CN101258152A - Pyridopyrimidine derivatives as PDE4 inhibitors for the treatment of inflammatory and immune diseases - Google Patents
Pyridopyrimidine derivatives as PDE4 inhibitors for the treatment of inflammatory and immune diseases Download PDFInfo
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- CN101258152A CN101258152A CNA200680032368XA CN200680032368A CN101258152A CN 101258152 A CN101258152 A CN 101258152A CN A200680032368X A CNA200680032368X A CN A200680032368XA CN 200680032368 A CN200680032368 A CN 200680032368A CN 101258152 A CN101258152 A CN 101258152A
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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 PDE4 mediated disease state.
Description
Technical field
The present invention relates to have the Pyridopyrimidine derivatives of pharmaceutical activity, the method that is used to prepare these derivatives, the pharmaceutical composition that comprises these derivatives and these derivatives purposes as active therapeutic agent.
Background technology
In EP-A-0260817, WO 98/02162, WO 93/19068 and WO 0045800, disclosed Pyridopyrimidine derivatives with pharmaceutical activity.
Phosphodiesterase (PDEs) plays a role 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 causes 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 hypotype more than 50.In addition, with regard to each hypotype 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).
At the internal lobe (inner leaflet) of plasma membrane, the effect of the adenylate cyclase of regulating by GPCR generates cAMP from ATP.In case generate cAMP, the unique channel of termination signal is exactly by the phosphodiesterase effect, and cAMP is degraded into 5 '-AMP.The concentration of cAMP increases main activation by the dependent protein kinase of cAMP (PKA) and is translated into cellular response.Partly regulate the specific activity of PKA by the Subcellular Localization of PKA, this has limited the phosphorylation of PKA near substrate it.Be difficult to illustrate the downstream events that causes by the PKA activation, and the various ingredients of these incidents when being involved in signal series connection beginning.What shown is, PDE4s brings into play a large amount of effects when regulating cell desensitization, adaptation, signal cross-talk (cross-talk), cAMP compartmentation (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: the activity that 1) extensively suppresses the panimmunity active cells; 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.
Find that PDE4 is main cAMP metabolism isozyme family, and the cAMP metabolism in airway smooth muscle mainly ascribes PDE4 family and PDE3 family in immunity and inflammatory cell.
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.Report 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 efficacy of these inhibitor is subject to the relevant side effect of PDE4, comprises nauseating, vomiting and gastric acid secretion.Recently described, s-generation PDE4 inhibitor (for example cilomilast (cilomilast), roflumilast (roflumilast) and AWD 12-281) significantly reduces the risk that emetic side effect occurs in vomiting animal model, thereby has the potentiality that improve the treatment ratio.
Cilomilast roflumilast AWD 12-281
Summary of the invention
The present invention discloses novel Pyridopyrimidine derivatives, and described Pyridopyrimidine derivatives behaviour PDE4 inhibitor can be used for treatment thus.
The invention provides formula (I) compound or its N-oxide compound or its pharmacologically acceptable salt:
Wherein
A is N or CA
1
E is N or CE
1
T is C (O) or S (O)
2
X is C or S;
W is (CH
2)
n
Y is (CH
2)
p
N and p independently are 0 or 1;
L is CH or N;
When L was CH, then J was NH; When L was N, then J did not exist, and T directly links to each other with L;
R
1Be aryl or heteroaryl, each in described aryl or the heteroaryl is optional by halogen, cyano group, hydroxyl, C
1-4Alkyl, C
1-4Alkoxyl group, CF
3, OCF
3, C
1-4Alkylthio, S (O) (C
1-4Alkyl), S (O)
2(C
1-4Alkyl) or C (O)
2(C
1-4Alkyl) replaces;
R
2Be C
1-6Alkyl is (optional by hydroxyl, C
1-6Alkoxyl group, heterocyclic radical (are chosen wantonly by C
1-6The alkyl replacement), aryl, heteroaryl, C
3-7Cycloalkyl, CO
2H, CO
2(C
1-6Alkyl) or NHC (O) R
3Replacement), C
1-6Alkoxyl group, C
3-6Cycloalkyl is (optional by hydroxyl or C
1-6The alkyl replacement), heterocyclic radical is (optional by C
1-6The alkyl replacement), aryl or heteroaryl;
R
3Be C
1-6Alkyl or phenyl;
Above-mentioned R
2And R
3In phenyl, aryl and heteroaryl independently optionally 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
1-6Alkyl, C
1-6Hydroxyalkyl, C
1-6Haloalkyl, C
1-6Alkoxyl group (C
1-6) alkyl, 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, C
3-10(itself is optional by C for cycloalkyl
1-4Alkyl or oxo (oxo) replacement), methylene radical dioxy base (methylenedioxy), difluoro methylene dioxy base, phenyl, phenyl (C
1-4) alkyl, phenoxy group, thiophenyl, phenyl (C
1-4) alkoxyl group, heteroaryl, heteroaryl (C
1-4) alkyl, heteroaryl oxygen base or heteroaryl (C
1-4) alkoxyl group; Wherein just above-mentioned phenyl and any one in the heteroaryl 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
A
1, 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
22And R
23Independent is C
1-6Alkyl is { optional by halogen, hydroxyl or C
1-6Alkoxyl group replaces }, CH
2(C
2-6Thiazolinyl), { itself is optional by halogen, hydroxyl, nitro, NH for phenyl
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
3Replace or heteroaryl { choosing wantonly by halogen, hydroxyl, nitro, NH own
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
3Replace };
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 R
23Also can be hydrogen.
Can different isomeric form there be (for example enantiomer, diastereomer, geometrical isomer or tautomer) in some compound of the present invention.The arbitrary proportion mixture of all these isomer and these isomer 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 trianion, oxalate, mesylate or tosilate.Selectable acid salt is a trifluoroacetate.
Compound of the present invention can solvate (for example hydrate) form exist, 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.
Alkyl 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; 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.Cycloalkyl oxy 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 non-aromatics 5 or 6 yuan of rings, comprises that at least one is selected from the heteroatoms in nitrogen, oxygen and the sulphur.Heterocyclic radical for example is pyrrolidyl, piperidyl or morpholinyl.
Hydroxyalkyl for example is CH
2OH; C
1-6Alkoxyl group (C
1-6) alkyl for example is CH
3OCH
2C
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
Heteroaryl for example is aromatics 5 or 6 yuan of rings, comprises that at least one is selected from the heteroatoms in nitrogen, oxygen and the sulphur, and optional and one or more other rings condense; Or be its N-oxide compound or its S-oxide compound or S-dioxide.Heteroaryl for example is a furyl, thienyl (being also referred to as thiophenyl), pyrryl, thiazolyl, isothiazolyl, pyrazolyl oxazolyl isoxazolyl, imidazolyl, [1,2,4]-triazolyl, [1,2,3]-triazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indyl, benzo [b] furyl (being also referred to as benzofuryl), benzo [b] thienyl (being also referred to as benzothienyl or benzothienyl), indazolyl, benzimidazolyl-, benzotriazole base benzoxazolyl, benzothiazolyl (for example 1, the 3-benzothiazolyl), 1,2,3-diazosulfide base, (for example imidazo [1 for imidazopyridyl, 2a] pyridyl), thieno-[3,2-b] pyridine-6-base, 1,2,3-Ben Bing oxadiazole base (is also referred to as benzo [1,2,3] thiadiazolyl group), 2,1,3-diazosulfide base, the benzo furazan (is also referred to 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), (for example imidazo [1 for imidazopyridine, 2-a] pyridyl), dihydro pyrido [2,3-d] pyrimidine (for example 1,4-dihydro pyrido [2,3-d] pyrimidyl), quinolyl, isoquinolyl or phthalazinyl (for example [1,6] phthalazinyl or [1,8] phthalazinyl); Or be its N-oxide compound or its S-oxide compound or S-dioxide.In yet another aspect, heteroaryl for example is 1,2,3-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.
Another aspect of the present invention provides formula (I) compound, and wherein A is CA
1E is CE
1A
1, E
1And G
1Independent is hydrogen or halogen (for example fluorine).
Another aspect of the present invention provides formula (I) compound, and wherein A is CA
1A
1For example be hydrogen.
Another aspect of the present invention provides formula (I) compound, and wherein E is CE
1E
1For example be halogen (for example fluorine).
Another aspect of the present invention provides formula (I) compound, wherein G
1Be hydrogen.
Another aspect of the present invention provides formula (I) compound, and wherein X is C.
Another aspect of the present invention provides formula (I) compound, and wherein n and p are 1.
Another aspect of the present invention provides formula (I) compound, and wherein L is CH.
Another aspect of the present invention provides formula (I) compound, and wherein J is NH.
Another aspect of the present invention provides formula (I) compound, and wherein T is C (O).
Another aspect of the present invention provides formula (I) compound, wherein R
1For choosing wantonly by halogen, C
1-4Alkylthio, S (O)
2(C
1-4Alkyl) or C (O)
2(C
1-4Alkyl) aryl of Qu Daiing (for example phenyl).Another aspect of the present invention provides formula (I) compound, wherein R
1For choosing wantonly by halogen (for example fluorine) or C
1-4Alkylthio (SCH for example
3) phenyl that replaces.Another aspect of the present invention provides formula (I) compound, wherein R
1Be the optional phenyl that is replaced by fluorine (for example by 2 fluorine).
Another aspect of the present invention provides formula (I) compound, wherein R
2Be C
1-6Alkyl is { optional by hydroxyl, phenyl (itself choose wantonly and replaced by hydroxyl), C
3-7Cycloalkyl, CO
2(C
1-4Alkyl) or NHC (O) R
3Replace }, phenyl is { optional by halogen, hydroxyl, C
1-4Alkyl, C
1-4Alkoxyl group, CO
2(C
1-4Alkyl) or C
2-4Alkynyl substituted } or heteroaryl { optional by halogen, hydroxyl, C
1-4Alkyl, C
1-4Alkoxyl group, CO
2(C
1-4Alkyl) or C
2-4Alkynyl substituted }; R wherein
3Be the optional phenyl that is replaced by hydroxyl.Heteroaryl for example is indyl, quinolyl, benzopyrazoles base, imidazo [1,2-a] pyridyl, pyrazolo [1,5-a] pyridyl or pyrrolo-[2,3-b] pyridyl.
Another aspect of the present invention provides formula (I) compound, wherein R
2Be C
1-6Alkyl is (optional by hydroxyl, aryl, C
3-7Cycloalkyl, CO
2(C
1-6Alkyl) or NHC (O) R
3Replace), aryl or heteroaryl (for example pyridyl, benzimidazolyl-or 1,4-dihydro pyrido [2,3-d] pyrimidyl); R
3Be phenyl.Aryl for example is a phenyl.
Another aspect of the present invention provides formula (I) compound, wherein above-mentioned R
2And R
3In phenyl, aryl and heteroaryl independently optionally replaced by following group: halogen, hydroxyl, CO
2(C
1-6Alkyl), C
1-6Alkyl, C
1-6Hydroxyalkyl or C
1-6Alkoxyl group.
Compound of the present invention is described in an embodiment.In the embodiment compound each is another aspect of the present invention.Thereby, the invention provides following compound or pharmaceutically acceptable salt thereof:
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-5-(methylol) benzamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-2-phenyl-acetamides;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-hydroxyl acetamide;
5-chloro-N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-hydroxybenzamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 3-hydroxybenzamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 4-hydroxybenzamide;
2-[({ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } amino) carbonyl] methyl benzoate;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-(4-hydroxy phenyl) ethanamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxy-4-methyl benzamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-hydroxybenzamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-3-pyridone-2-methane amide;
3-chloro-N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 4-hydroxybenzamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-3-hydroxy-2-methyl benzamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-4-hydroxy 3-methoxybenzene methane amide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-3-hydroxy-4-methyl benzamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-6-methoxy benzamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxy 3-methoxybenzene methane amide;
4-chloro-N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-hydroxybenzamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-4-methoxy benzamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-5-fluoro-2-hydroxybenzamide;
(2S)-and N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxy-4-methyl valeramide;
(2R)-and 2-cyclohexyl-N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-hydroxyl acetamide;
4-(suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] and cyclohexyl } amino)-4-ketobutyric acid methyl esters;
N-[2-(suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] and cyclohexyl } amino)-the 2-oxoethyl]-the 2-hydroxybenzamide;
4-[({ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } amino) carbonyl] methyl benzoate;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-3-hydroxyl-4-methoxy benzamide;
5-(suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] and cyclohexyl } amino)-5-oxopentanoic acid methyl esters;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-(3-hydroxy phenyl) ethanamide;
3-[({ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } amino) carbonyl] methyl benzoate;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-fluoro-6-hydroxybenzamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-3-(3-hydroxy phenyl) propionic acid amide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1H-indazole-3-methane amide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } imidazo [1,2-a] pyridine-2-carboxamide;
5-chloro-N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-hydroxybenzamide;
N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxy-5-methyl yl-benzamide;
N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-5-(methylol) benzamide;
(2R)-and N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-2-phenyl-acetamides;
(2S)-and N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-2-phenyl-acetamides;
N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-hydroxyl acetamide;
5-chloro-N-{ is suitable-4-[6-fluoro-1-[3-(methylsulfonyl) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-hydroxybenzamide;
N-{ is suitable-4-[6-fluoro-1-[3-(methylsulfonyl) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-5-(methylol) benzamide;
(2R)-and N-{ is suitable-4-[6-fluoro-1-[3-(methylsulfonyl) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-2-phenyl-acetamides;
(2S)-and N-{ is suitable-4-[6-fluoro-1-[3-(methylsulfonyl) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-2-phenyl-acetamides;
N-{ is suitable-4-[6-fluoro-1-[3-(methylsulfonyl) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-hydroxyl acetamide;
3-[6-fluoro-3-{ is suitable-4-[(2-hydroxy-5-methyl base benzoyl) and amino] cyclohexyl }-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } Toluidrin;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro-3H-pyrido [2,3-c] [1,2,6] thiadiazine-3-yl] cyclohexyl }-2-hydroxy-5-methyl yl-benzamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } cyclopropane carboxamide;
3-[6-fluoro-3-{ is suitable-4-[(1-methyl-L-prolyl) and amino] cyclohexyl }-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate;
5-[({ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } amino) carbonyl] the pyridine-2-carboxylic acids methyl esters;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-4-fluoro-2-hydroxybenzamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1-hydroxyl cyclopropane carboxamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } quinoline-8-methane amide;
N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-furoamide;
N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } cyclopropane carboxamide;
N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } propionic acid amide;
N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } benzamide;
N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } cyclopentane formamide;
N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxy-2-methyl propionic acid amide;
N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } benzsulfamide;
3-[3-{ is suitable-the 4-[(cyclobutyl carbonyl) and amino] cyclohexyl }-6-fluoro-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate;
3-[6-fluoro-3-[is suitable-4-(isobutyryl amino) cyclohexyl] and-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate;
3-[6-fluoro-3-{ is suitable-4-[(3-methylbutyryl base) and amino] cyclohexyl }-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate;
3-[3-{ is suitable-4-[(2, and 2-dimethyl propylene acyl group) amino] cyclohexyl }-6-fluoro-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate;
3-[6-fluoro-3-{ is suitable-4-[(methoxyl group ethanoyl) and amino] cyclohexyl }-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate;
3-[6-fluoro-2,4-dioxo-3-{ is suitable-the 4-[(2-thienyl carbonyl) amino] cyclohexyl }-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate;
3-[3-[is suitable-4-(kharophen) cyclohexyl]-6-fluoro-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate;
3-[6-fluoro-2,4-dioxo-3-{ is suitable-4-[(pyrazolo [1,5-a] pyridine-2-base carbonyl) amino] cyclohexyl }-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate;
3-[6-fluoro-3-{ is suitable-4-[(imidazo [1,2-a] pyridine-2-base carbonyl) and amino]-cyclohexyl }-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate;
3-[3-{ is suitable-the 4-[(cyclopropyl carbonyl) and amino] cyclohexyl }-6-fluoro-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate;
N-{ is suitable-4-[6-fluoro-1-[3-(methylsulfonyl) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } cyclopropane carboxamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxy-5-methyl yl-benzamide;
3-[6-fluoro-3-(suitable-4-{[(1-methyl piperidine-4-yl) carbonyl] amino } cyclohexyl)-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate;
3-[3-[is suitable-4-(the 5-[(dimethylamino) methyl]-2-furoyl base } amino) cyclohexyl]-6-fluoro-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate;
3-[3-{ is suitable-the 4-[(cyclohexyl-carbonyl) and amino] cyclohexyl }-6-fluoro-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate;
4-[({2-[(3, the 4-difluorophenyl) amino]-5-fluorine pyridin-3-yl } carbonyl) amino] piperidines-1-carboxylic acid tert-butyl ester;
4-[1-(3, the 4-difluorophenyl)-6-fluoro-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] piperidines-1-carboxylic acid tert-butyl ester;
(3R)-and 3-[({2-[(3, the 4-difluorophenyl) amino]-5-fluorine pyridin-3-yl } carbonyl) amino] tetramethyleneimine-1-carboxylic acid tert-butyl ester;
(3R)-and 3-[1-(3, the 4-difluorophenyl)-6-fluoro-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] tetramethyleneimine-1-carboxylic acid tert-butyl ester;
1-(3, the 4-difluorophenyl)-6-fluoro-3-[1-(1H-indazole-3-base carbonyl) piperidin-4-yl] and pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-diketone;
1-(3, the 4-difluorophenyl)-6-fluoro-3-{1-[(2R)-and 2-hydroxyl-2-phenyl acetyl] piperidin-4-yl } pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-diketone;
1-(3, the 4-difluorophenyl)-6-fluoro-3-{1-[2-hydroxyl-5-(methylol) benzoyl] piperidin-4-yl } pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-diketone;
1-(3, the 4-difluorophenyl)-6-fluoro-3-[(3R)-1-(1H-indazole-3-base carbonyl) tetramethyleneimine-3-yl] pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-diketone;
1-(3, the 4-difluorophenyl)-6-fluoro-3-{ (3R)-1-[(2R)-2-hydroxyl-2-phenyl acetyl] tetramethyleneimine-3-yl } pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-diketone;
3-{ (3R)-1-[(2R)-2-cyclohexyl-2-hydroxyacetyl] tetramethyleneimine-3-yl }-1-(3, the 4-difluorophenyl)-6-fluorine pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-diketone;
1-(3, the 4-difluorophenyl)-6-fluoro-3-{ (3R)-1-[2-hydroxyl-5-(methylol) benzoyl] tetramethyleneimine-3-yl } pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-diketone;
1-(3, the 4-difluorophenyl)-6-fluoro-3-[(3S)-1-(1H-indazole-3-base carbonyl) tetramethyleneimine-3-yl] pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-diketone;
1-(3, the 4-difluorophenyl)-6-fluoro-3-{ (3S)-1-[(2R)-2-hydroxyl-2-phenyl acetyl] tetramethyleneimine-3-yl } pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-diketone;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1H-indoles-5-methane amide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 3-nitrobenzamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1H-indoles-2-methane amide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1H-benzoglyoxaline-5-methane amide;
4-cyano group-N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } benzamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1H-1,2,3-benzotriazole-5-methane amide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1,3-benzothiazole-6-methane amide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-3-methyl-6,7-dihydro-5H-[1,3] thiazole [3,2-a] pyrimidine-2-methane amide also;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1,2,3-thiadiazoles-4-methane amide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 1H-pyrazole-4-carboxamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } thiophene-3-methane amide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 1H-pyrrole-3-carboxamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1-methyl isophthalic acid H-imidazoles-4-methane amide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 1H-pyrazole-3-formamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1-methyl piperidine-3-methane amide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-3-morpholine-4-base propionic acid amide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-4-vinyl benzene methane amide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-4-acetylenylbenzene methane amide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1H-pyrrolo-[2,3-b] pyridine-2-carboxamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1,3-benzothiazole-2-methane amide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } thieno-[2,3-b] pyridine-2-carboxamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } thieno-[2,3-b] pyrazine-6-methane amide; Or
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } [1,2,4] triazolo [1,5-a] pyrimidine-2-methane amide.
