CN101454318A - Pyridopyrimidine derivatives and their use as pde4 inhibitors - Google Patents
Pyridopyrimidine derivatives and their use as pde4 inhibitors Download PDFInfo
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- CN101454318A CN101454318A CNA2007800188625A CN200780018862A CN101454318A CN 101454318 A CN101454318 A CN 101454318A CN A2007800188625 A CNA2007800188625 A CN A2007800188625A CN 200780018862 A CN200780018862 A CN 200780018862A CN 101454318 A CN101454318 A CN 101454318A
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Abstract
The present invention provides a compound of a formula (I): wherein the variables are defined herein; to a process for preparing such a compound; and to the use of such a compound in the treatment of a PDE 4 mediated disease state.
Description
Technical field
The present invention relates to have the Pyridopyrimidine derivatives of pharmaceutical activity, the method for preparing these derivatives, the pharmaceutical composition that comprises these derivatives and these derivatives purposes as active therapeutic agent.
Background technology
The Pyridopyrimidine derivatives of pharmaceutical activity is disclosed among EP-A-0260817, WO 98/02162, WO 93/19068 and the WO 0045800.
Phosphodiesterase (PDEs) is brought into play its effect by the nonactive Nucleotide form that cAMP or cGMP is changed into AMP and GMP and maybe can not activate the downstream signal conducting path.Inhibition to PDEs has caused gathering of cAMP or cGMP, causes the activation of path downstream subsequently.PDEs comprises the second messenger of a big series, comprises 11 families and the isoform more than 50.In addition, with regard to each isoform splice variant (splice variant) has been described.PDEs can be cAMP specific (PDE4,7,8,10) or cGMP specific (PDE5,6,9), or has dual specificity (PDE1,2,3,11).
Because the effect of the adenylate cyclase that GPCR regulates, generate cAMP by ATP at the internal lobe (inner leaflet) of plasma membrane.In case generate cAMP, the unique channel of termination signal is exactly by the phosphodiesterase effect, and cAMP is degraded into 5 '-AMP.The cAMP that concentration increases mainly causes the response of cell by the activation of the dependent protein kinase of cAMP (PKA).The activity specific of PKA is partly regulated by the Subcellular Localization of PKA, and this has limited the phosphorylation of PKA near substrate it.Be difficult to illustrate by PKA and activate caused downstream events, and the various ingredients of these incidents when being involved in signal cascade and amplifying (signalling cascade) beginning.What shown is, PDE4s brings into play a large amount of effects when regulating cell desensitization, adaptation, signal communicating (cross-talk), cAMP zoning (compartmentalization) and feedback loop, and is the main conditioning agent of cAMP stable state.
The cAMP level improves the physiological action that is involved and comprises: 1) extensively suppress panimmunity and form cell activity; 2) lure that airway smooth muscle is lax into; 3) suppress unstriated muscle mitotic division; With 4) the nervus pulmonalis activity is had useful regulating effect.
What found is that PDE4 is the cAMP metabolism isozyme family that dominates in immunity and inflammatory cell, and the cAMP metabolism in the airway smooth muscle mainly ascribes PDE4 family and PDE3 family to.
In the past twenty years, the PDE4 selective depressant that is used for the treatment of inflammation and Immunological diseases is developed in very big concentrating on, described disease comprises asthma, rhinitis, bronchitis, COPD, sacroiliitis and psoriasis.What reported is that multiple compound (for example rolipram (rolipram), tibenelast (tibenelast) and denbufylline (denbufylline)) has mirable effect in inflammatory animal model (especially pneumonia animal model).
Rolipram tibenelast denbufylline
Unfortunately, the clinical application of these inhibitor is subject to the relevant side effect of PDE4, comprises nauseating, vomiting and gastric acid secretion.What recently described is, s-generation PDE4 inhibitor (for example cilomilast (cilomilast), roflumilast (roflumilast) and AWD12-281) in vomiting animal model, significantly reduce the risk that emetic side effect occurs, thereby have the potentiality that improve the treatment ratio.
Cilomilast roflumilast AWD12-281
The invention discloses new Pyridopyrimidine derivatives, the inhibitor of described aminopyridine sulfone amide derivative behaviour PDE4 can be used for treatment thus.
Summary of the invention
The invention provides formula (I) compound or its N-oxide compound or its pharmaceutical salts:
Wherein:
X is S, S (O) or S (O)
2
E is N or CE
1
T is C (O) or S (O)
2
W is (CH
2)
n
Y is (CH
2)
p
N and p independently are 0 or 1;
M is 0 or 1;
L is CH or N;
If L is CH, then J is NH; And if L is N, then J does not exist and T directly links to each other with L;
R
1Be C
1-10Alkyl (is chosen wantonly and is replaced by following group: halogen, hydroxyl, cyano group, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Alkoxyl group (C
1-6Alkoxyl group), aryl, heteroaryl, aryloxy, heteroaryl oxygen base, artyl sulfo, heteroaryl sulfenyl, aryl (C
1-4Alkoxyl group), aryl (C
1-4Alkylthio), C
3-7Cycloalkyl is (optional by hydroxyl, C
1-4Alkyl, C
1-4Alkoxyl group or phenyl replace), CO
2H, CO
2(C
1-6Alkyl), NHC (O) R
3, THP trtrahydropyranyl, C (O) NR
24R
25, S (O)
2R
26Or NHS (O)
2R
27); C
1-6Alkoxyl group; C
2-4Thiazolinyl (choose wantonly and replaced) by phenyl; C
3-6Cycloalkyl is (optional by hydroxyl, halogen, C
1-6Alkyl, C
1-6Alkoxyl group or phenyl replace); Heterocyclic radical (is chosen wantonly and is replaced by following group: oxo (oxo), hydroxyl, C
1-6Alkyl, S (O)
2(C
1-4Alkyl), C (O) (C
1-4Alkyl), aryl, heteroaryl, aryl (C
1-4Alkyl), C (O) heteroaryl or heterocyclic radical); Aryl or heteroaryl;
R
3Be C
1-6Alkyl or phenyl;
Above-mentioned R
1And R
3In phenyl, aryl and heteroaryl moieties optionally independently replaced by following group: halogen, cyano group, nitro, hydroxyl, S (O)
qR
4, OC (O) NR
5R
6, NR
7R
8, NR
9C (O) R
10, NR
11C (O) NR
12R
13, S (O)
2NR
14R
15, NR
16S (O)
2R
17, C (O) NR
18R
19, C (O) R
20, CO
2R
21, NR
22CO
2R
23, C
1-10Alkyl, C
1-6Hydroxyalkyl, C
1-6Haloalkyl, C
1-6Alkoxyl group (C
1-6) alkyl, C
1-6Alkyl (S (O)
2(C
1-4Alkyl)) two (C,
1-6) alkylamino (C
1-6) alkyl, C
1-6Alkoxyl group, C
1-6Halogenated alkoxy, C
1-6Alkoxyl group (C
1-6) alkoxyl group, C
1-6Alkylthio, C
2-6Thiazolinyl, C
2-6Alkynyl (choose wantonly and replaced), C by phenyl
3-10(itself is optional by C for cycloalkyl
1-4Alkyl or oxo replace), methylene-dioxy (methylenedioxy), OCH
2CH
2O, difluoro methylene-dioxy, heterocyclic radical (are chosen wantonly by hydroxyl, C
1-4Alkyl, phenyl or heteroaryl replace), phenyl, phenyl (C
1-4) alkyl, phenoxy group, phenyl sulfenyl, phenyl (C
1-4) alkoxyl group, heteroaryl, heteroaryl (C
1-4) alkyl, heteroaryl oxygen base or heteroaryl (C
1-4) alkoxyl group; Wherein just described arbitrarily phenyl or heteroaryl moieties are optional to be replaced by following group: halogen, hydroxyl, nitro, S (O)
r(C
1-4Alkyl), S (O)
2NH
2, S (O)
2NH (C
1-4Alkyl), S (O)
2N (C
1-4Alkyl)
2, cyano group, C
1-4Alkyl, C
1-4Alkoxyl group, C (O) NH
2, C (O) NH (C
1-4Alkyl), C (O) N (C
1-4Alkyl)
2, CO
2H, CO
2(C
1-4Alkyl), NHC (O) (C
1-4Alkyl), NHS (O)
2(C
1-4Alkyl), C (O) (C
1-4Alkyl), CF
3Or OCF
3
E
1And G
1Independent is hydrogen, halogen, cyano group, hydroxyl, C
1-4Alkyl, C
1-4Alkoxyl group, CF
3Or OCF
3
Q and r independently are 0,1 or 2;
R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11, R
12, R
13, R
14, R
15, R
16, R
17, R
18, R
19, R
20, R
21, R
22, R
23, R
24, R
25, R
26And R
27Independent is C
1-10Alkyl { is chosen wantonly and is replaced by following group: halogen, hydroxyl or C
1-6Alkoxyl group, or optional substituted phenyl as described below separately or heteroaryl }, CH
2(C
2-6Thiazolinyl), phenyl { itself is chosen wantonly and is replaced by following group: halogen, hydroxyl, nitro, NH
2, NH (C
1-4Alkyl), N (C
1-4Alkyl)
2, S (O)
2(C
1-4Alkyl), S (O)
2NH
2, S (O)
2NH (C
1-4Alkyl), S (O)
2N (C
1-4Alkyl)
2, cyano group, C
1-4Alkyl, C
1-4Alkoxyl group, C (O) NH
2, C (O) NH (C
1-4Alkyl), C (O) N (C
1-4Alkyl)
2, CO
2H, CO
2(C
1-4Alkyl), NHC (O) (C
1-4Alkyl), NHS (O)
2(C
1-4Alkyl), C (O) (C
1-4Alkyl), CF
3Or OCF
3Or heteroaryl { itself is optional to be replaced by following group: halogen, hydroxyl, nitro, NH
2, NH (C
1-4Alkyl), N (C
1-4Alkyl)
2, S (O)
2(C
1-4Alkyl), S (O)
2NH
2, S (O)
2NH (C
1-4Alkyl), S (O)
2N (C
1-4Alkyl)
2, cyano group, C
1-4Alkyl, C
1-4Alkoxyl group, C (O) NH
2, C (O) NH (C
1-4Alkyl), C (O) N (C
1-4Alkyl)
2, CO
2H, CO
2(C
1-4Alkyl), NHC (O) (C
1-4Alkyl), NHS (O)
2(C
1-4Alkyl), C (O) (C
1-4Alkyl), CF
3Or OCF
3;
R
5, R
6, R
7, R
8, R
9, R
10, R
11, R
12, R
13, R
14, R
15, R
16, R
18, R
19, R
20, R
21, R
22, R
23, R
24And R
25Also can be hydrogen.
Can there be (for example enantiomer, diastereomer, geometrical isomer or tautomer) by different isomeric form in some compound of the present invention.The mixture of all these isomer and their various ratios is contained in the present invention.
Suitable salt comprises acid salt, for example hydrochloride, dihydrochloride, hydrobromate, phosphoric acid salt, vitriol, acetate, diacetin, fumarate, maleate, malonate, succinate, tartrate, citrate, oxalate, mesylate or tosilate.Other example of acid salt has: hydrosulfate, benzene sulfonate, esilate, malonate, xinafoate (xinafoate), ascorbate salt, oleate, nicotinate, saccharinic acid (saccharinate), adipate, formate, oxyacetate, the L-lactic acid salt, D-lactate, aspartate, malate, the L-tartrate, the D-tartrate, stearate, the 2-furoate, the 3-furoate, napadisilate (naphthalene-1,5-stilbene-4,4'-bis-(1-azo-3, 4-dihydroxy-benzene)-2,2'-disulfonate or naphthalene-1-(sulfonic acid)-5-sulfonate), ethanedisulphonate (ethane-1,2-stilbene-4,4'-bis-(1-azo-3, 4-dihydroxy-benzene)-2,2'-disulfonate or ethane-1-(sulfonic acid)-2-sulfonate), isethionate (2-hydroxyethyl sulfonate), 2-mesitylene sulfonate and 2-naphthalenesulfonate.
Compound of the present invention can exist by the form of solvate (for example hydrate), and all these solvates are contained in the present invention.
Halogen comprises fluorine, chlorine, bromine and iodine.Halogen for example is a fluorine or chlorine.
Moieties is a straight or branched, for example is methyl, ethyl, n-propyl, sec.-propyl or the tertiary butyl.Haloalkyl for example is C
2F
5, CF
3Or CHF
2Alkoxyl group for example is a methoxy or ethoxy; And halogenated alkoxy for example is OCF
3Or OCHF
2
Thiazolinyl for example is vinyl or third-2-thiazolinyl.Alkynyl for example is a propargyl.
Cycloalkyl for example is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; Perhaps cycloalkyl can condense with phenyl ring, forms for example indanyl.Cycloalkyloxy for example is cyclopropyl oxygen base, cyclopentyloxy or cyclohexyl oxygen base.Cycloalkyl alkoxy for example is (cyclopropyl) methoxyl group or 2-(cyclopropyl) oxyethyl group.
Heterocyclic radical is 5 or 6 yuan of rings that comprise non-aromatics, optional the condensing on one or more other non-aromaticity rings of described 5 or 6 yuan of rings, and optional and phenyl ring or heteroaromatic rings (such as following hetero-aromatic ring) condense, and described heterocyclic radical comprises at least one heteroatoms that is selected from nitrogen, oxygen and sulphur.For example, heterocyclic radical is azetidinyl (azetidinyl), pyrrolidyl, piperidyl, piperazinyl, pseudoindoyl, morpholino, 3,8-diazabicylo [3.2.1] octyl group, 8-azabicyclic [2.2.2] octyl group, 2-oxa--6-azabicyclic [5.4.0] 11 carbon-7,9,11-trialkenyl, 7-oxa--10-azabicyclic [4.4.0] last of the ten Heavenly stems-1,3,5-trialkenyl, 6-thia-1,4-diazabicylo [3.3.0] hot-4,7-dialkylene, THP trtrahydropyranyl, azabicyclic [3.2.1] octyl group, 1,2,3,4-tetrahydric quinoline group, 1, the 4-diaza
Base (1,4-diazepinyl), quinuclidinyl (quinuclidinyl), 9-oxa--2,8-diaza spiro [4.4] ninth of the ten Heavenly Stems-7-thiazolinyl, 1,2-dihydroquinazoline base, 2,4,10-three azabicyclics [4.4.0] last of the ten Heavenly stems-1,3,5,8-apos, 2-oxa--5-aza-bicyclo [4.4.0] last of the ten Heavenly stems-7,9,11-trialkenyl, adamantyl, tetrahydrofuran base or thiazine alkyl (thiazinanyl) (for example being the form of S-titanium dioxide group).
Hydroxyalkyl for example is CH
2OH; C
1-6Alkoxyl group (C
1-6) alkyl for example is CH
3OCH
2And C
1-6Alkoxyl group (C
1-6) alkoxyl group for example is CH
3OCH
2O.Dialkyl aminoalkyl for example is (CH
3)
2NCH
2Or (CH
3) (CH
3CH
2) NCH
2
Aryl for example is a phenyl or naphthyl.Aryl for example is a phenyl.
Heteroaryl for example is aromatics 5 or 6 yuan of rings, and it is chosen wantonly with one or more other rings and condenses, and described ring comprises that at least one is selected from the heteroatoms in nitrogen, oxygen and the sulphur; Or be its N-oxide group or its S-oxide group or S-titanium dioxide group.Heteroaryl for example is a furyl, thienyl (also being known as thiophenyl), pyrryl, thiazolyl, isothiazolyl, pyrazolyl oxazolyl isoxazolyl, imidazolyl, [1,2,3]-thiadiazolyl group, [1,2,4]-triazolyl, [1,2,3]-triazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indyl, benzo [b] furyl (also being known as benzofuryl), benzo [b] thienyl (also being known as benzothienyl), indazolyl, benzimidazolyl-, 1,2,3-benzotriazole base benzoxazolyl, 1, the 3-benzothiazolyl, 1,2,3-diazosulfide base, (for example imidazo [1 for imidazopyridyl, 2a] pyridyl), thieno-[3,2-b] pyridine-6-base, 2,1,3-Ben Bing oxadiazole base (also is known as benzo [1,2,3] thiadiazolyl group), 2,1,3-diazosulfide base, benzo furazan (also being known as 2,1,3-Ben Bing oxadiazole base), quinoxalinyl, (for example the 1H-pyrazolo [3 for Pyrazolopyridine, 4-b] pyridyl or pyrazolo [1,5-a] pyridyl), imidazopyridine (for example imidazo [1,2-a] pyridyl), dihydro pyrido [2,3-d] pyrimidine (for example 1,4-dihydro pyrido [2,3-d] pyrimidyl), quinolyl, isoquinolyl, phthalazinyl ([1,6] phthalazinyl for example, [1,7] phthalazinyl or [1,8] phthalazinyl), 1,2, the 3-thiadiazolyl group, 1H-pyrrolo-[2,3-b] pyridyl, thieno-[2,3-b] pyridyl, thieno-[2,3-b] pyrazinyl, [1,2,4] triazolo [1,5-a] pyrimidyl or 6,7-dihydro-5H-[1,3] thiazole [3,2-a] pyrimidyl also; Or be its N-oxide group or its S-oxide group or S-titanium dioxide group.
One concrete aspect, the invention provides formula (I) compound, or its N-oxide or its pharmaceutical salts, wherein: X is S, S (O) or S (O)2 E is N or CE1 T is C (O) or S (O)2 W is (CH2)
n Y is (CH2)
p N and p are independently 0 or 1; M is 0 or 1; L is CH or N; If L is CH, J is NH; And if L is N, J does not exist and T directly is connected with L; R1For C1-10Alkyl (is chosen wantonly and is replaced by following group: halogen, hydroxyl, cyano group, C1-6Alkoxyl, C1-6Alkylthio group, C1-6Alkoxyl (C1-6Alkoxyl), aryl, heteroaryl, aryloxy, heteroaryl oxygen base, aryl (C1-4Alkoxyl), aryl (C1-4Alkylthio group), C3-7Cycloalkyl is (optional by C1-4The alkyl replacement), CO2H、CO
2(C
1-6Alkyl), NHC (O) R3, THP trtrahydropyranyl, C (O) NR24R
25、S(O)
2R
26Or NHS (O)2R
27)；C
1-6Alkoxyl; C2-4Thiazolinyl (optional by phenyl substituted); C3-6Cycloalkyl is (optional by hydroxyl, halogen, C1-6Alkyl, C1-6Alkoxyl or phenyl substituted); Heterocyclic radical (is chosen wantonly and is replaced by following group: oxo, hydroxyl, C1-6Alkyl, S (O)2(C
1-4Alkyl), C (O) (C1-4Alkyl), aryl, heteroaryl, aryl (C1-4Alkyl), C (O) heteroaryl or heterocyclic radical); Aryl or heteroaryl; R3For C1-6Alkyl or phenyl; Above-mentioned R1And R3In phenyl, aryl and heteroaryl moieties optionally independently by following group, replaced: halogen, cyano group, nitro, hydroxyl, S (O)qR
4、OC(O)NR
5R
6、NR
7R
8、
NR
9C(O)R
10、NR
11C(O)NR
12R
13、S(O)
2NR
14R
15、NR
16S(O)
2R
17、C(O)NR
18R
19、
C(O)R
20、CO
2R
21、NR
22CO
2R
23、C
1-10Alkyl, C1-6Hydroxy alkyl, C1-6Haloalkyl, C1-6Alkoxyl (C1-6) alkyl, C1-6Alkyl (S (O)2(C
1-4Alkyl)), two (C1-6) alkyl amino (C1-6) alkyl, C1-6Alkoxyl, C1-6Halogenated alkoxy, C1-6Alkoxyl (C1-6) alkoxyl, C1-6Alkylthio group, C2-6Thiazolinyl, C2-6Alkynyl (optional by phenyl substituted), C3-10(itself is optional by C for cycloalkyl1-4Alkyl or oxo replace), methylene-dioxy, OCH2CH
2O, difluoro methylene-dioxy, heterocyclic radical (are chosen wantonly by hydroxyl, C1-4Alkyl, phenyl or heteroaryl replace), phenyl, phenyl (C1-4) alkyl, phenoxy group, phenyl sulfenyl, phenyl (C1-4) alkoxyl, heteroaryl, heteroaryl (C1-4) alkyl, heteroaryl oxygen base or heteroaryl (C1-4) alkoxyl; Wherein just described phenyl or heteroaryl moieties are optional is arbitrarily replaced by following group: halogen, hydroxyl, nitro, S (O)r(C
1-4Alkyl), S (O)2NH
2、S(O)
2NH(C
1-4Alkyl), S (O)2N(C
1-4Alkyl)2, cyano group, C1-4Alkyl, C1-4Alkoxyl, C (O) NH2、C(O)NH(C
1-4Alkyl), C (O) N (C1-4Alkyl)2、CO
2H、CO
2(C
1-4Alkyl), NHC (O) (C1-4Alkyl), NHS (O)2(C
1-4Alkyl), C (O) (C1-4Alkyl), CF3Or OCF3；E
1And G1Independent is hydrogen, halogen, cyano group, hydroxyl, C1-4Alkyl, C1-4Alkoxyl, CF3Or OCF3 Q and r are independently 0,1 or 2; R4、R
5、R
6、R
7、R
8、R
9、R
10、R
11、R
12、R
13、R
14、R
15、R
16、R
17、
R
18、R
19、R
20、R
21、R
22、R
23、R
24、R
25、R
26And R27Independent is C1-10Alkyl { is chosen wantonly and is replaced by following group: halogen, hydroxyl or C1-6Alkoxyl or optional substituted phenyl as described below or heteroaryl separately }, CH2(C
2-6Thiazolinyl), phenyl { itself is chosen wantonly and is replaced by following group: halogen, hydroxyl, nitro, NH2、NH(C
1-4Alkyl), N (C1-4Alkyl)2、S(O)
2(C
1-4Alkyl), S (O)2NH
2、
S(O)
2NH(C
1-4Alkyl), S (O)2N(C
1-4Alkyl)2, cyano group, C1-4Alkyl, C1-4Alkoxyl, C (O) NH2、C(O)NH(C
1-4Alkyl), C (O) N (C1-4Alkyl)2、CO
2H、CO
2(C
1-4Alkyl), NHC (O) (C1-4Alkyl), NHS (O)2(C
1-4Alkyl), C (O) (C1-4Alkyl), CF3Or OCF3Or heteroaryl { itself is optional is replaced by following group: halogen, hydroxyl, nitro, NH2、NH(C
1-4Alkyl), N (C1-4Alkyl)2、S(O)
2(C
1-4Alkyl), S (O)2NH
2、S(O)
2NH(C
1-4Alkyl), S (O)2N(C
1-4Alkyl)2, cyano group, C1-4Alkyl, C1-4Alkoxyl, C (O) NH2、C(O)NH(C
1-4Alkyl), C (O) N (C1-4Alkyl)2、CO
2H、CO
2(C
1-4Alkyl), NHC (O) (C1-4Alkyl), NHS (O)2(C
1-4Alkyl), C (O) (C1-4Alkyl), CF3Or OCF3}；R
5、R
6、R
7、R
8、R
9、R
10、R
11、R
12、R
13、
R
14、R
15、R
16、R
18、R
19、R
20、R
21、R
22、R
23、R
24And R25Also can be hydrogen.
