CN101287734B - 2-amino-7,8-dihydro-6h-pyrido[4,3-d]pyrimidin-5-ones - Google Patents

2-amino-7,8-dihydro-6h-pyrido[4,3-d]pyrimidin-5-ones Download PDF

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CN101287734B
CN101287734B CN2006800365004A CN200680036500A CN101287734B CN 101287734 B CN101287734 B CN 101287734B CN 2006800365004 A CN2006800365004 A CN 2006800365004A CN 200680036500 A CN200680036500 A CN 200680036500A CN 101287734 B CN101287734 B CN 101287734B
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amino
phenyl
pyrimidine
methyl
fluoro
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CN101287734A (en
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蒂莫西·D·马哈约夫斯基
辛西娅·M·谢弗
克里斯托弗·麦克布赖德
威廉·安东尼-麦克雷
布兰登·M·多甘
巴里·H·莱文
夏奕
莫琳·麦克纳
X·迈克尔·王
克里斯·门登霍尔
周亚新
龚宝清
古丹
约翰·多兰
约翰·图林斯基
克里斯廷·布林纳
高振海
丹尼尔·彭
保罗·A·巴尔桑迪
林晓东
阿布兰·科斯塔莱斯
艾丽斯·里克
纳坦·布拉梅尔
特雷莎·皮科
保罗·A·雷恩霍韦
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Novartis AG
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Abstract

Disclosed are 2-amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one compounds, their stereoisomers, tautomers, pharmaceutically acceptable salts, and prodrugs thereof; compositions that include a pharmaceutically acceptable carrier and one or more of the 2-amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one compounds, either alone or in combination with at least one additional therapeutic agent. Disclosed also are methods of using the 2-amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one compounds, either alone or in combination with at least one additional therapeutic agent, in the prophylaxis or treatment of cellular proliferative, viral, autoimmune, cardiovascular, and central nevous system diseases.

Description

2-amino-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone
The cross reference of related application
According to 35U.S.C.119 (e), the U.S. Provisional Patent Application case the 60/722nd that the application's case opinion was filed an application on September 30th, 2005, reach the United States Patent (USP) the 60/836th of filing an application No. 796 on August 9th, 2006, No. 886 rights and interests, described case all is incorporated herein with way of reference separately.
Technical field
The present invention relates to novel 2-amino-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone compound, its steric isomer, tautomer, pharmaceutically acceptable salt and prodrug thereof; The composition of described compounds (use separately or be used in combination) and pharmaceutically acceptable supporting agent with at least a additional procedures medicament; And the purposes of described compounds and composition-use separately or be used in combination-in prevention or treatment hyperplasia, viral, autoimmunization, cardiovascular and central nervous system disease with at least a additional procedures medicament.
Background technology
The cell that heat-shocked or heat stress can significantly increase some classification high conservative chaperone proteins (so-called heat shock protein (HSP)) generates.These chaperone proteins (member who comprises HSP60, HSP70 and HSP90 family) be help/guarantee suitable object protein (for example, for reach its active and stable purpose need with the chaperone protein interacting proteins) fold, prevent non-specific aggregation and keep the ATP dependency molecule of active protein configuration.
The HSP90 family that is made up of HSP90 α and β, Grp94 and TRAP-1 represents the cell protein of the maximum abundance of a class, and it accounts for 1 to 2% of total protein in the mammalian cell that is under the standard state.HSP90 is unique in the cell chaperone protein, this is that and many described cell proteins are the decisive key signal molecules that participates in cell growth, differentiation and apoptosis because it is not folding required but be exclusively used in the cell protein of one group of uniqueness for common altogether translated protein.Up to now, confirmed and this object protein tabulation promptly expansion relevant of protein more than 100 kinds with HSP90.
Crystallographic Study has been disclosed in its N-end structure territory and has existed one to be subjected to the good unusual low affinity ATP that preserves in conjunction with the crack in 4 HSP90 family members.ATP combination and hydrolysis play crucial effect in conciliation chaperone protein function aspects.Can suppress the intrinsic atpase activity of HSP90 when incoherent fungus metabolite radicicol occupies ATP-binding site on ansa mycin class microbiotic geldanamycin (GM) and Antibiotic TAN 420F (HA) and the structure and block HSP90 and object protein between the association-disassociation that regulated by ATP/ADP circulate.Therefore, the competitive HSP90 inhibitor of ATP-can cause the unstable ubiquitin dependency that also finally causes of object protein to be degraded.
Finding that many HSP90 objects are that people have produced great interest to the HSP90 as novel anticancer target meeting usually be subjected to overexpression, sudden change or have the active real oncoprotein of composition in tumour cell after.These comprise the cancer therapy drug target that people people know and established, for example receptor tyrosine kinase class (HER-2/neu transmembrane glycoprotein, EGF-R ELISA (EGFR), Met and IGF-1R (IGF-1R), metastable serine/threonine kinase class (Akt and Raf-1), protein-based (the Flt3 of jump signal, v-Src), chimeric oncoprotein class (Bcr-Abl, NPM-ALK), Cycle Regulation agent (CDK4 and CDK6), transcription factor (oestrogenic hormon and androgen receptor ER and AR, hypoxia inducible factor HIF-1 α) and apoptosis conditioning agent (Survivin and Apaf-1).It should be noted that, HSP90 object protein can exert an influence on function to all 6 " cancer signs ", and described cancer sign comprises (is example with relevant HSP90 object protein in the parantheses): 1) growth signals self-sufficiency (ErbB2, Raf-1), 2) to the insensitivity (Plk, Myt1), 3 of growth inhibitory signal) apoptosis reduces (Akt, RIP), 4) acquisition (hTERT), 5 of infinite copy ability) angiogenesis (HIF-1 α, FAK) and 6 that continues) invasion and attack and shift (Met).Described HSP90 dependency guarantee these originally unsettled oncoprotein in many signal conducting paths that keeping having aspect random growth of tumour and the malignant phenotype vital role very, suitably play a role.
Can cause many oncoproteins while poornesss and can cause various carcinogenic signal conducting paths to be suppressed simultaneously by ATP competitive inhibitor deactivation HSP90.Therefore, by destroying the function of unit molecule entity HSP90, the HSP90 inhibitor can unique way provide combination attacks and all 6 the cancer signs capable of blocking that generate at the multistep tumour.Decide according to the cell situation, the HSP90 inhibitor can make growth of tumour cell stagnation, differentiation or apoptosis effectively in external and body.In addition, HSP90 self transforms (for example, the accumulation of mutein) and cellular stress (for example, low pH and shortage nutrient substance) and can be subjected to overexpression (about 2 to 20 times) in many tumor type owing to carinogenicity.The overexpression that has confirmed Hsp90 is relevant with the poor prognosis of breast cancer.
Cancer cells can highly adapt to hostile microenvironment and can obtain drug resistance, and this is by due to its intrinsic genetic instability and the genetic plasticity to a certain extent.And most of cancer forms are polygene and hide many signal conduction distortion.HSP90 can be and makes some cancer cells flee from apoptosis and cause another signal or overlapped signal and the key that concrete pharmacological agent produced effectively the mechanism of resistance is formed.Therefore, provablely be difficult to treat tumour by destroying many carcinogenic paths simultaneously to suppress Hsp90 being that a kind of opposing is various 20-23Very effective means.Described cancer comprises (for example) breast cancer 1, ovarian cancer 2, prostate cancer 3, chronic lymphocytic leukemia (CML) 4, melanoma 5, gastrointestinal stromal tumors (GIST) 6, mast cell leukemia 7, tumor of testis 7, acute myelogenous leukemia 8,9, gastric tumor 10, lung tumor 11, the head and the neck tumour 12, glioma 13, the colon knurl 14, thyroid tumor 15, cancer of the stomach, liver cancer, multiple myeloma 16, kidney 17And lymphoma 18,19
The Hsp90 inhibitor also can be used for treating the non-tumour indication that wherein diseased cells demonstration HSP90 expresses and utilization increases except that can be used for treating cancer.These indications include but not limited to be subjected to the virus disease of hepatitis B virus (HBV), hepatitis C virus (HCV) and herpes simplex types 1 virus (HSV-1) mediation and comprise those be subjected to persistence lymphocyte activation mediation person at interior autoimmune disease.In all these situations, high Hsp90 activity helps virus assembling and duplicates or it is transduceing required for abnormal signal in inappropriate activated lymphocyte.And the also known HSP90 inhibitor of people can cause other heat shock proteins, and (for example, HSP70) raise, this can provide neuroprotective and cardioprotection at ischemic injury and by the caused infringement of protein aggregation.Therefore, the HSP90 inhibitor can provide the treatment possibility aspect the treatment of central nervous system (CNS) illness and cardiovascular disorder.
Summary of the invention
In one aspect of the invention, provide novel 2-amino-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone compound, tautomer and steric isomer and pharmaceutically acceptable salt and prodrug.Described 2-amino-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone compound, pharmaceutically acceptable salt and prodrug are the HSP90 inhibitor and can be used for treating hyperplasia, viral, autoimmunization, cardiovascular and central nervous system disease.
In one embodiment, described 2-amino-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone compound has formula (I):
Figure S2006800365004D00031
Or its steric isomer, tautomer, pharmaceutically acceptable salt or prodrug, wherein
R aBe selected from the group that forms by following:
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4) C 1-C 6Alkoxyl group,
(5) mercaptan,
(6) C 1-C 6Alkyl sulfhydryl,
(7) be substituted or be unsubstituted C 1-C 6Alkyl,
It is (8) amino or be substituted amino,
(9) be substituted or be unsubstituted aryl,
(10) be substituted or be unsubstituted heteroaryl, and
(11) be substituted or be unsubstituted heterocyclic radical;
R is selected from the group that is made up of following:
(1) hydrogen,
(2) be substituted or be unsubstituted C 1-C 6Alkyl,
(3) be substituted or be unsubstituted C 2-C 6Thiazolinyl,
(4) be substituted or be unsubstituted C 2-C 6Alkynyl,
(5) be substituted or be unsubstituted C 3-C 7Cycloalkyl,
(6) be substituted or be unsubstituted C 5-C 7Cycloalkenyl group,
(7) be substituted or be unsubstituted aryl,
(8) be substituted or be unsubstituted heteroaryl, and
(9) be substituted or be unsubstituted heterocyclic radical;
R bBe selected from the group that forms by following:
(1) is substituted or is unsubstituted C 3-C 7Cycloalkyl,
(2) be substituted or be unsubstituted C 5-C 7Cycloalkenyl group,
(3) be substituted or be unsubstituted aryl,
(4) be substituted or be unsubstituted heteroaryl, and
(5) be substituted or be unsubstituted heterocyclic radical;
Restricted condition is to work as R aDuring for amino, R then bBe not phenyl, 4-alkyl-phenyl, 4-phenalkyloxy-or 4-halo-phenyl.
On the other hand, the invention provides the method for the cell proliferative diseases that is used for the treatment of the mankind that need this treatment or animal individual, it comprises to described individual the throwing with a certain amount of can reduce or prevent the outgrowth formula of described individual cells (I) compound effectively.
Aspect another, the invention provides the method for the cell proliferative diseases that is used for the treatment of the mankind that need this treatment or animal individual, it comprises to described individual the throwing with a certain amount of can reduce or prevent the outgrowth formula of described individual cells (I) compound and at least a combination that is used for the treatment of the additional agent of cancer effectively.
In other respects, the invention provides and comprise following therapeutic composition: at least a formula (I) compound and one or more are used for the treatment of the combination of the additional agent medicament of cancer therapy (as be usually used in) of cancer.
In one embodiment, provide compound, composition and the method for the treatment of the patient's condition by adjusting HSP90 activity.In some aspects, the described patient's condition is hyperplasia, viral, autoimmunization, cardiovascular or central nervous system disease.
In one embodiment, be provided for the compound of treatment such as cancers such as (for example) following, composition and method: lung cancer and bronchogenic carcinoma, prostate cancer, tumor of testis, breast cancer, carcinoma of the pancreas, the colorectal carcinoma and the rectum cancer, thyroid carcinoma, cancer of the stomach, liver cancer and stones in intrahepatic bile duct cancer, kidney and carcinoma of renal pelvis, bladder cancer, carcinoma of uterine body, cervical cancer, ovarian cancer, multiple myeloma, esophagus cancer, acute myelogenous leukemia, chronic lymphocytic leukemia, Lymphocytic leukemia, lymphoma, myelomatosis, mast cell leukemia, the cancer of the brain, oral carcinoma and pharynx cancer, laryngocarcinoma, head cancer knurl, neck cancer knurl, glioma, carcinoma of small intestine, gastrointestinal stromal tumors (GIST), gastric tumor, non-Hodgkin (non-hodgkin) lymphoma, melanoma and fine hair shape adenoma of colon.
In one embodiment, be provided for treating compound, composition and the method for virus disease.These diseases comprise that (for example) is subjected to the virus disease of hepatitis B virus (HBV), hepatitis C virus (HCV) or herpes simplex types 1 virus (HSV-1) mediation.
In one embodiment, be provided for treating compound, composition and the method for autoimmune disease.In some aspects, described autoimmune disease is mediated by the persistence lymphocyte activation.
In one embodiment, be provided for treating compound, composition and the method for cardiovascular or central nervous system disease.
The present invention further provides as at composition described in the specific embodiment of the present invention, cover group, using method and preparation method and relevant synthetic intermediate.
Description of drawings
Embodiment
In one aspect of the invention, provide novel 2-amino-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5 ketone compound, steric isomer and tautomer and pharmaceutically acceptable salt and prodrug.Described 2-amino-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5 ketone compound, steric isomer and tautomer and pharmaceutically acceptable salt thereof and prodrug are the HSP90 inhibitor and can be used for treating hyperplasia, viral, autoimmunization, cardiovascular and central nervous system disease.
In one embodiment, 2-amino-7 of the present invention, 8-dihydro-6H-pyrido [4,3-d] pyrimidine-5 ketone compound has formula (I):
Or its steric isomer, tautomer, pharmaceutically acceptable salt or prodrug, wherein
R aBe selected from the group that forms by following:
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4) C 1-C 6Alkoxyl group,
(5) mercaptan,
(6) C 1-C 6Alkyl sulfhydryl,
(7) be substituted or be unsubstituted C 1-C 6Alkyl,
It is (8) amino or be substituted amino,
(9) be substituted or be unsubstituted aryl,
(10) be substituted or be unsubstituted heteroaryl, and
(11) be substituted or be unsubstituted heterocyclic radical;
R is selected from the group that is made up of following:
(1) hydrogen,
(2) be substituted or be unsubstituted C 1-C 6Alkyl,
(3) be substituted or be unsubstituted C 2-C 6Thiazolinyl,
(4) be substituted or be unsubstituted C 2-C 6Alkynyl,
(5) be substituted or be unsubstituted C 3-C 7Cycloalkyl,
(6) be substituted or be unsubstituted C 5-C 7Cycloalkenyl group,
(7) be substituted or be unsubstituted aryl,
(8) be substituted or be unsubstituted heteroaryl, and
(9) be substituted or be unsubstituted heterocyclic radical;
R bBe selected from the group that forms by following:
(1) is substituted or is unsubstituted C 3-C 7Cycloalkyl,
(2) be substituted or be unsubstituted the C5-C7 cycloalkenyl group,
(3) be substituted or be unsubstituted aryl,
(4) be substituted or be unsubstituted heteroaryl, and
(5) be substituted or be unsubstituted heterocyclic radical; And
Restricted condition is to work as R aDuring for amino, R then bBe not phenyl, 4-alkyl-phenyl, 4-phenalkyloxy-or 4-halo-phenyl.
Other embodiment provide a kind of compound with formula (Ia):
Or tautomer, pharmaceutically acceptable salt or its prodrug, wherein R, R aAnd R bBy as before formula (I) was defined and restricted condition is to work as R aDuring for amino, R then bBe not phenyl, 4-alkyl-phenyl, 4-phenalkyloxy-or 4-halo-phenyl.
In formula (I) or (Ia) among some embodiment of compound, R aBe hydrogen.
In other embodiments, R aFor being substituted or being unsubstituted C 1-C 6Alkyl.
In certain embodiments, R aBe C 1-C 6Alkyl or halo C 1-C 6Alkyl.In some described embodiment, R aBe methyl.
In certain embodiments, R bBe aryl or heteroaryl.In some described embodiment, R bBe selected from the group that is made up of phenyl, pyridyl, pyrimidyl, pyrazinyl, indyl, thiazolyl and thienyl, described substituting group can be substituted or be unsubstituted separately.In some aspects, the invention provides wherein above-mentioned R bGroup is through being substituted or being unsubstituted aryl or being substituted or being unsubstituted the compound that heteroaryl replaces.In other respects, described R bGroup can replace through halogen.Aspect other, described R bGroup can replace through fluorine.Aspect other, described R bGroup can replace through alkyl, haloalkyl, alkoxyl group and halogenated alkoxy.In some aspects, described R bGroup can be through methyl substituted.In other respects, described R bGroup can replace through methoxyl group.
In other embodiments, R bBe selected from by being substituted aryl, being substituted heterocyclic radical, being substituted heteroaryl, being substituted C 3-C 7Cycloalkyl and be substituted C 5-C 7The group that cycloalkenyl group is formed, wherein said aryl, heterocyclic radical, heteroaryl, C 3-C 7Cycloalkyl and C 5-C 7Cycloalkenyl group is selected from the group that is made up of following: pyrryl, phenyl, pyridyl, pyrazinyl, pyrimidyl, clatter piperazine base, pyrazolyl, imidazolyl, triazolyl, indyl, oxadiazole base, thiadiazolyl group, furyl, quinolyl, isoquinolyl, isoxazolyl, oxazolyl, thiazolyl, morpholinyl, piperidyl, pyrrolidyl, thienyl, cyclohexyl, cyclopentyl, cyclohexenyl and cyclopentenyl.In some aspects, above-mentioned group can be selected from the substituting group replacement of being made of group halogen, alkoxyl group, alkyl, amino, alkylamino, haloalkyl and halogenated alkoxy through 1 to 2.
In certain embodiments, R is selected from by hydrogen, is unsubstituted alkyl and is substituted the group that alkyl is formed.In some described embodiment, R is selected from the group that is made up of methyl, ethyl, allyl group, 3-methyl-butyl and isobutyl-.In other embodiments, R is selected from by hydrogen, benzyl, 1-(4-p-methoxy-phenyl) ethyl, methyl, 3-aminopropyl and group that the 2-methyl-the 2-morpholinyl propyl is formed.In another embodiment, R is a hydrogen.
In another embodiment, described 2-amino-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5 ketone compound has formula (II):
Or its steric isomer, tautomer, pharmaceutically acceptable salt or prodrug, wherein
N is 0 or 1,
R wherein aBe selected from the group that forms by following:
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4) C 1-C 6Alkoxyl group,
(5) mercaptan,
(6) C 1-C 6Alkyl sulfhydryl,
(7) be substituted or be unsubstituted C 1-C 6Alkyl,
It is (8) amino or be substituted amino,
(9) be substituted or be unsubstituted aryl,
(10) be substituted or be unsubstituted heteroaryl, and
(11) be substituted or be unsubstituted heterocyclic radical;
Wherein R is selected from the group that is made up of following:
(1) hydrogen,
(2) be substituted or be unsubstituted C 1-C 6Alkyl,
(3) be substituted or be unsubstituted C 2-C 6Thiazolinyl,
(4) be substituted or be unsubstituted C 2-C 6Alkynyl,
(5) be substituted or be unsubstituted C 3-C 7Cycloalkyl,
(6) be substituted or be unsubstituted C 5-C 7Cycloalkenyl group,
(7) be substituted or be unsubstituted aryl,
(8) be substituted or be unsubstituted heteroaryl, and
(9) be substituted or be unsubstituted heterocyclic radical,
Wherein, when n was 1, then X was C, and the Y of each position is independently selected from CQ 1And N, and Z is selected from CR 2And N, restricted condition is to be no more than 3 Y and the Z group is N, and
Wherein, when n was 0, then X was C or N, and the Y of each position is independently selected from CQ 1, N, NQ 2, O and S, restricted condition is to be no more than 4 X and Y group is N and NQ 2And being no more than 1 Y group is S or O;
Wherein, the Q of each position 1Be independently selected from the group that forms by following:
(1) hydrogen,
(2) halogen,
(3) be substituted or be unsubstituted C 1-C 6Alkyl,
(4) be substituted or be unsubstituted C 2-C 6Thiazolinyl,
(5) be substituted or be unsubstituted the C2-C6 alkynyl,
(6) be substituted or be unsubstituted the C3-C7 cycloalkyl,
(7) be substituted or be unsubstituted C 5-C 7Cycloalkenyl group,
(8) be substituted or be unsubstituted aryl,
(9) be substituted or be unsubstituted heteroaryl,
(10) be substituted or be unsubstituted heterocyclic radical,
(11) be substituted or be unsubstituted amino,
(12)-OR 3Or-SR 3,
(13)-C (O) R 3,-CO 2R 3,-C (O) N (R 3) 2,-S (O) R 3,-SO 2R 3, or-SO 2N (R 3) 2,
(14)-OC (O) R 3,-N (R 3) C (O) R 3, or-N (R 3) SO 2R 3,
(15)-CN, and
(16)-NO 2；
Wherein, the Q of each position 2Be independently selected from the group that forms by following:
(1) hydrogen,
(3) be substituted or be unsubstituted C 1-C 6Alkyl,
(4) be substituted or be unsubstituted C 2-C 6Thiazolinyl,
(5) be substituted or be unsubstituted C 2-C 6Alkynyl,
(6) be substituted or be unsubstituted C 3-C 7Cycloalkyl,
(7) be substituted or be unsubstituted C 5-C 7Cycloalkenyl group,
(8) be substituted or be unsubstituted aryl,
(9) be substituted or be unsubstituted heteroaryl, and
(10) be substituted or be unsubstituted heterocyclic radical;
R wherein 2Be selected from the group that forms by following:
(1) hydrogen,
(2) halogen,
(3) be substituted or be unsubstituted C 1-C 3Alkyl, and
(4)-OR 3,-SR 3Or-NHR 3
Wherein, the R of each position 3Be independently selected from the group that forms by following:
(1) hydrogen,
(2) be substituted or be unsubstituted C 1-C 6Alkyl,
(3) be substituted or be unsubstituted C 2-C 6Thiazolinyl,
(4) be substituted or be unsubstituted C 2-C 6Alkynyl,
(5) be substituted or be unsubstituted C 3-C 7Cycloalkyl,
(6) be substituted or be unsubstituted C 5-C 7Cycloalkenyl group,
(7) be substituted or be unsubstituted aryl,
(8) be substituted or be unsubstituted heteroaryl, and
(9) be substituted or be unsubstituted heterocyclic radical,
Restricted condition is to work as R aDuring for amino, then X, Y, Z and n can not form phenyl, 4-alkyl-phenyl, 4-phenalkyloxy-or 4-halo-phenyl together.
In other embodiments, described 2-amino-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5 ketone compound has formula (IIa):
Figure S2006800365004D00091
Or its tautomer, pharmaceutically acceptable salt or prodrug, wherein R a, R, X, Y, Z and n by as before formula (II) was defined and restricted condition is to work as R aDuring for amino, then X, Y, Z and n can not form phenyl, 4-alkyl-phenyl, 4-phenalkyloxy-or 4-halo-phenyl together.
In certain embodiments, when n was 0, then X was that C and the Y that closes on X are not O.
In formula (II) or (IIa) among some embodiment of compound, R aBe hydrogen.
In other embodiments, R aFor being substituted or being unsubstituted C 1-C 6Alkyl.
In certain embodiments, R aBe C 1-C 6Alkyl or halo C 1-C 6Alkyl.In some described embodiment, R aBe methyl.
For formula (I), (Ia), (II) or (IIa) for the compound, representativeness is substituted alkyl and comprises arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclic radical alkyl, aminoalkyl group, alkylamino alkyl, dialkyl aminoalkyl and sulfoamido alkyl.
Representative aryl comprises phenyl.
Representative heteroaryl comprises pyridyl, pyrazinyl, pyrimidyl, clatter piperazine base, pyrazolyl, indyl, quinolyl, isoquinolyl, furyl, oxazolyl, thiazolyl and thienyl.
In one embodiment, Q 1Or Q 2In one be selected from the group that forms by following: be substituted and be unsubstituted phenyl, be substituted and be unsubstituted pyridyl, be substituted and be unsubstituted pyrimidyl, be substituted and be unsubstituted pyrazinyl, be substituted and be unsubstituted indyl, be substituted and be unsubstituted thiazolyl and be substituted and be unsubstituted thienyl.
In one embodiment, Q 1Or Q 2In one be selected from the group that forms by piperidyl, morpholinyl, pyrrolidone-base and benzylamino.
In one embodiment, Q 1Or Q 2In one be selected from the group that forms by cyclohexyl and cyclopentyl.
In one embodiment, Q 1Or Q 2In one be selected from the group that forms by cyclohexenyl and cyclopentenyl.
In one embodiment, Q 1Or Q 2In one be selected from by being substituted aryl, being substituted heterocyclic radical, being substituted heteroaryl, being substituted C 3-C 7Cycloalkyl and be substituted C 5-C 7The group that cycloalkenyl group is formed, wherein said aryl, heterocyclic radical, heteroaryl, C 3-C 7Cycloalkyl and C 5-C 7Cycloalkenyl group is selected from the group that is made up of following: pyrryl, phenyl, pyridyl, pyrazinyl, pyrimidyl, clatter piperazine base, pyrazolyl, imidazolyl, triazolyl, indyl, oxadiazole base, thiadiazolyl group, furyl, quinolyl, isoquinolyl, isoxazolyl, oxazolyl, thiazolyl, morpholinyl, piperidyl, pyrrolidyl, thienyl, cyclohexyl, cyclopentyl, cyclohexenyl and cyclopentenyl.In some aspects, above-mentioned group can be selected from the substituting group replacement of being made of group halogen, alkoxyl group, alkyl, amino, alkylamino, haloalkyl and halogenated alkoxy through 1 to 2.