Prepare compound of the present invention by following method or by the means known in the art of adjusting.
Another aspect of the present invention is provided for preparing wherein, and X is the method for formula (I) compound of C; described method comprises from formula (II) compound removes Boc blocking group (for example using acid (for example trifluoroacetic acid or hydrochloric acid)); make product and formula (III) acid or the acid derivative reaction of formation like this then
Formula (II) compound is as follows:
R wherein
1, G
1, E, A, Y, L, W and J be as definition in formula (I),
Formula (III) acid or acid derivative are as follows:
R wherein
2With T as in formula (I) definition, LG is a leavings group.In suitable temperature, be generally 0 ℃ to solvent boiling point, (for example carry out described method in methylene dichloride or the N-Methyl pyrrolidone at suitable solvent.Choose wantonly under the situation that has alkali and/or coupling agent (for example HATU, HOAT, HOBT or DIEA) and carry out described method.Suitable leavings group LG comprises OH and halogen, especially OH.
Can prepare wherein R by the following method
1, G
1, E, A, Y, L, W and J be as formula (II) compound of definition in formula (I): exist under the situation of appropriate base (for example sodium hydride), make formula (IV) compound and suitable carbonylation agent (for example carbonyl dimidazoles or Vinyl chloroformate) condensation,
Formula (IV) compound is as follows:
R wherein
1, G
1, E, A, Y, L, W and J be as definition in formula (I).In suitable temperature, be generally 0 ℃ to solvent boiling point, in suitable solvent (for example tetrahydrofuran (THF)), carry out described method.
Another aspect of the present invention is provided for preparing wherein by following process, and X is the method for formula (I) compound of S: make the reaction of formula (IIa) compound and formula (III) acid or acid derivative,
Formula (IIa) compound is as follows:
R wherein
1, G
1, E, A, Y, L, W and J be as definition in formula (I),
Formula (III) acid or acid derivative are as follows:
R wherein
2With T as in formula (I) definition, LG is a leavings group.In suitable temperature, be generally 0 ℃ to solvent boiling point, in suitable solvent (for example methylene dichloride or N-Methyl pyrrolidone), carry out described method.Choose wantonly under the situation that has alkali and/or coupling agent (for example HATU, HOAT, HOBT or DIEA) and carry out described method.Suitable leavings group LG comprises OH and halogen, especially OH.
Can prepare wherein R by the following method
1, G
1, E, A, Y, L, W and J be as formula (IIa) compound of definition in formula (I): exist under the situation of appropriate base (for example sodium hydride), make wherein R
1, G
1, E, A, Y, L, W and J be as formula (IV) compound of definition in formula (I) and suitable alkylsulfonyl reagent (for example thionyl chloride) condensation.In suitable temperature, be generally 0 ℃ to solvent boiling point, in suitable solvent (for example tetrahydrofuran (THF)), carry out described method.
Can prepare wherein R by the following method
1, G
1, E, A, Y, L, W and J be as formula (IV) compound of definition in formula (I): formula V compound and formula (VI) amine is reacted,
The formula V compound is as follows:
R wherein
1, G
1, E and A be as definition in formula (I),
Formula (VI) compound is as follows:
Wherein Y, L, W and J are as definition in formula (I).In suitable temperature, be generally 0 ℃ to solvent boiling point, in suitable solvent (for example methylene dichloride), carry out described method.Choose wantonly under the situation that has alkali and coupling agent (for example HATU, HOAT, HOBT or DIEA) and carry out described method.
Can prepare wherein R by the following method
1, G
1, E and A be as the formula V compound of definition in formula (I): formula (VII) compound and aniline (VIII) are reacted,
Formula (VII) compound is as follows:
G wherein
1, E and A be as definition in formula (I), Hal refers to halogen atom,
(VIII) is as follows for aniline:
R
1-NH
2(VIII)
R wherein
1As definition in formula (I).In suitable temperature, be generally 50 ℃ to solvent boiling point, in suitable solvent (for example dimethyl formamide), carry out described method.Choose wantonly under the situation that has alkali (for example salt of wormwood) and carry out described method.
Describe the preparation of various intermediates in the literature, maybe can prepare various intermediates by the described method of document is carried out path adjustment.
In above method expectation or essential be that protection acid groups or hydroxyl or other have the active group of potential reaction.Can be at " the Protective Groups in OrganicSynthesis " that Greene and Wuts showed, find suitable blocking group and the method details that is used to add and remove these blocking groups among the 3rd Edition (1999).
Another aspect of the present invention is provided for the method for preparation formula (I) compound.
Formula (I) compound specifically is to have activity as the PDE4 receptor activity modulators as medicine, 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 asthma (comprising what acetylsalicylic acid and NSAID brought out) and bringing out property of dust asthma, the airway hyperreactivity that the asthma of intermission asthma and persistence asthma and various severities and other reason cause; Chronic obstructive pulmonary disease (COPD); Bronchitis comprises infectivity 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 and chronic rhinitis comprises medicamentous rhinitis and vasomotor rhinitis; Property (perennial) 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;
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 chronic crystallographic synovitis 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 ' s disease); 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 ' s arteritis), Qiu-Shi syndrome (Churg-Strauss syndrome), polyarteritis nodosa, microscope polyarteritis and the vasculitis relevant with virus infection, allergy, cryoglobulin and M-band; Back of the body bottom pain; 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 long-term property (perennial) 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 can have away from the relevant transformation reactions of the food of intestines effect (for example migraine, rhinitis or eczema);
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 a matter 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 method for illness of the PDE4 mediation of Mammals (for example people), described Mammals suffers from described illness or faces the risk of described illness, and described method comprises that formula (I) compound or pharmaceutically acceptable salt thereof with the treatment significant quantity needs 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.
Another aspect of the present invention provides the purposes of formula (I) compound or pharmaceutically acceptable salt thereof in medication preparation, and described medicine is used for using (for example regulating the PDE4 enzymic activity) in treatment.
The present invention also provides the purposes of formula (I) compound or pharmaceutically acceptable salt thereof in medication preparation, and described medicine is used for the treatment of Mammals (for example people's) following disease:
1. respiratory tract: airway obstructive disease, comprise asthma, comprise bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, exercise-induced asthma, drug-induced property asthma (comprising what acetylsalicylic acid and NSAID brought out) and bringing out property of dust asthma, the airway hyperreactivity that the asthma of intermission asthma and persistence asthma and various severities and other reason cause; Chronic obstructive pulmonary disease (COPD); Bronchitis comprises infectivity 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 and chronic rhinitis comprises medicamentous rhinitis and vasomotor rhinitis; Property 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;
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 chronic crystallographic synovitis 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; Back of the body bottom pain; 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 long-term property 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 can have away from the relevant transformation reactions of the food of intestines effect (for example migraine, rhinitis or eczema);
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 a matter 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.
Another aspect of the present invention provides formula (I) compound or pharmaceutically acceptable salt thereof, it is used for the treatment of following disease: asthma { for example bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma or dust asthma, especially chronic asthma 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 the purposes of formula (I) compound or pharmaceutically acceptable salt thereof in medication preparation, described medicine is used for the treatment of following disease: asthma { for example bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma or dust asthma, especially chronic asthma or obstinate asthma (for example tardy property asthma or airway hyperreactivity) }; Or COPD.
In order to use compound or pharmaceutically acceptable salt thereof of the present invention to be 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, another aspect of the present invention provides the pharmaceutical composition that comprises formula (I) compound or pharmaceutically acceptable salt thereof (activeconstituents) and pharmaceutically acceptable auxiliaries, diluent or carrier.
Another aspect of the present invention is provided for preparing described method for compositions, and described composition comprises blended activeconstituents and pharmaceutically acceptable auxiliaries, 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, mode that can standard is 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 pharmaceutical composition of the present invention through enteral administration.For these purposes, can prepare compound of the present invention by the method that is known in the art.Suitable pharmaceutical composition of the present invention carries out pharmaceutical composition for oral administration for being suitable for unit dosage (for example sheet or capsule), and described unit dosage comprises the activeconstituents of 0.1mg to 1g.
Every patient can for example be 0.001mgkg by for example accepting institute's dosage that gives for 1 to 4 time/day
-1To 100mgkg
-1Scope for example be 0.1mgkg
-1To 20mgkg
-1Activeconstituents.
The invention still further relates to combined therapy, wherein with compound or pharmaceutically acceptable salt thereof of the present invention 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 as with another kind of therapeutical agent or multiple therapeutical agent together combination preparation and give, 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 the following drug regimens of listing.
NSAID (non-steroidal anti-inflammatory drug) (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 pharmacologically acceptable salt 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 pharmacologically acceptable salt 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 Il-15).
The invention still further relates to the combination of The compounds of this invention or its pharmacologically acceptable salt 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 pharmacologically acceptable salt 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 pharmacologically acceptable salt 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 x 1005.
The invention still further relates to the combination of The compounds of this invention or its pharmacologically acceptable salt 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 (CGP 45715A) and BAY x 7195.
The invention still further relates to the combination of The compounds of this invention or its pharmacologically acceptable salt and following material: phosphodiesterase (PDE) inhibitor, for example methyl xanthine (methylxanthanine) comprises theophylline and aminophylline; Selectivity PDE isozyme inhibitor comprises PDE4 inhibitor, hypotype PDE4D inhibitor or PDE5 inhibitor.
The invention still further relates to the combination of The compounds of this invention or its pharmacologically acceptable salt 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 pharmacologically acceptable salt 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 pharmacologically acceptable salt and following material: histamine 4 receptor antagonists.
The invention still further relates to the combination of The compounds of this invention or its pharmacologically acceptable salt 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 pharmacologically acceptable salt and following material: anticholinergic, comprise muscarinic receptor (M1, M2 and M3) antagonist, for example coromegine, Scopolamine, GLYCOPYRRONIUM (glycopyrrrolate), ipratropium bromide (ipratropium bromide), tiotropium bromide (tiotropium bromide), 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 pharmacologically acceptable salt 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 pharmacologically acceptable salt 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 pharmacologically acceptable salt 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 pharmacologically acceptable salt 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 pharmacologically acceptable salt 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 pharmacologically acceptable salt 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 pharmacologically acceptable salt 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 pharmacologically acceptable salt 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 pharmacologically acceptable salt 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 pharmacologically acceptable salt 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 pharmacologically acceptable salt 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 NSAID (non-steroidal anti-inflammatory drug) that plays a role in maincenter or periphery.
The invention still further relates to the combination of The compounds of this invention or its pharmacologically acceptable salt 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 pharmacologically acceptable salt 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 hypotype 1 acceptor or kassinin kinin B hypotype 2 receptor antagonists; (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 hypotype 1 acceptor or tachykinin NK-1 hypotype 3 receptor antagonists, 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) on the TH2 cell, expressing (for example CRTH2 antagonist); (xxiv) p38 inhibitor; (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) non-steroidal glucocorticoid receptor (GR acceptor) agonist.
Another aspect of the present invention provides formula (I) compound and the combination (for example being used for the treatment of COPD, asthma or allergic rhinitis) that is selected from one or more medicines in the following listed material:
Non-steroidal glucocorticoid receptor (GR acceptor) agonist;
Selectivity β
2Adrenoceptor agonists, for example Metaprel (metaproterenol), Racemic isoproterenol (isoproterenol), isopropyl noradrenalin, salbutamol (albuterol), salbutamol, formoterol, Salmeterol, terbutaline, Orciprenaline, bitolterol mesilate, pirbuterol or indenes Da Teluo (indacaterol);
Muscarinic receptor antagonist (for example M1, M2 or M3 antagonist, for example selectivity M3 antagonist), for example ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine;
Chemokine receptor function conditioning agent (for example CCR1 receptor antagonist); Or
P38 kinase function inhibitor.
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, AZD 1839), 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.
Embodiment
Now explain the present invention by following non-limiting example, in these embodiments, except as otherwise noted:
(i) when providing,
1H NMR data are to quote with the δ value form of principal character proton, to provide with respect to 1,000,000/(ppm) of interior mark tetramethylsilane (TMS), except as otherwise noted, use the full deuterium DMSO-d in generation
6(CD
3SOCD
3) or CDCl
3As solvent, measure with 300MHz or 400MHz
1H NMR data;
(ii) mass spectrum (MS) carries out under the following conditions: electronic energy is that 70 electron-volts, pattern are chemi-ionization (CI), use and directly expose probe (direct exposure probe) that wherein said ionization realizes by electron-bombardment (EI) or fast atom bombardment(FAB) (FAB); Wherein provide the m/z value, the common only ion of report indication parent quality, except as otherwise noted, the mass ion of being quoted is a positive mass ion-(M+H)
+
(iii) use and be derived from Advanced Chemistry Development Inc, 6.00 editions index naming program, title compound and inferior title compound in name embodiment and the method;
(iv) except as otherwise noted, following method being used for LC/MS analyzes:
Instrument is Agilent 1100, and post is Waters Symmetry 2.1 * 30mm, and mass spectrum is APCI, flow velocity is 0.7mL/min, and wavelength is 254nm, and solvent orange 2 A is water+0.1%TFA, solvent B is acetonitrile+0.1%TFA, and gradient is 15-95%/B 2.7min, 95%B 0.3min;
(v) except as otherwise noted, following method being used for LC analyzes:
Method A: instrument is Agilent 1100, post is that Kromasil C18 100 * 3mm, granularity are 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, 100%B 1min, 220,254 and 280nm measure absorption value:
Method B: instrument is Agilent 1100, and post is that XTerra C8 100 * 3mm, granularity are 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%/B20min, 100%B 1min, 220,254 and 280nm measure absorption value:
(abbreviation below vi) using:
The starting raw material that uses in following examples was both commercially available, also can easily prepare from the method for known starting raw material by standard.For example following reaction descriptions the preparation of some starting raw materials.
The preparation method 1
2-[(3, the 4-difluorophenyl) amino]-the 5-fluorine nicotinic acid
Under argon gas atmosphere with 2-chloro-5-fluorine nicotinic acid (5.0g, 28.5mmol) and K
2CO
3(4.7g 34.2mmol) adds to dry DMF (10ml).Add copper (0.11g, 1.71mmol), with methanol wash then the exsiccant cuprous bromide (0.16g, 1.14mmol) and 3, (4.8ml's 4-difluoroaniline then 48.4mmol), stirs the mixture in 150 ℃ of oil baths.Determine that according to LC-MS product forms behind 1.5h.Mixture is inclined in 1M HCl, subsequent filtration precipitation, with 1M HCl washing, with described resolution of precipitate at saturated Na
2CO
3In the solution, use ethyl acetate extraction then.Organic phase Mg
2SO
4Drying, evaporation obtains title compound (5.3g, 69%) then.
APCI-MS m/z；269[MH
+]。
The preparation method 2
Suitable-4-[({2-[(3,4-difluorophenyl) amino]-5-fluorine pyridin-3-yl } carbonyl) amino] cyclohexyl } t-butyl carbamate
At CH
2Cl
2The middle 2-[(3 that stirs, the 4-difluorophenyl) amino]-5-fluorine nicotinic acid (0.56g, 2.09mmol), N-(3-dimethylamino-propyl)-N '-ethyl-carbodiimide hydrochloride (0.60g, 3.14mmol), 1-hydroxyl-7-azepine benzotriazole (0.43g, 3.14mmol) and N, the N-diisopropylethylamine (1.07ml, 6.27mmol).(0.49g 2.30mmol) adds to mixture with (suitable-the 4-aminocyclohexyl) t-butyl carbamate.Determine that according to LC-MS product forms behind 1h.Add ethyl acetate, wash mixture then with water.Make organic solvent evaporation.Go up the purifying crude product at silica filler (silica plug), use ethyl acetate/heptane (1 then; 1) wash-out obtains title compound (0.90g, 93%).