One concrete aspect, the invention provides formula (I) compound, or its N-oxide or its pharmaceutical salts, wherein: X is S; E is N or CE1 T is C (O) or S (O)2 W is (CH2)
n Y is (CH2)
p N and p are independently 0 or 1; M is 0 or 1; L is CH or N; If L is CH, J is NH; And if L is N, J does not exist and T directly is connected with L; R1For C1-6Alkyl (is chosen wantonly and is replaced by following group: hydroxyl, C1-6Alkoxyl, aryl, heteroaryl, C3-7Cycloalkyl, CO2H、
CO
2(C
1-6Alkyl) or NHC (O) R3)、C
1-6Alkoxyl, C3-6Cycloalkyl is (optional by hydroxyl or C1-6The alkyl replacement), heterocyclic radical is (optional by C1-6The alkyl replacement), aryl or heteroaryl; R3For C1-6Alkyl or phenyl; Above-mentioned R1And R3In phenyl, aryl and heteroaryl moieties optionally independently by following group, replaced: halogen, cyano group, nitro, hydroxyl, S (O)qR
4、OC(O)NR
5R
6、NR
7R
8、NR
9C(O)R
10、
NR
11C(O)NR
12R
13、S(O)
2NR
14R
15、NR
16S(O)
2R
17、C(O)NR
18R
19、C(O)R
20、
CO
2R
21、NR
22CO
2R
23、C
1-6Alkyl, C1-6Hydroxy alkyl, C1-6Haloalkyl, C1-6Alkoxyl (C1-6) alkyl, two (C1-6) alkyl amino (C1-6) alkyl, C1-6Alkoxyl, C1-6Halogenated alkoxy, C1-6Alkoxyl (C1-6) alkoxyl, C1-6Alkylthio group, C2-6Thiazolinyl, C2-6Alkynyl, C3-10(itself chooses C wantonly to cycloalkyl1-4Alkyl or oxo replace), methylene-dioxy, difluoro methylene-dioxy, phenyl, phenyl (C1-4) alkyl, phenoxy group, phenyl sulfenyl, phenyl (C1-4) alkoxyl, heteroaryl, heteroaryl (C1-4) alkyl, heteroaryl oxygen base or heteroaryl (C1-4) alkoxyl; Wherein just described phenyl or heteroaryl moieties are optional is arbitrarily replaced by following group: halogen, hydroxyl, nitro, S (O)r(C
1-4Alkyl), S (O)2NH
2、
S(O)
2NH(C
1-4Alkyl), S (O)2N(C
1-4Alkyl)2, cyano group, C1-4Alkyl, C1-4Alkoxyl, C (O) NH2、C(O)NH(C
1-4Alkyl), C (O) N (C1-4Alkyl)2、CO
2H、CO
2(C
1-4Alkyl), NHC (O) (C1-4Alkyl), NHS (O)2(C
1-4Alkyl), C (O) (C1-4Alkyl), CF3Or OCF3；E
1And G1Independent is hydrogen, halogen, cyano group, hydroxyl, C1-4Alkyl, C1-4Alkoxyl, CF3Or OCF3 Q and r are independently 0,1 or 2; R4、R
5、R
6、R
7、R
8、R
9、R
10、R
11、R
12、R
13、
R
14、R
15、R
16、R
17、R
18、R
19、R
20、R
21、R
22And R23Independent is C1-6Alkyl is { optional by halogen, hydroxyl or C1-6Alkoxyl replaces }, CH2(C
2-6Thiazolinyl), phenyl { itself is chosen wantonly and is replaced by following group: halogen, hydroxyl, nitro, NH2、NH(C
1-4Alkyl), N (C1-4Alkyl)2、S(O)
2(C
1-4Alkyl), S (O)2NH
2、S(O)
2NH(C
1-4Alkyl), S (O)2N(C
1-4Alkyl)2, cyano group, C1-4Alkyl, C1-4Alkoxyl, C (O) NH2、C(O)NH(C
1-4Alkyl), C (O) N (C1-4Alkyl)2、CO
2H、CO
2(C
1-4Alkyl), NHC (O) (C1-4Alkyl), NHS (O)2(C
1-4Alkyl), C (O) (C1-4Alkyl), CF3Or OCF3Or heteroaryl { itself is optional is replaced by following group: halogen, hydroxyl, nitro, NH2、NH(C
1-4Alkyl), N (C1-4Alkyl)2、S(O)
2(C
1-4Alkyl), S (O)2NH
2、S(O)
2NH(C
1-4Alkyl), S (O)2N(C
1-4Alkyl)2, cyano group, C1-4Alkyl, C1-4Alkoxyl, C (O) NH2、C(O)NH(C
1-4Alkyl), C (O) N (C1-4Alkyl)2、CO
2H、CO
2(C
1-4Alkyl), NHC (O) (C1-4Alkyl), NHS (O)2(C
1-4Alkyl), C (O) (C1-4Alkyl), CF3Or OCF3}；R
5、R
6、R
7、R
8、R
9、R
10、R
11、R
12、R
13、
R
14、R
15、R
16、R
18、R
19、R
20、R
21、R
22And R23Also can be hydrogen.
On the other hand, the invention provides formula (I) compound, wherein E is CE
1One concrete aspect, the invention provides formula (I) compound, wherein E
1Be in hydrogen or halogen (for example fluorine).
Aspect another, the invention provides formula (I) compound, wherein n and p are 1.
One concrete aspect, the invention provides formula (I) compound, wherein L is CH.
On the other hand, the invention provides formula (I) compound, wherein L is CH, and J is that NH and T are C (O).
On the other hand, the invention provides formula (I) compound, wherein Y and W are CH
2, L is CH, J is that NH and T are C (O).
On the other hand, the invention provides formula (I) compound, wherein E
1And G
1Independent is hydrogen or halogen (for example fluorine).
One concrete aspect, the invention provides formula (I) compound, wherein G
1Be hydrogen.
Aspect another, the invention provides formula (I) compound, wherein n is 0.
One concrete aspect, the invention provides formula (I) compound, wherein n is 1.
On the other hand, the invention provides formula (I) compound, wherein m is 1.
On the other hand, the invention provides formula (I) compound, wherein X is S.
Aspect another, the invention provides formula (I) compound, wherein R
1Be C
1-6Alkyl (is chosen wantonly and is replaced by following group: halogen, hydroxyl, C
1-6Alkoxyl group, C
3-6Cycloalkyl is (optional by hydroxyl, C
1-4Alkyl, C
1-4Alkoxyl group or phenyl replace), aryl or heteroaryl), C
3-7Cycloalkyl is (optional by hydroxyl, halogen, C
1-6Alkyl, C
1-6Alkoxyl group or phenyl replace), heterocyclic radical (is chosen wantonly and is replaced by following group: oxo (oxo), hydroxyl, C
1-6Alkyl, S (O)
2(C
1-4Alkyl), C (O) (C
1-4Alkyl), aryl, heteroaryl, aryl (C
1-4Alkyl), C (O) heteroaryl or heterocyclic radical), aryl or heteroaryl; Above-mentioned R
1In phenyl, aryl and heteroaryl moieties optionally independently replaced by following group: halogen, cyano group, hydroxyl, S (O)
2R
4, NR
7R
8, NR
11C (O) NR
12R
13, S (O)
2NR
14R
15, C (O) NR
18R
19, C
1-10Alkyl, C
1-6Hydroxyalkyl, C
1-6Haloalkyl, C
1-6Alkoxyl group (C
1-6) alkyl, C
1-6Alkyl (S (O)
2(C
1-4Alkyl)) two (C,
1-6) alkylamino (C
1-6) alkyl, C
1-6Alkoxyl group, C
1-6Halogenated alkoxy, C
1-6Alkoxyl group (C
1-6) alkoxyl group, C
3-10(itself is optional by C for cycloalkyl
1-4Alkyl or oxo replace) or heterocyclic radical (optional by hydroxyl, C
1-4Alkyl, phenyl or heteroaryl replace); R
4Be C
1-4Alkyl; And R
7, R
8, R
11, R
12, R
13, R
14, R
15, R
18And R
19Independent is hydrogen or C
1-4Alkyl.
One concrete aspect, the invention provides formula (I) compound, wherein R
1Be C
1-6Alkyl (is chosen wantonly and is replaced by following group: hydroxyl, aryl, C
3-7Cycloalkyl, CO
2(C
1-6Alkyl) or NHC (O) R
3), aryl or heteroaryl (for example pyridyl, benzimidazolyl-, furyl or 1,4-dihydro pyrido [2,3-d] pyrimidyl); And R
3Be phenyl.
Aryl for example is a phenyl.
On the other hand, the invention provides formula (I) compound, wherein above-mentioned R
1And R
3In phenyl, aryl and heteroaryl moieties optionally independently replaced by following group: halogen, hydroxyl, CO
2(C
1-6Alkyl), C
1-6Alkyl, C
1-6Hydroxyalkyl or C
1-6Alkoxyl group.
On the other hand, the invention provides formula (I) compound, wherein R
1For heterocyclic radical (is chosen wantonly by C
1-6Alkyl replaces), R for example
1Be pyrryl, piperidyl or morpholino, each is optional by C
1-6Alkyl (such as methyl or ethyl) replaces.
Aspect another, the invention provides formula (I) compound, wherein R
1Be C
1-4Alkyl { by heteroaryl (replacing) } or heteroaryl (such as imidazo [1,2-a] pyridyl) such as imidazo [1,2-a] pyridyl; Heteroaryl is optional to be replaced by following group: halogen, C
1-4Alkyl, CF
3, C
1-4Alkoxyl group, OCF
3Or heterocyclic radical (such as pyrrolidyl); Heterocyclic radical is optional by C
1-4Alkyl replaces.
On the other hand, the invention provides formula (I) compound, wherein R
1Be the optional C that is replaced by following group
1-4Alkyl (for example methyl or ethyl): OH, C
1-4(itself is optional by OH, halogen, C for alkoxyl group, phenyl
1-4Alkoxyl group or C
1-4Alkyl replaces) or C
3-7(itself is optional by OH, phenyl, C for cycloalkyl
1-4Alkoxyl group or C
1-4Alkyl replaces).
Aspect another, the invention provides formula (I) compound, wherein R
1Be C
1-4Alkyl (for example methyl or ethyl), it is by OH or C
1-4Alkoxyl group (for example being replaced by OH) replaces, and further (itself is optional by OH, halogen, C by phenyl
1-4Alkoxyl group or C
1-4Alkyl replaces) replace.
One concrete aspect, the invention provides formula (I) compound, wherein R
1Be methyl, it is replaced by OH, and further (itself chooses OH, halogen, C wantonly by phenyl
1-4Alkoxyl group or C
1-4The alkyl replacement) replaces for example further by phenyl (is replaced (for example being replaced by 1 OH) by OH) replacement itself.
On the other hand, the invention provides formula (I) compound, wherein R
1Be C
1-4Alkyl (for example methyl or ethyl), (itself is optional by OH, halogen, C by phenyl for it
1-4Alkoxyl group or C
1-4Alkyl replaces) or C
3-7(itself is optional by OH, phenyl, C for cycloalkyl
1-4Alkoxyl group or C
1-4Alkyl replaces) replace.
On the other hand, the invention provides formula (I) compound, wherein R
1Be the monocyclic heterocycles base, it is optional, and (itself is optional by CF by phenyl
3, OCF
3, CN, OH, C
1-4Alkyl, C
1-4Alkoxy or halogen replaces) replacement (for example as embodiment 109a, the site that is connected at the rest part with formula (I) is substituted); And heterocyclic radical contains S, O or N atom in ring, and is 3 yuan to 8 yuan rings.
Aspect another, the invention provides formula (I) compound, wherein R
1Be C
3-7Cycloalkyl, it is optional, and (itself is optional by CF by phenyl
3, OCF
3, OH, CN, C
1-4Alkyl, C
1-4Alkoxy or halogen replaces) replacement (for example as embodiment 122, the site that is connected at the rest part with formula (I) is substituted).
One concrete aspect, the invention provides formula (I) compound, wherein R1 is aryl (a for example phenyl), it is optional by halogen, C
1-4Alkyl, C
1-4Alkoxyl group or OH replace.
On the other hand, the invention provides formula (I) compound, wherein R
1Be heteroaryl (for example pyrimidyl, pyridyl, imidazo [1,2-a] pyridyl, pyrazolo [1,5-a] pyridyl or indazolyl) that it is chosen wantonly and is replaced by following group: halogen (such as fluorine), C
1-4Alkyl, C
1-4Alkoxyl group, CF
3, OCF
3, OH, CN, C
1-4Alkylthio, phenyl sulfenyl or heterocyclic radical are (optional by OH or C
1-4Alkyl replaces).
On the other hand, the invention provides formula (I) compound, wherein R
1Be pyrimidyl, pyridyl or imidazo [1,2-a] pyridyl, described pyrimidyl, pyridyl or imidazo [1,2-a] pyridyl is all optional by halogen (such as fluorine), C
1-4Alkyl or C
1-4Alkoxyl group replaces.
Aspect another, the invention provides formula (I) compound, wherein R
1Be the C that is replaced by phenoxy group, heteroaryl oxygen base or heteroaryl sulfenyl
1-4Alkyl, each is chosen wantonly and is replaced by following group in described phenoxy group, heteroaryl oxygen base or the heteroaryl sulfenyl: halogen, CF
3, OCF
3, OH, CN, C
1-4Alkyl, C
1-4Alkoxyl group or tetrazyl.
One concrete aspect, the invention provides formula (I) compound, wherein if L is CH, then substituting group is cis and arranges on the ring of the following * of indicating.
Compound of the present invention is described among the embodiment.Each embodiment compound or pharmaceutically acceptable salt thereof all is an another aspect of the present invention.Thereby, the invention provides following compound or pharmaceutically acceptable salt thereof:
N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } cyclopropane carboxamide;
N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } imidazo [1,2-a] pyridine-2-carboxamide;
N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } quinoline-8-methane amide;
N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } pyrazolo [1,5-a] pyridine-2-carboxamide;
N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1H-indazole-3-methane amide;
N-[2-(cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] and cyclohexyl } amino)-the 2-oxoethyl]-the 2-hydroxybenzamide;
N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-3-hydroxyl-4-methoxy benzamide;
N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-(3-hydroxy phenyl) ethanamide;
N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxy-4-methyl benzamide;
N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-3-hydroxy-4-methyl benzamide;
N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-4-hydroxy 3-methoxybenzene methane amide;
(2R)-and 2-cyclohexyl-N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-hydroxyl acetamide;
5-(cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] and cyclohexyl } amino)-5-oxopentanoic acid methyl esters;
N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 3-hydroxybenzamide;
N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-(4-hydroxy phenyl) ethanamide;
N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 4-hydroxybenzamide;
N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-hydroxybenzamide;
N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } cyclohexane carboxamide;
N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-3-(3-hydroxy phenyl) propionic acid amide;
N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-3-pyridone-2-methane amide;
N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-3-methylbutyryl amine;
N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-2-phenyl-acetamides;
N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } benzamide;
N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-furoamide;
N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } imidazo [1,2-a] pyridine-8-methane amide;
N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-5-(methylol) benzamide;
N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-3-thienyl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } cyclopropane carboxamide;
N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-3-thienyl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } imidazo [1,2-a] pyridine-2-carboxamide;
N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-3-thienyl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-5-(methylol) benzamide;
N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-3-thienyl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-hydroxybenzamide;
N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-3-thienyl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxy-4-methyl benzamide;
N-{ cis-4-[2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } imidazo [1,2-a] pyridine-2-carboxamide;
N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-5,6,7, the 8-imidazolidine is [1,2-a] pyridine-2-carboxamide also;
N-{ cis-4-[6-methyl-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } imidazo [1,2-a] pyridine-2-carboxamide;
N-{ cis-4-[6-fluoro-1-[(1R)-and 1-oxidation tetrahydrochysene-2H-thiapyran-4-yl]-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } cyclopropane carboxamide;
N-{ cis-4-[6-fluoro-1-(1-oxidation tetrahydrochysene-2H-thiapyran-4-yl)-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } imidazo [1,2-a] pyridine-2-carboxamide;
N-{ cis-4-[1-(1,1-titanium dioxide tetrahydrochysene-2H-thiapyran-4-yl)-6-fluoro-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } cyclopropane carboxamide;
N-{ cis-4-[6-fluoro-1-[(1S)-and 1-oxidation tetrahydrochysene-2H-thiapyran-4-yl]-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } cyclopropane carboxamide;
N-{ cis-4-[1-(1,1-titanium dioxide tetrahydrochysene-2H-thiapyran-4-yl)-6-fluoro-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-5-(methylol) benzamide;
N-{ cis-4-[1-(1,1-titanium dioxide tetrahydrochysene-2H-thiapyran-4-yl)-6-fluoro-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } imidazo [1,2-a] pyridine-2-carboxamide;
6-fluoro-N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } imidazo [1,2-a] pyridine-2-carboxamide;
N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-2-(4-hydroxy phenyl) ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-3-nitro-benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1H-indoles-2-methane amide;
4-cyano group-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1H-benzotriazole-5-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] benzothiazole-6-methane amide;
N-[4-(3-fluoro-8,10-dioxo-7-tetrahydric thiapyran-4-group-5,7,9-three azabicyclics [4.4.0] last of the ten Heavenly stems-1,3,5-triolefin-9-yl) cyclohexyl]-9-methyl-7-thia-1,5-diazabicylo [4.3.0] ninth of the ten Heavenly Stems-5,8-diene-8-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] thiadiazoles-4-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] thiophene-3-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1-methyl-imidazoles-4-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1-methyl-piperidines-3-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-4-vinyl-benzamide;
4-ethynyl-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] benzothiazole-2-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-9-thia-2-azabicyclic [4.3.0] ninth of the ten Heavenly Stems-1,3,5,7-tetraene-8-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-9-thia-2,5-diazabicylo [4.3.0] ninth of the ten Heavenly Stems-1,3,5,7-tetraene-8-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1,5,7,9-4-azabicyclo [4.3.0] ninth of the ten Heavenly Stems-2,4,6,8-tetraene-8-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-the 4-methyl isophthalic acid, 7-diazabicylo [4.3.0] ninth of the ten Heavenly Stems-2,4,6,8-tetraene-8-methane amide;
N-[4-(3-fluoro-8,10-dioxo-7-tetrahydric thiapyran-4-group-5,7,9-three azabicyclics [4.4.0] last of the ten Heavenly stems-1,3,5-triolefin-9-yl) cyclohexyl]-the 3-methyl isophthalic acid, 7-diazabicylo [4.3.0] ninth of the ten Heavenly Stems-2,4,6,8-tetraene-8-methane amide;
3-chloro-N-[4-(3-fluoro-8,10-dioxo-7-tetrahydric thiapyran-4-group-5,7,9-three azabicyclics [4.4.0] last of the ten Heavenly stems-1,3,5-triolefin-9-yl) cyclohexyl]-1,7-diazabicylo [4.3.0] ninth of the ten Heavenly Stems-2,4,6,8-tetraene-8-methane amide;
5-chloro-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-3-(trifluoromethyl)-1,7-diazabicylo [4.3.0] ninth of the ten Heavenly Stems-2,4,6,8-tetraene-8-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1,5,7-three azabicyclics [4.3.0] ninth of the ten Heavenly Stems-2,4,6,8-tetraene-8-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-the 5-methyl isophthalic acid, 7-diazabicylo [4.3.0] ninth of the ten Heavenly Stems-2,4,6,8-tetraene-8-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-the 2-methyl isophthalic acid, 7-diazabicylo [4.3.0] ninth of the ten Heavenly Stems-2,4,6,8-tetraene-8-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-6-imidazoles-1-base-pyridine-3-carboxamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1-[5-(trifluoromethyl)-2-pyridyl] piperidines-4-methane amide;
4-dimethylamino-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] benzamide;
3-dimethylamino-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] benzamide;
4-diethylin-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] benzamide;
10-ethyl-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-7-oxo-3-tetramethyleneimine-1-base-2,4,10-three azabicyclics [4.4.0] last of the ten Heavenly stems-1,3,5,8-tetraene-8-methane amide;
(E)-and 3-(4-dimethylamino phenyl)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] third-2-enamine;
2-dimethylamino-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1-oxo-2-(2-pyridylmethyl) isoquinoline 99.9-4-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1-pyrimidine-2-base-piperidines-4-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1-methyl-imidazoles-2-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-morpholino-benzamide;
The 1-[(4-chloro-phenyl-) methyl]-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-5-methyl-imidazoles-4-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1-(pyridine-3-carbonyl) piperidines-4-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-6-morpholino-pyrazine-2-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-3-(glyoxal ethyline-1-yl) propionic acid amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-4-imidazoles-1-base-benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1-(3-pyridyl) piperidines-4-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-6-(piperidino) pyridine-3-carboxamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-5-methyl-2-oxa--5-azabicyclic [4.4.0] last of the ten Heavenly stems-7,9,11-triolefin-9-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-morpholino-pyridine-3-carboxamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1,2-dimethyl-benzoglyoxaline-5-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-morpholino-pyrimidine-5-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-3-imidazoles-1-base-butyramide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-6-(2-Phenylpyrrolidine-1-yl) pyridine-3-carboxamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-(2-Phenylpyrrolidine-1-yl) pyridine-3-carboxamide;
2-(4-dimethylamino phenyl)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-7-methyl-8-oxo-5-phenyl-1,7-naphthyridine-6-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-5-oxo-1-(6-quinolyl) tetramethyleneimine-3-methane amide;
2-chloro-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-4-morpholino-benzamide;
1-ethyl-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-7-methyl-4-oxo-1,8-naphthyridine-3-methane amide;
(2S)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1-methyl-tetramethyleneimine-2-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1-methyl-piperidines-4-methane amide;
3-(3,4-dihydro-2H-quinoline-1-yl)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] propionic acid amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-3-methyl-4-oxo-1,2-dihydroquinazoline-2-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] piperidines-3-methane amide;
(3R)-and N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] piperidines-3-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] piperidines-2-methane amide;
(2S)-and N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] piperidines-2-methane amide;
3-bromo-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1,7-diazabicylo [4.3.0] ninth of the ten Heavenly Stems-2,4,6,8-tetraene-8-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-[5-(trifluoromethyl)-2-pyridyl] piperidines-4-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] rubane-3-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1-methyl-4-phenyl-piperidines-4-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-(4-methylpiperazine-1-yl) pyridine-3-carboxamide;
1-butyl-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-4-(p-methylphenyl) piperidines-4-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-9-oxa--2,8-diaza spiro [4.4] ninth of the ten Heavenly Stems-7-alkene-7-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] methane amide;
2-(1,4-Diazesuberane-1-yl)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] pyridine-3-carboxamide;
6-(1,4-Diazesuberane-1-yl)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] pyridine-3-carboxamide;
N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-6-(1-methylpyrrolidin-2-yl) imidazo [1,2-a] pyridine-2-carboxamide;
3-ethyl-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-methyl-valeramide;
2-cyclopentyl-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-phenyl-ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-methyl-cyclopropane-1-methane amide;
4-(4-chloro-2-methyl-phenoxy group)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] butyramide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-3-methyl-2-phenyl-valeramide;
4-(3, the 4-Dimethoxyphenyl)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] butyramide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-4-methyl-cyclohexyl alkane-1-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-3-methoxyl group-hexanaphthene-1-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-(4-methylcyclohexyl) ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] tetrahydrofuran (THF)-3-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-3,3-phenylbenzene-propionic acid amide;
4,4,4-three fluoro-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-3-methyl-butyramide;
(3R)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-3-phenyl-butyramide;
3-cyclopentyl-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] propionic acid amide;
1-(4-chloro-phenyl-)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] pentamethylene-1-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1-phenyl-cyclopropane-1-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1-(4-p-methoxy-phenyl) cyclopropane-1-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1-(p-methylphenyl) pentamethylene-1-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-the 4-tertiary butyl-hexanaphthene-1-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-3-(2-p-methoxy-phenyl) propionic acid amide;
2-cyclopentyl-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-4-methyl-pelargonamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-4-(p-methylphenyl) butyramide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-3-methyl-2-phenyl-butyramide;
2-cyclopropyl-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-4-(2-methyl isophthalic acid-oxo-3-isoquinolyl) butyramide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-4-hydroxyl-hexanaphthene-1-methane amide;
N '-benzyl-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-N '-(2-thienyl methyl) succinic diamide;
