CN101400654B - 1,4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of MGLUR2-receptors - Google Patents

1,4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of MGLUR2-receptors Download PDF

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CN101400654B
CN101400654B CN200780009210.5A CN200780009210A CN101400654B CN 101400654 B CN101400654 B CN 101400654B CN 200780009210 A CN200780009210 A CN 200780009210A CN 101400654 B CN101400654 B CN 101400654B
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halogen
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CN101400654A (en
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哈桑·朱利安·伊莫盖
乔斯·玛丽亚·锡德-努涅斯
乔斯·伊格纳西奥·安德烈斯-吉尔
安德烈斯·阿韦利诺·特拉班科-苏亚雷斯
尤伦·奥亚萨瓦尔·圣玛丽娜
弗兰克·马蒂亚斯·道岑贝格
格列戈尔·詹姆斯·马克唐纳
雪莉·伊丽莎白·普兰
罗伯特·约翰内斯·吕特延斯
纪尧姆·艾伯特·雅克·迪韦
万西娅·严
特里·帕特里克·芬恩
加吉克·梅利基扬
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Addex Pharmaceuticals SA
Janssen Pharmaceuticals Inc
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Addex Pharmaceuticals SA
Ortho McNeil Janssen Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

The present invention relates to novel compounds, in particular novel pyridinone de- rivat ives according to Formula (I) wherein all radicals are defined in the application and claims. The compounds accord- ing to the invention are positive allosteric modulators of metabotropic receptors - sub- type 2 (''mGluR2'') which are useful for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved. In particular, such diseases are central nervous system disorders selectedfrom the group of anxiety, schizophrenia, migraine, depression, and epilepsy. The invention is also directed to pharmaceutical composit ions and processes to prepare such compounds and compositions, as well as to the use of such compounds for the prevention and treatment of such diseases in which mGluR2 is involved.

Description

Isosorbide-5-Nitrae-disubstituted 3-cyano-pyridone derivatives and as the purposes of MGLUR2 acceptor positive allosteric modulators
Technical field
The present invention relates to new compound, especially as new 1 of the positive allosteric modulators of metabotropic receptor-2 hypotype (" mGluR2 "), the 4-disubstituted 3-cyano-pyridone derivatives, it can be used for treating or prevention is relevant with the L-glutamic acid dysfunction nervous disorders and mental illness, and the disease that wherein relates to metabotropic receptor mGluR2 hypotype.The invention still further relates to the method for pharmaceutical composition and these compounds of preparation and composition, and these compounds are used for preventing and treating the purposes of these diseases that wherein relate to mGluR2.
Background technology
L-glutamic acid is main amino acid neurotransmitters in the mammalian central nervous system (CNS).L-glutamic acid is brought into play Main Function in different physiological roles, regulate such as learning and memory and sensory perception, cynapse Developmental Plasticity, motion control, breathing and cardiovascular function.In addition, L-glutamic acid is wherein to have the unbalance several different sacred diseases of Glutamatergic neurotransmission and the key problem of mental disorder.
Ionic glutamate receptor (iGluR) passage, nmda receptor, ampa receptor and kainic acid (kainate) acceptor that L-glutamic acid is responsible for quick excitability transmission by activation mediate cynapse neurotransmission (Nakanishi etc., (1998) Brain Res Brain Res Rev., 26:230-235).
In addition, L-glutamic acid activation metabotropic glutamate receptor (mGluR), described metabotropic glutamate receptor have and help more regulating effects that cynapse usefulness is finely tuned.
MGluR is the g protein coupled receptor (GPCR) of seven cross-films, belongs to GPCR family 3 with calcium sensitivity acceptor, GABAb acceptor and pheromone acceptor.
L-glutamic acid activates this receptor by large N-terminal district, extracellular (the being called the ortho position binding site herein) combination with mGluR.The conformational change of this zygotic induction this receptor causes the activation of signal pathway in G albumen and the cell.
MGluR family is by 8 member compositions.According to signal cascade character in its sequence homology, pharmacological characteristics and the cell that is activated, they are divided into three groups, and (group I comprises mGluR1 and mGluR5; Group II comprises mGluR2 and mGluR3; Group III comprises mGluR4, mGluR6, mGluR7 and mGluR8) (Schoepp etc. (1999) Neuropharmacology, 38:1431-76).
In mGluR member, the mGluR2 hypotype by activation G α i-albumen with the coupling of adenylate cyclase negativity, and its activation causes suppressing the release (Cartmell﹠amp of cynapse Glutamic Acid; Schoepp (2000) J Neurochem75:889-907).In CNS, the mGluR2 acceptor is abundant, mainly is distributed in cortex, thalamus district, accessory olfactory bulb, hippocampus, amygdala (amygdala), tail shell nuclear and nucleus accumbens septi (Ohishi etc. (1998) Neurosci Res30:65-82).
Find that in clinical trial activation mGluR2 can effectively treat anxiety disorder (Levine etc. (2002) Neuropharmacology43:294; Holden (2003) Science300:1866-68; Grillon etc. (2003) Psychopharmacology168:446-54; Kellner etc. (2005) Psychopharmacology179:310-15).In addition, find that in the different animals model activation mGluR2 is effectively, therefore represented and be used for the treatment of psychotic disorder and (summarize in Schoepp﹠amp; Marek (2002) Curr Drug Targets.1:215-25), epilepsy (summarizing in (2003) Eur J Pharmacol.476:3-16 such as Moldrich), migraine (Johnson etc. (2002) Neuropharmacology43:291), habituation/drug dependence (Helton etc. (1997) JPharmacol Exp Ther284:651-660), Parkinson's disease (Bradley etc. (2000) JNeurosci.20 (9): 3085-94), pain (Simmons etc. (2002) Pharmacol BiochemBehav73:419-27), a kind of possible new treatment of somnopathy (Feinberg etc. (2002) Pharmacol BiochemBehav73:467-74) and Huntington's disease (Schiefer etc. (2004) Brain Res1019:246-54).
Up to now, the pharmacological tool of most of available target mGluR is the activation several members' of this family ortho position part, because it is the analog (Schoepp etc. (1999) Neuropharmacology, 38:1431-76) of L-glutamic acid.
A kind of developmental function is the molecule that identification is worked by allosterism in the novel method of the alternative cpd of mGluR, and it is by regulating this receptor in conjunction with the site that is different from the ortho position binding site of high conservative.
Recently occurred as the mGluR positive allosteric modulators that the novel pharmacology entity of this attractive replacement scheme is provided.Had been found that this quasi-molecule (summarizing the Expert Opin.Ther.Patents12:1-8 in Mutel (2002)) that is used for several mGluR.Particularly, these molecules are expressed as mGluR2 positive allosteric modulators ((2003) J Med Chem.46:3189-92 such as Johnson MP; Pinkerton etc. (2004) J Med Chem.47:4595-9).
WO2004/092135 (NPS﹠amp; Astra Zeneca), WO2004/018386, WO2006/014918 and WO2006/015158 (Merck) and WO2001/56990 (Eli Lilly) have described respectively benzsulfamide, methyl phenyl ketone, 2 as the mGluR2 positive allosteric modulators, 3-bihydrogen-1-indenone (indanone) and picolyl sulfone amide derivative.Yet, structurally not relevant with compound of the present invention in these concrete disclosed compounds.
Confirm that these molecules itself do not activate described acceptor ((2003) J MedChem.46:3189-92 such as Johnson MP; Schaffhauser etc. (2003) Mol Pharmacol.64:798-810).Yet it can make this receptor that the aminoglutaric acid concentration of itself inducing minimum and replying is produced maximum and reply.The be unequivocally established combination of mGluR2 positive allosteric modulators of mutation analysis does not occur at the ortho position, but at the allosteric site that is positioned among seven cross-film districts of this receptor (Schaffhauser etc. (2003) Mol Pharmacol.64:798-810) occurs.
Animal data shows that the mGluR2 positive allosteric modulators is compared with the ortho position agonist, and anxiety and psychosis model are had same effect.Shown scaring (fear-potentiated startle) (Johnson etc. (2003) the J Med Chem.46:3189-92 that the mGluR2 allosteric modulators strengthens in fear; Johnson etc. (2005) Psychopharmacology179:271-83) and be activated in the high heat (Johnson etc. (2005) Psychopharmacology179:271-83) of stress-induced.In addition, studies show that these compounds are at counter-rotating ketamine (Govek etc. (2005) Bioorg Med ChemLett15 (18): 4068-72) or Amphetamine (Galici etc. (2005) J Pharm Exp Ther315 (3), (Galici etc. (2005) J PharmExp Ther315 (3) are activated in 1181-1187) to the prepulse inhibition disappearance to schizophrenia model Auditory Startle effect that how moving (hyperlocomotion) that 1181-1187) induce and counter-rotating Amphetamine are induced.
Positive allosteric modulators can strengthen L-glutamic acid replys, but it also demonstrates enhancing to ortho position mGluR2 agonist replying such as LY379268 (Johnson etc. (2004) Biochem Soc Trans32:881-87) or DCG-IV (Poisik etc. (2005) Neuropharmacology49:57-69).These data provide the evidence of the another kind of new methods for the treatment of of the sacred disease for the treatment of the above-mentioned mGluR2 of relating to, and are about to combined utilization mGluR2 positive allosteric modulators and mGluR2 ortho position agonist.
Summary of the invention
The present invention relates to have the compound of metabotropic glutamate receptor 2 conditioning agent activity.Aspect its most general compound, the invention provides compound, its pharmaceutically acceptable acid additive salt or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form or its quaternary ammonium salt according to general formula (I),
Figure G2007800092105D00041
Wherein
V 1Be selected from the alkyl of saturated or unsaturated, straight or branched of 1～6 carbon atom of covalent linkage and divalence;
M 1Be selected from hydrogen, ring C 3-7Alkyl, aryl, alkyl-carbonyl, alkoxyl group, aryloxy, alkoxy aryl, aryl carbonyl, six hydrogen thiapyran base and Het 1
L be selected from covalent linkage ,-O-,-OCH 2-,-OCH 2CH 2-,-OCH 2CH 2O-,-OCH 2CH 2OCH 2-,-S-,-NR 7-,-NR 7CH 2-,-NR 7Ring C 3-7,-NR 7CH 2CH 2-,-OCH 2CH 2N (R 7) CH 2-,-CH 2-,-CH 2CH 2-,-CH 2CH 2CH 2,-C ≡ C-,-C=O-and-C (R 8)=C (R 9)-, be each R wherein 7Be independently from each other hydrogen and C 1-3Alkyl, wherein R 8And R 9Be independently from each other hydrogen, halogen and C 1-3Alkyl;
R 2And R 3Be hydrogen, halogen or alkyl separately independently of one another;
A is Het 2Or phenyl, wherein each group is randomly by n radicals R 4Replace, wherein n equals 0,1,2 or 3 integer;
R 4Be selected from halogen, cyano group, hydroxyl, oxo, formyl radical, ethanoyl, carboxyl, nitro, sulfo-, alkyl, alkoxyl group, alkoxyalkyl, alkoxy carbonyl, alkoxy carbonyl alkyl, alkyl-carbonyl, alkyl-carbonyl oxygen base, alkyl-carbonyl alkoxyl group, many halogen C 1-3Alkyl, many halogen C 1-3Alkoxyl group, many halogen C 1-3Alkylthio, alkylthio, alkyl sulphonyl, Het 3, Het 3-alkyl, Het 3-oxygen base, Het 3-oxyalkyl, Het 3-alkoxyl group, Het 3-oxygen alkoxyl group, Het 3-carbonyl, Het 3-carbonylic alkyl, Het 3-sulfenyl, Het 3-sulfanyl, Het 3-alkylsulfonyl, aryl, aralkyl, aryloxy, aryloxy alkyl, alkoxy aryl, aryl alkenyl, aryl alkyl carbonyl, sulfur alkyl aryl, aryl sulfonyl ,-NR aR b, alkyl-NR aR b, O-alkyl-NR aR b,-C (=O)-NR aR b,-C (=O)-alkyl-NR aR bWith O-alkyl-C (=O)-NR aR b, R wherein aAnd R bBe selected from hydrogen, alkyl, alkyl-carbonyl, arylalkyl, alkoxyalkyl, Het 3, Het 3-alkyl, alkyl sulphonyl, alkyl-NR cR dAnd C (=O) alkyl-NR cR d, R wherein cAnd R dBe selected from hydrogen, alkyl and alkyl-carbonyl;
Perhaps two radicals R 4Can be in conjunction with forming divalent group-X 1-C 1-6-X 2-, C wherein 1-6Saturated or unsaturated, the straight or branched alkyl of 1～6 carbon atom, and X 1And X 2Be C, O or NH independently of one another; Wherein said divalent group randomly is selected from following one or more group and is replaced: halogen, many halogen C 1-3Alkyl, cyano group, hydroxyl, amino, oxo, carboxyl, nitro, sulfo-, formyl radical and ethanoyl;
Het 1Be selected from THP trtrahydropyranyl and pyridyl, wherein each group is randomly replaced by 1,2 or 3 substituting group, and described substituting group is independently from each other halogen, C 1-3Alkyl, many halogen C 1-3Alkyl, many halogen C 1-3Alkoxyl group, cyano group, hydroxyl, amino, oxo, carboxyl, nitro, sulfo-, formyl radical, ethanoyl and C 1-3Alkoxyl group;
Het 2Be selected from piperazinyl, piperidyl, thienyl, furyl, the 1H-indazolyl, the 1H-benzimidazolyl-, 1,2,3, the 4-tetrahydro isoquinolyl, 2,5-diaza-two ring [2.2.1] heptyl, pyrrolidyl, azetidinyl, 2,7-diaza-spiro [3.5]-nonyl, pyridyl, pyrazolyl, indolinyl, the 1H-indyl, the 1H-indazolyl, the benzo morpholinyl, thiazolyl, 1,2,3,4-tetrahydric quinoline group, 3,9-diaza spiro [5.5] undecyl, 1,2,3,4,4a, 5,6,10b-octahydro-benzo [f] quinolyl, 1,2,3,4,4a, 10a-six hydrogen-benzo [5,6] [Isosorbide-5-Nitrae] dioxa glutinous rehmannia (dioxino) [2,3-c] pyridyl also, 2,3,4,9-tetrahydrochysene-1H-indeno [2,1-c]-pyridyl, 2,3,4,9-tetrahydrochysene-1H-β-carboline base (carbolinyl), 1,2,3,4-tetrahydrochysene-benzo [4,5]-furo (furo) [2,3-c] pyridyl, 1,2,3,4-tetrahydro benzo [4,5] thieno-[2,3-c] pyridyl, [Isosorbide-5-Nitrae] Diazesuberane base (diazepyl) isoxazolyl, indanyl and indyl;
Het 3Be selected from pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, piperidyl, pyrryl, pyrrolidyl, piperazinyl, triazolyl, tetrazyl, indyl, thienyl, furyl, THP trtrahydropyranyl, tetrahydric thiapyran-1, the 1-dioxide, thiazolyl, thiadiazolyl group, isothiazolyl oxazolyl, morpholinyl oxadiazolyl isoxazolyl, imidazolyl, pyrazolyl, benzimidazolyl-benzoxazolyl, benzothienyl, benzothiazolyl, benzofuryl, the benzo morpholinyl, 1,2,3, the 4-tetrahydro isoquinolyl, sulfo-naphthyl (thionaphtyl), indyl, indolinyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl (phthalazyl), benzo [1,3] alkyl dioxins (benzo[1,1] dioxyl) and quinazolyl; Wherein each group is randomly replaced by 1,2 or 3 substituting group, and described each substituting group is independently from each other halogen, C 1-6Alkyl, many halogen C 1-3Alkyl, cyano group, hydroxyl, amino, oxo, carboxyl, nitro, sulfo-, formyl radical, ethanoyl, phenyl, pyrrolidyl, piperidyl, pyridyl, morpholinyl, list (alkyl) amino and two (alkyl) amino and C 1-3Alkoxyl group;
Aryl is naphthyl, phenyl or xenyl, and wherein each group is randomly replaced by 1,2 or 3 substituting group, and described each substituting group is independently from each other halogen, C 1-3Alkyl, many halogen C 1-3Alkyl, many halogen C 1-3Alkoxyl group, cyano group, hydroxyl, amino, oxo, carboxyl, nitro, sulfo-, formyl radical, ethanoyl, ethoxy carbonyl and C 1-3Alkoxyl group; Alkyl is the saturated straight or branched alkyl with 1～6 carbon atom, or has a saturated cyclic of 3～7 carbon atoms, or the saturated hydrocarbyl of 4～12 carbon atoms, it comprises at least one saturated straight or branched alkyl with 1～6 carbon atom and at least one has the saturated cyclic of 3～7 carbon atoms; Wherein each carbon atom randomly is selected from following one or more group and is replaced: halogen, many halogen C 1-3Alkyl, cyano group, hydroxyl, amino, oxo, carboxyl, nitro, sulfo-, formyl radical, ethanoyl, formamyl, phenyl and divalent group-OCH 2CH 2O-; With
Thiazolinyl is the alkyl that contains in addition one or more pairs of keys.
The invention still further relates to a kind of pharmaceutical composition, it comprises pharmaceutically acceptable carrier or thinner and as the compounds of this invention (especially according to formula (I) compound), its pharmaceutically acceptable acid additive salt or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form or its quaternary ammonium salt of the treatment significant quantity of activeconstituents.
The invention still further relates to the compounds of this invention as the purposes of medicine and for the preparation of the purposes in the medicine that prevents and/or treats the patient's condition in the Mammals (comprising the people), wherein said treatment or prevention can be by neuroregulation function influence or the promotions of mGluR2 positive allosteric modulators.
Particularly, the present invention relates to the compounds of this invention for the preparation for the treatment of or prevent, improve, control or alleviates various nervous disorders relevant with the L-glutamic acid dysfunction in the Mammals (comprising the people) and the medicine of the risk of mental illness in purposes, wherein said treatment or prevent can be by neuroregulation function influence or the promotion of mGluR2 positive allosteric modulators.
Embodiment
In one embodiment, the present invention relates to compound, its pharmaceutically acceptable acid additive salt or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form or its quaternary ammonium salt, the wherein V of general formula (I) 1Be selected from covalent linkage ,-CH 2-,-CH 2-CH 2-,-CH 2-CH 2-CH 2-,-CH 2-CH=CH-,-CH 2-CH 2-CH 2-CH 2-,-CH 2-CH (CH 3)-CH 2-,-CH (CH 3)-CH 2-CH 2-CH 2-,-CH 2-CH (CH 3)-CH 2-CH 2-and-CH 2-CH 2-CH (CH 3)-CH 2-.
In one embodiment, the present invention relates to compound, its pharmaceutically acceptable acid additive salt or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form or its quaternary ammonium salt, the wherein M of general formula (I) 1Be selected from hydrogen, ring C 3-7Alkyl, phenyl, xenyl, phenoxy group, benzyloxy, furyl and pyridyl; M wherein 1Randomly being selected from following one or more group replaces: halogen, C 1-3Alkyl, many halogen C 1-3Alkyl, many halogen C 1-3Alkoxyl group, cyano group, hydroxyl, amino, oxo, carboxyl, nitro, sulfo-, formyl radical, ethanoyl and C 1-3Alkoxyl group.
In one embodiment, the present invention relates to compound, its pharmaceutically acceptable acid additive salt or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form or its quaternary ammonium salt, the wherein M of general formula (I) 1Be selected from hydrogen, ring C 3-7Alkyl, phenyl, xenyl, phenoxy group, benzyloxy, furyl and pyridyl; Wherein any described group randomly is selected from following one or more group and is replaced: halogen, C 1-3Alkyl, many halogen C 1-3Alkyl, many halogen C 1-3Alkoxyl group and C 1-3Alkoxyl group.
In one embodiment, the present invention relates to compound, its pharmaceutically acceptable acid additive salt or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form or its quaternary ammonium salt, the wherein V of general formula (I) 1-M 1Be selected from-CH 2-CH 2-CH 2-CH 3,-CH 2-CH (CH 3)-CH 3,-CH (CH 3)-CH 2-CH 2-CH 3,-CH 2-CH (CH 3)-CH 2-CH 3,-CH 2-CH 2-CH (CH 3)-CH 3Perhaps V 1Be selected from covalent linkage ,-CH 2-,-CH 2-CH 2-,-CH 2-CH 2-CH 2-and-CH 2-CH=CH-; And M 1Be selected from cyclopropyl, cyclopentyl, cyclohexyl, phenyl, xenyl, phenoxy group, benzyloxy, furyl and pyridyl; Each group M wherein 1Randomly being selected from following one or more group replaces: halogen, C 1-3Alkyl, many halogen C 1-3Alkyl, many halogen C 1-3Alkoxyl group and C 1-3Alkoxyl group.In a specific embodiment, V 1-M 1Be-CH 2-CH 2-CH 2-CH 3
In one embodiment, the present invention relates to compound, its pharmaceutically acceptable acid additive salt or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form or its quaternary ammonium salt, the wherein R of general formula (I) 2And R 3Hydrogen, chlorine, fluorine or methyl independently of one another.In a specific embodiments, R 2And R 3Hydrogen or methyl independently of one another.In another specific embodiment, R 2And R 3Each is hydrogen naturally.In another specific embodiment, R 2Methyl, R 3Hydrogen.
In one embodiment, the present invention relates to compound, its pharmaceutically acceptable acid additive salt or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form or its quaternary ammonium salt of general formula (I), wherein L be selected from covalent linkage ,-O-,-OCH 2-,-OCH 2CH 2-,-OCH 2CH 2O-,-OCH 2CH 2OCH 2-,-NR 7-,-NR 7CH 2-,-NR 7Ring C 3-7,-OCH 2CH 2N (R 7) CH 2-,-CH 2CH 2-,-C ≡ C-,-C=O-and-CH=CH-, wherein each R 7Be independently from each other hydrogen and C 1-3Alkyl.
In another embodiment, the present invention relates to compound, its pharmaceutically acceptable acid additive salt or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form or its quaternary ammonium salt of general formula (I), wherein A is selected from phenyl, piperazinyl and piperidyl, and wherein each described group is randomly by n radicals R 4Replace, wherein n equals 0,1,2 or 3 integer.In a specific embodiment, n equals 0 or 1.In another specific embodiment, n equals 1.
In one embodiment, the present invention relates to compound, its pharmaceutically acceptable acid additive salt or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form or its quaternary ammonium salt, the wherein R of general formula (I) 4Be selected from halogen, cyano group, hydroxyl, ethanoyl, alkyl, alkoxyl group, alkoxyalkyl, alkoxy carbonyl, alkoxy carbonyl alkyl, alkyl-carbonyl, alkyl-carbonyl oxygen base, alkyl-carbonyl alkoxyl group, many halogen C 1-3Alkyl, many halogen C 1-3Alkoxyl group, many halogen C 1-3Alkylthio, alkylthio, alkyl sulphonyl, Het 3, Het 3-alkyl, Het 3-oxygen base, Het 3-oxyalkyl, Het 3-alkoxyl group, Het 3-oxygen alkoxyl group, Het 3-carbonyl, Het 3-sulfanyl, aryl, arylalkyl, aryloxy, aromatic yloxy yl alkyl, alkoxy aryl, aryl alkenyl, aryl alkyl carbonyl, aryl sulfonyl ,-NR aR b, alkyl-NR aR b, O-alkyl-NR aR b,-C (=O)-NR aR b,-C (=O)-alkyl-NR aR bWith O-alkyl-C (=O)-NR aR b, R wherein aAnd R bBe selected from hydrogen, alkyl, alkyl-carbonyl, arylalkyl, alkoxyalkyl, Het 3, Het 3Alkyl, alkyl sulphonyl, alkyl-NR cR dAnd C (=O) alkyl-NR cR d, R wherein cAnd R dBe selected from hydrogen, alkyl and alkyl-carbonyl; Perhaps two radicals R 4Can be in conjunction with forming divalent group-X 1-C 1-6-X 2-, C wherein 1-6Saturated or unsaturated, the straight or branched alkyl of 1～6 carbon atom, and X 1And X 2Be C or O independently of one another.
In another embodiment, the present invention relates to compound, its pharmaceutically acceptable acid additive salt or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form or its quaternary ammonium salt of general formula (I), wherein two radicals R 4Can be selected from conjunction with formation-CH 2CH 2-O-,-O-CH 2-O-and-O-CH 2CH 2The divalent group of-O-.
In one embodiment, the present invention relates to compound, its pharmaceutically acceptable acid additive salt or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form or its quaternary ammonium salt, the wherein Het of general formula (I) 1Be selected from THP trtrahydropyranyl and pyridyl, wherein each group Het 1Randomly by halogen C more than 1,2 or 3 1-3Alkyl substituent replaces.
In one embodiment, the present invention relates to compound, its pharmaceutically acceptable acid additive salt or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form or its quaternary ammonium salt, the wherein Het of general formula (I) 3Be selected from pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, piperidyl, pyrrolidyl, piperazinyl, triazolyl, THP trtrahydropyranyl, tetrahydric thiapyran-1,1-dioxide, thiazolyl, oxazolyl, morpholinyl, oxadiazolyl, imidazolyl, benzoxazolyl, benzothienyl, benzofuryl, 1,2,3,4-tetrahydro isoquinolyl, indyl, indolinyl, phthalazinyl and benzo [1,3] alkyl dioxin.In one embodiment, each group is randomly replaced by 1,2 or 3 substituting group, and described each substituting group is independently from each other halogen, C 1-6Alkyl, many halogen C 1-3Alkyl, cyano group, hydroxyl, oxo, ethanoyl, phenyl, pyrrolidyl, piperidyl, pyridyl, morpholinyl, list (alkyl) amino and two (alkyl) amino and C 1-3Alkoxyl group.
