3-(4-acetylamino-benzenesulfonyl)-propionic acid.
MS：574[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.12min.
Outside the embodiment G14:1-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-(4-fluoro-benzenesulfonyl)-third-1-ketone
Title compound prepares with being similar to the described method of embodiment G1, but replaces N-ethanoyl-L-L-Ala with 3-(4-fluoro-benzenesulfonyl)-propionic acid.
MS：499[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.28min.
Outside the embodiment G15:1-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-(4-thiophene-2-base-6-trifluoromethyl-pyrimidine-2-alkylsulfonyl)-third-1-ketone
Title compound prepares with being similar to the described method of embodiment G1, but replaces N-ethanoyl-L-L-Ala with 3-(4-thiophene-2-base-6-trifluoromethyl-pyrimidine-2-alkylsulfonyl)-propionic acid.
MS：663[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.21min.
Outside the embodiment G16:1-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-phenylmethane alkylsulfonyl-third-1-ketone
Title compound prepares with being similar to the described method of embodiment G1, but replaces N-ethanoyl-L-L-Ala with 3-phenylmethane alkylsulfonyl-propionic acid.
MS：495[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.18min.
Embodiment G17:2-(outside the 3-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-carbonyl }-benzyl)-isoindole-1, the 3-diketone
Title compound prepares with being similar to the described method of embodiment G1, but replaces N-ethanoyl-L-L-Ala with 3-(1,3-dioxo-1,3-dihydro-isoindole-2-base-methyl)-phenylformic acid.
MS：548[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.30min.
Embodiment G18:N-(outside the 3-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-carbonyl }-benzyl)-benzamide
Title compound is with being similar to embodiment E 21 described method preparations; but with (S)-2-methyl-propane-2--sulfinic acid [(R)-1-{3-is outer-8-[3-(1; 3-dioxo-1; 3-dihydro-isoindole-2-ylmethyl)-benzoyl]-8-aza-bicyclo [3.2.1] oct-3-yl }-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-acid amides replace (S)-2-methyl-propane-2--sulfinic acid [(R)-1-{3-is outer-8-[3-(1; 3-dioxo-1; 3-dihydro-isoindole-2-yl)-propionyl]-8-aza-bicyclo [3.2.1] oct-3-yl }-2-(2; 4,5-three fluoro-phenyl)-ethyl]-acid amides.
MS：522[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.28min.
Outside the embodiment G19:3-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-N-benzyl-3-oxo-propionic acid amide
Title compound prepares with being similar to the described method of embodiment G1, but replaces N-ethanoyl-L-L-Ala with N-benzyl-malonamic acid.
MS：462[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.25min.
Outside the embodiment G20:1-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-morpholine-4-base-propane-1, the 3-diketone
Title compound prepares with being similar to the described method of embodiment G1, but replaces N-ethanoyl-L-L-Ala with N-morpholine-malonamic acid.
MS：440[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.16min.
Embodiment G21:1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-phenylmethane alkylsulfonyl-third-1-ketone
Title compound is with being similar to the described method preparation of embodiment G16; but with (S)-2-methyl-propane-2--sulfinic acid [(R)-1-piperidin-4-yl-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-acid amides replace 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane.
MS：469[M+H]+
HPLC (YMC Pack ODS-AQ 3 μ m 2.1 * 50mm, and the 6min method (0-3.5min5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min5%ACN): 2.98min.
Embodiment G21a:1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-phenylmethane alkylsulfonyl-third-1-ketone maleate
Title compound is with being similar to the described method preparation of embodiment D2a; but use 1-{4-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-phenylmethane alkylsulfonyl-third-1-ketone replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment G21b:1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-phenylmethane alkylsulfonyl-third-1-ketone toluene-4-sulfonic acid salt
Title compound is with being similar to the described method preparation of embodiment D2b; but use 1-{4-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-phenylmethane alkylsulfonyl-third-1-ketone replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment G22:1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-(4-fluoro-benzenesulfonyl)-third-1-ketone
Title compound is with being similar to the described method preparation of embodiment G14; but with (S)-2-methyl-propane-2--sulfinic acid [(R)-1-piperidin-4-yl-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-acid amides replace 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane.
MS：473[M+H]+
HPLC (YMC Pack ODS-AQ 3 μ m 2.1 * 50mm, and the 6min method (0-3.5min5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min5%ACN): 2.78min.
Embodiment G23:1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-benzenesulfonyl-third-1-ketone
Title compound is with being similar to the described method preparation of embodiment G1; but with (S)-2-methyl-propane-2--sulfinic acid [(R)-1-piperidin-4-yl-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-acid amides replace 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane, and replace N-ethanoyl-L-L-Ala with 3-benzenesulfonyl-propionic acid.
MS：455[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.13min.
Embodiment G24:1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-(2,3-dihydro-benzo [1,4] dioxin-6-alkylsulfonyl)-third-1-ketone
Title compound is with being similar to the described method preparation of embodiment G12; but with (S)-2-methyl-propane-2--sulfinic acid [(R)-1-piperidin-4-yl-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-acid amides replace 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane.
MS：513[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.15min.
Embodiment G25:1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-2-methane sulfonyl-ethyl ketone
Title compound prepares with being similar to the described method of embodiment G22, but replaces 3-(4-fluoro-benzenesulfonyl)-propionic acid with methane sulfonyl-acetate.
MS：401[M+H]+
HPLC (YMC Pack ODS-AQ 3 μ m 2.1 * 50mm, and the 6min method (0-3.5min5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min5%ACN): 2.48min.
Outside the embodiment G26:3-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-carbonyl }-N-methyl-benzamide
Title compound prepares with being similar to the described method of embodiment G1, but replaces N-ethanoyl-L-L-Ala with N-methyl-different phthalamic acid.
MS：446 [M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.17min.
Outside the embodiment G26a:3-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-carbonyl }-N-methyl-benzamide maleate
Title compound is with being similar to the described method preparation of embodiment D2a; but with 3-{3-outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-carbonyl }-N-methyl-benzamide replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Outside the embodiment G26b:3-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-carbonyl }-N-methyl-benzamide toluene-4-sulfonic acid salt
Title compound is with being similar to the described method preparation of embodiment D2b; but with 3-{3-outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-carbonyl }-N-methyl-benzamide replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Outside the embodiment G27:{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-[3-(morpholine-4-carbonyl)-phenyl]-ketone
Title compound prepares with being similar to the described method of embodiment G1, but replaces N-ethanoyl-L-L-Ala with 3-(morpholine-4-carbonyl)-phenylformic acid.
MS：502[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.19min.
Embodiment G28:1-(outside the 3-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-carbonyl }-benzyl)-pyrrolidin-2-one
Title compound prepares with being similar to the described method of embodiment G1, but replaces N-ethanoyl-L-L-Ala with 3-(2-oxo-tetramethyleneimine-1-ylmethyl)-phenylformic acid.
MS：486[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.23min.
Embodiment G29:3-(outside the 3-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-carbonyl }-benzyl)-thiazolidine-2, the 4-diketone
Title compound prepares with being similar to the described method of embodiment G1, but replaces N-ethanoyl-L-L-Ala with 3-(2,4-dioxo-thiazolidine-3-ylmethyl)-phenylformic acid.
MS：518[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.25min.
Embodiment G30:1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-(propane-2-alkylsulfonyl)-third-1-ketone
A) 3-sec.-propyl sulfane base-benzyl propionate
To benzyl acrylate (100mg, in ethanol 0.617mmol) (2mL) solution, add triethylamine (95uL, 0.679mmol) and the 2-propylmercaptan (58uL, 0.617mmol).After stirring 2h under the room temperature,, obtain residue, it is used methylene dichloride and water treatment the solvent evaporate to dryness.Dry and evaporate to dryness obtains colorless oil with organic phase, then by preparation HPLC (Column Waters C18 ODB5 μ m 19 * 50, gradient: 0-2.5min 5%ACN, 2.5-12.5min 5-100%ACN, 12.5-15min 100%ACN) purifying, obtain title compound.
MS：239[M+H]+
HPLC (Waters Symmetry C183.5 μ m 2.1 * 50mm, and the 6min method (0-3min20-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min20%ACN): 3.97min.
B) 3-(propane-2-alkylsulfonyl)-benzyl propionate
(46mg in acetate 0.193mmol) (500uL) solution, adds 30% H to 3-sec.-propyl alkylsulfonyl-benzyl propionate
2O
2The aqueous solution (82uL).After stirring 2h under 80 ℃, with the saturated NaHCO of mixture
3The solution cancellation, and use dichloromethane extraction.Dry and evaporate to dryness obtains title compound with organic phase.
MS：271[M+H]+
HPLC (Waters Symmetry C183.5 μ m 2.1 * 50mm, and the 6min method (0-3min20-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min20%ACN): 2.92min.
C) 3-(propane-2-alkylsulfonyl)-propionic acid
To 3-(propane-2-alkylsulfonyl)-benzyl propionate (49.3mg in methyl alcohol 0.182mmol) (1mL) solution, adds Pd/C (5mg), and with mixture at H
2Stirring at room 16h under the atmosphere.The suspension that obtains is passed through diatomite filtration, and, obtain title compound the filtrate evaporate to dryness.
D) 1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-(propane-2-alkylsulfonyl)-third-1-ketone
Title compound is with being similar to the preparation of the described method of embodiment G24, but with 3-(propane-2-alkylsulfonyl)-propionic acid replacement 3-(2,3-dihydro-benzo [1,4] dioxin-6-sulfuryl amino)-propionic acid.
MS：421[M+H]+
HPLC (YMC Pack ODS-AQ 3 μ m 2.1 * 50mm, and the 6min method (0-3.5min5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min5%ACN): 2.6min.
Outside the embodiment G31:1-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-(4-trifluoromethyl-pyrimidine-2-alkylsulfonyl)-third-1-ketone
Title compound is with being similar to the described method preparation of embodiment G30; but replace the 2-propylmercaptan with 4-trifluoromethyl-pyrimidine-2-mercaptan; and with 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane replacement (S)-2-methyl-propane-2--sulfinic acid [(R)-1-piperidin-4-yl-2-(2; 4,5-three fluoro-phenyl)-ethyl]-acid amides.
MS：551[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.25min.
Outside the embodiment G32:1-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-benzenesulfonyl-third-1-ketone
Title compound prepares with being similar to the described method of embodiment G1, but replaces N-ethanoyl-L-L-Ala with 3-benzenesulfonyl-propionic acid.
MS：481[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.2min.
Embodiment G33:1-{4-[1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-2-(propane-2-alkylsulfonyl)-ethyl ketone
A) sec.-propyl sulfane base-jasmal
To benzyl acetate bromide (100mg, in dimethyl formamide 0.437mmol) (2mL) solution, add triethylamine (67uL, 0.481mmol) and the 2-propylmercaptan (41uL, 0.437mmol).After stirring 2h under the room temperature, with the solvent evaporate to dryness, with residue methylene dichloride and water treatment.Dry and evaporate to dryness obtains the crude product compound with organic phase, then by preparation HPLC (Column Waters C18 ODB 5 μ m19 * 50, gradient: 0-2.5min 5%ACN, 2.5-12.5min 5-100%ACN, 12.5-15min100%ACN) purifying obtains title compound.
MS：225[M+H]+
HPLC (Waters Symmetry C183.5 μ m 2.1 * 50mm, and the 6min method (0-3min20-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min20%ACN): 3.84min.
B) 1-{4-[1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-2-(propane-2-alkylsulfonyl)-ethyl ketone
Title compound prepares with being similar to the described method of embodiment G30, but replaces 3-sec.-propyl sulfane base-benzyl propionate with sec.-propyl sulfane base-jasmal.
MS：551[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.25min.
Embodiment G34: cyclopropane-carboxylic acid (outside (S)-1-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-carbonyl }-3-formamyl-propyl group)-acid amides
A) (S)-4-formamyl-2-(cyclopropane carbonyl-amino)-butyric acid
To (S)-2-amino-4-formamyl-butyric acid (100mg, in water 0.684mmol) (16mL) mixture, add Na2CO3 (218mg, 2.052mmol) and ethylene-acetic acid (62.1uL, tetrahydrofuran (THF) 0.684mmol) (8mL) solution.After stirring 2h under the room temperature, add ethyl acetate, and the adding 1N HCl aqueous solution makes pH reduce to 3.With the water evaporate to dryness,,, obtain title compound with the filtrate evaporate to dryness with residue and methanol mixed and filtration.
MS：237[M+H]+
HPLC (Waters Symmetry C183.5 μ m 2.1 * 50mm, and the 6min method (0-3min20-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min20%ACN): 0.504min.
B) cyclopropane-carboxylic acid ((S)-1-{3-is outer-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-carbonyl-3-formamyl-propyl group)-acid amides
Title compound prepares with being similar to the described method of embodiment G1, but replaces N-ethanoyl-L-L-Ala with (S)-4-formamyl-2-(cyclopropane carbonyl-amino)-butyric acid.
MS：482[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.13min.