In one embodiment, Q 1Or Q 2In one be to be selected to be substituted and to be unsubstituted pyridyl, be substituted and be unsubstituted pyrazinyl, be substituted and be unsubstituted phenyl, be substituted and be unsubstituted isoquinolyl, be substituted and be unsubstituted pyrimidyl, be substituted and be unsubstituted pyrazolyl and be substituted and be unsubstituted furyl.In some aspects, above-mentioned group can be selected from the substituting group replacement of being made of group halogen, alkoxyl group, alkyl, amino, alkylamino, haloalkyl and halogenated alkoxy through 1 to 2.
In other embodiments, Q 1Or Q 2In one be selected from the group that forms by following: (2-hydroxyl-ethylamino)-pyrazine-2-base; 1H-pyrazoles-4-base; 1-methyl isophthalic acid H-pyrazoles-4-base; 1-methyl isophthalic acid H-pyrazoles-4-base; 2-(5-methyl-pyridine-2-yl)-phenyl; 2; 3-two fluoro-phenyl; 2; 3-dimethoxy-phenyl; 2; 4-two fluoro-phenyl; 2; 4-dimethoxy-phenyl; 2; 4-dimethoxy-pyrimidine-5-base; 2; 5-two fluoro-phenyl; 2; 6-two fluoro-phenyl; 2; 6-dimethyl-pyridin-3-yl; 2-acetamido phenyl; the 2-aminocarbonyl-phenyl; 2-amino-pyrimidine-5-base; 2-chloro-4-methoxyl group-pyrimidine-5-base; 2-chloro-5-fluoro-pyridin-3-yl; 2-chloro-phenyl; 2-chloro-pyridin-3-yl; 2-chloro-pyridin-4-yl; 2-two fluoro-3-p-methoxy-phenyls; 2-ethyl-phenyl; 2-oxyethyl group-thiazole-4-base; 2-fluoro-3-methoxyl group-phenyl; 2-fluoro-3-aminomethyl phenyl; 2-fluoro-4-methyl-phenyl; 2-fluoro-5-methoxyl group-phenyl; 2-fluoro-5-aminomethyl phenyl; the 2-fluorophenyl; 2-fluoro-pyridin-3-yl; 2-hydroxymethyl-3-p-methoxy-phenyl; 2-hydroxymethyl phenyl; 2-isoquinoline 99.9-4-base; 2-methoxyl group-5-trifluoromethyl-phenyl; 2-methoxyl group-phenyl; 2-methoxyl group-pyridin-3-yl; 2-methoxyl group-pyrimidine-4-base; 2-methoxyl group-thiazole-4-base; 2-methyl-phenyl; 2-methyl-pyridin-3-yl; 2-oxo-1; 2-dihydro-pyridin-3-yl; the 2-Phenoxyphenyl; the 2-pyridin-3-yl; 2-pyrimidine-5-base; the 2-Trifluoromethoxyphen-l; 2-trifluoromethoxy-phenyl; 3; 4-dimethoxy-phenyl; 3; 5-dimethyl-isoxazole-4-bases; 3; 6-dimethyl-pyrazine-2-base; 3-acetamido phenyl; the 3-aminocarbonyl-phenyl; 3-bromo-phenyl; 3-chloro-pyrazine-2-base; the 3-cyano-phenyl; the 3-dimethylaminophenyl; 3-oxyethyl group-phenyl; 3-ethyl-4-methyl-phenyl; 3-ethynyl-phenyl; 3-fluoro-6-methoxyl group-pyridine-2-base; the 3-fluorophenyl; 3-fluoro-pyrazine-2-base; 3-sulfonyl methane amido phenyl; 3-methoxycarbonyl phenyl; the 3-p-methoxy-phenyl; 3-methoxyl group-pyrazine-2-base; 3-methyl-3H-imidazo [4; 5-b] pyrazine-5-base; the 3-aminomethyl phenyl; 3-methyl-pyridine-2-base; the 3-Trifluoromethoxyphen-l; the 3-trifluoromethyl; 4; 5-dimethoxy-pyrimidine-2-base; 4-amino-5-fluoro-pyrimidine-2-base; 4-chloro-2; 5-dimethoxy-phenyl; 4-chloro-2-fluoro-phenyl; 4-chloro-2-methoxyl group-5-methyl-phenyl; 4-chloro-pyridin-3-yl; 4-two fluoro-2-methyl-phenyl; 4-oxyethyl group-5-fluoro-pyrimidine-2-base; 4-oxyethyl group-pyrimidine-2-base; 4-oxyethyl group-pyrimidine-5-base; 4-ethyl-1H-pyrazole-3-yl; 4-fluoro-2-methoxyl group-phenyl; 4-fluoro-2-methyl-phenyl; the 4-fluorophenyl; 4-methoxyl group-5-methyl-pyrimidine-2-base; 4-methoxyl group-pyridin-3-yl; 4-methoxyl group-pyrimidine-2-base; 4-methoxyl group-pyrimidine-5-base; 4-methyl-phenyl; 4-methyl-pyridine-2-base; 4-methyl-pyridin-3-yl; 4-tetramethyleneimine-1-base-pyrimidine-2-base; 5; 6-dimethoxy-pyrazine-2-base; 5-ethanoyl-thiophene-2-base; 5-amino-6-oxyethyl group-pyrazine-2-base; 5-amino-6-methoxyl group-3-methyl-pyrazine-2-base; 5-amino-6-methoxyl group-pyridine-2-base; 5-chloro-4-methoxyl group-pyrimidine-2-base; 5-chloro-6-methoxyl group-pyrazine-2-base; 5-dimethylamino-6-methoxyl group-pyrazine-2-base; 5-fluoro-2-p-methoxy-phenyl; 5-fluoro-4-methoxyl group-pyrimidine-2-base; 5-fluoro-6-methoxyl group-pyrazine-2-base; 5-fluoro-pyridine-2-base; 5-methoxyl group-pyridin-3-yl; 5-methoxyl group-thiophene-2-base; 5-trifluoromethyl-pyrimidine-2-base; 6-ethanoyl-pyridine-2-base; 6-chloro-pyrazine-2-base; 6-oxyethyl group-pyrazine-2-base; 6-oxyethyl group-pyridine-2-base; 6-fluoro-pyridine-2-base; 6-fluoro-pyridin-3-yl; 6-hydroxyl-pyridine-2-base; 6-methoxyl group-5-methylamino-pyrazine-2-base; 6-methoxyl group-5-methyl-pyrazine-2-base; 6-methoxyl group-pyrazine-2-base; 6-methoxyl group-pyridine-2-base; 6-methoxyl group-pyridin-3-yl; 6-methylamino-pyrazine-2-base; 6-methyl-pyridine-2-base; 5-amino-6-(2; 2, the 2-trifluoro ethoxy) pyrazine-2-base and 6-trifluoromethyl-pyridine-2-base.
In one embodiment, Q 1Be halogen.
In one embodiment, Q 1Be alkyl.In some aspects, Q 1Be methyl.
In one embodiment, R 2Be selected from hydrogen and fluorine.In some aspects, R 2Be fluorine.
In one embodiment, R 2Be selected from alkyl.In some aspects, R 2Be methyl.
In one embodiment, R 2Be selected from alkoxyl group.In some aspects, R 2Be methoxyl group.
In one embodiment, Q 1Be OR 3
In one embodiment, R 3Be selected from the group that forms by methyl, ethyl, sec.-propyl, cyclopentyl and cyclohexyl.
In one embodiment, R 3Be selected from and be substituted and be unsubstituted phenyl, be substituted and be unsubstituted thiazolyl, be substituted and be unsubstituted pyridyl, be substituted and be unsubstituted pyrazinyl and be substituted and be unsubstituted pyrimidyl.
In one embodiment, R 3Be selected from the group that forms by 2-amino-ethyl, 2-piperidyl ethyl, 2-piperazine ethyl, 2-morpholinyl ethyl and 2-(N methyl piperazine) ethyl.
In certain embodiments, R is selected from by hydrogen, is unsubstituted alkyl and is substituted the group that alkyl is formed.In some described embodiment, R is selected from the group that is made up of methyl, ethyl, allyl group, 3-methyl-butyl and isobutyl-.In other embodiments, R is selected from by hydrogen, benzyl, 1-(4-p-methoxy-phenyl) ethyl, methyl, 3-aminopropyl and group that the 2-methyl-the 2-morpholinyl propyl is formed.
In another embodiment of the present invention, provide the compound of formula (III):
Figure S2006800365004D00121
Or its steric isomer, tautomer, pharmaceutically acceptable salt or prodrug, wherein
R wherein aBe selected from the group that forms by following:
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4) C 1-C 6Alkoxyl group,
(5) mercaptan,
(6) C 1-C 6Alkyl sulfhydryl,
(7) be substituted or be unsubstituted C 1-C 6Alkyl,
It is (8) amino or be substituted amino,
(9) be substituted or be unsubstituted aryl,
(10) be substituted or be unsubstituted heteroaryl, and
(11) be substituted or be unsubstituted heterocyclic radical;
R 4For hydrogen or be substituted or be unsubstituted C 1-C 6Alkyl;
R 5Be hydrogen, alkyl, alkoxyl group or halogen;
R 6, R 7, R 8And R 9Be selected from independently of one another by hydrogen, alkyl, alkoxyl group, halogen, be substituted or be unsubstituted aryl, and be substituted or be unsubstituted the group that heteroaryl is formed; Perhaps
Its steric isomer, tautomer, pharmaceutically acceptable salt or prodrug, and restricted condition is to work as R aBe amino and R 6, R 7, R 8And R 9During for hydrogen, R then 5Not can be hydrogen, alkyl, alkoxyl group or halogen.
In certain embodiments, provide formula (IIIa) compound:
Figure S2006800365004D00131
Or its tautomer, pharmaceutically acceptable salt or prodrug, wherein R a, R 4, R 5, R 6, R 7, R 8And R 9Be such as before to formula (III) definition and restricted condition be to work as R aBe amino and R 6, R 7, R 8And R 9During for hydrogen, R then 5Be not hydrogen, alkyl, alkoxyl group or halogen.
In certain embodiments, R aBe hydrogen.
In certain embodiments, R aFor being substituted or being unsubstituted C 1-C 6Alkyl.
In certain embodiments, R aBe C 1-C 6Alkyl or halo C 1-C 6Alkyl.In some described embodiment, R aBe methyl.
In certain embodiments of the present invention, R 4Be selected from by hydrogen, benzyl, 1-(4-p-methoxy-phenyl) ethyl, methyl, 3-aminopropyl and group that the 2-methyl-the 2-morpholinyl propyl is formed.In other embodiments, R is selected from the group that is made up of methyl, ethyl, allyl group, 3-methyl-butyl and isobutyl-.
In certain embodiments, R 5Be hydrogen or fluorine.In some aspects, R 5Be fluorine.
In certain embodiments, R 5Be methyl or methoxy.
In certain embodiments, R 7, R 8, R 9The hydrogen of respectively doing for oneself.
In certain embodiments, R 6For being selected from aryl or the heteroaryl of forming the substituting group replacement of group by halogen, alkoxyl group, alkyl, amino, alkylamino, haloalkyl and halogenated alkoxy through 1 to 2.
In certain embodiments, R 6Be selected from by being substituted aryl and being substituted the group that heteroaryl is formed, wherein said aryl and heteroaryl are selected from the group that is made up of following: furyl, pyrryl, phenyl, pyridyl, pyrazinyl, pyrimidyl, clatter piperazine base, pyrazolyl, imidazolyl, triazolyl, indyl, oxadiazole base, thiadiazolyl group, quinolyl, isoquinolyl, isoxazolyl, oxazolyl, thiazolyl and thienyl.In some aspects, above-mentioned group can be selected from the substituting group replacement of being made of group halogen, alkoxyl group, alkyl, amino, alkylamino, haloalkyl and halogenated alkoxy through 1 to 2.In other embodiments, R 6Be selected from the group that forms by following: (2-hydroxyl-ethylamino)-pyrazine-2-base; 1H-pyrazoles-4-base; 1-methyl isophthalic acid H-pyrazoles-4-base; 1-methyl isophthalic acid H-pyrazoles-4-base; 2-(5-methyl-pyridine-2-yl)-phenyl; 2; 3-two fluoro-phenyl; 2; 3-dimethoxy-phenyl; 2; 4-two fluoro-phenyl; 2; 4-dimethoxy-phenyl; 2; 4-dimethoxy-pyrimidine-5-base; 2; 5-two fluoro-phenyl; 2; 6-two fluoro-phenyl; 2; 6-dimethyl-pyridin-3-yl; 2-acetamido phenyl; the 2-aminocarbonyl-phenyl; 2-amino-pyrimidine-5-base; 2-chloro-4-methoxyl group-pyrimidine-5-base; 2-chloro-5-fluoro-pyridin-3-yl; 2-chloro-phenyl; 2-chloro-pyridin-3-yl; 2-chloro-pyridin-4-yl; 2-two fluoro-3-p-methoxy-phenyls; 2-ethyl-phenyl; 2-oxyethyl group-thiazole-4-base; 2-fluoro-3-methoxyl group-phenyl; 2-fluoro-3-aminomethyl phenyl; 2-fluoro-4-methyl-phenyl; 2-fluoro-5-methoxyl group-phenyl; 2-fluoro-5-aminomethyl phenyl; the 2-fluorophenyl; 2-fluoro-pyridin-3-yl; 2-hydroxymethyl-3-p-methoxy-phenyl; 2-hydroxymethyl phenyl; 2-isoquinoline 99.9-4-base; 2-methoxyl group-5-trifluoromethyl-phenyl; 2-methoxyl group-phenyl; 2-methoxyl group-pyridin-3-yl; 2-methoxyl group-pyrimidine-4-base; 2-methoxyl group-thiazole-4-base; 2-methyl-phenyl; 2-methyl-pyridin-3-yl; 2-oxo-1; 2-dihydro-pyridin-3-yl; the 2-Phenoxyphenyl; the 2-pyridin-3-yl; 2-pyrimidine-5-base; the 2-Trifluoromethoxyphen-l; 2-trifluoromethoxy-phenyl; 3; 4-dimethoxy-phenyl; 3; 5-dimethyl-isoxazole-4-bases; 3; 6-dimethyl-pyrazine-2-base; 3-acetamido phenyl; the 3-aminocarbonyl-phenyl; 3-bromo-phenyl; 3-chloro-pyrazine-2-base; the 3-cyano-phenyl; the 3-dimethylaminophenyl; 3-oxyethyl group-phenyl; 3-ethyl-4-methyl-phenyl; 3-ethynyl-phenyl; 3-fluoro-6-methoxyl group-pyridine-2-base; the 3-fluorophenyl; 3-fluoro-pyrazine-2-base; 3-sulfonyl methane amido phenyl; 3-methoxycarbonyl phenyl; the 3-p-methoxy-phenyl; 3-methoxyl group-pyrazine-2-base; 3-methyl-3H-imidazo [4; 5-b] pyrazine-5-base; the 3-aminomethyl phenyl; 3-methyl-pyridine-2-base; the 3-Trifluoromethoxyphen-l; the 3-trifluoromethyl; 4; 5-dimethoxy-pyrimidine-2-base; 4-amino-5-fluoro-pyrimidine-2-base; 4-chloro-2; 5-dimethoxy-phenyl; 4-chloro-2-fluoro-phenyl; 4-chloro-2-methoxyl group-5-methyl-phenyl; 4-chloro-pyridin-3-yl; 4-two fluoro-2-methyl-phenyl; 4-oxyethyl group-5-fluoro-pyrimidine-2-base; 4-oxyethyl group-pyrimidine-2-base; 4-oxyethyl group-pyrimidine-5-base; 4-ethyl-1H-pyrazole-3-yl; 4-fluoro-2-methoxyl group-phenyl; 4-fluoro-2-methyl-phenyl; the 4-fluorophenyl; 4-methoxyl group-5-methyl-pyrimidine-2-base; 4-methoxyl group-pyridin-3-yl; 4-methoxyl group-pyrimidine-2-base; 4-methoxyl group-pyrimidine-5-base; 4-methyl-phenyl; 4-methyl-pyridine-2-base; 4-methyl-pyridin-3-yl; 4-tetramethyleneimine-1-base-pyrimidine-2-base; 5; 6-dimethoxy-pyrazine-2-base; 5-ethanoyl-thiophene-2-base; 5-amino-6-oxyethyl group-pyrazine-2-base; 5-amino-6-methoxyl group-3-methyl-pyrazine-2-base; 5-amino-6-methoxyl group-pyridine-2-base; 5-chloro-4-methoxyl group-pyrimidine-2-base; 5-chloro-6-methoxyl group-pyrazine-2-base; 5-dimethylamino-6-methoxyl group-pyrazine-2-base; 5-fluoro-2-p-methoxy-phenyl; 5-fluoro-4-methoxyl group-pyrimidine-2-base; 5-fluoro-6-methoxyl group-pyrazine-2-base; 5-fluoro-pyridine-2-base; 5-methoxyl group-pyridin-3-yl; 5-methoxyl group-thiophene-2-base; 5-trifluoromethyl-pyrimidine-2-base; 6-ethanoyl-pyridine-2-base; 6-chloro-pyrazine-2-base; 6-oxyethyl group-pyrazine-2-base; 6-oxyethyl group-pyridine-2-base; 6-fluoro-pyridine-2-base; 6-fluoro-pyridin-3-yl; 6-hydroxyl-pyridine-2-base; 6-methoxyl group-5-methylamino-pyrazine-2-base; 6-methoxyl group-5-methyl-pyrazine-2-base; 6-methoxyl group-pyrazine-2-base; 6-methoxyl group-pyridine-2-base; 6-methoxyl group-pyridin-3-yl; 6-methylamino-pyrazine-2-base; 6-methyl-pyridine-2-base; 5-amino-6-(2; 2, the 2-trifluoro ethoxy) pyrazine-2-base and 6-trifluoromethyl-pyridine-2-base.
In another embodiment of the present invention, provide the compound of formula (IV):
Figure S2006800365004D00141
Or its steric isomer, tautomer, pharmaceutically acceptable salt or prodrug, wherein
R 4For hydrogen or be substituted or be unsubstituted C 1-C 6Alkyl,
R 5Be hydrogen or halogen,
R 6aBe selected from by halogen, be substituted or be unsubstituted aryl and be substituted or be unsubstituted the group that heteroaryl is formed.The compound of formula (IVa) is provided in certain embodiments:
Figure S2006800365004D00151
Or its tautomer, pharmaceutically acceptable salt or prodrug, wherein
R 4, R 5And R 6aBe such as before to formula (IV) definition.
In formula (IV) or (IVa) among some embodiment of compound, R 4Be selected from by hydrogen, benzyl, 1-(4-p-methoxy-phenyl) ethyl, methyl, 3-aminopropyl and group that the 2-methyl-the 2-morpholinyl propyl is formed.In other embodiments, R is selected from the group that is made up of methyl, ethyl, allyl group, 3-methyl-butyl and isobutyl-.
In certain embodiments, R 5Be hydrogen or fluorine.In some aspects, R 5Be fluorine.
In some aspects, R 6aFor being selected from aryl or the heteroaryl of forming the substituting group replacement of group by halogen, alkoxyl group, alkyl, amino, alkylamino, haloalkyl and halogenated alkoxy through 1 to 2.
In certain embodiments, R 6aBe selected from by being substituted aryl and being substituted the group that heteroaryl is formed, wherein said aryl and heteroaryl are selected from the group that is made up of following: furyl, pyrryl, phenyl, pyridyl, pyrazinyl, pyrimidyl, clatter piperazine base, pyrazolyl, imidazolyl, triazolyl, indyl, oxadiazole base, thiadiazolyl group, quinolyl, isoquinolyl, isoxazolyl, oxazolyl, thiazolyl and thienyl.In some aspects, above-mentioned group is for being selected from the substituting group replacement of being made of group halogen, alkoxyl group, alkyl, amino, alkylamino, haloalkyl and halogenated alkoxy through 1 to 2.
In certain embodiments, R 6aBe selected from the group that forms by following: (2-hydroxyl-ethylamino)-pyrazine-2-base; 1H-pyrazoles-4-base; 1-methyl isophthalic acid H-pyrazoles-4-base; 1-methyl isophthalic acid H-pyrazoles-4-base; 2-(5-methyl-pyridine-2-yl)-phenyl; 2; 3-two fluoro-phenyl; 2; 3-dimethoxy-phenyl; 2; 4-two fluoro-phenyl; 2; 4-dimethoxy-phenyl; 2; 4-dimethoxy-pyrimidine-5-base; 2; 5-two fluoro-phenyl; 2; 6-two fluoro-phenyl; 2; 6-dimethyl-pyridin-3-yl; 2-acetamido phenyl; the 2-aminocarbonyl-phenyl; 2-amino-pyrimidine-5-base; 2-chloro-4-methoxyl group-pyrimidine-5-base; 2-chloro-5-fluoro-pyridin-3-yl; 2-chloro-phenyl; 2-chloro-pyridin-3-yl; 2-chloro-pyridin-4-yl; 2-two fluoro-3-p-methoxy-phenyls; 2-ethyl-phenyl; 2-oxyethyl group-thiazole-4-base; 2-fluoro-3-methoxyl group-phenyl; 2-fluoro-3-aminomethyl phenyl; 2-fluoro-4-methyl-phenyl; 2-fluoro-5-methoxyl group-phenyl; 2-fluoro-5-aminomethyl phenyl; the 2-fluorophenyl; 2-fluoro-pyridin-3-yl; 2-hydroxymethyl-3-p-methoxy-phenyl; 2-hydroxymethyl phenyl; 2-isoquinoline 99.9-4-base; 2-methoxyl group-5-trifluoromethyl-phenyl; 2-methoxyl group-phenyl; 2-methoxyl group-pyridin-3-yl; 2-methoxyl group-pyrimidine-4-base; 2-methoxyl group-thiazole-4-base; 2-methyl-phenyl; 2-methyl-pyridin-3-yl; 2-oxo-1; 2-dihydro-pyridin-3-yl; the 2-Phenoxyphenyl; the 2-pyridin-3-yl; 2-pyrimidine-5-base; the 2-Trifluoromethoxyphen-l; 2-trifluoromethoxy-phenyl; 3; 4-dimethoxy-phenyl; 3; 5-dimethyl-isoxazole-4-bases; 3; 6-dimethyl-pyrazine-2-base; 3-acetamido phenyl; the 3-aminocarbonyl-phenyl; 3-bromo-phenyl; 3-chloro-pyrazine-2-base; the 3-cyano-phenyl; the 3-dimethylaminophenyl; 3-oxyethyl group-phenyl; 3-ethyl-4-methyl-phenyl; 3-ethynyl-phenyl; 3-fluoro-6-methoxyl group-pyridine-2-base; the 3-fluorophenyl; 3-fluoro-pyrazine-2-base; 3-sulfonyl methane amido phenyl; 3-methoxycarbonyl phenyl; the 3-p-methoxy-phenyl; 3-methoxyl group-pyrazine-2-base; 3-methyl-3H-imidazo [4; 5-b] pyrazine-5-base; the 3-aminomethyl phenyl; 3-methyl-pyridine-2-base; the 3-Trifluoromethoxyphen-l; the 3-trifluoromethyl; 4; 5-dimethoxy-pyrimidine-2-base; 4-amino-5-fluoro-pyrimidine-2-base; 4-chloro-2; 5-dimethoxy-phenyl; 4-chloro-2-fluoro-phenyl; 4-chloro-2-methoxyl group-5-methyl-phenyl; 4-chloro-pyridin-3-yl; 4-two fluoro-2-methyl-phenyl; 4-oxyethyl group-5-fluoro-pyrimidine-2-base; 4-oxyethyl group-pyrimidine-2-base; 4-oxyethyl group-pyrimidine-5-base; 4-ethyl-1H-pyrazole-3-yl; 4-fluoro-2-methoxyl group-phenyl; 4-fluoro-2-methyl-phenyl; the 4-fluorophenyl; 4-methoxyl group-5-methyl-pyrimidine-2-base; 4-methoxyl group-pyridin-3-yl; 4-methoxyl group-pyrimidine-2-base; 4-methoxyl group-pyrimidine-5-base; 4-methyl-phenyl; 4-methyl-pyridine-2-base; 4-methyl-pyridin-3-yl; 4-tetramethyleneimine-1-base-pyrimidine-2-base; 5; 6-dimethoxy-pyrazine-2-base; 5-ethanoyl-thiophene-2-base; 5-amino-6-oxyethyl group-pyrazine-2-base; 5-amino-6-methoxyl group-3-methyl-pyrazine-2-base; 5-amino-6-methoxyl group-pyridine-2-base; 5-chloro-4-methoxyl group-pyrimidine-2-base; 5-chloro-6-methoxyl group-pyrazine-2-base; 5-dimethylamino-6-methoxyl group-pyrazine-2-base; 5-fluoro-2-p-methoxy-phenyl; 5-fluoro-4-methoxyl group-pyrimidine-2-base; 5-fluoro-6-methoxyl group-pyrazine-2-base; 5-fluoro-pyridine-2-base; 5-methoxyl group-pyridin-3-yl; 5-methoxyl group-thiophene-2-base; 5-trifluoromethyl-pyrimidine-2-base; 6-ethanoyl-pyridine-2-base; 6-chloro-pyrazine-2-base; 6-oxyethyl group-pyrazine-2-base; 6-oxyethyl group-pyridine-2-base; 6-fluoro-pyridine-2-base; 6-fluoro-pyridin-3-yl; 6-hydroxyl-pyridine-2-base; 6-methoxyl group-5-methylamino-pyrazine-2-base; 6-methoxyl group-5-methyl-pyrazine-2-base; 6-methoxyl group-pyrazine-2-base; 6-methoxyl group-pyridine-2-base; 6-methoxyl group-pyridin-3-yl; 6-methylamino-pyrazine-2-base; 6-methyl-pyridine-2-base; 5-amino-6-(2; 2, the 2-trifluoro ethoxy) pyrazine-2-base and 6-trifluoromethyl-pyridine-2-base.
