CN101591332A - Compound and application method thereof based on 4-phenyl-6-(2,2,2-three fluoro-1-phenyl ethoxies) pyrimidine - Google Patents

Compound and application method thereof based on 4-phenyl-6-(2,2,2-three fluoro-1-phenyl ethoxies) pyrimidine Download PDF

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CN101591332A
CN101591332A CNA2008101084530A CN200810108453A CN101591332A CN 101591332 A CN101591332 A CN 101591332A CN A2008101084530 A CNA2008101084530 A CN A2008101084530A CN 200810108453 A CN200810108453 A CN 200810108453A CN 101591332 A CN101591332 A CN 101591332A
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phenyl
amino
fluoro
pyrimidine
propionic acid
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CN101591332B (en
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阿罗基亚萨米·德瓦萨加亚拉伊
金海虹
史志才
阿肖克·图努里
王英
张成敏
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Desselay biomedical Co., Ltd
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Lexicon Genetics Inc
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Abstract

The invention discloses formula I compound, and the composition that comprises them, and they be used for the treatment of, prevention and/or management of disease or disorderly method.

Description

Compound and application method thereof based on 4-phenyl-6-(2,2,2-three fluoro-1-phenyl ethoxies) pyrimidine
Invention field
The present invention relates to compound, contain described compound compositions based on 4-phenyl-6-(2,2,2-three fluoro-1-phenyl ethoxies) pyrimidine, and the application in treatment, prevention and management of disease and illness.
Background technology
Neurotransmitter serotonin [serotonine (5-HT)] participates in a plurality of central nervous systems aspect of emotion control, and participates in regulating sleep, anxiety, excessive drinking, drug abuse, ingestion of food and sexual behaviour.In peripheral tissues, serotonin it is reported and involves the adjusting antiotasis, intestinal motility, first phase hemostasis and cell-mediated immune response.Walther, D.J. etc., Science299:76 (2003).
The biosynthetic rate-limiting step of enzyme tryptophan hydroxylase (TPH) catalysis serotonin.Two kinds of isoforms of TPH are in the news: TPH1, and it is in peripheral tissues, mainly express in stomach and intestine (GI) road; And TPH2, it is expressed in serotoninergic neuron.Referring to the same.Isoform TPH1 is by the tph1 genes encoding; TPH2 is by the tph2 genes encoding.Referring to the same.
Reported the mouse (" knock out mice ") of tph1 gene genetic disappearance.Under a kind of situation, mouse it is reported can express the serotonin of normal amount in the brain district at the serotonin of classics, but lacks serotonin in a large number in periphery.Referring to the same.Under another situation, the cardiomotility that knock out mice shows abnormality, this lacks owing to the periphery serotonin. F. etc., PNAS100 (23): 13525-13530 (2003).
Because serotonin participates in so many biological process, the medicine that influences 5-hydroxytryptamine receptor is usually with side effect.Therefore, needing new approach to treat is subjected to serotonin to influence, mediate or associated disease and disorder.
Summary of the invention
The present invention partly relates to formula I compound:
Figure A20081010845300171
And pharmacologically acceptable salt and solvate, wherein: A 1It is the optional heterocycle that replaces; Each R 1Be halogen independently, hydrogen, C (O) R A, OR A, NR BR C, S (O 2) R A, or optional alkyl, alkyl-aryl or the alkyl-heterocycle that replaces; R 2Be halogen independently, hydrogen, C (O) R A, OR A, NR BR C, S (O 2) R A, or optional alkyl, alkyl-aryl or the alkyl-heterocycle that replaces; R 3Be hydrogen, C (O) R A, C (O) OR A, or optional alkyl, alkyl-aryl, alkyl-heterocycle, aryl or the heterocycle that replaces; R 4Be hydrogen or optional alkyl, alkyl-aryl, alkyl-heterocycle, aryl or the heterocycle that replaces; Each R ABe hydrogen or optional alkyl, alkyl-aryl or the alkyl-heterocycle that replaces independently; Each R BBe hydrogen or optional alkyl, alkyl-aryl or the alkyl-heterocycle that replaces independently; Each R CBe hydrogen or optional alkyl, alkyl-aryl or the alkyl-heterocycle that replaces independently; And m is 1-4.
Particular compound suppresses TPH (for example, TPH1) activity.
The invention still further relates to pharmaceutical composition, and relate to the method for the treatment of, preventing and managing multiple disease and illness.
Description of drawings
Fig. 1 shows (S)-2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl isophthalic acid H-pyrazol-1-yl) phenyl)-2,2,2-trifluoro ethoxy) phenyl pyrimidine-4-yl)) ethyl propionate in the mouse jejunum to the dose-dependently influence of 5-HT level.This compound is 15%
Figure A20081010845300172
Solution in 15,50,150 and the 300mpk oral administration.
Fig. 2 shows the influence of (S)-2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl isophthalic acid H-pyrazol-1-yl) phenyl)-2,2,2-trifluoro ethoxy) pyrimidine-4-yl) phenyl) ethyl propionate oral administration to rat stomach and intestine (GI) mobility.Asterisk has identified when utilizing t check or single factor ANOVA check to compare with medium, the data of p＜0.01.
Fig. 3 shows the influence of (S)-2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl isophthalic acid H-pyrazol-1-yl) phenyl)-2,2,2-trifluoro ethoxy) pyrimidine-4-yl) phenyl) ethyl propionate oral administration to the rat stomach emptying.Asterisk has identified the data of p＜0.01 when utilizing t check or single factor ANOVA check to compare with medium.
Fig. 4 shows (S)-2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl isophthalic acid H-pyrazol-1-yl) phenyl)-2,2, the 2-trifluoro ethoxy) phenyl pyrimidine-4-yl)) the ethyl propionate oral administration is to the blood of rat 5-HT and the influence of proximal colonic level, and its data are presented among Fig. 1 and Fig. 2.Under two kinds of situations, utilize single factor ANOVA to be all p＜0.0001.
Summary of the invention
The present invention is partly based on following discovery: the tph1 gene of knock-out mice significantly reduces the level of GI 5-hydroxytryptamine, yet also very little if any on measurable impact of central nervous system (CNS).
The present invention is also based on to suppressing TPH (for example, TPH1) the discovery of compound. When being administered to mammal, the preferred compound of the present invention reduces the serotonin level, the pharmacokinetics that has and pharmacodynamic property be so that they can be actually used in treatment, prevention and management of disease and illness, and have wide safety limit between pharmacological action and toxicity or disadvantageous side reaction.
Definition
Except as otherwise noted, term " thiazolinyl " expression is with 2-20 (for example, 2-10 or 2-6) carbon atom and comprise straight chain, side chain and/or the cyclic hydrocarbon of the two keys of at least one C-C. Representative alkenyl part comprises vinyl, pi-allyl, 1-cyclobutenyl, 2-cyclobutenyl, isobutenyl, the 1-pentenyl, 2-pentenyl, 3-methyl-1-butene base, 2-methyl-2-butene base, 2,3-dimethyl-2-cyclobutenyl, 1-hexenyl, 2-hexenyl, the 3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, the 1-octenyl, 2-octenyl, 3-octenyl, 1-nonene base, 2-nonene base, 3-nonene base, 1-decene base, 2-decene base and 3-decene base.
Except as otherwise noted, term " alkyl " expression is with straight chain, side chain and/or ring-type (" the cycloalkyl ") hydrocarbon of 1-20 (for example, 1-10 or 1-4) carbon atom. Moieties with 1-4 carbon is called " low alkyl group ". The example of alkyl comprises methyl, ethyl, and propyl group, isopropyl, just-and butyl, tert-butyl, isobutyl group, amyl group, hexyl, isohesyl, heptyl, 4,4-dimethyl amyl group, octyl group, 2,2,4-tri-methyl-amyl, nonyl, decyl, undecyl and dodecyl. Cycloalkyl moiety can be monocycle or many rings, and its example comprises cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, and adamantyl. Other examples of moieties have straight chain, side chain and/or annulus (for example, 1-ethyl-4-methyl-cyclohexyl base). Term " alkyl " comprises saturated hydrocarbons, and thiazolinyl and alkynyl part.
Except as otherwise noted, term " alkoxyl group " expression-O-alkyl.The example of alkoxyl group comprises-OCH 3,-OCH 2CH 3,-O (CH 2) 2CH 3,-O (CH 2) 3CH 3,-O (CH 2) 4CH 3And-O (CH 2) 5CH 3
Except as otherwise noted, term " alkaryl " or " alkyl-aryl " expression and aryl moiety bonded moieties.
Except as otherwise noted, term " miscellaneous alkyl aryl " or " alkyl-heteroaryl " expression and heteroaryl moieties bonded moieties.
Except as otherwise noted, term " alkyl heterocycle " or " alkyl-heterocycle " expression and heterocyclic moiety bonded moieties.
Except as otherwise noted, term " alkynyl " expression has 2-20 (for example, 2-20 or 2-6) carbon atom and comprises at least one C-C triple-linked straight chain, side chain and/or cyclic hydrocarbon.Representative alkynyl partly comprises ethynyl, proyl, ethyl acetylene base, 2-butyne base, the 1-pentynyl, valerylene base, 3-methyl isophthalic acid-butynyl, 4-pentynyl, 1-hexin base, 2-hexin base, 5-hexin base, 1-heptyne base, 2-heptyne base, 6-heptyne base, 1-octyne base, 2-octyne base, 7-octyne base, 1-n-heptylacetylene base, 2-n-heptylacetylene base, 8-n-heptylacetylene base, 1-decynyl, 2-decynyl and 9-decynyl.
Except as otherwise noted, aromatic nucleus or aromatics or the partially aromatic loop systems be made up of carbon and hydrogen atom represented in term " aryl ".Aryl moiety can comprise a plurality of combinations or condense together ring.The example of aryl moiety comprises anthryl, Azulene base (azulenyl), xenyl, fluorenyl, indanyl, indenyl, naphthyl, phenanthryl, phenyl, 1,2,3,4-tetrahydrochysene-naphthalene, and tolyl.
Except as otherwise noted, term " aralkyl " or " aryl-alkyl " expression and moieties bonded aryl moiety.
Except as otherwise noted, term " but acid amides of biological hydrolysis ", " but the ester of biological hydrolysis " " but carbamate of biological hydrolysis ", " but the carbonic ether of biological hydrolysis ", " but the urea groups of biological hydrolysis " and " but phosphoric acid ester of biological hydrolysis " represents acid amides, ester, carbamate, carbonic ether, urea groups or the phosphoric acid ester of compound respectively, itself or: 1) do not disturb the biological activity of described compound, but can give this compound favourable body internal characteristic, such as picked-up, acting duration, or onset of effect; Perhaps 2) be biological non-activity, but change into bioactive compounds in vivo.But the example of the ester of biological hydrolysis comprises lower alkyl esters, alkoxyl group acyloxy ester, alkyl acyl aminoalkyl ester, and cholinesterase.But the example of the acid amides of biological hydrolysis comprises the low alkyl group acid amides, alpha-amino acid amides, alkoxyl group acyl group acid amides and alkylamino alkyl-carbonyl acid amides.But the carbamate of biological hydrolysis comprises low-grade alkylamine, the quadrol of replacement, amino acid, hydroxyalkyl amine, heterocyclic amine and assorted arylamine, and polyetheramine.
Except as otherwise noted, phrase " is subjected to the disease or the illness of the mediation of periphery serotonin " and " being subjected to the disease and the illness of the mediation of periphery serotonin " expression has the disease and/or the illness of one or more symptoms, and its seriousness is subjected to the influence of periphery serotonin level.
Except as otherwise noted, term " halogen " and " halo " comprise fluorine, chlorine, bromine, and iodine.
Except as otherwise noted, term " assorted alkyl " is meant moieties (for example, straight chain, side chain or ring-type), and wherein at least one carbon atom is substituted (for example, N, O or S) by heteroatoms.
Except as otherwise noted, term " heteroaryl " represents that wherein at least one carbon atom is by the aryl moiety of heteroatoms (for example, N, O or S) replacement.Example comprises acridyl, benzimidazolyl-, benzofuryl, benzisothiazole base, benzoisoxazole base, the Benzoquinazole base, benzothiazolyl, benzoxazolyl, furyl, imidazolyl, indyl, isothiazolyl ， isoxazolyl ， oxadiazole Ji ， oxazolyl, phthalazinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl (pyrimidinyl), pyrimidyl (pyrimidyl), pyrryl, quinazolyl, quinolyl, tetrazyl, thiazolyl, and triazinyl.
Except as otherwise noted, term " heteroaralkyl " or " heteroaryl-alkyl " expression and moieties bonded heteroaryl.
Except as otherwise noted, term " heterocycle " is meant the monocycle of the aromatics, partially aromatic or the non-aromatics that contain carbon, hydrogen and at least one heteroatoms (for example, N, O or S) or encircles or loop systems more.Heterocycle can comprise many (that is, the two or more) ring that condenses or combine.Heterocycle comprises heteroaryl.Example comprises benzo [1,3] dioxolyl, 2,3-dihydro-benzo [1,4] dioxine bases, cinnolines base, furyl, glycolylurea base, morpholinyl, oxetanyl, Oxyranyle, piperazinyl, piperidyl, pyrrolidone-base, pyrrolidyl, tetrahydrofuran base, THP trtrahydropyranyl, tetrahydro pyridyl, tetrahydro-pyrimidine base, tetrahydro-thienyl, tetrahydrochysene sulfo-pyranyl and Valerolactim base.
Except as otherwise noted, term " Heterocyclylalkyl " or " heterocycle-alkyl " are meant and moieties bonded heterocyclic moiety.
Except as otherwise noted, term " Heterocyclylalkyl " is meant non-aromatic heterocyclic.
Except as otherwise noted, term " Heterocyclylalkyl alkyl " or " Heterocyclylalkyl-alkyl " are meant and moieties bonded Heterocyclylalkyl part.
Except as otherwise noted, term " management " is included in suffers from the recurrence that prevents described disease or disorder or its one or more symptoms among the patient who specifies disease or disorder, and/or the time that prolongation has suffered from described disease or disorderly patient keeps improvement.Described term comprises regulates described disease or disorderly beginning, development and/or time length, or changes the patient to described disease or disorderly reactive mode.
Except as otherwise noted, term " pharmacologically acceptable salt " is meant from the salt of pharmaceutically useful non-toxic acid or alkali preparation, comprises inorganic bronsted lowry acids and bases bronsted lowry and organic bronsted lowry acids and bases bronsted lowry.Suitable pharmaceutically acceptable base addition salt comprises the metal-salt of making from aluminium, calcium, lithium, magnesium, potassium, sodium and zinc, or from Methionin, N, the organic salt that N '-dibenzyl-ethylenediamin, chloroprocaine, choline, diethanolamine, quadrol, meglumine (N-methylglucosamine) and PROCAINE HCL, PHARMA GRADE are made.Suitable non-toxic acid comprises inorganic and organic acid, such as acetate, and alginic acid, anthranilic acid, Phenylsulfonic acid, phenylformic acid, camphorsulfonic acid, citric acid, vinyl sulfonic acid (ethenesulfonic), formic acid, fumaric acid, furancarboxylic acid, galacturonic acid, glyconic acid, glucuronic acid, L-glutamic acid, oxyacetic acid, Hydrogen bromide, hydrochloric acid, isethionic acid, lactic acid, toxilic acid, oxysuccinic acid, amygdalic acid, methylsulfonic acid, glactaric acid, nitric acid is pounced on acid (pamoic), pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, Whitfield's ointment, stearic acid, succsinic acid, sulfanilic acid, sulfuric acid, tartrate, and tosic acid.Concrete non-toxic acid comprises hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid, and methylsulfonic acid.And then the example of concrete salt comprises hydrochloride and mesylate (mesylatesalts).Other are well known in the art.Referring to, for example, Remington ' sPharmaceutical Sciences, 18 ThEd. (Lei Shi pharmaceutical science, the 18th edition) (MackPublishing, Easton PA:1990) and Remington:The Science and Practice ofPharmacy, 19 ThEd. (Lei Shi medicament science and practice, the 19th edition) (Mack Publishing, Easton PA:1995).
Except as otherwise noted, term " effectively TPH1 inhibitor " is meant TPH1_IC 50Compound less than about 10 μ M.
Except as otherwise noted, term " prevents from " to be intended to the patient and begins to suffer from the effect that takes place before disease or the illness of specifying, its inhibition or reduce described disease or the seriousness of disorder or its one or more symptoms.This term comprises prevention.
Except as otherwise noted, term " prodrug " comprises the pharmaceutically acceptable ester of compound disclosed herein, carbonic ether, thiocarbonic ester; the N-acyl derivative, N-acyloxy alkyl derivative, the quaternary ammonium derivative of tertiary amine, N-Mannich base; Schiff's base, amino acid conjugate, phosphoric acid ester, metal-salt and sulphonate.But the example of prodrug comprise the compound that contains biological hydrolysis part (for example, but the acid amides of biological hydrolysis, but the carbamate of biological hydrolysis, but the carbonic ether of biological hydrolysis, but the ester of biological hydrolysis, but the phosphoric acid ester of biological hydrolysis, but or the uride analogue of biological hydrolysis).The prodrug of compound disclosed herein is expected by those of ordinary skills easily and is prepared.Referring to, for example, Design of Prodrugs (prodrug design), Bundgaard, A.Ed., Elseview, 1985; Bundgaard, H., " Design and Application of Prodrugs (prodrug design and application) ", A Textbook of Drug Design and Development (establish by medicine Meter and exploitation textbook), Krosgaard-Larsen and H.Bundgaard write, 1991, the 5 chapters, 113-191 page or leaf; And Bundgaard, H., Advanced Drug Delivery Review (advanced drug delivery summary), 1992,8,1-38.
Except as otherwise noted, " the prevention significant quantity " of compound is to be enough to preventing disease or illness or one or more symptom relevant with this disease or illness or the amount of preventing its recurrence.The prevention significant quantity of compound be therapeutical agent separately or with the amount of other medicaments combinations, this amount provides the prevention benefit in disease prevention.Term " prevention significant quantity " can comprise the amount that improves whole prevention or strengthen the prevention effects of another preventive.
Except as otherwise noted; term " protecting group " or " protectiveness group "; when being used in reference to the molecular moiety that carries out chemical reaction, being illustrated in the chemical part that does not react under the condition of this chemical reaction, and can being removed the part of reacting under those conditions to be provided at.Protecting group is well known in the art.Referring to, for example, Greene, T.W. and Wuts, P.G.M., Protective Groups in Organic Synthesis(protecting group in the organic synthesis) (third edition., John Wiley; Sons:1999); Larock, R.C., Comprehensive Organic Transformations (comprehensive organic transformation)(second edition, John Wiley ﹠amp; Sons:1999).Some examples comprise benzyl, diphenyl methyl, trityl, Cbz, Boc, Fmoc, methoxycarbonyl, ethoxy carbonyl, and phthalimido.
Except as otherwise noted, term " pseudohalogen " is meant the polyatom negatively charged ion, at its acid-alkali, replacement and oxygen similar halide ions in the chemistry also, has low basicity usually, and form free radical under the atom transfer radical polymerization condition.The example of pseudohalogen comprises the trinitride ion, prussiate, cyanate, thiocyanate, thiosulphate, sulfonate, and sulfonic acid halide.
Except as otherwise noted, term " selectivity TPH1 inhibitor " is its TPH2_IC 50Than its TPH1_IC 50Greatly at least about 10 times compound.
Except as otherwise noted, " composition of stereoisomerism enrichment " of term compound is meant the mixture of name compound and steric isomer thereof, and the name compound that it contains is more than its steric isomer.For example, (S)-composition of the stereoisomerism enrichment of Ding-2-alcohol comprises that ratio is, for example, the mixture of about (S)-Ding-2-of 60/40,70/30,80/20,90/10,95/5 and 98/2 pure and mild (R)-Ding-2-alcohol.
Except as otherwise noted, term " three-dimensional heterogeneous mixture " comprises the mixture (for example, R/S=30/70,35/65,40/60,45/55,55/45,60/40,65/35 and 70/30) of racemic mixture and stereoisomerism enrichment.
Except as otherwise noted, term " stereoisomerism is pure " expression composition contains a kind of steric isomer of compound, and is substantially free of other steric isomers of this compound.For example, the pure composition of stereoisomerism with the compound at a three-dimensional center is substantially free of the relative steric isomer of this compound.The pure composition of stereoisomerism with the compound at two three-dimensional centers is substantially free of other diastereomers of this compound.The pure composition of steric isomer with the compound at a plurality of three-dimensional centers, but the mode of its drafting or name has defined the stereochemistry that is less than all three-dimensional centers, it is substantially free of the isomer of this compound, and these isomer have different stereochemistry at the three-dimensional center of stereochemistry definition.For example, " stereoisomerism pure ((1R)-1,2-two chloropropyls) benzene " is meant ((1R)-1, the 2-two chloropropyls) benzene that is substantially free of ((1S)-1,2-two chloropropyls) benzene.
Typical stereoisomerism pure compound comprises greater than a kind of steric isomer of this compound of about 80 weight % with less than other steric isomers of this compound of about 20 weight %, greater than a kind of steric isomer of this compound of about 90 weight % with less than other steric isomers of this compound of about 10 weight %, greater than a kind of steric isomer of this compound of about 95 weight % with less than other steric isomers of this compound of about 5 weight %, greater than a kind of steric isomer of this compound of about 97 weight % with less than other steric isomers of this compound of about 3 weight %, or greater than a kind of steric isomer of this compound of about 99 weight % with less than other steric isomers of this compound of about 1 weight %.
Except as otherwise noted, term " replacement " is when being used for represent chemical structure or part, be meant the derivative of this structure or part, wherein one or more hydrogen atoms are replaced by atom, chemical part or functional group, such as, but be not limited to, alcohol, aldehyde, alkoxyl group, alkanoyloxy, alkoxy carbonyl, thiazolinyl, alkyl are (for example, methyl, ethyl, propyl group, tert-butyl), alkynyl, alkyl-carbonyl oxygen base (OC (O) alkyl), acid amides (C (O) NH-alkyl-or-alkyl NHC (O) alkyl), amidino groups (C (NH) NH-alkyl or-C (NR) NH 2), amine (the primary, the second month in a season and tertiary amine, such as alkylamino, arylamino, aryl alkyl amino), aroyl, aryl, aryloxy, azo-group, formamyl (NHC (O) O-alkyl-or-OC (O) NH-alkyl), carbamyl (for example, CONH 2, and the CONH-alkyl, CONH-aryl, and CONH-aralkyl), carbonyl, carboxyl, carboxylic acid, carboxylic acid anhydride, carboxyl acyl chloride, cyano group, ester, epoxide, ether (for example, methoxyl group, oxyethyl group), guanidine radicals, halo, haloalkyl (for example ,-CCl 3,-CF 3,-C (CF 3) 3), assorted alkyl, hemiacetal, imines (primary and secondary imines), isocyanic ester, lsothiocyanates, ketone, nitrile, nitro, oxygen (that is, providing the oxygen base), phosphodiester, sulfide, sulphonamide (for example, SO 2NH 2), sulfone, sulphonyl (comprising alkyl sulfonyl, arylsulfonyl and aralkyl sulphonyl), sulfoxide, mercaptan (for example, sulfydryl, thioether) and urea (NHCONH-alkyl-).
Except as otherwise noted, " the treatment significant quantity " of compound amount for being enough in treatment or management of disease or illness, to provide the treatment benefit or postponing or minimize one or more symptoms relevant with described disease or illness.The treatment significant quantity of compound be therapeutical agent separately or with the amount of other therapies combinations, it provides the treatment benefit in treatment or management of disease or illness.Term " treatment significant quantity " can comprise the symptom or the cause of disease of improving wholistic therapy, reduce or avoid disease or illness or the amount that strengthens the therapeutic efficiency of another therapeutical agent.
Except as otherwise noted, term " TPH1_IC 50" be the IC of compound to TPH1 50, utilize the hereinafter described vitro inhibition analysis of embodiment to determine.
Except as otherwise noted, term " TPH2_IC 50" be the IC of compound to TPH2 50, utilize the hereinafter described vitro inhibition analysis of embodiment to determine.
Except as otherwise noted, term " treatment " is intended to the patient and is just suffering from the effect that takes place when specifying disease or disorder, and it reduces the seriousness of described disease or disorder or its one or more symptoms, or hinders or slow down the progress of described disease or disorder.
Except as otherwise noted, term " comprises " with " including, but are not limited to " having the identical meaning.Equally, term " such as " with " such as, but be not limited to " an identical meaning had.
Except as otherwise noted, being right after one or more adjectives before a series of nouns is construed to and is applicable to each noun.For example, phrase " optional alkyl, aryl or the heteroaryl that replaces " has the identical meaning with " the optional alkyl that replaces, the optional aryl that replaces, or the optional heteroaryl that replaces ".
It should be noted, form the chemical part than the part of large compound, the title that gives its title in the time of can utilizing it to exist with individual molecule usually or give its group is usually described at this.For example, term " pyridine " and " pyridyl " when being used to describe with part that other chemical parts are connected, give the identical meaning.Therefore, two phrases " XOH, wherein X is a pyridyl " and " XOH, wherein X is a pyridine " give the identical meaning, and comprise compound pyridine-2-alcohol, the pure and mild pyridine of pyridine-3--4-alcohol.
It shall yet further be noted that as the stereochemistry of the part of fruit structure or structure and do not indicate with for example thick line or dotted line that then the part of this structure or this structure is interpreted into and comprises its all steric isomers.Equally, have one or more chiral centres but do not specify the stereochemical compound title at described center to comprise pure stereoisomers and composition thereof.And the unsatisfied valent any atom that has shown in the figure is assumed to be and is connected to enough hydrogen atoms to satisfy valency.In addition, the chemical bond of describing with a solid line and a parallel dotted line comprises single and two (for example, aromatics) key, if valency allows.