In another embodiment, the present invention relates to compound, its pharmaceutically acceptable acid additive salt or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form or its quaternary ammonium salt of general formula (I), wherein
V 1Be selected from covalent linkage ,-CH 2-,-CH 2-CH 2-,-CH 2-CH 2-CH 2-,-CH 2-CH=CH-,-CH 2-CH 2-CH 2-CH 2-,-CH 2-CH (CH 3)-CH 2-,-CH (CH 3)-CH 2-CH 2-CH 2-,-CH 2-CH (CH 3)-CH 2-CH 2-and-CH 2-CH 2-CH (CH 3)-CH 2-;
M 1Be selected from hydrogen, ring C 3-7Alkyl, phenyl, xenyl, phenoxy group, benzyloxy, furyl and pyridyl; M wherein 1Randomly being selected from following one or more group replaces: halogen, C 1-3Alkyl, many halogen C 1-3Alkyl, many halogen C 1-3Alkoxyl group and C 1-3Alkoxyl group;
L be selected from covalent linkage ,-O-,-OCH 2-,-OCH 2CH 2-,-OCH 2CH 2O-,-OCH 2CH 2OCH 2-,-NR 7-,-NR 7CH 2-,-NR 7Ring C 3-7,-OCH 2CH 2N (R 7) CH 2-,-CH 2CH 2-,-C ≡ C-,-C=O-and-CH=CH-, wherein each R 7Be independently from each other hydrogen and C 1-3Alkyl;
R 2And R 3Hydrogen, halogen or alkyl independently of one another;
A is selected from phenyl, piperazinyl and piperidyl, and wherein each described group is randomly by n radicals R 4Replace, wherein n equals 0 or 1 integer;
R 4Be selected from halogen, cyano group, hydroxyl, ethanoyl, alkyl, alkoxyl group, alkoxyalkyl, alkoxy carbonyl, alkoxy carbonyl alkyl, alkyl-carbonyl, alkyl-carbonyl oxygen base, alkyl-carbonyl alkoxyl group, many halogen C 1-3Alkyl, many halogen C 1-3Alkoxyl group, many halogen C 1-3Alkylthio, alkylthio, alkyl sulphonyl, Het 3, Het 3-alkyl, Het 3-oxygen base, Het 3-oxyalkyl, Het 3-alkoxyl group, Het 3-oxygen alkoxyl group, Het 3-carbonyl, Het 3-sulfanyl, aryl, arylalkyl, aryloxy, aromatic yloxy yl alkyl, alkoxy aryl, aryl alkenyl, aryl alkyl carbonyl, aryl sulfonyl ,-NR aR b, alkyl-NR aR b, O-alkyl-NR aR b,-C (=O)-NR aR b,-C (=O)-alkyl-NR aR bWith O-alkyl-C (=O)-NR aR b, R wherein aAnd R bBe selected from hydrogen, alkyl, alkyl-carbonyl, arylalkyl, alkoxyalkyl, Het 3, Het 3-alkyl, alkyl sulphonyl, alkyl-NR cR dAnd C (=O) alkyl-NR cR d, R wherein cAnd R dBe selected from hydrogen, alkyl and alkyl-carbonyl; Perhaps two radicals R 4Can be selected from conjunction with formation-CH 2CH 2-O-,-O-CH 2-O-and-O-CH 2CH 2The divalent group of-O-;
Het 1Be selected from THP trtrahydropyranyl and pyridyl, wherein each group Het 1Randomly by halogen C more than 1,2 or 3 1-3Alkyl substituent replaces;
Het 2Be selected from piperazinyl, piperidyl, thienyl, furyl, the 1H-indazolyl, the 1H-benzimidazolyl-, 1,2,3,4-tetrahydro isoquinolyl, 2,5-diaza-two ring [2.2.1] heptyl, pyrrolidyl, azetidinyl, 2,7-diaza-spiro [3.5]-nonyl, pyridyl, pyrazolyl, indolinyl, the 1H-indyl, the 1H-indazolyl, the benzo morpholinyl, thiazolyl, 1,2,3,4-tetrahydric quinoline group, 3,9-diaza spiro [5.5] undecyl, 1,2,3,4,4a, 5,6,10b-octahydro-benzo [f] quinolyl, 1,2,3,4,4a, 10a-six hydrogen-benzo [5,6] [Isosorbide-5-Nitrae] dioxa glutinous rehmannia [2,3-c] pyridyl also, 2,3,4,9-tetrahydrochysene-1H-indeno [2,1-c]-pyridyl, 2,3,4,9-tetrahydrochysene-1H-β-carboline base, 1,2,3,4-tetrahydrochysene-benzo [4,5]-furo [2,3-c] pyridyl, 1,2,3,4-tetrahydro benzo [4,5] thieno-[2,3-c] pyridyl, [Isosorbide-5-Nitrae] Diazesuberane base isoxazolyl, indanyl and indyl;
Het 3Be selected from pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, piperidyl, pyrrolidyl, piperazinyl, triazolyl, THP trtrahydropyranyl, tetrahydric thiapyran-1,1-dioxide, thiazolyl, oxazolyl, morpholinyl, oxadiazolyl, imidazolyl, benzoxazolyl, benzothienyl, benzofuryl, 1,2,3,4-tetrahydro isoquinolyl, indyl, indolinyl, phthalazinyl and benzo [1,3] alkyl dioxin; Wherein each group is randomly replaced by 1,2 or 3 substituting group, and described each substituting group is independently from each other halogen, C 1-6Alkyl, many halogen C 1-3Alkyl, cyano group, hydroxyl, oxo, ethanoyl, phenyl, pyrrolidyl, piperidyl, pyridyl, morpholinyl, list (alkyl) amino and two (alkyl) amino and C 1-3Alkoxyl group; Aryl is phenyl or xenyl, and wherein each group is randomly replaced by 1,2 or 3 substituting group, and described each substituting group is independently from each other halogen, C 1-3Alkyl, many halogen C 1-3Alkyl, many halogen C 1-3Alkoxyl group, cyano group, nitro, ethoxy carbonyl and C 1-3Alkoxyl group; With alkyl be the saturated straight or branched alkyl with 1～6 carbon atom, or has a saturated cyclic of 3～7 carbon atoms, or the saturated hydrocarbyl of 4～12 carbon atoms, it comprises at least one saturated straight or branched alkyl with 1～6 carbon atom and at least one has the saturated cyclic of 3～7 carbon atoms; Wherein each carbon atom optionally is selected from following one or more group and is replaced: cyano group, hydroxyl, carboxyl, formamyl, phenyl and divalent group-OCH 2CH 2O-.
In another embodiment, the present invention relates to compound, its pharmaceutically acceptable acid additive salt or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form or its quaternary ammonium salt of general formula (I), wherein said compound is selected from following:
-4-(4-(N-ethanoyl methyl) phenyl)-3-cyano group-1-(3-methyl butyl) pyridine-2 (1H)-ketone (compound 1-179);
-4-(3,4-Dimethoxyphenyl)-3-cyano group-1-(3-methyl butyl) pyridine-2 (1H)-ketone (compound 1-110);
-3-cyano group-4-(3-fluoro-4-p-methoxy-phenyl)-1-(3-methyl butyl) pyridine-2 (1H)-ketone (compound 1-114);
-3-cyano group-4-(4-hydroxypropyl phenyl)-1-(3-methyl butyl) pyridine-2 (1H)-ketone (compound 1-095);
-3-cyano group-4-(4-methoxymethyl phenyl)-1-(3-methyl butyl) pyridine-2 (1H)-ketone (compound 1-103);
-3-cyano group-4-(2-fluoro-4-p-methoxy-phenyl)-1-(3-methyl butyl) pyridine-2 (1H)-ketone (compound 1-113);
-3-cyano group-4-(4-(N-morpholinyl (morpholyl) phenyl)-1-(3-methyl butyl) pyridine-2 (1H)-ketone (compound 1-223);
-3-cyano group-1-(3-methyl butyl)-4-(phenylene-ethynylene) pyridine-2 (1H)-ketone (compound 1-267);
-3-cyano group-1-butyl-4-[4-(2-methyl-pyridin-4-yl oxygen base)-phenyl]-pyridine-2 (1H)-ketone (compound 1-064); With
-3-cyano group-1-cyclopropyl methyl-4-(4-phenyl-piperidines-1-yl)-pyridine-2 (1H)-ketone (compound 4-047).
In the application's scope, alkyl is the saturated straight or branched alkyl with 1～6 carbon atom, or has a saturated cyclic of 3～7 carbon atoms, or the saturated hydrocarbyl of 4～12 carbon atoms, it comprises at least one saturated straight or branched alkyl with 1～6 carbon atom and at least one has the saturated cyclic of 3～7 carbon atoms; Wherein each carbon atom randomly is selected from following one or more group and is replaced: halogen, many halogen C 1-3Alkyl, cyano group, hydroxyl, amino, oxo, carboxyl, nitro, sulfo-, formyl radical, ethanoyl, formamyl, phenyl and divalent group-OCH 2CH 2O-.In one embodiment, alkyl is methyl, ethyl, n-propyl, sec.-propyl, butyl, amyl group, hexyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.In one embodiment, each carbon atom randomly is selected from cyano group, hydroxyl, carboxyl, formamyl, phenyl and divalent group-OCH 2CH 2One or more group of O-replaces.
Symbol C 1-6Alkyl has defined the saturated straight or branched alkyl with 1～6 carbon atom, such as C 6Alkyl, C 5Alkyl, C 4Alkyl, C 3Alkyl, C 2Alkyl and C 1Alkyl.C 1-6The example of alkyl is methyl, ethyl, n-propyl, sec.-propyl, butyl, isobutyl-, amyl group and heptyl.
Symbol ring C 3-7Alkyl has defined the saturated cyclic with 3～7 carbon atoms, such as ring C 7Alkyl, ring C 6Alkyl, ring C 6Alkyl, ring C 5Alkyl, ring C 4Alkyl, ring C 3Alkyl and ring C 3Alkyl.Ring C 3-7The example of alkyl is cyclopropyl, cyclobutyl, cyclopentyl, suberyl and cyclohexyl.
Symbol C 1-3Alkyl has defined the saturated straight or branched alkyl with 1～3 carbon atom, such as methyl, ethyl, n-propyl and sec.-propyl.
In a preferred embodiment, alkyl is C 1-6Alkyl; In another preferred embodiment, alkyl is C 3-7Cycloalkyl.
In the application's scope, thiazolinyl is the alkyl that contains in addition one or more pairs of keys.
In the application's scope, aryl is naphthyl, phenyl or xenyl; Wherein each group is randomly replaced by 1,2 or 3 substituting group, and described substituting group is independently from each other halogen, C 1-3Alkyl, many halogen C 1-3Alkyl, many halogen C 1-3Alkoxyl group, cyano group, hydroxyl, amino, oxo, carboxyl, nitro, sulfo-, formyl radical, ethanoyl, ethoxy carbonyl and C 1-3Alkoxyl group.More preferably, aryl is phenyl or xenyl.More preferably, aryl is randomly replaced by 1,2 or 3 substituting group, and described substituting group is independently from each other halogen, C 1-3Alkyl, many halogen C 1-3Alkyl, many halogen C 1-3Alkoxyl group, cyano group, nitro, ethoxy carbonyl and C 1-3Alkoxyl group.More preferably, aryl is phenyl or xenyl, is randomly replaced by 1,2 or 3 substituting group, and described substituting group is independently from each other halogen, C 1-3Alkyl, many halogen C 1-3Alkyl, many halogen C 1-3Alkoxyl group, cyano group, nitro, ethoxy carbonyl and C 1-3Alkoxyl group.
In the application's scope, halogen is the substituting group that is selected from fluorine, chlorine, bromine and iodine.Preferably, halogen is bromine, fluorine or chlorine.
In the application's scope, many halogen C 1-3Alkyl is the saturated hydrocarbyl with straight or branched of 1～3 carbon atom, and wherein one or more carbon atoms are replaced by one or more halogen atom.Preferably, many alkylhalide groups are trifluoromethyls.
In the application's scope, " the compounds of this invention " means compound, its pharmaceutically acceptable acid additive salt or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form or its quaternary ammonium salt of general formula (I).
The nontoxic acid salt form of the therapeutic activity that the pharmaceutically acceptable acid additive salt is defined as comprising that formula (I) compound can form.Described salt can obtain by the alkali form with suitable acid treatment formula (I) compound, and described suitable acid is mineral acid for example, haloid acid (particularly hydrochloric acid, Hydrogen bromide) for example, sulfuric acid, nitric acid and phosphoric acid; Organic acid, for example acetic acid, hydroxyethanoic acid, propionic acid, lactic acid, pyruvic acid, oxalic acid, propanedioic acid, succsinic acid, toxilic acid, fumaric acid, oxysuccinic acid, tartrate, citric acid, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, tosic acid, cyclohexane sulfamic acid, Whitfield's ointment, para-aminosalicylic acid and pamoic acid.
Otherwise described acid salt form can be by changing free alkali form into suitable alkaline purification.
Formula (I) compound that contains acid proton also can be by processing nontoxic metal additive salt or the amine additive salt form (base addition salt) that changes its therapeutic activity into suitable organic and mineral alkali.Suitable base salt forms comprises for example ammonium salt, an alkali metal salt and alkaline earth salt be lithium salts, sodium salt, sylvite, magnesium salts and calcium salt especially, the salt that becomes with organic bases is benzathine salt, N-methyl-D-glucamine salt, oxyamine (hybramine) salt for example, with the amino acid salt that becomes with Methionin of arginine for example.
Otherwise described salt form can be by changing free form into suitable acid treatment.
The quaternary ammonium salt of formula (I) compound has defined the basic nitrogen of energy through type (I) compound and suitable quaternizing agent reacts and the described compound of formation, described quaternizing agent for example is optional haloalkane, aryl halide or arylalkyl halogenide, particularly methyl iodide and the benzyl iodide that replaces.Also can use other reactant with good leavings group, for example trifluoromethanesulfonic acid alkyl ester, methylsulfonic acid alkyl ester and alkyl tosylate.Quaternary ammonium salt has positively charged nitrogen.Pharmaceutically acceptable gegenion comprises chlorion, bromide anion, iodide ion, trifluoroacetic acid radical ion and acetate ion.
The term additive salt that uses in the application's scope also comprises the solvate that formula (I) compound and salt thereof can form.Such solvate is for example hydrate and alcoholate.
The N-oxide form of formula (I) compound is intended to comprise that one of them or several nitrogen-atoms are oxidized to those formulas (I) compound of so-called N-oxide compound, and particularly uncle's nitrogen of wherein one or more (for example piperazine or piperidyls) is by those N-oxide compounds of N-oxidation.These N-oxide compounds can not needed any creative technology and easily obtained by those skilled in the art, and they are the apparent surrogates of formula (I) compound, because these compounds are the metabolites that form by oxidation when absorbing in human body.As everyone knows, oxidation normally the involved the first step in the drug metabolism (Textbook of Organic Medicinal and Pharmaceutical Chemistry, 1977, pages70-75).Also well-known, also can replace compound itself and use the metabolite form of described compound to the people, and have roughly the same effect.
Can change formula (I) compound into corresponding N-oxide form according to the step that trivalent nitrogen is changed into its N-oxide form well known in the art.Described N-oxidizing reaction usually can be by making formula (I) raw material and suitable organic or inorganic peroxide reactions carry out.Suitable inorganic peroxide comprises for example hydrogen peroxide, and alkali metal peroxide or alkaline earth metal peroxide be sodium peroxide, Potassium peroxide for example; Suitable organo-peroxide can comprise for example benzoyl peroxide formic acid that replaces of benzoyl peroxide formic acid or halogen of peroxy acid, 3-chloro peroxide acid for example, the peroxidation paraffinic acid is Peracetic Acid for example, and alkyl peroxide (alkylhydroperoxide) is tertbutyl peroxide for example.Suitable solvent is water for example, low-level chain triacontanol such as ethanol etc., and hydrocarbon is toluene for example, and ketone is 2-butanone for example, and halohydrocarbon is methylene dichloride for example, and the mixture of these solvents.
The term that uses in the preamble " stereochemistry heterogeneous forms " has defined all possible isomeric form that formula (I) compound may have.Unless otherwise mentioned or point out that the chemical name of compound represents the mixture of all possible stereochemistry heterogeneous forms, described mixture comprises all diastereomers and the enantiomorph of described base molecule structure.More specifically, Stereocenter (stereogeniccenter) can have R-or S-configuration; Substituting group on the saturated group of bivalent cyclic (part) can have cis or transconfiguration.Wrap double bond containing compound and can have E formula or the Z formula stereochemistry of described pair of key.The stereochemistry heterogeneous forms of formula (I) compound is intended to be contained in the scope of the present invention apparently.
According to the CAS naming rule, when having two Stereocenters of known absolute configuration in the molecule, specify (based on the Cahn-Ingold-Prelog Cahn-Ingold-Prelog sequence rule) to the chiral centre of lowest number-reference center R or S descriptor.The configuration of second Stereocenter uses relative descriptors [R *, R *] or [R *, S *] represent R wherein *Always be designated as the reference center, [R *, R *] expression have same chirality the center, [R *, S *] expression different chiralitys the center.For example, if the chiral centre of lowest number has the S configuration and second center is R in the molecule, then stereo descriptor will be designated as S-[R *, S *].If use " α " and " β ": the substituent position of the highest relative importance value on the unsymmetrical carbon in the ring system with minimum ring numbering always at random is on " α " position of the mean level of the sea that is determined by this ring system.The substituent position of the highest relative importance value on another unsymmetrical carbon of described ring system (hydrogen atom in formula (I) compound) is for the substituent position of the highest relative importance value on the described reference atom, if it is in the homonymy of the mean level of the sea that is determined by this ring system, called after " α " then, if it is in the opposite side of the mean level of the sea that is determined by this ring system, called after " β " then.
The present invention also comprises the derivative compound (being commonly referred to " prodrug ") according to pharmaceutically active compounds of the present invention, its degradation in vivo and produce the compounds of this invention.Prodrug is renderd a service low in the effectiveness common (but not always) at target acceptor place than compound that its degraded produces.When desired compound had the chemistry that makes its administration difficulty or poor efficiency or physical properties, prodrug was useful especially.For example, desired compound may have the solubleness of non-constant, and it may be difficult to pass mucous epithelium, and perhaps it may have short undesirably plasma half-life.Further discussion about prodrug is found in Stella, " Prodrugs " of V.J. etc., and Drug Delivery Systems, 1985, pp.112-176 and Drugs are among 1985,29, the pp.455-473.
Prodrug forms according to pharmaceutically active compounds of the present invention is incited somebody to action normally compound, its pharmaceutically acceptable acid additive salt or base addition salt, its stereochemistry heterogeneous forms and the N-oxide form thereof of general formula (I), and described prodrug forms has esterified or amidated acid groups.The acid groups of these esterifications comprises formula-COOR XGroup, R wherein xC 1-6One of alkyl, phenyl, benzyl or following group:
Figure G2007800092105D00151
Amidated group comprises formula-CONR yR zGroup, R wherein yH, C 1-6Alkyl, phenyl or benzyl, R zBe-OH, H, C 1-6Alkyl, phenyl or benzyl.Can use ketone or aldehyde (for example formaldehyde) will have amino the compounds of this invention derivatize to form Mannich alkali.This alkali will be hydrolyzed according to first order kinetics in the aqueous solution.
In the application's scope, " the compounds of this invention " means compound, its pharmaceutically acceptable acid additive salt or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form and prodrug thereof of general formula (I).
In the application's scope, especially when relating to formula (I) when compound is mentioned, element one word comprises naturally occurring or synthetic generation, all isotropic substances and the mixture of isotopes with natural abundance or isotopic enrichment form of this element.Especially, when mentioning hydrogen, it should be understood to refer to 1H, 2H, 3H and composition thereof; When mentioning carbon, it should be understood to refer to 11C, 12C, 13C, 14C and composition thereof; When mentioning nitrogen, it should be understood to refer to 13N, 14N, 15N and composition thereof; When mentioning oxygen, it should be understood to refer to 14O, 15O, 16O, 17O, 18O and composition thereof; When mentioning fluorine, it should be understood to refer to 18F, 19F and composition thereof.
Therefore, the compounds of this invention also comprises one or more isotopic compounds with one or more elements and composition thereof, comprise radioactive compound (being called again radio-labeled compound), wherein one or more on-radiation atoms are substituted by one of its radio isotope.Term " radio-labeled compound " means compound, its N-oxide form, pharmaceutically acceptable additive salt or the stereochemistry heterogeneous forms of any general formula (I), and it comprises at least one radioactive atom.For example, can or emit gamma-ray radio isotope and come tagged compound by positron.For radioligand combination technology (membrane receptor method), 3The H atom or 125The I atom is selected replaced atom.For imaging, the most frequently used positron radiation (PET) radio isotope is 11C, 18F, 15O and 13N, all these is that accelerator produces and the transformation period was respectively 20,100,2 and 10 minutes.Because these radioisotopic transformation period are so short, it only is adapted at using in the research institution that its generation place has accelerator, has therefore limited its use.The most widely usedly in these radio isotope be 18F, 99mTc, 201Tl and 123I.Known in those skilled in the art in these radioisotopic processing, its generation, separation and the introducing molecule.
Especially, described radioactive atom is selected from hydrogen, carbon, nitrogen, sulphur, oxygen and halogen.Preferably, described radioactive atom is selected from hydrogen, carbon and halogen.
Especially, described radio isotope is selected from 3H, 11C, 18F, 122I, 123I, 125I, 131I, 75Br, 76Br, 77Br and 82Br.Preferably, described radio isotope is selected from 3H, 11C and 18F.
A. The preparation of final compound
Experimental technique 1 (L is covalent linkage)
The final compound of formula (I-a) (wherein L is covalent linkage) can make by midbody compound and the reaction of formula (III) compound that makes formula (II) according to reaction scheme (1), described reaction is at the suitable solvent to reactionlessness (for example 1, the 4-diox) or the mixture of inert solvent (for example 1, in the 4-diox/DMF), at suitable alkali (NaHCO for example 3Or Na 2CO 3The aqueous solution), Pd-complex compound catalyst (Pd (PPh for example 3) 4) existence under, under heat condition, for example under microwave radiation at 150 ℃, the reacting by heating mixture for example carried out in 10 minutes.In being suitable for Pd mediation and reaction boric acid or boric acid ester coupling, for example halogen, triflate (salt) or pyridine moiety.Can prepare these midbody compounds (referring to following) according to reaction scheme (8), (9) and (10).R 5And R 6Can be hydrogen or alkyl, perhaps can form together for example formula-CH 2CH 2-,-CH 2CH 2CH 2-or-C (CH 3) 2C (CH 3) 2-divalent group.
Reaction scheme 1
Figure G2007800092105D00171
Experimental technique 2 (L is oxygen or sulphur)
The final compound of formula (I-b) (wherein L is oxygen or sulphur) can make by midbody compound and the reaction of formula (IV) compound that makes formula (II) according to reaction scheme (2), described reaction is in the suitable solvent to reactionlessness (for example THF), in the presence of suitable alkali (for example NaH), under heat condition, for example under microwave radiation for example at 80 ℃, reacting by heating mixture 10 minutes.In reaction scheme (2), all variablees all suc as formula in (I) define R 1V 1-M 1, Y is suitable leavings group, for example pyridine.
Reaction scheme 2
Experimental technique 3 (L is aminoalkyl group)
(wherein L is-NR the final compound of formula (I-c) 7-,-NR 7CH 2-or-NR 7CH 2CH 2-, each R wherein 7Be independently from each other hydrogen and alkyl) can make by midbody compound and the reaction of formula (V) compound that makes formula (II) according to reaction scheme (3), described reaction is at the suitable solvent to reactionlessness (for example 1, the 4-diox) in, at suitable alkali (K for example 3PO 4), the Pd-complex compound catalyst (for example
Figure G2007800092105D00182
) existence under, under heat condition, for example 80 ℃ for example the reacting by heating mixture carried out in 12 hours.In reaction scheme (3), all variablees all suc as formula in (I) define R 1V 1-M 1, Y is for Pd mediation and the proper group amine coupling, for example halogen.
Perhaps, formula (I-c) compound can make by midbody compound and the reaction of formula (V) compound that makes formula (II) according to reaction scheme (3), described reaction is in the suitable solvent to reactionlessness (for example glycol dimethyl ether or acetonitrile), at suitable alkali (Cs for example 2CO 3Or DIPEA) under the existence, under heat condition, for example under microwave radiation at 160 ℃, for example the reacting by heating mixture carried out in 30 minutes.
Reaction scheme 3
Figure G2007800092105D00183
Experimental technique 4 (L is alkynyl)
(wherein L is the final compound of formula (I-d) -C ≡ C-) can make according to midbody compound and formula (VI) the compound reaction of reaction scheme (4) by making formula (II), described reaction is in the suitable solvent to reactionlessness (for example THF), at suitable alkali (NEt for example 3), Pd-complex compound catalyst (PdCl for example 2(PPh 3) 2), phosphine (PPh for example 3), under the existence of mantoquita (for example CuI), under heat condition, for example at 80 ℃, for example the reacting by heating mixture carried out in 12 hours.In reaction scheme (4), all variablees all suc as formula in (I) define R 1V 1-M 1, Y is suitable for Pd mediation and the proper group alkynes coupling, for example halogen.