In another embodiment, provide the formula V compound
Figure S2006800365004D00161
R wherein 10And R 11Be Q independently 1, and R a, R, Q 1And Q 2By as before formula (II) was defined.
In another embodiment, 2-amino-quinazolines-5 ketone compound has formula (Va):
Figure S2006800365004D00171
R wherein 10And R 11Be Q independently 1, and R a, R, Q 1And Q 2By as before formula V was defined.
At formula V and (Va) aspect some of compound, R aBe methyl.
At formula V and (Va) aspect other of compound, R aBe hydrogen.
At formula V and (Va) aspect some of compound, R is selected from by hydrogen, benzyl, 1-(4-p-methoxy-phenyl) ethyl, methyl, 3-aminopropyl and group that the 2-methyl-the 2-morpholinyl propyl is formed.In other respects, R is selected from the group that is made up of methyl, ethyl, allyl group, 3-methyl-butyl and isobutyl-.
At formula V and (Va) aspect some of compound, Q 2Be selected from by being substituted or being unsubstituted aryl, be substituted or be unsubstituted heterocyclic radical, be substituted or be unsubstituted heteroaryl, be substituted or be unsubstituted C 3-C 7Cycloalkyl and be substituted or be unsubstituted C 5-C 7The group that cycloalkenyl group is formed.In other respects, described aryl, heterocyclic radical, heteroaryl, C 3-C 7Cycloalkyl and C 5-C 7Cycloalkenyl group is selected from the group that is made up of following: phenyl, pyridyl, pyrazinyl, pyrimidyl, clatter piperazine base, pyrazolyl, imidazolyl, triazolyl, indyl, oxadiazole base, thiadiazolyl group, furyl, quinolyl, isoquinolyl, isoxazolyl, oxazolyl, thiazolyl, morpholinyl, piperidyl, pyrrolidyl, thienyl, cyclohexyl, cyclopentyl, cyclohexenyl and cyclopentenyl.In some aspects, above-mentioned group can be selected from the substituting group replacement of being made of group halogen, alkoxyl group, alkyl, amino, alkylamino, haloalkyl and halogenated alkoxy through 1 to 2.
At formula V and (Va) aspect other of compound, Q 2Be selected from the group that forms by following: (2-hydroxyl-ethylamino)-pyrazine-2-base; 1H-pyrazoles-4-base; 1-methyl isophthalic acid H-pyrazoles-4-base; 1-methyl isophthalic acid H-pyrazoles-4-base; 2-(5-methyl-pyridine-2-yl)-phenyl; 2; 3-two fluoro-phenyl; 2; 3-dimethoxy-phenyl; 2; 4-two fluoro-phenyl; 2; 4-dimethoxy-phenyl; 2; 4-dimethoxy-pyrimidine-5-base; 2; 5-two fluoro-phenyl; 2; 6-two fluoro-phenyl; 2; 6-dimethyl-pyridin-3-yl; 2-acetamido phenyl; the 2-aminocarbonyl-phenyl; 2-amino-pyrimidine-5-base; 2-chloro-4-methoxyl group-pyrimidine-5-base; 2-chloro-5-fluoro-pyridin-3-yl; 2-chloro-phenyl; 2-chloro-pyridin-3-yl; 2-chloro-pyridin-4-yl; 2-two fluoro-3-p-methoxy-phenyls; 2-ethyl-phenyl; 2-oxyethyl group-thiazole-4-base; 2-fluoro-3-methoxyl group-phenyl; 2-fluoro-3-aminomethyl phenyl; 2-fluoro-4-methyl-phenyl; 2-fluoro-5-methoxyl group-phenyl; 2-fluoro-5-aminomethyl phenyl; the 2-fluorophenyl; 2-fluoro-pyridin-3-yl; 2-hydroxymethyl-3-p-methoxy-phenyl; 2-hydroxymethyl phenyl; 2-isoquinoline 99.9-4-base; 2-methoxyl group-5-trifluoromethyl-phenyl; 2-methoxyl group-phenyl; 2-methoxyl group-pyridin-3-yl; 2-methoxyl group-pyrimidine-4-base; 2-methoxyl group-thiazole-4-base; 2-methyl-phenyl; 2-methyl-pyridin-3-yl; 2-oxo-1; 2-dihydro-pyridin-3-yl; the 2-Phenoxyphenyl; the 2-pyridin-3-yl; 2-pyrimidine-5-base; the 2-Trifluoromethoxyphen-l; 2-trifluoromethoxy-phenyl; 3; 4-dimethoxy-phenyl; 3; 5-dimethyl-isoxazole-4-bases; 3; 6-dimethyl-pyrazine-2-base; 3-acetamido phenyl; the 3-aminocarbonyl-phenyl; 3-bromo-phenyl; 3-chloro-pyrazine-2-base; the 3-cyano-phenyl; the 3-dimethylaminophenyl; 3-oxyethyl group-phenyl; 3-ethyl-4-methyl-phenyl; 3-ethynyl-phenyl; 3-fluoro-6-methoxyl group-pyridine-2-base; the 3-fluorophenyl; 3-fluoro-pyrazine-2-base; 3-sulfonyl methane amido phenyl; 3-methoxycarbonyl phenyl; the 3-p-methoxy-phenyl; 3-methoxyl group-pyrazine-2-base; 3-methyl-3H-imidazo [4; 5-b] pyrazine-5-base; the 3-aminomethyl phenyl; 3-methyl-pyridine-2-base; the 3-Trifluoromethoxyphen-l; the 3-trifluoromethyl; 4; 5-dimethoxy-pyrimidine-2-base; 4-amino-5-fluoro-pyrimidine-2-base; 4-chloro-2; 5-dimethoxy-phenyl; 4-chloro-2-fluoro-phenyl; 4-chloro-2-methoxyl group-5-methyl-phenyl; 4-chloro-pyridin-3-yl; 4-two fluoro-2-methyl-phenyl; 4-oxyethyl group-5-fluoro-pyrimidine-2-base; 4-oxyethyl group-pyrimidine-2-base; 4-oxyethyl group-pyrimidine-5-base; 4-ethyl-1H-pyrazole-3-yl; 4-fluoro-2-methoxyl group-phenyl; 4-fluoro-2-methyl-phenyl; the 4-fluorophenyl; 4-methoxyl group-5-methyl-pyrimidine-2-base; 4-methoxyl group-pyridin-3-yl; 4-methoxyl group-pyrimidine-2-base; 4-methoxyl group-pyrimidine-5-base; 4-methyl-phenyl; 4-methyl-pyridine-2-base; 4-methyl-pyridin-3-yl; 4-tetramethyleneimine-1-base-pyrimidine-2-base; 5; 6-dimethoxy-pyrazine-2-base; 5-ethanoyl-thiophene-2-base; 5-amino-6-oxyethyl group-pyrazine-2-base; 5-amino-6-methoxyl group-3-methyl-pyrazine-2-base; 5-amino-6-methoxyl group-pyridine-2-base; 5-chloro-4-methoxyl group-pyrimidine-2-base; 5-chloro-6-methoxyl group-pyrazine-2-base; 5-dimethylamino-6-methoxyl group-pyrazine-2-base; 5-fluoro-2-p-methoxy-phenyl; 5-fluoro-4-methoxyl group-pyrimidine-2-base; 5-fluoro-6-methoxyl group-pyrazine-2-base; 5-fluoro-pyridine-2-base; 5-methoxyl group-pyridin-3-yl; 5-methoxyl group-thiophene-2-base; 5-trifluoromethyl-pyrimidine-2-base; 6-ethanoyl-pyridine-2-base; 6-chloro-pyrazine-2-base; 6-oxyethyl group-pyrazine-2-base; 6-oxyethyl group-pyridine-2-base; 6-fluoro-pyridine-2-base; 6-fluoro-pyridin-3-yl; 6-hydroxyl-pyridine-2-base; 6-methoxyl group-5-methylamino-pyrazine-2-base; 6-methoxyl group-5-methyl-pyrazine-2-base; 6-methoxyl group-pyrazine-2-base; 6-methoxyl group-pyridine-2-base; 6-methoxyl group-pyridin-3-yl; 6-methylamino-pyrazine-2-base; 6-methyl-pyridine-2-base; 5-amino-6-(2; 2, the 2-trifluoro ethoxy) pyrazine-2-base and 6-trifluoromethyl-pyridine-2-base.
At formula V and (Va) among the embodiment of compound, R 9And R 10Be hydrogen.On the other hand, R 9Or R 10In one be that hydrogen and another are halogen or C 1-C 6Alkoxyl group.In some aspects, R 9Or R 10In one be fluorine.In other respects, R 9Or R 10In one be methoxyl group.
In one embodiment, the invention provides and be selected from by example 9, compound is formed compound or steric isomer, tautomer, pharmaceutically acceptable salt or its prodrug of group among the table 1-5.
In another embodiment, the invention provides and be selected from compound or steric isomer, tautomer, pharmaceutically acceptable salt or its prodrug of forming group by following: (R)-2-amino-7-[2-(2-fluoro-pyridin-3-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(S)-2-amino-6-benzyl-7-[4-fluoro-2-(2-fluoro-pyridin-3-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(2-fluoro-pyridin-3-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-(2-bromo-4-fluoro-phenyl)-6-[(S)-1-(4-methoxyl group-phenyl)-ethyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(6-methoxyl group-pyridine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(6-methoxyl group-pyridine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-[4-fluoro-2-(6-methoxyl group-pyridine-2-yl)-phenyl]-4,6-dimethyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-[4-fluoro-2-(2-fluoro-pyridin-3-yl)-phenyl]-4,6-dimethyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-[4-fluoro-2-(6-methoxypyridine-2-yl) phenyl]-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
2-amino-7-[2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-[4-fluoro-2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-4,6-dimethyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-[2-(2-methoxyl group-pyridin-3-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-(5,2 '-two fluoro-xenyl-2-yl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-(5-fluoro-2 '-trifluoromethoxy-xenyl-2-yl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-[2-(2-chloro-pyridin-3-yl)-4-fluoro-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-[4-fluoro-2-(6-fluoro-pyridin-3-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-(4-fluoro-2-isoquinoline 99.9-4-base-phenyl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-(5.3 '-two fluoro-xenyl-2-yl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-[2-(4-chloro-pyridin-3-yl)-4-fluoro-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-(5,2 '-two fluoro-3 '-methoxyl group-xenyl-2-yl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-(5,4 '-two fluoro-2 '-methyl-xenyl-2-yl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-(5-fluoro-2 '-methoxyl group-xenyl-2-yl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-(4-fluoro-2-pyrimidine-5-base-phenyl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-[4-fluoro-2-(2-methoxyl group-pyridin-3-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-(5-fluoro-3 '-methoxyl group-xenyl-2-yl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-6-(3-amino-propyl group)-7-[4-fluoro-2-(6-methoxyl group-pyridine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-(5.2 '-two fluoro-4 '-methyl-xenyl-2-yl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-[4-fluoro-2-(1-methyl isophthalic acid H-pyrazoles-4-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-[4-fluoro-2-(1H-pyrazoles-4-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-4-methyl-7-(5,2 ', 3 '-three fluoro-xenyl-2-yls)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-(2-bromo-4-fluoro-phenyl)-4-methyl-6-(2-methyl-2-morpholine-4-base-propyl group)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-(3 '-dimethylamino-5-fluoro-xenyl-2-yl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-[2-(2,4-dimethoxy-pyrimidine-5-yl)-4-fluoro-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-[4-fluoro-2-(5-methoxyl group-pyridin-3-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-(4-fluoro-2-pyrimidine-5-base-phenyl)-4-methyl-6-(2-methyl-2-morpholine-4-base-propyl group)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-[4-fluoro-2-(2-methoxyl group-pyridin-3-yl)-phenyl]-4-methyl-6-(2-methyl-2-morpholine-4-base-propyl group)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-(5-fluoro-3 '-methoxyl group-xenyl-2-yl)-4-methyl-6-(2-methyl-2-morpholine-4-base-propyl group)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(4-methoxyl group-5-methyl-pyrimidine-2-base)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone; And
2-amino-7-(4-fluoro-2-furans-3-base-phenyl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone.
In another embodiment, to present volution asymmetric for compound of the present invention.More specifically, compound of the present invention can be the lag switch isomer, and it is to can be used as that independent chemical substance is separated and owing to the other conformation of the subclass that forms around the limited rotation of singly-bound.
In other respects, the invention provides and be used to prepare 2-amino-7, the method for 8-dihydro-6H-pyrido [4,3-d] pyrimidine-5 ketone compound.The method for preparing representative The compounds of this invention is set forth in the example 1 to 8.The present invention is further contained: except that formula (I) compound, its intermediate and corresponding synthetic method thereof also belong to the scope of the invention.
In other respects, the invention provides the composition that comprises HSP90 inhibitor described herein and utilize the method for HSP90 inhibitor described herein.
In one aspect, the invention provides and comprise at least a 2-amino-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5 ketone compound is (for example, formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va) compound) or steric isomer, tautomer or its pharmaceutically acceptable salt or prodrug and being suitable for throw medical composition with the pharmaceutically acceptable supporting agent of the mankind or animal individual, use separately or with being used in combination of other anticancer agents.
Estimate that many suitable anticancer agents that can be used as the combined therapy agent can be used for composition of the present invention and method.The suitable anticancer agent of intending being used in combination with The compounds of this invention comprises can cause apoptotic medicament; Polynucleotide (for example, ribozyme); Polypeptide (for example, ferment); Medicine; The biosimulation thing; Alkaloid; Alkylating reagent; Antitumor antibiotics; Metabolic antagonist; Hormone; Platinic compound; Can with cancer therapy drug, toxin and/or radionuclide bonded monoclonal antibody; Biological response modifier (for example, Interferon, rabbit [for example, IFN-a] and be situated between white plain [for example, IL-2]); The adoptive immunotherapy medicament; Hemopoieticgrowth factor; Can cause the medicament (for example, Vitamin-A Acid) of tumour cell differentiation; Gene therapy reagent; Antisense therapy reagent and Nucleotide; Tumor vaccine; Angiogenesis inhibitor; And similar substance.Be suitable for and 2-amino-7 of the present invention, 8-dihydro-6H-pyrido [4,3-d] pyrimidine-5 ketone compound throw together and chemotherapy compound and many other examples of anticancer therapeutic agent for those be familiar with under known to technician.
In certain embodiments, can with 2-amino-7 of the present invention, the anticancer agent that 8-dihydro-6H-pyrido [4,3-d] pyrimidine-5 ketone compound is used in combination comprises can cause or promote apoptotic medicament.Can cause apoptotic medicament to include but not limited to the radiation agent; Kinase inhibitor (for example, EGF-R ELISA [EGFR] kinase inhibitor, vascular endothelial growth factor receptor [VEGFR] kinase inhibitor, fibroblast growth factor acceptor [FGFR] kinase inhibitor, platelet derived growth factor acceptor [PGFR] I kinase inhibitor and such as STI 571[Gleevec or Glivec] etc. the Bcr-Abl kinase inhibitor); Antisense molecule; Antibody [for example, Qu Sizuo monoclonal antibody (Herceptin) and sharp appropriate Xidan anti-(Rituxan)]; Estrogen antagonist [for example, raloxifene (raloxifene) and tamoxifen (tamoxifen]); Androgen antagonist [for example, Flutan (flutamide), bicalutamide (bicalutamide), finasteride (finasteride), amino-glutethimide (amino-glutethamide), KETOKONAZOL (ketoconazole) and adrenocortical steroid]; Cyclooxygenase 2 (COX-2) inhibitor [for example, Sai Lixibu (Celecoxib), meloxicam (meloxicam), NS-398 and NSAID (non-steroidal anti-inflammatory drug) (NSAID)]; And the cancer chemotherapeutic medicine [for example, irinotecan (irinotecan) (Camptosar), CPT-11, fludarabine (fludarabine) (Fludara), Dacarbazine (dacarbazine) (DTIC), dexamethasone (dexamethasone), mitoxantrone (mitoxantrone), Mai Luota (Mylotarg), VP 16, cis-platinum (cisplatinum), 5-FU, Dx (Doxrubicin), taxotere (Taxotere) or taxol (Taxol)]; The cell signaling molecule; Ceramide type and cytokine class; And Staurosporine; And similar substance.
In other respects, the invention provides use compound described herein and method for compositions.For example, compound described herein and composition can be used for treating cancer.Compound described herein and composition also can be used for preparing the medicine that is used for the treatment of cancer.
In one embodiment, the invention provides treatment and suffer from the mankind of cell proliferative diseases (for example, cancer) or the method for animal individual.The invention provides treatment and need the mankind of this treatment or the method for animal individual, it comprises to the 2-amino-7 of described individual throwing with a treatment significant quantity, 8-dihydro-6H-pyrido [4,3-d] pyrimidine-5 ketone compound or composition are (for example, formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or compound (Va) or composition), use separately or be used in combination with other anticancer agents.
In another embodiment, the invention provides and be used for the treatment of the mankind that need this treatment or the method for animal individual cell proliferative diseases, it comprises to described individual the throwing and a certain amount of 2-amino-7 that can reduce or prevent described individual cells hyperplasia or tumor growth effectively, 8-dihydro-6H-pyrido [4,3-d] pyrimidine-5 ketone compound or composition (for example, the compound or the composition of formula (I) to (V)).
In another embodiment, the invention provides the method for the cell proliferative diseases that is used for the treatment of the mankind that need this treatment or animal individual, it comprises to described individual the throwing with a certain amount of can reduce or prevent the outgrowth 2-amino-7 of individual cells effectively, 8-dihydro-6H-pyrido [4,3-d] pyrimidine-5 ketone compound (for example, formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) reach (Va) compound) and at least a additional agent that is used for the treatment of cancer.
The invention provides compound as the HSP90 inhibitor.Described inhibitor is used in and wherein indicates the mankind that need to suppress HSP90 or the medical composition of beasts purposes, for example, and such as tumour and/or be subjected in the treatment of cell proliferative diseases such as growth of cancer cells of HSP90 mediation.Specifically, described compound (for example can be used for treating the mankind or animal, muroid) cancer comprises (for example) lung cancer and bronchogenic carcinoma, prostate cancer, breast cancer, carcinoma of the pancreas, the colorectal carcinoma and the rectum cancer, thyroid carcinoma, cancer of the stomach, liver cancer and stones in intrahepatic bile duct cancer, kidney and carcinoma of renal pelvis, bladder cancer, carcinoma of uterine body, cervical cancer, ovarian cancer, multiple myeloma, esophagus cancer, acute myelogenous leukemia, chronic lymphocytic leukemia, Lymphocytic leukemia, myelomatosis, the cancer of the brain, oral carcinoma and pharynx cancer, laryngocarcinoma, carcinoma of small intestine, non-Hodgkin lymphoma, melanoma and fine hair shape adenoma of colon.
In another embodiment, the invention provides the method that treatment is subjected to the illness of HSP90 mediation.In a method, to the patient that needs are arranged (for example, the mankind or animal individual) throw the 2-amino-7 with significant quantity, 8-dihydro-6H-pyrido [4,3-d] pyrimidine-5 ketone compound (for example, formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) and compound (Va)) (or adjusting) the HSP90 activity that is situated between to transfer.In some aspects, the illness of described HSP90 mediation is hyperplasia, viral, autoimmunization, cardiovascular and central nervous system disorders.
In another embodiment, the invention provides the method for treatment hyperplasia, viral, autoimmunization, cardiovascular or central nervous system disorders.In a method, to the patient that needs are arranged (for example, the mankind or animal individual) throw the 2-amino-7 with significant quantity, 8-dihydro-6H-pyrido [4,3-d] pyrimidine-5 ketone compound (for example, formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) and (Va) compound) is with treatment hyperplasia, viral, autoimmunization, cardiovascular and central nervous system disorders.
A kind ofly be used for measuring HSP90 and suppress active representative test and be set forth in example 10.In preferred embodiment, 2-amino-7 of the present invention, 8-dihydro-6H-pyrido [4,3-d] pyrimidine-5 ketone compound has the active IC of inhibition HSP90 that is less than or equal to 100 μ M 50Value.In better embodiment, described IC 50Value is for being less than or equal to 50 μ M, even more preferably, has the IC that is less than or equal to 25 μ M 50Value.Another better embodiment has the IC that is less than or equal to 10 μ M 50Value, and even better embodiment have a C who is less than or equal to 1 μ M 50Value.
Provide following definitions to understand the present invention better.
" alkyl " or " being unsubstituted alkyl " is meant and do not contain heteroatomic stable hydrocarbon group.Therefore, described term comprises straight chained alkyl, for example methyl, ethyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl, undecyl, dodecyl and similar group.Described term also comprises the side chain isomers of straight chained alkyl, includes but not limited to following example: CH (CH 3) 2, CH (CH 3) (CH 2CH 3), CH (CH 2CH 3) 2, C (CH 3) 3,-C (CH 2CH 3) 3,-CH 2CH (CH 3) 2, CH 2CH (CH 3) (CH 2CH 3), CH 2CH (CH 2CH 3) 2, CH 2C (CH 3) 3, CH 2C (CH 2CH 3) 3, CH (CH 3) CH (CH 3) (CH 2CH 3), CH 2CH 2CH (CH 3) 2, CH 2CH 2CH (CH 3) (CH 2CH 3), CH 2CH 2CH (CH 2CH 3) 2, CH 2CH 2C (CH 3) 3, CH 2CH 2C (CH 2CH 3) 3, CH (CH 3) CH 2CH (CH 3) 2, CH (CH 3) CH (CH 3) CH (CH 3) 2, CH (CH 2CH 3) CH (CH 3) CH (CH 3) (CH 2CH 3) and other.Therefore, term " alkyl " comprises one-level alkyl, secondary alkyl and three grades of alkyl.Preferable alkyl comprises straight chain and the branched-chain alkyl with 1 to 12,1 to 6 or 1 to 3 carbon atom.
" alkylidene group " or " being unsubstituted alkylidene group " is meant above described but have the identical residue of two tie points at " alkyl ".The exemplary alkylidene group comprises ethylidene (CH 2CH 2-), propylidene (CH 2CH 2CH 2-) and dimethyl propylidene (CH 2C (CH 3) 2CH 2-).
" thiazolinyl " or " being unsubstituted thiazolinyl " is meant to have one or more carbon-carbon double bond and have 2 straight chain and branched-chain hydrocarbon groups to about 20 carbon atoms.Preferable thiazolinyl comprises straight chain and the branched-chain alkenyl with 2 to 12 or 2 to 6 carbon atoms.
" alkynyl " or " being unsubstituted alkynyl " is meant to have one or more carbon-carbon triple bond and have 2 straight chain and branched-chain hydrocarbon groups to about 20 carbon atoms.Preferable alkynyl comprises a straight chain and the alkynyl group with 2 to 12 or 2 to 6 carbon atoms.
" cycloalkyl " or " being unsubstituted cycloalkyl " is meant monocycle or multi-ring alkyl substituting group.Representative cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group.Preferable cycloalkyl has 3 to 7 carbon atoms.
" cycloalkenyl group " or " being unsubstituted cycloalkenyl group " is meant monocycle or the multi-ring alkyl substituting group with at least one ring carbon-carbon double bond.Preferable cycloalkenyl group has 5 to 7 carbon atoms and comprises cyclopentenyl and cyclohexenyl.
" be substituted alkyl " and be meant wherein one or more carbon bond knot or hydrogen bond tying-in by such as (but being not limited to) the following abovementioned alkyl that waits non-hydrogen atom or the replacement of non-carbon atom bond: halogen atom, for example F, Cl, Br and I; Be stored in such as the Sauerstoffatom in the groups such as hydroxyl, alkoxyl group, aryloxy and ester group; Be stored in such as the sulphur atom in the groups such as thiol group, alkyl thioether and aryl thioethers, sulfone, alkylsulfonyl and sulfoxide radicals; Be stored in such as the nitrogen-atoms in the groups such as amino, amide group, alkylamino, arylamino, alkyl aryl amino, ammonia diaryl base, N-oxide compound, imide and enamine.Be substituted alkyl and comprise that also one or more carbon atom wherein or hydrogen atom bond (for example, are stored in oxygen in oxo base, carbonyl, carboxyl and the ester group via heteroatoms; Or be stored in such as the nitrogen in the groups such as imines, oxime, hydrazone and nitrile) group that replaces of senior bond (for example, two keys or three key).Be substituted the alkyl that alkyl comprises that further one or more carbon atom wherein or hydrogen atom bond replace via aryl, heteroaryl, heterocyclic radical, cycloalkyl or cycloalkenyl group bond.Preferablely be substituted the alkyl that alkyl comprises that especially one or more carbon atom bond wherein or hydrogen atom bond replace via one or more fluorine, chlorine or bromine group bond.Another preferable alkyl that is substituted is trifluoromethyl and other alkyl that contain trifluoromethyl.Other are preferable be substituted alkyl comprise those wherein the alkyl that replaces via the Sauerstoffatom bond of one or more carbon atom bond or hydrogen atom bond so that the described alkyl that is substituted contains hydroxyl, alkoxyl group or aryloxy.Other preferable alkyl that are substituted comprise having amino alkyl, or are substituted or are unsubstituted alkylamino, arylamino, heterocyclic radical amino.Other are preferable to be substituted alkyl and to comprise those wherein alkyl of replacing via aryl, heteroaryl, heterocyclic radical or cycloalkyl bond of one or more carbon atom or hydrogen atom bond.The example that is substituted alkyl is: (CH 2) 3NH 2, (CH 2) 3NH (CCH 3), (CH 2) 3NH (CH 3) 2, CH 2C (=CH 2) CH 2NH 2, CH 2C (=O) CH 2NH 2, CH 2S (=O) 2CCH 3, CH 2OCH 2NH 2, CH 2CO 2H.F 3The substituent example that is substituted alkyl is: CH 2OH, OH, OCH 3, OC 2H 5, OCF 3, OC (=O) CH 3, OC (=O) NH 2, OC (=O) N (CH 3) 2, CN, NO 2, C (=O) CH 3, CO 2H, CO 2CH 3, CONH 2, NH 2, N (CH 3) 2, NHSO 2CH 3, NHCOCH 3, NHC (=O) OCH 3, NHSO 2CH 3, SO 2CH 3, SO 2NH 2And halogen.