Compound
The present invention especially comprises formula I compound:
And pharmacologically acceptable salt and solvate, wherein: A 1It is the optional heterocycle that replaces; Each R 1Be halogen independently, hydrogen, C (O) R A, OR A, NR BR C, S (O 2) R A, or optional alkyl, alkyl-aryl or the alkyl-heterocycle that replaces; R 2Be halogen independently, hydrogen, C (O) R A, OR A, NR BR C, S (O 2) R A, or optional alkyl, alkyl-aryl or the alkyl-heterocycle that replaces; R 3Be hydrogen, C (O) R A, C (O) OR A, or optional alkyl, alkyl-aryl, alkyl-heterocycle, aryl or the heterocycle that replaces; R 4Be hydrogen or optional alkyl, alkyl-aryl, alkyl-heterocycle, aryl or the heterocycle that replaces; Each R ABe hydrogen or optional alkyl, alkyl-aryl or the alkyl-heterocycle that replaces independently; Each R BBe hydrogen or optional alkyl, alkyl-aryl or the alkyl-heterocycle that replaces independently; Each R CBe hydrogen or optional alkyl, alkyl-aryl or the alkyl-heterocycle that replaces independently; And m is 1-4.
In one embodiment, the formula of described compound is:
Figure A20081010845300272
In another embodiment, its formula is:
Or
Figure A20081010845300282
Wherein: each R 5Be halogen independently, hydrogen, C (O) R A, OR A, NR BR C, S (O 2) R A, or optional alkyl, alkyl-aryl or the alkyl-heterocycle that replaces; And n is 1-3.
In another embodiment, its formula is:
Figure A20081010845300283
Or
Figure A20081010845300291
Wherein: each R 5Be halogen independently, hydrogen, C (O) R A, OR A, NR BR C, S (O 2) R A, or optional alkyl, alkyl-aryl or the alkyl-heterocycle that replaces; And p is 1-4.
In another embodiment, its formula is:
Figure A20081010845300292
Wherein: each R 5Be halogen independently, hydrogen, C (O) R A, OR A, NR BR C, S (O 2) R A, or optional alkyl, alkyl-aryl or the alkyl-heterocycle that replaces; And q is 1-2.
In another embodiment, its formula is:
Figure A20081010845300293
Or
Figure A20081010845300302
Wherein: each R 5Be halogen independently, hydrogen, C (O) R A, OR A, NR BR C, S (O 2) R A, or the optional alkyl that replaces, alkyl-aryl or alkyl-heterocycle; And q is 1-2.
About multiple formula, especially The compounds of this invention disclosed herein, A 1Be aromatic.In other, A 1Not aromatic.In some, A 1Optional with one or more hydrogen or low alkyl group replacement.
In some, R 1It is hydrogen or halogen.
In some, m is 1.
In some, R 2Be hydrogen or amino.
In some, R 3Be hydrogen or low alkyl group.In other, R 3Be C (O) OR AAnd R AIt is alkyl.
In some, R 4Be hydrogen or low alkyl group.
In some, R 5Be hydrogen or low alkyl group (for example, methyl).
In some, n is 1.
In some, p is 1.
In some, q is 1.
The composition of pure compound of stereoisomerism and stereoisomerism enrichment thereof is contained in the present invention.Steric isomer can utilize standard technique, and such as chiral column, chirality is resolved agent, or enzymolysis is analysed and by asymmetric synthesis or parsing.Referring to, for example, Jacques, J. etc., Enantiomers, Racematesand Resolutions (enantiomorph, racemic modification and parsing) (Wiley Interscience, NewYork, 1981); Wilen, S.H. etc., Tetrahedron (tetrahedron) 33:2725 (1977); Eliel, E.L., Stereochemistry of Carbon Compounds (stereochemistry of carbon compound) (McGraw Hill, NY, 1962); And Wilen, S.H., Tables of ResolvingAgents and Optical Resolutions (resolving agent and light resolution table), p.268 (E.L.Eliel compiles, Univ.of Notre Dame Press, Notre Dame, IN, 1972).
Particular compound of the present invention is effective TPH1 inhibitor.The TPH1_IC of particular compound 50Less than about 10,5,2.5,1,0.75,0.5,0.4,0.3,0.2,0.1, or 0.05 μ M.
Particular compound is a selectivity TPH1 inhibitor.The TPH1_IC of particular compound 50Than its TPH2_IC 50Want little about 10,25,50,100,250,500, or 1000 times.
Particular compound does not significantly suppress human tyrosine hydroxylase (TH).For example, particular compound is to the IC of TH 50Greater than about 100,250,500 or 1000 μ M.
Particular compound does not significantly suppress people's Phenylalanine hydroxylase (PAH).For example, particular compound is to the IC of PAH 50Greater than about 100,250,500 or 1000 μ M.
Particular compound of the present invention is significantly in conjunction with (for example, with greater than about 10,25,50,100,250,500,750, or the IC of 1000 μ M 50Suppress) to following one or more: Zinc metallopeptidase Zace1, erythropoietin (EPO) acceptor, factors IX, factor XI, plasma thromboplastin antecedent, integrin (for example, α 4) isoxazoline Huo isoxazole fibrinogen deceptor, metalloprotease, neutral endopeptidase (NEP), Phosphoric acid esterase (for example, tyrosine phosphatase), phosphodiesterase is (for example, PDE-4), polysaccharase, PPAR γ, TNF-α, vascular cell adhesion molecule-1 (VCAM-1), or Vitronectic receptor.Compound combines the approach well known described in the reference that the ability utilization of (for example, suppressing) quotes as mentioned with in these targets any, can easily determine.Particular compound of the present invention does not suppress cell adhesion.
When to Mammals (for example, mouse, rat, dog, monkey or people) administration, some compound of the present invention be difficult for crossing blood/brain barrier (for example, in the blood less than about 5,2.5,2,1.5,1,0.5, or 0.01% compound enters brain).Compound can maybe can not be crossed blood/brain barrier and can determine by means commonly known in the art.Referring to, for example, Riant, P. etc., Journal of Neurochemistry51:421-425 (1988); Kastin, A.J., Akerstrom, V., J. Pharmacol.Exp.Therapeutics294:633-636 (2000); W.A.Banks, W.A. etc., J.Pharmacol.Exp.Therapeutics302:1062-1069 (2002).
Synthesizing of compound
The compounds of this invention can prepare with method described herein by means commonly known in the art.
For example, formula I compound can prepare shown in synthetic route I:
Figure A20081010845300331
Synthetic route 1
P wherein 1Be R 1Or protecting group; P 2It is protecting group; P 3Be OR 2Or protecting group; Y 1And Y 3Be halogen (for example, Br, Cl) or suitable pseudohalide (for example, fluoroform sulphonate (triflate)); And each group A 1, R 1, R 2, and R 3Define in this paper elsewhere.
The compounds of this invention also can be prepared by the approach shown in the following synthetic route 2:
Figure A20081010845300341
Synthetic route 2
Single reaction shown in the said synthesis route can utilize condition well known in the art to carry out.For example, the Suzuki link coupled palladium catalyst and the condition that are suitable for boron and halogen-containing part are well-known, and example provides hereinafter.In addition, the type of protecting group and suitable purposes are well-known, and be the same by the method for removing such as but not limited to the part of hydrogen and replace (for example, hydrolysis under acidity or alkaline condition) as it.
The method of the ester derivative utilization of The compounds of this invention shown in following synthetic route 3 can easily prepare:
Figure A20081010845300351
Synthetic route 3
Utilize method well known in the art, above-mentioned route of synthesis is easily made amendment, to obtain the compound of wide region.For example, chiral chromatography well known in the art and other technologies can be used for separating the steric isomer of end product.Referring to, for example, Jacques, J. etc., Enantiomers, Racemates and Resolutions(enantiomorph, racemic modification and parsing) (WileyInterscience, New York, 1981); Wilen, S.H. etc., Tetrahedron (on four sides Body)33:2725 (1977); Eliel, E.L., Stereochemistry of Carbon Compounds(McGraw Hill, NY, 1962); And Wilen, S.H., Tables of Resolving Agents And Optical Resolutions (resolving agent and optics resolution table), p.268 (E.L.Eliel compiles, Univ.of Notre Dame Press, Notre Dame, IN, 1972).In addition, shown in some synthetic route, synthesize and to utilize chiral raw material as mentioned, generate stereoisomerism product enrichment or pure.
Application method
The present invention comprises the method that suppresses TPH, and this method comprises TPH and The compounds of this invention (that is compound disclosed herein) contact.In concrete grammar, TPH is TPH1.In other method, TPH is TPH2.In a concrete grammar, inhibition is a vitro inhibition.In another, inhibition is to suppress in the body.
A kind of embodiment comprises the method that suppresses Mammals (for example, the people) TPH1, and this method comprises to the administration The compounds of this invention.In concrete grammar, TPH2 is not significantly suppressed.In a method, described compound is not easy to cross blood/brain barrier.In other method, described compound is the selective depressant of TPH1.
The present invention comprises multiple disease and the disorderly method that treatment, prevention and management are subjected to the mediation of periphery serotonin, and this method comprises the patient's of this treatment of inhibition needs, prevention or management TPH1 activity.In specific embodiments, suppress to realize by effective TPH1 inhibitor of giving patient's administering therapeutic or prevention significant quantity.Effectively the example of TPH1 inhibitor is open at this.
Disease specific and disorder comprise carcinoid syndrome and gastrointestinal illness and disorder.Disease specific and disorderly example comprise abdominal pain (for example, relevant with Tiroidina medullary substance knurl), anxiety, carcinoid syndrome, coeliac disease, constipation is (for example, the constipation that causes because of doctor's treatment and specially send out the property constipation), Crohn disease, melancholia, diabetes, diarrhoea is (for example, bile acide diarrhoea, enterotoxin-inductive secretory diarrhea, the diarrhoea that causes because of doctor's treatment, the special property sent out diarrhoea (for example, the special secretory diarrhea of sending out), and traveler's diarrhea), vomiting, functional abdominal pain, the anus bowel dysfunction, functional inflatable, functional dyspepsia, the gallbladder function disorder, irritable bowel syndrome (IBS; Comprise IBS-d, IBS-c and IBS-a), lactose intolerance, MEN I and II type are felt sick, Ogilvie's syndrome false colonic obstruction (Ogilvie ' s syndrome), watery diarrhea with hypokalemia and achlorhydria, pancreatic insufficiency, pheochromocytoma, scleroderma, somatization disorder, the Oddi sphincter dysfunction, ulcerative colitis, and Zuo-Ai syndrome (Zollinger-Ellison Syndrome).
Other diseases and disorder comprise cardiovascular and pulmonary disorder and disorder, such as acute and chronic hypertension, chronic obstructive pulmonary disease (COPD), pulmonary infarction (for example, bronchoconstriction and pulmonary hypertension after the pulmonary infarction), pulmonary hypertension (for example, the pulmonary hypertension relevant), and radiation pneumonia (comprising the radiation pneumonia that generates or help pulmonary hypertension) with portal hypertension.Other comprise abdomen migraine (abdominal migraine), adult respiratory distress syndrome (ARDS), the carcinoid crisis, CREST syndrome (calcinosis, and Raynaud's phenomenon (Raynaud ' s phenomenon), the esophagus dysfunction, sclerodactyly, telangiectasis), serotonin syndrome, and subarachnoid hemorrhage.
An embodiment comprises the method for patient's stomach and intestine transmission of slowing down, and this method comprises effective TPH1 inhibitor of using capacity to the patient.
Another embodiment comprises the method for the patient's stomach emptying that slows down, and this method comprises effective TPH1 inhibitor of using capacity to the patient.
In concrete grammar of the present invention, realize treatment, management and/or preventing disease or disorder, avoid simultaneously changing relevant side effect with the serotonin level of central nervous system (CNS).The example of this side effect comprises excited, anxiety disorder, melancholy and sleep disordered (for example, insomnia and somnopathy).In concrete grammar of the present invention, realize treatment, management and/or preventing disease or disorder, avoid simultaneously changing relevant side effect with the serotonin level of central nervous system (CNS).The example of this side effect comprises excited, anxiety disorder, melancholy and sleep disordered (for example, insomnia and somnopathy).
Pharmaceutical composition
The present invention includes the pharmaceutical composition that contains one or more The compounds of this invention.The some drugs composition is single unit dosage, is suitable for oral, mucous membrane (for example, nose, hypogloeeis, vagina, cheek, or rectum), parenteral (for example, subcutaneous, intravenously is injected, intramuscular, or intra-arterial) or percutaneous dosing to the patient.The example of formulation includes, but are not limited to: tablet; The capsule sheet; Capsule is such as soft elastic gelatin capsule; The bag agent; Lozenge (troches); Diamond pattern agent (lozenges); Dispersion agent; Suppository; Ointment; Cataplasma (poultice); Paste; Pulvis; Application; Creme; Plaster; Solution; Patch; Aerosol (for example, nasal spray or inhalation); Gel; Be suitable for oral or mucosa delivery to patient's liquid dosage form, comprise suspension agent (for example, water-based or the agent of on-aqueous liquid suspension, oil-in-water emulsion, or water-in-oil fluid emulsion), solution and elixir; Be suitable for the liquid dosage form of administered parenterally to the patient; And sterile solid (for example, crystal or armorphous solid), this solid can be redissolved is suitable for the liquid dosage form of administered parenterally to the patient to provide.
Preparation should mate administering mode.For example, utilize casing can realize easily the oral administration of the compound of degraded under one's belt.Similarly, preparation can contain the composition that promotes activeconstituents to be delivered to action site.For example, compound can exempt from degrading enzyme to protect them with the Liposomal formulation administration, promotes the transportation in the recycle system, and realizes sending of cross-cell membrane.
Equally, poorly soluble compound can mix under the help of solubilizing agent, emulsifying agent and tensio-active agent in the liquid dosage form (with the formulation that is suitable for redissolving), described solubilizing agent, emulsifying agent and tensio-active agent such as, but be not limited to cyclodextrin (for example, alpha-cylodextrin, beta-cyclodextrin
Figure A20081010845300381
And Encapsin TM(referring to, for example, Davis and Brewster, Nat.Rev.Drug Disc.3:1023-1034 (2004)),
Figure A20081010845300382
Cremafor, and non-aqueous solvent, such as, but be not limited to ethanol, Virahol, ethyl-carbonate, ethyl acetate, benzylalcohol, peruscabin, propylene glycol, 1,3 butylene glycol, dimethyl formamide, dimethyl sulfoxide (DMSO) (DMSO), biocompatibility oil (for example, Oleum Gossypii semen, peanut oil, Semen Maydis oil, germ oil, sweet oil, Viscotrol C, and sesame oil), glycerine, tetrahydrofurfuryl alcohol, polyoxyethylene glycol, the fatty acid ester of sorbitanic, and composition thereof (for example, DMSO: Semen Maydis oil).
Utilize other technologies well known in the art, also poorly soluble compound can be mixed in the suspension.For example, the nano particle of compound can be suspended in liquid, with provide nano suspending liquid (referring to, for example, Rabinow, Nature Rev.Drug Disc.3:785-796 (2004)).The compound of form of nanoparticles described here can prepare by the method for record in following: U.S. Patent Publication No.2004-0164194,2004-0195413,2004-0251332,2005-0042177A1,2005-0031691 A1, with U.S. Patent No. 5,145,684,5,510,118,5,518,187,5,534,270,5,543,133,5,662,883,5,665,331,5,718,388,5,718,919,5,834,025,5,862,999,6,431,478,6,742,734,6,745,962, each comfortable this is incorporated herein by reference in full.In one embodiment, form of nanoparticles comprises mean particle size less than about 2000nm, less than about 1000nm, or less than the particle of about 500nm.
The composition of formulation, shape and type change according to purposes usually.For example, the used formulation formulation more used than the chronic treatment of same disease of the acute treatment of disease can contain more substantial one or more activeconstituentss.Equally, parenteral dosage forms can contain one or more activeconstituentss of less amount than the oral dosage form that is used for the treatment of same disease.How to illustrate that this species diversity will be apparent to those skilled in the art.Referring to, for example, Remington ' s PharmaceuticalSciences, 18 ThEd. (Lei Shi pharmaceutical science, the 18th edition), Mack Publishing, EastonPA (1990).
Oral dosage form
The pharmaceutical composition of the present invention that is suitable for oral administration can be rendered as isolating formulation, for example, but is not limited to tablet (for example, can chew tablet), capsule sheet, capsule, and liquid (for example, seasoning syrup).Such formulation contains the activeconstituents of predetermined amount, and can be by well-known pharmaceutical methods preparation to those skilled in the art.Generally referring to, Remington ' sPharmaceutical Sciences, 18 ThEd. (Lei Shi pharmaceutical science, the 18th edition), MackPublishing, Easton PA (1990).
The preparation of typical oral dosage form is the medicament mixed technology according to routine, in homogenizing mixture with activeconstituents and at least a excipient composition.The dosage form required according to administration, vehicle can adopt diversified form.
Owing to be easy to administration, tablet and capsule are represented best oral dosage unit form.If desired, by standard aqueous or non-water technology, tablet can be by dressing.Such formulation can adopt conventional pharmaceutical methods preparation.Generally speaking, the preparation of pharmaceutical composition and formulation is that activeconstituents and liquid vehicle, solid carrier in small, broken bits or both are mixed equably and closely, then optionally, product is shaped to desired form.Stripping fast for the benefit of, disintegrating agent can mix solid dosage.(for example, tablet) preparation also can be mixed lubricant in order to make things convenient for formulation.
Parenteral dosage forms
Can use parenteral dosage forms to the patient by number of ways, these approach comprise subcutaneous, intravenously (comprise and injecting), intramuscular, and intra-arterial.Because the natural defence of patient to pollutent walked around in its administration usually, parenteral dosage forms is especially aseptic or can be by sterilization before being administered to the patient.The example of parenteral dosage forms comprises the solution of preparing injection, prepares to be dissolved or suspended in the dryed product in the pharmaceutically acceptable injectable media, prepares the suspension of injection, and emulsion.
Can be used for the suitable media of parenteral dosage forms of the present invention is provided is well-known to those skilled in the art.Example comprises: water for injection USP; Water-bearing media, such as sodium chloride injection, ringer's inj, dextrose injection liquid, dextrose and sodium chloride injection, and lactated ringer's inj; The medium that water soluble mixes, such as ethanol, polyoxyethylene glycol, and polypropylene glycol; And non-aqueous media, such as Semen Maydis oil, Oleum Gossypii semen, peanut oil, sesame oil, ethyl oleate, Isopropyl myristate, and peruscabin.
Embodiment
1. prepare tph1 gene break mouse
Basically as Wattler etc., Biotechniques26 (6): 1150-6 (1999) is described, by gene targeting the exon 3 of mouse TPH1 gene is removed.The gene knockout animal of gained shows normal TPH activity in brain, but the TPH in the internal organ expresses sharply reduction.
2.tph1 the physiologic effect of gene break
The mouse of isozygotying of tph1 fracture (/-) is in conjunction with the heterozygosis mouse of this gene break (+/-), and the littermate studies with wild-type (+/+).During this analyzes, be utilized as the function of estimating major organs system in the mammalian object and a whole set of medical diagnosis program that designs carried out medical inspection to mouse.In conjunction with heterozygosis (+/-) and wild-type (+/+) littermate, obtained more reliable and data repeatably by the isozygotying of research record quantity (/-) knock out mice.
The fracture of tph1 gene mainly influences the gi tract isoform (TPH1) of TPH, and the rare or not influence to the brain isoform (TPH2) of TPH.The fracture of this gene can not cause measurable side effect to central nervous system.This is confirmed that by the serotonin immunochemistry it shows serotonin at stomach, duodenum, jejunum, reduce greatly or shortage in ileum, caecum and the colon, and the serotonin level is uninfluenced in the seam neurone.
The mouse of isozygotying of some tph1 gene breaks (/-) demonstrate the thrombosis minimizing, and significantly do not increase hemorrhage or other unfavorable indications.
3.HPLC characterize
In following some synthetic example, provide high performance liquid chromatography (HPLC) retention time.The various conditions that are used to obtain these retention time are described below:
Method A:YMC-PACK ODS-A 3.0 * 50mm; Solvent orange 2 A=H 2O, 0.1%TFA; Solvent B=MeOH, 0.1%TFA; B% was with 4 minutes from 10% to 90%; Flow velocity=2ml/ minute; Observation wavelength=220 and 254nm.
Method B:YMC-PACK ODS-A 3.0 * 50mm; Solvent orange 2 A=90% water, 10%MeOH has 0.1%TFA; Solvent B=90%MeOH, 10% water has 0.1%TFA; B% was with 4 minutes from 0% to 100%; Flow velocity=2ml/ minute; Observation wavelength=220 and 254nm.
Method C:ShimPack VP ODS 4.6 * 50mm; Solvent orange 2 A=90%H 2O, 10%MeOH, 1%TFA; Solvent B=10%H 2O, 90%MeOH, 1%TFA; B% was with 2 minutes from 0% to 100%; Flow velocity=3.5ml/ minute; Observation wavelength=220 and 254nm.
Method D:Shim VP ODS 4.6 * 50mm; Solvent orange 2 A=H 2O has 0.1%TFA; Solvent B=MeOH has 0.1%TFA; B% was with 4 minutes from 0% to 100%; Flow velocity=3ml/ minute; Observation wavelength=254nm.
Method E:YMC Pack ODS-A 4.6 * 33mm; Solvent orange 2 A=H 2O, 0.1%TFA; Solvent B=MeOH has 0.1%TFA; B% was with 3 minutes from 10% to 90%; Flow velocity 2ml/ minute; Observation wavelength 220 and 254nm.
Method F:YMC-Pack ODS-A 3.0 * 50mm; Solvent orange 2 A=90%H 2O, 10%MeOH, 1%TFA; Solvent B=10%H 2O, 90%MeOH, 1%TFA; B% was with 4 minutes from 10% to 90%; Flow velocity=2ml/ minute.Observation wavelength=220 and 254nm.
4. synthetic (S)-2-amino-3-(4-{2-amino-6-[2,2,2-three fluoro-1-(4-pyridin-4-yl-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid
Figure A20081010845300421
With tetrabutyl ammonium fluoride (0.027ml; 1.0M tetrahydrofuran solution) be added under 0 ℃ 4-pyridin-4-yl-phenyl aldehyde (500mg, 2.73mmol) and trifluoromethyl trimethyl silane (TMSCF 3) (485 μ l are in 5ml THF solution 3.28mmol).The gained mixture is warm until room temperature, and at room temperature stirs 4 hours.Then, reaction mixture is handled with 5ml 1N HCl, and at room temperature stirs and spend the night.Solvent evaporation adds 9ml 1M aqueous sodium carbonate to doing, and (3 * 10ml), the chloroform layer of merging is with water washing, to MgSO with the chloroform extracting for water 4Dry.Vacuum is removed organic solvent, provides 360mg 2,2,2-three fluoro-1-(4-pyridin-4-yl-phenyl) ethanol, yield: 51%.
In the 50ml sealed tube, with 2,2,2-three fluoro-1-(4-pyridin-4-yl-phenyl) ethanol (100mg, 0.40mmol), 2-amino-4,6-dichloro pyrimidine (60mg, 0.38mmol) and cesium carbonate (468mg, mixture 1.44mmol) is dissolved in 2ml 1, the 4-diox.110 ℃ of following heated overnight of mixture are cooled to room temperature then; Add the 10ml ethyl acetate, then filter by C salt.Filtrate concentrates, and provides 120mg 4-chloro-6-[2, and 2,2-three fluoro-1-(4-pyridin-4-yl-phenyl)-oxyethyl group]-pyrimidine-2-base amine, yield: 80%.
In the microwave bottle, with 4-chloro-6-[2,2,2-three fluoro-1-(4-pyridin-4-yl-phenyl)-oxyethyl group]-pyrimidine-2-base amine (30mg, 0.080mmol), (21mg 0.098mmol) and the 1ml acetonitrile, mixes with 0.7ml water 4-borono--L-phenylalanine.Then, in mixture, add 0.3ml 1N aqueous sodium carbonate, then add the 5mol% dichloro two-(triphenylphosphine)-palladium (II).Sealed reaction vessel, and with microwave irradiation 150 ℃ of down heating 5 minutes.After the cooling, reaction mixture is evaporated to dried.Residue is dissolved in 2.5ml methyl alcohol, then through the Prep-LC purifying, provide 6.7mg (S)-2-amino-3-(4-{2-amino-6-[2,2,2-three fluoro-1-(4-pyrimidine-4-base-phenyl)-oxyethyl group]-pyrimidine-4-yl-phenyl)-propionic acid. 1H NMR(400MHz，CD 3OD)δ(ppm)8.82(s，2H)，8.26(s，2H)，8.02(d，J＝8Hz，2H)，7.97(d，J＝8.4Hz，2H)，7.86(d，J＝8.4Hz，2H)，7.45(d，J＝8Hz 2H)，6.89(q，J＝6.8Hz，1H)，6.81(d，J＝2Hz，1H)，4.29(t，J＝1.6Hz，1H)，3.39(m，1H)，3.19(m，1H)。
5. synthetic (S)-2-amino-3-(4-{6-[2,2,2-three fluoro-1-(2-pyridin-4-yl-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid
With tetrabutyl ammonium fluoride (0.027ml; 1.0M tetrahydrofuran solution) be added under 0 ℃ 2-pyridin-4-yl-phenyl aldehyde (500mg, 2.73mmol) and trifluoromethyl trimethyl silane (TMSCF 3) (485 μ l are in 5ml THF solution 3.28mmol).Formed mixture is warm until room temperature, and at room temperature stirs 4 hours.Then, reaction mixture is handled with 5ml 1N HCl, and at room temperature stirs and spend the night.Solvent evaporation adds 9ml 1M aqueous sodium carbonate to doing, and (3 * 10ml), the chloroform layer of merging is with water washing, to MgSO with the chloroform extracting for water 4Dry.The evaporation organic solvent provides 300mg 2,2,2-three fluoro-1-(2-pyridin-4-yl-phenyl) ethanol, yield: 43%.