Reaction scheme 4
Figure G2007800092105D00191
Experimental technique 5 (L is thiazolinyl)
(wherein L is-C (R the final compound of formula (I-e) 8)=C (R 9)-) can be by making formula (II) intermediate and the intermediate reaction of formula (VII) make, described reaction is in inert solvent (for example Isosorbide-5-Nitrae-dioxs), at suitable alkali (NaHCO for example 3Or Na 2CO 3), Pd-complex compound catalyst (Pd (PPh for example 3) 4) existence under, under heat condition, for example for example carried out in 8 hours at 85 ℃ of reacting by heating mixtures.In reaction scheme (5), all variablees all define suc as formula institute in (I), Y be suitable for Pd that mediate with group boric acid or boric acid ester coupling, for example halogen, trifyl or pyridine moiety.Such midbody compound can be according to reaction scheme (8), (9) and (10) preparations (vide infra).R 5And R 6Can be hydrogen or alkyl, perhaps can form together for example formula-CH 2CH 2-,-CH 2CH 2CH 2-or-C (CH 3) 2C (CH 3) 2-divalent group.In reaction scheme (5), all variablees all suc as formula in (I) define R 1V 1-M 1
Reaction scheme 5
Figure G2007800092105D00201
Experimental technique 6
Formula (I-e2) (wherein L be-CH=CH-) and formula (I-f2) (wherein L is-CH 2CH 2-) final compound can be according to reaction scheme (6), by means commonly known in the art (for example hydrogenation of the final compound of formula (I-d)) preparation.In addition, the final compound of formula (I-f1) and formula (I-f2) can be according to reaction scheme (6), by method for hydrogenation well known in the art, by the final compound preparation of formula (I-e1) and formula (I-e2).In addition, the final compound of formula (I-e2) can utilize methods known in the art through type (I-d) final compound three key partial reduction and make.In reaction scheme (6), all variablees all suc as formula in (I) define R 1V 1-M 1
Reaction scheme 6
Figure G2007800092105D00202
Experimental technique 7
Formula (I) compound can be by method as known in the art, uses suitable alkali (K for example 2CO 3) and salt compounded of iodine (for example KI), in inert solvent (for example acetonitrile), under suitable high-temperature (for example 120 ℃), make alkylating agent (for example isoamyl bromide) reaction of the compound of formula (VIII) and formula (IX) and make.In reaction scheme (7), all variablees all suc as formula in (I) define R 1V 1-M 1, Z is suitable leavings group, for example halogen.
Reaction scheme 7
Figure G2007800092105D00211
In addition, the final compound of formula (I) can adopt currently known methods to pass through the further modification of formula (I-a), (I-b), (I-c), (I-d), (I-e) and final compound (I-f) is made by those skilled in the art, for example:
Contain the alkylation that one or more hydroxyl substituents or amino substituent formula (I-a), (I-b), (I-c), (I-d), (I-e) and final compound (I-f) and suitable alkylating agent adopt suitable alkali to carry out in-the structure under heat condition.
Contain formula (I-a), (I-b), (I-c), (I-d), (I-e) and final compound (I-f) saponification by adopting suitable saponifying agent (for example NaOH or LiOH) to carry out of one or more alkoxy carbonyl functional group in-the structure.
Formula (I-a), (I-b), (I-c), (I-d), (I-e) and the final compound (I-f) that contains one or more carboxylic acid functionals in-the structure is by adopting suitable coupling agent (O-(7-azepine benzo triazol-1-yl)-N for example, N, N ', N '-tetramethyl-urea hexafluorophosphate) with the reaction of ammonia or primary amine or secondary amine, with obtain in its structure, containing accordingly primary, the final compound of the formula (I) of the second month in a season or uncle's carboxylic acid amides functional group.
Formula (I-a), (I-b), (I-c), (I-d), (I-e) and the final compound (I-f) that contains primary amine or secondary amine functional groups in-the structure is by adopting suitable coupling agent (O-(7-azepine benzo triazol-1-yl)-N for example, N, N ', N '-tetramethyl-urea hexafluorophosphate) with the reaction of carboxylic acid, with obtain in its structure, containing accordingly primary, the final compound of the formula (I) of the second month in a season or uncle's carboxylic acid amides functional group.
Contain the substituent formula of one or more amino (I-a), (I-b), (I-c), (I-d), (I-e) and final compound (I-f) in-the structure by adopting suitable reductive agent (for example sodium cyanoborohydride) and the suitable reductive amination process of aldehyde under heat condition.
Contain formula (I-a), (I-b), (I-c), (I-d), (I-e) and the final compound (I-f) of one or more hydroxyl substituents in-the structure by adopting suitable coupling system (for example di-t-butyl azodicarboxylate/triphenylphosphine) and the reaction of alcohol derivate under heat condition.
Contain 1 of formula (I-a), (I-b), (I-c), (I-d), (I-e) and the final compound (I-f) of activity double key or three key and suitable dipole (dipole) in-the structure, the 3-Dipolar Cycloaddition is to obtain the final compound of corresponding [3+2] affixture.
B. the preparation of midbody compound
Experimental technique 8
The intermediate that the midbody compound of formula (II-a) can be by making formula (X) and suitable halogenating agent (P (=O) Br for example 3) reaction and making, described reaction is carried out under the temperature (for example 110 ℃) that suitably raises in the suitable solvent to reactionlessness (for example DMF).In reaction scheme (8), all variablees all suc as formula in (I) define R 1V 1-M 1
Reaction scheme 8
Figure G2007800092105D00221
Experimental technique 9
The midbody compound of formula (II-b) can make by intermediate and trifluoromethanesulfanhydride anhydride (also the being called trifluoromethanesulfanhydride anhydride) reaction that makes formula (X) by methods known in the art, described reaction is being carried out under low temperature (for example-78 ℃) in the presence of the alkali (for example pyridine) in the suitable solvent to reactionlessness (for example methylene dichloride).In reaction scheme (9), all variablees all suc as formula in (I) define R 1V 1-M 1
Reaction scheme 9
Figure G2007800092105D00231
Experimental technique 10
The midbody compound of formula (II-c) can make in the lower reaction of suitably low temperature (for example 40 ℃) by midbody compound and the pyridine that makes formula (II-b) by methods known in the art.In reaction scheme (10), all variablees all suc as formula in (I) define R 1V 1-M 1
Reaction scheme 10
Figure G2007800092105D00232
Experimental technique 11
The midbody compound of formula (X) can by methods known in the art by making formula (XI) midbody compound and the suitable reagent (for example NaOH) that is used for the cracking methyl ether make in the lower reaction of suitably high temperature (for example 100 ℃) at solvent (for example water).In reaction scheme (11), all variablees all suc as formula in (I) define R 1V 1-M 1
Reaction scheme 11
Figure G2007800092105D00233
Experimental technique 12
The midbody compound of formula (XI) can by methods known in the art by making formula (XII) intermediate and the alkylating agent (for example isoamyl bromide) of formula (IX), utilize alkali (K for example 2CO 3) and salt compounded of iodine (for example KI) randomly, in inert solvent (for example acetonitrile), make in the lower reaction of suitably high temperature (for example 120 ℃).In reaction scheme (12), all variablees all suc as formula in (I) define R 1V 1-M 1, Z is suitable leavings group, for example halogen.
Reaction scheme 12
Figure G2007800092105D00241
Experimental technique 13
The midbody compound of formula (III) can utilize methods known in the art, intermediate by making formula (XIII) and suitable boron source (for example two (the tetramethyl ethylene ketone root closes) two boron (bis (pinacolato) diboron)), at palladium catalyst (for example 1,1 '-two (diphenylphosphino) ferrocene palladium (II) dichloride) under the existence, in inert solvent (for example methylene dichloride), in the presence of suitable salt (for example potassium acetate), for example made in 16 hours in the lower reaction of suitably high temperature (for example 110 ℃).In addition, formula (III) compound can utilize metal-halogen exchange known in the art and make with the method for reacting from the suitable boron source of formula (XIII) compound subsequently.Therefore, the for example midbody compound of formula (XIII) and organolithium compound (for example n-Butyl Lithium) reaction in inert solvent (for example THF) under suitably low temperature (for example-40 ℃) is reacted with suitable boron source (for example trimethoxy borane) subsequently.In reaction scheme (13), all variablees all suc as formula in (I) define R 5And R 6Can be hydrogen or alkyl, perhaps can form together for example formula-CH 2CH 2-,-CH 2CH 2CH 2-or-C (CH 3) 2C (CH 3) 2-divalent group.
Reaction scheme 13
Figure G2007800092105D00242
The raw material of formula (X) and formula (III), (IV), (V), (VI), (VII), (IX), (XII) and midbody compound (XIII) are commercially available compounds, perhaps can make according to popular response method as known in the art.
Obviously, in above-mentioned and following reaction, reaction product can be separated from reaction medium, and if necessary, can be further purified according to general known method (for example extraction, crystallization and chromatography) in this area.Also obvious, with the reaction product that exists more than a kind of enantiomeric form can by known technology particularly preparative chromatography (for example preparative HPLC) from its mixture, separate.
Pharmacology
Compound provided by the invention is the positive allosteric modulators of metabotropic receptor, and especially they are positive allosteric modulators of mGluR2.As if the compounds of this invention is not combined with L-glutamic acid recognition site-part site, ortho position, but is combined with the allosteric site in seven cross-film zones of acceptor.In the presence of L-glutamic acid or mGluR2 agonist, the compounds of this invention increases replying of mGluR2.Expect that thereby compound provided by the invention increases these acceptors by it and ability of replying of L-glutamic acid or mGluR2 agonist is come mGluR2 worked strengthens replying of described acceptor.Therefore, the present invention relates to as the compound of medicine and the compounds of this invention or pharmaceutical composition of the present invention for the preparation of the purposes in the medicine of the patient's condition in treatment or the prevention Mammals (comprising the people), wherein said treatment or the prevention by the mGluR2 allosteric modulators, particularly neuroregulation function influence or the promotion of positivity mGluR2 allosteric modulators.
In addition, the invention still further relates to the compounds of this invention or pharmaceutical composition of the present invention for the preparation for the treatment of or prevent, improve, control or alleviate purposes in the medicine of the risk that Mammals comprises various nervous disorders relevant with the L-glutamic acid dysfunction among the people and mental illness, wherein said treatment or prevent by neuroregulation function influence or the promotion of mGluR2 positive allosteric modulators.
Say in the present invention and to relate to compound of the present invention or composition in for the preparation of the situation of for example treating the purposes in the mammiferous medicine, should make to understand these purposes is interpreted as in some compass of competency comprising the compounds of this invention or the composition of the administration significant quantity that this is for example treated to needs as for example treating mammiferous method.
Especially, the nervous disorders relevant with the L-glutamic acid dysfunction or mental illness comprise one or more in the following patient's condition or the disease: acute nerve and mental illness, for example heart bypass is performed the operation and the brain defective of transplanting secondary, apoplexy, cerebral ischemia, contusion of spinal cord, head trauma, perinatal hypoxia, sudden cardiac arrest, the hypoglycemia nerve injury, dull-witted (comprising the dementia that acquired immune deficiency syndrome (AIDS) is induced), alzheimer's disease, Huntington Chorea, amyotrophic lateral sclerosis, ocular injury, retinopathy, cognitive disorder, idiopathic and drug-induced Parkinson's disease, muscle spasm and the illness relevant with muscle rigidity, comprise and trembling, epilepsy, faint from fear, migraine (comprises migraine (migranieheadache), the urinary incontinence, material tolerance (substance tolerance), material is given up (substance withdrawal) and (is comprised for example opium, Nicotine, tobacco product, alcohol, Benzodiazepine, Cocaine, tranquilizer, the material of soporific etc.), psychosis, schizophrenia, anxiety (comprises the general anxiety disorder, Phobias and obsession), emotional handicap (comprises dysthymia disorders, mania, the two-phase obstacle), trigeminal neuralgia, hearing disability, tinnitus, the eye macular degeneration, vomiting, cerebral edema, pain (comprises acute and chronic states, have an intense pain, intractable pain, pain after neuropathic pain and the wound), tardive dyskinesia, sleep illness (comprising lethargy), attention deficit/move obstacle, and conduct disorder more.
Especially, the described patient's condition or disease are to be selected from following central nervous system disorders: anxiety disorder, mental disorder, personality disorder, illness, eating disorder, emotional handicap, migraine, epilepsy or convulsions disease that material is relevant, childhood illness, cognitive disorder, neurodegeneration, neurotoxicity and ischemic.
Preferably, described central nervous system disorders is to be selected from following anxiety disorder: agoraphobia, general anxiety disorder (GAD), obsession (OCD), Phobias, posttraumatic stress disorder (PTSD), social phobia and other phobia.
Preferably, described central nervous system disorders is to be selected from following mental illness: the mental illness that schizophrenia, paranoea, schizoaffective disorder, division sample obstacle (schizophreniform disorder) and material are induced.
Preferably, described central nervous system disorders is to be selected from following personality disorder: compulsive personality disorder and schizophrenia sample (schizoid), Schizoid (schizotypal) obstacle.
Preferably, described central nervous system disorders is to be selected from the following illness relevant with material: mental illness, amphetamine dependence, the Amphetamine that alcohol abuse, alcohol dependence, ethanol withdrawal, ethanol withdrawal delirium, alcohol are induced given up, cocaine dependence, Cocaine are given up, nicotine dependence, nicotine withdrawal, opioid dependency and opioid are given up.
Preferably, described central nervous system disorders is to be selected from following eating disorder: anorexia nervosa and bulimia nervosa.
Preferably, described central nervous system disorders is to be selected from following emotional handicap: the emotional handicap that two-phase obstacle (I type and II type), circulation emotion disease, dysthymia disorders, dysthymic disorder, major depression and material are induced.
Preferably, described central nervous system disorders is migraine.
Preferably, described central nervous system disorders is to be selected from following epilepsy or convulsions disease: generalized nonconvulsive epilepsy, generalized convulsive epilepsy, petit mal status, epilepsy grand mal persistent state, with or without the epilepsy of partial seizure epilepsy, infantile spasm, epilepsy partialis continua and other form of consciousness damage.
Preferably, described central nervous system disorders is the moving obstacle of attention deficit/how.
Preferably, described central nervous system disorders is to be selected from following cognitive disorder: the persistence delirium that delirium, material are induced, dementia, because the dementia that the HIV disease causes, because the dementia that Huntington Chorea causes, because the dementia that Parkinson's disease causes, the alzheimer's disease type is dull-witted, material is induced persistence dementia and mild cognitive impairment.
In above-mentioned illness, be even more important for the treatment of anxiety, schizophrenia, migraine, dysthymia disorders and epilepsy.
At present, the 4th of APA,American Psychiatric Association the edition mental disorder diagnostic and statistical manual (theDiagnostic﹠amp; Statistical Manual of Mental Disorders) (DSM-IV) provides for the diagnostic tool of determining illness described herein.Those skilled in the art generally acknowledge to exist herein alternative nomenclature, nosonomy and the taxonomic hierarchies of described nervous disorders and mental illness, and it develops with medical science and scientific advance.
Strengthened mGluR2 to the replying of L-glutamic acid because comprise these mGluR2 positive allosteric modulators of formula (I) compound, therefore to utilize endogenous L-glutamic acid be favourable to method of the present invention.
Strengthened mGluR2 replying agonist because comprise the positive allosteric modulators of the mGluR2 of formula (I) compound, should be appreciated that the present invention extends to treatment sacred disease and the mental disorder relevant with the L-glutamic acid dysfunction by the mGluR2 positive allosteric modulators that comprises formula (I) compound and the coupling mGluR2 agonist of using significant quantity.
The compounds of this invention can be united with one or more other medicines and is used for the treatment of, prevent, control, improve or palliate a disease or the risk of illness, its Chinese style (I) compound or described other medicines can have effectiveness to described disease or illness, and wherein said drug combination is all safer or more effective compared with independent any medicine.
Pharmaceutical composition
The invention still further relates to and comprise pharmaceutically acceptable carrier or thinner and as the pharmaceutical composition of the compounds of this invention of the treatment significant quantity of activeconstituents, wherein said the compounds of this invention is compound, its pharmaceutically acceptable acid additive salt or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form or its quaternary ammonium salt of formula (I) especially.
Being formulated into be used to the various medicament forms of using purpose of the compound of compound of the present invention, especially formula (I), its pharmaceutically acceptable acid additive salt or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form or its quaternary ammonium salt or its any subgroup or combination.As long as composition is suitable, can adopt all to be generally used for the composition of general drug administration.
For preparing pharmaceutical composition of the present invention, the particular compound (optional additive salt form) of significant quantity is combined in the homogeneous mixture as activeconstituents and pharmaceutically acceptable carrier, described carrier can be taked various forms, depends on the form of using required preparation.It is desirable that these pharmaceutical compositions are taked unit dosage (unitary dosage form), the unit dosage that particularly is suitable for oral, rectum, uses or use by suction through skin, parenteral injection.For example, when the composition of preparation oral dosage form, can use any drug media commonly used, such as water, sugar alcohol, oil, alcohol etc. (at oral liquid for example in the situation of suspension, syrup, elixir, emulsion and solution); Perhaps solid carrier, (in the situations of powder, pill, capsule and tablet) such as starch, sugar, kaolin, thinner, lubricant, tackiness agent, disintegrating agent.Because Tablet and Capsula is used conveniently, it has represented best oral dosage unit form, therefore obviously uses in the case solid pharmaceutical carriers.For the parenteral composition, carrier comprises most at least sterilized water usually, although also can comprise other composition for example in order to increase the composition of solubleness.For example, can prepare the injection solution that carrier wherein comprises the mixture of salt brine solution, glucose solution or salt solution and glucose solution.Also can prepare the injection suspension that wherein can use suitable liquid vehicle, suspending agent etc.Also comprise the solid form preparation that is intended to change into soon before use liquid form preparation.In being suitable for the composition of applied dermally, carrier randomly comprises penetration enhancer and/or suitable wetting agent, and randomly with appropriate addn combination than any character of small proportion, described additive does not cause the obvious deleterious effect to skin.Described additive can promote using and/or can help to prepare desirable composition skin.These compositions can be used in every way, for example as transdermal patch, as the spray drops (spot-on), as ointment.
In order conveniently to use and the dosage homogeneity, it is particularly advantageous preparing aforementioned pharmaceutical composition with unit dosage.Unit dosage used herein refers to be suitable for the physically discrete unit as single dose, and each unit contains as calculated to produce the activeconstituents of the predetermined amount of desired curative effect with required pharmaceutical carrier.The example of such unit dosage is tablet (comprising scored tablet or coating tablet), capsule, pill, powder-product bag (powder packet), thin slice (wafer), suppository, injection solution or suspension etc., with and the multiple combination (segregatedmultiple) that separates.Since the compounds of this invention be effectively can be Orally administered dopamine antagonist, therefore comprise described compound to be used for Orally administered pharmaceutical composition be particularly advantageous.
Mention, the present invention relates to treat, prevent, control, improve or palliate a disease or the pharmaceutical composition that comprises the compounds of this invention and one or more other medicines of patient's condition risk, its Chinese style (I) compound or described other medicines can have effectiveness to described disease or disease risks, the invention still further relates to the purposes of such composition in the preparation medicine.
Following embodiment is intended to illustrate the present invention and is not to limit the scope of the invention.
Experimental section
Following examples illustrated for the preparation of the several method of the compounds of this invention.Except as otherwise noted, all starting raw materials all are available commercially and use without being further purified.
Particularly, can use following shortenings at embodiment and specification sheets in the whole text:
AcOEt (ethyl acetate) M (mole)
AcOH (acetic acid) MeOH (methyl alcohol)
BBr 3(boron tribromide) Mg (milligram)
BINAP (±)-1,1 '-two (beta naphthals) MgSO 4(sal epsom)
Br 2(bromine) MHz (megahertz)
CDCl 3(deuterochloroform) Min (minute)
CCl 4(tetracol phenixin) μ l (microlitre)
DCM (methylene dichloride) Ml (milliliter)
MCPBA (3-chlorine peroxybenzoic acid) Mmol (mmole)
DEAD (diethylazodicarboxylate) M.p. (fusing point)
DIBAL (diisobutyl aluminium hydride) NaBH(OAc) 3(sodium triacetoxy borohydride)
DME (glycol dimethyl ether) Na 2CO 3(yellow soda ash)
DMF (dimethyl formamide) NaH (sodium hydride)
DMSO (dimethyl sulfoxide (DMSO)) NaHCO 3(sodium bicarbonate)
Dppf (1,1 '-two (phenylbenzene phosphanyl) ferrocene) NaHMDS (hexamethyldisilazane sodium)
EDCI.HCl (1-3 (dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride) NaI (sodium iodide)
Et 3N (triethylamine) NaOtBu (sodium tert-butoxide)
Et 2O (ether) Na 2SO 4(sodium sulfate)
EtOH (ethanol) NBS (N-bromosuccinimide)
G (gram) NH 4Cl (ammonium chloride)
1H (proton) NH 4OH (ammonium hydroxide)
H 2(hydrogen) NMR (nucleus magnetic resonance)
HCl (hydrochloric acid) Pd 2(dba) 3(dibenzylideneacetonepalladium palladium (II))
HPLC (high pressure lipuid chromatography (HPLC)) PdCl 2(dppf) 2(two (phenylbenzene phosphanyl) ferrocene palladiums (II) dichloride)
Hz (hertz) PdCl 2(PPh 3) 2(two (triphenylphosphine) palladium chloride (II) dichloride)
KBr (Potassium Bromide) Pd(OAc) 2(acid chloride)
K 2CO 3(salt of wormwood) Pd(PPh 3) 4(tetrakis triphenylphosphine palladium (0))
KOAc (potassium acetate) P(＝O)Br 3(phosphoryl bromide)
KI (potassiumiodide) PPh 3(triphenylphosphine)
KOtBu (potassium tert.-butoxide) TFA (trifluoroacetic acid)
KOH (potassium hydroxide) THF (tetrahydrofuran (THF))
K 3PO 4(potassiumphosphate) TLC (tlc)
LCMS (liquid chromatography mass) Tf 2O (trifluoromethanesulfanhydride anhydride)
LiAlH 4(lithium aluminium hydride) Xantphos (two (diphenylphosphino)-9 of 4,5-, 9-dimethyl xanthene)
Every saturated aqueous solution that all means NaCl when mentioning salt solution.Except as otherwise noted, all temperature all with ℃ (degree centigrade) expression.Except as otherwise noted, all reactions are all carried out under non-inert atmosphere and room temperature.
At single mode reactor: Emrys TM(explanation of instrument is found in Optimizer microwave reactor (PersonalChemistry A.B. is Biotage now) Www.personalchemistry.com)In, and at multimode reactor: MicroSYNTHLabstation (Milestone, Inc.) (explanation of instrument is found in Www.milestonesci.com) in carry out the reaction of microwave-assisted.
A. The preparation of midbody compound
A1. Midbody compound 1
Figure G2007800092105D00311
Midbody compound 1
Reaction is at N 2Carry out under the atmosphere.To commercially available 4-methoxyl group-2-oxo-1, add K in the solution of 2-dihydro-pyridine-3-nitrile (1.00g, 6.60mmol, 1 equivalent) in acetonitrile (45ml) 2CO 3(2.73g, 19.8mmol, 3 equivalents) and isoamyl bromide (441mg, 8.65mmol, 1.3 equivalents).Heated the gained solution 12 hours at 100 ℃.Then reaction is cooled to room temperature and filters by diatomite layer.Then concentrated filtrate under the vacuum.The thick residue that will obtain thus subsequently is by flash chromatography (SiO 2, carry out gradient elution with the MeOH in DCM of 0-2%) purifying and obtain the creaminess solid midbody compound 1 (82%, 5.40mmol).
A2. Midbody compound 2 and 2 '
Figure G2007800092105D00312
Midbody compound 2
With the solution of midbody compound 1 (1.5g, 6.81mmol) in the NaOH aqueous solution (0.1N, 75ml) and THF (20ml) be heated to 100 ℃ 1 hour.Reaction is cooled to 0 ℃ and add 1M HCl and carry out acidifying, regulates pH to about 3, white solid is precipitated out at this moment.Cross filter solid and dry and obtain the midbody compound 2 (1.3g, 6.30mmol) that the N-isopentyl of white solid replaces under vacuum.Prepare the midbody compound 2 ' that the N-normal-butyl replaces in equal mode.
A3. Midbody compound 3,3 ' and 3 "
Figure G2007800092105D00321
Midbody compound 3
Reaction is at N 2Carry out under the atmosphere.The careful P (=O) Br that adds in the solution of midbody compound 2 (2.00g, 9.66mmol, 1 equivalent) in DMF (10ml) 3(5.54g, 19.0mmol, 2 equivalents), then the solution with gained heated 2 hours at 100 ℃ in sealed tube.Then reaction is cooled to room temperature and with H 2O (30ml) dilution, (3 * 30ml) extract gained solution with AcOEt subsequently.With organic layer with Na 2SO 4Dry and concentrated and obtain oil under vacuum.By flash chromatography (SiO 2, with the DCM wash-out) purifying crude product and obtain the midbody compound 3 that the N-isopentyl of creaminess solid replaces (2.13g, 82%, 7.92mmol).Prepare the midbody compound 3 ' of N-normal-butyl replacement and the intermediate 3 that N-methyl cyclopropyl replaces in equal mode ".
A4. Midbody compound 4
Figure G2007800092105D00322
Midbody compound 4
The pyridine (0.118ml, 1.44mmol) that in the round-bottomed flask that accommodates the midbody compound 2 (100mg, 0.48mmol) in DCM (5ml), adds 3 equivalents.Mixture is cooled to-78 ℃ and the slow Tf of adding 2O (0.217ml, 0.528mmol).Solution is warmed to room temperature and stirred 1/2 hour.Mixture is hydrolyzed with cold water, and (3 * 10ml) extractions clean twice with salt solution, with Na with DCM 2SO 4Drying is filtered and vapourisation under reduced pressure and obtain intermediate 4 (133mg).
A6. Midbody compound 6
Midbody compound 6
Reaction is carried out under nitrogen atmosphere.In N-(2-bromo-the benzyl)-solution of ethanamide (468mg, 2.02mmol) in acetonitrile (45ml), add tert-Butyl dicarbonate (1.34g, 6.15mmol) and N, N-dimethyl aminopyridine (501mg, 4.1mmol).Then stirred reaction mixture 20 minutes at room temperature, then with it with AcOEt (40ml) dilution and with saturated NaHCO 3Solution (2 * 40ml) and saturated NH 4(3 * 40ml) solution clean Cl.Then with organic layer with Na 2SO 4Dry and concentrated and obtain thick solid under vacuum.By short opening column chromatogram (SiO 2, carry out wash-out with 2% the MeOH in DCM) this thick solid of purifying and obtain yellow oil midbody compound 6 (590.00mg, 89%, 1.79mmol).