2-(sulfenyl-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8, the 10-triolefin-3-yl) cyclohexyl of 5-chloro-1-ethyl-benzimidazolyl-2 radicals-yl)] ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-the 4-hydroxyl-3-tertiary butyl-benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2,3-dimethyl-benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] isoxazole-5-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-methyl sulfenyl-ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-phenoxy group-ethanamide;
3-cyano group-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-3,3-phenylbenzene-propionic acid amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-methoxyl group-ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-(3-hydroxyl-1-adamantyl) ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-methyl isophthalic acid H-benzoglyoxaline-5-methane amide;
(2R)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-hydroxyl-2-phenyl-propionic acid amide;
3-(3, the 4-dichlorophenyl)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2,2-dimethyl-propionic acid amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-(5-methylpyrazole-1-yl) ethanamide;
1-ethanoyl-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] piperidines-3-methane amide;
1-ethanoyl-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] tetramethyleneimine-2-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-4-(4-pyridyl) benzamide;
2-(1H-benzimidazolyl-2 radicals-Ji sulfenyl)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] valeramide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2,5-dimethoxy-benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1H-benzoglyoxaline-5-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-(4-pyridyl sulfenyl) ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-5-sec.-propyl-3,8-dimethyl-2,4-dioxo-7-thia-3,5-diazabicylo [4.3.0] ninth of the ten Heavenly Stems-8,10-diene-9-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-(4-isobutyl phenenyl) propionic acid amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-3-isopropoxy-4-methoxyl group-benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-oxo-3H-benzothiazole-6-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-methyl sulphonyl-benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-(3-quinolyl oxygen base) ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-methyl-quinoline-3-methane amide;
2-oxyethyl group-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] pyridine-3-carboxamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-[[5-(trifluoromethyl)-2-pyridyl] alkylsulfonyl] propionic acid amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-6-methyl-pyridine-3-carboxamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] pyridine-2-carboxamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] quinoline-2-formamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-sec.-propyl sulfenyl-7,9-dimethyl-5,7,8-three azabicyclics [4.3.0] ninth of the ten Heavenly Stems-1,3,5,8-tetraene-3-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-methoxyl group-pyridine-3-carboxamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-(2,2, the 2-trifluoro ethoxy) pyridine-3-carboxamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-4-(2-methyl-4-pyridyl) benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-methoxyl group-benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-9-phenyl-pelargonamide;
(2S)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-hydroxyl-2-phenyl-ethanamide;
2-acetylaminohydroxyphenylarsonic acid N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] ethanamide;
2-(4-chloro-phenyl-)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-methyl-propionic acid amide;
N-[(1S)-and 1-[[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] formamyl]-2-phenyl-ethyl] benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-3-methoxyl group-propionic acid amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] naphthalene-1-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1-phenyl-5-propyl-pyrazole-4-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2,4,6-trimethylammonium-benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-3,5,5-trimethylammonium-hexanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-3-hydroxyl-2-phenyl-propionic acid amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-4-amyl group-benzamide;
2-cyclohexyl-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] ethanamide;
2-cyclohexyl-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-phenyl-ethanamide;
2-benzyl-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-5-phenyl-valeramide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-4-propyl group-benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-the 2-hydroxyl-6-methyl-3-tertiary butyl-benzamide;
3-oxyethyl group-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] propionic acid amide;
2-fluoro-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-(4-fluorophenyl) propionic acid amide;
3,4-two chloro-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-the 1H-pyrazole-4-carboxamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-6-phenyl-hexanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-4-sec.-propyl-benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-4-phenyl-butyramide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-methyl-benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-4-(4-p-methoxy-phenyl) butyramide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] cyclopentane formamide;
(2R)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-methoxyl group-2-phenyl-ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-4-methyl sulphonyl-benzamide;
4-benzyloxy-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-amyl group sulfenyl-pyridine-3-carboxamide;
4-butoxy-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-methyl sulfenyl-pyridine-3-carboxamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-phenoxy group-pyridine-3-carboxamide;
4,4-two fluoro-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] hexanaphthene-1-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-5-methyl isophthalic acid-phenyl-pyrazole-4-methane amide;
(1R, 2R)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-phenyl-cyclopropane-1-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-indane-2-base-ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-(p-methylphenyl sulfenyl) pyridine-3-carboxamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-(4-methylphenoxy) pyridine-3-carboxamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2,8-dimethyl-1,5,9-three azabicyclics [4.3.0] ninth of the ten Heavenly Stems-2,4,6,8-tetraene-3-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-3-methyl-furans-2-methane amide;
2-(4,6-dimethyl pyrimidine-2-yl) sulfenyl-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-3-(2-Yang is for benzoxazole-3-yl) propionic acid amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-hydroxyl-4-methoxyl group-benzamide;
2-(2-cyano-phenyl) sulfenyl-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-4-hexyloxy-benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-4-octyl group-benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-4-(methylol) benzamide;
N '-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-N-[(1S)-1-phenylethyl] phthalic diamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-hydroxy-5-methyl oxygen base-benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-3,4-dimethyl-benzamide;
3-fluoro-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-4-methoxyl group-benzamide;
1-benzyl-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-oxo-pyridine-3-carboxamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] butyramide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-(p-methylphenyl alkylsulfonyl) ethanamide;
4-butyl-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] hexanaphthene-1-methane amide;
2-(benzenesulfonyl)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-(p-methylphenyl sulfuryl amino) ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-hydroxy-3-methyl-butyramide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-3-(2-methoxy ethoxy) benzamide;
2-(3, the 4-Dimethoxyphenyl) sulfenyl-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-tetrahydropyran-4-base-ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1,5-dimethyl-pyrazole-3-formamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-methyl-3-oxo-5-thia-2-azabicyclic [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-9-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-phenoxy group-propionic acid amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-3-hydroxyl-butyramide;
(1R, 2S)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-hydroxyl-pentamethylene-1-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-4-(methylol)-1H-pyrazole-3-formamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-methoxyl group-3-methyl-benzamide;
3-oxyethyl group-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-4-methoxyl group-benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-the 4-tertiary butyl-benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2,3-Dihydrobenzofuranes-5-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-[4-(trifluoromethyl) phenoxy group] ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-5-methyl-isoxazoles-3-methane amide;
4-ethyl sulfenyl-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] benzamide;
6-chloro-2-fluoro-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-3-methyl-benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-the 8-methyl isophthalic acid, 7-diazabicylo [4.3.0] ninth of the ten Heavenly Stems-2,4,6,8-tetraene-9-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2,2-dimethyl-tetrahydropyrans-4-methane amide;
2-(3,5-dimethyl-1,2,4-triazol-1-yl)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-(sulfonyloxy methyl ylmethyl) benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] tetrahydropyrans-4-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-hydroxyl-2-(3-hydroxy phenyl) ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-(2-methoxy ethoxy) ethanamide;
4-(2,5-two oxabicyclos [4.4.0] last of the ten Heavenly stems-7,9,11-triolefin-9-yl)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] butyramide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-(3-methyl-isoxazole-5-yl) ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1-(p-methylphenyl) hexanaphthene-1-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1-(4-p-methoxy-phenyl) pentamethylene-1-methane amide;
2-benzyl sulfenyl-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-3-phenoxy group-propionic acid amide;
2-benzyloxy-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] propionic acid amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-(4-hydroxy phenyl) propionic acid amide;
2-(4-chloro-phenyl-)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-hydroxyl-ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-the 3-[(4-p-methoxy-phenyl) methyl sulphonyl]-3-methyl-butyramide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-(3-methyl sulphonyl phenyl) ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1-methyl-5-oxo-tetramethyleneimine-3-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-hydroxyl-2-[4-(trifluoromethyl) phenyl] ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-[(1S, 4R)-norcamphane-2-yl] ethanamide;
2-ethyl sulfenyl-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2,3-dimethyl-butyramide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-phenyl-propionic acid amide;
4-(1,1-dioxo thiazan-2-yl)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] benzamide;
(2S)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-hydroxyl-3-phenyl-propionic acid amide;
3-ethyl-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-4-phenyl-benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-5-(4-fluorophenyl) valeramide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-methyl-5-phenyl-furans-3-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-4-(1,1,2,2-tetrafluoro oxyethyl group) benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-5-(2-phenylacetylene base) furans-2-methane amide;
2-cyclohexyl-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-5-(2-phenylacetylene base) pyridine-3-carboxamide;
2-(5-chloro-2-fluoro-phenyl)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] ethanamide;
N-[2-[[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] formamyl] ethyl] benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-3-(3-methylpyrazole-1-yl) propionic acid amide;
3-(3, the 4-dichlorophenyl)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] propionic acid amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-3-styroyl oxygen base-propionic acid amide;
(2R)-2-acetylaminohydroxyphenylarsonic acid N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-phenyl-ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-(p-methylphenyl) benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-[4-(trifluoromethyl) phenyl] benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-5-methyl isophthalic acid H-imidazoles-4-methane amide;
5-ethyl-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1-phenyl-pyrazole-4-methane amide;
(2S)-2-acetylaminohydroxyphenylarsonic acid N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-3-phenyl-propionic acid amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2,3,5,6-tetramethyl--benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-4-hydroxyl-3,5-dimethyl-benzamide;
3-(benzenesulfinyl)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-5-methyl-thionaphthene-2-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-3-methyl-imidazoles-4-methane amide;
The 1-[(2-chloro-phenyl-) methyl]-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-5-oxo-tetramethyleneimine-3-methane amide;
(2S)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-hydroxy-4-methyl-valeramide;
1-benzoyl-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] piperidines-4-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1H-benzimidazolyl-2 radicals-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-methyl-4-phenyl-pyrimidine-5-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1,3,5-trimethylammonium-pyrazole-4-carboxamide;
4-(3-1-yl)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1-methyl-5-phenyl-pyrazole-4-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-5-phenyl-pyridine-3-carboxamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1-methyl-3-(trifluoromethyl) pyrazole-4-carboxamide;
3-(3,5-dimethyl-1H-pyrazoles-4-yl)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] propionic acid amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-3-(2-tolimidazole-1-yl) propionic acid amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-6-methoxyl group-benzothiazole-2-methane amide;
1-benzyl-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-5-oxo-tetramethyleneimine-3-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1-sec.-propyl-pyrazole-4-carboxamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] heptamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-methyl-4-[2-(tolyl) ethyl] thiazole-5-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1-methyl sulphonyl-piperidines-4-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-4,8-dimethyl-1,7-diazabicylo [4.3.0] ninth of the ten Heavenly Stems-2,4,6,8-tetraene-9-methane amide;
6-ethyl-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-4-hydroxyl-quinoline-3-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-isobutyl--3-oxo-isoindoline-4-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-[4-(tetrazolium-1-yl) phenoxy group] ethanamide;
3-(2,4-dimethyl-1,5,7,9-4-azabicyclo [4.3.0] ninth of the ten Heavenly Stems-2,4,6,8-tetraene-3-yl)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] propionic acid amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-3-(2-hydroxyethyl)-1,5,9-three azabicyclics [4.3.0] ninth of the ten Heavenly Stems-2,4,6,8-tetraene-8-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-10-oxo-1,7-diazabicylo [4.4.0] last of the ten Heavenly stems-2,4,6,8-tetraene-9-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-4-(5-methyl tetrazolium-1-yl) benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2,4-dimethyl-1,5,7,8-4-azabicyclo [4.3.0] ninth of the ten Heavenly Stems-2,4,6,8-tetraene-9-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1,5,9-three azabicyclics [4.3.0] ninth of the ten Heavenly Stems-2,4,6,8-tetraene-8-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-(o-tolyl) ethanamide;
2-(4-chloro-phenyl-)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] ethanamide;
2-(2-benzyloxy phenyl)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-(4-p-methoxy-phenyl) ethanamide;
2-benzo [1,3] dioxolane-5-base-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] ethanamide;
2-(3, the 5-3,5-dimethylphenyl)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-5-methoxyl group-benzofuran-2-carboxamides;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1-(2-hydroxy phenyl)-5-oxo-tetramethyleneimine-3-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-(4-methyl sulphonyl phenyl) ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-(2-naphthyl) ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-(2-styroyl sulfenyl ethyl sulfenyl) ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-[2-(2-pyridyl) tetramethyleneimine-1-yl] pyridine-3-carboxamide;
2-(4-butoxy phenyl)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] ethanamide;
2-(2,4-dimethylthiazole-5-yl)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-(4-methylphenoxy) propionic acid amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-(4-fluorophenoxy) propionic acid amide;
3-benzothiazole-2-base-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] propionic acid amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-(2-pyridyl oxygen base) ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-methyl-4-phenyl-thiazole-5-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-3-(4-fluorophenyl) propionic acid amide;
2-fluoro-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-4-(5-fluoro-2-methoxyl group-phenyl) benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-3-methoxyl group-5-(trifluoromethyl) benzamide;
3-(4-chloro-phenyl-) sulfenyl-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-Methyl-1H-indole-5-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-hydroxyl-naphthalene-1-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-(5-methyl-2-phenyl-thiazole-4-yl) ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-4-hexyl-benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-hydroxyl-butyramide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-6-oxo-2-(1,1,2,2, the 2-pentafluoroethyl group)-1H-pyridine-3-carboxamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-5-isobutyl--3-methyl-2,4-dioxo-8-[[2-(trifluoromethyl) phenyl] methyl]-3,5,7,8-4-azabicyclo [4.3.0] ninth of the ten Heavenly Stems-6,9-diene-9-methane amide;
2-chloro-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-6-methyl-benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] the dodecane acid amides;
(3R)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-the 5-oxo-1-[(1R)-the 1-phenylethyl] tetramethyleneimine-3-methane amide;
(2R)-3,3,3-three fluoro-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-hydroxy-2-methyl-propionic acid amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1-(2-p-methoxy-phenyl)-5-oxo-tetramethyleneimine-3-methane amide;
3,3,3-three fluoro-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-hydroxyl-propionic acid amide;
2,6-diethyl-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] benzamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-4-(2-methoxy ethoxy) benzamide;
(3R)-and 1-[(3, the 4-dichlorophenyl) methyl]-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] piperidines-3-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-1,5,9-three azabicyclics [4.3.0] ninth of the ten Heavenly Stems-2,4,6,8-tetraene-7-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-(4-hydroxyphenoxy) ethanamide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] indane-2-methane amide;
(2S, 5R)-1-butyl-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-5-(4-p-methoxy-phenyl) tetramethyleneimine-2-methane amide;
N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] isochroman-1-methane amide;
2-ethyl-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl] hexanamide;
(2R)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-2-(4-hydroxyphenoxy) propionic acid amide;
(2S)-N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-5-oxo-tetramethyleneimine-2-methane amide; Or,
(2S)-2-acetylaminohydroxyphenylarsonic acid N-[4-(9-fluoro-2,4-dioxo-5-tetrahydric thiapyran-4-group-3,5,7-three azabicyclics [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-3-yl) cyclohexyl]-4-methyl-valeramide.
Compound of the present invention can as described belowly prepare, or prepares by adjusting methods known in the art.
On the other hand, the invention provides the method for preparation formula (I) compound, described method comprises removes tertbutyloxycarbonyl (Boc) protecting group (for example, reacting with acid (such as trifluoroacetic acid or hydrochloric acid)) from formula (II) compound,
In formula (II), m, G
1, E, Y, L, W, X and J be suc as formula defining in (I), and makes the product of as above formation and the carboxylic acid reaction of formula (III):
In formula (III), R
1Define suc as formula (I) is middle with T, and LG represents leaving group.Described method is in suitable temperature, and the temperature between the boiling point of 0 ℃ and solvent is carried out in suitable solvent such as methylene dichloride or N-Methyl pyrrolidone usually.Described method is chosen wantonly at alkali and/or coupling agent (such as HATU, HOAT, HOBT, DIEA or T
3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxa three phosphines 2,4,6-trioxide) (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane2,4,6-trioxide) carry out under) the existence.Suitable leaving group LG comprises OH and halogen, particularly OH.
The compound of formula (II), wherein m, G
1, E, Y, L, W and J be suc as formula defining in (I), can prepare by the following method: make formula (IV) compound and suitable carbonylation agent such as carbonyl dimidazoles or Vinyl chloroformate, condensation in the presence of suitable alkali such as sodium hydride.Described method is in suitable temperature, and the temperature between the boiling point of 0 ℃ and solvent is usually carried out in such as tetrahydrofuran (THF) at suitable solvent; Formula (IV) compound is as follows:
Wherein m, G
1, E, Y, L, W, X and J be suc as formula defining in (I).
The compound of formula (IV), wherein m, G
1, E, Y, L, W, T and J be suc as formula defining in (I), can prepare by the following method: the amine of formula V compound and formula (VI) is reacted; The formula V compound is as follows:
Wherein m, X, G
1Define suc as formula (I) is middle with E; Formula (VI) amine is as follows:
Wherein Y, L, W and J are suc as formula defining in (I).Described method is in suitable temperature, and the temperature between the boiling point of 0 ℃ and solvent is usually carried out in such as methylene dichloride at suitable solvent.Described method is chosen wantonly at alkali and coupling agent (such as HATU, HOAT, HOBT, DIEA or T
3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxa three phosphines 2,4,6-trioxide)) carries out under the existence.
The compound of formula V, wherein m, G
1Define suc as formula institute in (I) with E, can prepare by the following method: make formula (VII) compound and 4-amino-thiapyran, 3-amino tetramethylene sulfide, or arbitrary S-oxide compound or S-dioxide in encircling with these react; Formula (VII) compound is as follows:
G wherein
1Define suc as formula (I) is middle with E, and Hal represents halogen atom.Described method is in suitable temperature, and the temperature between the boiling point of 50 ℃ and solvent is usually carried out in such as dimethyl formamide at suitable solvent.Described method is chosen wantonly in the presence of alkali (such as salt of wormwood) and is carried out.
The preparation of various intermediates is described in the literature, maybe can prepare by described method is in the literature carried out the route adjustment.
In above method, may expect or essential be that protection acid groups or hydroxyl or other have the group of potential reaction.Suitable protecting group and being used to is added and removed the method details of these protecting groups can be referring to " the Protective Groups in Organic Synthesis " that Greene and Wuts showed, 3rdEdition (1999).
In yet another aspect, the invention provides the method for preparation formula (I) compound.
Formula (I) compound has as medicine particularly as the activity of PDE4 receptor activity modulators, thereby can be used for treating inflammatory disease, asthma or COPD.