2,2, and 2-three fluoro-1-(2-pyridin-4-yl-phenyl) ethanol (100mg, 0.40mmol), 4, the 6-dichloro pyrimidine (54mg, 0.38mmol), cesium carbonate (468mg, 1.44mmol) and 1, the mixture of 4-diox (1ml).110 ℃ of following heated overnight of mixture.Reaction mixture is cooled to room temperature.Add the 10ml ethyl acetate, mixture filters by C salt then.Filtrate concentrates, and provides 110mg 4-chloro-6-[2, and 2,2-three fluoro-1-(2-pyridin-4-yl-phenyl)-oxyethyl group]-pyrimidine, yield: 76%.
In the microwave bottle,, 2,2-three fluoro-1-(4-pyridin-4-yl-phenyl)-oxyethyl group with 4-chloro-6-[2]-pyrimidine (30mg, 0.080mmol), 4-borono--L-phenylalanine (21mg, 0.098mmol), 1ml acetonitrile and 0.7ml water mixes.Then, in mixture, add 0.3ml 1N aqueous sodium carbonate, then add the 5mol% dichloro two-(triphenylphosphine)-palladium (II).Sealed reaction vessel, and with microwave irradiation 150 ℃ of down heating 5 minutes.After the cooling, reaction mixture is evaporated to dried.Residue is dissolved in 2.5ml methyl alcohol, then through the Prep-LC purifying, provide 19mg (S)-2-amino-3-(4-{6-[2,2,2-three fluoro-1-(2-pyridin-4-yl-phenyl)-oxyethyl group]-pyrimidine-4-yl-phenyl)-propionic acid. 1H NMR(400MHz，CD 3OD)δ(ppm)8.94(d，J＝6Hz，2H)，8.79(d，J＝1.2Hz，1H)，8.15(m，4H)，7.84(t，J＝5.2Hz，1H)，7.62(m，3H)，7.46(m，3H).6.66(q，J＝6.4Hz，1H)，4.31(q，J＝6Hz，1H)，3.41(m，1H)，3.26(m，1H).
6. synthetic (S)-2-amino-3-(4-{2-amino-6-[2,2,2-three fluoro-1-(2-(4-methyl-thiene-3-yl-)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid
In the microwave bottle, with 3-bromo-4-methyl-thiophene (653mg, 3.69mmol), 2-formylphenyl boric acid (500mg, 3.36mmol) and the 7ml acetonitrile mix.Add 6.7ml 1N aqueous sodium carbonate to above-mentioned solution, then add two (the triphenylphosphine)-palladiums (II) of 5mol% dichloro.Sealed reaction vessel, and with microwave irradiation 150 ℃ of down heating 5 minutes.After the cooling, add the 50ml ethyl acetate, separate organic layer,, use dried over sodium sulfate with water washing.The evaporation organic solvent provides crude product, through ISCO CombiFlash column purification, provides 530mg 2-(4-methyl-thiene-3-yl-) phenyl aldehyde, yield: 78%.
With tetrabutyl ammonium fluoride (0.013ml; 1.0M tetrahydrofuran solution) be added under 0 ℃ 2-(4-thiotolene-3-yl)-phenyl aldehyde (260mg, 1.29mmol) and trifluoromethyl trimethyl silane (TMSCF 3) (228 μ l are in 5ml THF solution 1.54mmol).The mixture that forms is warm until room temperature, and at room temperature stirs 4 hours.Then, reaction mixture is handled with 5ml 1N HCl, and at room temperature stirs and spend the night.Product is with ethyl acetate extracting (3 * 50ml).Separate organic layer and to dried over sodium sulfate.The evaporation organic solvent provides 340mg 2,2,2-three fluoro-1-[2-(4-methyl-thiene-3-yl-)-phenyl]-ethanol, yield: 97%.
2,2,2-three fluoro-1-[2-(4-methyl-thiene-3-yl-)-phenyl]-ethanol (100mg, 0.37mmol), 2-amino-4,6-two chloro-pyrimidines (54mg, 0.33mmol), cesium carbonate (481mg, 1.48mmol) and 1,110 ℃ of following heated overnight of the mixture of 4-diox (1ml).Reaction mixture is cooled to room temperature; Add the 10ml ethyl acetate.Mixture filters by C salt then, and filtrate concentrates, and provides 100mg 4-chloro-6-{2, and 2,2-three fluoro-1-[2-(4-methyl-thiene-3-yl-)-phenyl]-oxyethyl group }-pyrimidine-2-base amine, yield: 76%.
In the microwave bottle, mix 4-chloro-6-{2,2,2-three fluoro-1-[2-(4-methyl-thiene-3-yl-)-phenyl]-oxyethyl group }-pyrimidine-2-base amine (30mg, 0.075mmol), 4-borono--L-phenylalanine (19mg, 0.09mmol), 1ml acetonitrile and 0.7ml water.In mixture, add 0.3ml 1N aqueous sodium carbonate, then add the 5mol% dichloro two-(triphenylphosphine)-palladium (II).Sealed reaction vessel, and with microwave irradiation 150 ℃ of down heating 5 minutes.After the cooling, reaction mixture is evaporated to dried.Residue is dissolved in 2.5ml methyl alcohol, then through the Prep-HPLC purifying, provide 15.1mg (S)-2-amino-3-(4-{2-amino-6-[2,2,2-three fluoro-1-(2-(4-methyl-thiene-3-yl-)-phenyl]-oxyethyl group-pyrimidine-4-yl-phenyl)-propionic acid. 1H NMR(400MHz，CD 3OD)δ(ppm)7.94(d，J＝8Hz，2H)，7.80(s，1H)，7.50(m，5H)，7.25(m，2H)，7.03(s，1H)，6.94(s，1H)，4.31(t，J＝5.6，1H)，3.48(m，1H)，3.26(m，1H)，1.98(s，3H)。
7. synthetic (S)-2-amino-3-(4-{2-amino-6-[2,2,2-three fluoro-1-(2-(5-methyl-thiene-3-yl-)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid
Figure A20081010845300461
In the microwave bottle, mix 4-bromo-2-methyl-thiophene (653mg, 3.69mmol), 2-formylphenyl boric acid (500mg, 3.36mmol) and the 7ml acetonitrile.Add the 6.7ml1N aqueous sodium carbonate to above-mentioned solution, then add two (the triphenylphosphine)-palladiums (II) of 5mol% dichloro.Sealed reaction vessel, and with microwave irradiation 150 ℃ of down heating 5 minutes.After the cooling, add the 50ml ethyl acetate, separate organic layer,, use dried over sodium sulfate with water washing, the evaporation organic solvent, residue provides 550mg 2-(5-methyl-thiene-3-yl-) phenyl aldehyde, yield: 81% through the ISCO purifying.
With tetrabutyl ammonium fluoride (0.028ml; 1.0M tetrahydrofuran solution) be added under 0 ℃ 2-(5-thiotolene-3-yl)-phenyl aldehyde (550mg, 1.29mmol) and trifluoromethyl trimethyl silane (TMSCF 3) (483 μ l are in 10ml THF solution 3.27mmol).The mixture that forms is warm until room temperature, and at room temperature stirs 4 hours.Then, reaction mixture is handled with 10ml 1NHCl, and at room temperature stirs and spend the night.Product is with ethyl acetate extracting (3 * 50ml).Separate organic layer and to dried over sodium sulfate.The evaporation organic solvent provides 650mg 2,2,2-three fluoro-1-[2-(5-methyl-thiene-3-yl-)-phenyl]-ethanol, yield: 87%.
2,2,2-three fluoro-1-[2-(5-methyl-thiene-3-yl-)-phenyl]-ethanol (100mg, 0.37mmol), 2-amino-4,6-two chloro-pyrimidines (54mg, 0.33mmol), cesium carbonate (481mg, 1.48mmol) and 1,110 ℃ of following heated overnight of the mixture of 4-diox (2ml).Reaction mixture is cooled to room temperature; Add the 10ml ethyl acetate.Mixture filters by C salt then, and filtrate concentrates, and provides 90mg 4-chloro-6-{2, and 2,2-three fluoro-1-[2-(5-methyl-thiene-3-yl-)-phenyl]-oxyethyl group }-pyrimidine-2-base amine, yield: 68%.
In the microwave bottle, mix 4-chloro-6-{2,2,2-three fluoro-1-[2-(5-methyl-thiene-3-yl-)-phenyl]-oxyethyl group }-pyrimidine-2-base amine (30mg, 0.075mmol), 4-borono--L-phenylalanine (19mg, 0.09mmol), 1ml acetonitrile and 0.7ml water.In mixture, add 0.3ml 1N aqueous sodium carbonate, then add the 5mol% dichloro two-(triphenylphosphine)-palladium (II).Sealed reaction vessel, and with 150 ℃ of following heating of microwave irradiation 5 minutes.After the cooling, reaction mixture is evaporated to dried.Residue is dissolved in 2.5ml methyl alcohol, then through the Prep-LC purifying, provide 10.1mg (S)-2-amino-3-(4-{2-amino-6-[2,2,2-three fluoro-1-(2-(5-methyl-thiene-3-yl-)-phenyl]-oxyethyl group-pyrimidine-4-yl-phenyl)-propionic acid. 1H NMR(400MHz，CD 3OD)δ(ppm)7.83(d，J＝8.4Hz，2H)，7.63(d，J＝7.2Hz，1H)，7.34(m，4H)，7,26(m，1H)，7.12(d，J＝1.2Hz，1H)，6.92(q，J＝6.8，1H)，6.82(d，J＝1.2Hz，1H)，6.64(s，1H)，4.21(t，J＝5.6Hz，1H)，3.29(m，1H)，3.20(m，1H)，2.47(s，3H)。
8. synthetic (S)-2-amino-3-(4-{2-amino-6-[2,2,2-three fluoro-1-(4-furans-3-base-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid
In the microwave bottle, mix 3-bromo-furans (590mg, 4.02mmol), 4-formylphenyl boric acid (600mg, 4.02mmol) and the 7ml acetonitrile.Add 8ml 1N aqueous sodium carbonate to this mixture then, then add two (the triphenylphosphine)-palladiums (II) of 5mol% dichloro.Sealed reaction vessel, and with 150 ℃ of following heating of microwave irradiation 7 minutes.After the cooling, add the 50ml ethyl acetate, separate organic layer, with water washing, to dried over sodium sulfate.The evaporation organic solvent provides crude product, through the ISCO purifying, provides 410mg 4-furans-3-base-phenyl aldehyde, yield: 60%.
With tetrabutyl ammonium fluoride (0.024ml; 1.0M tetrahydrofuran solution) be added under 0 ℃ 4-furans-3-base-phenyl aldehyde (410mg, 2.38mmol) and trifluoromethyl trimethyl silane (TMSCF 3) (423 μ l, 5ml THF solution 2.86mmol).The mixture that forms is warm until room temperature, and at room temperature stirs 4 hours.Then, reaction mixture is handled with 5ml 1N HCl, and at room temperature stirs and spend the night.Product is with ethyl acetate extracting (3 * 50ml).Separate organic layer and to dried over sodium sulfate.The evaporation organic solvent provides 480mg 2,2,2-three fluoro-1-(4-furans-3-base-phenyl)-ethanol, yield: 83%.
2,2,2-three fluoro-1-(4-furans-3-base-phenyl)-ethanol (100mg, 0.4mmol), 2-amino-4,6-two chloro-pyrimidines (60mg, 0.36mmol), cesium carbonate (468mg, 1.44mmol) and 1,110 ℃ of following heated overnight of the mixture of 4-diox (1ml).Reaction mixture is cooled to room temperature; Add the 10ml ethyl acetate.Mixture filters by C salt then, and filtrate concentrates, and provides 100mg 4-chloro-6-[2, and 2,2-three fluoro-1-(4-furans-3-base-phenyl)-oxyethyl group]-pyrimidine-2-base amine, yield: 72%.
In the microwave bottle, mix 4-chloro-6-[2,2,2-three fluoro-1-(4-furans-3-base-phenyl)-oxyethyl group]-pyrimidine-2-base amine (30mg, 0.081mmol), 4-borono--L-phenylalanine (20mg, 0.098mmol), 1ml acetonitrile and 0.7ml water.Then, in mixture, add the 0.3ml1N aqueous sodium carbonate, then add the 5mol% dichloro two-(triphenylphosphine)-palladium (II).Sealed reaction vessel, and with 150 ℃ of following heating of microwave irradiation 5 minutes.After the cooling, reaction mixture is evaporated to dried.Residue is dissolved in 2.5ml methyl alcohol, then through the Prep-LC purifying, provide 7.2mg (S)-2-amino-3-(4-{2-amino-6-[2,2,2-three fluoro-1-(4-furans-3-base-phenyl)-oxyethyl group]-pyrimidine-4-yl-phenyl)-propionic acid. 1H NMR(400MHz，CD 3OD)δ(ppm)7.96(m，3H)，7.61(m，5H)，6.81(s，1H)，6.77(d，J＝6.8Hz，1H)，6.74(d，J＝4,8Hz，1H)，4.27(q，J＝5.6Hz，1H)，3.36(m，1H)，3.21(m，1H)。
9. synthetic (S)-2-amino-3-[4-{2-amino-6-{1-[2-(5-dimethylaminomethyl-furans-2-yl)-phenyl]-2,2,2-three fluoro-oxyethyl groups }-pyrimidine-4-yl)-phenyl]-propionic acid
Figure A20081010845300481
With nitrilotriacetic base sodium borohydride (844mg, 4mmol) add to 5-bromo-furans-2-formaldehyde (carbaldehyde) (350mg, 2mmol) and the 10ml 1 of dimethylamine (2ml, the THF solution of 2M), in the solution of 2-ethylene dichloride (DCE).Add 0.2ml HOAc then.Stir under the mixture room temperature and spend the night, then add 15ml DCE.Organic phase is with water washing, to dried over sodium sulfate.Remove solvent by centrifugal distiller (rotovap), provide 400mg (5-bromo-furans-2-ylmethyl)-dimethyl-amine, yield: 97%.
In the microwave bottle, mix (5-bromo-furans-2-ylmethyl)-dimethyl-amine (385mg, 1.88mmol), 2-formylphenyl boric acid (288mg, 1.93mmol) and the 3.7ml acetonitrile.Then, add 3.7ml 1N aqueous sodium carbonate, then add two (the triphenylphosphine)-palladiums (II) of 5mol% dichloro to this mixture.Sealed reaction vessel, and with 150 ℃ of following heating of microwave irradiation 5 minutes.After the cooling, add 20ml 1N HCl.This mixture is with ethyl acetate extracting (3 * 10ml), and discard ethyl acetate layer.Add 1N NaOH solution to water and regulate pH to 10, then with ethyl acetate extracting (3 * 20ml).The organic layer that merges is with water washing, and to dried over sodium sulfate.Evaporating solvent provides 300mg 2-(4-dimethylaminomethyl-ring penta-butadienyl)-phenyl aldehyde, yield: 69%.
With tetrabutyl ammonium fluoride (0.013ml; 1.0M tetrahydrofuran solution) be added into 2-(4-dimethylaminomethyl-ring penta-butadienyl)-phenyl aldehyde (287mg, 1.25) and trifluoromethyl trimethyl silane (TMSCF under 0 ℃ 3) (222 μ l are in 5ml THF solution 1.5mmol).The mixture that forms is warm until room temperature, and at room temperature stirs 4 hours.Then, reaction mixture is handled with 5ml 1N HCl, and at room temperature stirs and spend the night.Product is with ethyl acetate extracting (3 * 50ml).Separate organic layer and to dried over sodium sulfate.The evaporation organic solvent provides 250mg1-[2-(5-dimethylaminomethyl-furans-2-yl)-phenyl]-2,2,2-three fluoro-ethanol, yield: 66%.
1-[2-(5-dimethylaminomethyl-furans-2-yl)-phenyl]-2,2,2-three fluoro-ethanol (225mg, 0.75mmol), 2-amino-4,6-two chloro-pyrimidine (111mg, 0.67mmol), cesium carbonate (978mg, 3.01mmol) and 1,110 ℃ of following heated overnight of the mixture of 4-diox (3ml).Reaction mixture is cooled to room temperature; Add the 10ml ethyl acetate.Mixture filters by C salt then, and filtrate concentrates, and provides 110mg 4-chloro-6-{1-[2-(5-dimethylaminomethyl-furans-2-yl)-phenyl] 2,2,2-three fluoro-oxyethyl groups }-pyrimidine-2-base amine, yield: 87%.
In the microwave bottle, mix 4-chloro-6-{1-[2-(5-dimethylaminomethyl-furans-2-yl)-phenyl] 2,2,2-three fluoro-oxyethyl groups }-pyrimidine-2-base amine (37mg, 0.087mmol), 4-borono--L-phenylalanine (22mg, 0.10mmol), 1ml acetonitrile and 0.7ml water.Then, add 0.3ml 1N aqueous sodium carbonate, then add the 5mol% dichloro two-(triphenylphosphine)-palladium (II).Sealed reaction vessel, and with 150 ℃ of following heating of microwave irradiation 5 minutes.After the cooling, reaction mixture is evaporated to dried.Residue is dissolved in 2.5ml methyl alcohol, then through the Prep-LC purifying, provides 16mg (S)-2-amino-3-[4-{2-amino-6-{1-[2-(5-dimethylaminomethyl-furans-2-yl)-phenyl]-2,2,2-three fluoro-oxyethyl groups }-pyrimidine-4-yl)-phenyl]-propionic acid. 1H NMR(400MHz，CD 3OD)δ(ppm)7.88(d，J＝8.4Hz，2H)，7.71(d，J＝7.6Hz，1H)，7.62(d，J＝7.6Hz，1H)，7.42(m，2H)，7.40(d，J＝1.6Hz，2H)，7.34(d，J＝8.4Hz，1H)，6.89(q，J＝3.6Hz，2H)，6.66(s，1H)，4.54(s，2H)，4.20(q，J＝6Hz，1H)，3.3(m，1H)，3.14(m，1H)，2.84(s，6H)。
10. synthetic (S)-2-amino-3[4-(2-amino-6-{1-[2-(6-cyano group-pyridin-3-yl)-phenyl]-2,2,2-three fluoro-oxyethyl groups }-pyrimidine-4-yl)-phenyl]-propionic acid
In the microwave bottle, mix 5-(4,4,5,5-tetramethyl--[1,3,2] dioxy boron penta ring-2-yl)-pyridine-2-nitrile (279mg, 1.51mmol), (230mg is 1mmol) with the 2ml acetonitrile for 2-bromo-phenyl aldehyde.Then, add 2ml 1N aqueous sodium carbonate, then add two (the triphenylphosphine)-palladiums (II) of 5mol% dichloro.Sealed reaction vessel, and with 100 ℃ of following heating of microwave irradiation 10 minutes.After the cooling, add the 50ml ethyl acetate, separate organic layer, with water washing and to dried over sodium sulfate.The evaporation organic solvent provides crude product, through the ISCO purifying, provides 150mg 5-(2-formyl-phenyl)-pyridine-2-nitrile, yield: 72%.
Be added under 0 ℃ of the tetrabutyl ammonium fluoride (5.3 μ l, the tetrahydrofuran solution of 1.0M) 5-(2-formyl-phenyl)-pyridine-2-nitrile (110mg, 0.53mmol) and trifluoromethyl trimethyl silane (120 μ l, 5ml THF solution 0.81mmol).The mixture that forms is warm until room temperature, and at room temperature stirs 4 hours.Then, reaction mixture is handled with 5ml 1N HCl, and at room temperature stirs and spend the night.Product is with ethyl acetate extracting (3 * 50ml).Separate organic layer and to dried over sodium sulfate.The evaporation organic solvent provides 140mg 5-[2-(2,2,2-three fluoro-1-hydroxyl-ethyls)-phenyl]-pyridine-2-nitrile, yield: 95%.
5-[2-(2,2,2-three fluoro-1-hydroxyl-ethyls)-phenyl]-pyridine-2-nitrile (46mg, 0.165mmol), (S)-3-[4-(2-amino-6-chloro-pyrimidine-4-yl)-phenyl]-2-tert-butoxycarbonyl amino-propionic acid (59mg, 0.15mmol), cesium carbonate (195mg, 0.6mmol) and 1,110 ℃ of following heated overnight of the mixture of 4-diox (1ml).Reaction mixture is cooled to room temperature, pours into 5ml water then.Add 1N HCl and regulate pH to 4.5, water is with ethyl acetate extracting (3 * 10ml).The organic layer salt water washing that merges, and to dried over sodium sulfate.Evaporating solvent, provide thick (the S)-3-[4-of 80mg (2-amino-6-{1-[2-(6-cyanopyridine-3-yl)-phenyl]-2,2,2-three fluoro-oxyethyl groups }-pyrimidine-4-yl)-phenyl]-2-tert-butoxycarbonyl amino-propionic acid, yield: 84%.
With 80mg (S)-3-[4-(2-amino-6-{1-[2-(6-cyanopyridine-3-yl)-phenyl]-2,2,2-three fluoro-oxyethyl groups }-pyrimidine-4-yl)-phenyl]-2-tert-butoxycarbonyl amino-propionic acid is dissolved in the solution of methylene dichloride (5ml) of 30% trifluoroacetic acid.Stirred 1 hour under this mixture room temperature.Evaporating solvent, residue be through the preparation HPLC purifying, provide 12.6mg (S)-2-amino-3[4-(2-amino-6-{1-[2-(6-cyano group-pyridin-3-yl)-phenyl]-2,2,2-three fluoro-oxyethyl groups }-pyrimidine-4-yl)-phenyl]-propionic acid. 1H NMR(400MHz，CD 3OD)δ(ppm)8.86(s，1H)，8.17(d，J＝2Hz，1H)，8.15(d，J＝2Hz，1H)，7.96(m，2H)，7.59(m，1H)，7.36(m，3H)，6.7(s，1H)，6.65(d，J＝6.8Hz，1H)，4.25(m，1H)，3.47(m，1H)，3.23(m，1H)。
11. synthetic (S)-2-amino-3-(4-{2-amino-6-[2,2,2-three fluoro-1-(2-imidazoles-1-base-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid
Figure A20081010845300521
To 2-imidazoles-1-base-phenyl aldehyde (0.344g, 2mmol) THF solution (8ml) add the trifluoromethyl trimethyl silane (0.341g, 2.4mmol).Reaction mixture is cooled to 0-5 ℃ (ice-water bath), adds four-just-butyl Neutral ammonium fluoride (1M is in THF for 0.035ml, 0.035mmol).Shift out ice bath, stirred 6 hours under this mixture room temperature.Add 2N HCl (5ml), further stirred 3 hours under this reaction mixture room temperature.Reduce pressure down by centrifugal distiller and to desolventize.Thick residue is dissolved in DCM (30ml), with water (20ml), salt solution (20ml) washing, and to dried over sodium sulfate.Remove solvent, provide roughly 2,2,2-three fluoro-1-(2-imidazoles-1-base-phenyl)-ethanol (0.45g, 93%) are directly used in next step.
With 2-amino-4, the 6-dichloro pyrimidine (0.107g, 0.65mmol), 2,2,2-three fluoro-1-(2-imidazoles-1-base-phenyl)-ethanol (0.157g, 0.65mmol) and NaH (0.03g 0.78mmol) is added into anhydrous THF (10ml) under the nitrogen.This reaction was stirred 6 hours down for 40-45 ℃, was cooled to room temperature then, and water (0.2ml) cancellation.This reaction mixture concentrates, and provides rough 4-chloro-6-[2, and 2,2-three fluoro-1-(2-imidazoles-1-base-phenyl)-oxyethyl group]-pyrimidine-2-base amine (0.24g, LCMS record purity＞90%), be directly used in next step.
With above-mentioned rough intermediate (0.24g), L-right-borono--phenylalanine (0.140g, 0.67mmol), yellow soda ash (0.14g, 1.32mmol) and two (the triphenylphosphine)-palladiums (II) of dichloro (15mg 0.021mmol) is dissolved in MeCN (2.0ml) and H in the microwave bottle 2The mixture of O (2.0ml).Seal this reaction mixture, and in microwave reactor, stirred 6 minutes under 150 ℃.This mixture filters, and filtrate concentrates.Residue is dissolved in MeOH and H 2O (1: 1), and utilize MeOH/H by preparation HPLC 2O/TFA is as solvent systems and purifying, provide (S)-2-amino-3-(4-[2-amino-6-[2,2,2-three fluoro-1-(2-imidazoles-1-base-phenyl)-oxyethyl group]-pyrimidine-4-yl]-tfa salt of phenyl-propionic acid.LCMS：M+1＝499. 1H-NMR(400MHz，CD 3OD)：δ(ppm)3.20-3.41(m，2H)，4.30(t，1H)，6.61(m，1H)，6.88(s，1H)，7.48(d，2H)，7.69(d，1H)，7.72-7.81(m，2H)，7.83(m，1H)，7.98(m，3H)，8.02(m，1H)，9.40(m，1H)。
12. synthetic (S)-2-amino-3-(4-{6-[2,2,2-three fluoro-1-(2-pyrazol-1-yl-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid
Figure A20081010845300531
To 2-pyrazol-1-yl-phenyl aldehyde (0.344g, add in the THF solution (8ml) 2mmol) the trifluoromethyl trimethyl silane (0.341g, 2.4mmol).Mixture is cooled to 0-5 ℃ (ice-water bath), adds four-just-butyl Neutral ammonium fluoride (1M is in THF for 0.035ml, 0.035mmol).Shift out ice bath, stirred 6 hours under this mixture room temperature.Add 2N HCl (5ml), further stirred 3 hours under this reaction mixture room temperature.Reduce pressure down by centrifugal distiller and to desolventize.Residue is dissolved in DCM (30ml), with water (20ml), salt solution (20ml) washing, and to dried over sodium sulfate.Vacuum is removed solvent, provides slightly 2,2, and 2-three fluoro-1-(2-pyrazol-1-yl-phenyl)-ethanol (0.45g, 93%) are directly used in following experiment.