A7. Midbody compound 7
Figure G2007800092105D00332
Midbody compound 7
To midbody compound 6 (200mg, 0.61mmol) add two (the tetramethyl ethylene ketone root closes) two boron (bis (pinacolato) diboron) (232mg in the solution in DMSO (4ml), 0.913mmol) and potassium acetate KOAc (180mg, 1.83mmol), then utilize nitrogen gas stream that solution is degassed, then in reaction mixture, add 1,1 '-two (diphenylphosphino) ferrocene palladium (II) dichloride (1,1 '-bis (diphenylphosphino) ferrocenepalladium (II) dichloride), DCM (20.0mg, 0.0183mmol).Then under nitrogen atmosphere in 110 ℃ of reacting by heating mixtures 16 hours.Then reaction is cooled to room temperature and with AcOEt (30ml) dilution, (3 * 15ml) clean, then with Na with water with gained solution 2SO 4Dry organic fraction is also concentrated under vacuum, obtains desired compound.With the opening column chromatogram (SiO of product by weak point 2, with the DCM wash-out) purifying and obtain yellow oil midbody compound 7 (149.0mg, 89%, 0.054mmol).
A8. Midbody compound 8
Figure G2007800092105D00341
Midbody compound 8
Reaction is at N 2Carry out under the atmosphere.At room temperature to 1; add 4-bromobenzene boric acid tetramethyl ethylene ketone cyclic ester (300mg in the mixture of 4-diox (5.88ml) and DMF (0.12ml); 1.06mmol), N-acetylethylenediamine (0.155ml; 1.59mmol), Xantphos (123mg, 0.21mmol) and Cs 2CO 3(518mg, 1.59mmol), and use N 2Purge mixture 5 minutes.Add Pd (OAc) 2(24mg, 0.1mmol) and under microwave condition the mixture in 170 ℃ of irradiation sealed tubes 10 minutes.Then reaction is cooled to room temperature and filters by diatomite layer.Evaporate volatile matter under the vacuum, and the residue that will obtain thus is by short opening column chromatogram (SiO 2, with DCM/MeOH (NH 3) wash-out) purifying and obtain midbody compound 8 (80mg).
A9. Midbody compound 9
Figure G2007800092105D00342
Midbody compound 9
In the solution of 4-pyridine mercaptan (149mg, 1.35mmol) in dimethyl formamide (5ml), add K 2CO 3(186mg, 1.35mmol); Stir the solution 12 minutes of gained, with the backward 2-(4-brooethyl-phenyl)-4,4,5 that wherein adds, the solution of 5-tetramethyl--[1,3,2] dioxane pentaborane (400mg, 1.35mmol), and stir the solution 2 hours of gained.Then mixture is diluted in entry (30ml) and (3 * 15ml) extract with AcOEt by adding; Then with organic layer with Na 2SO 4Dry and concentrated and obtain crude product under vacuum.By Biotage method of purification (with the DCM wash-out) the crude product mixture purifying is obtained midbody compound 9 (406.0mg, 1.24mmol, 92%) subsequently.
A10. Midbody compound 10
Midbody compound 10
With commercially available 4-methoxyl group-2-oxo-1,2-dihydro-pyridine-3-nitrile (4.70g, 31.29mmol, 1 equivalent), 4-(trifluoromethoxy) bromotoluene (5.44ml, 32.86mmol, 1.05 equivalents) and K 2CO 3(12.9g, 93.8mmol, 3 equivalents) mix in acetonitrile (200ml).Mixture was heated 16 hours in 140 ℃ in sealed tube.Then reaction is cooled to room temperature and vaporising under vacuum solvent.The residue of gained is dissolved among the DCM and by diatomite layer filters.Then concentrated filtrate under vacuum.Subsequently, grind the white solid obtain thus with ether and obtain the midbody compound 10 (9.20g, 91%) of white solid.
A11. Midbody compound 11
Figure G2007800092105D00352
Midbody compound 11
In the solution of midbody compound 10 (9.20g, 28.37mmol) in THF (100ml), add the NaOH aqueous solution (0.1N, 300ml).Reaction mixture was heated 4 hours at 100 ℃.Then reaction is cooled to room temperature and vaporising under vacuum THF.By adding 2N HCl with the alkaline aqueous phase as acidified of gained, regulate pH to about 3, this time white solid be precipitated out.Filter out solid, clean and dry and obtain the midbody compound 11 (8.05g, 91%) of white solid under vacuum with ether.
A12. Midbody compound 12
Figure G2007800092105D00353
Midbody compound 12
With midbody compound 11 (6.57g, 21.19mmol, 1 equivalent) and P (=O) Br 3(12.15g, 42.39mmol, 2 equivalents) mix in DMF (125ml), and then the mixture with gained heated 1 hour at 110 ℃.Then reaction is cooled to room temperature and with H 2O (200ml) dilution is subsequently with the AcOEt (solution of 3 * 75ml) extraction gained.With organic layer with MgSO 4Dry and concentrated under vacuum.By flash chromatography (SiO 2, with the DCM wash-out) and purification of crude product and obtain the midbody compound 12 (6.75g) of white solid.Prepare midbody compound 12 ' with similar approach, wherein the contraposition of phenyl moiety is replaced by fluorine rather than is partly replaced by trifluoromethoxy.
A13. Midbody compound 13
Figure G2007800092105D00361
Midbody compound 13
Under 0 ℃, to 4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl) PPh of phenol (500mg, 2.27mmol), N-(2-hydroxyethyl) morpholine (330.8mg, 2.72mmol) and polymer-bound (load capacity 2.15mmol/g) 3Add azo-2-carboxylic acid's di tert butyl carbonate (784.0mg, 3.40mmol) in (2.11g, 4.54mmol) mixture in anhydrous DCM (30ml).At room temperature stirred reaction mixture is 2 hours.Then, filter out resin, clean and concentrated filtrate under vacuum with DCM.Residue (756.45mg) is used for next step reactions steps without being further purified.
A14. Midbody compound 14
Figure G2007800092105D00362
Midbody compound 14
At room temperature with midbody compound 3 (200mg, 0.74mmol), 1-tert-butoxycarbonyl piperazine (151mg, 0.81mmol), K 3PO 4(236mg, 1.1mmol) and catalyzer [577971-19-8] CAS (10mg) mixes in Isosorbide-5-Nitrae-dioxs (3ml).Corresponding mixture was heated 16 hours under 85 ℃ in sealed tube.Mixture is cooled to room temperature, filters and clean with DCM by diatomite layer.Filtrate is concentrated under vacuum, the residue that obtains is thus obtained midbody compound 14 (200mg, 72%) by purified by flash chromatography.
A16. Midbody compound 16
Figure G2007800092105D00371
Midbody compound 16
With 5-(4-bromophenyl)-1,3-oxazole (220mg, 0.98mmol), two (the tetramethyl ethylene ketone root closes) two boron (372mg, 1.47mmol), 1,1 '-two (diphenylphosphino) ferrocene palladium (II) dichloride, DCM (24mg, 0.0294mmol), the mixture of KOAc (288mg, 2.93mmol) in DMSO (7ml) be 110 ℃ of lower heating 16 hours.Mixture is cooled to room temperature, and (3 * 15ml) clean with AcOEt (30ml) dilution and with water.With the organic layer that merges with Na 2SO 4Evaporate under the drying, vacuum, the residue (200mg) that obtains thus is used for next reactions steps without being further purified.
A17. Midbody compound 17
Figure G2007800092105D00372
Midbody compound 17
With commercially available 4-methoxyl group-2-oxo-1,2-dihydro-pyridine-3-nitrile (4.0g, 0.0266mol), β-Bromoethyl phenyl ether (5.62g, 0.0279mol) and K 2CO 3(11.0g, 0.0799mol) is at CH 3Solution among the CN (150ml) heated 16 hours under refluxing.Then filter out reaction mixture and concentrated filtrate under vacuum.With residue recrystallization and obtain midbody compound 17 (7g, 97%) from ether.
A18. Midbody compound 18
Figure G2007800092105D00381
Midbody compound 18
In the solution of midbody compound 17 (7.0g, 0.0259mol) in MeOH (100ml), add the NaOH aqueous solution (0.1N, 200ml).With reaction mixture be heated to 100 ℃ 3 hours.Then reaction is cooled to room temperature and vaporising under vacuum MeOH.The alkaline water that adds 2N HCl acidifying gained is regulated pH to about 3, and white solid is precipitated out at this moment.Use sinter funnel to collect described solid, clean and dry and obtain the midbody compound 18 (5.78g, 87%) of white solid under vacuum with ether.
A19. Midbody compound 19
Figure G2007800092105D00382
Midbody compound 19
With midbody compound 18 (7.10g, 0.027mol) and P (=O) Br 3(15.886g, 0.055mol) mixes in DMF (150ml), and then the mixture with gained heated 3 hours at 110 ℃.Then reaction is cooled to room temperature and with water (100ml) dilution, subsequently with the solution of gained with AcOEt (3 * 150ml) extractions.With organic layer with Na 2SO 4Dry and concentrated under vacuum.With thick product with flash chromatography (SiO 2, with the DCM wash-out) and purifying and obtain midbody compound 19 (7.67g, 89%).
A20. Midbody compound 20
Figure G2007800092105D00383
Midbody compound 20
To 3-(trifluoromethyl) phenyl aldehyde ([454-89-7] the CAS) (0.872ml that fills in DCE (20-30ml), 0.0065mol) and the round-bottomed flask of 4-piperidine carbinols (0.5g, 0.0043mol) and several AcOH in add NaBH (OAc) 3(2.2g, 0.0107mol).Mixture at room temperature stirred spend the night, subsequently with saturated NaHCO 3Solution cleans and extracts with DCM.The organic layer that merges is passed through Na 2SO 4Dry and concentrated under vacuum.Crude product is obtained midbody compound 20 (0.610g, 56%) by purification by flash chromatography.
A23. Midbody compound 23
Figure G2007800092105D00391
Midbody compound 23
In the round-bottomed flask that fills 4-acyl radical methyl benzoate (5.6g, 0.034mol) in DCE (20ml) and morpholine (2g, 0.023mol), add several AcOH and molecular sieve (4A).Reaction mixture at room temperature stirred 40 minutes and add NaBH (OAc) 3(5g, 0.023mol).Mixture at room temperature stirred spend the night, and then add the NaBH (OAc) of equivalent 3(5g, 0.023mol).Mixture was at room temperature stirred 5 hours, clean with HCl (1N) subsequently and extract with DCM.Use at last saturated NaHCO 3Solution cleans organic layer.The organic layer that merges is passed through Na 2SO 4Dry and concentrated under vacuum.Crude product is passed through flash chromatography (DCM/MeOH (NH 3) mixture) purifying and obtain midbody compound 23 (3g, 60%).
A24. Midbody compound 24
Figure G2007800092105D00392
Midbody compound 24
At N 2React under the atmosphere.In the solution of midbody compound 23 (2g, 0.0085mol) in THF (12ml), slowly add lithium aluminium hydride (1M is in THF) (17ml, 0.017mol).Reaction mixture was at room temperature stirred 2 hours.Then, carefully add saturated NaHCO 3Solution also extracts with DCM.The organic layer that merges is passed through Na 2SO 4Dry and concentrated and obtain midbody compound 24 (1.75g, 100%) under vacuum, it is used for next reactions steps without being further purified.
A28. Midbody compound 28
Figure G2007800092105D00401
Midbody compound 28
With midbody compound 3 (250mg, 0.93mmol), tributyl (vinyl) tin (0.325ml, 1.11mmol) and Pd (PPh 3) 4(22mg, 0.0186mmol) mixture in degassed toluene (10ml) at 130 ℃ with microwave treatment 25 minutes.Then mixture is cooled to room temperature and vaporising under vacuum solvent.Residue is passed through flash chromatography (SiO 2, DCM/MeOH (NH 3) mixture) purifying and obtain the midbody compound 28 (100mg, 50%) of faint yellow solid.
A29. Midbody compound 29
Figure G2007800092105D00402
Midbody compound 29
In the solution of 4-pyridyl methyl alcohol (15g, 137.4mmol) in DCM (200ml), add thionyl chloride (43.6ml), and the reaction mixture of gained was at room temperature stirred 4 hours.Mixture is cooled to room temperature and vaporising under vacuum solvent.With residue with DCM dilution and with saturated NaHCO 3Solution cleans.The organic layer that merges is passed through Na 2SO 4Dry and concentrated and obtain midbody compound 29 (17.18g, 99%) under vacuum.
A30. Midbody compound 30
Figure G2007800092105D00403
Midbody compound 30
In the mixture of NaH (60%, in mineral oil) (0.718g, 17.96mmol) in THF (20ml), drip the solution of 5-bromo indole (2.34g, 11.8mmol) in THF (17ml).The mixture of gained was at room temperature stirred 1 hour.Then add midbody compound 29 (1.81g, 14.2mmol) and with mixture 80 ℃ of heated overnight.With the cooling reaction mixture with H 2O cleans and extracts with AcOEt.The organic layer that merges is passed through Na 2SO 4Dry also vaporising under vacuum.Residue is passed through flash chromatography (SiO 2, the DCM/MeOH mixture) and purifying and obtain midbody compound 30 (2.73g, 80%).
A31. Midbody compound 31
Figure G2007800092105D00411
Midbody compound 31
In the solution of midbody compound 30 (2.73g, 9.5mmol) in DMSO (27ml), add two (the tetramethyl ethylene ketone root closes) two boron (2.414g, 9.5mmol) and KOAc (2.8g, 28.5mmol).Then use nitrogen gas stream that solution is degassed, then in reaction mixture, add 1,1 '-two (diphenylphosphino) ferrocene palladium (II) dichloride, DCM (0.23g, 0.28mmol).Then with reaction mixture 110 ℃ of heated overnight under nitrogen atmosphere.Then reaction is cooled to room temperature, and two (the tetramethyl ethylene ketone root closes) two boron of adding additional quantity) (1.63g, 6.4mmol), KOAc (1.89g, 19.2mmol), 1,1 '-two (diphenylphosphino) ferrocene palladium (II) dichloride and DCM (0.155g, 0.19mmol), and with mixture 130 ℃ of heated overnight.The reaction mixture of cooling is diluted with AcOEt, filter by diatomite layer, with the water wash filtrate.The organic layer that merges is passed through Na 2SO 4Dry and concentrated and obtain midbody compound 31 (4.5g, quantitatively), it is used for next reactions steps without being further purified under vacuum.
A32. Midbody compound 32
Figure G2007800092105D00412
Midbody compound 32
To (N-tert-butoxycarbonyl)-1,2,3, add 4-chloro-2-methyl pyridine (0.308g in the mixture of 6-tetrahydropyridine-4-pinacol borate ([286961-14-6] CAS) (1.5g, 4.8mmol) in Isosorbide-5-Nitrae-dioxs (8ml) and DMF (2ml), 2.4mmol), 1,1 '-two (diphenylphosphino) ferrocene palladium (II) dichloride, DCM (0.293g, 0.36mmol) and salt of wormwood (0.993g, 7.2mmol).Then utilize nitrogen gas stream that mixture is degassed, then carried out microwave treatment 90 minutes at 160 ℃.The reaction mixture of cooling is filtered by diatomite layer and filtrate is concentrated under vacuum.Residue is passed through flash chromatography (SiO 2, DCM/MeOH (NH 3) mixture) purifying and obtain midbody compound 32 (0.5g, 38%).
A33. Midbody compound 33
Figure G2007800092105D00421
Midbody compound 33
The solution of midbody compound 32 (0.5g, 1.82mmol) in 20% the solution (10ml) of TFA in DCM was at room temperature stirred 4 hours, then evaporating solvent.Residue (0.5g) is used for next reactions steps without being further purified.
A35. Midbody compound 35
To midbody compound 2 ' (1.5g, 7.8mmol) in the solution in acetonitrile (13ml), add (4-2-bromomethylphenyl) pinacol borate (3.0g, 9.76mmol) ([138500-85-3] CAS) and cesium carbonate (5.92g, 15.6mmol).Reaction mixture was carried out microwave treatment 30 minutes at 160 ℃.Then, the vaporising under vacuum solvent and with residue by flash chromatography (SiO 2, the DCM/MeOH mixture) and purifying and obtain midbody compound 35 (2.93g, 92%).
A36. Midbody compound 36
Figure G2007800092105D00431
Midbody compound 36
With midbody compound 3 (0.366g, 1.361mmol),
Figure G2007800092105D00432
(compound described in the US2005187277A1) (0.436g, 1.63mmol), Pd (PPh 3) 4(0.157g, 0.136mmol) is at Isosorbide-5-Nitrae-dioxs (2ml) and saturated Na 2CO 3The mixture of solution (2ml) is 150 ℃ of lower microwave treatment 10 minutes of using.Then the reaction mixture with gained filters and vaporising under vacuum filtrate by diatomite layer.Subsequently residue is passed through flash chromatography (SiO 2, DCM/MeOH (NH 3) mixture) purifying and obtain midbody compound 36 (0.55g, 98%).
A39. Midbody compound 39
Figure G2007800092105D00433
Midbody compound 39
At room temperature to 4-aminomethyl phenyl pinacol borate (CAS138500-88-6) (1.2g, 5.14mmol) and Et 3Add tert-Butyl dicarbonate (1.68g, 7.72mmol) in the stirred solution of N (1.42ml, 10.28mmol) in DCM (50ml).At room temperature stirred the mixture 2 hours.The vaporising under vacuum solvent obtains residue, processes described residue with ether and obtains midbody compound 39 (1.7g, solid, 99%), and it is used for next reactions steps without being further purified.
A40. Midbody compound 40
Figure G2007800092105D00441
Midbody compound 40
To midbody compound 39 (1.7g, 5.14mmol) at Isosorbide-5-Nitrae-dioxs (3ml) and saturated Na 2CO 3Add midbody compound 3 (1.15g, 4.28mmol) in the solution in the solution (3ml).Utilize nitrogen gas stream that the solution of gained is degassed and to wherein adding Pd (PPh 3) 4(485.0mg, 0.42mmol).Then under 150 ℃, will react and in sealed tube, carry out microwave treatment 10 minutes.Then the reaction mixture with gained filters by diatomite layer and filtrate is concentrated under vacuum.Then crude product mixture is passed through flash chromatography (SiO 2, DCM/MeOH (NH 3) 9:1) purifying and obtain midbody compound 40 (1.3g, 77%).
A41. Midbody compound 41
Figure G2007800092105D00442
Midbody compound 41
Under 0 ℃ to midbody compound 40 (0.125g, 0.316mmol) DMF (anhydrous, add in the solution in 5ml) NaH (60%, mineral oil; 0.019mg, 0.474mmol).0 ℃ (nitrogen atmosphere) lower suspension that stirs gained 30 minutes.Then add 3-fluoro benzyl bromide (0.059ml, 0.474mmol).At room temperature stirred reaction mixture is 3 hours.Then, add entry and with the aqueous mixture of AcOEt extraction gained.Clean organic layer with saturated NaCl solution.The organic layer that merges is passed through Na 2SO 4Dry.Then crude product mixture is passed through flash chromatography (SiO 2, DCM/MeOH (NH 3) 9:1) purifying and obtain the midbody compound 41 (0.082g, 51%) of yellow oil.
A42. Midbody compound 42
Figure G2007800092105D00451
Midbody compound 42
To 4-bromo-2-fluoroaniline (0.6g, 3.15mmol), tetrahydrochysene-4H-pyrans-4-ketone (0.68g, 6.31mmol) and NaBH (OAc) 3Add molecular sieve (4A) (1g) in (0.96g, 4.72mmol) mixture in DCE (20ml).At room temperature stirred the mixture 16 hours.And then the tetrahydrochysene of adding additional quantity-4H-pyrans-4-ketone (0.34g, 3.15mmol) and NaBH (OAc) 3(0.66g, 3.15mmol), and at room temperature stirred the mixture 48 hours.Then, reaction mixture is filtered by diatomite layer and clean with DCM.Filtrate is concentrated and obtain midbody compound 42 (0.86g, quantitatively), it is used for next reactions steps without being further purified under vacuum.
A43. Midbody compound 43
Figure G2007800092105D00452
Midbody compound 43
In the solution of midbody compound 42 (0.86g, 3.15mmol) in DMSO (3ml), add two (the tetramethyl ethylene ketone root closes) two boron (0.80g, 3.15mmol) and KOAc (0.93g, 9.45mmol).Then utilize nitrogen gas stream that solution is degassed, then in reaction mixture, add 1,1 '-two (diphenylphosphino) ferrocene palladium (II) dichloride, DCM (0.07g, 0.09mmol).Then reaction mixture was heated 16 hours under nitrogen atmosphere at 120 ℃.Then reaction is cooled to room temperature and with water (50ml) dilution, the solution of gained is extracted with AcOEt, then organic fraction is passed through Na 2SO 4Dry and concentrated and obtain midbody compound 43 (1.01g, 100%) under vacuum, it is used for next reactions steps without being further purified.
A44. Midbody compound 44
Figure G2007800092105D00453
Midbody compound 44
In the solution of NaH (60%, in mineral oil) (0.13g, 3.25mmol) in DMF (5ml), add commercially available 4-bromophenol (0.50g, 2.89mmol), and will react and at room temperature stir 10 minutes.Then add 4-chloro-2-methyl pyridine (0.30g, 2.40mmol), then the reaction mixture with gained carried out microwave treatment 10 minutes at 150 ℃.After the cooling, with mixture with water dilution and with Et 2The O extraction.The organic layer that merges is passed through Na 2SO 4Dry and concentrated under vacuum.The residue of gained is obtained midbody compound 44 (0.52g, 81%) by flash chromatography (DCM) purifying.
A45. Midbody compound 45
Figure G2007800092105D00461
Midbody compound 45
In the solution of midbody compound 44 (0.50g, 1.89mmol) in DMSO (5ml), add two (the tetramethyl ethylene ketone root closes) two boron (0.72g, 2.84mmol) and KOAc (0.56g, 5.68mmol).Then utilize nitrogen gas stream that solution is degassed, then in reaction mixture, add 1,1 '-two (diphenylphosphino) ferrocene palladium (II) dichloride, DCM (0.05g, 0.06mmol).Then reaction mixture was heated 16 hours under nitrogen atmosphere at 110 ℃.Then reaction is cooled to room temperature and with water dilution, the solution of gained is extracted with AcOEt, organic fraction is passed through Na 2SO 4Dry and concentrated and obtain midbody compound 45 (0.58g, 100%) under vacuum, it is used for next reactions steps without being further purified.
B. The preparation of final compound
B1. Final compound 1-110
Figure G2007800092105D00462
Final compound 1-110 to 3,4-dimethoxy benzene ylboronic acid (740.0mg, 4.08mmol) at Isosorbide-5-Nitrae-diox (14ml) and NaHCO 3Add midbody compound 3 (1.00g, 3.70mmol) in the solution in the saturated solution (14ml).Utilize nitrogen gas stream that the solution of gained is degassed and to wherein adding Pd (PPh 3) 4(641.0mg, 0.55mmol).Then will react in sealed tube at 150 ℃ with microwave treatment 10 minutes.Then filter the reaction mixture of gained and concentrated filtrate under vacuum by diatomite layer.Then crude product mixture is obtained desired compound by flash chromatography (with the solvent gradient elution of the 0-2% of MeOH in DCM) purifying.Then the described compound of recrystallization and obtain final compound 1-110 (940.0mg, 2.88mmol, 78%) from ether.
B2. Final compound 1-179
Figure G2007800092105D00471
Final compound 1-179
At room temperature with midbody compound 4 (150mg, 0.44mmol) and 4-(acetylamino methyl) phenyl-boric acid (129mg, 0.67mmol) at Isosorbide-5-Nitrae-dioxs (5ml) and Et 3Mix among the N (0.12ml, 0.89mmol), and use N 2Flushing mixture 5 minutes.Add Pd (PPh 3) 4(77mg, 0.067mmol) and with the mixture of gained 90 ℃ of heating 2 hours.Mixture is cooled to room temperature, with AcOEt and salt solution dilution.With AcOEt (3 * 20ml) aqueous phase extracted.The organic layer that merges is passed through Na 2SO 4Dry also vaporising under vacuum passes through column chromatography (SiO with the residue that obtains thus 2, DCM/AcOEt) purifying and obtain the final compound 1-179 of 16mg white solid.
B3. Final compound 1-114
Figure G2007800092105D00472
Final compound 1-114
At room temperature with midbody compound 4 (150mg, 0.44mmol), 3-fluoro-4-anisole ylboronic acid (110mg, 0.67mmol) at Isosorbide-5-Nitrae-diox (5ml) and Et 3Mix among the N (0.12ml, 0.89mmol), and with N 2Flushing mixture 5 minutes.Add Pd (PPh 3) 4(77mg, 0.067mmol) and with the mixture of gained 90 ℃ of heating 2 hours.Mixture is cooled to room temperature, with AcOEt and salt solution dilution.With AcOEt (3 * 20ml) aqueous phase extracted.The organic layer that merges is passed through Na 2SO 4Dry also vaporising under vacuum passes through column chromatography (SiO with the residue that obtains thus 2, DCM/AcOEt) purifying and obtain the final compound 1-114 of 43mg yellow solid.
