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CN1246858A - Substituted pyrimidine compounds and their use - Google Patents

Substituted pyrimidine compounds and their use Download PDF

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Publication number
CN1246858A
CN1246858A CN97181563A CN97181563A CN1246858A CN 1246858 A CN1246858 A CN 1246858A CN 97181563 A CN97181563 A CN 97181563A CN 97181563 A CN97181563 A CN 97181563A CN 1246858 A CN1246858 A CN 1246858A
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amino
group
alkyl
pyridyl
phenyl
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U·D·斯波尔
M·J·马隆
N·B·曼特罗
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Amgen Inc
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Amgen Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C07D213/643—2-Phenoxypyridines; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Selected novel substituted pyrimidinone and pyridone compounds are effective for prophylaxis and treatment of diseases, such as TNF- alpha, IL-1 beta, IL-6 and/or IL-8 mediated diseases, and other maladies, such as pain and diabetes. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving inflammation, pain, diabetes and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.

Description

Pyrimidine compound that replaces and their application
Background of invention
The application is a non-provisional application, based on the U.S. Provisional Application 60/032 that proposed on December 5th, 1996,128, the U.S. Provisional Application 60/050 that proposed on June 13rd, 1997, U.S.'s non-provisional application of not assigning as yet that on November 21st, 950 and 1997 proposed, above-mentioned each application is incorporated this paper into as this paper reference in full with it.The present invention relates to a kind of for example disease of THF-α, IL-1 β, IL-6 and/or IL-8 mediation and other diseases new compound of pain and diabetes for example of disease that is used for the treatment of.Particularly, The compounds of this invention is used to prevent and the disease or the illness of treatment and inflammation-related.The invention still further relates to the intermediate and the method that are used to prepare this compounds.
Interleukin 1 (IL-1) and tumor necrosis factor alpha (THF-α) be many inflammatory stimulus elements (during for example lipopolysaccharides-LPS) or outside cellular stress (for example osmotic shock and superoxide) are replied, comprise monocyte and scavenger cell excretory by various different cells before-inflammatory cytokine.
The relative basal level of TNF-α and/or IL-1 level raises with the mediation of numerous disease or increases the weight of relevantly, and described disease comprises rheumatoid arthritis; Paget's disease; Osteoporosis; Multiple myeloma; Uveitis; Acute and chronic lymphocytic leukemia; Pancreatic; Osteoarthritis; Rheumatoid osteomyelitis; Urarthritis; Enteritis; Adult respiratory distress syndrome (ARDS); Psoriasis; Crohn disease; Rhinallergosis; Ulcerative colitis; Irritated; Contact dermatitis; Asthma; Muscle deterioration; Emaciation; Reiter syndrome; I type and type ii diabetes; Bone resorption disease; Graft-vs-host reaction; The ischemia reperfusion damage; Atherosclerosis; Cerebral trauma; Multiple sclerosis; Cerebral malaria; Sepsis; Septic shock; Toxic shock syndrome; The myalgia that causes because of infection, and fever.TNF-α also can make HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, simplexvirus (comprising HSV-1, HSV-2) and zoster worsen.
Existing report, in cerebral trauma, shock and local asphyxia, TNF-α plays an important role.For example, in cerebral trauma animal model (rat), the TNF-alpha levels of dampening hemisphere raise people such as (, J.Cereb.Blood Flow Metab.14,615 (1994)) Shohami.Cerebral arteries is by in the rat local asphyxia model of obturation therein, the TNF-α mRNA level of TNF-α raise people such as (, Neurosci.Lett.164,125 (1993)) Feurstein.Report is arranged, use TNF-α, found that wicking action and the adhesion at little blood vessel obviously has neutrophilic leukocyte to build up on to rat layer.TNF-α can promote the infiltration of other cytokines (IL-1 β, IL-6) and chemokines, and it can promote neutrophilic leukocyte to infiltrate infarct (Feurstein, Stroke 25,1481 (1994)).TNF-α also in type ii diabetes, play an important role (Endocrinol.130,43-52,1994; And Endocrinol.136,1474-1481,1995).
In some viral life cycle of enhancement and aspect their diseases associated, TNF-α plays an important role.For example, monocyte excretory TNF-α can induce that the HIV expression level raises in the chronically infected T-cell system people such as (, J.Immunol.142,431 (1989)) Clouse.People such as Lahdevirta (Am.J.Med.85,289 (1988)) have discussed the effect to TNF-α in HIV related cachexia and muscle deterioration illness.
In the cytokine cascade reaction of inflammation, TNF-α is in the upper end.As a result, the rising of TNF-alpha levels can cause for example rising of IL-1, IL-6 and IL-8 level of other inflammation and preceding-inflammatory cytokine.
The relative basal level of IL-1 level raises with the mediation of many illnesss and increases the weight of relevantly, and described illness comprises rheumatoid arthritis; Osteoporosis; Rheumatoid osteomyelitis; Urarthritis; Enteritis; Adult respiratory distress syndrome (ARDS); Psoriasis; Crohn disease; Ulcerative colitis; Irritated; Muscle deterioration; Emaciation; Reiter syndrome; I type and type ii diabetes; Bone resorption disease; The ischemic reperfusion injury; Atherosclerosis; Cerebral trauma; Multiple sclerosis; Sepsis; Septic shock and toxic shock syndrome.IL-1 also can influence the virus of TNF-α restraining effect sensitivity for example HIV-1, HIV-2, HIV-3.
TNF-α and IL-1 play an important role in pancreatic and diabetes.Pancreatic beta cell can produce Regular Insulin, and it can help the blood sugar regulation homeostasis.Type i diabetes is followed in the degeneration of pancreatic beta cell usually.The dysfunction of pancreatic beta cell may occur on one's body the type ii diabetes patient.The characteristics of II type glycosuria pain are the functional tolerance to Regular Insulin.In addition, type ii diabetes is also often followed the rising of blood plasma hyperglycemic-glycogenolytic factor level and the raising that hepatic glucose produces speed.Hyperglycemic-glycogenolytic factor is a kind of adjusting hormone, and it can make Regular Insulin that the restraining effect of liver gluconeogenesis is weakened.In liver, kidney and fatty tissue, found glucagon receptor now.Therefore, glucagon antagonist can be used for reducing glucose level in the blood plasma (WO97/16442, it incorporates this paper in full as this paper reference).Can suspect that by the antagonism glucagon receptor, the responsiveness of Regular Insulin will improve in the liver, thereby reduce gluconeogenesis and hepatic glucose generation speed is reduced.
In the rheumatoid arthritis animal model, a plurality of intra-articular injection IL-1 will cause acute, arthritis mutilans (people such as Chandrasekhar, Clinical ImmunolImmunopathol.55,382 (1990)).In the test of carrying out with the rheumatoid synovial fluid cell of cultivating, IL-1 is a kind of inductor (Firestein, Am.J.Pathol.140,1309 (1992)) of more effective stromelysin than TNF-α.In the injection site, observe neutrophilic leukocyte, lymphocyte and monocytic white corpuscle and ooze out.It is that chemokines (as IL-8) is induced the result (Dinarello, Eur.CytokineNetw.5,517-531 (1994)) who excessively regulates with adhesion molecule that white corpuscle oozes out.
Aspect some viral life cycle of promotion, IL-1 also plays an important role.For example, in chronically infected macrophage system, the HIV of cytokine induction express to strengthen with occur together and optionally IL-1 produce enhancing relevant people such as (, J.Immunol.136,40 (1986)) Folks.People such as Beutler (J.Immunol.135,3969 (1985)) have discussed the effect of IL-1 in emaciation.People such as Baracos (New Eng.J.Med.308,553 (1983)) have discussed the effect of IL-1 in muscle deterioration.
In rheumatoid arthritis, IL-1 and TNF-α all can induce synovial cell and chondrocyte to produce collagenase and neutral protease, and it can cause disorganization in suffering from arthritic joint.In arthritis model (collagen protein in rat and the mouse-inductive sacroiliitis (CIA)), before or after CIA induces, use TNF-α in intraarticular, can cause sacroiliitis outbreak to quicken and make the more serious (people such as Brahn of described disease, LymphokineCytokine Res.11,253 (1992); And Cooper, Clin.Exp.Immunol.898,244 (1992)).
The generation of IL-8 and many illnesss and/or worsen relevant, wherein a large amount of neutrophilic leukocytes are to regulate by the chemotaxis characteristic of IL-8 to inflammation and the infiltration of damage (for example local asphyxia) position, these illnesss include but not limited to following illness: asthma, enteritis, psoriasis, grownup's respiratory distress syndrome, the heart and renal reperfusion injury, myocardial infarction and glomerulonephritis.Except to the leukocytic chemotaxis effect of neutrality, IL-8 can also activate neutrophilic leukocyte.Therefore, reduce the level of IL-8, can cause neutrophilic leukocyte to infiltrate and reduce.
Now existing several method is used to block the effect of TNF-α.A kind of method is, uses the soluble receptors (for example TNFR-55 or TNFR-75) of TNF-α, shown that in the animal model of the alpha mediated disease of TNF-it is effective.Second method is, with among the monoclonal antibody cA2 of TNF-alpha specific and TNF-α, shown that there is improvement effect (people such as Feldmann, ImmunologicalReviews, pp.195-223 (1995)) in its joint to swelling in people II phase rheumatoid arthritis test.These methods are blocked the effect of TNF-α and IL-1 by albumen isolation or receptor antagonism.
People such as Bennett (J.Med.Chem.21,623 (1978)) have synthesized a large amount of following formula pyrimidines: Wherein, especially, R a 1Be 2-, 3-or 4-pyridyl, R a 2Be H, methyl or phenyl, and R a 1Be H, amino.They point out that for Chinese People's Anti-Japanese Military and Political College's mouse adjuvant-inductive oedema, the active water of these compound exhibits of being tested on average is not enough to allow the people further study, and, test in addition confirms that in carrageenin inductive edema model, described compound obtains a series of non-positivity effects.
People such as Ife (Bioorg, Med.Chem.Lett.5,543 (1995)) disclose the H than relevant 4-(2-pyridyl)-5-phenyl thiazole compound +/ K +Another kind of pyrimidine compound (the R of the low several times of-ATP enzyme inhibition activity a 1=2-aminomethyl phenyl, R a 2=2-pyridyl, and R a 3=n-propyl, wherein R a 1, R a 2And R a 3As shown in above-mentioned formula i).
WO 97/33883 discloses the pyrimidines of the replacement that is used for the treatment of cytokine mediated disease.
Summary of the invention
The present invention relates to a class is used to prevent and treats for example disease of THF-α, IL-1 β, IL-6 and/or IL-8 mediation and other diseases new compound of pain and diabetes for example of disease.Particularly, The compounds of this invention is used to prevent and the disease or the illness of treatment and inflammation-related.Thereby, the invention still further relates to the pharmaceutical composition that contains described compound, the disease of using prevention of compound of the present invention and composition and treatment TNF-α, IL-1 β, IL-6 and/or IL-8 mediation is the method for inflammation, pain and diabetes for example, and the intermediate and the method that are used to prepare compound of the present invention.
Compound of the present invention is by following general formula:
Figure A9718156300361
R wherein 1, R 2, R 11And R 12As give a definition.
Above the just general introduction of some aspect of the present invention is not attempted, and should not be that the present invention is constituted any qualification yet.The document of all patents that this paper quoted and wherein citation is all incorporated this paper in full as this paper reference.
Detailed Description Of The Invention
The invention provides following formula: compound or its pharmaceutically acceptable salt:
Figure A9718156300362
Wherein
R 1And R 2Be independently of one another-Z-Y, condition be (1) each-aryl, heteroaryl, cycloalkyl and heterocyclic radical among the Z-Y add up to 0-3; Preferred 0-2; More preferably 0-1; (2) R 1And R 2In aryl, heteroaryl, cycloalkyl and heterocyclic radical group add up to 0-4; Preferred 0-3; More preferably 0-2; Most preferably 0-1;
Preferably, R 2Be hydrogen, C 1-C 4Alkyl, halogen, hydroxyl, C 1-C 4Alkoxyl group, contain the C of 1-3 halogen 1-C 2Halogenated alkoxy, sulfydryl, C 1-C 4Alkylthio, amino-sulfonyl, C 1-C 4Alkyl amino sulfonyl, two-(C 1-C 4Alkyl) amino-sulfonyl, amino, C 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl is amino or contain the C of 1-3 halogen 1-C 2Halogenated alkyl group;
More preferably, R 2Be hydrogen, C 1-C 4Alkyl, halogen, hydroxyl, C 1-C 4Alkoxyl group, trifluoromethoxy, sulfydryl, C 1-C 4Alkylthio, amino, C 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino or trifluoromethyl;
More preferably, R 2Be hydrogen, methyl, ethyl, fluorine, chlorine, hydroxyl, methoxyl group, trifluoromethoxy, amino, methylamino-, dimethylamino, kharophen or trifluoromethyl; And most preferably, R 2Be hydrogen or hydroxyl;
Wherein each Z is independently
(1) chemical bond;
(2) alkyl, the alkenyl or alkynyl that is replaced arbitrarily by following group: (a) 1-3 is selected from the group of amino, alkylamino, dialkylamino, alkanoyl amido, alkoxycarbonyl amido, alkyl sulfonyl amino, hydroxyl, alkoxyl group, alkylthio or halogen and (b) 1-2 group that is selected from heterocyclic radical, aryl or heteroaryl; It can be replaced arbitrarily by 1-3 group that is selected from amino, alkylamino, dialkylamino, alkanoyl amido, alkoxycarbonyl amido, alkyl sulfonyl amino, hydroxyl, alkoxyl group, alkylthio, halogen, alkyl or haloalkyl;
(3) by 1-3 any heterocyclic radical that replaces of group that is selected from amino, alkylamino, dialkylamino, alkanoyl amido, alkoxycarbonyl amido, alkyl sulfonyl amino, hydroxyl, alkoxyl group, alkylthio, alkyl or haloalkyl; Perhaps
(4) by 1-3 any aryl or the heteroaryl that replaces of group that is selected from amino, alkylamino, dialkylamino, alkanoyl amido, alkoxycarbonyl amido, alkyl sulfonyl amino, hydroxyl, alkoxyl group, alkylthio, cyano group, halogen, alkyl or haloalkyl;
Preferably, each Z is independently
(1) chemical bond;
(2) C that is replaced arbitrarily by following group 1-C 8Alkyl, C 2-C 8Thiazolinyl or C 2-C 8Alkynyl: 1-3 is selected from amino, C 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4The group of alkylthio or halogen and (b) 1-2 be selected from the group of heterocyclic radical, aryl or heteroaryl, it can be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, halogen, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4The group of haloalkyl replaces arbitrarily;
(3) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4The heterocyclic radical that the group of haloalkyl replaces arbitrarily; Perhaps
(4) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, halogen, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4Aryl or heteroaryl that the group of haloalkyl replaces arbitrarily;
More preferably, each Z is independently
(1) chemical bond;
(2) C that is replaced arbitrarily by following group 1-C 8Alkyl, C 2-C 8Thiazolinyl or C 2-C 8Alkynyl: 1-3 is selected from amino, C 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4The group of alkylthio or halogen and (b) 1-2 be selected from the group of heterocyclic radical, aryl or heteroaryl, it can be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, halogen, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4The group of haloalkyl replaces arbitrarily;
(3) be selected from amino, C by 1-2 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4The heterocyclic radical that the group of haloalkyl replaces arbitrarily; Perhaps
(4) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, halogen, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4Aryl or heteroaryl that the group of haloalkyl replaces arbitrarily;
More preferably, each Z is independently
(1) chemical bond;
(2) C that is replaced arbitrarily by following group 1-C 8Alkyl or C 2-C 8Thiazolinyl: 1-3 is selected from amino, C 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4The group of alkylthio or halogen and (b) 1-2 be selected from the group of heterocyclic radical, aryl or heteroaryl, it can be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, halogen, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 2The group of haloalkyl replaces arbitrarily;
(3) be selected from amino, two-(C by 1-2 1-C 4Alkyl) amino, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio or C 1-C 4The heterocyclic radical that the group of alkyl replaces arbitrarily; Perhaps
(4) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, halogen, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 2Aryl or heteroaryl that the group of haloalkyl replaces arbitrarily;
More preferably, each Z is independently
(1) chemical bond;
(2) C that is replaced arbitrarily by following group 1-C 4Alkyl or C 2-C 5Thiazolinyl: 1-3 is selected from amino, two-(C 1-C 2Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 2Alkoxyl group, C 1-C 2The group of alkylthio or halogen and (b) 1-2 be selected from the group of heterocyclic radical, aryl or heteroaryl, it can be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 2Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, halogen, C 1-C 4The group of alkyl or trifluoromethyl replaces arbitrarily;
(3) be selected from amino, two-(C by 1-2 1-C 2Alkyl) amino, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 2Alkoxyl group, C 1-C 2Alkylthio or C 1-C 4The heterocyclic radical that the group of alkyl replaces arbitrarily; Perhaps
(4) be selected from amino, two-(C by 1-3 1-C 2Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 2Alkoxyl group, C 1-C 2Alkylthio, cyano group, halogen, C 1-C 4Aryl or heteroaryl that the group of alkyl or trifluoromethyl replaces arbitrarily;
More preferably, each Z is independently
(1) chemical bond;
(2) C that is replaced arbitrarily by following group 1-C 4Alkyl or C 2-C 5Thiazolinyl: 1-3 is selected from amino, two-(C 1-C 2Alkyl) amino, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 2Alkoxyl group, C 1-C 2The group of alkylthio or halogen and (b) 1-2 be selected from the group of aryl or heteroaryl, it can be selected from amino, two-(C by 1-2 1-C 2Alkyl) amino, kharophen, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 2Alkoxyl group, C 1-C 2Alkylthio, halogen, C 1-C 4The group of alkyl or trifluoromethyl replaces arbitrarily; Perhaps
(3) be selected from amino, two-(C by 1-3 1-C 2Alkyl) amino, kharophen, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 2Alkoxyl group, C 1-C 2Alkylthio, cyano group, halogen, C 1-C 4Aryl or heteroaryl that the group of alkyl or trifluoromethyl replaces arbitrarily;
More preferably, each Z is independently
(1) chemical bond; Or
(2) be selected from amino, two-(C by 1-2 1-C 2Alkyl) amino, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 2Alkoxyl group, C 1-C 2The C that the group of alkylthio, halogen or aryl or heteroaryl replaces arbitrarily 1-C 4Alkyl, described aryl or heteroaryl can be selected from hydroxyl, C by 1-2 1-C 2Alkoxyl group, C 1-C 2Alkylthio, halogen, C 1-C 4The group of alkyl or trifluoromethyl replaces arbitrarily; With
Most preferably, each Z is independently
(1) chemical bond; Or
(2) by 1-2 any C that replaces of group that is selected from amino, t-butoxycarbonyl amino, dimethylamino, hydroxyl, methoxyl group, methylthio group or halogen 1-C 4Alkyl;
Each Y is independently
(1) hydrogen;
(2) halogen or nitro;
(3)-C (O)-R 20Or-C (NR 5)-NR 5R 21Group;
(4)-OR 21,-O-C (O)-R 21,-O-C (O)-NR 5R 21Or-O-C (O)-NR 22-S (O) 2-R 20Group;
(5)-SR 21,-S (O)-R 20,-S (O) 2-R 20,-S (O) 2-NR 5R 21,-S (O) 2-NR 22-C (O)-R 21,-S (O) 2-NR 22-C (O)-OR 20Or-S (O) 2-NR 22-C (O)-NR 5R 21Group; Or
(6)-NR 5R 21,-NR 22-C (O)-R 21,-NR 22-C (O)-OR 20,-NR 22-C (O)-NR 5R 21,-NR 22-C (NR 5)-NR 5R 21,-NR 22-S (O) 2-R 20Or-NR 22-S (O) 2-NR 5R 21Group;
Preferably, each Y is independently
(1) hydrogen;
(2) halogen;
(3)-C (O)-R 20Or-C (NR 5)-NR 5R 21Group;
(4)-OR 21,-O-C (O)-R 21Or-O-C (O)-NR 5R 21Group;
(5)-SR 21,-S (O)-R 20,-S (O) 2-R 20Or-S (O) 2-NR 5R 21Group; Or
(6)-NR 5R 21,-NR 22-C (O)-R 21,-NR 22-C (O)-OR 20,-NR 22-C (O)-NR 5R 21,-NR 22-C (NR 5)-NR 5R 21,-NR 22-S (O) 2-R 20Or-NR 22-S (O) 2-NR 5R 21Group;
More preferably, each Y is independently
(1) hydrogen;
(2)-C (O)-R 20Group;
(3)-OR 21,-SR 21,-S (O)-R 20,-S (O) 2-R 20Or-S (O) 2-NR 5R 21Group; Or
(4)-NR 5R 12,-NR 22-C (O)-R 12,-NR 22-C (O)-OR 20,-NR 22-C (O)-NR 5R 21,-NR 22-S (O) 2-R 20Or-NR 22-S (O) 2-NR 5R 21Group;
More preferably, each Y is independently
(1) hydrogen;
(2)-C (O)-R 20Group;
(3)-OR 21,-SR 21,-S (O)-R 20,-S (O) 2-R 20Or-S (O) 2-NR 5R 21Group; Or
(4)-NR 5R 12,-NR 22-C (O)-R 12Or-NR 22-S (O) 2-R 20Group;
More preferably, each Y is independently
(1)-C (O)-R 20Group;
(2)-OR 20,-SR 21,-S (O)-R 20,-S (O) 2-R 20Or-S (O) 2-NR 5R 21Group; Or
(3)-NR 5R 21,-NR 22-C (O)-R 21Or-NR 22-S (O) 2-R 20Group;
Most preferably, each Y is-OR independently 21,-SR 21Or-NR 5R 21Group;
Each R wherein 5Be independently
(1) hydrogen;
(2) by 1-3 be selected from amino, alkylamino, dialkylamino, hydroxyl, alkoxyl group, alkylthio ,-SO 3Alkyl, alkenyl or alkynyl that the group of H or halogen replaces arbitrarily; Perhaps
(3) by 1-3 any aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclic radical, Heterocyclylalkyl, cycloalkyl or the cycloalkylalkyl that replaces of group that is selected from amino, alkylamino, dialkylamino, hydroxyl, alkoxyl group, alkylthio, alkyl or haloalkyl;
Preferably, each R 5Be independently
(1) hydrogen;
(2) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio ,-SO 3The C that the group of H or halogen replaces arbitrarily 1-C 8Alkyl, C 2-C 8Thiazolinyl or C 2-C 8Alkynyl; Perhaps
(3) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl or contain the C that 1-3 is selected from halogen 1-C 4Aryl, heteroaryl, aryl-C that the group of haloalkyl replaces arbitrarily 1-C 4-alkyl, heteroaryl-C 1-C 4-alkyl, heterocyclic radical, heterocyclic radical-C 1-C 4-alkyl, C 3-C 8Cycloalkyl or C 3-C 8-cycloalkyl-C 1-C 4-alkyl;
More preferably, each R 5Be independently
(1) hydrogen;
(2) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio ,-SO 3The C that the group of H or halogen replaces arbitrarily 1-C 4Alkyl, C 2-C 5Thiazolinyl or C 2-C 5Alkynyl; Perhaps
(3) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4Aryl, heteroaryl, aryl-C that the group of haloalkyl replaces arbitrarily 1-C 4-alkyl, heteroaryl-C 1-C 4-alkyl, heterocyclic radical, heterocyclic radical-C 1-C 4-alkyl, C 3-C 8Cycloalkyl or C 3-C 8-cycloalkyl-C 1-C 4-alkyl;
More preferably, each R 5Be independently
(1) hydrogen;
(2) be selected from amino, two-(C by 1-3 1-C 4Alkyl) amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio ,-SO 3The C that the group of H or halogen replaces arbitrarily 1-C 4Alkyl or C 2-C 5Thiazolinyl; Perhaps
(3) be selected from amino, two-(C by 1-3 1-C 4Alkyl) amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 2Phenyl-C that the group of haloalkyl replaces arbitrarily 1-C 2-alkyl, heteroaryl-C 1-C 2-alkyl, heterocyclic radical-C 1-C 2-alkyl or C 3-C 6-cycloalkyl-C 1-C 2-alkyl;
More preferably, each R 5Be independently
(1) hydrogen;
(2) be selected from amino, two-(C by 1-3 1-C 4Alkyl) amino, hydroxyl, C 1-C 2Alkoxyl group, C 1-C 2The C that the group of alkylthio or halogen replaces arbitrarily 1-C 4Alkyl; Perhaps
(3) be selected from amino, two-(C by 1-3 1-C 2Alkyl) amino, hydroxyl, C 1-C 2Alkoxyl group, C 1-C 2Alkylthio, methoxyl group, methylthio group, C 1-C 4Phenyl-C that the group of alkyl or trifluoromethyl replaces arbitrarily 1-C 2-alkyl, heteroaryl-C 1-C 2-alkyl, heterocyclic radical-C 1-C 2-alkyl or C 3-C 6-cycloalkyl-C 1-C 2-alkyl;
More preferably, each R 5Be independently
(1) hydrogen;
(2) C that is replaced arbitrarily by 1-3 halogen 1-C 4Alkyl; Perhaps
(3) by 1-3 any phenyl-C that replaces of group that is selected from amino, dimethylamino, hydroxyl, methoxyl group, methylthio group, methyl or trifluoromethyl 1-C 2-alkyl or heteroaryl-C 1-C 2-alkyl;
More preferably, each R 5Be hydrogen or C independently 1-C 4Alkyl; And most preferably, each R 5Be hydrogen independently;
Each R wherein 20Independently be
(1) is selected from the alkyl that following group replaces arbitrarily by 1-3, alkenyl or alkynyl: amino, alkylamino, dialkylamino, alkanoyl amido, alkoxycarbonyl amido, N-(carbalkoxy)-N-(alkyl) amino, amino carbonyl amino, alkyl sulfonyl amino, hydroxyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, halogen or aralkoxy, aromatic alkylthio, the aralkyl alkylsulfonyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl groups, it can be selected from amino by 1-3, alkylamino, dialkylamino, alkanoyl amido, alkoxycarbonyl amido, alkyl sulfonyl amino, alkanoyl, hydroxyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, halogen, the group of alkyl or haloalkyl replaces arbitrarily;
(2) by 1-3 any heterocyclic radical that replaces of group that is selected from amino, alkylamino, dialkylamino, alkanoyl amido, alkoxycarbonyl amido, alkyl sulfonyl amino, hydroxyl, alkoxyl group, alkylthio, alkyl or haloalkyl; Perhaps
(3) by 1-3 any aryl or the heteroaryl that replaces of group that is selected from amino, alkylamino, dialkylamino, alkanoyl amido, alkoxycarbonyl amido, alkyl sulfonyl amino, carbalkoxy, hydroxyl, alkoxyl group, alkylthio, cyano group, halogen, azido-, alkyl or haloalkyl;
Preferably, each R 20Be independently
(1) is selected from the C that following group replaces arbitrarily by 1-3 1-C 8Alkyl, C 2-C 8Thiazolinyl or C 2-C 8Alkynyl: amino, C 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, N-((C 1-C 4Alkoxyl group) carbonyl)-N-(C 1-C 4Alkyl) amino, amino carbonyl amino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl sulphinyl, C 1-C 4Alkyl sulphonyl, halogen or aryl-C 1-C 4-alkoxyl group, aryl-C 1-C 4-alkylthio, aryl-C 1-C 4-alkyl sulphonyl, C 3-C 8Cycloalkyl, heterocyclic radical, aryl or heteroaryl groups, it can be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, C 1-C 5Alkanoyl, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl sulphinyl, C 1-C 4Alkyl sulphonyl, halogen, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4The group of haloalkyl replaces arbitrarily;
(2) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4The heterocyclic radical that the group of haloalkyl replaces arbitrarily; Perhaps
(3) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, (C 1-C 4Alkoxyl group) carbonyl, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, halogen, azido-, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4Aryl or heteroaryl that the group of haloalkyl replaces arbitrarily;
More preferably, each R 20Be independently
(1) is selected from the C that following group replaces arbitrarily by 1-3 1-C 8Alkyl, C 2-C 5Thiazolinyl or C 2-C 5Alkynyl: amino, C 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, N-((C 1-C 4Alkoxyl group) carbonyl)-N-(C 1-C 4Alkyl) amino, amino carbonyl amino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl sulphinyl, C 1-C 4Alkyl sulphonyl, halogen or aryl-C 1-C 4-alkoxyl group, aryl-C 1-C 4-alkylthio, aryl-C 1-C 4-alkyl sulphonyl, C 3-C 8Cycloalkyl, heterocyclic radical, aryl or heteroaryl groups, it can be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, C 1-C 5Alkanoyl, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl sulphinyl, C 1-C 4Alkyl sulphonyl, halogen, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4The group of haloalkyl replaces arbitrarily;
(2) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4The heterocyclic radical that the group of haloalkyl replaces arbitrarily; Perhaps
(3) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, (C 1-C 4Alkoxyl group) carbonyl, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, halogen, azido-, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4Aryl or heteroaryl that the group of haloalkyl replaces arbitrarily;
More preferably, each R 20Be independently
(1) is selected from the C that following group replaces arbitrarily by 1-3 1-C 8Alkyl or C 2-C 5Thiazolinyl: amino, C 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, N-((C 1-C 4Alkoxyl group) carbonyl)-N-(C 1-C 4Alkyl) amino, amino carbonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl sulphinyl, C 1-C 4Alkyl sulphonyl, halogen or aryl-C 1-C 4-alkoxyl group, aryl-C 1-C 4-alkylthio, aryl-C 1-C 4-alkyl sulphonyl, C 3-C 6Cycloalkyl, heterocyclic radical, aryl or heteroaryl groups, it can be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, C 1-C 5Alkanoyl, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, halogen, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 2The group of haloalkyl replaces arbitrarily;
(2) be selected from amino, C by 1-2 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio or C 1-C 4The heterocyclic radical that the group of alkyl replaces arbitrarily; Perhaps
(3) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, (C 1-C 4Alkoxyl group) carbonyl, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, halogen, azido-, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 2Aryl or heteroaryl that the group of haloalkyl replaces arbitrarily;
More preferably, each R 20Be independently
(1) is selected from the C that following group replaces arbitrarily by 1-3 1-C 8Alkyl or C 2-C 5Thiazolinyl: amino, C 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, N-((C 1-C 4Alkoxyl group) carbonyl)-N-(C 1-C 4Alkyl) amino, amino carbonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl sulphinyl, C 1-C 4Alkyl sulphonyl, halogen or aryl-C 1-C 4-alkoxyl group, aryl-C 1-C 4-alkylthio, aryl-C 1-C 4-alkyl sulphonyl, C 3-C 6Cycloalkyl, heterocyclic radical, aryl or heteroaryl groups, it can be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, C 1-C 5Alkanoyl, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, halogen, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 2The group of haloalkyl replaces arbitrarily;
(2) be selected from amino, two-(C by 1-2 1-C 4Alkyl) amino, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio or C 1-C 4The heterocyclic radical that the group of alkyl replaces arbitrarily; Perhaps
(3) be selected from amino, C by 1-2 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, kharophen, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, (C 1-C 4Alkoxyl group) carbonyl, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, halogen, azido-, C 1-C 4Aryl or heteroaryl that the group of alkyl or trifluoromethyl replaces arbitrarily;
More preferably, each R 20Be independently
(1) is selected from the C that following group replaces arbitrarily by 1-3 1-C 8Alkyl: amino, C 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, N-((C 1-C 4Alkoxyl group) carbonyl)-N-(C 1-C 4Alkyl) amino, amino carbonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl sulphinyl, C 1-C 4Alkyl sulphonyl, halogen or C 3-C 6Cycloalkyl, heterocyclic radical, aryl or heteroaryl groups, it can be selected from amino, two-(C by 1-2 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, halogen, C 1-C 4The group of alkyl or trifluoromethyl replaces arbitrarily;
(2) be selected from hydroxyl, C by 1-2 1-C 4Alkoxyl group, C 1-C 4Alkylthio or C 1-C 4The heterocyclic radical that the group of alkyl replaces arbitrarily; Perhaps
(3) be selected from (C by 1-2 1-C 4Alkoxyl group) carbonyl, amino, C 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, halogen, azido-, C 1-C 4Aryl or heteroaryl that the group of alkyl or trifluoromethyl replaces arbitrarily;
More preferably, each R 20Be independently
(1) is selected from the C that following group replaces arbitrarily by 1-3 1-C 6Alkyl: amino, methylamino-, dimethylamino, t-butoxycarbonyl amino, N-((tert.-butoxy) carbonyl)-N-(methyl) amino, amino carbonyl amino, hydroxyl, butoxy, methoxyl group, butylthio, methylthio group, methylsulfinyl, methylsulfonyl, halogen or C 5-C 6Cycloalkyl, heterocyclic radical, phenyl or heteroaryl groups, it can be replaced arbitrarily by 1-2 group that is selected from amino, dimethylamino, kharophen, hydroxyl, methoxyl group, methylthio group, halogen, methyl or trifluoromethyl;
(2) be selected from hydroxyl or C by 1-2 1-C 4The heterocyclic radical that the group of alkyl replaces arbitrarily; Perhaps
(3) by 1-2 any aryl or the heteroaryl that replaces of group that is selected from amino, dimethylamino, hydroxyl, methoxyl group, methylthio group, halogen, methyl or trifluoromethyl;
More preferably, each R 20Be independently
(1) is selected from the C that following group replaces arbitrarily by 1-3 1-C 6Alkyl: amino, methylamino-, dimethylamino, t-butoxycarbonyl amino, N-((tert.-butoxy) carbonyl)-N-(methyl) amino, amino carbonyl amino, hydroxyl, butoxy, methoxyl group, butylthio, methylthio group, methylsulfinyl, methylsulfonyl, halogen or C 5-C 6Cycloalkyl, heterocyclic radical, phenyl or heteroaryl groups, it can be replaced arbitrarily by 1-2 group that is selected from amino, dimethylamino, kharophen, hydroxyl, methoxyl group, methylthio group, halogen, methyl or trifluoromethyl;
(2) heterocyclic radical; Perhaps
(3) by 1-2 any aryl or the heteroaryl that replaces of group that is selected from amino, dimethylamino, hydroxyl, methoxyl group, methylthio group, halogen, methyl or trifluoromethyl;
Most preferably, each R 20Be independently
(1) is selected from the C that following group replaces arbitrarily by 1-3 1-C 6Alkyl: amino, methylamino-, dimethylamino, hydroxyl or phenyl or heteroaryl groups, it can be replaced arbitrarily by 1-2 group that is selected from amino, dimethylamino, hydroxyl, methoxyl group, methylthio group, halogen, methyl or trifluoromethyl;
(2) heterocyclic radical; Perhaps
(3) by 1-2 any aryl or the heteroaryl that replaces of group that is selected from amino, dimethylamino, hydroxyl, methoxyl group, methylthio group, halogen, methyl or trifluoromethyl;
Each R 21Be hydrogen or R independently 20
Each R 22Be independently
(1) hydrogen;
(2) be selected from the alkyl that the group of heterocyclic radical, aryl or heteroaryl replaces arbitrarily, described heterocyclic radical, aryl or heteroaryl can be replaced arbitrarily by 1-3 group that is selected from amino, alkylamino, dialkylamino, alkanoyl amido, alkoxycarbonyl amido, alkyl sulfonyl amino, hydroxyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, cyano group, halogen, alkyl or haloalkyl; Perhaps
(3) by 1-3 any heterocyclic radical, aryl or the heteroaryl that replaces of group that is selected from amino, alkylamino, dialkylamino, alkanoyl amido, alkoxycarbonyl amido, alkyl sulfonyl amino, hydroxyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, cyano group, halogen, alkyl or haloalkyl; Condition is, when Z is that chemical bond and Y are-NR 22-C (O)-NH 2The time, R 22It or not any substituted aryl;
Preferably, each R 22Be independently
(1) hydrogen;
(2) be selected from the C that the group of heterocyclic radical, aryl or heteroaryl replaces arbitrarily 1-C 4Alkyl, described heterocyclic radical, aryl or heteroaryl can be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl sulphinyl, C 1-C 4Alkyl sulphonyl, cyano group, halogen, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4The group of haloalkyl replaces arbitrarily; Perhaps
(3) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl sulphinyl, C 1-C 4Alkyl sulphonyl, cyano group, halogen, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4Heterocyclic radical, aryl or heteroaryl that the group of haloalkyl replaces arbitrarily; Condition is, when Z is that chemical bond and Y are-NR 22-C (O)-NH 2The time, R 22It or not any substituted aryl;
More preferably, each R 22Be independently
(1) hydrogen;
(2) be selected from the C that the group of phenyl or heteroaryl replaces arbitrarily 1-C 4Alkyl, described phenyl or heteroaryl can be selected from amino, two-(C by 1-3 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, halogen, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 2The group of haloalkyl replaces arbitrarily;
More preferably, each R 22Be hydrogen or C independently 1-C 4Alkyl; And most preferably, each R 22Be hydrogen or methyl independently;
R 11And R 12Be selected from aryl or the heteroaryl that following group replaces arbitrarily by 1-3 independently of one another
(1)R 30；
(2) halogen or cyano group;
(3)-C (O)-R 30,-C (O)-OR 29,-C (O)-NR 31R 32Or-C (NR 31)-NR 31R 32Group;
(4)-OR 29,-O-C (O)-R 29,-O-C (O)-NR 31R 32Or-O-C (O)-NR 33-S (O) 2-R 30Group;
(5)-SR 29,-S (O)-R 30,-S (O) 2-R 30,-S (O) 2-NR 31R 32,-S (O) 2-NR 33-C (O)-R 30,-S (O) 2-NR 33-C (O)-OR 30Or-S (O) 2-NR 33-C (O)-NR 31R 32Group; Or
(6)-NR 31R 32,-NR 33-C (O)-R 29,-NR 33-C (O)-OR 30,-NR 33-C (O)-NR 31R 32,-NR 33-C (NR 31)-NR 31R 32,-NR 33-S (O) 2-R 30Or-NR 33-S (O) 2-NR 31R 32Group; Condition is (1) R 11Not by any 4-pyridyl, 4-pyrimidyl, 4-quinolyl or the 6-isoquinolyl that replaces of 1-2 substituting group; (2) R 11And R 12The aryl of replacement separately, heteroaryl, cycloalkyl and heterocyclic radical add up to 0-1;
Preferably, R 11And R 12Be selected from aryl or the heteroaryl that following group replaces arbitrarily by 1-2 independently of one another
(1)R 30；
(2) halogen or cyano group;
(3)-C (O)-R 30,-C (O)-OR 29,-C (O)-NR 31R 32Or-C (NR 31)-NR 31R 32Group;
(4)-OR 29,-O-C (O)-R 29,-O-C (O)-NR 31R 32Or-O-C (O)-NR 33-S (O) 2-R 30Group;
(5)-SR 29,-S (O)-R 30,-S (O) 2-R 30,-S (O) 2-NR 31R 32,-S (O) 2-NR 33-C (O)-R 30,-S (O) 2-NR 33-C (O)-OR 30Or-S (O) 2-NR 33-C (O)-NR 31R 32Group; Or
(6)-NR 31R 32,-NR 33-C (O)-R 29,-NR 33-C (O)-OR 30,-NR 33-C (O)-NR 31R 32,-NR 33-C (NR 31)-NR 31R 32,-NR 33-S (O) 2-R 30Or-NR 33-S (O) 2-NR 31R 32Group; Condition is (1) R 11Not by any 4-pyridyl, 4-pyrimidyl, 4-quinolyl or the 6-isoquinolyl that replaces of 1-2 substituting group; (2) R 11And R 12The aryl of replacement separately, heteroaryl, cycloalkyl and heterocyclic radical add up to 0-1;
More preferably, R 11And R 12Be selected from aryl or the heteroaryl that following group replaces arbitrarily by 1-2 independently of one another
(1)R 30；
(2) halogen or cyano group;
(3)-C (O)-R 30,-C (O)-OR 29,-C (O)-NR 31R 32Or-C (NR 31)-NR 31R 32Group;
(4)-OR 29,-SR 29,-S (O)-R 30,-S (O) 2-R 30,-S (O) 2-NR 31R 32,-NR 31R 32,-NR 33-C (O)-R 29, or-NR 33-C (O)-OR 30Group;
More preferably, R 11Be aryl and R 12Be heteroaryl, wherein said aryl and heteroaryl can be selected from following group by 1-2 and replace arbitrarily:
(1)R 30；
(2) halogen or cyano group;
(3)-C (O)-R 30,-C (O)-OR 29,-C (O)-NR 31R 32Or-C (NR 31)-NR 31R 32Group; Or
(4)-OR 29,-SR 29,-S (O)-R 30,-S (O) 2-R 30,-S (O) 2-NR 31R 32,-NR 31R 32Or-NR 33-C (O)-R 29Group;
More preferably, R 11Be aryl and R 12Be heteroaryl, wherein said aryl and heteroaryl can be selected from following group by 1-2 and replace arbitrarily:
(1)R 30；
(2) halogen or cyano group;
(3)-C (O)-NR 31R 32,-OR 29,-SR 29,-S (O)-R 30,-S (O) 2-R 30,-S (O) 2-NR 31R 32,-NR 31R 32Or-NR 33-C (O)-R 29Group;
More preferably, R 11Be can be by 1-2 aryl that is selected from any replacement of following group, described group be (1) R 30(2) halogen or cyano group; Perhaps (3)-C (O)-NR 31R 32,-OR 29,-SR 29,-S (O)-R 30,-S (O) 2-R 30,-S (O) 2-NR 31R 32,-NR 31R 32Or-NR 33-C (O)-R 29Group; More preferably, R 11Be can be by 1-2 aryl that is selected from any replacement of following group, described group be amino, dimethylamino, kharophen, hydroxyl, halogen, cyano group, methoxyl group, methylthio group, methylsulfinyl, methyl sulphonyl, aminocarboxyl, methyl or trifluoromethyl group; More preferably, R 11Be unsubstituted phenyl or naphthyl or can be selected from the phenyl that following group replaces arbitrarily that described group is amino, dimethylamino, kharophen, hydroxyl, halogen, cyano group, methoxyl group, methylthio group, methylsulfinyl, methyl sulphonyl, aminocarboxyl, methyl or trifluoromethyl group by 1-2; And most preferably, R 11Be unsubstituted phenyl or be selected from the phenyl that the group of amino, dimethylamino, kharophen, hydroxyl, halogen, cyano group, methoxyl group, methylthio group, methyl sulphonyl, methyl or trifluoromethyl replaces arbitrarily by 1-2;
More preferably, R 12Be can be by 1-2 heteroaryl that is selected from any replacement of following group, described group be (1) R 30(2) halogen or cyano group; Perhaps (3)-C (O)-NR 31R 32,-OR 29,-SR 29,-NR 31R 32Or-NR 33-C (O)-R 29Group; More preferably, R 12Be can be by 1-2 heteroaryl that is selected from any replacement of following group, described group be amino, dimethylamino, kharophen, hydroxyl, halogen, cyano group, methoxyl group, methyl or trifluoromethyl group; More preferably, R 12Be can be by any 4-pyridyl, 4-quinolyl, 4-imidazolyl or the 4-pyrimidyl that replaces of following groups, described group be amino, dimethylamino, kharophen, hydroxyl, halogen, cyano group, methoxyl group, methyl or trifluoromethyl group; And most preferably, R 12Be selected from any 4-pyridyl that replaces of group of amino, dimethylamino, kharophen, hydroxyl, halogen, cyano group, methoxyl group, methyl or trifluoromethyl;
Each R wherein 30Be independently
(1) is selected from alkyl, the alkenyl or alkynyl that following group replaces arbitrarily :-NR by 1-3 31R 31,-CO 2R 23, hydroxyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, cyano group, halogen or aralkoxy, aromatic alkylthio, aralkyl alkylsulfonyl, heterocyclic radical, aryl or heteroaryl groups, it can be replaced arbitrarily by 1-3 group that is selected from amino, alkylamino, dialkylamino, alkanoyl amido, alkoxycarbonyl amido, alkyl sulfonyl amino, hydroxyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, cyano group, halogen, alkyl or haloalkyl;
(2) by 1-3 any heterocyclic radical that replaces of group that is selected from amino, alkylamino, dialkylamino, alkanoyl amido, alkoxycarbonyl amido, alkyl sulfonyl amino, hydroxyl, alkoxyl group, alkylthio, cyano group, alkyl or haloalkyl; Perhaps
(3) by 1-3 any aryl or the heteroaryl that replaces of group that is selected from amino, alkylamino, dialkylamino, alkanoyl amido, alkoxycarbonyl amido, alkyl sulfonyl amino, hydroxyl, alkoxyl group, alkylthio, cyano group, halogen, alkyl or haloalkyl;
Preferably, each R 30Be independently
(1) is selected from the C that following group replaces arbitrarily by 1-3 1-C 4Alkyl, C 2-C 4Thiazolinyl or C 2-C 4Alkynyl :-NR 31R 31,-CO 2R 23, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl sulphinyl, C 1-C 4Alkyl sulphonyl, cyano group, halogen or aryl-C 1-C 4-alkoxyl group, aryl-C 1-C 4-alkylthio, aryl-C 1-C 4-alkyl sulphonyl, heterocyclic radical, aryl or heteroaryl groups, it can be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl sulphinyl, C 1-C 4Alkyl sulphonyl, cyano group, halogen, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4The group of haloalkyl replaces arbitrarily;
(2) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4The heterocyclic radical that the group of haloalkyl replaces arbitrarily; Perhaps
(3) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, halogen, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4Aryl or heteroaryl that the group of haloalkyl replaces arbitrarily;
More preferably, each R 30Be independently
(1) is selected from the C that following group replaces arbitrarily by 1-3 1-C 4Alkyl:
(a)-NR 31R 31；
(b) C 1-C 4-alkoxy carbonyl or carbobenzoxy or benzene methoxycarbonyl, it can be selected from amino, alkylamino, two-(C by 1-3 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, halogen, C 1-C 4The group of alkyl or trifluoromethyl replaces arbitrarily; Perhaps
(c) hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio or phenyl-C 1-C 4-alkoxyl group, phenyl-C 1-C 4-alkylthio, heterocyclic radical, phenyl or heteroaryl groups, it can be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, halogen, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4The group of haloalkyl replaces arbitrarily;
(2) contain the C of 1-3 halogen 1-C 4Haloalkyl; Perhaps
(3) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, halogen, C 1-C 4Aryl or heteroaryl that the group of alkyl or trifluoromethyl replaces arbitrarily;
More preferably, each R 30Be independently
(1) C that is replaced arbitrarily by following groups 1-C 4Alkyl:
(a) amino, C 1-C 4Alkylamino or two-(C 1-C 4Alkyl) amino; Perhaps
(b) hydroxyl, C 1-C 4Alkoxyl group, heterocyclic radical, phenyl or heteroaryl, it can be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, halogen, C 1-C 4The group of alkyl or trifluoromethyl replaces arbitrarily;
(2) contain the C of 1-3 halogen 1-C 2Haloalkyl; Perhaps
(3) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, halogen, C 1-C 4Aryl or heteroaryl that the group of alkyl or trifluoromethyl replaces arbitrarily;
More preferably, each R 30Be independently
(1) is selected from the C that the group of phenyl or heteroaryl replaces arbitrarily 1-C 4Alkyl, described phenyl or heteroaryl can be selected from amino, two-(C by 1-3 1-C 2Alkyl) amino, kharophen, hydroxyl, C 1-C 2Alkoxyl group, halogen, C 1-C 4The group of alkyl or trifluoromethyl replaces arbitrarily;
(2) trifluoromethyl; Perhaps
(3) be selected from amino, two-(C by 1-3 1-C 2Alkyl) amino, kharophen, hydroxyl, C 1-C 2Alkoxyl group, halogen, C 1-C 4Aryl or heteroaryl that the group of alkyl or trifluoromethyl replaces arbitrarily;
More preferably, each R 30Be independently
(1) is selected from the C that the group of phenyl or heteroaryl replaces arbitrarily 1-C 4Alkyl, described phenyl or heteroaryl can be replaced arbitrarily by 1-3 group that is selected from amino, dimethylamino, kharophen, hydroxyl, halogen, methoxyl group, methyl or trifluoromethyl;
(2) trifluoromethyl; Perhaps
(3) by 1-3 any aryl or the heteroaryl that replaces of group that is selected from amino, dimethylamino, kharophen, hydroxyl, halogen, methoxyl group, methyl or trifluoromethyl;
Most preferably, each R 30Be independently
(1) is selected from the C that the group of phenyl or heteroaryl replaces arbitrarily 1-C 4Alkyl, described phenyl or heteroaryl can be replaced arbitrarily by 1-2 group that is selected from amino, dimethylamino, kharophen, hydroxyl, halogen, methoxyl group, methyl or trifluoromethyl;
(2) trifluoromethyl; Perhaps
(3) by 1-3 any aryl or the heteroaryl that replaces of group that is selected from amino, dimethylamino, kharophen, hydroxyl, halogen, methoxyl group, methyl or trifluoromethyl;
Each R 29Be hydrogen or R independently 30And most preferably, R 29By 1-2 any aryl or the heteroaryl that replaces of group that is selected from amino, dimethylamino, kharophen, hydroxyl, halogen, methoxyl group, methyl or trifluoromethyl;
Each R 31Be independently
(1) hydrogen;
(2) alkyl that is replaced arbitrarily by cycloalkyl, aryl, heterocyclic radical or heteroaryl groups, described substituting group can be replaced arbitrarily by 1-3 group that is selected from amino, alkylamino, dialkylamino, alkanoyl amido, alkoxycarbonyl amido, alkyl sulfonyl amino, hydroxyl, alkoxyl group, alkylthio, cyano group, alkyl or haloalkyl; Perhaps
(3) by 1-3 any aryl, heteroaryl, heterocyclic radical or the cycloalkyl that replaces of group that is selected from amino, alkylamino, dialkylamino, alkanoyl amido, alkoxycarbonyl amido, alkyl sulfonyl amino, hydroxyl, alkoxyl group, alkylthio, cyano group, alkyl or haloalkyl;
Preferably, each R 31Be independently
(1) hydrogen;
(2) by C 3-C 8The C that cycloalkyl, aryl, heterocyclic radical or heteroaryl groups replace arbitrarily 1-C 4Alkyl, described substituting group can be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4The group of haloalkyl replaces arbitrarily; Perhaps
(3) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4Aryl, heteroaryl, heterocyclic radical or C that the group of haloalkyl replaces arbitrarily 3-C 8Cycloalkyl;
More preferably, each R 31Be independently
(1) hydrogen; Perhaps
(2) by phenyl or any C that replaces of heteroaryl groups 1-C 4Alkyl, described substituting group can be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, C 1-C 4The group of alkyl or trifluoromethyl replaces arbitrarily;
More preferably, each R 31Be hydrogen or C independently 1-C 4Alkyl; And most preferably, each R 31Be hydrogen, methyl or ethyl independently;
Each R 32Be independently
(1) hydrogen;
(2) alkyl that is replaced arbitrarily by cycloalkyl, aryl, heterocyclic radical or heteroaryl groups, described substituting group can be replaced arbitrarily by 1-3 group that is selected from amino, alkylamino, dialkylamino, alkanoyl amido, alkoxycarbonyl amido, alkyl sulfonyl amino, hydroxyl, alkoxyl group, alkylthio, cyano group, alkyl or haloalkyl; Perhaps
(3) by 1-3 any aryl, heteroaryl, heterocyclic radical or the cycloalkyl that replaces of group that is selected from amino, alkylamino, dialkylamino, alkanoyl amido, alkoxycarbonyl amido, alkyl sulfonyl amino, hydroxyl, alkoxyl group, alkylthio, cyano group, alkyl or haloalkyl;
Preferably, each R 32Be independently
(1) hydrogen;
(2) by C 3-C 8The C that cycloalkyl, aryl, heterocyclic radical or heteroaryl groups replace arbitrarily 1-C 4Alkyl, described substituting group can be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4The group of haloalkyl replaces arbitrarily; Perhaps
(3) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4Aryl, heteroaryl, heterocyclic radical or C that the group of haloalkyl replaces arbitrarily 3-C 8Cycloalkyl;
More preferably, each R 32Be independently
(1) hydrogen;
(2) by C 3-C 6The C that cycloalkyl, aryl, heterocyclic radical or heteroaryl groups replace arbitrarily 1-C 4Alkyl, described substituting group can be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4The group of haloalkyl replaces arbitrarily; Perhaps
(3) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4Aryl, heteroaryl, heterocyclic radical or C that the group of haloalkyl replaces arbitrarily 3-C 6Cycloalkyl;
More preferably, each R 32Be independently
(1) hydrogen;
(2) by phenyl or any C that replaces of heteroaryl groups 1-C 4Alkyl, described substituting group can be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4The group of alkyl or trifluoromethyl replaces arbitrarily; Perhaps
(3) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Phenyl or heteroaryl that the group of alkyl or trifluoromethyl replaces arbitrarily;
More preferably, each R 32Be independently
(1) hydrogen;
(2) C 1-C 4Alkyl or the C that is replaced by phenyl or heteroaryl groups 1-C 2Alkyl, described substituting group can be replaced arbitrarily by 1-3 group that is selected from amino, dimethylamino, kharophen, hydroxyl, methoxyl group, methyl or trifluoromethyl; Perhaps
(3) by 1-3 any phenyl or the heteroaryl that replaces of group that is selected from amino, dimethylamino, kharophen, hydroxyl, methoxyl group, methyl or trifluoromethyl;
Most preferably, each R 32Be independently
(1) hydrogen or C 1-C 4Alkyl; Perhaps
(2) by 1-2 any phenyl or the heteroaryl groups that replaces of group that is selected from amino, dimethylamino, kharophen, hydroxyl, methoxyl group, methyl or trifluoromethyl; With
Each R wherein 33Be independently
(1) hydrogen; Perhaps
(2) be selected from the alkyl that the group of heterocyclic radical, aryl or heteroaryl replaces arbitrarily, described substituting group can be replaced arbitrarily by 1-3 group that is selected from amino, alkylamino, dialkylamino, alkanoyl amido, alkoxycarbonyl amido, alkyl sulfonyl amino, hydroxyl, alkoxyl group, alkylthio, cyano group, alkyl or haloalkyl;
Preferably, each R 33Be independently
(1) hydrogen; Perhaps
(2) be selected from the C that the group of heterocyclic radical, aryl or heteroaryl replaces arbitrarily 1-C 4Alkyl, described substituting group can be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4The group of haloalkyl replaces arbitrarily;
More preferably, each R 33Be hydrogen or C independently 1-C 4Alkyl; And most preferably, each R 33Be hydrogen or methyl independently.
