CN104045626A - Compounds based on 4-phenyl-6-(2,2,2-trifluoro-1-phenyl ethoxy) pyrimidine and application method thereof - Google Patents

Compounds based on 4-phenyl-6-(2,2,2-trifluoro-1-phenyl ethoxy) pyrimidine and application method thereof Download PDF

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CN104045626A
CN104045626A CN201410196723.3A CN201410196723A CN104045626A CN 104045626 A CN104045626 A CN 104045626A CN 201410196723 A CN201410196723 A CN 201410196723A CN 104045626 A CN104045626 A CN 104045626A
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phenyl
amino
fluoro
pyrimidine
tri
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CN104045626B (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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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Organic Chemistry (AREA)
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Abstract

The present invention relates to compounds based on 4-phenyl-6-(2,2,2-trifluoro-1-phenyl ethoxy) pyrimidine and an application method thereof, particularly discloses compounds of formula I and compositions comprising the compounds, and the application method thereof in treatment, prevention and / or management of diseases or disorders.

Description

Compound and application method thereof based on 4-phenyl-6-(the fluoro-1-phenyl ethoxy of 2,2,2-tri-) pyrimidine
The application is dividing an application of the exercise question submitted on May 30th, 2008 Chinese patent application 200810108453.0 that is " compound and application method thereof based on 4-phenyl-6-(the fluoro-1-phenyl ethoxy of 2,2,2-tri-) pyrimidine ".
Technical field
The present invention relates to the compound based on 4-phenyl-6-(the fluoro-1-phenyl ethoxy of 2,2,2-tri-) pyrimidine, the composition that contains described compound, 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 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, in Qi peripheral tissues, mainly express in stomach and intestine (GI) road; And TPH2, it expresses in serotoninergic neuron.Referring to the same.Isoform TPH1 is by tph1 genes encoding; TPH2 is by 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 expresses the serotonin of normal amount in classical serotonin Neng Nao district, but lacks in a large number serotonin in periphery.Referring to the same.Under another situation, the cardiomotility that knock out mice shows abnormality, this lacks owing to periphery serotonin. , F. etc., pNAS100 (23): 13525-13530 (2003).
Because serotonin participates in so many biological process, affect the medicine of 5-hydroxytryptamine receptor conventionally with side effect.Therefore, needing new approach to treat is subject to serotonin to affect, mediate or associated disease and disorder.
Summary of the invention
The present invention partly relates to formula I compound:
And pharmacologically acceptable salt and solvate, wherein: A 1it is the optional heterocycle replacing; Each R 1halogen 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 replacing; R 2halogen 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 replacing; R 3hydrogen, C (O) R a, C (O) OR a, or optional alkyl, alkyl-aryl, alkyl-heterocycle, aryl or the heterocycle replacing; R 4hydrogen or optional alkyl, alkyl-aryl, alkyl-heterocycle, aryl or the heterocycle replacing; Each R ahydrogen or optional alkyl, alkyl-aryl or the alkyl-heterocycle replacing independently; Each R bhydrogen or optional alkyl, alkyl-aryl or the alkyl-heterocycle replacing independently; Each R chydrogen or optional alkyl, alkyl-aryl or the alkyl-heterocycle replacing 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 various diseases and illness.
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 GI5-hydroxy-tryptamine, yet also very little if any on measurable impact of central nervous system (CNS).
The present invention is also based on for example, to suppressing TPH (, the discovery of compound TPH1).When being administered to Mammals, the preferred compound of the present invention reduces serotonin level, the pharmacokinetics having and pharmacodynamic property make them can be actually used in treatment, prevention and management of disease and illness, and between pharmacological action and toxicity or disadvantageous side reaction, have wide safety limit.
Definition
Except as otherwise noted, term " thiazolinyl " for example represents, with 2-20 (, 2-10 or 2-6) carbon atom and comprises straight chain, side chain and/or the cyclic hydrocarbon of the two keys of at least one C-C.Representative alkenyl part comprises vinyl, allyl group, 1-butylene base, crotyl, isobutenyl, 1-pentenyl, pentenyl, 3-methyl-1-butene base, 2-methyl-2-butene base, 2,3-dimethyl-crotyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 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 " represents for example, straight chain, side chain and/or ring-type (" cycloalkyl ") hydrocarbon with 1-20 (, 1-10 or 1-4) carbon atom.Moieties with 1-4 carbon is called " low alkyl group ".The example of alkyl comprises methyl, ethyl, propyl group, sec.-propyl, n-butyl, tert-butyl, isobutyl-, amyl group, hexyl, isohexyl, 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 encircle more, and its example comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl.Other examples of moieties have straight chain, side chain and/or circular part (for example, 1-ethyl-4-methyl-cyclohexyl base).Term " alkyl " comprises stable hydrocarbon, and thiazolinyl and alkynyl part.
Except as otherwise noted, term " alkoxyl group " expression-O-alkyl.Comprise-OCH of the example of alkoxyl group 3,-OCH 2cH 3,-O (CH 2) 2cH 3,-O (CH 2) 3cH 3,-O (CH 2) 4cH 3, and-O (CH 2) 5cH 3.
Except as otherwise noted, term " alkaryl " or " alkyl-aryl " represent the moieties of being combined with aryl moiety.
Except as otherwise noted, term " miscellaneous alkyl aryl " or " alkyl-heteroaryl " represent the moieties of being combined with heteroaryl moieties.
Except as otherwise noted, term " alkyl heterocycle " or " alkyl-heterocycle " represent the moieties of being combined with heterocyclic moiety.
Except as otherwise noted, term " alkynyl " for example represents, with 2-20 (, 2-20 or 2-6) carbon atom and comprises straight chain, side chain and/or the cyclic hydrocarbon of at least one C-C triple bond.Representative alkynyl partly comprises ethynyl, proyl, ethyl acetylene base, 2-butyne base, 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, term " aryl " represents aromatic nucleus or the aromatics being comprised of carbon and hydrogen atom or partially aromatic loop systems.Aryl moiety can comprise a plurality of combinations or condense ring together.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 " represent the aryl moiety of being combined with moieties.