APCI-MS m/z；465.2[MH
+]。
The preparation method 3
Suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] and cyclohexyl } t-butyl carbamate
Under argon gas atmosphere with sodium hydride (55% oil solution; 0.80g, 18.21mmol) add to suitable-4-[({2-[(3,4-difluorophenyl) amino]-5-fluorine pyridin-3-yl } carbonyl) amino]-cyclohexyl } t-butyl carbamate (2.82g, anhydrous THF (10ml) solution 6.07mmol).Mixture is stirred 30min, then in cooled on ice.Add Vinyl chloroformate (2.92ml, 30.36mmol), then in 80 ℃ of oil baths with mixture heating up 40min.Add NH
4Cl solution is used the ethyl acetate extraction mixture then, makes the organic layer evaporation subsequently.Earlier by flash column chromatography [ethyl acetate/heptane (1; 4)] come the purifying crude product by HPLC (MeCN 70%-95%) again, obtain title compound (1.87g, 63%).
APCI-MS m/z；391.1[MH
+]。
1H NMR(300MHz，DMSO-d
6)δ8.59(d，1H)，8.30(m，1H)，7.65-7.55(m，2H)，7.33-7.27(m，1H)，6.54(s，1H)，4.73(t，1H)，3.55(s，1H)，2.57(d，2H)，1.90(d，2H)，1.54-1.43(m，4H)，1.39(s，9H)。
The preparation method 4
3-(suitable-the 4-aminocyclohexyl)-1-(3, the 4-difluorophenyl)-6-fluoro-1H-pyrido [2,3-c] [1,2,6] thiadiazines-4 (3H)-ketone 2-oxide compound
Under argon gas atmosphere, incite somebody to action suitable-4-[({2-[(3,4-difluorophenyl) amino]-5-fluorine pyridin-3-yl } carbonyl) amino] cyclohexyl } t-butyl carbamate (0.18g, 0.38mmol; According to preparation method's 2 preparations) be dissolved among the anhydrous THF (1ml).With sodium hydride (55% oil solution; 66mg 1.51mmol) adds to described solution, then mixture is stirred 0.5h.Make the mixture cooling then on ice, and the interpolation thionyl chloride (138 μ l, 1.89mmol), subsequently at 80 ℃ of backflow 1h.When determining that according to LC-MS product forms, add Na
2CO
3Solution is used the ethyl acetate extraction mixture then.Purifying on preparation property HPLC obtains title compound (25mg, 16%), and described title compound is reversed into starting raw material in water surrounding.
APCI-MS m/z；411[MH
+]。
The preparation method 5
5-fluoro-2-{[3-(methylthio group) phenyl] amino } nicotinic acid
Under argon gas atmosphere with 2-chloro-5-fluorine nicotinic acid (2.11g, 12mmol) and K
2CO
3(1.99g 14.4mmol) adds to anhydrous NMP (8ml).Add copper (46mg, 0.72mmol), the dry cuprous bromide crossed with methanol wash (86mg, 0.6mmol) and 3-(methylthio group) aniline (2.51ml 20.4mmol), stirs the mixture in 150 ℃ of oil baths then.Determine that according to LC-MS product forms behind 2h.Mixture is inclined in 1M HCl (20ml), and precipitation forms subsequently, filters, and with 1M HCl washing, washes with water, then 50 ℃ of vacuum-dryings, obtains title compound (1.72g, 52%).
APCI-MS m/z；279[MH
+]。
The preparation method 6
(suitable-4-{[(5-fluoro-2-{[3-(methylthio group) phenyl] amino } pyridin-3-yl) carbonyl] amino } cyclohexyl) t-butyl carbamate
In room temperature, with 5-fluoro-2-{[3-(methylthio group) phenyl] amino } nicotinic acid (1.72g, 6.2mmol), (suitable-the 4-aminocyclohexyl) t-butyl carbamate (1.46g, 6.8mmol), HATU (2.81g, 7.4mmol), HOAT (1.01mg, 7.4mmol) and DIEA (3.45ml, 20mmol) stirring of the mixture in NMP (20ml) 10min (pH is 8-9, regulates with DIEA).Add ethyl acetate, crude product 0.5M aqueous citric acid solution then, twice of sodium bicarbonate aqueous solution and water washing.Organic solvent Na
2SO
4Drying is filtered, and vacuum is removed organic solvent then.By using ethyl acetate/heptane (1; 2) the silica gel flash column chromatography as eluent comes the purifying resistates, obtains title compound (2g, 68%).
1H NMR(DMSO-d
6)；δ10.63(1H，s)；8.46(1H，d)；8.36(1H，d)；8.13(1H，dd)；7.63(1H，brs)；7.34(1H，d)；7.22(1H，t)；6.85(1H，d)；6.64(1H，brs)；3.84(1H，brs)；3.42(1H，brs)；2.47(3H，s)；1.73(4H，m)；1.56(4H，m)；1.39(9H，s)。
APCI-MS m/z；475[MH
+]。
LC (method A) rt=15.1min.
The preparation method 7
Suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } t-butyl carbamate
Under argon gas atmosphere with the oil solution (0.30g of 50%NaH, 6mmol) add to (suitable-4-{[(5-fluoro-2-{[3-(methylthio group) phenyl] amino }-pyridin-3-yl) carbonyl] amino } cyclohexyl) t-butyl carbamate (0.95g, anhydrous NMP (6ml) 2mmol) and anhydrous THF (3ml) mixing solutions.Mixture is stirred 30min, then in cooled on ice.(1.05ml 10mmol), with mixture heating up to 80 ℃, keeps 2h then to add Vinyl chloroformate.Add ethyl acetate, crude product 0.5M aqueous citric acid solution then, twice of sodium bicarbonate aqueous solution and water washing.Organic solvent Na
2SO
4Drying is filtered, and vacuum is removed organic solvent then.By using ethyl acetate/heptane (1; 2) the silica gel flash column chromatography as eluent comes the purifying resistates, obtains title compound (0.52g, 52%).
1H NMR(DMSO-d
6)；δ8.58(1H，d)；8.27(1H，dd)；7.45(1H，t)；7.34(1H，d)；7.30(1H，brs)；7.14(1H，d)；6.51(1H，brs)；4.74(1H，brt)；3.55(1H，brs)；2.57(2H，m)；2.47(3H，s)；1.90(2H，brd)；1.47(4H，m)；1.39(9H，s)。
APCI-MS m/z；401[MH
+-tBOC]。
LC (method A) rt=13.6min.
The preparation method 8
5-fluoro-2-{[3-(methoxycarbonyl) phenyl] amino } nicotinic acid
Under argon gas atmosphere with 2-chloro-5-fluorine nicotinic acid (2.11g, 12mmol) and K
2CO
3(1.99g 14.4mmol) adds to anhydrous NMP (8ml).Add copper (46mg, 0.72mmol), (86mg, 0.6mmol) (3.08ml 20.4mmol), stirs the mixture in 150 ℃ of oil baths then with the 3-Methyl anthranilate for the dry cuprous bromide crossed with methanol wash.Determine that according to LC-MS product forms behind 2h.Mixture is inclined in 1M HCl (20ml), and precipitation forms subsequently, filters, and with 1M HCl washing, washes with water, then 50 ℃ of vacuum-dryings, obtains title compound (2g, 57%).
APCI-MS m/z；291[MH
+]。
The preparation method 9
3-({ 3-[({ suitable-4-[(tert-butoxycarbonyl) amino] cyclohexyl } amino) carbonyl]-5-fluorine pyridine-2-yl } amino) methyl benzoate
In room temperature, with 5-fluoro-2-{[3-(methoxycarbonyl) phenyl] amino } nicotinic acid (2.91g, 10mmol), (suitable-the 4-aminocyclohexyl) t-butyl carbamate (2.57g, 12mmol), HATU (4.57g, 12mmol), HOAT (1.63mg, 12mmol) and DIEA (5.15ml, 30mmol) mixture in NMP (30ml) stirs 10min (pH is 8-9, regulates with DIEA).Add ethyl acetate, crude product 0.5M aqueous citric acid solution then, twice of sodium bicarbonate aqueous solution and water washing.Organic solvent Na
2SO
4Drying is filtered, and vacuum is removed organic solvent then.By using ethyl acetate/heptane (1; 2) the silica gel flash column chromatography as eluent comes the purifying resistates, obtains title compound (2.85g, 59%).
1H NMR(DMSO-d
6)；δ10.79(1H，s)；8.50(1H，d)；8.38(1H，d)；8.25(1H，brs)；8.16(1H，dd)；7.88(1H，d)；7.55(1H，d)；7.43(1H，t)；6.65(1H，brs)；3.86(4H，brs)；3.42(1H，brs)；1.74(4H，m)；1.56(4H，m)；1.39(9H，s)。
APCI-MS m/z；487[MH
+]。
LC (method A) rt=14.0min.
The preparation method 10
3-[3-{ is suitable-the 4-[(tert-butoxycarbonyl) and amino] cyclohexyl }-6-fluoro-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate
Under argon gas atmosphere with the oil solution (14mg of 50%NaH, 0.3mmol) and 1,1 '-carbonyl dimidazoles (50mg, 0.3mmol) add to 3-({ 3-[({ suitable-4-[(tert-butoxycarbonyl) amino] cyclohexyl-amino) carbonyl]-5-fluorine pyridine-2-yl } amino) methyl benzoate (50mg, anhydrous NMP (2ml) solution 0.1mmol).With mixture stirring at room one hour.Add ethyl acetate, crude product 0.5M aqueous citric acid solution then, twice of sodium bicarbonate aqueous solution and water washing.Organic solvent Na
2SO
4Drying is filtered, and vacuum is removed organic solvent then.Purifying on preparation property HPLC obtains title compound (40mg, 78%).
1H NMR(DMSO-d
6)；δ8.55(1H，d)；8.28(1H，dd)；8.04(1H，t)；8.01(1H，brs)；7.68(2H，brd)；4.74(1H，brt)；3.87(3H，s)；3.54(1H，brs)；2.57(2H，m)；1.90(2H，brd)；1.49(4H，m)；1.39(9H，s)。
APCI-MS m/z；413[MH
+-tBOC]。
LC (method A) rt=12.9min.
The preparation method 11
5-fluoro-2-{[3-(methylsulfonyl) phenyl] amino } nicotinic acid
Under argon gas atmosphere with 2-chloro-5-fluorine nicotinic acid (1.06g, 6mmol) and K
2CO
3(2.4g 17.4mmol) adds to anhydrous NMP (5ml).Add copper (23mg, 0.36mmol), the dry cuprous bromide crossed with methanol wash (43mg, 0.3mmol) and 3-(methylsulfonyl) anilinechloride (2.12ml 10.2mmol), stirs the mixture in 150 ℃ of oil baths then.Determine that according to LC-MS product forms behind 2h.Mixture is inclined in 1M HCl (20ml), and precipitation forms subsequently, filters, washs with 1M HCl, washes with water, then 50 ℃ of vacuum-dryings, obtains title compound (0.6g, 32%).
APCI-MS m/z；311[MH
+]。
The preparation method 12
(suitable-4-{[(5-fluoro-2-{[3-(methylsulfonyl) phenyl] amino } pyridin-3-yl) carbonyl] amino } cyclohexyl) t-butyl carbamate
In room temperature; with 5-fluoro-2-{[3-(methylsulfonyl) phenyl] amino } nicotinic acid (0.56g; 1.8mmol), (suitable-the 4-aminocyclohexyl) t-butyl carbamate (0.43g; 2mmol), HATU (0.823g; 2.17mmol), HOAT (0.3mg; 2.17mmol) and DIEA (0.93ml, 5.4mmol) stirring of the mixture in NMP (7ml) 10min (pH is 8-9, regulates with DIEA).Add ethyl acetate, crude product 0.5M aqueous citric acid solution then, twice of sodium bicarbonate aqueous solution and water washing.Organic solvent Na
2SO
4Drying is filtered, and vacuum is removed organic solvent then.By using ethyl acetate/heptane (1; 2) the silica gel flash column chromatography as eluent comes the purifying resistates, obtains title compound (0.38g, 42%).
1H NMR(DMSO-d
6)；δ10.91(1H，s)；8.52(1H，d)；8.41(1H，d)；8.26(1H，brs)；8.18(1H，dd)；7.93(1H，d)；7.55(1H，t)；7.48(1H，d)；6.65(1H，brs)；3.86(1H，brs)；3.43(1H，brs)；3.20(3H，s)；1.74(4H，m)；1.56(4H，m)；1.39(9H，s)。
APCI-MS m/z；507[MH
+]。
LC (method A) rt=11.8min.
The preparation method 13
Suitable-4-[6-fluoro-1-[3-(methylsulfonyl) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } t-butyl carbamate
Under argon gas atmosphere with the oil solution (99mg of 50%NaH; 2.07mmol) and 1; 1 '-carbonyl dimidazoles (336mg; 2.07mmol) add to (suitable-4-{[(5-fluoro-2-{[3-(methylsulfonyl) phenyl] amino }-pyridin-3-yl) carbonyl] amino } cyclohexyl) t-butyl carbamate (350mg, anhydrous NMP (10ml) solution 0.69mmol).With mixture stirring at room one hour.Add ethyl acetate, crude product 0.5M aqueous citric acid solution then, twice of sodium bicarbonate aqueous solution and water washing.Organic solvent Na
2SO
4Drying is filtered, and vacuum is removed organic solvent then.Purifying on preparation property HPLC obtains title compound (180mg, 49%).
1H NMR(DMSO-d
6)；δ8.57(1H，d)；8.30(1H，dd)；8.04(1H，d)；8.02(1H，brs)；7.82(1H，t)；7.77(1H，d)；4.74(1H，brt)；3.55(1H，brs)；3.28(3H，s)；2.58(2H，brd)；1.91(2H，brd)；1.49(4H，m)；1.39(9H，s)。
APCI-MS m/z；433[MH
+-tBOC]。
LC (method A) rt=11.2min.
The preparation method 14
A) 4-[({2-[(3, the 4-difluorophenyl) amino]-5-fluorine pyridin-3-yl } carbonyl) amino] piperidines-1-carboxylic acid tert-butyl ester
In room temperature, with 2-[(3, the 4-difluorophenyl) amino]-5-fluorine nicotinic acid (600mg, 2.3mmol), 4-amino piperidine-1-carboxylic acid tert-butyl ester (501mg, 2.5mmol), HATU (951mg, 2.5mmol), HOAT (340mg, 2.5mmol) and DIEA (1.17ml is 6.8mmol) at CH
2Cl
2Mixture (4ml) stirs 2h.Add CH
2Cl
2, crude product washs with sodium bicarbonate aqueous solution then, washes with water.Organic phase Na
2SO
4Drying is filtered, and vacuum is removed organic solvent then.Resistates is using ethyl acetate/heptane (1; 1), obtains title compound (660mg, 64%) as purifying on the silica filler of eluent.
APCI-MS m/z；451.5[MH
+]。
B) 4-[1-(3, the 4-difluorophenyl)-6-fluoro-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] piperidines-1-carboxylic acid tert-butyl ester
Under argon gas atmosphere with the oil solution (211mg of 50%NaH, 4.40mmol) add to 4-[({2-[(3, the 4-difluorophenyl) amino]-5-fluorine pyridin-3-yl } carbonyl) amino] piperidines-1-carboxylic acid tert-butyl ester (660mg, 1.47mmol) and 1,1 '-carbonyl dimidazoles (713mg, anhydrous NMP (5ml) solution 4.40mmol).With mixture in stirred overnight at room temperature.Add water, use the ethyl acetate extraction crude product then.Organic solvent Na
2SO
4Drying is filtered, and vacuum is removed organic solvent then.Resistates is using ethyl acetate/heptane (1; 2), obtain purity and be 90% title compound (524mg, 75%) as purifying on the silica filler of eluent.
APCI-MS m/z；377[MH
+]。
C) 1-(3, the 4-difluorophenyl)-6-fluoro-3-piperidin-4-yl pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-dione hydrochloride
In room temperature, with 4-[1-(3, the 4-difluorophenyl)-6-fluoro-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] piperidines-1-carboxylic acid tert-butyl ester (0.05g, 0.104mmol) and 4M HCl 1, mixture in the 4-diox (2ml) stirred one hour.Remove and desolvate, directly use pure crude product then.
APCI-MS m/z；377.1[MH
+]。
The preparation method 15
A) (3R)-3-[({2-[(3, the 4-difluorophenyl) amino]-5-fluorine pyridin-3-yl } carbonyl) amino] tetramethyleneimine-1-carboxylic acid tert-butyl ester
In room temperature, with 2-[(3, the 4-difluorophenyl) amino]-5-fluorine nicotinic acid (600mg, 2.3mmol), (3R)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (425 μ l, 2.5mmol), HATU (951mg, 2.5mmol), HOAT (340mg, 2.5mmol) and DIEA (1.17ml is 6.8mmol) at CH
2Cl
2Mixture (4ml) stirs 2h.Add CH
2Cl
2, crude product washs with sodium bicarbonate aqueous solution then, washes with water.Organic phase Na
2SO
4Drying is filtered, and vacuum is removed organic solvent then.Resistates is using ethyl acetate/heptane (1; 1), obtains title compound (613mg, 62%) as purifying on the silica filler of eluent.