Following precondition only relates to compound of the present invention, and does not relate to pharmaceutical composition or using method, and it comprises the compound (unless expressly stated otherwise) in the above-mentioned entire area:
1. work as R 1And R 12Identical and be contain heteroatoms that 1-3 is independently selected from N, S and O, can be at random with phenyl ring condensed 5-or 6-unit ring the time, R 11Be can be by halogen, C 1-C 6Alkyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, hydroxyl, amino, C 1-C 4The phenyl or naphthyl that alkylamino or dialkylamino replace arbitrarily, perhaps R 11Be to contain heteroatoms that 1-3 is independently selected from N, S and O, can at random condense and can be at random by C with phenyl ring 1-C 6When alkyl replaces 5-or 6-unit cycloalkyl, R then 2Not OH or NH 2
2. work as R 2Be H, R 11Be phenyl and R 12When being phenyl or 4-pyridyl, R 1Not H, methyl or amino;
3. work as R 2Be H, R 11Be 2-aminomethyl phenyl and R 12When being the 2-pyridyl, R 1It or not n-propyl; With
4. work as R 11And R 12During each any naturally substituted phenyl, R 1It or not any substituted 2-pyridyl.
Compound of the present invention generally can contain several asymmetric centers and represent with the racemic mixture form typically.The present invention includes racemic mixture, partial racemic compound and single enantiomorph and diastereomer.
Compound of interest comprises following compounds:
Figure A9718156300601
R wherein 2Be H and R 11, R 12And R 1Be one of listed combination in the following table:
R 11 R 12 R 1
Phenyl The 4-pyridyl The 1-piperazinyl
The 4-fluorophenyl The 4-pyridyl The 1-piperazinyl
The 3-fluorophenyl The 4-pyridyl The 1-piperazinyl
The 2-fluorophenyl The 4-pyridyl The 1-piperazinyl
The 4-chloro-phenyl- The 4-pyridyl The 1-piperazinyl
The 3-chloro-phenyl- The 4-pyridyl The 1-piperazinyl
The 2-chloro-phenyl- The 4-pyridyl The 1-piperazinyl
The 4-tolyl The 4-pyridyl The 1-piperazinyl
The 3-tolyl The 4-pyridyl The 1-piperazinyl
The 2-tolyl The 4-pyridyl The 1-piperazinyl
The 4-trifluoromethyl The 4-pyridyl The 1-piperazinyl
The 3-trifluoromethyl The 4-pyridyl The 1-piperazinyl
2, the 6-dichlorophenyl The 4-pyridyl The 1-piperazinyl
2, the 6-3,5-dimethylphenyl The 4-pyridyl The 1-piperazinyl
3, the 4-dichlorophenyl The 4-pyridyl The 1-piperazinyl
3, the 4-3,5-dimethylphenyl The 4-pyridyl The 1-piperazinyl
The 2,4 dichloro benzene base The 4-pyridyl The 1-piperazinyl
2, the 4-3,5-dimethylphenyl The 4-pyridyl The 1-piperazinyl
Phenyl 2-amino-4-pyridyl The 1-piperazinyl
The 4-fluorophenyl 2-amino-4-pyridyl The 1-piperazinyl
The 3-fluorophenyl 2-amino-4-pyridyl The 1-piperazinyl
The 2-fluorophenyl 2-amino-4-pyridyl The 1-piperazinyl
The 4-chloro-phenyl- 2-amino-4-pyridyl The 1-piperazinyl
The 3-chloro-phenyl- 2-amino-4-pyridyl The 1-piperazinyl
The 2-chloro-phenyl- 2-amino-4-pyridyl The 1-piperazinyl
The 4-tolyl 2-amino-4-pyridyl The 1-piperazinyl
The 3-tolyl 2-amino-4-pyridyl The 1-piperazinyl
The 2-tolyl 2-amino-4-pyridyl The 1-piperazinyl
The 4-trifluoromethyl 2-amino-4-pyridyl The 1-piperazinyl
The 3-trifluoromethyl 2-amino-4-pyridyl The 1-piperazinyl
2, the 6-dichlorophenyl 2-amino-4-pyridyl The 1-piperazinyl
2, the 6-3,5-dimethylphenyl 2-amino-4-pyridyl The 1-piperazinyl
3, the 4-dichlorophenyl 2-amino-4-pyridyl The 1-piperazinyl
3, the 4-3,5-dimethylphenyl 2-amino-4-pyridyl The 1-piperazinyl
The 2,4 dichloro benzene base 2-amino-4-pyridyl The 1-piperazinyl
2, the 4-3,5-dimethylphenyl 2-amino-4-pyridyl The 1-piperazinyl
Phenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl The 1-piperazinyl
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl The 1-piperazinyl
The 3-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl The 1-piperazinyl
The 2-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl The 1-piperazinyl
The 4-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl The 1-piperazinyl
The 3-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl The 1-piperazinyl
The 2-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl The 1-piperazinyl
The 4-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl The 1-piperazinyl
The 3-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl The 1-piperazinyl
The 2-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl The 1-piperazinyl
The 4-trifluoromethyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl The 1-piperazinyl
The 3-trifluoromethyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl The 1-piperazinyl
2, the 6-dichlorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl The 1-piperazinyl
2, the 6-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl The 1-piperazinyl
3, the 4-dichlorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl The 1-piperazinyl
3, the 4-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl The 1-piperazinyl
The 2,4 dichloro benzene base 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl The 1-piperazinyl
2, the 4-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl The 1-piperazinyl
Phenyl 2-amino-4-pyrimidyl The 1-piperazinyl
The 4-fluorophenyl 2-amino-4-pyrimidyl The 1-piperazinyl
The 3-fluorophenyl 2-amino-4-pyrimidyl The 1-piperazinyl
The 2-fluorophenyl 2-amino-4-pyrimidyl The 1-piperazinyl
The 4-chloro-phenyl- 2-amino-4-pyrimidyl The 1-piperazinyl
The 3-chloro-phenyl- 2-amino-4-pyrimidyl The 1-piperazinyl
The 2-chloro-phenyl- 2-amino-4-pyrimidyl The 1-piperazinyl
The 4-tolyl 2-amino-4-pyrimidyl The 1-piperazinyl
The 3-tolyl 2-amino-4-pyrimidyl The 1-piperazinyl
The 2-tolyl 2-amino-4-pyrimidyl The 1-piperazinyl
The 4-trifluoromethyl 2-amino-4-pyrimidyl The 1-piperazinyl
The 3-trifluoromethyl 2-amino-4-pyrimidyl The 1-piperazinyl
2, the 6-dichlorophenyl 2-amino-4-pyrimidyl The 1-piperazinyl
2, the 6-3,5-dimethylphenyl 2-amino-4-pyrimidyl The 1-piperazinyl
3, the 4-dichlorophenyl 2-amino-4-pyrimidyl The 1-piperazinyl
3, the 4-3,5-dimethylphenyl 2-amino-4-pyrimidyl The 1-piperazinyl
The 2,4 dichloro benzene base 2-amino-4-pyrimidyl The 1-piperazinyl
2, the 4-3,5-dimethylphenyl 2-amino-4-pyrimidyl The 1-piperazinyl
Phenyl The 4-pyridyl 2, the 6-dichloro benzyl
The 4-fluorophenyl The 4-pyridyl 2, the 6-dichloro benzyl
The 3-fluorophenyl The 4-pyridyl 2, the 6-dichloro benzyl
The 2-fluorophenyl The 4-pyridyl 2, the 6-dichloro benzyl
The 4-chloro-phenyl- The 4-pyridyl 2, the 6-dichloro benzyl
The 3-chloro-phenyl- The 4-pyridyl 2, the 6-dichloro benzyl
The 2-chloro-phenyl- The 4-pyridyl 2, the 6-dichloro benzyl
The 4-tolyl The 4-pyridyl 2, the 6-dichloro benzyl
The 3-tolyl The 4-pyridyl 2, the 6-dichloro benzyl
The 2-tolyl The 4-pyridyl 2, the 6-dichloro benzyl
The 4-trifluoromethyl The 4-pyridyl 2, the 6-dichloro benzyl
The 3-trifluoromethyl The 4-pyridyl 2, the 6-dichloro benzyl
2, the 6-dichlorophenyl The 4-pyridyl 2, the 6-dichloro benzyl
2, the 6-3,5-dimethylphenyl The 4-pyridyl 2, the 6-dichloro benzyl
3, the 4-dichlorophenyl The 4-pyridyl 2, the 6-dichloro benzyl
3, the 4-3,5-dimethylphenyl The 4-pyridyl 2, the 6-dichloro benzyl
The 2,4 dichloro benzene base The 4-pyridyl 2, the 6-dichloro benzyl
2, the 4-3,5-dimethylphenyl The 4-pyridyl 2, the 6-dichloro benzyl
Phenyl 2-amino-4-pyridyl 2, the 6-dichloro benzyl
The 4-fluorophenyl 2-amino-4-pyridyl 2, the 6-dichloro benzyl
The 3-fluorophenyl 2-amino-4-pyridyl 2, the 6-dichloro benzyl
The 2-fluorophenyl 2-amino-4-pyridyl 2, the 6-dichloro benzyl
The 4-chloro-phenyl- 2-amino-4-pyridyl 2, the 6-dichloro benzyl
The 3-chloro-phenyl- 2-amino-4-pyridyl 2, the 6-dichloro benzyl
The 2-chloro-phenyl- 2-amino-4-pyridyl 2, the 6-dichloro benzyl
The 4-tolyl 2-amino-4-pyridyl 2, the 6-dichloro benzyl
The 3-tolyl 2-amino-4-pyridyl 2, the 6-dichloro benzyl
The 2-tolyl 2-amino-4-pyridyl 2, the 6-dichloro benzyl
The 4-trifluoromethyl 2-amino-4-pyridyl 2, the 6-dichloro benzyl
The 3-trifluoromethyl 2-amino-4-pyridyl 2, the 6-dichloro benzyl
2, the 6-dichlorophenyl 2-amino-4-pyridyl 2, the 6-dichloro benzyl
2, the 6-3,5-dimethylphenyl 2-amino-4-pyridyl 2, the 6-dichloro benzyl
3, the 4-dichlorophenyl 2-amino-4-pyridyl 2, the 6-dichloro benzyl
3, the 4-3,5-dimethylphenyl 2-amino-4-pyridyl 2, the 6-dichloro benzyl
The 2,4 dichloro benzene base 2-amino-4-pyridyl 2, the 6-dichloro benzyl
2, the 4-3,5-dimethylphenyl 2-amino-4-pyridyl 2, the 6-dichloro benzyl
Phenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2, the 6-dichloro benzyl
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2, the 6-dichloro benzyl
The 3-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2, the 6-dichloro benzyl
The 2-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2, the 6-dichloro benzyl
The 4-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2, the 6-dichloro benzyl
The 3-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2, the 6-dichloro benzyl
The 2-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2, the 6-dichloro benzyl
The 4-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2, the 6-dichloro benzyl
The 3-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2, the 6-dichloro benzyl
The 2-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2, the 6-dichloro benzyl
The 4-trifluoromethyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2, the 6-dichloro benzyl
The 3-trifluoromethyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2, the 6-dichloro benzyl
2, the 6-dichlorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2, the 6-dichloro benzyl
2, the 6-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2, the 6-dichloro benzyl
3, the 4-dichlorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2, the 6-dichloro benzyl
3, the 4-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2, the 6-dichloro benzyl
The 2,4 dichloro benzene base 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2, the 6-dichloro benzyl
2, the 4-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2, the 6-dichloro benzyl
Phenyl 2-amino-4-pyrimidyl 2, the 6-dichloro benzyl
The 4-fluorophenyl 2-amino-4-pyrimidyl 2, the 6-dichloro benzyl
The 3-fluorophenyl 2-amino-4-pyrimidyl 2, the 6-dichloro benzyl
The 2-fluorophenyl 2-amino-4-pyrimidyl 2, the 6-dichloro benzyl
The 4-chloro-phenyl- 2-amino-4-pyrimidyl 2, the 6-dichloro benzyl
The 3-chloro-phenyl- 2-amino-4-pyrimidyl 2, the 6-dichloro benzyl
The 2-chloro-phenyl- 2-amino-4-pyrimidyl 2, the 6-dichloro benzyl
The 4-tolyl 2-amino-4-pyrimidyl 2, the 6-dichloro benzyl
The 3-tolyl 2-amino-4-pyrimidyl 2, the 6-dichloro benzyl
The 2-tolyl 2-amino-4-pyrimidyl 2, the 6-dichloro benzyl
The 4-trifluoromethyl 2-amino-4-pyrimidyl 2, the 6-dichloro benzyl
The 3-trifluoromethyl 2-amino-4-pyrimidyl 2, the 6-dichloro benzyl
2, the 6-dichlorophenyl 2-amino-4-pyrimidyl 2, the 6-dichloro benzyl
2, the 6-3,5-dimethylphenyl 2-amino-4-pyrimidyl 2, the 6-dichloro benzyl
3, the 4-dichlorophenyl 2-amino-4-pyrimidyl 2, the 6-dichloro benzyl
3, the 4-3,5-dimethylphenyl 2-amino-4-pyrimidyl 2, the 6-dichloro benzyl
The 2,4 dichloro benzene base 2-amino-4-pyrimidyl 2, the 6-dichloro benzyl
2, the 4-3,5-dimethylphenyl 2-amino-4-pyrimidyl 2, the 6-dichloro benzyl
Phenyl The 4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 4-fluorophenyl The 4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 3-fluorophenyl The 4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 2-fluorophenyl The 4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 4-chloro-phenyl- The 4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 3-chloro-phenyl- The 4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 2-chloro-phenyl- The 4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 4-tolyl The 4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 3-tolyl The 4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 2-tolyl The 4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 4-trifluoromethyl The 4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 3-trifluoromethyl The 4-pyridyl 2-(2-chloro-phenyl-) ethylamino
2, the 6-dichlorophenyl The 4-pyridyl 2-(2-chloro-phenyl-) ethylamino
2, the 6-3,5-dimethylphenyl The 4-pyridyl 2-(2-chloro-phenyl-) ethylamino
3, the 4-dichlorophenyl The 4-pyridyl 2-(2-chloro-phenyl-) ethylamino
3, the 4-3,5-dimethylphenyl The 4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 2,4 dichloro benzene base The 4-pyridyl 2-(2-chloro-phenyl-) ethylamino
2, the 4-3,5-dimethylphenyl The 4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 4-fluorophenyl The 4-pyridyl 2-(3-fluorophenyl) third amino
The 4-fluorophenyl 2-amino-4-pyrimidyl 2-(3-fluorophenyl) third amino
Benzyl The 4-pyridyl 3-phenyl third amino
Benzyl The 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 2-thienyl The 4-pyridyl 3-phenyl third amino
The 2-thienyl The 4-pyridyl 2-(4-fluorophenyl) ethylamino
Cyclohexyl The 4-pyridyl 3-phenyl third amino
Cyclohexyl The 4-pyridyl 2-(4-fluorophenyl) ethylamino
The tertiary butyl The 4-pyridyl 3-phenyl third amino
The tertiary butyl The 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 4-fluorophenyl The 4-piperidyl 3-phenyl third amino
The 4-fluorophenyl The 4-piperidyl 2-(4-fluorophenyl) ethylamino
The 4-fluorophenyl The 4-pyranyl 3-phenyl third amino
The 4-fluorophenyl The 4-pyranyl 2-(4-fluorophenyl) ethylamino
Phenyl 2-amino-4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 4-fluorophenyl 2-amino-4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 3-fluorophenyl 2-amino-4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 2-fluorophenyl 2-amino-4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 4-chloro-phenyl- 2-amino-4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 3-chloro-phenyl- 2-amino-4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 2-chloro-phenyl- 2-amino-4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 4-tolyl 2-amino-4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 3-tolyl 2-amino-4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 2-tolyl 2-amino-4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 4-trifluoromethyl 2-amino-4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 3-trifluoromethyl 2-amino-4-pyridyl 2-(2-chloro-phenyl-) ethylamino
2, the 6-dichlorophenyl 2-amino-4-pyridyl 2-(2-chloro-phenyl-) ethylamino
2, the 6-3,5-dimethylphenyl 2-amino-4-pyridyl 2-(2-chloro-phenyl-) ethylamino
3, the 4-dichlorophenyl 2-amino-4-pyridyl 2-(2-chloro-phenyl-) ethylamino
3, the 4-3,5-dimethylphenyl 2-amino-4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 2,4 dichloro benzene base 2-amino-4-pyridyl 2-(2-chloro-phenyl-) ethylamino
2, the 4-3,5-dimethylphenyl 2-amino-4-pyridyl 2-(2-chloro-phenyl-) ethylamino
Phenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 3-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 2-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 4-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 3-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 2-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 4-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 3-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 2-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 4-trifluoromethyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 3-trifluoromethyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(2-chloro-phenyl-) ethylamino
2, the 6-dichlorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(2-chloro-phenyl-) ethylamino
2, the 6-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(2-chloro-phenyl-) ethylamino
3, the 4-dichlorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(2-chloro-phenyl-) ethylamino
3, the 4-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(2-chloro-phenyl-) ethylamino
The 2,4 dichloro benzene base 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(2-chloro-phenyl-) ethylamino
2, the 4-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(2-chloro-phenyl-) ethylamino
Phenyl 2-amino-4-pyrimidyl 2-(2-chloro-phenyl-) ethylamino
The 4-fluorophenyl 2-amino-4-pyrimidyl 2-(2-chloro-phenyl-) ethylamino
The 3-fluorophenyl 2-amino-4-pyrimidyl 2-(2-chloro-phenyl-) ethylamino
The 2-fluorophenyl 2-amino-4-pyrimidyl 2-(2-chloro-phenyl-) ethylamino
The 4-chloro-phenyl- 2-amino-4-pyrimidyl 2-(2-chloro-phenyl-) ethylamino
The 3-chloro-phenyl- 2-amino-4-pyrimidyl 2-(2-chloro-phenyl-) ethylamino
The 2-chloro-phenyl- 2-amino-4-pyrimidyl 2-(2-chloro-phenyl-) ethylamino
The 4-tolyl 2-amino-4-pyrimidyl 2-(2-chloro-phenyl-) ethylamino
The 3-tolyl 2-amino-4-pyrimidyl 2-(2-chloro-phenyl-) ethylamino
The 2-tolyl 2-amino-4-pyrimidyl 2-(2-chloro-phenyl-) ethylamino
The 4-trifluoromethyl 2-amino-4-pyrimidyl 2-(2-chloro-phenyl-) ethylamino
The 3-trifluoromethyl 2-amino-4-pyrimidyl 2-(2-chloro-phenyl-) ethylamino
2, the 6-dichlorophenyl 2-amino-4-pyrimidyl 2-(2-chloro-phenyl-) ethylamino
2, the 6-3,5-dimethylphenyl 2-amino-4-pyrimidyl 2-(2-chloro-phenyl-) ethylamino
3, the 4-dichlorophenyl 2-amino-4-pyrimidyl 2-(2-chloro-phenyl-) ethylamino
3, the 4-3,5-dimethylphenyl 2-amino-4-pyrimidyl 2-(2-chloro-phenyl-) ethylamino
The 2,4 dichloro benzene base 2-amino-4-pyrimidyl 2-(2-chloro-phenyl-) ethylamino
2, the 4-3,5-dimethylphenyl 2-amino-4-pyrimidyl 2-(2-chloro-phenyl-) ethylamino
Phenyl The 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 4-fluorophenyl The 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 3-fluorophenyl The 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 2-fluorophenyl The 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 4-chloro-phenyl- The 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 3-chloro-phenyl- The 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 2-chloro-phenyl- The 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 4-tolyl The 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 3-tolyl The 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 2-tolyl The 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 4-trifluoromethyl The 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 3-trifluoromethyl The 4-pyridyl 2-(4-fluorophenyl) ethylamino
2, the 6-dichlorophenyl The 4-pyridyl 2-(4-fluorophenyl) ethylamino
2, the 6-3,5-dimethylphenyl The 4-pyridyl 2-(4-fluorophenyl) ethylamino
3, the 4-dichlorophenyl The 4-pyridyl 2-(4-fluorophenyl) ethylamino
3, the 4-3,5-dimethylphenyl The 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 2,4 dichloro benzene base The 4-pyridyl 2-(4-fluorophenyl) ethylamino
2, the 4-3,5-dimethylphenyl The 4-pyridyl 2-(4-fluorophenyl) ethylamino
Phenyl 2-amino-4-pyridyl 2-(4-fluorophenyl) ethylamino
The 4-fluorophenyl 2-amino-4-pyridyl 2-(4-fluorophenyl) ethylamino
The 3-fluorophenyl 2-amino-4-pyridyl 2-(4-fluorophenyl) ethylamino
The 2-fluorophenyl 2-amino-4-pyridyl 2-(4-fluorophenyl) ethylamino
The 4-chloro-phenyl- 2-amino-4-pyridyl 2-(4-fluorophenyl) ethylamino
The 3-chloro-phenyl- 2-amino-4-pyridyl 2-(4-fluorophenyl) ethylamino
The 2-chloro-phenyl- 2-amino-4-pyridyl 2-(4-fluorophenyl) ethylamino
The 4-tolyl 2-amino-4-pyridyl 2-(4-fluorophenyl) ethylamino
The 3-tolyl 2-amino-4-pyridyl 2-(4-fluorophenyl) ethylamino
The 2-tolyl 2-amino-4-pyridyl 2-(4-fluorophenyl) ethylamino
The 4-trifluoromethyl 2-amino-4-pyridyl 2-(4-fluorophenyl) ethylamino
The 3-trifluoromethyl 2-amino-4-pyridyl 2-(4-fluorophenyl) ethylamino
2, the 6-dichlorophenyl 2-amino-4-pyridyl 2-(4-fluorophenyl) ethylamino
2, the 6-3,5-dimethylphenyl 2-amino-4-pyridyl 2-(4-fluorophenyl) ethylamino
3, the 4-dichlorophenyl 2-amino-4-pyridyl 2-(4-fluorophenyl) ethylamino
3, the 4-3,5-dimethylphenyl 2-amino-4-pyridyl 2-(4-fluorophenyl) ethylamino
The 2,4 dichloro benzene base 2-amino-4-pyridyl 2-(4-fluorophenyl) ethylamino
2, the 4-3,5-dimethylphenyl 2-amino-4-pyridyl 2-(4-fluorophenyl) ethylamino
Phenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 3-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 2-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 4-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 3-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 2-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 4-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 3-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 2-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 4-trifluoromethyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 3-trifluoromethyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-fluorophenyl) ethylamino
2, the 6-dichlorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-fluorophenyl) ethylamino
2, the 6-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-fluorophenyl) ethylamino
3, the 4-dichlorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-fluorophenyl) ethylamino
3, the 4-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 2,4 dichloro benzene base 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-fluorophenyl) ethylamino
2, the 4-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-fluorophenyl) ethylamino
Phenyl 2-amino-4-pyrimidyl 2-(4-fluorophenyl) ethylamino
The 4-fluorophenyl 2-amino-4-pyrimidyl 2-(4-fluorophenyl) ethylamino
The 3-fluorophenyl 2-amino-4-pyrimidyl 2-(4-fluorophenyl) ethylamino
The 2-fluorophenyl 2-amino-4-pyrimidyl 2-(4-fluorophenyl) ethylamino
The 4-chloro-phenyl- 2-amino-4-pyrimidyl 2-(4-fluorophenyl) ethylamino
The 3-chloro-phenyl- 2-amino-4-pyrimidyl 2-(4-fluorophenyl) ethylamino
The 2-chloro-phenyl- 2-amino-4-pyrimidyl 2-(4-fluorophenyl) ethylamino
The 4-tolyl 2-amino-4-pyrimidyl 2-(4-fluorophenyl) ethylamino
The 3-tolyl 2-amino-4-pyrimidyl 2-(4-fluorophenyl) ethylamino
The 2-tolyl 2-amino-4-pyrimidyl 2-(4-fluorophenyl) ethylamino
The 4-trifluoromethyl 2-amino-4-pyrimidyl 2-(4-fluorophenyl) ethylamino
The 3-trifluoromethyl 2-amino-4-pyrimidyl 2-(4-fluorophenyl) ethylamino
2, the 6-dichlorophenyl 2-amino-4-pyrimidyl 2-(4-fluorophenyl) ethylamino
2, the 6-3,5-dimethylphenyl 2-amino-4-pyrimidyl 2-(4-fluorophenyl) ethylamino
3, the 4-dichlorophenyl 2-amino-4-pyrimidyl 2-(4-fluorophenyl) ethylamino
3, the 4-3,5-dimethylphenyl 2-amino-4-pyrimidyl 2-(4-fluorophenyl) ethylamino
The 2,4 dichloro benzene base 2-amino-4-pyrimidyl 2-(4-fluorophenyl) ethylamino
2, the 4-3,5-dimethylphenyl 2-amino-4-pyrimidyl 2-(4-fluorophenyl) ethylamino
Phenyl The 4-pyridyl 3-phenyl third amino
The 4-fluorophenyl The 4-pyridyl 3-phenyl third amino
The 3-fluorophenyl The 4-pyridyl 3-phenyl third amino
The 2-fluorophenyl The 4-pyridyl 3-phenyl third amino
The 4-chloro-phenyl- The 4-pyridyl 3-phenyl third amino
The 3-chloro-phenyl- The 4-pyridyl 3-phenyl third amino
The 2-chloro-phenyl- The 4-pyridyl 3-phenyl third amino
The 4-tolyl The 4-pyridyl 3-phenyl third amino
The 3-tolyl The 4-pyridyl 3-phenyl third amino
The 2-tolyl The 4-pyridyl 3-phenyl third amino
The 4-trifluoromethyl The 4-pyridyl 3-phenyl third amino
The 3-trifluoromethyl The 4-pyridyl 3-phenyl third amino
2, the 6-dichlorophenyl The 4-pyridyl 3-phenyl third amino
2, the 6-3,5-dimethylphenyl The 4-pyridyl 3-phenyl third amino
3, the 4-dichlorophenyl The 4-pyridyl 3-phenyl third amino
3, the 4-3,5-dimethylphenyl The 4-pyridyl 3-phenyl third amino
The 2,4 dichloro benzene base The 4-pyridyl 3-phenyl third amino
2, the 4-3,5-dimethylphenyl The 4-pyridyl 3-phenyl third amino
Phenyl 2-amino-4-pyridyl 3-phenyl third amino
The 4-fluorophenyl 2-amino-4-pyridyl 3-phenyl third amino
The 3-fluorophenyl 2-amino-4-pyridyl 3-phenyl third amino
The 2-fluorophenyl 2-amino-4-pyridyl 3-phenyl third amino
The 4-chloro-phenyl- 2-amino-4-pyridyl 3-phenyl third amino
The 3-chloro-phenyl- 2-amino-4-pyridyl 3-phenyl third amino
The 2-chloro-phenyl- 2-amino-4-pyridyl 3-phenyl third amino
The 4-tolyl 2-amino-4-pyridyl 3-phenyl third amino
The 3-tolyl 2-amino-4-pyridyl 3-phenyl third amino
The 2-tolyl 2-amino-4-pyridyl 3-phenyl third amino
The 4-trifluoromethyl 2-amino-4-pyridyl 3-phenyl third amino
The 3-trifluoromethyl 2-amino-4-pyridyl 3-phenyl third amino
2, the 6-dichlorophenyl 2-amino-4-pyridyl 3-phenyl third amino
2, the 6-3,5-dimethylphenyl 2-amino-4-pyridyl 3-phenyl third amino
3, the 4-dichlorophenyl 2-amino-4-pyridyl 3-phenyl third amino
3, the 4-3,5-dimethylphenyl 2-amino-4-pyridyl 3-phenyl third amino
The 2,4 dichloro benzene base 2-amino-4-pyridyl 3-phenyl third amino
2, the 4-3,5-dimethylphenyl 2-amino-4-pyridyl 3-phenyl third amino
Phenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-phenyl third amino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-phenyl third amino
The 3-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-phenyl third amino
The 2-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-phenyl third amino
The 4-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-phenyl third amino
The 3-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-phenyl third amino
The 2-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-phenyl third amino
The 4-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-phenyl third amino
The 3-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-phenyl third amino
The 2-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-phenyl third amino
The 4-trifluoromethyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-phenyl third amino
The 3-trifluoromethyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-phenyl third amino
2, the 6-dichlorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-phenyl third amino
2, the 6-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-phenyl third amino
3, the 4-dichlorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-phenyl third amino
3, the 4-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-phenyl third amino
The 2,4 dichloro benzene base 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-phenyl third amino
2, the 4-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-phenyl third amino
Phenyl 2-amino-4-pyrimidyl 3-phenyl third amino
The 4-fluorophenyl 2-amino-4-pyrimidyl 3-phenyl third amino
The 3-fluorophenyl 2-amino-4-pyrimidyl 3-phenyl third amino
The 2-fluorophenyl 2-amino-4-pyrimidyl 3-phenyl third amino
The 4-chloro-phenyl- 2-amino-4-pyrimidyl 3-phenyl third amino
The 3-chloro-phenyl- 2-amino-4-pyrimidyl 3-phenyl third amino
The 2-chloro-phenyl- 2-amino-4-pyrimidyl 3-phenyl third amino
The 4-tolyl 2-amino-4-pyrimidyl 3-phenyl third amino
The 3-tolyl 2-amino-4-pyrimidyl 3-phenyl third amino
The 2-tolyl 2-amino-4-pyrimidyl 3-phenyl third amino
The 4-trifluoromethyl 2-amino-4-pyrimidyl 3-phenyl third amino
The 3-trifluoromethyl 2-amino-4-pyrimidyl 3-phenyl third amino
2, the 6-dichlorophenyl 2-amino-4-pyrimidyl 3-phenyl third amino
2, the 6-3,5-dimethylphenyl 2-amino-4-pyrimidyl 3-phenyl third amino
3, the 4-dichlorophenyl 2-amino-4-pyrimidyl 3-phenyl third amino
3, the 4-3,5-dimethylphenyl 2-amino-4-pyrimidyl 3-phenyl third amino
The 2,4 dichloro benzene base 2-amino-4-pyrimidyl 3-phenyl third amino
2, the 4-3,5-dimethylphenyl 2-amino-4-pyrimidyl 3-phenyl third amino
Phenyl The 4-pyridyl 3-imidazolyl third amino
The 4-fluorophenyl The 4-pyridyl 3-imidazolyl third amino
The 3-fluorophenyl The 4-pyridyl 3-imidazolyl third amino
The 2-fluorophenyl The 4-pyridyl 3-imidazolyl third amino
The 4-chloro-phenyl- The 4-pyridyl 3-imidazolyl third amino
The 3-chloro-phenyl- The 4-pyridyl 3-imidazolyl third amino
The 2-chloro-phenyl- The 4-pyridyl 3-imidazolyl third amino
The 4-tolyl The 4-pyridyl 3-imidazolyl third amino
The 3-tolyl The 4-pyridyl 3-imidazolyl third amino
The 2-tolyl The 4-pyridyl 3-imidazolyl third amino
The 4-trifluoromethyl The 4-pyridyl 3-imidazolyl third amino
The 3-trifluoromethyl The 4-pyridyl 3-imidazolyl third amino
2, the 6-dichlorophenyl The 4-pyridyl 3-imidazolyl third amino
2, the 6-3,5-dimethylphenyl The 4-pyridyl 3-imidazolyl third amino
3, the 4-dichlorophenyl The 4-pyridyl 3-imidazolyl third amino
3, the 4-3,5-dimethylphenyl The 4-pyridyl 3-imidazolyl third amino
The 2,4 dichloro benzene base The 4-pyridyl 3-imidazolyl third amino
2, the 4-3,5-dimethylphenyl The 4-pyridyl 3-imidazolyl third amino
Phenyl 2-amino-4-pyridyl 3-imidazolyl third amino
The 4-fluorophenyl 2-amino-4-pyridyl 3-imidazolyl third amino
The 3-fluorophenyl 2-amino-4-pyridyl 3-imidazolyl third amino
The 2-fluorophenyl 2-amino-4-pyridyl 3-imidazolyl third amino
The 4-chloro-phenyl- 2-amino-4-pyridyl 3-imidazolyl third amino
The 3-chloro-phenyl- 2-amino-4-pyridyl 3-imidazolyl third amino
The 2-chloro-phenyl- 2-amino-4-pyridyl 3-imidazolyl third amino
The 4-tolyl 2-amino-4-pyridyl 3-imidazolyl third amino
The 3-tolyl 2-amino-4-pyridyl 3-imidazolyl third amino
The 2-tolyl 2-amino-4-pyridyl 3-imidazolyl third amino
The 4-trifluoromethyl 2-amino-4-pyridyl 3-imidazolyl third amino
The 3-trifluoromethyl 2-amino-4-pyridyl 3-imidazolyl third amino
2, the 6-dichlorophenyl 2-amino-4-pyridyl 3-imidazolyl third amino
2, the 6-3,5-dimethylphenyl 2-amino-4-pyridyl 3-imidazolyl third amino
3, the 4-dichlorophenyl 2-amino-4-pyridyl 3-imidazolyl third amino
3, the 4-3,5-dimethylphenyl 2-amino-4-pyridyl 3-imidazolyl third amino
The 2,4 dichloro benzene base 2-amino-4-pyridyl 3-imidazolyl third amino
2, the 4-3,5-dimethylphenyl 2-amino-4-pyridyl 3-imidazolyl third amino
Phenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-imidazolyl third amino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-imidazolyl third amino
The 3-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-imidazolyl third amino
The 2-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-imidazolyl third amino
The 4-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-imidazolyl third amino
The 3-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-imidazolyl third amino
The 2-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-imidazolyl third amino
The 4-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-imidazolyl third amino
The 3-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-imidazolyl third amino
The 2-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-imidazolyl third amino
The 4-trifluoromethyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-imidazolyl third amino
The 3-trifluoromethyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-imidazolyl third amino
2, the 6-dichlorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-imidazolyl third amino
2, the 6-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-imidazolyl third amino
3, the 4-dichlorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-imidazolyl third amino
3, the 4-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-imidazolyl third amino
The 2,4 dichloro benzene base 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-imidazolyl third amino
2, the 4-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-imidazolyl third amino
Phenyl 2-amino-4-pyrimidyl 3-imidazolyl third amino
The 4-fluorophenyl 2-amino-4-pyrimidyl 3-imidazolyl third amino
The 3-fluorophenyl 2-amino-4-pyrimidyl 3-imidazolyl third amino
The 2-fluorophenyl 2-amino-4-pyrimidyl 3-imidazolyl third amino
The 4-chloro-phenyl- 2-amino-4-pyrimidyl 3-imidazolyl third amino
The 3-chloro-phenyl- 2-amino-4-pyrimidyl 3-imidazolyl third amino
The 2-chloro-phenyl- 2-amino-4-pyrimidyl 3-imidazolyl third amino
The 4-tolyl 2-amino-4-pyrimidyl 3-imidazolyl third amino
The 3-tolyl 2-amino-4-pyrimidyl 3-imidazolyl third amino
The 2-tolyl 2-amino-4-pyrimidyl 3-imidazolyl third amino
The 4-trifluoromethyl 2-amino-4-pyrimidyl 3-imidazolyl third amino
The 3-trifluoromethyl 2-amino-4-pyrimidyl 3-imidazolyl third amino
2, the 6-dichlorophenyl 2-amino-4-pyrimidyl 3-imidazolyl third amino
2, the 6-3,5-dimethylphenyl 2-amino-4-pyrimidyl 3-imidazolyl third amino
3, the 4-dichlorophenyl 2-amino-4-pyrimidyl 3-imidazolyl third amino
3, the 4-3,5-dimethylphenyl 2-amino-4-pyrimidyl 3-imidazolyl third amino
The 2,4 dichloro benzene base 2-amino-4-pyrimidyl 3-imidazolyl third amino
2, the 4-3,5-dimethylphenyl 2-amino-4-pyrimidyl 3-imidazolyl third amino
The 4-fluorophenyl The 4-pyridyl 4-luorobenzyl amino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 4-luorobenzyl amino
The 4-fluorophenyl 2-amino-4-pyrimidyl 4-luorobenzyl amino
The 4-fluorophenyl The 4-pyridyl 2-(2-chloro-phenyl--1-methyl) ethyl) amino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(2-chloro-phenyl--1-methyl) ethyl) amino
The 4-fluorophenyl 2-amino-4-pyrimidyl 2-(2-chloro-phenyl--1-methyl) ethyl) amino
The 4-fluorophenyl The 4-pyridyl (3-(4-fluorophenyl) propyl group) amino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (3-(4-fluorophenyl) propyl group) amino
The 4-fluorophenyl 2-amino-4-pyrimidyl (3-(4-fluorophenyl) propyl group) amino
The 4-fluorophenyl The 4-pyridyl (3-(4-fluorophenyl)-1-methyl-propyl group) amino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (3-(4-fluorophenyl)-1-methyl-propyl group) amino
The 4-fluorophenyl 2-amino-4-pyrimidyl (3-(4-fluorophenyl)-1-methyl-propyl group) amino
The 4-fluorophenyl The 4-pyridyl (1,1-dimethyl-3-(4-fluorophenyl)-propyl group) amino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (1,1-dimethyl-3-(4-fluorophenyl)-propyl group) amino
The 4-fluorophenyl 2-amino-4-pyrimidyl (1,1-dimethyl-3-(4-fluorophenyl)-propyl group) amino
The 4-fluorophenyl The 4-pyridyl (3-(2-fluorophenyl) propyl group) amino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (3-(2-fluorophenyl) propyl group) amino
The 4-fluorophenyl 2-amino-4-pyrimidyl (3-(2-fluorophenyl) propyl group) amino
The 4-fluorophenyl The 4-pyridyl (3-methyl-3-phenyl propyl) amino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (3-methyl-3-phenyl propyl) amino
The 4-fluorophenyl 2-amino-4-pyrimidyl (3-methyl-3-phenyl propyl) amino
The 4-fluorophenyl The 4-pyridyl (2-methyl-3-phenyl propyl) amino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (2-methyl-3-phenyl propyl) amino
The 4-fluorophenyl 2-amino-4-pyrimidyl (2-methyl-3-phenyl propyl) amino
The 3-fluorophenyl The 4-pyridyl (S)-tetrahydroisoquinoline-3-Ji methylamino-
The 2-fluorophenyl 2-amino-4-pyridyl (S)-3-benzyl diethylenediamine base
The 3-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (S)-2-N-isopropylamino-3-phenyl third amino
The 2-chloro-phenyl- 2-amino-4-pyrimidyl (S)-2-N-glycyl amino-3-phenyl third amino
The 4-tolyl The 4-pyridyl (S)-2-amino-3-
Phenyl third amino
The 3-tolyl 2-amino-4-pyridyl (R)-2-amino-3-phenyl third amino
The 2-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-amino-3-phenyl third amino
The 4-trifluoromethyl 2-amino-4-pyrimidyl (S)-2-amino-3-(2-fluorophenyl) third amino
The 3-trifluoromethyl The 4-pyridyl (S)-2-amino-3-(2-fluorophenyl) third amino
2, the 6-dichlorophenyl 2-amino-4-pyridyl 3-amino-3-(2-fluorophenyl) third amino
2, the 6-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-amino-3-(2-aminomethyl phenyl) third amino
3, the 4-dichlorophenyl 2-amino-4-pyrimidyl 2-amino-2-methyl-3-phenyl third amino
3, the 4-3,5-dimethylphenyl The 4-pyridyl 3-amino-2-methyl-3-phenyl third amino
The 3-fluorophenyl 2-amino-4-pyridyl (S)-2-amino-3-phenyl third amino
The 2-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (S)-2-amino-3-(2-fluorophenyl) third amino
The 3-chloro-phenyl- 2-amino-4-pyrimidyl (S)-2-amino-3-(2-aminomethyl phenyl) third amino
The 2-chloro-phenyl- The 4-pyridyl (S)-2-N-isopropylamino-3-phenyl third amino
The 4-tolyl 2-amino-4-pyridyl (S)-2-N-glycyl amino-3-phenyl third amino
The 3-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-amino-2-methyl-3-phenyl third amino
The 2-tolyl 2-amino-4-pyrimidyl (R)-2-amino-3-phenyl third amino
The 4-trifluoromethyl The 4-pyridyl 3-amino-3-phenyl third amino
The 3-trifluoromethyl 2-amino-4-pyridyl 3-amino-3-(2-fluorophenyl) third amino
2, the 6-dichlorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-amino-3-(2-aminomethyl phenyl) third amino
2, the 6-3,5-dimethylphenyl 2-amino-4-pyrimidyl 2-amino-2-methyl-3-phenyl third amino
3, the 4-dichlorophenyl The 4-pyridyl (S)-tetrahydroisoquinoline-3-Ji methylamino-
3, the 4-3,5-dimethylphenyl The 4-pyridyl (S)-3-benzyl diethylenediamine base
With
Figure A9718156300781
R wherein 2Be-OH and R 11, R 12And R 1Be one of listed combination in the following table:
R 11 R 12 R 1
Phenyl The 4-pyridyl The 4-pyridyl
The 4-fluorophenyl The 4-pyridyl The 4-pyridyl
The 3-fluorophenyl The 4-pyridyl The 4-pyridyl
The 2-fluorophenyl The 4-pyridyl The 4-pyridyl
The 4-chloro-phenyl- The 4-pyridyl The 4-pyridyl
The 3-chloro-phenyl- The 4-pyridyl The 4-pyridyl
The 2-chloro-phenyl- The 4-pyridyl The 4-pyridyl
The 4-tolyl The 4-pyridyl The 4-pyridyl
The 3-tolyl The 4-pyridyl The 4-pyridyl
The 2-tolyl The 4-pyridyl The 4-pyridyl
The 4-trifluoromethyl The 4-pyridyl The 4-pyridyl
The 3-trifluoromethyl The 4-pyridyl The 4-pyridyl
2, the 6-dichlorophenyl The 4-pyridyl The 4-pyridyl
2, the 6-3,5-dimethylphenyl The 4-pyridyl The 4-pyridyl
3, the 4-dichlorophenyl The 4-pyridyl The 4-pyridyl
3, the 4-3,5-dimethylphenyl The 4-pyridyl The 4-pyridyl
The 2,4 dichloro benzene base The 4-pyridyl The 4-pyridyl
2, the 4-3,5-dimethylphenyl The 4-pyridyl The 4-pyridyl
Phenyl 2-amino-4-pyridyl The 4-pyridyl
The 4-fluorophenyl 2-amino-4-pyridyl The 4-pyridyl
The 3-fluorophenyl 2-amino-4-pyridyl The 4-pyridyl
The 2-fluorophenyl 2-amino-4-pyridyl The 4-pyridyl
The 4-chloro-phenyl- 2-amino-4-pyridyl The 4-pyridyl
The 3-chloro-phenyl- 2-amino-4-pyridyl The 4-pyridyl
The 2-chloro-phenyl- 2-amino-4-pyridyl The 4-pyridyl
The 4-tolyl 2-amino-4-pyridyl The 4-pyridyl
The 3-tolyl 2-amino-4-pyridyl The 4-pyridyl
The 2-tolyl 2-amino-4-pyridyl The 4-pyridyl
The 4-trifluoromethyl 2-amino-4-pyridyl The 4-pyridyl
The 3-trifluoromethyl 2-amino-4-pyridyl The 4-pyridyl
2, the 6-dichlorophenyl 2-amino-4-pyridyl The 4-pyridyl
2, the 6-3,5-dimethylphenyl 2-amino-4-pyridyl The 4-pyridyl
3, the 4-dichlorophenyl 2-amino-4-pyridyl The 4-pyridyl
3, the 4-3,5-dimethylphenyl 2-amino-4-pyridyl The 4-pyridyl
The 2,4 dichloro benzene base 2-amino-4-pyridyl The 4-pyridyl
2, the 4-3,5-dimethylphenyl 2-amino-4-pyridyl The 4-pyridyl
Phenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl The 4-pyridyl
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl The 4-pyridyl
The 3-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl The 4-pyridyl
The 2-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl The 4-pyridyl
The 4-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl The 4-pyridyl
The 3-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl The 4-pyridyl
The 2-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl The 4-pyridyl
The 4-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl The 4-pyridyl
The 3-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl The 4-pyridyl
The 2-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl The 4-pyridyl
The 4-trifluoromethyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl The 4-pyridyl
The 3-trifluoromethyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl The 4-pyridyl
2, the 6-dichlorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl The 4-pyridyl
2, the 6-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl The 4-pyridyl
3, the 4-dichlorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl The 4-pyridyl
3, the 4-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl The 4-pyridyl
The 2,4 dichloro benzene base 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl The 4-pyridyl
2, the 4-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl The 4-pyridyl
Phenyl 2-amino-4-pyrimidyl The 4-pyridyl
The 4-fluorophenyl 2-amino-4-pyrimidyl The 4-pyridyl
The 3-fluorophenyl 2-amino-4-pyrimidyl The 4-pyridyl
The 2-fluorophenyl 2-amino-4-pyrimidyl The 4-pyridyl
The 4-chloro-phenyl- 2-amino-4-pyrimidyl The 4-pyridyl
The 3-chloro-phenyl- 2-amino-4-pyrimidyl The 4-pyridyl
The 2-chloro-phenyl- 2-amino-4-pyrimidyl The 4-pyridyl
The 4-tolyl 2-amino-4-pyrimidyl The 4-pyridyl
The 3-tolyl 2-amino-4-pyrimidyl The 4-pyridyl
The 2-tolyl 2-amino-4-pyrimidyl The 4-pyridyl
The 4-trifluoromethyl 2-amino-4-pyrimidyl The 4-pyridyl
The 3-trifluoromethyl 2-amino-4-pyrimidyl The 4-pyridyl
2, the 6-dichlorophenyl 2-amino-4-pyrimidyl The 4-pyridyl
2, the 6-3,5-dimethylphenyl 2-amino-4-pyrimidyl The 4-pyridyl
3, the 4-dichlorophenyl 2-amino-4-pyrimidyl The 4-pyridyl
3, the 4-3,5-dimethylphenyl 2-amino-4-pyrimidyl The 4-pyridyl
The 2,4 dichloro benzene base 2-amino-4-pyrimidyl The 4-pyridyl
2, the 4-3,5-dimethylphenyl 2-amino-4-pyrimidyl The 4-pyridyl
Phenyl The 4-pyridyl 4-methylsulfinyl phenyl
The 4-fluorophenyl The 4-pyridyl 4-methylsulfinyl phenyl
The 3-fluorophenyl The 4-pyridyl 4-methylsulfinyl phenyl
The 2-fluorophenyl The 4-pyridyl 4-methylsulfinyl phenyl
The 4-chloro-phenyl- The 4-pyridyl 4-methylsulfinyl phenyl
The 3-chloro-phenyl- The 4-pyridyl 4-methylsulfinyl phenyl
The 2-chloro-phenyl- The 4-pyridyl 4-methylsulfinyl phenyl
The 4-tolyl The 4-pyridyl 4-methylsulfinyl phenyl
The 3-tolyl The 4-pyridyl 4-methylsulfinyl phenyl
The 2-tolyl The 4-pyridyl 4-methylsulfinyl phenyl
The 4-trifluoromethyl The 4-pyridyl 4-methylsulfinyl phenyl
The 3-trifluoromethyl The 4-pyridyl 4-methylsulfinyl phenyl
2, the 6-dichlorophenyl The 4-pyridyl 4-methylsulfinyl phenyl
2, the 6-3,5-dimethylphenyl The 4-pyridyl 4-methylsulfinyl phenyl
3, the 4-dichlorophenyl The 4-pyridyl 4-methylsulfinyl phenyl
3, the 4-3,5-dimethylphenyl The 4-pyridyl 4-methylsulfinyl phenyl
The 2,4 dichloro benzene base The 4-pyridyl 4-methylsulfinyl phenyl
2, the 4-3,5-dimethylphenyl The 4-pyridyl 4-methylsulfinyl phenyl
Phenyl 2-amino-4-pyridyl 4-methylsulfinyl phenyl
The 4-fluorophenyl 2-amino-4-pyridyl 4-methylsulfinyl phenyl