Embodiment G35:N-[4-(3-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propane-1-alkylsulfonyl)-phenyl]-ethanamide
Title compound prepares with being similar to the described method of embodiment G21, but replaces 3-phenylmethane alkylsulfonyl-propionic acid with 3-(4-acetylamino benzenesulfonyl)-propionic acid.
MS：512[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.19min.
Embodiment G35a:N-[4-(3-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propane-1-alkylsulfonyl)-phenyl]-the ethanamide maleate
Title compound is with being similar to the described method preparation of embodiment D2a; but with N-[4-(3-{4-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propane-1-alkylsulfonyl)-phenyl]-ethanamide replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment G35b:N-[4-(3-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propane-1-alkylsulfonyl)-phenyl]-ethanamide toluene-4-sulfonic acid salt
Title compound is with being similar to the described method preparation of embodiment D2b; but with N-[4-(3-{4-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propane-1-alkylsulfonyl)-phenyl]-ethanamide replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment G36:1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-(tetrahydrochysene-furans-2-methylmethane alkylsulfonyl)-third-1-ketone
A) 3-(2-carbobenzoxy-(Cbz)-ethyl disulphanes base)-benzyl propionate
To 3, the acid of 3 '-dithio dipropyl (1g, in DCM 4.75mmol) (6mL) solution, add DIPEA (2.86mL, 16.64mmol), DMAP (76mg, 0.618mmol) and bromotoluene (1.42mL, 11.89mmol).After stirring 16h under the room temperature, with mixture water, salt solution, the 1N HCl aqueous solution and 10%NaHCO3 solution washing.Dry and evaporate to dryness obtains orange-yellow oily thing with organic phase, by flash chromatography on silica gel (cyclohexane/ethyl acetate 1/0 to 8/2) purifying, obtains yellow oil then.
MS：391[M+H]+
HPLC (Waters Symmetry C183.5 μ m 2.1 * 50mm, and the 6min method (0-3min20-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min20%ACN): 4.206min.
B) 3-sulfydryl-benzyl propionate
With 3-(2-carbobenzoxy-(Cbz)-ethyl disulphanes base)-benzyl propionate (1.73g, THF 4.353mmol) (15mL) and water (1.5mL) the solution N that is stirring
2Air-flow deoxidation 15 minutes.Add tributylphosphine (2.15mL, 8.706mmol) after, mixture is at room temperature stirred 6h, and with the solvent evaporate to dryness.Water is handled with the DCM and the 1N HCl aqueous solution, then water is extracted with DCM, and, obtain yellow oil, by flash chromatography on silica gel (cyclohexane/ethyl acetate 1/0 to 8/2) purifying, obtain yellow oil then the dry also evaporate to dryness of the organic phase that merges.
MS：219[M+Na]+
HPLC (Waters Symmetry C18 3.5 μ m 2.1 * 50mm, and the 6min method (0-3min20-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min20%ACN): 3.365min.
C) 3-(tetrahydrochysene-furans-2-ylmethyl sulfane base)-benzyl propionate
To 3-sulfydryl-benzyl propionate (200mg, add in 1.019mmol) the tetrahydrofurfuryl bromine (505mg, 3.057mmol) and sodium methylate (55mg, 1.019mmol).After stirring 2h under the room temperature, mixture is gone out with ethyl acetate and shrend, with organic phase water and salt water washing, dry also evaporate to dryness obtains yellow oil, then by preparation HPLC (Column interchim C18 ODB 5 μ m 19 * 50, gradient: 0-5min 20% ACN, 5-15min 20-100% ACN, 15-20min 100% ACN) purifying, obtain colorless oil.
MS：281[M+H]+
HPLC (Waters Symmetry C18 3.5 μ m 2.1 * 50mm, and the 6min method (0-3min20-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min20%ACN): 3.522min.
D) 3-(tetrahydrochysene-furans-2-methylmethane alkylsulfonyl)-propionic acid
Title compound prepares with being similar to the described method of embodiment G30, but replaces 3-sec.-propyl alkylsulfonyl-benzyl propionate with 3-(tetrahydrochysene-furans-2-ylmethyl alkylsulfonyl)-benzyl propionate.
MS：245[M+Na]+
E) 1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-(tetrahydrochysene-furans-2-methylmethane alkylsulfonyl)-third-1-ketone
Title compound is with being similar to the preparation of the described method of embodiment G24, but with 3-(tetrahydrochysene-furans-2-methylmethane alkylsulfonyl)-propionic acid replacement 3-(2,3-dihydro-benzo [1,4] dioxin-6-sulfuryl amino)-propionic acid.
MS：463[M+H]+
HPLC (YMC Pack ODS-AQ 3 μ m 2.1 * 50mm, and the 6min method (0-3.5min5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min5%ACN): 2.469min.
Embodiment G37:1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-pentamethylene alkylsulfonyl-third-1-ketone
Title compound prepares with being similar to the described method of embodiment G30, but replaces the 2-propylmercaptan with cyclopentyl mercaptan.
MS：447[M+H]+
HPLC (YMC Pack ODS-AQ 3 μ m 2.1 * 50mm, and the 6min method (0-3.5min5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min5%ACN): 2.641min.
Embodiment G38:1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-ethane alkylsulfonyl-third-1-ketone
Title compound prepares with being similar to the described method of embodiment G30, but replaces the 2-propylmercaptan with sulfur alcohol.
MS：407[M+H]+
HPLC (YMC Pack ODS-AQ 3 μ m 2.1 * 50mm, and the 6min method (0-3.5min5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min5%ACN): 2.43min.
Embodiment G39:1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-(2-methyl-propane-2-alkylsulfonyl)-third-1-ketone
Title compound prepares with being similar to the described method of embodiment G30, but replaces the 2-propylmercaptan with tert-butyl mercaptan.
MS：435[M+H]+
HPLC (YMC Pack ODS-AQ 3 μ m 2.1 * 50mm, and the 6min method (0-3.5min5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min5%ACN): 2.63min.
Embodiment G40:1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-(tetrahydrochysene-pyrans-2-methylmethane alkylsulfonyl)-third-1-ketone
Title compound prepares with being similar to the described method of embodiment G36, but replaces the tetrahydrofurfuryl bromine with 2-(brooethyl) tetrahydrochysene-2H-pyrans.
MS：477[M+H]+
HPLC (YMC Pack ODS-AQ 3 μ m 2.1 * 50mm, and the 6min method (0-3.5min5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min5%ACN): 2.585min.
Embodiment G41:1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-(2-methoxyl group-ethane alkylsulfonyl)-third-1-ketone
Title compound prepares with being similar to the described method of embodiment G36, but replaces the tetrahydrofurfuryl bromine with 2-bromotrifluoromethane-methyl ether.
MS：437[M+H]+
HPLC (YMC Pack ODS-AQ 3 μ m 2.1 * 50mm, and the 6min method (0-3.5min5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min5%ACN): 2.295min.
Embodiment G41a:1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-(2-methoxyl group-ethane alkylsulfonyl)-third-1-ketone maleate
Title compound is with being similar to the described method preparation of embodiment D2a; but use 1-{4-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-(2-methoxyl group-ethane alkylsulfonyl)-third-1-ketone replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment G41b:1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-(2-methoxyl group-ethane alkylsulfonyl)-third-1-ketone toluene-4-sulfonic acid salt
Title compound is with being similar to the described method preparation of embodiment D2b; but use 1-{4-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-(2-methoxyl group-ethane alkylsulfonyl)-third-1-ketone replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment G42:1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-2-(2-methyl-propane-2-alkylsulfonyl)-ethyl ketone
Title compound prepares with being similar to the described method of embodiment G33, but replaces the 2-propylmercaptan with tert-butyl mercaptan.
MS：421[M+H]+
HPLC (YMC Pack ODS-AQ 3 μ m 2.1 * 50mm, and the 6min method (0-3.5min5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min5%ACN): 2.56min.
Embodiment G43:1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-2-pentamethylene alkylsulfonyl-ethyl ketone
Title compound prepares with being similar to the described method of embodiment G33, but replaces the 2-propylmercaptan with cyclopentyl mercaptan.
MS：433[M+H]+
HPLC (YMC Pack ODS-AQ 3 μ m 2.1 * 50mm, and the 6min method (0-3.5min5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min5%ACN): 2.68min.
Embodiment G44:1-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-(2-methyl-propane-2-alkylsulfonyl)-ethyl ketone
Title compound is with being similar to the described method preparation of embodiment G42; but with 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane replacement (S)-2-methyl-propane-2--sulfinic acid [(R)-1-piperidin-4-yl-2-(2; 4,5-three fluoro-phenyl)-ethyl]-acid amides.
MS：447[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.659min.
Embodiment G45:1-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-pentamethylene alkylsulfonyl-ethyl ketone
Title compound is with being similar to the described method preparation of embodiment G43; but with 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane replacement (S)-2-methyl-propane-2--sulfinic acid [(R)-1-piperidin-4-yl-2-(2; 4,5-three fluoro-phenyl)-ethyl]-acid amides.
MS：459[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.755min.
Embodiment G46:1-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-(propane-2-alkylsulfonyl)-ethyl ketone
Title compound is with being similar to the described method preparation of embodiment G33; but with 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane replacement (S)-2-methyl-propane-2--sulfinic acid [(R)-1-piperidin-4-yl-2-(2; 4,5-three fluoro-phenyl)-ethyl]-acid amides.
MS：433[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.601min.
Embodiment G47:N-[4-(3-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-oxo-propane-1-alkylsulfonyl)-phenyl]-ethanamide
Title compound is with being similar to the described method preparation of embodiment G35; but with 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane replacement (S)-2-methyl-propane-2--sulfinic acid [(R)-1-piperidin-4-yl-2-(2; 4,5-three fluoro-phenyl)-ethyl]-acid amides.
MS：574[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.12min.
Embodiment G48:1-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-(3-methoxyl group-benzenesulfonyl)-third-1-ketone
Title compound prepares with being similar to the described method of embodiment G44, but replaces tert-butyl mercaptan with the 3-methoxybenzenethiol.
MS：511[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.26min.
Embodiment G49:1-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-(Toluene-3,4-dithiol-alkylsulfonyl)-third-1-ketone
Title compound prepares with being similar to the described method of embodiment G44, but replaces tert-butyl mercaptan with the 3-thiocresol.
MS：495[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.27min.
Embodiment G50:1-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-(pyrimidine-2-alkylsulfonyl)-third-1-ketone
Title compound prepares with being similar to the described method of embodiment G44, but replaces tert-butyl mercaptan with pyrimidine-2-mercaptan.
MS：483[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.17min.
Embodiment G51:1-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-(6-methyl-pyridine-2-sulfuryl base)-third-1-ketone
Title compound prepares with being similar to the described method of embodiment G44, but replaces tert-butyl mercaptan with 6-methyl-pyridine-2-mercaptan.
MS：498[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.24min.
Embodiment G52:7-(3-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-oxo-propane-1-alkylsulfonyl)-3,4-dihydro-2H-isoquinoline 99.9-1-ketone
Title compound is with being similar to the preparation of the described method of embodiment G44, but with 7-sulfydryl-3,4-dihydro-2H-isoquinoline 99.9-1-ketone replacement tert-butyl mercaptan.
MS：550[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.20min.
Embodiment G53:3-(3-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-oxo-propane-1-alkylsulfonyl)-benzamide
Title compound prepares with being similar to the described method of embodiment G44, but replaces tert-butyl mercaptan with 3-sulfydryl-benzamide.
MS：525[M+H]+
Embodiment G53a:3-(3-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-oxo-propane-1-alkylsulfonyl)-the benzamide maleate
Title compound is with being similar to the described method preparation of embodiment D2a; but with 3-(3-{ (1S; 3S; 5R)-3-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-oxo-propane-1-alkylsulfonyl)-benzamide replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment G53b:3-(3-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-oxo-propane-1-alkylsulfonyl)-benzamide toluene-4-sulfonic acid salt
Title compound is with being similar to the described method preparation of embodiment D2b; but with 3-(3-{ (1S; 3S; 5R)-3-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-oxo-propane-1-alkylsulfonyl)-benzamide replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment G54:1-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-pentamethylene alkylsulfonyl-third-1-ketone
Title compound is with being similar to the described method preparation of embodiment G37; but with 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane replacement (S)-2-methyl-propane-2--sulfinic acid [(R)-1-piperidin-4-yl-2-(2; 4,5-three fluoro-phenyl)-ethyl]-acid amides.
MS：473[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.731min.
Embodiment G55:1-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-(tetrahydrochysene-furans-2-methylmethane alkylsulfonyl)-third-1-ketone
Title compound is with being similar to the described method preparation of embodiment G36; but with 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane replacement (S)-2-methyl-propane-2--sulfinic acid [(R)-1-piperidin-4-yl-2-(2; 4,5-three fluoro-phenyl)-ethyl]-acid amides.
MS：489[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.565min.
Embodiment G56:1-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-(2-methyl-propane-2-alkylsulfonyl)-third-1-ketone
Title compound is with being similar to the described method preparation of embodiment G39; but with 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane replacement (S)-2-methyl-propane-2--sulfinic acid [(R)-1-piperidin-4-yl-2-(2; 4,5-three fluoro-phenyl)-ethyl]-acid amides.