B4. Final compound 1-095
Figure G2007800092105D00481
Final compound 1-095
At room temperature with midbody compound 4 (150mg, 0.44mmol), 4-(3-hydroxypropyl)-phenyl-boron dihydroxide (120mg, 0.67mmol) at Isosorbide-5-Nitrae-dioxs (5ml) and Et 3Mix among the N (0.12ml, 0.89mmol), and with N 2Flushing mixture 5 minutes.Add Pd (PPh 3) 4(77mg, 0.067mmol) and with the mixture of gained 90 ℃ of heating 2 hours.Mixture is cooled to room temperature, with AcOEt and salt solution dilution.With AcOEt (3 * 20ml) aqueous phase extracted.The organic layer that merges is passed through Na 2SO 4Dry also vaporising under vacuum passes through column chromatography (SiO with the residue that obtains thus 2, DCM/AcOEt) purifying and obtain the final compound 1-095 of 40mg white solid.
B5. Final compound 1-103
Figure G2007800092105D00482
Final compound 1-103
At room temperature with midbody compound 4 (150mg, 0.44mmol), 4-(methoxymethyl)-phenyl-boron dihydroxide (110mg, 0.67mmol) at Isosorbide-5-Nitrae-dioxs (5ml) and Et 3Mix among the N (0.12ml, 0.89mmol), and with N 2Flushing mixture 5 minutes.Add Pd (PPh 3) 4(77mg, 0.067mmol) and with the mixture of gained 90 ℃ of heating 2 hours.Mixture is cooled to room temperature, with AcOEt and salt solution dilution.With AcOEt (3 * 20ml) aqueous phase extracted.The organic layer that merges is passed through Na 2SO 4Dry also vaporising under vacuum passes through column chromatography (SiO with the residue that obtains thus 2, DCM/AcOEt) purifying and obtain the final compound 1-103 of 52mg white solid.
B6. Final compound 1-178
Final compound 1-178
To midbody compound 7 (220.0mg, 0.58mmol) at Isosorbide-5-Nitrae-dioxs (6ml) and saturated Na 2CO 3Add midbody compound 3 (173mg, 0.65mmol) in the solution in the solution (6ml).Utilize nitrogen gas stream that the solution of gained is degassed and to wherein adding Pd (PPh 3) 4(101.0mg, 0.088mmol).Then will react at 150 ℃ with microwave treatment 10 minutes.Then the reaction mixture with gained filters by diatomite layer and filtrate is concentrated under vacuum.Then obtain pure final compound 1-178 (51mg, 0.15mmol, 26%) by preparative HPLC purification of crude reaction mixture.
B7. Final compound 1-097
Final compound 1-097
To 4-hydroxy phenyl boric acid (336mg, 2.44mmol) at Isosorbide-5-Nitrae-dioxs (20ml) and saturated NEt 3Add final compound 5-052 (750mg, 1.79mmol) in the solution in the solution (0.615ml, 4.43mmol).Utilize nitrogen gas stream that the solution of gained is degassed and to wherein adding Pd (PPh 3) 4(384mg, 0.33mmol).To react in sealed tube 90 ℃ of heating 2 hours.The reaction mixture of gained is cooled to room temperature, extracts with the dilution of water and salt solution and with AcOEt.Pass through Na 2SO 4Dry organic layer is also concentrated under vacuum.Then by flash chromatography (SiO 2, with the mixture wash-out of heptane/AcOEt) and the crude product mixture purifying is obtained final compound 1-097 (230mg, 45%).
B8. Final compound 1-274
Figure G2007800092105D00501
Final compound 1-274
At room temperature add NaH (60%, in mineral oil, 13.83mg, 0.96mmol) in the solution of phenol (0.042ml, 0.48mmol) in anhydrous THF (3ml).At room temperature stirred the gained mixture 5 minutes.Add final compound 5-052 (100mg, 0.24mmol).With mixture in sealed tube 80 ℃ of microwave treatment 10 minutes.Mixture is cooled to room temperature, evaporating solvent under the vacuum, and the residue that will obtain thus is by column chromatography (SiO 2, DCM/MeOH (NH 3) mixture) purifying and obtain the final compound 1-274 of 55mg white solid.
B9. Final compound 1-298
Figure G2007800092105D00502
Final compound 1-298
With midbody compound 3 (100mg, 0.371mmol), aniline (0.067ml, 0.743mmol), K 3PO 4(158mg, 0.745mmol) and catalyzer [577971-19-8] CAS (10mg) at room temperature mixes in Isosorbide-5-Nitrae-dioxs (15ml).Corresponding mixture was stirred 12 hours in sealed tube at 80 ℃ (oil bath temperatures).Mixture is cooled to room temperature and adds AcOEt (30ml) and NaHCO in reaction mixture 3(10ml, saturated aqueous solution).Isolate layer and organic layer is passed through Na 2SO 4Dry.Evaporating solvent under the vacuum, and the residue that will obtain thus obtains final compound 1-298 (50mg) by purification by flash chromatography.
B10. Final compound 1-267
Figure G2007800092105D00503
Final compound 1-267
Under nitrogen atmosphere, react.With midbody compound 3 (150mg, 0.557mmol), phenylacetylene (0.064ml, 0.580mmol), PdCl 2(PPh 3) 2(19.6mg, 0.028mmol), PPh 3(3.7mg, 0.014mmol) and NEt 3(0.078ml, 2.23mmol) at room temperature mixes in THF (6ml), and uses N 2Purge mixture 5 minutes.Add CuI (1.3mg, 0.007mmol) and the gained mixture was heated 10 hours in sealed tube at 90 ℃ (oil bath temperatures).Reaction mixture is cooled to room temperature and adds Na 2S 2O 4The aqueous solution (saturated solution).Add DCM (30ml) and separating layer.With organic layer NaHCO 3Na is passed through in the aqueous solution (saturated solution) washing 2SO 4Dry also vacuum concentration.The residue that obtains is thus passed through flash chromatography (SiO 2, DCM/MeOH (NH 3) mixture) purifying and obtain final compound 1-267 (57mg).
B11. Final compound 1-260
Final compound 1-260
At room temperature add 10%Pd/C (10mg) to final compound 1-267 (45mg, 0.155mmol) and 1，4-cyclohexadiene (0.22ml, 2.32mmol) in the solution in MeOH (5ml).The mixture of gained was stirred in sealed tube 12 hours.Filter out catalyzer and vaporising under vacuum solvent.The residue of gained is placed MeOH (15ml) and adds 10%Pd/C (10mg).The mixture of gained is used hydrogen (20psi) hydrogenation 3 hours.Filter out catalyzer and evaporating solvent.The residue that obtains is thus passed through flash chromatography (SiO 2, DCM/MeOH (NH 3) mixture) and then by the reversed-phase HPLC chromatogram purification, obtain the final compound 1-260 (1.63mg) of white solid.
B12. Final compound 1-182
Figure G2007800092105D00512
Final compound 1-182
To midbody compound 8 (80mg, 0.62mmol) at Isosorbide-5-Nitrae-dioxs (1ml) and saturated Na 2CO 3Add midbody compound 3 (64.34mg, 0.239mmol) in the solution in the solution (1ml).Utilize nitrogen gas stream that the solution of gained is degassed and add Pd (PPh in this solution 3) 4(41.4mg, 0.035mmol).Then will react and under 140 ℃, carry out microwave treatment 5 minutes.Reaction mixture with gained filters by diatomite layer and adding AcOEt (10ml) subsequently.Add H 2O (10ml) and separating layer.With organic layer with Mg 2SO 4Dry also vacuum concentration.Then the residue with gained passes through column chromatography (SiO 2, DCM/MeOH (NH 3) mixture) purifying, obtain the pure final compound 1-182 (28mg) of glassy yellow solid.
B13. Final compound 1-258
Figure G2007800092105D00521
Final compound 1-258
To midbody compound 9 (121mg, 0.371mmol) at Isosorbide-5-Nitrae-dioxs (3ml) and saturated NaHCO 3Add midbody compound 3 (100g, 3.71mmol) in the solution in the solution (3ml).Utilize nitrogen gas stream that the solution of gained is degassed and add Pd (PPh in this solution 3) 4(64.0mg, 0.056mmol).Then will react and under 150 ℃, carry out microwave treatment 10 minutes.Then the reaction mixture with gained filters by diatomite layer and filtrate is concentrated under vacuum.Then crude product mixture is passed through the HPLC purifying, obtain final compound 1-258 (13.0mg, 0.034mmol, 10%).
B14. Final compound 1-239
Figure G2007800092105D00523
Final compound 1-239
At room temperature (3-methyl propionate (methyl-3-propanoate) phenyl-boric acid (140mg, 0.67mmol) is at Isosorbide-5-Nitrae-dioxs (5ml) and Et with midbody compound 4 (150mg, 0.44mmol) and 4- 3Mix among the N (0.12ml, 0.89mmol), and use N 2Flushing mixture 5 minutes.In mixture, add Pd (PPh 3) 4(77mg, 0.06mmol) and with the mixture of gained 90 ℃ of heating 2 hours.Mixture is cooled to room temperature, with AcOEt and salt solution dilution.With AcOEt (3 * 20ml) aqueous phase extracted.The organic layer that merges is passed through Na 2SO 4Drying, evaporation and the residue that will obtain thus are by column chromatography (SiO under the vacuum 2, DCM/AcOEt) purifying obtains the final mixture 1-239 of 63mg yellow solid.
B15. Final compound 1-240
Figure G2007800092105D00531
Final compound 1-14
Under 0 ℃ to final compound 1-239 (20mg, 0.057mmol) at THF/H 2Add lithium hydroxide (24mg, 0.57mmol) in the solution among the O1:1 (4ml).Stirred reaction mixture 30 minutes is also concentrated with solution.With the HCl solution of 1N with pH regulator to pH=2, and the precipitation that will form thus leaches and dry, obtains the final compound 1-240 of 10mg white solid.
B16. Final compound 2-043
Figure G2007800092105D00532
Final compound 2-043
At room temperature with midbody compound 12 (300mg, 0.804mmol), 1-(2-phenylethyl) piperazine (0.176ml, 0.964mmol), K 3PO 4(341mg, 1.60mmol) and catalyzer [577971-19-8] CAS (10mg) mixes in Isosorbide-5-Nitrae-dioxs (6ml).Corresponding mixture was heated 16 hours at 110 ℃ in sealed tube.Mixture is cooled to room temperature, filters and wash with AcOEt by diatomite layer.Filtrate is concentrated under vacuum, the residue that obtains is thus filtered by flash chromatography, obtain the final compound 2-043 (349mg, 90%) of light yellow solid.
B17. Final compound 1-037
Figure G2007800092105D00541
Final compound 1-037
With midbody compound 12 (350mg, 0.938mmol) and midbody compound 13 (375mg, 1.12mmol) at Isosorbide-5-Nitrae-dioxs (3ml) and saturated Na 2CO 3Mix in the solution (3ml).Utilize nitrogen gas stream that the solution of gained is degassed, and to wherein adding Pd (PPh 3) 4(108.3mg, 0.093mmol).Then will react in sealed tube 150 ℃ of microwave treatment 10 minutes.Then the gained reaction mixture is filtered by diatomite layer and wash with AcOEt.Filtrate is concentrated under vacuum, the residue that obtains is thus passed through purification by flash chromatography, obtain final compound 1-037 (305.6mg, 65%).
B18. Final compound 2-022
Figure G2007800092105D00542
Final compound 2-022
With final compound 2-056 (150mg, 0.55mmol), 3-chloro-4-(trifluoromethoxy) bromotoluene (0.16ml, 0.55mmol) and K 2CO 3(150mg, 1.1mmol) mixture in DMF (2ml) at room temperature stirs and spends the night.Then the reaction mixture with gained filters by diatomite layer and washs with AcOEt.Filtrate is concentrated under vacuum, and the residue that will obtain thus obtains desired compound by purification by flash chromatography.Then with described compound recrystallization from ether, obtain final compound 2-022 (170mg, 64%).
B19. Final compound 1-250
Figure G2007800092105D00551
Final compound 1-250
With midbody compound 3 (198mg, 0.74mmol) and midbody compound 16 (200mg, 0.74mmol) at Isosorbide-5-Nitrae-dioxs (5ml) and saturated Na 2CO 3Mix in the solution (5ml).Utilize nitrogen gas stream that the solution of gained is degassed, and to wherein adding Pd (PPh 3) 4(128mg, 0.115mmol).Then will react in sealed tube 150 ℃ of microwave treatment 10 minutes.Then the gained reaction mixture is filtered by diatomite layer and wash with AcOEt.Filtrate is concentrated under vacuum, the residue that obtains thus by purification by flash chromatography, is obtained final compound 1-250 (63.9mg, 26%, the productive rate that calculates based on two-step reaction subsequently).
B20. Final compound 1-223
Final compound 1-223
With midbody compound 3 (727mg, 2.70mmol) and commercially available 4-(morpholinyl) phenyl-boron dihydroxide (560mg, 2.70mmol) at Isosorbide-5-Nitrae-dioxs (10ml) and saturated Na 2CO 3Mix in the solution (10ml).Utilize nitrogen gas stream that the solution of gained is degassed, and to wherein adding Pd (PPh 3) 4(468mg, 0.405mmol).Then will react in sealed tube 150 ℃ of microwave treatment 10 minutes.Then the reaction mixture of gained is filtered by diatomite layer and with water (10ml) wash filtrate.The organic layer that merges is passed through Na 2SO 4Dry also vaporising under vacuum.Then crude product mixture is obtained desired compound by purification by flash chromatography.Then with described compound recrystallization from ether, obtain final compound 1-223 (620mg, 65%).
B21. Final compound 1-049
Figure G2007800092105D00561
Final compound 1-049
With midbody compound 19 (250mg, 0.783mmol)) and 3-chloro-4-isopropoxy-phenyl-boron dihydroxide (159mg, 0.86mmol) at Isosorbide-5-Nitrae-dioxs (2.5ml) and saturated NaHCO 3Mix in the solution (2.5ml).Utilize nitrogen gas stream that the solution of gained is degassed, and to wherein adding Pd (PPh 3) 4(130mg, 0.11mmol).Then will react in sealed tube 150 ℃ of microwave treatment 10 minutes.Then the reaction mixture with gained filters and vaporising under vacuum filtrate by diatomite layer.Then crude product mixture is obtained desired compound by purification by flash chromatography.Then with described compound recrystallization from ether, obtain the final compound 1-049 (65mg, 21%) of white solid.
B22. Final compound 4-020
Figure G2007800092105D00562
Final compound 4-020
At room temperature with midbody compound 3 (100mg, 0.37mmol), 4-(3-trifluoromethyl benzyl oxygen base)-piperidines (115.11mg, 0.444mmol), K 3PO 4(150mg, 0.70mmol) and catalyzer [577971-19-8] CAS (10mg) mixes in Isosorbide-5-Nitrae-dioxs (5ml).Corresponding mixture was heated 16 hours at 85 ℃ in sealed tube.Filter with the mixture cool to room temperature and by diatomite layer.The residue that concentrated filtrate also will obtain thus under vacuum obtains the final compound 4-020 (90mg, 55%) of white colloidal solid by purification by flash chromatography.
B23. Final compound 4-044
Figure G2007800092105D00571
Final compound 4-044
At room temperature with midbody compound 3 (150mg, 0.406mmol), 4,4-(Phenylpiperidine-4-yl)-morpholine (113.3mg, 0.46mmol), K 3PO 4(200mg, 0.94mmol) and catalyzer [577971-19-8] CAS (10mg) mixes in Isosorbide-5-Nitrae-dioxs (4ml).Corresponding mixture was heated 36 hours at 85 ℃ in sealed tube.Filter with the mixture cool to room temperature and by diatomite layer.The residue that concentrated filtrate also will obtain thus under vacuum obtains the final compound 4-044 (123mg, 51%) of light yellow solid by the preparative HPLC purifying.
B24. Final compound 2-028
Figure G2007800092105D00572
Final compound 2-028
At room temperature with midbody compound 3 (226mg, 0.84mmol), 1-(2-pyrimidyl) piperazine dihydrochloride (228mg, 0.96mmol), K 3PO 4(612mg, 2.88mmol) and catalyzer [577971-19-8] CAS (10mg) mixes in Isosorbide-5-Nitrae-dioxs (5ml).Corresponding mixture was heated 36 hours at 85 ℃ in sealed tube.Filter with the mixture cool to room temperature and by diatomite layer.The residue that concentrated filtrate also will obtain thus under vacuum obtains the final compound 2-028 (258mg, 87%) of shallow cream-colored solid by purification by flash chromatography.
B25. Final compound 3-009
Figure G2007800092105D00573
Final compound 3-009
Mixture in DME (1.5ml) at room temperature stirred 10 minutes with midbody compound 20 (0.223g, 0.00081mol, 1.1 equivalents) and NaH (60%, be scattered in the mineral oil 0.035g, 0.00088mol, 1.2 equivalents).Then slowly add midbody compound 3 (0.20g, 0.00074mol, 1 equivalent).The reaction mixture of gained was processed 20 minutes at 130 ℃ with microwave.Mixture is cooled to room temperature and vaporising under vacuum solvent.Residue is suspended among the DCM, filters and filtrate is concentrated under vacuum.Then crude product mixture is passed through purification by flash chromatography, obtain final compound 3-009 (146mg, 47%).
B26. Final compound 3-008
Figure G2007800092105D00581
Final compound 3-008
Add in batches NaBH (OAc) to final compound 3-016 (346mg, 1.19mmol) and 3-(trifluoromethyl) phenyl aldehyde ([454-89-7] CAS) (262mg, 1.5mmol) in the solution in DCE (40ml) 3(760mg, 3.6mmol).Reaction mixture was at room temperature stirred 3 hours.Then, use NH 4Cl aqueous solution quencher mixture.The organic layer that merges is concentrated under vacuum.Crude product by purification by flash chromatography, is obtained the final compound 3-008 (370mg) of light brown solid.
B27. Final compound 1-271
Figure G2007800092105D00582
Final compound 1-271
To midbody compound 11 (200mg, 0.64mmol), midbody compound 24 (267mg, 1.28mmol) and PPh 3Add azo-2-carboxylic acid's di tert butyl carbonate (279mg, 1.21mmol) in (309mg, 1.15mmol) mixture in THF (5ml).Reaction mixture was carried out microwave treatment 20 minutes under 120 ℃.Then reaction mixture is cooled to room temperature and concentrated under vacuum.Residue is passed through flash chromatography (with 10-20%DCM/MeOH (NH 3) solvent gradient elution) purifying, obtain final compound 1-271 (219.7mg, 70%).
B28. Final compound 3-014
Figure G2007800092105D00591
Final compound 3-014
Add in batches NaBH (OAc) to final compound 3-018 (191mg, 0.70mmol) and 3-(trifluoromethyl) phenyl aldehyde ([454-89-7] CAS) (174mg, 1mmol) in the solution in DCE (16ml) 3(443mg, 2.1mmol).Mixture was at room temperature stirred 3 hours, after this use saturated NH 4Cl solution is with its quencher.The organic layer that merges is passed through Na 2SO 4Dry and concentrated under vacuum.Crude product by purification by flash chromatography, is obtained the final compound 3-014 (270mg, 89%) of white solid.
B29. Final compound 2-036
Figure G2007800092105D00592
Final compound 2-036
To midbody compound 2 (0.2g, 0.971mmol), K 2CO 3Add 1-(2-chloroethyl)-4-pyridine-2-base-piperazine (0.393g, 1.748mmol) in (0.268g, 1.942mmol) and NaI (catalytic amount) mixture in acetonitrile (12ml).Reaction mixture is carried out microwave treatment 10 minutes twice under 150 ℃.Then add DCM and filtering mixt.With saturated NaHCO 3Solution washing filtrate.The organic layer that merges is passed through Na 2SO 4Dry and concentrated under vacuum.Residue is passed through flash chromatography (DCM/MeOH (NH 3) mixture) purifying, obtain the final compound 2-036 (152.5mg, 40%) of near-white solid.
B30. Final compound 5-007
Figure G2007800092105D00601
Final compound 1-131
In the solution of midbody compound 28 (35mg, 0.161mmol) in DCM (6ml), add a TFA.Then slowly add N-(methoxymethyl)-N-(trimethyl silyl methyl)-benzylamine (46mg, 0.193mmol), and the reaction mixture of gained was at room temperature stirred 2 hours.Then the vaporising under vacuum solvent and with residue by flash chromatography (SiO 2, DCM/MeOH (NH 3) mixture) purifying, obtain final compound 1-131 (6mg, 10%).
B31. Final compound 2-055
Figure G2007800092105D00602
Final compound 2-055
With midbody compound 12 ' (250mg, 0.81mmol), 1-(2-pyridyl)-piperazine (0.129ml, 0.85mmol) and the mixture of diisopropylethylamine (0.416ml, 2.4mmol) in acetonitrile (5ml) under 160 ℃, carried out microwave treatment 30 minutes.Mixture is cooled to room temperature and vaporising under vacuum solvent.The residue that obtains is thus passed through flash chromatography (SiO 2, the DCM/MeOH mixture) and purifying, obtain the final compound 2-055 (192mg, 61%) of white solid.
B32. Final compound 5-020
Figure G2007800092105D00603
Final compound 5-020
With midbody compound 3 (0.6g, 2.20mmol) and midbody compound 31 (3.69g, 3.79mmol) at Isosorbide-5-Nitrae-dioxs (7ml) and saturated Na 2CO 3Mix in the solution (6ml).Utilize nitrogen gas stream that the solution of gained is degassed and to wherein adding Pd (PPh 3) 4(0.39g, 0.33mmol).Then will react in sealed tube 140 ℃ of microwave treatment 5 minutes.Then the reaction mixture with gained dilutes with AcOEt, filters and filtrate water (10ml) is washed by diatomite layer.The organic layer that merges is passed through Na 2SO 4Dry also vaporising under vacuum.Then crude product mixture is passed through purification by flash chromatography, obtain desired compound.Then with described compound recrystallization and obtain final compound 5-020 (0.39g, 44%) from ether.
B33. Final compound 4-047
Figure G2007800092105D00611
Final compound 4-047
With midbody compound 3 " (0.3g; 1.18mmol), the 4-Phenylpiperidine (0.286g; 1.77mmol) and the mixture of diisopropylethylamine (0.615ml, 3.54mmol) in acetonitrile (5ml) under 150 ℃, carried out microwave treatment 20 minutes.Mixture is cooled to room temperature and vaporising under vacuum solvent.The residue that obtains is thus passed through flash chromatography (SiO 2, DCM/MeOH (NH 3) mixture) purifying, obtain desired compound.Then with described compound recrystallization and obtain final compound 4-047 (0.29g, 73%) from ether.
B34. Final compound 4-003
Figure G2007800092105D00612
Final compound 1-196
Final compound 5-054 (0.37g, 1.05mmol) and palladium (10%, on gac) (catalytic amount) were stirred 3 hours under the nitrogen atmosphere of mixture at 50psi in EtOH (10ml).Then filter out catalyzer and vaporising under vacuum filtrate.The residue that obtains is thus passed through flash chromatography (SiO 2, DCM/MeOH (NH 3) mixture) purifying, obtain final compound 4-003 (0.21g, 57%).
B35. Final compound 1-306
Figure G2007800092105D00621
Final compound 1-306
With midbody compound 35 (0.25g, 0.61mmol) and commercially available 2-bromo-6-picoline (0.158g, 0.92mmol) at Isosorbide-5-Nitrae-dioxs (2ml) and saturated NaHCO 3Mix in the solution (2ml).Utilize nitrogen gas stream that the solution of gained is degassed and to wherein adding Pd (PPh 3) 4(0.10g, 0.09mmol).Then will react in sealed tube and under 150 ℃, carry out microwave treatment 10 minutes.The reaction mixture of gained is filtered and water (10ml) wash filtrate by diatomite layer.The organic layer that merges is passed through Na 2SO 4Dry also vaporising under vacuum.Then crude product mixture is passed through purification by flash chromatography, obtain final compound 1-306 (0.078g, 34%).
B36. Final compound 5-015
Final compound 5-015
Add Acetyl Chloride 98Min. (0.014ml, 0.196mmol) to the final compound 5-014 (0.04g, 0.130mmol) that makes by reaction path B1 and diisopropylethylamine (0.068ml, 0.392mmol) in the solution in DCM (2ml).Reaction mixture was at room temperature stirred 12 hours.Then vaporising under vacuum solvent and the residue that will obtain thus are by flash chromatography (SiO 2, DCM/MeOH (NH 3) mixture) purifying, obtain final compound 5-015 (0.045g, 99%).
B37. Final compound 1-198
Figure G2007800092105D00631
Final compound 1-198
In the solution of midbody compound 41 (0.082mg.0.163mmol) in DCM (10ml), add TFA (5ml).The solution of gained was at room temperature stirred 3 hours.Then vaporising under vacuum solvent and residue is dissolved among the DCM is with NaHCO 3Wash with the NaCl saturated solution.The organic layer that merges is passed through Na 2SO 4Dry and concentrated under vacuum.Residue is passed through flash chromatography (DCM/MeOH (NH 3) mixture) purifying, obtain the final compound 1-198 (17mg, 26%) of white solid.
B38. Final compound 1-185
Figure G2007800092105D00632
Final compound 1-185
To final compound 1-308 (0.2g, 0.533mmol) 1, add N-methyl-2-methoxyethyl amine (0.0711mg in the mixture in the 4-diox (10ml), 0.8mmol), palladium diacetate (0.0118mg, 0.053mmol) and Xantphos (0.0616mg, 0.8mmol).Reaction mixture was stirred 16 hours at 120 ℃ in sealed tube.Then the reaction mixture with gained filters by diatomite layer, washs with AcOEt.With filtrate with saturated NaCl solution washing.The organic layer that merges is passed through Na 2SO 4Dry and concentrated under vacuum.Residue by flash chromatography (DCM/MeOH9:1) purifying, is obtained the final compound 1-185 (24mg, 12%) of yellow solid.