With 4, and the 6-dichloro pyrimidine (0.082g, 0.55mmol), 2,2,2-three fluoro-1-(2-pyrazol-1-yl-phenyl)-ethanol (0.121g, 0.50mmol), (0.03g 0.78mmol) is added under nitrogen atmosphere among the anhydrous THF (10ml) NaH.This reaction was stirred 6 hours down for 40-45 ℃, was cooled to room temperature then, and water (0.2ml) cancellation.This reaction mixture concentrates, and provides rough 4-chloro-6-[2, and 2,2-three fluoro-1-(2-pyrazol-1-yl-phenyl)-oxyethyl group]-pyrimidine (0.20g, LCMS record purity＞90%), be directly used in next step.
Should rough intermediate (0.20g), L-is right-borono--phenylalanine (0.105g, 0.50mmol), yellow soda ash (0.105g, 1mmol), (15mg 0.021mmol) is dissolved in MeCN (2.0ml) and H to two (the triphenylphosphine)-palladiums (II) of dichloro in the microwave bottle 2The mixture of O (2.0ml).Seal this microwave bottle, allow this reaction mixture in microwave reactor, heat 6 minutes under 150 ℃.This mixture filters, and filtrate concentrates.Residue is dissolved in MeOH and H 2O (1: 1) utilizes MeOH/H by preparation HPLC then 2O/TFA is as solvent systems and purifying, provide (S)-2-amino-3-(4-[6-[2,2,2-three fluoro-1-(2-pyrazol-1-yl-phenyl)-oxyethyl group]-pyrimidine-4-yl]-tfa salt of phenyl-propionic acid.LCMS：M+1＝484. 1H-NMR(400MHz，CD 3OD)：δ(ppm)3.20-3.40(m，2H)，4.30(t，1H)，6.63(s，1H)，7.10(m，1H)，7.50(m，3H)，7.60(m，3H)，7.84(m，2H)，8.16(m，3H)，8.68(s，1H)。
13. synthetic (S)-2-amino-3-[4-(2-amino-6-{2,2,2-three fluoro-1-[2-(3-trifluoromethyl-pyrazol-1-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid
With 2,2,2-three fluoro-1-(2-iodo-phenyl)-ethanol (0.331g, 1.1mmol), the 3-trifluoromethyl pyrazol (0.136g, 1.0mmol), CuI (0.019g, 0.1mmol), K 2CO 3(0.290g, 2.1mmol), (1R, 2R)-N, N '-dimethyl-hexanaphthene-1, the 2-diamines (0.028g, 0.2mmol) and toluene (10ml) in the 20ml penstock, merge.This mixture 130 ℃ (oil bath temperatures) heated 12 hours down.Reaction mixture dilutes with ethyl acetate, uses H 2O (2 * 20ml), the salt water washing, and to dried over sodium sulfate.Provide crude product after removing solvent, utilize the hexane solution of 5-10% ethyl acetate to carry out purifying by the ISCO column chromatography, obtain 140mg 2,2,2-three fluoro-1-[2-(3-trifluoromethyl-pyrazol-1-yl)-phenyl as solvent]-ethanol.
With 2-amino-4, and the 6-dichloro pyrimidine (0.074g, 0.45mmol), 2,2,2-three fluoro-1-[2-(3-trifluoromethyl-pyrazol-1-yl)-phenyl]-ethanol (0.140g, 0.45mmol) and NaH (0.022g 0.59mmol) is added into anhydrous THF (10ml) under nitrogen atmosphere.This reaction was stirred 6 hours down for 40-45 ℃, was cooled to room temperature then, and water (0.2ml) cancellation.This reaction mixture concentrates, and provides rough 4-chloro-6-[2, and 2,2-three fluoro-1-[2-(3-trifluoromethyl-pyrazol-1-yl) phenyl]-oxyethyl group]-pyrimidine-2-base amine (0.21g, LCMS measures purity＞90%), be directly used in next step.
Should rough intermediate (0.21g), L-is right-borono--phenylalanine (0.1g, 0.48mmol), yellow soda ash (0.1g, 0.94mmol) and two (the triphenylphosphine)-palladiums (II) of dichloro (15mg 0.021mmol) is dissolved in MeCN (2.0ml) and H in the microwave bottle 2In the mixture of O (2.0ml).Seal this bottle, allow reaction mixture in microwave reactor, heat 6 minutes under 150 ℃.Filter reaction mixture, concentrated filtrate is to provide crude product, and this crude product is dissolved in MeOH and H 2O (1: 1), and utilize MeOH/H by preparation HPLC 2O/TFA carries out purifying as solvent systems, provide (S)-2-amino-3-[4-(2-amino-6-[2,2,2-three fluoro-1-(2-(3-trifluoromethyl-pyrazol-1-yl-phenyl)-oxyethyl group]-pyrimidine-4-yl]-tfa salt of phenyl-propionic acid.LCMS：M+1＝567. 1H-NMR(400MHz，CD 3OD)：δ(ppm)3.2(m，1H)，3.35(m，1H)，4.30(t，1H)，6.80(s，1H)，6.85(m，1H)，6.98(d，1H)，7.45(d，2H)，7.59(m，1H)，7.68(m，2H)，7.88(m，1H)，7.95(d，2H)，8.20(1H)。
14. synthetic (S)-2-amino-3-[4-(2-amino-6-{1-[2-(3,5-dimethyl-pyrazol-1-yl)-phenyl]-2,2,2-three fluoro-oxyethyl groups }-pyrimidine-4-yl)-phenyl]-propionic acid
With 2,2,2-three fluoro-1-(2-iodo-phenyl)-ethanol (0.331g, 1.1mmol), 3 (0.096g, 1.0mmol), CuI (0.019g, 0.1mmol), K 2CO 3(0.290g, 2.1mmol), (1R, 2R)-N, N '-dimethyl-hexanaphthene-1, the 2-diamines (0.028g, 0.2mmol) and toluene (10ml) in the 20ml penstock, merge this mixture 130 ℃ (oil bath temperatures) heating 12 hours down.Reaction mixture dilutes with ethyl acetate, uses H 2O (2 * 20ml), the salt water washing, and to dried over sodium sulfate.Remove solvent and provide crude product, utilize the hexane solution of 5-10% ethyl acetate to carry out purifying by the ISCO column chromatography, obtain 1-[2-(3,5-dimethyl-pyrazol-1-yl)-phenyl as solvent]-2,2,2-three fluoro-ethanol (120mg).
With 2-amino-4, and the 6-dichloro pyrimidine (0.074g, 0.45mmol), 1-[2-(3,5-dimethyl-pyrazol-1-yl)-and phenyl]-2,2,2-three fluoro-ethanol (0.120g, 0.45mmol), (0.022g 0.59mmol) is added into anhydrous THF (10ml) to NaH under nitrogen atmosphere.This reaction was stirred 6 hours down for 40-45 ℃, was cooled to room temperature then, and water (0.2ml) cancellation.This reaction mixture concentrates, and provides rough 4-chloro-6-{1-[2-(3,5-dimethyl-pyrazol-1-yl)-phenyl]-2,2,2-three fluoro-oxyethyl groups]-pyrimidine-2-base amine (0.195g, LCMS measures purity＞90%), be directly used in next step.
Should rough intermediate (0.195g), L-is right-borono--phenylalanine (0.10g, 0.48mmol), yellow soda ash (0.10g, 0.95mmol) and two (the triphenylphosphine)-palladiums (II) of dichloro (15mg 0.021mmol) is dissolved in MeCN (2.0ml) and H in the microwave bottle 2The mixture of O (2.0ml).Seal this bottle, allow this reaction mixture in microwave reactor, heat 6 minutes under 150 ℃.Filtering mixt, concentrated filtrate provides crude product, and this crude product is dissolved in MeOH and H 2O (1: 1), and utilize MeOH/H by preparation HPLC 2O/TFA carries out purifying as solvent systems, provide (S)-2-amino-3-[4-(2-amino-6-[1-(and 2-(3,5-dimethyl-pyrazol-1-yl)-phenyl]-2,2,2-three fluoro-oxyethyl groups }-pyrimidine-4-yl)-phenyl]-tfa salt of propionic acid.LCMS：M+1＝527. 1H-NMR(400MHz，CD 3OD)：δ(ppm)4.32(t，1H)，3.39(m，1H)，3.25(m，1H)，2.30(s，3H)，2.10(s，3H)，7.92(m，3H)，7.68(m，2H)，7.50(d，2H)，7.42(m，1H)，6.92(m，1H)，6.89(s，1H)，6.17(s，1H)。
15. synthetic (S)-2-amino-3-[4-(2-amino-6-{2,2,2-three fluoro-1-[2-(3-phenyl-pyrazole-1-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid
With 2,2,2-three fluoro-1-(2-iodo-phenyl)-ethanol (0.331g, 1.1mmol), the 3-phenylpyrazole (0.144g, 1.0mmol), CuI (0.019g, 0.1mmol), K 2CO 3(0.290g, 2.1mmol), (1R, 2R)-N, N '-dimethyl-hexanaphthene-1, the 2-diamines (0.028g, 0.2mmol) and toluene (10ml) place the 20ml penstock, this mixture 130 ℃ (oil bath temperatures) heating 12 hours down.Mixture dilutes with ethyl acetate, uses H 2O (2 * 20ml), the salt water washing, and to dried over sodium sulfate.Remove solvent and provide crude product, utilize the hexane solution of 5-10% ethyl acetate to carry out purifying by the ISCO column chromatography, obtain 2,2,2-three fluoro-1-[2-(3-phenyl-pyrazole-1-yl)-phenyl as solvent]-ethanol (75mg).
With 2-amino-4, and the 6-dichloro pyrimidine (0.041g, 0.25mmol), 2,2,2-three fluoro-1-[2-(3-phenyl-pyrazole-1-yl)-phenyl]-ethanol (0.070g, 0.22mmol) and NaH (0.012g 0.31mmol) is added into anhydrous THF (7ml) under nitrogen atmosphere.This reaction was stirred 6 hours down for 40-45 ℃, was cooled to room temperature then, and water (0.04ml) cancellation.This reaction mixture concentrates, and provides rough 4-chloro-6-{2, and 2,2-three fluoro-1-[2-(3-phenyl-pyrazole-1-yl)-phenyl]-oxyethyl group]-pyrimidine-2-base amine (0.110g, LCMS measures purity＞90%), be directly used in next step.
Should rough intermediate (0.110g), L-is right-borono--phenylalanine (0.050g, 0.24mmol), yellow soda ash (0.050g, 0.48mmol) and two (the triphenylphosphine)-palladiums (II) of dichloro (8mg 0.010mmol) is dissolved in MeCN (2.0ml) and H in the microwave bottle 2The mixture of O (2.0ml).Seal this bottle, allow reaction mixture in microwave reactor, heat 6 minutes under 150 ℃.Filtering mixt, concentrated filtrate provides crude product, and this crude product is dissolved in MeOH and H 2O (1: 1), and utilize MeOH/H by preparation HPLC 2O/TFA carries out purifying as solvent systems, provide (S)-2-amino-3-[4-(2-amino-6-{2,2,2-three fluoro-1-[2-(3-phenyl-pyrazole-1-yl)-phenyl]-oxyethyl group-pyrimidine-4-yl)-phenyl]-tfa salt of propionic acid.LCMS：M+1＝575. 1H-NMR(400MHz，CD 3OD)：δ(ppm)3.20(m，1H)，3.38(m，1H)，4.30(t，1H)，6.80(s，1H)，7.00(s，1H)，7.30-7.48(m，7H)，7.62(m，3H)，7.90(m，4H)，8.10(s，1H)。
16. synthetic (S)-2-amino-3-[4-(2-amino-6-{2,2,2-three fluoro-1-[5-methoxyl group-2-(4-methyl-pyrazol-1-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid
Figure A20081010845300581
With 1-(2-bromo-5-methoxyl group-phenyl)-2,2,2-three fluoro-ethanol (0.570g, 2.0mmol), 4-methylpyrazole (0.164g, 2.0mmol), CuI (0.057g, 0.3mmol), K 2CO 3(0.580g, 4.2mmol), (1R, 2R)-N, N '-dimethyl-hexanaphthene-1, the 2-diamines (0.071g, 0.5mmol) and toluene (10ml) be incorporated in the 20ml penstock this mixture 130 ℃ (oil bath temperatures) heating 12 hours down.Mixture dilutes with ethyl acetate, uses H 2O (2 * 20ml), the salt water washing, and to dried over sodium sulfate.Remove solvent and provide crude product, utilize the hexane solution of 5-10% ethyl acetate to carry out purifying by the ISCO column chromatography, obtain 2,2,2-three fluoro-1-[5-methoxyl group-2-(4-methyl-pyrazol-1-yl)-phenyl as solvent]-ethanol (90mg).
With 2,2,2-three fluoro-1-[5-methoxyl group-2-(4-methyl-pyrazol-1-yl)-phenyl]-ethanol (0.090g, 0.31mmol), (S)-3-[4-(2-amino-6-chloro-pyrimidine-4-yl)-phenyl]-2-tert-butoxycarbonyl amino-propionic acid (0.122g, 0.31mmol), 1,4-diox (2ml), Cs 2CO 3(0.503g 1.55mmol) is incorporated in the microwave bottle, is heated to 180 ℃, lasts 45 minutes.This mixture filters and concentrates.The DCM (50ml) that adds 5% methyl alcohol to residue.Filter this mixture.Concentrated filtrate provides crude product, and this crude product places the DCM solution (30ml) of 20%TFA, stirs 30 minutes under the room temperature.LCMS indicates the reaction of required product to finish.This reaction mixture concentrates, and provides crude product, and this crude product is dissolved in MeOH and H 2O (1: 1) utilizes MeOH/H by preparation HPLC 2O/TFA carries out purifying as solvent systems, obtain (S)-2-amino-3-[4-(2-amino-6-{2,2,2-three fluoro-1-[5-methoxyl group-2-(4-methyl-pyrazol-1-yl)-phenyl]-oxyethyl group-pyrimidine-4-yl)-phenyl]-propionic acid.
LCMS：M+1＝543. 1H-NMR(400MHz，CD 3OD)：δ(ppm)2.20(s，3H)，3.22(m，1H)，3.40(m，1H)，3.84(s，3H)，4.35(t，1H)，6.84(s，1H)，6.98(m，1H)，7.18(m，1H)，7.26(m，1H)，7.40(d，1H)，7.48(d，2H)，7.66(d，2H)，7.96(d，2H).
17. synthetic (S)-2-amino-3-[4-(2-amino-6-{ (R)-2,2,2-three fluoro-1-[2-(3-methyl-pyrazol-1-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid
Figure A20081010845300591
With R-1-(2-bromo-phenyl)-2,2,2-three fluoro-ethanol (1.53g, 6mmol), the 3-methylpyrazole (0.492g, 6mmol), CuI (0.456g, 2.4mmol), K 2CO 3(2.07g, 15mmol), (1R, 2R)-N, N '-dimethyl-hexanaphthene-1, the 2-diamines (0.170g, 1.2mmol) and toluene (10ml) be incorporated in the 20ml penstock this mixture 130 ℃ (oil bath temperatures) heating 12 hours down.Reaction mixture dilutes with ethyl acetate, uses H 2O (2 * 20ml), the salt water washing, and to dried over sodium sulfate.Remove solvent and provide crude product, utilize the hexane solution of 5-10% ethyl acetate to carry out purifying by the ISCO column chromatography, obtain R-2 as solvent, 2,2-three fluoro-1-[2-(3-methyl-pyrazol-1-yl)-phenyl]-ethanol (1.8g).
With 2-amino-4, the 6-dichloro pyrimidine (1.2g, 7.4mmol), R-2,2,2-three fluoro-1-[2-(3-methyl-pyrazol-1-yl)-phenyl]-ethanol (1.8g, 7.03mmol) and NaH (0.380g 10mmol) is added into anhydrous THF (40ml) under nitrogen atmosphere.This reaction was stirred 6 hours down for 40-45 ℃, was cooled to room temperature then, and water (0.1ml) cancellation.This reaction mixture concentrates, and provides 4-chloro-6-{R-2, and 2,2-three fluoro-1-[2-(3-methyl-pyrazol-1-yl)-phenyl]-oxyethyl group]-pyrimidine-2-base amine (3.0g, LCMS measures purity＞90%), be directly used in next step.
Should rough intermediate (0.750g), L-is right-borono--phenylalanine (0.420g, 2.0mmol), yellow soda ash (0.430g, 4.0mmol) and two (the triphenylphosphine)-palladiums (II) of dichloro (30mg 0.043mmol) is dissolved in MeCN (7.0ml) and H in the microwave bottle 2The mixture of O (7.0ml).Seal this bottle, allow this reaction mixture in microwave reactor, heat 7 minutes under 150 ℃.Filtering mixt, concentrated filtrate provides crude product, and this crude product is dissolved in MeOH and H 2O (1: 1), and utilize MeOH/H by preparation HPLC 2O/TFA carries out purifying as solvent systems, provide (S)-2-amino-3-[4-(2-amino-6-{R-2,2,2-three fluoro-1-[2-(3-methyl-pyrazol-1-yl)-phenyl]-oxyethyl group-pyrimidine-4-yl)-phenyl]-tfa salt of propionic acid.LCMS：M+1＝514. 1H-NMR(400MHz，CD 3OD)：δ(ppm)2.40(s，3H)，3.30(m，1H)，3.42(m，1H)，4.38(t，1H)，6.21(s，1H)，7.02(s，1H)，7.18(m，1H)，7.54(d，1H)，7.61(m，4H)，7.82(m，2H)，7.97(d，2H)。
18. synthetic (S)-2-amino-3-[4-(2-amino-6-{1-[4-chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2-three fluoro-oxyethyl groups }-pyrimidine-4-yl)-phenyl]-propionic acid
Figure A20081010845300601
With 1-(4-chloro-2-iodo-phenyl)-2,2,2-three fluoro-ethanol (0.840g, 2.5mmol), the 3-methylpyrazole (0.230g, 2.8mmol), CuI (0.190g, 1.0mmol), K 2CO 3(0.863g, 6.25mmol), (1R, 2R)-N, N '-dimethyl-hexanaphthene-1, the 2-diamines (0.071g, 0.5mmol) and toluene (10ml) be incorporated in the 20ml penstock this mixture 130 ℃ (oil bath temperatures) heating 12 hours down.Mixture dilutes with ethyl acetate, uses H 2O (2 * 20ml), the salt water washing, and to dried over sodium sulfate.Remove solvent and provide crude product, utilize the hexane of 5-10% ethyl acetate to carry out purifying by the ISCO column chromatography, obtain 1-[4-chloro-2-(3-methyl-pyrazol-1-yl)-phenyl as solvent]-2,2,2-three fluoro-ethanol (240mg).
With 1-[4-chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2-three fluoro-ethanol (0.120g, 0.41mmol), (S)-3-[4-(2-amino-6-chloro-pyrimidine-4-yl)-phenyl]-2-tert-butoxycarbonyl amino-propionic acid (0.176g, 0.45mmol), 1,4-diox (4ml) and Cs 2CO 3(0.533g 1.64mmol) is incorporated in the 20ml sealed tube, and this mixture heated 12 hours down for 100 ℃.Concentrate this mixture.Add the DCM solution (50ml) of 10% methyl alcohol to residue, and filter this mixture.Filtrate concentrates, and provides crude product, and this crude product places THF/3N HCl (30ml/15ml), and the gained mixture stirred 12 hours down for 40-45 ℃.LCMS indicates the reaction of required product to finish.This mixture concentrates, and provides crude product, and this crude product is dissolved in MeOH and H 2O (1: 1) utilizes MeOH/H by preparation HPLC 2O/TFA carries out purifying as solvent systems, obtain (S)-2-amino-3-[4-(2-amino-6-{1-[4-chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2-three fluoro-oxyethyl groups }-pyrimidine-4-yl)-phenyl]-tfa salt of propionic acid.LCMS：M+1＝547. 1H-NMR(400MHz，CD 3OD)：δ(ppm)2.30(s，3H)，3.10-3.30(m，2H)，4.20(t，1H)，6.32(d，1H)，6.74(s，1H)，7.0(q，1H)，7.38(d，2H)，7.50(m，2H)，7.72(m，1H)，7.90(m，3H)。
19. synthetic (S)-2-amino-3-[4-(2-amino-6-{R-1-[4-chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2-three fluoro-oxyethyl groups }-pyrimidine-4-yl)-phenyl]-ethyl propionate
Figure A20081010845300611
Title compound progressively preparation as described below:
Step 1: synthetic 1-(2-bromo-4-chloro-phenyl)-2,2,2-three fluoro-ethyl ketonesIn the 500ml 2 neck RB flasks that contain anhydrous methanol (300ml) 0-5 ℃ (ice-water bath) down with 10 minutes thionyl chloride (29.2ml, 400mmol).Shift out ice-water bath, and adding 2-bromo-4-chloro-phenylformic acid (25g, 106mmol).This mixture heating up was to gentle reflux 12 hours.The reaction progress is by TLC and LCMS monitoring.After reaction is finished, concentrated reaction mixture.Crude product be dissolved in methylene dichloride (DCM, 250ml), water (50ml), saturated NaHCO 3The aqueous solution (50ml), salt solution (50ml) washing to dried over sodium sulfate, concentrate and provide 2-bromo-4-chloro-methyl benzoate (26g, 99%), are directly used in next step.
2-bromo-4-chloro-methyl benzoate (12.4g, toluene 50mmol) (200ml) are cooled to-70 ℃, and adding trifluoromethyl trimethyl silane (13ml, 70mmol).(1M 2.5ml), and makes this mixture be warmed to room temperature with 4 hours, stirs 10 hours under the room temperature thereafter to drip tetrabutyl ammonium fluoride.Concentrate this reaction mixture, provide rough [1-(2-bromo-4-chloro-phenyl)-2,2,2-three fluoro-1-methoxyl group-oxyethyl groups]-trimethylammonium-silane.Should be dissolved in methyl alcohol (100ml) by rough intermediate, and add 6N HCl (100ml).This mixture maintain 45-50 ℃ following 12 hours.Remove methyl alcohol, crude product is with methylene dichloride (200ml) extracting.The DCM layer water (50ml), the NaHCO that merge 3(50ml), salt solution (50ml) washing, and to dried over sodium sulfate.Remove solvent and provide crude product, this crude product utilizes the hexane solution of 1-2% ethyl acetate to carry out purifying as solvent by the ISCO column chromatography, obtain 1-(2-bromo-4-chloro-phenyl)-2,2,2-three fluoro-ethyl ketones (10g, 70%). 1H-NMR (300MHz, CDCl 3): δ (ppm) 7.50 (d, 1H), 7.65 (d, 1H), 7.80 (s, 1H).
Step 2: synthetic R-1-(2-bromo-4-chloro-phenyl)-2,2,2-three fluoro-ethanol(1M, in THF 280ml, (7.76g 28mmol), stirred 20 minutes under the gained mixture room temperature catecholborane under nitrogen in 2L 3-neck RB flask 280mmol) to add S-2-methyl-CBS oxazole borine.Reaction mixture is cooled to-78 ℃ (dry ice/acetone batch), and with dripping 1-(2-bromo-4-chloro-phenyl)-2,2,2-three fluoro-ethyl ketones (40g, THF solution (400ml) 139mmol) in 2 hours.Make reaction mixture be warmed to-36 ℃, under this temperature, stirred 24 hours, and further stirred other 24 hours at-32 ℃.Add 3N NaOH (250ml), cooling bath is replaced with ice-water bath.Then with the aqueous solution (250ml) that dripped 30% hydrogen peroxide in 30 minutes.Shift out ice-water bath, stirred 4 hours under this mixture room temperature.Separate organic layer, the concentrated ether (200ml) that also is dissolved in again.Water layer is with ether extracting (2 * 200ml).The organic layer that merges with the 1N NaOH aqueous solution (4 * 100ml), the salt water washing, and to dried over sodium sulfate.Remove solvent, provide crude product, this crude product utilizes the hexane of 2-5% ethyl acetate to carry out purifying as solvent by column chromatography, provide required pure 36.2g (90%, e.e.＞95%).Alcohol (36.2g) obtains R-1-(2-bromo-4-chloro-phenyl)-2,2,2-three fluoro-ethanol 28.2g (70% from hexane (80ml) crystallization; 99-100%e.e.). 1H-NMR(400MHz，CDCl 3)δ(ppm)5.48(m，1H)，7.40(d，1H)，7.61(d，2H)。
Step 3: synthetic R-1-[4-chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2-three fluoro-second AlcoholWith R-1-(2-bromo-4-chloro-phenyl)-2,2,2-three fluoro-ethanol (15.65g, 54.06mmol), the 3-methylpyrazole (5.33g, 65mmol), CuI (2.06g, 10.8mmol), K 2CO 3(15.7g, 113.5mmol), (1R, 2R)-N, N '-dimethyl-hexanaphthene-1, the 2-diamines (1.54g, 10.8mmol) and toluene (80ml) be incorporated in the 250ml penstock, and be heated to 130 ℃ (oil bath temperatures), last 12 hours.Reaction mixture dilutes with ethyl acetate, uses H 2O (4 * 100ml), the salt water washing, and to dried over sodium sulfate.Obtain crude product after removing solvent, this crude product utilizes the hexane solution of 5-10% ethyl acetate to carry out purifying as solvent by the ISCO column chromatography, obtain R-1-[4-chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2-three fluoro-ethanol (13.5g; 86%). 1H-NMR(400MHz，CDCl 3)：δ(ppm)2.30(s，3H)，4.90(m，1H)，6.20(s，1H)，6.84(d，1H)，7.20(s，1H)，7.30(d，1H)，7.50(d，1H)。
Step 4: synthetic (S)-2-amino-3-[4-(2-amino-6-{R-1-[4-chloro-2-(3-methyl-pyrazoles -1-yl)-and phenyl]-2,2,2-three fluoro-oxyethyl groups }-pyrimidine-4-yl)-phenyl]-ethyl propionateR-1-[4-chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2-three fluoro-ethanol (17.78g, 61.17mmol), (S)-3-[4-(2-amino-6-chloro-pyrimidine-4-yl)-phenyl]-2-tert-butoxycarbonyl amino-propionic acid (20.03g, 51mmol), 1,4-diox (250ml) and Cs 2CO 3(79.5g 244mmol) is incorporated in the 3-neck 500ml RB flask and is heated to 100 ℃ (oil bath temperatures), lasts 12-24 hour.The reaction progress is monitored by LCMS.After reaction was finished, this mixture was cooled to 60 ℃, added (250ml) and THF (400ml).Separate organic layer, and wash with salt solution (150ml).Remove the product that solvent provides rough BOC protection, this product places THF (400ml), 3N HCl (200ml).Mixture 35-40 ℃ was heated 12 hours down.Vacuum is removed THF.(2 * 100ml) washings concentrate separately the residue water layer, reclaim unreacted alcohol (3.5g) with isopropyl acetate.From moisture fraction, remove the residue organic solvent of trace under the vacuum.