MS：461[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.700min.
Embodiment G57:1-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-ethane alkylsulfonyl-third-1-ketone
Title compound is with being similar to the described method preparation of embodiment G38; but with 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane replacement (S)-2-methyl-propane-2--sulfinic acid [(R)-1-piperidin-4-yl-2-(2; 4,5-three fluoro-phenyl)-ethyl]-acid amides.
MS：433[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.572min.
Embodiment G58:1-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-(tetrahydrochysene-pyrans-2-methylmethane alkylsulfonyl)-third-1-ketone
Title compound is with being similar to the described method preparation of embodiment G40; but with 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane replacement (S)-2-methyl-propane-2--sulfinic acid [(R)-1-piperidin-4-yl-2-(2; 4,5-three fluoro-phenyl)-ethyl]-acid amides.
MS：503[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.666min.
Embodiment G59:1-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-(2-methoxyl group-ethane alkylsulfonyl)-third-1-ketone
Title compound is with being similar to the described method preparation of embodiment G41; but with 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane replacement (S)-2-methyl-propane-2--sulfinic acid [(R)-1-piperidin-4-yl-2-(2; 4,5-three fluoro-phenyl)-ethyl]-acid amides.
MS：463[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.435min.
Embodiment G60:3-(3-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-carbonyl }-benzyl)-1-methyl-imidazolidine-2, the 4-diketone
A) 3-(3-methyl-2,5-dioxo-imidazolidine-1-ylmethyl)-methyl benzoate
Under 0 ℃, to methyl glycolylurea (hydantoine) (50mg, in DMF 0.438mmol) (2mL) solution, add sodium hydride (23mg, 0.525mmol).Stir down 1h at 0 ℃, (121mg 0.525mmol), and at room temperature stirs 2h with mixture, uses saturated NaHCO then to add 2-2-bromomethylphenyl methyl-formiate
3The aqueous solution and DCM cancellation.Dry and evaporate to dryness obtains the crude product compound with organic phase, then by preparation HPLC (Column Waters C18 ODB 5 μ m 19 * 50, gradient: 0-2.5min 5% ACN, 2.5-12.5min5-100% ACN, 12.5-15min 100%ACN) purifying, obtain title compound.
MS：285[M+Na]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.216min.
B) 3-(3-methyl-2,5-dioxo-imidazolidine-1-ylmethyl)-phenylformic acid
To 3-(3-methyl-2,5-dioxo-imidazolidine-1-ylmethyl)-methyl benzoate (100mg, 0.381mmol) THF/ water (2/1,2mL) in the solution, add lithium hydroxide monohydrate (24mg, 0.572mmol), and reactant at room temperature stirred 16h, water and ethyl acetate cancellation then.Use 1N HCl acidified aqueous solution to pH2 isolating water, use ethyl acetate extraction, dry and evaporate to dryness obtains title compound with organic phase.
MS：267[M+H2O+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 0.25min.
C) 3-(3-{ (and 1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-carbonyl-benzyl)-1-methyl-imidazolidine-2, the 4-diketone
Title compound prepares with being similar to the described method of embodiment G17, but replaces 3-(1,3-dioxo-1,3-dihydro-isoindole-2-base-methyl)-phenylformic acid with 3-(3-methyl-2,5-dioxo-imidazolidine-1-ylmethyl)-phenylformic acid.
MS：515[M+H]+
HPLC (Waters Symmetry C18 3.5 μ m 2.1 * 50mm, and the 6min method (0-3min5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min5%ACN): 2.91min.
Embodiment G61:3-(4-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-carbonyl }-benzyl)-thiazolidine-2, the 4-diketone
Title compound prepares with being similar to the described method of embodiment G1, but replaces N-ethanoyl-L-L-Ala with 4-(2,4-dioxo-thiazolidine-3-ylmethyl)-phenylformic acid.
MS：518[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.245min.
Embodiment G62:1-(4-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-carbonyl }-benzyl)-tetramethyleneimine-2, the 5-diketone
A) 2-methyl-propane-2--sulfinic acid [(R)-1-{ (1S, 3S, 5R)-8-[3-(2,5-dioxo-tetramethyleneimine-1-ylmethyl)-benzoyl]-8-aza-bicyclo [3.2.1] oct-3-yl-2-(2,4,5-three fluoro-phenyl)-ethyl]-acid amides
To 2-methyl-propane-2--sulfinic acid [(R)-1-[(1S; 3S; 5R)-8-(3-amino methyl-benzoyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-acid amides (228mg; 0.437mmol) toluene (10ml) solution in, add succinyl oxide (53mg, 0.524mmol) and molecular sieve (200mg).110 ℃ down stir 6h after, add CDI (107mg, 0.655mmol) and triethylamine (183uL, 1.311mmol), and with mixture at 110 ℃ of stirring 24h down.Behind filtration and the evaporating solvent, with residue DCM and saturated NaHCO
3The aqueous solution is handled, dry and the evaporate to dryness with organic phase, obtain the crude product compound, then by preparation HPLC (Column Waters C18 ODB5 μ m 19 * 50, gradient: 0-2.5min 5% ACN, 2.5-12.5min 5-100% ACN, 12.5-15min 100% ACN) purifying, obtain title compound.
MS：604[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.370min.
B) 1-(4-{ (and 1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-carbonyl-benzyl)-tetramethyleneimine-2, the 5-diketone
Title compound is with being similar to the described method preparation of embodiment G1; but with (S)-2-methyl-propane-2--sulfinic acid [(R)-1-{ (1S; 3S; 5R)-8-[3-(2; 5-dioxo-tetramethyleneimine-1-ylmethyl)-benzoyl]-8-aza-bicyclo [3.2.1] oct-3-yl }-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-acid amides replacement N-(outside (S)-1-methyl-2-{3--[and (R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl)-ethanamide.
MS：500[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.212min.
Embodiment G63:1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-[2-(1,1-dioxo-1 λ
*6
*-thiomorpholine-4-yl)-2-oxo-ethane alkylsulfonyl]-third-1-ketone
A) 3-carboxyl methyl sulfane base-benzyl propionate
Title compound prepares with being similar to the described method of embodiment G36, but replaces the tetrahydrofurfuryl bromine with bromoacetic acid.
MS：255[M+H]+
HPLC (Waters Symmetry C18 3.5 μ m 2.1 * 50mm, and the 6min method (0-3min20-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min20%ACN): 2.841min.
B) 3-(2-oxo-2-thiomorpholine-4-base-ethyl sulfane base)-benzyl propionate
To 3-carboxyl methyl sulfane base-benzyl propionate (763mg, 3mmol), HBTU (1.71g, 4.5mmol) and DIPEA (2.05mL, in DCM 12mmol) (10mL) solution, add thiomorpholine (283uL, 3mmol).After stirring 2h under the room temperature,, residue is dissolved in ethyl acetate with the solvent evaporate to dryness, and with the 1NHCl aqueous solution and saturated NaHCO
3Solution washing, dry and evaporate to dryness obtains title compound with organic phase.
MS：340[M+H]+
HPLC (Waters Symmetry C183.5 μ m 2.1 * 50mm, and the 6min method (0-3min20-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min20%ACN): 3.529min.
C) 1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-[2-(1,1-dioxo-1 λ
*6
*-thiomorpholine-4-yl)-2-oxo-ethane alkylsulfonyl]-third-1-ketone
Title compound prepares with being similar to the described method of embodiment G36, but replaces 3-(tetrahydrochysene-furans-2-ylmethyl alkylsulfonyl)-benzyl propionate with 3-(2-oxo-2-thiomorpholine-4-base-ethyl sulfane base)-benzyl propionate.
MS：554[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.214min.
Embodiment G63a:1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-[2-(1,1-dioxo-1 λ
*6
*-thiomorpholine-4-yl)-2-oxo-ethane alkylsulfonyl]-third-1-ketone maleate
Title compound prepares with being similar to the described method of embodiment D2a, but uses 1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-[2-(1,1-dioxo-1 λ
*6
*-thiomorpholine-4-yl)-2-oxo-ethane alkylsulfonyl]-third-1-ketone replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment G63b:1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-[2-(1,1-dioxo-1 λ
*6
*-thiomorpholine-4-yl)-2-oxo-ethane alkylsulfonyl]-third-1-ketone toluene-4-sulfonic acid salt
Title compound prepares with being similar to the described method of embodiment D2b, but uses 1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-[2-(1,1-dioxo-1 λ
*6
*-thiomorpholine-4-yl)-2-oxo-ethane alkylsulfonyl]-third-1-ketone replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment G64:1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-(2-morpholine-4-base-2-oxo-ethane alkylsulfonyl)-third-1-ketone
Title compound prepares with being similar to the described method of embodiment G63, but replaces thiomorpholine with morpholino.
MS：506[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.296min.
Embodiment G65:1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-(tetrahydrochysene-pyrans-2-methylmethane alkylsulfonyl)-third-1-ketone
Title compound is with being similar to the described method preparation of embodiment G58; but with (S)-2-methyl-propane-2--sulfinic acid [(R)-1-piperidin-4-yl-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-acid amides replace 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane.
MS：477[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.372min.
Embodiment G66:1-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-[2-(1,1-dioxo-1 λ
*6
*-thiomorpholine-4-yl)-2-oxo-ethane alkylsulfonyl]-third-1-ketone
Title compound is with being similar to the described method preparation of embodiment G63; but with 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane replacement (S)-2-methyl-propane-2--sulfinic acid [(R)-1-piperidin-4-yl-2-(2; 4,5-three fluoro-phenyl)-ethyl]-acid amides.
MS：580[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.352min.
Embodiment G67:1-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-(2-morpholine-4-base-2-oxo-ethane alkylsulfonyl)-third-1-ketone
Title compound is with being similar to the described method preparation of embodiment G64; but with 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane replacement (S)-2-methyl-propane-2--sulfinic acid [(R)-1-piperidin-4-yl-2-(2; 4,5-three fluoro-phenyl)-ethyl]-acid amides.
MS：532[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.379min.
Outside the embodiment H1:1-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-(morpholine-4-alkylsulfonyl)-ethyl ketone
This compound prepares according to flow process H:
Flow process H
A) chlorosulfonyl-methyl acetate
Under 0 ℃, to the chlorine SULPHURYL CHLORIDE (3.34g, add in ether 17.9mmol) (30mL) solution methyl alcohol (800 μ L, 19.7mmol).The mixture that obtains is stirred 1h down at 0 ℃, and, obtain title compound the solvent evaporate to dryness.
B) (morpholine-4-alkylsulfonyl)-methyl acetate
To chlorosulfonyl-methyl acetate (3.39g, in methylene dichloride 19.6mmol) (50mL) solution, add morpholine (8.6mL, 98mmol).The mixture that obtains is at room temperature stirred 2h,, obtain title compound the solvent evaporate to dryness.
MS：223[M-H]+
C) (morpholine-4-alkylsulfonyl)-acetate
With (morpholine-4-alkylsulfonyl)-methyl acetate (0.5g, 2.24mmol) be dissolved in 0.66N KOH aqueous ethanol solution (1/1,150mL), and with the mixture heating up 16h that refluxes.With the solvent evaporate to dryness, and, obtain title compound with residue methylene chloride 4:1 extraction.
MS：232[M+Na]
D) 1-{3-outer-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl-2-(morpholine-4-alkylsulfonyl)-ethyl ketone
Title compound prepares with being similar to the described method of embodiment G1, but replaces N-ethanoyl-L-L-Ala with (morpholine-4-alkylsulfonyl)-acetate.
MS：476[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 0.94min.
Outside the embodiment H1a:1-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-(morpholine-4-alkylsulfonyl)-ethyl ketone maleate
Title compound is with being similar to the described method preparation of embodiment D2a; but with 1-{3-outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-(morpholine-4-alkylsulfonyl)-ethyl ketone replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Outside the embodiment H1b:1-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-(morpholine-4-alkylsulfonyl)-ethyl ketone toluene-4-sulfonic acid salt
Title compound is with being similar to the described method preparation of embodiment D2b; but with 1-{3-outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-(morpholine-4-alkylsulfonyl)-ethyl ketone replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Outside the embodiment H2:1-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-benzenesulfonyl-ethyl ketone
Title compound prepares with being similar to the described method of embodiment H1, but replaces (morpholine-4-alkylsulfonyl)-acetate with phenyl sulfonyl acetate.
MS：466[M+H]+
HPLC (Nucleosil 100-5 C18, and the 10min method (0-1min 10%ACN, 1-6min10-100%ACN, 6-8.5min 100%ACN, 8.5-9min 100-10%ACN, 9-10min10%ACN): 3.88min.
Outside the embodiment H3:1-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-methane sulfonyl-ethyl ketone
Title compound prepares with being similar to the described method of embodiment H1, but replaces (morpholine-4-alkylsulfonyl)-acetate with the sulfonyl methane guanidine-acetic acid.
MS：405[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 0.87min.
Outside the embodiment H4:1-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-(piperidines-1-alkylsulfonyl)-ethyl ketone
Title compound prepares with being similar to the described method of embodiment H1, but replaces morpholine with piperidines.