The 3-fluorophenyl 2-amino-4-pyridyl 4-methylsulfinyl phenyl
The 2-fluorophenyl 2-amino-4-pyridyl 4-methylsulfinyl phenyl
The 4-chloro-phenyl- 2-amino-4-pyridyl 4-methylsulfinyl phenyl
The 3-chloro-phenyl- 2-amino-4-pyridyl 4-methylsulfinyl phenyl
The 2-chloro-phenyl- 2-amino-4-pyridyl 4-methylsulfinyl phenyl
The 4-tolyl 2-amino-4-pyridyl 4-methylsulfinyl phenyl
The 3-tolyl 2-amino-4-pyridyl 4-methylsulfinyl phenyl
The 2-tolyl 2-amino-4-pyridyl 4-methylsulfinyl phenyl
The 4-trifluoromethyl 2-amino-4-pyridyl 4-methylsulfinyl phenyl
The 3-trifluoromethyl 2-amino-4-pyridyl 4-methylsulfinyl phenyl
2, the 6-difluorophenyl 2-amino-4-pyridyl 4-methylsulfinyl phenyl
2, the 6-3,5-dimethylphenyl 2-amino-4-pyridyl 4-methylsulfinyl phenyl
3, the 4-dichlorophenyl 2-amino-4-pyridyl 4-methylsulfinyl phenyl
3, the 4-3,5-dimethylphenyl 2-amino-4-pyridyl 4-methylsulfinyl phenyl
The 2,4 dichloro benzene base 2-amino-4-pyridyl 4-methylsulfinyl phenyl
2, the 4-3,5-dimethylphenyl 2-amino-4-pyridyl 4-methylsulfinyl phenyl
Phenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 4-methylsulfinyl phenyl
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 4-methylsulfinyl phenyl
The 3-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 4-methylsulfinyl phenyl
The 2-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 4-methylsulfinyl phenyl
The 4-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 4-methylsulfinyl phenyl
The 3-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 4-methylsulfinyl phenyl
The 2-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 4-methylsulfinyl phenyl
The 4-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 4-methylsulfinyl phenyl
The 3-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 4-methylsulfinyl phenyl
The 2-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 4-methylsulfinyl phenyl
The 4-trifluoromethyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 4-methylsulfinyl phenyl
The 3-trifluoromethyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 4-methylsulfinyl phenyl
2, the 6-dichlorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 4-methylsulfinyl phenyl
2, the 6-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 4-methylsulfinyl phenyl
3, the 4-dichlorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 4-methylsulfinyl phenyl
3, the 4-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 4-methylsulfinyl phenyl
The 2,4 dichloro benzene base 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 4-methylsulfinyl phenyl
2, the 4-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 4-methylsulfinyl phenyl
Phenyl 2-amino-4-pyrimidyl 4-methylsulfinyl phenyl
The 4-fluorophenyl 2-amino-4-pyrimidyl 4-methylsulfinyl phenyl
The 3-fluorophenyl 2-amino-4-pyrimidyl 4-methylsulfinyl phenyl
The 2-fluorophenyl 2-amino-4-pyrimidyl 4-methylsulfinyl phenyl
The 4-chloro-phenyl- 2-amino-4-pyrimidyl 4-methylsulfinyl phenyl
The 3-chloro-phenyl- 2-amino-4-pyrimidyl 4-methylsulfinyl phenyl
The 2-chloro-phenyl- 2-amino-4-pyrimidyl 4-methylsulfinyl phenyl
The 4-tolyl 2-amino-4-pyrimidyl 4-methylsulfinyl phenyl
The 3-tolyl 2-amino-4-pyrimidyl 4-methylsulfinyl phenyl
The 2-tolyl 2-amino-4-pyrimidyl 4-methylsulfinyl phenyl
The 4-trifluoromethyl 2-amino-4-pyrimidyl 4-methylsulfinyl phenyl
The 3-trifluoromethyl 2-amino-4-pyrimidyl 4-methylsulfinyl phenyl
2, the 6-dichlorophenyl 2-amino-4-pyrimidyl 4-methylsulfinyl phenyl
2, the 6-3,5-dimethylphenyl 2-amino-4-pyrimidyl 4-methylsulfinyl phenyl
3, the 4-dichlorophenyl 2-amino-4-pyrimidyl 4-methylsulfinyl phenyl
3, the 4-3,5-dimethylphenyl 2-amino-4-pyrimidyl 4-methylsulfinyl phenyl
The 2,4 dichloro benzene base 2-amino-4-pyrimidyl 4-methylsulfinyl phenyl
2, the 4-3,5-dimethylphenyl 2-amino-4-pyrimidyl 4-methylsulfinyl phenyl
Phenyl The 4-pyridyl 2, the 6-dichloro benzyl
The 4-fluorophenyl The 4-pyridyl 2, the 6-dichloro benzyl
The 3-fluorophenyl The 4-pyridyl 2, the 6-dichloro benzyl
The 2-fluorophenyl The 4-pyridyl 2, the 6-dichloro benzyl
The 4-chloro-phenyl- The 4-pyridyl 2, the 6-dichloro benzyl
The 3-chloro-phenyl- The 4-pyridyl 2, the 6-dichloro benzyl
The 2-chloro-phenyl- The 4-pyridyl 2, the 6-dichloro benzyl
The 4-tolyl The 4-pyridyl 2, the 6-dichloro benzyl
The 3-tolyl The 4-pyridyl 2, the 6-dichloro benzyl
The 2-tolyl The 4-pyridyl 2, the 6-dichloro benzyl
The 4-trifluoromethyl The 4-pyridyl 2, the 6-dichloro benzyl
The 3-trifluoromethyl The 4-pyridyl 2, the 6-dichloro benzyl
2, the 6-dichlorophenyl The 4-pyridyl 2, the 6-dichloro benzyl
2, the 6-3,5-dimethylphenyl The 4-pyridyl 2, the 6-dichloro benzyl
3, the 4-dichlorophenyl The 4-pyridyl 2, the 6-dichloro benzyl
3, the 4-3,5-dimethylphenyl The 4-pyridyl 2, the 6-dichloro benzyl
The 2,4 dichloro benzene base The 4-pyridyl 2, the 6-dichloro benzyl
2, the 4-3,5-dimethylphenyl The 4-pyridyl 2, the 6-dichloro benzyl
Phenyl 2-amino-4-pyridyl 2, the 6-dichloro benzyl
The 4-fluorophenyl 2-amino-4-pyridyl 2, the 6-dichloro benzyl
The 3-fluorophenyl 2-amino-4-pyridyl 2, the 6-dichloro benzyl
The 2-fluorophenyl 2-amino-4-pyridyl 2, the 6-dichloro benzyl
The 4-chloro-phenyl- 2-amino-4-pyridyl 2, the 6-dichloro benzyl
The 3-chloro-phenyl- 2-amino-4-pyridyl 2, the 6-dichloro benzyl
The 2-chloro-phenyl- 2-amino-4-pyridyl 2, the 6-dichloro benzyl
The 4-tolyl 2-amino-4-pyridyl 2, the 6-dichloro benzyl
The 3-tolyl 2-amino-4-pyridyl 2, the 6-dichloro benzyl
The 2-tolyl 2-amino-4-pyridyl 2, the 6-dichloro benzyl
The 4-trifluoromethyl 2-amino-4-pyridyl 2, the 6-dichloro benzyl
The 3-trifluoromethyl 2-amino-4-pyridyl 2, the 6-dichloro benzyl
2, the 6-dichlorophenyl 2-amino-4-pyridyl 2, the 6-dichloro benzyl
2, the 6-3,5-dimethylphenyl 2-amino-4-pyridyl 2, the 6-dichloro benzyl
3, the 4-dichlorophenyl 2-amino-4-pyridyl 2, the 6-dichloro benzyl
3, the 4-3,5-dimethylphenyl 2-amino-4-pyridyl 2, the 6-dichloro benzyl
The 2,4 dichloro benzene base 2-amino-4-pyridyl 2, the 6-dichloro benzyl
2, the 4-3,5-dimethylphenyl 2-amino-4-pyridyl 2, the 6-dichloro benzyl
Phenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2, the 6-dichloro benzyl
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2, the 6-dichloro benzyl
The 3-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2, the 6-dichloro benzyl
The 2-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2, the 6-dichloro benzyl
The 4-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2, the 6-dichloro benzyl
The 3-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2, the 6-dichloro benzyl
The 2-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2, the 6-dichloro benzyl
The 4-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2, the 6-dichloro benzyl
The 3-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2, the 6-dichloro benzyl
The 2-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2, the 6-dichloro benzyl
The 4-trifluoromethyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2, the 6-dichloro benzyl
The 3-trifluoromethyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2, the 6-dichloro benzyl
2, the 6-dichlorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2, the 6-dichloro benzyl
2, the 6-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2, the 6-dichloro benzyl
3, the 4-dichlorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2, the 6-dichloro benzyl
3, the 4-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2, the 6-dichloro benzyl
The 2,4 dichloro benzene base 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2, the 6-dichloro benzyl
2, the 4-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2, the 6-dichloro benzyl
Phenyl 2-amino-4-pyrimidyl 2, the 6-dichloro benzyl
The 4-fluorophenyl 2-amino-4-pyrimidyl 2, the 6-dichloro benzyl
The 3-fluorophenyl 2-amino-4-pyrimidyl 2, the 6-dichloro benzyl
The 2-fluorophenyl 2-amino-4-pyrimidyl 2, the 6-dichloro benzyl
The 4-chloro-phenyl- 2-amino-4-pyrimidyl 2, the 6-dichloro benzyl
The 3-chloro-phenyl- 2-amino-4-pyrimidyl 2, the 6-dichloro benzyl
The 2-chloro-phenyl- 2-amino-4-pyrimidyl 2, the 6-dichloro benzyl
The 4-tolyl 2-amino-4-pyrimidyl 2, the 6-dichloro benzyl
The 3-tolyl 2-amino-4-pyrimidyl 2, the 6-dichloro benzyl
The 2-tolyl 2-amino-4-pyrimidyl 2, the 6-dichloro benzyl
The 4-trifluoromethyl 2-amino-4-pyrimidyl 2, the 6-dichloro benzyl
The 3-trifluoromethyl 2-amino-4-pyrimidyl 2, the 6-dichloro benzyl
2, the 6-dichlorophenyl 2-amino-4-pyrimidyl 2, the 6-dichloro benzyl
2, the 6-3,5-dimethylphenyl 2-amino-4-pyrimidyl 2, the 6-dichloro benzyl
3, the 4-dichlorophenyl 2-amino-4-pyrimidyl 2, the 6-dichloro benzyl
3, the 4-3,5-dimethylphenyl 2-amino-4-pyrimidyl 2, the 6-dichloro benzyl
The 2,4 dichloro benzene base 2-amino-4-pyrimidyl 2, the 6-dichloro benzyl
2, the 4-3,5-dimethylphenyl 2-amino-4-pyrimidyl 2, the 6-dichloro benzyl
Phenyl The 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 4-fluorophenyl The 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 3-fluorophenyl The 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 2-fluorophenyl The 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 4-chloro-phenyl- The 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 3-chloro-phenyl- The 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 2-chloro-phenyl- The 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 4-tolyl The 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 3-tolyl The 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 2-tolyl The 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 4-trifluoromethyl The 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 3-trifluoromethyl The 4-pyridyl 2-(4-fluorophenyl) ethylamino
2, the 6-dichlorophenyl The 4-pyridyl 2-(4-fluorophenyl) ethylamino
2, the 6-3,5-dimethylphenyl The 4-pyridyl 2-(4-fluorophenyl) ethylamino
3, the 4-dichlorophenyl The 4-pyridyl 2-(4-fluorophenyl) ethylamino
3, the 4-3,5-dimethylphenyl The 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 2,4 dichloro benzene base The 4-pyridyl 2-(4-fluorophenyl) ethylamino
2, the 4-3,5-dimethylphenyl The 4-pyridyl 2-(4-fluorophenyl) ethylamino
Phenyl 2-amino-4-pyridyl 2-(4-fluorophenyl) ethylamino
The 4-fluorophenyl 2-amino-4-pyridyl 2-(4-fluorophenyl) ethylamino
The 3-fluorophenyl 2-amino-4-pyridyl 2-(4-fluorophenyl) ethylamino
The 2-fluorophenyl 2-amino-4-pyridyl 2-(4-fluorophenyl) ethylamino
The 4-chloro-phenyl- 2-amino-4-pyridyl 2-(4-fluorophenyl) ethylamino
The 3-chloro-phenyl- 2-amino-4-pyridyl 2-(4-fluorophenyl) ethylamino
The 2-chloro-phenyl- 2-amino-4-pyridyl 2-(4-fluorophenyl) ethylamino
The 4-tolyl 2-amino-4-pyridyl 2-(4-fluorophenyl) ethylamino
The 3-tolyl 2-amino-4-pyridyl 2-(4-fluorophenyl) ethylamino
The 2-tolyl 2-amino-4-pyridyl 2-(4-fluorophenyl) ethylamino
The 4-trifluoromethyl 2-amino-4-pyridyl 2-(4-fluorophenyl) ethylamino
The 3-trifluoromethyl 2-amino-4-pyridyl 2-(4-fluorophenyl) ethylamino
2, the 6-dichlorophenyl 2-amino-4-pyridyl 2-(4-fluorophenyl) ethylamino
2, the 6-3,5-dimethylphenyl 2-amino-4-pyridyl 2-(4-fluorophenyl) ethylamino
3, the 4-dichlorophenyl 2-amino-4-pyridyl 2-(4-fluorophenyl) ethylamino
3, the 4-3,5-dimethylphenyl 2-amino-4-pyridyl 2-(4-fluorophenyl) ethylamino
The 2,4 dichloro benzene base 2-amino-4-pyridyl 2-(4-fluorophenyl) ethylamino
2, the 4-3,5-dimethylphenyl 2-amino-4-pyridyl 2-(4-fluorophenyl) ethylamino
Phenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 3-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 2-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 4-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 3-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 2-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 4-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 3-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 2-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 4-trifluoromethyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 3-trifluoromethyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-fluorophenyl) ethylamino
2, the 6-dichlorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-fluorophenyl) ethylamino
2, the 6-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-fluorophenyl) ethylamino
3, the 4-dichlorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyrrole 2-(4-fluorophenyl) ethylamino
The pyridine base
3, the 4-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 2,4 dichloro benzene base 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-fluorophenyl) ethylamino
2, the 4-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-fluorophenyl) ethylamino
Phenyl 2-amino-4-pyrimidyl 2-(4-fluorophenyl) ethylamino
The 4-fluorophenyl 2-amino-4-pyrimidyl 2-(4-fluorophenyl) ethylamino
The 3-fluorophenyl 2-amino-4-pyrimidyl 2-(4-fluorophenyl) ethylamino
The 2-fluorophenyl 2-amino-4-pyrimidyl 2-(4-fluorophenyl) ethylamino
The 4-chloro-phenyl- 2-amino-4-pyrimidyl 2-(4-fluorophenyl) ethylamino
The 3-chloro-phenyl- 2-amino-4-pyrimidyl 2-(4-fluorophenyl) ethylamino
The 2-chloro-phenyl- 2-amino-4-pyrimidyl 2-(4-fluorophenyl) ethylamino
The 4-tolyl 2-amino-4-pyrimidyl 2-(4-fluorophenyl) ethylamino
The 3-tolyl 2-amino-4-pyrimidyl 2-(4-fluorophenyl) ethylamino
The 2-tolyl 2-amino-4-pyrimidyl 2-(4-fluorophenyl) ethylamino
The 4-trifluoromethyl 2-amino-4-pyrimidyl 2-(4-fluorophenyl) ethylamino
The 3-trifluoromethyl 2-amino-4-pyrimidyl 2-(4-fluorophenyl) ethylamino
2, the 6-dichlorophenyl 2-amino-4-pyrimidyl 2-(4-fluorophenyl) ethylamino
2, the 6-3,5-dimethylphenyl 2-amino-4-pyrimidyl 2-(4-fluorophenyl) ethylamino
3, the 4-dichlorophenyl 2-amino-4-pyrimidyl 2-(4-fluorophenyl) ethylamino
3, the 4-3,5-dimethylphenyl 2-amino-4-pyrimidyl 2-(4-fluorophenyl) ethylamino
The 2,4 dichloro benzene base 2-amino-4-pyrimidyl 2-(4-fluorophenyl) ethylamino
2, the 4-3,5-dimethylphenyl 2-amino-4-pyrimidyl 2-(4-fluorophenyl) ethylamino
Phenyl The 4-pyridyl 3-phenyl third amino
The 4-fluorophenyl The 4-pyridyl 3-phenyl third amino
The 3-fluorophenyl The 4-pyridyl 3-phenyl third amino
The 2-fluorophenyl The 4-pyridyl 3-phenyl third amino
The 4-chloro-phenyl- The 4-pyridyl 3-phenyl third amino
The 3-chloro-phenyl- The 4-pyridyl 3-phenyl third amino
The 2-chloro-phenyl- The 4-pyridyl 3-phenyl third amino
The 4-tolyl The 4-pyridyl 3-phenyl third amino
The 3-tolyl The 4-pyridyl 3-phenyl third amino
The 2-tolyl The 4-pyridyl 3-phenyl third amino
The 4-trifluoromethyl The 4-pyridyl 3-phenyl third amino
The 3-trifluoromethyl The 4-pyridyl 3-phenyl third amino
2, the 6-dichlorophenyl The 4-pyridyl 3-phenyl third amino
2, the 6-3,5-dimethylphenyl The 4-pyridyl 3-phenyl third amino
3, the 4-dichlorophenyl The 4-pyridyl 3-phenyl third amino
3, the 4-3,5-dimethylphenyl The 4-pyridyl 3-phenyl third amino
The 2,4 dichloro benzene base The 4-pyridyl 3-phenyl third amino
2, the 4-3,5-dimethylphenyl The 4-pyridyl 3-phenyl third amino
Phenyl 2-amino-4-pyridyl 3-phenyl third amino
The 4-fluorophenyl 2-amino-4-pyridyl 3-phenyl third amino
The 3-fluorophenyl 2-amino-4-pyridyl 3-phenyl third amino
The 2-fluorophenyl 2-amino-4-pyridyl 3-phenyl third amino
The 4-chloro-phenyl- 2-amino-4-pyridyl 3-phenyl third amino
The 3-chloro-phenyl- 2-amino-4-pyridyl 3-phenyl third amino
The 2-chloro-phenyl- 2-amino-4-pyridyl 3-phenyl third amino
The 4-tolyl 2-amino-4-pyridyl 3-phenyl third amino
The 3-tolyl 2-amino-4-pyridyl 3-phenyl third amino
The 2-tolyl 2-amino-4-pyridyl 3-phenyl third amino
The 4-trifluoromethyl 2-amino-4-pyridyl 3-phenyl third amino
The 3-trifluoromethyl 2-amino-4-pyridyl 3-phenyl third amino
2, the 6-dichlorophenyl 2-amino-4-pyridyl 3-phenyl third amino
2, the 6-3,5-dimethylphenyl 2-amino-4-pyridyl 3-phenyl third amino
3, the 4-dichlorophenyl 2-amino-4-pyridyl 3-phenyl third amino
3, the 4-3,5-dimethylphenyl 2-amino-4-pyridyl 3-phenyl third amino
The 2,4 dichloro benzene base 2-amino-4-pyridyl 3-phenyl third amino
2, the 4-3,5-dimethylphenyl 2-amino-4-pyridyl 3-phenyl third amino
Phenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-phenyl third amino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-phenyl third amino
The 3-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-phenyl third amino
The 2-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-phenyl third amino
The 4-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-phenyl third amino
The 3-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-phenyl third amino
The 2-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-phenyl third amino
The 4-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-phenyl third amino
The 3-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-phenyl third amino
The 2-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-phenyl third amino
The 4-trifluoromethyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-phenyl third amino
The 3-trifluoromethyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-phenyl third amino
2, the 6-dichlorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-phenyl third amino
2, the 6-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-phenyl third amino
3, the 4-dichlorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-phenyl third amino
3, the 4-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-phenyl third amino
The 2,4 dichloro benzene base 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-phenyl third amino
2, the 4-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-phenyl third amino
Phenyl 2-amino-4-pyrimidyl 3-phenyl third amino
The 4-fluorophenyl 2-amino-4-pyrimidyl 3-phenyl third amino
The 3-fluorophenyl 2-amino-4-pyrimidyl 3-phenyl third amino
The 2-fluorophenyl 2-amino-4-pyrimidyl 3-phenyl third amino
The 4-chloro-phenyl- 2-amino-4-pyrimidyl 3-phenyl third amino
The 3-chloro-phenyl- 2-amino-4-pyrimidyl 3-phenyl third amino
The 2-chloro-phenyl- 2-amino-4-pyrimidyl 3-phenyl third amino
The 4-tolyl 2-amino-4-pyrimidyl 3-phenyl third amino
The 3-tolyl 2-amino-4-pyrimidyl 3-phenyl third amino
The 2-tolyl 2-amino-4-pyrimidyl 3-phenyl third amino
The 4-trifluoromethyl 2-amino-4-pyrimidyl 3-phenyl third amino
The 3-trifluoromethyl 2-amino-4-pyrimidyl 3-phenyl third amino
2, the 6-dichlorophenyl 2-amino-4-pyrimidyl 3-phenyl third amino
2, the 6-3,5-dimethylphenyl 2-amino-4-pyrimidyl 3-phenyl third amino
3, the 4-dichlorophenyl 2-amino-4-pyrimidyl 3-phenyl third amino
3, the 4-3,5-dimethylphenyl 2-amino-4-pyrimidyl 3-phenyl third amino
The 2,4 dichloro benzene base 2-amino-4-pyrimidyl 3-phenyl third amino
2, the 4-3,5-dimethylphenyl 2-amino-4-pyrimidyl 3-phenyl third amino
Phenyl The 4-pyridyl (1-methyl-3-phenyl) third amino
The 4-fluorophenyl The 4-pyridyl (1-methyl-3-phenyl) third amino
The 3-fluorophenyl The 4-pyridyl (1-methyl-3-phenyl) third amino
The 2-fluorophenyl The 4-pyridyl (1-methyl-3-phenyl) third amino
The 4-chloro-phenyl- The 4-pyridyl (1-methyl-3-phenyl) third amino
The 3-chloro-phenyl- The 4-pyridyl (1-methyl-3-phenyl) third amino
The 2-chloro-phenyl- The 4-pyridyl (1-methyl-3-phenyl) third amino
The 4-tolyl The 4-pyridyl (1-methyl-3-phenyl) third amino
The 3-tolyl The 4-pyridyl (1-methyl-3-phenyl) third amino
The 2-tolyl The 4-pyridyl (1-methyl-3-phenyl) third amino
The 4-trifluoromethyl The 4-pyridyl (1-methyl-3-phenyl) third amino
The 3-trifluoromethyl The 4-pyridyl (1-methyl-3-phenyl) third amino
2, the 6-dichlorophenyl The 4-pyridyl (1-methyl-3-phenyl) third amino
2, the 6-3,5-dimethylphenyl The 4-pyridyl (1-methyl-3-phenyl) third amino
3, the 4-dichlorophenyl The 4-pyridyl (1-methyl-3-phenyl) third amino
3, the 4-3,5-dimethylphenyl The 4-pyridyl (1-methyl-3-phenyl) third amino
The 2,4 dichloro benzene base The 4-pyridyl (1-methyl-3-phenyl) third amino
2, the 4-3,5-dimethylphenyl The 4-pyridyl (1-methyl-3-phenyl) third amino
Phenyl 2-amino-4-pyridyl (1-methyl-3-phenyl) third amino
The 4-fluorophenyl 2-amino-4-pyridyl (1-methyl-3-phenyl) third amino
The 3-fluorophenyl 2-amino-4-pyridyl (1-methyl-3-phenyl) third amino
The 2-fluorophenyl 2-amino-4-pyridyl (1-methyl-3-phenyl) third amino
The 4-chloro-phenyl- 2-amino-4-pyridyl (1-methyl-3-phenyl) third amino
The 3-chloro-phenyl- 2-amino-4-pyridyl (1-methyl-3-phenyl) third amino
The 2-chloro-phenyl- 2-amino-4-pyridyl (1-methyl-3-phenyl) third amino
The 4-tolyl 2-amino-4-pyridyl (1-methyl-3-phenyl) third amino
The 3-tolyl 2-amino-4-pyridyl (1-methyl-3-phenyl) third amino
The 2-tolyl 2-amino-4-pyridyl (1-methyl-3-phenyl) third amino
The 4-trifluoromethyl 2-amino-4-pyridyl (1-methyl-3-phenyl) third amino
The 3-trifluoromethyl 2-amino-4-pyridyl (1-methyl-3-phenyl) third amino
2, the 6-dichlorophenyl 2-amino-4-pyridyl (1-methyl-3-phenyl) third amino
2, the 6-3,5-dimethylphenyl 2-amino-4-pyridyl (1-methyl-3-phenyl) third amino
3, the 4-dichlorophenyl 2-amino-4-pyridyl (1-methyl-3-phenyl) third amino
3, the 4-3,5-dimethylphenyl 2-amino-4-pyridyl (1-methyl-3-phenyl) third amino
The 2,4 dichloro benzene base 2-amino-4-pyridyl (1-methyl-3-phenyl) third amino
2, the 4-3,5-dimethylphenyl 2-amino-4-pyridyl (1-methyl-3-phenyl) third amino
Phenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (1-methyl-3-phenyl) third amino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (1-methyl-3-phenyl) third amino
The 3-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (1-methyl-3-phenyl) third amino
The 2-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (1-methyl-3-phenyl) third amino
The 4-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (1-methyl-3-phenyl) third amino
The 3-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (1-methyl-3-phenyl) third amino
The 2-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (1-methyl-3-phenyl) third amino
The 4-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (1-methyl-3-phenyl) third amino
The 3-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (1-methyl-3-phenyl) third amino
The 2-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (1-methyl-3-phenyl) third amino
The 4-trifluoromethyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (1-methyl-3-phenyl) third amino
The 3-trifluoromethyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (1-methyl-3-phenyl) third amino
2, the 6-dichlorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (1-methyl-3-phenyl) third amino
2, the 6-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (1-methyl-3-phenyl) third amino
3, the 4-dichlorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (1-methyl-3-phenyl) third amino
3, the 4-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (1-methyl-3-phenyl) third amino
The 2,4 dichloro benzene base 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (1-methyl-3-phenyl) third amino
2, the 4-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (1-methyl-3-phenyl) third amino
Phenyl 2-amino-4-pyrimidyl (1-methyl-3-phenyl) third amino
The 4-fluorophenyl 2-amino-4-pyrimidyl (1-methyl-3-phenyl) third amino
The 3-fluorophenyl 2-amino-4-pyrimidyl (1-methyl-3-phenyl) third amino
The 2-fluorophenyl 2-amino-4-pyrimidyl (1-methyl-3-phenyl) third amino
The 4-chloro-phenyl- 2-amino-4-pyrimidyl (1-methyl-3-phenyl) third amino
The 3-chloro-phenyl- 2-amino-4-pyrimidyl (1-methyl-3-phenyl) third amino
The 2-chloro-phenyl- 2-amino-4-pyrimidyl (1-methyl-3-phenyl) third amino
The 4-tolyl 2-amino-4-pyrimidyl (1-methyl-3-phenyl) third amino
The 3-tolyl 2-amino-4-pyrimidyl (1-methyl-3-phenyl) third amino
The 2-tolyl 2-amino-4-pyrimidyl (1-methyl-3-phenyl) third amino
The 4-trifluoromethyl 2-amino-4-pyrimidyl (1-methyl-3-phenyl) third amino
The 3-trifluoromethyl 2-amino-4-pyrimidyl (1-methyl-3-phenyl) third amino
2, the 6-dichlorophenyl 2-amino-4-pyrimidyl (1-methyl-3-phenyl) third amino
2, the 6-3,5-dimethylphenyl 2-amino-4-pyrimidyl (1-methyl-3-phenyl) third amino
3, the 4-dichlorophenyl 2-amino-4-pyrimidyl (1-methyl-3-phenyl) third amino
3, the 4-3,5-dimethylphenyl 2-amino-4-pyrimidyl (1-methyl-3-phenyl) third amino
The 2,4 dichloro benzene base 2-amino-4-pyrimidyl (1-methyl-3-phenyl) third amino
2, the 4-3,5-dimethylphenyl 2-amino-4-pyrimidyl (1-methyl-3-phenyl) third amino
The 4-fluorophenyl The 4-pyridyl 4-luorobenzyl amino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 4-luorobenzyl amino
The 4-fluorophenyl 2-amino-4-pyrimidyl 4-luorobenzyl amino
The 4-fluorophenyl The 4-pyridyl (2-(4-fluorophenyl)-1-methyl-ethyl) amino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (2-(4-fluorophenyl)-1-methyl-ethyl) amino
The 4-fluorophenyl 2-amino-4-pyrimidyl (2-(4-fluorophenyl)-1-methyl-ethyl) amino
The 4-fluorophenyl The 4-pyridyl (1,1-dimethyl-2-(4-fluorophenyl) ethyl) amino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (1,1-dimethyl-2-(4-fluorophenyl) ethyl) amino
The 4-fluorophenyl 2-amino-4-pyrimidyl (1,1-dimethyl-2-(4-fluorophenyl) ethyl) amino
The 4-fluorophenyl The 4-pyridyl 2-(4-fluorophenyl)-2-methyl-ethylamino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-fluorophenyl)-2-methyl-ethylamino
The 4-fluorophenyl 2-amino-4-pyrimidyl 2-(4-fluorophenyl)-2-methyl-ethylamino
The 4-fluorophenyl The 4-pyridyl (2-methyl-2-phenylethyl) amino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (2-methyl-2-phenylethyl) amino
The 4-fluorophenyl 2-amino-4-pyrimidyl (2-methyl-2-phenylethyl) amino
The 4-fluorophenyl The 4-pyridyl Methyl-(2-styroyl) amino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl Methyl-(2-styroyl) amino
The 4-fluorophenyl 2-amino-4-pyrimidyl Methyl-(2-styroyl) amino
The 4-fluorophenyl The 4-pyridyl (2-(4-trifluoromethyl) ethylamino)
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (2-(4-trifluoromethyl) ethylamino)
The 4-fluorophenyl 2-amino-4-pyrimidyl (2-(4-trifluoromethyl) ethylamino)
The 4-fluorophenyl The 4-pyridyl 2-(4-tolyl) ethylamino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-(4-tolyl) ethylamino
The 4-fluorophenyl 2-amino-4-pyrimidyl 2-(4-tolyl) ethylamino
The 4-fluorophenyl The 4-pyridyl (2-(3-fluorophenyl) ethyl) amino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (2-(3-fluorophenyl) ethyl) amino
The 4-fluorophenyl 2-amino-4-pyrimidyl (2-(3-fluorophenyl) ethyl) amino
The 4-fluorophenyl The 4-pyridyl (2-(2-fluorophenyl) ethyl) amino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (2-(2-fluorophenyl) ethyl) amino
The 4-fluorophenyl 2-amino-4-pyrimidyl (2-(2-fluorophenyl) ethyl) amino
The 4-fluorophenyl The 4-pyridyl Methyl-(2-(2-pyridyl) ethyl) amino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl Methyl-(2-(2-pyridyl) ethyl) amino
The 4-fluorophenyl 2-amino-4-pyrimidyl Methyl-(2-(2-pyridyl) ethyl) amino
The 4-fluorophenyl The 4-pyridyl (1,1-dimethyl-3-phenyl propyl) amino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (1,1-dimethyl-3-phenyl propyl) amino
The 4-fluorophenyl 2-amino-4-pyrimidyl (1,1-dimethyl-3-phenyl propyl) amino
The 4-fluorophenyl The 4-pyridyl (3-(4-fluorophenyl) propyl group) amino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (3-(4-fluorophenyl) propyl group) amino
The 4-fluorophenyl 2-amino-4-pyrimidyl (3-(4-fluorophenyl) propyl group) amino
The 4-fluorophenyl The 4-pyridyl (3-(4-fluorophenyl)-1-methyl-propyl) amino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyrrole (3-(4-fluorophenyl)-1
The pyridine base -methyl-propyl) amino
The 4-fluorophenyl 2-amino-4-pyrimidyl (3-(4-fluorophenyl)-1-methyl-propyl) amino
The 4-fluorophenyl The 4-pyridyl (1,1-dimethyl-3-(4-fluorophenyl) propyl group) amino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (1,1-dimethyl-3-(4-fluorophenyl) propyl group) amino
The 4-fluorophenyl 2-amino-4-pyrimidyl (1,1-dimethyl-3-(4-fluorophenyl) propyl group) amino
The 4-fluorophenyl The 4-pyridyl (3-(2-fluorophenyl) propyl group) amino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (3-(2-fluorophenyl) propyl group) amino
The 4-fluorophenyl 2-amino-4-pyrimidyl (3-(2-fluorophenyl) propyl group) amino
The 4-fluorophenyl The 4-pyridyl (3-methyl-3-phenyl propyl) amino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (3-methyl-3-phenyl propyl) amino
The 4-fluorophenyl 2-amino-4-pyrimidyl (3-methyl-3-phenyl propyl) amino
The 4-fluorophenyl The 4-pyridyl (2-methyl-3-phenyl propyl) amino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (2-methyl-3-phenyl propyl) amino
The 4-fluorophenyl 2-amino-4-pyrimidyl (2-methyl-3-phenyl propyl) amino
The 4-fluorophenyl The 4-pyridyl (3, the 3-dimethylbutyl) amino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (3, the 3-dimethylbutyl) amino
The 4-fluorophenyl 2-amino-4-pyrimidyl (3, the 3-dimethylbutyl) ammonia
Base
The 4-fluorophenyl The 4-pyridyl Isoamylamino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl Isoamylamino
The 4-fluorophenyl 2-amino-4-pyrimidyl Isoamylamino
The 4-fluorophenyl The 4-pyridyl Penta amino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl Penta amino
The 4-fluorophenyl 2-amino-4-pyrimidyl Penta amino
The 4-fluorophenyl The 4-pyridyl (2, the 5-dimethyl) penta amino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (2, the 5-dimethyl) penta amino
The 4-fluorophenyl 2-amino-4-pyrimidyl (2, the 5-dimethyl) penta amino
The 4-fluorophenyl The 4-pyridyl Piperazinyl
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl Piperazinyl
The 4-fluorophenyl 2-amino-4-pyrimidyl Piperazinyl
The 4-fluorophenyl The 4-pyridyl (3-(3-fluorophenyl) propyl group) amino
The 4-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (3-(3-fluorophenyl) propyl group) amino
The 4-fluorophenyl 2-amino-4-pyrimidyl (3-(3-fluorophenyl) propyl group) amino
Benzyl The 4-pyridyl 3-phenyl third amino
Benzyl The 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 2-thienyl The 4-pyridyl 3-phenyl third amino
The 2-thienyl The 4-pyridyl 2-(4-fluorophenyl) ethylamino
Cyclohexyl The 4-pyridyl 3-phenyl third amino
Cyclohexyl The 4-pyridyl 2-(4-fluorophenyl) ethylamino
The tertiary butyl The 4-pyridyl 3-phenyl third amino
The tertiary butyl The 4-pyridyl 2-(4-fluorophenyl) ethylamino
The 4-fluorophenyl The 4-piperidyl 3-phenyl third amino
The 4-fluorophenyl The 4-piperidyl 2-(4-fluorophenyl) ethylamino
The 4-fluorophenyl The 4-pyranyl 3-phenyl third amino
The 4-fluorophenyl The 4-pyranyl 2-(4-fluorophenyl) ethylamino
Phenyl The 4-pyridyl Amino third amino of 3-phenyl-2-
The 4-fluorophenyl The 4-pyridyl Amino third amino of 3-phenyl-2-
The 3-fluorophenyl The 4-pyridyl Amino third amino of 3-phenyl-2-
The 2-fluorophenyl The 4-pyridyl Amino third amino of 3-phenyl-2-
The 4-chloro-phenyl- The 4-pyridyl Amino third amino of 3-phenyl-2-
The 3-chloro-phenyl- The 4-pyridyl Amino third amino of 3-phenyl-2-
The 2-chloro-phenyl- The 4-pyridyl Amino third amino of 3-phenyl-2-
The 4-tolyl The 4-pyridyl Amino third amino of 3-phenyl-2-
The 3-tolyl The 4-pyridyl Amino third amino of 3-phenyl-2-
The 2-tolyl The 4-pyridyl Amino third amino of 3-phenyl-2-
The 4-trifluoromethyl The 4-pyridyl Amino third amino of 3-phenyl-2-
The 3-trifluoromethyl The 4-pyridyl Amino third amino of 3-phenyl-2-
2, the 6-dichlorophenyl The 4-pyridyl Amino third amino of 3-phenyl-2-
2, the 6-3,5-dimethylphenyl The 4-pyridyl Amino third amino of 3-phenyl-2-
3, the 4-dichlorophenyl The 4-pyridyl Amino third amino of 3-phenyl-2-
3, the 4-3,5-dimethylphenyl The 4-pyridyl Amino third amino of 3-phenyl-2-
The 2,4 dichloro benzene base The 4-pyridyl Amino third amino of 3-phenyl-2-
2, the 4-3,5-dimethylphenyl The 4-pyridyl Amino third amino of 3-phenyl-2-
Phenyl The 4-pyridyl Amino third amino of 3-phenyl-3-
The 4-fluorophenyl The 4-pyridyl Amino third amino of 3-phenyl-3-
The 3-fluorophenyl The 4-pyridyl Amino third amino of 3-phenyl-3-
The 2-fluorophenyl The 4-pyridyl Amino third amino of 3-phenyl-3-
The 4-chloro-phenyl- The 4-pyridyl Amino third amino of 3-phenyl-3-
The 3-chloro-phenyl- The 4-pyridyl Amino third amino of 3-phenyl-3-
The 2-chloro-phenyl- The 4-pyridyl Amino third amino of 3-phenyl-3-
The 4-tolyl The 4-pyridyl Amino third amino of 3-phenyl-3-
The 3-tolyl The 4-pyridyl Amino third amino of 3-phenyl-3-
The 2-tolyl The 4-pyridyl Amino third amino of 3-phenyl-3-
The 4-trifluoromethyl The 4-pyridyl Amino third amino of 3-phenyl-3-
The 3-trifluoromethyl The 4-pyridyl Amino third amino of 3-phenyl-3-
2, the 6-dichlorophenyl The 4-pyridyl Amino third amino of 3-phenyl-3-
2, the 6-3,5-dimethylphenyl The 4-pyridyl Amino third amino of 3-phenyl-3-
3, the 4-dichlorophenyl The 4-pyridyl Amino third amino of 3-phenyl-3-
3, the 4-3,5-dimethylphenyl The 4-pyridyl Amino third amino of 3-phenyl-3-
The 2,4 dichloro benzene base The 4-pyridyl Amino third amino of 3-phenyl-3-
2, the 4-3,5-dimethylphenyl The 4-pyridyl Amino third amino of 3-phenyl-3-
The 3-fluorophenyl The 4-pyridyl (S)-tetrahydroisoquinoline-3-base methylamino-
The 2-fluorophenyl 2-amino-4-pyridyl (S)-3-benzyl diethylenediamine base
The 3-chloro-phenyl- 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (S)-2-N-isopropylamino-3-phenyl third amino
The 2-chloro-phenyl- 2-amino-4-pyrimidyl (S)-2-N-glycyl amino-3-phenyl third amino
The 4-tolyl The 4-pyridyl (S)-2-amino-3-phenyl third amino
The 3-tolyl 2-amino-4-pyridyl (R)-2-amino-3-phenyl third amino
The 2-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-amino-3-phenyl third amino
The 4-trifluoromethyl 2-amino-4-pyrimidyl (S)-2-amino-3-(2-fluorophenyl) third amino
The 3-trifluoromethyl The 4-pyridyl (S)-2-amino-3-(2-fluorophenyl) third amino
2, the 6-dichlorophenyl 2-amino-4-pyridyl 3-amino-3-(2-fluorophenyl) third amino
2, the 6-3,5-dimethylphenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-amino-3-(2-aminomethyl phenyl) third amino
3, the 4-dichlorophenyl 2-amino-4-pyrimidyl 2-amino-2-methyl-3-phenyl third amino
3, the 4-3,5-dimethylphenyl The 4-pyridyl 3-amino-2-methyl-3-benzene
Base third amino
The 3-fluorophenyl 2-amino-4-pyridyl (S)-2-amino-3-phenyl third amino
The 2-fluorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl (S)-2-amino-3-(2-fluorophenyl) third amino
The 3-chloro-phenyl- 2-amino-4-pyrimidyl (S)-2-amino-3-(2-aminomethyl phenyl) third amino
The 2-chloro-phenyl- The 4-pyridyl (S)-2-N-isopropylamino-3-phenyl third amino
The 4-tolyl 2-amino-4-pyridyl (S)-2-N-glycyl amino-3-phenyl third amino
The 3-tolyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 2-amino-2-methyl-3-phenyl third amino
The 2-tolyl 2-amino-4-pyrimidyl (R)-2-amino-3-phenyl third amino
The 4-trifluoromethyl The 4-pyridyl 3-amino-3-phenyl third amino
The 3-trifluoromethyl 2-amino-4-pyridyl 3-amino-3-(2-fluorophenyl) third amino
2, the 6-dichlorophenyl 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl 3-amino-3-(2-aminomethyl phenyl) third amino
2, the 6-3,5-dimethylphenyl 2-amino-4-pyrimidyl 2-amino-2-methyl-3-phenyl third amino
3, the 4-dichlorophenyl The 4-pyridyl (S)-tetrahydroisoquinoline-3-base methylamino-
3, the 4-3,5-dimethylphenyl The 4-pyridyl (S)-3-benzyl diethylenediamine base
Preferred in addition compound is the compound of hereinafter enumerating especially among the embodiment.
Following term used herein has following implication:
Independent or " alkyl " that be used in combination is meant and contains preferred 1-15 carbon atom (C 1-C 15), more preferably 1-8 carbon atom (C 1-C 8), further preferred 1-6 carbon atom (C 1-C 6), preferred 1-4 carbon atom (C also 1-C 4), more preferably 1-3 carbon atom (C 1-C 3) and 1-2 carbon atom (C most preferably 1-C 2) the straight or branched alkyl.This type of examples of groups comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, hexyl, octyl group etc.
Separately or " hydroxyalkyl " that be used in combination be meant that wherein at least one hydrogen is replaced by hydroxyl, preferred 1-3 hydrogen is replaced by hydroxyl, more preferably 1-2 hydrogen is replaced by hydroxyl and 1 alkyl as defined above that hydrogen is replaced by hydroxyl most preferably.This type of examples of groups comprises methylol, 1-, 2-hydroxyethyl, 1-, 2-, 3-hydroxypropyl, 1,3-dihydroxyl-2-propyl group, 1,3-dihydroxyl butyl, 1,2,3,4,5,6-hexahydroxy--2-hexyl etc.
Separately or " thiazolinyl " that be used in combination be meant to have one or more pairs of keys, preferred 1-2 two keys, more preferably 1 two key, and contain 2-15 carbon atom (C 2-C 15), more preferably 2-8 carbon atom (C 2-C 8), further preferred 2-6 carbon atom (C 2-C 6), preferred 2-4 carbon atom (C also 2-C 4) and still can further preferred 2-3 carbon atom (C 2-C 3) the straight or branched alkyl.The example of this type of thiazolinyl comprises vinyl, propenyl, 2-methylpropenyl, 1,4-butadienyl etc.
Independent or " alkoxyl group " that be used in combination typically is meant " R-O-" group, and wherein " R " is that alkyl is a Sauerstoffatom with " O " as defined above.The example of this type of alkoxyl group comprises methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy etc.
Independent or " carbalkoxy " that be used in combination typically is meant " R-O-C (O)-" group, and wherein " R-O-" is that alkoxyl group is a carbonyl with " C (O) " as defined above.
Independent or " alkoxycarbonyl amido " that be used in combination typically is meant " R-O-C (O)-NH-" group, wherein " R-O-C (O) " is carbalkoxy as defined above, and wherein said amino can be replaced arbitrarily by for example alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl etc.
Independent or " alkylthio " that be used in combination typically is meant " R-S-" group, and wherein " R " is that alkyl is a sulphur atom with " S " as defined above.The example of this type of alkylthio comprises methylthio group, ethylmercapto group, positive rosickyite base, iprotiazem base, positive butylthio, isobutyl sulfenyl, secondary butylthio, uncle's butylthio etc.
Separately or " alkyl sulphinyl " that be used in combination typically be meant " R-S (O)-" group, wherein " R " is alkyl and " S (O) is " by the sulphur atom of an oxidation as defined above.The example of this type of alkyl sulphinyl comprises methylsulfinyl, ethyl sulfinyl, n-propyl sulfinyl, sec.-propyl sulfinyl, normal-butyl sulfinyl, isobutyl-sulfinyl, sec-butyl sulfinyl, tertiary butyl sulfinyl etc.
Independent or " alkyl sulphonyl " that be used in combination typically is meant " R-S (O) 2-" group, wherein " R " is alkyl and " S (O) as defined above 2" by the sulphur atom of titanium dioxide.The example of this type of alkyl sulphonyl comprises methylsulfonyl, ethylsulfonyl, n-propyl alkylsulfonyl, sec.-propyl alkylsulfonyl, normal-butyl alkylsulfonyl, isobutyl-alkylsulfonyl, sec-butyl alkylsulfonyl, tertiary butyl alkylsulfonyl etc.
Independent or " aryl " that be used in combination is meant phenyl or xenyl; it can at random condense with phenyl ring or with heterocyclic fused and can be selected from following group and replace arbitrarily by one or more; described group is selected from alkyl; alkoxyl group; halogen; hydroxyl; amino; azido-; nitro; cyano group; haloalkyl; carboxyl; carbalkoxy; cycloalkyl; alkanoyl amino; amido; amidino groups; alkoxycarbonyl amido; the N-alkyl amidine; alkylamino; dialkylamino; aminoalkyl group; alkyl amino alkyl; dialkylaminoalkyl; the N-alkyl amido; N, N-dialkyl group amido; aralkoxycarbonyl amino; alkylthio; alkyl sulphinyl; alkyl sulphonyl; oxo etc.The example of aryl has phenyl, neighbour-tolyl, 4-p-methoxy-phenyl, 2-(tert.-butoxy) phenyl, 3-methyl-4-p-methoxy-phenyl, 2-CF 3-phenyl, the 2-fluorophenyl, the 2-chloro-phenyl-, the 3-nitrophenyl, the 3-aminophenyl, the 3-acetylamino phenyl, 2-amino-3-(amino methyl) phenyl, 6-methyl-3-acetylamino phenyl, 6-methyl-2-aminophenyl, 6-methyl-2, the 3-diamino-phenyl, 2-amino-3-aminomethyl phenyl, 4,6-dimethyl-2-aminophenyl, the 4-hydroxy phenyl, 3-alkyl-4-hydroxy phenyl, 4-(2-p-methoxy-phenyl) phenyl, 2-amino-1-naphthyl, the 2-naphthyl, 3-amino-2-naphthyl, 1-methyl-3-amino-2-naphthyl, 2,3-diaminostilbene-naphthyl, 4,8-dimethoxy-2-naphthyl etc.
Separately or " aralkyl " and " arylalkyl " that be used in combination be meant wherein at least one, preferred 1-2 the abovementioned alkyl group that hydrogen atom is replaced by above-mentioned aryl, for example benzyl, 1-, 2-styroyl, dibenzyl methyl, hydroxyphenyl methyl, tolyl methyl, diphenyl methyl, dichlorophenylmethyl, 4-anisole ylmethyl etc.
Separately or " aralkoxy " that be used in combination be meant wherein at least one, preferred 1-2 the above-mentioned alkoxy base that hydrogen atom is replaced by above-mentioned aryl, for example benzyloxy, 1-, 2-phenyl ethoxy, dibenzyl methoxyl group, hydroxyphenyl methoxyl group, tolyl methoxyl group, dichlorophenyl methoxyl group, 4-anisole ylmethoxy etc.
Separately or " aromatic alkoxy carbonyl " that be used in combination typically be meant " R-O-C (O)-" group, wherein " R-O-" is aralkoxy as defined above, and " C (O)-" is carbonyl.
Separately or " alkanoyl " that be used in combination typically be meant " R-C (O)-", wherein " R " is alkyl as defined above, and " C (O)-" is carbonyl.The example of this type of alkanoyl comprises ethanoyl, trifluoroacetyl group, hydroxyacetyl, propionyl, butyryl radicals, pentanoyl, 4-methylpent acyl group etc.
Independent or " alkanoyl amino " that be used in combination typically is meant " R-C (O)-NH-"; wherein " R-C (O)-" is alkanoyl as defined above, and wherein said amino can be replaced arbitrarily by for example alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl etc.
Separately or " aminocarboxyl " that be used in combination be meant the amino carbonyl (formamyl) that replaces, wherein said amino can be at random by for example alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkanoyl, carbalkoxy, aromatic alkoxy carbonyl etc.-or two-replace.