APCI-MS m/z；437.5[MH
+]。
B) (3R)-and 3-[1-(3, the 4-difluorophenyl)-6-fluoro-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] tetramethyleneimine-1-carboxylic acid tert-butyl ester
Under argon gas atmosphere with the oil solution (202mg of 50%NaH, 4.21mmol) add to (3R)-3-[({2-[(3, the 4-difluorophenyl) amino]-5-fluorine pyridin-3-yl } carbonyl) amino] tetramethyleneimine-1-carboxylic acid tert-butyl ester (613mg, 1.40mmol) and 1,1 '-carbonyl dimidazoles (683mg, anhydrous NMP (3ml) solution 4.21mmol).With mixture in stirred overnight at room temperature.Add water, use the ethyl acetate extraction crude product then.Organic solvent Na
2SO
4Drying is filtered, and vacuum is removed organic solvent then.By using ethyl acetate/heptane (1; 2) silica filler as eluent comes the purifying resistates, obtains title compound (294mg, 45%).
APCI-MS m/z；363.2[MH
+]。
C) 1-(3, the 4-difluorophenyl)-6-fluoro-3-[(3R)-tetramethyleneimine-3-yl] pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-dione hydrochloride
In room temperature, with (3R)-3-[1-(3, the 4-difluorophenyl)-6-fluoro-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] tetramethyleneimine-1-carboxylic acid tert-butyl ester (0.053g, 0.114mmol) and 4M HCl 1, mixture in the 4-diox (2ml) stirred one hour.Remove and desolvate, directly use pure crude product then.
APCI-MS m/z；363.1[MH
+]。
The preparation method 16
A) (3S)-3-[({2-[(3, the 4-difluorophenyl) amino]-5-fluorine pyridin-3-yl } carbonyl) amino] tetramethyleneimine-1-carboxylic acid tert-butyl ester
In room temperature, with 2-[(3, the 4-difluorophenyl) amino]-5-fluorine nicotinic acid (600mg, 2.3mmol), (3S)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (425 μ l, 2.5mmol), HATU (951mg, 2.5mmol), HOAT (340mg, 2.5mmol) and DIEA (1.17ml is 6.8mmol) at CH
2Cl
2Mixture (4ml) stirs 2h.Add CH
2Cl
2, crude product washs with sodium bicarbonate aqueous solution then, washes with water.Organic phase Na
2SO
4Drying is filtered, and vacuum is removed organic solvent then.Resistates is using ethyl acetate/heptane (1; 1), obtains title compound (530mg, 53%) as purifying on the silica filler of eluent.
APCI-MS m/z；437.1[MH
+]。
B) (3S)-and 3-[1-(3, the 4-difluorophenyl)-6-fluoro-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] tetramethyleneimine-1-carboxylic acid tert-butyl ester
Under argon gas atmosphere with the oil solution (175mg of 50%NaH, 3.64mmol) add to (3S)-3-[({2-[(3, the 4-difluorophenyl) amino]-5-fluorine pyridin-3-yl } carbonyl) amino] tetramethyleneimine-1-carboxylic acid tert-butyl ester (530mg, 1.21mmol) and 1,1 '-carbonyl dimidazoles (590mg, anhydrous NMP (3ml) solution 3.64mmol).With mixture in stirred overnight at room temperature.Add water, use the ethyl acetate extraction crude product then.Organic phase Na
2SO
4Drying is filtered, and vacuum is removed organic solvent then.By using ethyl acetate/heptane (1; 3) silica filler as eluent comes the purifying resistates, obtains purity and be 85% title compound (500mg, 89%), is oily matter.
APCI-MS m/z；363[MH
+。
C) 1-(3, the 4-difluorophenyl)-6-fluoro-3-[(3S)-tetramethyleneimine-3-yl] pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-dione hydrochloride
In room temperature, with (3S)-3-[1-(3, the 4-difluorophenyl)-6-fluoro-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] tetramethyleneimine-1-carboxylic acid tert-butyl ester (0.08g, 0.17mmol) and 4M HCl 1, mixture in the 4-diox (2ml) stirred one hour.Remove and desolvate, directly use pure crude product then.
APCI-MS m/z；363[MH
+]。
The preparation method 17
3-(suitable-the 4-aminocyclohexyl)-1-(3, the 4-difluorophenyl)-6-fluoro-1H-pyrido [2,3-c] [1,2,6] thiadiazines-4 (3H)-ketone 2-oxide compound
Under argon gas atmosphere, incite somebody to action suitable-4-[({2-[(3,4-difluorophenyl) amino]-5-fluorine pyridin-3-yl } carbonyl) amino] cyclohexyl } (175mg 0.38mmol) is dissolved among the anhydrous THF (1ml) t-butyl carbamate.(66mg 1.5mmol), stirs 0.5h with mixture to the oil solution of interpolation 55%NaH then.Make mixture cooling on ice, add then thionyl chloride (138 μ l, 1.9mmol), subsequently at 80 ℃ of backflow 1h.When determining that according to LC-MS reaction is finished, add Na
2CO
3(aqueous solution) uses the ethyl acetate extraction mixture then.Purifying on preparation property HPLC obtains title compound (25mg, 16%).
APCI-MS m/z；411[MH
+]。
Embodiment 1
Present embodiment explain N-{ suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl-preparation method of 2-hydroxyl-5-(methylol) benzamide.
Step a:3-(suitable-the 4-aminocyclohexyl)-1-(3, the 4-difluorophenyl)-6-fluorine pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-dione hydrochloride
In room temperature, with { suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } t-butyl carbamate (98mg, 0.2mmol) and 4M HCl 1, mixture in the 4-diox (2mL) stirred one hour.Remove and desolvate, in next procedure, directly use pure crude product then.
APCI-MS m/z；391[MH
+]。
Step b:N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-5-(methylol) benzamide
In room temperature, with 3-(suitable-the 4-aminocyclohexyl)-1-(3, the 4-difluorophenyl)-6-fluorine pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-dione hydrochloride (85mg, 0.2mmol), 2-hydroxyl-5-(methylol) phenylformic acid (45mg, 0.26mmol), HATU (100mg, 0.26mmol), HOAT (36mg, 0.26mmol) and DIEA (200 μ L, 1.16mmol) stirring of the mixture in NMP (3.5mL) 10min (pH is 8-9).Add ethyl acetate, crude product in solution sodium bicarbonate aqueous solution then, twice of 0.5M aqueous citric acid solution and water washing.Organic solution Na
2SO
4Drying is filtered, then solvent removed in vacuo.HPLC comes the purifying resistates by preparation property, obtains title compound (46mg, 43%).
1H NMR(400MHz，DMSO-d
6)；δ11.66(1H，s)；8.61(1H，s)；8.59(1H，d)；8.31(1H，dd)；7.92(1H，d)；7.65-7.56(2H，m)；7.31(2H，m)；6.91(1H，d)；4.84(1H，t)；4.40(2H，s)；4.16(1H，m)；3.36(1H，m)；2.69-2.53(2H，m)2.00；(2H，m)；1.74-1.58(4H，m)。
APCI-MS m/z；541[MH
+]。
LC (method A) rt=10.5min.
Embodiment 2 to 45
According to the synthetic following compound of the method for in embodiment 1, describing.
| Embodiment | Compound | 1H NMR | m/z |
| Embodiment | Compound | 1H NMR | m/z |
| 2 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-2-phenyl-acetamides | (400MHz，DMSO-d 6)δ8.60(d，1H)， 8.35(dd，1H)，7.66-7.59(m，3H)，7.44(d， 2H)，7.34-7.23(m，4H)，4.96(s，1H)，4.80(t， 1H)，3.91(s，1H)，2.57(d，1H)， *(1H is in solvent peak), and 1.85-1.77 (m, 2H), 1.65-1.55 (m, 4H) | 525.2 |
| 3 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-hydroxyl acetamide | (400MHz，DMSO-d 6)δ8.60(d，1H)， 8.33(dd，1H)，7.64-7.57(m，2H)， 7.31-7.29(m，1H)，4.80(t，1H)，3.99(s，1H)， 3.81(s，2H)， *(2H is in solvent peak), 1.81 (d, 2H), 1.66-1.56 (m, 4H) | 449.2 |
| 4 | 5-chloro-N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-hydroxybenzamide | (400MHz，DMSO-d 6)δ8.63-8.59(m，2H)， 8.31(dd，1H)，7.98(d，1H)，7.64-7.57(m， 2H)，7.42(dd，1H)，7.32-7.29(m，1H)， 7.00(d，1H)，4.84(t，1H)，4.15(s，1H)， 2.67-2.55(m，2H)，2.00(d，2H)，1.72-1.60(m， 4H) | 545.2， 547.1 |
| 5 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 3-hydroxybenzamide | (500MHz，DMSO-d 6)δ9.59(s，1H)，8.56(d， 1H)，8.29(dd，1H)，7.77(d，1H)， 7.60-7.54(m，2H)，7.29-7.18(m，4H)， 6.87(dt，1H)，4.78(t，1H)，3.92(s，1H)， 2.71-2.66(m，1H)， *(1H is in solvent peak), 2.06 (d, 2H), 1.60-1.46 (m, 4H) | 511.1 |
| 6 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 4-hydroxybenzamide | (500MHz，DMSO-d 6)δ9.88(s，1H)，8.56(d， 1H)，8.30(dd，1H)，7.70(d，2H)， 7.60-7.54(m，3H)，7.29-7.26(m，1H)，6.76(d， 2H)，4.78(t，1H)，3.92(s，1H)，2.72-2.66(m， 1H)， *(1H is in solvent peak), 2.05 (d, 2H), 1.60-1.45 (m, 4H) | 511.1 |
| 7 | 2-[({ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } amino) carbonyl]-methyl benzoate | (500MHz，DMSO-d 6)δ8.55(d，1H)， 8.26(dd，1H)，8.22(d，1H)，7.73(dd，1H)， 7.60-7.48(m，4H)，7.46(d，1H)，7.28-7.24(m， 1H)，4.75(t，1H)，3.92(s，1H)，3.69(s，3H)， 2.72-2.66(m，1H)， *(1H is in solvent peak), 2.03 (d, 2H), 1.60-1.45 (m, 4H) | 553.1， 554.2 |
| 8 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-(4-hydroxy phenyl) ethanamide | (500MHz，DMSO-d 6)δ8.57(d，1H)， 8.28(dd，1H)，7.78(d，1H)，7.61-7.55(m， 2H)，7.31-7.26(m，1H)，7.05(d，2H)，6.61(d， 2H)，4.71(t，1H)，3.73(s，1H)， *(4H is in solvent peak), 1.84 (d, 2H), 1.54-1.42 (m, 4H) | 525.2， 526.2 |
| 9 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxy-4-methyl benzamide | (500MHz，DMSO-d 6)δ11.83(s，1H)， 8.56(d，1H)，8.43(d，1H)，8.27(dd，1H)， 7.82(d，1H)，7.60-7.55(m，2H)，7.27(d，1H)， 6.71-6.68(m，2H)，4.79(t，1H)，4.09(s，1H)， *(2H is in solvent peak), 2.23 (s, 3H), 1.98 (d, 2H), 1.67-1.53 (m, 4H) | 525.1， 526.1 |
| 10 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-hydroxybenzamide | (500MHz，DMSO-d 6)δ11.81(s，1H)， 8.57-8.54(m，2H)，8.27(dd，1H)，7.92(dd， 1H)，7.60-7.54(m，2H)，7.35-7.31(m，1H)， 7.27(d，1H)，6.92-6.86(m，2H)，4.80(t，1H)， 4.11(s，1H)， *(2H is in solvent peak), 1.97 (d, 2H), 1.67-1.55 (m, 4H) | 511.1， 513.1 |
| Embodiment | Compound | 1H NMR | m/z |
| 11 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-3-pyridone-2-methane amide | (500MHz，DMSO-d 6)δ12.32(s，1H)， 8.56(d，1H)，8.44(d，1H)，8.31(dd，1H)， 8.17(dd，1H)，7.61-7.51(m，3H)，7.41(dd， 1H)，7.29-7.25(m，1H)，4.82(t，1H)，4.15(s， 1H)， *(2H is in solvent peak), 1.99 (d, 2H), 1.72 (t, 2H), 1.62 (d, 2H) | 512.2 |
| 12 | 3-chloro-N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 4-hydroxybenzamide | (500MHz，DMSO-d 6)δ10.69(s，1H)， 8.56(d，1H)，8.29(dd，1H)，7.91(d，1H)， 7.77(d，1H)，7.65(dd，1H)，7.59-7.54(m， 2H)，7.29-7.25(m，1H)，6.96(d，1H)，4.79(t， 1H)，3.90(s，1H)， *(2H is in solvent peak), 2.06 (d, 2H), 1.59-1.47 (m, 4H) | 545， 547.1 |
| 13 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-3-hydroxy-2-methyl benzamide | (500MHz，DMSO-d 6)δ9.39(s，1H)，8.55(d， 1H)，8.26(dd，1H)，7.94(d，1H)， 7.59-7.53(m，2H)，7.28-7.24(m，1H)，6.97(t， 1H)，6.79(d，1H)，6.72(d，1H)，4.74(t，1H)， 3.92(s，1H)，2.70-2.66(m，1H)， *(1H is in solvent peak), 2.09 (s, 3H), 2.02 (d, 2H), 1.56 (t, 2H), 1.47 (d, 2H) | 525.2， 526.1 |
| 14 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-4-hydroxy 3-methoxybenzene methane amide | (500MHz，DMSO-d 6)δ9.44(s，1H)，8.56(d， 1H)，8.29-8.26(m，1H)，7.60-7.55(m，3H)， 7.37(s，1H)，7.32-7.25(m，2H)，6.77(d，1H)， 4.82(t，1H)，3.91(s，1H)，3.68(s，3H)， *(2H is in solvent peak), 2.06 (d, 2H), 1.58-1.46 (m, 4H) | 541.1 |
| 15 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-3-hydroxy-4-methyl benzamide | (500MHz，DMSO-d 6)δ9.47(s，1H)，8.56(d， 1H)，8.29(dd，1H)，7.64(d，1H)， 7.60-7.54(m，2H)，7.29-7.24(m，1H)， 7.23-7.20(m，2H)，7.09(d，1H)，4.78(t，1H)， 3.93(s，1H)， *(2H is in solvent peak), 2.15 (s, 3H), 2.05 (d, 2H), 1.60-1.46 (m, 4H) | 525.1 |
| 16 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-6-methoxy benzamide | (500MHz，DMSO-d 6)δ13.90(s，1H)， 8.94(s，1H)，8.57(d，1H)，8.31(dd，1H)， 7.60-7.55(m，2H)，7.33-7.28(m，2H)，6.59(d， 1H)，6.49(d，1H)，4.83(t，1H)，4.28(s，1H)， 3.53(s，3H)， *(2H is in solvent peak), 1.85 (d, 2H), 1.73-1.61 (m, 4H) | 541.1， 542.2 |
| 17 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxy 3-methoxybenzene methane amide | (500MHz，DMSO-d 6)δ11.86(s，1H)， 8.55(d，1H)，8.36-8.27(m，2H)，7.60-7.48(m， 3H)，7.26(d，1H)，7.08(d，1H)，6.81(t，1H)， 4.79(t，1H)，4.04(s，1H)，3.76(s，3H)， *(2H is in solvent peak), 2.02 (s, 2H), 1.67-1.49 (m, 4H) | 541.1 |