Except as otherwise noted, the term acid amides of biological hydrolysis " can ", the ester of biological hydrolysis " can " carbamate of biological hydrolysis " can ", the carbonic ether of biological hydrolysis " can ", the urea groups of biological hydrolysis " can " and the phosphoric acid ester of biological hydrolysis " can " represents respectively acid amides, ester, carbamate, carbonic ether, urea groups or the phosphoric acid ester of compound, itself or: the biological activity of 1) not disturbing described compound, but can give this compound favourable body internal characteristic, such as picked-up, acting duration, or onset of effect; Or 2) be biological non-activity, but change in vivo bioactive compounds.The example of ester that can biological hydrolysis comprises lower alkyl esters, alkoxyl group acyloxy ester, alkyl acyl aminoalkyl ester, and cholinesterase.The example of acid amides that can biological hydrolysis comprises low alkyl group acid amides, alpha-amino acid amides, alkoxyl group acyl group acid amides, and alkylamino alkyl-carbonyl acid amides.Carbamate that can 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 subject to disease or the illness of the mediation of periphery serotonin " and " being subject to disease and the illness of the mediation of periphery serotonin " expression has disease and/or the illness of one or more symptoms, and its seriousness is subject to the impact 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 " refers to 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 the aryl moiety that wherein at least one carbon atom for example, has been replaced by heteroatoms (, N, O or S).Example comprises acridyl, benzimidazolyl-, benzofuryl, benzisothiazole base, benzisoxa azoles base, Benzoquinazole base, benzothiazolyl, benzo azoles base, furyl, imidazolyl, indyl, isothiazolyl, different azoles base, di azoly, azoles base, 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 " represent the heteroaryl of being combined with moieties.
Except as otherwise noted, term " heterocycle " refers to the aromatics that contains carbon, hydrogen and at least one heteroatoms (for example, N, O or S), partially aromatic or non-aromatic monocycle 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 [Isosorbide-5-Nitrae] two thiazolinyl, 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 " refer to the heterocyclic moiety of being combined with moieties.
Except as otherwise noted, term " Heterocyclylalkyl " refers to non-aromatic heterocyclic.
Except as otherwise noted, term " Heterocyclylalkyl alkyl " or " Heterocyclylalkyl-alkyl " refer to the Heterocyclylalkyl part of being combined with moieties.
Except as otherwise noted, term " management " is included in to suffer to specify in disease or disorderly patient and prevents the recurrence of described disease or disorder or its one or more symptoms, and/or extends and suffered from the time that described disease or disorderly patient maintain improvement.Described term comprises beginning, development and/or the time length that regulates described disease or disorder, or changes patient to described disease or disorderly reactive mode.
Except as otherwise noted, term " pharmacologically acceptable salt " refers to the salt of preparing from pharmaceutically useful non-toxic acid or alkali, 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-METHYL-ALPHA-L-GLUCOSAMINE) and PROCAINE HCL, PHARMA GRADE are made.Suitable non-toxic acid comprises inorganic and organic acid, such as acetic acid, 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, flutter 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 (mesylate salts).Other are well known in the art.Referring to, for example, Remington ' s Pharmaceutical Sciences, 18 thed. (Lei Shi pharmaceutical science, the 18th edition) (Mack Publishing, Easton PA:1990) and Remington:The Science and Practice of Pharmacy, 19 thed. (Lei Shi medicament science and practice, the 19th edition) (Mack Publishing, Easton PA:1995).
Except as otherwise noted, term " effectively TPH1 inhibitor " refers to TPH1_IC 50be less than the compound of approximately 10 μ M.
Except as otherwise noted, term " prevents from " being intended to patient and starts to suffer from the effect occurring before disease or 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; 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.The example of prodrug comprise containing can biological hydrolysis compound (for example, acid amides that can biological hydrolysis, the carbamate that can biological hydrolysis of part, carbonic ether that can biological hydrolysis, ester that can biological hydrolysis, phosphoric acid ester that can biological hydrolysis, or uride analogue that can biological hydrolysis).The prodrug of compound disclosed herein is easily expected and prepares by those of ordinary skills.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; 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 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 not reacting under the condition of this chemical reaction, and can being removed to provide the part of reacting under those conditions.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 organic synthesis) (third edition., John Wiley & Sons:1999); Larock, R.C., comprehensive Organic? transformations (comprehensive organic transformation)(second edition, John Wiley & Sons:1999).Some examples comprise benzyl, diphenyl methyl, trityl, Cbz, Boc, Fmoc, methoxycarbonyl, ethoxy carbonyl, and phthalimido.
Except as otherwise noted, term " pseudohalogen " refers to polyatom negatively charged ion, at its acid-alkali, replacement and oxygen similar halide ions in chemistry also, conventionally has low basicity, and form free radical under atom transfer radical polymerization condition.The example of pseudohalogen comprises 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 the compound of 10 times.
Except as otherwise noted, " composition of stereoisomerism enrichment " of term compound refers to the mixture of name compound and steric isomer thereof, and the name compound that it contains is more than its steric isomer.For example, the composition of the stereoisomerism enrichment of (S)-Ding-2-alcohol comprises that ratio is, for example, and approximately 60/40,70/30,80/20,90/10,95/5, and the mixture of 98/2 (S)-Ding-2-alcohol and (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 " represents a kind of steric isomer that composition contains compound, and does not basically contain other steric isomers of this compound.For example, the pure composition of stereoisomerism that has a compound of a Stereocenter does not basically contain the relative steric isomer of this compound.The pure composition of stereoisomerism with the compound of two Stereocenters does not basically contain other diastereomers of this compound.The pure composition of steric isomer with the compound of a plurality of Stereocenters, but the mode of its drafting or name has defined the stereochemistry that is less than all Stereocenters, it does not basically contain the isomer of this compound, and these isomer have different stereochemistry at the Stereocenter of stereochemistry definition.For example, " stereoisomerism pure ((1R)-1,2-bis-chloropropyls) benzene " refers to ((1R)-1, the 2-bis-chloropropyls) benzene that does not basically contain ((1S)-1,2-bis-chloropropyls) benzene.
A kind of steric isomer that typical stereoisomerism pure compound comprises this compound that is greater than approximately 80 % by weight and other steric isomers that are less than this compound of approximately 20 % by weight, be greater than a kind of steric isomer and other steric isomers that are less than this compound of approximately 10 % by weight of this compound of approximately 90 % by weight, be greater than a kind of steric isomer and other steric isomers that are less than this compound of approximately 5 % by weight of this compound of approximately 95 % by weight, be greater than a kind of steric isomer and other steric isomers that are less than this compound of approximately 3 % by weight of this compound of approximately 97 % by weight, or be greater than approximately 99 % by weight this compound a kind of steric isomer and be less than other steric isomers of this compound of approximately 1 % by weight.