MS：474[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.28min.
Outside the embodiment H5:2-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl sulfonic acid benzyl acid amides
Title compound prepares with being similar to the described method of embodiment H1, but replaces morpholine with benzylamine.
MS：496[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.28min.
Outside the embodiment H6:2-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl sulfonic acid benzyl-methyl-acid amides
Title compound prepares with being similar to the described method of embodiment H1, but replaces morpholine with N-methyl-benzyl amine.
MS：510[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.30min.
Outside the embodiment H7:1-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-methyl-2-(morpholine-4-alkylsulfonyl)-third-1-ketone
A) 2-methyl-2-(morpholine-4-alkylsulfonyl)-methyl propionate
To (morpholine-4-alkylsulfonyl)-methyl acetate (500mg, in tetrahydrofuran (THF) 2.24mmol) (10mL) solution, add two (trimethyl silicon based) amination potassium (1.18g, 5.6mmol).After stirring 1h under the room temperature, (349uL 5.6mmol), and at room temperature stirs 1h with the mixture that obtains, and stirs weeks down at 50 ℃ to add methyl iodide.(eluent: cyclohexane/ethyl acetate 100/0 to 0/100) purifying obtains yellow solid by flash chromatography on silica gel with solution.
MS：252[M+H]+
B) 1-{3-outer-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl-2-methyl-2-(morpholine-4-alkylsulfonyl)-third-1-ketone
Title compound prepares with being similar to the described method of embodiment H1, but replaces (morpholine-4-alkylsulfonyl)-methyl acetate with 2-methyl-2-(morpholine-4-alkylsulfonyl)-methyl propionate.
MS：504[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.26min.
Outside the embodiment H8:2-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl sulfonic acid (2-methoxyl group-ethyl)-methyl-acid amides
Title compound prepares with being similar to the described method of embodiment H1, but replaces morpholine with N-methyl-2-methoxy ethyl amine.
MS：478[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.22min.
Outside the embodiment H8a:2-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl sulfonic acid (2-methoxyl group-ethyl)-methyl-acid amides maleate
Title compound is with being similar to the described method preparation of embodiment D2a; but with 2-{3-outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl sulfonic acid (2-methoxyl group-ethyl)-methyl-acid amides replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Outside the embodiment H8b:2-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl sulfonic acid (2-methoxyl group-ethyl)-methyl-acid amides toluene-4-sulfonic acid salt
Title compound is with being similar to the described method preparation of embodiment D2b; but with 2-{3-outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-oxo-ethyl sulfonic acid (2-methoxyl group-ethyl)-methyl-acid amides replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment H9:1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-2-(morpholine-4-alkylsulfonyl)-ethyl ketone
Title compound is with being similar to the described method preparation of embodiment H1; but with (S)-2-methyl-propane-2--sulfinic acid [(R)-1-piperidin-4-yl-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-acid amides replace 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane.
MS：450[M+H]+
HPLC (Waters Symmetry C18 3.5 μ m 2.1 * 50mm, and the 6min method (0-3min20-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min20%ACN): 2.70min.
Outside the embodiment H10:1-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-methyl isophthalic acid-oxo-propane-2-sulfonic acid (2-methoxyl group-ethyl)-methyl-acid amides
Title compound prepares with being similar to the described method of embodiment H7, but replaces morpholine with N-methyl-2-methoxyethyl amine.
MS：506[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.29min.
Outside the embodiment H11:1-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-methyl isophthalic acid-oxo-propane-2-sulfonic acid benzyl-methyl-acid amides
Title compound prepares with being similar to the described method of embodiment H7, but replaces morpholine with N-methyl-benzyl amine.
MS：538[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.36min.
Outside the embodiment H12:{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-[1-(morpholine-4-alkylsulfonyl)-cyclopropyl]-ketone
Title compound prepares with being similar to the described method of embodiment H7, but replaces methyl iodide with glycol dibromide.
MS：502[M+H]+
Outside the embodiment H13:1-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-(1,3-dihydro-isoindole-2-alkylsulfonyl)-ethyl ketone
Title compound prepares with being similar to the described method of embodiment H1, but replaces morpholine with isoindoline.
MS：508[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.26min.
Embodiment H14:1-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-(4,4-two fluoro-piperidines-1-alkylsulfonyl)-ethyl ketone
Title compound prepares with being similar to the described method of embodiment H1, but with 4,4-difluoro piperidines replaces morpholine.
MS：510[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.23min.
Example I 1:N-(outside the 3-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-oxo-propyl group)-3-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-propionic acid amide
This compound prepares according to flow process I:
Flow process I
A) (S)-2-methyl-propane-2--sulfinic acid [(R)-1-piperidin-4-yl-2-(2,4,5-three fluoro-phenyl)-ethyl]-acid amides
Title compound is with being similar to Embodiment B 1 described method preparation; but use 4-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-piperidines-1-benzyl formate replace 3-outer-[(S)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-benzyl formate.
MS：363[M+H]+
HPLC (Waters Symmetry C18 3.5 μ m 2.1 * 50mm, and the 6min method (0-3min20-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min20%ACN): 2.45min.
B) (3-{4-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propyl group)-benzyl carbamate
To Cbz-Beta-alanine (339mg, 1.52mmol) methylene dichloride (10mL) solution in, add O-benzotriazole-1-base-tetramethyl-urea hexafluorophosphate (785mg, 2.07mmol) and diisopropylethylamine (960uL, 5.52mmol), add then (S)-2-methyl-propane-2--sulfinic acid [(R)-1-piperidin-4-yl-2-(2,4,5-three fluoro-phenyl)-ethyl]-acid amides (500mg, 1.379mmol).The solution that obtains is at room temperature stirred 2h, and water and salt water washing.Dry and the evaporate to dryness with organic phase, then by preparation HPLC (Column Interchrom C18 ODB 10 μ m 28 * 250, gradient: 0-2.5min5% ACN, 2.5-25.5min 5-100% ACN, 25.5-30min 100% ACN) purifying obtains yellow solid.
MS：568[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.41min.
C) (S)-2-methyl-propane-2--sulfinic acid [(R)-1-[1-(3-amino-propionyl)-piperidin-4-yl]-2-(2,4,5-three fluoro-phenyl)-ethyl]-acid amides
To (3-{4-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propyl group)-benzyl carbamate (684mg; 1.205mmol) methyl alcohol (10mL) solution in; add ammonium formiate (ammonium formiate) (379mg, 6.025mmol) and Pd/C (171mg).After stirring 72h under the room temperature, solution by diatomite filtration and evaporation, is obtained yellow solid.
MS：434[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.17min.
D) 3-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-N-(3-{4-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propyl group)-propionic acid amide
To 2-methyl-propane-2--sulfinic acid [(R)-1-[1-(3-amino-propionyl)-piperidin-4-yl]-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-acid amides (104mg; 0.241mmol) methylene dichloride (3mL) solution in; add triethylamine (101uL, 0.723), N, N-dimethyl amido SULPHURYL CHLORIDE (28.5uL; 0.265mmol) and 4-dimethylaminopyridine (6mg, 0.05mmol).After stirring 4h under the room temperature, with mixture with saturated NaHCO3 solution washing, dry and the evaporate to dryness with organic phase, obtain residue, by preparation HPLC (Column Interchrom C18 ODB 5 μ m 19 * 50, gradient: 0-5min 10%ACN, 5-15min 10-90% ACN, 15-20min 90% ACN) purifying obtains yellow oil.
MS：[M+H]+541
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.309min.
E) N-(3-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propyl group)-3-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-propionic acid amide
To 3-(1; 3-dioxo-1; 3-dihydro-isoindole-2-yl)-N-(3-{4-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propyl group)-propionic acid amide (22.3mg; 0.041mmol) in, the dioxane solution (2mL) of adding 4N HCl.The mixture that obtains is at room temperature stirred 1h, then that it is freezing, freeze-drying, and by preparation HPLC (Column YMC ODS-AQ 20 * 505uM, gradient: 0-2.5min 5% ACN, 2.5-12.5min 5-100 %ACN, 12.5-15min 100% CAN) purifying obtains white solid.
MS 437[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.09min.
Example I 1a:N-(3-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propyl group)-3-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-propionic acid amide maleate
Title compound is with being similar to the described method preparation of embodiment D2a; but with N-(3-{4-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propyl group)-3-(1; 3-dioxo-1; 3-dihydro-isoindole-2-yl)-propionic acid amide replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Example I 1b:N-(3-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propyl group)-3-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-propionic acid amide toluene-4-sulfonic acid salt
Title compound is with being similar to the described method preparation of embodiment D2b; but with N-(3-{4-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propyl group)-3-(1; 3-dioxo-1; 3-dihydro-isoindole-2-yl)-propionic acid amide replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Example I 2: cyclopropane sulfonic acid (3-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propyl group)-acid amides
Title compound prepares with being similar to example I 1 described method, but replaces N, N-dimethyl amido SULPHURYL CHLORIDE with the cyclopropane SULPHURYL CHLORIDE.
MS：434[M+H]+
HPLC (Nucleosil C18 HD CC70,6min method (0-3.5min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 5%ACN): 4.008min.
Example I 3: ethylsulfonic acid (3-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propyl group)-acid amides
Title compound prepares with being similar to example I 1 described method, but replaces N with ethyl chloride, N-dimethyl amido SULPHURYL CHLORIDE.
MS：422[M+H]+
HPLC (Nucleosil C18 HD CC70,6min method (0-3.5min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 5%ACN): 3.957min.
Example I 4: methylsulphonic acid (3-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propyl group)-acid amides
Title compound prepares with being similar to example I 1 described method, but replaces N with Methanesulfonyl chloride, N-dimethyl amido SULPHURYL CHLORIDE.
MS：408[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.58min.
Example I 5:N-(3-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propyl group)-methane amide
Title compound is with being similar to the described method preparation of example I 1, but with 3-formyl radical amino-propionic acid replaced C bz-Beta-alanine.
MS：358[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.45min.
Example I 6:
A) 3-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-N-(3-{4-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propyl group)-propionic acid amide
To 3-(1; 3-dioxo-1; 3-dihydro-isoindole-2-yl)-(83mg in methylene dichloride 0.381mmol) (2mL) solution, adds O-benzotriazole-1-base-tetramethyl-urea hexafluorophosphate (196mg to propionic acid; 0.519mmol) and diisopropylethylamine (237uL; 1.384mmol), add (S)-2-methyl-propane-2--sulfinic acid [(R)-1-[1-(3-amino-propionyl)-piperidin-4-yl]-2-(2,4 then; 5-three fluoro-phenyl)-ethyl]-acid amides (150mg, 0.346mmol).The solution that obtains is at room temperature stirred 16h, and with the 1NHCl aqueous solution and saturated NaHCO3 solution washing.Dry and evaporate to dryness by preparation HPLC (Column Interchrom C18 ODB 10 μ m 50 * 28, gradient: 0-10min 5% ACN, 10-20min 5-90%ACN, 20-25min 90% ACN) purifying, obtains orange/yellow solid then with organic phase.
MS：635[M+H]+
HPLC (Waters Symmetry C183.5 μ m 2.1 * 50mm, and the 6min method (0-3min20-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min20%ACN): 3.14min.
B) N-(3-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propyl group)-3-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-propionic acid amide
To 3-(1; 3-dioxo-1; 3-dihydro-isoindole-2-yl)-N-(3-{4-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propyl group)-propionic acid amide (137mg; 0.216mmol) in, the dioxane solution (2mL) of adding 4N HCl.The mixture that obtains is at room temperature stirred 1h, then that it is freezing, freeze-drying, and by preparation HPLC (Column Interchrom C18 ODS-AQ 10 μ m 50 * 20, gradient: 0-2.5min2% ACN, 2.5-12.5min 2-90% ACN, 12.5-15min 90% ACN) purifying obtains light yellow solid.
MS：553[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.87min.
Example I 7:N-(3-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propyl group)-isobutyramide
Title compound prepares with being similar to example I 6 described methods, but replaces 3-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-propionic acid with isopropylformic acid.
MS：400[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.096min.
Example I 8: cyclopropane-carboxylic acid (3-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propyl group)-acid amides
Title compound prepares with being similar to example I 6 described methods, but replaces 3-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-propionic acid with cyclopropane-carboxylic acid.
MS：398[M+H]+
HPLC (Waters Symmetry C18 3.5 μ m 2.1 * 50mm, and the 6min method (0-3min20-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min20%ACN): 1.75min.
Example I 9:5-oxo-tetramethyleneimine-2-formic acid (3-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propyl group)-acid amides
Title compound prepares with being similar to example I 6 described methods, but replaces 3-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-propionic acid with 5-oxo-tetramethyleneimine-2-formic acid.
MS：441[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.40min.