| 18 | 4-chloro-N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-hydroxybenzamide | (500MHz，DMSO-d 6)δ12.22-12.20(m， 1H)，8.56-8.50(m，2H)，8.27(dd，3.1Hz， 1H)，7.94(d，1H)，7.60-7.54(m，2H)， 7.29-7.26(m，1H)，6.99-6.95(m，2H)，4.80(t， 1H)，4.12(s，1H)， *(2H is in solvent peak), 1.95 (d, 2H), 1.69-1.55 (m, 4H) | 545 |
| 19 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-4-methoxy benzamide | (500MHz，DMSO-d 6)δ12.27-12.25(m，1H)， 8.56(d，1H)，8.29-8.23(m，2H)，7.88(d，1H)， 7.60-7.55(m，2H)，7.28-7.26(m，1H)， 6.48-6.45(m，1H)，6.42(t，1H)，4.79(t，1H)， 4.06(s，1H)，3.73(s，3H)， *(2H is in solvent peak), 1.99 (d, 2H), 1.65-1.53 (m, 4H) | 541.1 |
| Embodiment | Compound | 1H NMR | m/z |
| 20 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-5-fluoro-2-hydroxybenzamide | (500MHz，DMSO-d 6)δ11.70-11.68(m，1H)， 8.67-8.62(m，1H)，8.56(d，1H)，8.27(dd， 1H)，7.71-7.67(m，1H)，7.60-7.54(m，2H)， 7.29-7.19(m，2H)，6.96-6.93(m，1H)，4.80(t， 1H)，4.12(s，1H)， *(2H is in solvent peak), 1.95 (d, 2H), 1.68-1.57 (m, 4H) | 529.1， 530.2 |
| 21 | (2S)-and N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxy-4-methyl valeramide | (500MHz，DMSO-d 6)δ8.56(d，1H)， 8.28(dd，1H)，7.60-7.54(m，2H)，7.35(d， 1H)，7.29-7.25(m，1H)，4.76(t，1H)，3.91(s， 1H)，3.85(dd，1H)， *(2H is in solvent peak), and 1.78-1.70 (m, 3H), 1.61-1.51 (m, 4H), 1.45-1.39 (m, 1H), 1.37-1.30 (m, 1H), 0.85-0.82 (m, 6H) | 505.1 |
| 22 | (2R)-and 2-cyclohexyl-N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-hydroxyl acetamide | (500MHz，DMSO-d 6)δ8.56(d，1H)， 8.29(dd，1H)，7.60-7.54(m，2H)，7.35(d， 1H)，7.27-7.25(m，1H)，4.76(t，1H)，3.93(s， 1H)，3.66(d，1H)， *(2H is in solvent peak), 1.74 (t, 2H), 1.66-1.49 (m, 9H), 1.39-1.30 (m, 1H), 1.21-0.94 (m, 5H) | 531.2 |
| 23 | 4-(suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] and cyclohexyl } amino)-4-ketobutyric acid methyl esters | (500MHz，DMSO-d 6)δ8.56(d，1H)， 8.27(dd，1H)，7.70(d，1H)，7.60-7.54(m， 2H)，7.28-7.25(m，1H)，4.70(t，1H)，3.74(s， 1H)，3.53(s，3H)， *(6H is in solvent peak), 1.83 (d, 2H), 1.51-1.43 (m, 4H) | 505.1 |
| 24 | N-[2-(suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] and cyclohexyl } amino)-the 2-oxoethyl]-the 2-hydroxybenzamide | (500MHz，DMSO-d 6)δ12.15-12.14(m，1H)， 8.99-8.95(m，1H)，8.56(d，1H)，8.23-8.20(m， 1H)，7.87-7.83(m，2H)，7.60-7.54(m，2H)， 7.36(t，1H)，7.29-7.25(m，1H)，6.89-6.83(m， 2H)，4.73(t，1H)，3.96(d，2H)，3.84(s，1H)， *(2H is in solvent peak), 1.85 (d, 2H), 1.57-1.47 (m, 4H) | 568.1 |
| 25 | 4-[({ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } amino) carbonyl]-methyl benzoate | (500MHz，DMSO-d 6)δ8.56(d，1H)， 8.30(dd，3.0Hz，1H)，8.16(d，1H)，8.00(d， 2H)，7.94(d，2H)，7.60-7.54(m，2H)， 7.29-7.25(m，1H)，4.79(t，1H)，3.96(s，1H)， 3.85(s，3H)，2.72-2.66(m，1H)， *(1H is in solvent peak), 2.09 (d, 2H), 1.63-1.46 (m, 4H) | 553.1 |
| 26 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-3-hydroxyl-4-methoxy benzamide | (500MHz，DMSO-d 6)δ9.12(s，1H)，8.55(d， 1H)，8.29(dd，1H)，7.60-7.54(m，3H)， 7.32(dd，1H)，7.29-7.26(m，2H)，6.93(d， 1H)，4.78(t，1H)，3.92(s，1H)，3.78(s，3H)， *(2H is in solvent peak), 2.05 (d, 2H), 1.58-1.48 (m, 4H) | 541.1 |
| 27 | 5-(suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] and cyclohexyl } amino)-5-oxopentanoic acid methyl esters | (500MHz，DMSO-d 6)δ8.55(d，1H)， 8.26(dd，1H)，7.63(d，1H)，7.60-7.54(m， 2H)，7.28-7.25(m，1H)，4.70(t，1H)，3.75(s， 1H)，3.53(s，3H)， *(2H is in solvent peak), 2.26 (t, 2H), 2.13 (t, 2H), 1.84 (d, 2H), 1.70 (q, 2H), 1.52-1.43 (m, 4H) | 519.1 |
| Embodiment | Compound | 1H NMR | m/z |
| 28 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-(3-hydroxy phenyl) ethanamide | (500MHz，DMSO-d 6)δ8.56(d，1H)， 8.28(dd，1H)，7.87(d，1H)，7.60-7.55(m， 2H)，7.29-7.26(m，1H)，7.00(t，1H)，6.68(d， 1H)，6.65(s，1H)，6.54(dd，1.7Hz，1H)， 4.71(t，1H)，3.76(s，1H)， *(4H is in solvent peak), 1.84 (d, 2H), 1.53-1.44 (m, 4H) | 525.1， 527.1 |
| 29 | 3-[({ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } amino) carbonyl]-methyl benzoate | (500MHz，DMSO-d 6)δ8.56(d，1H)，8.39(s， 1H)，8.29(dd，1H)，8.18(d，1H)，8.08(dd， 2H)，7.61-7.54(m，3H)，7.28-7.26(m，1H)， 4.80(t，1H)，3.96(s，1H)，3.83(s，3H)， *(1H is in solvent peak), 2.72-2.66 (m, 1H), 2.10 (d, 2H), 1.59 (t, 2H), 1.51 (d, 2H) | 553.1 |
| 30 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-fluoro-6-hydroxybenzamide | (500MHz，DMSO-d 6)δ11.29(s，1H)， 8.55(d，1H)，8.27(dd，3.0Hz，1H)，8.00(t， 1H)，7.59-7.53(m，2H)，7.29-7.23(m，2H)， 6.71-6.66(m，2H)，4.76(t，1H)，4.07(s，1H)， *(2H is in solvent peak), 1.96 (d, 2H), 1.62 (t, 2H), 1.53 (d, 2H) | 529.1 |
| 31 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-3-(3-hydroxy phenyl) propionic acid amide | (500MHz，DMSO-d 6)δ8.55(d，1H)， 8.27(dd，1H)，7.64(d，1H)，7.59-7.53(m， 2H)，7.28-7.26(m，1H)，6.99(t，1H)， 6.59-6.56(m，2H)，6.51(dd，1H)，4.70(t，1H)， 3.77(s，1H)，2.69-2.66(m，1H)， *(4H is in solvent peak), 2.39-2.36 (m, 1H), 1.83 (d, 2H), 1.53-1.42 (m, 4H) | 539.1 |
| 32 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1H-indazole-3-methane amide | (500MHz，DMSO-d 6)δ13.54(s，1H)， 8.56(d，1H)，8.31(dd，1H)，8.14(d，1H)， 7.60-7.55(m，4H)，7.39(dd，1H)， 7.29-7.27(m，1H)，7.21(t，1H)，4.83(t，1H)， 4.20(s，1H)， *(2H is in solvent peak), 1.98 (d, 2H), 1.68 (t, 2H), 1.61 (d, 2H) | 535.1 |
| 33 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } imidazo [1,2-a] pyridine-2-carboxamide | (500MHz，DMSO-d 6)δ8.65(d，1H)，8.56(d， 1H)，8.49(s，1H)，8.30(dd，1H)，7.90(s，1H)， 7.68(d，1H)，7.60-7.54(m，2H)，7.46(t，1H)， 7.28-7.26(m，1H)，7.08(t，1H)，4.81(t，1H)， 4.11(s，1H)， *(2H is in solvent peak), 2.00 (d, 2H), 1.68 (t, 2H), 1.59 (d, 2H) | 535.1 |
| 34 | 5-chloro-N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-hydroxybenzamide | (500MHz，DMSO-d 6)δ12.00(s，1H)， 8.64(d，1H)，8.54(d，1H)，8.24(dd 1H)， 7.93(d，1H)，7.42(t，1H)，7.37(dd，1H)， 7.30(d，1H)，7.27(t，1H)，7.11(dd，1H)， 6.95(d，1H)，4.80(t，1H)，4.12(s，1H)， *(5H is in solvent peak), 1.95 (d, 2H), 1.68-1.57 (m, 4H) | 555.1， 557.1 |
| 35 | N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxy-5-methyl yl-benzamide | (500MHz，DMSO-d 6)δ11.51(s，1H)， 8.54(d，1H)，8.52(d，1H)，8.24(dd，1H)， 7.72(d，1H)，7.42(t，1H)，7.31-7.29(m，1H)， 7.27(t，1H)，7.14-7.10(m，2H)，6.80(d，1H)， 4.81(t，1H)，4.11(s，1H)， *(5H is in solvent peak), 2.18 (s, 3H), 1.95 (d, 2H), 1.67-1.56 (m, 4H) | 535.1 |
| Embodiment | Compound | 1H NMR | m/z |
| 36 | N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-5-(methylol) benzamide | (500MHz，DMSO-d 6)δ11.61(d，1H)， 8.59(d，1H)，8.54(d，1H)，8.24(dd，1H)， 7.88(d，1H)，7.42(t，1H)，7.31-7.26(m，3H)， 7.11(dd，1H)，6.88(d，1H)，5.06(t，1H)， 4.80(t，1H)，4.37(d，2H)，4.13(s，1H)， *(5H is in solvent peak), 1.95 (d, 2H), 1.68-1.57 (m, 4H) | 533.2， 551.2 |
| 37 | (2R)-and N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-2-phenyl-acetamides | (500MHz，DMSO-d 6)δ8.55(d，1H)， 8.28(dd，1H)，7.60(d，1H)，7.45-7.39(m， 3H)，7.31-7.19(m，5H)，7.12(dd，1H)，4.92(s， 1H)，4.77(t，1H)，3.87(s，1H)， *(5H is in solvent peak), and 1.82-1.72 (m, 2H), 1.60-1.53 (m, 4H) | 535.1， 536.2 |
| 38 | (2S)-and N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-2-phenyl-acetamides | (500MHz，DMSO-d 6)δ8.55(d，1H)， 8.28(dd，1H)，7.60(d，1H)，7.45-7.39(m， 3H)，7.32-7.19(m，5H)，7.13(d，1H)，4.92(s， 1H)，4.77(t，1H)，3.87(s，1H)， *(5H is in solvent peak), and 1.81-1.73 (m, 2H), 1.60-1.52 (m, 4H) | 535.1 |
| 39 | N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-hydroxyl acetamide | (500MHz，DMSO-d 6)δ8.54(d，1H)， 8.26(dd，1H)，7.42(t，1H)，7.31-7.26(m，3H)， 7.11(dd，1H)，4.77(t，1H)，3.96(s，1H)， 3.78(s，2H)， *(5H is in solvent peak), 1.77 (d, 2H), 1.61-1.53 (m, 4H) | 459.1 |
| 40 | 5-chloro-N-{ is suitable-4-[6-fluoro-1-[3-(methylsulfonyl) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-hydroxybenzamide | (500MHz，DMSO-d 6)δ12.01(s，1H)， 8.63(d，1H)，8.53(d，1H)，8.27(dd，1H)， 8.02-7.99(m，2H)，7.94(d，1H)，7.81-7.74(m， 2H)，7.37(dd，1H)，6.95(d，1H)，4.80(t，1H)， 4.11(s，1H)， *(5H is in solvent peak), 1.96 (d, 2H), 1.68-1.58 (m, 4H) | 587 |
| 41 | N-{ is suitable-4-[6-fluoro-1-[3-(methylsulfonyl) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-5-(methylol) benzamide | (500MHz，DMSO-d 6)δ11.64(s，1H)， 8.58(d，1H)，8.53(d，1H)，8.27(dd，1H)， 8.02-7.99(m，2H)，7.88(d，1H)，7.81-7.74(m， 2H)，7.27(dd，1H)，6.87(d，1H)，4.80(t，1H)， 4.37(d，2H)，4.13(s，1H)， *(5H is in solvent peak), 1.96 (d, 2H), 1.68-1.59 (m, 4H) | 565.1， 583.1 |
| 42 | (2R)-and N-{ is suitable-4-[6-fluoro-1-[3-(methylsulfonyl) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-2-phenyl-acetamides | (500MHz，DMSO-d 6)δ8.54(d，1H)， 8.31(dd，1H)，8.03-8.01(m，2H)， 7.82-7.75(m，2H)，7.60(d，1H)，7.40(d，2H)， 7.27-7.19(m，3H)，4.92(s，1H)，4.77(t，1H)， 3.87(s，1H)， *(5H is in solvent peak), and 1.80-1.74 (m, 2H), 1.61-1.52 (m, 4H) | 567.1 |
| 43 | (2S)-and N-{ is suitable-4-[6-fluoro-1-[3-(methylsulfonyl) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-2-phenyl-acetamides | (500MHz，DMSO-d 6)δ8.54(d，1H)， 8.31(dd，1H)，8.03-8.01(m，2H)， 7.82-7.75(m，2H)，7.60(d，1H)，7.40(d，2H)， 7.27-7.19(m，3H)，4.92(s，1H)，4.77(t，1H)， 3.87(d，1H)， *(5H is in solvent peak), and 1.80-1.73 (m, 2H), 1.59-1.52 (m, 4H) | 567.2 |
| 44 | N-{ is suitable-4-[6-fluoro-1-[3-(methylsulfonyl) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-hydroxyl acetamide | (500MHz，DMSO-d 6)δ8.53(d，1H)， 8.29(dd，1H)，8.02-7.98(m，2H)， 7.81-7.73(m，2H)，7.29(d，1H)，4.77(t，1H)， 3.96(s，1H)，3.78(s，2H)， *(5H is in solvent peak), 1.77 (d, 2H), 1.62-1.55 (m, 4H) | 491.2 |
| Embodiment | Compound | 1H NMR | m/z |
| 45 | 3-[6-fluoro-3-{ is suitable-4-[(2-hydroxy-5-methyl base benzoyl) and amino] cyclohexyl }-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate | (400MHz，DMSO-d 6)δ8.55(d，1H)，8.50(d， 1H)，8.29(dd，1H)，8.05-8.02(m，2H)，7.75(s， 1H)，7.69(d，2H)，7.16(d，1H)，6.83(d，1H)， 4.85(t，1H)，4.14(s，1H)，3.86(s，3H)， 2.68-2.55(m，2H)，2.20(s，3H)，1.99(d，2H)， 1.70-1.61(m，4H) | 547.1 |
Embodiment 46
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro-3H-pyrido [2,3-c] [1,2,6] thiadiazine-3-yl] cyclohexyl }-2-hydroxy-5-methyl yl-benzamide
According to embodiment 1 preparation title compound, step b begins from 3-(suitable-the 4-aminocyclohexyl)-1-(3, the 4-difluorophenyl)-6-fluoro-1H-pyrido [2,3-c] [1,2,6] thiadiazines-4 (3H)-ketone 2-oxide compound.
1H NMR(400MHz，DMSO-d
6)δ11.69(s，1H)，8.67(d，1H)，8.52-8.45(m，1H)，8.40(dd，1H)，7.71-7.63(m，3H)，7.39-7.35(m，1H)，7.18(d，1H)，6.82(d，1H)，4.54(t，1H)，4.13(s，1H)，2.24(s，3H)，2.12-1.93(m，5H)，1.84-1.74(m，3H)。
APCI-MS m/z；545.1[MH
+]。
Embodiment 47
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } Toluidrin
Step a:3-(suitable-the 4-aminocyclohexyl)-1-(3, the 4-difluorophenyl)-6-fluorine pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-dione hydrochloride
In room temperature, with { suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } t-butyl carbamate (98mg, 0.2mmol) and 4M HCl 1, mixture in the 4-diox (2mL) stirred one hour.Remove and desolvate, directly use crude product then.
APCI-MS m/z；391[MH
+]。
Step b:N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } Toluidrin
With 3-(suitable-the 4-aminocyclohexyl)-1-(3, the 4-difluorophenyl)-6-fluorine pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-(25mg 0.051mmol) is dissolved in the pyridine (500 μ l) dione hydrochloride, add then methylsulfonyl chloride (150 μ l, 1.93mmol).Stir the mixture at 60 ℃, product forms behind 1h.After by preparation property HPLC purifying, obtain title compound (8mg, 33%).
1H NMR(400MHz，DMSO-d
6)δ8.59(d，1H)，8.30(dd，1H)，7.64-7.57(m，2H)，7.32-7.29(m，1H)，4.74(t，1H)，3.51(s，1H)，2.90(s，3H)，2.73-2.64(m，2H)，1.91(d，2H)，1.58(t，2H)，1.48(d，2H)。
APCI-MS m/z；469[MH
+]。
Embodiment 48 to 75
By being similar to the synthetic following compound of the method for in embodiment 1, describing.