Except as otherwise noted, term " replacement ", when for represent chemical structure or part, the derivative that refers to 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 is (for example, methyl, ethyl, propyl group, tert-butyl), alkynyl, alkyl-carbonyl oxygen base (OC (O) alkyl), acid amides (C (O) NH-alkyl-Huo – 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-Huo – OC (O) NH-alkyl), carbamyl (for example, CONH 2, and 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 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 to provide treatment benefit in treatment or management of disease or illness or postponing or minimize one or more symptoms relevant to described disease or illness.The treatment significant quantity of compound be therapeutical agent separately or with the amount of other therapies combinations, it provides treatment benefit in treatment or management of disease or illness.Term " treatment significant quantity " can comprise 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 vitro inhibition Analysis deterrmination described in embodiment below.
Except as otherwise noted, term " TPH2_IC 50" be the IC of compound to TPH2 50, utilize the vitro inhibition Analysis deterrmination described in embodiment below.
Except as otherwise noted, term " treatment " is intended to patient and is just suffering from the effect occurring while 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 " the identical meaning there is.
Except as otherwise noted, immediately the one or more adjectives before a series of nouns are construed to and are applicable to each noun.For example, phrase " optional alkyl, aryl or the heteroaryl replacing " has the identical meaning with " the optional alkyl replacing, the optional aryl replacing, or the optional heteroaryl replacing ".
It should be noted, form compared with the chemical part of the part of large compound, the title that conventionally gives its title in the time of can utilizing it to exist with individual molecule or conventionally give its group is described at this.For example, term " pyridine " and " pyridyl ", when when describing the part being connected with other chemical parts, give the identical meaning.Therefore, two phrases " XOH, wherein X is pyridyl " and " XOH, wherein X is pyridine " give the identical meaning, and comprise compound pyridine-2-alcohol, pyridine-3-alcohol and pyridine-4-alcohol.
It shall yet further be noted that as the stereochemistry of the part of fruit structure or structure and with for example thick line or dotted line, do not indicate, the part of this structure or this structure is construed as comprising its all steric isomers.Equally, there are one or more chiral centres but do not specify the stereochemical compound title at described center to comprise pure stereoisomers and composition thereof.And, being assumed to be and being connected to enough hydrogen atoms to meet valency with unsatisfied valent any atom shown in figure.In addition, the chemical bond of describing with the solid line dotted line parallel with comprises single and double (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 replacing; Each R 1halogen 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 replacing; R 2halogen 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 replacing; R 3hydrogen, C (O) R a, C (O) OR a, or optional alkyl, alkyl-aryl, alkyl-heterocycle, aryl or the heterocycle replacing; R 4hydrogen or optional alkyl, alkyl-aryl, alkyl-heterocycle, aryl or the heterocycle replacing; Each R ahydrogen or optional alkyl, alkyl-aryl or the alkyl-heterocycle replacing independently; Each R bhydrogen or optional alkyl, alkyl-aryl or the alkyl-heterocycle replacing independently; Each R chydrogen or optional alkyl, alkyl-aryl or the alkyl-heterocycle replacing independently; And m is 1-4.
In one embodiment, the formula of described compound is:
In another embodiment, its formula is:
Wherein: each R 5halogen 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 replacing; And n is 1-3.
In another embodiment, its formula is:
Wherein: each R 5halogen 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 replacing; And p is 1-4.
In another embodiment, its formula is:
Wherein: each R 5halogen 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 replacing; And q is 1-2.
In another embodiment, its formula is:
Wherein: each R 5halogen independently, hydrogen, C (O) R a, OR a, NR br c, S (O 2) R a, or the optional alkyl replacing, alkyl-aryl or alkyl-heterocycle; And q is 1-2.
About multiple formula, especially the compounds of this invention disclosed herein, A 1aromatic.In other, A 1not aromatic.In some, A 1optionally with one or more hydrogen or low alkyl group, replace.
In some, R 1it is hydrogen or halogen.
In some, m is 1.
In some, R 2hydrogen or amino.
In some, R 3hydrogen or low alkyl group.In other, R 3c (O) OR aand R ait is alkyl.
In some, R 4hydrogen or low alkyl group.
In some, R 5hydrogen 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 the pure compound of stereoisomerism and stereoisomerism enrichment thereof is contained in the present invention.Steric isomer usable criterion technology, 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, Racemates and Resolutions (enantiomorph, racemic modification and parsing) (Wiley Interscience, New York, 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 Resolving Agents 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 50be less than approximately 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 selectivity TPH1 inhibitor.The TPH1_IC of particular compound 50than its TPH2_IC 50want little by approximately 10,25,50,100,250,500, or 1000 times.
Particular compound does not significantly suppress human tyrosine hydroxylase (TH).For example, the IC of particular compound to TH 50be greater than approximately 100,250,500 or 1000 μ M.
Particular compound does not significantly suppress people's Phenylalanine hydroxylase (PAH).For example, the IC of particular compound to PAH 50be greater than approximately 100,250,500 or 1000 μ M.
Not significantly combination of particular compound of the present invention (for example, to be greater than approximately 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), different azoles quinoline or different azoles fibrinogen deceptor, metalloprotease, neutral endopeptidase (NEP), Phosphoric acid esterase is (for example, tyrosine phosphatase), phosphodiesterase (for example, PDE-4), polysaccharase, PPAR γ, TNF-α, vascular cell adhesion molecule-1 (VCAM-1), or Vitronectic receptor.The approach well known of the ability utilization of any combination in compound and these targets (for example, suppressing) described in above-cited reference, can easily determine.Particular compound of the present invention does not suppress cell adhesion.
When for example, to Mammals (, mouse, rat, dog, monkey or people) administration, some compound of the present invention is difficult for crossing blood/brain barrier (for example, be less than approximately 5,2.5,2,1.5,1,0.5 in blood, or 0.01% compound entering 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 be prepared with method described herein by means commonly known in the art.
For example, formula I compound can be prepared as shown in synthetic route I:
P wherein 1r 1or protecting group; P 2it is protecting group; P 3oR 2or protecting group; Y 1and Y 3halogen (for example, Br, Cl) or suitable pseudohalide (for example, fluoroform sulphonate (triflate)); And each group A 1, R 1, R 2, and R 3in this paper elsewhere, define.