The example of the illness of available The compounds of this invention treatment has:
1. respiratory tract: airway obstructive disease, comprise asthma, comprise bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, exercise-induced asthma, drug-induced property (comprising what acetylsalicylic acid and NSAID brought out) asthma and bringing out property of dust asthma, intermission asthma and persistence asthma, and the asthma of various severities, reach the airway hyperreactivity that other reason causes; Chronic obstructive pulmonary disease (COPD); Bronchitis comprises infectious bronchitis and acidophilia bronchitis; Pulmonary emphysema; Bronchiectasis; Cystic fibrosis; Sarcoidosis; Farmer lung and relative disease; Hypersensitivity pneumonitis; Pulmonary fibrosis comprises the concurrent fibrosis of CFA, idiopathic interstitial pneumonia, antineoplaston and chronic infection (comprising tuberculosis and aspergillosis and other fungi infestation); The complication of lung transplantation; Pulmonary vascular vasculitis and thrombotic disease and pulmonary hypertension; Antitussive activity comprises chronic cough and iatrogenic cough that treatment and airway inflammation are relevant with the secretion situation; Acute rhinitis and chronic rhinitis comprise medicamentous rhinitis and vasomotor rhinitis; Property (perennial) allergic rhinitis and seasonal allergic rhinitis comprise nervous rhinitis's (pollinosis) throughout the year; Nasal polyposis; Acute viral infection comprises common cold and the infection that is caused by respiratory syncytial virus, influenza, coronavirus (comprising SARS) or adenovirus; Or acidophilia esophagitis (eosinophilic esophagitis);
2. bone and joint: relevant with osteoarthritis/osteoarthropathy or comprise and the sacroiliitis of osteoarthritis/osteoarthropathy comprise primary and Secondary cases sacroiliitis, for example congenital hip dysplasia; Neck and lumbar spine inflammation and lumbago and backache and cervical pain; Osteoporosis; Rheumatoid arthritis and Still disease (Still ' sdisease); Seronegative spondyloanthropathy comprises ankylosing spondylitis, arthritic psoriasis, reactive arthritis and does not break up SpA; Septic arthritis infects relevant joint disease and osteopathia with other, and tuberculosis for example comprises Pott's disease (Potts ' disease) and Poncet syndrome (Poncet ' ssyndrome); Acute and the chronic synovitis that crystal brings out comprises the relevant tendon of urate deposition disease, calcium pyrophosphate deposition disease and apatite calcium, mucous bursa and synovial membrane inflammation; Behcet's disease (Behcet ' sdisease); Primary and Secondary cases xerodermosteosis (Sjogren ' s syndrome); Sjogren's syndrome and local scleroderma; Systemic lupus erythematous, mixed connective tissue disease and undifferentiated connective tissue disease; Inflammatory myopathy comprises dermatomyositis and polymyositis; Polymyalgia rheumatica; Juvenile arthritis comprises spy's property the sent out inflammatory arthritis and related syndromes and rheumatic fever and the general complication thereof that are distributed in any joint; Vasculitis (vasculitis) comprises giant cell arteritis, aortic arch syndrome (Takayasu ' sarteritis), Qiu-Shi syndrome (Churg-Strauss syndrome), polyarteritis nodosa, microscope polyarteritis and the vasculitis relevant with virus infection, allergy, cryoglobulin and M-band; Lumbago and backache; Familial Mediterranean fever, Mu-Wei syndrome (Muckle-Wells syndrome) and familial Ireland heat (Familial Hibernian Fever), Kikuchi disease (Kikuchi disease); Drug-induced property arthrodynia, tendonitis and myopathy;
3. the musculoskeletal disease that reproduces of pain that causes by damage (for example sport injury) or disease and reticular tissue: sacroiliitis (rheumatoid arthritis for example, osteoarthritis, gout or crystallographic joint disease), other joint disease (for example degeneration of intervertebral disc or temporomandibular joint (TMJ) sex change), bone remodelling disease (osteoporosis for example, Paget's disease (Paget ' s disease) or osteonecrosis), polychondritis, scleroderma, mixed connective tissue disease, spondyloarthropathy or periodontopathy (for example periodontitis);
4. skin: psoriasis, atopic dermatitis, contact dermatitis or other eczema dermatoses and delayed type hypersensitivity; Vegetalitas and solar dermatitis; Seborrheic dermatitis, dermatitis herpetiformis, lichen planus, atrophic sclerosis lichen, PG, skin tag disease, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema toxicum, skin eosinophilia, alopecia areata, male pattern alopecia, sweet's syndrome (Sweet ' ssyndrome), Wei-Ke syndrome (Weber-Christian syndrome), erythema multiforme; Cellulitis comprises infectivity and non-infectious cellulitis; Pimelitis; Lymphoma cutis, non-melanoma skin cancer and other dysplasia damage; Drug-induced disease comprises fixed drug eruption;
The eye: blepharitis; Conjunctivitis, comprise the perennial allergic conjunctivitis or spring anaphylaxis conjunctivitis; Iritis; Anterior uveitis and posterior uveitis; Choroiditis; Autoimmunization; Influence amphiblestroid sex change or inflammatory diseases; Ophthalmia comprises sympathetic ophthalmia; Sarcoidosis; Infect, comprise virus, fungi and infectation of bacteria;
6. gi tract: glossitis, oulitis, periodontitis; Esophagitis comprises and backflowing; Eosinophilic Gastroenteritis, mastocyte increase, Crohn's disease (Crohn ' s disease), colitis comprise ulcerative colitis, rectitis, pruritus ani; Coeliac disease, irritable bowel syndrome, and have away from the relevant transformation reactions (for example migraine, rhinitis or eczema) of the food of intestines effect;
7. belly: hepatitis comprises autoimmunity, alcohol and viral hepatitis; Hepatic fibrosis and sclerosis; Cholecystitis; Pancreatitis comprises acute and chronic pancreatitis;
8. urogenital system: ephritis comprises interstitial nephritis and glomerulonephritis; Nephrotic syndrome; Urocystitis comprises acute and chronic (matter) urocystitis and hunner's ulcer (Hunner ' s ulcer); Acute and chronic urethritis, prostatitis, epididymitis, ovaritis and salpingitis; Vulvo-vaginitis; Perun alunite disease (Peyronie ' s disease); Erectile dysfunction (masculinity and femininity);
9. allograft rejection: after for example kidney, heart, liver, lungs, marrow, skin or corneal transplantation or the acute and chronic allograft rejection that after blood transfusion, occurs; Or chronic graft versus host disease;
10.CNS: degenerative brain disorder (Alzheimer ' s disease) and other dementia disease comprise CJD and nvCJD; Amyloidosis; Multiple sclerosis and other demyelination syndrome; Cerebral atherosclerosis and vasculitis; Temporal arteritis; Myasthenia gravis; Acute and chronic pain (acute, intermittence or rest pain, no matter be maincenter source property or outer perigene), comprise Encelialgia, headache, migraine, trigeminal neuralgia, atypical facial pain, joint and ostalgia, invade the pain, the neuropathic pain syndrome that cause by cancer and tumour and comprise the neuropathy relevant after diabetic, the bleb with HIV; The nervosa sarcoidosis; The maincenter and the peripheral nervous system complication of pernicious, infectivity or autoimmunity process;
11. other autoimmunity and allergic disorder comprise Hashimoto thyroiditis (Hashimoto ' s thyroiditis), Graves disease (Graves ' disease), bronzed disease (Addison ' sdisease), diabetes, idiopathic thrombocytopenic purpura, eosinophilic fasciitis, high IgE syndrome, antiphospholipid syndrome;
12. the disease that other has inflammatory or immunity composition comprises acquired immune deficiency syndrome (AIDS) (AIDS), leprosy, Sezary syndrome (Sezary syndrome) and paraneoplastic syndrome;
13. it is cardiovascular: the atherosclerosis that influences coronary artery and peripheral circulation; Pericarditis; Myocarditis; Inflammatory and autoimmunity myocardosis comprise myocardial sarcoisosis; Ischemic damage and reperfusion damage; Endocarditis, cardiovalvulitis and aortitis comprise infectivity (for example syphilis); Vasculitis; The disease of near-end and peripheral vein comprises that phlebitis and thrombosis comprise venous thrombosis and cirsoid complication;
14. tumour:, comprise prostate gland, mammary gland, lung, ovary, pancreas, intestines and colon, stomach, skin and cerebral tumor and influence marrow (comprising leukemia) and the malignant tumour of lymphocytic hyperplasia system (for example He Jiejin (Hodgkin ' s) and non Hodgkin lymphoma) to general treatment for cancer; Comprise prevention and treatment to metastatic disease and tumor recurrence and paraneoplastic syndrome; Or
15. gi tract: coeliac disease, rectitis, Eosinophilic Gastroenteritis, Mastocytosis, Crohn's disease, ulcerative colitis, microscope colitis, uncertain colitis, intestines stress disease, irritable bowel syndrome, non-inflammatory diarrhoea, have away from the relevant transformation reactions (for example migraine, rhinitis or eczema) of the food of intestines effect.
Another aspect of the present invention is provided for treating the illness of suffering from PDE4 mediation or faces the method for described illness of the Mammals (for example people) of described illness risk, described method comprise will the treatment significant quantity formula (I) compound or pharmaceutically acceptable salt thereof need the Mammals of this treatment.
The present invention also provides formula (I) compound or pharmaceutically acceptable salt thereof, and it is used for the treatment of.
In yet another aspect, the invention provides purposes in formula (I) compound or pharmaceutically acceptable salt thereof is used for the treatment of (for example regulating the PDE4 enzymic activity) in preparation the medicine.
The present invention also provides formula (I) compound or pharmaceutically acceptable salt thereof to be used for the treatment of purposes in the medicine of following disease in the Mammals (for example people) in preparation:
1. respiratory tract: airway obstructive disease, comprise asthma, comprise bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, exercise-induced asthma, drug-induced property (comprising what acetylsalicylic acid and NSAID brought out) asthma and bringing out property of dust asthma, intermission asthma and persistence asthma, and the asthma of various severities, reach the airway hyperreactivity that other reason causes; Chronic obstructive pulmonary disease (COPD); Bronchitis comprises infectious bronchitis and acidophilia bronchitis; Pulmonary emphysema; Bronchiectasis; Cystic fibrosis; Sarcoidosis; Farmer lung and relative disease; Hypersensitivity pneumonitis; Pulmonary fibrosis comprises the concurrent fibrosis of CFA, idiopathic interstitial pneumonia, antineoplaston and chronic infection (comprising tuberculosis and aspergillosis and other fungi infestation); The complication of lung transplantation; Pulmonary vascular vasculitis and thrombotic disease and pulmonary hypertension; Antitussive activity comprises chronic cough and iatrogenic cough that treatment and airway inflammation are relevant with the secretion situation; Acute rhinitis and chronic rhinitis comprise medicamentous rhinitis and vasomotor rhinitis; Catarrhus perennialis and seasonal allergic rhinitis comprise nervous rhinitis's (pollinosis); Nasal polyposis; Acute viral infection comprises common cold and the infection that is caused by respiratory syncytial virus, influenza, coronavirus (comprising SARS) or adenovirus; Or acidophilia esophagitis;
2. bone and joint: relevant with osteoarthritis/osteoarthropathy or comprise and the sacroiliitis of osteoarthritis/osteoarthropathy comprise primary and Secondary cases sacroiliitis, for example congenital hip dysplasia; Neck and lumbar spine inflammation and lumbago and backache and cervical pain; Osteoporosis; Rheumatoid arthritis and Still disease; Seronegative spondyloanthropathy comprises ankylosing spondylitis, arthritic psoriasis, reactive arthritis and does not break up SpA; Septic arthritis infects relevant joint disease and osteopathia with other, and for example tuberculosis comprises Pott's disease and Poncet syndrome; Acute and the chronic synovitis that crystal brings out comprises the relevant tendon of urate deposition disease, calcium pyrophosphate deposition disease and apatite calcium, mucous bursa and synovial membrane inflammation; Behcet's disease; Primary and Secondary cases xerodermosteosis; Sjogren's syndrome and local scleroderma; Systemic lupus erythematous, mixed connective tissue disease and undifferentiated connective tissue disease; Inflammatory myopathy comprises dermatomyositis and polymyositis; Polymyalgia rheumatica; Juvenile arthritis comprises spy's property the sent out inflammatory arthritis and related syndromes and rheumatic fever and the general complication thereof that are distributed in any joint; Vasculitis comprises giant cell arteritis, aortic arch syndrome, Qiu-Shi syndrome, polyarteritis nodosa, microscope polyarteritis and the vasculitis relevant with virus infection, allergy, cryoglobulin and M-band; Lumbago and backache; Familial Mediterranean fever, Mu-Wei syndrome and familial Ireland heat, Kikuchi are sick; Drug-induced property arthrodynia, tendonitis and myopathy;
3. the musculoskeletal disease that reproduces of pain that causes by damage (for example sport injury) or disease and reticular tissue: sacroiliitis (for example rheumatoid arthritis, osteoarthritis, gout or crystallographic joint disease), other joint disease (for example degeneration of intervertebral disc or temporomandibular joint (TMJ) sex change), bone remodelling disease (for example osteoporosis, Paget's disease or osteonecrosis), polychondritis, scleroderma, mixed connective tissue disease, spondyloarthropathy or periodontopathy (for example periodontitis);
4. skin: psoriasis, atopic dermatitis, contact dermatitis or other eczema dermatoses and delayed type hypersensitivity; Vegetalitas and solar dermatitis; Seborrheic dermatitis, dermatitis herpetiformis, lichen planus, atrophic sclerosis lichen, PG, skin tag disease, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema toxicum, skin eosinophilia, alopecia areata, male pattern alopecia, sweet's syndrome, Wei-Ke syndrome, erythema multiforme; Cellulitis comprises infectivity and non-infectious cellulitis; Pimelitis; Lymphoma cutis, non-melanoma skin cancer and other dysplasia damage; Drug-induced disease comprises fixed drug eruption;
The eye: blepharitis; Conjunctivitis, comprise the perennial allergic conjunctivitis or spring anaphylaxis conjunctivitis; Iritis; Anterior uveitis and posterior uveitis; Choroiditis; Autoimmunization; Influence amphiblestroid sex change or inflammatory diseases; Ophthalmia comprises sympathetic ophthalmia; Sarcoidosis; Infect, comprise virus, fungi and infectation of bacteria;
6. gi tract: glossitis, oulitis, periodontitis; Esophagitis comprises and backflowing; Eosinophilic Gastroenteritis, mastocyte increase, Crohn's disease, colitis comprise ulcerative colitis, rectitis, pruritus ani; Coeliac disease, irritable bowel syndrome, and have away from the relevant transformation reactions (for example migraine, rhinitis or eczema) of the food of intestines effect;
7. belly: hepatitis comprises autoimmunity, alcohol and viral hepatitis; Hepatic fibrosis and sclerosis; Cholecystitis; Pancreatitis comprises acute and chronic pancreatitis;
8. urogenital system: ephritis comprises interstitial nephritis and glomerulonephritis; Nephrotic syndrome; Urocystitis comprises acute and chronic (matter) urocystitis and hunner's ulcer; Acute and chronic urethritis, prostatitis, epididymitis, ovaritis and salpingitis; Vulvo-vaginitis; Perun alunite disease; Erectile dysfunction (masculinity and femininity);
9. allograft rejection: after for example kidney, heart, liver, lungs, marrow, skin or corneal transplantation or the acute and chronic allograft rejection that after blood transfusion, occurs; Or chronic graft versus host disease;
10.CNS: degenerative brain disorder and other dementia disease comprise CJD and nvCJD; Amyloidosis; Multiple sclerosis and other demyelination syndrome; Cerebral atherosclerosis and vasculitis; Temporal arteritis; Myasthenia gravis; Acute and chronic pain (acute, intermittence or rest pain, no matter be maincenter source property or outer perigene), comprise Encelialgia, headache, migraine, trigeminal neuralgia, atypical facial pain, joint and ostalgia, invade the pain, the neuropathic pain syndrome that cause by cancer and tumour and comprise the neuropathy relevant after diabetic, the bleb with HIV; The nervosa sarcoidosis; The maincenter and the peripheral nervous system complication of pernicious, infectivity or autoimmunity process;
11. other autoimmunity and allergic disorder comprise Hashimoto thyroiditis, Graves disease, bronzed disease, diabetes, idiopathic thrombocytopenic purpura, eosinophilic fasciitis, high IgE syndrome, antiphospholipid syndrome;
12. the disease that other has inflammatory or immunity composition comprises acquired immune deficiency syndrome (AIDS) (AIDS), leprosy, Sezary syndrome and paraneoplastic syndrome;
13. it is cardiovascular: the atherosclerosis that influences coronary artery and peripheral circulation; Pericarditis; Myocarditis; Inflammatory and autoimmunity myocardosis comprise myocardial sarcoisosis; Ischemic damage and reperfusion damage; Endocarditis, cardiovalvulitis and aortitis comprise infectivity (for example syphilis); Vasculitis; The disease of near-end and peripheral vein comprises that phlebitis and thrombosis comprise venous thrombosis and cirsoid complication;
14. tumour:, comprise prostate gland, mammary gland, lung, ovary, pancreas, intestines and colon, stomach, skin and cerebral tumor and influence marrow (comprising leukemia) and the malignant tumour of lymphocytic hyperplasia system (for example He Jiejin and non Hodgkin lymphoma) to general treatment for cancer; Comprise prevention and treatment to metastatic disease and tumor recurrence and paraneoplastic syndrome; Or
15. gi tract: coeliac disease, rectitis, Eosinophilic Gastroenteritis, Mastocytosis, Crohn's disease, ulcerative colitis, microscope colitis, uncertain colitis, intestines stress disease, irritable bowel syndrome, non-inflammatory diarrhoea, have away from the relevant transformation reactions (for example migraine, rhinitis or eczema) of the food of intestines effect.
In yet another aspect, the invention provides formula (I) compound or pharmaceutically acceptable salt thereof, be used for the treatment of following disease: asthma { for example bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma or dust asthma, especially chronic or obstinate asthma (for example tardy property asthma or airway hyperreactivity) }; Or COPD.
In yet another aspect, formula (I) compound or pharmaceutically acceptable salt thereof can be used for treating COPD.
The present invention also provides formula (I) compound or pharmaceutically acceptable salt thereof to be used for the treatment of purposes in the medicine of following disease in preparation: asthma { for example bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma or dust asthma, especially chronic or obstinate asthma (for example tardy property asthma or airway hyperreactivity) }; Or COPD.
For compound or pharmaceutically acceptable salt thereof of the present invention being used for the treatment of Mammals (for example people), the pharmaceutical operation according to standard is mixed with pharmaceutical composition with described composition usually.Therefore, in yet another aspect, the invention provides the pharmaceutical composition that comprises formula (I) compound or pharmaceutically acceptable salt thereof (activeconstituents) and pharmaceutical excipient, diluent or carrier.
In yet another aspect, the invention provides the described method for compositions of preparation, described method comprises mixed active composition and pharmaceutical excipient, diluent or carrier.Depend on mode of administration, pharmaceutical composition for example comprise 0.05 to 99%w (weight percent), for example 0.05 to 80%w, for example 0.10 to 70%w, 0.10 to 50%w activeconstituents for example, all wt per-cent is all based on total composition.
For the illness of expectation treatment, pharmaceutical composition of the present invention can be by the mode of standard for example by part (for example be administered into lung and/or air flue or be administered into skin), suction, oral, rectum or non-ly give through enteral administration.For these purposes, compound of the present invention can be prepared by methods known in the art.Suitable pharmaceutical composition of the present invention is the unit dosage (for example tablet or capsule) that is suitable for oral administration, and described unit dosage comprises the activeconstituents of 0.1mg to 1g.
Every patient can for example be 0.001mgkg by the dosage of for example accepting over 1 to 4 time/day to be given
-1To 100mgkg
-1Scope for example be 0.1mgkg
-1To 20mgkg
-1Activeconstituents.
The invention still further relates to combined therapy, compound or pharmaceutically acceptable salt thereof wherein of the present invention or comprise the pharmaceutical composition of The compounds of this invention or preparation and another kind of therapeutical agent or multiple therapeutical agent simultaneously or successively give, or give as combination preparation with another kind of therapeutical agent or multiple therapeutical agent, be used for the treatment of in the listed illness one or more.
Particularly, in order to treat inflammatory disease, for example (but being not limited to) rheumatoid arthritis, osteoarthritis, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), psoriasis and inflammatory bowel can be with compound of the present invention and following drug regimens.
Nonsteroidal anti-inflammatory agent (being NSAIDs hereinafter) comprises that topical application no matter still is the non-selective cyclooxygenase COX-1/COX-2 inhibitor used of a whole body (piroxicam for example; Diclofenac; Propionic acid class, for example Naproxen Base, flurbiprofen, fenoprofen, Ketoprofen and Ibuprofen BP/EP; Fragrant that acids, for example mefenamic acid, indomethacin, sulindac, Azapropazone (azapropazone); Pyrazolone, for example Phenylbutazone; Salicylate (ester), for example acetylsalicylic acid); Selective COX-2-2 inhibitor (for example meloxicam, celecoxib, rofecoxib, valdecoxib, Lu Makao former times (lumarocoxib), parecoxib and L-791456); The nitric oxide donors (CINODs) that suppresses cyclooxygenase; Glucocorticosteroid (no matter still coming administration) by the intraarticular approach by local, oral, intramuscular, intravenous route; Methotrexate; Leflunomide; Oxychloroquine; The d-Trolovol; Auranofin or other are non-through intestines or oral golden preparation; Anodyne; Diacerein (diacerein); Intraarticular therapeutical agent, for example derivatives of hyaluronic acids; And nutritional supplement, for example glucosamine.
The invention still further relates to the combination of The compounds of this invention or its pharmaceutical salts and following material: the agonist of cytokine or cytokine function or antagonist (comprise the medicine that acts on the cytokine signaling conducting path, the conditioning agent of SOCS system for example), comprise α-, β-and gamma-interferon; I type rhIGF-1 (IGF-1); Interleukin (IL) comprises IL1 to 17 and interleukin antagonist or inhibitor (for example Kineret); Cachectin (TNF-α) inhibitor, for example anti-TNF monoclonal antibody (for example infliximab (infliximab), adalimumab (adalimumab) and CDP-870) and TNF receptor antagonist (comprising immunoglobulin molecules (for example etanercept) and low-molecular-weight drug (for example pentoxifylline (pentoxyfylline))).
In addition, the present invention relates to the combination of The compounds of this invention or its pharmaceutical salts and following material: target in the monoclonal antibody (for example CD20 (Rituximab (rituximab)), MRA-aIL16R) of bone-marrow-derived lymphocyte and target in the lymphocytic monoclonal antibody of T (CTLA4-Ig, HuMax I1-15).
The invention still further relates to the combination of The compounds of this invention or its pharmaceutical salts and following material: chemokine receptor function conditioning agent, for example antagonist of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (C-C family); The antagonist of CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (C-X-C family); And CX
3CR1 (C-X
3-C family) antagonist.
The invention still further relates to the combination of The compounds of this invention or its pharmaceutical salts and following material: the inhibitor of the instant stromatin enzyme of matrix metalloproteinase (MMPs) (stromelysin), collagenase and gelatinase and proteoglycan enzyme (aggrecanase) (for example collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), molten stromatin enzyme-1 (MMP-3), molten stromatin enzyme-2 (MMP-10) and molten stromatin enzyme-3 (MMP-11) and MMP-9 and MMP-12), comprise medicine, for example Vibravenos.
The invention still further relates to the combination of The compounds of this invention or its pharmaceutical salts and following material: inhibitors of leukotriene biosynthesis, 5-lipoxidase (5-LO) inhibitor or 5-lipoxidase activated protein (FLAP) antagonist, for example zileuton; ABT-761; Fenleuton; Tepoxalin; Abbott-79175; Abbott-85761; N-(5-replaces)-thiophene-2-alkyl sulfonamide; 2,6-two-tert.-butyl phenol hydrazone; Methoxyl group tetrahydropyrans, for example Zeneca ZD-2138; Compound S B-210661; The 2-cyano group naphthalene compound that pyridyl replaces, L-739 for example, 010; 2-cyano quinolines compound, L-746 for example, 530; Or indoles or quinoline compound, for example MK-591, MK-886 and BAY * 1005.
The invention still further relates to the combination of The compounds of this invention or its pharmaceutical salts and following material: the receptor antagonist of leukotriene (LT) B4, LTC4, LTD4 and LTE4 is selected from thiodiphenylamine-3-based compound, L-651 for example, 392; Amidino compounds, for example CGS-25019c; Ben Bing Evil amine (benzoxalamine), for example Ontazolast; Benzenyl amidine (benzenecarboximidamide), for example BIIL 284/260; And compound, for example Zafirlukast, Ro 23-3544, Singulair, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP45715A) and BAY * 7195.
The invention still further relates to the combination of The compounds of this invention or its pharmaceutical salts and following material: phosphodiesterase (PDE) inhibitor, for example methyl xanthine (methylxanthanine) comprises theophylline and aminophylline; Selectivity PDE isozyme inhibitor comprises PDE4 inhibitor or isoform PDE4D inhibitor, or the PDE5 inhibitor.
The invention still further relates to the combination of The compounds of this invention or its pharmaceutical salts and following material: histamine 1 receptor antagonist, for example cetirizine, Loratadine, Desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, nitrogen
Si Ting, levocabastine, chlorphenamine, promethazine, cyclizine (cyclizine) or mizolastine; Oral, local or non-through enteral administration.
The invention still further relates to the combination of The compounds of this invention or its pharmaceutical salts and following material: proton pump inhibitor (for example omeprazole) or stomach protectiveness histamine 2 receptor antagonist.
The invention still further relates to the combination of The compounds of this invention or its pharmaceutical salts and following material: histamine 4 receptor antagonists.