| Embodiment | Compound | 1H NMR | m/z |
| 48 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } cyclopropane carboxamide | (400MHz，DMSO-d 6)；δ8.60(1H，d)； 8.32(1H，dd)；7.88(1H，d)；7.65-7.57(2H， m)；7.31(1H，m)；4.75(1H，t)；3.78(1H， s)；2.64(2H，q)；1.90(2H，d)；1.76(1H， m)1.59-1.46(4H，m)；0.63(4H，m). | 459 |
| 49 | 3-[6-fluoro-3-{ is suitable-4-[(1-methyl-L-prolyl) and amino] cyclohexyl }-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate | (400MHz，DMSO-d 6)；δ8.55(1H，d)； 8.29(1H，dd)；8.04(1H，dt)；8.01(1H， brs)；7.69(2H，brd)；7.65(1H，brd)； 4.78(1H，brt)；3.90(1H，brs)；3.87(3H，s)； 3.05(1H，brs)；2.74(1H，m)； *(2H is in solvent peak); 2.33 (3H, s); 2.27 (1H, q); 2.07 (1H, m); 1.83 (2H, t); 1.73-1.54 (7H, m). | 524 |
| 50 | 5-[({ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } amino) carbonyl] the pyridine-2-carboxylic acids methyl esters | (500MHz，DMSO-d 6)；δ9.15(1H，d)； 8.60(1H，d)；8.50(1H，dd)；8.42(1H，d)； 8.35(1H，dd)；8.20(1H，d)；7.64-7.58(2H， m)；7.31(1H，d)；4.86(1H，t)；4.18(1H，s)； 3.93(3H，s)；2.59(2H，d)；2.02(2H，d)； 1.74(2H，s)；1.64(2H，d). | 554.1 |
| 51 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-4-fluoro-2-hydroxybenzamide | (400MHz，DMSO-d 6)；δ8.60(1H，d)； 8.31(1H，m)；8.05-7.98；(1H，m)； 7.65-7.57(2H，m)；7.32-7.29(1H，m)； 6.73(2H，s)；4.83(1H，t)；4.13(1H，s)； 2.61(2H，d)；2.00(2H，d)；1.71-1.59(4H， m). | 529.1 |
| 52 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1-hydroxyl cyclopropane carboxamide | (400MHz，DMSO-d 6)；δ8.60(1H，d)； 8.33(1H，dd)；7.64-7.57(2H，m)； 7.41(1H，d)；7.32-7.29(1H，m)；4.82(1H， t)；4.00(1H，s)；1.81-1.78(2H，m)； 1.68-1.59(4H，m)；1.03(2H，q)；0.85(2H， q). | 475.1 |
| 53 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } quinoline-8-methane amide | (400MHz，DMSO-d 6)；δ11.91(1H，d)； 9.21(1H，s)；8.66(1H，d)；8.62-8.59(2H， m)；8.41(1H，dd)；8.22(1H，d)；7.77(1H， t)；7.68-7.60(3H，m)；7.37-7.34(1H，m)； 4.90(1H，t)；4.47(1H，s)；2.90-2.80(2H， m)；1.94-1.90(2H，m)；1.79-1.70(4H，m). | 546.1 |
| 54 | N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-furoamide | (400MHz，DMSO-d 6)；δ8.58(1H，d)； 8.30(1H，dd)；7.84(1H，s)；7.54(1H，d)； 7.45(1H，t)；7.35-7.30(2H，m)； 7.17-7.13(2H，m)；6.63-6.62(1H，m)； 4.82(1H，t)；4.00(1H，s)；2.67-2.61(2H， m)；2.47(3H，s)；2.05(2H，d)； 1.66-1.54(4H，m). | 495.1 |
| Embodiment | Compound | 1H NMR | m/z |
| 55 | N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } cyclopropane carboxamide | (400MHz，DMSO-d 6)；δ8.58(1H，d)； 8.29(1H，dd)；7.86(1H，d)；7.45(1H，t)； 7.35-7.30(2H，m)；7.15(1H，d)；4.76(1H， t)；3.78(1H，s)；2.69-2.58(2H，m)； 2.47(3H，s)；1.90(2H，d)；1.79-1.73(1H， m)；1.56-1.48(4H，m)；0.64-0.60(4H，m). | 469.1 |
| 56 | N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } propionic acid amide | (400MHz，DMSO-d 6)；δ8.58(1H，d)； 8.28(1H，dd)；7.45(1H，t)；7.34-7.30(2H， m)；7.14(1H，dd)；4.75(1H，t)；3.77(1H， s)；2.65-2.56(2H，m)；2.47(3H，s)； 2.14(2H，q)；1.89(2H，d)；1.55-1.46(4H， m)；0.99(3H，t). | 457.1 |
| 57 | N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } benzamide | (400MHz，DMSO-d 6)；δ8.58(1H，d)； 8.30(1H，dd)；7.93(1H，d)；7.86(2H，d)； 7.54-7.44(4H，m)；7.35-7.30(2H，m)； 7.15(1H，d)；4.83(1H，t)；3.98(1H，s)； 2.77-2.67(2H，m)；2.47(3H，s)；2.11(2H， d)；1.65-1.53(4H，m). | 505.1 |
| 58 | N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } cyclopentane formamide | (400MHz，DMSO-d 6)；δ8.58(1H，d)； 8.28(1H，dd)；7.45(1H，t)；7.34-7.30(3H， m)；7.14(1H，d)；4.74(1H，t)；3.77(1H，s)； 2.72-2.57(3H，m)；2.47(3H，s)；1.89(2H， d)；1.76-1.69(2H，m)；1.61-1.48(10H，m). | 497.2 |
| 59 | N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxy-2-methyl propionic acid amide | (400MHz，DMSO-d 6)；δ8.58(1H，d)； 8.30(1H，dd)；7.46(1H，t)；7.39(1H，d)； 7.35-7.30(2H，m)；7.14(1H，d)；4.80(1H， t)；3.92(1H，s)；2.48(3H，s)；1.77(2H，d)； 1.65-1.58(4H，m)；1.25(6H，s). | 487.1 |
| 60 | N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } benzsulfamide | (400MHz，DMSO-d 6)；δ8.58(1H，d)； 8.28(1H，dd)；7.88-7.86(2H，m)； 7.65-7.56(4H，m)；7.45(1H，t)； 7.34-7.30(2H，m)；7.16-7.13(1H，m)； 4.69(1H，t)；3.06(1H，s)；2.77-2.67(2H， m)；2.47(3H，s)；1.74(2H，d)； 1.49-1.42(4H，m). | 541.1 |
| 61 | 3-[3-{ is suitable-the 4-[(cyclobutyl carbonyl) and amino] cyclohexyl }-6-fluoro-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate | (400MHz，DMSO-d 6)；δ8.55(1H，d)； 8.29(1H，dd)；8.06-8.03(1H，m)； 8.01(1H，s)；7.69-7.67(2H，m)；4.74(1H， t)；3.87(3H，s)；3.77(1H，s)； 3.17-3.09(1H，m)；2.59-2.54(2H，m)； 2.15-2.06(2H，m)；2.03-1.95(2H，m)； 1.91-1.83(3H，m)；1.78-1.71(1H，m)； 1.55-1.48(4H，m). | 495.1 |
| 62 | 3-[6-fluoro-3-[is suitable-4-(isobutyryl amino) cyclohexyl] and-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate | (400MHz，DMSO-d 6)；δ8.55(1H，d)； 8.30(1H，dd)；8.05-8.01(2H，m)； 7.68(2H，d)；4.75(1H，t)；3.87(3H，s)； 3.75(1H，s)；2.67-2.56(2H，m)；1.89(2H， d)；1.54-1.48(4H，m)；0.98(6H，d). | 483.1 |
| 63 | 3-[6-fluoro-3-{ is suitable-4-[(3-methylbutyryl base) and amino] cyclohexyl }-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate | (400MHz，DMSO-d 6)；δ8.55(1H，d)； 8.29(1H，dd)；8.06-8.01(2H，m)； 7.68(2H，d)；4.74(1H，t)；3.87(3H，s)； 3.80(1H，s)；2.67-2.57(2H，m)； 2.01-1.85(5H，m)；1.56-1.49(4H，m)； 0.87(6H，d). | 497.1 |
| Embodiment | Compound | 1H NMR | m/z |
| 64 | 3-[3-{ is suitable-4-[(2, and 2-dimethyl propylene acyl group) amino] cyclohexyl }-6-fluoro-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate | (400MHz，DMSO-d 6)；δ8.55(1H，d)； 8.31(1H，dd)；8.06-8.01(2H，m)； 7.69-7.68(2H，m)；6.62(1H，d)；4.78(1H， t)；3.87(3H，s)；3.80(1H，s)； 2.63-2.53(2H，m)；1.93-1.90(2H，m)； 1.55-1.49(4H，m)；1.14(9H，s). | 497.1 |
| 65 | 3-[6-fluoro-3-{ is suitable-4-[(methoxyl group ethanoyl) and amino] cyclohexyl }-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate | (400MHz，DMSO-d 6)；δ8.55(1H，d)； 8.31(1H，dd)；8.06-8.01(2H，m)； 7.69(2H，d)；7.25(1H，d)；4.79(1H，t)； 3.94(1H，s)；3.87(3H，s)；3.83(2H，s)； 3.33(3H，s)；1.86(2H，d)；1.63-1.56(4H， m). | 485.1 |
| 66 | 3-[6-fluoro-2,4-dioxo-3-{ is suitable-the 4-[(2-thienyl carbonyl) amino] cyclohexyl }-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate | (400MHz，DMSO-d 6)；δ8.55(1H，d)； 8.31(1H，dd)；8.05-8.01(2H，m)； 7.92-7.88(2H，m)；7.73(1H，d)；7.68(2H， d)；7.14(1H，dd)；4.82(1H，t)；3.95(1H， s)；3.86(3H，s)；2.74-2.64(2H，m)； 2.12-2.08(2H，m)；1.64-1.53(4H，m). | 523.1 |
| 67 | 3-[3-[is suitable-4-(kharophen) cyclohexyl]-6-fluoro-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate | (400MHz，DMSO-d 6)；δ8.55(1H，d)； 8.30(1H，dd)；8.06-8.01(2H，m)； 7.69(2H，d)；4.74(1H，t)；3.87(3H，s)； 3.77(1H，s)；2.62-2.56(2H，m)； 1.91-1.84(5H，m)；1.57-1.49(4H，m). | 455.1 |
| 68 | 3-[6-fluoro-2,4-dioxo-3-{ is suitable-4-[(pyrazolo [1,5-a] pyridine-2-base carbonyl) amino] cyclohexyl }-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate | (400MHz，DMSO-d 6)；δ8.74(1H，d)； 8.56(1H，d)；8.32(1H，dd)；8.06-8.02(2H， m)；7.77(1H，d)；7.70-7.68(2H，m)； 7.62(1H，d)；7.29(1H，t)；7.04-7.00(2H， m)；4.85(1H，t)；4.16(1H，s)；3.86(3H，s)； 2.66-2.56(2H，m)；2.04(2H，d)； 1.74-1.63(4H，m). | 557.1 |
| 69 | 3-[6-fluoro-3-{ is suitable-4-[(imidazo [1,2-a] pyridine-2-base carbonyl) and amino] cyclohexyl }-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate | (400MHz，DMSO-d 6)；δ8.80(1H，s)； 8.55(1H，d)；8.31(1H，dd)；8.15(1H，s)； 8.05-8.01(3H，m)；7.68(3H，d)；7.13(1H， s)；4.85(1H，t)；4.21(1H，s)；3.86(3H，s)； 2.76-2.69(2H，m)；2.10-2.02(2H，m)； 1.76-1.65(4H，m). | 557.1 |
| 70 | 3-[3-{ is suitable-the 4-[(cyclopropyl carbonyl) and amino] cyclohexyl }-6-fluoro-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate | (400MHz，DMSO-d 6)；δ8.55(1H，d)； 8.30(1H，dd)；8.06-8.02(2H，m)； 7.86(1H，d)；7.69(2H，dd)；4.76(1H，t)； 3.87(3H，s)；3.78(1H，s)；2.69-2.58(2H， m)；1.90(2H，d)；1.79-1.71(1H，m)； 1.57-1.49(4H，m)；0.66-0.58(4H，m). | 481.1 |
| 71 | N-{ is suitable-4-[6-fluoro-1-[3-(methylsulfonyl) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } cyclopropane carboxamide | (400MHz，DMSO-d 6)；δ8.58(1H，d)； 8.32(1H，dd)；8.06-8.03(2H，m)； 7.89-7.76(3H，m)；4.76(1H，t)；3.79(1H， s)；3.28(3H，s)；2.69-2.59(2H，m)； 1.90(2H，d)；1.79-1.73(1H，m)； 1.56-1.49(4H，m)；0.64-0.60(4H，m). | 501.1 |
| 72 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxy-5-methyl yl-benzamide | (400MHz，DMSO-d 6)；δ11.56(1H，s)； 8.60(1H，d)；8.53(1H，d)；8.31(1H，dd)； 7.76(1H，d)；7.65-7.56(2H，m)； 7.34-7.28(1H，m)；7.17(1H，dd)； 6.84(1H，d)；4.84(1H，t)；4.14(1H，s)； 2.61(2H，d)；2.22(3H，s)；2.00(2H，d)； 1.72-1.58(4H，m). | 525.1 |
| Embodiment | Compound | 1H NMR | m/z |
| 73 | 3-[6-fluoro-3-(suitable-4-{[(1-methyl piperidine-4-yl) carbonyl] amino } cyclohexyl)-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate | (400MHz，DMSO-d 6)δ8.55(1H，d)； 8.30(1H，dd)；8.04(1H，td)；8.01(1H，d)； 7.69(2H，d)；7.55(1H，d)；4.75(1H，t)； 3.87(3H，s)；3.76(1H，s)；2.76(2H，d)； 2.64-2.54(2H，m)；2.25-2.16(1H，m)； 2.13(3H，s)；1.91-1.79(4H，m)； 1.59-1.48(8H，m). | 538.3 |
| 74 | 3-[3-[is suitable-4-(the 5-[(dimethylamino) methyl]-2-furoyl base } amino) cyclohexyl]-6-fluoro-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate | (400MHz，DMSO-d 6)；δ8.55(1H，d)； 8.30(1H，dd)；8.06-8.03(1H，m)； 8.01(1H，d)；7.69(2H，d)；7.44(1H，d)； 7.12(1H，d)；6.40(1H，d)；4.84(1H，t)； 4.01(1H，s)；3.86(3H，s)；3.43(2H，s)； 2.66-2.56(2H，m)；2.12(6H，s)；2.02(2H， d)；1.65-1.56(4H，m). | 564.2 |
| 75 | 3-[3-{[is suitable-the 4-[(cyclohexyl-carbonyl) and amino] cyclohexyl }-6-fluoro-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate | (400MHz，DMSO-d 6)；δ8.55(1H，d)； 8.30(1H，dd)；8.06-8.03(1H，m)； 8.01(1H，s)；7.69(2H，d)；7.46(1H，d)； 4.74(1H，t)；3.87(3H，s)；3.75(1H，s)； 2.66-2.54(2H，m)；2.25(1H，t)；1.87(2H， d)；1.70-1.59(5H，m)；1.54-1.48(4H，m)； 1.35-1.10(5H，m). | 523.2 |
Embodiment 76
1-(3, the 4-difluorophenyl)-6-fluoro-3-[1-(1H-indazole-3-base carbonyl) piperidin-4-yl] and pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-diketone
In room temperature, with 1-(3, the 4-difluorophenyl)-6-fluoro-3-piperidin-4-yl pyrido [2,3-d] and pyrimidine-2,4 (1H, 3H)-dione hydrochloride (0.104mmol), 1H-indazole-3-carboxylic acid (34mg, 0.210mmol), HATU (80mg, 0.210mmol), HOAT (29mg, 0.210mmol) and DIEA (89 μ l, 0.520mmol) mixture in NMP (1ml) stirs 2h.Obtain title compound (18mg, 33%) by purifying on RP-HPLC.
1H NMR(400MHz，DMSO-d
6)；δ8.60(1H，d)；8.33(1H，dd)；7.96(1H，d)；7.64-7.57(3H，m)；7.42(1H，t)；7.32-7.28(1H，m)；7.22(1H，t)；5.13(1H，t)；4.93-4.84(1H，m)；4.79-4.72(1H，m)；3.29-3.21(1H，m)；2.96-2.85(1H，m)；2.63-2.52(1H，m)；1.86-1.72(2H，m)。
APCI-MS m/z；521.1[MH
+]。
LC (method A) rt=10.6min.
Embodiment 77 to 78
By the synthetic following compound of the method that is similar to embodiment 49.
| Embodiment | Compound | 1H NMR | m/z |
| Embodiment | Compound | 1H NMR | m/z |
| 77 | 1-(3, the 4-difluorophenyl)-6-fluoro-3-{1-[(2R)-and 2-hydroxyl-2-phenyl acetyl] piperidin-4-yl } pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-diketone | (400MHz，DMSO-d 6)δ8.59(1H，s)； 8.31-8.27(1H，m)；7.63-7.52(2H，m)； 7.38-7.33(4H，m)；7.30-7.24(2H，m)； 5.41(1H，d)；4.99-4.88(1H，m)； 4.58-4.50(1H，m)；4.10-4.02(1H，m)； 2.72-2.58(1H，m)；2.42-2.29(1H，m)； 1.75-1.41(2H，m) | 511.1 |
| 78 | 1-(3, the 4-difluorophenyl)-6-fluoro-3-{1-[2-hydroxyl-5-(methylol) benzoyl] piperidin-4-yl } pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-diketone | (400MHz，DMSO-d 6)δ8.60(1H，d)； 8.32(1H，dd)；7.62-7.56(2H，m)； 7.30-7.27(1H，m)；7.14(1H，d)； 7.05(1H，s)；6.80(1H，d)； 5.05-4.99(1H，m)；4.72-4.56(1H，m)； 4.37(2H，s)；3.59-3.46(1H，m)； 3.14-3.01(1H，m)；2.90-2.78(1H，m)； 1.82-1.59(2H，m) | 527.1 |
Embodiment 79
1-(3, the 4-difluorophenyl)-6-fluoro-3-[(3R)-1-(1H-indazole-3-base carbonyl) tetramethyleneimine-3-yl] pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-diketone
In room temperature, with 1-(3, the 4-difluorophenyl)-6-fluoro-3-[(3R)-tetramethyleneimine-3-yl] pyrido [2,3-d] and pyrimidine-2,4 (1H, 3H)-dione hydrochloride (0.114mmol), 1H-indazole-3-carboxylic acid (37mg, 0.228mmol), HATU (87mg, 0.228mmol), HOAT (31mg, 0.228mmol) and DIEA (98 μ l, 0.570mmol) mixture in NMP (0.8ml) stirs 2h.Obtain title compound (18mg, 33%) by purifying on RP-HPLC.
1H NMR(400MHz，DMSO-d
6)；δ8.61(1H，dd)；8.38-8.33(1H，m)；8.19-8.14(1H，m)；7.65-7.54(3H，m)；7.41(1H，t)；7.32-7.28(1H，m)；7.25-7.21(1H，m)；5.74(1H，q)；4.35(2H，d)；4.10-3.92(2H，m)；3.74-3.67(1H，m)；2.61-2.41(1H，m)；2.25-2.18(1H，m)。
APCI-MS m/z；507.1[MH
+]。
LC (method A) rt=10.3min.