The compounds of this invention also can be prepared by the approach shown in following synthetic route 2:
Single reaction shown in said synthesis route can utilize condition well known in the art to carry out.For example, the palladium catalyst and the condition that are suitable for the Suzuki coupling of boron and halogen-containing part are well-known, and example is below providing.In addition, the type of protecting group and suitable purposes are well-known, as it is removed for example, with the method (, being hydrolyzed under acidity or alkaline condition) of replacement the same by the part such as but not limited to hydrogen.
The method of the ester derivative utilization of the compounds of this invention shown in following synthetic route 3 can easily be prepared:
Utilize method well known in the art, above-mentioned route of synthesis is easily modified, to obtain the compound of wide region.For example, chiral chromatography well known in the art and other technologies can be used for the steric isomer of separated end product.Referring to, for example, Jacques, J. etc., enantiomers, racemates and Resolutions(enantiomorph, racemic modification and parsing) (Wiley Interscience, 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, as shown in some synthetic route above, synthesize and can utilize chiral raw material, generate stereoisomerism product enrichment or pure.
Application method
The present invention comprises the method that suppresses TPH, and the 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 vitro inhibition.In another, inhibition is to suppress in body.
A kind of embodiment comprises the method that suppresses Mammals (for example, people) TPH1, and the method comprises to 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 various diseases and the disorderly method that treatment, prevention and management are subject to the mediation of periphery serotonin, and the method comprises the patient's of this treatment of inhibition needs, prevention or management TPH1 activity.In specific embodiments, suppress by realizing to effective TPH1 inhibitor of 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 that abdominal pain (for example, relevant with Tiroidina medullary substance knurl), anxiety, carcinoid syndrome, coeliac disease, constipation (for example, the constipation causing because of doctor's treatment, with idiopathic constipation), Crohn disease, melancholia, diabetes, diarrhoea (for example, bile acide diarrhoea, the secretory diarrhea of enterotoxin-induction, the diarrhoea causing because of doctor's treatment, idiopathic diarrhoea (for example, the special secretory diarrhea of sending out), and traveler's diarrhea), vomiting, functional abdominal pain, anus bowel dysfunction, functional inflatable, functional dyspepsia, gallbladder function is disorderly, irritable bowel syndrome (IBS, comprise IBS-d, IBS-c and IBS-a), lactose intolerance, MEN I and II type, feel sick, Ogilvie's syndrome false colonic obstruction (Ogilvie ' s syndrome), watery diarrhea with hypokalemia and achlorhydria, pancreatic insufficiency, pheochromocytoma, scleroderma, somatization disorder, 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 pulmonary infarction), pulmonary hypertension (for example, the pulmonary hypertension relevant with portal hypertension), and radiation pneumonia (comprising the radiation pneumonia that generates or contribute to pulmonary hypertension).Other comprise abdomen migraine (abdominal migraine), adult respiratory distress syndrome (ARDS), carcinoid crisis, CREST syndrome (calcinosis, and Raynaud's phenomenon (Raynaud ' s phenomenon), 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 the method comprises to patient uses enough effective TPH1 inhibitor.
Another embodiment comprises the method for the Gastric Emptying that slows down, and the method comprises to patient uses enough effective TPH1 inhibitor.
In concrete grammar of the present invention, realize treatment, management and/or preventing disease or disorder, avoid changing relevant side effect to the serotonin level of central nervous system (CNS) simultaneously.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 changing relevant side effect to the serotonin level of central nervous system (CNS) simultaneously.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 containing one or more the compounds of this invention.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, injects, intramuscular, or intra-arterial) or percutaneous dosing to patient.The example of formulation includes, but are not limited to: tablet; Capsule sheet; Capsule, such as soft elastic gelatin capsule; 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 administered parenterally to patient's liquid dosage form; And sterile solid (for example, crystal or armorphous solid), this solid can be redissolved to provide to be suitable for administered parenterally to patient's liquid dosage form.
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, with Liposomal formulation administration, to protect them to exempt from degrading enzyme, promote the transportation in the recycle system, and realize sending of cross-cell membrane.
Equally, poorly soluble compound can mix in liquid dosage form (with the formulation that is suitable for redissolving) under the help of solubilizing agent, emulsifying agent and tensio-active agent, described solubilizing agent, emulsifying agent and tensio-active agent such as, but be not limited to cyclodextrin (for example, alpha-cylodextrin, beta-cyclodextrin , and Encapsin tM(referring to, for example, Davis and Brewster, nat.Rev.Drug Disc.3:1023-1034 (2004)), 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 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 be prepared by the method for following middle record: U.S. Patent Publication No.2004-0164194,2004-0195413,2004-0251332,2005-0042177A1,2005-0031691A1, 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, which is hereby incorporated by reference separately.In one embodiment, form of nanoparticles comprises that mean particle size is less than about 2000nm, is less than about 1000nm, or is less than the particle of about 500nm.
The composition of formulation, shape and type change according to purposes conventionally.For example, the acute treatment of the disease formulation formulation more used than the chronic treatment of same disease used 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 Pharmaceutical Sciences, 18 thed. (Lei Shi pharmaceutical science, the 18th edition), Mack Publishing, Easton PA (1990).
Oral dosage form
The pharmaceutical composition of the present invention that is suitable for oral administration can be rendered as separated formulation, for example, such as, but not limited to, tablet (, can chew tablet), and capsule sheet, capsule, and liquid (for example, seasoning syrup).The activeconstituents that such formulation contains predetermined amount, and can prepare by well-known pharmaceutical methods to those skilled in the art.Generally referring to, Remington ' s Pharmaceutical Sciences, 18 thed. (Lei Shi pharmaceutical science, the 18th edition), Mack Publishing, Easton PA (1990).
The preparation of typical oral dosage form is according to conventional medicament mixed technology, in homogenizing mixture by activeconstituents and at least one excipient composition.The dosage form required according to administration, vehicle can adopt diversified form.
Owing to being easy to administration, Tablet and Capsula represents best oral dosage unit form.If needed, 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.Fast Stripping for the benefit of, disintegrating agent can mix solid dosage.For example, for convenience of the preparation of formulation (, tablet), also can mix lubricant.