" be substituted thiazolinyl " and have identical meanings as being substituted alkyl for being unsubstituted alkyl for being unsubstituted thiazolinyl.Be substituted thiazolinyl and comprise that wherein non-carbon atom or non-hydrogen atom bond are to a key bond of the thiazolinyl of the carbon of two another carbon atoms of key bond and those wherein non-carbon atoms or the non-hydrogen atom thiazolinyl to the carbon atom of the two keys that have neither part nor lot in another carbon atom.
" be substituted alkynyl " and have identical meanings as being substituted alkyl for being unsubstituted alkyl for being unsubstituted alkynyl.Be substituted alkynyl and comprise that wherein non-carbon atom or non-hydrogen atom bond are to a bond of the alkynyl of the carbon of three another carbon atom of key bond and those wherein non-carbon atoms or the non-hydrogen atom alkynyl to the carbon atom of three key that has neither part nor lot in another carbon atom.
" be substituted cycloalkyl " and have identical meanings as being substituted alkyl for being unsubstituted alkyl for being unsubstituted cycloalkyl.
" be substituted cycloalkenyl group " and have identical meanings as being substituted alkyl for being unsubstituted alkyl for being unsubstituted cycloalkenyl group.
" aryl " or " being unsubstituted aryl " is meant monocycle and the polycyclic aromatic group that does not contain ring hetero atom.These groups can contain 6 to 14 carbon atoms but be preferably 6 carbon atoms.Substituent exemplary aryl moiety as The compounds of this invention comprises phenyl, naphthyl and similar group.
" aralkyl " or " arylalkyl " is meant the alkyl that replaces through aryl as mentioned above.Usually, used aralkyl has 1 to 6 carbon atom of incorporating in the described aralkyl moieties in the The compounds of this invention.Used suitable aralkyl comprises (for example) benzyl and similar group in the The compounds of this invention." heteroarylalkyl " or " heteroaralkyl " is meant the alkyl that replaces through heteroaryl as mentioned above.Usually, used heteroarylalkyl has 1 to 6 carbon atom of incorporating in the described aralkyl moieties in the The compounds of this invention.Used suitable heteroarylalkyl comprises (for example) picolyl and similar group in the The compounds of this invention.
" alkoxyl group " is meant wherein R 20Be C 1-C 7Alkyl or be substituted the R of alkyl 20O-.In certain embodiments, R 20Be C 1-C 6Alkyl.The representative example of alkoxyl group comprises methoxyl group, oxyethyl group, the 3rd-butoxy, trifluoromethoxy and similar group.
" amino " in this article refers to group-NH 2
" be substituted amino " and be meant wherein R 60And R 61For being independently selected from the group-NR that forms group by following 60R 61: hydrogen, alkyl, be substituted alkyl, thiazolinyl, be substituted thiazolinyl, alkynyl, be substituted alkynyl, aryl, be substituted aryl, cycloalkyl, be substituted cycloalkyl, heteroaryl, be substituted heteroaryl, heterocyclic radical, be substituted heterocyclic radical ,-SO 2-alkyl ,-SO 2-be substituted alkyl; And R wherein 60And R 61Connect nitrogen-atoms via it and be joined together to form heterocyclic radical or be substituted heterocyclic radical, restricted condition is R 60And R 61The two all is not a hydrogen.Work as R 60Be hydrogen and R 61During for alkyl, then be substituted amino and often be called alkylamino in this article.Work as R 60And R 61When being alkyl, then being substituted amino and often being called dialkyl amido in this article.When mentioning through the single substituted-amino, it means R 60Or R 61For hydrogen but the two can not be a hydrogen simultaneously.When mentioning through twice replacement amino, it means R 60And R 61All be not hydrogen.Term " alkylamino " in this article refers to wherein R 60Be C 1-C 7Alkyl and R 60Be hydrogen or C 1-C 7Group-the NR of alkyl 60R 61Term " dialkyl amido " is meant wherein R 60And R 61Be C 1-C 7Group-the NR of alkyl 60R 61Term " arylamino " in this article refers to wherein R 60Be C 5-C 7Aryl and R 61Be hydrogen, C 1-C 7Alkyl or C 5-C 7Group-the NR of aryl 60R 61Term " aryl alkyl amino " in this article refers to wherein R 60Be aralkyl and R 61Be hydrogen, C 1-C 7Alkyl, C 5-C 7Aryl or C 5-C 7Group-the NR of aralkyl 60R 61
" amidino groups " is meant R 40-C (=N)-NR 41-(described group is positioned at " N 1" the nitrogen-atoms place) and R 40(NR 41) (described group is positioned at " N to C=N- 2" the nitrogen-atoms place) part, wherein R 40And R 41Can be hydrogen, C 1-C 7Alkyl, aryl or C 5-C 7Aralkyl.
" alkoxyalkyl " is meant wherein alk 1Be C 1-C 7Alkyl and alk 2Be C 1-C 7Group-the alk of alkyl 1-O-alk 2Term " aryloxy alkyl " is meant group-(C 1-C 7Alkyl)-O-(C 5-C 7Aryl).
" alkoxyalkyl amino " in this article refers to group-NR 27-(alkoxyalkyl), wherein R 27Be generally hydrogen, C 5-C 7Aralkyl or C 1-C 7Alkyl.
" aminocarboxyl " in this article refers to group-C (O)-NH 2" be substituted aminocarboxyl " and in this article refer to group-C (O)-NR 28R 29, R wherein 28Be C 1-C 7Alkyl and R 29Be hydrogen or C 1-C 7Alkyl.Term " aromatic yl aminocarbonyl " in this article refers to wherein R 30Be C 5-C 7Aryl and R 31Be hydrogen, C 1-C 7Alkyl or C 5-C 7Group-the C of aryl (O)-NR 30R 31" aryl alkyl amino carbonyl " in this article refers to group-C (O) NR 32R 33, R wherein 32Be C 5-C 7Aralkyl and R 33Be hydrogen, C 1-C 7Alkyl, C 5-C 7Aryl or C 5-C 7Aralkyl.
" amino-sulfonyl " in this article refers to group-S (O) 2-NH 2" be substituted amino-sulfonyl " and in this article refer to wherein R 34Be C 1-C 7Alkyl and R 35Be hydrogen or C 1-C 7Group-the S of alkyl (O) 2-NR 34R 35Term " aryl alkyl amino sulfonyl aryl " in this article refers to group-(C 5-C 7Aryl)-S (O) 2-NH-aralkyl.
" aryloxy " is meant wherein R 50R for aryl 50O-.
" carbonyl " is meant divalent group-C (O)." alkyl-carbonyl " is meant group-C (O) alkyl." aryl carbonyl " is meant group-C (O) aryl.Similarly, term " heteroaryl carbonyl ", " aromatic alkyl carbonyl " reach " heteroaralkyl carbonyl " be meant R wherein be respectively heteroaryl, aralkyl and heteroaralkyl-C (O)-R.
" ketonic oxygen base " typically refers to group-C (O)-O-.These groups comprise ester ,-C (O)-O-R 36, R wherein 36Be C 1-C 7Alkyl, C 3-C 7Cycloalkyl, aryl or C 5-C 7Aralkyl.Term " aryl carbonyl oxygen base " in this article refers to group-C (O)-O-(aryl).Term " aromatic alkyl carbonyl oxygen base " in this article refers to group-C (O)-O-(C 5-C 7Aralkyl).
" cycloalkylalkyl " is meant through the alkyl of cycloalkyl substituted as mentioned above.Usually, cycloalkylalkyl has 1 to 6 carbon atom in the moieties of incorporating described cycloalkylalkyl into.
" carbonylamino " is meant that the hydrogen atom of the amide nitrogen of wherein said carbonylamino can be through C 1-C 7Alkyl, aryl or C 5-C 7Divalent group-NH-C (O) that aralkyl replaces-.Carbonylamino comprises such as carbamate (NH-C (O)-O-R 28) and amide group-NH-C (O) R 28Etc. part, R wherein 28Be straight or branched C 1-C 7Alkyl, C 3-C 7Cycloalkyl or aryl or C 5-C 7Aralkyl.Term " alkyl-carbonyl-amino " is meant group-NH-C (O)-R 28 ', R wherein 28 'For in its backbone structure, having 1 alkyl to about 7 carbon atoms.Term " aryl-amino-carbonyl " is meant wherein R 29Be C 5-C 7Group-the NH-C of aryl (O)-R 29Similarly, term " aromatic alkyl carbonyl amino " is meant wherein R 29Be C 5-C 7The carbonylamino of aralkyl.
" guanidine radicals (Guanidino or guanidyl) " is meant derived from guanidine H 2N-C (=NH)-NH 2Part.These parts comprise those be subjected at the nitrogen-atoms place that carries the two keys of formal the part of bond (" 2 " of guanidine-position, for example, diamino methylene amino, (H 2N) 2C=NH) and those carry the single bonded arbitrary nitrogen-atoms of formal place be subjected to bond part (" 1 " of guanidine-and/or " 3 "-position, for example, H 2N-C (=NH)-NH-).The hydrogen atom at arbitrary nitrogen-atoms place can be via suitable substituting group (such as C 1-C 7Alkyl, aryl or C 5-C 7Aralkyl) replaces.
" halogen " or " halo " is meant chlorine, bromine, fluorine and iodine group.Term " haloalkyl " is meant the alkyl group that replaces through one or more halogen atom.F 3" haloalkyl " group comprises-CF 3Term " halogenated alkoxy " is meant the alkoxy base that replaces through one or more halogen atom.F 3F 3" halogenated alkoxy " group comprises-OCF 3And-OCH 2CF 3
" hydroxyl (hydroxyl or hydroxy) is meant group-OH.
" heterocyclic radical " used herein or " being unsubstituted heterocyclic group ", " heterocycle " or " being unsubstituted heterocycle " reach " heterocyclic radical " or " being unsubstituted heterocyclic radical ", " Heterocyclylalkyl " or " being unsubstituted Heterocyclylalkyl " is meant and contains heteroatomic arbitrary monocycle or the polycyclic non-aromatic cyclic cpds that is selected from nitrogen, oxygen or sulphur.Example comprises containing the heteroatomic 3 or 4 Yuans rings that are selected from nitrogen, oxygen and sulphur or containing 1 to 3 and is selected from by nitrogen, oxygen or sulphur and forms the heteroatomic 5 or 6 Yuans rings of group; Wherein said 5 Yuans rings have 0 to 1 two key and described 6 Yuans rings have 0 to 2 two key; Wherein said nitrogen-atoms and sulphur atom according to circumstances can be through oxidations; Wherein said nitrogen and sulfur heteroatom according to circumstances can be through level Fourization; And comprise that wherein arbitrary above-mentioned heterocyclic ring is fused to phenyl ring or another 5-that above defines independently or arbitrary bicyclic radicals of 6-element heterocycle basic ring, restricted condition is that tie point is via heterocyclic ring.
The heterocyclic radical part can be independently selected from but be not limited to following substituting group and replace 1 time or 2 times through (for example): hydroxyl, alkoxyl group, halogen, oxo (C=O), alkyl imino (R 31N=, wherein R 31Be alkyl or alkoxyl group), amino, alkylamino, acylaminoalkyl, alkoxyl group, thio alkoxy, poly-alkoxyl group, alkyl, cycloalkyl or haloalkyl.
Described heterocyclic group can be connected in position as follows, can understand in conjunction with this paper disclosure as those technician that are familiar with organic chemistry and medical chemistry.
Figure S2006800365004D00271
Wherein R is H or heterocyclic radical substituting group, and is as described herein.
" heteroaryl " or " being unsubstituted heteroaryl " in this article refers to has the aromatic group of 1 to 4 heteroatoms as annular atoms in aromatic nucleus, all the other annular atomses are carbon atom.Term " heteroaryl " comprise wherein nitrogen be heteroatomic ring and wherein at least one ring structure be the part and the complete saturated rings of aromatic nucleus, for example, Ben Bing Er oxazolyl (it has the heterocyclic radical structure that is fused to phenyl, that is,
Figure S2006800365004D00272
Restricted condition is that tie point is via heteroaryl ring.Heteroaryl can further be substituted and can be connected in the position, can understand in conjunction with this paper disclosure as those technician that have the knack of organic chemistry and medical chemistry.Representativeness is substituted and is unsubstituted heteroaryl and comprises (for example) those are found in the application's case and hereinafter disclose heteroaryl in the compound in the example illustrated.
Preferable heterocycle and heteroaryl have 3 to 14 annular atomses and comprise (for example): phenodiazine Boom base, pyrryl, pyrrolidyl, pyrazolyl, pyrazolidyl, imidazolyl, imidazolidyl, pyridyl, piperidyl, pyrazinyl, piperazine, azelidinyl, pyrimidyl, clatter piperazine base oxazolyl oxazolidinyl isoxazolyl isoxazole alkyl, morpholinyl, thiazolyl, thiazolidyl, isothiazolyl, the isothiazole alkyl, indyl, quinolyl, isoquinolyl, benzimidazolyl-, benzothiazolyl benzoxazolyl, furyl, thienyl, triazolyl, quinoxalinyl, dai piperazine base, the naphtho-pyridyl, indazolyl and benzothienyl.
" heteroarylalkyl " or " heteroaralkyl " is meant the alkyl that replaces through heteroaryl as mentioned above.Usually, heteroarylalkyl has 1 to 6 carbon atom in the moieties of incorporating described heteroarylalkyl into.
" imino-" is meant group=NH.
" nitro " is meant group NO 2
" alkylsulfonyl " in this article refers to group-SO 2-.C 1-C 7" alkyl sulphonyl " is meant wherein R 52Be C 1-C 7Structure-the SO of alkyl 2R 52-be substituted alkylsulfonyl.Used alkyl sulphonyl is generally the alkyl sulphonyl that has 1 to 6 carbon atom in its backbone structure in the The compounds of this invention.Therefore, used typical alkyl sulphonyl comprises (for example) methyl sulphonyl (that is R wherein, in the The compounds of this invention 52Be methyl), ethylsulfonyl (that is R wherein, 52Be ethyl), sulfonyl propyl base (that is R wherein, 52Be propyl group) and similar group.Term " aryl sulfonyl " in this article refers to group-SO 2-aryl.Term " heterocyclic radical alkylsulfonyl " in this article refers to group-SO 2-heterocyclic radical.Term " aralkyl alkylsulfonyl " in this article refers to group-SO 2-aralkyl.Term " sulfoamido " in this article refers to-SO 2NH 2Term " sulfoamido alkyl " is meant (alkyl) SO 2NH 2-.
" thio group or mercaptan " is meant group-SH." alkyl thio-base or alkyl sulfhydryl " is meant through alkyl (for example, C 1-C 6Alkyl) the thio group group of Qu Daiing is substituted.
" thioamides base " is meant group-C (=S) NH 2
" be substituted according to circumstances " and be meant that hydrogen can replace through unit price or divalent group according to circumstances." be substituted " and be meant that hydrogen can replace through unit price or divalent group.Except as otherwise noted, otherwise suitable substituted radical comprises (for example) hydroxyl; alkoxyl group; nitro; amino; imino-; cyano group; halogen; thio group; alkylsulfonyl; the thioamides base; amidino groups; the oxo base; the amidoxime base; the methylamine oximido; guanidine radicals; sulfoamido; carboxyl; formyl radical; alkyl; haloalkyl; alkylamino; haloalkyl amino; alkoxyl group; halogenated alkoxy; alkoxyl group-alkyl; alkyl-carbonyl; aminocarboxyl; aryl carbonyl; aromatic alkyl carbonyl; the heteroaryl carbonyl; heteroaralkyl-carbonyl; alkyl sulfide; aminoalkyl group; the cyano group alkyl; aryl and similar group.Other suitable substituted radicals comprise that those are to being substituted the specified substituting group of alkyl.With reference to whole the application's compound that case discloses, also can find the example of each suitable substituted radical.
Self can be substituted described substituted radical.Substituting group on the substituted radical can be carboxyl, halogen, nitro, amino, cyano group, hydroxyl, alkyl, alkoxyl group, aminocarboxyl ,-SR 42, the thioamides base ,-SO 3H, SO 2R 42Or cycloalkyl, wherein R 42Be generally hydrogen, hydroxyl or alkyl.
When being substituted substituting group and comprising straight chain group, (for example, 2-hydroxypropyl, the amino butyl of 2-and similar group) can take place or at described chain end (for example, 2-hydroxyethyl, 3-cyano group propyl group and similar group) take place in then described replacement in described chain.Be substituted substituting group and can be covalency bond carbon atom or heteroatomic straight chain, side chain or circular permutation.
Except as otherwise noted, otherwise the substituent name that this paper does not clearly define can be by naming functional group successively end group part and obtain towards the functional group that adjoins of tie point.For example, substituting group " alkoxyl group heteroaryl " be meant group (alkoxyl group)-(heteroaryl)-.
Preferred compounds of the present invention has less than 1000 dalton, and is preferable less than 750 daltonian total molecular weights.The compounds of this invention has at least 150 daltonian minimum molecular weights usually.Preferred embodiment of the present invention has the molecular weight between between 150 and 750 dalton, and better embodiment has the molecular weight between between 200 and 500 dalton.Other embodiment of the present invention are the compound with the molecular weight between between 300 and 450 dalton.In another aspect of this invention, The compounds of this invention has the molecular weight between between 350 and 400 dalton.
Similarly, should understand above-mentioned definition and not desire to comprise the substitute mode (for example, the methyl that replaces through 5 fluorin radicals) that can not occur.The described substitute mode that can not occur is known by technician under being familiar with.
" carboxyl-blocking group " is meant the carbonyl through the ester group esterification of a protection carboxylic acid commonly used, sealing or protect described carboxylic acid functional when described ester group is used in the reaction of other functional site of implementing to relate to compound.In addition, carboxy protective group can be connected to solid phase carrier, is connected with solid phase carrier with maintenance before discharging corresponding free acid thereby compound is dissociated by method for hydrolysis at carboxylate radical.Representative carboxyl-blocking group comprises (for example) alkyl ester, secondary acid amides and similar substance.
Some The compounds of this invention comprises the carbon atom through asymmetric replacement.Described carbon atom through asymmetric replacement can make The compounds of this invention comprise steric isomer (presenting stereoisomerism at the carbon atom place through specific asymmetric replacement) mixture or single stereoisomers.Therefore, the present invention includes racemic mixture, enantiomeric mixture and the enantiomer of The compounds of this invention.Term used herein " S " reaches " R " and is configured as defining by IUPAC 1974 " RECOMMENDATIONS FOR SECTION E, FUNDAMENTALSTEREOCHEMISTRY, " (Pure Appl.Chem.45:1330,1976).Term α and β are used for the loop mapping of ring compound.The α side of reference plane is positioned at the side of less numbered positions for preferable substituting group on it.Those substituting groups that are positioned at the reference plane offside are endowed the β descriptor.Should understand this usage and be different from wherein the three-dimensional parent usage of ring-type and its expression absolute configuration that " α " means " being lower than described plane ".Term α used herein and beta comfiguration are as " Chemical Abstracts Index Guide, " (appendix IV, the 203rd section, 1987) define.
Term used herein " pharmaceutically acceptable salt " is meant 2-amino-7 of the present invention, the non-toxic acid or the alkaline earth salt of 8-dihydro-6H-pyrido [4,3-d] pyrimidine-5 ketone compound.These salt can be at 2-amino-7, prepares on the spot or prepare by alkali or acid functional group are reacted independently with suitable organic or inorganic acid or alkali respectively during final separation of 8-dihydro-6H-pyrido [4,3-d] pyrimidine-5 ketone compound and the purifying.Exemplary salt includes but not limited to following: acetate, adipate, alginate, Citrate trianion, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, camphorate, camsilate, digluconate, cyclopentane propionate, dodecyl sulfate, ethane sulfonate, gluceptate, glycerophosphate, Hemisulphate, enanthate, hexanoate, fumarate, hydrochloride, hydrobromate, hydriodate, 2-hydroxyethanesulfonic acid salt, lactic acid salt, maleate, methane sulfonates, the nicotine hydrochlorate, the 2-naphthalenesulfonate, oxalate, palmitate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, Pivalate, propionic salt, succinate, vitriol, tartrate, thiocyanate-, tosilate and undecane hydrochlorate.And alkaline nitrogenous base is also available such as following reagent level Four ammoniumization: alkylogen, for example muriate of methyl, ethyl, propyl group and butyl, bromide and iodide; Dialkyl sulfate is as methyl-sulfate, ethyl sulfate, dibutyl sulfate and sulfuric acid diamyl ester; Long-chain halogenide, for example muriate of decyl, lauryl, myristyl and stearyl, bromide and iodide; Aralkyl halide is as bromotoluene and phenethyl bromide and other.Obtain water or oil soluble or dispersibility product by this.
The example that can be used for forming the acid of pharmaceutically acceptable acid salt comprises mineral acid (for example, spirit of salt, sulfuric acid and phosphoric acid) and organic acid (for example, oxalic acid, toxilic acid, methanesulfonic, succsinic acid and citric acid).Base addition salt can be at 2-amino-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5 ketone compound final separate and purifying during preparation on the spot, or prepare by making carboxylic moiety and suitable alkali (for example, the oxyhydroxide of pharmaceutically acceptable metallic cation, carbonate or supercarbonate) or reacting with ammonium or one-level, secondary or three grades of organic amines.Pharmaceutically acceptable salt includes but not limited to the cationic salts based on alkalies and alkaline earth, for example, sodium salt, lithium salts, sylvite, calcium salt, magnesium salts, aluminium salt and analogue and nontoxic ammonium, quaternary ammonium compound and amine positively charged ion include but not limited to ammonium, tetramethyl-ammonium, tetraethyl ammonium, methylamine, dimethyl amine, Trimethylamine, triethylamine, ethylamine and analogue.Other representative organic amines that can be used for forming base addition salt comprise diethylamide, quadrol, thanomin, diethanolamine, piperazine and analogue.
Term used herein " pharmaceutically acceptable prodrug " is meant the prodrug that possesses following condition of The compounds of this invention, described prodrug is suitable for contacting human in reliable medical judgment scope or zootic tissue and can not produce uncomfortable toxicity, stimulation, transformation reactions and similar reaction, and have rational interests/risk ratio and effective to its desired use, when possibility, also refer to the zwitterionic form of The compounds of this invention.Term " prodrug " is meant and can (for example) transforms the compound that produces the following formula parent compound rapidly by hydrolysis in blood in body.Comprehensively discuss that be provided in can south (Higuchi), T. reach " prodrug is as novel delivery system (Pro-drugs asNovel Delivery Systems) " (the A.C.S. health care series (Symposium Series) 14) of V. Si Tela (Stella) and " bioreversible carrier of medicinal design (Bioreversible Carriersin Drug Design) " (american pharmaceutical association (American Pharmaceutical Association) of Edward (Edward) B. Luo Xi (Roche) editor, Berlin press (Pergamon Press), 1987) in, the two all is incorporated herein with way of reference.
Term " illness of HSP90 mediation " is meant can be advantageously by suppressing the illness of HSP90 treatment.
Term " cell proliferative diseases " is meant including (for example) cancer, tumour, hyperplasia, restenosis, cardiac hypertrophy, immune disorders and inflammation in interior disease.
Term " cancer " is meant can be advantageously by suppressing the Cancerous disease of HSP90 treatment, and it comprises (for example) lung cancer and bronchogenic carcinoma, prostate cancer, breast cancer, carcinoma of the pancreas, the colorectal carcinoma and the rectum cancer, thyroid carcinoma, cancer of the stomach, liver cancer and stones in intrahepatic bile duct cancer, kidney and carcinoma of renal pelvis, bladder cancer, carcinoma of uterine body, cervical cancer, ovarian cancer, multiple myeloma, esophagus cancer, acute myelogenous leukemia, chronic lymphocytic leukemia, Lymphocytic leukemia, myelomatosis, the cancer of the brain, oral carcinoma and pharynx cancer, laryngocarcinoma, carcinoma of small intestine, non-Hodgkin lymphoma, melanoma and fine hair shape adenoma of colon.
Compound of the present invention is used in external or the interior anticancer growth of body.Described compound can use separately or use with the form of composition with pharmaceutically acceptable supporting agent or vehicle.Suitable pharmaceutically acceptable supporting agent or vehicle comprise that (for example) processing aid and medicine send modifying agent and toughener, for example, calcium phosphate, Magnesium Stearate, talcum powder, monose, disaccharides, starch, gelatin, Mierocrystalline cellulose, methylcellulose gum, Xylo-Mucine, dextrose, hydroxypropyl-beta-cyclodextrin, polyvinylpyrrolidone, low melt wax, ion exchange resin and similar substance, and the combination of any two or multiple described material.Other suitable pharmaceutically acceptable vehicle are set forth in way of reference to be incorporated in " Remington ' s Pharmaceutical Sciences, " (Mack Pub.Co., New Jersey, 1991) of this paper.
The significant quantity of The compounds of this invention generally includes to be enough to by arbitrary test described herein, suppress the active arbitrary amount of HSP90 by other HSP90 activity tests known to those those of ordinary skill or by inhibition or the mitigation detectability ground that detects cancer symptoms.
Can should look closely desire treatment main body and specific throwing and mode with the amount of the active ingredient that produces one-pack type with the supporting agent combinations of substances and change.Yet, should be appreciated that, the specific administration amount that is used for any particular patient should be looked closely multiple factor and be decided, and described factor comprises activity, patient age, body weight, general health, sex, meals, dispensing time, dosing way, drainage rate, the drug regimen of used particular compound and the severity of the specified disease that stands to treat.For given situation, the treatment significant quantity can easily be determined and it belongs to common clinicist's technology and determination range by normal experiment.