Example I 9a:5-oxo-tetramethyleneimine-2-formic acid (3-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propyl group)-the acid amides maleate
Title compound is with being similar to the described method preparation of embodiment D2a; but with 5-oxo-tetramethyleneimine-2-formic acid (3-{4-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propyl group)-acid amides replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Example I 9b:5-oxo-tetramethyleneimine-2-formic acid (3-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propyl group)-acid amides toluene-4-sulfonic acid salt
Title compound is with being similar to the described method preparation of embodiment D2b; but with 5-oxo-tetramethyleneimine-2-formic acid (3-{4-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propyl group)-acid amides replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Example I 10: pyridazine-4-formic acid (3-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propyl group)-acid amides
Title compound prepares with being similar to example I 6 described methods, but replaces 3-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-propionic acid with pyridazine-4-formic acid.
MS：436[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.49min.
Embodiment K1:3-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-N-cyclopropyl-3-oxo-propionic acid amide
This compound prepares according to flow process I:
Flow process K
A) 3-{4-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-benzyl propionate
Title compound is with being similar to the described method preparation of example I 1, but with propanedioic acid list benzyl ester replaced C bz-Beta-alanine.
MS：539[M+H]+
HPLC (Waters Symmetry C18 3.5 μ m 2.1 * 50mm, and the 6min method (0-3min20-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min20%ACN): 3.44min.
B) 3-{4-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propionic acid
Title compound is with being similar to example I 1 described method preparation; but use 3-{4-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-benzyl propionate replacement (3-{4-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propyl group)-benzyl carbamate.
MS：449[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.24min.
C) N-cyclopropyl-3-{4-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propionic acid amide
To 3-{4-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propionic acid (45mg; 0.0.1mmol) methylene dichloride (2mL) solution in; add O-benzotriazole-1-base-tetramethyl-urea hexafluorophosphate (57mg, 0.15mmol) and diisopropylethylamine (69uL, 0.4mmol); add then cyclopropylamine (8uL, 0.11mmol).The solution that obtains is at room temperature stirred 3h, and water and salt water washing.Dry and the evaporate to dryness with organic phase, then by preparation HPLC (Column Interchrom C18 ODB 10 μ m 50 * 28, gradient: 0-2min 10% ACN, 2-12min 10-100% ACN, 12-15 min100% ACN) purifying obtains colorless oil.
MS：488[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.27min.
D) 3-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-N-cyclopropyl-3-oxo-propionic acid amide
To N-cyclopropyl-3-{4-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-piperidines-1-yl-3-oxo-propionic acid amide (40mg, 0.082mmol) in, add the dioxane solution (2mL) of 4NHCl.The mixture that obtains is at room temperature stirred 1h, then that it is freezing, freeze-drying, and by preparation HPLC (Column nucleosil C18HD 5um 50 * 21, gradient: 0-2.5min 5% ACN, 2.5-12.5min 5-100% ACN, 12.5-15min 100% ACN) purifying obtains white solid.
MS：384[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.57min.
Embodiment K1a:3-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-N-cyclopropyl-3-oxo-propionic acid amide maleate
Title compound is with being similar to the described method preparation of embodiment D2a; but use 3-{4-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-N-cyclopropyl-3-oxo-propionic acid amide replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment K1b:3-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-N-cyclopropyl-3-oxo-propionic acid amide toluene-4-sulfonic acid salt
Title compound is with being similar to the described method preparation of embodiment D2b; but use 3-{4-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-N-cyclopropyl-3-oxo-propionic acid amide replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment K2:3-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-N, N-diethyl-3-oxo-propionic acid amide
Title compound prepares with being similar to the described method of embodiment K1, but replaces cyclopropylamine with diethylamine.
MS：400[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.75min.
Embodiment K3:3-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-N-((R)-2-hydroxyl-propyl group)-3-oxo-propionic acid amide
Title compound prepares with being similar to the described method of embodiment K1, but replaces cyclopropylamine with (R)-1-amino-propan-2-ol.
MS：402[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.39min.
Embodiment K4:4-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-N, N-dimethyl-4-oxo-butyramide
Title compound prepares with being similar to the described method of embodiment K1, but replaces propanedioic acid list benzyl ester with mono succinate benzyl ester, and replaces cyclopropylamine with dimethylamine.
MS：386[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.260min.
Embodiment K5:4-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-N-(4-hydroxyl-cyclohexyl)-4-oxo-butyramide
Title compound prepares with being similar to the described method of embodiment K4, but replaces dimethylamine with 4-amino-hexalin.
MS：456[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.46min.
Embodiment K6:4-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-N-cyclopropyl-4-oxo-butyramide
Title compound prepares with being similar to the described method of embodiment K1, but replaces propanedioic acid list benzyl ester with mono succinate benzyl ester.
MS：398[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.56min.
Outside the embodiment K7:3-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-N-cyclopropyl-3-oxo-propionic acid amide
Title compound is with being similar to the described method preparation of embodiment K1; but with 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane replacement (S)-2-methyl-propane-2--sulfinic acid [(R)-1-piperidin-4-yl-2-(2; 4,5-three fluoro-phenyl)-ethyl]-acid amides.
MS：412[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.56min.
Outside the embodiment K83-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-N-(the 4-tertiary butyl-cyclohexyl)-3-oxo-propionic acid amide
Title compound prepares with being similar to the described method of embodiment K7, but replaces cyclopropylamine with 4-tert-butylcyclohexyl amine.
MS：508[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 3.38min.
Outside the embodiment K9:{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-[1-(morpholine-4-carbonyl)-cyclopropyl]-ketone
A) 1-{3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-carbonyl-cyclopropane-carboxylic acid benzyl ester
Title compound is with being similar to the preparation of the described method of embodiment K7, but with cyclopropane-1,1-diformazan acid benzyl ester replacement propanedioic acid list benzyl ester.
MS：591[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.5min.
B) 1-{3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-carbonyl-cyclopropane-carboxylic acid
Outside 1-{3--[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-carbonyl }-cyclopropane-carboxylic acid benzyl ester (50mg; 0.085mmol) MeOH (0.425mL) solution in; the adding 1N LiOH aqueous solution (93.5uL, 0.093mmol).After stirring 16h under the room temperature, regulate pH to 3 with the 1N HCl aqueous solution, with the mixture chloroform extraction, dry and evaporate to dryness obtains the crude product compound with organic phase, and it is used preparation HPLC (Column Waters ODB 19 * 505 uM, gradient: 0-2.5min 5%ACN, 2.5-12.5min 5-100% ACN, 12.5-15min 100% ACN) purifying, obtain white solid.
MS501[M+H]+
LCMS (Waters Symmetry C183.5 μ m 2.1 * 50mm, and the 6min method (0-3min20-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min20%ACN): 3.3min.
C) outside the 3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-[1-(morpholine-4-carbonyl)-cyclopropyl]-ketone
Title compound is with being similar to the described method preparation of embodiment K7; but with 1-{3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-carbonyl-cyclopropane-carboxylic acid replace 3-{3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl-3-oxo-propionic acid, and with morpholino for cyclopropylamine.
MS：466[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.23min.
Outside the embodiment K10:1-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-carbonyl }-cyclopropane-carboxylic acid benzyl acid amides
Title compound prepares with being similar to the described method of embodiment K9, but replaces morpholine with benzyl amine.
MS：487[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.17min.
Outside the embodiment K10a:1-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-carbonyl }-cyclopropane-carboxylic acid benzyl acid amides maleate
Title compound is with being similar to the described method preparation of embodiment D2a; but with 1-{3-outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-carbonyl }-cyclopropane-carboxylic acid benzyl acid amides replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Outside the embodiment K10b:1-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-carbonyl }-cyclopropane-carboxylic acid benzyl acid amides toluene-4-sulfonic acid salt
Title compound is with being similar to the described method preparation of embodiment D2b; but with 1-{3-outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-carbonyl }-cyclopropane-carboxylic acid benzyl acid amides replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Outside the embodiment K11:1-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-carbonyl }-cyclopropane-carboxylic acid benzyl-methyl-acid amides
Title compound prepares with being similar to the described method of embodiment K9, but replaces morpholine with N-methyl-benzyl amine.
MS：500[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.27min.
Outside the embodiment K12:1-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-carbonyl }-cyclopropane-carboxylic acid (2-methoxyl group-ethyl)-methyl-acid amides
Title compound prepares with being similar to the described method of embodiment K9, but replaces morpholine with N-methyl-2-methoxy ethyl amine.
MS：468[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.22min.
Outside the embodiment K13:1-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-carbonyl }-the cyclopropane-carboxylic acid dimethylformamide
Title compound prepares with being similar to the described method of embodiment K9, but replaces morpholine with dimethylamine.
MS：424[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.22min.
Outside the embodiment K14:1-{3--[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-carbonyl }-the cyclopropane-carboxylic acid acid amides
Title compound prepares with being similar to the described method of embodiment K9, but replaces morpholine with volatile salt.
MS：396[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.11 min.
Embodiment K15:4-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-N-cyclopropyl-4-oxo-butyramide
Title compound is with being similar to the described method preparation of embodiment K6; but with 4-{3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-4-oxo-butyric acid replacement 4-{4-[(R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-4-oxo-butyric acid.
MS：424[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.61min.
Outside the embodiment K16:4-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-N-(the 4-tertiary butyl-cyclohexyl)-4-oxo-butyramide
Title compound prepares with being similar to the described method of embodiment K15, but replaces cyclopropylamine with 4-tert-butylcyclohexyl amine.
MS：522[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 3.36min.
Outside the embodiment K17:4-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-N-benzyl-4-oxo-butyramide
Title compound prepares with being similar to the described method of embodiment K15, but replaces cyclopropylamine with benzyl amine.
MS：473[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.89min.
Outside the embodiment K18:3-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-N-benzyl-2,2-dimethyl-3-oxo-propionic acid amide
Title compound is with being similar to the preparation of the described method of embodiment K7, but with dimethyl-1,1-diformazan acid benzyl ester replaces cyclopropane-1,1-diformazan acid benzyl ester, and with benzyl amine replacement morpholine.
MS：489[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.29min.
Outside the embodiment K19:1-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2,2-dimethyl-3-morpholine-4-base-propane-1,3-diketone
Title compound prepares with being similar to the described method of embodiment K18, but replaces benzyl amine with morpholino.
MS：468[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.22min.
Embodiment K20:{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-[1-(morpholine-4-carbonyl)-cyclopropyl]-ketone
Title compound is with being similar to the described method preparation of embodiment K9; but with (S)-2-methyl-propane-2--sulfinic acid [(R)-1-piperidin-4-yl-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-acid amides replace 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane.
MS：440[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.594min.
Embodiment K20a:{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-[1-(morpholine-4-carbonyl)-cyclopropyl]-ketone maleate
Title compound is with being similar to the described method preparation of embodiment D2a; but with 4-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-[1-(morpholine-4-carbonyl)-cyclopropyl]-ketone replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment K20b:{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-[1-(morpholine-4-carbonyl)-cyclopropyl]-ketone toluene-4-sulfonic acid salt
Title compound is with being similar to the described method preparation of embodiment D2b; but with 4-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-[1-(morpholine-4-carbonyl)-cyclopropyl]-ketone replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment K21:1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-carbonyl }-cyclopropane-carboxylic acid benzyl-methyl-acid amides
Title compound is with being similar to the described method preparation of embodiment K11; but with (S)-2-methyl-propane-2--sulfinic acid [(R)-1-piperidin-4-yl-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-acid amides replace 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane.
MS：474[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 3.00min.
Embodiment K22:1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-carbonyl }-cyclopropane-carboxylic acid benzyl acid amides
Title compound is with being similar to the described method preparation of embodiment K10; but with (S)-2-methyl-propane-2--sulfinic acid [(R)-1-piperidin-4-yl-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-acid amides replace 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane.
MS：457[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.881min.
Embodiment K233-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-N-(4-hydroxyl-cyclohexyl)-3-oxo-propionic acid amide
Title compound prepares with being similar to the described method of embodiment K7, but replaces cyclopropylamine with the 4-Trans-4-Amino Cyclohexanol.
MS：468[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.500min.
Embodiment K243-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-N, N-dimethyl-3-oxo-propionic acid amide
Title compound prepares with being similar to the described method of embodiment K7, but replaces cyclopropylamine with dimethylamine.
MS：398[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.413min.
Embodiment K25:{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-(1-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-two ring [3.2.1] octane-8-carbonyls }-cyclopropyl)-ketone
Title compound is with being similar to the preparation of the described method of embodiment K9, but with 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane replaces morpholine.
MS：663[M+H]+
HPLC (Waters Symmetry C18 3.5 μ m 2.1 * 50mm, and the 6min method (0-3min20-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min20%ACN): 2.974min.
Embodiment K26:4-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-N, N-dimethyl-4-oxo-butyramide
Title compound is with being similar to the described method preparation of embodiment K4; but with 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane replacement (S)-2-methyl-propane-2--sulfinic acid [(R)-1-piperidin-4-yl-2-(2; 4,5-three fluoro-phenyl)-ethyl]-acid amides.
MS：412[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.643min.
Embodiment K27:4-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-N-(4-hydroxyl-cyclohexyl)-4-oxo-butyramide
Title compound is with being similar to the described method preparation of embodiment K5; but with 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane replacement (S)-2-methyl-propane-2--sulfinic acid [(R)-1-piperidin-4-yl-2-(2; 4,5-three fluoro-phenyl)-ethyl]-acid amides.