Parenteral dosage forms
Can to patient, use parenteral dosage forms 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 conventionally, parenteral dosage forms is especially aseptic or can be by sterilization before being administered to patient.The example of parenteral dosage forms comprises the solution of preparing injection, prepares to be dissolved or suspended in the dryed product in pharmaceutically acceptable injectable media, prepares the suspension of injection, and emulsion.
Can be used for providing the suitable media of parenteral dosage forms of the present invention 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 is mixed, 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.
Accompanying drawing explanation
Fig. 1 shows (S)-2-amino-3-(4-(2-amino-6-((R)-1-(the chloro-2-of 4-(3-methyl isophthalic acid H-pyrazol-1-yl) phenyl)-2,2,2-trifluoro ethoxy) pyrimidine-4-yl) phenyl) ethyl propionate dose-dependently impact on 5-HT level in mouse jejunum.This compound is 15% solution in 15,50,150 and 300mpk oral administration.
Fig. 2 shows (S)-2-amino-3-(4-(2-amino-6-((R)-1-(the chloro-2-of 4-(3-methyl isophthalic acid H-pyrazol-1-yl) phenyl)-2,2,2-trifluoro ethoxy) pyrimidine-4-yl) phenyl) impact of ethyl propionate oral administration on rat stomach and intestine (GI) mobility.Asterisk has identified while utilizing t check or single factor ANOVA check to compare with medium, the data of p<0.01.
Fig. 3 shows (S)-2-amino-3-(4-(2-amino-6-((R)-1-(the chloro-2-of 4-(3-methyl isophthalic acid H-pyrazol-1-yl) phenyl)-2,2,2-trifluoro ethoxy) pyrimidine-4-yl) phenyl) the ethyl propionate oral administration impact emptying on rat stomach.Asterisk has identified the data of p<0.01 while 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-(the chloro-2-of 4-(3-methyl isophthalic acid H-pyrazol-1-yl) phenyl)-2,2,2-trifluoro ethoxy) pyrimidine-4-yl) phenyl) impact of ethyl propionate oral administration on the blood of rat 5-HT and proximal colonic level, its data are presented in Fig. 1 and Fig. 2.Under two kinds of situations, utilize single factor ANOVA to be all p<0.0001.
Embodiment
Embodiment
1. prepare tph1 gene break mouse
Substantially as Wattler etc., biotechniques26 (6): described in 1150-6 (1999), by gene targeting, the exon 3 of mouse TPH1 gene is removed.The Gene Knock-Out Animal Model of gained shows that in brain normal TPH is active, but TPH in internal organ expresses sharply and reduces.
The physiologic effect of 2.tph1 gene break
The mouse of isozygotying of tph1 fracture (/-) is in conjunction with the heterozygosis mouse (+/-) of this gene break, studies together with wild-type (+/+) littermate.During this analyzes, be utilized as a whole set of medical diagnosis program of evaluating the function of major organs system in mammalian object and designing, mouse is carried out to medical inspection.By research, record the isozygotying of quantity (/-) knock out mice in conjunction with heterozygosis (+/-) and wild-type (+/+) littermate, obtained more reliable and data repeatably.
The gi tract isoform (TPH1) of the fracture major effect TPH of tph1 gene, and the brain isoform (TPH2) of TPH is with or without to impact less.The fracture of this gene can not cause measurable side effect to central nervous system.This is confirmed by serotonin immunochemistry, and it shows that serotonin is at Stomach duodenum, jejunum, greatly reduce or lack, and serotonin level is uninfluenced in seam neurone in ileum, caecum and colon.
The mouse of isozygotying of some tph1 gene breaks (/-) demonstrate thrombosis minimizing, and significantly do not increase hemorrhage or other unfavorable indications.
3.HPLC characterizes
In following some synthetic example, provide high performance liquid chromatography (HPLC) retention time.For obtaining the various conditions of these retention time, be described below:
Method A:YMC-PACK ODS-A3.0 * 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-A3.0 * 50mm; Solvent orange 2 A=90% water, 10%MeOH is with 0.1%TFA; Solvent B=90%MeOH, 10% water is with 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 ODS4.6 * 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 ODS4.6 * 50mm; Solvent orange 2 A=H 2o is with 0.1%TFA; Solvent B=MeOH is with 0.1%TFA; B% was with 4 minutes from 0% to 100%; Flow velocity=3ml/ minute; Observation wavelength=254nm.
Method E:YMC Pack ODS-A4.6 * 33mm; Solvent orange 2 A=H 2o, 0.1%TFA; Solvent B=MeOH is with 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-A3.0 * 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, the fluoro-1-of 2,2-tri-(4-pyridin-4-yl-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid
By tetrabutyl ammonium fluoride (0.027ml; The tetrahydrofuran solution of 1.0M) be added into 4-pyridin-4-yl-phenyl aldehyde (500mg, 2.73mmol) and trifluoromethyl trimethyl silane (TMSCF at 0 ℃ 3) in the 5ml THF solution of (485 μ l, 3.28mmol).Warm until the room temperature of gained mixture, and at room temperature stir 4 hours.Then, reaction mixture is processed with 5ml1N HCl, and at room temperature stirs and spend the night.Solvent is evaporated to dry, adds 9ml1M aqueous sodium carbonate, and water is with chloroform extracting (3 * 10ml), and the chloroform layer of merging is with water washing, to MgSO 4dry.Vacuum is removed organic solvent, provides 360mg2, the fluoro-1-of 2,2-tri-(4-pyridin-4-yl-phenyl) ethanol, yield: 51%.
In 50ml sealed tube, by 2,2, the fluoro-1-of 2-tri-(4-pyridin-4-yl-phenyl) ethanol (100mg, 0.40mmol), ADCP (60mg, 0.38mmol) and the mixture of cesium carbonate (468mg, 1.44mmol) be dissolved in 2ml1,4-bis- alkane.Heated overnight at 110 ℃, mixture, is then cooled to room temperature; Add 10ml ethyl acetate, then by celite, filter.Filtrate is concentrated, provides the chloro-6-[2 of 120mg4-, the fluoro-1-of 2,2-tri-(4-pyridin-4-yl-phenyl)-oxyethyl group]-pyrimidine-2-base amine, yield: 80%.