B39. Final compound 1-226
Figure G2007800092105D00633
Final compound 1-226
In the solution of final compound 1-224 (0.147mg, 0.385mmol) in DCM (20ml), add BBr at 0 ℃ 3(0.182ml, 1.92mmol).Gained solution is warmed to room temperature and stirred 16 hours.Then add NH 4The OH aqueous solution.With the aqueous solution of gained with dichloromethane extraction, with saturated NaCl solution washing.The organic layer that merges is passed through MgSO 4Dry and concentrated under vacuum.Residue is passed through flash chromatography (DCM/MeOH (NH 3) 9:1) purifying, obtain the final compound 1-226 (28mg, 20%) of yellow solid.
B40. Final compound 5-052
Figure G2007800092105D00641
Final compound 5-052
Described reaction is at N 2Carry out under the atmosphere.Midbody compound 4 (26mg, 0.077mmol) is dissolved in the pyridine (1ml, 12.26mmol).The solution of gained was heated 1 hour at 40 ℃.Mixture is cooled to room temperature and vaporising under vacuum solvent.Process the residue that obtains thus with Isosorbide-5-Nitrae-dioxs, obtain white solid, with its filtration, dry under vacuum, be accredited as final compound 5-052 (25mg; White solid).
B41. Final compound 2-056
Figure G2007800092105D00642
Final compound 2-056
Midbody compound 14 (200mg, 0.53mmol) at room temperature stirred at the solution of TFA/DCM mixture (20%) in (5ml) spend the night.By adding K 2CO 3(saturated solution) alkalizes mixture.Then organic layer is passed through MgSO 4Dry and concentrated under vacuum.Residue is accredited as final compound 2-056 (150mg), and it is without being further purified for next reactions steps.
B42. Final compound 3-015
Final compound 3-015
In the mixture of 1-tert-butoxycarbonyl-4-hydroxy piperidine (447mg, 2.22mmol) in DME (8ml), add NaH (60%, in mineral oil), and reaction mixture was at room temperature stirred 5 minutes.Then add midbody compound 3 (500mg, 1.85mmol) and with the reaction mixture of gained at 130 ℃ with microwave treatment 30 minutes.Then reaction is cooled to room temperature and filtration.Filtrate is concentrated under vacuum, obtain the final compound 3-015 (460mg) of brown oil.
B43. Final compound 3-016
Figure G2007800092105D00652
Final compound 3-016
The amberlyst-15 (load capacity 4.6mmol/g) (0.77g, 3.54mmol) that adds polymer-bound in the solution of final compound 3-015 (460mg, 1.18mmol) in MeOH (50ml).The mixture of gained was at room temperature shaken 12 hours.Then filter out resin and solvent is discarded.Described resin is suspended from MeOH/NH 3Also at room temperature shook 3 hours (50ml).Filter out resin and filtrate is concentrated and obtain the final compound 3-016 (350mg) of light brown solid under vacuum.
B44. Final compound 5-053
Figure G2007800092105D00661
Final compound 5-053
With midbody compound 3 (1g, 3.71mmol), (N-tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-pinacol borate (1.26g, 4.08mmol) and Pd (PPh 3) 4(0.642g, 0.556mmol) is at Isosorbide-5-Nitrae-dioxs (6ml) and saturated NaHCO 3Mixture in the solution (6ml) at 150 ℃ with microwave treatment 10 minutes.Then the reaction mixture with gained filters and vaporising under vacuum filtrate by diatomite layer.Then crude product mixture is passed through flash chromatography (SiO 2, DCM/MeOH (NH 3) mixture) purifying, obtain the final compound 5-053 (0.57g, 41%) of white solid.
B45. Final compound 3-017
Final compound 3-017
Final compound 5-053 (530mg, 1.42mmol) and palladium (10%, on gac) (catalytic amount) were stirred 4 hours under the nitrogen atmosphere of mixture at 50psi in AcOEt (50ml).Filter out catalyzer and filtrate is concentrated under vacuum, obtain the final compound 3-017 (540mg, quantitative) of water white oil.The compound that obtains thus is used for next reactions steps without being further purified.
B46. Final compound 3-018
Final compound 3-018
In the solution of final compound 3-017 (540mg, 1.44mmol) in MeOH (50ml), add amberlyst-15 (load capacity 4.6mmol/g) (1g, 4.6mmol).The mixture of gained was at room temperature shaken 12 hours.Then filter out resin and solvent is discarded.Resin is suspended from MeOH/NH 3Also at room temperature shook 3 hours (50ml).Filter out resin and filtrate is concentrated under vacuum, obtain the final compound 3-018 (198mg) of yellow oil.
B47. Final compound 5-054
Figure G2007800092105D00671
Final compound 5-054
With midbody compound 3 ' (0.34g, 1.33mmol), midbody compound 33 (0.5g, 1.73mmol) and the mixture of diisopropylethylamine (0.925ml, 5.32mmol) in acetonitrile (3ml) at 150 ℃ with microwave treatment 20 minutes.Mixture is cooled to room temperature and vaporising under vacuum solvent.The residue that obtains is thus passed through flash chromatography (SiO 2, DCM/MeOH (NH 3) mixture) purifying and obtain final compound 5-054 (0.37g, 79%).
B48. Final compound 1-307
Figure G2007800092105D00672
Final compound 1-307
In the solution of midbody compound 36 (0.55mg, 1.76mmol) in DCM (20ml), add TFA (10ml).The solution of gained was at room temperature stirred 2 hours.Then vaporising under vacuum solvent and residue is dissolved among the DCM is with NaHCO 3Saturated solution washing with NaCl.With the organic layer that merges with Na 2SO 4Dry and concentrated under vacuum, obtain final compound 1-307 (0.310g, 74%), it is used for next reactions steps without being further purified.
B49. Final compound 1-308
Figure G2007800092105D00681
Final compound 1-308
Under 0 ℃ in 5 minutes to cupric bromide (II) (0.2g, 0.89mmol) and nitrite tert-butyl (0.178ml, 1.48mmol) drip final compound 1-307 (0.31g, 0.99mmol) in the suspension (0 ℃) in acetonitrile (29ml).Mixture 0 ℃ of lower stirring 1 hour, then is warmed to room temperature also progressively 65 ℃ of heating 1 hour.Then the reaction mixture with gained filters by diatomite layer, with acetonitrile washing and vaporising under vacuum filtrate, obtains final compound 1-308 (0.464g), and it is used for next reactions steps without being further purified.
B50. Final compound 1-190
Figure G2007800092105D00682
Final compound 1-190
With midbody compound 43 (0.30g, 1.11mmol) and midbody compound 3 (0.43g, 1.33mmol) at Isosorbide-5-Nitrae-dioxs (3ml) and saturated Na 2CO 3Mix in the solution (3ml).Utilize nitrogen gas stream that the solution of gained is degassed, and to wherein adding Pd (PPh 3) 4(0.12g, 0.1mmol).Then will react in sealed tube and carry out microwave treatment 10 minutes at 150 ℃.Then the reaction mixture with gained filters by diatomite layer and washs with AcOEt.With the salt solution wash filtrate.The organic layer that merges is passed through MgSO 4Dry and concentrated under vacuum.The residue that obtains is thus obtained final compound 1-190 (0.04g, 9%) by the preparative HPLC purifying.
B51. Final compound 1-064
Figure G2007800092105D00691
Final compound 1-064
With midbody compound 3 (0.48g, 1.89mmo) and midbody compound 45 (0.59g, 1.89mmol) at Isosorbide-5-Nitrae-dioxs (4ml) and saturated NaHCO 3Mix in the solution (4ml).Utilize nitrogen gas stream that the solution of gained is degassed, and to wherein adding Pd (PPh 3) 4(0.22g, 0.19mmol).Then will react in sealed tube and carry out microwave treatment 10 minutes at 150 ℃.Then the reaction mixture with gained filters by diatomite layer and washs with AcOEt.With the salt solution wash filtrate.The organic layer that merges is passed through MgSO 4Dry and concentrated under vacuum.The residue that obtains is thus obtained final compound 1-064 (0.16g, 25%) by flash chromatography (DCM/MeOH mixture) purifying.
Synthesized the final compound in the following table according to previous embodiment (it is shown in the row that are marked with " embodiment numbering ").The compound of beating asterisk illustrates in an embodiment.
Table 1A:Wherein L is the compound of covalent linkage.
Figure G2007800092105D00692
Figure G2007800092105D00701
Figure G2007800092105D00711
Figure G2007800092105D00721
Figure G2007800092105D00751
Figure G2007800092105D00761
Figure G2007800092105D00771
Figure G2007800092105D00781
Figure G2007800092105D00791
Figure G2007800092105D00801
Figure G2007800092105D00811
Figure G2007800092105D00821
Figure G2007800092105D00831
Figure G2007800092105D00841
Figure G2007800092105D00851
Figure G2007800092105D00861
Figure G2007800092105D00881
Figure G2007800092105D00891
Figure G2007800092105D00901
Figure G2007800092105D00911
Figure G2007800092105D00921
Table 1B:Wherein L is saturated or the compound of undersaturated alkyl chain.
Figure G2007800092105D00931
Figure G2007800092105D00932
Figure G2007800092105D00941
Table 1C:Wherein L comprises the compound of O atom.
Figure G2007800092105D00942
Figure G2007800092105D00943
Figure G2007800092105D00951
Figure G2007800092105D00961
Table 1D:Wherein L comprises the compound of N atom.
Figure G2007800092105D00963
Figure G2007800092105D00971
Table 2: be the compound of the embodiment preparation of piperazinyl according to A wherein.
Figure G2007800092105D00981
Figure G2007800092105D00991
Figure G2007800092105D01001
Figure G2007800092105D01011
Table 3: be the compound of the embodiment preparation of 4-piperidyl according to A wherein.
Figure G2007800092105D01031
Figure G2007800092105D01032
Figure G2007800092105D01041
Table 4: be the compound of the embodiment preparation of piperidino according to A wherein.
Figure G2007800092105D01051
Figure G2007800092105D01052
Figure G2007800092105D01061
Figure G2007800092105D01071
Figure G2007800092105D01081
Figure G2007800092105D01091
Figure G2007800092105D01101
Table 5: be other compound of embodiment preparation that contains the heterocycle of N according to A wherein.
Figure G2007800092105D01111
A--A--b:a is R 4One side of part; B is a side of L part
Figure G2007800092105D01121
Figure G2007800092105D01122
Figure G2007800092105D01131
Figure G2007800092105D01132
Figure G2007800092105D01141
Figure G2007800092105D01142
Table 6: according to R wherein 2It or not the compound of the embodiment preparation of hydrogen.
Figure G2007800092105D01152
Figure G2007800092105D01153
C. physical-chemical data
The LCMS-method:
LCMS-general method A
The HPLC gradient is provided by Alliance2795XE, comprises specifically described post in quaternary pump, automatic sampler, column oven, photodiode array detector detector (PDA2996) and following each method with de-gassing vessel.The effluent liquid shunting of post enters in the MS detector.The MS detector is furnished with the electron spray ionisation source.Use nitrogen as atomizing gas.Within 0.5 second, obtain 50 to 600 mass spectrum.Kapillary pin hole voltage (needle voltage) is 3.5kV, and source temperature remains on 140 ℃.Utilize Waters-Micromass MassLynx-Openlynx data system to obtain data.
LCMS-general method B
The HPLC gradient is provided by the HP1100 of Agilent Technologies, comprises specifically described post in pump (quaternary or binary), automatic sampler, column oven, diode-array detector (DAD) and following each method with de-gassing vessel.The effluent liquid shunting of post enters in the MS detector.The MS detector is furnished with the electron spray ionisation source.Use nitrogen as atomizing gas.Source temperature remains on 140 ℃.Utilize MassLynx-Openlynx software to obtain data.
ICMS-general method C
The LC gradient is provided by Acquity UPLC (Waters) system, comprises binary pump, sample tissue device (sample organizer), post well heater (being set in 55 ℃) and diode-array detector (DAD).The effluent liquid shunting of post enters in the MS detector.The MS detector is furnished with the electron spray ionisation source.Adopt 0.02 second retention time (dwell time) in 0.18 second, to obtain from 100 to 1000 mass spectrum by scanning.Kapillary pin hole voltage is 3.5kV, and source temperature remains on 140 ℃.Use nitrogen as atomizing gas.Utilize the Waters-MicromassMassLynx-Openlynx data system to obtain data.
Method 1
Except general method A, utilize Agilent Technologies Zorbax-C18 post (cartridge) (3.5 μ m, 4.6 * 50mm) carry out reversed-phase HPLC, flow velocity is 1ml/ minute.Column oven is set in 25 ℃.Use two kinds of moving phases (mobile phase A: water+0.5% formic acid; Mobile phase B: acetonitrile+0.5% formic acid).At first, carry out 95%A and 5%B0.1 minute.Then in the time of 5 minutes, gradient is adjusted to 100%B, remains to 6.0 minutes, and 6.5 to 7.0 minutes balances to starting condition.Use the typical sampling volume of 5-20 μ L.Use ES MS detector, obtain and just ionize pattern and negative electricity from the data of pattern.Align the ionization pattern, taper hole voltage is 30V; From pattern, taper hole voltage is 63V for negative electricity.
Method 2
Except general method A, utilize Agilent Technologies the Zorbax-C18 post (1.8 μ m, 4.6 * 30mm) carry out reversed-phase HPLC, flow velocity is 1.5ml/ minute.Column oven is set in 30 ℃.Use two kinds of moving phases (mobile phase A: water+0.05% formic acid; Mobile phase B: acetonitrile+0.05% formic acid).The gradient condition of using is: 3.5 o'clock from 90%A and 10%B to 100%B, when remaining to 3.7 minutes, balance is to starting condition in the time of 3.8 to 4.5 minutes.Use the typical sampling volume of 5-20 μ L.Use ES MS detector, obtain and just ionize pattern and negative electricity from the data of pattern.Align the ionization pattern, taper hole voltage is 30V; From pattern, taper hole voltage is 63V for negative electricity.
Method 3
Except general method B, utilize Advanced ChromatographyTechnologies the ACE-C18 post (3.0 μ m, 4.6 * 30mm) carry out reversed-phase HPLC, 40 ℃, flow velocity is 1.5ml/ minute.The gradient condition of using is: in 6.5 minutes by 80%A (0.5g/l ammonium acetate solution), 10%B (acetonitrile), 10%C (methyl alcohol) to 50%B and 50%C, the 100%B during by 7 minutes, balance is to starting condition in the time of 7.5 to 9.0 minutes.Sampling volume is 5 μ l.Adopt 0.1 second retention time, in 0.5 second only with just ionize pattern by scanning obtain from 100 to 750 high resolution mass spectrum (flight time, TOF).Align the ionization pattern, kapillary pin hole voltage is 2.5kV, and taper hole voltage is 20V.Leucine enkephalin is to proofread and correct the reference material of (lock mass calibration) for lock mass.
Method 4
Except general method B, identical with method 3, but use 10 μ L sampling volumes.
Method 5
Except general method B, utilize Advanced ChromatographyTechnologies the ACE-C18 post (3.0 μ m, 4.6 * 30mm) carry out reversed-phase HPLC, 40 ℃, flow velocity is 1.5ml/ minute.The gradient condition of using is: in 6.5 minutes by 80%A (0.5g/l ammonium acetate solution), 10%B (acetonitrile), 10%C (methyl alcohol) to 50%B and 50%C, 100%B in the time of 7 minutes, balance is to starting condition in the time of 7.5 to 9.0 minutes.Sampling volume is 5 μ l.Adopt 0.3 second retention time, in 1.0 seconds, obtain from 100 to 1000 Low Resolution Mass Spectra (ZQ detector, level Four bar) by scanning.Kapillary pin hole voltage is 3kV.Align the ionization pattern, taper hole voltage is 20V and 50V, and from pattern, taper hole voltage is 20V for negative electricity.
Method 6
Except general method C, utilize bridge joint ethylsiloxane/silicon-dioxide (BEH) C18 post (1.7 μ m, 2.1 * 50mm) carry out anti-phase UPLC, flow velocity is 0.8ml/ minute.(mobile phase A: 0.1% formic acid is at H to use two kinds of moving phases 2In the O/ methyl alcohol 95/5; Mobile phase B: methyl alcohol) carry out gradient condition: in 1.3 minutes by 95%A to 5%A, 95%B and kept 0.2 minute.Use the sampling volume of 0.5 μ l.Align ionization pattern and negative electricity from pattern, taper hole voltage is respectively 10V and 20V.
Method 7
Except general method B, utilize Agilent the XDB-C18 post (1.8 μ m, 2.1 * 30mm) carry out reversed-phase HPLC, 60 ℃, flow velocity is 1ml/ minute.The gradient condition of using is: in 6.5 minutes by 90%A (0.5g/l ammonium acetate solution), 5%B (acetonitrile), 5%C (methyl alcohol) to 50%B and 50%C, the 100%B during by 7 minutes, balance is to starting condition in the time of 7.5 to 9.0 minutes.Sampling volume is 2 μ l.Adopt 0.1 second retention time, in 0.5 second only with just ionize mode by scanning obtain from 100 to 750 high resolution mass spectrum (flight time, TOF).Kapillary pin hole voltage is 2.5kV, and taper hole voltage is 20V.Leucine enkephalin is the reference material of proofreading and correct for lock mass.
Method 8
Except general method B, utilize Agilent the XDB-C18 post (1.8 μ m, 4.6 * 30mm) carry out reversed-phase HPLC, 60 ℃, flow velocity is 1.5ml/ minute.The gradient condition of using is: in 6.5 minutes by 80%A (0.5g/l ammonium acetate solution), 20%B (mixture of acetonitrile/methanol, 1/1), to 100%B, remain to 7 minutes, balance is to starting condition in the time of 7.5 to 9.0 minutes.Sampling volume is 5 μ l.Adopt 0.3 second retention time, in 1.0 seconds, obtain from 100 to 1000 Low Resolution Mass Spectra (ZQ detector, level Four bar) by scanning.Kapillary pin hole voltage is 3kV.Align the ionization pattern, taper hole voltage is 20V and 50V respectively, and from pattern, taper hole voltage is 20V for negative electricity.
Method 9
Except general method B, utilize Advanced ChromatographyTechnologies the ACE-C18 post (3.0 μ m, 4.6 * 30mm) carry out reversed-phase HPLC, 40 ℃, flow velocity is 1.5ml/ minute.The gradient condition of using is: in 6.5 minutes by 80%A (0.5g/l ammonium acetate solution), 10%B (acetonitrile), 10%C (methyl alcohol) to 50%B and 50%C, the 100%B during by 7 minutes, balance is to starting condition in the time of 7.5 to 9.0 minutes.Sampling volume is 5 μ l.Adopt 0.3 second retention time, in 0.5 second by scanning obtain from 100 to 750 high resolution mass spectrum (flight time, TOF).For just ionizing pattern and negative electricity for the pattern, kapillary pin hole voltage is respectively 2.5kV and 2.9kV.Align ionization pattern and negative electricity from pattern, taper hole voltage is 20V.Leucine enkephalin is the reference material of proofreading and correct for lock mass.
In open capillaries or at Buchi B-540 or Mettler FP62, carry out fusing point test.
Table 7: the physical-chemical data of compound.For salt form, reported [MH+] of free alkali.