MS：482[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.559min.
Embodiment L1: tetrahydropyrans-4-formic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-methyl-acid amides
This compound prepares according to flow process L:
Flow process L
A) methyl-(2-{3-is outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl-ethyl)-benzyl carbamate
Title compound prepares with being similar to the described method of embodiment D1, but replaces 2-phthaloyl imino ethyl sulfonyl chloride with (2-chlorosulfonyl-ethyl)-methyl-benzyl carbamate.
MS：644[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.53min.
B) (S)-2-methyl-propane-2--sulfinic acid [(R)-and 1-[3-is outer-8-(2-methylamino-ethane alkylsulfonyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-2-(2,4,5-three fluoro-phenyl)-ethyl]-acid amides
To methyl-(outside the 2-{3--[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-benzyl carbamate (530mg; 0.799mmol) ethanol (20mL) solution in; adding Pd/C (85mg, 0.799mmol).At H
2After stirring 2h under atmosphere, the room temperature, solution by diatomite filtration and evaporation, is obtained yellow solid.
MS：510[M+H]+
C) tetrahydropyrans-4-formic acid (2-{3-is outer-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl-ethyl)-methyl-acid amides
Title compound is with being similar to the described method preparation of embodiment D6; but with (S)-2-methyl-propane-2--sulfinic acid [(R)-1-[3-is outer-8-(2-methylamino-ethane alkylsulfonyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-acid amides replace 2-{3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethylamine.
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.13min.
Embodiment L1a: tetrahydropyrans-4-formic acid (outside the 2-{3--[and (R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-methyl-acid amides maleate
Title compound is with being similar to the described method preparation of embodiment D2a; but with tetrahydropyrans-4-formic acid (2-{3-is outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-methyl-acid amides replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment L2b: tetrahydropyrans-4-formic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-methyl-acid amides toluene-4-sulfonic acid salt title compound is with being similar to the preparation of the described method of embodiment D2b; but with tetrahydropyrans-4-formic acid (2-{3-is outer-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-methyl-acid amides replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Outside the embodiment L2:(2-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-methyl-urethanum
Title compound is with being similar to the described method preparation of embodiment D13; but with (S)-2-methyl-propane-2--sulfinic acid [(R)-1-[3-is outer-8-(2-methylamino-ethane alkylsulfonyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-acid amides replace 2-{3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethylamine.
MS：478[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.21min.
Outside the embodiment M1:1-{3--[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-(morpholine-4-alkylsulfonyl)-ethyl ketone
This compound prepares according to flow process M:
Flow process M
A) cyclohexyl sulphur alkyl-acetic acid
To cyclohexyl mercaptan (147uL, in DMF 1.2mmol) (1mL) solution, add bromoacetic acid (167mg, 1.2mmol) and DIPEA (616uL, 3.6mmol).The mixture that obtains is at room temperature stirred 2h, and be directly used in next step.
B) (S)-2-methyl-propane-2--sulfinic acid [(R)-1-[1-(2-cyclohexyl sulfane base-ethanoyl)-piperidin-4-yl]-2-(2,4,5-three fluoro-phenyl)-ethyl]-acid amides
To (S)-2-methyl-propane-2--sulfinic acid [(R)-1-piperidin-4-yl-2-(2,4,5-three fluoro-phenyl)-ethyl]-acid amides (200mg, 0.552mmol) methylene dichloride (1mL) solution in, add EDC (127mg, 0.662mmol), HOBt (97mg, 0.718mmol), DIPEA (283uL, 1.656mmol) and the DMF solution of cyclohexyl sulphur alkyl-acetic acid (2mL, 1.2mmol).Stir under the room temperature after 3 days, mixture with 1N HCl solution washing, with the dry also evaporate to dryness of organic phase, is obtained title compound.
MS 519[M+H]+
LCMS (Waters Symmetry C18 3.5 μ m 2.1 * 50mm, and the 6min method (0-3min20-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-20%ACN, 5.55-6min20%ACN): 4.236min.
C) 1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-2-cyclohexyl sulfane base-ethyl ketone
To (S)-2-methyl-propane-2--sulfinic acid [(R)-1-[1-(2-cyclohexyl sulfane base-ethanoyl)-piperidin-4-yl]-2-(2,4,5-three fluoro-phenyl)-ethyl]-(367mg adds the dioxane solution (2mL) of 4N HCl in 0.552mmol) to acid amides.The mixture that obtains is at room temperature stirred 20min.Freezing and freeze-drying obtains yellow oil with solution, then by preparation HPLC (Column YMCODS-AQ 20 * 505uM, gradient: 0-2.5min 5% ACN, 2.5-12.5min 5-100%ACN, 12.5-15min 100% ACN) purifying, obtain colorless oil.
MS 415[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.287min.
D) 1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-2-hexanaphthene alkylsulfonyl-ethyl ketone
To 1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-(84mg in acetate 0.203mmol) (465uL) solution, adds 30% H to 2-cyclohexyl sulfane base-ethyl ketone
2O
2The aqueous solution (83uL, 0.812mmol).The mixture that obtains is stirred 30min down at 80 ℃.Freezing and freeze-drying obtains colorless oil with solution.
MS：447[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.219min.
Embodiment M1a:1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-2-hexanaphthene alkylsulfonyl-ethyl ketone maleate
Title compound is with being similar to the described method preparation of embodiment D2a; but use 1-{4-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-2-hexanaphthene alkylsulfonyl-ethyl ketone replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment M1b:1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-2-hexanaphthene alkylsulfonyl-ethyl ketone toluene-4-sulfonic acid salt
Title compound is with being similar to the described method preparation of embodiment D2b; but use 1-{4-[(R)-1-amino-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-2-hexanaphthene alkylsulfonyl-ethyl ketone replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment M2:2-(3-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propane-1-alkylsulfonyl)-N, N-diethyl-ethanamide
A) 3-diethylamino formyl radical methyl sulfane base-propionic acid
To the 3-thiohydracrylic acid (200mg, in methyl alcohol 1.884mmol) (3mL) solution, add sodium methylate (204mg, 3.768mmol) and 2-bromo-N, N-diethyl-ethanamide (402mg, 2.070mmol).After stirring 4h under 80 ℃,, residue with ethyl acetate and water treatment, is regulated pH to 10 with the NaHCO3 aqueous solution, and used the ethyl acetate extraction water the solvent evaporate to dryness.With the 1N HCl aqueous solution with aqueous phase as acidified to pH2, it is used ethyl acetate extraction, the dry and evaporate to dryness with organic phase obtains title compound then.
MS：220[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 0.9min.
B) 2-(3-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propane-1-alkylsulfonyl)-N, N-diethyl-ethanamide
Title compound prepares with being similar to the described method of embodiment M1, but replaces cyclohexyl sulphur alkyl-acetic acid with 3-diethylamino formyl radical methyl sulfane base-propionic acid.
MS：492[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.548min.
Embodiment M3:1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-cyclopropyl methane sulfonyl-third-1-ketone
Title compound prepares with being similar to the described method of embodiment M2, but replaces 2-bromo-N, N-diethyl-ethanamide with the brooethyl cyclopropane.
MS：433[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.48min.
Embodiment M4:1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-methane sulfonyl-third-1-ketone
Title compound prepares with being similar to the described method of embodiment M1, but replaces cyclohexyl sulphur alkyl-acetic acid with 3-methylthio group propionic acid.
MS：392[M+H]+
Embodiment M5:1-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-hexanaphthene alkylsulfonyl-third-1-ketone
Title compound prepares with being similar to the described method of embodiment M1, but replaces bromoacetic acid with the 3-bromo-propionic acid.
MS：461[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.221min.
Embodiment M6:7-(3-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propane-1-alkylsulfonyl)-3,4-dihydro-2H-isoquinoline 99.9-1-ketone
A) 1-oxo-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-7-SULPHURYL CHLORIDE
Under 0 ℃, in chlorsulfonic acid (30mL), add 3,4-dihydro-2H-isoquinoline 99.9-1-ketone (5g, 34mmol).After stirring 1h under the room temperature, mixture is heated 16h down at 50 ℃, then it is poured in the ice bath carefully, and stirs 30min down at 0 ℃.With sedimentation and filtration, and dry under 60 ℃ in baking oven, obtain title compound.
MS：246[M+H]+
B) 7-sulfydryl-3,4-dihydro-2H-isoquinoline 99.9-1-ketone
To zinc powder (2.79g, 42.7mmol) and dichlorodimethylsilane (5.15mL, 42.7mmol) DCE (45mL) mixture in, add 1-oxo-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-7-SULPHURYL CHLORIDE (3g, 12.2mmol) and 1,3-methylimidazole alkane-2-ketone (3.96mL, DCE 36.6mmmol) (5mL) solution.After stirring 2h under the room temperature, mixture is concentrated.
MS：180[M+H]+
C) 7-(3-{4-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-piperidines-1-yl }-3-oxo-propane-1-alkylsulfonyl)-3,4-dihydro-2H-isoquinoline 99.9-1-ketone
Title compound is with being similar to the preparation of the described method of embodiment M1, but with 7-sulfydryl-3,4-dihydro-2H-isoquinoline 99.9-1-ketone replacement cyclohexyl mercaptan.
MS：510[M+H]+
HPLC (Waters Symmetry C18 3.5 μ m 2.1 * 50mm, and the 6min method (0-3min5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min5%ACN): 2.776min.
Embodiment M7:1-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-2-hexanaphthene alkylsulfonyl-ethyl ketone
Title compound is with being similar to the described method preparation of embodiment M1; but with 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane replacement (S)-2-methyl-propane-2--sulfinic acid [(R)-1-piperidin-4-yl-2-(2; 4,5-three fluoro-phenyl)-ethyl]-acid amides.
MS：473[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.239min.
Embodiment M8:2-(3-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-oxo-propane-1-alkylsulfonyl)-N, N-diethyl-ethanamide
Title compound is with being similar to the described method preparation of embodiment M2; but with 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane replacement (S)-2-methyl-propane-2--sulfinic acid [(R)-1-piperidin-4-yl-2-(2; 4,5-three fluoro-phenyl)-ethyl]-acid amides.
MS：518[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.648min.
Embodiment M8a:2-(3-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-oxo-propane-1-alkylsulfonyl)-N, N-diethyl-ethanamide maleate
Title compound is with being similar to the described method preparation of embodiment D2a; but with 2-(3-{ (1S; 3S; 5R)-3-[(R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-oxo-propane-1-alkylsulfonyl)-N, N-diethyl-ethanamide replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment M8b:2-(3-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-oxo-propane-1-alkylsulfonyl)-N, N-diethyl-ethanamide toluene-4-sulfonic acid salt
Title compound is with being similar to the described method preparation of embodiment D2b; but with 2-(3-{ (1S; 3S; 5R)-3-[(R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-oxo-propane-1-alkylsulfonyl)-N, N-diethyl-ethanamide replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment M9:1-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-cyclopropyl methane sulfonyl-third-1-ketone
Title compound is with being similar to the described method preparation of embodiment M3; but with 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane replacement (S)-2-methyl-propane-2--sulfinic acid [(R)-1-piperidin-4-yl-2-(2; 4,5-three fluoro-phenyl)-ethyl]-acid amides.
MS：459[M+H]+
HPLC (YMC, 6min method (0-3min 5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min 20%ACN): 2.573min.
Embodiment M10:1-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-hexanaphthene alkylsulfonyl-third-1-ketone
Title compound is with being similar to the described method preparation of embodiment M5; but with 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane replacement (S)-2-methyl-propane-2--sulfinic acid [(R)-1-piperidin-4-yl-2-(2; 4,5-three fluoro-phenyl)-ethyl]-acid amides.
MS：487[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.241min.
Embodiment M11:1-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-yl }-3-methane sulfonyl-third-1-ketone
Title compound is with being similar to the described method preparation of embodiment M4; but with 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane replacement (S)-2-methyl-propane-2--sulfinic acid [(R)-1-piperidin-4-yl-2-(2; 4,5-three fluoro-phenyl)-ethyl]-acid amides.
Embodiment N1:2-(3-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-ylmethyl }-benzyl)-isoindole-1, the 3-diketone
This compound prepares according to flow process N:
Flow process N
A) 2-(3-hydroxymethyl-benzyl)-isoindole-1, the 3-diketone
Under 0 ℃, to 3-(1,3-dioxo-1,3-dihydro-isoindole-2-ylmethyl)-phenylformic acid (300mg, in DCM 1.066mmol) (1mL) solution, add triethylamine (164uL, 1.173mmol) and Vinyl chloroformate (112uL, 1.173mmol).After 0 ℃ stirring was also filtered in 15 minutes down, under 0 ℃, the solution that obtains is joined NaBH
4(61mg in water 1.599mmol) (400uL) mixture, stirred 30 minutes down at 0 ℃ then, and at room temperature stirs 2h.Use the 1NHCl acidified aqueous solution to pH3 solution, use ethyl acetate extraction, dry and evaporate to dryness obtains the crude product compound with organic phase, and (eluent: cyclohexane/ethyl acetate 9/1 to 1/1) purifying obtains colourless jelly by flash chromatography on silica gel then.