Independent or " amino-sulfonyl " that be used in combination is meant the amino alkylsulfonyl that replaces.
Independent or " benzo " that be used in combination is meant phenyl ring deutero-divalent group C 6H 4=." benzo-fused " is that wherein benzene and cycloalkyl or aryl have the ring system of two shared carbon atoms, for example naphthane etc.
" dicyclo " used herein means ring system for example naphthyl and the β-Ka Lin base that comprises two fused rings, and the ring system that replaces for example xenyl, phenylpyridyl and phenylbenzene piperazinyl.
Independent or " cycloalkyl " that be used in combination is meant and preferably contains 5-12 carbon atom (C 5-C 12), more preferably 5-10 carbon atom (C 5-C 10), further preferred 5-7 carbon atom (C 5-C 7), saturated or fractional saturation, preferably contain monocycle, dicyclo or the three ring carbocyclic ring alkyl of two keys, preferred monocycle, it can at random condense with phenyl ring or with heterocyclic fused and can be optionally substituted described in the aryl definition.The example of this type of cycloalkyl comprises cyclopentyl, cyclohexyl, dihydroxyl cyclohexyl, methylene-dioxy cyclohexyl, suberyl, octahydro naphthyl, tetralyl, octahydro quinolyl, dimethoxy tetralyl, 2,3-dihydro-1H-indenyl, azabicyclo [3.2.1] octyl group etc.
" heteroatoms " is meant nitrogen, oxygen and sulfur heteroatom.
" heterocycle (condense) " is that wherein 5-6 unit's heterocyclic radical or heteroaryl and cycloalkyl or aryl have the ring system of two shared carbon atoms, for example indoles, isoquinoline 99.9, tetrahydroquinoline, methylenedioxybenzenes etc.
" heterocyclic radical " is meant and contains at least one, preferred 1-4, more preferably 1-3, further preferred 1-2 nitrogen, oxygen or sulphur annular atoms and each ring are preferably 3-8 unit ring, each encircles 5-8 unit ring more preferably and each and encircles that 5-6 unit more preferably encircles, saturated or fractional saturation, the monocycle or the dicyclo that preferably contain two keys, preferred monocyclic heterocycles group." heterocyclic radical " means the sulfone that comprises the sulphur annular atoms and the N-oxide compound of sulfoxide derivant and uncle's azo-cycle atom, and with a preferred 3-6 ring carbon atom and more preferably 5-6 ring carbon atom carbocyclic fused and with phenyl ring condensed ring system." heterocyclic radical " can be by any replacement as described below; and at least one; preferred 1-4; more preferably 1-3; on further preferred 1-2 the carbon atom by replacements such as halogen, alkyl, alkoxyl group, hydroxyl, oxo, sulfo-, aryl, aralkyl, heteroaryl, heteroaralkyl, amidino groups, N-alkyl amidine, alkoxycarbonyl amido, alkyl sulfonyl amino, and/or on second nitrogen-atoms by hydroxyl, alkyl, aromatic alkoxy carbonyl, alkanoyl, carbalkoxy, heteroaralkyl, aryl or aralkyl replacement.More preferably, independent or " heterocyclic radical " that be used in combination is that wherein 1-3 annular atoms is oxygen, sulphur or nitrogen heteroatom, can be that at random part is undersaturated or with the phenyl ring condensed and at random replaced by 1-2 oxo or thio group, each ring is monocycle or dicyclo saturated heterocyclic system of 5-8 unit ring.The example of this type of heterocyclic radical comprises pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, 4-benzyl-piperazine-1-base, pyrimidyl, tetrahydrofuran base, pyrazolidine ketone group, pyrazolinyl, pyridazine ketone group, pyrrolidone-base, tetrahydro-thienyl and sulfoxide and sulfone derivatives, 2,3-indolinyl, tetrahydric quinoline group, 1,2,3,4-tetrahydro isoquinolyl, 1,2,3,4-tetrahydrochysene-1-oxo-isoquinolyl, 2,3-dihydro benzo furyl, benzopyranyl, methylenedioxyphenyl, ethylenedioxy phenyl etc.
" heteroaryl " is meant and contains at least one, preferred 1-4, more preferably 1-3, that further preferred 1-2 nitrogen, oxygen or thia annular atoms and each are encircled is that preferred 5-6 unit encircles, monocycle or dicyclo, preferred monocyclic aromatic heterocyclic radical, it can be at random and preferred 3-4 carbon atom (C 3-C 4) saturated carbon ring condense and form 5-6 unit ring and can described in above-mentioned aryl definition, be optionally substituted.The example of this type of heteroaryl comprises imidazolyl, 1-carbobenzoxy-(Cbz) imidazol-4 yl, pyrryl, pyrazolyl, pyridyl, 3-(2-methyl) pyridyl, 3-(4-trifluoromethyl) pyridyl, pyrimidyl, 5-(4-trifluoromethyl) pyrimidyl, pyrazinyl, triazolyl, furyl, thienyl, oxazolyl, thiazolyl, indyl, quinolyl, 5,6,7,8-tetrahydric quinoline group, 5,6,7,8-tetrahydro isoquinolyl, quinoxalinyl, benzothiazolyl, benzofuryl, benzimidazolyl-, benzoxazolyl etc.
Separately or " heteroaralkyl " and " heteroarylalkyl " that be used in combination be meant wherein at least one, preferred 1-2 hydrogen atom quilt is the abovementioned alkyl group of heteroaryl replacement, for example 3-furyl propyl group, 2-pyrryl propyl group, chloroquinoline ylmethyl, 2-thienyl ethyl, pyridylmethyl, 1-imidazolyl ethyl etc. as defined above.
Independent or " halogen " and " halo " that be used in combination is meant fluorine, chlorine, bromine or iodine.
Separately or " haloalkyl " that be used in combination be meant wherein at least one, preferred 1-3 hydrogen atom be by halogen, more preferably the abovementioned alkyl group of fluorine or chlorine replacement.The example of this type of haloalkyl comprises 1,1,1-trifluoroethyl, chloromethyl, 1-brooethyl, methyl fluoride, difluoromethyl, trifluoromethyl, two (trifluoromethyl) methyl etc.
" 4 (3H)-pyrimidone " is two kinds of tautomers of same compound (B) with " 4-hydroxyl-pyrimidine " (A), and it can exchange use.Be understandable that, use one of them term must comprise another.
Figure A9718156301051
" pharmaceutically acceptable salt " be meant through the preparation of conventional method and be to well known to a person skilled in the art salt.Described " pharmaceutically acceptable salt " comprises inorganic and the organic acid basic salt, comprise, but be not limited only to hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, ethyl sulfonic acid, oxysuccinic acid, acetate, oxalic acid, tartrate, citric acid, lactic acid, fumaric acid, succsinic acid, toxilic acid, Whitfield's ointment, phenylformic acid, toluylic acid, amygdalic acid etc.When compound of the present invention contains the acid function base for example during carboxyl, joining on the paired appropriate drug acceptable positively charged ion with described carboxyl is to well known to a person skilled in the art and comprise basic metal, alkaline-earth metal, ammonium, quaternary ammonium cation etc.The example of other " pharmaceutically acceptable salt " can vide infra and people's such as Berge J.Pharm.Sci.66, and 1 (1977).
" cytokine " is a kind of secretory protein that influences other cell functions, particularly it with the immune system cell interphase interaction or with inflammatory response relevant cell regulate relevant.The example of cytokine include but not limited to, interleukin 1 (IL-1), preferred IL-1 β, interleukin 6 (IL-6), interleukin 8 (IL-8) and TNF, preferred TNF-α (tumor necrosis factor-alpha).
" disease or the illness of TNF, IL-1, IL-6 and/or IL-8 mediation " is meant the disease of all these, wherein the effect of TNF, IL-1, IL-6 and/or IL-8 is with the performance of TNF, IL-1, IL-6 and/or IL-8 self form, perhaps induces the release of another kind of cytokine to bring into play by TNF, IL-1, IL-6 and/or IL-8.For example, wherein IL-1 plays a major role, but wherein the generation of IL-1 or effect are the illnesss that the result's of TNF effect this illness is considered to the THF mediation.
" leavings group " is often referred to easily by nucleophilic reagent for example amine, mercaptan or pure nucleophilic reagent metathetical group.This type of leavings group is well known in the art.The example of this class leavings group include but not limited to, N-hydroxy-succinamide, N-hydroxybenzotriazole, halogenide, triflate, tosylate etc.Preferred leavings group is a suitable group described herein.
" protecting group " is often referred to and is used to protect selected active group for example carboxyl, amino, hydroxyl, sulfydryl etc. are avoided for example groups well known in the art such as nucleophilic reaction, electrophilic reaction, oxidizing reaction, reduction reaction of undesirable reaction.Preferred protecting group is a suitable protecting group as herein described.The example of amino protecting group include but not limited to, the allyl group of the cycloalkenyl alkyl of the aralkyl of aralkyl, replacement, cycloalkenyl alkyl and replacement, allyl group, replacement, acyl group, carbalkoxy, aromatic alkoxy carbonyl, silyl etc.The example of aralkyl include but not limited to, and benzyl, neighbour-methyl-benzyl, trityl and diphenyl-methyl that can be replaced arbitrarily by halogen, alkyl, alkoxyl group, hydroxyl, nitro, amido, acyl group etc. and salt are for example and ammonium salt.The example of aryl comprises phenyl, naphthyl, 2,3-indanyl, anthryl, 9-(9-phenyl fluorenyl), phenanthryl, durol base etc.The example of the cycloalkenyl alkyl of cycloalkenyl alkyl or replacement is preferably 6-10 carbon atom, include but not limited to cyclohexenyl methyl etc.Suitable acyl group, carbalkoxy and aromatic alkoxy carbonyl comprises the benzoyl, butyryl radicals, ethanoyl, trifluoroacetyl group, tribromo-acetyl base, phthaloyl of carbobenzoxy-(Cbz), tertbutyloxycarbonyl, isobutyl boc, benzoyl, replacement etc.The mixture of protecting group can be used for protecting same amino group, and for example primary amino can be used aralkyl and two kinds of protections of aromatic alkoxy carbonyl.Amino protecting group also can form heterocycle with the nitrogen-atoms that they connected, and for example 1,2-two (methylene radical) benzene, phthaloyl imino, succinimido, maleimide amino etc., and this heterocycle can further wrap the aryl of adjacency and cycloalkyl etc.In addition, described heterocyclic radical can this one-, two-or three-replace nitro phthaloyl imino for example.Amino can also be protected to avoid for example oxidizing reaction of undesirable reaction by forming additive salt, and described additive salt for example is hydrochloride, tosylate, trifluoroacetate etc.Many amino protecting groups also are suitable for protecting carboxyl, hydroxyl and sulfydryl, for example aralkyl.The alkyl for example tertiary butyl also is the suitable protecting group of hydroxyl and sulfydryl.
The Siliciumatom that the silyl protecting group is replaced arbitrarily by one or more alkyl, aryl and aralkyl.Suitable silyl protecting group comprises; but be not limited only to; trimethyl silyl, triethylsilyl, triisopropyl silyl, t-butyldimethylsilyl, 3,5-dimethylphenyl silyl, 1; 2-two (dimetylsilyl) benzene, 1,2-two (dimetylsilyl) ethane and diphenyl methyl silyl.Amino silyl cycloalkyl can form one-or two-silyl amino group.The silylanizing of amino alcohol compound can obtain N, N, O-three-silyl derivative.By removing the silyl functional group in the silyl ether functional group by removing at an easy rate with for example metal hydroxides or Neutral ammonium fluoride agent treated, its both can be in the reactions steps of separating or with the alcohol radical reaction process in remove on the spot.Suitable sillylation reagent is the product that combines of trimethylsilyl chloride, tert-butyldimethylsilyl chloride thing, phenyl dimetylsilyl muriate, diphenyl methyl silyl chlorination thing or they and imidazoles or DMF for example.Removing of the silylanizing method of amine and silyl protecting group is well known to a person skilled in the art.The method that is prepared this class sulfonamide derivatives by corresponding amino acid, amino acid amide or amino acid ester also is an organic chemistry filed, comprises that amino acid/amino acid ester or amino alcohol chemical field technician are known.
Removing under the condition of other parts that do not influence described molecule of protecting group carried out.These methods are well known in the art and comprise acid-hydrolysis method, hydrogenolysis method etc.The preferred method that removes protecting group for example for example in alcohol, acetate etc. or their mixture, removes carbobenzoxy-(Cbz) by carrying out hydrogenolysis with palladium-carbon in the suitable solvent system.In the The suitable solvent system for example in diox or the methylene dichloride, can for example HCl or trifluoroacetic acid remove with inorganic or organic acid.The gained amide is neutralized at an easy rate, generates unhindered amina.Carboxyl-protecting group for example methyl, ethyl, benzyl, the tertiary butyl, 4-anisole ylmethyl etc. can remove well known to a person skilled in the art under hydrolysis and the hydrogenolysis condition.Above used symbol has following meanings:
Figure A9718156301071
The prodrug of compound of the present invention is also included among the present invention.Prodrug is a kind of activity or non-active compound through chemically modified, and it is after using to the patient, and for example hydrolysis, metabolism etc. are transformed into The compounds of this invention through the body physiological effect.The adaptability and the method for prodrug preparation and application facet are well known to a person skilled in the art.The generality discussion that comprises the relevant prodrug of ester can be referring to Svensson and Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985).The example of covering up the carboxylate anion comprises various esters, for example alkyl (for example methyl, ethyl), cycloalkyl (for example cyclohexyl), aralkyl (for example benzyl, to methoxy-benzyl) and alkane carbonyl oxygen base alkyl (for example oxy acid methyl neopentyl) ester.Amine is covered up into the methyl substituted derivative of aryl-carbonyl oxygen, and it can discharge free drug and formaldehyde (Bungaard J.Med.Chem.2503 (1989)) in vivo by the esterase cracking.In addition, contain acid NH group for example the medicine of imidazoles, imide, indoles etc. can cover up (Bundgaard Design of Prodrugs, Elsevier (1985) with N-acyloxy methyl.Hydroxyl can be covered up into ester and ether.EP 039,051 (Sloan and Little, 4/11/81) discloses mannich base hydroxamic acid prodrug, their preparation and application.
The compounds of this invention can be synthetic according to following one or more methods.Be understandable that described general method relates to the method for preparing nonspecific stereochemistry compound.But this method is usually applicable to specific stereochemistry compound, and it is (S) or (R) that for example described stereochemistry relates to group.In addition, with known method conversion method for example, a certain compound (for example (R)) with stereochemistry characteristic can be used to prepare the compound (i.e. (S)) with opposite stereochemistry characteristic usually.Pyrimidines:
The general method of preparation I compound comprises 1, and 3-dicarbapentaborane intermediate compound IV and the compound that contains the N-C-N structure be amidine V, guanidine VI or urea VII condensation (reaction scheme 1 for example; Relevant synthetic method can be referring to D.J.Brown, Heterocyclic Compounds:thePyrimidines, and Chapter 3,1994, John Wiley ﹠amp; Sons).
Reaction circuit 1
Figure A9718156301081
In addition, of people such as (, J.Med.Chem.21,623-628,1978) G.B.Bennett, as 1,3-dicarbapentaborane synthesis unit, b-dimethylamino-a, the unsubstituted ketone IX of b-can with amidine V or guanidine VI reaction (reaction scheme 2).This b-dimethylamino-a, the unsubstituted ketone IX of b-can pass through activatory methylene radical ketone VIII Bredereck reagent, promptly two (dimethylamino) methoxyl group methane carries out carbamyl preparation (people such as H.Bredereck, Chem.Ber.101,41-50 (1968); People such as G.B.Bennett, J.Org.Chem.43,221-225 (1977)).
Reaction circuit 2
Figure A9718156301091
Reaction scheme 3
Figure A9718156301092
According to this method, reaction scheme 3 has been illustrated 2-(4-fluorophenyl)-1-(4-pyridyl) ethane ketone (VIII; Sheldrake, Synthetic Communications 23,1967 (1993)) be transformed into the method for described enamine IX.Intermediate compound I X can with various amidine V and guanidine VI condensation, obtain 5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidines i that 2-replaces.
In addition, make raw material with other heteroaryl formaldehyde, 2-picoline-4-formaldehyde, 2 for example, 6-lutidine-4-formaldehyde (Mathes and Sauermilch, Chem.Ber.88,1276-1283 (1995)), quinoline-4-formaldehyde, pyrimidine-4-formaldehyde, 6-methylpyrimidine-4-formaldehyde, 2-methylpyrimidine-4-formaldehyde, 2,6-dimethyl pyrimidine-4-formaldehyde (people such as Bredereck, Chem.Ber.97,3407-3417 (1964) can prepare ketone VIII (for example, according to Sheldrake, Synthetic communications 23,1967-1971 (1993) is described).And, oxygenizement (people such as Venemalm by described methyl, Tet.Lett.34,5495-5496 (1993)), can be by 2-nitro-4-methyl pyridine (Stanonis, J.Org.Chem.22,475 (1957)) preparation 2-nitropyridine-4-formaldehyde, it can further be transformed into 2-nitro-4-pyridinyl derivatives I (reaction scheme 4) through ketone VIII.Described nitro is catalysed and reduced into amino, can obtains R 12The formula I derivative of expression 2-amino-4-pyridyl.Described amino is carried out conventional acetylize, can be transformed into 2-acetylaminohydroxyphenylarsonic acid 4-pyridinyl derivatives.
Reaction scheme 4
Shown in reaction scheme 5, intermediate compound I X also can be condensed into 2 (1H)-pyrimidone derivatives X with urea VII.By with for example phosphoryl chloride reaction of halogenating agent, X can be transformed into muriate XI.As mentioned above, handle muriate XI, can further prepare R with primary amine and secondary amine, thiolate or alkoxide 1The pyrimidines i of representing substituted N, S and O group.Equally, hydrazine and muriate XI reaction can be obtained the pyrimidines i that the 2-diazanyl replaces.
Reaction scheme 5
Reaction scheme 6
Muriate XI and aryl boric acid or aryl zinc halogenide are carried out palladium or the catalytic cross coupling of nickel, can obtain wherein R 1It is the formula I compound of aryl or heteroaryl.
Reaction scheme 6 illustrates intermediate compound I X and guanidine VI reaction can prepare 2-amino-substituted compounds I.2-aminocompound I is the useful intermediates that the amino further acidylate of described 2-and sulfonation is prepared amido and sulfonamido derivative.
Synthetic for 4-hydroxyl-pyrimidines i I, can carry out according to method shown in the reaction scheme 7 (relevant synthetic method can be referring to D.J.Brown, Heterocyclic Compounds:thePyrimidines, supra).This method comprises carries out ring-closure reaction with acrylate XII and amidine V, with gained dihydropyrimidinonesand XIII oxidation, obtains Compound I I subsequently.
Reaction scheme 7
Figure A9718156301121
Synthetic (reaction scheme 8) of 5-(4-fluorophenyl)-6-(4-the pyridyl)-4-hydroxyl-pyrimidines i I that replaces for 2-usually can be with Pyridine-4-Carboxaldehyde and the condensation of 4-fluorophenyl acetate, and esterification subsequently can prepare dibasic acrylate XII.Compounds X II can react at elevated temperatures with various amidine V.Be transformed into dehydrogenating agent in the Compound I I reaction as compounds X III, suitable is Sodium Nitrite/acetate.
Therefore, by raw material is done suitable selection, can further prepare wherein R 12Be R 12The formula II compound of any other heteroaryl ring in the definition.This type of raw material comprises, but be not limited only to, 2-picoline-4-formaldehyde, 2,6-lutidine-4-formaldehyde (Mathes and Sauermilch, Chem.Ber.88,1276-1283 (1955)), quinoline-4-formaldehyde, pyrimidine-4-formaldehyde, 6-methylpyrimidine-4-formaldehyde, 2-methylpyrimidine-4-formaldehyde, 2,6-dimethyl pyrimidine-4-formaldehyde (people such as Bredereck, Chem.Ber.97,3407-3417 (1964)).With 2-nitropyridine-4-formaldehyde, can obtain R 12The formula II derivative of expression 2-nitro-4-pyridyl.Described nitro is catalysed and reduced into amino, will obtains 2-amino-4-pyridinyl derivatives II.Method shown in the reaction scheme 8 can obtain R applicable in the reaction with other Arylacetic acids 11Formula II compound for different aromatic yl groups.
Reaction scheme 8
Figure A9718156301131
Another kind of preparation 5, the method for 6-diaryl-4-hydroxyl-pyrimidines comprise, with b-ketone ester XIV and thiocarbamide cyclization, form sulfur uracil derivative XV.Compounds X V can be generated compounds X VI by the S-monomethylation.Compounds X VI and primary amine and secondary amine reaction can prepare the amino 4-hydroxyl-pyrimidines i I that replaces of 2-.For example, with compounds X V alkylation, can further obtain R with alkyl halide 1=SR 212-sulfide derivative II.With compounds X V or XVI Raney nickel and H 2Handle, can prepare wherein R 1It is the formula II compound of H.
Reaction scheme 9
Figure A9718156301141
Although reaction scheme 9 is illustrated is R wherein 12Be the synthetic method of 4-pyridyl, but by selecting suitable raw material, this method is equally applicable to R 12Any other heteroaryl ring in the definition.This type of raw material comprises, but be not limited only to 2-methyl iso methyl nicotinate (Efimovsky and Rumpf, Bull.Soc.Chim.FR.648-649 (1954)), pyrimidine-4-carboxylate methyl ester, 2-methylpyrimidine-4-carboxylate methyl ester, 6-methylpyrimidine-4-carboxylate methyl ester and 2,6-dimethyl pyrimidine-4-carboxylate methyl ester (people such as Sakasi, Heterocycles 13,235 (1978)).Equally, 2-nitro iso methyl nicotinate (Stanonis, J.Org.Chem.22,475 (1957)) can react with aryl acetate, subsequently according to reaction scheme 9 similarity methods, with the thiocarbamide cyclization of gained b-ketone ester.Then, described nitro is catalysed and reduced into amino, will obtains wherein R 124-hydroxyl-pyrimidines i the I (reaction scheme 10) of expression 2-amino-4-pyridyl.
Reaction scheme 10
Figure A9718156301151
In addition, with (P such as t-butyldimethylsilyloxy ylmethyl group for example people such as (, Acta Chem, Scand.B 42 384-389 (1988)) Benneche, t-butyldimethylsilyl, benzyloxymethyl, benzyls 1) nitrogen-atoms of described acid amides is suited 2-kharophen iso methyl nicotinate (reaction scheme 11) to be similar to the reaction of reaction scheme 9 after the protection.
Reaction scheme 11
With suitable reagent (for example, at P 1Be under tertiary butyl dimethyl-siloxy-methyl situation, use tetrabutyl ammonium fluoride) remove protecting group P 1, can obtain R 12The pyrimidines i I of expression 2-acetylaminohydroxyphenylarsonic acid 4-pyridyl.Beyond all doubt, in reaction scheme 9 described methods, can replace with any Arylacetic acids ethyl ester the fluorophenyl ethyl acetate, thereby obtain having different R 11The formula II compound of aryl substituent.
In another kind of method, (L is a leavings group to the XVIII derivative that formula II compound can be by will be suitable, for example halogen etc., and P 2Be for example benzyl etc. of protecting group) with suitable aryl equivalent coupling preparation.
This type of aryl/hetaryl coupled reaction is to well known to a person skilled in the art and relate in the presence of catalyzer and the reactive derivative of the second kind of compound organic-metallic composition of halo derivatives reaction for example.Described metal-organic component both can be provided by described pyrimidone under described aryl component provides the situation of described reactive halogen equivalent, perhaps described pyrimidone can be can with the organic aryl compound reactive activity of metal 5-halo derivatives form.Therefore, at inert solvent for example in the tetrahydrofuran (THF), at palladium catalyst for example in the presence of two (triphenyl phosphine) palladium (II) dichloride, the 5-bromine of XVIII and the available arylalkyl tin compound of 5-iodine derivative (L=Br, I) for example trimethylammonium stannyl benzene are handled (people such as Peters, J.Heterocyclic Chem.27,2165-2173, (1990)).In addition, by reacting, carry out lithium saltsization and can in the presence of catalyzer,, the halogen derivative of XVIII can be transformed into trialkyltin derivative (L=Bu with butyllithium subsequently with the aryl halide reaction with for example tributyl stannyl muriate 3Sn) (Sandosham and Undheim, Acta Chem.Scand.43,684-689 (1989)).Two kinds of methods all can obtain wherein R 11The pyrimidines i I of expression aryl and heteroaryl.
(Kabbe, Lieb.Ann.Chem.704,144 (1967) described in document; GermanPatent 1271116 (1968)) and reaction scheme 12 shown in, in the presence of sodium methylate, by with cyanopyridine and for example phenylacetic acid ethyl ester reaction of aryl acetate, can prepare 5-aryl-2 with one-step synthesis, 6-bipyridyl-4-hydroxyl-pyrimidines i I.
Reaction scheme 12
Figure A9718156301162
Similarly, as described in the article of above-mentioned Kabbe and shown in the reaction scheme 13,, can prepare 4-amino-5-(aryl)-2 with one-step synthesis, 6-bipyridyl-pyrimidine XIX by with cyanopyridine and for example 4-fluorophenyl acetonitrile reaction of aryl acetonitrile.
Reaction scheme 13
Figure A9718156301171
By being transformed into chlorinated derivative XX with the phosphoryl chloride reaction, can be to the 4-position (R among the formula I of pyrimidines i I 2) carry out possible modification (reaction scheme 14).By carrying out nucleophilic substitution, can prepare 4-alkoxy derivative XXI by chlorinated derivative XX with alkoxide.In addition, except chlorine, also can use other leavings groups for example tosylate, methanesulfonates etc.Also have, this type of leavings group can also be substituted by nucleophilic reagents such as amino, thiolate, alkoxide.For example, chlorinated derivative XX can be reduced into wherein R by catalytic hydrogenation 2Be the pyrimidines i of H, perhaps, form wherein R with alkyl or aryl boric acid or alkyl or aryl zinc halide reaction 2Be the pyrimidines i of alkyl or aryl.
Reaction scheme 14
Figure A9718156301172
In reaction scheme 15, formula XXX compound of the present invention can pass through methylthio group intermediate X XXI and described amine NHR 5R 21Reaction for example preferably is being higher than under 100 ℃ of temperature, more preferably heats described mixture down at 150-210 ℃, can make at an easy rate.In addition, formula XXX compound can pass through methylsulfonyl intermediate X XXII and described amine NHR 5R 21Reaction for example preferably is being higher than under 40 ℃ of temperature, more preferably heats described mixture down at 50-210 ℃, can make at an easy rate.
Reaction scheme 15
Figure A9718156301181
Formula NHR 5R 21Amine can be prepared by the raw material of commercially available acquisition at an easy rate by commercially available acquisition or those skilled in the art.For example, under reductive condition, as in the presence of reductive agent such as lithium aluminium hydride etc., can be with acid amides, nitro or cyano reduction, to form corresponding amine.Amino alkylation and acylation reaction are well known to a person skilled in the art.Use method well known in the art, can make the amine of chirality and achirality replacement by chiral amino acid and amino acid amide (for example glycine of replacements such as alkyl, aryl, heteroaryl, cycloalkyl, aralkyl, heteroaralkyl, cycloalkylalkyl, Beta-alanine etc.), H.Brunner for example, P.Hankofer, U.Hofzinger, B.Treittinger and H.Schoenenberger, Eur.J.Med.Chem.25,35-44,1990; M.Freiberger and R.B.Hasbrouck.J.Am.Chem.Soc.82,696-698,1960; Domow and Fust, Chem.Ber.87,984,1954; M.Kojima and J.Eujita.Bull.Chem.Soc.Jpn.55,1454-1459,1982; W.Wheeler and D.O ' Bannon, Journal of LabelledCompounds and Radiopharmaceuticals XXXI, 306,1992. and S.Davies, N.Garrido, O.Ichihara and I.Walters, J.Dhem.Soc., Chem.Commun.1153,1993.
The following example only is used for illustration purpose, and is not intended to, and also should not constitute any restriction to the present invention.It will be appreciated by persons skilled in the art that in spirit and scope of the invention, can make modification and change compound described herein.
Embodiment
The general method of 5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidines that embodiment 1 preparation 2-replaces is (dimethylamino)-2-(4-fluorophenyl)-1-(4-pyridyl)-3-propylene-1-ketone a.3-: (according to people such as Bennett at J.Org.Chem.43, the method described in 221 (1977))
Figure A9718156301191
Under argon atmospher, (300mg, 1.39mmol) (300mml 1.95mmol) heated 1.5 hours down in 110 ℃ with two (dimethylamino) methoxyl group methane with 2-(4-fluorophenyl)-1-(4-pyridyl) ethane ketone.Before carrying out the next step, vacuumize down drying in oil pump with its evaporation and with the yellow crystal resistates.MS (m/z): 270.8 (M+H); C 16H 15FN 2The O theoretical value.270.3。 1H-NMR (CDCl 3): d8.57,7.25 (2m, each is 2H, pyridine), 7.36 (s, 1H, CH=), 7.13,6.99 (2m, each is 2H, PhF), 3.00 (bs, 6H, 2CH 3).B. general method: (according to people such as Bennett in method described in the J.Med.Chem.21 623 (1978))
Dehydrated alcohol (9ml) solution of 3-(dimethylamino)-2-(4-fluorophenyl)-1-(4-pyridyl)-3-propylene-1-ketone (1.39mmol) is transferred to R by sodium (1.67mmol) and amidine or guanidinesalt hydrochlorate (1.67mmol) preparation 1-C (NH) NH 2In ethanol (1.67mmol) (2ml) solution.Reflux heating down after 1.5-24 hour, be applied directly on the silicagel column (1-5% ethanol/methylene) with its evaporation and with products therefrom or be dissolved in the methylene dichloride, wash with water subsequently, with organic solution dry and carry out column chromatography separate before evaporation.
According to described general method, by 3-(dimethylamino)-2-(4-fluorophenyl)-1-(4-pyridyl)-3-propylene-1-ketone and amidine compound reaction can be prepared following pyrimidines: 1-1 5-(4-fluorophenyl)-2-methyl-4-(4-pyridyl)-pyrimidine:
MS (m/z): 266.0 (M+H); C 16H 12FN 3Theoretical value .265.3. 1H-NMR (CDCl 3): d8.70 (d, 1H, H-6, pyrimidine .), 8.59,7.32 (2m, each is 2H, pyridine .), 7.20-7.00 (m, 4H, PhF), 2.88 (s, 3H, CH 3) .R 1=CH 3-1-25-(4-fluorophenyl)-2-sec.-propyl-4-(4-pyridyl)-pyrimidine:
MS (m/z): 294.4 (M+H) +C 15H 16FN 3Theoretical value .293.4. 1H-NMR (CDCl 3): d8.73 (s, 1H, H-6, pyrimidine .), 8.60,7.35 (2m, each is 2H, pyridine .), 7.20-7.04 (m, 4H, PhF), 3.37 (m, 1H, CH (CH 3) 2), 1.50,1.47 (2s, each is 3H, 2CH 3) .R 1=(CH 3) 2The CH-1-3 2-tertiary butyl-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine:
MS (m/z): 307.8 (M+H) +C 15H 18FN 3Theoretical value .307.4. 1H-NMR (CDCl 3): d8.72 (s, 1H, H-6, pyrimidine .), 8.59,7.38 (2m, each is 2H, pyridine .), 7.21-7.06 (m, 4H, PhF), 1.52 (s, 9H, 3CH 3) .R 1=(CH 3) 3C-1-4 2-(1-chloro-2-methoxy ethyl)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine: MS (m/z): 344.2 (M+H) +C 18H 15ClFN 3O theoretical value .343.8. 1H-NMR (CDCl 3): d8.81 (s, 1H, H-6, pyrimidine .), 8.61,7.35 (2m, each is 2H, pyridine .), (PhF), 5.29 (CHCl), 4.31,4.04 (2dd, each is 1H to 7.22-7.08, CH for dd, 1H for m, 4H 2O), 3.47 (s, 3H, CH 3O) .R 1=CH 3OCH 2CH (Cl)-1-5 2-(cyclopropyl)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine
MS (m/z): 292.0 (M+H) +C 18H 14FN 3Theoretical value .291.3. 1H-NMR (CDCl 3): d8.60 (s, 1H, H-6, pyrimidine .), 8.57,7.32 (2d, each is 2H, pyridine .), 7.16-7.00 (m, 4H, PhF), 2.32 (m, 1H ,-CH-), 1.2,1.1 (2m, each is 2H, 2CH 2).
Figure A9718156301211
1-6 2-(golden steel alkane-1-yl)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine:
MS (m/z): 386.0 (M+H) +C 25H 24FN 3Theoretical value .385.5. 1H-NMR (CDCl 3): d8.76 (s, 1H, H-6, pyrimidine .), 8.61,7.51 (2m, each is 2H, pyridine .), 7.22-7.08 (m, 4H, PhF) ,-1.9-1.5 (broad peak, 15H, CH 2, CH).
Figure A9718156301212
1-7 2-benzyl-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine:
MS (m/z): 342.2 (M+H) +C 22H 16FN 3Theoretical value .341.4. 1H-NMR (CDCl 3): d8.71 (s, 1H, H-6, pyrimidine .), 8.60,7.48 (2m, each is 2H, pyridine .), 7.42-7.04 (m, 9H, PhFPh), 4.42 (s, 2H, CH 2Ph).
Figure A9718156301213
1-8 2-(2, the 6-dichloro benzyl)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine:
MS (m/z): 410.2 (M) +C 22H 14Cl 2FN 3Theoretical value .410.3. 1H-NMR (CDCl 3): d8.68 (s, 1H, H-6, pyrimidine .), 8.57 (d, 2H, pyridines .), 7.44-7.03 (m, 9H, pyridine., PhF, PhCl 2), 4.93 (s, 2H, CH 2).
Figure A9718156301214
1-9 5-(4-fluorophenyl)-2-phenoxymethyl-4-(4-pyridyl)-pyrimidine:
MS (m/z): 358.2 (M+H) +C 22H 16FN 3O theoretical value .357.4. 1H-NMR (CDCl 3): d8.83 (s, 1H, H-6, pyrimidine .), 8.60 (m, 2H, pyridines .), 7.36-6.98 (m, 11H, pyridine., PhF, Ph), 5.43 (s, 2H, CH 2).
Figure A9718156301221
1-10 5-(4-fluorophenyl)-2-thiophenyl methyl-4-(4-pyridyl)-pyrimidine:
MS (m/z): 374.2 (M+H) +C 22H 16FN 3S theoretical value .373.5. 1H-NMR (CDCl 3): d8.72 (s, 1H, H-6, pyrimidine .), 8.56,7.49 (each is 2H for 2m, pyridine .), 7.32-7.02 (m, 9H, PhF, Ph), 4.50 (s, 2H, CH 2). 1-11 5-(4-fluorophenyl)-2-phenyl-4-(4-pyridyl)-pyrimidine:
MS (m/z): 328.2 (M+H) +C 21H 14FN 3Theoretical value .327.4. 1H-NMR (CDCl 3): d8.85 (s, 1H, H-6, pyrimidine .), 8.63,7.4 (2m, each is 2H, pyridine .), 8.56,7.6-7.5,7.25-7.05 (m, 9H, PhF, Ph).
Figure A9718156301223
1-12 5-(4-fluorophenyl)-2-(4-hydroxyphenyl)-4-(4-pyridyl)-pyrimidine:
MS (m/z): 344.2 (M+H) +C 21H 14FN 3O theoretical value .343.4. 1H-NMR (DMSO-d 6): d10.2 (bs, 1H, OH), and 8.90 (s, 1H, H-6, pyrimidine, pyrimidines .), 8.60,7.42 (2m, each is 2H, pyridine .), 8.35,7.40-6.92 (m, 8H, PhF, PhOH).
Figure A9718156301224
1-13 5-(4-fluorophenyl)-2-(4-aminophenyl)-4-(4-pyridyl)-pyrimidine:
MS (m/z): 343.2 (M+H) +C 21H 15FN 4Theoretical value .342.4. 1H-NMR (CDCl 3): d8.75 (s, 1H, H-6, pyrimidine .), 8.60,7.41 (2m, each is 2H, pyridine .), 8,40,7.22-6.79 (m, 8H, PhF, Ph), 4.00 (bs, 2H, NH 2).
Figure A9718156301231
1-14 5-(4-fluorophenyl)-2-(3-pyridyl)-4-(4-pyridyl)-pyrimidine:
MS (m/z): 329.0 (M+H) +C 20H 13FN 4Theoretical value .328.4. 1H-NMR (CDCl 3): d9.80 (bs, H-2,3-pyridine .), 8.90 (s, 1H, H-6, pyrimidines .), 8.84,8.80 (2m, each is 1H, the 3-pyridine .), 8.66,7.45 (2m, each is 2H, the 4-pyridine .), 7.50 (m, 1H, 3-pyridines .), 7.28-7.10 (m, 4H, PhF). 1-15 5-(4-fluorophenyl)-2-(2-pyridyl)-4-(4-pyridyl)-pyrimidine:
MS (m/z): 329.0 (M+H) +C 20H 13FN 4Theoretical value .328.4. 1H-NMR (CDCl 3): d9.01 (s, 1H, H-6, pyrimidine .), 8.92,8.66,7.94,7.48 (4m, each is 1H, the 2-pyridine .), 8.66,7.47 (2m, pyridine 2H, 4-pyridines .), 7.26,7.14 (2m, each is 2H, PhF).
Figure A9718156301233
1-16 5-(4-fluorophenyl)-2-(2-pyrazinyl)-4-(4-pyridyl)-pyrimidine:
MS (m/z): 330.2 (M+H) +C 19H 12FN 5Theoretical value 329.3. 1H-NMR (CDCl 3): 9.84 (m, 1H, H-3, pyrazines .), 9.01 (s, 1H, H-6, pyrimidines .), 8.84,8.76 (2m, each is 1H, H-5, H-6, pyrazine .), 8.65,7.44 (2m, each is 2H, pyridine .), 7.26,7.13 (2m, each is 2H, PhF).
Figure A9718156301234
1-17 5-(4-fluorophenyl)-2-(2-methylthiazol-4-yl)-4-(4-pyridyl)-pyrimidine: MS (m/z): 349.0 (M+H) +C 19H 13FN 4S theoretical value .348.4. 1H-NMR (CDCl 3): d8.90 (s, 1H, H-6, pyrimidine .), 8.63,7.42 (2m, each is 2H, pyridine .), 8.32 (s, 1H, H-5, thiazoles .), 7.22,7.10 (2m, each is 2H, PhF), 2.88 (s, 3H, CH 3).
Figure A9718156301241
1-18 5-(4-fluorophenyl)-4-(4-pyridyl)-2-(2-thienyl)-pyrimidine.
MS (m/z): 334.2 (M+H) +C 19H 12FN 3S theoretical value .333.4. 1H-NMR (CDCl 3): d8.74 (s, 1H, H-6, pyrimidine .), 8.63,7.41 (2m, each is 2H, pyridine .), 8.13,7.55 (2m, each is 1H, thiophene .), 7.20 (m, 3H, PhF, thiophene .) .7.10 (m, 2H, PhF).
Figure A9718156301242
According to general method, by 3-(dimethylamino)-2-(4-fluorophenyl)-1-(4-pyridyl)-3-propylene-1-ketone and guanidine compound reaction can be prepared following pyrimidines: 1-19 2-amino-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine:
MS (m/z): 267.0 (M+H) +C 15H 11FN 4Theoretical value .266.3. 1H-NMR (DMSO-d 6): d8.54,7.26 (2m, each is 2H, pyridine .), 8.35 (s, 1H, H-6, pyrimidines .), 7.22-7.12 (m, 4H, PhF), 6.97 (s, 2H, NH 2) .R1=NH 2-1-20 2-ethylamino-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine:
MS (m/z): 295.0 (M+H) +C 17H 15FN 4Theoretical value .294.3. 1H-NHR (CDCl 3): d8.56,7.32 (m, each is 2H, pyridine .), 8.36 (s, 1H, H-6, pyrimidine), 7.12-6.99 (m, 4H, PhF), and 5.33 unresolvable .t, 1H, NH), 3.58 (m, 2H, CH 2), 1.32 (t, 3H, CH 3) .R1=CH 3CH 2-NH-1-21 5-(4-fluorophenyl)-4-(4-pyridyl)-2-(2-sulphur ethylamino)-pyrimidine:
MS (m/z): 375.2 (M+H) +C 17H 15FN 4O 3S theoretical value .374.4. 1H-NMR (DMSO-d 6): d8.51,7.25 (2d, each is 2H, pyridine .), 8.36 (s, 1H, H-6, pyrimidines .), 7.32 (t, 1H, NH), 7.2-7.1 (m, 4H, PhF), 3.62 (q, 2H, CH 2N), 2.72 (t, 2H, CH 2) .R1=HO 3S-CH 2-CH 2-NH-1-22 2-(2-diethylin ethylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine:
MS (m/z): 365.8 (M+H) +C 21H 24FN 5Theoretical value .365.5. 1H-NMR (CDCl 3): d8.55,7.28 (2m, each is 2H, pyridine .), 8.34 (s, 1H, H-6, pyrimidines .), 7.08,7.01 (2m, each is 2H, PhF), 5.95 (bs, 1H, NH), 3.60 (q, 2H, CH 2N), 2.76 (t, 2H, CH 2), 2.65 (q, 4H, 2CH 2CH 3), 1.08 (t, 6H, 2CH 3) .R1=(CH 3CH 2) 2NCH 2CH 2NH-1-23 (4-fluorophenyl)-4-(4-pyridyl)-2-(thioureido)-pyrimidine:
MS (m/z): 326.2 (M+H) +C 16H 12FN 5S theoretical value .325.4. 1H-NMR (DMSO-d 6): d10.84,10.11,9.20 (3s, each is 1H, NH, SH), and 8.75 (s, 1H, H-6, pyrimidines .), 8.59,7.32 (2m, each is 2H, pyridine .), 7.28,7.21 (2m, each is 2H, Ph) F.
Figure A9718156301251
1-24 2-(2,6-dichlorophenyl amino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine.
MS (m/z): 410.8 (M) +C 21H 13Cl 2FN 4Theoretical value .411.3. 1H-NMR (CDCl 3): d8.54,7.30 (2m, each is 2H, pyridine .), 8.45 (s, 1H, H-6, pyrimidines .), 7.45 (d, 2H, PhCl 2), 7.21 (t, 1H, PhCl 2), 7.12,7.04 (2m, each is 2H, PhF).
Figure A9718156301252
1-25 2-(2,6-3,5-dimethylphenyl amino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine:
MS (m/z): 371.0 (M+H) +C 23H 19FN 4Theoretical value .370.4. 1H-NMR (CDCl 3): d8.56,7.32 (2d, each is 2H, pyridine .), 8.40 (s, 1H, H-6, pyrimidines .), 7.20 (s, 3H, PhCl 2), 7.11,7.04 (2m, each is 2H, PhF), 6.66 (s, 1H, NH), 2.20 (s, 6H, 2CH 3).
Figure A9718156301261
1-26 5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine: MS (m/z): 373.0 (M+H) +C 22H 17FN 4O theoretical value .372.4. 1H-NMR (CDCl 3): d8.62,7.40 (2m, each is 2H, pyridine .), 8.60 (m, 1H, PhOMe), 8.52 (s, 1H, H-6, pyrimidines .), 7.99 (s, 1H, NH), 7.18-6.94 (m, 7H, PhF, PhOMe), 3.96 (s, 3H, CH 3O). 1-27 5-(4-fluorophenyl)-2-(4-fluorophenyl amino)-4-(4-pyridyl)-pyrimidine:
MS (m/z): 361.0 (M+H) +C 21H 14F 2N 4Theoretical value .360.4. 1H-NMR (CDCl 3): d8.58,7.32 (m, 2H, pyridines .), 8.46 (s, 1H, H-6, pyrimidines .), 7.62 (m, 2H, PhF), 7.24 (bs, 1H, NH), 7.13-7.00 (m, 6H, PhF). 1-28 2-(4-ethylphenyl amino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine: MS (m/z): 371.2 (M+H) +C 23H 19FN 4Theoretical value .370.4. 1H-NMR (CDCl 3): d8.61,7.41 (2m, each is 2H, pyridine .), 8.49 (s, 1H, H-6, pyrimidines .), 7.60,7.23 (2d, each is 2H, PhEth) ,～7.28 (NH), 7.13,7.06 (2m, each is 2H, PhF), 2.67 (q, 2H, CH 2), 1.27 (t, 3H, CH 3).
Figure A9718156301271
1-29 5-(4-fluorophenyl)-4-(4-pyridyl)-2-(3-trifluoromethyl amino)-pyrimidine: MS (m/z): 411.0 (M+H) +C 22H 14F 4N 4Theoretical value .410.4. 1H-NMR (CDCl 3): d8.60,7.35 (2m, each is 2H, pyridine .), 8.52 (s, 1H, H-6, pyrimidines .), 8.23,7.73,7.46 (s, dd, t, each is 1H, PhCF 3), 7.44 (s, 1H, NH), 7.31 (dd, 1H, PhCF 3), 7.13,7.05 (2m, each is 2H, PhF). 1-30 2-(benzylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine:
MS (m/z): 357.0 (M+H) +C 22H 17FN 4Theoretical value .356.4. 1H-NMR (CDCl 3): d8.55,7.28 (2m, each is 2H, pyridine .), 8.36 (s, 1H, H-6, pyrimidines .), 7.44-7.28 (m, 5H, Ph), 7.09,7.02 (2m, each is 2H, PhF), 5.71 (t, 1H, NH), 4.75 (d, 1H, CH 2).
Figure A9718156301273
1-31 5-(4-fluorophenyl)-2-(2-phenyl ethylamino)-4-(4-pyridyl)-pyrimidine: MS (m/z): 371.0 (M+H) +C 23H 19FN 4Theoretical value .370.4. 1H-NMR (CDCl 3): d8.56 (m, 2H, pyridine .), 8.35 (s, 1H, H-6, pyrimidines .), 7.38-7.22 (m, 7H, Ph, pyridine .), 7.08,7.02 (2m, each is 2H, PhF), 5.32 (t, 1H, NH), 3.80 (q, 2H, CH 2N), 2.92 (t, 2H, CH 2).
Figure A9718156301281
1-32 5-(4-fluorophenyl)-4-(4-pyridyl)-2-pyrrolidino-pyrimidine:
MS (m/z): 321.2 (M+H) +C 19H 17FN 4Theoretical value .320.4. 1H-NMR (CDCl 3): d8.54,7.32 (2d, each is 2H, pyridine .), 8.37 (s, 1H, H-6, pyrimidines .), 7.06,7.00 (2m, each is 2H, PhF), 3.68,2.05 (2m, each is 4H, 4CH 2). 1-33 5-(4-fluorophenyl)-2-morpholino-4-(4-pyridyl)-pyrimidine:
MS (m/z): 337.2 (M+H) +C 19H 17FN 4O theoretical value .336.4. 1H-NMR (CDCl 3): d8.56,7.31 (2m, each is 2H, pyridine .), 8.40 (s, 1H, H-6, pyrimidines .), 7.10,7.03 (2m, each is 2H, PhF), 3.94,3.83 (2m, each is 4H, 4CH 2).
Figure A9718156301283
1-34 2-(3 base)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine: MS (m/z): 346.0 (M+H) +C 20H 16FN 5Theoretical value .345.4. 1H-NMR (CDCl 3): d8.80 (s, 1H, H-6, pyrimidine .), 8.60,7.35 (2m, each is 2H, pyridine .), 7.18,7.08 (2m, each is 2H, PhF), and 6.08 (s, 1H, pyrazoles .), 2.70,2.30 (2s, each is 3H, 2CH 3).
Figure A9718156301284
1-35 5-(4-fluorophenyl)-4-(4-pyridyl)-2-(3.5-two (trifluoromethyl) phenylsulfonamido)-pyrimidine: MS (m/z): 542.8 (M+H) +C 23H 13F 7O 2S theoretical value 542.4. 1H-NMR (DMSO-d 6): d8.63 (s, 1H, H-6, pyrimidine), 8.56 (m, 2H, pyridines), 8.49,8.43 (2s, 2H, 1H, Ph (CF 3) 2), 7.26-7.15 (m, 6H, PhF, pyridine). 1-36 2-(4-amino phenyl sulfonyl amido)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine: MS (m/z): 421.8 (M+H) +C 21H 16FN 5O 2S theoretical value .421.5. 1H-NMR (DMSO-d 6): d8.58 (s, 1H, H-6, pyrimidine .), 8.575 (m, 2H, pyridines .), 7.64,6.56 (2d, each is 2H, PhNH 2), 7.28-7.15 (m, 6H, PhF, pyridine .), 5.99 (s, 2H, NH 2).
Figure A9718156301292
1-37 2-(2-dimethylamino ethylmercapto group)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine, according to described general method, by with 3-(dimethylamino)-2-(4-fluorophenyl)-1-(4-pyridyl)-3-propylene-1-ketone and S-(2-dimethylaminoethyl) isothiourea prepared in reaction.MS (m/z): 355.2 (M+H) +C 19H 19FN 4S theoretical value, 354.5. 1H-NMR (CDCl 3): d8.59,7.32 (2m, each is 2H, pyridine .), 8.58 (s, 1H, H-6, pyrimidine .) .7.16,7.08 (2m, each is 2H, PhF), 3.40,2.76 (2m, each is 2H, 2CH 2), 2.37 (s, 6H, 2CH 3) .R1=(CH 3) 2NCH 2CH 2S-
The general method of 2-amino-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidines that embodiment 2 preparation 2-N replace is (4-fluorophenyl)-4-(4-pyridyl)-2 (1H)-pyrimidones a.5-:
Figure A9718156301301
With urea (0.67g, 11.15mmol) join in the ethanolic soln (15ml) of the 0.62N sodium ethylate under stirring, the ethanolic soln (60ml) that adds 3-(dimethylamino)-2-(4-fluorophenyl)-1-(4-pyridyl)-3-propylene-1-ketone (9.29mmol) spends the night the mixture backflow.With its evaporation, carry out column chromatography (5% ethanol/methylene-100% methyl alcohol) subsequently, will dissolve the crystallization (may be urea) that obtains behind the products therefrom with methylene chloride and filter.With the filtrate evaporation, resistates carries out chromatographic separation (chloroform/methanol/water=70: 20: 1) again on silicagel column, obtain the described title compound of yellow spumescence.MS (m/z): 268.2 (M+H) -C 15H 10FN 3O theoretical value .267.3. 1H-NMR (DMSO-d 6): d8.55,7.24 (2m, each is 2H, pyridine .), 8.22 (bs, 1H, H-6, pyrimidines .), 7.20-7.10 (m, 4H, PhF) .b.2-chloro-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine:
Figure A9718156301302
The mixture backflow of 5-(4-fluorophenyl)-4-(4-pyridyl)-2 (1H)-pyrimidones (2.41mmol) and phosphoryl chloride (3ml) was heated 45 minutes down.Under bath temperature＞50 ℃, it is evaporated to driedly, flask cooled off in ice bath and adds frozen water.If it still is acid finding pH, then mixture is neutralized with 5% ammonium hydroxide aqueous solution, use dichloromethane extraction, organic solution is washed with sodium chloride aqueous solution subsequently, and dry and evaporation obtains the described title compound of yellow spumescence, need not to be further purified.MS (m/z): 286.1 (M+H) +C 15H 19ClFN 3Theoretical value .285.7. 1H-NMR (CDCl 3): d8.68 (s, 1H, H-6, pyrimidine .), 8.62,7.42 (2m, each is 2H, pyridine .), 7.23-7.10 (m, 4H, PhF).