For reaching the present invention's purpose, the treatment significant quantity is often referred to branch single or multiple dosage and throws total per daily dose with main body, and described per daily dose can be body weight and be more preferred from body weight every days 1.0 to 30mg/kg (for example) every day 0.001 to 1000mg/kg.Therefore, units dosage composition can comprise described quantity or its repeatedly the combination of divided dose to constitute dosage every day.
The compounds of this invention can contain in case of necessity the desired dose unit composite form of commonly using nontoxic pharmaceutically acceptable supporting agent, adjuvant and mediator by the aerosolization effect or suck spraying with through the oral cavity, non-through intestines, hypogloeeis, rectum or external application throw with.External application is thrown and also can be related to through skin dispensing, for example use of transdermal patch or ionophoresis.Term used herein " non-through intestines " comprises subcutaneous injection, intravenous injection, intramuscularly, breastbone inner injection or infusion techniques.
Can use suitable dispersion agent or wetting agent and suspension agent to allocate injectable formulation according to knowing technology, for example, sterile injectable water-based or oily suspensions.Sterile injectable preparation also can be and is stored in nontoxic non-sterile injectable solution or suspension in intestines acceptable diluent or solvent, for example, as is dissolved in 1, the solution of ammediol.Adoptable mediator and the solvent accepted especially is water, Ringer's solution (Ringer ' s solution) and isotonic sodium chlorrde solution.In addition, often adopt aseptic fixed oil as solvent or suspension media.For reaching this purpose, can adopt any gentle fixed oil, comprise synthetic glycerine monoesters or triglyceride.In addition, in the injection preparation, can use such as lipid acid such as oleic acid.
The suppository that is used for rectal administration can prepare with mixing such as suitable non-irritating excipients such as theobroma oil and polyoxyethylene glycol by making described medicine, described non-irritating excipient is solid at normal temperatures but is liquid and therefore under rectal temperature, its can be in rectum fusing and discharge described medicine.
The solid dosage that is used for oral administration medicine supplying can comprise capsule, tablet, pill, pulvis and granule.In described solid dosage, active compound can mix such as inert diluents such as sucrose, lactose or starch with at least a.As normal practice, described formulation also can comprise the additional material except that inert diluent, and lubricant for example is as Magnesium Stearate.Under the situation that is capsule, tablet and pill, described formulation also can comprise buffer reagent.Tablet and pill can be in addition with the preparations of enteric coating.
Be suitable for peroral administration liquid dosage form and can comprise pharmaceutically acceptable emulsion, solution, suspension, syrup and the elixir that contains inert diluent (for example water) commonly used in this technology.These compositions also can comprise adjuvant, such as wetting agent, emulsifying agent and suspension agent, cyclodextrin and sweeting agent, correctives and perfuming agent.
The compounds of this invention can also the liposome form throw with.Known to this technology, liposome generally is derived from phosphatide or other lipid materials.Liposome can by intersperse among list in the aqueous medium-or multilayer hydration liquid crystal form.Can accept on any physiology and metabolizable nontoxic liposome that can form liposome all available.Except that The compounds of this invention, the composition that the present invention is the liposome form can contain stablizer, sanitas, vehicle and similar substance.Preferable lipid is natural and synthetic phospholipid and phosphatidylcholine (Yelkin TTS).The method that forms liposome is known to this technology.Referring to (for example) Prescott (ed.), " Method in Cell Biology, " (XIV volume, Academic Press, New York, 1976, the 33 pages and following or the like).
Although The compounds of this invention can be used as independent active pharmaceutical preparation throw with, it also can use by used one or more other medicaments in cancer therapy.For the treatment cancer, can comprise (for example) irinotecan (irinotecan) with the representative medicaments that The compounds of this invention uses, topotecan (topotecan), gemcitabine (gemcitabine), Gefitinib (gefitinib), cut down Ta Lani (vatalanib), Sutent (sunitinib), Xarelto (sorafenib), erlotinib (erlotinib), dexrazoxane (dexrazoxane), imatinib mesylate (gleevec), Trastuzumab, 5 FU 5 fluorouracil, formyl tetrahydrofolic acid (leucovorin), carbon platinum (carboplatin), cis-platinum (cisplatin), taxanes, for pricking his shore (tezacitabine), endoxan (cyclophosphamide), vinca alkaloids, imatinib (imatinib), the anthracene nucleus class, Rituximab (rituximab), Qu Sizuo monoclonal antibody (trastuzumab), the topoisomerase I inhibitor, and other cancer chemotherapeutic agents.
Can should use with therapeutic dose with the above-claimed cpd that The compounds of this invention uses, as handbook on doctor's table of incorporating this paper with way of reference into (Physicians ' Desk Reference) (PDR), described in the 47th edition (1993) or described treatment have consumption to can be known to the those of ordinary skill.
Compound of the present invention and other anticancer agents can recommend maximum clinical dosage or with smaller dose throw with.The visual dosing way of the dosage of active compound, disease severity and patient react and change with acquisition and expect therapeutic response in the present composition.Described combination can be used as the independent groups compound or as the single formulation that contains two kinds of medicaments throw with.When throw as combination and the time, described healing potion can be formulated into the independent groups compound that gives at identical time or different time, perhaps described healing potion can be used as single composition and gives.
Can suppress the breast cancer cell growth by causing cell cycle to be stagnated such as antiestrogens such as tamoxifens, this needs the effect of cell cycle inhibitor p27Kip.Recently, people are verified, and the activation in Ras-Raf-MAP kinases path can change the phosphorylation state of p27Kip so that it is weakened the inhibition activity aspect the cell cycle stagnation, thereby causes estrogen antagonist resistance (people such as Donovan, J.Biol.Chem.276:40888,2001).Report as people such as Donovan, thereby suppress the phosphorylation state preservation hormone-sensitive that the MAPK signal can change p27 in the intractable breast cancer cell line of hormone by using mek inhibitor to treat.Therefore, in one aspect, formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or compound (Va) can be used for treating hormone and rely on disease, for example breast cancer and prostate cancer, the common hormone resistance when in these cancers, using conventional anticancer agent to reverse.
In such as chronic lymphocytic leukemia leukemia such as (CML), chromosome translocation is the reason that forms constitutively activate BCR-ABL Tyrosylprotein kinase.The patient can produce reaction to imatinib mesylate (a small molecules tyrosine kinase inhibitor) because the Ab1 kinase activity is suppressed.Yet many patients that suffer from terminal illness begin and can produce reaction to imatinib mesylate, but make described palindromia owing to produce the sudden change of giving resistance in Abl kinases territory afterwards.In vitro study has shown that Bcr-Abl adopts Raf kinases path to draw its effect.In addition, the kinases that suppresses more than one in same paths can provide Additional Protection at the sudden change of giving resistance.Therefore, in the present invention on the other hand, formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va) compound can use together to reverse or to prevent with at least a additional agent (for example, imatinib mesylate) in treatment described at least a additional agent is produced resistance such as chronic lymphocytic leukemia leukemia such as (CML).
In another aspect of this invention, provide the cover group that comprises one or more The compounds of this invention.Representative cover group comprises 2-amino-7 of the present invention, 8-dihydro-6H-pyrido [4,3-d] pyrimidine-5 ketone compound is (for example, formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or compound (Va)) and a package insert or other labels, comprise by the guidance of throwing with the described compounds for treating cell proliferative diseases of HSP90 amount of suppression.
Representative 2-amino-7, synthetic being set forth in the example 1 to 8 of 8-dihydro-6H-pyrido [4,3-d] pyrimidine-5 ketone compound.Prepared representative 2-amino-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5 ketone compound is shown in the table 1 of example 9 in 5.
In one aspect, having some The compounds of this invention that is substituted the 7-phenyl moiety can be according to reacting shown in Figure 1 the preparation.Make benzyl amine 1-C (making from Chiral Amine 1-A) and laurate 1-D (making) coupling to generate conjugate addition product 1-E (Shi Diwen (Steven) D. boolean (Bull) Shi Difen (Stephen) G. David (Davies) from Wordsworth-Ai Mengsi of aldehyde 1-B (Wadsworth Emmons) serial reaction by reductive amination process, three for lattice Dell dagger-axe many-Bu Leix tower (Santiago Delgado-Ballester), the triumphant profit of Bi Te (Peter) M. (Kelly), Lu Ke (Luke) J. examines very (Kotchie), Ma Ximo gill promise enlightening (Massimo Gianotti), Mario Rider Luo Si (Mario LadeRas) and Andrew (Andrew) D. Smith (Smith), Chemical Society's periodical (J.Chem.Soc.), periodical (Perkin Trans) 1 is translated in Berlin, 2001, (23), 3112).Use 1.1 equivalents to be stored in the removal that the ceric ammonium nitrate in acetonitrile and the water is reached benzyl.Gained amine 1-F generates compound 1-H through propanedioic acid acyl chlorides methyl esters 1-G acidylate.When using, implement cyclization by the Dieckmann condensation reaction such as alkaline purifications such as sodium ethylates.Thereby use subsequently such as acid treatment gained lactan such as HCl and provide compound 1-I to implement decarboxylic reaction.Use Acetyl Chloride 98Min. implement the O-acylation reaction and use be stored in boiling solvent (such as acetonitrile or toluene) thus in catalytic dimethylaminopyridine handle to realize that acetate group shifts and generate Compound I-J.Pyrimidines i-K is for forming by using guanidine/EtOH and dimethyl amine to handle I-J.Can remove right-methoxy-benzyl by ceric ammonium nitrate or trifluoroacetic acid in this stage (or after Suzuki (Suzuki) coupled reaction).The phenyl ring of I-K according to circumstances can by with one, suitable boric acid generation Suzuki coupled reaction comes functionalized to generate biaryl compound I-L.Next, go protection to generate amine I-M to right-methoxy-benzyl.
Response diagram 1
Figure S2006800365004D00341
On the other hand, some compound of the present invention can be according to reacting shown in Figure 2 the preparation.(for example make suitable amine, methylamine) with oxalic acid and the expectation aldehyde (for example, 2-A) condensation generates sour 2-B in backflow ethanol, next with described sour 2-B at enzymatic synthesis condition (for example, use is stored in the thionyl chloride in the suitable alcoholic solvent, 0 ℃) under change into corresponding ester 2-C.Generate ethanamide 2-E by using diketene 2-D to handle the 2-C ester.Next, in existing down such as alkali such as sodium methylates and 2-D being implemented cyclization to generate lactan 2-F by microwave heating.Aminopyridine generates carries out in two steps: the first step, and the lactan that is stored in the tetramethyleneimine ethanolic soln by heating under microwave condition forms the intermediate enamine; Second step added guanidine-HCl in this solution, implement microwave heating then once more.By reversed-phase HPLC separation of ammonia yl pyrimidines 2-G, then under Suzuki condition and microwave heating with suitable aryl boric acid coupling to generate biaryl compound 2-H.
Response diagram 2
Response diagram 3 is showed the other method that is used for synthetic some compound of the present invention.Right-methyl-phenoxide 3-A with (S)-1-(4-p-methoxy-phenyl) ethamine 3-B and sodium borohydride reduction amination behind molecular sieve generates amine 3-C.Subsequently by (for example) make 3-C with just-butyllithium reaction generates the amine ion and handles with suitable laurate 3-D and generate conjugate addition product 3-E.Use trifluoroacetic acid to implement to go protection to generate amine 3-F, it can change into 3-I according to reaching above described step shown in the response diagram 2.
Response diagram 3.
Figure S2006800365004D00352
In one embodiment, provide the method for a kind of preparation formula (I) compound, it comprises:
(a) make formula (I) compound and acid-respons to generate acid salt; Or
(b) reaction formula (I) acid salt is with production (I) free alkali compound; Or
(c) make the reaction of formula (VI) midbody compound and guanidine or guanidine derivative with production (I) compound
Figure S2006800365004D00361
R wherein a, R and R bBy as formula (I) defined and W is O or NR ' R ", wherein to reach R " be H or alkyl to R ' independently.
In one embodiment, provide a kind of formula (VI) midbody compound.In one aspect, R aBe methyl.On the other hand, described formula (VI) midbody compound is formula (VII) compound
Figure S2006800365004D00362
Wherein
R by as formula (VI) is defined;
R 5Be hydrogen or halogen; And
R 6aR 6aBe selected from by halogen, be substituted or be unsubstituted aryl, and be substituted or be unsubstituted the group that heteroaryl is formed.
In formula (VI) or (VII) among some embodiment of compound, R is selected from by hydrogen, is unsubstituted alkyl and is substituted the group that alkyl is formed.In some described embodiment, R is selected from the group that is made up of methyl, ethyl, allyl group, 3-methyl-butyl and isobutyl-.In other embodiments, R is selected from by hydrogen, benzyl, 1-(4-p-methoxy-phenyl) ethyl, methyl, 3-aminopropyl and group that the 2-methyl-the 2-morpholinyl propyl is formed.In another embodiment, R is a hydrogen.
In certain embodiments, R 5Be halogen.In some aspects, R 5Be fluorine.
In other embodiments, R 5Be hydrogen.
R 6aIn certain embodiments, R 6aBe halogen.R 6aIn some aspects, R 6aBe bromine.
R 6aIn certain embodiments, R 5And R 6aThe two is halogen.R 6aIn other embodiments, R 5Be fluorine and R 6aBe bromine.
R 6aIn certain embodiments, R 6aBe selected from by being substituted aryl and being substituted the group that heteroaryl is formed, wherein said aryl and heteroaryl are selected from the group that is made up of following: furyl, pyrryl, phenyl, pyridyl, pyrazinyl, pyrimidyl, clatter piperazine base, pyrazolyl, imidazolyl, triazolyl, indyl, oxadiazole base, thiadiazolyl group, quinolyl, isoquinolyl, isoxazolyl, oxazolyl, thiazolyl and thienyl.
R 6aIn certain embodiments, R 6aBe selected from the group that forms by following: (2-hydroxyl-ethylamino)-pyrazine-2-base; 1H-pyrazoles-4-base; 1-methyl isophthalic acid H-pyrazoles-4-base; 1-methyl isophthalic acid H-pyrazoles-4-base; 2-(5-methyl-pyridine-2-yl)-phenyl; 2; 3-two fluoro-phenyl; 2; 3-dimethoxy-phenyl; 2; 4-two fluoro-phenyl; 2; 4-dimethoxy-phenyl; 2; 4-dimethoxy-pyrimidine-5-base; 2; 5-two fluoro-phenyl; 2; 6-two fluoro-phenyl; 2; 6-dimethyl-pyridin-3-yl; 2-acetamido phenyl; the 2-aminocarbonyl-phenyl; 2-amino-pyrimidine-5-base; 2-chloro-4-methoxyl group-pyrimidine-5-base; 2-chloro-5-fluoro-pyridin-3-yl; 2-chloro-phenyl; 2-chloro-pyridin-3-yl; 2-chloro-pyridin-4-yl; 2-two fluoro-3-p-methoxy-phenyls; 2-ethyl-phenyl; 2-oxyethyl group-thiazole-4-base; 2-fluoro-3-methoxyl group-phenyl; 2-fluoro-3-aminomethyl phenyl; 2-fluoro-4-methyl-phenyl; 2-fluoro-5-methoxyl group-phenyl; 2-fluoro-5-aminomethyl phenyl; the 2-fluorophenyl; 2-fluoro-pyridin-3-yl; 2-hydroxymethyl-3-p-methoxy-phenyl; 2-hydroxymethyl phenyl; 2-isoquinoline 99.9-4-base; 2-methoxyl group-5-trifluoromethyl-phenyl; 2-methoxyl group-phenyl; 2-methoxyl group-pyridin-3-yl; 2-methoxyl group-pyrimidine-4-base; 2-methoxyl group-thiazole-4-base; 2-methyl-phenyl; 2-methyl-pyridin-3-yl; 2-oxo-1; 2-dihydro-pyridin-3-yl; the 2-Phenoxyphenyl; the 2-pyridin-3-yl; 2-pyrimidine-5-base; the 2-Trifluoromethoxyphen-l; 2-trifluoromethoxy-phenyl; 3; 4-dimethoxy-phenyl; 3; 5-dimethyl-isoxazole-4-bases; 3; 6-dimethyl-pyrazine-2-base; 3-acetamido phenyl; the 3-aminocarbonyl-phenyl; 3-bromo-phenyl; 3-chloro-pyrazine-2-base; the 3-cyano-phenyl; the 3-dimethylaminophenyl; 3-oxyethyl group-phenyl; 3-ethyl-4-methyl-phenyl; 3-ethynyl-phenyl; 3-fluoro-6-methoxyl group-pyridine-2-base; the 3-fluorophenyl; 3-fluoro-pyrazine-2-base; 3-sulfonyl methane amido phenyl; 3-methoxycarbonyl phenyl; the 3-p-methoxy-phenyl; 3-methoxyl group-pyrazine-2-base; 3-methyl-3H-imidazo [4; 5-b] pyrazine-5-base; the 3-aminomethyl phenyl; 3-methyl-pyridine-2-base; the 3-Trifluoromethoxyphen-l; the 3-trifluoromethyl; 4; 5-dimethoxy-pyrimidine-2-base; 4-amino-5-fluoro-pyrimidine-2-base; 4-chloro-2; 5-dimethoxy-phenyl; 4-chloro-2-fluoro-phenyl; 4-chloro-2-methoxyl group-5-methyl-phenyl; 4-chloro-pyridin-3-yl; 4-two fluoro-2-methyl-phenyl; 4-oxyethyl group-5-fluoro-pyrimidine-2-base; 4-oxyethyl group-pyrimidine-2-base; 4-oxyethyl group-pyrimidine-5-base; 4-ethyl-1H-pyrazole-3-yl; 4-fluoro-2-methoxyl group-phenyl; 4-fluoro-2-methyl-phenyl; the 4-fluorophenyl; 4-methoxyl group-5-methyl-pyrimidine-2-base; 4-methoxyl group-pyridin-3-yl; 4-methoxyl group-pyrimidine-2-base; 4-methoxyl group-pyrimidine-5-base; 4-methyl-phenyl; 4-methyl-pyridine-2-base; 4-methyl-pyridin-3-yl; 4-tetramethyleneimine-1-base-pyrimidine-2-base; 5; 6-dimethoxy-pyrazine-2-base; 5-ethanoyl-thiophene-2-base; 5-amino-6-oxyethyl group-pyrazine-2-base; 5-amino-6-methoxyl group-3-methyl-pyrazine-2-base; 5-amino-6-methoxyl group-pyridine-2-base; 5-chloro-4-methoxyl group-pyrimidine-2-base; 5-chloro-6-methoxyl group-pyrazine-2-base; 5-dimethylamino-6-methoxyl group-pyrazine-2-base; 5-fluoro-2-p-methoxy-phenyl; 5-fluoro-4-methoxyl group-pyrimidine-2-base; 5-fluoro-6-methoxyl group-pyrazine-2-base; 5-fluoro-pyridine-2-base; 5-methoxyl group-pyridin-3-yl; 5-methoxyl group-thiophene-2-base; 5-trifluoromethyl-pyrimidine-2-base; 6-ethanoyl-pyridine-2-base; 6-chloro-pyrazine-2-base; 6-oxyethyl group-pyrazine-2-base; 6-oxyethyl group-pyridine-2-base; 6-fluoro-pyridine-2-base; 6-fluoro-pyridin-3-yl; 6-hydroxyl-pyridine-2-base; 6-methoxyl group-5-methylamino-pyrazine-2-base; 6-methoxyl group-5-methyl-pyrazine-2-base; 6-methoxyl group-pyrazine-2-base; 6-methoxyl group-pyridine-2-base; 6-methoxyl group-pyridin-3-yl; 6-methylamino-pyrazine-2-base; 6-methyl-pyridine-2-base; 5-amino-6-(2; 2, the 2-trifluoro ethoxy) pyrazine-2-base and 6-trifluoromethyl-pyridine-2-base.
In another embodiment, described guanidine derivative is the ethanoyl guanidine.
In another embodiment, be provided for the formula (VI) of preparation formula (I) compound or (VII) purposes of compound.
Can more easily understand the present invention with reference to following example, described example is for reaching illustration purpose and provide and being not desire restriction the present invention.
Example
With reference to following example, can use methods described herein or know additive method in the industry and synthesize The compounds of this invention.
(Milford MA) implements signature analysis to described compound and/or intermediate to use the Waters Millenium chromatographic system with 2690 Separation Module by high performance liquid chromatography (HPLC).Analytical column is that (Deerfield, Alltima C-18 IL) is anti-phase, 4.6 * 250 millimeters available from Alltech.Use gradient elution, begin with 5% acetonitrile/95% water usually and proceeded to 100% acetonitrile through 40 minutes.All solvents contain 0.1% trifluoroacetic acid (TFA).Be absorbed in 220 or 254 nanometers detection compound by UV-light (UV).The HPLC solvent be available from Burdick and Jackson (Muskegan, MI) or Fisher Scientific (Pittsburgh, PA).In some cases, use silica gel plate (for example, Baker-Flex Silica Gel 1B2-F flexible flake) the evaluation purity of the back side by thin-layer chromatography (TLC) as glass or plastic cement.TLC result can be under UV-light knows iodine vapor or other various dye technologies in the range estimation mode or by employing and easily observes.
A kind of enforcement in following two kinds of LC/MS equipment used in mass spectroscopy: Waters System (Alliance HTHPLC and Micromass ZQ mass spectrograph; Tubing string: Eclipse XDB-C18,2.1 * 50mm; Solvent systems: 5-95% (or 35-95% or 65-95% or 95-95%) is stored in acetonitrile and 0.05%TFA in the water; Flow velocity 0.8mL/min; Molecular weight ranges 500-1500; 20 volts of awl voltages; 40 ℃ of tubing string temperature) or Hewlett Packard System (Series1100 HPLC; Tubing string: Eclipse XDB-C18,2.1 * 50 millimeters; Solvent systems: 1-95% is stored in acetonitrile and the 0.05%TFA in the water; Flow velocity: 0.4mL/min; Molecular weight ranges: 150-850; 50 volts of awl voltages; 30 ℃ of tubing string temperature).All quality reports are those quality of protonated parent ion.
GCMS analyzes and uses Hewlett Packard equipment (the HP6890Series gas chromatograph with Mass Selective Detector 5973; Syringe volume: 1 liter; Original tube column temperature: 50 ℃; Final tubing string temperature: 250 ℃; The slope time: 20 minutes; Airflow rate: 1mL/min; Tubing string: 5% phenyl methyl siloxanes, model HP 190915443, size: 30.0 meters * 25 meters * 0.25 meter) implement.
(Palo Alto CA) implements nucleus magnetic resonance (NMR) analysis to some compound to use Varian 300MHz NMR.The spectrum reference substance is the solvent of TMS or known chemical displacement.Some compound sample is operated down to impel more various product dissolving at high temperature (for example, 75 ℃).
(Desert Analytics, Tucson AZ) evaluates the purity of some The compounds of this invention by ultimate analysis.
(Holliston MA) measures fusing point to use Laboratory Devices Mel-Temp instrument.
Use Flash 40 chromatographic systems and KP-Sil, (Biotage, Charlottesville VA) or by quick tubing string chromatogram use silica gel (230 to 400 order) wrapping material or use the anti-phase tubing string of C-18 to implement the preparation separation by HPLC 60A.Be used for Flash 40Biotage system and quick tubing string stratographic typical solvent is methylene dichloride, methyl alcohol, ethyl acetate, hexane, acetone, water-based hydroxyl amine and triethylamine.The typical solvent that is used for reversed-phase HPLC is acetonitrile and the aqueous solution and 0.1% trifluoroacetic acid of various concentration.
In described example, used following abbreviation:
Aq.: water-based
Boc: the 3rd butoxy carbonyl
BSA: bovine serum albumin
Celite: diatomite
DCM: methylene dichloride
Eq.: equivalent
Et 3N: triethylamine
EtOAc: ethyl acetate
The GC gas-chromatography
H: hour
HPLC: high performance liquid chromatography
IC 50Value: the concentration L that makes the inhibitor that measures active minimizing 50%: rise
The LC/MS liquid chromatography/mass spectrometry
LRMS: low-res mass spectrum
MeOH methyl alcohol
Min: minute
ML: milliliter
Mm: millimeter
MM: millimolar concentration
Mmol: mmole
Nm: nanometer
The NMP:N-methyl-2-pyrrolidone
RP-HPLC: RPLC
The rt room temperature
Sat: saturated
THF: tetrahydrofuran (THF)
TMS: trimethyl silane
TLC: thin-layer chromatography
TRF: time resolution fluorescence.
The name of the compound that discloses provides by ACD Name version 5.07 softwares (calendar year 2001, November 14) that can buy from Advanced Chemistry Development company or ACD Name Batch version 5.04 (May 28 in 2002) or by the ISIS/Base AutoNom 2000 (AutomaticNomenclature) that carries out the IUPAC standardized denomination in the application's case.Other compounds, intermediate and original material use the name of standard I UPAC nomenclature.
It is to be understood that organic compound of the present invention can present tautomerism.Because chemical structure only can be represented a kind of in the possible tautomeric forms in the application's case, therefore should understand arbitrary tautomeric forms that the structure that illustrates is contained in the present invention.
It is to be understood that the present invention is not limited to illustrative embodiment described herein, but contain all these forms that it belongs to above-mentioned disclosure scope.
Following example explanation is used to prepare the method for representative compounds of the present invention.
Example 1
The representative program that is used for The compounds of this invention
Steps A: alpha, beta-unsaturated esters
At-78 ℃, N 2Be stored in stirred solution, dropwise just adding-butyllithium (84mmol) of dry THF (176mL) to triethyl phosphine acyl acetic acid ester (88mmol) down.With described solution stirring 30min, keep internal temperature to be lower than-70 ℃.At-78 ℃ and N 2By sleeve pipe phosphoric acid ester solution is transferred to 2-bromo-4-fluorobenzaldehyde 1-1 (80mmol) and be stored in the solution of THF (160mL) down.Gained solution is warming up to room temperature, 2 hours.By adding water-based NH 4The described reaction mixture of Cl cancellation is also used EtOAc (* 3) extraction subsequently.Organic moiety is merged, use H 2O (* 3), saturated brine (* 3) washing, dry then (Na 2SO 4), filter and under low pressure evaporate to generate light yellow oil.But form white crystal in the back in refrigerator and cooled.Described crystal after filtration and with methanol wash so that neat compounds 1-2 to be provided.Mother liquor is through concentrating, cool off and filtering.Repeat E-3-(the 2-bromo-4-fluorophenyl) ethyl propenoate that this process generates in theory until the major part of collecting as white crystal.