In the 1L beaker that temperature controller and pH meter are housed, add H 3PO 4(40ml, 85% the aqueous solution) and water (300ml) add the aqueous solution of 50%NaOH then, regulate pH to 6.15.Temperature is increased to 58 ℃, drips above-mentioned acidic aqueous solution in damping fluid, adds the aqueous solution of 50%NaOH simultaneously, makes pH maintain between the 6.1-6.3.After adding is finished, the solid of filtering-depositing, with hot water (50-60 ℃) (2 * 200ml) washings, drying obtain rough (S)-2-amino-3-[4-(2-amino-6-{R-1-[4-chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2-three fluoro-oxyethyl groups }-pyrimidine-4-yl)-phenyl }-propionic acid (26.8g; 95%).LCMS and HPLC analysis revealed, compound purity is about 96-97%.
In dehydrated alcohol (400ml), drip SOCl under 0-5 ℃ 2(22ml, 306mmol).The crude acid (26.8g) that adds above-mentioned reaction.Shift out ice-water bath, reaction mixture 40-45 ℃ was heated 6-12 hour down.After reaction was finished, vacuum was removed ethanol.Add frozen water (300ml) to residue, and with isopropyl acetate (2 * 100ml) extractings.The saturated Na of this aqueous solution 2CO 3PH to 6.5 is regulated in neutralization.Ethyl acetate (2 * 300ml) extractings of this solution.The ethyl acetate layer salt water washing that merges concentrates and obtains the rough ester of 24g (HPLC purity 96-97%).Then, rough ester utilizes 5% alcoholic acid DCM solution to carry out purifying as solvent by the ISCO column chromatography, obtain (S)-2-amino-3-[4-(2-amino-6-{R-1-[4-chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2-three fluoro-oxyethyl groups }-pyrimidine-4-yl)-phenyl }-ethyl propionate (20.5g; 70%; HPLC purity 98%).LCMS M+1＝575. 1H-NMR(400MHz，CD 3OD)：δ(ppm)1.10(t，3H)，2.25(s，3H)，2.85(m，2H)，3.65(m，1H)，4.00(q，2H)，6.35(s，1H)，6.60(s，1H)，6.90(m，1H)，7.18(d，2H)，7.45(m，2H)，7.70(d，1H)，7.85(m，3H)。
20. synthetic (S)-2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl isophthalic acid H-pyrazol-1-yl) phenyl)-2,2,2-trifluoro ethoxy) pyrimidine-4-yl) phenyl) propionic acid
Figure A20081010845300641
(S)-2-amino-3-[4-(2-amino-6-{R-1-[4-chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2-three fluoro-oxyethyl groups }-pyrimidine-4-yl)-phenyl }-(22.2g 38.6mmol) is dissolved in THF (220ml) and water (50ml) to ethyl propionate.The adding lithium hydroxide monohydrate (5.56g, 132mmol).Stirred 12 hours under the reaction mixture room temperature.Remove THF, (100ml) is added in the residue with water, obtains settled solution.
Add H to the 1L beaker that temperature controller and pH meter are housed 3PO 4(40ml, 85%, the aqueous solution), the aqueous solution of water (300ml) and 50%NaOH, regulate pH to 6.15.Temperature is increased to 58 ℃, drips the Li-salt brine solution of this compound in damping fluid, adds 3N HCl simultaneously, makes pH maintain 6.1-6.2.After adding is finished, the solid of filtering-depositing, with hot water (50-60 ℃) (2 * 200ml) washings, and it is dry, obtain (S)-2-amino-3-[4-(2-amino-6-{R-1-[4-chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2-three fluoro-oxyethyl groups }-pyrimidine-4-yl)-phenyl }-propionic acid (19.39g; 92%).LCMS and HPLC analysis revealed, the about 98-99% of this compound purity.LCMS M+1＝547. 1H-NMR(400MHz，CD 3OD)：δ(ppm)2.40(s，3H)，3.22-3.42(m，2H)，4.38(t，1H)，6.42(s，1H)，7.10(s，1H)，7.21(m，1H)，7.60(m，4H)，7.81(d，1H)，7.92(m，3H)。
21. synthetic (S)-2-amino-3-(4-{2-amino-6-[2,2,2-three fluoro-1-(2-thiazol-2-yl-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid
Figure A20081010845300651
In the 40ml microwave reactor, add 1.04g 2-formylphenyl boric acid (6.9mmol) 1.14g 2-bromo thiazole (6.9mmol), 240mg bi triphenyl-phosphine dichloride palladium (Pd (PPh 3) 2Cl 2, 0.34mmol).Then, add 13.8ml 1M Na to this mixture 2CO 3(13.8mmol) with 10ml CH 3CN.Sealed reactor is reflected at the following 160 ℃ of operations of microwave 5 minutes.LCMS shows that the reaction of required product finishes.Then, this reaction mixture is poured into separatory funnel.Add 200ml methylene dichloride and 100ml water, be used for extracting.Dichloromethane layer is to MgSO 4Dry.Remove solvent and provide crude product, this crude product carries out purifying by silica gel column chromatography with hexane/ethyl acetate mixture (5/1 to 2/1) wash-out, obtains pure 2-thiazol-2-yl-phenyl aldehyde (0.5g, yield: 38%).
Add 184mg 2-thiazol-2-yl-phenyl aldehyde (0.97mmol) and 10ml anhydrous tetrahydro furan (THF) to the 50ml round-bottomed flask.Then, the THF solution (0.02mmol) that adds 145.4mg trifluoromethyl trimethyl silane (1.02mmol) and 20 μ l 1M tert-butyl Neutral ammonium fluorides to this solution.Stir under this mixture room temperature and spend the night, add 10ml 1N HCl thereafter, stirred 15 minutes under the reaction mixture room temperature.Vacuum is removed THF, the methylene dichloride extracting (3 * 50ml) of this mixture.The CH that merges 2Cl 2Layer is to MgSO 4Dry.Remove solvent and provide the 262mg crude product, purity is about 95%, and is used for next step, need not to be further purified.
In the 50ml sealed tube, with 2,2,2-three fluoro-1-(2-thiazol-2-yl-phenyl)-ethanol (260mg, 1mmol), (S)-3-[4-(2-amino-6-chloro-pyrimidine-4-yl)-phenyl]-2-tert-butoxycarbonyl amino-propionic acid (390mg, 1mmol), (1.3g, 4mmol) with 10ml 1, the 4-diox mixes cesium carbonate.Reaction mixture heated 3 days down for 100 ℃.Add entry (20ml), slowly add the 1N HCl aqueous solution then, regulate pH to 4, vacuum removes 1 then, 4-diox, the methylene dichloride extracting (3 * 50ml) of gained mixture.The dichloromethane layer that merges is to MgSO 4Dry.Remove solvent and provide crude product, this crude product places next step reaction, need not to be further purified.
Above-mentioned crude product is dissolved in the 5ml methylene dichloride, adds the 0.4ml trifluoroacetic acid.Stir under the mixture room temperature and spend the night.Vacuum is removed trifluoroacetic acid then, provides crude product, and this crude product provides the 63mg pure products by the preparation HPLC purifying.HPLC; YMC Pack ODS-A 3 * 50mm, 7um; Solvent orange 2 A=the contain water of 0.1%TFA; Solvent B=contains the methyl alcohol of 0.1%TFA.Solvent B was with 4 minutes from 10 to 90%; Flow velocity=2ml/ minute; RT=3 minute.HPLC purity=100%.LCMS：M+1＝515.9。 1H NMR(400MHz，CD 3OD)δ 8.06ppm(2H，m)；7.92(2H，d，J＝8Hz)；7.84(1H，m)；7.81(1H，m)；7.77(1H，d，J＝4Hz)；7.57(2H，m)；7.45(2H，d，J＝8Hz)；6.84(1H，s)；4.30(2H，dd，J＝8Hz)；3.38(2H，dd，J＝12,2Hz)；3.23(2H，dd，J＝12,8Hz)。
22. synthetic (S)-2-amino-3-[4-(2-amino-6-{2,2,2-three fluoro-1-[2-(pyridin-3-yl oxygen base)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid; (S)-2-amino-3-[4-(2-amino-6-{2,2,2-three fluoro-1-[4-(pyridin-3-yl oxygen base)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid; (S)-2-amino-3-[4-(6-{2,2,2-three fluoro-1-[4-(pyridin-3-yl oxygen base)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid; (S)-2-amino-3-(4-{2-amino-6-[2,2,2-three fluoro-1-(4-thiophene-2-base-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid; (S)-2-amino-3-(4-{6-[2,2,2-three fluoro-1-(4-imidazoles-1-base-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid; (S)-2-amino-3-(4-{2-amino-6-[2,2,2-three fluoro-1-(4-[1,2,4] triazol-1-yl-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid
Figure A20081010845300671
Figure A20081010845300672
Utilize following general approach to prepare title compound:
In this approach, in the mixture of the THF solution of phenyl aldehyde (1 equivalent) that replaces and trifluoromethyl trimethyl silane (1.2 equivalent), 0 ℃ of adding four-just-butyl Neutral ammonium fluoride (0.05 equivalent) down.Allow temperature be warmed to room temperature then.Stirred 5 hours under this mixture room temperature, then with the ethyl acetate dilution, water, salt water washing, and use MgSO 4Dry.Decompression goes down to desolventize, and provides three fluoro-alcohol crude product, and this crude product is used for next step, need not to be further purified.
It is anhydrous 1 that the alcohol of above-mentioned preparation (1 equivalent) is dissolved in, the 4-diox.Add sodium hydride (60% mineral oil solution, 1.2 equivalents) immediately, stirred 30 minutes under this mixture room temperature.Add 2-amino-4,6-dichloro pyrimidine (1 equivalent), the gained mixture stirred 2 hours down for 80 ℃.Remove solvent, residue is suspended in ethyl acetate, washes with water, to MgSO 4Drying concentrates then and provides required monochloride product, and this product is used for next step, need not to be further purified.
To containing 4-borono--L-phenylalanine (1 equivalent), Na 2CO 3Add above-mentioned crude product (1 equivalent) in the 5ml microwave bottle of two (the triphenylphosphine)-palladiums (0.05 equivalent) of (2 equivalent), acetonitrile (2ml), water (2ml) and dichloro.This bottle adds cap, under 150 ℃ in this mixture with microwave irradiation heating 5 minutes.This mixture cooling is filtered by injection filter, then by anti-phase preparation type-HPLC, utilizes YMC-Pack ODS 100 * 30mm ID post (MeOH/H 2The O/TFA solvent systems) separates.Pure fraction merges, vacuum concentration.Then this product is suspended in 5ml water, freezing and freeze-drying provides trifluoroacetic acid (TFA) salt of product.
(S)-2-amino-3-[4-(2-amino-6-{2,2,2-three fluoro-1-[2-(pyridin-3-yl oxygen base)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl }-propionic acid. 1H-NMR(400MHz，CD 3OD)δ：3.05-3.40(m，2H)，3.81(m，1H)，6.64(s，1H)，7.01(d，1H)，7.15-7.54(m，7H)，7.74(d，1H)，7.94(d，2H)，8.35(m，2H)。
(S)-2-amino-3-[4-(2-amino-6-{2,2,2-three fluoro-1-[4-(pyridin-3-yl oxygen base)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl }-propionic acid. 1H-NMR(400MHz，CD 3OD)δ：3.20-3.41(m，2H)，4.30(m，1H)，6.81(m，2H)，7.17(m，2H)，7.46-7.69(m，6H)，7.93(d，2H)，8.41(s，2H)。
(S)-2-amino-3-[4-(6-{2,2,2-three fluoro-1-[4-(pyridin-3-yl oxygen base)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl }-propionic acid. 1H-NMR(300MHz，CD 3OD)δ：3.15-3.35(m，2H)，4.25(t，1H)，6.90(q，1H)，7.25(d，2H)，7.45(d，2H)，7.71(m，3H)，7.99(m，3H)，8.14-8.18(m，1H)，8.55(d，1H)，8.63(d，1H)，8.84(d，1H)。
(S)-2-amino-3-[4-(2-amino-6-{2,2,2-three fluoro-1-(4-thiophene-2-base-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl }-propionic acid. 1H-NMR(400MHz，CD 3OD)δ：3.03-3.31(m，2H)，4.19(m，1H)，6.68(m，2H)，7.00(m，1H)，7.31-7.36(m，4H)，7.52(m，2H)，7.62(d，2H)，7.85(d，2H)。
(S)-2-amino-3-(4-{6-[2,2,2-three fluoro-1-(4-imidazoles-1-base-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid. 1H-NMR(400MHz，CD 3OD)δ：3.03-3.31(m，2H)，4.19(m，1H)，6.88(m，1H)，7.32-8.63(m，11H)，8.64(s，1H)，9.25(s，1H)。
(S)-2-amino-3-(4-{2-amino-6-[2,2,2-three fluoro-1-(4-[1,2,4] triazol-1-yl-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid. 1H-NMR(400MHz，CD 3OD)δ：3.07-3.36(m，2H)，4.16(m，1H)，6.65(s，1H)，6.75(m，1H)，7.31(d，2H)，7.69(d，2H)，7.85(m，4H)，8.08(s，1H)，9.03(s，1H)。
23. synthetic (S)-2-amino-3-(4-{2-amino-6-[2,2,2-three fluoro-1-(4-fluoro-2-thiene-3-yl--phenyl) oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid; (S)-2-amino-3-[4-(2-amino-6-{2,2,2-three fluoro-1-[4-fluoro-2-(4-methyl-thiophene-2-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid; (S)-2-amino-3-[4-(2-amino-6-{1-[2-(3,5-dimethyl-isoxazole-4-base)-4-fluoro-phenyl]-2,2,2-three fluoro-oxyethyl groups }-pyrimidine-4-yl)-phenyl]-propionic acid
Figure A20081010845300701
Figure A20081010845300702
Utilize following general approach to prepare title compound:
Figure A20081010845300703
In this approach, the phenyl aldehyde (1 equivalent) that bromine is replaced is added into 20ml microwave bottle, and this bottle contains heteroaromatic boric acid (1 equivalent), Na 2CO 3Two (the triphenylphosphine)-palladiums (0.05 equivalent) of (2 equivalent), acetonitrile (8ml)/water (8ml) and dichloro.This bottle adds cap, and stirs 6 minutes down at 150 ℃ with microwave irradiation.The reaction mixture cooling is filtered by injection filter, dilutes with ethyl acetate then.Wash with water.Add the preparation of silica gel plug then, and carry out purifying with hexane and eluent ethyl acetate by chromatogram.
Then, the aldehyde of above-mentioned preparation experience embodiment 22 described identical reactions.
(S)-2-amino-3-(4-{2-amino-6-[2,2,2-three fluoro-1-(4-fluoro-2-thiene-3-yl--phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid. 1H-NMR(400MHz，CD 3OD)δ：3.08-3.30(m，2H)，4.19(m，1H)，6.61(s，1H)，6.84(m，1H)，7.02-7013(m，2H)，7.22(dd，1H)，7.32(d，2H)，7.47(m，1H)，7.77(m，1H)，7.84(d，2H)。
(S)-2-amino-3-(4-{2-amino-6-{2,2,2-three fluoro-1-(4-fluoro-2-(4-methyl-thiophene-2-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl }-phenyl)-propionic acid. 1H-NMR(400MHz，CD 3OD)δ：2.26(s，3H)，3.09-3.30(m，2H)，4.20(m，1H)，6.64(s，1H)，6.95(m，2H)，7.13(m，3H)，7.34(d，2H)，7.69(m，1H)，7.83(d，2H)。
(S)-2-amino-3-[4-(2-amino-6-{1-[2-(3,5-dimethyl-isoxazole-4-base)-4-fluoro-phenyl]-2,2,2-three fluoro-oxyethyl groups }-pyrimidine-4-yl)-phenyl]-propionic acid. 1H-NMR(400MHz，CD 3OD)δ：1.89-2.19(m，6H)，2.97-3.30(m，2H)，3.83(m，1H)，6.55(d，1H)，6.74-6.87(m，1H)，7.00(m，1H)，7.7.24-7.33(m，3H)，7.88(m，3H)。
24. synthetic (S)-2-amino-3-[4-(2-amino-6-{2,2,2-three fluoro-1-[5-fluoro-2-(3-methyl-pyrazol-1-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid
Figure A20081010845300721
2-bromo-5-fluoro-methyl benzoate (1g, 4.292mmol), NaBH 4(0.423g, 11.159mmol) and LiCl (0.474g stirs under the mixture room temperature of THF/EtOH solution (20ml/10ml) 11.159mmol) and spends the night.The adding HCl aqueous solution (10ml, 2N), stir about 10 minutes.Remove organic solvent under the rough vacuum then.The residue dilute with water, and with the ethyl acetate extracting.Organic layer NaHCO 3The aqueous solution (10%), water and salt water washing, dry then (MgSO 4), and concentrate and to obtain 852mg (96.8% thick yield) crude product, (2-bromo-5-fluoro-phenyl) methyl alcohol of white solid, use need not to be further purified.
(0.852g, the solution of DCM 4.156mmol) (15ml) adds MnO to (2-bromo-5-fluoro-phenyl) methyl alcohol 2(4.254g, 85%, 41.56mmol).Stirred two days under this mixture room temperature, filter then and wash with DCM.Filtrate concentrating obtains 777mg 2-bromo-5-fluoro-phenyl aldehyde (92% yield).(0.777g 3.828mmol) is dissolved in anhydrous THF (10ml), and is cooled to 0 ℃ with freshly prepd aldehyde then.Add the trifluoromethyl trimethyl silane (1.13ml, 7.656mmol), then add tetrabutyl ammonium fluoride (0.020g, 0.076mmol).Allow temperature be warmed to room temperature.Stirred 5 hours under this mixture room temperature, then with the ethyl acetate dilution, water, salt water washing, and through MgSO 4Dry.Decompression goes down to desolventize, and obtains crude product (2-bromo-5-fluoro-phenyl) 2,2,2-three fluoro-ethanol, and 1.1g (90% purity) is used for next step, need not to be further purified.
With (2-bromo-5-fluoro-phenyl) 2,2,2-three fluoro-ethanol (0.990g, 3.263mmol, 90%), 3-methylpyrazole (0.476g, 4.895mmol), CuI (0.367g, 1.632mmol), K 2CO 3(1.334g, 8.158mmol), (1R, 2R)-N, N '-dimethyl-hexanaphthene-1, the 2-diamines (0.110g, 0.653mmol) and toluene (10ml) be incorporated in the 20ml microwave bottle then sealing, 180 ℃ of heating 40 minutes down.This mixture filters, and washs with ethyl acetate.Filtrate water washing 3 times adds the preparation of silica gel plug then.This compound utilizes the hexane solution of 5-10% ethyl acetate to carry out purifying as solvent by the ISCO column chromatography, obtains 1-(5-fluoro-2-(3-methyl-pyrazol-1-yl)-phenyl)-2,2,2-three fluoro-ethanol 75mg. 1H-NMR(400MHz，CDCl 3)δ：2.29(s，3H)，4.90(m，1H)，6.21(d，1H)，7.07-7.11(m，1H)，7.19-7.22(m，1H)，7.29-7.32(m，1H)，7.51(d，1H)。
The alcohol of above-mentioned preparation (0.075g, 0.273mmol) be dissolved in anhydrous 1,4-diox (3ml).Add sodium hydride (0.013g, 0.328mmol, 60% mineral oil solution) immediately, stirred 30 minutes under this mixture room temperature.Add 2-amino-4, and 6-two chloro-pyrimidines (0.045g, 0.273mmol).80 ℃ of following stir abouts of this mixture 2 hours.Remove solvent, residue is suspended in ethyl acetate, wash with water, and to MgSO 4Drying concentrates then and provides required monochloride product 100mg (0.249mmol), this product be added into contain 4-borono--L-phenylalanine (0.052g, 0.249mmol), Na 2CO 3(0.053g, 0.498mmol), (5mg is in 5ml microwave bottle 0.007mmol) for two (the triphenylphosphine)-palladiums of acetonitrile (2ml)/water (2ml) and dichloro.This bottle adds cap, and under microwave irradiation 150 ℃ stirred 5 minutes.The reaction mixture cooling is filtered by injection filter, utilizes YMC-Pack ODS 100 * 30mmID post (MeOH/H by anti-phase preparation type-HPLC then 2The O/TFA solvent systems) separates.The pure fraction of vacuum concentration.This product is suspended in 5ml water then, freezing and freeze-drying, provide (S)-2-amino-3-[4-(2-amino-6-{ (R)-1-[5-fluoro-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2-three fluoro-oxyethyl groups }-pyrimidine-4-yl)-phenyl }-triflate salt of propionic acid, 37mg. 1H-NMR(400MHz，CD 3OD)：δ2.29(s，3H)，3.08-3.30(m，2H)，4.19(q，1H)，6.32(d，1H)，6.82(s，1H)，6.85(m，1H)，7.26(m，1H)，7.33(d，2H)，7.42(m，2H)，7.75(d，1H)，7.87(d，2H)。
25. synthetic (S)-2-amino-3-[4-(2-amino-6{2,2,2-three fluoro-1-[5-chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid
Figure A20081010845300731
The title compound preparation is from R-1-[5-chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2-three fluoro-ethanol are to utilize R-1-[4-chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2, the above-mentioned identical approach preparation of 2-three fluoro-alcoholic acid.Particularly, R-1-[5-chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2-three fluoro-ethanol (0.959g, 3.318mmol) be dissolved in anhydrous 1, in the 4-diox (8ml).Add sodium hydride (0.159g, 3.982mmol, 60% mineral oil solution) immediately, stirred 30 minutes under this mixture room temperature.Add 2-amino-4, and 6-two chloro-pyrimidines (0.544g, 3.318mmol).80 ℃ of following stir abouts of mixture 2 hours.Remove solvent, residue is suspended in ethyl acetate, washes with water, to MgSO 4Drying concentrates then, provides required monochloride product 1.38g, directly uses, and need not to be further purified.
With the monochloride of above-mentioned preparation (0.460g 1.104mmol) is added into 20ml microwave bottle, this bottle contain 4-borono--L-phenylalanine (0.277g, 1.325mmol), Na 2CO 3(0.234g, 2.208mmol), two (the triphenylphosphine)-palladiums of acetonitrile (8ml)/water (8ml) and dichloro (0.039g, 0.055mmol).This bottle adds cap, and mixture stirred 10 minutes down at 150 ℃ with microwave irradiation.The mixture cooling is filtered by injection filter, then by anti-phase preparation type-HPLC, utilizes YMC-Pack ODS 100 * 30mm ID post (MeOH/H 2The O/TFA solvent systems) separates.The pure fraction of vacuum concentration.This product is suspended in the 5ml water then, freezing and freeze-drying, provide 580mg (S)-2-amino-3-[4-(2-amino-6-{R-1-[5-chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2-three fluoro-oxyethyl groups }-pyrimidine-4-yl)-phenyl-propionic acid. 1H-NMR(400MHz，CD 3OD)：δ2.40(s，3H)，3.29-3.46(m，2H)，4.38(q，1H)，6.45(d，1H)，7.09(s，1H)，7.24(m，1H)，7.53-7.70(m，4H)，7.82(s，1H)，7.90(d，1H)，7.97(d，2H)。
26. synthetic (S)-2-amino-3-[4-(2-amino-6-{2,2,2-three fluoro-1-[4-(2-oxo-tetramethyleneimine-1-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid
Figure A20081010845300741
4-(2-oxygen-tetramethyleneimine-1-yl)-phenyl aldehyde (500mg, THF 2.64mmol) (20ml) solution is cooled to 0 ℃, and adding trifluoromethyl trimethyl silane (375mg, 2.64mmol).Drip tetrabutyl ammonium fluoride (1M 0.1ml), allows this mixture be warmed to room temperature with 1 hour, under the room temperature further stirring spend the night.After reaction is finished, add 3N HCl (5ml), this reaction mixture stirred 2 hours.Concentrate this mixture.Add water (20ml), this mixture with the EtOAc extracting (2 * 20ml), use NaHCO 3(20ml), salt solution (20ml) washing, and, concentrate and obtain the required product of 590mg dried over sodium sulfate, this product is used for next step, need not to be further purified (yield: 86%).