In addition, according to identical reaction process, just with 2-(3-aminomethyl phenyl)-1-(4-pyridyl) ethane ketone (according to people such as I.Lantos at J.Org.Chem.53,4223-4227, described in 1988 the preparation) and 1-(4-pyridyl)-2-(3-trifluoromethyl) ethane ketone (according to P.W.Sheldrake, Synth.Commun.23 (24), 1967-1971,1993) and WO 97/12876 described preparation) synthetic 2-chloro-5-(3-aminomethyl phenyl)-4-(the 4-pyridyl)-pyrimidine (MS (m/z): 282 (M+H) that obtains +C 16H 12ClN 3Theoretical value 281.7) and 2-chloro-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine (MS (m/z): 336.0 (M) +C 16H 9ClF 3N 3Theoretical value 335.7).Also available thionyl chloride/N, dinethylformamide (excessive/3 equivalents, as to reflux) replaces phosphoryl chloride.C. general method.
Figure A9718156301311
Typically, (50-120mg is 0.18-0.42mmol) with amine HNR with 2-chloro-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine 5R 21Mixture (0.5-5.5mmol) is in 50-100 ℃ of heating 5-60 minute (thin-layer chromatography monitoring) down.Mixture is directly placed on the silicagel column, launch with methylene chloride or methylene chloride/dense ammonium hydroxide.
As described in embodiment 2-6,2-11,2-12,2-20 and 2-26, the method that another kind can Gong be selected for use is to make solvent with ethanol.
According to this method, can prepare following pyrimidines: 2-1 2-(the amino ethylamino of 2-)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine hydrochloride: MS (m/z): 310.2 (M+H) with the suitable amine and the 2-chloropyrimide of replacement +C 17H 16FN 5-HCl theoretical value .309.4+36.5. 1H-NMR (CD 3OD): d8.84,8.10 (2m, each is 2H, pyridine .), 8.58 (s, 1H, H-6, pyrimidines .), 7.28,7.15 (2m, each is 2H, PhF), 3.83 (t, 2H, CH 2), 3.27 (t, 2H, CH 2) .R1=NH 2CH 2CH 2NH-2-2 2-(amino third amino of 3-)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine hydrochloride: MS (m/z): 324.0 (M+H) +C 18H 15FN 5-HCl theoretical value .323.4+36.5. 1H-NMR (CD 3OD): d8.85,8.10 (m, 2H, pyridines .), 8.54 (s, 1H, H-6, pyrimidines .), 7.27,7.14 (2m, each is 2H, PhF), 3.84,3.68 (2t, each is 2H, 2CH 2N), 2.18 (m, 2H, CH 2) .R1=NH 2CH 2CH 2CH 2NH-2-3 2-(the amino fourth amino of 4-)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine hydrochloride: MS (m/z): 338.0 (M+H) +C 19H 20FN 5-HCl theoretical value 337.4+36.5. 1H-NMR (CD 3OD): d8.80,8.05 (2m, each is 2H, pyridine .), 8.50 (s, 1H, H-6, pyrimidines .), 7.25,7.14 (2m, each is 2H, PhF), 3.58 (bt, 2H, CH 2), 3.02 (bt, 1H, CH 2), 1.80 (m, 4H, 2CH 2) .R1=NH 2CH 2CH 2CH 2CH 2NH-2-4 2-(2-dimethylamino ethylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine: MS (m/z): 338.2 (M+H) +C 19H 20FN 5Theoretical value .337.4. 1H-NMR (CDCl 3): d8.57,7.30 (2m, each is 2H, pyridine .), 8.37 (s, 1H, H-6, pyrimidines .), 7.10,7.03 (2m, each is 2H, PhF), 6.00 (t, 1H, NH), 3.66 (q, 2H, CH 2), 2.71 (t, 2H, CH 2), 2.41 (s, 6H, 2CH 3) .R1=(CH 3) 2NCH 2CH 2NH-2-5 5-(4-fluorophenyl)-2-(2-phenylamino ethylamino)-4-(4-pyridyl)-pyrimidine: MS (m/z): 386 (M+H) +C 23H 20FN 5Theoretical value .385.5. 1H-NMR (CDCl 3): d8.57,7.28 (m, 2H, pyridines .), 8.36 (s, 1H, H-6, pyrimidines .), 7.18 (t, 2H, Ph), 7.08,7.02 (2m, each is 2H, PhF), 6.73 (t, 1H, Ph), 6.64 (d, 2H, Ph), 5.62 (bt, 1H, NH), 3.80 (q, 2H, CH 2), 3.47 (t, 2H, CH 2).
Figure A9718156301331
2-6 5-(4-fluorophenyl)-2-(2-(4-fluoroanilino) ethylamino)-4-(4-pyridyl)-pyrimidine: (103mg 0.36mmol) and under the backflow of ethanol (1ml) solution of N-(4-fluorophenyl) quadrol (1ml) heated 3 hours with 2-chloro-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine.Evaporation is carried out column chromatography subsequently and is separated (3% ethanol/methylene), obtains the described title compound of yellow solid shape.MS (m/z): 404.2 (M+H) +C 23H 19F 2N 5Theoretical value .403.4. 1H-NMR (CDCl 3): 8.60 7.31 (2m, each is 2H, pyridine .), 8.40 (s, 1H, H-6, pyrimidines .), 7.11-7.02 (2m, each is 2H, PhF), 6.90,6.60 (each is 2H for t, dd, PhF), 5.62 (t, 1H, NH), 3.82 (q, 2H, CH 2), 3.44 (t, 2H, CH 2). 2-7 5-(4-fluorophenyl)-2-(4-methyl benzyl amino)-4-(4-pyridyl)-pyrimidine:
MS (m/z): 371.2 (M+H) +C 23H 19FN 4Theoretical value .370.4. 1H-NMR (CDCl 3): d8.55,7.34 (2m, each is 2H, pyridine .), 8.36 (s, 1H, H-6, pyrimidines .), 7.30,7.18 (2d, each is 2H, PhMe), 7.08,7.02 (2m, each is 2H, PhF), 5.69 (bs, 1H, NH), 4.69 (d, 2H, CH 2), 2.36 (s, 3H, CH 3)
Figure A9718156301333
2-8 5-(4-fluorophenyl)-2-(2-(4-fluorophenyl) ethylamino)-4-(4-pyridyl)-pyrimidine: MS (m/z): 389.2 (M+H) +C 23H 18F 2N 4Theoretical value .388.4. 1H-NMR (CDCl 3): d8.57 (m, 2H, pyridine .), 8.36 (s, 1H, H-6, pyrimidines .), 7.32-7.20,7.12-6.98 (2m, 10H, 2PhF, pyridine .), 5.37 (bt, 1H, NH), 3.79 (q, 2H, CH 2N), 2.97 (t, 2H, CH 2). 2-9 2-(2-(4-chloro-phenyl-)-ethylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine: MS (m/z): 405.0 (M+H) +C 23H 18ClFN 4Theoretical value, 404.9. 1H-NMR (CDCl 3): d8.56 (bs, 2H, pyridine .), 8.34 (s, 1H, H-6, pyrimidines .), 7.29 (m, d, 4H, pyridine., PhCl), 7.20 (d, 2H, PhCl), 7.08,7.02 (2m, each is 2H, PhF), 5.35 (t, 1H, NH), 3.78 (q, CH 2N), 2.96 (t, 2H, CH 2).
Figure A9718156301342
2-10 2-(2-(4-bromophenyl)-ethylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine: MS (m/z): 449.0 (M) +C 23H 18BrFN 4Theoretical value .449.3. 1H-NMR (CDCl 3): d8.58,7.47 (m, 2H, pyridines .), 8.37 (s, 1H, H-6, pyrimidines .), 7.29,7.17 (2d, each is 2H, PhCl), 7.10,7.02 (2d, each is 2H, PhF), 5.34 (t, 1H, NH), 3.80 (q, 2H, CH 2N), 2.97 (t, 2H, CH 2).
Figure A9718156301343
2-11 5-(4-fluorophenyl)-2-(2-(4-hydroxyphenyl)-ethylamino)-4-(4-pyridyl)-pyrimidine: with 2-chloro-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine (61mg, 0.21mmol), Hydrphenacetamine Hydrochloride (186mg, 1.01mmol) and sodium bicarbonate (90mg, the 1.07mmol) heating down 1 hour that refluxes of the mixture in aqueous ethanol (1ml).Steaming desolventizes, and carries out column chromatography subsequently and separates (5% ethanol/methylene), obtains the described title compound of yellow solid shape.MS (m/z): 387.2 (M+H) +C 23H 19FN 4O theoretical value .386.4. 1H-NMR (DMSO-d 6): d9.12 (bs, 1H, OH), and 8.54,7.26 (2m, each is 2H, pyridine .), 8.38 (s, 1H, H-6, pyrimidines .), 7.52 (t, 1H, NH), 7.20-7.10 (m, 4H, PhF), 7.05,6.69 (2d, each is 2H, PhOH), 3.52 (q, 2H, CH 2N), 2.78 (t, 2H, CH 2).
Figure A9718156301351
2-12 2-(2-(4-aminophenyl)-ethylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine: with 2-chloro-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine (71mg, 0.25mmol) and 2-(4-aminophenyl) ethamine (0.5ml, ethanol 3.80mmol) (1.5ml) vlil 20 minutes.Evaporation separates (2% ethanol/methylene) in the enterprising circumstances in which people get things ready for a trip spectrum of silicagel column subsequently, obtains the described title compound of yellow syrupy shape.
MS (m/z): 386.4 (M+H) +C 23H 20FN 5Theoretical value.385.5。 1H-NMR (CDCl 3): d8.56,7.32 (2m, each is 2H, pyridine .), 8.35 (s, 1H, H-6, pyrimidines .), 7.12-6.99 (m, 6H, PhF, PhNH 2), 6.68 (d, 2H, PhNH 2), 5.37 (t, 1H, NH), 3.75 (q, 2H, CH 2N), 2.88 (t, 2H, CH 2).
Figure A9718156301352
2-13 5-(4-fluorophenyl)-2-(2-(2-fluorophenyl) ethylamino)-4-(4-pyridyl)-pyrimidine: MS (m/z): 389.2 (M+H) +C 23H 18F 2N 4Theoretical value .388.4. 1H-NMR (CDCl 3): 8.57 (m, 2H, pyridines .), 8.35 (s, 1H, H-6, pyrimidines .), 7.34-7.20,7.14-7.00 (2m, 10H, 2PhF, pyridine .), 5.42 (bt, 1H, NH), 3.82 (q, 2H, CH 2N), 3.05 (t, 2H, CH 2).
Figure A9718156301353
2-14 2-(2-(2-chloro-phenyl-)-ethylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine: MS (m/z): 405.0 (M+H) +C 23H 18ClFN 4Theoretical value .404.9. 1H-NMR (CDCl 3): d8.57 (m, 2H, pyridine .), 8.36 (s, 1H, H-6, pyrimidines .), 7.40-7.00 (m, 10H, PhF, PhCl 2, pyridine .), 5.44 (bt, 1H, NH), 3.84 (q, 2H, CH 2N), 3.15 (t, 2H, CH 2).
Figure A9718156301361
2-15 5-(4-fluorophenyl)-2-(2-(2-p-methoxy-phenyl) ethylamino)-4-(4-pyridyl)-pyrimidine: MS (m/z): 401.2 (M+H) +C 24H 21FN 4O theoretical value .400.5 1H-NMR (CDCl 3): d8.56,7.30 (2m, each is 2H, pyridine .), 8.34 (s, 1H, H-6, pyrimidines .), 7.24,7.08,7.02,6.92 (4m, each is 2H, PhF, PhOMe), 5.50 (bt, 1H, NH), 3.87 (s, 3H, CH 3), 3.78 (q, 2H, CH 2N), 3.02 (t, 2H, CH 2).
Figure A9718156301362
2-16 2-(2-(2,4 dichloro benzene base)-ethylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine: MS (m/z): 439.0 (M) +C 23H 17Cl 2FN 4Theoretical value .439.3. 1H-NMR (CDCl 3): 8.56 (bs, 2H, pyridines .), 8.34 (s, 1H, H-6, pyrimidines .), 7.37 (s, 1H, PhCl), 7.30 (bd, 2H, pyridines .), 7.22-7.15 (m, 2H, PhCl), 7.08,7.05 (2m, each is 2H, PhF), 5.40 (t, 1H, NH), 3.80 (q, 2H, CH 2N), 3.10 (t, 2H, CH 2).
Figure A9718156301363
2-17 2-(2-(2, the 6-dichlorophenyl)-ethylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine: MS (m/z): 439.0 (M) +C 23H 17Cl 2FN 4Theoretical value .439.3. 1H-NMR (CDCl 3): 8.57 (m, 2H, pyridines .), 8.36 (s, 1H, H-6, pyrimidines .), 7.35 (d, 2H, PhCl), 7.11 (m, 3H, PhF, PhCl), 7.03 (m, 2H, PhF), 5.45 (t, 1H, NH), 3.86 (q, 2H, CH 2N), 3.38 (t, 2H, CH 2). 2-18 5-(4-fluorophenyl)-2-(2-(3-p-methoxy-phenyl) ethylamino)-4-(4-pyridyl)-pyrimidine: MS (m/z): 401.2 (M+H) +C 24H 21FN 4O theoretical value .400.5. 1H-NMR (CDCl 3): d8.56 (m, 2H, pyridine .), 8.34 (s, 1H, H-6, pyrimidines .), 7.32-7.22,7.11-6.98,6.89-6.77 (3m, 10H, PhF, PhOMe, pyridine .), 5.38 (t, 1H, NH), 3.82 (m, 5H, CH 2N, CH 3), 2.96 (t, 2H, CH 2).
Figure A9718156301372
2-19 2-(2-(3-chloro-phenyl-)-ethylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine: MS (m/z): 405.4 (M+H) +C 23H 18ClFN 4Theoretical value .404.9. 1H-NMR (CDCl 3): d8.60 (d, 2H, pyridine .), 8.38 (s, 1H, H-6, pyrimidines .), 7.32-7.24 (m, 5H, pyridine., PhCl), 7.18 (m, 1H, PhCl), 7.11,7.04 (2m, each is 2H, PhF), 5.35 (t, 1H, NH), 3.83 (q, 2H, CH 2N), 3.00 (t, 2H, CH 2). 2-20 5-(4-fluorophenyl)-2-((2-hydroxyl-2-phenyl)-ethylamino)-4-(4-pyridyl)-pyrimidine: with 2-chloro-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine (87mg, 0.31mmol) and 2-amino-1-phenylethyl alcohol (300mg, 2.19mmol) mixture heating up in ethanol (2ml) refluxed 2 hours.Evaporation separates (4% ethanol/methylene) in the enterprising circumstances in which people get things ready for a trip spectrum of silicagel column subsequently, obtains the described title compound of yellow spumescence.MS (m/z): 387.0 (M+H) +C 23H 19FN 4O theoretical value .386.4. 1H-NMR (CDCl 3): d8.58 (d, 2H, pyridine .), 8.38 (s, 1H, H-6, pyrimidine .), 7.47 (d, 2H, Ph), 7.41 (t, 2H, Ph), 7.34 (t, 1H, Ph), (7.28 d, 2H, pyridine .), 7.10,7.02 (2m, 2H, PhF), 5.72 (t, 1H, NH), (5.06 m CHOH)), 4.02-3.92 (m, 2H, OH, 1CH 2), 3.72 (ddd, 1H, 1CH 2). 2-21 5-(4-fluorophenyl)-2-(methyl-(2-phenylethyl)-amino)-4-(4-pyridyl)-pyrimidine: MS (m/z): 385.0 (M+H) +C 24H 21FN 4Theoretical value .384.5. 1H-NMR (CDCl 3): d8.57,7.35 (2m, each is 2H, pyridine .), 8.40 (s, 1H, H-6, pyrimidines .), 7.34-7.21 (m, 5H, Ph), 7.10,7.03 (2m, each is 2H, PhF), 3.96 (t, 2H, CH 2N), 3.23 (s, 3H, CH 3), 3.00 (t, 2H, CH 2).
Figure A9718156301382
2-22 5-(4-fluorophenyl)-2-((3-phenyl propyl)-amino)-4-(4-pyridyl)-pyrimidine: MS (m/z): 385.2 (M+H) +C 24H 21FN 4Theoretical value .384.5. 1H-NMR (CDCl 3): d8.56 (m, 2H, pyridine .), 8.34 (s, 1H, H-6, pyrimidines .), 7.34-7.20 (m, 7H, Ph, pyridine .), 7.08,7.01 (2m, each is 2H, PhF), 5.38 (t, 1H, NH), 3.58 (q, 2H, CH 2N), 2.78 (t, 2H, CH 2), 2.03 (m, 2H, CH 2).
Figure A9718156301383
2-23 5-(4-fluorophenyl)-2-((1-methyl-3-phenyl propyl)-amino)-4-(4-pyridyl)-pyrimidine: MS (m/z): 339.0 (M+H) +C 25H 23FN 4Theoretical value .398.5. 1H-NMR (CDCl 3): d8.56 (m, 2H, pyridine .), 8.32 (s, 1H, H-6, pyrimidines .), 7.32-7.17 (m, 7H, pyridine., Ph), 7.09-7.02 (2m, each is 2H, PhF), 5.16 (d, 1H, NH), 4.28 (m, 1H, CH), 2.77 (m, 2H, CH 2), 1.94 (m, 2H, CH 2), 1.34 (d, 3H, CH 3).
Figure A9718156301391
2-24 5-(4-fluorophenyl)-2-((3-imidazolyl propyl group)-amino)-4-(4-pyridyl)-pyrimidine: MS (m/z): 375.0 (M+H) +C 21H 19FN 6Theoretical value .374.4. 1H-NMR (CDCl 3): d8.57,7.26 (2m, each is 2H, pyridine .), 8.36 (s, 1H, H-6, pyrimidines .), 7.56 (s, 1H, imidazoles .), 7.16-6.96 (m, 6H, PhF, imidazoles .), 5.38 (bt, 1H, NH), 4.12 (t, 2H, CH 2N), 3.56 (q, 2H, CH 2NH), 2.20 (m, 2H, CH 2).
Figure A9718156301392
2-25 5-(4-fluorophenyl)-2-((4-phenyl-normal-butyl)-amino)-4-(4-pyridyl)-pyrimidine: MS (m/z): 399.0 (M+H) +C 25H 23FN 4Theoretical value .398.5. 1H-NMR (CDCl 3): d8.56 (m, 2H, pyridine .), 8.34 (s, 1H, H-6, pyrimidines .), 7.33-7.17 (m, 7H, Ph, pyridine .), 7.08,7.02 (2m, each is 2H, PhF), 5.33 (bt, 1H, NH), 3.56 (q, 2H, CH 2N), 2.71 (t, 2H, CH 2), 1.76 (m, 4H, 2CH 2).
Figure A9718156301393
2-26 5-(4-fluorophenyl)-2-(1-piperazinyl)-4-(4-pyridyl)-pyrimidine: with 2-chloro-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine (71mg, 0.25mmol) and piperazine (214mg, 2.48mmol) mixture heating up in ethanol (1ml) refluxed 5 minutes.Evaporation separates (5% ethanol/methylene) in the enterprising circumstances in which people get things ready for a trip spectrum of silicagel column subsequently, obtains the described title compound of yellow solid shape.MS (m/z): 336.2 (M+H) +C 19H 18FN 5Theoretical value 335.4. 1H-NMR (CDCl 3): d8.54,7.29 (2m, each is 2H, pyridine), 8.37 (s, 1H, H-6, pyrimidines .), 7.08,7.00 (2m, each is 2H, PhF), 3.95 (t, 4H, 2CH 2), 3.01 (t, 4H, 2CH 2). 2-27 5-(4-fluorophenyl)-2-(piperidino)-4-(4-pyridyl)-pyrimidine:
MS (m/z): 335.2 (M+H) +C 20H 19FN 4Theoretical value .334.4. 1H-NMR (CDCl 3): d8.55,7.30 (2m, each is 2H, pyridine .), 8.36 (s, 1H, H-6, pyrimidines .), 7.08,7.01 (2m, 2H, PhF), 3.91 (t, 4H, 2CH 2N), 1.74,1.68 (2m, 6H, 3CH 2).
Figure A9718156301402
2-28 5-(4-fluorophenyl)-2-(4-methyl isophthalic acid-piperazinyl)-4-(4-pyridyl)-pyrimidine: MS (m/z): 350.0 (M+H) +C 20H 20FN 5Theoretical value .349.4. 1H-NMR (CDCl 3): d8.58,7.32 (2m, each is 2H, pyridine .), 8.40 (s, 1H, H-6, pyrimidines .), 7.10,7.04 (2m, each is 2H, PhF), 4.00 (t, 4H, 2CH 2), 2.57 (t, 4H, 2CH 2), 2.42 (s, 3H, CH 3).
Figure A9718156301403
2-29 5-(4-fluorophenyl)-2-(4-phenyl-peiperazinyl)-4-(4-pyridyl)-pyrimidine: MS (m/z): 412.2 (M+H) +C 25H 22FN 5Theoretical value .411.5. 1H-NMR (CDCl 3): d8.58 (bd, 2H, pyridine .), 8.42 (s, 1H, H-6, pyrimidines .), 7.38-7.30 (m, 4H, pyridine .Ph), 7.15-7.00 (m, 6H, PhF, Ph), 6.94 (t, 1H, Ph), 4.13 (t, 4H, 2CH 2), 3.33 (t, 4H, 2CH 2).
Figure A9718156301411
2-30 5-(4-fluorophenyl)-2-(2-morpholino ethylamino)-4-(4-pyridyl)-pyrimidine: MS (m/z): 380.4 (M+H) +C 21H 22FN 5O theoretical value .379.4. 1H-NMR (CDCl 3): d8.58,7.30 (2m, each is 2H, pyridine .), 8.38 (s, 1H, H-6, pyrimidines .), 7.10,7.03 (2m, each is 2H, PhF), 5.91 (bs, 1H, NH), 3.79 (bs, 4H, 2CH 2), 3.66 (bs, 2H, CH 2), 2.71 (bs, 2H, CH 2), 2.59 (bs, 4H, 2CH 2). 2-31 5-(4-fluorophenyl)-2-(2-piperidino-(1-position only) ethylamino)-4-(4-pyridyl)-pyrimidine: MS (m/z): 378.2 (M+H) +C 22H 24FN 5Theoretical value .377.5 1H-NMR (CDCl 3): d8.54,7.27 (2d, each is 2H, pyridine .), 8.34 (s, 1H, H-6, pyrimidines .), 7.06,7.00 (2m, each is 2H, PhF), 6.04 (bt, 1H, NH), 3.66 (q, 2H, CH 2NH), 2.74 (t, 2H, CH 2), 2.61 (bs, 4H, 2CH 2), 1.68 (m, 4H, 2CH 2), 1.50 (m, 2H, CH 2). 2-32 5-(4-fluorophenyl)-4-(4-pyridyl)-2-(2-pyrrolidino ethylamino)-pyrimidine: MS (m/z): 364.0 (M+H) +C 21H 22FN 5Theoretical value .363.4 1H-NMR (CDCl 3): d8.55,7.28 (2m, each is 2H, pyridine .), 8.36 (s, 1H, H-6, pyrimidines .), 7.08,7.02 (2m, each is 2H, PhF), 6.28 (t, 1H, NH), 3.86 (q, 2H, CH 2NH), 3.18 (t, 2H, CH 2N), 3.10 (bs, 4H, 2CH 2N), 2.02 (bs, 4H, 2CH 2).
Figure A9718156301421
2-33 5-(4-fluorophenyl)-2-(3-morpholino third amino)-4-(4-pyridyl)-pyrimidine: MS (m/z): 394.2 (M+H) +C 22H 24FN 5O theoretical value .393.5. 1H-NMR (CDCl 3): d8.54,7.27 (2m, each is 2H, pyridine .), 8.33 (s, 1H, H-6, pyrimidines .), 7.06,7.00 (2m, each is 2H, PhF), 6.00 (t, 1H, NH), 3.76 (t, 4H, 2CH 2O), 3.60 (q, 2H, CH 2NH), 2.52 (t, 2H, CH 2N), 2.50 (m, 4H, CH 2N), 1.86 (m, 2H, CH 2). 2-34 5-(4-fluorophenyl)-2-(3-(2-Pyrrolidone-1-yl)-third amino)-4-(4-pyridyl)-pyrimidine: MS (m/z): 392.2 (M+H) +C 22H 22FN 5O theoretical value .391.5. 1H-NMR (CDCl 3): d8.58,7.30 (m, 2H, pyridines .), 8.36 (s, 1H, H-6, pyrimidines .), 7.10,7.04 (m, 2H, PhF), 5.88 (t, 1H, NH), 3.56 (q, 2H, CH 2NH), 3.48,3.45 (2t, each is 2H, 2CH 2), 2.46 (t, 2H, CH 2), 2.08 (m, 2H, CH 2), 1.90 (m, 2H, CH 2).
Figure A9718156301423
2-35 2-(((S)-2-amino-3-phenyl propyl)-amino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine hydrochloride: MS (m/z): 400.1 (M+H) +C 24H 22FN 5Theoretical value, 399.5.(free alkali).
Figure A9718156301424
2-36 2-(((S)-2-amino-3-phenyl propyl)-amino)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine hydrochloride, according to described general method step C, with 2-chloro-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine and (S)-1, (70 ℃ of 2-benzyl reacting ethylenediamines, 75 minutes), obtain described title compound.MS (m/z): 450.4 (M+H) +C 25H 22F 3N 5Theoretical value, 4449.5.(free alkali). 2-37 2-(((S)-2-amino-3-phenyl propyl)-amino)-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine hydrochloride: according to described general method step C, with 2-chloro-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine and (S)-1,2-benzyl reacting ethylenediamine (100 ℃ 20 minutes) obtains described title compound.MS (m/z): 396.2 (M+H) +C 25H 25N 5Theoretical value, 395.5.(free alkali).
Figure A9718156301432
2-38 2-(((S)-2-N, N-dimethylamino-3-phenyl propyl)-amino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine: according to described general method step C, with 2-chloro-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine and (S)-2-N, N-dimethylamino-3-phenylpropylamine is reacted (100 ℃, 45 minutes), obtain described title compound.MS (m/z): 427.8 (M+H) +C 26H 26FN 5Theoretical value, 427.5. 2-39 2-(((S)-2-N.N-dimethylamino-3-phenyl propyl)-amino)-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine: according to described general method step C, with 2-chloro-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine and (S)-2-N, N-dimethylamino-3-phenylpropylamine is reacted (100 ℃, 30 minutes), obtain described title compound.MS (m/z): 424.2 (M+H) +C 27H 29FN 5Theoretical value, 423.6.
Figure A9718156301441
2-40 2-((3-amino-3-phenyl propyl)-amino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine hydrochloride: according to described general method step C, with 2-chloro-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine and 1-phenyl-1, (100 ℃ of 3-propylene diamine reactions, 30 minutes), obtain described title compound.MS (m/z): 4001. (M+H) +C 24H 22FN 5Theoretical value, 399.5.(free alkali). 2-41 2-((3-amino-3-phenyl propyl)-amino)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine hydrochloride, according to described general method step C, with 2-chloro-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine and 1-phenyl-1, (100 ℃ of 3-propylene diamine reactions, 1 hour), obtain described title compound.MS (m/z): 450.3 (M+H) +C 25H 22F 3N 5Theoretical value, 449.5.(free alkali).
Figure A9718156301443
2-42 2-((3-amino-3-(2-fluorophenyl) propyl group)-amino)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine hydrochloride: according to described general method step C, with 2-chloro-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine and 1-(2-fluorophenyl)-1, (100 ℃ of 3-propylene diamine reactions, 30 minutes), obtain described title compound.MS (m/z): 468.4 (M+H) +C 25H 21F 4N 5Theoretical value, 467.5.(free alkali).
Figure A9718156301444
2-43 2-((3-amino-3-phenyl propyl)-amino)-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine hydrochloride, according to described general method step C, with 2-chloro-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine and 1-phenyl-1, (100 ℃ of 3-propylene diamine reactions, 30 minutes), obtain described title compound.MS (m/z): 396.1 (M+H) +C 25H 25N 5Theoretical value, 395.5.(free alkali).
Figure A9718156301451
2-44 2-((2-amino-2-methyl-3-phenyl propyl)-amino)-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine hydrochloride, according to described general method step C, 2-chloro-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine and 2-amino-2-methyl-3-phenylpropylamine are reacted (100 ℃, 30 minutes), obtain described title compound.MS (m/z): 410.2 (M+H) +C 26H 27N 5Theoretical value, 409.5.(free alkali).
Figure A9718156301452
2-45 2-((3-hydroxyl-3-phenyl propyl)-amino)-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine: according to described general method step C, 2-chloro-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine and 3-hydroxyl-3-phenylpropylamine are reacted (100 ℃, 30 minutes), obtain described title compound.MS (m/z): 397.2 (M+H) +C 25H 24N 4The O theoretical value, 396.5. 2-46 2-(((2R, 3R)-3-amino-2-methyl-3-phenyl propyl)-amino)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine hydrochloride: according to described general method step C, with 2-chloro-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine and (1R, 2R)-2-methyl isophthalic acid-phenyl-1, (50 ℃ of 3-propylene diamine reactions, 1 hour), obtain described title compound.MS (m/z): 464.4 (M+H) +C 26H 24F 3N 5Theoretical value, 463.5.(free alkali).
Figure A9718156301461
2-47 2-(((2S, 3S)-3-amino-2-methyl-3-phenyl propyl)-amino)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine hydrochloride: according to described general method step C, with 2-chloro-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine and (1S, 2S)-2-methyl isophthalic acid-phenyl-1, (90 ℃ of 3-propylene diamine reactions, 45 minutes), obtain described title compound.MS (m/z): 464.1 (M+H) +C 26H 24F 3N 5Theoretical value, 463.5.(free alkali). 2-48 2-((S)-3-benzyl diethylenediamine base)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine hydrochloride: according to described general method step C, with (70 ℃ of 2-chloro-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidines and (S)-2-benzyl diethylenediamine reaction, 30 minutes), obtain described title compound.MS (m/z): 475.5 (M+H) +C 27H 24F 3N 5Theoretical value, 476.1.(free alkali).
Figure A9718156301463
2-49 4-(4-pyridyl)-2-(((S)-tetrahydroisoquinoline-3-ylmethyl) amino)-5-(3-trifluoromethyl)-pyrimidine hydrochloride: according to described general method step C, with (50 ℃ of 2-chloro-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine and (S)-tetrahydroisoquinolines-3-base methylamine reaction, 1.5 hour), obtain described title compound.MS (m/z): 462.4 (M+H) +C 26H 22F 3N 5Theoretical value, 461.5.(free alkali). 2-50 5-(3-aminomethyl phenyl)-4-(4-pyridyl)-2-(((S)-tetrahydroisoquinoline-3-ylmethyl) amino)-pyrimidine hydrochloride: according to described general method step C, with (100 ℃ of 2-chloro-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine and (S)-tetrahydroisoquinolines-3-base methylamine reaction, 45 minutes), obtain described title compound.MS (m/z): 408.2 (M+H) +C 26H 25N 5Theoretical value, 407.5.(free alkali).
Figure A9718156301472
The general method of embodiment 3 preparation 2-amido-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidines
Figure A9718156301473
R=R 21, OR 20Or NR 5R 21
Under the ice bath temperature, acyl chlorides R-C (O) Cl (0.57mmol) is added drop-wise in pyridine (3ml) solution of 2-amino-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine (0.38mmol).It was stirred under room temperature 3 hours,, in the impouring frozen water, use dichloromethane extraction, dry and evaporation through the thin-layer chromatography monitoring.Crude product can be through silica gel column chromatography purifying (hexane-acetone) and in suitable solvent recrystallization in the ethyl acetate for example.
According to this method, can prepare following compounds with suitable acyl chlorides: 3-1 2-acetylaminohydroxyphenylarsonic acid 5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine:
MS (m/z): 309.0 (M+H) +C 17H 13FN 4O theoretical value .308.3. 1H-NMR (CDCl 3): d8.63 (s, 1H, H-6, pyrimidine .), 8.60,7.29 (2m, each is 2H, pyridine .), 8.26 (bs, 1H, NH), 7.14,7.08 (2m, each is 2H, PhF), 2.58 (s, 3H, CH 3CO) .R=CH 3-3-2 2-butyrylamino-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine.
MS (m/z): 337.2 (M+H) +C 19H 17FN 4O theoretical value .336.4. 1H-NMR (CDCl 3): d8.64, (s, 1H, H-6, pyrimidine .), 8.60,7.31 (2m, each is 2H, pyridine .), 8.17 (bs, 1H, NH), 7.14,7.08 (2m, each is 2H, PhF), 2.80 (t, 2H, CH 2CO), 1.82 (m, 2H, CH 2), 1.06 (t, 3H, CH 3) .R=CH 3CH 2CH 2-3-3 5-(4-fluorophenyl)-2-valeryl amino-4-(4-pyridyl)-pyrimidine:
MS (m/z): 351.0 (M+H) +C 20H 19FN 4O theoretical value .350.4. 1H-NMR (CDCl 3): d8.69 (s, 1H, H-6, pyrimidine .), 8.60,7.35 (2m, each is 2H, pyridine .), 8.25 (bs, 1H, NH), 7.15,7.08 (2m, each is 2H, PhF), 1.4 (s, 9H, 3CH 3) .R=(CH 3) 3C-3-4 2-benzamido-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine:
MS (m/z): 371.0 (M+H) +C 22H 15FN 4O theoretical value .370.4. 1H-NMR (CDCl 3): d8.75 (s, 2H, NH, H-6, pyrimidine .), 8.61,7.36 (2m, each is 2H, pyridine .), 8.00,7.63,7.55 (d, t, t, 2H, 1H, 2H, Ph), 7.18,7.10 (2m, each is 2H, PhF).
Figure A9718156301481
3-5 5-(4-fluorophenyl)-2-phenyl acetylaminohydroxyphenylarsonic acid 4-(4-pyridyl)-pyrimidine:
MS (m/z): 385.0 (M+H) +C 23H 17FN 4O theoretical value .384.4. 1H-NMR (CDCl 3): d8.66 (s, 1H, H-6, pyrimidine .), 8.59,7.28 (2m, each is 2H, pyridine .), 8.21 (bs, 1H, NH), 7.43-7.30 (m, 5H, Ph), 7.14,7.08 (2m, each is 2H, PhF), 4.13 (s, 2H, CH 2).
Figure A9718156301491
3-6 5-(4-fluorophenyl)-2-hydrocinnamamide amino-4-(4-pyridyl)-pyrimidine: MS (m/z): 399.2 (M+H) +C 24H 19FN 4O theoretical value .398.4. 1H-NMR (CDCl 3): d8.60 (s, 1H, H-6, pyrimidine .), 8.54 (m, 2H, pyridines .), 8.20 (bs, 1H, NH), 7.31-7.16 (m, 7H, Ph, pyridine .), 7.11,7.05 (2m, each is 2H, PhF), 3.20,3.09 (2t, each is 2H, 2CH 2).
Figure A9718156301492
The general method of 5-(4-fluorophenyl)-6-(4-pyridyl)-4 (3H)-pyrimidinones that embodiment 4 preparation 2-replace
Figure A9718156301493
A.2-(4-fluorophenyl)-3-(4-pyridyl)-vinylformic acid: with 4-fluorophenyl acetate (9g, 58.4mmol), 4-pyridylaldehyde (5.6ml, 58.6mmol), the mixture of pyridine (6ml) and diacetyl oxide (6ml) is in 150 ℃ of heating 1 hour down, evaporation subsequently and with the water condistillation.Make the products therefrom crystallization after adding ethanol, cross filter solid and, obtain described title compound with ethanol and ethyl acetate washing.MS (m/z): 244.0 (M+H) +C 14H 10FNO 2Theoretical value .243.2 1H-NMR (DMSO-d 6): d8.43,6.98 (2d, each is 2H, pyridine .), 7.73 (s, 1H, CH=), 7.21 (d, 4H, PhF) .b.2-(4-fluorophenyl)-3-(4-pyridyl)-ethyl propenoate: the vitriol oil (2.2ml) is joined 2-(4-fluorophenyl)-3-(4-pyridyl)-vinylformic acid carefully, and (6.7g heated 24 hours down in refluxing in ethanol 27.5mmol) (120ml) suspension and with mixture.Steaming desolventizes, and resistates is dissolved in methylene dichloride, and organic solution is also evaporated with sodium bicarbonate aqueous solution and water washing, subsequent drying.On silica gel, carry out flash column chromatography (hexane-acetone=2: 1), obtain pure described title compound.MS (m/z) 271.8 (M+H) +C 16H 14FNO 2Theoretical value, 271.3 1H-NMR (CDCl 3): 8.44,6.88 (2m, each is 2H, pyridine .), 7.72 (s, 1H, CH=), 7.16,7.06 (2m, each is 2H, PhF), 4.28 (q, 2H, CH 2), 1.28 (t, 3H, CH 3) the .c. general method: in the test tube of a sealing, under 120 ℃, with 2-(4-fluorophenyl)-3-(the 4-pyridyl)-ethyl propenoate (357mg under stirring, 1.38mmol), (250mg, 4.62mmol) mixture heating up in ethanol (5ml) is 3 hours for amidine hydrochloride (2.61mmol) and sodium methylate.Before evaporation, it is neutralized with 2N hydrochloric acid, resistates is dissolved in acetate (25ml) and (670mg 9.71mmol) handled 20 minutes with Sodium Nitrite down in 44 ℃.After the evaporation, products therefrom is dissolved in methylene dichloride, solution sodium bicarbonate aqueous solution and water washing, dry afterwards and evaporation.Product is by recrystallization purifying in methyl alcohol.If the crude product of nitrite-oxidizing reaction is water miscible, 5-(4-fluorophenyl)-2-methyl-6-(4-pyridyl)-4 (3H)-pyrimidones for example, then do not carry out anhydrous aftertreatment, but before recrystallization, will evaporate the back products therefrom and place (5% ethanol/methylene) on the silicagel column.
Therefore, can prepare following compounds with suitable amidine hydrochloride: 4-1 5-(4-fluorophenyl)-2-methyl-6-(4-pyridyl)-4 (3H)-pyrimidones:
MS (m/z): 282.2 (M+H) +C 16H 12FN 3O theoretical value .281.3 1H-NMR (DMSO-d 6): d8.46 (m 2H, pyridine .), 7.2-7.03 (m, 6H, PhF, pyridine .) .2.38 (s, 3H, CH 3) .R1=CH 3-4-2 5-(4-fluorophenyl)-2-sec.-propyl-6-(4-pyridyl)-4 (3H)-pyrimidone: MS (m/z): 310.0 (M+H) +C 18H 16FN 3O theoretical value 309.4 1H-NMR (DMSO-d 6): 8.45 (m, 2H, pyridines .), 7.21-7.03 (m, 6H, PhF, pyridine .), 2.90 (m, 1H, CH (CH 3) 2) 1.26,1.24 (2s, each is 3H, 2CH 3) .R1=(CH 3) 2CH-4-3 2-(2, the 6-dichloro benzyl)-5-(4-fluorophenyl)-6-(4-pyridyl)-4 (3H)-pyrimidone: MS (m/z): 426.0 (M) +C 22H 14Cl 2FN 3O theoretical value .426.3 1H-NMR (DMSO-d 6): d8.37 (m, 2H, pyridine .), 7.50 (d, 2H, PhCl 2), 7.35 (t, 1H, PhCl 2), 7.18-7.08 (m, 4H, PhF), 6.96 (m, 2H, pyridines .), 4.36 (s, 2H, CH 2).
Figure A9718156301511
4-4 5-(4-fluorophenyl)-2-phenyl-6-(4-pyridyl)-4 (3H)-pyrimidones:
MS (m/z): 344.2 (M+H) +C 21H 14FN 3O theoretical value .343.4 1H-NMR (DMSO-d 6): d8.49 (d, 2H, pyridine .), 8.20 (d, 2H, Ph), 7.66-7.50 (m, 3H, pyridine., Ph), 7.32-7.11 (m, 6H, PhF, Ph).
Figure A9718156301512
4-5 5-(4-fluorophenyl)-2-(4-phenyl butyl)-6-(4-pyridyl)-4 (3H)-pyrimidones: with 2-(4-fluorophenyl)-3-oxo-3-(4-pyridyl)-ethyl propionate (293mg, 1.02mmol), 4-phenyl butane carbonamidine (315mg, 1.79mmol) and pyridine tosilate (10mg) be suspended in the p-Xylol (10ml).Fully stir down, mixture heating up is refluxed, remove water continuously with Dean and Stark apparatus.After 16 hours, steaming desolventizes, product on silica gel through column chromatography purifying (3% ethanol/methylene), recrystallization in acetone subsequently.MS (m/z): 400.3 (M+H) +C 25H 22FN 3The O theoretical value, 399.5.R1＝Ph(CH 2) 4-
General method steps A .2-(4-fluorophenyl)-3-oxo-3-(4-pyridyl) ethyl propionate of embodiment 5 preparation 5-(4-fluorophenyl)-6-(4-pyridyl)-2-alkylthio-4 (3H)-pyrimidinones:
Figure A9718156301521
(according to: Legrand and Lozac ' h, Bull.Soc.Chim.Fr., 79-81 (1955)).
Under the argon atmospher, with 4-fluorophenyl ethyl acetate (13g, 71.35mmol), iso ethyl nicotinate (10.7ml, 71.4mmol) and the sodium particle (1.64g, mixture 71.34mmol) are in 90-95 ℃ of down heating, and mixture begins to reflux and become solid gradually.2.5 after hour, cooling neutralizes mixture down with acetic acid,diluted, use dichloromethane extraction subsequently.Organic solution washes with water, dry and evaporation.On silicagel column, carry out flash chromatography (hexane-acetone=4: 1,3: 1.2: 1), obtain the described title compound of oily.MS (m/z): 287.8 (M+H) +C 16H 14FNO 3Theoretical value .287.3 1H-NMR (CDCl 3), (ketone: enol=1: 0.33): d13.50 (s, 0.3H, OH-E), and 8.81 (m, 2H, pyridine .-K), 8.48 (m, 0.66H, pyridine .-E), 7.72 (m, 2H, pyridine .-K), 7.38 (m, 2H, PhF-K), 7.14-7.04 (m, 2H, PhF-K;-0.65H, pyridine .-E;-0.65H, PhF-E), 6.96 (t, 0.64H, PhF-E), 5.51 (s, 1H, CH-K), 4.23-4.2-(m, CH 2-K, E), 1.26 (t, CH 3-K, E). step is (4-fluorophenyl)-6-(4-pyridyl)-2-thiouracil B.5-
Under the argon atmospher, with stir 2-(4-fluorophenyl)-3-oxo-3-(4-pyridyl) ethyl propionate down (22.3g, 77.6mmol) and thiocarbamide (5.9g, mixture 77.6mmol) reacted 40 minutes in 190 ℃ times.Make reaction mixture be cooled to room temperature, be dissolved in acetone and, obtain described title compound sedimentation and filtration.MS (m/z): 300.2 (M+H) +C 15H 10FN 3OS theoretical value .299.3 1H-NMR (DMSO-d 6): d12.74,12.65 (2s, 2H), 8.51 (m, 2H, pyridines .), 7.26 (m, 2H, pyridines .), 7.09 and d7.03 (2m, each is 2H, PhF).
In addition, under agitation condition fully, with 2-(4-fluorophenyl)-3-oxo-3-(4-pyridyl) ethyl propionate (2.87g, 10mmol) and thiocarbamide (2.28g, 30mmol) be suspended in the p-Xylol (50ml), in described mixture, add pyridine tosilate (100mg) and with Dean and Stark apparatus under the condition that removes water (0.2ml) continuously backflow 12-16 hour.With the reaction mixture cooling, the chocolate solid is filtered with B.The solid suspension of collecting is also filtered in acetone (25ml).Product with washing with acetone still contains the trace thiocarbamide, and its hot water (20-30ml) development is removed.Product is filtered and dry air.Step C. general method:
With aralkyl bromide (0.36mmol) be added drop-wise to 5-(4-fluorophenyl)-6-(4-pyridyl)-2-thiouracil under stirring (100mg, 0.33mmol) and salt of wormwood (46mg is 0.33mmol) at N, in the mixture in the dinethylformamide (4.6ml).Continue to stir 3 hours, subsequently evaporation.On silicagel column, carry out flash chromatography (hexane-acetone=3: 1,2: 1,1: 1) and in hot methanol recrystallization, obtain the purpose compound.
According to the method described above, can obtain following compounds with suitable aralkyl bromide: 5-1 5-(4-fluorophenyl)-2-(2-styroyl) sulfenyl-6-(4-pyridyl)-4 (3H)-pyrimidone: MS (m/z): 404.2 (M+H) +C 23H 18FN 3OS theoretical value .403.4. 1H-NMR (DMSO-d 6): d13.08 (bs, 0.7H), 8.49 (m, 2H, pyridines .), 7.30-7.06 (m, 11H, pyridine .Ph, PhF), 3.41 (dd, 2H, CH 2S), 3.00 (t, 2H, CH 2).
Figure A9718156301531
5-2 5-(4-fluorophenyl)-2-(3-hydrocinnamyl) sulfenyl-6-(4-pyridyl)-4 (3H)-pyrimidone: MS (m/z): 418.0 (M+H) +C 24H 20FN 3OS theoretical value .417.5. 1H-NMR (DMSO-d 6): d13.10 (bs, 0.7H), 8.47 (m, 2H, pyridines .), 7.29-7.06 (m, 11H, pyridine., Ph, PhF), 3.18 (t, 2H, CH 2S), 2.71 (t, 2H, CH 2Ph), 2.03 (m, 2H, CH 2).
Figure A9718156301541
5-3 5-(4-fluorophenyl)-2-(2-benzene oxygen ethyl) sulfenyl-6-(4-pyridyl)-4 (3H)-pyrimidone: MS (m/z): 420.0 (M+H) +C 22H 18FN 3O 2S theoretical value .419.5. 1H-NMR (DMSO-d 6): d13.20 (bs, 0.7H), 8.46 (m, 2H, pyridines .), 7.24-7.07 (m, 8H, pyridine., PhF, Ph), 6.95 (d, 2H, Ph), 6.92 (t, eclipsed, 1H, Ph), 4.30 (t, 2H, CH 2O), 3.58 (t, 2H, CH 2S).
Figure A9718156301542
5-4 5-(4-fluorophenyl)-2-(2-phenylamino ethyl) sulfenyl-6-(4-pyridyl)-4 (3H)-pyrimidone: MS (m/z): 419.0 (M+H) +C 23H 19FN 4OS theoretical value .418.5. 1H-NMR (DMSO-d 6): d13.20 (bs, 0.8H), 8.48,7.22 (2m, each is 2H, pyridine .), 7.16,7.10 (2m, each is 2H, PhF), 6.89 (t, 2H, Ph), 6.54 (d, 2H, Ph), 6.48 (t, 1H, Ph), 5.90 (bs, 0.6H, NH), 3.43-3.25 (m, 2CH 2).
Figure A9718156301543
The general method of 2-amino-5-(4-fluorophenyl)-6-(4-pyridyl)-4 (3H)-pyrimidinones that embodiment 6 preparation 2-N replace: steps A .5-(4-fluorophenyl)-2-methylthio group-6-(4-pyridyl)-4 (3H)-pyrimidones:
Under the ice bath temperature, with methyl iodide (90ml, 1.44mmol) be added drop-wise to 5-(4-fluorophenyl)-6-(4-pyridyl)-2-thiouracil under stirring (430mg, 1.44mmol) and salt of wormwood (198mg, 1.43mmol) in N, in the mixture in the dinethylformamide (13ml).After 40 minutes, with its evaporation, crude product through flash chromatography method purifying (hexane-acetone=2: 1,1: 1,1: 2), obtains the described title compound of solid state on silicagel column.
MS (m/z): 314.2 (M+H) +C 16H 12FN 3Each is .313.3. for OS 1H-NMR (DMSO-d 6): d13.10 (bs), 8.47,7.22 (2m, each is 2H, theoretical value), 7.16,7.10 (2m, pyridine 2H, PhF), 2.56 (s, 3H, CH 3). step B. general method:
(100mg is 0.32mmol) with amine HNR with 5-(4-fluorophenyl)-2-methylthio group-6-(4-pyridyl)-4 (3H)-pyrimidones 5R 21Mixture (1mmol) heated 2 hours down in 180 ℃.Products therefrom through flash chromatography method purifying (hexane-acetone or methyl alcohol-methylene dichloride or methylene chloride-methanol-dense ammonium hydroxide), obtains described purpose compound on silicagel column.
Can prepare following compounds with above-mentioned general method and suitable amine: 6-1 2-(2-(2-chloro-phenyl-) ethyl-amino)-5-(4-fluorophenyl)-6-(4-pyridyl)-4 (3H)-pyrimidone: MS (m/z): 421.2 (M+H) +C 23H 16ClFN 4The O theoretical value, 420.9. 1H-NMR (DMSO-d 6): d11.24 (bs), 8.44,7.16 (2m, each is 2H, pyridine .), 7.43,7.38 (2dd, each is 1H, PhCl), 7.30,7.26 (2dt, each is 1H, PhCl), 7.10-7.00 (m, 2H, PhF), 6.74 (bs, 1H, NH), 3.60 (q, 2H, CH 2N), 3.03 (t, 2H, CH 2).