Step B: asymmetric amine is to the conjugate addition of alpha, beta-unsaturated esters
Figure S2006800365004D00402
Be stored in the adding compound 1-2 in stirred solution of dry THF (116mL) to (S)-N-benzyl-1-(4-p-methoxy-phenyl) ethamine 1-3 (58mmol).Make described reaction be cooled to-78 ℃ and, N at-78 ℃ 2Dropwise just adding-butyllithium (56.2mmol) down.After interpolation, described reaction mixture is stirred 40min down at-78 ℃.Make described reaction mixture at water-based NH subsequently 4Distribute between Cl and the EtOAc,, isolate organic moiety, use H then with EtOAc (* 3) extraction 2O (* 3), saturated brine (* 3) washing, dry then (Na 2SO 4), filter and under low pressure evaporate generating rough oily matter, it is with (purifying of hexane/EtOAc) is to provide compound 1-4 after the silicone tube post.
Step C:CAN (ceric ammonium nitrate) goes protection
Figure S2006800365004D00411
Original material 1-4 (81.78mmol) is dissolved in acetonitrile: in the water (5: 1,1.6 liters).Add 3 parts of independent CAN (490.68mmol) compound 1-4 while stirring, between per twice interpolation, stirred 1 hour.Subsequently described reactant is at room temperature stirred and spend the night.Next, under vacuum, remove acetonitrile and extract all the other aqueous layer (4 * 400mL) with EtOAc.Described EtOAc is also laminated, with dried over sodium sulfate, filtration and concentrated to generate raw product compound 1-5.Use the described raw product of quick tubing string (being stored in the 5%MeOH among the DCM) purifying.
Step D: acylation reaction
Figure S2006800365004D00412
At room temperature, in stirred solution, add triethylamine (21.08mmol) and diketene (6.33mmol) to what unhindered amina 1-5 (5.27mmol) was stored in DCM (26mL).Stir described reactant until conclude described reacting completely by LCMS.Make described mixture at DCM and water-based NaHCO subsequently 3Between distribute, with DCM (* 3) extraction, merge organic layer, use H subsequently 2O (* 3), saturated brine (* 3) washing, dry then (Na 2SO 4), filter and under low pressure evaporate generating rough oily matter, it is with (purifying of hexane/EtOAc) is to provide compound 1-6 after the silicone tube post.
Step e: cyclization
Figure S2006800365004D00413
In containing the reaction flask that is stored in compound 1-6 (1.1mmol) in the methyl alcohol (5mL), add the 25%NaOMe that is stored among the MeOH (0.5mL).Described reaction mixture is heated 5min down in 144 ℃ in microwave.After being cooled to room temperature, DCM (* 3), H are used in described reaction mixture use ammonium chloride dilution successively 2O (* 3), saturated brine (* 3) washing, dry then (Na 2SO 4), filter and under low pressure evaporate to generate raw product piperidines-diketone 1-7, it can be directly used in next step.
Step F: amino-pyrimidine-lactan
Figure S2006800365004D00414
In being stored in the mixture of ethanol (9mL), dioxopiperidine 1-7 (0.915mmol) and guanidine HCl (4.573mmol) add tetramethyleneimine (18.3mmol).Described reaction mixture is handled 10min down in 160 ℃ in microwave (Power MAX setting).After being cooled to room temperature, described reaction mixture is used H subsequently with DCM (* 3) extraction 2O (* 3), saturated brine (* 3) washing, dry then (Na 2SO 4), filtering and under low pressure evaporate generating raw product 1-8, it is with after silicone tube post (EtOAc) purifying.
Step G: Suzuki coupled reaction
Figure S2006800365004D00421
In being stored in the mixture of DMA, amino-pyrimidine-lactan 1-8 (1eq.), boric acid or ester (4eq.) add Pd (dppf) 2Cl 2(0.4eq.) and 2M K 2CO 3(8eq).Described reaction mixture is handled 15min down in 120 ℃ in microwave.After being cooled to room temperature, described reaction mixture is used H with DCM (* 3) dilution 2O (* 3), saturated brine (* 3) washing, dry then (Na 2SO 4), filter and under low pressure evaporate generating raw product, its with after anti-phase preparation HPLC purifying to generate pure HSP90 inhibitor.
Example 2
Synthesizing of the present invention's representative N-alkylated compound
Steps A: reductive amination process
Figure S2006800365004D00422
At room temperature, in stirred solution, add sodium triacetoxy borohydride (1.1eq.) to what unhindered amina 1-5 (1eq.), aldehyde 2-1 (1eq.) were stored in DCM.At room temperature stir described reactant until concluding that by LCMS described reaction finishes.Make described mixture at DCM and water-based NaHCO subsequently 3Between layering, also merge organic moiety with DCM (* 3) extraction, use H subsequently 2O (* 3), saturated brine (* 3) washing, dry then (Na 2SO 4), filter and under low pressure evaporate to generate raw product compound 2-2, it is directly used in next step reaction.
Step B-E: acylation reaction, cyclization, amino-pyrimidine-lactan formation reaction, Suzuki coupled reaction
Figure S2006800365004D00431
Step B to step e be with example 1 in step e identical to step G.
Step F: go protection
Figure S2006800365004D00432
The N-alkylation lactan that uses the 50%TFA processing to protect through Boc-is stored in the solution among the DCM.At room temperature stir described reaction mixture.After finishing, described reaction mixture concentrated and with anti-phase preparation HPLC purifying with the generation neat compounds.
Prepare other alkylated amines compounds of the present invention in a similar manner.
Example 3
Figure S2006800365004D00433
Sodium methylate (is stored in the 25wt% solution in the methyl alcohol, 0.193mol), the mixture of methyl acetate (0.0644mol) and 100mL anhydrous methanol stirred 1 hour under room temperature, nitrogen atmosphere.Add subsequently pure acid amides 1-6 (24.1g, 0.0644mol).Described reactant is reached 85 ℃ in refluxed under nitrogen 1 hour and slow subsequently distilling off solvent until internal temperature.Using HPLC to monitor described reaction falls until the 1-6 completely consumed.Reactant is cooled to room temperature and under low pressure removes remaining solvent.Be dissolved in described residue in the 100mL water and in ice/water-bath, be cooled to 5 ℃ subsequently.In this solution, add 1N HCl subsequently until pH=1, during this period, make internal temperature keep below 10 ℃.Stir described mixture until forming unit for uniform suspension and subsequent filtration.Collected solid water (100mL * 3) washing is also spent the night generating 20.7g light yellow solid shape lactan 1-7 at air drying, productive rate be 98.1% and purity be 98.3% (HPLC area than).
Example 4
Figure S2006800365004D00441
Step 1:
Use dry THF (50mL), titanium ethanolate (41mL), (S)-(-)-the 3rd-butane sulfinyl amine (AdvancedAsymmetrics, 12.0g, 99.1mmol, 1.1 equivalent) and 2-bromo-4-fluorobenzaldehyde 4.1 (Matrix Scientific, catalog number 011279,18.2g, 90.1mmol, 1.0 equivalents) and filling 500mL round-bottomed flask.With the gained reaction mixture at N 2, stirred 4 hours under the room temperature.Monitor by LCMS reaction when finishing, add salt solution (200mL) and diatomaceous mixture with EtOAc (360mL) described reaction mixture of dilution and vigorous stirring limit, limit.The gained emulsion is filtered via Celite pad and is washed with EtOAc (200mL).Filtrate is transferred in the separating funnel, and removed aqueous layer.Organic moiety is washed with salt solution (200mL), subsequent drying (Na 2SO 4) and concentrate in a vacuum so that light yellow oil 4.2 (26.5g, 86.3mmol, 96%) curable when leaving standstill to be provided. 1H?NMR(300MHz，CD 3Cl)δ8.86(s，1H)，8.03(m，1H)，7.35(m，1H)，7.11(m，1H)，1.11(s，9H)LCMS?m/z?307.9(MH+)，t R＝3.22min。
Step 2:
With 100mL three neck round-bottomed flasks, backflow condenser and feed hopper dried overnight in baking oven.After in baking oven, taking out, assemble described instrument and be placed on positive N 2Following and the cool to room temperature of pressure.Fill described flask with Zn powder (21.3g, 326.0mmol, 15.0 equivalents), CuCl (32.6g, 32.6mmol, 1.5 equivalents) and dry THF (60mL).The gained reaction mixture is heated to reflux temperature (bathe temperature and be about 90 ℃) and uses overhead type agitator vigorous stirring 30min.In oil bath, take out reactant (maintenance vigorous stirring) and use ethyl bromoacetate (3.6mL, 32.6mmol, 1.5 equivalents) subsequently and dry THF (30mL) filling feed hopper.Should add ethyl bromoacetate with the speed of the described reaction mixture that keeps slowly refluxing.When finishing when adding, with described reaction mixture restir 20min, postheating to 50 ℃, 30min.Make described reaction mixture be cooled to 0 ℃ then and also fill feed hopper with 4.2 (6.60g, 21.5mmol, 1.0 equivalents) and dry THF (20mL).Subsequently this solution is dropwise added in the reaction mixture, with described reaction mixture 0 ℃ of following restir 4 hours.When judging that by LCMS described reaction has been finished, described reaction mixture is filtered via Celite pad, use Et 2O (2 * 100mL) washing Zn and filter beds.Filtrate is used 0.25M citric acid (200mL), saturated NaHCO 3(aq) (2 * 200mL) washings, dry (Na 2SO 4) and concentrate in a vacuum so that clarification oily 4.3 (7.30g, 18.4mmol, 86%) to be provided.： 1H?NMR(300MHz，CD 3Cl)δ7.39(m，1H)，7.28(m，1H)，7.01(m，1H)，5.14(m，1H)，4.92(d，J＝5.4，2H)，4.1(m，2H)，2.90(ddd，?J 1＝，J 2＝，J 3＝，2H)，1.22(m，3H，9H)。LCMS?m/z?396.0(MH+)，t R＝2.96min。HPLC (frac_10min_2070%B), t R=4.108 (main diastereomers), t R=3.962 (Claisen condensation by-product) t R=3.888 (less important diastereomers), 95.5: 2.1: 2.1.de=96%.
Step 3:
Use 4.3 (7.30g, 18.4mmol, 1.0 equivalents), Et 2O (37mL), EtOH (1.2mL, 1.1 equivalents) and 4M HCl are stored in Et 2Mixture among the O (37mL, 2.0 equivalents) is filled the 500mL round-bottomed flask.Described reaction mixture was at room temperature stirred 30 minutes.Filter gained suspension and use Et 2O (3 * 40mL) and hexane (2 * 40mL) abrasive solid.Described solid is dry so that white solid 4.4 (5.23g, 15.2mmol, 83%) to be provided under vacuum. 1H?NMR(300MHz，CD 3OD)δ7.61(m，2H)，7.33(m，1H)，5.18(m，1H)，4.85(bs，3H)，4.13(q，J＝7.2，2H)，3.15(ddd，2H)，1.22(t，J＝7.5，3H)LCMS?m/z?292.0(MH+)，t R?＝1.97min。For the HCl salt of free alkali, be dissolved in 4.4 (50mg) among the EtOAc (20mL) and use 10%Na 2CO 3(3 * 20mL) washings.Organic moiety drying (Na 2SO 4) and concentrate so that free alkali to be provided in a vacuum.Prepare the racemic mixture of final beta-amino ester products and pass through chirality HPLC analysis to determine stage enantiomer separation (ChiralpakAD tubing string, 1mL/min, S, t R=5.84; R, t R=7.47min)
Example 5
Figure S2006800365004D00451
Step 1:
Use dry THF (54mL), titanium ethanolate (18.25g, 3 equivalents), (S)-(-)-the 3rd-butane sulfinyl amine (4.85g, 1.5 equivalents) and 5-bromo thiazole-4-formaldehyde 5.1 (5.12g, 1.0 equivalents) to fill the 250mL round-bottomed flask.In N 2, stir the gained reaction mixture under the room temperature.When finishing by LCMS monitoring reaction, described reaction mixture adds salt solution (200mL) and diatomaceous mixture with EtOAc (360mL) dilution and vigorous stirring limit, limit.The gained emulsion is filtered via a Celite pad and is washed with EtOAc (200mL).Filtrate is transferred in the separating funnel, and removed aqueous layer.Organic moiety is washed with salt solution (200mL), subsequent drying (Na 2SO 4) and concentrate so that light yellow oily 5.2 (7.9g, 100%) to be provided in a vacuum. 1H?NMR(300MHz，CD 3Cl)δ8.88(s，1H)，8.72(s，1H)，1.21(s，9H)LCMS?m/z?296.9(MH+)，t R＝2.35min。
Step 2:
With 100mL three neck round-bottomed flasks, backflow condenser and feed hopper dried overnight in baking oven.After in baking oven, taking out, assemble described instrument and be placed on positive N 2Pressure descends and is cooled to room temperature.Use Zn powder (25.4g, 400.0mmol, 15.0 equivalents), CuCl (3.96g, 40mmol, 1.5 equivalents) and dry THF (80mL) to fill described flask.The gained reaction mixture is heated to reflux temperature (bath temperature is about 90 ℃) and uses overhead type agitator vigorous stirring 30min.In oil bath, take out reactant (maintenance vigorous stirring) and use ethyl bromoacetate (6.68g, 40mmol, 1.5 equivalents) subsequently and dry THF (40mL) filling feed hopper.Should add ethyl bromoacetate with the speed of the described reaction mixture that keeps slowly refluxing.Finishing when adding, with described reaction mixture restir 30min, postheating to 50 ℃, 30min.Make described reaction mixture be cooled to 0 ℃ then and also fill feed hopper with 5.2 (26.67mmol, 1.0 equivalents) and dry THF (27mL).Subsequently this solution is dropwise added in the reaction mixture, with described reaction mixture 0 ℃ of following restir 4 hours.After judging that by LCMS described reaction has been finished, described reaction mixture is filtered via Celite pad, use Et 2O (2 * 100mL) washing Zn and filter beds.With 0.25M citric acid (200mL), saturated NaHCO 3(aq) (2 * 200mL) washings, dry (Na 2SO 4) and concentrate in a vacuum so that clarification oily 5.3 (10g) to be provided.
Step 3:
Use 5.3 (10g, 26.67mmol, 1.0 equivalents), Et 2O (27mL), EtOH (1.7mL) and 4M HCl are stored in Et 2Mixture among the O (53mL, 2.0 equivalents) is filled the 500mL round-bottomed flask.Described reaction mixture was at room temperature stirred 30 minutes.Filter gained suspension and use Et 2O (3 * 40mL) and hexane (2 * 40mL) abrasive solid.Described solid is dry so that white solid 5.4 (6.6g, 88.7%) to be provided under vacuum.LCMS?m/z?280.9(MH+)，t R＝1.63min。
Example 6
Preparation (R)-2-amino-7-(2-(cyclopentyloxy)-4-fluorophenyl)-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone
Figure S2006800365004D00461
Use (R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidine-5 (6H)-ketone, cesium carbonate (2eq), cuprous iodide (I) (10mol%), 1,10-phenanthroline (20mol%) and cyclopentanol are filled the microwave bottle.By microwave radiation described reaction mixture is heated to 180 ℃ of temperature, 20min.After being cooled to RT, described reaction mixture through concentrate and by the reversed-phase HPLC purifying to provide (R)-2-amino-7-(2-(cyclopentyloxy)-4-fluorophenyl)-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H) ketone (m/z=357 (M+H)).
Example 7
Figure S2006800365004D00471
Spirit of salt amino ester 7.1 (according to the general procedure preparation of example 1) is absorbed in the methylene dichloride and with gained solution is cooled to 0 ℃.Add triethylamine (3eq), dropwise add propanedioic acid acyl chlorides methyl esters (1.3eq) then.Described reactant was stirred 2 hours, it is distributed between water and methylene dichloride.Separate described layer and also concentrated in a vacuum to generate compound 7.2 with the anhydrous sodium sulfate drying organic layer, productive rate is 71%.
Compound 7.2 is dissolved in the methyl alcohol, is stored in sodium methylate in the methyl alcohol to wherein adding the 4.2M just made.Heat (microwave) 10min down with the reaction vessel sealing and at 140 ℃.Described reaction mixture is cooled to room temperature and it is distributed between the 1M spirit of salt aqueous solution and methylene dichloride.Separate organic layer and aqueous layer and organic layer and also concentrate so that compound 7.3 to be provided in a vacuum with anhydrous sodium sulfate drying, productive rate is 93%.
Compound 7.3 is absorbed in the acetonitrile that contains 1% water.Heat 10min (microwave) down with the reaction vessel sealing and at 120 ℃.Concentrate compound 7.4 in a vacuum so that quantitative yield to be provided.
Compound 7.4 is absorbed in the dimethylacetamide dimethylacetal and at 140 ℃ heats 5min down.Be cooled to room temperature and concentrated in a vacuum, make it be absorbed in dimethyl amine at once and be stored in the alcoholic acid 5.0M solution so that orange solids shape 7.5 to be provided.Add ethanoyl guanidine (1.5eq) and the gained mixture is heated 10min down at 140 ℃.Crude reaction mixture concentrated in a vacuum and gained solid 7.6 need not purifying and can use.
Bromizate in 1: 1 mixture that thing 7.6 is absorbed in glycol dimethyl ether and 2M aqueous sodium carbonate.Add boric acid 6-methoxyl group-pyrazine-2-ylboronic acid, add Pd (dppf) Cl then 2.CH 2Cl 2Described reaction mixture is heated (microwave) 10min down at 120 ℃.After being cooled to room temperature, separating described layer and under nitrogen gas stream, concentrate organic layer.By the reversed-phase HPLC purifying so that compound 7.7 to be provided.
Example 8
Preparation (R)-2-amino-7-[5-(6-methoxyl group-pyrazine-2-yl)-thiazole-4-yl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone
Figure S2006800365004D00481
From 5.4 preparation compounds 88, it synthesizes in example 5 and provides according to mentioned above.General procedure according to example 1 uses appointment reagent that compound 5.4 is changed into 88.
Example 9
Representative 2-amino-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5 ketone compound
Representative 2-amino-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5 ketone compound are shown among the table 1-5.In described form, m/z is meant the molion of observing by mass spectrum.
The representative 2-amino-7 of table 1., 8-dihydro-6H-pyrido [4,3-d] pyrimidine-5 ketone compound.
Figure S2006800365004D00491
Figure S2006800365004D00531
Figure S2006800365004D00541
Table 2
Figure S2006800365004D00542
Figure S2006800365004D00551
Figure S2006800365004D00561
Figure S2006800365004D00571
Figure S2006800365004D00581
Figure S2006800365004D00591
Figure S2006800365004D00601
Table 3
Figure S2006800365004D00611
Figure S2006800365004D00621
Figure S2006800365004D00641
Figure S2006800365004D00651
Figure S2006800365004D00671
Figure S2006800365004D00681
Figure S2006800365004D00691
Figure DEST_PATH_GSB00000310430000021
Figure DEST_PATH_GSB00000310430000031
Table 4
Figure S2006800365004D00721
Figure S2006800365004D00731
Figure S2006800365004D00751
Figure S2006800365004D00761
Figure S2006800365004D00771
Figure S2006800365004D00781
Figure S2006800365004D00791
Figure S2006800365004D00811
Table 5
Figure S2006800365004D00812
Figure S2006800365004D00831
Figure S2006800365004D00841
Figure S2006800365004D00851
Figure S2006800365004D00861
Figure S2006800365004D00871
Figure S2006800365004D00881
By program described in the example 10, some compound is at the IC less than 25 μ M among the table 1-5 50Following demonstration has HSP90 and suppresses active.Some compound has the IC less than about 10 μ M 50
Example 10
The HSP90 inhibitor is in conjunction with usefulness: TRF is in conjunction with test
In this example, set forth by TRF in conjunction with test measure the HSP90 inhibitor in conjunction with usefulness.
Implement the TRF competition in conjunction with test with measure the HSP90 inhibitor in conjunction with usefulness (IC 50Value).With HSP90 α (HSP90 α GeneID:3320; MRNA Sequence NM_005348) purifying through the terminal ATP binding domains of His-mark N-(amino-acid residue 9-236) at room temperature in binding buffer liquid (50mM HEPES, the 6mM MgCl of the competing compound that contains biotinylation radicicol and progressive concentration 2, 20mM KCl and 0.1%BSA) and middle the cultivation 2 hours.The described mixture of a part is transferred to capture board (being coated with streptavidin) also at room temperature to be cultivated 1 hour.After with the washing of DELFIA lavation buffer solution, add through anti--his antibody of europium mark and also at room temperature cultivated 2 hours, then with the washing of DELFIA damping fluid.Add DELFIA subsequently and strengthen solution.After slowly shaking 10 minutes, in VICTOR, read the europium counting of described flat board.
Attention: also can use the method for announcing in the following reference to measure IC 50Value: 1.
1.Carreras, C.W., people such as A.Schirmer (2003). and " Filter binding assay for thegeldanamycin-heat shock protein 90 interaction. " Anal Biochem 317 (1): 40-6;
2.Kim, J., people such as S.Felts (2004). and " Development of a fluorescence polarization assayfor the molecular chaperone HSP90. " J Biomol Screen 9 (5): 375-81; And
3.Zhou, V., people (2004) such as S.Han. " A time-resolved fluorescence resonance energytransfer-based HTS assay and a surface plasmon resonance-based binding assay for-heatshock protein 90 inhibitors. " Anal Biochem 331 (2): 349-57.
Although this paper explanation has also been set forth preferred embodiment of the present invention, should understand can be to the various changes of the invention process under the situation that does not deviate from spirit of the present invention and scope.
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Claims (39)

1. a formula (I) compound:
Figure FSB00000461545400011
Or its steric isomer or pharmaceutically acceptable salt, wherein
R bFor
Figure FSB00000461545400012
N is 0 or 1,
R wherein aBe selected from the group that forms by following:
(1) hydrogen, and
(2) C 1-C 6Alkyl,
Wherein R is selected from the group that is made up of following:
(1) hydrogen,
(2) C 1-C 6Alkyl or through amino, hydroxyl, be substituted or be unsubstituted the C that aryl, heteroaryl and/or heterocyclic radical replace 1-C 6Alkyl, wherein being substituted aryl is through halogen, halo C 1-C 6Alkyl and/or C 1-C 6The aryl that alkoxyl group replaces, and
(3) C 2-C 6Thiazolinyl,
Wherein, when n was 1, then X was C, and the Y of each position is independently selected from CQ 1And N, and Z is selected from CR 2And N, restricted condition is to be no more than 3 Y and the Z group is N, and
Wherein, when n was 0, then X was C, and the Y of each position is independently selected from CQ 1, N and S, restricted condition is that to be no more than 1 Y group be S;
Wherein, the Q of each position 1Be independently selected from the group that forms by following:
(1) hydrogen,
(2) halogen,
(3) through halogen, halo C 1-C 6Alkoxyl group, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, two C 1-C 6Alkylamino and/or halo C 1-C 6The aryl that alkyl replaces,
(4) heteroaryl, 4-tetramethyleneimine-1-base-pyrimidine-2-base or through halogen, C 1-C 6Alkoxyl group, halo C 1-C 6Alkoxyl group, C 1-C 6Alkyl, amino, C 1-C 6Alkylamino, two C 1-C 6The heteroaryl that alkylamino and/or hydroxyl replace,
(5) oxo heterocycle base,
(6)-OR 3, and
(7)-CN；
R wherein 2Be selected from the group that forms by following:
(1) hydrogen,
(2) halogen,
(3) C 1-C 3Alkyl, and
(4)-OR 3；
Wherein, the R of each position 3Be independently selected from the group that forms by following:
(1) C 1-C 6Alkyl, and
(2) C 3-C 7Cycloalkyl,
Wherein, described aryl is monocycle and the polycyclic aromatic group that does not contain ring hetero atom and contain 6 to 14 carbon atoms;
Described heteroaryl is for to have the aromatic group of 1 to 4 heteroatoms as annular atoms in aromatic nucleus, all the other annular atomses are carbon atom;
Described heterocyclic radical is to contain the heteroatomic 3 or 4 Yuans rings that are selected from nitrogen, oxygen and sulphur or contain 1 to 3 to be selected from by nitrogen, oxygen or sulphur and to form the heteroatomic 5 or 6 Yuans rings of group.
2. compound as claimed in claim 1, wherein R aBe hydrogen.
3. compound as claimed in claim 1, wherein R aBe C 1-C 6Alkyl.
4. compound as claimed in claim 3, wherein R aBe methyl.
5. compound as claimed in claim 1, wherein Q 1Be selected from by through halogen, halo C 1-C 6Alkoxyl group, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, two C 1-C 6Alkylamino and/or halo C 1-C 6The aryl that alkyl replaces, heteroaryl, 4-tetramethyleneimine-1-base-pyrimidine-2-base is through halogen, C 1-C 6Alkoxyl group, halo C 1-C 6Alkoxyl group, C 1-C 6Alkyl, amino, C 1-C 6Alkylamino, two C 1-C 6The group that heteroaryl that alkylamino and/or hydroxyl replace and oxo heterocycle base are formed.
6. compound as claimed in claim 5, wherein said aryl, heterocyclic radical and heteroaryl are selected from the group that is made up of following: phenyl, pyridyl, pyrazinyl, pyrimidyl, clatter piperazine base, pyrazolyl, imidazolyl, triazolyl, indyl, oxadiazole base, thiadiazolyl group, furyl, quinolyl, isoquinolyl, isoxazolyl, oxazolyl, thiazolyl, morpholinyl, piperidyl, pyrrolidyl and thienyl.