In microwave bottle, by the chloro-6-[2 of 4-, 2, the fluoro-1-of 2-tri-(4-pyridin-4-yl-phenyl)-oxyethyl group]-pyrimidine-2-base amine (30mg, 0.080mmol), 4-borono--L-Phe (21mg, 0.098mmol) and 1ml acetonitrile, mix with 0.7ml water.Then, in mixture, add 0.3ml1N aqueous sodium carbonate, then add 5mol% dichloro two-(triphenylphosphine)-palladium (II).Sealed reaction vessel, and at 150 ℃, heat 5 minutes with microwave irradiation.After cooling, reaction mixture is evaporated to dry.Residue is dissolved in 2.5ml methyl alcohol, then through Prep-LC purifying, provides 6.7mg (S)-2-amino-3-(4-{2-amino-6-[2, the fluoro-1-of 2,2-tri-(4-pyrimidine-4-yl-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＝8Hz2H)，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, the fluoro-1-of 2,2-tri-(2-pyridin-4-yl-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid
By tetrabutyl ammonium fluoride (0.027ml; The tetrahydrofuran solution of 1.0M) be added into 2-pyridin-4-yl-phenyl aldehyde (500mg, 2.73mmol) and trifluoromethyl trimethyl silane (TMSCF at 0 ℃ 3) in the 5ml THF solution of (485 μ l, 3.28mmol).Warm until the room temperature of formed mixture, and at room temperature stir 4 hours.Then, reaction mixture is processed with 5ml1N HCl, and at room temperature stirs and spend the night.Solvent is evaporated to dry, adds 9ml1M aqueous sodium carbonate, and water is with chloroform extracting (3 * 10ml), and the chloroform layer of merging is with water washing, to MgSO 4dry.Evaporation organic solvent, provides 300mg2, the fluoro-1-of 2,2-tri-(2-pyridin-4-yl-phenyl) ethanol, yield: 43%.
The fluoro-1-of 2,2,2-tri-(2-pyridin-4-yl-phenyl) ethanol (100mg, 0.40mmol), 4,6-dichloro pyrimidine (54mg, 0.38mmol), cesium carbonate (468mg, 1.44mmol) and Isosorbide-5-Nitrae-bis- the mixture of alkane (1ml).Heated overnight at 110 ℃, mixture.Reaction mixture is cooled to room temperature.Add 10ml ethyl acetate, then mixture filters by celite.Filtrate is concentrated, provides the chloro-6-[2 of 110mg4-, the fluoro-1-of 2,2-tri-(2-pyridin-4-yl-phenyl)-oxyethyl group]-pyrimidine, yield: 76%.
In microwave bottle, by the chloro-6-[2 of 4-, the fluoro-1-of 2,2-tri-(4-pyridin-4-yl-phenyl)-oxyethyl group]-pyrimidine (30mg, 0.080mmol), 4-borono--L-Phe (21mg, 0.098mmol), 1ml acetonitrile and 0.7ml water mix.Then, in mixture, add 0.3ml1N aqueous sodium carbonate, then add 5mol% dichloro two-(triphenylphosphine)-palladium (II).Sealed reaction vessel, and at 150 ℃, heat 5 minutes with microwave irradiation.After cooling, reaction mixture is evaporated to dry.Residue is dissolved in 2.5ml methyl alcohol, then through Prep-LC purifying, provides 19mg (S)-2-amino-3-(4-{6-[2, the fluoro-1-of 2,2-tri-(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).
Synthetic (S)-2-amino-3-(4-{2-amino-6-[2, the fluoro-1-of 2,2-tri-(2-(4-methyl-thiene-3-yl-)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid
In microwave bottle, the bromo-4-methyl-thiophene of 3-(653mg, 3.69mmol), 2-formylphenyl boric acid (500mg, 3.36mmol) and 7ml acetonitrile are mixed.To above-mentioned solution, add 6.7ml1N aqueous sodium carbonate, then add two (the triphenylphosphine)-palladiums (II) of 5mol% dichloro.Sealed reaction vessel, and at 150 ℃, heat 5 minutes with microwave irradiation.After cooling, add 50ml ethyl acetate, separated organic layer, with water washing, uses dried over sodium sulfate.Evaporation organic solvent, provides crude product, through ISCO CombiFlash column purification, provides 530mg2-(4-methyl-thiene-3-yl-) phenyl aldehyde, yield: 78%.
By tetrabutyl ammonium fluoride (0.013ml; The tetrahydrofuran solution of 1.0M) be added into 2-(4-thiotolene-3-yl)-phenyl aldehyde (260mg, 1.29mmol) and trifluoromethyl trimethyl silane (TMSCF at 0 ℃ 3) in the 5ml THF solution of (228 μ l, 1.54mmol).Warm until the room temperature of the mixture that forms, and at room temperature stir 4 hours.Then, reaction mixture is processed with 5ml1N HCl, and at room temperature stirs and spend the night.Product is with ethyl acetate extracting (3 * 50ml).Separated organic layer to dried over sodium sulfate.Evaporation organic solvent, provides 340mg2, the fluoro-1-[2-of 2,2-tri-(4-methyl-thiene-3-yl-)-phenyl]-ethanol, yield: 97%.
The fluoro-1-[2-of 2,2,2-tri-(4-methyl-thiene-3-yl-)-phenyl]-ethanol (100mg, 0.37mmol), 2-is amino-4, the chloro-pyrimidine of 6-bis-(54mg, 0.33mmol), cesium carbonate (481mg, 1.48mmol) and Isosorbide-5-Nitrae-bis- heated overnight at 110 ℃, the mixture of alkane (1ml).Reaction mixture is cooled to room temperature; Add 10ml ethyl acetate.Then mixture filters by celite, and filtrate is concentrated, provides the chloro-6-{2 of 100mg4-, the fluoro-1-[2-of 2,2-tri-(4-methyl-thiene-3-yl-)-phenyl]-oxyethyl group }-pyrimidine-2-base amine, yield: 76%.