Figure A9718156301561
6-2 5-(4-fluorophenyl)-2-((3-phenyl propyl)-amino)-6-(4-pyridyl)-4 (3H)-pyrimidone: MS (m/z): 401.2 (M+H) +C 24H 21FN 4O theoretical value .400.5. 1H-NMR (DMSO-d 6): d11.16 (bs), 8.44,7.14 (2m, each is 2H, pyridine .), 7.32-7.01 (m, 9H, Ph, PhF), 6.78 (bs, NH), 3.36 (q, 2H, CH 2N), 2.67 (t, 2H, CH 2Ph), 1.89 (m, 2H, CH 2).
Figure A9718156301562
6-3 5-(4-fluorophenyl)-2-((1-methyl-3-phenyl propyl)-amino)-6-(4-pyridyl)-4 (3H)-pyrimidones: need be 180 ℃ of reactions 15 hours.MS (m/z): 415.0 (M+H) +C 25H 23FN 4The O theoretical value, 414.5. 1H-NMR (CDCl 3): d8.48 (m, 2H, pyridine .), 7.28-7.08 (m, 9H, pyridine., Ph, PhF), 6.94 (m, 2H, PhF), 5.67 (bs, 1H, NH), 4.08 (m, 1H, CHCH 3), 2.61 (t, 2H, CH 2Ph), 1.67 (m, 2H, CH 2), 1.08 (d, 3H, CH 3).
Figure A9718156301563
6-4 5-(4-fluorophenyl)-2-((3-imidazolyl propyl group)-amino)-6-(4-pyridyl)-4 (3H)-pyrimidone: MS (m/z): 391.0 (M+H) +C 21H 19FN 6O theoretical value .390.4. 1H-NMR (DMSO-d 6): d11.24 (bs), 8.42,7.12 (2m, each is 2H, pyridine .), 7.62,7.18 (2s, each is 1H, imidazoles .), 7.08-6.99 (m, 4H, PhF), 6.88 (s, 1H, imidazoles .), 4.02 (t, 2H, CH 2N), 3.28 (covered by the signal of water,
CH 2NH), 2.00 (m, 2H, CH 2).
Figure A9718156301571
6-5 2-(((S)-2-amino-3-phenyl propyl)-amino)-5-(4-fluorophenyl)-6-(4-pyridyl)-4 (3H)-pyrimidone hydrochlorides: 170 ℃ of reactions 7 hours.MS (m/z): 416.1 (M+H) +C 26H 22FN 5O theoretical value .415.5.
Figure A9718156301572
Embodiment 75-(4-fluorophenyl)-2-diazanyl-6-(4-pyridyl)-4 (3H)-pyrimidones
With 5-(4-fluorophenyl)-6-(4-pyridyl)-2-thiouracil (500mg, 1.66mmol) and hydrazine hydrate (800ml ,～14mmol) mixture is in 120 ℃ of heating 60 minutes down.With its evaporation, reaction product obtains described title compound in recrystallization from hot methanol.
MS (m/z): 298.0 (M+H) +C 15H 12FN 3O theoretical value .297.3. 1H-NMR (DMSO-d 6): d8.41,7.12 (2m, each is 2H, pyridine .), 7.05,7.00 (2m, each is 2H, PhF) .R 1=NH-NH 2
Embodiment 8 preparation 5-aryl-2, the general method of 6-bipyridyl-3 (H)-pyrimidinones
Figure A9718156301573
Figure A9718156301581
According to the described document (article of Kabbe mentioned above; German Patent 1271116 (1968)), this compounds of preparation as described below:
Phenylacetic acid ethyl ester (3.13mmol), cyanopyridine (6.24mmol) and the mixture of sodium methylate (3.5mmol) in propyl carbinol (1.2ml) under stirring were heated 2 hours down in 110 ℃.Reaction mixture is concentrated and water-soluble (4ml), add saturated aqueous ammonium chloride (2ml) subsequently.With sedimentation and filtration and in hot methanol recrystallization.
According to this method, can prepare following compounds with suitable raw material: 8-1 5-phenyl-2,6-two-(4-pyridyl)-4 (3H)-pyrimidone: MS (m/z): 327.2 (M+H) +C 20H 14N 4O theoretical value .326.4. 1H-NMR (DMSO-d 6): d8.78,8.47,8.13 (3m, each is 2H, pyridine .), 7.40-7.14 (m, 7H, Ph, pyridine .) .8-2 5-(4-fluorophenyl)-2,6-two-(4-pyridyl)-4 (3H)-pyrimidones:
MS (m/z): 345.2 (M+H) +C 20H 13FN 4O theoretical value .344.4 1H-NMR (DMSO-d 6): d8.80,8.49,8.13 (3m, each is 2H, pyridine .), 7.40-7.08 (m, 6H, PhF, pyridine .) .8-3 2,5,6-three-(4-pyridyl)-4 (3H)-pyrimidones, according to described general method, in the presence of sodium methylate, by with 4-pyridyl ethyl acetate and 4-cyanopyridine prepared in reaction.MS (m/z): 328.2 (M+H) +C 19H 13N 5The O theoretical value.327.4 1H-NMR (DMSO-d 6): 8.65,8.45,8.35,8.18,7.25,7.13 (6m, each is 2H, pyridine).8-4 5-(4-fluorophenyl)-2,6-two-(3-pyridyl)-4 (3H)-pyrimidones:
MS (m/z): 345.2 (M+H) +C 20H 13FN 4O theoretical value .344.4 1H-NMR (DMSO-d 6): d9.34,8.77,8.54,8.48,7.78,7.60,7.34 (7m, 3 * 1H, 2H, 3 * 1H, pyridines .), 7.26,7.15 (2m, each is 2H, PhF).
Embodiment 94-amino-5-(4-fluorophenyl)-2,6-two-(4-pyridyl)-pyrimidine
Figure A9718156301591
4-amino-5-(4-fluorophenyl)-2,6-two-(4-pyridyl)-pyrimidine prepares according to described document (article of Kabbe mentioned above):
(180mg, (650mg, 6.24mmol) (375mml is in propyl carbinol 3.12mmol) (1.5ml) solution with 4-fluorophenyl acetonitrile 3.33mmol) to join 4-cyanopyridine under stirring with sodium methylate.Mixture was stirred under room temperature 20 minutes, afterwards it was heated 1.5 hours down in 110 ℃.Make it be cooled to room temperature and add ethanol (2.5ml).With sedimentation and filtration and in acetic acid/water (3.5/10ml) recrystallization, obtain described title compound.MS (m/z): 344.2 (M+H) +C 20H 14FN 5Theoretical value 343.4 1H-NMR (DMSO-d 6): 8.76,8.47,8.22, (3m, each is 2H, pyridine), 7.4-7.16 (m, 6H, PhF, pyridine).
Embodiment 104-methoxyl group-5-phenyl-2,6-two-(4-pyridyl)-pyrimidine
Figure A9718156301601
With 5-phenyl-2, (360mg 1.10mmol) and under the backflow of the mixture of phosphoryl chloride (2ml) heated 1.5 hours 6-two-(4-pyridyl)-4 (3H)-pyrimidones.As handle as described in when preparing 2-chloro-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine.To 4-chloro-5-phenyl-2,6-two-(4-pyridyl)-pyrimidine (250mg, 0.73mmol) add in the methyl alcohol of crude product (5ml) solution 0.5N sodium methylate methanol solution (1.45ml, 0.73mmol) and with it in the heating down 1 hour that refluxes.After the evaporation, products therefrom is partition between ethyl acetate and water, and organic solution washes with water, dry and evaporation.Described crude product obtains described title compound in the enterprising circumstances in which people get things ready for a trip spectrum of silicagel column purifying (ethyl acetate).
MS (m/z): 341.2 (M+H) +C 21H 16N 4O theoretical value 340.4 1H-NMR (CDCl 3): 8.82,8.54,8.40 (3m, each is 2H, pyridine .), 7.40-7.18 (m, 7H, Ph, pyridine .), 4.15 (s, 3H, CH 3O).
Embodiment 115-(4-fluorophenyl)-2, preparation method's steps A .4-chloro-5-(4-fluorophenyl)-2 of 4-two-(4-pyridyl)-pyrimidine, 6-two-(4-pyridyl)-pyrimidine:
Figure A9718156301602
With 5-(4-fluorophenyl)-2, (760mg 2.21mmol) and under the backflow of the mixture of phosphoryl chloride (3ml) heated 1 hour 6-two-(4-pyridyl)-4 (3H)-pyrimidones.As handle as described in when preparing 2-chloro-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine.Will the part (290mg) products therefrom (495mg) on silica gel through flash chromatography method purifying (ethyl acetate, trace of triethylamine).MS (m/z): 363.2 (M+H) +C 20H 12ClFN 4Theoretical value .362.8 1H-NMR (CDCl 3): d8.84,8.60,8.38,7.30 (4m, each is 2H, pyridine .), 7.22,7.13 (2m, each is 2H, PhF). step is (4-fluorophenyl)-2.4-two-(4-pyridyl)-pyrimidine B.5-:
Figure A9718156301611
To stir 4-chloro-5-(4-fluorophenyl)-2 down, (99mg is 0.27mmol) with the hydrogenation 28 hours under nitrogen atmosphere of the mixture of 10% palladium-carbon (70mg) for 6-two-(4-pyridyl)-pyrimidine.Filtration and steaming desolventize, and carry out flash chromatography (ethyl acetate) subsequently on silicagel column, obtain described title compound.MS (m/z): 329.2 (M+H) +C 20H 13FN 4Theoretical value 328.4. 1H-NMR (CDCl 3): d8.91 (s, 1H, H-6, pyrimidine), 8.83,8.65,8.40,7.45 (4m, each is 2H, pyridine), 7.30-7.06 (m, 4H, PhF).
The preparation method of embodiment 122-(((S)-2-N-glycyl amino-3-phenyl propyl)-amino)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine hydrochloride 12-1 2-(((S)-2-N-glycyl amino-3-phenyl propyl)-amino)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine hydrochloride: under the ice bath temperature; with Vinyl chloroformate (86 μ l; 0.901mmol) join N-(tertbutyloxycarbonyl) glycine (160mg under stirring; 0.911mmol) and the 4-methylmorpholine (110 μ l are 1.00mmol) in the mixture in tetrahydrofuran (THF) (10ml).After 40 minutes, under the ice bath temperature, add 2-(((S)-2-amino-3-phenyl propyl)-amino)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine (409mg, tetrahydrofuran (THF) 0.911mmol) (15ml) solution, in 1 hour, make mixture be cooled to room temperature.It is diluted with methylene dichloride, with the sodium bicarbonate aqueous solution washing, the dry and evaporation with organic solution subsequently.Products therefrom is purifying (5% ethanol/methylene) on silicagel column, is dissolved in methyl alcohol (2ml) then and adds 4N hydrogenchloride/diox (2ml).After following 1 hour of the room temperature, be dissolved in methylene dichloride with its evaporation and with resistates, with the sodium bicarbonate aqueous solution washing, column chromatography (methylene chloride-methanol-dense ammonium hydroxide=95: 5: 0 is carried out in dry and evaporation on silica gel with organic solution subsequently; 90: 10: 0.6), obtain the described title compound of free alkali form, by add 4N hydrogenchloride/diox (85 μ l) in its methanol solution (3ml), evaporation is converted into hydrochloride subsequently.MS (m/z): 507.4 (M+H) +C 27H 25F 3N 6The O theoretical value, 506.5.(free alkali).
Can prepare following compounds with aforesaid method and suitable raw material: 12-2 2-(((S)-2-N-glycyl amino-3-phenyl propyl)-amino)-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine hydrochloride: MS (m/z): 453.2 (M+H) +C 27H 28N 6The O theoretical value, 452.6.(free alkali).
Embodiment 13 (S)-1, the preparation method of 2-benzyl quadrol (S)-1,2-benzyl quadrol: according to described document (H.Brunner, P.Hankofer, U.Holzinger, B.Treittinger and H.Schoenenberger, Eur, J.Med.Chem.25,35-44 (1990)), by preparing described diamines with lithium aluminium hydride reduction L-DL-Phenylalanine amide.According to identical method, can prepare (R)-enantiomorph by the D-DL-Phenylalanine amide.
The preparation method of embodiment 142-(((S)-2-acetylaminohydroxyphenylarsonic acid 3-phenyl propyl)-amino)-5-(4-fluorophenyl)-3-methyl-6-(4-pyridyl)-4 (3H)-pyrimidones
Figure A9718156301631
2-(((S)-2-acetylaminohydroxyphenylarsonic acid 3-phenyl propyl)-amino)-5-(4-fluorophenyl)-3-methyl-6-(4-pyridyl)-4 (3H)-pyrimidones: with 2-(((S)-2-amino-3-phenyl propyl)-amino)-5-(4-fluorophenyl)-3-methyl-6-(4-pyridyl)-4 (3H)-pyrimidones (25mg, 0.058mmol) and methyl alcohol (2ml) solution of diacetyl oxide (200ml) under room temperature, kept 1 hour.Evaporation composes products therefrom to purifying (10% ethanol/methylene) in the enterprising circumstances in which people get things ready for a trip of silicagel column subsequently, obtains described title compound.MS (m/z): 472.3 (M+H) +C 27H 26FN 5O 2Theoretical value, 471.5.
The preparation method of embodiment 152-(((S)-2-N-isopropylamino-3-phenyl propyl)-amino)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine hydrochloride 15-1 2-(((S)-2-N-isopropylamino-3-phenyl propyl)-amino)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine hydrochloride: with sodium triacetoxy borohydride (184mg, 0.868mmol) join 2-(((S)-2-amino-3-phenyl propyl)-amino)-4-(4-pyridyl)-5-(the 3-trifluoromethyl)-pyrimidine (300mg under stirring, 0.668mmol) and acetone (50 μ l, 0.675mmol) in 1, in the mixture in the 2-C2H4F2 C2H4F2 (4ml).After 16 hours, make the stopping of reaction, use dichloromethane extraction subsequently, dry and evaporation organic solution by adding saturated sodium bicarbonate aqueous solution.In the enterprising circumstances in which people get things ready for a trip spectrum of silicagel column purifying (5% methyl alcohol/chloroform), obtain the described title compound of free alkali form, by add 6N hydrochloride (73 μ l) in its methanol solution (3ml), evaporation is converted into a hydrochloride subsequently.MS (m/z): 491.7 (M) +C 28H 28F 3N 5Theoretical value, 491.6.(free alkali).
Can prepare following compounds with aforesaid method and suitable raw material: 15-2 2-(((S)-2-N-cyclohexyl amino-3-phenyl propyl)-amino)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine hydrochloride, MS (m/z): 532.0 (M+H) +C 31H 32F 3N 5Theoretical value, 531.6.(free alkali).
Figure A9718156301641
15-3 2-(((S)-2-N-isopropylamino-3-phenyl propyl)-amino)-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine hydrochloride: MS (m/z): 439.1 (M+H) +C 28H 31N 5The O theoretical value, 437.6.(free alkali).
Figure A9718156301642
15-4 2-(((S)-uncle 2-N-fourth amino-3-phenyl propyl)-amino)-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine hydrochloride: MS (m/z): 452.1 (M+H) +C 29H 33N 5Theoretical value, 451.6.(free alkali).
Figure A9718156301643
15-5 2-(((S)-2-N-cyclohexyl amino-3-phenyl propyl)-amino)-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine hydrochloride: MS (m/z): 478.3 (M+H) +C 31H 35N 5Theoretical value, 477.7.(free alkali). 15-6 5-(4-fluorophenyl)-2-(((S)-2-N-isopropylamino-3-phenyl propyl)-amino)-4-(4-pyridyl)-pyrimidine hydrochloride: MS (m/z): 442.1 (M+H) +C 27H 28FN 5Theoretical value, 441.6.(free alkali).
Figure A9718156301652
15-7 5-(4-fluorophenyl)-2-((3-N-isopropylamino-3-phenyl propyl)-amino)-4-(4-pyridyl)-pyrimidine hydrochloride: MS (m/z): 442.2 (M+H) +C 27H 28FN 5Theoretical value, 441.6.(free alkali).
The preparation method of embodiment 162-(((S)-2-amino-3-phenyl propyl)-amino)-5-(3-chloro-4-fluorophenyl)-4-(4-pyridyl)-pyrimidine hydrochloride
Figure A9718156301661
Steps A: 4-(4-pyridyl)-2 (1H)-pyrimidones: with 4-acetylpyridine (25ml226.0mmol) and two (dimethylamino) methoxyl group methane (44ml; 293.8mmol) mixture in 85 ℃ of down heating 30 minutes; be evaporated to subsequently dried, to reclaim 3-(dimethylamino)-1-(4-pyridyl)-3-propylene-1-ketone solid.Its ethanolic soln (200ml) is transferred to 1.13N to be contained urea (16.3g in the ethanolic soln of sodium ethylate 271mmol) (200ml), refluxes mixture heating up and spends the night, and is cooled to the ice bath temperature then.With sedimentation and filtration, be dissolved in the minimum water and with aqueous solution washed with dichloromethane.By also filtering by being settled out described title compound in the described aqueous solution with the neutralization of 6N hydrochloric acid.Concentrate, dilute and use washed with dichloromethane with minimum water, can be by obtaining more product in the former reactant filtrate.With aqueous solution usefulness 6N hydrochloric acid neutralization and with sedimentation and filtration.MS (m/z): 174.1 (M+H) +C 9H 7N 3The O theoretical value, 173.2.Step B:2-chloro-4-(4-pyridyl)-pyrimidine: in argon atmospher ice bath cooling down, with 4-(4-pyridyl)-2 (1H)-pyrimidones (13.45g, 77.7mmol) and thionyl chloride (92ml) mixing.Add N lentamente, (13.2ml's dinethylformamide 170.5mmol) and with mixture heating up refluxed 1 hour.With its evaporation ice bath toluene condistillation.Under 0 ℃, in described resistates, add entry, add 10% ammonium hydroxide then, until reaching neutral, use dichloromethane extraction subsequently.With the organic solution drying, subsequently the evaporation and with gained solid recrystallization in acetone.MS (m/z): 192.1,194.0 (M+H) +C 9H 6ClN 3Theoretical value, 191.6.Step C:2-(((S)-2-amino-3-phenyl propyl)-amino)-4-(4-pyridyl)-pyrimidine: with 2-chloro-4-(4-pyridyl)-pyrimidine (4.5g, 23.7mmol) and (S)-1, (8.0g, mixture 53.3mmol) heated 25 minutes down in 100 ℃ 2-benzyl quadrol.On silica gel, carry out column chromatography (methylene chloride-methanol-dense ammonium hydroxide=95: 5: 0.4), obtain described title compound.MS (m/z): 306.5 (M+H) +C 18H 19N 5Theoretical value, 305.4.Step D:2-(((S)-2-amino-3-phenyl propyl)-amino)-5-bromo-4-(4-pyridyl)-pyrimidine: with bromine (787 μ l, 15.28mmol) join 2-(((S)-2-amino-3-phenyl propyl)-amino)-4-(the 4-pyridyl)-pyrimidine (2.33g under stirring, 7.64mmol) chloroform (25ml) solution in, continue to stir 2 days.With mixture partition between methylene dichloride and sodium bicarbonate aqueous solution, organic solution salt water washing, dry and evaporation.Products therefrom is purifying (methylene chloride-methanol-dense ammonium hydroxide=92: 8: 0.6) on silicagel column.MS (m/z): 384.0,386.0 (M+H) +C 18H 18BrN 5Theoretical value, 384.0.Step e: 2-(((S)-2-amino-3-phenyl propyl)-amino)-5-(3-chloro-4-fluorophenyl)-4-(4-pyridyl)-pyrimidine hydrochloride: under the argon atmospher, with 2-((2 (S)-amino-3-phenyl propyl)-amino)-5-bromo-4-(4-pyridyl)-pyrimidine (204mg, 0.53mmol), 2M aqueous sodium carbonate (1.66ml, 3.32mmol) and 3-chloro-4-fluorobenzoic boric acid (103mg, 0.637mmol) mixture in toluene (5ml) stirred 10 minutes.Mixture is fully outgased (10 times), add afterwards four (triphenyl phosphine) palladium (O) (18mg, 0.016mmol).Reflux heating down after 16 hours, and reaction mixture is with dilution with toluene and use the salt water washing.Dry and the evaporation with organic solution, on silica gel, carry out column chromatography (methylene chloride-methanol-dense ammonium hydroxide=95: 5: 0.4) subsequently, obtain described title compound, by in its methanol solution (2ml), adding 6N hydrochloric acid (64 μ l), evaporation is converted into hydrochloride subsequently.MS (m/z): 434.1 (M) +C 24H 21ClFN 5Theoretical value, 433.9.(free alkali).
According to this method steps E, can prepare following compounds with suitable boric acid and 5-bromo pyrimi piperidine: 16-2 2-(((S)-2-amino-3-phenyl propyl)-amino)-5-(3-fluorophenyl)-4-(4-pyridyl)-pyrimidine hydrochloride: MS (m/z): 400.1 (M+H) +C 24H 22FN 5Theoretical value, 399.5 (free alkalis).16-3 2-(((S)-2-amino-3-phenyl propyl)-amino)-5-(3-isopropyl phenyl)-4-(4-pyridyl)-pyrimidine hydrochloride: MS (m/z): 424.2 (M+H) +C 27H 29N 5Theoretical value, 423.6 (free alkalis).16-4 5-(3-acetylamino phenyl)-2-(((S)-2-amino-3-phenyl propyl)-amino)-4-(4-pyridyl)-pyrimidine hydrochloride: MS (m/z): 439.1 (M+H) +C 26H 26N 6The O theoretical value, 438.5 (free alkalis).16-5 2-(((S)-2-amino-3-phenyl propyl)-amino)-5-(4-chloro-phenyl-)-4-(4-pyridyl)-pyrimidine hydrochloride: MS (m/z): 416.3 (M+H) +C 24H 22ClN 5Theoretical value, 415.9 (free alkalis).16-6 2-(((S)-2-amino-3-phenyl propyl)-amino)-5-(benzothienyl)-4-(4-pyridyl)-pyrimidine hydrochloride: MS (m/z): 438.3 (M+H) +C 26H 23N 5The S theoretical value, 437.6 (free alkalis).16-7 2-(((S)-2-amino-3-phenyl propyl)-amino)-5-(2-naphthyl)-4-(4-pyridyl)-pyrimidine hydrochloride: MS (m/z): 432.5 (M+H) +C 28H 25N 5Theoretical value, 431.5 (free alkalis).
The preparation method of embodiment 17 (S)-2-benzyl diethylenediamine
Figure A9718156301681
(S)-and the 2-benzyl diethylenediamine: under the ice bath temperature, (1.6g 42.16mmol) joins (S)-2-benzyl diethylenediamine-3 under stirring in batches, and (3.0g is 14.70mmol) and in tetrahydrofuran (THF) (80ml) mixture for the 6-diketone with lithium aluminium hydride.After following 30 minutes, mixture is stirred backflow down 4 hours in the ice bath temperature.Make the reaction quenching by add sodium sulfate decahydrate and some methyl alcohol in batches, until there not being hydrogen to emit.With its filtration, solid with washed with dichloromethane for several times.Filtrate evaporation with merging obtains a white solid.MS (m/z): 177.1 (M+H) +C 11H 16N 2Theoretical value, 176.3.
Embodiment 18 (S)-2-N, the preparation method of N-dimethylamino-3-phenylpropylamine
Figure A9718156301682
(S)-2-N.N-dimethylamino-3-phenylpropylamine: with triacetyl oxygen base sodium hydride (13.0g, 61.3mmol) join the DL-Phenylalanine amide (3.6g under stirring, 21.9mmol) and 37% formaldehyde solution (4.4ml is 58.7mmol) in 1, in the mixture in the 2-ethylene dichloride (77ml).Stir after 2 hours, make the stopping of reaction, add the potassium hydroxide particle then, use dichloromethane extraction subsequently, dry and evaporation organic solution by adding saturated sodium bicarbonate aqueous solution.Method (H.Brunner according to described document, P.Hankofer, U.Holzinger, B.Treittinger and H.Schoenenberger, Eur, J.Med.Chem.25,35-44 (1990)), with gained (S)-2-N, N-dimethylamino-3-hydrocinnamamide reduces with lithium aluminium hydride, obtains described title compound.
The preparation method of embodiment 192-(((S)-2-N, N-dimethylamino-3-phenyl propyl)-amino)-5-(4-fluorophenyl)-3-methyl-6-(4-pyridyl)-4 (3H)-pyrimidone hydrochlorides
Figure A9718156301691
Steps A .5-(4-fluorophenyl)-3-methyl-2-methylsulfonyl-6-(4-pyridyl)-4 (3H)-pyrimidones: with 5-(4-fluorophenyl)-3-methyl-2-methylthio group-6-(4-pyridyl)-4 (3H)-pyrimidones (400mg, 1.22mmol) and Oxone R(3.74mmol) mixture in methyl alcohol (100ml) and water (45ml) stirred 13 hours for permonosulphuric acid potassium, 2.3g.Solvent is concentrated into about 50ml, uses dichloromethane extraction subsequently.Dry and the evaporation with organic solution.Need not purifying, the gained white solid is directly used in next step.Step is (((S)-2-N.N-dimethylamino-3-phenyl propyl)-amino)-5-(4-fluorophenyl)-3-methyl-6-(4-pyridyl)-4 (3H)-pyrimidone hydrochlorides B.2-: with 5-(4-fluorophenyl)-3-methyl-2-methylsulfonyl-6-(4-pyridyl)-4 (3H)-pyrimidone crude product (430mg; 1.19mmol) and (S)-2-N; N-dimethylamino-3-phenylpropylamine (600mg;～3.4mmol) mixture stirred under room temperature 1 hour, and is of short duration warm down in 50 ℃ then.Carry out column chromatography (3-5% methyl alcohol/chloroform) on silica gel, obtain the described title compound of free alkali form, (160mml 0.64mmol) and subsequently evaporates, and is converted into a hydrochloride by add 4N hydrogenchloride/diox in its methanol solution (4ml).MS (m/z): 458.0 (M+H) +C 27H 28FN 5The O theoretical value, 457.5 (free alkalis).
Embodiment 205-(4-fluorophenyl)-6-(4-(2-kharophen)-pyridyl)-2-alkylthio-4 (3H)-pyrimidinones steps A .2-(4-fluorophenyl)-3-oxo-3-(4-(2-kharophen)-pyridyl)-ethyl propionate:
In a steel bomb, with the 2-chloroisonicotinic acid (25.0g, 65ml ammonium hydroxide solution,stronger 0.16mmol) be warmed to 205 ℃ 72 hours.After being cooled to 23 ℃, with 6N HCl described solution is acidified to pH1, subsequent filtration is to remove unreacting material.With 1/4th (the about 200mls) of solution for vacuum concentration, transfer to pH6 carefully with 1N NaOH to original volume.Turbid solution after placing 20 hours under 0 ℃, is leached the amino Yi Yansuan of required 2-.In ethanol (600ml) suspension of the amino Yi Yansuan of 2-, add the anhydrous HCl De of 47.1ml 4N dioxane solution.Be warmed to backflow after 20 hours, add the dioxane solution of the anhydrous HCl of 47.1ml 4N again and again reaction is warmed to and refluxed 20 hours.In stink cupboard, concentrate with nitrogen gas stream, further subsequently vacuum concentration, residual solid is with saturated bicarbonate solution (200ml) dilution, with ethyl acetate (2 * 200ml) extractions, drying (Na 2SO 4).Behind the vacuum concentration, obtain the amino iso ethyl nicotinate of required 2-.Under 0 ℃ of argon atmospher, in 5 minutes, dripping acetyl chloride in pyridine (45ml) solution of the amino iso ethyl nicotinate of 2-, in 0 ℃ after 2 hours, with reactant impouring 300g on ice, (2 * 300ml) extractions, (salt solution (2 * 100ml) washings and dry (Na are used in 2 * 100ml) washings to water subsequently with ethyl acetate 2SO 4).Behind the vacuum concentration, and resistates flash chromatography method purifying (gradient elution, ethyl acetate: hexane 1: 4, use ethyl acetate then: hexane 1: 1), obtain 2-kharophen iso ethyl nicotinate.
In-78 ℃ in 5 minutes, to Isopropylamine (14.15ml, 101mmol) and drip in THF (40ml) solution n-Butyl Lithium (38.1ml, 95mmol).After 10 minutes, add 4-fluorophenyl ethyl acetate (17.3g, 40ml anhydrous THF solution 95mmol).After 10 minutes, (6.0g, 20ml anhydrous THF solution 29mmol) are warmed to 23 ℃ with reaction and spend the night, a collection of then adding acetate (95mmol) to add 2-kharophen iso ethyl nicotinate.To react vacuum concentration, partition repeatedly between saturated bicarbonate solution (200ml) and ether (300ml) neutralizes the hydrogen-carbonate salt deposit that merges with 10% citric acid then, and (2 * 300ml) extract the diacetyl oxide ethyl acetate.With organic layer drying (Na 2SO 4), vacuum concentration obtains 2-(4-fluorophenyl)-3-oxo-3-(4-(2-kharophen)-pyridyl)-ethyl propionate.Step is (4-fluorophenyl)-6-(4-(2-kharophen) pyridyl) B.5-)-the 2-thiouracil.
Under abundant stirring, with 2-(4-fluorophenyl)-3-oxo-3-(4-(2-kharophen)-pyridyl)-ethyl propionate (1.3g, 3.78mmol) and thiocarbamide (863mg 11.3mmol) is suspended in the anhydrous p-Xylol (15ml).In described mixture, add pyridine tosilate (38mg) and, remove water (0.1ml) simultaneously continuously with Dean and Stark apparatus backflow 12-16 hour.With the reaction mixture cooling, the chocolate solid is filtered with B.The solid suspension of collecting is also filtered in acetone (25ml).Product through washing with acetone still contains the trace thiocarbamide, and it is removed with hot water (20-30ml) development.Product is filtered and dry air, subsequently with methylbenzene azeotropic.
The preparation method of embodiment 21 (S)-2-N-ethylamino-3-phenylpropylamine
Figure A9718156301711
(S)-and 2-N-ethylamino-3-phenylpropylamine, (1.2ml, (1.0g is in methyl alcohol 6.10mmol) (25ml) solution 12.7mmol) to join L-DL-Phenylalanine amide under stirring with diacetyl oxide.After following 1.5 hours of the room temperature,, vacuumize down dry subsequently in oil pump with its evaporation.Under 55 ℃, (570mg is 15.0mmol) in tetrahydrofuran (THF) (65ml) reduction 4 hours with lithium aluminium hydride with gained L-N-ethylbenzene ala amide (6.1mmol).In reaction mixture impouring saturated sodium bicarbonate aqueous solution, use dichloromethane extraction subsequently, dry and evaporation.On silica gel, carry out column chromatography (chloroform: methyl alcohol: triethylamine=90: 7: 3), obtain yellow oily amine.MS (m/z): 179.1 (M+H) +C 11H 18N 2Theoretical value, 178.3.
The preparation method of embodiment 222-amino-2-methyl-3-phenylpropylamine
Figure A9718156301712
2-amino-2-methyl-3-phenylpropylamine: with the D of commercially available acquisition, L-Alpha-Methyl phenylalanine methyl ester (5.0g, placed 3 days under room temperature by 28% ammonium hydroxide aqueous solution (50ml) 25.7mmol).With gained D, the white precipitate of L-Alpha-Methyl DL-Phenylalanine amide filters and dry (2.5g).(2.0g, 11.22mmol) (1.3g, 34.26mmol) reductase 12 is 4 hours with lithium aluminium hydride in the ebullient tetrahydrofuran (THF) with this product.Under the ice bath temperature, make the stopping of reaction by adding the sodium sulfate decahydrate.Described salt is filtered, and evaporation obtains the described title compound of oily subsequently.MS (m/z): 165.1 (M+H) +C 10H 16N 2Theoretical value 164.2.M.Freiberger and R.B.Hasbrouck, J.Am.Chem.Soc.82,696-698 (1960) discloses another kind of preparation method.
The preparation method of embodiment 232-methyl-3-phenylpropylamine
Figure A9718156301721
2-methyl-3-phenylpropylamine: with the 2-methyl-3-hydrocinnamamide of commercially available acquisition (4.32g, 26.5mmol) and lithium aluminium hydride (1.3g, 34.3mmol) mixture in tetrahydrofuran (THF) (184ml) stirred under room temperature 5 hours.To also use dichloromethane extraction in its impouring saturated aqueous sodium sulfate, the dry and evaporation with organic solution subsequently obtains the described amine of oily.For example Dornow and Fust, Chem.Ber.87 discloses other synthetic methods in 984 (1954).
The preparation method of embodiment 245-(4-fluorophenyl)-3-methyl-2-((2-methyl-3-phenyl propyl) amino)-6-(4-pyridyl)-4 (3H)-pyrimidone hydrochlorides
Figure A9718156301722
5-(4-fluorophenyl)-3-methyl-2-((2-methyl-3-phenyl propyl) amino)-6-(4-pyridyl)-4 (3H)-pyrimidone hydrochlorides: with 5-(4-fluorophenyl)-3-methyl-2-methylsulfonyl-6-(4-pyridyl)-4 (3H)-pyrimidone crude product (520mg; 1.45mmol) and 2-methyl-3-hydrocinnamamide (1.5g, mixture 10.1mmol) is in 50 ℃ of down heating 30 minutes.On silica gel, carry out column chromatography (2-5% ethanol/methylene; Hexane-acetone=2: 1), obtain described title compound.MS (m/z): 429.4 (M+H) +C 26H 25FN 4The O theoretical value, 428.5 (free alkalis).
Embodiment 251-phenyl-1, the preparation method of 3-propylene diamine
Figure A9718156301731
1-phenyl-1,3-propylene diamine: (S.G.Cohen and S.Y.Weinstein as described, J.Am.Chem.Soc.86,725-728,1964) described in, with 3-phenyl-3-alanine (M.Kojima and J.Fujita, Bull.Chem.Soc.Jpn.55,1454-1459 (1982)) is transformed into 1-phenyl-1,3-propylene diamine.
Be, can prepare 1-(2-fluorophenyl)-1,3-propylene diamine, 1-(2-aminomethyl phenyl)-1,3-propylene diamine and 1-(2-chloro-phenyl-)-1,3-propylene diamine similarly with aforesaid method and suitable raw material.
The preparation method of embodiment 263-ethyl-5-(4-fluorophenyl)-2-methylthio group-6-(4-pyridyl)-4 (3H)-pyrimidones 3-ethyl-5-(4-fluorophenyl)-2-methylthio group-6-(4-pyridyl)-4 (3H)-pyrimidones: under the room temperature, with monobromoethane (600ml, 8.03mmol) join 5-(4-fluorophenyl)-2-methylthio group-6-(4-pyridyl)-4 (3H)-pyrimidone (1.8g under stirring, 5.97mmol) and sodium hydride (60% oil suspension, 320mg, 8mmol) in N, in the mixture of dinethylformamide (60ml).After 2 hours and 3.5 hours, add monobromoethane (2 * 600ml, 2 * 8.03mmol) again.After 8 hours, reaction mixture neutralizes and evaporation with acetate, and resistates is dissolved in methylene dichloride, and organic solution washes with water, dry and evaporation.On silicagel column, carry out flash chromatography (hexane-acetone=3: 1,2: 1), in second main flow part, obtain the described title compound of solid state.
The preparation method of embodiment 273-ethyl-5-(4-fluorophenyl)-2-methylsulfonyl-6-(4-pyridyl)-4 (3H)-pyrimidones 3-ethyl-5-(4-fluorophenyl)-2-methylsulfonyl-6-(4-pyridyl)-4 (3H)-pyrimidones: with 3-ethyl-5-(4-fluorophenyl)-2-methylthio group-6-(4-pyridyl)-4 (3H)-pyrimidones (300mg, 0.88mmol) and Oxone R(4.14mmol) mixture in methyl alcohol (71ml) and water (33ml) stirred 14 hours for permonosulphuric acid potassium, 2.54g.Solvent is concentrated into about 35ml, uses dichloromethane extraction subsequently, dry and evaporation need not purifying, and the gained white solid can be directly used in next step.
The preparation method of embodiment 282-(((S)-2-amino-3-phenyl propyl)-amino)-3-ethyl-5-(4-fluorophenyl)-6-(4-pyridyl)-4 (3H)-pyrimidone hydrochlorides
Figure A9718156301742
2-(((S)-2-amino-3-phenyl propyl)-amino)-3-ethyl-5-(4-fluorophenyl)-6-(4-pyridyl)-4 (3H)-pyrimidone hydrochlorides: with 3-ethyl-5-(4-fluorophenyl)-2-methylsulfonyl-6-(4-pyridyl)-4 (3H)-pyrimidone (150mg; 0.44mmol) and (S)-1; (200ml ,～1.3mmol) mixture is in 190 ℃ of heating 4.5 hours down for 2-benzyl quadrol.In Iatrobeads ROn carry out column chromatography (chloroform: methyl alcohol: triethylamine=90: 7: 3), obtain the described title compound of free alkali form, by add 2N hydrochloric acid (165ml, 0.33mmol) and methyl alcohol (1.5ml) be converted into a hydrochloride, filter, obtain described title compound.MS (m/z): 444.0 (M+H) +C 265H 27FN 5The O theoretical value, 443.5 (free alkalis).
The preparation method of embodiment 293-ethyl-5-(4-fluorophenyl)-2-((2-methyl-3-phenyl propyl) amino)-6-(4-pyridyl)-4 (3H)-pyrimidone hydrochlorides
Figure A9718156301751
3-ethyl-5-(4-fluorophenyl)-2-((2-methyl-3-phenyl propyl) amino)-6-(4-pyridyl)-4 (3H)-pyrimidone hydrochlorides: with 3-ethyl-5-(4-fluorophenyl)-2-methylsulfonyl-6-(4-pyridyl)-4 (3H)-pyrimidone crude product (320mg; 0.89mmol) and 2-methyl-3-phenylpropylamine (600ml ,～4mmol) mixture is in 60 ℃ of heating 2 hours down.On silica gel, carry out column chromatography (hexane-acetone=2: 1; The 2-5% ethanol/methylene), obtain described title compound.MS (m/z): 443.2 (M+H) +C 27H 27FN 4The P theoretical value, 442.5.
The preparation method of embodiment 303-(2-tolyl) propylamine
Figure A9718156301752
3-(2-tolyl) propylamine: under the argon atmospher, (5.0ml, (60% oil suspension, 1.24g is in the suspension of tetrahydrofuran (THF) 31mmol) (50ml) 30.9mmol) to join sodium hydride under stirring with diethyl cyano methyl phosphoric acid ester.After 30 minutes, (3.6ml 31.1mmol) also continues to stir 1 hour to add the 2-tolyl aldehyde.Reaction is by adding the entry quenching and using dichloromethane extraction, subsequently with the dry also evaporation of organic solution.Carry out column chromatography (hexane; Hexane: ethyl acetate=3: 1), obtain oily 2-(2-tolyl) vinyl cyanide.(11.8ml, 142mmol) normal pressure is used hydrogen hydrogenation 2 days down in methyl alcohol (125ml) with this product (3.8g), 10% palladium/carbon (3.8g) and 12N hydrochloric acid.Filtration catalizer is with solvent evaporation.Products therefrom is partition between methylene dichloride and water, and water layer transfers to alkalescence with 10N sodium hydroxide, uses dichloromethane extraction, subsequent drying and evaporation.Products therefrom is purifying (chloroform: methyl alcohol: triethylamine=85: 10: 5), obtain the described title compound of oily on silicagel column.
The preparation method of embodiment 312-amino-3-(2-fluorophenyl)-propylamine
Figure A9718156301761
Steps A .2-amino-3-(2-fluorophenyl) methyl propionate: (D, L)-(2-fluorophenyl) L-Ala is suspended in the 50ml HCl methanol solution and stirred 3 days under room temperature with 5g (27.3mmol).With reaction mixture vacuum concentration and dry, obtain a yellow oil.MS (m/z): 198 (M+H) +C 10H 12FNO 2Theoretical value, 197.2.Step is amino-3-(2-fluorophenyl) propionic acid amide B.2-: be suspended in 2-amino-3-(2-fluorophenyl) methyl propionate in 50ml 30% ammonium hydroxide and stirred under room temperature 18 hours.Mixture is filtered, with cold water washing and collect white solid 2-amino-3-(2-fluorophenyl) propionic acid amide.MS (m/z): 183.1 (M+H) +C 9H 11FN 2The O theoretical value, 182.2.Step is amino-3-(2-fluorophenyl) propylamine C.2-: under argon atmospher, 2-amino-3-(2-fluorophenyl) propionic acid amide is joined carefully the LAH (1.0g of cooling (5 ℃), 26.3mmol) and the mixture of 20ml THF in, will react on the heating down 10 hours that refluxes then.Reaction is cooled to 5 ℃ also uses Na carefully 2SO 410H 2O handles, and the gained mixture is stirred 18 hours, then solids removed by filtration.With the filtrate vacuum concentration, obtain an amber oily thing.MS (m/z): 169 (M+H) +C 9H 13FN 2Theoretical value, 168.19.
Embodiment 32 (1R, 2R)-2-methyl isophthalic acid-phenyl-1, the preparation method of 3-propylene diamine
Figure A9718156301771
Steps A: (2S, 3R, α S)-3-(N-benzyl-N-alpha-methyl benzyl amino)-2-methyl-3-phenylpropionic acid methyl esters: as (S) .G.Davies and I.A.S.Walters, J.Chem.Soc.Perkin Trans.I, preparation 2R among the 1129-1139 (1994), 3S, the described method preparation of α R-enantiomorph.Step B:(2S.3R)-3-amino-2-methyl-3-phenylpropionic acid methyl esters: with (2S.3R. α S)-3-(N-benzyl-N-alpha-methyl benzyl amino)-2-methyl-3-phenylpropionic acid methyl esters (13.0g, 33.55mmol) and the hydrogenation 24 hours under hydrogen-pressure of the mixture of 10% palladium-carbon (13.0g) in Glacial acetic acid (260ml).Remove by filter crystallization, subsequently the evaporation and with the toluene condistillation, obtain the described title compound of white solid.MS (m/z): 194.2 (M+H) +C 11H 15NO 2Theoretical value, 193.3.Step C:(2S, 3R)-3-amino-2-methyl-3-Phenylpropionamide: with (2S, 3R)-(6.3g, (28-30%, 40ml) solution stirs under room temperature 3-amino-2-methyl-3-phenylpropionic acid methyl esters for the ammoniacal liquor (20ml) of 2N methyl alcohol 33mmol) and ammonium hydroxide.After 4 days,, separate (methylene chloride-methanol-dense ammonium hydroxide=93: 7: 0.7 in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel short column subsequently with its evaporation; 90: 10: 0.8), obtain the described acid amides of white solid.MS (m/z): 179.2 (M+H) +C 10H 14N 2The O theoretical value, 178.2.Step D:(1R, 2R)-and 2-methyl isophthalic acid-phenyl-1.3-propylene diamine: under the ice bath temperature, (2.3g 60.60mmol) joins (2S under stirring in batches with lithium aluminium hydride, 3R)-(2.6g is in tetrahydrofuran (THF) 14.59mmol) (54ml) solution for 3-amino-2-methyl-3-Phenylpropionamide.After 45 minutes, the mixture backflow was heated 16 hours down.The ice bath cooling is reacted by adding sodium sulfate decahydrate and some methyl alcohol quenchings, until there not being hydrogen to emit down.Solid filtering is also used washed with dichloromethane, and the filtrate evaporation with merging obtains described title compound.MS (m/z): 165.2 (M+H) +C 10H 16N 2Theoretical value, 164.3.
Similarly, by (2R, 3S, α R)-3-(N-benzyl-N-alpha-methyl benzyl amino)-2-methyl-3-phenylpropionic acid methyl esters can prepare enantiomorph (1S, 2S)-2-methyl isophthalic acid-phenyl-1, the 3-propylene diamine.MS (m/z): 165.3 (M+H) +C 10H 16N 2Theoretical value, 164.3.
Similarly, by (2S, 3S, α R)-and (2R, 3R, α S)-3-(N-benzyl-N-alpha-methyl benzyl amino)-2-methyl-3-phenylpropionic acid tertiary butyl ester (people such as Davies, J.Chem.Soc.Chem.Commun.1153-1155,1993) can prepare enantiomorph (1S, 2R)-2-methyl isophthalic acid-phenyl-1, the 3-propylene diamine and (1R, 2S)-2-methyl isophthalic acid-phenyl-1, the 3-propylene diamine.
The preparation method of embodiment 335-(4-fluorophenyl)-2-(4-phenyl butyl)-6-(4-pyridyl)-4 (3H)-pyrimidones
Figure A9718156301781
5-(4-fluorophenyl)-2-(4-phenyl butyl)-6-(4-pyridyl)-4 (3H)-pyrimidones: with 2-(4-fluorophenyl)-3-oxo-3-(4-pyridyl)-ethyl propionate (293mg, 1.02mmol), 4-phenyl butane carbonamidine (315mg, 1.79mmol) and pyridine tosilate (10mg) be suspended in the p-Xylol (10ml).Fully stir down, mixture is refluxed, simultaneously continuously dehydrating with Dean and Stark apparatus.After 16 hours, steaming desolventizes, product on silica gel through column chromatography purifying (3% ethanol/methylene), recrystallization in acetone subsequently.MS (m/z): 400.3 (M+H) +C 25H 22FN 3The O theoretical value, 399.5.
The preparation method of embodiment 345-(4-fluorophenyl)-2-(N-methyl-N-(2-styroyl) amino)-6-(4-pyridyl)-4 (3H)-pyrimidones 5-(4-fluorophenyl)-2-(N-methyl-N-(2-styroyl) amino)-6-(4-pyridyl)-4 (3H)-pyrimidones uses method for preparing.MS (m/z): 401.2 (M+H) +C 24H 21FN 4The O theoretical value, 400.5.
The described method of embodiment 35 usefulness embodiment 1-33 can prepare compound shown in Table I-II.
Table I
Figure A9718156301811
Table II
Figure A9718156301821
Figure A9718156301831
Embodiment 36
Biological test
Following test is used to illustrate the ability that The compounds of this invention suppresses TNF-α and 1L-1-β generation.Second test is behind oral described test compound, and the restraining effect of TNF-α and I/ in the mouse or L-1-β is measured.The 3rd test is the in vitro tests of a hyperglycemic-glycogenolytic factor in conjunction with inhibition, can be used for illustrating The compounds of this invention glucagon suppression binding ability.The 4th test is that a cyclooxygenase (COX-1 and COX-2) suppresses active in vitro tests, can be used for illustrating the ability that The compounds of this invention suppresses COX-1 and/or COX-2.Lipopolysaccharides activatory monocyte TNF produces the monocytic separation of test
By with bacteria lipopolysaccharide (LPS) activatory monocyte, test compound vitro inhibition TNF generation ability is estimated.The white corpuscle source (by product of platelet removal method) that obtains fresh remnants by local blood bank, and go up by density gradient centrifugation at Ficol-Paque Plus (Pharmacia), isolate peripheral blood lymphocytes (PBMC).With 2 * 10 6The concentration of/ml is suspended in PBMC and is supplemented with 2%FCS, 10mM, among the DMEM of 0.3mg/ml glutaminate, 100U/ml penicillin G and 100mg/ml Vetstrep (perfect medium).Cell placed the flat 96 hole culture dish of Falcon (200 μ l/ hole) and in 6%CO 2With 37 ℃ of following overnight incubation.Clean with 200 μ l/ hole fresh cultures, remove the cell of not adhesion.The hole that to contain AC (～70% monocyte) is filled up with 100 μ l fresh cultures again.The preparation of test compound stock solution
Test compound is dissolved in DMZ.It is 10-50 μ M that the stock solution of compound is made initial concentration.At first, stock solution is diluted to 20-200 μ M with perfect medium, uses 9 twice serial dilutions of complete each compound of medium preparation then.Handle cell and with the generation of lipopolysaccharides activation TNF with test compound
The diluent of every kind of test compound of 100 microlitres is joined in the microtitre hole of containing adhesion monocyte and 100 μ l perfect mediums.Monocyte was cultivated 60 minutes with test compound, at this moment, in every hole, added and contain the 25 μ l perfect mediums of 30ng/ml by intestinal bacteria K532 gained lipopolysaccharides.Each hole was cultivated 4 hours again, remove culture supernatants then, measure the quantity of the TNF that exists in the supernatant liquor with ELISA.TNF?ELISA
With flat 96 hole Corning High Binding ELISA culture dish with 150 μ l/ holes, 3 μ g/ml mouse-antis-humanTNF-MAb (R﹠amp; D Systems #MAB210) covers spend the night (4 ℃).Under room temperature, each hole is supplemented with 20mg/ml BSA (standard ELISA damping fluid: 20mM, 150mM NaCl, 2mM CaCl with 200 μ l/ holes then 2, 0.15mM Thiomersalate, no CaCl pH7.4) 2ELISA damping fluid blocking-up 1 hour.Cleaning culture dish also fills up with 100 μ l test supernatant liquor (diluting 1: 3) or reference liquid again.Reference liquid is by 11 1ng/ml recombinant human TNF stock solution (R ﹠amp; D Systems) 1.5 times of serial dilutions constitute.On orbital shaker (300rpm), culture dish was hatched under room temperature 1 hour, clean and with 100 μ l/ holes with 4: 1 biotinylated 0.5 μ g/ml goat-anti-humanTNF-(R﹠amp of ratio; D systems %AB-210-NA) fills up again.Culture dish was hatched 40 minutes, clean and fill up again with 100 μ l/ holes, 0.02 μ g/ml alkaline phosphatase-conjugated streptavidins (Jackson ImmunoResearch #016-050-084).Culture dish was hatched 30 minutes, clean and fill up again with 200 μ l/ hole 1mg/ml p-nitrophenyl phosphoric acid ester.After 30 minutes, at V MaxUnder 405nm, read the culture dish data on the culture dish reader.Data analysis
The typical curve data are adjusted into the secondary polynomial expression and determine unknown TNF-α concentration by separating this concentration equation formula by their OD value.Use the secondary polynomial expression, draw TNF concentration the test compound concentration map.The concentration of test compound when producing inhibition with this equation calculating causing 50%TNF then.