4, and 6-two chloro-pyrimidine-2-base amine (700mg, 2.69mmol), NaH (194mg, 8.07mmol, 60%) and 1-(4-(2,2,2-three fluoro-1-hydroxyl-ethyls)-phenyl)-(441mg stirs under anhydrous THF (10ml) solution room temperature 2.69mmol) and spends the night pyrrolidin-2-one.After reaction was finished, THF was removed in decompression down.Add entry (10ml), this mixture is cooled to 0 ℃ simultaneously.This mixture methylene dichloride extracting (2 * 40ml) then.The organic solution that merges is to Na 2SO 4Dry.Remove solvent and obtain the required product of 498mg, purity 92%, this product is used for next step, need not to be further purified (yield 498mg, 48%).
Microwave (20ml) is equipped with 1-(4-(2-amino-6-chloro-pyrimidine-4-base oxygen base)-2 with Emrys processing bottle (Emrys process vial), 2,2-three fluoro-ethyls)-phenyl)-pyrrolidin-2-one (200mg, 0.51mmol), 4-borono--L-phenylalanine (108mg, 0.51mmol) and the 5ml acetonitrile.Add 5ml aqueous sodium carbonate (1M) to above-mentioned solution, then add two (the triphenylphosphine)-palladiums (II) of 5mol% dichloro.Sealed reaction vessel, and be heated to 160 ℃ with microwave irradiation, last 7 minutes.After the cooling, evaporation reaction mixture is to doing.Residue is dissolved in 4ml methyl alcohol, and uses the Prep-LC purifying, provides 153mg product (yield 58%). 1H-NMR(400MHz，CD 3OD)：δ(ppm)2.1(m，2H)，2.5(t，2H)，3.05-3.4(m，2H)，3.85(t，2H)，4.2(m，1H)，6.6(m，1H)，6.75(s，1H)，7.3(d，2H)，7.5(d，2H)，7.6(d，2H)，7.9(d，2H)。
27. synthetic (S)-2-amino-3-[4-(2-amino-6-{ (R)-2,2,2-three fluoro-1-[5-fluoro-2-(3-methyl-pyrazol-1-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid
Figure A20081010845300761
With R-1-(2-bromo-5-fluoro-phenyl)-2,2,2-three fluoro-ethanol (4.0g, 14.65mmol), the 3-methylpyrazole (1.56g, 19.04mmol), CuI (0.557g, 2.93mmol), K 2CO 3(4.25g, 30.76mmol), (1R, 2R)-N, N '-dimethyl-hexanaphthene-1, the 2-diamines (0.416g, 2.93mmol) and toluene (15ml) place the 50ml sealed tube, 130 ℃ of (oil bath temperatures) heating of gained mixture two days.Mixture dilutes with ethyl acetate, uses H 2O (4 * 30ml), the salt water washing, and to dried over sodium sulfate.Remove solvent and provide crude product, this crude product utilizes the hexane solution of 5-10% ethyl acetate to carry out purifying as solvent by the ISCO column chromatography, obtains 1.75g R-2,2,2-three fluoro-1-[5-fluoro-2-(3-methyl-pyrazol-1-yl)-phenyl]-ethanol (yield: 44%). 1H-NMR(400MHz，CDCl 3)：δ(ppm)2.35(s，3H)，5.0(m，1H)，6.3(s，1H)，7.1(m，1H)，7.20(s，1H)，7.35(d，1H)，7.50(s，1H)。
With 4,6-two chloro-pyrimidine-2-base amine (938mg, 5.72mmol), NaH (188mg, 1.5 equivalent 8.17mmol, 60%) and R-2,2,2-three fluoro-1-[5-fluoro-2-(3-methyl-pyrazol-1-yl)-phenyl]-ethanol (1.5g, 1 equivalent 5.45mmol) stirred 10 minutes under anhydrous THF (10ml) the solution room temperature, 50 ℃ of following stirrings are spent the night then.After reaction was finished, THF was removed in decompression down.Add this reaction of entry (10ml) cancellation.This mixture is with methylene dichloride (2 * 40ml) extractings then.The organic solution that merges is to Na 2SO 4Dry.Remove solvent and provide required product, purity 92%, this product need not purifying and is used for next step (yield: 85%).
Microwave is equipped with chloro-6-R-2 with Emrys processing bottle (20ml), 2,2-three fluoro-1-(5-fluoro-2-(3-methyl-pyrazol-1-yl)-phenyl)-oxyethyl group)-pyrimidine-2-base amine (2.18g, 5.45mmol), 4-borono--L-phenylalanine (1.13g, 5.45mmol), add yellow soda ash (1M10.90ml, 2 equivalents) to above-mentioned solution, (191mg is 0.27mmol) with 5ml acetonitrile and 5ml H then to add two (the triphenylphosphine)-palladiums (II) of 5mol% dichloro 2O.Under the sealed reaction vessel, 160 ℃ in this mixture with microwave irradiation heating 10 minutes.After the cooling, reaction mixture is evaporated to dried.Residue is dissolved in H 2O (10ml) and with the ether extracting.Discard the ether layer.Vacuum is removed most of water of aqueous phase then, then adds 10ml methyl alcohol.Crude product carries out purifying through Prep-HPLC, obtains 1.163g (yield 75%) product. 1H-NMR(400MHz，CD 3OD)：δ(ppm)2.4(s，3H)，3.35(m，1H)，3.5(m，1H)，4.36(m，1H)，6.4(s，1H)，7.0(s，1H)，7.1(m，1H)，7.4(m，1H)，7.55(m，4H)，7.85(s，1H)，8.0(d，2H)。
28. synthetic (S)-2-amino-3-[4-(2-amino-6-{2,2,2-three fluoro-1-[4-(6-methoxyl group-pyridine-2-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid
Figure A20081010845300771
(213mg, 1mmol) (0.2ml, 0 ℃ adds tetrabutyl ammonium fluoride (TBAF) (0.1ml, the THF solution of 1M) down in 10ml THF solution 1.2mmol) with the trifluoromethyl trimethyl silane to 4-(6-methoxyl group-pyridine-2-yl)-phenyl aldehyde.This mixture is warm until room temperature, and stirs 4 hours.Then, this reaction mixture is handled and is stirred and spend the night with 12ml 1M HCl.The ethyl acetate extracting (3 * 20ml) of this product.Separate organic layer, and to dried over sodium sulfate.The evaporation organic solvent provides 0.25g 1-[4-(6-methoxyl group-pyridine-2-yl)-phenyl]-2,2,2-three fluoro-ethanol are directly used in next step, need not purifying.Yield: 90%.
To 1-[4-(6-methoxyl group-pyridine-2-yl)-phenyl]-2,2, (67mg, 10ml 0.2mmol) is anhydrous 1, adds Cs in the 4-dioxane solution for 2-three fluoro-ethanol 2CO 3(375mg, 1mmol).This mixture stirred 5 minutes, added (S)-3-[4-(2-amino-6-chloro-pyrimidine-4-yl)-phenyl then]-2-tert-butoxycarbonyl amino-propionic acid (78mg, 0.2mmol), 110 ℃ of following heated overnight of this mixture.After the cooling, add 5ml water, ethyl acetate (20ml) is used for extract product.Organic layer is to dried over sodium sulfate.Remove solvent by centrifugal distiller, provide 112mg (S)-3-[4-(2-amino-6-{2,2,2-three fluoro-1-[4-(6-methoxyl group-pyridine-2-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-2-tert-butoxycarbonyl amino-propionic acid (yield: 88%).
Above-mentioned product (112mg) is added into 5ml 30%TFA/DCM solution.After reaction was finished, evaporating solvent provided crude product, this crude product is by the preparation HPLC purifying, provide 5mg (S)-2-amino-3-[4-(2-amino-6-{2,2,2-three fluoro-1-[4-(6-methoxyl group-pyridine-2-yl)-phenyl]-oxyethyl group-pyrimidine-4-yl)-phenyl] propionic acid. 1H NMR(300MHz，CD 3OD)δ(ppm)8.18(d，J＝8.4Hz，2H)，7.94(d，J＝8.4Hz，2H)，7.74(m，3H)，7.60(d，J＝8.4Hz，2H)，7.52(d，J＝7.2Hz，1H)，7.08(s，1H)，6.86(m，1H)，6.82(d，J＝8.1Hz 1H)，4.37(t，1H)，4.03(s，3H)，3.5(m，2H)。
29. synthetic (S)-2-amino-3-[4-(2-amino-6-{2,2,2-three fluoro-1-[2-fluoro-4-(5-methoxyl group-pyridin-3-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid
Figure A20081010845300781
Be added under 0 ℃ of the TBAF (0.1ml) 4-bromo-2-fluoro-phenyl aldehyde (2.03g, 10mmol) and TMSCF 3(20ml, 10ml THF solution 12mmol).The mixture that forms is warm until room temperature, and stirs 4 hours.This reaction mixture is handled with 12ml 3M HCl then, and stirs and spend the night.Ethyl acetate (3 * 20ml) extractings of this product.Separate organic layer, and to dried over sodium sulfate.The evaporation organic solvent provides 2.4g 1-(4-bromo-2-fluoro-phenyl)-2,2,2-three fluoro-ethanol (yields: 90%).
To 1-(4-bromo-2-fluoro-phenyl)-2,2, and 2-three fluoro-ethanol (1.4g, 10ml 5.2mmol) is anhydrous 1, and the 4-dioxane solution adds Cs 2CO 3(8.45g, 26mmol), this mixture stirred 5 minutes, added (S)-3-[4-(2-amino-6-chloro-pyrimidine-4-yl)-phenyl then]-2-tert-butoxycarbonyl amino-propionic acid (2.0g, 5mmol), 110 ℃ of following heated overnight of gained mixture.After the cooling, add 5ml water, ethyl acetate (20ml) is used for extract product.Organic layer is to dried over sodium sulfate.Remove solvent by centrifugal distiller, provide 2.6g (S)-3-(4-{2-amino-6-[1-(4-bromo-2-fluoro-phenyl)-2,2,2-three fluoro-oxyethyl groups]-pyrimidine-4-yl phenyl) 2-tert-butoxycarbonyl amino-propionic acid (yield: 82%).
Microwave bottle (2ml) is equipped with (S)-3-(4-{2-amino-6-[1-(4-bromo-2-fluoro-phenyl)-2,2,2-three fluoro-oxyethyl groups]-pyrimidine-4-yl }-phenyl)-2-tert-butoxycarbonyl amino-propionic acid (130mg, 0.2mmol), 3-methoxyl group-5-(4,4,5,5-tetramethyl--[1,3,2] dioxy boron penta ring-2-yl)-and pyridine (70mg, 0.3mmol), 1ml acetonitrile and 0.7ml water.Add 0.4ml aqueous sodium carbonate (1M) to this mixture, then add two (triphenylphosphine) palladiums (II) of 14mg (5mol%) dichloro.Sealed reaction vessel, and be heated to 150 ℃ with microwave irradiation, last 5 minutes.After the cooling, this reaction mixture is evaporated to dried, residue is dissolved in 2.5ml methyl alcohol, and carry out purifying by Prep HPLC, provide 51mg (S)-3-[4-(2-amino-6-{2,2,2-three fluoro-1-[2-fluoro-4-(5-methoxyl group-pyridin-3-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-2-tert-butoxycarbonyl amino-propionic acid.
Above-mentioned product (51mg) is dissolved in 5ml 30%TFA/DCM solution.Stir under this mixture room temperature and spend the night.Remove solvent and provide crude product, this crude product carries out purifying by Prep HPLC, provide 17mg (S)-2-amino-3-[4-(2-amino-6-{2,2,2-three fluoro-1-[2-fluoro-4-(5-methoxyl group-pyridin-3-yl)-phenyl]-oxyethyl group-pyrimidine-4-yl)-phenyl]-propionic acid. 1H NMR(300MHz，CD 3OD)δ(ppm)：8.73(s，1H)，8.56(s，1H)，8.25(s，1H)，7.94(d，J＝8.2Hz，2H)，7.77(m，3H)，7.55(d，J＝8.4Hz，2H)，7.16(m，1H)，7.00(s，1H)，4.35(t，1H)，4.09(s，3H)，3.4(m，2H)。
30. synthetic (S)-2-amino-3-[4-(2-amino-6-{ (S)-2,2,2-three fluoro-1-[4-(2-fluoro-pyridin-4-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid
Figure A20081010845300801
To (S)-1-(4-bromo-phenyl)-2,2, and 2-three fluoro-ethanol (2.55g, 10ml 11.0mmol) is anhydrous 1, and the 4-dioxane solution adds Cs 2CO 3(16.25g, 50mmol), this mixture stirred 5 minutes, added (S)-3-[4-(2-amino-6-chloro-pyrimidine-4-yl)-phenyl then]-2-tert-butoxycarbonyl amino-propionic acid (3.92g, 10mmol).110 ℃ of following heated overnight of gained mixture.After the cooling, add 5ml water, ethyl acetate (20ml) is used for extract product.Organic layer is to dried over sodium sulfate.Remove solvent by centrifugal distiller, provide 5.2g (S)-3-(4-{2-amino-6-[(S)-1-(4-bromo-phenyl)-2,2,2-three fluoro-oxyethyl groups]-pyrimidine-4-yl phenyl)-2-tert-butoxycarbonyl amino-propionic acid (yield: 82%).
Microwave bottle (2ml) is equipped with (S)-3-(4-{2-amino-6-[(S)-1-(4-bromo-phenyl)-2,2,2-three fluoro-oxyethyl groups]-pyrimidine-4-yl }-phenyl)-2-tert-butoxycarbonyl amino-propionic acid (139mg, 0.23mmol), 2-fluorine pyridine-4-boric acid (40mg, 0.27mmol), 1ml acetonitrile and 0.7ml water.Add 0.4ml aqueous sodium carbonate (1M) to this mixture, then add two (triphenylphosphine) palladiums (II) of 14mg (5mol%) dichloro.Sealed reaction vessel, and be heated to 150 ℃ with microwave irradiation, last 5 minutes.After the cooling, this reaction mixture is evaporated to dried, and residue is dissolved in 2.5ml methyl alcohol.Product carries out purifying with preparation HPLC, provide 70mg (S)-3-[4-(2-amino-6-{ (S)-2,2,2-three fluoro-1-[4-(2-fluoro-pyridin-4-yl)-phenyl]-oxyethyl group-pyrimidine-4-yl)-phenyl]-2-tert-butoxycarbonyl amino-propionic acid.
Above-mentioned product (70mg) is dissolved in the DCM solution of 5ml 30%TFA.Stir under this reaction mixture room temperature and spend the night.Remove solvent and provide crude product, this crude product carries out purifying by preparation HPLC, provide 52mg (S)-2-amino-3-[4-(2-amino-6-{ (S)-2,2,2-three fluoro-1-[4-(2-fluoro-pyridin-4-yl)-phenyl]-oxyethyl group-pyrimidine-4-yl)-phenyl]-propionic acid. 1H NMR(300MHz，CD 3OD)δ(ppm)8.17(d，J＝5.7Hz，1H)，7.85(d，J＝8.4Hz，2H)，7.77(d，J＝6.9Hz，2H)，7.67(d，J＝8.2Hz，2H)，7.53(m，1H)，7.38(d，J＝8.4Hz，，2H)，7.30(s，1H)，6.76(m，2H)，4.21(t，1H)，3.2(m，2H)。
31. synthetic (S)-2-amino-3-[4-(2-amino-6-{ (S)-2,2,2-three fluoro-1-[4-(5-methoxyl group-pyridin-3-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid
Figure A20081010845300811
Microwave bottle (2ml) is equipped with (S)-3-(4-{2-amino-6-[(S)-1-(4-bromo-phenyl)-2,2,2-three fluoro-oxyethyl groups]-pyrimidine-4-yl }-phenyl)-2-tert-butoxycarbonyl amino-propionic acid (139mg, 0.23mmol), 3-methoxyl group-5-(4,4,5,5-tetramethyl--[1,3,2]-dioxy boron penta ring-2-yl)-pyridine (69mg, 0.27mmol), 1ml acetonitrile and 0.7ml water.Add 0.4ml aqueous sodium carbonate (1M) to this mixture, then add two (the triphenylphosphine)-palladiums (II) of 14mg dichloro.Sealed reaction vessel, and be heated to 150 ℃ with microwave irradiation, last 5 minutes.After the cooling, this reaction mixture is evaporated to dried, residue is dissolved in 2.5ml methyl alcohol and carries out purifying by preparation HPLC, provide 60mg (S)-3-[4-(2-amino-6-{ (S)-2,2,2-three fluoro-1-[4-(5-methoxyl group-pyridin-3-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-2-tert-butoxycarbonyl amino-propionic acid.
Above-mentioned product (60mg) is dissolved in the DCM solution of 5ml 30%TFA.Stir under this reaction mixture room temperature and spend the night.Remove solvent and provide crude product, this crude product carries out purifying by preparation HPLC, provide 48mg (S)-2-amino-3-[4-(2-amino-6-{ (S)-2,2,2-three fluoro-1-[4-(5-methoxyl group-pyridin-3-yl)-phenyl]-oxyethyl group-pyrimidine-4-yl)-phenyl]-propionic acid. 1HNMR(300MHz，CD 3OD)δ(ppm)：8.54(d，J＝1.5Hz，1H)，8.37(d，J＝2.7Hz，1H)，8.03(dd，J＝2.7Hz，1.5Hz，1H)，7.84(d，J＝8.2Hz，2H)，7.78(d，J＝8.4Hz，2H)，7.70(d，J＝8.4Hz，2H)，7.41(d，J＝8.4Hz，，2H)，6.81(s，1H)，6.75(m，1H)，4.22(t，1H)，3.95(t，3H)，3.25(m，2H)。
32. synthetic (S)-2-amino-3-[4-(2-amino-6-{ (S)-2,2,2-three fluoro-1-[4-(4-trifluoromethyl-pyridin-3-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid
Figure A20081010845300821
Microwave bottle (2ml) is equipped with (S)-3-(4-{2-amino-6-[(S)-1-(4-bromo-phenyl)-2,2,2-three fluoro-oxyethyl groups]-pyrimidine-4-yl }-phenyl)-2-tert-butoxycarbonyl amino-propionic acid (139mg, 0.23mmol), 4-5-flumethiazine-3-boric acid (61mg, 0.3mmol), 1ml acetonitrile and 0.7ml water.Add 0.4ml aqueous sodium carbonate (1M) to this mixture, then add two (the triphenylphosphine)-palladiums (II) of 14mg dichloro.Sealed reaction vessel, and be heated to 150 ℃ with microwave irradiation, last 5 minutes.After the cooling, this reaction mixture is evaporated to dried, residue is dissolved in 2.5ml methyl alcohol and carries out purifying by preparation HPLC, provide 20mg (S)-3-[4-(2-amino-6-{ (S)-2,2,2-three fluoro-1-[4-(4-trifluoromethyl-pyridin-3-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-2-tert-butoxycarbonyl amino-propionic acid.
Above-mentioned product (20mg) is dissolved in the DCM solution of 5ml 30%TFA.Stir under this reaction mixture room temperature and spend the night.Remove solvent and provide crude product, this crude product carries out purifying by preparation HPLC, provide 10mg (S)-2-amino-3-[4-(2-amino-6-{ (S)-2,2,2-three fluoro-1-[4-(4-trifluoromethyl-pyridin-3-yl)-phenyl]-oxyethyl group-pyrimidine-4-yl)-phenyl]-propionic acid. 1HNMR(300MHz，CD 3OD)δ(ppm)：8.72(d，J＝5.1Hz，1H)，8.55(s，1H)，7.87(d，J＝8.2，2H)，7.72(d，J＝5.0Hz，1H)，7.63(d，J＝8.2Hz，2H)，7.36(m，4H)，6.81(m，1H)，6.70(s，1H)，4.20(t，1H)，3.22(m，2H)。
33. synthetic (S)-2-amino-3-(4-{2-amino-6-[(S)-2,2,2-three fluoro-1-(4-isoxazole-4-base-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid
Microwave bottle (2ml) is equipped with (S)-3-(4-{2-amino-6-[(S)-1-(4-bromo-phenyl)-2,2,2-three fluoro-oxyethyl groups]-pyrimidine-4-yl }-phenyl)-2-tert-butoxycarbonyl amino-propionic acid (139mg, 0.23mmol), 4-(4,4,5,5-tetramethyl--[1,3,2] dioxy boron penta ring-2-yl)-isoxazoles (57.5mg, 0.3mmol), 1ml acetonitrile and 0.7ml water.Add 0.4ml aqueous sodium carbonate (1M) to this mixture, then add two (the triphenylphosphine)-palladiums (II) of 14mg dichloro.Sealed reaction vessel, and be heated to 150 ℃ with microwave irradiation, last 5 minutes.After the cooling, this reaction mixture is evaporated to dried, residue is dissolved in 2.5ml methyl alcohol and carries out purifying by preparation HPLC, provide 20mg (S)-3-(4-{2-amino-6-[(S)-2,2,2-three fluoro-1-(4-isoxazole-4-base-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-2-tert-butoxycarbonyl alanine.
Above-mentioned product (20mg) is dissolved in the DCM solution of 5ml 30%TFA.Stir under this mixture room temperature and spend the night.Remove solvent and provide crude product, this crude product carries out purifying by preparation HPLC, provide 10mg (S)-2-amino-3-(4-{2-amino-6-[(S)-2,2,2-three fluoro-1-(4-isoxazole-4-base-phenyl)-oxyethyl group]-pyrimidine-4-yl-phenyl)-propionic acid. 1H NMR(300MHz，CD 3OD)δ(ppm)9.03(s，1H)，8.77(s，1H)，7.84(m，2H)，7.63(d，J＝8.2，1H)，7.56(d，J＝8.4Hz，1H)，7.50(m，1H)，7.37(m，3H)，6.70(m，2H)，4.20(t，1H)，3.22(m，2H)。
34. synthetic (S)-2-amino-3-(4-{2-amino-6-[2,2,2-three fluoro-1-(2-pyrimidine-5-base-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid
Figure A20081010845300841
Microwave bottle (20ml) be equipped with 2-formylphenyl boric acid (290mg, 2.0mmol), 5-bromo-pyrimidine (316mg, 2.0mmol) and the 8ml acetonitrile.Add 4ml aqueous sodium carbonate (1M) to this mixture, then add two (the triphenylphosphine)-palladiums (II) of 100mg dichloro.Sealed reaction vessel, and with microwave irradiation 150 ℃ of down heating 5 minutes.After the cooling, this reaction mixture is with the ethyl acetate extracting.The evaporation organic layer provides roughage, and this roughage carries out purifying by ISCO, provides 220mg 2-pyrimidine-5-base-phenyl aldehyde.
Be added under 0 ℃ of the tetrabutyl ammonium fluoride (TBAF, 0.1ml, the THF solution of 1M) 2-pyrimidine-5-base-phenyl aldehyde (184mg, 1mmol) and trifluoromethyl trimethyl silane (TMSCF 3, 0.2ml, 10ml THF solution 1.2mmol).Mixture is warm until room temperature, and stirs 4 hours.This mixture is handled with 3ml 1M HCl then, and stirs and spend the night.Ethyl acetate (3 * 20ml) extractings of this product.Separate organic layer, and to dried over sodium sulfate.The evaporation organic solvent provides 0.21 g 2,2,2-three fluoro-1-(2-pyrimidine-5-base-phenyl)-ethanol (yield: 84%), be directly used in next step and need not purifying.
To 2,2, (72mg, 10ml anhydrous THF solution 0.28mmol) adds Cs to 2-three fluoro-1-(2-pyrimidine-5-base-phenyl)-ethanol 2CO 3(325mg, 1.0mmol).This mixture stirred 20 minutes, added 2-amino-4, and 6-two chloro-pyrimidines (36.7mg, 0.22mmol), finish up to reaction by 110 ℃ of heating down of reaction mixture then.After being cooled to room temperature, add 5ml water, ethyl acetate (20ml) is used for extract product.Organic layer is to dried over sodium sulfate.Remove solvent by centrifugal distiller, provide the rough 4-chloro-6-[2 of 76mg, 2,2-three fluoro-1-(2-pyrimidine-5-base-phenyl)-oxyethyl group]-pyrimidine-2-base amine (yield: 92%).
Microwave bottle (2ml) be equipped with above-mentioned rough intermediate (38mg, 0.1mmol), 4-borono--L-phenylalanine (31mg, 0.15mmol), 1ml acetonitrile and 0.7ml water.Add 0.3ml aqueous sodium carbonate (1M) to this mixture, then add two (the triphenylphosphine)-palladiums (II) of dichloro of 4mg, 5mol%.Sealed reaction vessel, and be heated to 150 ℃ with microwave irradiation, last 5 minutes.After the cooling, this reaction mixture is evaporated to dried, and residue is dissolved in 2.5ml methyl alcohol, and carry out purifying by preparation HPLC, provide 10mg (S)-2-amino-3-(4-{2-amino-6-[2,2,2-three fluoro-1-(2-pyrimidine-5-base-phenyl)-oxyethyl group]-pyrimidine-4-yl-phenyl)-propionic acid. 1HNMR(300MHz，CD 3OD)δ(ppm)9.21(s，1H)，8.87(s，2H)，7.86(d，J＝8.4，2H)，7.75(m，1H)，7.53(m，2H)，7.37(d，J＝8.2，1H)，7.33(m，1H)，6.72(s，1H)，6.58(m，1H)，4.20(t，1H)，3.22(m，2H)。
35. synthetic (S)-2-amino-3-(4-{2-amino-6-[2,2,2-three fluoro-1-(2-thiene-3-yl--phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid
Microwave bottle (20ml) be equipped with 2-formylphenyl boric acid (290mg, 2.0mmol), 3-bromo-thiophene (326mg, 2.0mmol) and the 8ml acetonitrile.Add 4ml aqueous sodium carbonate (1M) to this mixture, then add two (the triphenylphosphine)-palladiums (II) of 50mg dichloro.Sealed reaction vessel, and with microwave irradiation 150 ℃ of down heating 5 minutes.After the cooling, the ethyl acetate extracting of this reaction mixture.The evaporation organic layer provides roughage, and this roughage carries out purifying by ISCO, provides 211mg 2-thiene-3-yl--phenyl aldehyde.