7. compound as claimed in claim 1, wherein Q 1Be selected from the group that forms by following: 1H-pyrazoles-4-base, 1-methyl isophthalic acid H-pyrazoles-4-base, 1-methyl isophthalic acid H-pyrazoles-4-base, 2,3-two fluoro-phenyl, 2,3-dimethoxy-phenyl, 2,4-two fluoro-phenyl, 2,4-dimethoxy-phenyl, 2,4-dimethoxy-pyrimidine-5-base, 2,5-two fluoro-phenyl, 2,6-two fluoro-phenyl, 2,6-dimethyl-pyridin-3-yl, 2-amino-pyrimidine-5-base, 2-chloro-4-methoxyl group-pyrimidine-5-base, 2-chloro-5-fluoro-pyridin-3-yl, 2-chloro-phenyl, 2-chloro-pyridin-3-yl, 2-chloro-pyridin-4-yl, 2-two fluoro-3-p-methoxy-phenyls, 2-ethyl-phenyl, 2-oxyethyl group-thiazole-4-base, 2-fluoro-3-methoxyl group-phenyl, 2-fluoro-3-aminomethyl phenyl, 2-fluoro-4-methyl-phenyl, 2-fluoro-5-methoxyl group-phenyl, 2-fluoro-5-aminomethyl phenyl, the 2-fluorophenyl, 2-fluoro-pyridin-3-yl, 2-isoquinoline 99.9-4-base, 2-methoxyl group-5-trifluoromethyl-phenyl, 2-methoxyl group-phenyl, 2-methoxyl group-pyridin-3-yl, 2-methoxyl group-pyrimidine-4-base, 2-methoxyl group-thiazole-4-base, 2-methyl-phenyl, 2-methyl-pyridin-3-yl, the 2-pyridin-3-yl, 2-pyrimidine-5-base, 2-trifluoromethoxy-phenyl, 3,4-dimethoxy-phenyl, 3,5-dimethyl-isoxazole-4-bases, 3,6-dimethyl-pyrazine-2-base, 3-bromo-phenyl, 3-chloro-pyrazine-2-base, the 3-dimethylaminophenyl, 3-oxyethyl group-phenyl, 3-ethyl-4-methyl-phenyl, 3-fluoro-6-methoxyl group-pyridine-2-base, the 3-fluorophenyl, 3-fluoro-pyrazine-2-base, the 3-p-methoxy-phenyl, 3-methoxyl group-pyrazine-2-base, 3-methyl-3H-imidazo [4,5-b] pyrazine-5-base, the 3-aminomethyl phenyl, 3-methyl-pyridine-2-base, the 3-Trifluoromethoxyphen-l, the 3-trifluoromethyl, 4,5-dimethoxy-pyrimidine-2-base, 4-amino-5-fluoro-pyrimidine-2-base, 4-chloro-2,5-dimethoxy-phenyl, 4-chloro-2-fluoro-phenyl, 4-chloro-2-methoxyl group-5-methyl-phenyl, 4-chloro-pyridin-3-yl, 4-two fluoro-2-methyl-phenyl, 4-oxyethyl group-5-fluoro-pyrimidine-2-base, 4-oxyethyl group-pyrimidine-2-base, 4-oxyethyl group-pyrimidine-5-base, 4-ethyl-1H-pyrazole-3-yl, 4-fluoro-2-methoxyl group-phenyl, 4-fluoro-2-methyl-phenyl, the 4-fluorophenyl, 4-methoxyl group-5-methyl-pyrimidine-2-base, 4-methoxyl group-pyridin-3-yl, 4-methoxyl group-pyrimidine-2-base, 4-methoxyl group-pyrimidine-5-base, 4-methyl-phenyl, 4-methyl-pyridine-2-base, 4-methyl-pyridin-3-yl, 4-tetramethyleneimine-1-base-pyrimidine-2-base, 5,6-dimethoxy-pyrazine-2-base, 5-amino-6-oxyethyl group-pyrazine-2-base, 5-amino-6-methoxyl group-3-methyl-pyrazine-2-base, 5-amino-6-methoxyl group-pyridine-2-base, 5-chloro-4-methoxyl group-pyrimidine-2-base, 5-chloro-6-methoxyl group-pyrazine-2-base, 5-dimethylamino-6-methoxyl group-pyrazine-2-base, 5-fluoro-2-p-methoxy-phenyl, 5-fluoro-4-methoxyl group-pyrimidine-2-base, 5-fluoro-6-methoxyl group-pyrazine-2-base, 5-fluoro-pyridine-2-base, 5-methoxyl group-pyridin-3-yl, 5-methoxyl group-thiophene-2-base, 5-trifluoromethyl-pyrimidine-2-base, 6-chloro-pyrazine-2-base, 6-oxyethyl group-pyrazine-2-base, 6-oxyethyl group-pyridine-2-base, 6-fluoro-pyridine-2-base, 6-fluoro-pyridin-3-yl, 6-hydroxyl-pyridine-2-base, 6-methoxyl group-5-methylamino-pyrazine-2-base, 6-methoxyl group-5-methyl-pyrazine-2-base, 6-methoxyl group-pyrazine-2-base, 6-methoxyl group-pyridine-2-base, 6-methoxyl group-pyridin-3-yl, 6-methylamino-pyrazine-2-base, 6-methyl-pyridine-2-base and 5-amino-6-(2,2, the 2-trifluoro ethoxy) pyrazine-2-base.
8. compound as claimed in claim 1, it has formula (IIa):
Figure FSB00000461545400041
Or its pharmaceutically acceptable salt, wherein R a, R, X, Y, Z and n be by being defined as claim 1 pair formula (I).
9. compound as claimed in claim 1, it has formula (III):
Figure FSB00000461545400042
Or its steric isomer or pharmaceutically acceptable salt, wherein
R aBe selected from the group that forms by following:
(1) hydrogen, and
(2) C 1-C 6Alkyl,
R 4Be hydrogen, C 1-C 6Alkyl, through amino, hydroxyl, be substituted or be unsubstituted aryl, heteroaryl, and/or the C that replaces of heterocyclic radical 1-C 6Alkyl, wherein being substituted aryl is through halogen, halo C 1-C 6Alkyl and/or C 1-C 6The aryl that alkoxyl group replaces;
R 5Be hydrogen, C 1-C 3Alkyl, C 1-C 6Alkoxyl group or halogen;
R 6, R 7, R 8And R 9Be selected from independently of one another by hydrogen, C 1-C 6Alkoxyl group, halogen, through halogen, halo C 1-C 6Alkoxyl group, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, two C 1-C 6Alkylamino and/or halo C 1-C 6The aryl that alkyl replaces, heteroaryl, 4-tetramethyleneimine-1-base-pyrimidine-2-base and through halogen, C 1-C 6Alkoxyl group, halo C 1-C 6Alkoxyl group, C 1-C 6Alkyl, amino, C 1-C 6Alkylamino, two C 1-C 6The group that the heteroaryl that alkylamino and/or hydroxyl replace is formed; Perhaps
Its steric isomer or pharmaceutically acceptable salt.
10. compound as claimed in claim 9, wherein R aBe hydrogen.
11. compound as claimed in claim 9, wherein R aBe C 1-C 6Alkyl.
12. compound as claimed in claim 11, wherein R aBe methyl.
13. compound as claimed in claim 12, wherein R 4Be selected from by hydrogen, benzyl, 1-(4-p-methoxy-phenyl) ethyl, methyl, 3-aminopropyl and group that the 2-methyl-the 2-morpholinyl propyl is formed.
14. compound as claimed in claim 13, wherein R 4Be hydrogen.
15. compound as claimed in claim 9, wherein R 5Be hydrogen or fluorine.
16. compound as claimed in claim 9, wherein R 7, R 8, R 9The hydrogen of respectively doing for oneself.
17. compound as claimed in claim 9, wherein R 6Be selected from by through halogen, halo C 1-C 6Alkoxyl group, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, two C 1-C 6Alkylamino and/or halo C 1-C 6The aryl that alkyl replaces, 4-tetramethyleneimine-1-base-pyrimidine-2-base and through halogen, C 1-C 6Alkoxyl group, halo C 1-C 6Alkoxyl group, C 1-C 6Alkyl, amino, C 1-C 6Alkylamino, two C 1-C 6The group that the heteroaryl that alkylamino and/or hydroxyl replace is formed.
18. compound as claimed in claim 17, wherein said aryl heteroaryl is selected from the group that is made up of following: furyl, pyrryl, phenyl, pyridyl, pyrazinyl, pyrimidyl, clatter piperazine base, pyrazolyl, imidazolyl, triazolyl, indyl, oxadiazole, thiadiazoles, quinolyl, isoquinolyl, isoxazolyl, oxazolyl, thiazolyl and thienyl.
19. compound as claimed in claim 9, wherein R 6Be selected from the group that forms by following: 1H-pyrazoles-4-base, 1-methyl isophthalic acid H-pyrazoles-4-base, 1-methyl isophthalic acid H-pyrazoles-4-base, 2,3-two fluoro-phenyl, 2,3-dimethoxy-phenyl, 2,4-two fluoro-phenyl, 2,4-dimethoxy-phenyl, 2,4-dimethoxy-pyrimidine-5-base, 2,5-two fluoro-phenyl, 2,6-two fluoro-phenyl, 2,6-dimethyl-pyridin-3-yl, 2-amino-pyrimidine-5-base, 2-chloro-4-methoxyl group-pyrimidine-5-base, 2-chloro-5-fluoro-pyridin-3-yl, 2-chloro-phenyl, 2-chloro-pyridin-3-yl, 2-chloro-pyridin-4-yl, 2-two fluoro-3-p-methoxy-phenyls, 2-ethyl-phenyl, 2-oxyethyl group-thiazole-4-base, 2-fluoro-3-methoxyl group-phenyl, 2-fluoro-3-aminomethyl phenyl, 2-fluoro-4-methyl-phenyl, 2-fluoro-5-methoxyl group-phenyl, 2-fluoro-5-aminomethyl phenyl, the 2-fluorophenyl, 2-fluoro-pyridin-3-yl, 2-isoquinoline 99.9-4-base, 2-methoxyl group-5-trifluoromethyl-phenyl, 2-methoxyl group-phenyl, 2-methoxyl group-pyridin-3-yl, 2-methoxyl group-pyrimidine-4-base, 2-methoxyl group-thiazole-4-base, 2-methyl-phenyl, 2-methyl-pyridin-3-yl, the 2-pyridin-3-yl, 2-pyrimidine-5-base, 2-trifluoromethoxy-phenyl, 3,4-dimethoxy-phenyl, 3,5-dimethyl-isoxazole-4-bases, 3,6-dimethyl-pyrazine-2-base, 3-bromo-phenyl, 3-chloro-pyrazine-2-base, the 3-dimethylaminophenyl, 3-oxyethyl group-phenyl, 3-ethyl-4-methyl-phenyl, 3-fluoro-6-methoxyl group-pyridine-2-base, the 3-fluorophenyl, 3-fluoro-pyrazine-2-base, the 3-p-methoxy-phenyl, 3-methoxyl group-pyrazine-2-base, 3-methyl-3H-imidazo [4,5-b] pyrazine-5-base, the 3-aminomethyl phenyl, 3-methyl-pyridine-2-base, the 3-Trifluoromethoxyphen-l, the 3-trifluoromethyl, 4,5-dimethoxy-pyrimidine-2-base, 4-amino-5-fluoro-pyrimidine-2-base, 4-chloro-2,5-dimethoxy-phenyl, 4-chloro-2-fluoro-phenyl, 4-chloro-2-methoxyl group-5-methyl-phenyl, 4-chloro-pyridin-3-yl, 4-two fluoro-2-methyl-phenyl, 4-oxyethyl group-5-fluoro-pyrimidine-2-base, 4-oxyethyl group-pyrimidine-2-base, 4-oxyethyl group-pyrimidine-5-base, 4-ethyl-1H-pyrazole-3-yl, 4-fluoro-2-methoxyl group-phenyl, 4-fluoro-2-methyl-phenyl, the 4-fluorophenyl, 4-methoxyl group-5-methyl-pyrimidine-2-base, 4-methoxyl group-pyridin-3-yl, 4-methoxyl group-pyrimidine-2-base, 4-methoxyl group-pyrimidine-5-base, 4-methyl-phenyl, 4-methyl-pyridine-2-base, 4-methyl-pyridin-3-yl, 4-tetramethyleneimine-1-base-pyrimidine-2-base, 5,6-dimethoxy-pyrazine-2-base, 5-amino-6-oxyethyl group-pyrazine-2-base, 5-amino-6-methoxyl group-3-methyl-pyrazine-2-base, 5-amino-6-methoxyl group-pyridine-2-base, 5-chloro-4-methoxyl group-pyrimidine-2-base, 5-chloro-6-methoxyl group-pyrazine-2-base, 5-dimethylamino-6-methoxyl group-pyrazine-2-base, 5-fluoro-2-p-methoxy-phenyl, 5-fluoro-4-methoxyl group-pyrimidine-2-base, 5-fluoro-6-methoxyl group-pyrazine-2-base, 5-fluoro-pyridine-2-base, 5-methoxyl group-pyridin-3-yl, 5-methoxyl group-thiophene-2-base, 5-trifluoromethyl-pyrimidine-2-base, 6-chloro-pyrazine-2-base, 6-oxyethyl group-pyrazine-2-base, 6-oxyethyl group-pyridine-2-base, 6-fluoro-pyridine-2-base, 6-fluoro-pyridin-3-yl, 6-hydroxyl-pyridine-2-base, 6-methoxyl group-5-methylamino-pyrazine-2-base, 6-methoxyl group-5-methyl-pyrazine-2-base, 6-methoxyl group-pyrazine-2-base, 6-methoxyl group-pyridine-2-base, 6-methoxyl group-pyridin-3-yl, 6-methylamino-pyrazine-2-base, 6-methyl-pyridine-2-base and 5-amino-6-(2,2, the 2-trifluoro ethoxy) pyrazine-2-base.
20. compound as claimed in claim 9, it has formula (IIIa):
Figure FSB00000461545400061
Or its pharmaceutically acceptable salt, wherein R a, R 4, X, Y, Z and n be by being defined as claim 9 pair formula (III).
21. compound as claimed in claim 1, it has formula (IV):
Figure FSB00000461545400062
Or its steric isomer or pharmaceutically acceptable salt,
Wherein
R 4Be hydrogen, C 1-C 6Alkyl, perhaps through amino, hydroxyl, be substituted or be unsubstituted the C that aryl, heteroaryl and/or heterocyclic radical replace 1-C 6Alkyl, wherein being substituted aryl is through halogen, halo C 1-C 6Alkyl and/or C 1-C 6The aryl that alkoxyl group replaces,
R 5Be hydrogen or halogen,
R 6aBe selected from by hydrogen, halogen, through halogen, halo C 1-C 6Alkoxyl group, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, two C 1-C 6Alkylamino and/or halo C 1-C 6The aryl that alkyl replaces, heteroaryl, 4-tetramethyleneimine-1-base-pyrimidine-2-base and through halogen, C 1-C 6Alkoxyl group, halo C 1-C 6Alkoxyl group, C 1-C 6Alkyl, amino, C 1-C 6Alkylamino, two C 1-C 6The group that the heteroaryl that alkylamino and/or hydroxyl replace is formed.
22. compound as claimed in claim 21, wherein R 4Be selected from by hydrogen, benzyl, 1-(4-p-methoxy-phenyl) ethyl, methyl, 3-aminopropyl and group that the 2-methyl-the 2-morpholinyl propyl is formed.
23. compound as claimed in claim 22, wherein R 5Be hydrogen or fluorine.
24. compound as claimed in claim 21, wherein R 6aBe selected from by through halogen, halo C 1-C 6Alkoxyl group, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, two C 1-C 6Alkylamino and/or halo C 1-C 6The aryl that alkyl replaces, 4-tetramethyleneimine-1-base-pyrimidine-2-base and through halogen, C 1-C 6Alkoxyl group, halo C 1-C 6Alkoxyl group, C 1-C 6Alkyl, amino, C 1-C 6Alkylamino, two C 1-C 6The group that the heteroaryl that alkylamino and/or hydroxyl replace is formed.
25. compound as claimed in claim 24, wherein said aryl heteroaryl is selected from the group that is made up of following: furyl, pyrryl, phenyl, pyridyl, pyrazinyl, pyrimidyl, clatter piperazine base, pyrazolyl, imidazolyl, triazolyl, indyl, oxadiazole, thiadiazoles, quinolyl, isoquinolyl, isoxazolyl, oxazolyl, thiazolyl and thienyl.
26. compound as claimed in claim 21, wherein R 6aBe selected from the group that forms by following: 1H-pyrazoles-4-base, 1-methyl isophthalic acid H-pyrazoles-4-base, 1-methyl isophthalic acid H-pyrazoles-4-base, 2,3-two fluoro-phenyl, 2,3-dimethoxy-phenyl, 2,4-two fluoro-phenyl, 2,4-dimethoxy-phenyl, 2,4-dimethoxy-pyrimidine-5-base, 2,5-two fluoro-phenyl, 2,6-two fluoro-phenyl, 2,6-dimethyl-pyridin-3-yl, 2-amino-pyrimidine-5-base, 2-chloro-4-methoxyl group-pyrimidine-5-base, 2-chloro-5-fluoro-pyridin-3-yl, 2-chloro-phenyl, 2-chloro-pyridin-3-yl, 2-chloro-pyridin-4-yl, 2-two fluoro-3-p-methoxy-phenyls, 2-ethyl-phenyl, 2-oxyethyl group-thiazole-4-base, 2-fluoro-3-methoxyl group-phenyl, 2-fluoro-3-aminomethyl phenyl, 2-fluoro-4-methyl-phenyl, 2-fluoro-5-methoxyl group-phenyl, 2-fluoro-5-aminomethyl phenyl, the 2-fluorophenyl, 2-fluoro-pyridin-3-yl, 2-isoquinoline 99.9-4-base, 2-methoxyl group-5-trifluoromethyl-phenyl, 2-methoxyl group-phenyl, 2-methoxyl group-pyridin-3-yl, 2-methoxyl group-pyrimidine-4-base, 2-methoxyl group-thiazole-4-base, 2-methyl-phenyl, 2-methyl-pyridin-3-yl, the 2-pyridin-3-yl, 2-pyrimidine-5-base, 2-trifluoromethoxy-phenyl, 3,4-dimethoxy-phenyl, 3,5-dimethyl-isoxazole-4-bases, 3,6-dimethyl-pyrazine-2-base, 3-bromo-phenyl, 3-chloro-pyrazine-2-base, the 3-dimethylaminophenyl, 3-oxyethyl group-phenyl, 3-ethyl-4-methyl-phenyl, 3-fluoro-6-methoxyl group-pyridine-2-base, the 3-fluorophenyl, 3-fluoro-pyrazine-2-base, the 3-p-methoxy-phenyl, 3-methoxyl group-pyrazine-2-base, 3-methyl-3H-imidazo [4,5-b] pyrazine-5-base, the 3-aminomethyl phenyl, 3-methyl-pyridine-2-base, the 3-Trifluoromethoxyphen-l, the 3-trifluoromethyl, 4,5-dimethoxy-pyrimidine-2-base, 4-amino-5-fluoro-pyrimidine-2-base, 4-chloro-2,5-dimethoxy-phenyl, 4-chloro-2-fluoro-phenyl, 4-chloro-2-methoxyl group-5-methyl-phenyl, 4-chloro-pyridin-3-yl, 4-two fluoro-2-methyl-phenyl, 4-oxyethyl group-5-fluoro-pyrimidine-2-base, 4-oxyethyl group-pyrimidine-2-base, 4-oxyethyl group-pyrimidine-5-base, 4-ethyl-1H-pyrazole-3-yl, 4-fluoro-2-methoxyl group-phenyl, 4-fluoro-2-methyl-phenyl, the 4-fluorophenyl, 4-methoxyl group-5-methyl-pyrimidine-2-base, 4-methoxyl group-pyridin-3-yl, 4-methoxyl group-pyrimidine-2-base, 4-methoxyl group-pyrimidine-5-base, 4-methyl-phenyl, 4-methyl-pyridine-2-base, 4-methyl-pyridin-3-yl, 4-tetramethyleneimine-1-base-pyrimidine-2-base, 5,6-dimethoxy-pyrazine-2-base, 5-amino-6-oxyethyl group-pyrazine-2-base, 5-amino-6-methoxyl group-3-methyl-pyrazine-2-base, 5-amino-6-methoxyl group-pyridine-2-base, 5-chloro-4-methoxyl group-pyrimidine-2-base, 5-chloro-6-methoxyl group-pyrazine-2-base, 5-dimethylamino-6-methoxyl group-pyrazine-2-base, 5-fluoro-2-p-methoxy-phenyl, 5-fluoro-4-methoxyl group-pyrimidine-2-base, 5-fluoro-6-methoxyl group-pyrazine-2-base, 5-fluoro-pyridine-2-base, 5-methoxyl group-pyridin-3-yl, 5-methoxyl group-thiophene-2-base, 5-trifluoromethyl-pyrimidine-2-base, 6-chloro-pyrazine-2-base, 6-oxyethyl group-pyrazine-2-base, 6-oxyethyl group-pyridine-2-base, 6-fluoro-pyridine-2-base, 6-fluoro-pyridin-3-yl, 6-hydroxyl-pyridine-2-base, 6-methoxyl group-5-methylamino-pyrazine-2-base, 6-methoxyl group-5-methyl-pyrazine-2-base, 6-methoxyl group-pyrazine-2-base, 6-methoxyl group-pyridine-2-base, 6-methoxyl group-pyridin-3-yl, 6-methylamino-pyrazine-2-base, 6-methyl-pyridine-2-base and 5-amino-6-(2,2, the 2-trifluoro ethoxy) pyrazine-2-base.
27. compound as claimed in claim 21, it has formula (IVa):
Figure FSB00000461545400081
Or its pharmaceutically acceptable salt, wherein
R 4, R 5And R 6aBy being defined as claim 21 pair formula (IV).