With well known to a person skilled in the art method,, show that The compounds of this invention also can suppress LPS-inductive monocyte and discharge IL-1 β, IL-6 and/or IL-8 by measuring the concentration of IL-1 β, IL-6 and/or IL-8.According to discharging the described similarity method of test of TNF-α with above-mentioned relevant LPS inductive monocyte, with well known to a person skilled in the art method, by measuring the concentration of IL-1 β, IL-6 and/or IL-8, show that The compounds of this invention also can suppress LPS inductive monocyte and discharge IL-1 β, IL-6 and/or IL-8.Like this, The compounds of this invention can reduce TNF-α, IL-1 β, IL-6 and the IL-8 concentration of rising.The level that this type of inflammatory cytokine is raise is reduced to basal level or low again, is favourable for controlling, alleviating the course of disease and improve numerous disease.All compounds of the present invention can be used in the treatment of diseases method, and wherein in the whole range of definition of disease of TNF-α described herein-mediation, TNF-α, IL-1 β, IL-6 and IL-8 play an important role.Restraining effect to mouse LPS-inductive TNF-α generation
(2mg/kg I.V.) before, uses vehicle or the test compound in vehicle (vehicle is made of 0.5% tragakanta in 0.03N HCl) for male DBA/1LACJ mouse at the injection lipopolysaccharides.Behind the injection LPS 90 minutes, gather blood and the TNF level in the blood plasma is analyzed with ELISA.
In monocyte test (LPS inductive TNF release), following compounds has activity, its IC 50Value is 20 μ M or lower: 5-(4-fluorophenyl)-2-(4-pyridyl)-4-(4-pyridyl)-pyrimidine; 5-(4-fluorophenyl)-2-(2-methylthiazol-4-yl)-4-(4-pyridyl)-pyrimidine; 5-(4-fluorophenyl)-4-(4-pyridyl)-2-(2-thienyl)-pyrimidine; 2-(2-diethyllaminoethyl amino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine; 2-(the amino ethylamino of 2-)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine; 2-(amino third amino of 3-)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine; 2-(the amino fourth amino of 4-)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine; 2-(2; the 6-dichloro benzyl)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine; 2-(2; 6-dichlorophenyl amino)-and 5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine, 2-(2,6-3,5-dimethylphenyl amino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine; 5-(4-fluorophenyl)-2-(2-p-methoxy-phenyl amino)-4-(4-pyridyl)-pyrimidine; 5-(4-fluorophenyl)-2-(4-fluorophenyl amino)-4-(4-pyridyl)-pyrimidine, 5-(4-fluorophenyl)-2-thiophenyl methyl-4-(4-pyridyl)-pyrimidine, 2-(benzylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine; 5-(4-fluorophenyl)-2-(2-phenyl ethylamino)-4-(4-pyridyl)-pyrimidine; 5-(4-fluorophenyl)-2-(methyl-(2-styroyl)-amino)-4-(4-pyridyl)-pyrimidine, 5-(4-fluorophenyl)-2-((2-hydroxyl-2-phenyl-ethyl) amino)-4-(4-pyridyl)-pyrimidine, 5-(4-fluorophenyl)-2-(2-(4-hydroxyphenyl) ethylamino)-4-(4-pyridyl)-pyrimidine; 2-(2-(4-aminophenyl) ethylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine; 5-(4-fluorophenyl)-2-(2-(4-fluorophenyl) ethylamino)-4-(4-pyridyl)-pyrimidine, 5-(4-fluorophenyl)-2-(2-(2-fluorophenyl) ethylamino)-4-(4-pyridyl)-pyrimidine, 2-(2-(2-chloro-phenyl-) ethylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine; 2-(2-(4-chloro-phenyl-) ethylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine; 2-(2-(3-chloro-phenyl-) ethylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine, 2-(2-(2,4 dichloro benzene base) ethylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine; 2-(2-(4-bromophenyl) ethylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine; 5-(4-fluorophenyl)-2-(2-(2-p-methoxy-phenyl) ethylamino)-4-(4-pyridyl)-pyrimidine, 5-(4-fluorophenyl)-2-(2-(3-p-methoxy-phenyl) ethylamino)-4-(4-pyridyl)-pyrimidine, 5-(4-fluorophenyl)-2-((3-hydrocinnamyl) amino)-4-(4-pyridyl)-pyrimidine; 5-(4-fluorophenyl)-2-((1-methyl-3-phenyl propyl)-amino)-4-(4-pyridyl)-pyrimidine; 2-(((S)-2-amino-3-phenyl propyl)-amino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine, 5-(4-fluorophenyl)-2-(2-phenylamino ethylamino)-4-(4-pyridyl)-pyrimidine, 5-(4-fluorophenyl)-2-((3-imidazolyl propyl group)-amino)-4-(4-pyridyl)-pyrimidine; 5-(4-fluorophenyl)-2-((4-phenyl butyl)-amino)-4-(4-pyridyl)-pyrimidine; 5-(4-fluorophenyl)-4-(4-pyridyl)-2-pyrrolidino-pyrimidine, 5-(4-fluorophenyl)-2-morpholino-4-(4-pyridyl)-pyrimidine, 5-(4-fluorophenyl)-2-(1-piperazinyl)-4-(4-pyridyl)-pyrimidine; 5-(4-fluorophenyl)-4-(4-pyridyl)-2-(2-pyrrolidino ethylamino)-pyrimidine; 5-(4-fluorophenyl)-2-(2-morpholino ethylamino)-4-(4-pyridyl)-pyrimidine, 5-(4-fluorophenyl)-2-(2-piperidino-(1-position only) ethylamino)-4-(4-pyridyl)-pyrimidine, 5-(4-fluorophenyl)-2-(3-(2-Pyrrolidone-1-yl) third amino)-4-(4-pyridyl)-pyrimidine; 2-(2; the 6-dichloro benzyl)-and 5-(4-fluorophenyl)-6-(4-pyridyl)-4 (3H)-pyrimidones, 5-(4-fluorophenyl)-2-(2-styroyl) sulfenyl-6-(4-pyridyl)-4 (3H)-pyrimidones, 5-(4-fluorophenyl)-2-(3-hydrocinnamyl) sulfenyl-6-(4-pyridyl)-4 (3H)-pyrimidones; 5-(4-fluorophenyl)-2-(2-phenoxy group ethyl) sulfenyl-6-(4-pyridyl)-4 (3H)-pyrimidones; 5-(4-fluorophenyl)-2-(2-phenylamino ethyl) sulfenyl-6-(4-pyridyl)-4 (3H)-pyrimidones, 2-(2-(2-chloro-phenyl-) ethylamino)-5-(4-fluorophenyl)-6-(4-pyridyl)-4 (3H)-pyrimidones, 5-(4-fluorophenyl)-2-((3-hydrocinnamyl) amino)-6-(4-pyridyl)-4 (3H)-pyrimidones; 5-(4-fluorophenyl)-2-((1-methyl-3-phenyl propyl)-amino)-6-(4-pyridyl)-4 (3H)-pyrimidones; 5-(4-fluorophenyl)-2-((3-imidazolyl propyl group) amino)-6-(4-pyridyl)-4 (3H)-pyrimidones, 2-((S)-2-amino-3-phenyl propyl)-amino)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine, 2-((S)-2-amino-3-phenyl propyl)-amino)-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine; 2-((S)-2-N; N-dimethylamino-3-phenyl propyl)-amino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine, 2-((S)-2-N, N-dimethylamino-3-phenyl propyl)-amino)-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine; 2-((3-amino-3-phenyl propyl)-amino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine; 2-((3-amino-3-phenyl propyl)-amino)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine, 2-((3-amino-3-(2-fluorophenyl) propyl group)-amino)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine, 2-((3-amino-3-phenyl propyl)-amino)-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine; 2-((2-amino-2-methyl-3-phenyl propyl)-amino)-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine; 2-((3-hydroxyl-3-phenyl propyl)-amino)-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine, 2-(((2S, 3S)-3-amino-2-methyl-3-phenyl propyl)-amino)-4-(4-pyridyl)-5-(4-trifluoromethyl)-pyrimidine; 2-(((2R; 3R)-3-amino-2-methyl-3-phenyl propyl)-amino)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine, 2-((S)-3-benzyl diethylenediamine base)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine, 4-(4-pyridyl)-2-(((S)-tetrahydroisoquinoline-3-ylmethyl) amino)-5-(3-trifluoromethyl)-pyrimidine; 5-(3-aminomethyl phenyl)-4-(4-pyridyl)-2-(((S)-tetrahydroisoquinoline-3-ylmethyl) amino)-pyrimidine; 2-(((S)-2-N-isopropylamino-3-phenyl propyl) amino)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine, 2-(((S)-2-N-cyclohexyl amino-3-phenyl propyl)-amino)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine, 2-(((S)-2-N-isopropylamino-3-phenyl propyl)-amino)-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine; 2-(((S)-2-N-fourth amino-3-phenyl propyl)-amino)-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine; 2-(((S)-2-N-cyclohexyl amino-3-phenyl propyl)-amino)-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine, 5-(4-fluorophenyl)-2-(((S)-2-N-isopropylamino-3-phenyl propyl)-amino)-4-(4-pyridyl)-pyrimidine, 5-(4-fluorophenyl)-2-((3-N-isopropylamino-3-phenyl propyl)-amino)-4-(4-pyridyl)-pyrimidine; 2-(((S)-2-N-glycyl amino-3-phenyl propyl)-amino)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine; 2-(((S)-2-N-glycyl amino-3-phenyl propyl)-amino)-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine, 2-(((S)-2-amino-3-phenyl propyl)-amino)-5-(3-chloro-4-fluorophenyl)-4-(4-pyridyl)-pyrimidine, 2-(((S)-2-amino-3-phenyl propyl)-amino)-5-(3-fluorophenyl)-4-(4-pyridyl)-pyrimidine; 2-(((S)-2-amino-3-phenyl propyl)-amino)-5-(3-isopropyl phenyl)-4-(4-pyridyl)-pyrimidine; 5-(3-acetylamino phenyl)-2-(((S)-2-amino-3-phenyl propyl)-amino)-4-(4-pyridyl)-pyrimidine, 2-(((S)-2-amino-3-phenyl propyl)-amino)-5-(4-chloro-phenyl-)-4-(4-pyridyl)-pyrimidine, 2-(((S)-2-amino-3-phenyl propyl)-amino)-5-(benzothienyl)-4-(4-pyridyl)-pyrimidine; 2-(((S)-2-amino-3-phenyl propyl)-amino)-5-(2-naphthyl)-4-(4-pyridyl)-pyrimidine, 2-(((S)-2-amino-3-phenyl propyl)-amino)-5-(4-fluorophenyl)-6-(4-pyridyl)-4 (3H)-pyrimidones.
In monocyte test (LPS inductive TNF release), following compounds has activity, its IC 50Value is 5 μ M or lower: 2-(the amino ethylamino of 2-)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine; 2-(amino third amino of 3-)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine; 2-(benzylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine; 5-(4-fluorophenyl)-2-(2-phenyl ethylamino)-4-(4-pyridyl)-pyrimidine; 5-(4-fluorophenyl)-2-(N-methyl-N-(2-styroyl)-amino)-4-(4-pyridyl)-pyrimidine; 5-(4-fluorophenyl)-2-(2-hydroxyl-2-phenyl-ethyl) amino-4-(4-pyridyl)-pyrimidine; 5-(4-fluorophenyl)-2-(2-(4-hydroxy phenyl) ethylamino)-4-(4-pyridyl)-pyrimidine; 5-(4-fluorophenyl)-2-(2-(4-fluorophenyl) ethylamino)-4-(4-pyridyl)-pyrimidine; 5-(4-fluorophenyl)-2-(2-(2-fluorophenyl) ethylamino)-4-(4-pyridyl)-pyrimidine; 2-(2-(2-chloro-phenyl-) ethylamino))-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine; 2-(2-(4-chloro-phenyl-) ethylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine; (2-(2 for 2-; the 4-dichlorophenyl) ethylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine; 5-(4-fluorophenyl)-2-(3-hydrocinnamyl) amino-4-(4-pyridyl)-pyrimidine; 2-((S)-2-amino-3-phenyl propyl) amino-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine; 5-(4-fluorophenyl)-2-(2-phenyl amino ethylamino)-4-(4-pyridyl)-pyrimidine; 5-(4-fluorophenyl)-2-(3-imidazolyl propyl group)-amino-4-(4-pyridyl)-pyrimidine; 5-(4-fluorophenyl)-4-(4-pyridyl)-2-pyrrolidino-pyrimidine; 5-(4-fluorophenyl)-2-(1-piperazinyl)-4-(4-pyridyl)-pyrimidine; 5-(4-fluorophenyl)-2-(2-phenylethyl) sulfenyl-6-(4-pyridyl)-4 (3H)-pyrimidones; 5-(4-fluorophenyl)-2-(3-hydrocinnamyl) sulfenyl-6-(4-pyridyl)-4 (3H)-pyrimidones; 2-(2-(2-chloro-phenyl-) ethylamino)-5-(4-fluorophenyl)-6-(4-pyridyl)-4 (3H)-pyrimidones; 5-(4-fluorophenyl)-2-(3-hydrocinnamyl)-amino-6-(4-pyridyl)-4 (3H)-pyrimidones; 5-(4-fluorophenyl)-2-(1-methyl-3-phenyl propyl) amino-6-(4-pyridyl)-4 (3H)-pyrimidones; 2-(((S)-2-amino-3-phenyl propyl)-amino)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine; 2-(((S)-2-amino-3-phenyl propyl)-amino)-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine; 2-(((S)-2-N; N-dimethylamino-3-phenyl propyl)-amino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine; 2-(((S)-2-N; N-dimethylamino-3-phenyl propyl)-amino)-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine; 2-((3-amino-3-phenyl propyl)-amino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine; 2-((3-amino-3-phenyl propyl)-amino)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine; 2-((3-amino-3-(2-fluorophenyl) propyl group)-amino)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine; 2-((3-amino-3-phenyl propyl)-amino)-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine; 2-((2-amino-2-methyl-3-phenyl propyl)-amino)-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine; 2-((3-hydroxyl-3-phenyl propyl)-amino)-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine; 2-(((2S; 3S)-3-amino-2-methyl-3-phenyl propyl)-amino)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine; 2-(((2R; 3R)-3-amino-2-methyl-3-phenyl propyl)-amino)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine; 2-((S)-3-benzyl diethylenediamine base)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine; 4-(4-pyridyl)-2-(((S)-tetrahydroisoquinoline-3-ylmethyl) amino)-5-(3-trifluoromethyl)-pyrimidine; 5-(3-aminomethyl phenyl)-4-(4-pyridyl)-2-(((S)-tetrahydroisoquinoline-3-ylmethyl) amino)-pyrimidine; 2-(((S)-2-N-isopropylamino-3-phenyl propyl) amino)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine; 2-(((S)-2-N-cyclohexyl amino-3-phenyl propyl)-amino)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine; 2-(((S)-2-N-isopropylamino-3-phenyl propyl)-amino)-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine; 2-(((S)-2-N-fourth amino-3-phenyl propyl)-amino)-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine; 2-(((S)-2-N-cyclohexyl amino-3-phenyl propyl)-amino)-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine; 5-(4-fluorophenyl)-2-(((S)-2-N-isopropylamino-3-phenyl propyl)-amino)-4-(4-pyridyl)-pyrimidine; 5-(4-fluorophenyl)-2-((3-N-isopropylamino-3-phenyl propyl)-amino)-4-(4-pyridyl)-pyrimidine; 2-(((S)-2-N-glycyl amino-3-phenyl propyl)-amino)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine; 2-(((S)-2-N-glycyl amino-3-phenyl propyl)-amino)-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine; 2-(((S)-2-amino-3-phenyl propyl)-amino)-5-(3-chloro-4-fluorophenyl)-4-(4-pyridyl)-pyrimidine; 2-(((S)-2-amino-3-phenyl propyl)-amino)-5-(3-fluorophenyl)-4-(4-pyridyl)-pyrimidine; 2-(((S)-2-amino-3-phenyl propyl)-amino)-5-(3-isopropyl phenyl)-4-(4-pyridyl)-pyrimidine; 5-(3-acetylamino phenyl)-2-(((S)-2-amino-3-phenyl propyl)-amino)-4-(4-pyridyl)-pyrimidine; 2-(((S)-2-amino-3-phenyl propyl)-amino)-5-(4-chloro-phenyl-)-4-(4-pyridyl)-pyrimidine; 2-(((S)-2-amino-3-phenyl propyl)-amino)-5-(benzothienyl)-4-(4-pyridyl)-pyrimidine; 2-(((S)-2-amino-3-phenyl propyl)-amino)-5-(2-naphthyl)-4-(4-pyridyl)-pyrimidine, 2-(((S)-2-amino-3-phenyl propyl)-amino)-5-(4-fluorophenyl)-6-(4-pyridyl)-4 (3H) pyrimidone.
In inflammation, comprise in the animal model of carrageenin pawl oedema, collagen protein inductive sacroiliitis and adjuvant arthritis, for example carrageenin pawl edema model (C.A.Winter et al Proc.Soc.Exp.Biol.Med. (1962) vol 111, p 544; K.F.Swingle, in R.A.Scherrer and M.W.Whitehouse, Eds., Antiinflammatory Agents, Chemistry and Pharmacology, Vol.13-II, Academic, New York, 1974, p.33) and collagen protein inductive sacroiliitis (p 857 for people such as D.E.Trentham, J.Exp.Mad. (1977) vol.146; J.S.Courtenay, Nature (New Biol.) (1980), Vol 283, and p666), The compounds of this invention all can show anti-inflammatory property.Carry out with the CHO/hGLUR cell 125The I-hyperglycemic-glycogenolytic factor is in conjunction with screening
This test is disclosed among the WO97/16442, and the document is incorporated this paper into as a reference in full.Reagent
Described reagent can as described belowly prepare: (a) the fresh 1M phenanthrolene (Aldrich) (198.2mg/ml ethanol) of preparation; (b) the fresh 0.5M DTT (Sigma) of preparation; (c) protease inhibitor cocktail (1000X): every milliliter of DMSO contains 5mg leupeptin, 10mg benzamidine, 40mg bacitracin and 5mg Trypsin inhibitor SBTI and aliquots containig is descended storage in-20 ℃; (d) 250 μ M Porcine glucagons (Peninsula): the bottle of 0.5mg is dissolved in 575 μ l 0.1N acetate (for nonspecific binding test, the ultimate density that 1 μ l produces is 1 μ M) and stores aliquots containig down in-20 ℃; (e) test damping fluid: 20mM Tris (pH7.8), 1mM DTT and 3mM phenanthrolene; (f) the test damping fluid that contains 0.1%BSA (only is used to dilute mark; Ultimate density is 0.01% in the test): 10 μ l 10%BSA (hot deactivation) and 990 μ l test damping fluid; (g) 125The I-hyperglycemic-glycogenolytic factor (NEN, the acceptor level, 2200Ci/mmol): be diluted to 50,000cpm/25 μ l (ultimate density is about 50pM in the test) with the test damping fluid that contains BSA.The results of test CHO/hGLUR cell
1. remove substratum by merging in the flask, (Specialty Media, Inc.) each cleans once respectively to use PBS (Ca, no Mg) and Enzyme-free Dissociation Fluid then respectively.
2. add 10ml Enzyme-free Dissoc.Fluid and be incubated about 4 minutes down in 37 ℃.
3. make cellular segregation, development is got aliquots containig counting and with residuum under 1000rpm centrifugal 5 minutes.
With granular precipitation with 75000 cells/100 μ l resuspending in test is slow in the liquid.
With identical tested number, replace full cell with the film preparation of CHO/hGLUR cell.Based on every batch, measure the final protein concentration of film preparation.Test
In the presence of formula I compound, by measuring 125I-hyperglycemic-glycogenolytic factor bonded reduces can be determined hyperglycemic-glycogenolytic factor bonded restraining effect.The following combination of described reagent:
Compound/250 μ M 125I-CHO/hGLUR vehicle hyperglycemic-glycogenolytic factor pancreas hyperglycemia is a cell
Total binding+compound non-specific binding --/5μl??--??????????25μl???????100μl 5μl/--??--??????????25μl???????100μl --/5μl??1μl????????25μl???????100μl
In on the jolting device under 22 ℃ of 275rpm, mixture was hatched 60 minutes.Mixture cleans four times with ice-cooled 20mM Tris damping fluid (pH 7.8) through the GF/C strainer of wetting (0.5% polymine (PEI)) Innotech Harvester or Tomtec Harvester filtration in advance.Measure the radioactivity of strainer with γ-scintillometer.
So also show, but the combining of The compounds of this invention glucagon suppression and glucagon receptor.The cyclooxygenase-2 activity test
By being the alienation of THP-1 contact phorbol ester with people's monocyte, only express COX-1; Human osteosarcoma cell line 143B mainly expresses COX-2.The THP-1 cell is carried out routine cultivate in being supplemented with the RPMI perfect medium of 10%FBS, and human osteosarcoma cell (HOSC) cultivates in being supplemented with 10% N of tire serum minimum essential medium (MEM-10%FBS); All cells is containing 5%CO 2Under 37 ℃, hatch under the wet condition.The COX-1 test
Prepare the COX-1 test, the THP-1 cell is grown to fusion, split among the RPMI that contains 2%FBS and 10mM phorbol 12-myristinate 13-acetic ester (TPA) with 1: 3, and on the jolting device, hatched 48 hours, prevent that it from adhering to.Cell made granular precipitation and with 2.5 * 10 6The concentration resuspending of individual cell/ml is in Hank ' s Buffered Saline (HBS), with 5 * 10 5The density of individual cell/ml joins in the 96 hole culture dish.With HBS dilution test compound and join required ultimate density, cell was hatched 4 hours again.Add arachidonic acid, reaching ultimate density is 30mM, cell is hatched 20 minutes mensuration enzymic activity as described below under 37 ℃.The COX-2 test
For COX-2 test, inferior fusion HOSC carried out tryptic digestion and with 3 * 10 6Individual cell/ml resuspending is in the MEM-FBS that contains 1ng people IL-1b/ml, with every hole 3 * 10 4The density of individual cell is added in the 96 hole tissue culture wares, hatches on the jolting device 1 hour, so that cell is evenly distributed, static more subsequently hatching 2 hours makes it adhere to.Substitute substratum with the MEM that contains 2%FBS (MEM-2%FBS) and 1ng people IL-1b/ml then, described cell was hatched 18-22 hour.Substitute substratum with 190ml MEM subsequently, add the test compound of 10ml, reach desired concn and cell was hatched 4 hours with the HBS dilution.Remove supernatant liquor, substitute, cell was hatched 20 minutes mensuration enzymic activity as described below under 37 ℃ with containing the arachidonic MEM of 30mM.The determination of activity of COX
After arachidonic acid is hatched, by adding 1N HCl, make to react with 1N NaOH neutralization subsequently to stop, centrifugally go out granular cell debris.ELISA (Neogen#404110) with commercially available acquisition passes through to measure PGE 2Concentration is determined the activity of cyclooxygenase in HOSC and two kinds of cell conditioned medium liquid of THP-1.Use PGE 2Typical curve is calibrated, and makes standard control with the COX-1 and the cox 2 inhibitor of commercially available acquisition.
Therefore, compound of the present invention or pharmaceutical composition can be used for prevention and treatment rheumatoid arthritis; Paget's disease; Osteoporosis; Multiple myeloma; Uveitis; Acute and chronic lymphocytic leukemia; Pancreatic; Osteoarthritis; Rheumatoid osteomyelitis; Urarthritis; Enteritis; Adult respiratory distress syndrome (ARDS); Psoriasis; Crohn disease; Rhinallergosis; Ulcerative colitis; Irritated; Contact dermatitis; Asthma; Muscle deterioration; Emaciation; Reiter syndrome; I type and type ii diabetes; Bone resorption disease; Graft-vs-host reaction; The ischemia reperfusion damage; Atherosclerosis; Cerebral trauma; Presenile dementia; Apoplexy; Myocardial infarction; Multiple sclerosis; Cerebral malaria; Sepsis; Septic shock; Toxic shock syndrome; The myalgia that causes because of infection, and fever.To HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, simplexvirus (comprising HSV-1, HSV-2) and the zoster of restraining effect or the glucagon antagonist sensitivity of TNF-α and/or IL-1, Compounds and methods for of the present invention also has good action for all.
Compound of the present invention also has the pain relieving characteristic and can be used for treating pain disease, for example hyperpathia that causes because of IL-1 is excessive.Compound of the present invention also can comprise that cyclooxygenase (WO96/03387 incorporates this paper into as a reference in full) stops the generation of prostaglandin(PG) by suppressing the enzyme in people's arachidonic acid/prostaglandin(PG) action path.
Because compound of the present invention can reduce combining of the concentration of TNF-α and IL-1 or glucagon suppression and its acceptor, so they also can be used in the test method of the physiological Study relevant with this class effect of blocking-up.
The method of the invention comprises that giving needs to reduce curee's (optimum is chosen for animal, preferred mammal) of TNF-α, IL-1, IL-6 and/or IL-8 level and/or lowering blood glucose level and/or may suffer from rheumatoid arthritis; The Paget pain; Osteoporosis; Multiple myeloma; Uveitis; Acute and chronic lymphocytic leukemia; Pancreatic; Osteoarthritis; Rheumatoid osteomyelitis; Urarthritis; Enteritis; Adult respiratory distress syndrome (ARDS); Psoriasis; Crohn disease; Rhinallergosis; Ulcerative colitis; Irritated; Contact dermatitis; Asthma; Muscle deterioration; Emaciation; Reiter syndrome; I type and type ii diabetes; Bone resorption disease; Graft-vs-host reaction; Presenile dementia; Apoplexy; Myocardial infarction; The ischemia reperfusion damage; Atherosclerosis; Cerebral trauma; Multiple sclerosis; Cerebral malaria; Sepsis; Septic shock; Toxic shock syndrome; The myalgia that causes because of infection, curee with fever, perhaps the curee of infected by HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, simplexvirus (comprising HSV-1, HSV-2) and zoster uses The compounds of this invention, its pharmaceutically acceptable salt, perhaps pharmaceutical composition of significant quantity.
In addition, the present invention also comprises The compounds of this invention or its pharmaceutically acceptable salt disease in the acute or chronic TNF-α of preparation treatment, IL-1, IL-6 and/or IL-8 mediation, comprises the application in the medicine of above-mentioned disease.And compound of the present invention also can be used for preparing anodyne and for example hyperalgesic medicine of treatment pain disease.Compound of the present invention also can be used for preparing by suppressing the medicine of enzyme to stop arachidonic acid to produce in people's arachidonic acid/prostaglandin(PG) action path.
In addition, the present invention also provides a kind of pharmaceutical composition, said composition comprises effective reduction TNF-α, IL-1, IL-6 and/or the amount of IL-8 and/or The compounds of this invention and the pharmaceutically acceptable carrier or the thinner of effective lowering blood glucose level amount, and also can contain other active ingredients if desired.Compound of the present invention can be used preferably in the suitable mode of pharmaceutical composition, and with dose therapeutically effective by any suitable mode.The dose therapeutically effective of compound of the present invention need stop advancing of disease or prevent and the tissue injury of described disease-related that this is that those of ordinary skills determine easily with ordinary method.
For TNF-α, IL-1, IL-6 and the disease of IL-8 mediation and/or the treatment of hyperglycemia, can be with the unit dosage that contains acceptable carrier on the conventional medicine, adjuvant and vehicle by oral, non-enteron aisle, by suction, rectum or the topical application compound of the present invention of spraying.That the non-enteron aisle of term used herein comprises is subcutaneous, in the intravenously, intramuscular, breastbone, infusion methods or intraperitoneal.
Dosage range with the disease of compound of the present invention and/or present composition treatment TNF-α, IL-1, IL-6 and IL-8 mediation and/or hyperglycemia can be based on various different factors, and these factors comprise type, patient's age, body weight, sex, the physical appearance of disease, severity, application method and the used specific compound of disease.Like this, described dosage range can change in wide range, but can determine with ordinary method usually.The dosage rule that can be used for all application methodes described herein is the about 0.01mg-30mg of per kilogram of body weight every day, preferably about 0.1mg-10mg/kg, more preferably from about 0.25mg-1mg/kg.
According to the pharmaceutics ordinary method, pharmaceutical active compounds of the present invention can be processed, make and be suitable for the pharmaceutical preparation that the patient comprises that people and other animals are used.
When Orally administered, described pharmaceutical composition can be for example capsule, tablet, suspension or liquor.Described pharmaceutical composition preferred preparation becomes to contain the unit dosage of given described active ingredient.For example, they can contain the 1-2000mg that has an appointment, preferably about 1-500mg, more preferably from about 5-150mg active ingredient.For people or other animals, suitable per daily dose can change according to patient's situation and other factors, but can determine with ordinary method once more.
Described active ingredient can also be used through injection to contain the composition forms that appropriate carrier comprises physiological saline, glucose or water.The per daily dose scope that non-enteron aisle is used is about 0.1-30mg/kg of TBW, preferably about 0.1-10mg/kg, and 0.25-1mg/kg more preferably from about.
Injection for example aseptic injection aqua or oiliness suspension agent can be prepared according to known method with suitable dispersion agent or wetting agent and suspension agent.Described aseptic injection can also be injection solution or the suspension that nontoxic non-enteron aisle is used acceptable diluent or solvent, for example 1,3 butylene glycol solution.The acceptable carrier that can Gong use and solvent are water, normal saline solution and isotonic sodium chlorrde solution.In addition, aseptic expressed oil can be used as solvent or suspension medium usually.For this reason, the expressed oil of any gentleness all can use, and comprises synthetic list-or two glyceryl ester.In addition, in injection, also can use for example oleic acid of lipid acid.
The suppository of rectal application can be by will described medicine being solid down with typical temperature, and be that for example theobroma oil and polyoxyethylene glycol are mixed with for liquid and the non-stimulated vehicle that suits that therefore fusion discharges described medicine simultaneously in rectum at internal rectum.
The dosage that is suitable for topical application of active ingredient of the present invention is 0.1mg-150mg, and use 1-4 every day, preferably once or twice.During topical application, the 0.001-10%w/w that described active ingredient accounts for described preparation is 1%-2% (weight ratio) for example, although its proportion can preferably be not more than 5%w/w greater than 10%w/w, and more preferably accounts for the 0.1%-01% of described preparation.
The preparation that is suitable for topical application comprises that the liquid or the semiliquid (for example liniment, lotion, ointment, emulsion or paste) that are suitable for transdermal flux are suitable for the drops that eye, ear or nose are used.
During medication, compound of the present invention mixes with the suitable adjuvant of described application method with one or more usually.Described compound can mix with lactose, sucrose, starch, paraffinic acid cellulose ester, stearic acid, talcum, Magnesium Stearate, magnesium dioxide, phosphoric acid and vitriolic sodium salt and calcium salt, gum arabic, gelatin, sodiun alginate, polyvinylpyrrolidone and/or polyvinyl alcohol, and can be made into tablet or the capsule that routine is used.In addition, The compounds of this invention dissolves in physiological saline, water, polyoxyethylene glycol, propylene glycol, ethanol, Semen Maydis oil, peanut oil, cotton seed oil, sesame oil, tragakanta and/or various damping fluid.Other adjuvants and application method are that pharmaceutical field is known.Described carrier or thinner can comprise slow-release material, for example separately or with wax blended glyceryl monostearate or stearic acid two glyceryl ester, other materials perhaps well known in the art.
Described pharmaceutical composition can be mixed with solid form (comprising granule, pulvis or suppository) or liquid form (for example solution, suspension or emulsion).Described pharmaceutical composition can carry out conventional medicine operational example as sterilizing and/or can containing conventional adjuvant, for example sanitas, stablizer, wetting agent, emulsifying agent, damping fluid etc.
Be suitable for oral solid dosage and can comprise capsule, tablet, pill, pulvis and granule.In this type of solid dosage, described active compound can for example sucrose, lactose or starch mix with at least a inert diluent.Under normal conditions, other materials except inert diluent, this type of acute for example lubricant such as Magnesium Stearate of also can containing.Under the situation of capsule, tablet and pill, described formulation also can contain buffer reagent.Tablet and pill also can be used enteric coating again.
Be suitable for oral liquid dosage form and can comprise that containing this area uses inert diluent for example pharmaceutically acceptable emulsion, solution, suspension, syrup and the elixir of water always.This based composition also can contain adjuvant for example wetting agent, sweeting agent, seasonings and spices.
The compounds of this invention can have one or more unsymmetrical carbons and can with the optical isomer form with and racemize or non-racemic mixture form exist.According to ordinary method, by resolving racemic mixtures, for example by forming diastereoisomeric salt, passing through to obtain described optical isomer with optics active acid or alkaline purification.The example of suitable acid is tartrate, diacetyl tartrate, dibenzoyl tartaric acid, dimethylbenzene acyl group tartrate and camphorsulfonic acid, then by the described non-enantiomer mixture of Crystallization Separation, subsequently by the described optical active alkali that dissociates in this salt.The another kind of method of separating optical isomeric body comprises, utilizes the chiral chromatographic column of optimal selection, with enantiomer separation to greatest extent.Another kind of operational method comprises, by with The compounds of this invention and optically pure acid-respons, the covalency diastereomer molecule of synthetic inactive form or optical purity isocyanic ester form, described synthetic diastereomer can for example chromatography, distillation method, crystallization process or subliming method be separated through conventional method, hydrolysis then discharges the compound of described enantiomeric pure.Can obtain optically active compound of the present invention equally with the optics activated feedstock.These isomer can be the forms of free acid, free alkali, ester or salt.
Compound of the present invention can use with the form of the salt that generates with mineral acid or organic acid.Described salt comprises, but be not limited only to following salt: acetate, adipate, alginate, Citrate trianion, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, camphorate, camsilate, digluconate, cyclopentane propionate, dodecane sulfonate, esilate, glucoheptose salt, glycerophosphate, Hemisulphate, enanthate, hexanoate, fumarate, hydrochloride, hydrobromate, hydriodate, 2-hydroxyl-esilate, lactic acid salt, maleate, mesylate, nicotinate, the 2-naphthalenesulfonate, oxalate, palmitate, tartaric acid salt, persulphate, 2-phenylpropionic acid salt, picrate, Pivalate, propionic salt, succinate, tartrate, thiocyanate-, tosylate, mesylate and undecane hydrochlorate.In addition, alkaline nitrogen-containing group can be used quaternized as the reagent of elementary alkyl halide, for example the muriate of methyl, ethyl, propyl group and butyl, bromide and iodide; Sulfuric acid dialkyl such as methyl-sulfate, diethyl ester, dibutylester and diamyl ester, long-chain halogenide be decyl, lauryl, myristyl and stearyl fluorochemical, bromide and iodide for example, aralkyl halide such as benzyl, styroyl bromination thing etc.Like this, can obtain water-soluble or oily molten or dispersible products.
The example that can be used for forming the acid of pharmaceutically acceptable acid salt comprises the mineral acid of example hydrochloric acid, sulfuric acid and phosphoric acid and as the organic acid of oxalic acid, toxilic acid, succsinic acid and citric acid.Other examples comprise the salt that forms with basic metal or alkaline-earth metal for example sodium, potassium, calcium or magnesium salts or the salt that forms with organic bases.
When compound of the present invention was used as active agent formulation, they can also be used in combination with one or more The compounds of this invention or other preparations.When using, described therapeutical agent can be mixed with can be at one time or the independently composition of different time administration, and perhaps described therapeutical agent can single composition forms administration.
Above only be used to illustrate the present invention, and unintentionally the present invention be limited on the described compound.Conspicuous for those skilled in the art variation and change all are considered in the scope of the invention and spirit of claim definition.
By foregoing description, those skilled in the art can easily determine essential feature of the present invention, and without departing from the spirit and scope of the present invention, can make various variations and modification to the present invention, so that itself and various service condition and condition adapt.

Claims (31)

1. following formula: compound or its pharmaceutically acceptable salt;
Figure A9718156300021
R wherein 1And R 2Be independently of one another-Z-Y, condition be (1) each-aryl, heteroaryl, cycloalkyl and heterocyclic radical among the Z-Y add up to 0-3; (2) R 1And R 2In aryl, heteroaryl, cycloalkyl and heterocyclic radical group add up to 0-4;
Wherein each Z is independently
(1) chemical bond;
(2) alkyl, the alkenyl or alkynyl that is replaced arbitrarily by following group: (a) 1-3 group that is selected from amino, alkylamino, dialkylamino, alkanoyl amido, alkoxycarbonyl amido, alkyl sulfonyl amino, hydroxyl, alkoxyl group, alkylthio or halogen, (b) 1-2 group that is selected from heterocyclic radical, aryl or heteroaryl, it can be replaced arbitrarily by 1-3 group that is selected from amino, alkylamino, dialkylamino, alkanoyl amido, alkoxycarbonyl amido, alkyl sulfonyl amino, hydroxyl, alkoxyl group, alkylthio, halogen, alkyl or haloalkyl;
(3) by 1-3 any heterocyclic radical that replaces of group that is selected from amino, alkylamino, dialkylamino, alkanoyl amido, alkoxycarbonyl amido, alkyl sulfonyl amino, hydroxyl, alkoxyl group, alkylthio, alkyl or haloalkyl; Perhaps
(4) by 1-3 any aryl or the heteroaryl that replaces of group that is selected from amino, alkylamino, dialkylamino, alkanoyl amido, alkoxycarbonyl amido, alkyl sulfonyl amino, hydroxyl, alkoxyl group, alkylthio, cyano group, halogen, alkyl or haloalkyl;
Each Y is independently
(1) hydrogen;
(2) halogen or nitro;
(3)-C (O)-R 20Or-C (NR 5)-NR 5R 21Group;
(4)-OR 21,-O-C (O)-R 21,-O-C (O)-NR 5R 21Or-O-C (O)-NR 22-S (O) 2-R 20Group;
(5)-SR 21,-S (O)-R 20,-S (O) 2-R 20,-S (O) 2-NR 5R 21,-S (O) 2-NR 22-C (O)-R 21,-S (O) 2-NR 22-C (O)-OR 20Or-S (O) 2-NR 22-C (O)-NR 5R 21Group; Or
(6)-NR 5R 21,-NR 22-C (O)-R 21,-NR 22-C (O)-OR 20,-NR 22-C (O)-NR 5R 21,-NR 22-C (NR 5)-NR 5R 21,-NR 22-S (O) 2-R 20Or-NR 22-S (O) 2-NR 5R 21Group;
Each R wherein 5Be independently
(1) hydrogen;
(2) by 1-3 be selected from amino, alkylamino, dialkylamino, hydroxyl, alkoxyl group, alkylthio ,-SO 3Alkyl, alkenyl or alkynyl that the group of H or halogen replaces arbitrarily; Perhaps
(3) by 1-3 any aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclic radical, Heterocyclylalkyl, cycloalkyl or the cycloalkylalkyl that replaces of group that is selected from amino, alkylamino, dialkylamino, hydroxyl, alkoxyl group, alkylthio, alkyl or haloalkyl;
Each R wherein 20Be independently
(1) is selected from the alkyl that following group replaces arbitrarily by 1-3, alkenyl or alkynyl: amino, alkylamino, dialkylamino, alkanoyl amido, alkoxycarbonyl amido, N-(carbalkoxy)-N-(alkyl) amino, amino carbonyl amino, alkyl sulfonyl amino, hydroxyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, halogen or aralkoxy, aromatic alkylthio, the aralkyl alkylsulfonyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl groups, it can be selected from amino by 1-3, alkylamino, dialkylamino, alkanoyl amido, alkoxycarbonyl amido, alkyl sulfonyl amino, alkanoyl, hydroxyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, halogen, the group of alkyl or haloalkyl replaces arbitrarily;
(2) by 1-3 any heterocyclic radical that replaces of group that is selected from amino, alkylamino, dialkylamino, alkanoyl amido, alkoxycarbonyl amido, alkyl sulfonyl amino, hydroxyl, alkoxyl group, alkylthio, alkyl or haloalkyl; Perhaps
(3) by 1-3 any aryl or the heteroaryl that replaces of group that is selected from amino, alkylamino, dialkylamino, alkanoyl amido, alkoxycarbonyl amido, alkyl sulfonyl amino, carbalkoxy, hydroxyl, alkoxyl group, alkylthio, cyano group, halogen, azido-, alkyl or haloalkyl;
Each R 21Be hydrogen or R independently 20
Each R 22Be independently
(1) hydrogen;
(2) be selected from the alkyl that the group of heterocyclic radical, aryl or heteroaryl replaces arbitrarily, described substituting group can be replaced arbitrarily by 1-3 group that is selected from amino, alkylamino, dialkylamino, alkanoyl amido, alkoxycarbonyl amido, alkyl sulfonyl amino, hydroxyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, cyano group, halogen, alkyl or haloalkyl; Perhaps
(3) by 1-3 any heterocyclic radical, aryl or the heteroaryl that replaces of group that is selected from amino, alkylamino, dialkylamino, alkanoyl amido, alkoxycarbonyl amido, alkyl sulfonyl amino, hydroxyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, cyano group, halogen, alkyl or haloalkyl; Condition is, when Z is that chemical bond and Y are-NR 22-C (O)-NH 2The time, R 22It or not the aryl that replaces arbitrarily; With
R 11And R 12Be selected from aryl and the heteroaryl that following group replaces arbitrarily by 1-3 independently of one another
(1)R 30；
(2) halogen or cyano group;
(3)-C (O)-R 30,-C (O)-OR 29,-C (O)-NR 31R 32Or-C (NR 31)-NR 31R 32Group;
(4)-OR 29,-O-C (O)-R 29,-O-C (O)-NR 31R 32Or-O-C (O)-NR 33-S (O) 2-R 30Group;
(5)-SR 29,-S (O)-R 30,-S (O) 2-R 30,-S (O) 2-NR 31R 32,-S (O) 2-NR 33-C (O)-R 30,-S (O) 2-NR 33-C (O)-OR 30Or-S (O) 2-NR 33-C (O)-NR 31R 32Group; Or
(6)-NR 31R 32,-NR 33-C (O)-R 29,-NR 33-C (O)-OR 30,-NR 33-C (O)-NR 31R 32,-NR 33-C (NR 31)-NR 31R 32,-NR 33-S (O) 2-R 30Or-NR 33-S (O) 2-NR 31R 32Group;
Condition is (1) R 11Not by any 4-pyridyl, 4-pyrimidyl, 4-quinolyl or the 6-isoquinolyl that replaces of 1-2 substituting group; (2) at R 11And R 12Aryl, heteroaryl, cycloalkyl and the heterocyclic radical that go up to replace separately add up to 0-1;
Each R wherein 30Be independently
(1) is selected from alkyl, the alkenyl or alkynyl that following group replaces arbitrarily :-NR by 1-3 31R 31,-CO 2R 23, hydroxyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, cyano group, halogen or aralkoxy, aromatic alkylthio, aralkyl alkylsulfonyl, heterocyclic radical, aryl or heteroaryl groups, it can be replaced arbitrarily by 1-3 group that is selected from amino, alkylamino, dialkylamino, alkanoyl amido, alkoxycarbonyl amido, alkyl sulfonyl amino, hydroxyl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, cyano group, halogen, alkyl or haloalkyl;
(2) by 1-3 any heterocyclic radical that replaces of group that is selected from amino, alkylamino, dialkylamino, alkanoyl amido, alkoxycarbonyl amido, alkyl sulfonyl amino, hydroxyl, alkoxyl group, alkylthio, cyano group, alkyl or haloalkyl; Perhaps
(3) by 1-3 any aryl or the heteroaryl that replaces of group that is selected from amino, alkylamino, dialkylamino, alkanoyl amido, alkoxycarbonyl amido, alkyl sulfonyl amino, hydroxyl, alkoxyl group, alkylthio, cyano group, halogen, alkyl or haloalkyl;
Each R 29Be hydrogen or R independently 30
Each R 31And R 32Be independently of one another
(1) hydrogen;
(2) alkyl that is replaced arbitrarily by cycloalkyl, aryl, heterocyclic radical or heteroaryl groups, described substituting group can be replaced arbitrarily by 1-3 group that is selected from amino, alkylamino, dialkylamino, alkanoyl amido, alkoxycarbonyl amido, alkyl sulfonyl amino, hydroxyl, alkoxyl group, alkylthio, cyano group, alkyl or haloalkyl; Perhaps
(3) by 1-3 any aryl, heteroaryl, heterocyclic radical or the cycloalkyl that replaces of group that is selected from amino, alkylamino, dialkylamino, alkanoyl amido, alkoxycarbonyl amido, alkyl sulfonyl amino, hydroxyl, alkoxyl group, alkylthio, cyano group, alkyl or haloalkyl; With
Each R wherein 33Be independently
(1) hydrogen; Perhaps
(2) be selected from the alkyl that the group of heterocyclic radical, aryl or heteroaryl replaces arbitrarily, described substituting group can be replaced arbitrarily by 1-3 group that is selected from amino, alkylamino, dialkylamino, alkanoyl amido, alkoxycarbonyl amido, alkyl sulfonyl amino, hydroxyl, alkoxyl group, alkylthio, cyano group, alkyl or haloalkyl;
Condition is that (1) works as R 1And R 12Identical and be contain heteroatoms that 1-3 is independently selected from N, S and O, can be at random with phenyl ring condensed 5-or 6-unit ring the time, R 11Be can be by halogen, C 1-C 6Alkyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, hydroxyl, amino, C 1-C 4The phenyl or naphthyl that alkylamino or dialkylamino replace arbitrarily, perhaps R 11Be to contain heteroatoms that 1-3 is independently selected from N, S and O, can at random condense and can be by C with phenyl ring 1-C 6When 5-that alkyl replaces arbitrarily or 6-unit ring, R 2Not OH or NH 2(2) work as R 2Be H, R 11Be phenyl and R 12When being phenyl or 4-pyridyl, R 1Not H, methyl or amino; (3) work as R 2Be H, R 11Be 2-aminomethyl phenyl and R 12When being the 2-pyridyl, R 1It or not n-propyl; (4) work as R 11And R 12During each any naturally substituted phenyl, R 1It or not any substituted 2-pyridyl.
2. the described compound of claim 1 or its pharmaceutically acceptable salt, wherein
R wherein 1And R 2Be independently of one another-Z-Y, condition be (1) each-aryl, heteroaryl, cycloalkyl and heterocyclic radical among the Z-Y add up to 0-3; (2) R 1And R 2In aryl, heteroaryl, cycloalkyl and heterocyclic radical group add up to 0-4;
Each Z is independently
(1) chemical bond;
(2) C that is replaced arbitrarily by following group 1-C 8Alkyl, C 2-C 8Thiazolinyl or C 2-C 8Alkynyl: (a) 1-3 is selected from amino, C 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4The group of alkylthio or halogen and (b) 1-2 be selected from the group of heterocyclic radical, aryl or heteroaryl, it can be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, halogen, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4The group of haloalkyl replaces arbitrarily;
(3) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4The heterocyclic radical that the group of haloalkyl replaces arbitrarily; Perhaps
(4) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, halogen, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4Aryl or heteroaryl that the group of haloalkyl replaces arbitrarily;
Each Y is independently
(1) hydrogen;
(2) halogen or nitro;
(3)-C (O)-R 20Or-C (NR 5)-NR 5R 21Group;
(4)-OR 21,-O-C (O)-R 21,-O-C (O)-NR 5R 21Or-O-C (O)-NR 22-S (O) 2-R 20Group;
(5)-SR 21,-S (O)-R 20,-S (O) 2-R 20,-S (O) 2-NR 5R 21,-S (O) 2-NR 22-C (O)-R 21,-S (O) 2-NR 22-C (O)-OR 20Or-S (O) 2-NR 22-C (O)-NR 5R 21Group; Or
(6)-NR 5R 21,-NR 22-C (O)-R 21,-NR 22-C (O)-OR 20,-NR 22-C (O)-NR 5R 21,-NR 22-C (NR 5)-NR 5R 21,-NR 22-S (O) 2-R 20Or-NR 22-S (O) 2-NR 5R 21Group;
Each R 5Be independently
(1) hydrogen;
(2) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio ,-SO 3The C that the group of H or halogen replaces arbitrarily 1-C 8Alkyl, C 2-C 8Thiazolinyl or C 2-C 8Alkynyl; Perhaps
(3) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4Aryl, heteroaryl, aryl-C that the group of haloalkyl replaces arbitrarily 1-C 4-alkyl, heteroaryl-C 1-C 4-alkyl, heterocyclic radical, heterocyclic radical-C 1-C 4-alkyl, C 3-C 8Cycloalkyl or C 3-C 8-cycloalkyl-C 1-C 4-alkyl;
Each R 20Be independently
(1) is selected from the C that following group replaces arbitrarily by 1-3 1-C 8Alkyl, C 2-C 8Thiazolinyl or C 2-C 8Alkynyl: amino, C 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, N-((C 1-C 4Alkoxyl group) carbonyl)-N-(C 1-C 4Alkyl) amino, amino carbonyl amino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl sulphinyl, C 1-C 4Alkyl sulphonyl, halogen or aryl-C 1-C 4-alkoxyl group, aryl-C 1-C 4-alkylthio, aryl-C 1-C 4-alkyl sulphonyl, C 3-C 8Cycloalkyl, heterocyclic radical, aryl or heteroaryl groups, it can be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, C 1-C 5Alkanoyl, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl sulphinyl, C 1-C 4Alkyl sulphonyl, halogen, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4The group of haloalkyl replaces arbitrarily;
(2) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4The heterocyclic radical that the group of haloalkyl replaces arbitrarily; Perhaps
(3) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, (C 1-C 4Alkoxyl group) carbonyl, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, halogen, azido-, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4Aryl or heteroaryl that the group of haloalkyl replaces arbitrarily;
Each R 21Be hydrogen or R independently 20
Each R 22Be independently
(1) hydrogen;
(2) be selected from the C that the group of heterocyclic radical, aryl or heteroaryl replaces arbitrarily 1-C 4Alkyl, described substituting group can be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl sulphinyl, C 1-C 4Alkyl sulphonyl, cyano group, halogen, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4The group of haloalkyl replaces arbitrarily; Perhaps
(3) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl sulphinyl, C 1-C 4Alkyl sulphonyl, cyano group, halogen, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4Heterocyclic radical, aryl or heteroaryl that the group of haloalkyl replaces arbitrarily; Condition is, when Z is that chemical bond and Y are-NR 22-C (O)-NH 2The time, R 22It or not any substituted aryl;
R 11And R 12Be selected from aryl or the heteroaryl that following group replaces arbitrarily by 1-3 independently of one another
(1)R 30；
(2) halogen or cyano group;
(3)-C (O)-R 30,-C (O)-OR 29,-C (O)-NR 31R 32Or-C (NR 31)-NR 31R 32Group;
(4)-OR 29,-O-C (O)-R 29,-O-C (O)-NR 31R 32Or-O-C (O)-NR 33-S (O) 2-R 30Group;
(5)-SR 29,-S (O)-R 30,-S (O) 2-R 30,-S (O) 2-NR 31R 32,-S (O) 2-NR 33-C (O)-R 30,-S (O) 2-NR 33-C (O)-OR 30Or-S (O) 2-NR 33-C (O)-NR 31R 32Group; Or
(6)-NR 31R 32,-NR 33-C (O)-R 29,-NR 33-C (O)-OR 30,-NR 33-C (O)-NR 31R 32,-NR 33-C (NR 31)-NR 31R 32,-NR 33-S (O) 2-R 30Or-NR 33-S (O) 2-NR 31R 32Group;
Condition is (1) R 11Not by any 4-pyridyl, 4-pyrimidyl, 4-quinolyl or the 6-isoquinolyl that replaces of 1-2 substituting group; (2) at R 11And R 12Aryl, heteroaryl, cycloalkyl and the heterocyclic radical that go up to replace separately add up to 0-1;
Each R 30Be independently
(1) is selected from the C that following group replaces arbitrarily by 1-3 1-C 4Alkyl, C 2-C 4Thiazolinyl or C 2-C 4Alkynyl :-NR 31R 31,-CO 2R 23, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl sulphinyl, C 1-C 4Alkyl sulphonyl, cyano group, halogen or aryl-C 1-C 4-alkoxyl group, aryl-C 1-C 4-alkylthio, aryl-C 1-C 4-alkyl sulphonyl, heterocyclic radical, aryl or heteroaryl groups, it can be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl sulphinyl, C 1-C 4Alkyl sulphonyl, cyano group, halogen, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4The group of haloalkyl replaces arbitrarily;
(2) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4The heterocyclic radical that the group of haloalkyl replaces arbitrarily; Perhaps
(3) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, halogen, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4Aryl or heteroaryl that the group of haloalkyl replaces arbitrarily;
Each R 29Be hydrogen or R independently 30
Each R 31And R 32Be independently of one another
(1) hydrogen;
(2) by C 3-C 8The C that cycloalkyl, aryl, heterocyclic radical or heteroaryl groups replace arbitrarily 1-C 4Alkyl, described substituting group is selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4The group of haloalkyl replaces arbitrarily; Perhaps
(3) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4Aryl, heteroaryl, heterocyclic radical or C that the group of haloalkyl replaces arbitrarily 3-C 8Cycloalkyl;
Each R 33Be independently
(1) hydrogen; Perhaps
(2) be selected from the C that the group of heterocyclic radical, aryl or heteroaryl replaces arbitrarily 1-C 4Alkyl, described substituting group is selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4The group of haloalkyl replaces arbitrarily;
Wherein heterocyclic radical is that wherein 1-3 annular atoms is oxygen, sulphur or nitrogen heteroatom, and each ring is monocycle or dicyclo saturated heterocyclic system of 5-8 unit ring, and at random part is unsaturated or condense with phenyl ring and at random by 1-2 oxo or thio group replacement for it; Aryl is a phenyl or naphthyl; With heteroaryl be that wherein 1-3 annular atoms is oxygen, sulphur or nitrogen heteroatom, each ring is monocycle or bicyclic aromatic heterocycle system of 5-6 unit ring, its can at random condense with phenyl ring or with saturated C 3-C 4-carbocyclic fused.