Be added under 0 ℃ of the tetrabutyl ammonium fluoride (TBAF, 0.1ml, the THF solution of 1M) 2-thiene-3-yl--phenyl aldehyde (100mg, 0.53mmol) and trifluoromethyl trimethyl silane (0.1ml, 10ml THF solution 0.64mmol).Mixture is warm until room temperature, and stirs 4 hours.This reaction mixture is handled with 3ml 1M HCl then, and stirs and spend the night.Ethyl acetate (3 * 20ml) extractings of this product.Organic layer separates, and to dried over sodium sulfate.The evaporation organic solvent provides 0.12 g 2,2, and 2-three fluoro-1-(2-pyrimidine-5-base-phenyl)-ethanol are directly used in next step and need not purifying (yield: 89%).
To 2,2, (72mg, 10ml anhydrous THF solution 0.28mmol) adds Cs to 2-three fluoro-1-(2-thiene-3-yl--phenyl)-ethanol 2CO 3(325mg, 1.0mmol), this mixture stirred 20 minutes.Add 2-amino-4 then, 6-two chloro-pyrimidines (36.7mg, 0.22mmol), finish up to reaction by 110 ℃ of heating down of mixture.After the cooling, add 5ml water, ethyl acetate (20ml) is used for extract product.Organic layer is to dried over sodium sulfate.Remove solvent by centrifugal distiller, provide 67mg 4-chloro-6-[2,2,2-three fluoro-1-(2-pyrimidine-5-base-phenyl)-oxyethyl group]-pyrimidine-2-base amine (yield: 78%).
Microwave bottle (2ml) be equipped with above-mentioned roughage (40mg, 0.1mmol), 4-borono--L-phenylalanine (31mg, 0.15mmol), 1ml acetonitrile and 0.7ml water.Add 0.3ml aqueous sodium carbonate (1M) to this mixture, then add two (the triphenylphosphine)-palladiums (II) of 5mol% dichloro.Sealed reaction vessel, and be heated to 150 ℃ with microwave irradiation, last 5 minutes.After the cooling, this reaction mixture is evaporated to dried.Residue is dissolved in 2.5ml methyl alcohol, carries out purifying with preparation HPLC then, obtain 11.8mg (S)-2-amino-3-(4-{2-amino-6-[2,2,2-three fluoro-1-(2-thiene-3-yl--phenyl)-oxyethyl group]-pyrimidine-4-yl-phenyl)-propionic acid. 1H NMR(300MHz，CD 3OD)δ(ppm)：7.84(d，J＝8.0Hz，2H)，7.66(d，J＝7.6Hz，1H)，7.53(m，1H)，7.40(m，5H)，7.30(m，1H)，7.17(m，1H)，6.91(m，1H)，6.82(s，1H)，4.23(t，1H)，3.25(m，2H)。
36. synthetic (S)-2-amino-3-[4-(2-amino-6-{2,2,2-three fluoro-1-[2-(1-methyl isophthalic acid H-pyrazoles-4-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid
Figure A20081010845300861
Microwave bottle (20ml) be equipped with 2-bromo-phenyl aldehyde (208mg, 1.0mmol), 1-methyl-4-(4,4,5,5-tetramethyl--[1,3,2] dioxy boron penta ring-2-yl)-1H-pyrazoles (222mg, 1.2mmol) and the 8ml acetonitrile.Add 2.4ml aqueous sodium carbonate (1M) to this mixture, then add two (the triphenylphosphine)-palladiums (II) of 50mg dichloro.Sealed reaction vessel, and with microwave irradiation 150 ℃ of down heating 5 minutes.After the cooling, the ethyl acetate extracting of this reaction mixture.The evaporation organic layer provides roughage, and this roughage carries out purifying by ISCO, provides 181mg 2-(1-methyl isophthalic acid H-pyrazoles-4-yl)-phenyl aldehyde (96% yield).
Be added under 0 ℃ of the tetrabutyl ammonium fluoride (0.1ml, the THF solution of 1M) 2-(1-methyl isophthalic acid H-pyrazoles-4-yl)-phenyl aldehyde (100mg, 0.53mmol) and trifluoromethyl trimethyl silane (0.12ml, 10ml THF solution 0.6mmol).Mixture is warm until room temperature, and stirs 4 hours.This mixture is handled with 3ml 1M HCl then, and stirs and spend the night.Ethyl acetate (3 * 20ml) extractings of this product.Separate organic layer, and to dried over sodium sulfate.The evaporation organic solvent provides 0.12 g 2,2, and 2-three fluoro-1-[2-(1-methyl isophthalic acid H-pyrazoles-4-base-phenyl)-ethanol are directly used in next step and need not purifying (yield: 89%).
To 2,2,2-three fluoro-1-[2-(1-methyl isophthalic acid H-pyrazoles-4-yl)-phenyl]-(60mg, 10ml anhydrous THF solution 0.2mmol) adds Cs to ethanol 2CO 3(325mg, 1.0mmol), this mixture stirred 20 minutes.Add 2-amino-4,6-two chloro-pyrimidines (32mg, 0.2mmol), finish up to reaction by 110 ℃ of heating down of reaction mixture then.After the cooling, add 5ml water, ethyl acetate (20ml) is used for extract product.Organic layer is to dried over sodium sulfate.Remove solvent by centrifugal distiller, obtain 70mg 4-chloro-6-{2,2,2-three fluoro-1-[2-(1-methyl isophthalic acid H-pyrazoles-4-yl)-phenyl]-oxyethyl group }-pyrimidine-2-base amine (yield: 92%).
Microwave bottle (2ml) be equipped with above-mentioned roughage (38mg, 0.1mmol), 4-borono--L-phenylalanine (31mg, 0.15mmol), 1ml acetonitrile and 0.7ml water.Add 0.3ml aqueous sodium carbonate (1M) to this mixture, then add two (the triphenylphosphine)-palladiums (II) of 5mol% dichloro.Sealed reaction vessel, and be heated to 150 ℃ with microwave irradiation, last 5 minutes.After the cooling, this mixture is evaporated to dried, residue is dissolved in 2.5ml methyl alcohol, and carry out purifying by preparation HPLC, obtain 5.6mg (S)-2-amino-3-[4-(2-amino-6-{2,2,2-three fluoro-1-[2-(1-methyl isophthalic acid H-pyrazoles-4-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid.
37. synthetic (S)-2-amino-3-(4-{6-[2,2,2-three fluoro-1-(2-furans-3-base-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid
Figure A20081010845300881
Microwave bottle (20ml) be equipped with 2-formylphenyl boric acid (298mg, 2.0mmol), 3-bromo-furans (350mg, 2.4mmol) and the 8ml acetonitrile.Add 4ml aqueous sodium carbonate (1M) to this mixture, then add two (the triphenylphosphine)-palladiums (II) of 100mg dichloro.Sealed reaction vessel, and with microwave irradiation 150 ℃ of down heating 5 minutes.After the cooling, this reaction mixture is with the ethyl acetate extracting.The evaporation organic layer provides roughage, and this roughage carries out purifying by ISCO, provides 110mg 2-furans-3-base-phenyl aldehyde (30% yield).
Be added under 0 ℃ of the tetrabutyl ammonium fluoride (0.1ml is under the THF of 1M) 2-furans-3-base-phenyl aldehyde (110mg, 0.64mmol) and trifluoromethyl trimethyl silane (109mg, 10ml THF solution 0.78mmol).Mixture is warm until room temperature, and stirs 4 hours.This mixture is handled with 3ml 1M HCl then, and stirs and spend the night.Product ethyl acetate (3 * 20ml) extractings.Separate organic layer, and to dried over sodium sulfate.The evaporation organic solvent provides 0.130 g 2,2, and 2-three fluoro-1-(2-furans-3-base-phenyl)-ethanol are directly used in next step, need not purifying (yield: 90%).
(12mg 0.3mmol) is added into 2,2,2-three fluoro-1-(2-furans-3-base-phenyl)-ethanol (54mg, 10ml anhydrous THF solution 0.2mmol) with 60%NaH.This mixture stirred 20 minutes, added 4 thereafter, and 6-two chloro-pyrimidines (30mg, 0.2mmol).70 ℃ of heating down of this mixture are then finished up to reaction.After the cooling, add 5ml water, with the cancellation reaction, ethyl acetate (20ml) is used for extract product.Organic layer is to dried over sodium sulfate.Remove solvent by centrifugal distiller, obtain 67mg 4-chloro-6-[2,2,2-three fluoro-1-(2-furans-3-base-phenyl)-oxyethyl group]-pyrimidine (yield: 94%).
Microwave bottle (2ml) be equipped with above-mentioned roughage (38mg, 0.1mmol), 4-borono--L-phenylalanine (31mg, 0.15mmol), 1ml acetonitrile and 0.7ml water.Add 0.3ml aqueous sodium carbonate (1M) to this mixture, then add two (the triphenylphosphine)-palladiums (II) of 5mol% dichloro.Sealed reaction vessel, and be heated to 150 ℃ with microwave irradiation, last 5 minutes.After the cooling, this reaction mixture is evaporated to dried, and residue is dissolved in 2.5ml methyl alcohol, carry out purifying by preparation HPLC then, obtain 6mg (S)-2-amino-3-(4-{6-[2,2,2-three fluoro-1-(2-furans-3-base-phenyl)-oxyethyl group]-pyrimidine-4-yl-phenyl)-propionic acid. 1H NMR(300MHz，CD 3OD)δ(ppm)：8.82(s，1H)，8.13(d，J＝8.4Hz，2H)，7.73(m，2H)，7.46(m，6H)，6.82(m，1H)，6.54(s，1H)，4.20(t，1H)，3.22(m，2H)。
38. synthetic (S)-2-amino-3-(4-{6-[2,2,2-three fluoro-1-(2-furans-2-base-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid
Figure A20081010845300891
Microwave bottle (20ml) be equipped with 2-formylphenyl boric acid (298mg, 2.0mmol), 2-bromo-furans (350mg, 2.4mmol) and the 8ml acetonitrile.Add 4ml aqueous sodium carbonate (1M) to this mixture, then add two (the triphenylphosphine)-palladiums (II) of 100mg dichloro.Sealed reaction vessel, and with microwave irradiation 150 ℃ of down heating 5 minutes.After the cooling, the ethyl acetate extracting of this reaction mixture.The evaporation organic layer provides roughage, and this roughage carries out purifying by ISCO, provides 123mg 2-furans-2-base-phenyl aldehyde (34% yield).
Be added under 0 ℃ of the tetrabutyl ammonium fluoride (0.1ml, the THF solution of 1M) 2-furans-2-base-phenyl aldehyde (123mg, 0.71mmol) and trifluoromethyl trimethyl silane (120mg, 10ml THF solution 0.86mmol).Mixture is warm until room temperature, and stirs 4 hours.This mixture is handled with 3ml 1M HCl then, and stirs and spend the night.Ethyl acetate (3 * 20ml) extractings of this product.Separate organic layer, and to dried over sodium sulfate.The evaporation organic solvent provides 0.150 g 2,2, and 2-three fluoro-1-(2-furans-3-base-phenyl)-ethanol are directly used in next step, need not purifying (yield: 90%).
(12mg 0.3mmol) is added into 2,2,2-three fluoro-1-(2-furans-2-base-phenyl)-ethanol (55mg, 10ml anhydrous THF solution 0.2mmol) with 60%NaH.This mixture stirred 20 minutes, added 4 thereafter, and 6-two chloro-pyrimidines (29mg, 0.2mmol).This mixture in 110 ℃ of heating down, is finished up to reaction then.After the cooling, add 5ml water, ethyl acetate (20ml) is used for extract product.Organic layer is to dried over sodium sulfate.Remove solvent by centrifugal distiller, obtain 60mg 4-chloro-6-[2,2,2-three fluoro-1-(2-furans-2-base-phenyl)-oxyethyl group]-pyrimidine (yield 80%).
Microwave bottle (2ml) be equipped with above-mentioned roughage (60mg, 0.2mmol), 4-borono--L-phenylalanine (62mg, 0.3mmol), 1ml acetonitrile and 0.6ml water.Add 0.4ml aqueous sodium carbonate (1M) to this mixture, then add two (the triphenylphosphine)-palladiums (II) of 5mol% dichloro.Sealed reaction vessel, and be heated to 150 ℃ with microwave irradiation, last 5 minutes.After the cooling, this reaction mixture is evaporated to drying, and residue is dissolved in 2.5ml methyl alcohol, and carry out purifying by preparation HPLC, obtain 6mg (S)-2-amino-3-(4-{6-[2,2,2-three fluoro-1-(2-furans-2-base-phenyl)-oxyethyl group]-pyrimidine-4-yl-phenyl)-propionic acid. 1H NMR(300MHz，CD 3OD)δ(ppm)：8.66(s，1H)，8.11(d，J＝8.4Hz，2H)，7.77(m，2H)，7.54(m，6H)，6.86(d，J＝3.3Hz，1H)，6.66(m，1H)，4.20(t，1H)，3.22(m，2H)。
39. other compounds
Other that utilize method known in this field and/or described here preparation are listed below the compound:
Table 1
Compound LCMS (M+1) HPLC method (time (branch))
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(4-(pyridin-3-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 510 A--
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(2-(2-picoline-4-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 524 A--
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(2-(4-thiotolene-3-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 529 A--
(2S)-3-(4-(6-(1-(2-(1H-pyrazol-1-yl) phenyl)-2,2,2-trifluoro ethoxy)-2-aminopyrimidine-4-yl) phenyl)-2-alanine 499 A(2.86)
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(4-(furans-2-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 499 A--
(2S)-2-amino-3-(4-(6-(2,2,2-three fluoro-1-(2-(pyridin-3-yl oxygen base) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 512 A(1.36)
(2S)-3-(4-(6-(1-(2-(1H-1,2,4-triazol-1-yl) phenyl)-2,2,2-trifluoro ethoxy)-2-aminopyrimidine-4-yl) phenyl)-2-alanine 500 A(2.17)
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(2-(furans-3-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 499 A--
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(4-(furans-2-yl)-3-p-methoxy-phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 529 A(3.32)
(2S)-2-amino-3-(4-(5-(2,2,2-three fluoro-1-(2-(furans-2-yl) phenyl) oxyethyl group) pyrazine-2-yl) phenyl) propionic acid 484 E--
(2S)-3-(4-(5-(1-(2-(1H-pyrazol-1-yl) phenyl)-2,2,2-trifluoro ethoxy) pyrazine-2-yl) phenyl)-2-alanine 484 E--
(2S)-2-amino-3-(4-(2-amino-6-(1-(4,5-dimethoxy-2-(1H-pyrazol-1-yl) phenyl)-2,2,2-trifluoro ethoxy) pyrimidine-4-yl) phenyl) propionic acid 559 A(2.86)
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(2-(2-methyl isophthalic acid H-imidazoles-1-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 513 A(2.30)
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(2-(5-thiotolene-2-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 529 A--
(2S)-2-amino-3-(4-(2-amino-6-(1-(2-(5-(formyl-dimethylamino) furans-2-yl) phenyl)-2,2,2-trifluoro ethoxy) pyrimidine-4-yl) phenyl) propionic acid 570 A--
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(4-fluoro-2-(thiophene-2-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 533 A(1.61)
(2S)-2-amino-3-(4-(6-(2,2,2-three fluoro-1-(4-fluoro-2-(thiophene-2-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 518 A(1.65)
(2S)-2-amino-3-(4-(6-(2,2,2-three fluoro-1-(4-fluoro-2-(thiene-3-yl-) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 518 A(3.76)
(2S)-2-amino-3-(4-(6-(2,2,2-three fluoro-1-(4-fluoro-2-(4-thiotolene-2-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 532 A(3.88)
(S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-three fluoro-1-(4-(6-fluorine pyridin-3-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 528 A(2.96)
(2S)-3-(4-(6-(1-(4-(1H-imidazoles-1-yl) phenyl)-2,2,2-trifluoro ethoxy)-2-aminopyrimidine-4-yl) phenyl)-2-alanine 499 A(2.07)
(2S)-2-amino-3-(4-(6-(2,2,2-three fluoro-1-(4-(thiophene-2-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 500 A(3.74)
(S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-three fluoro-1-(4-(pyrimidine-5-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 511 A(2.67)
(2S)-2-amino-3-(4-(6-(1-(2-(3,5-dimethyl isoxazole-4-yl)-4-fluorophenyl)-2,2,2-trifluoro ethoxy) pyrimidine-4-yl) phenyl) propionic acid 531 A(1.55)
(S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-three fluoro-1-(4-(2-picoline-4-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 524 A(2.28)
(2S)-3-(4-(6-(1-(4-(1H-1,2,4-triazol-1-yl) phenyl)-2,2,2-trifluoro ethoxy) pyrimidine-4-yl) phenyl)-2-alanine 485 A(1.24)
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(4-(piperidines-1-ylmethyl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 530 B(3.00)
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(2-fluoro-4-(2-picoline-4-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 542 A(2.42)
(2S)-2-amino-3-(4-(2-amino-6-(1-(4-(6-chlorine pyridazine-3-yl) phenyl)-2,2,2-trifluoro ethoxy) pyrimidine-4-yl) phenyl) propionic acid 545 A(3.33)
(2S)-2-amino-3-(4-(2-amino-6-(1-(4-(4-tert-butyl thiazol-2-yl) phenyl)-2,2,2-trifluoro ethoxy) pyrimidine-4-yl) phenyl) propionic acid 572 A(1.82)
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(3 '-methoxyl group-3-(3-methyl isophthalic acid H-pyrazol-1-yl) biphenyl-4-yl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 619 A(3.54)
(2S)-2-amino-3-(4-(2-amino-6-(1-(5-chloro-2-(3-methyl isophthalic acid H-pyrazol-1-yl) phenyl)-2,2,2-trifluoro ethoxy) pyrimidine-4-yl) phenyl) propionic acid 547 A(3.20)
40. vitro inhibition analysis
People TPH1, TPH2, tyrosine hydroxylase (TH) and Phenylalanine hydroxylase (PH) all utilize the gene that has following accession number respectively to generate: X52836, AY098914, X05290, and U49897.
The complete encoding sequence of people TPH1 be cloned into bacterial expression vector pET24 (Novagen, Madison, WI, USA) in.Single bacterium colony BL21 (DE3) cell inoculation that contains expression vector is spent the night to 50ml L meat soup (LB)-kantlex substratum and at 37 ℃ of oscillating growths.Then half culture (25ml) is transferred to the 3L substratum, described substratum contains 1.5% yeast extract, 2%Bacto peptone, 0.1mM tryptophane, 0.1mM ferrous ammonium sulphate and 50mM phosphate buffered saline buffer (pH 7.0), and under 37 ℃, replenish 40% oxygen, keep pH 7.0, with increase glucose, culture grows to OD 600=6.Utilize the 15%D-lactose, 25 ℃ of following expression with 10 hours temporal induction TPH1.Cell rotation sedimentation, and with phosphate buffered saline (PBS) (PBS) washing once.
Based on itself and the combining of pterin, TPH1 is by the affinity chromatography purifying.Cell mass is resuspended to lysis buffer (100ml/20g), described lysis buffer contains 50mM Tris-Cl, and pH 7.6,0.5M NaCl, 0.1%Tween-20,2mM EDTA, 5mM DTT, protease inhibitor cocktail (Roche Applied Science, Indianapolis, IN, USA) with 1mM phenylmethylsulfonyl fluoride (PMSF), cell is with microjet nanometer clarifixator (microfluidizer) cracking.Lysate is centrifugal, and with sample on the supernatant liquor to pterin link coupled sepharose 4B post, this post is to contain 50mM Tris, pH 8.0,2M NaCl, 0.1%Tween-20, the damping fluid balance of 0.5mM EDTA and 2mM DTT.This post is with the washing of this damping fluid of 50ml, and TPH1 is with buffer solution elution, and described damping fluid contains 30mM NaHCO 3, pH 10.5,0.5M NaCl, 0.1%Tween-20,0.5mM EDTA, 2mM DTT and 10% glycerine.The enzyme of wash-out is immediately with 200mM KH 2PO 4, pH 7.0,0.5M NaCl, and 20mM DTT, 0.5mMEDTA and the neutralization of 10% glycerine, and be stored in-80 ℃.
Basically express in the same manner and purifying people tryptophan hydroxylase II type (TPH2), tyrosine hydroxylase (TH) and Phenylalanine hydroxylase (PAH), except that at growing period the TH cell being replenished tyrosine and PAH being replenished the phenylalanine.
TPH1 that in reaction mixture, measures and TPH2 activity, described mixture contains 50mM 4-morpholine propanesulfonic acid (MOPS), pH 7.0,60 μ M tryptophanes, 100mM ammonium sulfate, 100 μ M ferrous ammonium sulphates, 0.5mM three (2-propyloic) phosphines (TCEP), 0.3mM 6-methyl tetrahydrochysene pterin, 0.05mg/ml catalase and 0.9mM DTT.Add TPH1 to final concentration 7.5nM, begin reaction.(change in fluorescence of excitation wavelength=300nm) locate is determined the original speed of reaction by following 360nm.By measuring under the different compound concentrations their activity, determine that TPH1 and TPH2 suppress, and utilize the effectiveness of the given compound of following Equation for Calculating:
v = b + v 0 - b 1 + ( [ C ] [ I c 50 ] ) D
Wherein v is the original speed of given compound concentration C, v 0V when being C=0, b are background signals, and D is near equaling 1 Hill slope, and I C50Be that compound suppresses half concentration of maximum enzyme activity.
Utilize L-[3,4-respectively by measuring 3H]-tyrosine and L-[4- 3H]-the phenylalanine generation 3H 2The amount of O is determined people TH and PAH activity.At first with about 10 minutes of enzyme (100nM) and its 0.1mM substrate incubation, and be added into reaction mixture, and described mixture contains 50mMMOPS, and pH 7.2,100mM ammonium sulfate, 0.05%Tween-20,1.5mM TCEP, 100 μ M ferrous ammonium sulphates, 0.1mM tyrosine or phenylalanine, 0.2mM 6-methyl tetrahydrochysene pterin, 0.05mg/ml catalase and 2mM DTT.Allow reaction continue 10-15 minute, and stop by adding 2M HCl.Then, this mixture passes through activated carbon filtration, and determines the radioactivity of filtrate by scintillation counting.Utilize this analysis to determine the activity of compound to TH and PAH, and so that the TPH1 mode identical with TPH2 calculated.
64. based on the cell inhibiting analysis
It is rat hypertrophy cell oncocyte system that two types clone is used for screening: RBL2H3, and it contains TPH1, and spontaneous preparation serotonin (5HT); BON is the human cancer cell line, and it contains TPH1, and preparation 5-hydroxytryptophan (5HTP).CBA carries out with the 96-well plate format.Used moving phase contains the 97%100mM sodium acetate among the HPLC, pH 3.5 and 3% acetonitrile.(4.6 * 50mm) use with Waters HPLC (model 2795) Waters C18 post.By set 280nm as excitation wavelength and 360nm as emission wavelength, hyperchannel photofluorometer (model 2475) is used to monitor through-flow.
RBL CBA: the cell 3-4 that grows in perfect medium (containing 5% bovine serum) is little, makes cell attachment in plate hole (7K cells/well).Then compound is added into each hole with the concentration range of 0.016 μ M-11.36 μ M.Contrast is without any the cell in the perfect medium of compound.Hatch collecting cell after 3 days under 37 ℃.Cell when not having compound＞95% converge.Remove substratum in the slave plate, cell is with isopyknic 0.1N NaOH cracking.Most cell lysate by with isopyknic 1M TCA combination treatment, filter by glass fibre then.Sample is used to analyze 5HT concentration to reversed-phase HPLC on the filtrate.The cell lysate of small portion also is removed, to measure the protein concentration of cell, the cytotoxicity of this concentration reflection compound under working concentration.Utilize the BCA method to measure protein concentration.
According to above-mentioned equation, the mean level (ML) of 5HT is as IC in without the cell of compound treatment 50Maximum value in the derivation.The minimum value of 5HT or be set at 0 is perhaps from the cell with the compound treatment of maximum concentration, if the compound of this concentration does not have cytotoxicity.
BON CBA: cell is 3-4 hour (20K cells/well) of growth in isopyknic DMEM that has 5% bovine serum and F12K, and adds the compound of 0.07 μ M-50 μ M concentration range.Cell is in 37 ℃ of following overnight incubation.Take out 50 μ M culture supernatants then, be used for 5HTP and measure.Supernatant mixes with isopyknic 1M TCA, filters by glass fibre then.Filtrate is gone up sample to reversed-phase HPLC, be used for the 5HTP measurement of concetration.Utilize the Celltiter-Glo photogenic cell vigor analysis of Promega,, measure cell viability by handling remaining cell.Then, with RBL CBA in same way as computerized compound render a service.