In microwave bottle, mix the chloro-6-{2 of 4-, the fluoro-1-[2-of 2,2-tri-(4-methyl-thiene-3-yl-)-phenyl]-oxyethyl group }-pyrimidine-2-base amine (30mg, 0.075mmol), 4-borono--L-Phe (19mg, 0.09mmol), 1ml acetonitrile and 0.7ml water.In mixture, add 0.3ml1N aqueous sodium carbonate, then add 5mol% dichloro two-(triphenylphosphine)-palladium (II).Sealed reaction vessel, and at 150 ℃, heat 5 minutes with microwave irradiation.After cooling, reaction mixture is evaporated to dry.Residue is dissolved in 2.5ml methyl alcohol, then through Prep-HPLC purifying, provide 15.1mg (S)-2-amino-3-(4-{2-amino-6-[2, the fluoro-1-of 2,2-tri-(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)。
Synthetic (S)-2-amino-3-(4-{2-amino-6-[2, the fluoro-1-of 2,2-tri-(2-(5-methyl-thiene-3-yl-)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid
In microwave bottle, mix the bromo-2-methyl-thiophene of 4-(653mg, 3.69mmol), 2-formylphenyl boric acid (500mg, 3.36mmol) and 7ml acetonitrile.To above-mentioned solution, add 6.7ml1N aqueous sodium carbonate, then add two (the triphenylphosphine)-palladiums (II) of 5mol% dichloro.Sealed reaction vessel, and at 150 ℃, heat 5 minutes with microwave irradiation.After cooling, add 50ml ethyl acetate, separated organic layer, with water washing, by dried over sodium sulfate, evaporation organic solvent, residue, through ISCO purifying, provides 550mg2-(5-methyl-thiene-3-yl-) phenyl aldehyde, yield: 81%.
By tetrabutyl ammonium fluoride (0.028ml; The tetrahydrofuran solution of 1.0M) be added into 2-(5-thiotolene-3-yl)-phenyl aldehyde (550mg, 1.29mmol) and trifluoromethyl trimethyl silane (TMSCF at 0 ℃ 3) in the 10ml THF solution of (483 μ l, 3.27mmol).Warm until the room temperature of the mixture that forms, and at room temperature stir 4 hours.Then, reaction mixture is processed with 10ml1N HCl, and at room temperature stirs and spend the night.Product is with ethyl acetate extracting (3 * 50ml).Separated organic layer to dried over sodium sulfate.Evaporation organic solvent, provides 650mg2, the fluoro-1-[2-of 2,2-tri-(5-methyl-thiene-3-yl-)-phenyl]-ethanol, yield: 87%.
The fluoro-1-[2-of 2,2,2-tri-(5-methyl-thiene-3-yl-)-phenyl]-ethanol (100mg, 0.37mmol), 2-is amino-4, the chloro-pyrimidine of 6-bis-(54mg, 0.33mmol), cesium carbonate (481mg, 1.48mmol) and Isosorbide-5-Nitrae-bis- heated overnight at 110 ℃, the mixture of alkane (2ml).Reaction mixture is cooled to room temperature; Add 10ml ethyl acetate.Then mixture filters by celite, and filtrate is concentrated, provides the chloro-6-{2 of 90mg4-, the fluoro-1-[2-of 2,2-tri-(5-methyl-thiene-3-yl-)-phenyl]-oxyethyl group }-pyrimidine-2-base amine, yield: 68%.
In microwave bottle, mix the chloro-6-{2 of 4-, the fluoro-1-[2-of 2,2-tri-(5-methyl-thiene-3-yl-)-phenyl]-oxyethyl group }-pyrimidine-2-base amine (30mg, 0.075mmol), 4-borono--L-Phe (19mg, 0.09mmol), 1ml acetonitrile and 0.7ml water.In mixture, add 0.3ml1N aqueous sodium carbonate, then add 5mol% dichloro two-(triphenylphosphine)-palladium (II).Sealed reaction vessel, and heat 5 minutes with at 150 ℃ of microwave irradiations.After cooling, reaction mixture is evaporated to dry.Residue is dissolved in 2.5ml methyl alcohol, then through Prep-LC purifying, provide 10.1mg (S)-2-amino-3-(4-{2-amino-6-[2, the fluoro-1-of 2,2-tri-(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, the fluoro-1-of 2,2-tri-(4-furans-3-base-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid
In microwave bottle, mix the bromo-furans of 3-(590mg, 4.02mmol), 4-formylphenyl boric acid (600mg, 4.02mmol) and 7ml acetonitrile.Then to this mixture, add 8ml1N aqueous sodium carbonate, then add two (the triphenylphosphine)-palladiums (II) of 5mol% dichloro.Sealed reaction vessel, and heat 7 minutes with at 150 ℃ of microwave irradiations.After cooling, add 50ml ethyl acetate, separated organic layer, with water washing, to dried over sodium sulfate.Evaporation organic solvent, provides crude product, through ISCO purifying, provides 410mg4-furans-3-base-phenyl aldehyde, yield: 60%.
By tetrabutyl ammonium fluoride (0.024ml; The tetrahydrofuran solution of 1.0M) be added into 4-furans-3-base-phenyl aldehyde (410mg, 2.38mmol) and trifluoromethyl trimethyl silane (TMSCF at 0 ℃ 3) the 5ml THF solution of (423 μ l, 2.86mmol).Warm until the room temperature of the mixture that forms, and at room temperature stir 4 hours.Then, reaction mixture is processed with 5ml1N HCl, and at room temperature stirs and spend the night.Product is with ethyl acetate extracting (3 * 50ml).Separated organic layer to dried over sodium sulfate.Evaporation organic solvent, provides 480mg2, the fluoro-1-of 2,2-tri-(4-furans-3-base-phenyl)-ethanol, yield: 83%.
The fluoro-1-of 2,2,2-tri-(4-furans-3-base-phenyl)-ethanol (100mg, 0.4mmol), 2-amino-4, the chloro-pyrimidine of 6-bis-(60mg, 0.36mmol), cesium carbonate (468mg, 1.44mmol) and Isosorbide-5-Nitrae-bis- heated overnight at 110 ℃, the mixture of alkane (1ml).Reaction mixture is cooled to room temperature; Add 10ml ethyl acetate.Then mixture filters by celite, and filtrate is concentrated, provides the chloro-6-[2 of 100mg4-, the fluoro-1-of 2,2-tri-(4-furans-3-base-phenyl)-oxyethyl group]-pyrimidine-2-base amine, yield: 72%.