Compound number Fusing point (℃) [MH +] RT (minute) The LCMS method Physical aspect
1-003 339 4.38 Method 3 White solid
1-004 378 4.00 Method 3 White solid
1-005 413 4.54 Method 3 Faint yellow solid
1-006 427 4.43 Method 8 Faint yellow solid
1-007 159 363 2.92 Method 2 Light yellow solid
1-008 148 299 4.59 Method 1 White solid
1-009 149 293 4.43 Method 3 Yellow solid
1-010 Decompose 336 5.00 Method 5 Yellow solid
1-011 60 323 4.43 Method 3 Yellow solid
1-012 Decompose 323 4.55 Method 3 Yellow solid
1-013 128 337 2.95 Method 2 White solid
1-014 143 391 3.22 Method 2 Yellow solid
1-015 307 Method 1 Solid
1-016 331 2.56 Method 2 Light yellow solid
1-017 331 2.60 Method 2 Light brown solid
Compound number Fusing point (℃) [MH +] RT (minute) The LCMS method Physical aspect
1-018 155 291 4.19 Method 1 Yellow solid
1-019 118 307 4.45 Method 1 White solid
1-021 331 2.59 Method 2 Light yellow solid
1-022 335 3.92 Method 3 Light brown solid
1-023 295 1.15 Method 6 The beige solid
1-024 181 385 2.70 Method 2 Light yellow solid
1-025 397 4.92 Method 3 Light brown solid
1-026 351 2.62 Method 2 White solid
1-027 351 2.63 Method 2 Light yellow solid
1-028 180 327 4.54 Method 1 Pink solid
1-030 153 371 2.76 Method 2 White solid
1-031 167 468 4.62 Method 3 White solid
1-032 190 456 2.70 Method 2 Yellow solid
1-033 97 470 4.47 Method 3 White solid
1-034 498 4.53 Method 8 White solid
1-035 136 498 4.52 Method 8 White solid
1-036 498 5.19 Method 3 White solid
1-037 184 500 4.47 Method 3 White solid
1-038 140 514 4.64 Method 3 White solid
1-039 169 401 2.78 Method 2 White solid
1-040 180 429 2.47 Method 2 White solid
1-041 155 463 3.17 Method 2 The beige solid
1-042 185 363 2.90 Method 2 White solid
1-043 185 288 2.71 Method 1 The beige solid
1-044 141 288 3.34 Method 1 White solid
1-045 160 288 2.81 Method 1 Solid
1-046 185 362 3.96 Method 1 White solid
1-047 317 4.09 Method 3 Faint yellow solid
Compound number Fusing point (℃) [MH +] RT (minute) The LCMS method Physical aspect
1-048 188 347 4.20 Method 4 White solid
1-049 Decompose 409 5.13 Method 3 White solid
1-050 135 245 3.85 Method 1 Yellow solid
1-051 305 4.29 Method 1 Yellow solid
1-052 118 321 4.40 Method 1 Yellow solid
1-053 Decompose 315 4.25 Method 3 White solid
1-055 123 337 2.73 Method 2 White solid
1-056 195 352 3.64 Method 7 The glassy yellow solid
1-057 136 371 4.04 Method 3 White solid
1-058 122 336 4.72 Method 7 Yellow solid
1-059 103 259 4.18 Method 1 Yellow solid
1-060 347 3.00 Method 3 Filbert solid
1-061 346 3.93 Method 3 Faint yellow solid
1-062 346 3.61 Method 7 White solid
1-063 102 374 4.16 Method 3 White solid
1-064 121 360 3.97 Method 7 White solid
1-065 360 4.22 Method 7 White solid
1-066 364 3.79 Method 3 White solid
1-067 414 4.68 Method 7 White solid
1-068 Decompose 414 4.67 Method 7 The near-white solid
1-069 414 4.40 Method 7 The near-white solid
1-070 380 4.10 Method 7 The near-white solid
1-071 371 3.86 Method 7 White solid
1-072 371 3.90 Method 7 White solid
1-073 431 4.32 Method 3 The near-white solid
1-074 347 3.32 Method 7 White solid
1-075 347 3.36 Method 7 White solid
1-076 347 3.55 Method 7 White solid
Compound number Fusing point (℃) [MH +] RT (minute) The LCMS method Physical aspect
1-077 108 259 3.92 Method 1 The beige solid
1-078 170 346 3.06 Method 8 White solid
1-079 103 273 4.22 Method 1 White solid
1-080 149 267 4.45 Method 1 White solid
1-081 257 4.13 Method 1 Yellow solid
1-082 123 273 4.29 Method 1 Yellow solid
1-083 307 4.66 Method 4 Yellow solid
1-084 142 267 4.25 Method 1 White solid
1-085 102 281 2.72 Method 2 White solid
1-086 168 323 3.16 Method 2 Orange solids
1-087 125 285 3.97 Method 3 Faint yellow solid
1-088 161 285 4.09 Method 4 White solid
1-089 Decompose 285 4.07 Method 3 White solid
1-090 123 301 2.74 Method 2 White solid
1-091 137 301 2.76 Method 2 Yellow solid
1-092 423 5.01 Method 3 White solid
1-093 172 343 3.05 Method 2 The near-white solid
1-094 131 343 3.03 Method 2 Light yellow solid
1-095 85 325 3.76 Method 1 White solid
1-096 201 283 3.72 Method 1 Light brown solid
1-097 210 283 3.66 Method 1 White solid
1-098 145 297 2.04 Method 2 White solid
1-099 327 3.35 Method 3 The beige solid
1-100 297 4.11 Method 5 Yellow oil
1-101 96 297 4.31 Method 1 White solid
1-102 99 270 4.07 Method 1 Light yellow solid
1-103 91 311 4.22 Method 1 White solid
1-104 311 4.52 Method 3 Cream-colored solid
Compound number Fusing point (℃) [MH +] RT (minute) The LCMS method Physical aspect
1-105 107 325 2.96 Method 2 The light orange solid
1-106 339 4.54 Method 3 Faint yellow solid
1-107 67 311 2.51 Method 2 Light yellow solid
1-108 313 3.51 Method 3 Cream-colored solid
1-109 357 3.35 Method 3 White solid
1-110 52 327 4.03 Method 3 Yellow solid
1-111 129 325 2.89 Method 2 Light yellow solid
1-112 149 331 4.33 Method 7 White solid
1-113 65 315 4.35 Method 1 White solid
1-114 133 315 4.30 Method 1 Yellow solid
1-115 154 357 3.06 Method 2 White solid
1-116 333 2.69 Method 2 Liquid Paraffin
1-117 166 359 5.21 Method 5 White solid
1-118 Decompose 339 3.68 Method 3 White solid
1-119 Decompose 333 4.39 Method 5 Cream-colored solid
1-120 122 351 4.74 Method 3 Yellow solid
1-121 363 4.67 Method 3 White solid
1-122 131 381 4.61 Method 3 White solid
1-123 189 399 4.92 Method 3 White solid
1-124 385 5.88 Method 3 Faint yellow solid
1-125 355 4.00 Method 3 White solid
1-126 Decompose 353 4.08 Method 5 Cream-colored solid
1-127 156 354 3.52 Method 1 White solid
1-128 107 368 2.05 Method 1 White solid
1-129 384 3.23 Method 3 Cream-colored solid
1-130 159 340 3.06 Method 3 White solid
1-131 132 322 2.42 Method 2 Pink solid
1-132 336 3.98 Method 3 White solid
Compound number Fusing point (℃) [MH +] RT (minute) The LCMS method Physical aspect
1-133 337 4.72 Method 7 White solid
1-134 294 371 5.40 Method 3 Cream-colored solid
1-135 351 5.33 Method 4 White solid
1-136 397 4.64 Method 5 Cream-colored solid
1-137 411 4.78 Method 3 White solid
1-138 441 4.70 Method 3 Cream-colored solid
1-139 396 3.95 Method 3 Filbert solid
1-140 359 5.13 Method 3 White solid
1-141 373 5.38 Method 3 White solid
1-142 403 5.01 Method 3 White solid
1-143 118 389 3.07 Method 2 White solid
1-144 100 403 3.03 Method 2 White solid
1-145 212 403 3.02 Method 2 White solid
1-146 139 391 3.07 Method 2 White solid
1-147 146 391 3.07 Method 2 White solid
1-148 173 391 3.06 Method 2 Yellow solid
1-149 120 407 3.23 Method 2 White solid
1-150 177 407 3.18 Method 2 White solid
1-151 154 398 2.89 Method 2 White solid
1-152 193 384 2.86 Method 2 White solid
1-153 171 398 2.89 Method 2 Yellow solid
1-154 360 4.23 Method 3 White solid
1-155 132 360 4.07 Method 7 The near-white solid
1-156 139 360 4.09 Method 3 The near-white solid
1-157 162 374 4.36 Method 5 White solid
1-158 142 374 4.23 Method 5 Cream-colored solid
1-159 171 374 4.25 Method 5 White solid
1-160 374 4.18 Method 3 Cream-colored solid
Compound number Fusing point (℃) [MH +] RT (minute) The LCMS method Physical aspect
1-161 378 4.17 Method 3 White solid
1-162 156 392 4.21 Method 3 Filbert solid
1-163 202 442 2.94 Method 2 White solid
1-164 165 408 2.82 Method 2 White solid
1-165 408 2.15 Method 2 White solid
1-166 404 4.05 Method 3 Cream-colored solid
1-167 404 4.05 Method 3 White solid
1-168 Decompose 364 3.27 Method 5 Freeze-drying
1-169 144 3.94 2.62 Method 2 The beige solid
1-170 282 3.10 Method 3 Yellow solid
1-171 189 296 3.97 Method 3 The glassy yellow solid
1-172 137 310 4.51 Method 1 Green solid
1-173 130 324 1.81 Method 2 Gray solid
1-174 340 4.02 Method 9 Yellow solid
1-175 75 324 3.54 Method 1 Brown solid
1-176 198 324 3.55 Method 1 White solid
1-177 112 352 2.13 Method 2 White solid
1-178 157 338 3.39 Method 1 The beige solid
1-179 144 338 3.39 Method 1 White solid
1-180 Yellow solid
1-181 Decompose 353 2.79 Method 3 Faint yellow solid
1-182 367 3.31 Method 3 The glassy yellow solid
1-183 354 5.04 Method 3 Faint yellow solid
1-184 368 3.30 Method 3 White solid
1-185 384 4.45 Method 4 Yellow solid
1-186 269 321 3.47 Method 3 Filbert solid
1-187 322 4.52 Method 3 Yellow
Compound number Fusing point (℃) [MH +] RT (minute) The LCMS method Physical aspect
1-188 364 5.66 Method 3 The glassy yellow solid
1-189 384 4.22 Method 3 Yellow solid
1-190 384 4.21 Method 7 Yellow solid
1-191 Decompose 400 4.48 Method 7 Faint yellow solid
1-192 119 The glassy yellow solid
1-193 358 5.21 Method 3 Brown solid
1-194 372 5.17 Method 3 Yellow solid
1-195 372 5.35 Method 3 Glassy yellow oil
1-196 386 5.33 Method 3 Yellow solid
1-197 418 5.47 Method 3 White solid
1-198 404 4.71 Method 3 White solid
1-199 136 390 2.93 Method 2 Yellow solid
1-200 162 390 2.94 Method 2 Yellow solid
1-201 342 3.35 Method 3 Cream-colored solid
1-202 146 406 3.07 Method 2 Yellow solid
1-203 173 402 2.90 Method 2 Yellow solid
1-204 157 397 2.75 Method 2 Yellow solid
1-205 456 5.69 Method 3 Yellow solid
1-206 209 397 2.74 Method 2 Yellow solid
1-207 379 2.68 Method 3 Yellow solid
1-208 359 3.35 Method 7 Faint yellow solid
1-209 373 4.08 Method 3 Yellow solid
1-210 73 373 4.01 Method 3 Yellow solid
1-211 142 401 4.53 Method 3 Faint yellow solid
1-212 294 401 4.44 Method 3 Faint yellow solid
1-213 96 401 1.61 Method 2 White solid
1-214 326 4.26 Method 3 Brown solid
1-215 70 360 3.70 Method 1 White solid
Compound number Fusing point (℃) [MH +] RT (minute) The LCMS method Physical aspect
1-216 191 360 3.67 Method 1 White solid
1-217 414 3.49 Method 7 The glassy yellow solid
1-218 336 5.10 Method 3 Yellow solid
1-219 350 5.32 Method 5 The glassy yellow solid
1-220 213 366 3.79 Method 3 Yellow solid
1-221 380 4.60 Method 4 Yellow solid
1-222 352 4.17 Method 5 Yellow solid
1-223 171 352 4.09 Method 3 Yellow solid
1-224 Decompose 368 3.67 Method 4 Yellow solid
1-225 151 382 4.08 Method 3 Yellow solid
1-226 118 430 4.80 Method 3 Yellow solid
1-227 162 380 4.79 Method 3 Yellow solid
1-228 148 400 5.19 Method 3 The glassy yellow solid
1-229 148 366 3.94 Method 3 White solid
1-230 143 393 3.98 Method 3 Yellow solid
1-231 Decompose 393 3.68 Method 3 Yellow solid
1-232 391 4.77 Method 3 Yellow solid
1-233 427 5.45 Method 4 Orange solids
1-234 428 3.94 Method 3 Orange solids
1-235 151 333 3.57 Method 5 White solid
1-236 Decompose 334 3.50 Method 5 Faint yellow solid
1-237 Yellow solid
1-238 130 309 4.02 Method 1 The beige solid
1-239 120 353 4.34 Method 1 Yellow solid
1-240 169 339 3.73 Method 1 White solid
1-241 172 338 1.94 Method 2 White solid
1-242 (oil) 325 2.54 Method 2 Black oil
1-243 166 338 2.05 Method 2 The near-white solid
Compound number Fusing point (℃) [MH +] RT (minute) The LCMS method Physical aspect
1-244 122 352 2.10 Method 2 White solid
1-245 135-140 414 2.62 Method 2 White solid
1-246 350 3.50 Method 3 Cream-colored solid
1-247 217 587 5.02 Method 8 White solid
1-248 347 3.44 Method 3 White solid
1-249 350 3.68 Method 7 Yellow solid
1-250 334 3.89 Method 3 White solid
1-251 117 309 4.09 Method 3 The near-white solid
1-252 120-121 311 4.24 Method 1 The beige solid
1-253 325 4.14 Method 3 White solid
1-254 122 306 2.37 Method 2 White solid
1-255 233 494 2.78 Method 2 Yellow solid
1-256 128 313 4.55 Method 1 Yellow solid
1-257 181 345 3.69 Method 1 White solid
1-258 390 4.35 Method 4 Water white oil
1-259 323 4.62 Method 3 The light gray solid
1-260 295 4.46 Method 4 White solid
1-261 293 4.70 Method 3 Yellow solid
1-262 338 4.75 Method 3 White solid
1-263 Decompose 338 4.83 Method 5 The butteriness green solid
1-264 325 4.46 Method 3 White solid
1-265 88 325 4.52 Method 5 White solid
1-266 323 4.51 Method 3 Yellow solid
1-267 291 4.78 Method 3 Brown solid
1-268 321 4.85 Method 3 Cream-colored solid
1-269 334 5.24 Method 3 White solid
1-270 166 334 5.24 Method 5 Orange solids
1-271 500 4.41 Method 3 White solid
Compound number Fusing point (℃) [MH +] RT (minute) The LCMS method Physical aspect
1-272 401 4.78 Method 3 White solid
1-273 347 4.15 Method 7 White solid
1-274 Decompose 283 4.05 Method 3 White solid
1-275 174 297 4.10 Method 5 White solid
1-276 311 4.33 Method 5 White
1-277 365 4.65 Method 3 White solid
1-278 375 4.54 Method 3 White solid
1-279 116 381 4.69 Method 3 White solid
1-280 327 4.18 Method 5 White solid
1-281 83 341 4.21 Method 5 White solid
1-282 153 313 4.12 Method 3 White solid
1-283 345 4.08 Method 3 The pale pink solid
1-284 190 363 4.32 Method 5 White solid
1-285 200 381 4.83 Method 5 White solid
1-286 322 3.73 Method 3 Faint yellow solid
1-287 397 4.99 Method 3 Faint yellow solid
1-288 169 323 4.30 Method 3 White solid
1-289 403 5.02 Method 3 Yellowish
1-290 148 445 5.24 Method 3 White solid
1-291 352 5.16 Method 3 Faint yellow solid
1-292 154 396 3.82 Method 3 White solid
1-293 209 372 4.43 Method 3 White solid
1-294 306 3.97 Method 3 White solid
1-295 359 3.31 Method 3 Yellow solid
1-296 151 361 3.57 Method 7 The near-white solid
1-297 350 4.78 Method 7 Faint yellow solid
1-298 Decompose 282 3.97 Method 3 Cream-colored solid
1-299 296 4.00 Method 3 Brownish oil
Compound number Fusing point (℃) [MH +] RT (minute) The LCMS method Physical aspect
1-300 Decompose 367 3.91 Method 3 White solid
1-301 Decompose 374 5.13 Method 3 Yellow solid
1-302 375 4.01 Method 3 Yellow solid
1-303 310 4.14 Method 3 White solid
1-304 322 4.51 Method 7 White solid
1-306 374 4.22 Method 7
2-001 183 437 4.95 Method 3 Faint yellow solid
2-002 127 469 5.26 Method 3 White solid
2-003 134 455 5.13 Method 3 Faint yellow solid
2-004 338 3.36 Method 3 Faint yellow solid
2-005 367 4.07 Method 3 White solid
2-006 379 4.08 Method 3 Faint yellow solid
2-007 369 3.76 Method 3 The near-white solid
2-008 382 3.45 Method 3 Faint yellow solid
2-009 424 3.34 Method 3 Faint yellow solid
2-010 112 469 5.21 Method 3 White solid
2-011 351 4.40 Method 3 Yellow solid
2-012 365 4.44 Method 3 White solid
2-013 381 4.32 Method 3 Faint yellow solid
2-014 433 5.04 Method 3 White solid
2-015 Decompose 401 4.66 Method 3 The beige solid
2-016 409 4.33 Method 3 White solid
2-017 379 4.55 Method 3 Filbert solid
2-018 391 4.75 Method 3 Light yellow oil
2-019 413 4.49 Method 3 Yellow glue
2-020 463 5.05 Method 3 Faint yellow solid
2-021 379 4.99 Method 3 Faint yellow solid
2-022 256 483 5.49 Method 3 White solid
Compound number Fusing point (℃) [MH +] RT (minute) The LCMS method Physical aspect
2-023 366 3.32 Method 3 Yellow glue
2-024 352 3.83 Method 3 Yellow solid
2-025 366 4.17 Method 3 Yellow solid
2-026 135 420 4.69 Method 3 White solid
2-027 377 3.72 Method 3 The near-white solid
2-028 353 3.56 Method 3 Evaporated milk oil colours solid
2-029 155 421 4.71 Method 3 Filbert solid
2-030 353 2.80 Method 3 Yellow solid
2-031 245 387 3.38 Method 3 Yellow solid
2-032 383 3.40 Method 3 Yellow solid
2-033 429 4.23 Method 3 Yellow glue
2-034 Decompose 417 3.89 Method 3 Faint yellow solid
2-035 288 392 4.15 Method 3 White solid
2-036 159 396 3.67 Method 3 The near-white solid
2-037 223 White solid
2-038 140 435 4.73 Method 3 White solid
2-039 125 467 5.05 Method 3 White solid
2-040 157 Faint yellow solid
2-041 Decompose 365 3.38 Method 3 Filbert solid
2-042 Decompose 469 4.91 Method 3 White solid
2-043 110 483 4.97 Method 3 Faint yellow solid
2-044 156 487 4.93 Method 4 White solid
2-045 Decompose 519 5.47 Method 3 Faint yellow solid
2-046 92 497 3.96 Method 8 Yellow solid
2-047 470 3.94 Method 3 Yellow solid
2-048 258 524 5.04 Method 3 White solid
2-049 403 4.27 Method 4 Light brown solid
2-050 421 4.39 Method 3 White solid
Compound number Fusing point (℃) [MH +] RT (minute) The LCMS method Physical aspect
2-051 239 439 4.49 Method 3 White solid
2-052 439 4.59 Method 3 White solid
2-053 415 4.48 Method 3 White solid
2-054 429 4.42 Method 3 Yellow oil
2-055 390 3.59 Method 3 White solid
3-001 124 338 3.57 Method 7 Faint yellow solid
3-002 White solid
3-003 125 379 4.41 Method 3 White solid
3-004 188 434 4.90 Method 3 The near-white solid
3-005 393 4.47 Method 3 White solid
3-006 131 461 5.22 Method 3 White solid
3-007 208 380 4.35 Method 3 White solid
3-008 448 5.10 Method 3 Filbert solid
3-009 117 462 5.20 Method 3 The near-white solid
3-010 187 White solid
3-011 Decompose 351 2.55 Method 3 White solid
3-012 432 4.60 Method 3 Cream-colored solid
3-013 211 497 4.95 Method 3 White solid
3-014 432 5.35 Method 3 White solid
4-001 337 3.28 Method 3 White solid
4-002 337 3.22 Method 7 White solid
4-003 132 351 3.33 Method 7
4-004 188 353 3.20 Method 3 Cream-colored solid
4-005 353 3.87 Method 3 Cream-colored solid
4-006 367 3.94 Method 7 White solid
4-007 367 3.51 Method 7 Faint yellow solid
4-008 381 3.79 Method 7 White solid
4-009 377 3.91 Method 7 White solid
Compound number Fusing point (℃) [MH +] RT (minute) The LCMS method Physical aspect
4-010 342 4.19 Method 3 White solid
4-012 296 378 4.48 Method 3 White solid
4-013 350 5.06 Method 3 White solid
4-014 Decompose 350 4.76 Method 3 White solid
4-015 364 5.33 Method 3 Yellow oil
4-016 112 418 5.09 Method 7 White solid
4-017 380 5.18 Method 3 White solid
4-018 384 4.94 Method 3 White solid
4-019 100 412 5.18 Method 3 White solid
4-020 448 5.43 Method 3 The white colloidal solid
4-021 Decompose 410 4.82 Method 3 White solid
4-022 464 5.30 Method 3 White solid
4-023 365 4.43 Method 3 The beige solid
4-025 283 447 4.63 Method 3 White solid
4-026 393 4.41 Method 3 Brown solid
4-027 113 411 4.57 Method 3 White solid
4-028 461 5.25 Method 3 White solid
4-029 91 461 5.28 Method 3 White solid
4-030 425 5.09 Method 3 White foam
4-031 141 447 5.31 Method 3 White solid
4-032 475 5.02 Method 3
4-033 475 5.03 Method 3 Yellow solid
4-034 253 405 4.4 Method 3 Filbert solid
4-035 389 4.93 Method 3 Faint yellow solid
4-036 405 5.29 Method 3 The brown gelled fuel
4-037 78 407 4.86 Method 3 Yellow solid
4-038 214 391 4.35 Method 3 The beige solid
4-039 123 408 5.09 Method 3 White solid
Compound number Fusing point (℃) [MH +] RT (minute) The LCMS method Physical aspect
4-040 113 412 4.91 Method 3 Evaporated milk oil colours solid
4-041 418 4.82 Method 3 Filbert solid
4-042 Decompose 433 4.13 Method 7 Yellow solid
4-043 138 379 4.64 Method 3 White solid
4-044 435 4.53 Method 3 Faint yellow solid
4-045 380 4.93 Method 3 White solid
4-046 282 414 3.73 Method 3 White solid
4-047 128 334 4.05 Method 7 White solid
4-048 378 4.38 Method 7 The near-white solid
4-049 138 497 4.89 Method 3 White solid
4-050 Decompose 491 4.20 Method 3 White solid
4-051 Decompose 509 4.88 Method 3 Filbert solid
4-052 499 4.39 Method 7 Filbert solid
4-053 485 3.85 Method 7 Yellow solid
4-054 Cream-colored solid
4-055 155 435 3.85 Method 3 Cream-colored solid
4-056 431 4.16 Method 3 Cream-colored solid
4-057 242 449 4.54 Method 3 Cream-colored solid
4-058 499 5.05 Method 3 White solid
4-059 157 475 5.27 Method 3 White solid
4-060 96 The near-white solid
4-061 175 447 4.20 Method 3 Cream-colored solid
4-062 139 454 5.06 Method 3 White solid
4-063 471 3.56 Method 7 The near-white solid
4-064 159 443 4.43 Method 3 White solid
4-065 511 5.24 Method 3 White solid
4-066 400 4.83 Method 3 White solid
5-001 Decompose 384 3.31 Method 3 The near-white solid
Compound number Fusing point (℃) [MH +] RT (minute) The LCMS method Physical aspect
5-002 164.7 398 3.24 Method 3 White solid
5-003 Decompose 322 4.33 Method 3 White solid
5-004 377 4.2 Method 3 The unsalted butter coloring agent
5-005 96 447 5.16 Method 3 White solid
5-006 100 397 4.71 Method 3 White solid
5-007 350 4.75 Method 3 Water white oil
5-008 102 436 5.11 Method 3 White solid
5-009 473 4.97 Method 3 White solid
5-010 118 298 2.37 Method 2 White solid
5-011 326 2.96 Method 3 Filbert solid
5-012 257 2.72 Method 3 White solid
5-013 347 4.26 Method 3 White solid
5-014 308 3.92 Method 5 Orange solids
5-015 350 3.75 Method 5 Faint yellow solid
5-016 Decompose 306 3.93 Method 3 Filbert solid
5-017 Decompose 306 3.84 Method 3 The light green solid
5-018 281 320 4.37 Method 3 Faint yellow solid
5-019 382 5.31 Method 3 Faint yellow solid
5-020 232 397 4.21 Method 3 Cream-colored solid
5-021 Decompose 307 3.31 Method 3 Slurry
5-022 307 2.93 Method 3 The beige solid
5-023 Decompose 384 3.51 Method 3 Cream-colored solid
5-024 284 398 3.53 Method 3 Cream-colored solid
5-025 398 3.72 Method 3 Cream-colored solid
5-026 Decompose 338 4.43 Method 5 The glassy yellow solid
5-027 Decompose 347 4.08 Method 7 White solid
5-028 364 4.87 Method 3 White solid
5-029 234 307 3.89 Method 3 Faint yellow solid
Compound number Fusing point (℃) [MH +] RT (minute) The LCMS method Physical aspect
5-030 324 4.4 Method 3 Cream-colored solid
5-031 134 322 4.72 Method 3 Yellow solid
5-032 382 4.04 Method 3 White solid
5-033 376 5.35 Method 3 White solid
5-034 421 4.44 Method 3 Evaporated milk oil colours solid
5-035 169 406 5.04 Method 3 White solid
5-036 394 4.96 Method 3 White solid
5-037 217 380 4.57 Method 3 Cream-colored solid
5-038 141 Cream-colored solid
5-039 276 361 4.52 Method 3 White solid
5-040 111 393 4.87 Method 3 Cream-colored solid
5-041 130 362 4.85 Method 3 White solid
5-042 412 5.73 Method 3 Faint yellow
5-043 Decompose 365 4.57 Method 3 Faint yellow solid
5-044 395 4.51 Method 3 The brown colloidal solid
5-045 378 4.06 Method 3 White solid
5-046 370 4.08 Method 4 White solid
5-047 349 4.37 Method 3 White solid
5-048 441 5.22 Method 3 Water white oil
5-049 318 4.39 Method 3 The light gray solid
5-050 407 3.66 Method 3 White solid
5-051 166 410 2.63 Method 2 Gray solid
6-001 175 341 5.54 Method 2 The beige solid
Decomposition=product decomposes in the mensuration process
D. pharmacological examples
Compound provided by the invention is the positive allosteric modulators of mGluR2.As if these compounds strengthen L-glutamic acid and reply by being combined with the allosteric site that is different from the L-glutamic acid binding site.When having formula (I) compound, mGluR2 is to the enhancing of replying of aminoglutaric acid concentration.Expectation formula (I) compound is brought into play it to the effect of mGluR2 by the ability that it strengthens function of receptors basically.Utilize following be suitable for identifying these compounds (more specifically saying the compound according to formula (I), as shown in table 4) [ 35S] GTP γ S detects positive allosteric modulators to the characteristic of mGluR2 in conjunction with measuring method.
[ 35 S] GTP γ S is in conjunction with test
[ 35S] GTP γ S is in conjunction with being a kind of function test based on film, its be used for by measuring the non-hydrolysable form of introducing GTP namely [ 35S] and GTP γ S (5 '-GTP (guanosine triphosphate), gamma-ray with radiating 35The S mark) and research g protein coupled receptor (GPCR) function.G protein alpha subunit passes through the transformation of GTP (guanosine triphosphate) (GTP) catalysis 5 '-guanosine diphosphate (GDP) (GDP), and by agonist activation GPCR the time, [ 35S] thus GTP γ S is introduced into and can not cleavedly can not continue described transition loop (Harper (1998) Current Protocols inPharmacology2.6.1-10, John Wiley﹠amp; Sons, Inc.).Radioactivity [ 35S] binding capacity of GTP γ S is the direct observed value of G protein-active, therefore can measure the activity of agonist.The mGluR2 acceptor demonstrates preferred and G α i albumen coupling, be preferred for the coupling of this method, therefore and it is widely used in the receptor activation of mGluR2 acceptor in research recombinant cell lines and the tissue (Schaffhauser etc. 2003, Pinkerton etc. 2004, Mutel etc. (1998) Journal ofNeurochemistry.71:2558-64; Schaffhauser etc. (1998) MolecularPharmacology53:228-33).In this article, we described [ 35S] GTP γ S regulates the purposes of (PAM) character in conjunction with test for detection of the positivity allosteric of the compounds of this invention, described [ 35S] GTP γ S is used to cytolemma from the transfection of employment mGluR2 acceptor in conjunction with test, and this test is from ((2003) Molecular Pharmacology4:798-810) such as Schaffhauser and adjust.
The preparation of film
Cultivate Chinese hamster ovary celI to pre-full scale (pre-confluence), butyrates with 5mM before cleaning in PBS stimulated 24 hours, then in homogenate buffer (50mM Tris-HCl damping fluid, pH7.4,4 ℃), collect by smashing (scrap).Utilize the ultra-turrax homogenizer with the of short duration homogenate of cell lysate (15 seconds).With homogenate with centrifugal 10 minutes of 23500 * g and supernatant discarded.Again be suspended among the 5mM Tris-HCl (pH7.4) agglomerate and recentrifuge (30000 * g, 20 minutes, 4 ℃).Final agglomerate is suspended among the 50mM HEPES (pH7.4) again, and before using, is stored in-80 ℃ with suitable equal portions.Take bovine serum albumin as standard substance, measure protein concentration by Bradford method (Bio-Rad, USA).
[ 35S] GTP γ S is in conjunction with test
Utilize freezing film (carrying out preincubate (15 μ g/ test holes, 30 minutes, 30 ℃) in 96 hole microwell plates thaws and of short duration homogenate before) at assay buffer (50mM HEPESpH7.4,100mM NaCl, 3mM MgCl 2, 50 μ M GDP, 10 μ g/ml saponin(es) in contain the mensuration of the mGluR2 positive allosteric modulators in the film of people mGluR2, contain the L-glutamic acid (PAM method) of the positive allosteric modulators of high density (from 0.3nM to 50 μ M) more and more or minimum preliminary assay concentration in the wherein said damping fluid or do not add L-glutamic acid.For the PAM method, with film and EC 25The L-glutamic acid of concentration (namely providing the concentration of the L-glutamic acid that 25% maximum replys) is hatched together in advance, and with disclosed data consistent (Pin etc. (1999) Eur.J.Pharmacol.375:277-294).Add [ 35S] GTP γ S (0.1nM, f.c.) with the total reaction volume that reaches 200 μ l after, with microwell plate is of short duration shakes and further hatch to allow to introduce when (30 minutes, 30 ℃) in activation [ 35S] GTP γ S.By at glass fibre filter plate (Unifilter96 hole GF/B filter plate, Perkin-Elmer, Downers Grove, USA) use 96 orifice plate cell harvestor (Filtermate on the microwell plate, Perkin-Elmer, USA) carry out fast vacuum and filter, then pass through with the freezing cleaning buffer solution (Na of 300 μ l 2PO 4.2H 2O10mM, NaH 2PO 4.H 2O10mM, pH=7.4) clean three times and stopped reaction.Then strainer is dried, and add 40 μ l liquid scintillation solutions (liquid scintillation cocktail) (Microscint-O) to every hole, and 96 holes flickers plate readout instruments (Top-Count, Perkin-Elmer, USA) upper measure membrane-bound [ 35S] GTP γ S.In the situation that has the cold GTP of 10 μ M, measure nonspecific [ 35S] GTP γ S combination.The double sample of each data point of utilization under 11 concentration creates every curve, and every curve creates at least one times.