TLC, Rf (cyclohexane/ethyl acetate 1/1)=0.15.
B) 3-(1,3-dioxo-1,3-dihydro-isoindole-2-ylmethyl)-phenyl aldehyde
Under-78 ℃, to oxalyl chloride (43uL, in DCM 0.449mmol) (400uL) solution, add DMSO (43uL, 0.598mmol).-78 ℃ down stir 15 minutes after, add 2-(3-hydroxymethyl-benzyl)-isoindole-1, the 3-diketone (80mg, DCM 0.299mmol) (600uL) solution stir mixture 45 minutes down at-78 ℃, add then triethylamine (210uL, 1.495mmol).After stirring 4h under the room temperature, will react the water cancellation,, use 10%NaHSO with the DCM extraction
4The aqueous solution and saturated NaHCO
3The solution washing organic phase.Dry and evaporate to dryness obtains the crude product compound with organic phase, and (eluent: cyclohexane/ethyl acetate 9/1 to 2/1) purifying obtains colourless jelly by flash chromatography on silica gel then.
MS：266[M+H]+
TLC, Rf (cyclohexane/ethyl acetate 1/1)=0.7.
C) (S)-2-methyl-propane-2--sulfinic acid [(R)-1-{ (1S, 3S, 5R)-8-[3-(1,3-dioxo-1,3-dihydro-isoindole-2-ylmethyl)-benzyl]-8-aza-bicyclo [3.2.1] oct-3-yl }-2-(2,4,5-three fluoro-phenyl)-ethyl]-acid amides
At room temperature; with 3-(1; 3-dioxo-1; 3-dihydro-isoindole-2-ylmethyl)-phenyl aldehyde (44mg, 0.166mmol) and 3-outer-[(R)-1-((S)-2-methyl-propane-2-sulfinyl amino)-2-(2,4; 5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane (54mg; 0.138mmol) in DCE (500uL), stir 1h, add then sodium triacetoxy borohydride (74mg, 0.345mmol).Mixture is at room temperature stirred 16h, with the solvent evaporate to dryness, obtain the crude product compound, then by preparation HPLC (Column Waters C18 ODB 5 μ m 19 * 50, gradient: 0-2.5min 5% ACN, 2.5-12.5min 5-100% ACN, 12.5-15min 100% ACN) purifying, obtain title compound.
MS：638[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.361min.
D) 2-(3-{ (and 1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-ylmethyl-benzyl)-isoindole-1, the 3-diketone
Title compound is with being similar to the described method preparation of embodiment G17; but use S)-2-methyl-propane-2--sulfinic acid [(R)-1-{ (1S; 3S; 5R)-8-[3-(1; 3-dioxo-1; 3-dihydro-isoindole-2-ylmethyl)-benzyl]-8-aza-bicyclo [3.2.1] oct-3-yl }-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-acid amides replacement (S)-2-methyl-propane-2--sulfinic acid [(R)-and 1-{ (1S, 3S, 5R)-8-[3-(1; 3-dioxo-1; 3-dihydro-isoindole-2-ylmethyl)-benzoyl]-8-aza-bicyclo [3.2.1] oct-3-yl }-2-(2,4,5-three fluoro-phenyl)-ethyl]-acid amides.
MS：534[M+H]+
HPLC (Zorbax SB C18,2min method (0-0.8min 10-95%ACN, 0.8-1.5min95%ACN, 1.5-1.6min 95-10%ACN, 1.6-2min 10%ACN): 1.228min.
Embodiment N1a:2-(3-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-ylmethyl }-benzyl)-isoindole-1, the 3-dione maleate
Title compound is with being similar to the described method preparation of embodiment D2a; but with 2-(3-{ (1S; 3S; 5R)-3-[(R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-ylmethyl }-benzyl)-isoindole-1,3-diketone replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment N1b:2-(3-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-ylmethyl }-benzyl)-isoindole-1,3-diketone toluene-4-sulfonic acid salt
Title compound is with being similar to the described method preparation of embodiment D2b; but with 2-(3-{ (1S; 3S; 5R)-3-[(R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-ylmethyl }-benzyl)-isoindole-1,3-diketone replacement cyclopropane sulfonic acid (outside the 2-{3--[and (R)-1-amino-2-(2; 4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] octane-8-alkylsulfonyl }-ethyl)-acid amides.
Embodiment N2:N-(3-{ (1S, 3S, 5R)-3-[(R)-1-amino-2-(2,4,5-three fluoro-phenyl)-ethyl]-8-aza-bicyclo [3.2.1] suffering-8-ylmethyl }-benzyl)-benzamide
Title compound is with being similar to the described method preparation of embodiment G18; but with (S)-2-methyl-propane-2--sulfinic acid [(R)-1-{ (1S; 3S; 5R)-8-[3-(1; 3-dioxo-1; 3-dihydro-isoindole-2-ylmethyl)-benzyl]-8-aza-bicyclo [3.2.1] oct-3-yl }-2-(2; 4; 5-three fluoro-phenyl)-ethyl]-acid amides replace (S)-2-methyl-propane-2--sulfinic acid [(R)-1-{3-is outer-8-[3-(1; 3-dioxo-1; 3-dihydro-isoindole-2-ylmethyl)-benzoyl]-8-aza-bicyclo [3.2.1] oct-3-yl }-2-(2,4,5-three fluoro-phenyl)-ethyl]-acid amides.
MS：508[M+H]+
HPLC (Waters Symmetry C18 3.5 μ m 2.1 * 50mm, and the 6min method (0-3min5-95%ACN, 3.5-5.5min 95%ACN, 5.5-5.55min 95-5%ACN, 5.55-6min5%ACN): 2.863min.
Embodiment P: activity experiment
Various The compounds of this invention are tested with regard to the activity that they suppress people DPP-IV.
Material
Adopt rhabdovirus system expression to constitute by amino acid 39-766 and have the people DPP-IV of streptavidin-mark at the C end, and be purified to 80% purity.This enzyme is stored in the Tris damping fluid that contains 300mM NaCl under-80 ℃, among the pH9.0.
Fluorescent probe substrate H-Gly-Pro-AMC is available from Bachem AG (Bubendorf, Switzerland).This substrate is kept under-20 ℃ with the 5mM storing solution in DMSO.All other chemical substances are available from Sigma (Buchs, Switzerland).
The experiment damping fluid that is used for the DPP-IV reaction is 25mM Tris/HCl, pH7.5, and it contains 140mM NaCl, 10mM KCl and 0.05% (w/v) CHAPS.
Compound and liquid treatment
Test compounds is dissolved in 90% DMSO/10%H
2Among the O (v/v).Adopt CyBio Dilus8-passage liquid-transfering gun (CyBio AG, Jena, Germany), (3mM to 0.03 μ M is at 90% DMSO/10%H to carry out the serial dilution of compound in 96 hole polypropylene boards
2Among the O (v/v)), 1:33.3 is diluted in the experiment damping fluid subsequently, and each changes the rifle head after drawing step.With CyBi-Well 96 passage liquid-transfering guns (CyBio AG, Jena, Germany) compound solution and substrate and enzyme solution are transferred to brassboard (384 hole black visiting plates (Cliniplate); Catalog number (Cat.No.) 95040020 Labsystems Oy, Finland) in.
Kinetic measurement
Mix with 10 μ l corresponding compounds solution by substrate solution (final concentration of substrate is 10 μ M), measure enzyme kinetics 3 times of concentration of 10 μ l in the experiment damping fluid.The enzyme solution that adds the 3 times concentration of 10 μ l in the experiment damping fluid starts reaction.For DPP-IV, final enzyme (avtive spot) concentration in the experiment is 10pM.Adopt the 350nm excitation wavelength in TECANUltra fluorescence readout instrument (TECAN, Maennedorf, Switzerland),, at interval the formation of fluorescence-causing substance (AMC) was monitored 1 hour with 35 seconds in room temperature by measuring fluorescent emission at 500nm.Measure for each, the fluorescence in every hole is by a light flash excitation.(MA USA) generates all figures and carry out IC50 and calculate for Origin 7.5Mircocal, Northampton with the Origin software package.
The result
Find that described compound is 4.7 μ M or lower to the inhibition activity (IC50 value) of people DPP-IV, and be 0.01 μ M or lower in many cases.In the situation of exemplary compounds, find that their IC50 value is 4.7-0.0001 μ M or 4.7 μ M to 0.0053 μ M.
Representative embodiment.
| Embodiment | hDPPIV IC50(μM) |
| D1 | 0.0077 |
| E7 | 0.0006 |
| G4 | 0.01 |
| H13 | 0.007 |
Claims (59)
1. formula (I) compound or its pharmacy acceptable salt or prodrug:
Wherein
Asterisk * refers to (R) or (S) chiral centre of configuration;
V does not exist or ethylidene;
W is-C (O)-or-S (O)
1-;
X is the linker that contains atom in the individual chain of 1-12 (for example 1-6) and comprise one or more connectors, described connector is selected from-O-,-C (O)-,-S (O)
1-,-N (R
9)-and optional by 1,2,3,4 or 5 R
11The alkylene that replaces;
Y be selected from-O-,-N (R
9)-,-C (O)-,-C (O) O-,-C (O) N (R
9)-,-S (O)
1-and-S (O)
1N (R
9)-linker;
R
1Be selected from hydrogen;-N (R
9) (R
10); Optional by 1,2,3,4 or 5 R
11The alkyl that replaces; Optional by 1,2,3,4 or 5 R
11The-oxyl that replaces; With optional by 1,2,3,4 or 5 R
11Replace-(CH
2)
k-heterocyclic radical;
Perhaps, as Y be-N (R
9)-time, R
1And R
9Can form heterocycle with the nitrogen-atoms that they connected, wherein this heterocycle is bonded to X and optional by 1,2,3,4 or 5 R by described nitrogen-atoms
11Replace;
R
2And R
3Be selected from R independently of one another
8,-OR
8,-C (O) R
8,-C (O) OR
8With-S (O)
1R
9
R
4And R
5Be selected from hydrogen, hydroxyl, halogen and optional independently of one another by 1,2,3,4 or 5 R
11The C that replaces
1-6Alkyl;
R
6Be aryl or heteroaryl, it is optional separately by 1,2,3,4 or 5 R
11Replace;
R
8Be selected from hydrogen; Optional by 1,2,3,4 or 5 R
11The alkyl that replaces; With optional by 1,2,3,4 or 5 R
11Replace-(CH
2)
k-heterocyclic radical;
R
9And R
10Be selected from R independently of one another
8,-OR
8,-C (O) R
8,-C (O) OR
8With-S (O)
1R
8Or R
9And R
10Form optional by 1,2,3,4 or 5 R with the nitrogen-atoms that they connected
11The heterocyclic radical that replaces;
Each R
11Be independently selected from: R
12Optional by 1,2,3,4 or 5 R
12The alkyl that replaces; With optional by 1,2,3,4 or 5 R
12Replace-(CH
2)
k-heterocyclic radical;
R
12Be independently selected from halogen, trifluoromethyl, cyano group, nitro, oxo ,=NR
13,-OR
13,-C (O) R
12,-C (O) N (R
13) R
14,-C (O) OR
13,-OC (O) R
13,-S (O)
1R
13,-S (O)
1N (R
13) R
14,-N (R
13) R
14,-N (R
13) N (R
13) R
14,-N (R
13) C (O) R
14With-N (R
13) S (O)
1R
13
R
13And R
14Be independently of one another hydrogen or be selected from alkyl and-(CH
2)
k-heterocyclic radical, it is optional separately by 1,2,3,4 or 5 substituting group replacement, and described substituting group is independently selected from oxo, halogen, cyano group, amino, hydroxyl, C
1-6Alkyl and C
1-6Alkoxyl group;
K is 0,1,2,3,4,5 or 6; And
1 is 0,1 or 2.
2. according to compound or its pharmacy acceptable salt or the prodrug of claim 1, described compound is formula (II) compound:
3. according to compound or its pharmacy acceptable salt or the prodrug of claim 1, described compound is formula (III) compound:
4. according to the compound of any aforementioned claim, wherein X is-X
1-, and X wherein
1Be selected from-O-,-C (O)-,-S (O)
1-,-N (R
9)-and optional by 1,2,3,4 or 5 R
11The alkylene that replaces (C for example
1-6Alkylidene group).
5. according to compound or its pharmacy acceptable salt or the prodrug of claim 4, described compound is formula (IV) compound:
X wherein
1Be-N (R
9)-or optional by 1,2,3,4 or 5 R
11The alkylene that replaces (C for example
1-6Alkylidene group).
6. according to the compound of claim 5, X wherein
1For choosing wantonly by 1,2,3,4 or 5 R
11The C that replaces
1-6Alkylidene group.
7. according to the compound of claim 6, wherein-W-X
1-Y-is one of following linker:
X wherein
1Be optional by 1,2,3,4 or 5 R
11Replace.
8. according to the compound of claim 7, wherein-W-X
1-Y-is one of following linker:
X wherein
1Be optional by 1,2,3,4 or 5 R
11Replace.