Embodiment 80 to 82
By the synthetic following compound of the method that is similar to embodiment 52.
| Embodiment | Compound | 1H NMR | m/z |
| 80 | 1-(3, the 4-difluorophenyl)-6-fluoro-3-{ (3R)-1-[(2R)-2-hydroxyl-2-phenyl acetyl] tetramethyleneimine-3-yl } pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-diketone | (400MHz，DMSO-d 6)δ8.60(1H，dd)； 8.32(1H，ddd)；7.64-7.22(8H，m)； 5.59-5.52(1H，m)；5.24(1H，d)；3.93-3.83(2H， m)；3.63-3.56(2H，m)；3.21-3.14(1H，m)； 2.43-2.34(1H，m)；2.16-2.08(1H，m). | 497.1 |
| 81 | 3-{ (3R)-1-[(2R)-2-cyclohexyl-2-hydroxyacetyl] tetramethyleneimine-3-yl }-1-(3, the 4-difluorophenyl)-6-fluorine pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-diketone | (400MHz，DMSO-d 6)δ8.61(1H，t)； 8.37-8.32(1H，m)；7.65-7.54(2H，m)； 7.29(1H，d)；5.63(1H，dt)；3.95-3.78(3H，m)； 3.67-3.46(2H，m)；2.47-2.40(1H，m)； 2.23-2.10(1H，m)；1.65-1.48(6H，m)； 1.20-0.94(5H，m). | 503.1 |
| Embodiment | Compound | 1H NMR | m/z |
| 82 | 1-(3, the 4-difluorophenyl)-6-fluoro-3-{ (3R)-1-[2-hydroxyl-5-(methylol) benzoyl] tetramethyleneimine-3-yl } pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-diketone | (400MHz，DMSO-d 6)δ8.65-8.57(1H，m)； 8.38-8.31(1H，m)；7.64-7.52(2H，m)； 7.31-7.24(1H，m)；7.17(2H，s)；6.82(1H，s)； 5.60(1H，d)；4.36(2H，s)；3.86-3.53(5H，m)； 2.89(1H，s)；2.63-2.41(1H，m)；2.22-2.09(1H， m). | 513.1 |
Embodiment 83
1-(3, the 4-difluorophenyl)-6-fluoro-3-[(3S)-1-(1H-indazole-3-base carbonyl) tetramethyleneimine-3-yl] pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-diketone
In room temperature, with 1-(3, the 4-difluorophenyl)-6-fluoro-3-[(3S)-tetramethyleneimine-3-yl] pyrido [2,3-d] and pyrimidine-2,4 (1H, 3H)-dione hydrochloride (0.17mmol), 1H-indazole-3-carboxylic acid (56mg, 0.35mmol), HATU (133mg, 0.35mmol), HOAT (48mg, 0.35mmol) and DIEA (146 μ l, 0.85mmol) mixture in NMP (1ml) stirs 2h.Obtain title compound (12mg, 14%) by purifying on RP-HPLC.
1H NMR(400MHz，DMSO-d
6)；δ8.61(1H，dd)；8.39-8.33(1H，m)；8.19-8.14(1H，m)；7.64-7.56(3H，m)；7.41(1H，t)；7.34-7.27(1H，m)；7.26-7.20(1H，m)；5.74(1H，q)；4.35(2H，d)；4.10-3.93(2H，m)；3.75-3.67(1H，m)；2.57-2.41(1H，m)；2.26-2.17(1H，m)。
APCI-MS m/z；507.1[MH
+]。
LC (method A) rt=10.3min.
Embodiment 84
By the synthetic following compound of the method that is similar to embodiment 56.
| Embodiment | Compound | 1H NMR | m/z |
| 84 | 1-(3, the 4-difluorophenyl)-6-fluoro-3-{ (3S)-1-[(2R)-2-hydroxyl-2-phenyl acetyl] tetramethyleneimine-3-yl } pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-diketone | (400MHZ，DMSO-d 6)δ8.60(1H，dd)； 8.32(1H，ddd)；7.64-7.22(8H，m)； 5.59-5.52(1H，m)；5.24(1H，d)；3.93-3.83(2H， m)；3.63-3.56(2H，m)；3.21-3.14(1H，m)； 2.43-2.34(1H，m)；2.16-2.08(1H，m). | 497.1 |
Embodiment 85-107 prepares according to the method for embodiment 1.
| Embodiment | Compound | 1H NMR | m/z |
| 85 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1H-indoles-5-methane amide | (500MHz，DMSO-d 6)；δ11.25(1H，s)；8.56(1H， d)；8.30(1H，dd)；8.13(1H，s)；7.64(1H， d)；7.61-7.55(3H，m)；7.40-7.35(2H， m)；7.30-7.25(1H，m)；6.45(1H，s)；4.82(1H， d)；3.98(1H，s)；2.77-2.64(2H，m)；2.09(2H， d)；1.63-1.46(4H，m) | 534 |
| 86 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 3-nitrobenzamide | (500MHz，DMSO-d 6)；δ8.66(1H，t)；8.55(1H， d)；8.36-8.32(2H，m)；8.29-8.24(2H，m)；7.74(1H， t)；7.59-7.52(2H，m)；7.28-7.23(1H， m)；4.84-4.76(1H，m)；3.97(1H，s)；2.74-2.61(2H， m)；2.11(2H，d)；1.64-1.47(4H，m) | 540 |
| Embodiment | Compound | 1H NMR | m/z |
| 87 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1H-indoles-2-methane amide | (500MHz，DMSO-d 6)；δ11.54(1H，s)；8.55(1H， d)；8.29(1H，dd)；7.81(1H，d)；7.60-7.50(3H， m)；7.39(1H，d)；7.29-7.25(1H，m)；7.22(1H， d)；7.16-7.12(1H，m)；7.00(1H，dd)；4.80(1H， ddd)；4.01(1H，s)；2.73-2.60(2H，m)；2.09(2H， d)；1.67-1.48(4H，m) | 534 |
| 88 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1H-benzoglyoxaline-5-methane amide | (500MHz，DMSO-d 6)；δ9.07(1H，s)；8.88(1H， s)；8.56(1H，d)；8.29(1H，dd)；8.23(1H，s)；8.07(1H， d)；7.91(1H，dd)；7.77-7.72(1H，m)；7.60-7.53(2H， m)；7.29-7.23(1H，m)；4.86-4.73(1H，m)；3.98(1H， s)；2.76-2.61(2H，m)；2.11(2H，d)；1.65-1.46(4H， m) | 535 |
| 89 | 4-cyano group-N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } benzamide | (500MHz，DMSO-d 6)；δ8.55(1H，d)；8.29(1H， dd)；8.23(1H，d)；7.95(4H，dd)；7.60-7.53(2H， m)；7.29-7.23(1H，m)；4.79(1H，d)；3.94(1H， s)；2.73-2.62(2H，m)；2.11-2.04(2H， m)；1.63-1.45(4H，m) | 520 |
| 90 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1H-1,2,3-benzotriazole-5-methane amide | (500MHz，DMSO-d 6)；δ8.55(1H，d)；8.48(1H， s)；8.30(1H，dd)；8.14(1H，d)；7.90(2H， s)；7.60-7.52(2H，m)；7.27(1H，d)；4.85-4.76(1H， m)；3.98(1H，s)；2.73(2H，d)；2.12(2H， d)；1.66-1.47(4H，m) | 536 |
| 91 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1,3-benzothiazole-6-methane amide | (500MHz，DMSO-d 6)；δ9.49(1H，s)；8.64(1H， d)；8.56(1H，d)；8.29(1H，dd)；8.12(1H，d)；8.07(1H， d)；7.98(1H，dd)；7.61-7.52(2H，m)；7.30-7.24(1H m)；4.82(1H，d)；3.98(1H，s)；2.76-2.65(2H， m)；2.11(2H，d)；1.66-1.47(4H，m) | 552 |
| 92 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-3-methyl-6,7-dihydro-5H-[1,3] thiazole [3,2-a] pyrimidine-2-methane amide also | (500MHz，DMSO-d 6)；δ10.37(1H，s)；8.56(1H， d)；8.23(1H，s)；7.94(1H，d)；7.61-7.52(2H， m)；7.29-7.23(1H，m)；4.83-4.73(1H，m)；3.99(2H， t)；3.92-3.87(1H，m)；3.47(1H，s)； *(5H is in solvent peak); 2.09-1.96 (4H, m); 1.63-1.46 (4H, m) | 571 |
| 93 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1,2,3-thiadiazoles-4-methane amide | (500MHz，DMSO-d 6)；δ9.65(1H，s)；8.55(1H， d)；8.30(2H，dd)；7.55(2H，d)；7.28-7.23(1H， m)；4.85-4.76(1H，m)；4.18-4.11(1H，m)； *(2H is in solvent peak); 2.08-2.00 (2H, m); 1.73-1.54 (4H, m) | 503 |
| 94 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 1H-pyrazole-4-carboxamide | (500MHz，DMSO-d 6)；δ8.55(1H，d)；8.28(1H， dd)；8.06(2H，s)；7.60-7.51(2H，m)；7.40(1H， d)；7.28-7.23(1H，m)；4.81-4.70(1H，m)；3.89(1H， s)； *(2H is in solvent peak); 2.03 (2H, d); 1.61-1.43 (4H, m) | 485 |
| 95 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } thiophene-3-methane amide | (500MHz，DMSO-d 6)；δ8.55(1H，d)；8.28(1H， dd)；8.17(1H，dd)；7.66(1H，d)；7.60-7.52(3H， m)；7.50(1H，dd)；7.29-7.22(1H，m)；4.82-4.73(1H， m)；3.91(1H，s)； *(2H is in solvent peak); 2.06 (2H, d); 1.60-1.42 (4H, m) | 501 |
| 96 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 1H-pyrrole-3-carboxamide | (500MHz，DMSO-d 6)；δ11.06(1H，s)；8.55(1H， d)；8.28(1H，dd)；7.60-7.51(2H，m)；7.33(1H， dt)；7.29-7.22(1H，m)；6.98(1H，d)；6.70(1H， q)；6.45(1H，q)； *(2H is in solvent peak); 2.00 (2H, d); 1.57-1.44 (4H, m) | 484 |
| Embodiment | Compound | 1H NMR | m/z |
| 97 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1-methyl isophthalic acid H-imidazoles-4-methane amide | (500MHz，DMSO-d 6)；δ8.55(1H，d)；8.29(1H， dd)；8.25-8.10(1H，m)；7.87(1H，s)；7.72(1H， s)；7.61-7.51(2H，m)；7.29-7.23(1H，m)；4.78(1H， s)；4.04(1H，t)；3.72(3H，s)； *(2H is in solvent peak); 1.91 (2H, d); 1.69-1.49 (4H, m) | 499 |
| 98 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 1H-pyrazole-3-formamide | (500MHz，DMSO-d 6)；δ8.55(1H，d)；8.29(1H， dd)；7.76(1H，s)；7.63-7.50(2H，m)；7.41(1H， d)；7.29-7.22(1H，m)；6.64(1H，s)；4.79(1H，s)；4.08 *(2H is in solvent peak); (1H, d); 1.91 (2H, d); 1.68-1.50 (4H, m) | 485 |
| 99 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1-methyl piperidine-3-methane amide | (500MHz，DMSO-d 6)；δ9.23-9.10(1H， m)；8.56(1H，d)；8.26(1H，dd)；7.92(1H， d)；7.60-7.52(2H，m)；7.29-7.22(1H， m)；4.77-4.67(1H，m)；3.73(1H，s)；3.02-2.90(3H， m)；2.88-2.77(1H，m)；2.76-2.67(3H，m)； *(2H is in solvent peak); 1.99-1.28 (10H, m) | 516 |
| 100 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-3-morpholine-4-base propionic acid amide | (500MHz，DMSO-d 6)；δ8.56(1H，d)；8.26(1H， dd)；7.99-7.92(1H，m)；7.61-7.51(2H， m)；7.28-7.22(1H，m)；4.79-4.69(1H， m)；3.95-3.87(2H，m)；3.81-3.76(1H， m)；3.64-3.54(2H，m)；3.08-2.96 *(8H is in solvent peak); (1H, m); 1.90-1.81 (2H, m); 1.58-1.42 (4H, m) | 532 |
| 101 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-4-vinyl benzene methane amide | (500MHz，DMSO-d 6)；δ8.55(1H，d)；8.29(1H， dd)；7.88(1H，d)；7.81(2H，d)；7.61-7.49(4H， m)；7.29-7.24(1H，m)；6.75(1H，dd)；5.91(1H， d)；5.33(1H，d)；4.79(1H，dd)；3.94(1H， s)；2.73-2.60(2H，m)；2.12-2.03(2H， m)；1.63-1.44(4H，m) | 521 |
| 102 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-4-acetylenylbenzene methane amide | (500MHz，DMSO-d 6)；δ8.55(1H， d)；8.32-8.24(1H，m)；8.04-7.98(1H， m)；7.85-7.79(2H，m)；7.61-7.49(4H， m)；7.29-7.23(1H，m)；4.83-4.73(1H，m)；4.31(1H， s)；3.95-3.90(1H，m)；2.71-2.61 *(2H is in solvent peak); (2H, m); 2.11-2.03 (2H, m); 1.64-1.44 (4H, m) | 519 |
| 103 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1H-pyrrolo-[2,3-b] pyridine-2-methane amide | (500MHz，DMSO-d 6)；δ12.28(1H，s)；8.55(1H， d)；8.31(1H，dd)；8.28(1H，dd)；8.05(1H， dd)；7.88(1H，d)；7.59-7.51(2H，m)；7.28-7.24(1H， m)；7.16(1H，d)；7.10(1H，dd)；4.79(1H， s)；4.01(1H，s)；2.73-2.60(2H，m)；2.10-2.04(2H， m)；1.68-1.48(4H，m) | 535 |
| 104 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1,3-benzothiazole-2-methane amide | (500MHz，DMSO-d 6)；δ8.55(1H，d)；8.29(1H， dd)；8.27(1H，d)；8.19(1H，d)；8.14(1H， d)；7.62-7.52(4H，m)；7.29-7.25(1H， m)；4.88-4.76(1H，m)；4.12-4.04 *(2H is in solvent peak); (1H, m); 2.14-2.03 (2H, m); 1.73-1.54 (4H, m) | 552 |
| 105 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } thieno-[2,3-b] pyridine-2-carboxamide | (500MHz，DMSO-d 6)；δ8.61(1H，dd)；8.55(1H， d)；8.34(1H，dd)；8.32-8.26(2H，m)；8.23(1H， s)；7.59-7.52(2H，m)；7.46(1H，dd)；7.29-7.24(1H， m)；4.84-4.74(1H，m)；3.96(1H，s)；2.75-2.60(2H， m)；2.15-2.05(2H，m)；1.66-1.46(4H，m) | 552 |
| Embodiment | Compound | 1H NMR | m/z |
| 106 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } thieno-[2,3-b] pyrazine-6-methane amide | (500MHz，DMSO-d 6)；δ8.80(1H，d)；8.67(1H， d)；8.55(1H，d)；8.50(1H，s)；8.47(1H，d)；8.29(1H， dd)；7.58-7.50(2H，m)；7.28-7.24(1H， m)；4.86-4.73(1H，m)；4.00-3.93(1H，m)；2.71(2H， d)；2.12(2H，d)；1.68-1.48(4H，m) | 553 |
| 107 | N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } [1,2,4] triazolo [1,5-a] pyrimidine-2-methane amide | (500MHz，DMSO-d 6)；δ9.44(1H，dd)；8.96(1H， dd)；8.55(1H，d)；8.30(1H，dd)；8.06(1H， d)；7.60-7.51(2H，m)；7.44(1H，dd)；7.32-7.22(1H， m)；4.86-4.74(1H，m)；4.18-4.10(1H，m)； *(2H is in solvent peak); 2.06-1.93 (2H, m); 1.76-1.52 (4H, m) | 537 |
Embodiment 108
Human phosphodiester enzyme B2 α screening assay
Measure to use be stored in-20 ℃ self-control recombinant human phosphodiesterase B2 (PDE4B2) (PrAZL0133).Substrate uses and is stored in 4 ℃ cAMP, is Alpha ScreencAMP test kit (Perkin Elmer, part Cat#6760625M).Alpha Screen test kit also comprises biotinylated cAMP, acceptor globule (acceptor bead) and donor globule (donor bead).
Measure to add following carrying out: with test compound and contrast (the 100%DMSO solution of 0.2 μ l) add to white 384 hole flat undersides (Greiner, Cat#781075) in, then add the reaction buffer of 10 μ l PDE4B2.The composition of reaction buffer has: 50mM Tris (pH7.5), 8.3mM MgCl
2, 1.7mM EGTA and 0.01% (w/v) Brij
35.With enzyme and compound incubated at room 15 minutes.Add the reaction buffer of 10 μ l cAMP then.After 60 minutes, mensuration is stopped in incubated at room by the mensuration damping fluid (containing 40mM EDTA) that adds 10 μ l acceptor globules.The composition of measuring damping fluid has: 5mM Tris (pH7.5), 0.1% (w/v) BSA and 0.1% (v/v) Tween 20.After this step interpolation, add the mensuration damping fluid and the biotinylated cAMP of 10 μ l donor globules.Then this 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 shown in Table 1).