The invention still further relates to the combination of The compounds of this invention or its pharmaceutical salts and following material: α 1/ α 2 adrenoceptor agonists, vasoconstrictor, sympathomimetic, for example propylhexedrine (propylhexedrine), phenylephrine, Phenylpropanolamine, ephedrine, pseudoephedrine, naphcon, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorephinephrine hydrochloride.
The invention still further relates to the combination of The compounds of this invention or its pharmaceutical salts and following material: anticholinergic, comprise M-ChR (M1, M2 and M3) antagonist, for example coromegine, Scopolamine, GLYCOPYRRONIUM (glycopyrrrolate), ipratropium bromide (ipratropium bromide), tiotropium bromide (tiotropiumbromide), oxitropium bromide (oxitropium bromide), pirenzepine (pirenzepine) or telenzepine (telenzepine).
The invention still further relates to the combination of The compounds of this invention or its pharmaceutical salts and following material: receptor, agonist (comprising beta receptor hypotype 1-4), for example isopropyl noradrenalin (isoprenaline), salbutamol (salbutamol), formoterol (formoterol), Salmeterol (salmeterol), terbutaline (terbutaline), Orciprenaline (orciprenaline), bitolterol mesilate (bitolterol mesylate) or pirbuterol (pirbuterol) or its chirality enantiomer.
The invention still further relates to the combination of The compounds of this invention or its pharmaceutical salts and following material: chromone, for example Sodium Cromoglicate or sodium nedocromil.
The invention still further relates to the combination of The compounds of this invention or its pharmaceutical salts and following material: glucocorticosteroid, for example flunisolide, Triamcinolone Acetonide, Beconase Nasal Syray, budesonide, fluticasone propionate, ciclesonide or furoic acid momisone.
The invention still further relates to the combination of The compounds of this invention or its pharmaceutical salts and following material: the medicine of regulating nuclear hormone receptor (for example PPARs).
The invention still further relates to the combination of The compounds of this invention or its pharmaceutical salts and following material: immunoglobulin (Ig) (Ig) or Ig goods; Or the antagonist or the antibody of adjusting Ig function, for example anti-IgE (horse pearl monoclonal antibody for example difficult to understand (omalizumab)).
The invention still further relates to the combination of The compounds of this invention or its pharmaceutical salts and following material: the antiphlogiston of another kind of whole body or topical application, for example Thalidomide (thalidomide) or derivatives thereof, retinoid, Dithranol (dithranol) or calcipotriol (calcipotriol).
The invention still further relates to the combination of The compounds of this invention or its pharmaceutical salts and following material: the combination of aminosalicylate (ester) and sulfapyridine (for example sulfasalazine, mesalazine, Balsalazide and Olsalazine); And immunomodulator, for example thio-purine and reflunomide (for example budesonide).
The invention still further relates to the combination of The compounds of this invention or its pharmaceutical salts and following material: antimicrobial drug, for example penicillin derivative, tsiklomitsin, macrolide, beta-lactam, fluoroquinolone, metronidazole, imbedibility aminoglycoside; Antiviral drug comprises acyclovir, Famciclovir, valacyclovir, ganciclovir, cidofovir, amantadine, Rimantadine, ribavirin, zanamivir (zanamavir) and special quick clothes (oseltamavir); Proteinase inhibitor, for example Indinavir, viracept see nelfinaivr, ritonavir and Saquinavir; Nucleoside reverse transcriptase inhibitor, for example didanosine, lamivudine, stavudine (stavudine), zalcitabine or zidovudine; Or non-nucleoside reverse transcriptase inhibitor, for example nevirapine (nevirapine) or efavirenz (efavirenz).
The invention still further relates to the combination of The compounds of this invention or its pharmaceutical salts and following material: cardiovascular drug, for example calcium channel blocker, receptor, blocker, angiotensin-converting enzyme (ACE) inhibitor, hypertensin 2 receptor antagonist; Lipid lowerers, for example special class of statin or shellfish; The blood cell morphology conditioning agent is for example joined the appropriate western film (pentoxyfylline); Thrombolysis medicine or anti-freezing medicine, for example anticoagulant.
The invention still further relates to the combination of The compounds of this invention or its pharmaceutical salts and following material: CNS medicine, for example thymoleptic (for example Sertraline), anti-Parkinson medicine (selegiline for example, the L-DOPA, Ropinirole, pramipexole, MAOB inhibitor (for example selegiline and rasagiline), comP inhibitor (for example tolcapone (tasmar)), the A-2 inhibitor, the dopamine reuptake inhibitor, nmda antagonist, the Nicotine agonist, dopamine agonist or neuronal nitric oxide synthase inhibitor) or anti-Alzheimer medicine (E2020 (donepezil) for example, profit is cut down the bright of this, tacrine, cox 2 inhibitor, propentofylline or Metrifonate).
The invention still further relates to the combination of The compounds of this invention or its pharmaceutical salts and following material: be used for the treatment of the medicine of acute or chronic pain, for example anodyne (for example opioid or derivatives thereof), Carbamzepine, Phenytoin Sodium Salt, Sodium Valproate, amitriptyline (amitryptiline) or other thymoleptic, paracetamol or the nonsteroidal anti-inflammatory agent that plays a role in maincenter or periphery.
The invention still further relates to the combination of The compounds of this invention or its pharmaceutical salts and following material: non-through (the comprising suction) of intestines or topical application local anaesthetics, for example lignocaine or derivatives thereof.
Compound or pharmaceutically acceptable salt thereof of the present invention also can with following material coupling: anti-osteoporotic comprises hormonal medicaments (for example raloxifene (raloxifene)) or diphosphonate (for example alendronate (alendronate)).
The invention still further relates to the combination of The compounds of this invention or its pharmaceutical salts and following material: (i) tryptase (tryptase) inhibitor; (ii) platelet activation factor (PAF) antagonist; (iii) interleukin converting enzyme (ICE) inhibitor; (iv) IMPDH inhibitor; (v) the adhesion molecule inhibitor comprises the VLA-4 antagonist; (vi) kethepsin; (vii) kinase inhibitor, Tyrosylprotein kinase (for example Btk, Itk, Jak3 or MAP) inhibitor (for example Gefitinib (gefitinib) or imatinib mesylate (imatinib)), serine/threonine kinase inhibitor (map kinase (p38 for example for example for example, JNK, protein kinase A, B or C, or IKK) inhibitor) or the inhibitor of the kinases (for example cell cycle protein dependent kinase) that in Cycle Regulation, involves; (viii) glucose-6 monophosphate dehydrogenase inhibitor; (ix) kassinin kinin B
1Acceptor or kassinin kinin B
2Receptor antagonist; (x) antigout drug, for example colchicine; (xi) xanthine oxidase inhibitor, for example allopurinol; (xii) uricosuric, for example probenecid, sulfinpyrazone or benzbromarone; (xiii) tethelin succagoga; (xiv) transforming growth factor (TGF β); (xv) platelet-derived growth factor (PDGF); (xvi) fibroblast growth factor, for example basic fibroblast growth factor (bFGF); (xvii) rHuGM-CSF (GM-CSF); (xviii) capsicum vegetable oil (capsaicin cream); (xix) tachykinin NK-1
1Acceptor or tachykinin NK-1
3Receptor antagonist, for example NKP-608C, SB-233412 (Talnetant (talnetant)) or D-4418; (xx) elastatinal, for example UT-77 or ZD-0892; (xxi) TNF-α converting enzyme inhibitor (TACE); (xxii) inductive nitricoxide synthase (iNOS) inhibitor; The chemoattractant receptor homolog molecule of (xxiii) expressing on the TH2 cell (for example CRTH2 antagonist); (xxiv) inhibitor of P38; (xxv) medicine of adjusting Toll sample acceptor (TLR) function; (xxvi) regulate the active medicine of purinergic receptor, for example P2X7; (xxvii) transcription factor activation inhibitor, for example NFkB, API or STATS; Or (xxviii) glucocorticoid receptor (GR-acceptor) agonist.
On the other hand, the invention provides a kind of medicament production (pharmaceutical product), it comprises first activeconstituents, promptly aforesaid formula (I) compound or pharmaceutically acceptable salt thereof, and the another kind of at least combination that is selected from following activeconstituents:
Beta 2 adrenoreceptor agonists,
The conditioning agent of chemokine receptor function,
The inhibitor of kinase function,
Proteinase inhibitor,
The steroidal glucocoricoid receptor agonist,
Anticholinergic, and
The non-steroidal glucocoricoid receptor agonist.
The medicament production of the present embodiment for example can be pharmaceutical composition, and it comprises the mixture of first activeconstituents and another kind of activeconstituents.Alternatively, medicament production for example can comprise first activeconstituents and the another kind of activeconstituents in the independent pharmaceutical preparation, to be suitable for patient's while, priority or the order administration to the described treatment of needs.
The medicament production of the present embodiment is used in particular for treating respiratory system disease, such as asthma, COPD or rhinitis.
The beta 2 adrenoreceptor agonists that can be used for the medicament production of the present embodiment comprises Metaprel (metaproterenol), isopropyl noradrenalin (isoproterenol), Racemic isoproterenol (isoprenaline), salbutamol (albuterol), salbutamol (for example being vitriol), formoterol (for example being fumarate), Salmeterol (for example being xinafoate), terbutaline, Orciprenaline, bitolterol (for example being mesylate), pirbuterol or indenes Da Teluo (indacaterol).The beta 2 adrenoreceptor agonists of the present embodiment can be long lasting β
2Agonist, for example Salmeterol (for example being xinafoate), formoterol (for example being fumarate), bambuterol (for example being hydrochloride), (TA 2005, chemically are accredited as 2 (1H)-quinolones for Ka Moteluo carmoterol; 8-hydroxyl-5-[1-hydroxyl-2-[[2-(4-methoxyl group-phenyl)-1-methylethyl]-amino] ethyl]-one hydrochloride, [R-(R
*, R
*)] also identify by chemistry summary service registration number (Chemical Abstract Service RegistryNumber) 137888-11-0, and be disclosed in United States Patent (USP) 4,579, in 854), indenes Da Teluo (CAS 312753-06-3; QAB-149); the formamido group benzene derivative for example WO 2002/76933 disclosed 3-(4-{[6-((2R)-2-[3-(formyl radical amino)-4-hydroxy phenyl]-the 2-hydroxyethyl amino) hexyl] the oxygen base-butyl)-benzsulfamide; benzenesulfonamide derivatives is WO 2002/88167 disclosed 3-(4-{[6-({ (2R)-2-hydroxyl-2-[4-hydroxyl-3-(hydroxyl-methyl) phenyl] ethyl } amino)-hexyl] oxygen base } butyl) benzsulfamide for example; as disclosed aryl aniline receptor stimulant among WO 2003/042164 and the WO 2005/025555; as disclosed indole derivatives among WO 2004/032921 and the US 2005/222144, and compound GSK 159797; GSK 159802; GSK 597901; GSK 642444 and GSK678007.
The example of chemokine receptor function conditioning agent that can be used for the medicament production of the present embodiment comprises the CCR1 receptor antagonist.
The example of kinase function inhibitor that can be used for the medicament production of the present embodiment comprises p38 kinase inhibitor and IKK inhibitor.
The example of proteinase inhibitor that can be used for the medicament production of the present embodiment comprises NE (neutrophil elastase) inhibitor or MMP12 inhibitor.
The example of steroidal glucocoricoid receptor agonist that can be used for the medicament production of the present embodiment comprises budesonide, fluticasone (for example being propionic ester), Mometasone (for example being furoate), beclometasone (for example is 17-propionic ester or 17, the 21-dipropionate), ciclesonide, loteprednol (for example being etabonate), sprinkle promise (etiprednol) (for example being dichloroacetate) according to replacing, triamcinolone (for example being acetonide), flunisolide, zoticasone, flumoxonide, Rofleponide, Butixocort (for example being propionic ester), prednisolone, prednisone, tipredane, steroid class ester is 6 α for example, 9 α-two fluoro-, 17 α-[(2-furyl carbonyl) oxygen base]-11 beta-hydroxy-16 Alpha-Methyls-3-oxo-androstane-1,4-diene-17 β-thiocarboxylic acid S-fluorine methyl esters, 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha--methyl-3-oxo-17 α-propionyloxy-androstane-1,4-diene-17 β-thiocarboxylic acid S-(2-oxo-tetrahydrofuran (THF)-3S-yl) ester and 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha--methyl-17-alpha-[(4-methyl isophthalic acid, 3-thiazole-5-carbonyl) oxygen base]-3-oxo-androstane-1,4-diene-17 β-thiocarboxylic acid S-fluorine methyl esters, DE 4129535 disclosed steroid class esters, WO 2002/00679, disclosed steroid class among the WO 2005/041980, or steroid class GSK 870086, GSK 685698 and GSK 799943.
The example of anticholinergic that can be used for the medicament production of the present embodiment for example comprises muscarinic receptor antagonist (for example M1, M2 and M3 antagonist, such as the M3 antagonist); Rinovagos (for example bromide) for example; Tiotropium bromide (for example being bromide); Oxitropium bromide (for example being bromide); Tolterodine; Pirenzepine; Telenzepine; Glycopyrronium Bromide (such as R, R-Glycopyrronium Bromide or R, S-and S, the mixture of R-Glycopyrronium Bromide); Mepenzolate bromide (for example being bromide); Quinuclidine derivatives is such as disclosed 3 (R) among the US 2003/0055080-(2-hydroxyl-2,2-dithiene-2-base acetoxyl group)-1-(3-phenoxy propyl)-1-nitrogen-two ring [2.2.2] octane bromide; As disclosed quinuclidine derivatives among WO 2003/087096 and WO 2005/115467 and the DE10050995; Or GSK 656398 or GSK 961081.
The example of non-steroidal glucocoricoid receptor agonist that can be used for the medicament production of the present embodiment comprises disclosed medicine among the WO2006/046916.
Also compound or pharmaceutically acceptable salt thereof of the present invention and existing medicine coupling can be used for the treatment of cancer, suitable medicine for example comprises:
(i) antiproliferative/antitumour drug that in medical oncology, uses or its combination, for example alkylating agent (for example cis-platinum, carboplatin, endoxan, mustargen, melphalan, Chlorambucil, busulfan or nitrosourea); Antimetabolite (for example antifol, for example fluorine pyrimidine sample 5 FU 5 fluorouracil or Tegafur, Raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or taxol); Antitumor antibiotics (for example anthracycline antibiotics, for example Zorubicin, bleomycin, Dx, daunorubicin, epirubicin, idarubicin, ametycin, gengshengmeisu or Plicamycin); Antimitotic agent (for example catharanthus alkaloid, for example vincristine(VCR), vinealeucoblastine(VLB), vindesine or vinorelbine; Or Taxan, for example safe plain (taxol) or taxotere (taxotere)); Or topological isozyme inhibitor (for example epipodophyllotoxin, for example Etoposide, teniposide, Amsacrine, Hycamtin or camptothecine);
(ii) cell growth-inhibiting medicine, for example antiestrogen (for example tamoxifen, toremifene, raloxifene, droloxifene or iodoxyfene); Adjust under the estrogen receptor (for example fulvestrant); Antiandrogen (for example bicalutamide, flutamide, Nilutamide or acetate cyproterone); Lhrh antagonist or LHRH agonist (for example goserelin, Leuprolide or buserelin); Progestogen (for example acetate megestrol); Aromatization enzyme (aromatase) inhibitor (for example being Anastrozole, letrozole, vorozole (vorazole) or Exemestane); Or 5 inhibitor (for example finasteride);
The (iii) anticancer medicine (for example inhibitors of metalloproteinase (for example Marimastat) or UPA function of receptors inhibitor) of invading;
(iv) somatomedin depressant of functions, for example: growth factor antibodies (for example anti-erb b2 antibody trastuzumab or anti-erb b1 antibody Cetuximab [C225]); Farnesyl transferase inhibitor; Tyrosine kinase inhibitor or serine/threonine kinase inhibitor; Epidermal growth factor family inhibitor (EGFR family tyrosine kinase inhibitor for example, N-(3-chloro-4-fluorophenyl)-7-methoxyl group-6-(3-morpholino propoxy-) quinazoline-4-amine (Gefitinib for example, AZD1839), N-(3-ethynyl phenyl)-6,7-two (2-methoxy ethoxy) quinazoline-4-amine (erlotinib (erlotinib), OSI-774) or 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholino propoxy-) quinazoline-4-amine (CI 1033)); Platelet-derived growth factor man group inhibitor; Or pHGF man group inhibitor;
(v) angiogenesis inhibitor medicine for example suppresses the angiogenesis inhibitor medicine (for example anti-vascular endothelial cell growth factor antibody rhuMAb-VEGF, the compound that discloses) of vascular endothelial growth factor effect in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354; Or the compound (for example linomide, beta 2 integrin alpha v β 3 depressant of functions or angiostatin) that plays a role by another kind of mechanism;
(vi) blood vessel injury agent, for example compound of combretastatin A4 or disclosure in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213;
(medicine that vii) in antisense therapy, uses, the antisense therapy medicine of one of listed target, for example ISIS 2503, anti-ras antisense thing more than for example pointing to;
(the viii) medicine that in following gene therapy method for example, uses: the method for displacement aberrant gene (for example unusual p53 or unusual BRCA1 or BRCA2); The GDEPT enzyme prodrug of the gene mediated (treatment) method is for example used the GDEPT method of Isocytosine deaminase, thymidine kinase or bacterium nitroreductase; With the method that improves patient's chemotherapy or radiotherapy tolerance, for example multiple drug resistance gene therapy; Or
(ix) medicine that in following immunotherapy method for example, uses: improve exsomatizing and, for example using cytokine (for example interleukin-22, interleukin 4 or granulocyte-macrophage colony stimutaing factor) transfection of patient tumors cell immunogenicity at body method; Reduce the method for T cell anergy; Use the method for the immunocyte (for example dendritic cell of cytokine transfection) of transfection; Use the method for the tumor cell line of cytokine transfection; With the method for using anti-id AB.
Concrete embodiment
Except as otherwise noted, now explain the present invention by following non-limiting example:
(i) if provide
1H NMR data, except as otherwise noted, then
1H NMR data are the δ value form of principal character proton and quote with described form,
1H NMR data are used perdeuterated (Perdeuterio) DMSO-D6 (CD with respect to providing as 1,000,000/(ppm) of interior target tetramethylsilane (TMS)
3SOCD
3) or CDCl
3Measure at 300MHz or 400MHz as solvent;
(ii) in chemi-ionization (CI) model, use direct exposure probe (direct exposure probe) to carry out mass spectrum (MS) experiment with the electronic energy of 70 ev; Wherein said ionizing effect is by electrospray ionization (ES), or atmospheric pressure chemical ionization (APCI), or the multimode ionization, i.e. the combination of ES ionization and APCI is carried out; Wherein provide the m/z value, only write down the ion of expression parent quality (parent mass) usually, and positive mass spectrum ion of the mass spectrum ion of quoting (mass ion) or negative mass spectrum ion: [M]
+, [M+H]
+Or [M-H]
(iii) use Advanced Chemistry Development Inc, the index naming program of version 8.00 (index name program), or use the IUPAC naming program of Openeye to name title compound and subtitle compounds and the method for embodiment, and manually add the stereochemistry descriptor (referring to
Www.eyesopen.com/products/applications/ogham.html);
(iv) except as otherwise noted, use is all purchased in the Symmetry of Waters Corp.
TM, NovaPak
TMOr Xterra
TMThe reverse phase silica gel post carries out reversed-phase HPLC;
(v) except as otherwise noted, analyze the following method of having used for LC:
Method A: instrument is Agilent 1100, chromatographic column is Kromasil C18 100 * 3mm (granularity is 5 μ), solvent orange 2 A is a 0.1%TFA/ water, solvent B is the 0.08%TFA/ acetonitrile, flow velocity is 1mL/min, gradient is 10-100%/B 20min, and 100%B 1min measures 220,254 and the absorption value of 280nm.
Method B: instrument is Agilent 1100, and chromatographic column is XTerra C 8 100 * 3mm (granularity is 5 μ), and solvent orange 2 A is 15mM NH
3/ water, solvent B are acetonitrile, and flow velocity is 1mL/min, and gradient is 10-100%/B 20min, and 100%B 1min measures 220,254 and the absorption value of 280nm.
The starting raw material that is used for following examples is purchased, or easily prepares from known starting raw material by standard method.For example, below react the preparation of having set forth to some starting raw materials.
Preparation 1
5-fluoro-2-(tetrahydrochysene-2H-thiapyran-4-base is amino) nicotinic acid
With 2-chloro-5-fluorine nicotinic acid (5.27g, 30mmol), K
2CO
3(5g 36mmol) is added under argon gas atmosphere in the dry DMF (30ml).Add copper (95mg, 1.8mmol), the anhydrous cuprous bromide (I) of methanol wash (215mg, 1.5mmol) and tetrahydrochysene-2H-thiapyran-4-amine (6g, 51mmol), then with mixture 150 ℃ of stirrings 4 hours.Add ethyl acetate, then crude product is used 0.5M aqueous solution of citric acid washed twice, organic solvent is through Na
2SO
4Drying is filtered then vacuum and is removed, and obtains title compound (6g, 78%).
1H?NMR(400?MHz，DMSO-d
6)：δ?13.43(1H，brs)；8.31(1H，d)；7.97(1H，brd)；7.91(1H，dd)；3.99(1H，brs)；2.76-2.61(4H，m)；2.21(2H，m)；1.64-1.53(2H，m).
APCI-MS?m/z：257[MH
+].
Preparation 2
[cis-4-({ [5-fluoro-2-(tetrahydrochysene-2H-thiapyran-4-base is amino) pyridin-3-yl] carbonyl } amino) cyclohexyl] t-butyl carbamate
With 5-fluoro-2-(tetrahydrochysene-2H-thiapyran-4-base is amino) nicotinic acid (5.9g, 23mmol), (cis-4-aminocyclohexyl) t-butyl carbamate (5.42g, 25.3mmol), HATU (9.6g, 25.3mmol), HOAT (3.44g, 25.3mmol) and DIEA (12ml, 70mmol) mixture in NMP (100ml) is stirring at room 10 minutes (regulating pH to 8-9 with DIEA).Add ethyl acetate, then with crude product with twice of 0.5M aqueous solution of citric acid, sodium bicarbonate aqueous solution and water washing.Organic solvent is through Na
2SO
4Drying is filtered then vacuum and is removed.Resistates carries out purifying (using ethyl acetate/heptane (1:3) as eluent) through silica gel, obtains title compound (8.45g, 81%).
1H?NMR(400MHz，DMSO-d
6)：δ?8.22(1H，d)；8.17(1H，brd)；8.16(1H，brd)；7.96(1H，dd)；6.61(1H，brs)；3.92(1H，brs)；3.77(1H，brs)；3.40(1H，brs)；2.74-2.60(4H，m)；2.18(2H，m)；1.70(4H，m)；1.54(6H，m)；1.39(9H，s).
APCI-MS?m/z：453[MH
+].