9. according to the compound of claim 4, wherein-W-X
1-Y-is one of following linker:
X wherein
1Be optional by 1,2,3,4 or 5 R
11Replace.
10. according to the compound of claim 9, wherein-W-X
1-Y-is one of following linker:
X wherein
1Be optional by 1,2,3,4 or 5 R
11Replace.
11. according to any one compound among the claim 1-3, wherein X is-X
1-X
2-, X wherein
1And X
2Be selected from independently of one another-O-,-C (O)-,-S (O)
1-,-N (R
9)-and optional by 1,2,3,4 or 5 R
11The C that replaces
1-6Alkylidene group.
12. according to compound or its pharmacy acceptable salt or the prodrug of claim 11, described compound is the formula V compound:
Wherein
X
1And X
2One of be-N (R
9)-; And another is optional by 1,2,3,4 or 5 R
11The C that replaces
1-6Alkylidene group.
13. according to the compound of claim 11 or claim 12, wherein-W-X
1-X
2-Y-is one of following linker:
X wherein
1Be optional by 1,2,3,4 or 5 R
11Replace.
14. according to the compound of claim 13, wherein-W-X
1-X
2-Y-is one of following linker:
X wherein
1Be optional by 1,2,3,4 or 5 R
11Replace.
15. according to the compound of any aforementioned claim, wherein R
1Be C
1-6Alkyl ,-(CH
2)
k-cycloalkyl or-(CH
2)
k-aryl, it is optional separately by 1,2,3,4 or 5 R
11Replace.
16. according to the compound of claim 15, wherein R
1Be selected from methyl; Optional by 1 or 2 R
11The cyclopropyl that replaces; With optional by 1,2,3,4 or 5 R
11The phenyl that replaces.
17. according to any one compound among the claim 1-14, wherein R
1Be optional by 1,2,3,4 or 5 R
11The heterocyclic radical (for example morpholinyl) that replaces.
18. according to the compound of any aforementioned claim, wherein R
2And R
3Each is hydrogen naturally.
19. according to the compound of any aforementioned claim, wherein R
4And R
5Each is hydrogen naturally.
20. according to the compound of any aforementioned claim, wherein R
6Be optional by 1,2,3,4 or 5 R
11The aryl that replaces.
21. according to the compound of claim 20, wherein R
6Be optional by 1,2,3,4 or 5 R
11The phenyl that replaces.
22., wherein be somebody's turn to do or each R according to the compound of claim 19
11Be halogen independently.
23. according to the compound of the following formula of any one among any one or the claim 15-17 among the claim 5-10 or, in each case, its pharmacy acceptable salt or prodrug:
Wherein:
-p is 1,2,3,4 or 5, preferably 0,1,2 or 3,
-R
11Be halogen independently.
24. according to formula (XIV) compound of claim 23, it has the represented exo configuration of following formula (XIVb)
Or, in each case, its pharmacy acceptable salt or prodrug.
25. according among the claim 11-17 any one following formula compound or, in each case, its pharmacy acceptable salt or prodrug
Wherein:
-p is 1,2,3,4 or 5, and is preferred 0,1,2 or 3,
-R
11Be halogen independently.
26. according to formula (XX) compound of claim 25, it has the represented exo configuration of following formula (XXb),
Or, in each case, its pharmacy acceptable salt or prodrug.
27. according among the claim 22-26 any one compound or, in each case, its pharmacy acceptable salt or prodrug, wherein R
6Be 2,4, the 5-trifluorophenyl.
28. according among the claim 1-21 any one compound or, in each case, its pharmacy acceptable salt or prodrug, wherein V is an ethylidene, and described compound is " external form " configuration.
29. according among the claim 1-28 any one compound or, in each case, its pharmacy acceptable salt or prodrug, wherein:
I) Y be-C (O)-; R
1Be C
1-6Alkyl, cycloalkyl, aryl or heterocyclic radical, it is optional separately by 1,2,3,4 or 5 R
11Replace, wherein R
11Be independently selected from halogen, hydroxyl, cyano group, amino ,-C (O) OH, C
1-6Alkyl, C
1-6Alkoxyl group ,-C (O)-C
1-6Alkyl ,-C (O) O-C
1-6Alkyl ,-S (O)
1-C
1-6Alkyl ,-NH (C
1-6Alkyl) and-N (C
1-6Alkyl)
2, the C of any existence wherein
1-6Alkyl group is optional to be replaced by 1,2,3,4 or 5 substituting group, and described substituting group independently is selected from halogen, cyano group, amino, hydroxyl and C
1-6Alkoxyl group,
Ii) Y is-S (O)
2-or-S (O) N (R
9)-; R
1Be hydrogen, C
1-6Alkyl, cycloalkyl, aryl or heterocyclic radical, it is optional separately by 1,2,3,4 or 5 R
11Replace, wherein R
11Be independently selected from halogen, hydroxyl, cyano group, amino ,-C (O) OH, C
1-6Alkyl, C
1-6Alkoxyl group ,-C (O)-C
1-6Alkyl ,-C (O) O-C
1-6Alkyl ,-S (O)
1-C
1-6Alkyl ,-NH (C
1-6Alkyl) and-N (C
1-6Alkyl)
2, the C of any existence wherein
1-6Alkyl group is optional to be replaced by 1,2,3,4 or 5 substituting group, and described substituting group independently is selected from halogen, cyano group, amino, hydroxyl and C
1-6Alkoxyl group, or
Iii) R
1Be-N (R
9) (R
10).
30. according to compound or its pharmacy acceptable salt or the prodrug of claim 1, described compound is formula (VI) compound:
31. according to compound or its pharmacy acceptable salt or the prodrug of claim 20, described compound is formula (IX) compound:
X wherein
1Be selected from-O-,-C (O)-,-S (O)
1-,-N (R
9)-and optional by 1,2,3,4 or 5 R
11The alkylene that replaces (C for example
1-6Alkylidene group).
32. according to compound or its pharmacy acceptable salt or the prodrug of claim 31, described compound is formula (XII) compound:
Wherein p is 0,1,2,3,4 or 5.
33. according to the compound of claim 31 or claim 32, wherein X
1Be
I)-N (R
9)-or optional by 1,2,3,4 or 5 R
11The alkylene that replaces (C for example
1-6Alkylidene group), or
Ii)-N (R
9)-or optional by 1,2,3,4 or 5 R
11The C that replaces
1-6Alkylidene group.
34. according to compound or its pharmacy acceptable salt or the prodrug of claim 31, described compound is formula (XV) compound:
X wherein
1And X
2Be selected from independently of one another-O-,-C (O)-,-S (O)
1-,-N (R
9)-and optional by 1,2,3,4 or 5 R
11The C that replaces
1-6Alkylidene group.
35. according to compound or its pharmacy acceptable salt or the prodrug of claim 34, described compound is formula (XVIII) compound:
Wherein p is 0,1,2,3,4 or 5.
36. according to the compound of claim 34 or claim 35, wherein X
1And X
2One of be-N (R
9)-; And another is optional by 1,2,3,4 or 5 R
11The C that replaces
1-6Alkylidene group.
37. according to any one compound in claim 11 or claim 12 or the claim 15 to 22, wherein-W-X
1-Y-is one of following linker:
X wherein
1Be optional by 1,2,3,4 or 5 R
11Replace.
38. according to any one compound in claim 13 or the claim 15 to 22, wherein-W-X
1-Y-is one of following linker:
X wherein
1Be optional by 1,2,3,4 or 5 R
11Replace, or work as X
2X when being alkylidene group
2Be optional by 1,2,3,4 or 5 R
11Replace.
39. according to any one compound in the aforementioned claim, wherein X
1Or X
2By 1,2,3,4 or 5 R
11, preferred 1 or 2 R
11The alkylidene group or the arylidene that replace.
40. according to the compound of claim 39, wherein R
11Be selected from tap bolt group, C
1-6Alkyl ,-O-C
1-6Alkyl ,-NH-C (O)-(C
1-6Alkyl), phenyl, benzyl, hydroxyl, halogen, amino, wherein alkyl group be optional by amino, hydroxyl ,-C (O)-N (C
1-6Alkyl) (C
1-6Alkyl) ,-C (O)-NH (C
1-6Alkyl) ,-C (O)-NH
2, (C
1-6Alkyl) or halogen replace.
41. according to any one compound in the aforementioned claim, wherein R
1Be
I)-oxyl, it is optional by 1,2,3,4 or 5 R
11Replace, or
Ii) C
1-6Alkoxyl group, it is optional by 1,2,3,4 or 5 R
11Replace.
42. according to the compound of claim 1 or, in each case, its pharmacy acceptable salt or prodrug, described compound is selected from:
43. according to the compound of claim 1 or, in each case, its pharmacy acceptable salt or prodrug, described compound is selected from:
44. according to the compound of any aforementioned claim, it exists with pure substantially (R) enantiomeric forms, wherein (R) refers to C
*The three-dimensional chemical configuration at place.
45. according to the compound of any aforementioned claim, its exo configuration form with pure substantially bridging piperidine ring exists.
46. according to the compound of claim 45, its moderate purity is greater than 95%.
47. according to the compound of any aforementioned claim, it uses in treatment.
48. pharmaceutical preparation, this pharmaceutical preparation comprise among the claim 1-43 compound of any one.
49. according to the preparation of claim 48, it also comprises pharmaceutically acceptable vehicle or carrier.
50. preparation according to claim 48 or claim 49, it also comprises the therapeutic activity agent, and described therapeutic activity agent is selected from: antidiabetic, hypolipidemic, anti-obesity or appetite stimulator, antihypertensive drug, HDL-dose, cholesterol absorption conditioning agent, Apo-A1 analogue and stand-in, thrombin inhibitors, aldosterone inhibitor, anticoagulant, oestrogenic hormon, testosterone, selective estrogen receptor modulators, SARM, chemotherapeutics and 5-HT
3Or 5-HT
4Receptor modulators, perhaps its pharmacy acceptable salt or prodrug.
51. preparation according to claim 50, wherein said promoting agent is: Tegaserod, imatinib, Vildagliptin, N1,N1-Dimethylbiguanide, thiazolidinone derivatives, sulfonylurea receptors ligand, aliskiren, valsartan, orlistat or his spit of fland, perhaps its pharmacy acceptable salt or prodrug.
52. product, this product comprise among the claim 1-43 any one compound and claim 50 in defined promoting agent, its as in the treatment simultaneously, respectively or the combination preparation that uses successively.
53. according to the product of claim 52, wherein said promoting agent in the claim 51 definition.
54. the purposes of the compound of any one in the medicine of preparation treatment or preventing disease or illness among the claim 1-43, described disease or illness are selected from non-insulin-dependent diabetes mellitus (NIDDM), sacroiliitis, fat, allograft is transplanted, thyrocalcitonin-osteoporosis, in heart failure, impaired glucose metabolism or glucose tolerance reduce, neurodegenerative disease, cardiovascular or kidney disease and neurodegenerative disorders or cognitive disorder, hyperglycemia, insulin resistant, lipid disorders, hyperlipemia, hyperlipidaemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL level, atherosclerosis, vascular restenosis, irritable bowel syndrome, inflammatory bowel disease, pancreatitis, retinopathy, ephrosis, neuropathy, X syndrome, ovarian androgens increase disease (polycystic ovarian syndrome), diabetes B, growth hormone deficiency, neutrophilic granulocytopenia, the neurone illness, metastases, benign prostatauxe, gingivitis, hypertension and osteoporosis.
55. according to the purposes of claim 54, wherein said disease or illness are Alzheimer, Parkinson's disease, Crohn disease or ulcerative colitis.
56. according to the purposes of claim 54, wherein said disease is hypertrophy medial thickness, mesentery vascular system hypertrophy or the glomerular mesangium hypertrophy of diabetic cardiomyopathy, a left side or right ventricular hypertrophy, artery and/or great vessels.
57. the compound of any one is in the purposes of preparation in the medicine among the claim 1-43, described medicine is used to produce calmness or angst resistance effect, the alienation of minimizing postoperative changes or to stress hormone response, mortality ratio after the myocardial infarction and sickness rate, adjusting hyperlipidaemia or relevant illness or reduce VLDL, LDL or Lp (a) level.
58. the method for treatment or preventing disease or illness in the patient, this method comprise any one compound administration among the claim 1-43 of treatment significant quantity.
59. according to the method for claim 58, wherein said disease or illness are as any one is defined among the claim 54-56.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0607309A GB0607309D0 (en) | 2006-04-11 | 2006-04-11 | Organic compounds |
| GB0607309.2 | 2006-04-11 | ||
| EP06122445.7 | 2006-10-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101472892A true CN101472892A (en) | 2009-07-01 |
Family
ID=36571654
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007800215552A Pending CN101472892A (en) | 2006-04-11 | 2007-04-10 | Organic compounds |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101472892A (en) |
| GB (1) | GB0607309D0 (en) |
-
2006
- 2006-04-11 GB GB0607309A patent/GB0607309D0/en not_active Ceased
-
2007
- 2007-04-10 CN CNA2007800215552A patent/CN101472892A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| GB0607309D0 (en) | 2006-05-24 |
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