Table 1
| Embodiment | PDE4B2 IC50(nM) | Embodiment | PDE4B2 IC50(nM) | |
| 1 | 4.9 | 55 | 2.6 | |
| 2 | 0.9 | 56 | 7.2 | |
| 3 | 16.3 | 57 | 4.2 | |
| 4 | 5.0 | 58 | 3.9 | |
| 5 | 2.2 | 59 | 14.9 | |
| 6 | 2.3 | 60 | 32.4 |
| 7 | 3.0 | 61 | 5.2 | |
| 8 | 2.2 | 62 | 6.3 | |
| 9 | 1.3 | 63 | 5.7 | |
| 10 | 2.6 | 64 | 4.4 | |
| 11 | 3.4 | 65 | 11.1 | |
| 12 | 2.2 | 66 | 4.8 | |
| 13 | 3.2 | 67 | 21.2 | |
| 14 | 1.5 | 68 | 0.6 | |
| 15 | 1.3 | 69 | 1.0 | |
| 16 | 2.1 | 70 | 6.6 | |
| 17 | 1.8 | 71 | 41.2 | |
| 18 | 2.7 | 72 | 2.3 | |
| 19 | 2.0 | 73 | 62.6 | |
| 20 | 3.6 | 74 | 5.1 | |
| 21 | 3.6 | 75 | 2.6 | |
| 22 | 1.0 | 76 | 9.5 | |
| 23 | 3.8 | 77 | 147.0 | |
| 24 | 0.6 | 78 | 293.0 | |
| 25 | 1.9 | 79 | 15.4 | |
| 26 | 1.0 | 80 | 73.3 | |
| 27 | 1.7 | 81 | 8.1 | |
| 28 | 0.9 | 82 | 71.8 | |
| 29 | 1.2 | 83 | 9.2 | |
| 30 | 1.1 | 84 | 57.3 | |
| 31 | 1.5 | 85 | 0.996 | |
| 32 | 0.6 | 86 | 4.13 | |
| 33 | 0.5 | 87 | 0.885 | |
| 34 | 3.2 | 88 | 3.38 | |
| 35 | 1.4 | 89 | 10.8 | |
| 36 | 2.9 | 90 | 6.11 | |
| 37 | 0.5 | 91 | 2.09 | |
| 38 | ＜16 | 92 | 7.83 | |
| 39 | 23.7 | 93 | 11.7 | |
| 40 | 90.6 | 94 | 5.31 |
| 41 | 51.9 | 95 | 3.39 | |
| 42 | ＜16 | 96 | 6.68 | |
| 43 | 36.4 | 97 | 2.18 | |
| 44 | 432.0 | 98 | 50.1 | |
| 45 | ＜16 | 99 | 6.01 | |
| 46 | 129.0 | 100 | 2.12 | |
| 47 | 60.1 | 101 | 2.05 | |
| 48 | 8.8 | 102 | 1 | |
| 49 | 14.5 | 103 | 0.741 | |
| 50 | 2.1 | 104 | 2.09 | |
| 51 | 5.2 | 105 | 6.03 | |
| 52 | 18.6 | 106 | 3.89 | |
| 53 | 0.4 | 107 | 30.1 | |
| 54 | 3.9 |
Claims (16)
1. formula (I) compound or its N-oxide compound or its pharmacologically acceptable salt:
Wherein
A is N or CA
1
E is N or CE
1
T is C (O) or S (O)
2
X is C or S;
W is (CH
2)
n
Y is (CH
2)
p
N and p independently are 0 or 1;
L is CH or N;
When L was CH, then J was NH; When L was N, then J did not exist, and T directly links to each other with L;
R
1Be aryl or heteroaryl, each in described aryl or the heteroaryl is optional by halogen, cyano group, hydroxyl, C
1-4Alkyl, C
1-4Alkoxyl group, CF
3, OCF
3, C
1-4Alkylthio, S (O) (C
1-4Alkyl), S (O)
2(C
1-4Alkyl) or C (O)
2(C
1-4Alkyl) replaces;
R
2Be C
1-6Alkyl is (optional by hydroxyl, C
1-6Alkoxyl group, heterocyclic radical (are chosen wantonly by C
1-6The alkyl replacement), aryl, heteroaryl, C
3-7Cycloalkyl, CO
2H, CO
2(C
1-6Alkyl) or NHC (O) R
3Replacement), C
1-6Alkoxyl group, C
3-6Cycloalkyl is (optional by hydroxyl or C
1-6The alkyl replacement), heterocyclic radical is (optional by C
1-6The alkyl replacement), aryl or heteroaryl;
R
3Be C
1-6Alkyl or phenyl;
Above-mentioned R
2And R
3In phenyl, aryl and heteroaryl independently optionally 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
1-6Alkyl, C
1-6Hydroxyalkyl, C
1-6Haloalkyl, C
1-6Alkoxyl group (C
1-6) alkyl, 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, C
3-10(itself is optional by C for cycloalkyl
1-4Alkyl or oxo replace), methylene radical dioxy base, difluoro methylene dioxy base, phenyl, phenyl (C
1-4) alkyl, phenoxy group, thiophenyl, phenyl (C
1-4) alkoxyl group, heteroaryl, heteroaryl (C
1-4) alkyl, heteroaryl oxygen base or heteroaryl (C
1-4) alkoxyl group; Wherein just above-mentioned phenyl and any one in the heteroaryl 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
A
1, 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
22And R
23Independent is C
1-6Alkyl is { optional by halogen, hydroxyl or C
1-6Alkoxyl group replaces }, CH
2(C
2-6Thiazolinyl), { itself is optional by halogen, hydroxyl, nitro, NH for phenyl
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
3Replace or heteroaryl { choosing wantonly by halogen, hydroxyl, nitro, NH own
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
3Replace };
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 R
23Also can be hydrogen.
2. the formula of claim 1 (I) compound, wherein A is CA
1E is CE
1A
1, E
1And G
1Independent is hydrogen or halogen.
3. claim 1 or 2 formula (I) compound, wherein X is C.
4. claim 1,2 or 3 formula (I) compound, wherein n and p are 1.
5. claim 1,2,3 or 4 formula (I) compound, wherein L is CH.
6. aforesaid right requires any one formula (I) compound, and wherein J is NH.
7. aforesaid right requires any one formula (I) compound, and wherein T is C (O).
8. aforesaid right requires any one formula (I) compound, wherein R
1For choosing wantonly by halogen, C
1-4Alkylthio, S (O)
2(C
1-4Alkyl) or C (O)
2(C
1-4Alkyl) aryl of Qu Daiing.
9. aforesaid right requires any one formula (I) compound, wherein R
2Be C
1-6Alkyl is { optional by hydroxyl, phenyl (itself choose wantonly and replaced by hydroxyl), C
3-7Cycloalkyl, CO
2(C
1-4Alkyl) or NHC (O) R
3Replace }, phenyl is { optional by halogen, hydroxyl, C
1-4Alkyl, C
1-4Alkoxyl group, CO
2(C
1-4Alkyl) or C
2-4Alkynyl substituted } or heteroaryl { optional by halogen, hydroxyl, C
1-4Alkyl, C
1-4Alkoxyl group, CO
2(C
1-4Alkyl) or C
2-4Alkynyl substituted }; R wherein
3Be the optional phenyl that is replaced by hydroxyl.
10. the formula of claim 1 (I) compound or pharmaceutically acceptable salt thereof, described compound is:
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-5-(methylol) benzamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-2-phenyl-acetamides;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-hydroxyl acetamide;
5-chloro-N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-hydroxybenzamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 3-hydroxybenzamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 4-hydroxybenzamide;
2-[({ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } amino) carbonyl] methyl benzoate;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-(4-hydroxy phenyl) ethanamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxy-4-methyl benzamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-hydroxybenzamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-3-pyridone-2-methane amide;
3-chloro-N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 4-hydroxybenzamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-3-hydroxy-2-methyl benzamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-4-hydroxy 3-methoxybenzene methane amide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-3-hydroxy-4-methyl benzamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-6-methoxy benzamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxy 3-methoxybenzene methane amide;
4-chloro-N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-hydroxybenzamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-4-methoxy benzamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-5-fluoro-2-hydroxybenzamide;
(2S)-and N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxy-4-methyl valeramide;
(2R)-and 2-cyclohexyl-N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-hydroxyl acetamide;
4-(suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] and cyclohexyl } amino)-4-ketobutyric acid methyl esters;
N-[2-(suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] and cyclohexyl } amino)-the 2-oxoethyl]-the 2-hydroxybenzamide;
4-[({ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } amino) carbonyl] methyl benzoate;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-3-hydroxyl-4-methoxy benzamide;
5-(suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] and cyclohexyl } amino)-5-oxopentanoic acid methyl esters;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-(3-hydroxy phenyl) ethanamide;
3-[({ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } amino) carbonyl] methyl benzoate;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-fluoro-6-hydroxybenzamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-3-(3-hydroxy phenyl) propionic acid amide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1H-indazole-3-methane amide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } imidazo [1,2-a] pyridine-2-carboxamide;
5-chloro-N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-hydroxybenzamide;
N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxy-5-methyl yl-benzamide;
N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-5-(methylol) benzamide;
(2R)-and N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-2-phenyl-acetamides;
(2S)-and N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-2-phenyl-acetamides;
N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-hydroxyl acetamide;
5-chloro-N-{ is suitable-4-[6-fluoro-1-[3-(methylsulfonyl) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-hydroxybenzamide;
N-{ is suitable-4-[6-fluoro-1-[3-(methylsulfonyl) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-5-(methylol) benzamide;
(2R)-and N-{ is suitable-4-[6-fluoro-1-[3-(methylsulfonyl) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-2-phenyl-acetamides;
(2S)-and N-{ is suitable-4-[6-fluoro-1-[3-(methylsulfonyl) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxyl-2-phenyl-acetamides;
N-{ is suitable-4-[6-fluoro-1-[3-(methylsulfonyl) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-hydroxyl acetamide;
3-[6-fluoro-3-{ is suitable-4-[(2-hydroxy-5-methyl base benzoyl) and amino] cyclohexyl }-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } Toluidrin;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro-3H-pyrido [2,3-c] [1,2,6] thiadiazine-3-yl] cyclohexyl }-2-hydroxy-5-methyl yl-benzamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } cyclopropane carboxamide;
3-[6-fluoro-3-{ is suitable-4-[(1-methyl-L-prolyl) and amino] cyclohexyl }-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate;
5-[({ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } amino) carbonyl] the pyridine-2-carboxylic acids methyl esters;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-4-fluoro-2-hydroxybenzamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1-hydroxyl cyclopropane carboxamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } quinoline-8-methane amide;
N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 2-furoamide;
N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } cyclopropane carboxamide;
N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } propionic acid amide;
N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } benzamide;
N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } cyclopentane formamide;
N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxy-2-methyl propionic acid amide;
N-{ is suitable-4-[6-fluoro-1-[3-(methylthio group) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } benzsulfamide;
3-[3-{ is suitable-the 4-[(cyclobutyl carbonyl) and amino] cyclohexyl }-6-fluoro-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate;
3-[6-fluoro-3-[is suitable-4-(isobutyryl amino) cyclohexyl] and-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate;
3-[6-fluoro-3-{ is suitable-4-[(3-methylbutyryl base) and amino] cyclohexyl }-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate;
3-[3-{ is suitable-4-[(2, and 2-dimethyl propylene acyl group) amino] cyclohexyl }-6-fluoro-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate;
3-[6-fluoro-3-{ is suitable-4-[(methoxyl group ethanoyl) and amino] cyclohexyl }-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate;
3-[6-fluoro-2,4-dioxo-3-{ is suitable-the 4-[(2-thienyl carbonyl) amino] cyclohexyl }-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate;
3-[3-[is suitable-4-(kharophen) cyclohexyl]-6-fluoro-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate;
3-[6-fluoro-2,4-dioxo-3-{ is suitable-4-[(pyrazolo [1,5-a] pyridine-2-base carbonyl) amino] cyclohexyl }-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate;
3-[6-fluoro-3-{ is suitable-4-[(imidazo [1,2-a] pyridine-2-base carbonyl) and amino]-cyclohexyl }-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate;
3-[3-{ is suitable-the 4-[(cyclopropyl carbonyl) and amino] cyclohexyl }-6-fluoro-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate;
N-{ is suitable-4-[6-fluoro-1-[3-(methylsulfonyl) phenyl] and-2,4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } cyclopropane carboxamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-2-hydroxy-5-methyl yl-benzamide;
3-[6-fluoro-3-(suitable-4-{[(1-methyl piperidine-4-yl) carbonyl] amino } cyclohexyl)-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate;
3-[3-[is suitable-4-(the 5-[(dimethylamino) methyl]-2-furoyl base } amino) cyclohexyl]-6-fluoro-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate;
3-[3-{ is suitable-the 4-[(cyclohexyl-carbonyl) and amino] cyclohexyl }-6-fluoro-2,4-dioxo-3,4-dihydro pyrido [2,3-d] pyrimidines-1 (2H)-yl] methyl benzoate;
1-(3, the 4-difluorophenyl)-6-fluoro-3-[1-(1H-indazole-3-base carbonyl) piperidin-4-yl] and pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-diketone;
1-(3, the 4-difluorophenyl)-6-fluoro-3-{1-[(2R)-and 2-hydroxyl-2-phenyl acetyl] piperidin-4-yl } pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-diketone;
1-(3, the 4-difluorophenyl)-6-fluoro-3-{1-[2-hydroxyl-5-(methylol) benzoyl] piperidin-4-yl } pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-diketone;
1-(3, the 4-difluorophenyl)-6-fluoro-3-[(3R)-1-(1H-indazole-3-base carbonyl) tetramethyleneimine-3-yl] pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-diketone;
1-(3, the 4-difluorophenyl)-6-fluoro-3-{ (3R)-1-[(2R)-2-hydroxyl-2-phenyl acetyl] tetramethyleneimine-3-yl } pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-diketone;
3-{ (3R)-1-[(2R)-2-cyclohexyl-2-hydroxyacetyl] tetramethyleneimine-3-yl }-1-(3, the 4-difluorophenyl)-6-fluorine pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-diketone;
1-(3, the 4-difluorophenyl)-6-fluoro-3-{ (3R)-1-[2-hydroxyl-5-(methylol) benzoyl] tetramethyleneimine-3-yl } pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-diketone;
1-(3, the 4-difluorophenyl)-6-fluoro-3-[(3S)-1-(1H-indazole-3-base carbonyl) tetramethyleneimine-3-yl] pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-diketone;
1-(3, the 4-difluorophenyl)-6-fluoro-3-{ (3S)-1-[(2R)-2-hydroxyl-2-phenyl acetyl] tetramethyleneimine-3-yl } pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)-diketone;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1H-indoles-5-methane amide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 3-nitrobenzamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1H-indoles-2-methane amide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1H-benzoglyoxaline-5-methane amide;
4-cyano group-N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } benzamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1H-1,2,3-benzotriazole-5-methane amide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1,3-benzothiazole-6-methane amide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-3-methyl-6,7-dihydro-5H-[1,3] thiazole [3,2-a] pyrimidine-2-methane amide also;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1,2,3-thiadiazoles-4-methane amide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 1H-pyrazole-4-carboxamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } thiophene-3-methane amide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 1H-pyrrole-3-carboxamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1-methyl isophthalic acid H-imidazoles-4-methane amide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-the 1H-pyrazole-3-formamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1-methyl piperidine-3-methane amide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-3-morpholine-4-base propionic acid amide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-4-vinyl benzene methane amide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-4-acetylenylbenzene methane amide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1H-pyrrolo-[2,3-b] pyridine-2-carboxamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl }-1,3-benzothiazole-2-methane amide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } thieno-[2,3-b] pyridine-2-carboxamide;
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } thieno-[2,3-b] pyrazine-6-methane amide; Or
N-{ is suitable-4-[1-(3, the 4-difluorophenyl)-6-fluoro-2, and 4-dioxo-1,4-dihydro pyrido [2,3-d] pyrimidines-3 (2H)-yl] cyclohexyl } [1,2,4] triazolo [1,5-a] pyrimidine-2-methane amide.
11. the method for preparation formula (I) compound comprises:
A. when X was C, described method was included in suitable temperature and in suitable solvent, removes the Boc blocking group from formula (II) compound, made product and formula (III) acid or the acid derivative reaction of formation like this then,
Described formula (II) compound is as follows:
R wherein
1, G
1, E, A, Y, L, W and J be as definition in claim 1,
(III) acid of described formula or acid derivative are as follows:
R wherein
2Define in claim 1 with T, LG is a leavings group; Or
B. when X is S,, make the reaction of formula (IIa) compound and formula (III) acid or acid derivative by in suitable temperature and in suitable solvent,
Described formula (IIa) compound is as follows:
R wherein
1, G
1, E, A, Y, L, W and J be as definition in claim 1,
(III) acid of described formula or acid derivative are as follows:
R wherein
2Define in claim 1 with T, LG is a leavings group.
12. a pharmaceutical composition, described pharmaceutical composition comprise formula (I) compound or pharmaceutically acceptable salt thereof of claim 1 and pharmaceutically acceptable auxiliaries, diluent or carrier.
13. a combination comprises that formula (I) compound and one or more are selected from following medicine:
Non-steroidal glucocorticoid receptor (GR acceptor) agonist;
Selectivity β
2Adrenoceptor agonists, for example Metaprel, Racemic isoproterenol, isopropyl noradrenalin, salbutamol, salbutamol, formoterol, Salmeterol, terbutaline, Orciprenaline, bitolterol mesilate, pirbuterol or indenes Da Teluo;
Muscarinic receptor antagonist (for example M1, M2 or M3 antagonist, for example selectivity M3 antagonist), for example ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine;
Chemokine receptor function conditioning agent (for example CCR1 receptor antagonist); Or
P38 kinase function inhibitor.
14. the formula of claim 1 (I) compound or pharmaceutically acceptable salt thereof, it is used for the treatment of.
15. the purposes of the formula of claim 1 (I) compound or pharmaceutically acceptable salt thereof in the medicine that preparation is used for the treatment of.
16. treatment suffers from the disease of PDE4 mediation or faces the method for illness described in the Mammals of described disease risks, described method comprises that formula (I) compound or pharmaceutically acceptable salt thereof of claim 1 that will the treatment significant quantity needs the Mammals of this treatment.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105593221A (en) * | 2013-09-30 | 2016-05-18 | 小野药品工业株式会社 | Compound having agonistic activity to somatostatin receptor and medicinal use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105593221A (en) * | 2013-09-30 | 2016-05-18 | 小野药品工业株式会社 | Compound having agonistic activity to somatostatin receptor and medicinal use thereof |
| US9643951B2 (en) | 2013-09-30 | 2017-05-09 | Ono Pharmaceutical Co., Ltd. | Compound having somatostatin receptor agonistic activity and pharmaceutical use thereof |
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