28. a compound or its steric isomer or pharmaceutically acceptable salt, it is selected from the group that is made up of following:
(R)-2-amino-7-[2-(2-fluoro-pyridin-3-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(S)-and 2-amino-6-benzyl-7-[4-fluoro-2-(2-fluoro-pyridin-3-yl)-phenyl] 4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(2-fluoro-pyridin-3-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-(2-bromo-4-fluoro-phenyl)-6-[(S)-1-(4-methoxyl group-phenyl)-ethyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(6-methoxyl group-pyridine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(6-methoxyl group-pyridine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-[4-fluoro-2-(6-methoxyl group-pyridine-2-yl)-phenyl]-4,6-dimethyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-[4-fluoro-2-(2-fluoro-pyridin-3-yl)-phenyl]-4,6-dimethyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-[4-fluoro-2-(6-methoxypyridine-2-yl) phenyl]-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
2-amino-7-[2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-[4-fluoro-2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-4,6-dimethyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-[2-(2-methoxyl group-pyridin-3-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-(5,2 '-two fluoro-xenyl-2-yl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-(5-fluoro-2 '-trifluoromethoxy-xenyl-2-yl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-[2-(2-chloro-pyridin-3-yl)-4-fluoro-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-[4-fluoro-2-(6-fluoro-pyridin-3-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-(4-fluoro-2-isoquinoline 99.9-4-base-phenyl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-(5,3 '-two fluoro-xenyl-2-yl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-[2-(4-chloro-pyridin-3-yl)-4-fluoro-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-(5,2 '-two fluoro-3 '-methoxyl group-xenyl-2-yl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-(5,4 '-two fluoro-2 '-methyl-xenyl-2-yl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-(5-fluoro-2 '-methoxyl group-xenyl-2-yl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-(4-fluoro-2-pyrimidine-5-base-phenyl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-[4-fluoro-2-(2-methoxyl group-pyridin-3-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-(5-fluoro-3 '-methoxyl group-xenyl-2-yl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-6-(3-amino-propyl group)-7-[4-fluoro-2-(6-methoxyl group-pyridine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-(5,2 '-two fluoro-4 '-methyl-xenyl-2-yl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-[4-fluoro-2-(1-methyl isophthalic acid H-pyrazoles-4-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-[4-fluoro-2-(1H-pyrazoles-4-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-4-methyl-7-(5,2 ', 3 '-three fluoro-xenyl-2-yls)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-(2-bromo-4-fluoro-phenyl)-4-methyl-6-(2-methyl-2-morpholine-4-base-propyl group)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-(3 '-dimethylamino-5-fluoro-xenyl-2-yl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-[2-(2,4-dimethoxy-pyrimidine-5-yl)-4-fluoro-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-[4-fluoro-2-(5-methoxyl group-pyridin-3-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-(4-fluoro-2-pyrimidine-5-base-phenyl)-4-methyl-6-(2-methyl-2-morpholine-4-base-propyl group)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-[4-fluoro-2-(2-methoxyl group-pyridin-3-yl)-phenyl]-4-methyl-6-(2-methyl-2-morpholine-4-base-propyl group)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-(5-fluoro-3 '-methoxyl group-xenyl-2-yl)-4-methyl-6-(2-methyl-2-morpholine-4-base-propyl group)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(4-methoxyl group-5-methyl-pyrimidine-2-base)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-(4-fluoro-2-furans-3-base-phenyl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-[2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-[2-(6-methoxyl group-pyridine-2-yl)-phenyl]-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(5-amino-6-methoxyl group-pyridine-2-yl)-4-fluoro-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(5-amino-6-methoxyl group-pyridine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-[2-(5-amino-6-methoxyl group-pyridine-2-yl)-4-fluoro-phenyl]-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(4-oxyethyl group-pyrimidine-2-base)-4-fluoro-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(4-methoxyl group-pyrimidine-2-base)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(4-tetramethyleneimine-1-base-pyrimidine-2-base)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-((R)-2-amino-4-methyl-5-oxo-5,6,7,8-tetrahydrochysene-pyrido [4,3-d] pyrimidin-7-yl)-5-fluoro-benzonitrile;
(R)-2-amino-7-[2-(4,5-dimethoxy-pyrimidine-2-base)-4-fluoro-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(5-chloro-4-methoxyl group-pyrimidine-2-base)-4-fluoro-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-[4-fluoro-2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-(5-fluoro-2 '-methoxyl group-xenyl-2-yl)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-(5,5 '-two fluoro-2 '-methoxyl group-xenyl-2-yl)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-(5,4 '-two fluoro-2 '-methoxyl group-xenyl-2-yl)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-(5-fluoro-3 ', 4 '-dimethoxy-xenyl-2-yl)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-(5-fluoro-3 '-methyl-xenyl-2-yl)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-(5-fluoro-4 '-methyl-xenyl-2-yl)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-(5,4 '-two fluoro-2 '-methyl-xenyl-2-yl)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-[2-(2,4-dimethoxy-pyrimidine-5-yl)-4-fluoro-phenyl]-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(5-fluoro-4-methoxyl group-pyrimidine-2-base)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(5-methoxyl group-thiophene-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-(2-bromo-phenyl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(2-methoxyl group-thiazole-4-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(5,6-dimethoxy-pyrazine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-(2-bromo-4-fluoro-phenyl)-4-ethyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(6-oxyethyl group-pyrazine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(4-oxyethyl group-5-fluoro-pyrimidine-2-base)-4-fluoro-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-(5-fluoro-2 ', 3 '-dimethoxy-xenyl-2-yl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(6-oxyethyl group-pyridine-2-yl)-4-fluoro-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(5-amino-6-oxyethyl group-pyrazine-2-yl)-4-fluoro-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(5-amino-6-oxyethyl group-pyrazine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-4-ethyl-7-[2-(6-methoxyl group-pyridine-2-yl)-phenyl]-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-4-ethyl-7-[2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(5-amino-6-methoxyl group-pyrazine-2-yl)-phenyl]-4-ethyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-4-ethyl-7-[2-(2-methoxyl group-thiazole-4-yl)-phenyl]-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-4-ethyl-7-[4-fluoro-2-(6-methoxyl group-pyridine-2-yl)-phenyl]-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-4-ethyl-7-[4-fluoro-2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-[2-(5-amino-6-oxyethyl group-pyrazine-2-yl)-4-fluoro-phenyl]-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-4-ethyl-7-[4-fluoro-2-(2-methoxyl group-thiazole-4-yl)-phenyl]-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(6-oxyethyl group-pyrazine-2-yl)-4-fluoro-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(6-oxyethyl group-pyrazine-2-yl)-4-fluoro-phenyl]-4-ethyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-[2-(6-oxyethyl group-pyrazine-2-yl)-4-fluoro-phenyl]-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[5-(6-methoxyl group-pyrazine-2-yl)-thiazole-4-yl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-(5-fluoro-2 '-trifluoromethyl-xenyl-2-yl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-(4-fluoro-2-pyridin-4-yl-phenyl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-(5,3 '-two fluoro-4 '-methoxyl group-xenyl-2-yl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-4-methyl-7-phenyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-6-(2-amino-ethyl)-7-[4-fluoro-2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-(2-bromo-4-fluoro-phenyl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(2-methoxyl group-thiazole-4-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-[4-fluoro-2-(6-methoxyl group-pyridine-2-yl)-phenyl]-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-[2-(5-amino-6-methoxyl group-pyrazine-2-yl)-4-fluoro-phenyl]-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-(4-fluoro-phenyl)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-[2-(5-amino-6-methoxyl group-pyrazine-2-yl)-4-fluoro-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(S)-2-amino-7-[2-(5-amino-6-methoxyl group-pyrazine-2-yl)-4-fluoro-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(5-amino-6-methoxyl group-pyrazine-2-yl)-4-fluoro-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-(4-fluoro-phenyl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-4-methyl-7-phenyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(5-amino-6-methoxyl group-pyrazine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-6-allyl group-2-amino-7-[2-(5-amino-6-methoxyl group-pyrazine-2-yl)-4-fluoro-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-6-ethyl-7-[4-fluoro-2-(6-methoxyl group-pyridine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-6-ethyl-7-[4-fluoro-2-(2-methoxyl group-pyridin-3-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-6-ethyl-7-[4-fluoro-2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-6-ethyl-7-(5-fluoro-3 '-methoxyl group-xenyl-2-yl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-6-ethyl-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(2,4-dimethoxy-pyrimidine-5-yl)-4-fluoro-phenyl]-6-ethyl-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-6-benzyl-7-[2-(5-chloro-4-hydroxyl-pyrimidine-2-base)-4-fluoro-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-6-(2-hydroxyl-ethyl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-(2-bromo-4-fluoro-phenyl)-6-(2,4-dimethoxy-benzyl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-6-(3-chloro-benzyl)-7-[4-fluoro-2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-6-(3-chloro-benzyl)-7-[4-fluoro-2-(6-methoxyl group-pyridine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-6-(3-chloro-benzyl)-7-[2-(5,6-dimethoxy-pyrazine-2-yl)-4-fluoro-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-6-(2,4-dimethoxy-benzyl)-7-[4-fluoro-2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-6-(2,4-dimethoxy-benzyl)-7-[4-fluoro-2-(6-methoxyl group-pyridine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(6-methoxyl group-pyridine-2-yl)-phenyl]-4-methyl-6-pyridin-4-yl methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-4-methyl-6-pyridin-4-yl methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(5-amino-6-methoxyl group-pyrazine-2-yl)-4-fluoro-phenyl]-4-methyl-6-pyridin-4-yl methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-6-(2-fluoro-benzyl)-7-[4-fluoro-2-(6-methoxyl group-pyridine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(5-amino-6-methoxyl group-pyrazine-2-yl)-4-fluoro-phenyl]-6-(2-fluoro-benzyl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-6-(2-chloro-benzyl)-7-[4-fluoro-2-(6-methoxyl group-pyridine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(5-amino-6-methoxyl group-pyrazine-2-yl)-4-fluoro-phenyl]-6-(2-chloro-benzyl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-4-methyl-6-(3-trifluoromethyl-benzyl)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(6-methoxyl group-pyridine-2-yl)-phenyl]-4-methyl-6-(3-trifluoromethyl-benzyl)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-6-(2-fluoro-benzyl)-7-[4-fluoro-2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-6-(2-chloro-benzyl)-7-[4-fluoro-2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-4-methyl-6-(tetrahydrochysene-pyrans-4-ylmethyl)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(6-methoxyl group-pyridine-2-yl)-phenyl]-4-methyl-6-(tetrahydrochysene-pyrans-4-ylmethyl)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-4-methyl-6-(2-methyl-2-morpholine-4-base-propyl group)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-6-benzyl-7-[4-fluoro-2-(6-methoxyl group-pyridine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-6-benzyl-7-[4-fluoro-2-(2-methoxyl group-pyridin-3-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-6-benzyl-7-[4-fluoro-2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-6-benzyl-7-(5-fluoro-3 '-methoxyl group-xenyl-2-yl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-6-benzyl-4-methyl-7-(5,2 ', 3 '-three fluoro-xenyl-2-yls)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-6-benzyl-7-(5,3 '-two fluoro-4 '-methoxyl group-xenyl-2-yl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-6-benzyl-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-6-benzyl-7-[2-(2,4-dimethoxy-pyrimidine-5-yl)-4-fluoro-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-6-benzyl-7-(5,2 '-two fluoro-4 '-methyl-xenyl-2-yl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-6-benzyl-7-[4-fluoro-2-(2-fluoro-pyridin-3-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-6-benzyl-7-(5,2 '-two fluoro-3 '-methoxyl group-xenyl-2-yl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-amino-7-[2-(5,6-dimethoxy-pyrazine-2-yl)-4-fluoro-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-4-methyl-6-(3-methyl-butyl)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(5,6-dimethoxy-pyrazine-2-yl)-4-fluoro-phenyl]-4-methyl-6-(3-methyl-butyl)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-(2-bromo-4-fluoro-phenyl)-4-methyl-6-(3-methyl-butyl)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-(2-bromo-4-fluoro-phenyl)-6-isobutyl--4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(6-methoxyl group-pyridine-2-yl)-phenyl]-4-methyl-6-(3-methyl-butyl)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(2-fluoro-pyridin-3-yl)-phenyl]-4-methyl-6-(3-methyl-butyl)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(2-methoxyl group-pyridin-3-yl)-phenyl]-4-methyl-6-(3-methyl-butyl)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(4-methoxyl group-pyridin-3-yl)-phenyl]-4-methyl-6-(3-methyl-butyl)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-6-isobutyl--4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(6-methoxyl group-pyridine-2-yl)-phenyl]-6-isobutyl--4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(5,6-dimethoxy-pyrazine-2-yl)-4-fluoro-phenyl]-6-isobutyl--4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(2-fluoro-pyridin-3-yl)-phenyl]-6-isobutyl--4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(2-methoxyl group-pyridin-3-yl)-phenyl]-6-isobutyl--4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(4-methoxyl group-pyridin-3-yl)-phenyl]-6-isobutyl--4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-6-(4-fluoro-benzyl)-7-[4-fluoro-2-(6-methoxyl group-pyridine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-6-(4-fluoro-benzyl)-7-[4-fluoro-2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(5-amino-6-methoxyl group-pyrazine-2-yl)-4-fluoro-phenyl]-6-(4-fluoro-benzyl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(5-amino-6-methoxyl group-pyrazine-2-yl)-4-fluoro-phenyl]-6-isobutyl--4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-4-methyl-6-pyridin-3-yl methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
3-[(R)-2-amino-7-(2-bromo-4-fluoro-phenyl)-4-methyl-5-oxo-7,8-dihydro-5H-pyrido [4,3-d] pyrimidine-6-yl]-propyl group }-the carboxylamine tertiary butyl ester;
(R)-and 2-amino-6-(3-amino-propyl group)-7-(2-bromo-4-fluoro-phenyl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
3-[(R)-2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-5-oxo-7,8-dihydro-5H-pyrido [4,3-d] pyrimidine-6-yl]-propyl group }-the carboxylamine tertiary butyl ester;
(R)-and 2-amino-6-(3-amino-propyl group)-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(3-{ (R)-2-amino-7-[4-fluoro-2-(2-fluoro-pyridin-3-yl)-phenyl]-4-methyl-5-oxo-7,8-dihydro-5H-pyrido [4,3-d] pyrimidine-6-yl }-propyl group)-the carboxylamine tertiary butyl ester;
(R)-2-amino-6-(3-amino-propyl group)-7-[4-fluoro-2-(2-fluoro-pyridin-3-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-6-(3-amino-propyl group)-7-[4-fluoro-2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[5-(6-methoxyl group-pyridine-2-yl)-thiazole-4-yl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-(5-bromo-thiazole-4-yl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(4-oxyethyl group-5-fluoro-pyrimidine-2-base)-4-fluoro-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-[4-fluoro-2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-(5-fluoro-2 '-methoxyl group-xenyl-2-yl)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-(5,5 '-two fluoro-2 '-methoxyl group-xenyl-2-yl)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-(5,4 '-two fluoro-2 '-methoxyl group-xenyl-2-yl)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-(5-fluoro-3 ', 4 '-dimethoxy-xenyl-2-yl)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-(5-fluoro-3 '-methyl-xenyl-2-yl)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-(5-fluoro-2 '-methyl-xenyl-2-yl)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-(5-fluoro-4 '-methyl-xenyl-2-yl)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-(5,4 '-two fluoro-2 '-methyl-xenyl-2-yl)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-(2-bromo-phenyl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(4,5-dimethoxy-pyrimidine-2-base)-4-fluoro-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[5-(6-methoxyl group-pyrazine-2-yl)-thiazole-4-yl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(6-oxyethyl group-pyridine-2-yl)-4-fluoro-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(2-methoxyl group-thiazole-4-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(5,6-dimethoxy-pyrazine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(5-amino-6-methoxyl group-pyridine-2-yl)-4-fluoro-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-[2-(2,4-dimethoxy-pyrimidine-5-yl)-4-fluoro-phenyl]-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(4-oxyethyl group-pyrimidine-2-base)-4-fluoro-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(4-methoxyl group-pyrimidine-2-base)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(5-amino-6-oxyethyl group-pyrazine-2-yl)-4-fluoro-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(5-amino-6-oxyethyl group-pyrazine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-4-ethyl-7-[2-(6-methoxyl group-pyridine-2-yl)-phenyl]-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-4-ethyl-7-[2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(5-amino-6-methoxyl group-pyrazine-2-yl)-phenyl]-4-ethyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-4-ethyl-7-[2-(2-methoxyl group-thiazole-4-yl)-phenyl]-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(5-chloro-4-methoxyl group-pyrimidine-2-base)-4-fluoro-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-[2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(5-fluoro-4-methoxyl group-pyrimidine-2-base)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(5-amino-6-methoxyl group-pyridine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-[2-(6-methoxyl group-pyridine-2-yl)-phenyl]-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(4-tetramethyleneimine-1-base-pyrimidine-2-base)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-[2-(5-amino-6-methoxyl group-pyridine-2-yl)-4-fluoro-phenyl]-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(5-methoxyl group-thiophene-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-(2-bromo-4-fluoro-phenyl)-4-ethyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-4-ethyl-7-[4-fluoro-2-(6-methoxyl group-pyridine-2-yl)-phenyl]-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-4-ethyl-7-[4-fluoro-2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-(5-fluoro-2 ', 3 '-dimethoxy-xenyl-2-yl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-[2-(5-amino-6-oxyethyl group-pyrazine-2-yl)-4-fluoro-phenyl]-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-4-ethyl-7-[4-fluoro-2-(2-methoxyl group-thiazole-4-yl)-phenyl]-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(6-oxyethyl group-pyrazine-2-yl)-4-fluoro-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(6-oxyethyl group-pyrazine-2-yl)-4-fluoro-phenyl]-4-ethyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-[2-(6-oxyethyl group-pyrazine-2-yl)-4-fluoro-phenyl]-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
2-((R)-2-amino-4-methyl-5-oxo base-5,6,7,8-tetrahydrochysene-pyrido [4,3-d] pyrimidin-7-yl)-5-fluoro-benzonitrile;
(R)-2-amino-7-[2-(6-oxyethyl group-pyrazine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(4-methoxyl group-5-methyl-pyrimidine-2-base)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(5-oxo-4, the 5-dihydro-[1,3,4] oxadiazole-2-yls)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(the 5-methoxyl group-[1,3,4] oxadiazole-2-yls)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(S)-and 2-amino-7-[5-(6-methoxyl group-pyrazine-2-yl)-thiazole-4-yl]-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(2-methoxyl group-thiazole-5-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(5-amino-6-oxyethyl group-pyrazine-2-yl)-4-fluoro-phenyl]-4-ethyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-methoxyl group-2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-(2-bromo-phenyl)-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-[2-(5-amino-6-methoxyl group-pyrazine-2-yl)-phenyl]-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(2-oxyethyl group-thiazole-4-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(2-oxyethyl group-thiazole-4-yl)-4-fluoro-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(S)-2-amino-7-[5-(6-methoxyl group-pyridine-2-yl)-thiazole-4-yl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(S)-2-amino-7-[5-(6-methoxyl group-pyrazine-2-yl)-thiazole-4-yl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-[2-(5-amino-6-oxyethyl group-pyrazine-2-yl)-phenyl]-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(5-amino-6-ethyl-pyrazine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-(2-bromo-4-methoxyl group-phenyl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-methoxyl group-2-(6-methoxyl group-pyridine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(5-amino-6-oxyethyl group-pyrazine-2-yl)-4-methoxyl group-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(6-oxyethyl group-pyrazine-2-yl)-4-methoxyl group-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(5-amino-6-methoxyl group-pyrazine-2-yl)-4-methoxyl group-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-methoxyl group-2-(2-methoxyl group-thiazole-4-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(2-oxyethyl group-thiazole-4-yl)-4-methoxyl group-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(6-methoxyl group-5-methylamino-pyrazine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(6-methoxyl group-5-methylamino-pyrazine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[5-methoxyl group-2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-[5-methoxyl group-2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(5-dimethylamino-6-methoxyl group-pyrazine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(5-dimethylamino-6-methoxyl group-pyrazine-2-yl)-4-fluoro-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-(5-bromo-2-methoxyl group-pyridin-4-yl) 4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-(6,6 '-dimethoxy-[2,3 '] dipyridyl-4 '-yl)-and 4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[5-methoxyl group-2-(6-methoxyl group-pyridine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-[5-methoxyl group-2-(6-methoxyl group-pyridine-2-yl)-phenyl]-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(5-amino-6-oxyethyl group-pyrazine-2-yl)-4-oxyethyl group-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[2-(5-amino-6-methoxyl group-pyrazine-2-yl)-4-oxyethyl group-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-oxyethyl group-2-(6-methoxyl group-pyridine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-oxyethyl group-2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-(2-(cyclopentyloxy)-4-fluorophenyl)-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
(R)-and 2-amino-7-(2-(cyclopentyloxy) phenyl)-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
(R)-and 2-amino-7-(4-fluoro-2-isopropyl phenyl)-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
(R)-and 2-amino-7-((R)-5-fluoro-2-(6-methoxypyridine-2-yl) phenyl)-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
(R)-and 2-amino-7-((R)-2-(6-methoxypyridine-2-yl)-4-aminomethyl phenyl)-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
(R)-and 2-amino-7-((R)-5-fluoro-2-(6-methoxypyrazine-2-yl) phenyl)-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
(R)-and 2-amino-7-((R)-2-(6-methoxypyrazine-2-yl)-4-aminomethyl phenyl)-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
(R)-and 2-amino-7-(2-((R)-5-amino-6-(2,2, the 2-trifluoro ethoxy) pyrazine-2-yl)-4-fluorophenyl)-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
(R)-and 2-amino-7-((R)-5-fluoro-2-(2-methoxy thiazole-4-yl) phenyl)-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
(R)-and 2-amino-7-((R)-2-(5-amino-6-methoxypyrazine-2-yl)-5-fluorophenyl)-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
(R)-and 2-amino-7-((R)-2-(2-methoxy thiazole-4-yl)-4-aminomethyl phenyl)-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
(R)-and 2-amino-7-((R)-2-(5-amino-6-methoxypyrazine-2-yl)-4-aminomethyl phenyl)-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
(R)-and 2-amino-7-(2-(cyclopentyloxy)-4-fluorophenyl)-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
(R)-and 2-amino-7-(2-((R)-5-amino-6-(2,2, the 2-trifluoro ethoxy) pyrazine-2-yl) phenyl)-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
(R)-and 2-amino-7-(2-((R)-5-amino-6-(2,2, the 2-trifluoro ethoxy) pyrazine-2-yl) phenyl)-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
(R)-and 2-amino-7-(2-((R)-5-amino-6-(2,2, the 2-trifluoro ethoxy) pyrazine-2-yl)-4-fluorophenyl)-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
(R)-and 2-amino-7-((S)-2-(5-amino-6-methoxypyrazine-2-yl)-4-fluoro-5-p-methoxy-phenyl)-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
(R)-and 2-amino-7-((S)-4-fluoro-5-methoxyl group-2-(6-methoxypyrazine-2-yl) phenyl)-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
(R)-and 2-amino-7-(4-fluoro-5-methoxyl group-2-((S)-6-methoxypyridine-2-yl) phenyl)-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
(R)-and 2-amino-7-((R)-4-fluoro-5-methoxyl group-2-(2-methoxy thiazole-4-yl) phenyl)-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
(R)-and 2-amino-7-((S)-2-(5-amino-6-methoxypyrazine-2-yl)-4-isopropoxy-5-p-methoxy-phenyl)-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
(R)-and 2-amino-7-((S)-4-isopropoxy-5-methoxyl group-2-(6-methoxypyrazine-2-yl) phenyl)-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
(R)-and 2-amino-7-(4-isopropoxy-5-methoxyl group-2-((S)-6-methoxypyridine-2-yl) phenyl)-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
(R)-and 2-amino-7-((R)-4-isopropoxy-5-methoxyl group-2-(2-methoxy thiazole-4-yl) phenyl) 4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
(R)-and 2-amino-7-((S)-4,5-dimethoxy-2-(6-methoxypyridine-2-yl) phenyl)-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
(R)-and 2-amino-7-((S)-4,5-dimethoxy-2-(6-methoxypyrazine-2-yl) phenyl)-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
(R)-and 2-amino-7-(2-bromo-4,5-Dimethoxyphenyl)-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
(R)-and 2-amino-7-((R)-4,5-dimethoxy-2-(2-methoxy thiazole-4-yl) phenyl)-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
(R)-and 2-amino-7-((R)-2-(5-amino-6-oxyethyl group pyrazine-2-yl)-4,5-Dimethoxyphenyl)-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
(R)-and 2-amino-7-(2-bromo-4-ethoxyl phenenyl)-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
(R)-and 2-amino-7-((S)-4-fluoro-2-(6-pyridone-2-yl) phenyl)-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
(R)-and 2-amino-7-((R)-4-fluoro-2-(6-hydroxyl pyrazine-2-yl) phenyl)-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
(R)-and 2-amino-7-(2-bromo-4,5-diethoxy phenyl)-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone; And
(R)-and 2-amino-7-((R)-4-fluoro-2-(2-hydroxyl thiazole-4-yl) phenyl)-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone.
29. a compound, it is selected from the group that is made up of following:
(R)-2-amino-7-[4-fluoro-2-(6-methoxyl group-pyridine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-(2-bromo-4-fluoro-phenyl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(2-methoxyl group-thiazole-4-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-((R)-2-(5-amino-6-methoxypyrazine-2-yl)-4-aminomethyl phenyl]-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
(R)-and 2-amino-7-((S)-4-fluoro-2-(6-pyridone-2-yl)-phenyl)-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone; With
(R)-2-amino-7-((R)-4-fluoro-2-(6-hydroxyl pyrazine-2-yl)-phenyl]-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
Or its pharmaceutically acceptable salt.
30. a compound, it is (R)-2-amino-7-[4-fluoro-2-(6-methoxyl group-pyridine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone, or its pharmaceutically acceptable salt.
31. one kind comprises that pharmaceutically acceptable supporting agent reaches as each described compound compositions in the claim 1 to 30.
32. composition as claimed in claim 31, it further comprises at least a additional agent of forming group by following that is selected from: irinotecan, topotecan, gemcitabine, imatinib, Qu Sizuo monoclonal antibody, 5 FU 5 fluorouracil, formyl tetrahydrofolic acid, carbon platinum, cis-platinum, Taxan, for pricking his shore, endoxan, vinca alkaloids, Gefitinib, cutting down Ta Lani, Sutent, Xarelto, erlotinib, dexrazoxane, anthracene nucleus class and Rituximab.
33. one kind comprises pharmaceutically acceptable supporting agent and is selected from by the following compound of group or the composition of its pharmaceutically acceptable salt formed:
(R)-2-amino-7-[4-fluoro-2-(6-methoxyl group-pyridine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(6-methoxyl group-pyrazine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-and 2-amino-7-(2-bromo-4-fluoro-phenyl)-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-[4-fluoro-2-(2-methoxyl group-thiazole-4-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone;
(R)-2-amino-7-((R)-2-(5-amino-6-methoxypyrazine-2-yl)-4-aminomethyl phenyl]-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone;
(R)-and 2-amino-7-((S)-4-fluoro-2-(6-pyridone-2-yl)-phenyl)-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone; With
(R)-2-amino-7-((R)-4-fluoro-2-(6-hydroxyl pyrazine-2-yl)-phenyl]-4-methyl-7,8-dihydro pyrido [4,3-d] pyrimidines-5 (6H)-ketone.
34. one kind comprises that pharmaceutically acceptable supporting agent reaches (R)-2-amino-7-[4-fluoro-2-(6-methoxyl group-pyridine-2-yl)-phenyl]-4-methyl-7, the composition of 8-dihydro-6H-pyrido [4,3-d] pyrimidine-5-ketone or its pharmaceutically acceptable salt.
35. purposes that is used for treating the medicine of the mankind or the animal individual patient's condition as each described compound in the claim 1 to 30 in preparation by adjusting HSP90 activity.
36. purposes as claimed in claim 35, the wherein said patient's condition are cancer.
37. a method that is used to prepare formula as claimed in claim 1 (I) compound or its steric isomer or pharmaceutically acceptable salt, it comprises:
(a) make formula (I) compound and acid-respons to generate acid salt; Or
(b) make formula (I) acid addition salt reaction with production (I) free alkali compound; Or
(c) make the reaction of formula (VI) midbody compound and guanidine or guanidine derivative with production (I) compound
Figure FSB00000461545400261
R wherein a, R and R bBy as in the claim 1 formula (I) being defined and W is O or NR ' R ", wherein R ' and R " are H or alkyl independently.
38. the midbody compound with formula (VI),
Figure FSB00000461545400271
Wherein R and R bBy as in the claim 1 formula (I) being defined R aFor methyl and W are O or NR ' R ", wherein R ' and R " are H or alkyl independently.
39. the midbody compound with formula (VII),
Figure FSB00000461545400272
Wherein
R is by as being defined formula (VI) in the claim 38;
R 5Be hydrogen or halogen; And R 6aBe selected from by halogen, through halogen, halo C 1-C 6Alkoxyl group, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, two C 1-C 6Alkylamino and/or halo C 1-C 6The aryl that alkyl replaces, heteroaryl, 4-tetramethyleneimine-1-base-pyrimidine-2-base and through halogen, C 1-C 6Alkoxyl group, halo C 1-C 6Alkoxyl group, C 1-C 6Alkyl, amino, C 1-C 6Alkylamino, two C 1-C 6The group that the heteroaryl that alkylamino and/or hydroxyl replace is formed.
CN2006800365004A 2005-09-30 2006-09-28 2-amino-7,8-dihydro-6h-pyrido[4,3-d]pyrimidin-5-ones Expired - Fee Related CN101287734B (en)

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