3. the described compound of claim 2 or its pharmaceutically acceptable salt, wherein
Each Z is independently
(1) chemical bond;
(2) C that is replaced arbitrarily by following group 1-C 8Alkyl, C 2-C 8Thiazolinyl or C 2-C 8Alkynyl: (a) 1-3 is selected from amino, C 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4The group of alkylthio or halogen and (b) 1-2 be selected from the group of heterocyclic radical, aryl or heteroaryl, it can be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, halogen, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4The group of haloalkyl replaces arbitrarily;
(3) be selected from amino, C by 1-2 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4The heterocyclic radical that the group of haloalkyl replaces arbitrarily; Perhaps
(4) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, halogen, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4Aryl or heteroaryl that the group of haloalkyl replaces arbitrarily;
Each R 5Be independently
(1) hydrogen;
(2) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio ,-SO 3The C that the group of H or halogen replaces arbitrarily 1-C 4Alkyl, C 2-C 5Thiazolinyl or C 2-C 5Alkynyl; Perhaps
(3) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4Aryl, heteroaryl, aryl-C that the group of haloalkyl replaces arbitrarily 1-C 4-alkyl, heteroaryl-C 1-C 4-alkyl, heterocyclic radical, heterocyclic radical-C 1-C 4-alkyl, C 3-C 8Cycloalkyl or C 3-C 8-cycloalkyl-C 1-C 4-alkyl;
Each R 20Be independently
(1) is selected from the C that following group replaces arbitrarily by 1-3 1-C 8Alkyl, C 2-C 5Thiazolinyl or C 2-C 5Alkynyl: amino, C 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, N-((C 1-C 4Alkoxyl group) carbonyl)-N-(C 1-C 4Alkyl) amino, amino carbonyl amino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl sulphinyl, C 1-C 4Alkyl sulphonyl, halogen or aryl-C 1-C 4-alkoxyl group, aryl-C 1-C 4-alkylthio, aryl-C 1-C 4-alkyl sulphonyl, C 3-C 8Cycloalkyl, heterocyclic radical, aryl or heteroaryl groups, it can be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, C 1-C 5Alkanoyl, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl sulphinyl, C 1-C 4Alkyl sulphonyl, halogen, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4The group of haloalkyl replaces arbitrarily;
(2) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4The heterocyclic radical that the group of haloalkyl replaces arbitrarily; Perhaps
(3) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, (C 1-C 4Alkoxyl group) carbonyl, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, halogen, azido-, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4Aryl or heteroaryl that the group of haloalkyl replaces arbitrarily;
Each R 21Be hydrogen or R independently 20
Each R 30Be independently
(1) is selected from the C that following group replaces arbitrarily by 1-3 1-C 4Alkyl:
(a)-NR 31R 31；
(b) C 1-C 4-alkoxy carbonyl or carbobenzoxy or phenyl methoxycarbonyl, it can be selected from amino, alkylamino, two-(C by 1-3 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, halogen, C 1-C 4The group of alkyl or trifluoromethyl replaces arbitrarily; Perhaps
(c) hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, perhaps phenyl-C 1-C 4-alkoxyl group, phenyl-C 1-C 4-alkylthio, heterocyclic radical, phenyl or heteroaryl groups, it can be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, halogen, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4The group of haloalkyl replaces arbitrarily;
(2) contain the C of 1-3 halogen 1-C 4Haloalkyl; Perhaps
(3) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, halogen, C 1-C 4Aryl or heteroaryl that the group of alkyl or trifluoromethyl replaces arbitrarily;
Each R 29Be hydrogen or R independently 30
Each R 31Be independently
(1) hydrogen; Perhaps
(2) by phenyl or any C that replaces of heteroaryl groups 1-C 4Alkyl, described substituting group can be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, C 1-C 4The group of alkyl or trifluoromethyl replaces arbitrarily; With
Each R 32Be independently
(1) hydrogen;
(2) by C 3-C 6The C that cycloalkyl, aryl, heterocyclic radical or heteroaryl groups replace arbitrarily 1-C 4Alkyl, described substituting group can be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4The group of haloalkyl replaces arbitrarily; Perhaps
(3) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 4Aryl, heteroaryl, heterocyclic radical or C that the group of haloalkyl replaces arbitrarily 3-C 6Cycloalkyl;
Each R 33Be hydrogen or C independently 1-C 4Alkyl.
4. the described compound of claim 3 or its pharmaceutically acceptable salt, wherein
R 1Be-Z-Y that condition is (1) R 1In aryl, heteroaryl, cycloalkyl and heterocyclic radical group add up to 0-3;
Z is
(1) chemical bond;
(2) C that is replaced arbitrarily by following group 1-C 8Alkyl or C 2-C 8Thiazolinyl: (a) 1-3 is selected from amino, C 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4The group of alkylthio or halogen and (b) 1-2 be selected from the group of heterocyclic radical, aryl or heteroaryl, it can be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, halogen, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 2The group of haloalkyl replaces arbitrarily;
(3) be selected from amino, two-(C by 1-2 1-C 4Alkyl) amino, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio or C 1-C 4The heterocyclic radical that the group of alkyl replaces arbitrarily; Perhaps
(4) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, halogen, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 2Aryl or heteroaryl that the group of haloalkyl replaces arbitrarily;
Y is
(1) hydrogen;
(2) halogen;
(3)-C (O)-R 20Or-C (NR5)-NR 5R 21Group;
(4)-OR 21,-O-C (O)-R 21Or-O-C (O)-NR 5R 21Group;
(5)-SR 21,-S (O)-R 20,-S (O) 2-R 20Or-S (O) 2-NR 5R 21Group; Or
(6)-NR 5R 21,-NR 22-C (O)-R 21,-NR 22-C (O)-OR 20,-NR 22-C (O)-NR 5R 21,-NR 22-C (NR 5)-NR 5R 21,-NR 22-S (O) 2-R 20Or-NR 22-S (O) 2-NR 5R 21Group;
Each R 5Be independently
(1) hydrogen;
(2) be selected from amino, two-(C by 1-3 1-C 4Alkyl) amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio ,-SO 3The C that the group of H or halogen replaces arbitrarily 1-C 4Alkyl or C 2-C 5Thiazolinyl; Perhaps
(3) be selected from amino, two-(C by 1-3 1-C 4Alkyl) amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 2Phenyl-C that the group of haloalkyl replaces arbitrarily 1-C 2-alkyl, heteroaryl-C 1-C 2-alkyl, heterocyclic radical-C 1-C 2-alkyl or C 3-C 6-cycloalkyl-C 1-C 2-alkyl;
Each R 20Be independently
(1) is selected from the C that following group replaces arbitrarily by 1-3 1-C 8Alkyl or C 2-C 5Thiazolinyl: amino, C 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, N-((C 1-C 4Alkoxyl group) carbonyl)-N-(C 1-C 4Alkyl) amino, amino carbonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl sulphinyl, C 1-C 4Alkyl sulphonyl, halogen or aryl-C 1-C 4-alkoxyl group, aryl-C 1-C 4-alkylthio, aryl-C 1-C 4-alkyl sulphonyl, C 3-C 6Cycloalkyl, heterocyclic radical, aryl or heteroaryl groups, it can be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, C 1-C 5Alkanoyl, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, halogen, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 2The group of haloalkyl replaces arbitrarily;
(2) be selected from amino, C by 1-2 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio or C 1-C 4The heterocyclic radical that the group of alkyl replaces arbitrarily; Perhaps
(3) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, (C 1-C 4Alkoxyl group) carbonyl, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, halogen, azido-, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 2Aryl or heteroaryl that the group of haloalkyl replaces arbitrarily;
Each R 21Be hydrogen or R independently 20
Each R 22Be independently
(1) hydrogen; Perhaps
(2) be selected from the C that the group of phenyl or heteroaryl replaces arbitrarily 1-C 4Alkyl, described substituting group can be selected from amino, two-(C by 1-3 1-C 2Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, halogen, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 2The group of haloalkyl replaces arbitrarily;
R 2Be hydrogen, C 1-C 4Alkyl, halogen, hydroxyl, C 1-C 4Alkoxyl group, contain the C of 1-3 halogen 1-C 2Halogenated alkoxy, sulfydryl, C 1-C 4Alkylthio, amino-sulfonyl, C 1-C 4Alkyl amino sulfonyl, two-(C 1-C 4Alkyl) amino-sulfonyl, amino, C 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl is amino or contain the C of 1-3 halogen 1-C 2Halogenated alkyl group;
R 11And R 12Be selected from aryl or the heteroaryl that following group replaces arbitrarily by 1-2 independently of one another
(1)R 30；
(2) halogen or cyano group;
(3)-C (O)-R 30,-C (O)-OR 29,-C (O)-NR 31R 32Or-C (NR 31)-NR 31R 32Group; Or
(4)-OR 29,-SR 29,-S (O)-R 30,-S (O) 2-R 30,-S (O) 2-NR 31R 32,-NR 31R 32,-NR 33-C (O)-R 29Or-NR 33-C (O)-OR 30Group; Condition is (1) R 11Not by any 4-pyridyl, 4-pyrimidyl, 4-quinolyl or the 6-isoquinolyl that replaces of 1-2 substituting group; (2) at R 11And R 12Aryl, heteroaryl, cycloalkyl and the heterocyclic radical that go up to replace separately add up to 0-1;
Each R 30Be independently
(1) C that is replaced arbitrarily by following groups 1-C 4Alkyl:
(a) amino, C 1-C 4Alkylamino or two-(C 1-C 4Alkyl) amino; Perhaps
(b) hydroxyl, C 1-C 4Alkoxyl group, heterocyclic radical, phenyl or heteroaryl, it can be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, halogen, C 1-C 4The group of alkyl or trifluoromethyl replaces arbitrarily;
(2) contain the C of 1-3 halogen 1-C 2Haloalkyl; Perhaps
(3) aryl or heteroaryl, it can be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, halogen, C 1-C 4The group of alkyl or trifluoromethyl replaces arbitrarily;
Each R 29Be hydrogen or R independently 30
Each R 31Be hydrogen or C independently 1-C 4Alkyl; With
Each R 32Be independently
(1) hydrogen;
(2) by phenyl or any C that replaces of heteroaryl groups 1-C 4Alkyl, described substituting group can be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4The group of alkyl or trifluoromethyl replaces arbitrarily; Perhaps
(3) be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Phenyl or heteroaryl that the group of alkyl or trifluoromethyl replaces arbitrarily; With
Each R 33Be hydrogen or methyl independently; With
Wherein heterocyclic radical is 1-3 annular atoms monocycle saturated heterocyclic system of 5-6 unit that is oxygen, sulphur or nitrogen heteroatom wherein, and it can at random condense with phenyl ring and at random be replaced by 1-2 group that is selected from oxo or sulfo-; Aryl is a phenyl or naphthyl; With heteroaryl be 1-3 annular atoms monocyclic aromatic heterocycle system of 5-6 unit that is oxygen, sulphur or nitrogen heteroatom wherein, its can at random condense with phenyl ring or with saturated C 3-C 4-carbocyclic fused.
5. the described compound of claim 4 or its pharmaceutically acceptable salt, wherein
Z is
(1) chemical bond;
(2) C that is replaced arbitrarily by following group 1-C 4Alkyl or C 2-C 5Thiazolinyl: (a) 1-3 is selected from amino, two-(C 1-C 2Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 2Alkoxyl group, C 1-C 2The group of alkylthio or halogen and (b) 1-2 be selected from the group of heterocyclic radical, aryl or heteroaryl, it can be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 2Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, halogen, C 1-C 4The group of alkyl or trifluoromethyl replaces arbitrarily;
(3) be selected from amino, two-(C by 1-2 1-C 2Alkyl) amino, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 2Alkoxyl group, C 1-C 2Alkylthio or C 1-C 4The heterocyclic radical that the group of alkyl replaces arbitrarily; Perhaps
(4) be selected from amino, two-(C by 1-3 1-C 2Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 2Alkoxyl group, C 1-C 2Alkylthio, cyano group, halogen, C 1-C 4Aryl or heteroaryl that the group of alkyl or trifluoromethyl replaces arbitrarily;
Each R 5Be independently
(1) hydrogen;
(2) be selected from amino, two-(C by 1-3 1-C 2Alkyl) amino, hydroxyl, C 1-C 2Alkoxyl group, C 1-C 2The C that the group of alkylthio or halogen replaces arbitrarily 1-C 4Alkyl; Perhaps
(3) be selected from amino, two-(C by 1-3 1-C 2Alkyl) amino, hydroxyl, C 1-C 2Alkoxyl group, C 1-C 2Alkylthio, methoxyl group, methylthio group, C 1-C 4Phenyl-C that the group of alkyl or trifluoromethyl replaces arbitrarily 1-C 2-alkyl, heteroaryl-C 1-C 2-alkyl, heterocyclic radical-C 1-C 2-alkyl or C 3-C 6-cycloalkyl-C 1-C 2-alkyl;
Each R 22Be hydrogen or C independently 1-C 4Alkyl;
R 11Be aryl and R 12Be heteroaryl, wherein said aryl and heteroaryl can be selected from following group by 1-2 and replace arbitrarily:
(1)R 30；
(2) halogen or cyano group;
(3)-C (O)-R 30,-C (O)-OR 29,-C (O)-NR 31R 32Or-C (NR 31)-NR 31R 32Group; Or
(4)-OR 29,-SR 29,-S (O)-R 30,-S (O) 2-R 30,-S (O) 2-NR 31R 32,-NR 31R 32Or-NR 33-C (O)-R 29Group; Condition is, at R 11And R 12Aryl, heteroaryl, cycloalkyl and the heterocyclic radical that go up to replace separately add up to 0-1;
Each R 30Be independently
(1) by phenyl or any C that replaces of heteroaryl 1-C 4Alkyl, described substituting group can be selected from amino, two-(C by 1-3 1-C 2Alkyl) amino, kharophen, hydroxyl, C 1-C 2Alkoxyl group, halogen, C 1-C 4The group of alkyl or trifluoromethyl replaces arbitrarily;
(2) trifluoromethyl; Perhaps
(3) be selected from amino, two-(C by 1-3 1-C 2Alkyl) amino, kharophen, hydroxyl, C 1-C 2Alkoxyl group, halogen, C 1-C 4Aryl or heteroaryl that the group of alkyl or trifluoromethyl replaces arbitrarily;
Each R 29Be hydrogen or R independently 30With
Each R 32Be independently
(1) hydrogen;
(2) C 1-C 4Alkyl or the C that is replaced by phenyl or heteroaryl groups 1-C 2Alkyl, described substituting group can be selected from amino, two-(C by 1-3 1-C 2Alkyl) amino, kharophen, hydroxyl, C 1-C 2Alkoxyl group, C 1-C 4The group of alkyl or trifluoromethyl replaces arbitrarily; Perhaps
(3) phenyl or heteroaryl, it can be selected from amino, two-(C by 1-3 1-C 2Alkyl) amino, kharophen, hydroxyl, C 1-C 2Alkoxyl group, C 1-C 4The group of alkyl or trifluoromethyl replaces arbitrarily; With
Wherein heterocyclic radical is 1-2 annular atoms monocycle saturated heterocyclic system of 5-6 unit that is oxygen, sulphur or nitrogen heteroatom wherein, and it can at random condense with phenyl ring and at random by 1-2 oxo or thio group replacement; Aryl is a phenyl or naphthyl; With heteroaryl be 1-2 annular atoms monocyclic aromatic heterocycle system of 5-6 unit that is oxygen, sulphur or nitrogen heteroatom wherein, it can at random condense with phenyl ring.
6. the described compound of claim 5 or its pharmaceutically acceptable salt, wherein
R wherein 1Be-Z-Y that condition is (1) R 1In aryl, heteroaryl, cycloalkyl and heterocyclic radical group add up to 0-2;
Z is
(1) chemical bond;
(2) C that is replaced arbitrarily by following group 1-C 4Alkyl or C 2-C 5Thiazolinyl: (a) 1-3 is selected from amino, two-(C 1-C 2Alkyl) amino, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 2Alkoxyl group, C 1-C 2The group of alkylthio or halogen and (b) 1-2 be selected from the group of aryl or heteroaryl, it can be selected from amino, two-(C by 1-2 1-C 2Alkyl) amino, kharophen, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 2Alkoxyl group, C 1-C 2Alkylthio, halogen, C 1-C 4The group of alkyl or trifluoromethyl replaces arbitrarily; Perhaps
(3) be selected from amino, two-(C by 1-3 1-C 2Alkyl) amino, kharophen, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 2Alkoxyl group, C 1-C 2Alkylthio, cyano group, halogen, C 1-C 4Aryl or heteroaryl that the group of alkyl or trifluoromethyl replaces arbitrarily;
Y is
(1) hydrogen;
(2)-C (O)-R 20Group;
(3)-OR 21,-SR 21,-S (O)-R 20,-S (O) 2-R 20Or-S (O) 2-NR 5R 21Group; Or
(4)-NR 5R 12,-NR 22-C (O)-R 21,-NR 22-C (O)-OR 20,-NR 22-C (O)-NR 5R 21,-NR 22-S (O) 2-R 20Or-NR 22-S (O) 2-NR 5R 21Group;
Each R 5Be independently
(1) hydrogen;
(2) C that is replaced arbitrarily by 1-3 halogen 1-C 4Alkyl; Perhaps
(3) by 1-3 any phenyl-C that replaces of group that is selected from amino, dimethylamino, hydroxyl, methoxyl group, methylthio group, methyl or trifluoromethyl 1-C 2-alkyl or heteroaryl-C 1-C 2-alkyl;
Each R 20Be independently
(1) is selected from the C that following group replaces arbitrarily by 1-3 1-C 8Alkyl or C 2-C 5Thiazolinyl; Amino, C 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, N-((C 1-C 4Alkoxyl group) carbonyl)-N-(C 1-C 4Alkyl) amino, amino carbonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl sulphinyl, C 1-C 4Alkyl sulphonyl, halogen or aryl-C 1-C 4-alkoxyl group, aryl-C 1-C 4-alkylthio, aryl-C 1-C 4-alkyl sulphonyl, C 3-C 6Cycloalkyl, heterocyclic radical, aryl or heteroaryl groups, it can be selected from amino, C by 1-3 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, C 1-C 5Alkanoyl, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, halogen, C 1-C 4Alkyl or contain the C of 1-3 halogen 1-C 2The group of haloalkyl replaces arbitrarily;
(2) be selected from amino, two-(C by 1-2 1-C 4Alkyl) amino, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio or C 1-C 4The heterocyclic radical that the group of alkyl replaces arbitrarily; Perhaps
(3) be selected from amino, C by 1-2 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, kharophen, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, (C 1-C 4Alkoxyl group) carbonyl, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, halogen, azido-, C 1-C 4Aryl or heteroaryl that the group of alkyl or trifluoromethyl replaces arbitrarily;
Each R 21Be hydrogen or R independently 20
R 2Be hydrogen, C 1-C 4Alkyl, halogen, hydroxyl, C 1-C 4Alkoxyl group, trifluoromethoxy, sulfydryl, C 1-C 4Alkylthio, amino, C 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino or trifluoromethyl;
R 11Be aryl and R 12Be heteroaryl, wherein said aryl and heteroaryl can be selected from following group by 1-2 and replace arbitrarily:
(1)R 30；
(2) halogen or cyano group; Perhaps
(3)-C (O)-NR 31R 32,-OR 29,-SR 29,-S (O)-R 30,-S (O) 2-R 30,-S (O) 2-NR 31R 32,-NR 31R 32Or-NR 33-C (O)-R 29Group; Condition is, at R 11And R 12Aryl, heteroaryl, cycloalkyl and the heterocyclic radical that go up to replace separately add up to 0-1;
Each R 30Be independently
(1) by phenyl or any C that replaces of heteroaryl 1-C 4Alkyl, described substituting group can be replaced arbitrarily by 1-3 group that is selected from amino, dimethylamino, kharophen, hydroxyl, halogen, methoxyl group, methyl or trifluoromethyl;
(2) trifluoromethyl; Perhaps
(3) by 1-3 any aryl or the heteroaryl that replaces of group that is selected from amino, dimethylamino, kharophen, hydroxyl, halogen, methoxyl group, methyl or trifluoromethyl;
Each R 29Be hydrogen or R independently 30
Each R 31Be hydrogen, methyl or ethyl independently; With
Each R 32Be independently
(1) hydrogen;
(2) C 1-C 4Alkyl or the C that is replaced by phenyl or heteroaryl 1-C 2Alkyl, described substituting group can be replaced arbitrarily by 1-3 group that is selected from amino, dimethylamino, kharophen, hydroxyl, methoxyl group, methyl or trifluoromethyl; Perhaps
(3) by 1-3 any phenyl or the heteroaryl that replaces of group that is selected from amino, dimethylamino, kharophen, hydroxyl, methoxyl group, methyl or trifluoromethyl.
7. the described compound of claim 6 or its pharmaceutically acceptable salt, wherein
R 11Be to be selected from the aryl that following group replaces arbitrarily by 1-2:
(1)R 30；
(2) halogen or cyano group; Perhaps
(3)-C (O)-NR 31R 32,-OR 29,-SR 29,-S (O)-R 30,-S (O) 2-R 30,-S (O) 2-NR 31R 32,-NR 31R 32Or-NR 33-C (O)-R 29Group; With
R 12Be to be selected from the heteroaryl that following group replaces arbitrarily by 1-2:
(1)R 30；
(2) halogen or cyano group; Perhaps
(3)-C (O)-NR 31R 32,-OR 29,-SR 29,-NR 31R 32Or-NR 33-C (O)-R 29Group;
Condition is, at R 11And R 12Aryl, heteroaryl, cycloalkyl and the heterocyclic radical that go up to replace separately add up to 0-1;
R 30Be independently
(1) by phenyl or any C that replaces of heteroaryl 1-C 4Alkyl, described substituting group can be replaced arbitrarily by 1-2 group that is selected from amino, dimethylamino, kharophen, hydroxyl, halogen, methoxyl group, methyl or trifluoromethyl;
(2) trifluoromethyl; Perhaps
(3) by 1-3 any aryl or the heteroaryl that replaces of group that is selected from amino, dimethylamino, kharophen, hydroxyl, halogen, methoxyl group, methyl or trifluoromethyl;
R 29By 1-2 any aryl or the heteroaryl that replaces of group that is selected from amino, dimethylamino, kharophen, hydroxyl, halogen, methoxyl group, methyl or trifluoromethyl; With
R 32Be independently
(1) hydrogen or C 1-C 4Alkyl; Perhaps
(2) by 1-2 any phenyl or the heteroaryl groups that replaces of group that is selected from amino, dimethylamino, kharophen, hydroxyl, methoxyl group, methyl or trifluoromethyl.
8. the described compound of claim 7 or its pharmaceutically acceptable salt, wherein
R wherein 1Be-Z-Y that condition is (1) R 1In aryl, heteroaryl, cycloalkyl and heterocyclic radical group add up to 0-1;
Z is
(1) chemical bond; Or
(2) be selected from amino, two-(C by 1-2 1-C 2Alkyl) amino, (C 1-C 4Alkoxyl group) carbonylamino, hydroxyl, C 1-C 2Alkoxyl group, C 1-C 2The C that the group of alkylthio or halogen or aryl or heteroaryl replaces arbitrarily 1-C 4Alkyl, described aryl or heteroaryl can be selected from hydroxyl, C by 1-2 1-C 2Alkoxyl group, C 1-C 2Alkylthio, halogen, C 1-C 4The group of alkyl or trifluoromethyl replaces arbitrarily;
Each R 5Be hydrogen or C independently 1-C 4Alkyl;
Each R 20Be independently
(1) is selected from the C that following group replaces arbitrarily by 1-3 1-C 8Alkyl: amino, C 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, N-((C 1-C 4Alkoxyl group) carbonyl)-N-(C 1-C 4Alkyl) amino, amino carbonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl sulphinyl, C 1-C 4Alkyl sulphonyl, halogen or C 3-C 6Cycloalkyl, heterocyclic radical, aryl or heteroaryl groups, it can be selected from amino, two-(C by 1-2 1-C 4Alkyl) amino, C 1-C 5Alkanoyl amido, (C 1-C 4Alkoxyl group) carbonylamino, C 1-C 4Alkyl sulfonyl amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, halogen, C 1-C 4The group of alkyl or trifluoromethyl replaces arbitrarily;
(2) be selected from hydroxyl, C by 1-2 1-C 4Alkoxyl group, C 1-C 4Alkylthio or C 1-C 4The heterocyclic radical that the group of alkyl replaces arbitrarily; Perhaps
(3) be selected from (C by 1-2 1-C 4Alkoxyl group) carbonyl, amino, C 1-C 4Alkylamino, two-(C 1-C 4Alkyl) amino, hydroxyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, cyano group, halogen, azido-, C 1-C 4Aryl or heteroaryl that the group of alkyl or trifluoromethyl replaces arbitrarily;
Each R 21Be hydrogen or R independently 20
R 2Be hydrogen, methyl, ethyl, fluorine, chlorine, hydroxyl, methoxyl group, trifluoromethoxy, amino, methylamino-, dimethylamino, kharophen or trifluoromethyl;
R 11Be can be by 1-2 aryl that is selected from any replacement of following group, described group be amino, dimethylamino, kharophen, hydroxyl, halogen, cyano group, methoxyl group, methylthio group, methylsulfinyl, methyl sulphonyl, aminocarboxyl, methyl or trifluoromethyl group; With
R 12Be can be by 1-2 heteroaryl that is selected from any replacement of following group, described group be amino, dimethylamino, kharophen, hydroxyl, halogen, cyano group, methoxyl group, methyl or trifluoromethyl group.
9. the described compound of claim 8 or its pharmaceutically acceptable salt, wherein
Z is
(1) chemical bond; Or
(2) by 1-2 any C that replaces of group that is selected from amino, t-butoxycarbonyl amino, dimethylamino, hydroxyl, methoxyl group, methylthio group or halogen 1-C 4Alkyl;
Y is
(1) hydrogen;
(2)-C (O)-R 20Group;
(3)-OR 21,-SR 21,-S (O)-R 20,-S (O) 2-R 20Or-S (O) 2-NR 5R 21Group; Or
(4)-NR 5R 21,-NR 22-C (O)-R 21Or-NR 22-S (O) 2-R 20Group;
R 5Be hydrogen;
Each R 20Be independently
(1) is selected from the C that following group replaces arbitrarily by 1-3 1-C 6Alkyl: amino, methylamino-, dimethylamino, t-butoxycarbonyl amino, N-((tert.-butoxy) carbonyl)-N-(methyl) amino, amino carbonyl amino, hydroxyl, butoxy, methoxyl group, butylthio, methylthio group, methylsulfinyl, methylsulfonyl, halogen or C 5-C 6Cycloalkyl, heterocyclic radical, phenyl or heteroaryl groups, it can be replaced arbitrarily by 1-2 group that is selected from amino, dimethylamino, kharophen, hydroxyl, methoxyl group, methylthio group, halogen, methyl or trifluoromethyl;
(2) be selected from hydroxyl or C by 1-2 1-C 4The heterocyclic radical that the group of alkyl replaces arbitrarily; Perhaps
(3) by 1-2 any aryl or the heteroaryl that replaces of group that is selected from amino, dimethylamino, hydroxyl, methoxyl group, methylthio group, halogen, methyl or trifluoromethyl;
Each R 21Be hydrogen or R independently 20
Each R 22Be hydrogen or methyl independently;
R 11Be unsubstituted phenyl or naphthyl or can be selected from the phenyl that following group replaces arbitrarily that described group is amino, dimethylamino, kharophen, hydroxyl, halogen, cyano group, methoxyl group, methylthio group, methylsulfinyl, methyl sulphonyl, aminocarboxyl, methyl or trifluoromethyl group by 1-2; With
R 12Be can be by any 4-pyridyl, 4-quinolyl, 4-imidazolyl or the 4-pyrimidyl that replaces of following groups, described group be amino, dimethylamino, kharophen, hydroxyl, halogen, cyano group, methoxyl group, methyl or trifluoromethyl group.
10. the described compound of claim 9 or its pharmaceutically acceptable salt, wherein
Y is
(1)-C (O)-R 20Group;
(2)-OR 21,-SR 21,-S (O)-R 20,-S (O) 2-R 20Or-S (O) 2-NR 5R 21Group; Or
(3)-NR 5R 21,-NR 22-C (O)-R 21Or-NR 22-S (O) 2-R 20Group;
Each R 20Be independently
(1) is selected from the C that following group replaces arbitrarily by 1-3 1-C 6Alkyl: amino, methylamino-, dimethylamino, t-butoxycarbonyl amino, N-((tert.-butoxy) carbonyl)-N-(methyl) amino, amino carbonyl amino, hydroxyl, butoxy, methoxyl group, butylthio, methylthio group, methylsulfinyl, methylsulfonyl, halogen or C 5-C 6Cycloalkyl, heterocyclic radical, phenyl or heteroaryl groups, it can be replaced arbitrarily by 1-2 group that is selected from amino, dimethylamino, kharophen, hydroxyl, methoxyl group, methylthio group, halogen, methyl or trifluoromethyl;
(2) heterocyclic radical; Perhaps
(3) by 1-2 any aryl or the heteroaryl that replaces of group that is selected from amino, dimethylamino, hydroxyl, methoxyl group, methylthio group, halogen, methyl or trifluoromethyl;
Each R 21Be hydrogen or R independently 20
11. the described compound of claim 10 or its pharmaceutically acceptable salt, wherein
Y is-OR 21,-SR 21Or-NR 5R 21Group;
Each R 20Be independently
(1) is selected from the C that following group replaces arbitrarily by 1-3 1-C 6Alkyl: amino, methylamino-, dimethylamino, hydroxyl or phenyl or heteroaryl groups, it can be replaced arbitrarily by 1-2 group that is selected from amino, dimethylamino, hydroxyl, methoxyl group, methylthio group, halogen, methyl or trifluoromethyl;
(2) heterocyclic radical; Perhaps
(3) by 1-2 any aryl or the heteroaryl that replaces of group that is selected from amino, dimethylamino, hydroxyl, methoxyl group, methylthio group, halogen, methyl or trifluoromethyl;
Each R 21Be hydrogen or R independently 20
R 11Be unsubstituted phenyl or be selected from the phenyl that the group of amino, dimethylamino, kharophen, hydroxyl, halogen, cyano group, methoxyl group, methylthio group, methyl sulphonyl, methyl or trifluoromethyl replaces arbitrarily by 1-2; With
R 12By any 4-pyridyl that replaces of amino, dimethylamino, kharophen, hydroxyl, halogen, cyano group, methoxyl group, methyl or trifluoromethyl.
12. the described compound of claim 1, this compound is:
5-(4-fluorophenyl)-2-(4-pyridyl)-4-(4-pyridyl)-pyrimidine,
5-(4-fluorophenyl)-2-(2-methylthiazol-4-yl)-4-(4-pyridyl)-pyrimidine,
5-(4-fluorophenyl)-4-(4-pyridyl)-2-(2-thienyl)-pyrimidine,
2-(2-diethyllaminoethyl amino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine,
2-(the amino fourth amino of 4-)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine,
2-(2, the 6-dichloro benzyl)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine,
2-(2,6-dichlorophenyl amino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine,
2-(2,6-3,5-dimethylphenyl amino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine,
5-(4-fluorophenyl)-2-(2-p-methoxy-phenyl amino)-4-(4-pyridyl)-pyrimidine,
5-(4-fluorophenyl)-2-(4-fluorophenyl amino)-4-(4-pyridyl)-pyrimidine,
5-(4-fluorophenyl)-2-thiophenyl methyl-4-(4-pyridyl)-pyrimidine,
2-(2-(4-aminophenyl) ethylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine,
2-(2-(2-chloro-phenyl-) ethylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine,
2-(2-(4-chloro-phenyl-) ethylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine,
2-(2-(3-chloro-phenyl-) ethylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine,
2-(2-(2,4 dichloro benzene base) ethylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine,
2-(2-(4-bromophenyl) ethylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine,
5-(4-fluorophenyl)-2-(2-(2-p-methoxy-phenyl) ethylamino)-4-(4-pyridyl)-pyrimidine,
5-(4-fluorophenyl)-2-(2-(3-p-methoxy-phenyl) ethylamino)-4-(4-pyridyl)-pyrimidine,
5-(4-fluorophenyl)-2-((1-methyl-3-phenyl propyl)-amino)-4-(4-pyridyl)-pyrimidine,
5-(4-fluorophenyl)-2-((4-phenyl-butyl)-amino)-4-(4-pyridyl)-pyrimidine,
5-(4-fluorophenyl)-2-morpholino-4-(4-pyridyl)-pyrimidine,
5-(4-fluorophenyl)-4-(4-pyridyl)-2-(2-pyrrolidino ethylamino)-pyrimidine,
5-(4-fluorophenyl)-2-(2-morpholino ethylamino)-4-(4-pyridyl)-pyrimidine,
5-(4-fluorophenyl)-2-(2-piperidino-(1-position only) ethylamino)-4-(4-pyridyl)-pyrimidine,
5-(4-fluorophenyl)-2-(3-(2-Pyrrolidone-1-yl) third amino)-4-(4-pyridyl)-pyrimidine,
5-(4-fluorophenyl)-2-(2-phenoxy group ethyl) sulfenyl-6-(4-pyridyl)-4-hydroxyl-pyrimidine,
5-(4-fluorophenyl)-2-(2-phenylamino ethyl) sulfenyl-6-(4-pyridyl)-4-hydroxyl-pyrimidine,
2-(the amino ethylamino of 2-)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine,
2-(amino third amino of 3-)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine,
2-(benzylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine,
5-(4-fluorophenyl)-2-(2-phenyl ethylamino)-4-(4-pyridyl)-pyrimidine,
5-(4-fluorophenyl)-2-(N-methyl-N-(2-styroyl)-amino)-4-(4-pyridyl)-pyrimidine,
5-(4-fluorophenyl)-2-(2-hydroxyl-2-phenyl-ethyl) amino-4-(4-pyridyl)-pyrimidine,
5-(4-fluorophenyl)-2-(2-(4-hydroxy phenyl) ethylamino)-4-(4-pyridyl)-pyrimidine,
5-(4-fluorophenyl)-2-(2-(4-fluorophenyl) ethylamino)-4-(4-pyridyl)-pyrimidine,
5-(4-fluorophenyl)-2-(2-(2-fluorophenyl) ethylamino)-4-(4-pyridyl)-pyrimidine,
5-(4-fluorophenyl)-2-((3-hydrocinnamyl)-amino)-4-(4-pyridyl)-pyrimidine,
2-((2 (S)-amino-3-phenyl propyl)-amino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine,
5-(4-fluorophenyl)-2-(2-phenyl amino ethylamino)-4-(4-pyridyl)-pyrimidine,
5-(4-fluorophenyl)-2-((3-imidazolyl propyl group)-amino)-4-(4-pyridyl)-pyrimidine,
5-(4-fluorophenyl)-4-(4-pyridyl)-2-pyrrolidino-pyrimidine,
5-(4-fluorophenyl)-2-(1-piperazinyl)-4-(4-pyridyl)-pyrimidine,
2-(2, the 6-dichloro benzyl)-5-(4-fluorophenyl)-6-(4-pyridyl)-4-hydroxyl-pyrimidine,
5-(4-fluorophenyl)-2-(2-phenylethyl) sulfenyl-6-(4-pyridyl)-4-hydroxyl-pyrimidine,
5-(4-fluorophenyl)-2-(3-hydrocinnamyl) sulfenyl-6-(4-pyridyl)-4-hydroxyl-pyrimidine,
2-(2-(2-chloro-phenyl-) ethylamino)-5-(4-fluorophenyl)-6-(4-pyridyl)-4-hydroxyl-pyrimidine,
5-(4-fluorophenyl)-2-((3-hydrocinnamyl)-amino)-6-(4-pyridyl)-4-hydroxyl-pyrimidine,
5-(4-fluorophenyl)-2-((1-methyl-3-phenyl propyl)-amino)-6-(4-pyridyl)-4-hydroxyl-pyrimidine,
2-(2-(2-chloro-phenyl-) ethylamino)-5-(4-fluorophenyl)-6-(4-pyridyl)-4-hydroxyl-pyrimidine;
2-((S)-2-amino-3-phenyl propyl)-amino)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine,
2-((S)-2-amino-3-phenyl propyl)-amino)-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine,
2-((S)-2-N, N-dimethylamino-3-phenyl propyl)-amino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine,
2-((S)-2-N, N-dimethylamino-3-phenyl propyl)-amino)-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine,
2-((3-amino-3-phenyl propyl)-amino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine,
2-((3-amino-3-phenyl propyl)-amino)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine,
2-((3-amino-3-(2-fluorophenyl) propyl group)-amino)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine,
2-((3-amino-3-phenyl propyl)-amino)-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine,
2-((2-amino-2-methyl-3-phenyl propyl)-amino)-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine,
2-((3-hydroxyl-3-phenyl propyl)-amino)-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine,
2-(((2S, 3S)-3-amino-2-methyl-3-phenyl propyl)-amino)-4-(4-pyridyl)-5-(4-trifluoromethyl)-pyrimidine,
2-(((2R, 3R)-3-amino-2-methyl-3-phenyl propyl)-amino)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine,
2-((S)-3-benzyl diethylenediamine base)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine,
4-(4-pyridyl)-2-(((S)-tetrahydroisoquinoline-3-ylmethyl) amino)-5-(3-trifluoromethyl)-pyrimidine,
5-(3-aminomethyl phenyl)-4-(4-pyridyl)-2-(((S)-tetrahydroisoquinoline-3-ylmethyl) amino)-pyrimidine,
2-(((S)-2-N-isopropylamino-3-phenyl propyl) amino)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine,
2-(((S)-2-N-cyclohexyl amino-3-phenyl propyl)-amino)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine,
2-(((S)-2-N-isopropylamino-3-phenyl propyl)-amino)-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine,
2-(((S)-2-N-fourth amino-3-phenyl propyl)-amino)-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine,
2-(((S)-2-N-cyclohexyl amino-3-phenyl propyl)-amino)-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine,
5-(4-fluorophenyl)-2-(((S)-2-N-isopropylamino-3-phenyl propyl)-amino)-4-(4-pyridyl)-pyrimidine,
5-(4-fluorophenyl)-2-((3-N-isopropylamino-3-phenyl propyl)-amino)-4-(4-pyridyl)-pyrimidine,
2-(((S)-2-N-glycyl amino-3-phenyl propyl)-amino)-4-(4-pyridyl)-5-(3-trifluoromethyl)-pyrimidine,
2-(((S)-2-N-glycyl amino-3-phenyl propyl)-amino)-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-pyrimidine,
2-(((S)-2-amino-3-phenyl propyl)-amino)-5-(3-chloro-4-fluorophenyl)-4-(4-pyridyl)-pyrimidine,
2-(((S)-2-amino-3-phenyl propyl)-amino)-5-(3-fluorophenyl)-4-(4-pyridyl)-pyrimidine,
2-(((S)-2-amino-3-phenyl propyl)-amino)-5-(3-isopropyl phenyl)-4-(4-pyridyl)-pyrimidine,
5-(3-acetylamino phenyl)-2-(((S)-2-amino-3-phenyl propyl)-amino)-4-(4-pyridyl)-pyrimidine,
2-(((S)-2-amino-3-phenyl propyl)-amino)-5-(4-chloro-phenyl-)-4-(4-pyridyl)-pyrimidine,
2-(((S)-2-amino-3-phenyl propyl)-amino)-5-(benzothienyl)-4-(4-pyridyl)-pyrimidine,
2-(((S)-2-amino-3-phenyl propyl)-amino)-5-(2-naphthyl)-4-(4-pyridyl)-pyrimidine, or
2-(((S)-2-amino-3-phenyl propyl)-amino)-5-(4-fluorophenyl)-6-(4-pyridyl)-4 (3H) pyrimidone
Or its pharmaceutically acceptable salt.
13. a pharmaceutical composition, said composition contain described compound of claim 1-12 and pharmaceutically acceptable carrier.
14. the method for preventing or treating inflammation, this method comprises the described compound of the claim 1-12 that uses significant quantity.
15. the method for preventing or treating inflammation, this method comprises the described composition of the claim 13 of using significant quantity.
16. one kind is prevented or treatment Mammals rheumatoid arthritis, Paget's disease, osteoporosis, multiple myeloma, uveitis, acute and chronic lymphocytic leukemia, pancreatic, osteoarthritis, rheumatoid osteomyelitis, urarthritis, enteritis, adult respiratory distress syndrome (ARDS), psoriasis, Crohn disease, rhinallergosis, ulcerative colitis, irritated, contact dermatitis, asthma, muscle deterioration, emaciation, reiter syndrome, I type and type ii diabetes, bone resorption disease, graft-vs-host reaction, presenile dementia, apoplexy, myocardial infarction forms, the ischemia reperfusion damage, atherosclerosis, cerebral trauma, multiple sclerosis, cerebral malaria, sepsis, septic shock, toxic shock syndrome, fever, because of HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, simplexvirus or zoster infect the method for the myalgia that causes, this method comprises the described compound of the claim 1-12 that uses significant quantity.
17. one kind is prevented or treatment Mammals rheumatoid arthritis, Paget's disease, osteoporosis, multiple myeloma, uveitis, acute and chronic lymphocytic leukemia, pancreatic, osteoarthritis, rheumatoid osteomyelitis, urarthritis, enteritis, adult respiratory distress syndrome (ARDS), psoriasis, Crohn disease, rhinallergosis, ulcerative colitis, irritated, contact dermatitis, asthma, muscle deterioration, emaciation, reiter syndrome, I type and type ii diabetes, bone resorption disease, graft-vs-host reaction, presenile dementia, apoplexy, myocardial infarction forms, the ischemia reperfusion damage, atherosclerosis, cerebral trauma, multiple sclerosis, cerebral malaria, sepsis, septic shock, toxic shock syndrome, fever, because of HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, simplexvirus or zoster infect the method for the myalgia that causes, this method comprises the described composition of the claim 13 of using significant quantity.
18. a method that reduces plasma concentrations any one or two kinds of among TNF-α and the IL-1, this method are used the described compound of claim 1-12 of significant quantity.
19. a method that reduces plasma concentrations any one or two kinds of among TNF-α and the IL-1, this method are used the described composition of claim 13 of significant quantity.
20. a method that reduces plasma concentrations any one or two kinds of among IL-6 and the IL-8, this method are used the described compound of claim 1-12 of significant quantity.
21. a method that reduces plasma concentrations any one or two kinds of among IL-6 and the IL-8, this method are used the described composition of claim 13 of significant quantity.
22. the method for preventing or treating the Mammals diabetes, this method comprise that the described compound of the claim 1-12 that uses significant quantity is to produce the antagonistic action to hyperglycemic-glycogenolytic factor.
23. the method for preventing or treating the Mammals diabetes, this method comprise that the described composition of the claim 13 of using significant quantity is to produce the antagonistic action to hyperglycemic-glycogenolytic factor.
24. the method for preventing or treating the Mammals pain disease, this method comprises the described compound of the claim 1-12 that uses significant quantity.
25. the method for preventing or treating the Mammals pain disease, this method comprises the described composition of the claim 13 of using significant quantity.
26. one kind is reduced the method that the Mammals prostaglandin(PG) produces, this method comprises the described compound of the claim 1-12 that uses significant quantity.
27. one kind is reduced the method that the Mammals prostaglandin(PG) produces, this method comprises the described composition of the claim 13 of using significant quantity.
28. a method that reduces the Mammals cyclooxygenase-2 activity, this method comprise the described compound of the claim 1-12 that uses significant quantity.
29. the described method of claim 28, wherein said cyclooxygenase is COX-2.
30. a method that reduces the Mammals cyclooxygenase-2 activity, this method comprise the described composition of the claim 13 of using significant quantity.
31. the described method of claim 30, wherein said cyclooxygenase is COX-2.
CN97181563A 1996-12-05 1997-12-04 Substituted pyrimidine compounds and their use Pending CN1246858A (en)

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CN100441581C (en) * 2002-02-28 2008-12-10 赛诺菲-安万特 1- [ alkyl ], 1- [ (heteroaryl) alkyl ] and 1- [ (aryl) alkyl ] -7- (pyrimidin-4-yl) -imidazo [1, 2-a ] pyrimidin-5 (1H) -one derivatives
CN100506801C (en) * 2000-09-06 2009-07-01 诺华疫苗和诊断公司 Inhibitors of glycogen synthase kinase 3
CN100519549C (en) * 2001-10-22 2009-07-29 卫材R&D管理有限公司 Pyrimidine derivatives and pharmaceutical compositions containing the compounds
CN106167483A (en) * 2010-10-18 2016-11-30 塞伦尼斯医疗控股有限公司 Can be used for compound, compositions and method that cholesterol is mobilized
CN106232585A (en) * 2014-02-20 2016-12-14 日本烟草产业株式会社 Triaizine compounds and its medicinal usage
CN108137513A (en) * 2015-10-29 2018-06-08 Aska 制药株式会社 Pyrimidine derivatives

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AR043700A1 (en) 2001-09-21 2005-08-10 Mitsubishi Pharma Corp DERIVATIVES OF 3-SUBSTITUIDA-4-PIRIMIDONA
US7683069B2 (en) 2002-12-16 2010-03-23 Mitsubishi Tanabe Pharma Corporation 3-substituted-4-pyrimidone derivatives
TWI357408B (en) 2003-03-26 2012-02-01 Mitsubishi Tanabe Pharma Corp 3-substituted-4-pyrimidone derivatives

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Cited By (9)

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CN100506801C (en) * 2000-09-06 2009-07-01 诺华疫苗和诊断公司 Inhibitors of glycogen synthase kinase 3
CN100519549C (en) * 2001-10-22 2009-07-29 卫材R&D管理有限公司 Pyrimidine derivatives and pharmaceutical compositions containing the compounds
CN100441581C (en) * 2002-02-28 2008-12-10 赛诺菲-安万特 1- [ alkyl ], 1- [ (heteroaryl) alkyl ] and 1- [ (aryl) alkyl ] -7- (pyrimidin-4-yl) -imidazo [1, 2-a ] pyrimidin-5 (1H) -one derivatives
CN106167483A (en) * 2010-10-18 2016-11-30 塞伦尼斯医疗控股有限公司 Can be used for compound, compositions and method that cholesterol is mobilized
CN106167483B (en) * 2010-10-18 2019-02-15 塞伦尼斯医疗控股有限公司 It can be used for compound, composition and the method for cholesterol mobilization
CN106232585A (en) * 2014-02-20 2016-12-14 日本烟草产业株式会社 Triaizine compounds and its medicinal usage
CN106232585B (en) * 2014-02-20 2019-04-02 日本烟草产业株式会社 Triaizine compounds and its medicinal usage
CN108137513A (en) * 2015-10-29 2018-06-08 Aska 制药株式会社 Pyrimidine derivatives
CN108137513B (en) * 2015-10-29 2022-03-01 Aska 制药株式会社 Pyrimidine derivatives

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CA2274063A1 (en) 1998-06-11
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NZ335997A (en) 2001-08-31
IL130180A0 (en) 2000-06-01
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CA2274063C (en) 2007-09-04
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AU733877C (en) 2003-05-08
BG103512A (en) 2000-07-31

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