LC (method A) rt=11.6 minute
Preparation 3
Cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] and cyclohexyl } t-butyl carbamate
The oil dispersion (1.24g that lasts 1 hour under argon gas atmosphere with 50%NaH, 25.7mmol) be divided into 10 batches and be added to [cis-4-({ [5-fluoro-2-(tetrahydrochysene-2H-thiapyran-4-base is amino) pyridin-3-yl] carbonyl } amino) cyclohexyl] t-butyl carbamate (3.9g, 8.58mmol) and 1, (4.17g is 25.7mmol) in the solution in anhydrous NMP (100ml) for 1 '-carbonyl dimidazoles.With mixture stirring at room 2 days.Add ethyl acetate, then with crude product with twice of 0.5M aqueous solution of citric acid, sodium bicarbonate aqueous solution and water washing.Organic solvent is through Na
2SO
4Drying is filtered then vacuum and is removed.Resistates carries out purifying (using ethyl acetate/heptane (1:4) as eluent) through silica gel, obtains title compound (1.95mg, 48%) and is recovered to 0.9g (23%) starting raw material.
1H?NMR(400MHz，DMSO-d
6)：δ?8.78(1H，d)；8.21(1H，dd)；6.58(1H，brs)；5.20(1H，brs)；4.72(1H，brt)；3.56(1H，brs)；2.84-2.68(6H，m)；2.58(2H，q)；2.01-1.86(4H，m)；1.49(2H，brt)；1.42(11H，brs).
APCI-MS?m/z：379[MH
+-tBOC].
LC (method A) rt=14.8 minute
Preparation 4
3-(cis-4-aminocyclohexyl)-6-fluoro-1-(tetrahydrochysene-2H-thiapyran-4-yl) pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-dione hydrochloride
With cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } t-butyl carbamate (0.36g, 0.75mmol) and 4M HCl in 1, the mixture in the 4-diox (10ml) was stirring at room 1 hour.Remove and desolvate, and pure crude product is directly used.
APCI-MS?m/z：379[MH
+].
Preparation 5
5-fluoro-2-(tetrahydrochysene-3-thienyl amino) nicotinic acid
With 2-chloro-5-fluorine nicotinic acid (3.51g, 20mmol), K
2CO
3(3.32g 24mmol) is added under argon gas atmosphere in the dry DMF (20ml).Add copper (76mg, 1.2mmol), the anhydrous cuprous bromide (I) of methanol wash (144mg, 1mmol) and tetramethylene sulfide 3-amine (3.1g 30mmol), stirs mixture 4 hours at 150 ℃ then.Add ethyl acetate, then crude product is used 0.5M aqueous solution of citric acid washed twice, organic solvent is through Na
2SO
4Drying is filtered then vacuum and is removed, and obtains title compound (3.98g, 82%).
1H?NMR(400MHz，DMSO-d
6)：δ?13.5(1H，brs)；8.35(1H，d)；8.10(1H，brs)；7.92(1H，dd)；4.75(1H，qv)；3.1(1H，dd)；2.90(1H，m)；2.82(1H，m)；2.71(1H，m)；2.06(2H，m).
APCI-MS?m/z：243[MH
+].
Preparation 6
[cis-4-({ [5-fluoro-2-(tetrahydrochysene-3-thienyl amino) pyridin-3-yl] carbonyl } amino) cyclohexyl] t-butyl carbamate
With 5-fluoro-2-(tetrahydrochysene-3-thienyl amino) nicotinic acid (3.98g, 16.4mmol), (cis-4-aminocyclohexyl) t-butyl carbamate (3.87g, 18.1mmol), HATU (6.9g, 18.1mmol), HOAT (2.46g, 18.1mmol) and DIEA (8.6ml, 50mmol) mixture in NMP (70ml) is stirring at room 1 hour (regulating pH to 8-9 with DIEA).Add ethyl acetate, then with crude product with twice of 0.5M aqueous solution of citric acid, sodium bicarbonate aqueous solution and water washing.Organic solvent is through Na
2SO
4Drying is filtered then vacuum and is removed.Resistates carries out purifying (using ethyl acetate/heptane (1:3) as eluent) through silica gel, obtains title compound (3.95g, 55%).
1H?NMR(400MHz，DMSO-d
6)：δ?8.34(1H，d)；8.21(1H，d)；8.19(1H，brd)；7.98(1H，dd)；6.61(1H，brs)；4.68(1H，m)；3.77(1H，brs)；3.40(1H，brs)；3.08(1H，dd)；2.91-2.77(2H，m)；2.65(1H，dd)；2.02(2H，m)；1.70(4H，m)；1.52(4H，m)；1.39(9H，s).
APCI-MS?m/z：439[MH
+].
LC (method A) rt=11.6 minute
Preparation 7
Cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-3-thienyl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] and cyclohexyl } t-butyl carbamate
The oil dispersion (0.36g that lasts 30 minutes under argon gas atmosphere with 50%NaH, 7.5mmol) be divided into three batches and be added to [cis-4-({ [5-fluoro-2-(tetrahydrochysene-3-thienyl amino) pyridin-3-yl] carbonyl } amino) cyclohexyl] t-butyl carbamate (2.2g, 5mmol) with 1, (2.43g is 15mmol) in the solution in anhydrous NMP (30ml) for 1 '-carbonyl dimidazoles.With mixture stirring at room 1 hour.Add ethyl acetate, then with crude product with twice of 0.5M aqueous solution of citric acid, sodium bicarbonate aqueous solution and water washing.Organic solvent is through Na
2SO
4Drying is filtered then vacuum and is removed.Resistates carries out purifying (using ethyl acetate/heptane (1:4) as eluent) through silica gel, obtains title compound (2.0mg, 86%).
1H?NMR(400MHz，DMSO-d
6)：δ?8.79(1H，d)；8.24(1H，dd)；6.57(1H，brs)；5.86(1H，qv)；4.72(1H，brt)；3.55(1H，brs)；3.45(1H，t)；2.99(1H，m)；2.86(2H，m)；2.76(1H，qv)；2.58(2H，q)；2.16(1H，m)；1.90(2H，d)；1.50(2H，brt)；1.42(11H，brs).
APCI-MS?m/z：365[MH
+-tBOC].
LC (method A) rt=14.5 minute
Preparation 8
3-(cis-4-aminocyclohexyl)-6-fluoro-1-(tetrahydrochysene-3-thienyl) pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-dione hydrochloride
With { cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-3-thienyl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } t-butyl carbamate (0.7g, 1.5mmol) and 4M HCl in 1, the mixture in the 4-diox (20ml) was stirring at room 2 hours.Remove and desolvate, and pure crude product is directly used.
APCI-MS?m/z：365[MH
+].
Embodiment 1
N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } cyclopropane carboxamide
With 3-(cis-4-aminocyclohexyl)-6-fluoro-1-(tetrahydrochysene-2H-thiapyran-4-yl) pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-dione hydrochloride (310mg, 0.75mmol), cyclopropane-carboxylic acid (100mg, 1.16mmol), HATU (380mg, 1.0mmol), HOAT (140mg, 1.0mmol) and DIEA (600 μ l, 3.5mmol) compound in NMP (20ml) is in stirring at room 10 minutes (pH is 8-9).Add ethyl acetate then with crude product with twice of sodium bicarbonate aqueous solution, 0.5M aqueous solution of citric acid and water washing.Organic solvent is through Na
2SO
4Drying is filtered then vacuum and is removed.Resistates carries out purifying (using ethyl acetate/heptane (1:1) as eluent) through silica gel, obtains title compound (280mg, 84%).
1H?NMR(400MHz，DMSO-d
6)：δ?8.78(1H，d)；8.23(1H，dd)；7.93(1H，brd)；5.21(1H，brs)；4.74(1H，t)；3.79(1H，brs)；2.86-2.69(6H，m)；2.63(2H，q)；2.01-1.86(4H，m)；1.81(1H，m)；1.53(2H，t)；1.44(2H，brd)；0.66(4H，m).
APCI-MS?m/z：447[MH
+].
Embodiment 2
N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } imidazo [1,2-a] pyridine-2-carboxamide
With 3-(cis-4-aminocyclohexyl)-6-fluoro-1-(tetrahydrochysene-2H-thiapyran-4-yl) pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-dione hydrochloride (600mg, 1.5mmol), imidazo [1,2-a] pyridine-2-formic acid (292mg, 1.8mmol), HATU (685mg, 1.8mmol) and DIEA (1.02ml, 6mmol) mixture in NMP (80ml) is stirring at room 1h (pH is 8-9).Add ethyl acetate, then with crude product with twice of sodium bicarbonate aqueous solution, 0.5M aqueous solution of citric acid and water washing.Organic solvent is through Na
2SO
4Drying is filtered then vacuum and is removed.Resistates is recrystallization (5ml) in ethyl acetate, obtains title compound (750mg, 96%).
1H?NMR(400MHz，DMSO-d
6)：δ?8.79(1H，d)；8.68(1H，d)；8.52(1H，s)；8.25(1H，dd)；7.94(1H，brs)；7.75(1H，d)；7.49(1H，t)；7.10(1H，t)；5.22(1H，brs)；4.84(1H，t)；4.16(1H，s)；2.84-2.69(6H，m)；2.61(2H，q)；1.99(4H，m)；1.71(2H，t)；1.57(2H，brd)
APCI-MS?m/z：523[MH
+].
Embodiment 3-31
Following compound is to follow the operation of describing among the embodiment 1 to come synthetic.
| Embodiment | Compound | 1HNMR | m/z |
| 3 | N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } quinoline-8-methane amide | (400MHz，DMSO-d 6)：δ?9.47(1H，s)；8.76(1H， d)；8.64(1H，d)；8.59(1H，d)；8.28(1H，dd)；8.20 (1H，d)；7.76-7.73(2H，m)；5.18(1H，brs)；4.87 (1H，t)；4.45(1H，s)；2.85-2.72(8H，m)；1.98(2H， d)；1.85(2H，d)；1.72(2H，t)；1.60(2H，d). | 534.3 |
| 4 | N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } pyrazolo [1,5-a] pyridine-2-carboxamide | (500MHz，DMSO-d 6)：δ?8.75(1H，d)；8.71(1H， d)；8.19(1H，dd)；7.76(1H，d)；7.68-7.65(1H，m)； 7.29-7.26(1H，m)；7.03-7.00(2H，m)；5.16(1H， brs)；4.79(1H，t)；4.12(1H，s)；2.77-2.66(5H，m)； *(3H is in solvent peak) 1.98-1.91 (4H, m); 1.64 (2H, t); 1.51 (2H, d). | 523.3 |
| 5 | N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1H-indazole-3-methane amide | (500MHz，DMSO-d 6)：δ8?.74(1H，d)；8.22(1H， dd)；8.16(1H，d)；7.62-7.59(2H，m)；740(1H，t)； 7.24(1H，t)；5.18(1H，brs)；4.81(1H，t)；4.19(1H， d)；2.79-2.67(5H，m)； *(3H is in solvent peak) 1.99-1.93 (4H, m); 1.67 (2H, t); 1.53 (2H, d). | 523.3 |
| 6 | N-[2-(cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] and cyclohexyl } amino)-the 2-oxoethyl]-the 2-hydroxybenzamide | (500MHz，DMSO-d 6)：δ?8.99(1H，t)；8.74(1H，t)； 8.13(1H，dd)；7.90(1H，d)；7.86(1H，d)；7.36(1H， t)；6.89-6.86(2H，m)；5.18(1H，brs)；4.70(1H，t)； 4.00(2H，d)；3.84(1H，s)；2.80-2.67(4H，m)； *(4H is in solvent peak) 1.92 (2H, d); 1.85 (2H, d); 1.53 (2H, t); 1.42 (2H, d). | 556.3 |
| 7 | N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-3-hydroxyl-4-methoxy benzamide | (500MHz，DMSO-d 6)：δ?8.74(1H，d)；8.21(1H， dd)；7.59(1H，d)；7.41(1H，d)；7.31(1H，d)；6.99 (1H，d)；5.19(1H，brs)；4.78(1H，t)；3.93(1H，s)； 3.80(3H，s)；2.81-2.67(6H，m)； *(2H is in solvent peak) 2.02 (2H, d); 1.95-1.93 (2H, m); 1.54 (2H, t); 1.43 (2H, d). | 529.3 |
| 8 | N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-(3-hydroxy phenyl) ethanamide | (500MHz，DMSO-d 6)：δ?8.74(1H，d)；8.19(1H， dd)；7.88(1H，d)；7.05(1H，t)；6.72(1H，d)；6.67 (1H，s)；6.56(1H，dd)；5.18(1H，brs)；4.69(1H，t)； 3.75(1H，s)；2.78-2.67(6H，m)； *(2H is in solvent peak) 1.93 (2H, dd); 1.83 (2H, d); 1.50 (2H, t); 1.40 (2H, d). | 513.3 |
| 9 | N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxy-4-methyl benzamide | (500MHz，DMSO-d 6)：δ?11.91(1H，s)；8.74(1H， d)；8.41(1H，d)；8.18(1H，dd)；7.86(1H，d)； 6.74-6.73(2H，m)；5.18(1H，brs)；4.77(1H，s)； 4.08(1H，s)；2.78-2.66(5H，m)； *(3H is in solvent peak) 2.25 (3H, s); 1.98-1.91 (4H, m); 1.62 (2H, t); 1.49 (2H, d). | 513.3 |
| 10 | N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-3-hydroxy-4-methyl benzamide | (500MHz，DMSO-d 6)：δ?8.74(1H，d)；8.20(1H， dd)；7.63(1H，d)；7.29(1H，d)；7.23(1H，s)；7.15 (1H，d)；5.18(1H，brs)；4.77(1H，dd)；3.94(1H，s)； 2.76-2.66(5H，m)； *(3H is in solvent peak) 2.13 (3H, s); 2.02 (2H, d); 1.94-1.92 (2H, m); 1.55 (2H, t); 1.43 (2H, d). | 513.4 |
| Embodiment | Compound | 1HNMR | m/z |
| 11 | N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-4-hydroxy 3-methoxybenzene methane amide | (500MHz，DMSO-d 6)：δ?8.74(1H，d)；8.18(1H， dd)；7.58(1H，d)；7.42-7.41(1H，m)；7.38(1H，dd)； 6.82(1H，d)；5.18(1H，brs)；4.78(1H，t)；3.92(1H， s)；3.86(3H，s)；2.75-2.67(6H，m)； *(2H is in solvent peak) 2.05 (2H, d); 1.94-1.92 (2H, m); 1.54 (2H, t); 1.43 (2H, d). | 529.3 |
| 12 | (2R)-and 2-cyclohexyl-N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-hydroxyl acetamide | (500MHz，DMSO-d 6)：δ?8.73(1H，d)；8.19(1H， dd)；7.37(1H，d)；5.16(1H，brs)；4.73(1H，t)；3.91 (1H，d)；3.70(1H，d)；2.75-2.66(4H，m)； *(4H is in solvent peak) 1.93-1.91 (2H, m); 1.75 (2H, t); 1.67-1.53 (8H, m); 1.46 (2H, d); 1.40-1.38 (1H, m); 1.24-1.02 (6H, m). | 519.4 |
| 13 | 5-(cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] and cyclohexyl } amino)-5-oxopentanoic acid methyl esters | (500MHz，DMSO-d 6)：δ?8.73(1H，d)；8.17(1H， dd)；7.66(1H，d)；5.18(1H，brs)；4.68(1H，t)；3.75 (1H，s)； *(4H is in solvent peak) 2.75-2.67 (4H, m); *(3H is in solvent peak) 2.29 (2H, t); 2.17 (2H, t); 1.93-1.91 (2H, m); 1.83 (2H, d); (1.73 2H, quintet); 1.48 (2H, t); 1.38 (2H, d). | 507.3 |
| 14 | N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 3-hydroxybenzamide | (500MHz，DMSO-d 6)：δ?9.63(1H，s)；8.73(1H， d)；8.20(1H，dd)；7.77(1H，d)；7.32(1H，d)； 7.28-7.23(2H，m)；6.89(1H，dd)；5.16(1H，brs)； 4.76(1H，t)；3.93(1H，s)；2.76-2.66(5H，m)； *(3H is in solvent peak) 2.04 (2H, d); 1.94-1.92 (2H, m); 1.55 (2H, t); 1.43 (2H, d). | 499.3 |
| 15 | N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-(4-hydroxy phenyl) ethanamide | (500MHz，DMSO-d 6)：δ?8.74(1H，d)；8.19(1H， dd)；7.78(1H，d)；7.09(2H，d)；6.65(2H，d)；5.19 (1H，brs)；4.69(1H，t)；3.72(1H，s)； *(2H is in solvent peak) 2.77-2.68 (5H, m); *(3H is in solvent peak) 1.95-1.92 (2H, m); 1.82 (2H, d); 1.47 (2H, t); 1.38 (2H, d). | 513.3 |
| 16 | N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 4-hydroxybenzamide | (500MHz，DMSO-d 6)：δ?8.73(1H，d)；8.20(1H， dd)；7.75(2H，d)；7.58(1H，d)；6.81(2H，d)；5.18 (1H，brs)；4.78(1H，t)；3.93(1H，s)；2.76-2.65(5H， m)； *(3H is in solvent peak) 2.02 (2H, d); 1.94-1.92 (2H, m); 1.54 (2H, t); 1.43 (2H, d). | 499.3 |
| 17 | N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-hydroxybenzamide | (500MHz，DMSO-d 6)：δ?11.88(1H，s)；8.73(1H， d)；8.53(1H，d)；8.18(1H，dd)；7.96(1H，d)；7.36 (1H，dd)；6.94-6.90(2H，m)；5.15(1H，brs)；4.77 (1H，t)；4.10(1H，s)；2.76-2.67(5H，m)； *(3H is in solvent peak) 1.98-1.91 (4H, m); 1.63 (2H, t); 1.50 (2H, d). | 499.2 |
| 18 | N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } cyclohexane carboxamide | (500MHz，DMSO-d 6)：δ?8.73(1H，d)；8.18(1H， dd)；7.46(1H，d)；5.18(1H，brs)；4.68(1H，t)；3.71 (1H，s)；2.75-2.67(5H，m)；2.29-2.23(1H，m)； *(3H is in solvent peak) 1.93-1.91 (2H, m); 1.82 (2H, d); 1.70-1.65 (4H, m); 1.59 (1H, d); 1.46 (2H, t); 1.38-1.07 (7H, m). | 489.4 |
| Embodiment | Compound | 1HNMR | m/z |
| 19 | N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-3-(3-hydroxy phenyl) propionic acid amide | (500MHz，DMSO-d 6)：δ?8.73(1H，d)；8.17(1H， dd)；7.67(1H，d)；7.02(1H，t)；6.62(1H，d)；6.58 (1H，s)；6.52(1H，dd)；5.17(1H，brs)；4.67(1H，s)； 3.77(1H，s)；2.74-2.67(5H，m)； *(7H is in solvent peak) 1.93-1.91 (2H, m); 1.82 (2H, d); 148 (2H, t); 1.37 (2H, d). | 527.4 |
| 20 | N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-3-pyridone-2-methane amide | (500MHz，DMSO-d 6)：δ?8.73(1H，d)；8.50(1H， s)；8.23-8.20(3H，m)；7.54(1H，dd)；7.42(1H，dd)； 5.18(1H，brs)；4.81(2H，t)；4.15(1H，s)；2.76-2.66 (5H，m)； *(3H is in solvent peak) 1.97-1.92 (4H, m); 1.70 (2H, t); 1.55 (2H, d). | 500.4 |
| 21 | N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-3-methylbutyryl amine | (500MHz，DMSO-d 6)：δ?8.72(1H，d)；8.17(1H， dd)；7.60(1H，d)；5.17(1H，brs)；4.68(1H，t)；3.76 (1H，s)；2.74-2.66(5H，m)； *(3H is in solvent peak) 2.01 (2H, d); 1.98-1.91 (3H, m); 1.83 (2H, d); 1.48 (2H, t); 1.38 (2H, d); 0.87 (6H, d). | 463.3 |
| 22 | N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-2-phenyl-acetamides | (500MHz，DMSO-d 6)：δ?8.74(1H，d)；8.21(1H， dd)；7.61(1H，d)；7.44(2H，d)；7.30(2H，t)；7.23 (1H，t)；5.17(1H，brs)；4.95(1H，s)；4.74(1H，t)； 3.86(1H，s)；2.76-2.68(5H，m)； *(3H is in solvent peak) 1.93 (2H, s); 1.76 (2H, t); 1.59-1.43 (4H, m). | 513.4 |
| 23 | N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } benzamide | (500MHz，DMSO-d 6)：δ?8.73(1H，d)；8.20(1H， dd)；7.90-7.87(3H，m)；7.53-7.46(3H，m)；5.18 (1H，brs)；4.79(1H，t)；3.95(1H，s)；2.76-2.65(5H， m)； *(3H is in solvent peak) 2.06 (2H, d); 1.94-1.92 (2H, m); 1.56 (2H, t); 1.44 (2H, d). | 483.3 |
| 24 | N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-furoamide | (500MHz，DMSO-d 6)：δ?8.73(1H，d)；8.20(1H， dd)；7.84(1H，t)；7.57(1H，d)；7.16(1H，d)；6.62 (1H，dd)；5.17(1H，brs)；4.76(1H，t)；3.97(1H，s)； 2.76-2.67(5H，m)； *(3H is in solvent peak) 1.99 (2H, d); 1.93-1.92 (2H, m); 1.58 (2H, t); 1.45 (2H, d). | 473.2 |
| 25 | N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } imidazo [1,2-a] pyridine-8-methane amide | (500MHz，DMSO-d 6)：δ?8.85(1H，d)；8.73(1H， d)；8.22-8.18(3H，m)；7.90(1H，s)；7.30(1H，s)； 5.18(1H，brs)；4.80(1H，t)；4.17(1H，s)；2.74-2.66 (5H，m)； *(3H is in solvent peak) 2.01 (2H, d); 1.94-1.92 (2H, m); 1.68 (2H, t); 1.52 (2H, d). | 523.3 |
| 26 | N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-5-(methylol) benzamide | (400MHz，DMSO-d 6)：δ?11.74(1H，s)；8.79(1H， d)；8.60(1H，d)；8.22(1H，dd)；7.95(1H，d)；7.34 (1H，dd)；6.95(1H，d)；5.20(1H，brs)；5.11(1H， brs)；4.82(1H，t)；4.45(2H，s)；4.15(1H，brs)； 2.84-2.69(6H，m)；2.61(2H，q)；1.99(4H，m)；1.68 (2H，t)；1.55(2H，d) | 529 |
| 27 | N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-3-thienyl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } cyclopropane carboxamide | (400MHz，DMSO-d 6)：δ?8.80(1H，d)；8.25(1H， dd)；5.87(1H，m)；4.74(1H，t)；3.78(1H，brs)；3.46 (1H，t)； *(1H is in solvent peak); 3.00 (1H, m); 2.91-2.80 (2H, m); 2.77 (1H, m); 2.63 (2H, q); 2.17 (1H, m); 1.91 (2H, brd); 1.81 (1H, m); 1.53 (2H, t); 1.45 (2H, brd); 0.65 (4H, m) | 433 |
| Embodiment | Compound | 1HNMR | m/z |
| 28 | N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-3-thienyl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } imidazo [1,2-a] pyridine-2-carboxamide | (400MHz，DMSO-d 6)：δ?8.80(1H，d)；8.74(1H， d)；8.59(1H，brs)；8.27(1H，dd)；8.05(1H，brs)； 7.75(1H，d)；7.56(1H，t)；7.16(1H，t)；5.86(1H， m)；4.83(1H，t)；4.15(1H，brs)； *(1H is in solvent peak); 3.01 (1H, m); 2.91-2.83 (2H, m); 2.77 (1H, m); 2.63 (2H, q); 2.17 (1H, m); 2.03 (2H, brd); 1.71 (2H, m); 1.59 (2H, t) | 509 |
| 29 | N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-3-thienyl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-5-(methylol) benzamide | (400MHz，DMSO-d 6)：δ?8.80(1H，d)；8.59(1H， d)；8.24(1H，dd)；7.94(1H，d)；7.35(1H，dd)；6.95 (1H，d)；5.84(1H，m)；4.82(1H，t)；4.44(2H，s)； 4.16(1H，brs)；3.47(1H，t)； *(2H is in solvent peak); 3.00 (1H, m); 2.91-2.81 (2H, m); 2.77 (1H, m); 2.61 (2H, q); 2.17 (1H, m); 2.00 (2H, brd); 1.68 (2H, t); 1.57 (2H, brd) | 515 |
| 30 | N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-3-thienyl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-hydroxybenzamide | (400MHz，DMSO-d 6)：δ?11.90(1H，s)；δ8.79(1H， d)；8.59(1H，d)；8.24(1H，dd)；8.00(1H，dd)；7.39 (1H，t)；6.98(1H，d)；6.94(1H，t)；5.84(1H，m)； 4.83(1H，t)；4.14(1H，brs)；3.47(1H，t)；3.00(1H， m)；2.91-2.81(2H，m)；2.77(1H，m)；2.63(2H，q)； 2.17(1H，m)；2.01(2H，brd)；1.67(2H，t)；1.56 (2H，brd) | 485 |
| 31 | N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-3-thienyl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxy-4-methyl benzamide | (400MHz，DMSO-d 6)：δ?9.52(1H，brs)；δ8.79 (1H，d)；8.27(1H，dd)；7.68(1H，d)；7.31(1H，dd)； 7.28(1H，d)；7.18(1H，d)；5.86(1H，m)；4.81(1H， t)；3.97(1H，brs)；3.46(1H，t)；3.01(1H，m)； 2.90-2.82(2H，m)；2.76(1H，m)；2.67(2H，q)；2.18 (4H，brs)；2.08(2H，brd)；1.59(2H，t)；1.49(2H， brd) | 499 |
Embodiment 32
N-{ cis-4-[2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } imidazo [1,2-a] pyridine-2-carboxamide
Step (a) 2-(tetrahydrochysene-2H-thiapyran-4-base is amino) nicotinic acid
With the 2-chlorine apellagrin (5g, 31.7mmol) and salt of wormwood (5g 36.2mmol) is added under nitrogen among the anhydrous NMP (20ml).Add copper (80mg, 1.26mmol) and cuprous bromide (I) (200mg, 1.39mmol), (2g 17.1mmol), heats mixture 30 minutes at 150 ℃ in oil bath then to add the amino thiapyran of 4-subsequently.Mixture is poured in the water, and the product that goes out of collecting precipitation grinds with acetonitrile then after filtration, obtains subtitle compounds (5g, 66%).