42. in vitro effects
Utilize aforesaid method, the ability of test compounds vitro inhibition people TPH1.Data are provided at following table 2:
Table 2
Compound IC 50(μM)
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(4-(2-oxo-pyrrolidine-1-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 0.068
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(4-(pyridin-4-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 0.0352
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(4-(pyridin-3-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 0.0327
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(2-(2-picoline-4-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 0.0362
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(2-(4-thiotolene-3-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 0.1891
(2S)-2-amino-3-(4-(6-(2,2,2-three fluoro-1-(2-(pyridin-4-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 0.0214
(2S)-3-(4-(6-(1-(2-(1H-pyrazol-1-yl) phenyl)-2,2,2-trifluoro ethoxy)-2-aminopyrimidine-4-yl) phenyl)-2-alanine 0.0031
(2S)-3-(4-(6-(1-(2-(1H-imidazoles-1-yl) phenyl)-2,2,2-trifluoro ethoxy)-2-aminopyrimidine-4-yl) phenyl)-2-alanine 0.0209
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(4-(furans-3-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 0.3592
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(4-(furans-2-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 0.4562
(2S)-3-(4-(6-(1-(2-(1H-1,2,4-triazol-1-yl) phenyl)-2,2,2-trifluoro ethoxy)-2-aminopyrimidine-4-yl) phenyl)-2-alanine 0.0143
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(2-(furans-3-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 0.0415
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(4-(furans-2-yl)-3-p-methoxy-phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 0.3583
(2S)-the amino propionic acid amide of 3-(4-(5-(1-(2-(1H-pyrazol-1-yl) phenyl)-2,2,2-trifluoro ethoxy) pyrazine-2-yl) phenyl)-2- 0.1839
(2S)-2-amino-3-(4-(6-(2,2,2-three fluoro-1-(2-(furans-3-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid amide 0.1025
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(2-(4-methyl isophthalic acid H-pyrazol-1-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 0.0122
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(2-(thiazol-2-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 0.0115
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(2-(thiene-3-yl-) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 0.052
(2S)-2-amino-3-(4-(2-amino-6-(1-(2-(5-(dimethylamino formyl) furans-2-yl) phenyl)-2,2,2-trifluoro ethoxy) pyrimidine-4-yl) phenyl) propionic acid 0.2845
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(4-fluoro-2-(thiophene-2-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 0.1755
(2S)-2-amino-3-(4-(6-(2,2,2-three fluoro-1-(4-fluoro-2-(thiophene-2-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 0.2096
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(4-fluoro-2-(thiene-3-yl-) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 0.2869
(2S)-2-amino-3-(4-(6-(2,2,2-three fluoro-1-(4-fluoro-2-(thiene-3-yl-) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 0.3262
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(4-fluoro-2-(4-thiotolene-2-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 0.5943
(2S)-2-amino-3-(4-(6-(2,2,2-three fluoro-1-(4-fluoro-2-(4-thiotolene-2-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 1.1832
(S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-three fluoro-1-(4-(6-fluorine pyridin-3-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 0.219
(S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-three fluoro-1-(4-(isoxazole-4-base) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 0.1563
(2S)-3-(4-(6-(1-(4-(1H-imidazoles-1-yl) phenyl)-2,2,2-trifluoro ethoxy)-2-aminopyrimidine-4-yl) phenyl)-2-alanine 0.1077
(S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-three fluoro-1-(4-(5-methoxypyridine-3-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 0.0312
(S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-three fluoro-1-(4-(pyrimidine-5-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 0.0825
(2S)-2-amino-3-(4-(6-(1-(2-(3,5-dimethyl isoxazole-4-yl)-4-fluorophenyl)-2,2,2-trifluoro ethoxy) pyrimidine-4-yl) phenyl) propionic acid 1.4637
(2S)-3-(4-(6-(1-(4-(1H-1,2,4-triazol-1-yl) phenyl)-2,2,2-trifluoro ethoxy)-2-aminopyrimidine-4-yl) phenyl)-2-alanine 0.3576
(2S)-2-amino-3-(4-(2-amino-6-(1-(2-(3,5-dimethyl isoxazole-4-yl)-4-fluorophenyl)-2,2,2-trifluoro ethoxy) pyrimidine-4-yl) phenyl) propionic acid 0.5087
(S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-three fluoro-1-(2-(3-methyl isophthalic acid H-pyrazoles-1-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 0.0167
(S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-three fluoro-1-(4-(2-fluorine pyridin-4-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 0.3575
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(2-fluoro-4-(2-picoline-4-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 0.1464
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(2-fluoro-4-(5-methoxypyridine-3-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 0.2926
(S)-2-amino-3-(4-(2-amino-6-((5-(1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-yl) thiophene-2-yl) methoxyl group) pyrimidine-4-yl) phenyl) propionic acid 0.2897
(2S)-2-amino-3-(4-(2-amino-6-(1-(5-chloro-2-(3-methyl isophthalic acid H-pyrazol-1-yl) phenyl)-2,2,2-trifluoro ethoxy) pyrimidine-4-yl) phenyl) propionic acid 0.0919
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(5-fluoro-2-(3-methyl isophthalic acid H-pyrazol-1-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 0.0351
(S)-2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl isophthalic acid H-pyrazol-1-yl) phenyl)-2,2,2-trifluoro ethoxy) pyrimidine-4-yl) phenyl) propionic acid 0.0275
(S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-three fluoro-1-(5-fluoro-2-(3-methyl isophthalic acid H-pyrazol-1-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid 0.0156
(S)-2-amino-3-(4-(2-amino-6-((R)-1-(5-chloro-2-(3-methyl isophthalic acid H-pyrazol-1-yl) phenyl)-2,2,2-trifluoro ethoxy) pyrimidine-4-yl) phenyl) propionic acid 0.0264
43. serotonin reduces in the body
(S)-2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl isophthalic acid H-pyrazol-1-yl) phenyl)-2,2,2-trifluoro ethoxy) phenyl pyrimidine-4-yl)) in the body of ethyl propionate effect with they be mixed with solution, oral administration is determined then.Generally speaking, 14-male C57 albinism mouse through port in age in week gavages 5-10ml/kg, and be administered once every day, continuous 4 days.Behind the last potion 5 hours, put to death animal fast.Each animal utilizes 1ml syringe and 25 5/8 pins in order to isoflurane anesthesia, extracts blood by the cardiac puncture method, and 250 μ l blood place the pipe that contains Capiject EDTA, keeps rotation gently.Animal decaptitates then, takes out full brain, and quick-frozen, disposes the fat and the chamber content of jejunum, ileum and colon, quick-frozen.5-HT is from blood or organize extracting, and the high performance liquid chromatography through online fluorescence detector is housed (HPLC) is measured.Gather blood sample, be used for exposure analysis.Utilize the rules of the management of laboratory animal and the use council (The InstitutionalAnimal Care and Use Committee) approval, carry out all zooscopies.
Fig. 1 shows the dose-dependently influence of compound to mouse 5-HT level.
44. influence to stomach transportation and emptying
Effective TPH1 inhibitor of the present invention, (S)-2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl isophthalic acid H-pyrazol-1-yl) phenyl)-2,2,2-trifluoro ethoxy) phenyl pyrimidine-4-yl)) ethyl propionate is determined in the Sprague-Dawley rat the influence of stomach and intestine (GI) haulage time and stomach emptying.Compound is with 50,125 and the dosed administration of 250mpk, and is oral, and one day four times, 14 days by a definite date.Respectively take medicine and organize with 9 rats.Also make negative control group (only administration media), and have 6 in addition as positive control (coromegine) with 9 rats.
Rat is with 10ml/kg take medicine compound or medium.Coromegine only gave to positive control group at the 14th day, and medium gave at 1-14 days.Omnidistance body weight and the observed data of gathering of research, the 13rd day, charcoal is the rat overnight fasting before the meal.The 14th day, charcoal 30 minutes before the meal, the effective TPH1 inhibitor of oral administration, coromegine or medium.Charcoal meal (5% charcoal is arranged in the medium) is with the 15ml/kg oral administration.Charcoal meal is taken medicine and was carried out ptomatopsia in back 25 minutes.By measuring the distance that charcoal meal is walked along small intestine downwards, should determine the GI haulage time apart from divided by the small intestine length overall.By the stomach of the rat of weighing, determine the gastric emptying time.
As shown in Figure 2, use effective TPH1 inhibitor and slowed down the GI mobility in the dose-dependently mode.As shown in Figure 3, it has also slowed down stomach emptying in the dose-dependently mode.And as shown in Figure 4, this compound is relevant with the variation of 5-HT level in blood and nearly colon to the influence of GI transportation and stomach emptying.Brain 5-HT level is not subjected to this compounds affect.
Above-mentioned all publications (for example, patent and patent application) are incorporated in full with it and are hereby incorporated by reference.

Claims (53)

1. formula I compound:
Or its pharmacologically acceptable salt, wherein:
A 1It is the optional heterocycle that replaces;
Each R 1Be halogen independently, hydrogen, C (O) R A, OR A, NR BR C, S (O 2) R A, or optional alkyl, alkyl-aryl or the alkyl-heterocycle that replaces;
R 2Be halogen independently, hydrogen, C (O) R A, OR A, NR BR C, S (O 2) R A, or optional alkyl, alkyl-aryl or the alkyl-heterocycle that replaces;
R 3Be hydrogen, C (O) R A, C (O) OR A, or optional alkyl, alkyl-aryl, alkyl-heterocycle, aryl or the heterocycle that replaces;
R 4Be hydrogen or optional alkyl, alkyl-aryl, alkyl-heterocycle, aryl or the heterocycle that replaces;
Each R ABe hydrogen or optional alkyl, alkyl-aryl or the alkyl-heterocycle that replaces independently;
Each R BBe hydrogen or optional alkyl, alkyl-aryl or the alkyl-heterocycle that replaces independently;
Each R CBe hydrogen or optional alkyl, alkyl-aryl or the alkyl-heterocycle that replaces independently; And
M is 1-4.
2. the compound of claim 1, it is the compound of following formula:
Figure A2008101084530003C1
3. the compound of claim 1, it is the compound of following formula:
Figure A2008101084530003C2
Wherein:
Each R 5Be halogen independently, hydrogen, C (O) R A, OR A, NR BR C, S (O 2) R A, or optional alkyl, alkyl-aryl or the alkyl-heterocycle that replaces; And
N is 1-3.
4. the compound of claim 3, it is the compound of following formula:
Figure A2008101084530003C3
5. the compound of claim 1, it is the compound of following formula:
Figure A2008101084530003C4
Wherein:
Each R 5Be halogen independently, hydrogen, C (O) R A, OR A, NR BR C, S (O 2) R A, or optional alkyl, alkyl-aryl or the alkyl-heterocycle that replaces; And
N is 1-3.
6. the compound of claim 5, it is the compound of following formula:
Figure A2008101084530004C1
7. the compound of claim 1, it is the compound of following formula:
Figure A2008101084530004C2
Wherein:
Each R 5Be halogen independently, hydrogen, C (O) R A, OR A, NR BR C, S (O 2) R A, or optional alkyl, alkyl-aryl or the alkyl-heterocycle that replaces; And
N is 1-3.
8. the compound of claim 7, it is the compound of following formula:
Figure A2008101084530004C3
9. the compound of claim 1, it is the compound of following formula:
Figure A2008101084530005C1
Wherein:
Each R 5Be halogen independently, hydrogen, C (O) R A, OR A, NR BR C, S (O 2) R A, or optional alkyl, alkyl-aryl or the alkyl-heterocycle that replaces; And
P is 1-4.
10. the compound of claim 9, it is the compound of following formula:
Figure A2008101084530005C2
11. the compound of claim 1, it is the compound of following formula:
Wherein:
Each R 5Be halogen independently, hydrogen, C (O) R A, OR A, NR BR C, S (O 2) R A, or optional alkyl, alkyl-aryl or the alkyl-heterocycle that replaces; And
Q is 1-2.
12. the compound of claim 11, it is the compound of following formula:
13. the compound of claim 1, it is the compound of following formula:
Figure A2008101084530006C2
Wherein:
Each R 5Be halogen independently, hydrogen, C (O) R A, OR A, NR BR C, S (O 2) R A, or optional alkyl, alkyl-aryl or the alkyl-heterocycle that replaces; And
Q is 1-2.
14. the compound of claim 13, it is the compound of following formula:
Figure A2008101084530006C3
15. the compound of claim 1, it is the compound of following formula:
Wherein:
Each R 5Be halogen independently, hydrogen, C (O) R A, OR A, NR BR C, S (O 2) R A, or optional alkyl, alkyl-aryl or the alkyl-heterocycle that replaces; And
Q is 1-2.
16. the compound of claim 1, it is the compound of following formula:
Figure A2008101084530007C1
17. the compound of claim 1, it is effective TPH1 inhibitor.
18. the compound of claim 17, its TPH1_IC 50Less than about 1 μ M.
19. the compound of claim 18, its TPH1_IC 50Less than about 0.5 μ M.
20. the compound of claim 19, its TPH1_IC 50Less than about 0.1 μ M.
21. the compound of claim 20, its TPH1_IC 50Less than about 0.05 μ M.
22. the compound of claim 1, wherein A 1Be aromatic.
23. the compound of claim 1, wherein A 1Not aromatic.
24. the compound of claim 1, wherein A 1Optional with one or more halogens or low alkyl group replacement.
25. the compound of claim 1, wherein R 1It is hydrogen or halogen.
26. each compound of claim 2-16, wherein R 1It is hydrogen or halogen.
27. the compound of claim 1, wherein m is 1.
28. each compound of claim 2-16, wherein m is 1.
29. the compound of claim 1, wherein R 2Be hydrogen or amino.
30. each compound of claim 2-16, wherein R 2Be hydrogen or amino.
31. the compound of claim 1, wherein R 3Be hydrogen or low alkyl group.
32. the compound of claim 1, wherein R 3Be C (O) OR AAnd R AIt is alkyl.
33. each compound of claim 2-16, wherein R 3Be hydrogen or low alkyl group.
34. each compound of claim 2-16, wherein R 3Be C (O) OR AAnd R AIt is alkyl.
35. the compound of claim 1, wherein R 4Be hydrogen or low alkyl group.
36. each compound of claim 2-16, wherein R 4Be hydrogen or low alkyl group.
37. each compound of claim 2-16, wherein R 5Be hydrogen or low alkyl group.
38. the compound of claim 37, wherein R 5It is methyl.
39. each compound of claim 3-8, wherein n is 1.
40. the compound of claim 9 or 10, wherein p is 1.
41. each compound of claim 11-16, wherein q is 1.
42. a compound or pharmaceutically acceptable salt thereof, wherein said compound is:
(S)-2-amino-3-(4-{2-amino-6-[2,2,2-three fluoro-1-(4-pyridin-4-yl-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid;
(S)-2-amino-3-(4-{6-[2,2,2-three fluoro-1-(2-pyridin-4-yl-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid;
(S)-2-amino-3-(4-{2-amino-6-[2,2,2-three fluoro-1-(2-(4-methyl-thiene-3-yl-)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-(4-{2-amino-6-[2,2,2-three fluoro-1-(2-(5-methyl-thiene-3-yl-)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-(4-{2-amino-6-[2,2,2-three fluoro-1-(4-furans-3-base-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid;
(S)-and 2-amino-3-[4-{2-amino-6-{1-[2-(5-dimethylaminomethyl-furans-2-yl)-phenyl]-2,2,2-three fluoro-oxyethyl groups }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3[4-(2-amino-6-{1-[2-(6-cyano group-pyridin-3-yl)-phenyl]-2,2,2-three fluoro-oxyethyl groups }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-(4-{2-amino-6-[2,2,2-three fluoro-1-(2-imidazoles-1-base-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid;
(S)-2-amino-3-(4-{6-[2,2,2-three fluoro-1-(2-pyrazol-1-yl-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid;
(S)-2-amino-3-[4-(2-amino-6-{2,2,2-three fluoro-1-[2-(3-trifluoromethyl-pyrazol-1-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-[4-(2-amino-6-{1-[2-(3,5-dimethyl-pyrazol-1-yl)-phenyl]-2,2,2-three fluoro-oxyethyl groups }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-[4-(2-amino-6-{2,2,2-three fluoro-1-[2-(3-phenyl-pyrazole-1-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-[4-(2-amino-6-{2,2,2-three fluoro-1-[5-methoxyl group-2-(4-methyl-pyrazol-1-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-[4-(2-amino-6-{ (R)-2,2,2-three fluoro-1-[2-(3-methyl-pyrazol-1-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-[4-(2-amino-6-{1-[4-chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2-three fluoro-oxyethyl groups }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-[4-(2-amino-6-{R-1-[4-chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2-three fluoro-oxyethyl groups }-pyrimidine-4-yl)-phenyl]-ethyl propionate;
(S)-2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl isophthalic acid H-pyrazol-1-yl) phenyl)-2,2,2-trifluoro ethoxy) pyrimidine-4-yl) phenyl) propionic acid;
(S)-2-amino-3-(4-{2-amino-6-[2,2,2-three fluoro-1-(2-thiazol-2-yl-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid;
(S)-2-amino-3-[4-(2-amino-6-{2,2,2-three fluoro-1-[2-(pyridin-3-yl oxygen base)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-[4-(2-amino-6-{2,2,2-three fluoro-1-[4-(pyridin-3-yl oxygen base)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-[4-(6-{2,2,2-three fluoro-1-[4-(pyridin-3-yl oxygen base)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-(4-{2-amino-6-[2,2,2-three fluoro-1-(4-thiophene-2-base-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid;
(S)-2-amino-3-(4-{6-[2,2,2-three fluoro-1-(4-imidazoles-1-base-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid;
(S)-2-amino-3-(4-{2-amino-6-[2,2,2-three fluoro-1-(4-[1,2,4] triazol-1-yl-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid;
(S)-2-amino-3-(4-{2-amino-6-[2,2,2-three fluoro-1-(4-fluoro-2-thiene-3-yl--phenyl) oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid;
(S)-2-amino-3-[4-(2-amino-6-{2,2,2-three fluoro-1-[4-fluoro-2-(4-methyl-thiophene-2-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-[4-(2-amino-6-{1-[2-(3,5-dimethyl-isoxazole-4-base)-4-fluoro-phenyl]-2,2,2-three fluoro-oxyethyl groups }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-[4-(2-amino-6-{2,2,2-three fluoro-1-[5-fluoro-2-(3-methyl-pyrazol-1-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-[4-(2-amino-6{2,2,2-three fluoro-1-[5-chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-[4-(2-amino-6-{2,2,2-three fluoro-1-[4-(2-oxo-tetramethyleneimine-1-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-[4-(2-amino-6-{ (R)-2,2,2-three fluoro-1-[5-fluoro-2-(3-methyl-pyrazol-1-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-[4-(2-amino-6-{2,2,2-three fluoro-1-[4-(6-methoxyl group-pyridine-2-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-[4-(2-amino-6-{2,2,2-three fluoro-1-[2-fluoro-4-(5-methoxyl group-pyridin-3-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-[4-(2-amino-6-{ (S)-2,2,2-three fluoro-1-[4-(2-fluoro-pyridin-4-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-[4-(2-amino-6-{ (S)-2,2,2-three fluoro-1-[4-(5-methoxyl group-pyridin-3-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-[4-(2-amino-6-{ (S)-2,2,2-three fluoro-1-[4-(4-trifluoromethyl-pyridin-3-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-(4-{2-amino-6-[(S)-2,2,2-three fluoro-1-(4-isoxazole-4-base-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid;
(S)-2-amino-3-(4-{2-amino-6-[2,2,2-three fluoro-1-(2-pyrimidine-5-base-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid;
(S)-2-amino-3-(4-{2-amino-6-[2,2,2-three fluoro-1-(2-thiene-3-yl--phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid;
(S)-2-amino-3-[4-(2-amino-6-{2,2,2-three fluoro-1-[2-(1-methyl isophthalic acid H-pyrazoles-4-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-(4-{6-[2,2,2-three fluoro-1-(2-furans-3-base-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid;
(S)-2-amino-3-(4-{6-[2,2,2-three fluoro-1-(2-furans-2-base-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(4-(pyridin-3-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(2-(2-picoline-4-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(2-(4-thiotolene-3-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid;
(2S)-3-(4-(6-(1-(2-(1H-pyrazol-1-yl) phenyl)-2,2,2-trifluoro ethoxy)-2-aminopyrimidine-4-yl) phenyl)-2-alanine;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(4-(furans-2-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid;
(2S)-2-amino-3-(4-(6-(2,2,2-three fluoro-1-(2-(pyridin-3-yl oxygen base) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid;
(2S)-3-(4-(6-(1-(2-(1H-1,2,4-triazol-1-yl) phenyl)-2,2,2-trifluoro ethoxy)-2-aminopyrimidine-4-yl) phenyl)-2-alanine;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(2-(furans-3-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(4-(furans-2-yl)-3-p-methoxy-phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid;
(2S)-2-amino-3-(4-(5-(2,2,2-three fluoro-1-(2-(furans-2-yl) phenyl) oxyethyl group) pyrazine-2-yl) phenyl) propionic acid;
(2S)-3-(4-(5-(1-(2-(1H-pyrazol-1-yl) phenyl)-2,2,2-trifluoro ethoxy) pyrazine-2-yl) phenyl)-2-alanine;
(2S)-2-amino-3-(4-(2-amino-6-(1-(4,5-dimethoxy-2-(1H-pyrazol-1-yl) phenyl)-2,2,2-trifluoro ethoxy) pyrimidine-4-yl) phenyl) propionic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(2-(2-methyl isophthalic acid H-imidazoles-1-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(2-(5-thiotolene-2-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid;
(2S)-2-amino-3-(4-(2-amino-6-(1-(2-(5-(formyl-dimethylamino) furans-2-yl) phenyl)-2,2,2-trifluoro ethoxy) pyrimidine-4-yl) phenyl) propionic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(4-fluoro-2-(thiophene-2-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid;
(2S)-2-amino-3-(4-(6-(2,2,2-three fluoro-1-(4-fluoro-2-(thiophene-2-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid;
(2S)-2-amino-3-(4-(6-(2,2,2-three fluoro-1-(4-fluoro-2-(thiene-3-yl-) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid;
(2S)-2-amino-3-(4-(6-(2,2,2-three fluoro-1-(4-fluoro-2-(4-thiotolene-2-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid;
(S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-three fluoro-1-(4-(6-fluorine pyridin-3-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid;
(2S)-3-(4-(6-(1-(4-(1H-imidazoles-1-yl) phenyl)-2,2,2-trifluoro ethoxy)-2-aminopyrimidine-4-yl) phenyl)-2-alanine;
(2S)-2-amino-3-(4-(6-(2,2,2-three fluoro-1-(4-(thiophene-2-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid;
(S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-three fluoro-1-(4-(pyrimidine-5-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid;
(2S)-2-amino-3-(4-(6-(1-(2-(3,5-dimethyl isoxazole-4-yl)-4-fluorophenyl)-2,2,2-trifluoro ethoxy) pyrimidine-4-yl) phenyl) propionic acid;
(S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-three fluoro-1-(4-(2-picoline-4-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid;
(2S)-3-(4-(6-(1-(4-(1H-1,2,4-triazol-1-yl) phenyl)-2,2,2-trifluoro ethoxy) pyrimidine-4-yl) phenyl)-2-alanine;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(4-(piperidines-1-ylmethyl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(2-fluoro-4-(2-picoline-4-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid;
(2S)-2-amino-3-(4-(2-amino-6-(1-(4-(6-chlorine pyridazine-3-yl) phenyl)-2,2,2-trifluoro ethoxy) pyrimidine-4-yl) phenyl) propionic acid;
(2S)-2-amino-3-(4-(2-amino-6-(1-(4-(4-tert-butyl thiazol-2-yl) phenyl)-2,2,2-trifluoro ethoxy) pyrimidine-4-yl) phenyl) propionic acid;
(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-three fluoro-1-(3 '-methoxyl group-3-(3-methyl isophthalic acid H-pyrazol-1-yl) biphenyl-4-yl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid; Or
(2S)-2-amino-3-(4-(2-amino-6-(1-(5-chloro-2-(3-methyl isophthalic acid H-pyrazol-1-yl) phenyl)-2,2,2-trifluoro ethoxy) pyrimidine-4-yl) phenyl) propionic acid.
43. the compound of claim 42, it is that stereoisomerism is pure.
44. composition comprises compound and the pharmaceutically acceptable vehicle or the thinner of claim 1.
45. single unit dosage comprises the composition of claim 44.
46. suppress the active method of TPH1, it comprises makes TPH1 contact with the compound of claim 1.
47. treatment, prevention or management are by the disease or the disorderly method of the mediation of periphery serotonin, it comprises the compound to the claim 1 of patient's administering therapeutic of this treatment of needs, prevention or management or prevention significant quantity.
48. treatment, prevention or management of disease or disorderly method, it comprises that wherein said disease or disorder are carcinoid crisis or carcinoid syndrome to the compound of the claim 1 of patient's administering therapeutic of this treatment of needs, prevention or management or prevention significant quantity.
49. treatment, prevention or management of disease or disorderly method, it comprises that wherein said disease or disorder are gastrointestinal illness or disorder to the compound of the claim 1 of patient's administering therapeutic of this treatment of needs, prevention or management or prevention significant quantity.
50. the method for claim 49, wherein said gastrointestinal illness and disorder are coeliac diseases, constipation, Crohn disease, diarrhoea, vomiting, functional abdominal pain, anus bowel dysfunction, functional inflatable, functional dyspepsia, gallbladder function disorder, irritable bowel syndrome (IBS; Comprise IBS-d, IBS-c and IBS-a), lactose intolerance, MEN I and II type are felt sick Ogilvie's syndrome false colonic obstruction, watery diarrhea with hypokalemia and achlorhydria, pancreatic insufficiency, Oddi sphincter dysfunction, ulcerative colitis, and Zuo-Ai syndrome.
51. treatment, prevention or management of disease or disorderly method, it comprises that wherein said disease or disorder are cardiovascular or pulmonary disorder or disorder to the compound of the claim 1 of patient's administering therapeutic of this treatment of needs, prevention or management or prevention significant quantity.
52. the method for claim 51, wherein said cardiovascular or pulmonary disorder or disorder are adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), CREST syndrome, (acute or chronic) hypertension, pheochromocytoma, pulmonary infarction, pulmonary hypertension, radiation pneumonia, or subarachnoid hemorrhage.
53. treatment, prevention or management of disease or disorderly method, it comprises that wherein said disease or disorder are scleroderma or serotonin syndrome to the compound of the claim 1 of patient's administering therapeutic of this treatment of needs, prevention or management or prevention significant quantity.
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US9611201B2 (en) 2015-03-05 2017-04-04 Karos Pharmaceuticals, Inc. Processes for preparing (R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanol and 1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanone
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