Data analysis
There is the EC that adds 25MGluR2 agonist L-glutamic acid regulate in the situation of (PAM) to measure the positivity allosteric, utilize Prism GraphPad (Graph Pad Inc, San Diego, USA) software to produce the concentration-response curve of representative compounds of the present invention.Fitting of a curve is become four parameter logical equatiions (Y=bottom+(top-bottom)/(1+10^ ((LogEC 50-X) * Hill slope), so that can measure EC 50Value.
Table 8.The pharmacology data of the compounds of this invention
At predetermined EC 25Under the existence of the mGluR2 agonist L-glutamic acid of concentration, all compounds are tested to measure positivity allosteric regulating effect (GTP γ S-PAM).Institute's indicating value is the mean value from the paired value of 11 concentration-response curves of at least one experiment.All compounds all demonstrate the pEC greater than 5.0 50Value is from 5.1 (weak activity) to 7.6 (high activity).For single experiment, pEC 50The measuring error of value is estimated as about 0.3 log unit.
Figure G2007800092105D01411
Figure G2007800092105D01421
Figure G2007800092105D01431
Figure G2007800092105D01471
Compound number GTPgS-hR2 PAM pEC 50
1-108 5.2
5-011 5.2
2-019 5.2
1-173 5.2
5-030 5.2
5-031 5.2
1-244 5.2
4-024 5.2
3-007 5.2
2-027 5.2
1-061 5.2
2-009 5.2
5-002 5.2
1-062 5.2
1-084 5.1
1-050 5.1
5-010 5.1
1-127 5.1
1-098 5.1
1-181 5.1
1-281 5.1
1-222 5.1
1-235 5.1
5-029 5.1
1-129 5.1
1-229 5.1
1-213 5.1
3-011 5.1
E. composition embodiment
Used " activeconstituents " (a.i.) refers to final compound, its pharmaceutically acceptable acid additive salt or base addition salt, its stereochemistry heterogeneous forms, its N oxide form, its quaternary ammonium salt and the prodrug thereof of formula (i) among all these embodiment.
The exemplary embodiments of preparation prescription of the present invention is as follows:
1. tablet
Activeconstituents 5～50mg
Si Liaodengji dicalcium phosphate feed grade 20mg
Lactose 30mg
Talcum 10mg
Magnesium Stearate 5mg
Yam starch adds to 200mg
In the present embodiment, activeconstituents can substitute with of the present invention any compound of same amount, particularly any exemplary compound of same amount.
2. suspensoid
For the preparation of Orally administered water suspension, so that per 1 milliliter of a kind of active compound, 50mg Xylo-Mucine, 1mg Sodium Benzoate, 500mg sorb alcohol and water (adding to 1ml) that contains 1～5mg.
3. injection
By being stirred, the activeconstituents of the present invention of 1.5% (by weight) prepares the parenteral composition in the propylene glycol of 10% (by volume) and water.
4. ointment
Activeconstituents 5～1000mg
Stearyl alcohol 3g
Lanolin 5g
White vaseline 15g
Water adds to 100g
In the present embodiment, activeconstituents can substitute with of the present invention any compound of same amount, particularly any exemplary compound of same amount.
Reasonably changing not is to be considered as deviating from scope of the present invention.The present invention that can change in many ways description like this will be apparent to those skilled in the art.

Claims (34)

1. the compound of general formula (I), its pharmaceutically acceptable acid additive salt or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form or its quaternary ammonium salt,
Figure FSB00000894325100011
Wherein,
V 1Be selected from the alkyl of saturated or unsaturated, straight or branched of 1～6 carbon atom of covalent linkage and divalence;
M 1Be selected from hydrogen, ring C 3-7Alkyl, aryl, alkyl-carbonyl, alkoxyl group, aryloxy, alkoxy aryl, aryl carbonyl, six hydrogen thiapyran bases, furyl and Het 1
L be selected from covalent linkage ,-O-,-OCH 2-,-OCH 2CH 2-,-OCH 2CH 2O-,-OCH 2CH 2OCH 2-,-S-,-NR 7-,-NR 7CH 2-,-NR 7Ring C 3-7,-NR 7CH 2CH 2-,-OCH 2CH 2N (R 7) CH 2-,-CH 2-,-CH 2CH 2-,-CH 2CH 2CH 2,-C ≡ C-,-C=O-and-C (R 8)=C (R 9)-, be each R wherein 7Be independently from each other hydrogen and C 1-3Alkyl, wherein R 8And R 9Be independently from each other hydrogen, halogen and C 1-3Alkyl;
R 2And R 3Be hydrogen, halogen or alkyl separately independently of one another;
A is selected from piperazinyl and piperidyl, and wherein each group is randomly by n radicals R 4Replace, wherein n equals 0,1,2 or 3 integer;
R 4Be selected from halogen, cyano group, hydroxyl, oxo, formyl radical, ethanoyl, carboxyl, nitro, sulfo-, alkyl, alkoxyl group, alkoxyalkyl, alkoxy carbonyl, alkoxy carbonyl alkyl, alkyl-carbonyl, alkyl-carbonyl oxygen base, alkyl-carbonyl alkoxyl group, many halogen C 1-3Alkyl, many halogen C 1-3Alkoxyl group, many halogen C 1-3Alkylthio, alkylthio, alkyl sulphonyl, Het 3, Het 3-alkyl, Het 3-oxygen base, Het 3-oxyalkyl, Het 3-alkoxyl group, Het 3-oxygen alkoxyl group, Het 3-carbonyl, Het 3-carbonylic alkyl, Het 3-sulfenyl, Het 3-sulfanyl, Het 3-alkylsulfonyl, aryl, arylalkyl, aryloxy, aromatic yloxy yl alkyl, alkoxy aryl, aryl alkenyl, aryl alkyl carbonyl, sulfur alkyl aryl, aryl sulfonyl ,-NR aR b, alkyl-NR aR b, O-alkyl-NR aR b,-C (=O)-NR aR b,-C (=O)-alkyl-NR aR bWith O-alkyl-C (=O)-NR aR b, R wherein aAnd R bBe selected from hydrogen, alkyl, alkyl-carbonyl, arylalkyl, alkoxyalkyl, Het 3, Het 3-alkyl, alkyl sulphonyl, alkyl-NR cR dAnd C (=O) alkyl-NR cR d, R wherein cAnd R dBe selected from hydrogen, alkyl and alkyl-carbonyl;
Perhaps two radicals R 4Can be in conjunction with forming divalent group-X 1-C 1-6-X 2-, C wherein 1-6Saturated or unsaturated, the straight or branched alkyl of 1～6 carbon atom, and X 1And X 2Be O or NH independently of one another; Wherein said divalent group randomly is selected from following one or more group and is replaced: halogen, many halogen C 1-3Alkyl, cyano group, hydroxyl, amino, oxo, carboxyl, nitro, sulfo-, formyl radical and ethanoyl;
Het 1Be selected from THP trtrahydropyranyl and pyridyl, wherein each group is randomly replaced by 1,2 or 3 substituting group, and described each substituting group is independently from each other halogen, C 1-3Alkyl, many halogen C 1-3Alkyl, many halogen C 1-3Alkoxyl group, cyano group, hydroxyl, amino, oxo, carboxyl, nitro, sulfo-, formyl radical, ethanoyl and C 1-3Alkoxyl group;
Het 3Be selected from pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, piperidyl, pyrryl, pyrrolidyl, piperazinyl, triazolyl, tetrazyl, indyl, thienyl, furyl, THP trtrahydropyranyl, tetrahydric thiapyran-1,1-dioxide, thiazolyl, thiadiazolyl group, isothiazolyl,
Figure FSB00000894325100021
Azoles base, morpholinyl, Di azoly, different
Figure FSB00000894325100023
Azoles base, imidazolyl, pyrazolyl, benzimidazolyl-, benzo
Figure FSB00000894325100024
Azoles base, benzothienyl, benzothiazolyl, benzofuryl, benzo morpholinyl, 1,2,3,4-tetrahydro isoquinolyl, sulfo-naphthyl, indyl, indolinyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzo [1,3] two
Figure FSB00000894325100025
Alkyl and quinazolyl; Wherein each group is randomly replaced by 1,2 or 3 substituting group, and described substituting group is independently from each other halogen, C 1-6Alkyl, many halogen C 1-3Alkyl, cyano group, hydroxyl, amino, oxo, carboxyl, nitro, sulfo-, formyl radical, ethanoyl, phenyl, pyrrolidyl, piperidyl, pyridyl, morpholinyl, list (alkyl) amino and two (alkyl) amino and C 1-3Alkoxyl group;
Aryl is naphthyl, phenyl or xenyl, and wherein each group is randomly replaced by 1,2 or 3 substituting group, and described each substituting group is independently from each other halogen, C 1-3Alkyl, many halogen C 1-3Alkyl, many halogen C 1-3Alkoxyl group, cyano group, hydroxyl, amino, oxo, carboxyl, nitro, sulfo-, formyl radical, ethanoyl, ethoxy carbonyl and C 1-3Alkoxyl group;
Alkyl is the saturated straight or branched alkyl with 1～6 carbon atom, or has a saturated cyclic of 3～7 carbon atoms, or the saturated hydrocarbyl of 4～12 carbon atoms, it comprises at least one saturated straight or branched alkyl with 1～6 carbon atom and at least one has the saturated cyclic of 3～7 carbon atoms; Wherein each carbon atom optionally is selected from following one or more group and is replaced: halogen, many halogen C 1-3Alkyl, cyano group, hydroxyl, amino, oxo, carboxyl, nitro, sulfo-, formyl radical, ethanoyl, formamyl, phenyl and divalent group-OCH 2CH 2O-; With
Thiazolinyl is the alkyl that contains in addition one or more pairs of keys.
2. according to claim 1 compound is characterized in that V 1Be selected from covalent linkage ,-CH 2-,-CH 2-CH 2-,-CH 2-CH 2-CH 2-,-CH 2-CH=CH-,-CH 2-CH 2-CH 2-CH 2-,-CH 2-CH (CH 3)-CH 2-,-CH (CH 3)-CH 2-CH 2-CH 2-,-CH 2-CH (CH 3)-CH 2-CH 2-and-CH 2-CH 2-CH (CH 3)-CH 2-.
3. each compound is characterized in that M according to claim 1～2 1Be selected from hydrogen, ring C 3-7Alkyl, phenyl, xenyl, phenoxy group, benzyloxy, furyl and pyridyl; Wherein any one described group based on benzene randomly is selected from 1 to 3 following group and is replaced: halogen, C 1-3Alkyl, many halogen C 1-3Alkyl, many halogen C 1-3Alkoxyl group and C 1-3Alkoxyl group; And described ring C 3-7Alkyl is randomly by one or more halogens or many halogen C 1-3Alkyl replaces.
4. each compound is characterized in that V according to claim 1～2 1-M 1Be selected from-CH 2-CH 2-CH 2-CH 3,-CH 2-CH (CH 3)-CH 3,-CH (CH 3)-CH 2-CH 2-CH 3,-CH 2-CH (CH 3) CH 2-CH 3,-CH 2-CH 2-CH (CH 3)-CH 3Perhaps V 1Be selected from covalent linkage ,-CH 2-,-CH 2-CH 2-,-CH 2-CH 2-CH 2-and-CH 2-CH=CH-; And M 1Be selected from cyclopropyl, cyclopentyl, cyclohexyl, phenyl, xenyl, phenoxy group, benzyloxy, furyl and pyridyl; Wherein each is based on the group M of benzene 1Randomly being selected from 1 to 3 following group replaces: halogen, C 1-3Alkyl, many halogen C 1-3Alkyl, many halogen C 1-3Alkoxyl group and C 1-3Alkoxyl group.
5. each compound, wherein R according to claim 1～2 2And R 3Hydrogen or methyl independently of one another.
6. each compound according to claim 1～2, it is characterized in that L be selected from covalent linkage ,-O-,-OCH 2-,-OCH 2CH 2-,-OCH 2CH 2O-,-OCH 2CH 2OCH 2-,-NR 7-,-NR 7CH 2-,-NR 7Ring C 3-7,-OCH 2CH 2N (R 7) CH 2-,-CH 2CH 2-,-C ≡ C-,-C=O-and-CH=CH-, wherein each R 7Be independently from each other hydrogen and C 1-3Alkyl.
7. each compound is characterized in that R according to claim 1～2 4Be selected from halogen, cyano group, hydroxyl, ethanoyl, alkyl, alkoxyl group, alkoxyalkyl, alkoxy carbonyl, alkoxy carbonyl alkyl, alkyl-carbonyl, alkyl-carbonyl oxygen base, alkyl-carbonyl alkoxyl group, many halogen C 1-3Alkyl, many halogen C 1-3Alkoxyl group, many halogen C 1-3Alkylthio, alkylthio, alkyl sulphonyl, Het 3, Het 3Alkyl, Het 3-oxygen base, Het 3-oxyalkyl, Het 3-alkoxyl group, Het 3-oxygen alkoxyl group, Het 3-carbonyl, Het 3-sulfanyl, aryl, arylalkyl, aryloxy, aromatic yloxy yl alkyl, alkoxy aryl, aryl alkenyl, aryl alkyl carbonyl, aryl sulfonyl ,-NR aR b, alkyl-NR aR b, O-alkyl-NR aR b,-C (=O)-NR aR b,-C (=O)-alkyl-NR aR bWith O-alkyl-C (=O)-NR aR b, R wherein aAnd R bBe selected from hydrogen, alkyl, alkyl-carbonyl, arylalkyl, alkoxyalkyl, Het 3, Het 3-alkyl, alkyl sulphonyl, alkyl-NR cR dAnd C (=O) alkyl-NR cR d, R wherein cAnd R dBe selected from hydrogen, alkyl and alkyl-carbonyl;
Perhaps two radicals R 4Can be in conjunction with forming divalent group-X 1-C 1-6-X 2-, C wherein 1-6Saturated or unsaturated, the straight or branched alkyl of 1～6 carbon atom, and X 1And X 2Be O independently of one another.
8. each compound according to claim 1～2 is characterized in that two radicals R 4Can be selected from conjunction with formation-CH 2CH 2-O-,-O-CH 2-O-and-O-CH 2CH 2The divalent group of-O-.
9. according to claim 1 compound is characterized in that Het 1Be selected from THP trtrahydropyranyl and pyridyl, wherein each group Het 1Randomly by halogen C more than 1,2 or 3 1-3Alkyl substituent replaces.
10. each compound is characterized in that Het according to claim 1～2 3Be selected from pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, piperidyl, pyrrolidyl, piperazinyl, triazolyl, THP trtrahydropyranyl, tetrahydric thiapyran-1,1--dioxide, thiazolyl,
Figure FSB00000894325100041
Azoles base, morpholinyl, Di azoly, imidazolyl, benzo
Figure FSB00000894325100043
Azoles base, benzothienyl, benzofuryl, 1,2,3,4-tetrahydro isoquinolyl, indyl, indolinyl, phthalazinyl and benzo [1,3] two
Figure FSB00000894325100044
Alkyl; Wherein each group is randomly replaced by 1,2 or 3 substituting group, and described each substituting group is independently from each other halogen, C 1-6Alkyl, many halogen C 1-3Alkyl, cyano group, hydroxyl, oxo, ethanoyl, phenyl, pyrrolidyl, piperidyl, pyridyl, morpholinyl, list (alkyl) amino and two (alkyl) amino and C 1-3Alkoxyl group.
11. compound according to claim 1 is characterized in that:
V 1Be selected from covalent linkage ,-CH 2-,-CH 2-CH 2-,-CH 2-CH 2-CH 2-,-CH 2-CH=CH-,-CH 2-CH 2-CH 2-CH 2-,-CH 2-CH (CH 3)-CH 2-,-CH (CH 3)-CH 2-CH 2-CH 2-,-CH 2-CH (CH 3)-CH 2-CH 2-and-CH 2-CH 2-CH (CH 3)-CH 2-;
M 1Be selected from hydrogen, ring C 3-7Alkyl, phenyl, xenyl, phenoxy group, benzyloxy, furyl and pyridyl; Wherein each is based on the M of phenyl 1Randomly being selected from 1 to 3 following group replaces: halogen, C 1-3Alkyl, many halogen C 1-3Alkyl, many halogen C 1-3Alkoxyl group and C 1-3Alkoxyl group; And described ring C 3-7Alkyl is randomly by one or more halogens or many halogen C 1-3Alkyl replaces;
L be selected from covalent linkage ,-O-,-OCH 2-,-OCH 2CH 2-,-OCH 2CH 2O-,-OCH 2CH 2OCH 2-,-NR 7-,-NR 7CH 2-,-NR 7Ring C 3-7,-OCH 2CH 2N (R 7) CH 2-,-CH 2CH 2-,-C ≡ C-,-C=O-and-CH=CH-, wherein each R 7Be independently from each other hydrogen and C 1-3Alkyl;
R 2And R 3Hydrogen, halogen or alkyl independently of one another;
A is selected from piperazinyl and piperidyl, and wherein each described group is randomly by n radicals R 4Replace, wherein n equals 0 or 1 integer;
R 4Be selected from halogen, cyano group, hydroxyl, ethanoyl, alkyl, alkoxyl group, alkoxyalkyl, alkoxy carbonyl, alkoxy carbonyl alkyl, alkyl-carbonyl, alkyl-carbonyl oxygen base, alkyl-carbonyl alkoxyl group, many halogen C 1-3Alkyl, many halogen C 1-3Alkoxyl group, many halogen C 1-3Alkylthio, alkylthio, alkyl sulphonyl, Het 3, Het 3-alkyl, Het 3-oxygen base, Het 3-oxyalkyl, Het 3-alkoxyl group, Het 3-oxygen alkoxyl group, Het 3-carbonyl, Het 3-sulfanyl, aryl, arylalkyl, aryloxy, aromatic yloxy yl alkyl, alkoxy aryl, aryl alkenyl, aryl alkyl carbonyl, aryl sulfonyl ,-NR aR b, alkyl-NR aR b, O-alkyl-NR aR b,-C (=O)-NR aR b,-C (=O)-alkyl-NR aR bWith O-alkyl-C (=O)-NR aR b, R wherein aAnd R bBe selected from hydrogen, alkyl, alkyl-carbonyl, arylalkyl, alkoxyalkyl, Het 3, Het 3-alkyl, alkyl sulphonyl, alkyl-NR cR dAnd C (=O) alkyl-NR cR d, R wherein cAnd R dBe selected from hydrogen, alkyl and alkyl-carbonyl; Perhaps two radicals R 4Can be selected from conjunction with formation-CH 2CH 2-O-,-O-CH 2-O-and-O-CH 2CH 2The divalent group of-O-;
Het 1Be selected from THP trtrahydropyranyl and pyridyl, wherein each group Het 1Randomly by halogen C more than 1,2 or 3 1-3Alkyl substituent replaces;
Het 3Be selected from pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, piperidyl, pyrrolidyl, piperazinyl, triazolyl, THP trtrahydropyranyl, tetrahydric thiapyran-1,1-dioxide, thiazolyl,
Figure FSB00000894325100051
Azoles base, morpholinyl,
Figure FSB00000894325100052
Di azoly, imidazolyl, benzo Azoles base, benzothienyl, benzofuryl, 1,2,3,4-tetrahydro isoquinolyl, indyl, indolinyl, phthalazinyl and benzo [1,3] two
Figure FSB00000894325100054
Alkyl; Wherein each group is randomly replaced by 1,2 or 3 substituting group, and described each substituting group is independently from each other halogen, C 1-6Alkyl, many halogen C 1-3Alkyl, cyano group, hydroxyl, oxo, ethanoyl, phenyl, pyrrolidyl, piperidyl, pyridyl, morpholinyl, list (alkyl) amino and two (alkyl) amino and C 1-3Alkoxyl group;
Aryl is phenyl or xenyl, and wherein each group is randomly replaced by 1,2 or 3 substituting group, and described each substituting group is independently from each other halogen, C 1-3Alkyl, many halogen C 1-3Alkyl, many halogen C 1-3Alkoxyl group, cyano group, nitro, ethoxy carbonyl and C 1-3Alkoxyl group; With
Alkyl is the saturated straight or branched alkyl with 1～6 carbon atom, or has a saturated cyclic of 3～7 carbon atoms, or the saturated hydrocarbyl of 4～12 carbon atoms, it comprises at least one saturated straight or branched alkyl with 1～6 carbon atom and at least one has the saturated cyclic of 3～7 carbon atoms; Wherein each carbon atom optionally is selected from following one or more group and is replaced: cyano group, hydroxyl, carboxyl, formamyl, phenyl and divalent group-OCH 2CH 2O-.
12. compound according to claim 1, wherein said compound is selected from:
(compound 2-006), and
-3-cyano group-1-cyclopropyl methyl-4-(4-phenyl-piperidines-1-yl)-pyridine-2 (1H)-ketone
(compound 4-047).
13. according to claim 1 or 12 compound, it exists as optical isomer, and wherein said compound is racemic mixture or single optical isomer.
14. a pharmaceutical composition, its comprise the treatment significant quantity according to claim 1～13 in each compound and pharmaceutically acceptable carrier.
15. each compound is for the preparation of the purposes of medicine according to claim 1～13.
16. each compound or the pharmaceutical composition according to claim 14 purposes in the medicine of illness that comprises the people for the preparation for the treatment of or prevention Mammals according to claim 1～13, wherein said treatment or prevention are by the neuroregulation function influence of mGluR2 positive allosteric modulators.
17. each compound or pharmaceutical composition according to claim 14 be for the preparation for the treatment of or prevent, improve, control or alleviate purposes in the medicine of the risk that Mammals comprises various nervous disorders relevant with the L-glutamic acid dysfunction among the people and mental illness according to claim 1～13, wherein said treatment or prevent by the neuroregulation function influence of mGluR2 positive allosteric modulators.
18. according to claim 16 with 17 in each purposes, wherein said illness or disease are to be selected from following central nervous system disorders: anxiety disorder, mental disorder, personality disorder, illness, eating disorder, emotional handicap, migraine, epilepsy or convulsions disease that material is relevant, childhood illness, cognitive disorder, neurodegeneration, neurotoxicity and ischemic.
19. purposes according to claim 18, wherein said central nervous system disorders are to be selected from following anxiety disorder: phobia, general anxiety disorder (GAD), obsession (OCD), Phobias, posttraumatic stress disorder (PTSD).
20. purposes according to claim 19, wherein said phobia is selected from agoraphobia and social phobia.
21. purposes according to claim 18, wherein said central nervous system disorders are to be selected from following mental disorder: the mental illness that schizophrenia, paranoea, schizoaffective disorder, division sample obstacle and material are induced.
22. purposes according to claim 18, wherein said central nervous system disorders are to be selected from following personality disorder: compulsive personality disorder and schizophrenia sample, schizotypal disorder.
23. purposes according to claim 18, wherein said central nervous system disorders are to be selected from the following illness relevant with material: mental illness, amphetamine dependence, the Amphetamine that alcohol abuse, alcohol dependence, ethanol withdrawal, ethanol withdrawal delirium, alcohol are induced given up, cocaine dependence, Cocaine are given up, nicotine dependence, nicotine withdrawal, opioid dependency and opioid are given up.
24. purposes according to claim 18, wherein said central nervous system disorders are to be selected from following eating disorder: anorexia nervosa and bulimia nervosa.
25. purposes according to claim 18, wherein said central nervous system disorders are to be selected from following emotional handicap: the emotional handicap that two-phase obstacle I type and II type, circulation emotion disease, dysthymia disorders, dysthymic disorder and material are induced.
26. purposes according to claim 18, wherein said central nervous system disorders is migraine.
27. purposes according to claim 18, wherein said central nervous system disorders are to be selected from following epilepsy or convulsions disease: generalized nonconvulsive epilepsy, generalized convulsive epilepsy, petit mal status, epilepsy grand mal persistent state, with or without partial epilepsy, infantile spasm, the epilepsy partialis continua of consciousness damage.
28. purposes according to claim 18, wherein said childhood, illness was the moving obstacle of attention deficit/how.
29. purposes according to claim 18, wherein said central nervous system disorders are to be selected from following cognitive disorder: delirium, dementia and mild cognitive impairment.
30. purposes according to claim 29, wherein said central nervous system disorders are to be selected from following cognitive disorder: the persistence delirium that material is induced, because the dementia that causes of HIV disease, because the dementia that Huntington Chorea causes, because the persistence that dementia, alzheimer's disease type dementia and material that Parkinson's disease causes are induced is dull-witted.
31. purposes according to claim 18, wherein said central nervous system disorders is selected from anxiety, schizophrenia, migraine, dysthymia disorders and epilepsy.
32. each purposes according to claim 16～17, the EC of wherein said mGluR2 positive allosteric modulators 501 μ M or less.
33. compound according to claim 1～13 is for the preparation of the purposes in the tracer agent of imaging mGluR2 acceptor.
34. according to claim 1～13 each compound and mGluR2 ortho position agonist unite for the preparation of the treatment or the prevention Mammals comprise among the people such as the purposes in the medicine of the illness that each is quoted in the claim 16～29, wherein said treatment or the prevention by the neuroregulation function influence of mGluR2 allosteric modulators.
CN200780009210.5A 2006-03-15 2007-03-15 1,4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of MGLUR2-receptors Expired - Fee Related CN101400654B (en)

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M. Tutonda et al..DIELS-ALDER REACTIONS OF THE HETERODIENE SYSTEM IN 2(1H)-PYRAZINONES.《Tetrahedron Letters》.1986,第27卷(第22期),2509-2512. *
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