1H?NMR(300MHz，DMSO-d
6)δ?8.25(dd，1H)，8.13(d，1H)，8.08(dd，2H)，6.60(m，1H)，4.06(m，1H)，2.69(m，3H)，2.22(d，2H)，1.60(m，2H)
APCI (multimode) m/z:239[M+H]
Step (b) [cis-4-({ [2-(tetrahydrochysene-2H-thiapyran-4-base is amino) pyridin-3-yl] carbonyl } amino) cyclohexyl] t-butyl carbamate
2-(tetrahydrochysene-thiapyran-4-base amino)-nicotinic acid (3g 12.6mmol) is dissolved in the dry DMF (20ml), add then DIEA (4ml, 22.9mmol), add subsequently HATU (4.79g, 12.6mmol), then with mixture stirring at room 10 minutes.Add (cis-4-aminocyclohexyl) t-butyl carbamate (2.71g, 12.6mmol), then with compound in stirred overnight at room temperature.Mixture is poured in the water, and the product that goes out of collecting precipitation through flash chromatography on silica gel (use ethyl acetate: isohexane (1:2) is as eluent) purifying, obtains subtitle compounds (2.5g, 45%) then after filtration.
1H?NMR(300MHz、CDCl
3)δ?8.19(d，2H)，7.51(d，1H)，6.47(dd，1H)，5.95(d，1H)，4.54(s，1H)，4.07(m，3H)，3.67(s，1H)，2.73(m，4H)，2.32(dd，2H)，1.76(m，9H)，1.45(s，9H)
APCI (multimode) m/z:435[M+H]
Step (c) cis-4-[2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] and cyclohexyl } t-butyl carbamate
Will (4-{[2-(tetrahydrochysene-thiapyran-4-base is amino)-pyridine-3-carbonyl]-amino }-cyclohexyl)-t-butyl carbamate (2.2g, 5.1mmol) be dissolved among the anhydrous NMP (5ml), add carbonyl dimidazoles (2.46g then, 15.2mmol), last 5 minutes subsequently and add in batches 60% sodium hydride (0.61g, 15.2mmol).Then with mixture heating up to 70 ℃, and kept 15 minutes.Mixture is cooled to room temperature, carefully pours in the water then.The crude product that goes out of collecting precipitation through flash chromatography on silica gel (use ethyl acetate: isohexane 1:3 is as eluent) purifying, obtains subtitle compounds (1.8g, 77%) then after filtration.
1H?NMR(400MHz、CDCl
3)δ?8.63(d，1H)，8.43(d，1H)，7.19(d，1H)，5.06(d，1H)，4.91(m，1H)，3.94(s，1H)，2.92(m，2H)，2.76(m，2H)，2.57(m，2H)，2.02(m，2H)，1.91(m，2H)，1.62(m，7H)，1.48(s，9H)
APCI(ES+)m/z：361[MH+-BOC]
Step (d) 3-(cis-4-aminocyclohexyl)-1-(tetrahydrochysene-2H-thiapyran-4-yl) pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-diketone
With 4.0M hydrogenchloride Yu diox (20ml, solution 80mmol) is added to { 4-[2,4-dioxo-1-(tetrahydrochysene-thiapyran-4-yl)-1,4-dihydro-2H-pyrido [2,3-d] pyrimidin-3-yl]-cyclohexyl }-t-butyl carbamate (230mg, 0.5mmol) in, then with mixture at stirring at room 2h.Solvent evaporation to doing, is ground resistates then with acetonitrile, obtain subtitle compounds (200mg, 100%).
1H?NMR(300MHz，DMSO-d
6)δ?8.73(m，1H)，8.39(m，1H)，8.06(s，2H)，7.36(dd，1H)，5.31(s，1H)，4.76(t，1H)，3.43(d，1H)，2.79(m，5H)，2.58(t，2H)，1.96(d，4H)，1.77(t，2H)，1.57(d，3H).
APCI (multimode) m/z:361[M+H]
Step (e) N-{ cis-4-[2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } imidazo [1,2-a] pyridine-2-carboxamide.
(72mg 0.43mmol) is dissolved in the dry DMF (5ml), and (0.2ml, 1.15mmol), (167mg 0.43mmol), stirs mixture 10 minutes to add HATU subsequently to add DIEA then with imidazoles [1,2a] pyridine-2-formic acid.Add 3-(4-amino-cyclohexyl)-1-(tetrahydrochysene-thiapyran-4-yl)-1H-pyrido [2,3-d] pyrimidine-2 then, (220mg 0.43mmol), and stirs mixture and spends the night the 4-diketone.Mixture is poured in the water, and the solid that goes out of collecting precipitation through reversed-phase HPLC (ammonia soln of 25-95% acetonitrile) purifying, obtains title compound (130mg, 59%) then after filtration.
1H?NMR(400MHz，DMSO-d
6)δ?8.73(dd，1H)，8.62(d，1H)，8.44(s，1H)，8.40(dd，1H)，7.81(d，1H)，7.73(d，1H)，7.40(t，1H)，7.35(dd，1H)，7.03(t，1H)，5.32(s，1H)，4.85(t，1H)，4.18(s，1H)，2.71(m，8H)，1.99(d，4H)，1.71(t，2H)，1.58(d，2H)
APCI (multimode) m/z:505[M+H]
Embodiment 33
N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-5,6,7, the 8-imidazolidine is [1,2-a] pyridine-2-carboxamide also
Step (a) 5,6,7,8-imidazolidine be [1,2-a] pyridine-2-formic acid also
(500mg 3.1mmol) is dissolved in the ethanol (20ml), adds platinum oxide (100mg), then mixture hydrogenation under the pressure of 4 crust is spent the night with imidazo [1,2-a] pyridine-2-formic acid.Mixture is filtered, then filtrate is evaporated to driedly, obtain subtitle compounds (500mg, 97%).
1H?NMR(400MHz，DMSO-d
6)δ?7.63(s，1H)，3.96(t，2H)，2.70(t，2H)，1.85(m，4H)
Step (b) N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-5,6,7, the 8-imidazolidine is [1,2-a] pyridine-2-carboxamide also
With 5,6,7, (64mg 0.4mmol) is dissolved in the dry DMF (5ml) 8-tetrahydrochysene-imidazo [1,2-a] pyridine-2-formic acid, and (0.2ml, 1.15mmol), (160mg 0.42mmol), stirs mixture 10 minutes then to add HATU subsequently to add DIEA.Add 3-(4-amino-cyclohexyl)-1-(tetrahydrochysene-thiapyran-4-yl)-1H-pyrido [2,3-d] pyrimidine-2, (150mg 0.4mmol), stirs mixture and spends the night the 4-diketone then.Mixture is poured in the water, and the solid that goes out of collecting precipitation then through reversed-phase HPLC purifying (ammonia soln of 25-95% acetonitrile), obtains title compound (124mg, 59%) after filtration.
1H?NMR(400MHz，DMSO-d
6)δ?8.78(d，1H)，8.24(dd，1H)，7.51(s，1H)，7.35(d，1H)，5.29(s，1H)，4.80(t，1H)，4.09(s，1H)，3.99(t，2H)，2.76(m，6H)，2.57(m，1H)，2.50(m，5H)，1.97(m，2H)，1.91(m，4H)，1.66(t，2H)，1.54(d，2H)，
APCI (multimode) m/z:527[M+H]
Embodiment 34
N-{ cis-4-[6-methyl-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } imidazo [1,2-a] pyridine-2-carboxamide
Step (a) 2-chloro-5-methylnicotinic acid
(6.03g, 58.8ml 94.1mmol) are added among the THF (200ml), then mixture are cooled to-78 ℃ with the hexane solution of 1.6M butyllithium.With 2,2,6, (13.29g, 17.6ml 94.1mmol) dropwise handle the 6-tetramethyl piperidine, stir 30 minutes at-78 ℃ then with mixture.Then with solution with 2-chloro-5-methyl-pyridine (12g, 94.1mmol) solution in THF (20ml) is dropwise handled, with reaction mixture at-78 ℃ of restir 2.5h.Then mixture is poured on the dry ice, makes it be warmed to room temperature then and spend the night.Mixture is distributed between ether and water, and then water layer being acidified to pH with 2M HCl is 2, and solvent is concentrated into about 100ml.Suspension was stored in refrigerator 48 hours, filtered then and drying, obtain subtitle compounds (5.6g, 35%).
1H?NMR(400MHz，DMSO-d
6)δ?13.70(broad?s，1H)，8.38(d，1H)，8.05(d，1H)，2.34(s，3H)
Step (b) 5-methyl-2-(tetrahydrochysene-2H-thiapyran-4-base is amino) nicotinic acid
With 2-chloro-5-methyl-nicotinic acid (2.5g, 14.6mmol) and K
2CO
3(2.4g 17.5mmol) is added in the dry DMF (20ml).Add copper (55.6mg, 0.87mmol), cuprous bromide (I) (104.5mg, 0.73mmol) and tetrahydrochysene-thiapyran-4-base amine (2.9g, 24.8mmol), then with reaction mixture at 150 ℃ of stirring 1.5h.Mixture is cooled to room temperature adds ethyl acetate then.Reaction mixture is washed with the 0.5M aqueous solution of citric acid.It is 5 that water layer is adjusted to pH with ammoniacal liquor, uses ethyl acetate (* 3) extraction then.With the organic extract drying (anhydrous Na that merges
2SO
4), filter evaporation then.Water is added in the resistates, collects the solid that obtains after filtration, vacuum-drying obtains subtitle compounds (1.48g, 40%) then.
1H?NMR(400MHz，DMSO-d
6)δ?8.10(dd，1H)，7.94-7.88(m，1H)，4.06-3.98(m，1H)，2.75-2.61(m，4H)，2.21-2.18(m，2H)，2.14(s，3H)，1.57(dtd，2H)
Step (c) [cis-4-({ [5-methyl-2-(tetrahydrochysene-2H-thiapyran-4-base is amino) pyridin-3-yl] carbonyl } amino) cyclohexyl] t-butyl carbamate
(tetrahydrochysene-thiapyran-4-base is amino)-(1.48g 5.87mmol) is dissolved among the NMP (20ml) nicotinic acid, adds HATU (2.66g then with 5-methyl-2-, 7.04mmol), add DIEA (2.28g, 3ml subsequently, 17.6mmol), then with mixture stirring at room 10 minutes.Add (4-amino-cyclohexyl)-t-butyl carbamate (1.51g, 7mmol), then with reaction mixture stirring at room 30 minutes.Vacuum evaporating solvent stirs resistates then and spends the night in water.Collect the solid that obtains after filtration, be dissolved in the ethyl acetate, dry (anhydrous magnesium sulfate) filters evaporation then.Resistates carries out purifying through silica gel flash column chromatography (the isohexane solution that uses 40% ethyl acetate is as eluent), obtains subtitle compounds (704mg, 27%).
1H?NMR(400MHz，DMSO-d
6)δ?8.14(d，1H)，8.03(d，1H)，7.97(d，1H)，7.80(d，1H)，6.60(s，1H)，3.96-3.92(m，1H)，3.80-3.75(m，1H)，3.45-3.39(m，1H)，2.72-2.62(m，4H)，2.21-2.17(m，2H)，2.15(s，3H)，1.75-1.68(m，4H)，1.57-1.49(m，6H)，1.39(s，9H)
APCI (multimode) m/z:449[M+H]
Step (d) cis-4-[6-methyl-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] and cyclohexyl } t-butyl carbamate
Will (4-{[5-methyl-2-(tetrahydrochysene-thiapyran-4-base is amino)-pyridine-3-carbonyl]-amino }-cyclohexyl)-t-butyl carbamate (660mg, 1.47mmol) be dissolved among the NMP (5ml), add 1,1 '-carbonyl dimidazoles (716mg, 4.41mmol), drip subsequently 60% sodium hydride mineral oil dispersion (177mg, 4.41mmol).With reaction mixture stirring at room 20 minutes, then at 70 ℃ of heating 2h.Then ice is added in the reaction mixture, and with mixture restir 2h.Collect the solid that obtains after filtration, be dissolved in the ethyl acetate, dry (anhydrous magnesium sulfate) filters evaporation then.Resistates carries out purifying through silica gel flash column chromatography (the isohexane solution that uses 25% ethyl acetate is as eluent), obtains subtitle compounds (268mg, 38%).
1H?NMR(400MHz，DMSO-d
6)δ?8.56(d，1H)，8.19(d，1H)，6.57(s，1H)，4.73(t，1H)，3.56(s，1H)，2.82-2.67(m，4H)，2.68-2.58(m，2H)，2.48-2.43(m，2H)，2.36(s，3H)，1.96-1.90(m，4H)，1.49(t，2H)，1.42(s，9H)，1.39-1.35(m，2H)
APCI (multimode) m/z:475[M+H]
Step (e) 3-(cis-4-aminocyclohexyl)-6-methyl isophthalic acid-(tetrahydrochysene-2H-thiapyran-4-yl) pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-diketone
With 4.0M hydrogenchloride in 1,4-diox (10ml, solution 40mmol) is added to { 4-[6-methyl-2,4-dioxo-1-(tetrahydrochysene-thiapyran-4-yl)-1,4-dihydro-2H-pyrido [2,3-d] pyrimidin-3-yl]-cyclohexyl-t-butyl carbamate (190mg, 0.4mmol) in, then with solution at stirring at room 1h.Evaporating solvent distributes resistates then between chloroform and saturated sodium carbonate solution.Water layer extracts 3 times with chloroform again.With the organic extract drying (anhydrous Na that merges
2SO
4), filter evaporation then, obtain subtitle compounds (137mg, 92%).
1H?NMR(400MHz，DMSO-d
6)δ?8.56(d，1H)，8.20(d，1H)，4.76-4.69(m，1H)，3.07(s，1H)，2.83-2.68(m，9H)，2.38(s，3H)，1.97-1.88(m，2H)，1.62(d，2H)，1.55(d，1H)，1.50-1.39(m，2H)，1.33(d，2H)，1.23(s，1H)
Step (f) N-{ cis-4-[6-methyl-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } imidazo [1,2-a] pyridine-2-carboxamide.
With imidazo [1,2-a] pyridine-2-formic acid (71.2mg 0.44mmol) is suspended among the DMF (2ml), add then DIEA (142mg, 191ul, 1.1mmol), add subsequently HATU (167mg, 0.44mmol), and with reaction mixture stirring at room 10 minutes.Add 3-(4-amino-cyclohexyl)-6-methyl isophthalic acid-(tetrahydrochysene-thiapyran-4-yl)-1H-pyrido [2,3-d] pyrimidine-2, the 4-diketone (137mg, the 0.37mmol) suspension in DMF (2ml), then with reaction mixture stirring at room 48 hours.Evaporating solvent stirs resistates then in water.Collect the solid that obtains after filtration,, obtain title compound (100mg, 53%) then through reversed-phase HPLC purifying (ammonia soln of 25-95% acetonitrile).
1H?NMR(300MHz，DMSO-d
6)δ?8.65-8.55(m，2H)，8.43(s，1H)，8.24(s，1H)，7.84-7.67(m，2H)，7.40(t，1H)，7.02(t，1H)，5.26(s，1H)，4.85(d，1H)，4.20(s，1H)，2.89-2.70(m，6H)，2.63(d，2H)，2.39(s，3H)，2.03-1.91(m，4H)，1.72(t，2H)，1.58(d，2H)
APCI (multimode) m/z:519[M+H]
Embodiment 35 and 36
A) N-{ cis-4-[6-fluoro-1-[(1R)-1-oxidation tetrahydrochysene-2H-thiapyran-4-yl]-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl cyclopropane carboxamide and
B) N-{ cis-4-[6-fluoro-1-[(1S)-and 1-oxidation tetrahydrochysene-2H-thiapyran-4-yl]-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } cyclopropane carboxamide
With metachloroperbenzoic acid (70-75%) (50mg, 0.2mmol) be divided into three batches at-10 ℃ and be added to N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidine-3 (2H)-yl] cyclohexyl } imidazo [1,2-a] (90mg is 0.2mmol) in the solution in THF (20ml) for pyridine-2-carboxamide.Continue to stir 30 minutes at-10 ℃, add Na
2SO
3(5%, the 5ml) aqueous solution is used ethyl acetate extraction then.With organic solvent sodium bicarbonate aqueous solution, salt solution, water washing, then through Na
2SO
4Drying is filtered evaporation then.Carry out purifying on preparation property HPLC, obtain the mixture (90mg, 97%) of title compound, the a/b ratio is 5:1.On preparation property HPLC, be separated to two kinds of isomer.
a)
1H?NMR(DMSO-d
6)：δ?8.79(1H，d)，8.25(1H，dd)，7.96(1H，brd)，5.45(1H，brs)，4.72(1H，t)，3.78(1H，brs)，3.41(2H，brs)，2.84(4H，m)，2.62(2H，q)，2.01-1.86(4H，m)，1.81(1H，m)，1.52(2H，t)，1.43(2H，brd)，0.65(4H，m).
LC (method A) rt=6.1 minute
B)
1H NMR (DMSO-d
6): δ 8.77 (1H, d), 8.25 (1H, dd), 7.99 (1H, brd), 5.42 (1H, brs), 4.75 (1H, t), 3.78 (1H, brs),
*(2H is in solvent peak), 3.00 (2H, brd), 2.84 (2H, t), 2.64 (2H, m), 1.90 (2H, brd), 1.83 (1H, m), 1.68 (2H, d), 1.53 (2H, brt), 1.45 (2H, brd), 0.65 (4H, m).
LC (method A) rt=6.3 minute
APCI-MS?m/z：463[MH+].
Embodiment 37
N-{ cis-4-[6-fluoro-1-(1-oxidation tetrahydrochysene-2H-thiapyran-4-yl)-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } imidazo [1,2-a] pyridine-2-carboxamide
This title compound is to make in the mode that is similar to embodiment 35.
1H?NMR(400MHz，DMSO-d
6)：δ?8.78(1H，d)，8.60(1H，d)，8.41(1H，s)，8.27(1H，dd)，7.75(1H，d)，7.70(1H，d)，7.39(1H，t)，7.01(1H，t)，5.45(1H，brs)，4.82(1H，t)，4.17(1H，s)，3.40(2H，brs)，2.85(4H，brm)，2.59(2H，q)，1.98(4H，brm)，1.70(2H，t)，1.57(2H，t).
APCI-MS?m/z：539[MH
+].
LC (method A) rt=5.5 minute
Embodiment 38
N-{ cis-4-[1-(1,1-titanium dioxide tetrahydrochysene-2H-thiapyran-4-yl)-6-fluoro-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } cyclopropane carboxamide
With metachloroperbenzoic acid (70-75%) (120mg, 0.48mmol) be divided into three batches at 0 ℃ and be added to N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidine-3 (2H)-yl] cyclohexyl } imidazo [1,2-a] (90mg is 0.2mmol) in the solution in THF (20ml) for pyridine-2-carboxamide.Continue to stir 2 hours at 0 ℃, add Na
2SO
3(5%, the 10ml) aqueous solution is used ethyl acetate extraction then.With organic solvent sodium bicarbonate aqueous solution, salt solution, water washing, then through Na
2SO
4Drying is filtered evaporation then.Resistates carries out purifying through silica gel (using ethyl acetate/heptane (4:1) as eluent), obtains title compound (95mg, 99%).
1H?NMR(DMSO-d
6)：δ?8.78(1H，d)，8.25(1H，dd)，7.95(1H，brd)，5.58(1H，brs)，4.74(1H，t)，3.79(1H，brs)，3.43(2H，t)，3.24-3.07(4H，m)，2.64(2H，m)，2.01(2H，brd)，1.90(2H，brd)，1.82(1H，m)，1.53(2H，t)，1.45(2H，brd)，0.65(4H，m).
APCI-MS?m/z：479[MH
+].
Embodiment 39
N-{ cis-4-[1-(1,1-titanium dioxide tetrahydrochysene-2H-thiapyran-4-yl)-6-fluoro-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-5-(methylol) benzamide.
This title compound is to make in the mode that is similar to embodiment 38.
1H?NMR(400MHz，DMSO-d
6)：δ?11.78(1H，s)，8.78(1H，d)，8.59(1H，d)，8.23(1H，dd)，7.95(1H，d)，7.34(1H，dd)，6.94(1H，d)，5.55(1H，brs)，5.12(1H，brs)，4.81(1H，t)，4.45(2H，s)，4.14(1H，brs)，3.43(2H，t)，3.23-3.08(4H，m)，2.61(2H，q)，2.00(4H，m)，1.68(2H，t)，1.56(2H，d).
APCI-MS?m/z：561[MH
+].
Embodiment 40
N-{ cis-4-[1-(1,1-titanium dioxide tetrahydrochysene-2H-thiapyran-4-yl)-6-fluoro-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } imidazo [1,2-a] pyridine-2-carboxamide
This title compound is to make in the mode that is similar to embodiment 38.
1H NMR (400MHz, DMSO-d
6): δ 8.78 (1H, d), 8.68 (1H, d), 8.51 (1H, s), 8.27 (1H, dd), 7.93 (1H, brs), 7.74 (1H, d), 7.48 (1H, t), 7.09 (1H, t), 5.57 (1H, brs), 4.84 (1H, t), 4.17 (1H, s),
*(2H is in solvent peak), 3.21 (2H, brt), 3.11 (2H, brd), 2.62 (2H, q), 2.01 (4H, m), 1.72 (2H, t), 1.58 (2H, brd).
APCI-MS?m/z：555[MH
+].
Embodiment 41
6-fluoro-N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } imidazo [1,2-a] pyridine-2-carboxamide
With 3-(4-amino-cyclohexyl)-6-fluoro-1-(tetrahydrochysene-thiapyran-4-yl)-1H-pyrido [2,3-d] pyrimidine-2,4-diketone (189mg, 0.5mmol) and6-fluoro-imidazo [1,2-a] pyridine-2-ethyl formate (90mg, 0.5mmol) and DIEA (1ml 5.5mmol) is dissolved among the NMP (6ml), add then HATU (210mg, 0.55mmol).Reaction mixture was stirred 40 minutes, be poured on waterborne then and use extracted with diethyl ether.Organic extract is evaporated, and resistates is through flash chromatography on silica gel purifying (use ethyl acetate: ethane (3:1) is as eluent).The product that obtains grinds with ether, stirs 1 hour under ether, collects title compound and dry (130mg, 48%).
1H?NMR(300MHz，DMSO-d
6)δ?8.50(d，1H)，8.21-8.12(m，2H)，8.10(td，1H)，7.86(d，1H)，7.72(dd，1H)，7.21(ddd，1H)，5.34-5.15(m，1H)，5.01(dd，1H)，4.52-4.38(m，1H)，3.12-2.86(m，4H)，2.84-2.65(m，4H)，2.20-1.92(m，4H)，1.84-1.72(m，2H)，1.71-1.60(m，2H)
APCI (multimode) m/z:541[M+H]
Embodiment 64b
N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-2-(4-hydroxy phenyl) ethanamide
To 3-(4-amino-cyclohexyl)-6-fluoro-1-(tetrahydrochysene-thiapyran-4-yl)-1H-pyrido [2,3-d] pyrimidine-2,4-diketone (0.25g, 0.66mmol) add hydroxyl (4-hydroxy phenyl) acetate (0.1223g in the solution in NMP (2ml), 0.73mmol) and DIPEA (0.588mL, 3.31mmol), add subsequently HATU (0.3016g, 0.79mmol).With reaction mixture stirring at room 12 hours.Add entry, then with the title compound ethyl acetate extraction.The organic phase anhydrous magnesium sulfate drying filters, and vacuum concentration obtains crude mixture then.Resistates obtains title compound (32mg, 10%) through reversed-phase HPLC purifying (ammonia soln of 32-40% acetonitrile).
1H?NMR(400MHz，DMSO-d
6)：δ?9.31(1H，s)，8.79(1H，d)，8.26(1H，dd)，7.57(1H，d)，7.25(2H，d)，6.71(2H，dt)，6.14(1H，d)，4.86(1H，d)，4.79(1H，s)，3.91(1H，s)，2.82-2.73(6H，m)，2.60-2.54(2H，m)，1.99(2H，s)，1.80(2H，s)，1.65-1.50(4H，m).
APCI (multimode) m/z:529[M+H]
Embodiment in the table 1,2 and 3 prepares in the mode that is similar among the embodiment 1.Use the IUPAC naming program of Openeye to come described compound, and manually add the stereochemistry descriptor (referring to
Www.eyesopen.com/products/applications/ogham.html).Wherein compound is separated to as elementary or secondary amine, and product prepares by using 4M HCl/ diox that ' BOC ' group is carried out deprotection.
Table 1 and 2 compound are the compound of formula (Ia), and the variable radicals R 1 in the formula (Ia) has the implication that provides in these tables.Each R1 group of listing in the table 1 and 2 comprises R1, and this has shown the tie point of described group and formula (Ia).
Table 1
Table 2
Embodiment 118a
N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-6-(1-methylpyrrolidin-2-yl) imidazo [1,2-a] pyridine-2-carboxamide
Step (a) 6-(1-methylpyrrolidin-2-yl) imidazo [1,2-a] pyridine-2-formic acid.
With 5-(1-methyl-tetramethyleneimine-2-yl)-pyridine-2-base amine (600mg, 3mmol) and ethyl bromide acetone (1.17g, 6.0mmol) mixture in ethanol (20ml) heats 2h at 70 ℃.Mixture is evaporated to dried, then resistates is ground (10ml) with acetonitrile.Collect thick ester after filtration, in water-soluble then/diox (1:1) mixture (20ml).In this solution, add lithium hydroxide monohydrate (0.3g, 7.14mmol), then with mixture in stirred overnight at room temperature.Mixture is evaporated to dried, then resistates water (20ml) is absorbed, and by add acetate with pH regulator to 4-5.Collect solid and dry then after filtration, obtain subtitle compounds (310mg, 42%).
1H?NMR(400MHz，DMSO-d
6)δ?8.46(s，1H)，8.35(s，1H)，7.55(d，1H)，7.29(dd，1H)，3.12(m，2H)，2.50(m，3H)，2.27(q，1H)，2.17(m，1H)，1.75(m，3H)
Step (b) N-{ cis-4-[6-fluoro-2,4-dioxo-1-(tetrahydrochysene-2H-thiapyran-4-yl)-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-6-(1-methylpyrrolidin-2-yl) imidazo [1,2-a] pyridine-2-carboxamide
(98mg 0.4mmol) is dissolved in the dry DMF (5ml) 6-(1-methyl-tetramethyleneimine-2-yl)-imidazo [1,2-a] pyridine-2-formic acid, (0.2ml 1.15mmol), adds HATU (160mg subsequently to add DIEA, 0.42mmol), then mixture was stirred 10 minutes.Add 3-(4-amino-cyclohexyl)-6-fluoro-1-(tetrahydrochysene-thiapyran-4-yl)-1H-pyrido [2,3-d] pyrimidine-2, the 4-diketone (150mg, 0.4mmol), then with mixture in stirred overnight at room temperature.Mixture is poured in the water, and the solid that goes out of collecting precipitation after filtration is with after reversed-phase HPLC purifying (ammonia soln of 25-95% acetonitrile) obtains title compound (94mg, 39%).
1H?NMR(300MHz，DMSO-d
6)δ?8.79(d，1H)，8.52(s，1H)，8.37(s，1H)，8.26(dd，1H)，7.74(d，1H)，7.68(d，1H)，7.36(dd，1H)，5.32(s，1H)，4.84(t，1H)，4.16(s，1H)，3.15(dd，2H)，2.72(m，6H)，2.28(m，2H)，2.14(s，3H)，1.97(s，4H)，1.68(m，9H)
APCI (multimode) m/z:606[M+H]
Table 3
Embodiment 395
Human phosphodiester enzyme B2 α screening assay
The recombinant human phosphodiesterase B2 (PDE4B2) that described mensuration is used homemade being stored in-20 ℃ (PrAZL0133).Substrate uses and is stored in 4 ℃ cAMP, and described cAMP is the part of Alpha Screen cAMP test kit (Perkin Elmer, Cat# 6760625M).The AlphaScreen test kit also comprises biotinylated cAMP, acceptor globule (acceptor bead) and donor globule (donor bead).
The interpolation process of measuring is as follows: the 100%DMSO solution of 0.2 μ l test compound and the 100%DMSO solution of 0.2 μ l reference substance are added to white 384 hole flat undersides (Greiner, Cat# 781075), add the reaction buffer of 10 μ l PDE4B2 subsequently.The composition of described reaction buffer has: 50mMTris (pH7.5), 8.3mM MgCl
2, 1.7mM EGTA and 0.01% (w/v)
With enzyme and compound incubated at room 15 minutes.Then, add the reaction buffer of 10 μ l cAMP., stop measuring after 60 minutes in incubated at room by the mensuration damping fluid (containing 40mM EDTA) that adds 10 μ l acceptor globules.The composition of described mensuration damping fluid has: 5mM Tris (pH7.5), 0.1% (w/v) BSA and 0.1% (v/v) Tween20.After this step interpolation, add the mensuration damping fluid and the biotinylated cAMP of 10 μ l donor globules.Then, plate was hatched 5 hours in the room temperature lucifuge, then at Fusion
TMMeasure on-α the analyser.Utilization is determined IC by the Xlfit curve of pattern 205 matches
50Value (being provided in the table 4).
Table 4
Embodiment 396
Human phosphodiester enzyme B2 radiation degree is measured
The recombinant human phosphodiesterase B2 (PDE4B2) that described mensuration is used homemade being stored in-20 ℃ (PrAZL0133).This mensuration is based on following observation: 5 ' AMP, and promptly by the catalytic reaction product of PDE4, cAMP compares with substrate, preferential and yttrium silicate SPA globule (AmershamBiosciences, UK) combination.With the compound of proper concn with measure damping fluid 30 ℃ of preincubates 30 minutes, described mensuration damping fluid contains 50mMHEPES (pH7.5), 8.3mM MgCl
2, 1.7mMEGTA, 0.01% (w/v)
With 0.1 μ g/mL reorganization PDE4B2.Begin reaction by adding [3H] ring-type AMP, obtain the ultimate density of 8nM, and contain 18mM ZnSO by adding after 20 minutes at the adding substrate
4Yttrium silicate SPA globule come stopped reaction.(Packard Bioscience UK) measures bonded [3H] ring-type to use Topcount NXT.Utilization is determined IC by the Xlfit3 curve of pattern 205 matches
50Value (being provided in the table 5).
Table 5
| Ex | PDE4B2?pIC 50 |
| 41 | 9.9 |
| 33 | 9.4 |
| 64b | 9.5 |
| 67 | 9.3 |
Claims (16)
1. formula (I) compound or its N-oxide compound or its pharmaceutical salts:
Wherein:
X is S, S (O) or S (O)
2
E is N or CE
1
T is C (O) or S (O)
2
W is (CH
2)
n
Y is (CH
2)
p
N and p independently are 0 or 1;
M is 0 or 1;
L is CH or N;
If L is CH, then J is NH; And if L is N, then J does not exist and T directly links to each other with L;
R
1Be C
1-10Alkyl (is chosen wantonly and is replaced by following group: halogen, hydroxyl, cyano group, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Alkoxyl group (C
1-6Alkoxyl group), aryl, heteroaryl, aryloxy, heteroaryl oxygen base, artyl sulfo, heteroaryl sulfenyl, aryl (C
1-4Alkoxyl group), aryl (C
1-4Alkylthio), C
3-7Cycloalkyl is (optional by C
1-4The alkyl replacement), CO
2H, CO
2(C
1-6Alkyl), NHC (O) R
3, THP trtrahydropyranyl, C (O) NR
24R
25, S (O)
2R
26Or NHS (O)
2R
27); C
1-6Alkoxyl group; C
2-4Thiazolinyl (choose wantonly and replaced) by phenyl; C
3-6Cycloalkyl (is chosen wantonly and is replaced by following group: hydroxyl, halogen, C
1-6Alkyl, C
1-6Alkoxyl group or phenyl); Heterocyclic radical (is chosen wantonly and is replaced by following group: oxo, hydroxyl, C
1-6Alkyl, S (O)
2(C
1-4Alkyl), C (O) (C
1-4Alkyl), aryl, heteroaryl, aryl (C
1-4Alkyl), C (O) heteroaryl or heterocyclic radical); Aryl or heteroaryl;
R
3Be C
1-6Alkyl or phenyl;
Above-mentioned R
1And R
3In phenyl, aryl and heteroaryl moieties optionally independently replaced by following group: halogen, cyano group, nitro, hydroxyl, S (O)
qR
4, OC (O) NR
5R
6, NR
7R
8, NR
9C (O) R
10, NR
11C (O) NR
12R
13, S (O)
2NR
14R
15, NR
16S (O)
2R
17, C (O) NR
18R
19, C (O) R
20, CO
2R
21, NR
22CO
2R
23, C
1-10Alkyl, C
1-6Hydroxyalkyl, C
1-6Haloalkyl, C
1-6Alkoxyl group (C
1-6) alkyl, C
1-6Alkyl (S (O)
2(C
1-4Alkyl)) two (C,
1-6) alkylamino (C
1-6) alkyl, C
1-6Alkoxyl group, C
1-6Halogenated alkoxy, C
1-6Alkoxyl group (C
1-6) alkoxyl group, C
1-6Alkylthio, C
2-6Thiazolinyl, C
2-6Alkynyl (choose wantonly and replaced), C by phenyl
3-10(itself is optional by C for cycloalkyl
1-4Alkyl or oxo replace), methylene-dioxy, OCH
2CH
2O, difluoro methylene-dioxy, heterocyclic radical (are chosen wantonly and are replaced by following group: hydroxyl, C
1-4Alkyl, phenyl or heteroaryl), phenyl, phenyl (C
1-4) alkyl, phenoxy group, phenyl sulfenyl, phenyl (C
1-4) alkoxyl group, heteroaryl, heteroaryl (C
1-4) alkyl, heteroaryl oxygen base or heteroaryl (C
1-4) alkoxyl group; Wherein just described arbitrarily phenyl or heteroaryl moieties are optional to be replaced by following group: halogen, hydroxyl, nitro, S (O)
r(C
1-4Alkyl), S (O)
2NH
2, S (O)
2NH (C
1-4Alkyl), S (O)
2N (C
1-4Alkyl)
2, cyano group, C
1-4Alkyl, C
1-4Alkoxyl group, C (O) NH
2, C (O) NH (C
1-4Alkyl), C (O) N (C
1-4Alkyl)
2, CO
2H, CO
2(C
1-4Alkyl), NHC (O) (C
1-4Alkyl), NHS (O)
2(C
1-4Alkyl), C (O) (C
1-4Alkyl), CF
3Or OCF
3
E
1And G
1Independent is hydrogen, halogen, cyano group, hydroxyl, C
1-4Alkyl, C
1-4Alkoxyl group, CF
3Or OCF
3
Q and r independently are 0,1 or 2;
R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11, R
12, R
13, R
14, R
15, R
16, R
17, R
18, R
19, R
20, R
21, R
22, R
23, R
24, R
25, R
26And R
27Independent is C
1-10Alkyl { is chosen wantonly and is replaced by following group: halogen, hydroxyl or C
1-6Alkoxyl group or optional substituted phenyl as described below separately or heteroaryl }, CH
2(C
2-6Thiazolinyl), phenyl { itself is chosen wantonly and is replaced by following group: halogen, hydroxyl, nitro, NH
2, NH (C
1-4Alkyl), N (C
1-4Alkyl)
2, S (O)
2(C
1-4Alkyl), S (O)
2NH
2, S (O)
2NH (C
1-4Alkyl), S (O)
2N (C
1-4Alkyl)
2, cyano group, C
1-4Alkyl, C
1-4Alkoxyl group, C (O) NH
2, C (O) NH (C
1-4Alkyl), C (O) N (C
1-4Alkyl)
2, CO
2H, CO
2(C
1-4Alkyl), NHC (O) (C
1-4Alkyl), NHS (O)
2(C
1-4Alkyl), C (O) (C
1-4Alkyl), CF
3Or OCF
3Or heteroaryl { itself is optional to be replaced by following group: halogen, hydroxyl, nitro, NH
2, NH (C
1-4Alkyl), N (C
1-4Alkyl)
2, S (O)
2(C
1-4Alkyl), S (O)
2NH
2, S (O)
2NH (C
1-4Alkyl), S (O)
2N (C
1-4Alkyl)
2, cyano group, C
1-4Alkyl, C
1-4Alkoxyl group, C (O) NH
2, C (O) NH (C
1-4Alkyl), C (O) N (C
1-4Alkyl)
2, CO
2H, CO
2(C
1-4Alkyl), NHC (O) (C
1-4Alkyl), NHS (O)
2(C
1-4Alkyl), C (O) (C
1-4Alkyl), CF
3Or OCF
3;
R
5, R
6, R
7, R
8, R
9, R
10, R
11, R
12, R
13, R
14, R
15, R
16, R
18, R
19, R
20, R
21, R
22, R
23, R
24And R
25Also can be hydrogen.
2. as formula (I) compound of claim 1 requirement, wherein E is CE
1
3. as claim 1 or 2 formula (I) compound that requires, wherein E
1Be hydrogen or halogen.
4. as claim 1,2 or 3 formula (I) compounds that require, wherein n and p are 1.
5. as claim 1,2,3 or 4 formula (I) compounds that require, wherein L is CH, and J is that NH and T are C (O).
6. as formula (I) compound of above-mentioned each requirement of claim, wherein G
1Be hydrogen.
7. as formula (I) compound of above-mentioned each requirement of claim, wherein m is 1.
8. as formula (I) compound of above-mentioned each requirement of claim, wherein X is S.
9. as formula (I) compound of above-mentioned each requirement of claim, wherein R
1Be C
1-6Alkyl (is chosen wantonly and is replaced by following group: halogen, hydroxyl, C
1-6Alkoxyl group, C
3-6Cycloalkyl (is chosen wantonly and is replaced by following group: hydroxyl, C
1-4Alkyl, C
1-4Alkoxyl group or phenyl), aryl or heteroaryl), C
3-7Cycloalkyl (is chosen wantonly and is replaced by following group: hydroxyl, halogen, C
1-6Alkyl, C
1-6Alkoxyl group or phenyl), heterocyclic radical (optional replaces by following group: oxo, hydroxyl, C
1-6Alkyl, S (O)
2(C
1-4Alkyl), C (O) (C
1-4Alkyl), aryl, heteroaryl, aryl (C
1-4Alkyl), C (O) heteroaryl or heterocyclic radical), aryl or heteroaryl; Above-mentioned R
1In phenyl, aryl and heteroaryl moieties optionally independently replaced by following group: halogen, cyano group, hydroxyl, S (O)
2R
4, NR
7R
8, NR
11C (O) NR
12R
13, S (O)
2NR
14R
15, C (O) NR
18R
19, C
1-10Alkyl, C
1-6Hydroxyalkyl, C
1-6Haloalkyl, C
1-6Alkoxyl group (C
1-6) alkyl, C
1-6Alkyl (S (O)
2(C
1-4Alkyl)) two (C,
1-6) alkylamino (C
1-6) alkyl, C
1-6Alkoxyl group, C
1-6Halogenated alkoxy, C
1-6Alkoxyl group (C
1-6) alkoxyl group, C
3-10(itself is optional by C for cycloalkyl
1-4Alkyl or oxo replace) or heterocyclic radical (optionally replaced: hydroxyl, C by following group
1-4Alkyl, phenyl or heteroaryl); R
4Be C
1-4Alkyl; And R
7, R
8, R
11, R
12, R
13, R
14, R
15, R
18And R
19Independent is hydrogen or C
1-4Alkyl.
10. preparation is as the method for formula (I) compound of claim 1 requirement, and described method comprises from formula (II) compound removes the tert-butoxycarbonyl protecting group, makes the product of as above formation and the carboxylic acid or derivatives thereof reaction of formula (III) then; Described formula (II) compound is as follows:
Wherein m, G
1, E, Y, L, W, X and J as defined in claim 1; Formula (III) compound is as follows:
R wherein
1With T as defined in claim 1, and LG is a leaving group.
11. a pharmaceutical composition, it comprises formula (I) compound or pharmaceutically acceptable salt thereof that requires as claim 1, and pharmaceutical excipient, diluent or carrier.
12. as formula (I) compound or pharmaceutically acceptable salt thereof that claim 1 requires, it is used for the treatment of.
13. the purposes of formula (I) compound or pharmaceutically acceptable salt thereof in the medicine that preparation is used for the treatment of as claim 1 requirement.
14. treatment suffers from the illness of PDE4 mediation or faces the method for the mammiferous described illness of described illness risk, described method comprises that formula (I) compound or pharmaceutically acceptable salt thereof with the claim 1 of treatment significant quantity needs the Mammals of this treatment.
15. a medicament production, it comprises first activeconstituents, promptly aforesaid formula (I) compound or pharmaceutically acceptable salt thereof, and the another kind of at least combination that is selected from following activeconstituents:
Beta 2 adrenoreceptor agonists,
The conditioning agent of chemokine receptor function,
The inhibitor of kinase function,
Proteinase inhibitor,
The steroidal glucocoricoid receptor agonist,
Anticholinergic, and
The non-steroidal glucocoricoid receptor agonist.
16. the intermediate compound of formula (II)
Wherein m, G
1, E, Y, L, W, X and J as defined in claim 1.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US78485506P | 2006-03-22 | 2006-03-22 | |
| US60/784,855 | 2006-03-22 | ||
| US60/884,456 | 2007-01-11 |
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| Publication Number | Publication Date |
|---|---|
| CN101454318A true CN101454318A (en) | 2009-06-10 |
Family
ID=40735880
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007800188625A Pending CN101454318A (en) | 2006-03-22 | 2007-03-20 | Pyridopyrimidine derivatives and their use as pde4 inhibitors |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104350058A (en) * | 2012-06-08 | 2015-02-11 | 格兰马克药品股份有限公司 | Amides of 2-amino-4-arylthiazole compounds and their salts |
-
2007
- 2007-03-20 CN CNA2007800188625A patent/CN101454318A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104350058A (en) * | 2012-06-08 | 2015-02-11 | 格兰马克药品股份有限公司 | Amides of 2-amino-4-arylthiazole compounds and their salts |
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