In microwave bottle, mix the chloro-6-[2 of 4-, the fluoro-1-of 2,2-tri-(4-furans-3-base-phenyl)-oxyethyl group]-pyrimidine-2-base amine (30mg, 0.081mmol), 4-borono--L-Phe (20mg, 0.098mmol), 1ml acetonitrile and 0.7ml water.Then, in mixture, add 0.3ml1N aqueous sodium carbonate, then add 5mol% dichloro two-(triphenylphosphine)-palladium (II).Sealed reaction vessel, and heat 5 minutes with at 150 ℃ of microwave irradiations.After cooling, reaction mixture is evaporated to dry.Residue is dissolved in 2.5ml methyl alcohol, then through Prep-LC purifying, provides 7.2mg (S)-2-amino-3-(4-{2-amino-6-[2, the fluoro-1-of 2,2-tri-(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. synthesize (S)-2-amino-3-[4-{2-amino-6-{1-[2-(5-dimethylaminomethyl-furans-2-yl)-phenyl]-2,2, the fluoro-oxyethyl group of 2-tri-}-pyrimidine-4-yl)-phenyl]-propionic acid
By nitrilotriacetic base sodium borohydride (844mg, 4mmol) add to the bromo-furans-2-of 5-formaldehyde (carbaldehyde) (350mg, 2mmol) and the 10ml1 of dimethylamine (2ml, the THF solution of 2M), in the solution of 2-ethylene dichloride (DCE).Then add 0.2ml HOAc.Under mixture room temperature, stir and spend the night, then add 15ml DCE.Organic phase is with water washing, to dried over sodium sulfate.By centrifugal distiller (rotovap), remove solvent, provide 400mg (the bromo-furans-2-of 5-ylmethyl)-dimethyl-amine, yield: 97%.
In microwave bottle, mix (the bromo-furans-2-of 5-ylmethyl)-dimethyl-amine (385mg, 1.88mmol), 2-formylphenyl boric acid (288mg, 1.93mmol) and 3.7ml acetonitrile.Then, to this mixture, add 3.7ml1N aqueous sodium carbonate, then add two (the triphenylphosphine)-palladiums (II) of 5mol% dichloro.Sealed reaction vessel, and heat 5 minutes with at 150 ℃ of microwave irradiations.After cooling, add 20ml1N HCl.This mixture is with ethyl acetate extracting (3 * 10ml), and discards ethyl acetate layer.To water, add 1N NaOH solution to regulate pH to 10, then with ethyl acetate extracting (3 * 20ml).The organic layer merging is with water washing, and to dried over sodium sulfate.Evaporating solvent, provides 300mg2-(4-dimethylaminomethyl-ring penta-butadienyl)-phenyl aldehyde, yield: 69%.
By tetrabutyl ammonium fluoride (0.013ml; The tetrahydrofuran solution of 1.0M) be added into 2-(4-dimethylaminomethyl-ring penta-butadienyl)-phenyl aldehyde (287mg, 1.25) and trifluoromethyl trimethyl silane (TMSCF at 0 ℃ 3) in the 5ml THF solution of (222 μ l, 1.5mmol).Warm until the room temperature of the mixture that forms, and at room temperature stir 4 hours.Then, reaction mixture is processed with 5ml1N HCl, and at room temperature stirs and spend the night.Product is with ethyl acetate extracting (3 * 50ml).Separated organic layer to dried over sodium sulfate.Evaporation organic solvent, provides 250mg1-[2-(5-dimethylaminomethyl-furans-2-yl)-phenyl]-2,2, the fluoro-ethanol of 2-tri-, yield: 66%.
1-[2-(5-dimethylaminomethyl-furans-2-yl)-phenyl]-2,2, the fluoro-ethanol (225mg of 2-tri-, 0.75mmol), 2-is amino-4, the chloro-pyrimidine of 6-bis-(111mg, 0.67mmol), cesium carbonate (978mg, 3.01mmol) and Isosorbide-5-Nitrae-bis- heated overnight at 110 ℃, the mixture of alkane (3ml).Reaction mixture is cooled to room temperature; Add 10ml ethyl acetate.Then mixture filters by celite, and filtrate is concentrated, provides the chloro-6-{1-[2-of 110mg4-(5-dimethylaminomethyl-furans-2-yl)-phenyl] 2,2, the fluoro-oxyethyl group of 2-tri-}-pyrimidine-2-base amine, yield: 87%.
In microwave bottle, mix the chloro-6-{1-[2-of 4-(5-dimethylaminomethyl-furans-2-yl)-phenyl] 2,2, the fluoro-oxyethyl group of 2-tri-}-pyrimidine-2-base amine (37mg, 0.087mmol), 4-borono--L-Phe (22mg, 0.10mmol), 1ml acetonitrile and 0.7ml water.Then, add 0.3ml1N aqueous sodium carbonate, then add 5mol% dichloro two-(triphenylphosphine)-palladium (II).Sealed reaction vessel, and heat 5 minutes with at 150 ℃ of microwave irradiations.After cooling, reaction mixture is evaporated to dry.Residue is dissolved in 2.5ml methyl alcohol, then through Prep-LC purifying, provide 16mg (S)-2-amino-3-[4-{2-amino-6-{1-[2-(5-dimethylaminomethyl-furans-2-yl)-phenyl]-2,2, the fluoro-oxyethyl group of 2-tri-}-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)。
Synthetic (S)-2-amino-3[4-(2-amino-6-{1-[2-(6-cyano group-pyridin-3-yl)-phenyl]-2,2, the fluoro-oxyethyl group of 2-tri-}-pyrimidine-4-yl)-phenyl]-propionic acid
In microwave bottle, mix 5-(4,4,5,5-tetramethyl--[1,3,2] dioxy boron, penta ring-2-yl)-pyridine-2-nitrile (279mg, 1.51mmol), the bromo-phenyl aldehyde of 2-(230mg, 1mmol) and 2ml acetonitrile.Then, add 2ml1N aqueous sodium carbonate, then add two (the triphenylphosphine)-palladiums (II) of 5mol% dichloro.Sealed reaction vessel, and heat 10 minutes with at 100 ℃ of microwave irradiations.After cooling, add 50ml ethyl acetate, separated organic layer, with water washing and to dried over sodium sulfate.Evaporation organic solvent, provides crude product, through ISCO purifying, provides 150mg5-(2-formyl-phenyl)-pyridine-2-nitrile, yield: 72%.
By tetrabutyl ammonium fluoride (5.3 μ l, the tetrahydrofuran solution of 1.0M) be added into 5-(2-formyl-phenyl)-pyridine-2-nitrile (110mg at 0 ℃, 0.53mmol) and the 5ml THF solution of trifluoromethyl trimethyl silane (120 μ l, 0.81mmol).Warm until the room temperature of the mixture that forms, and at room temperature stir 4 hours.Then, reaction mixture is processed with 5ml1N HCl, and at room temperature stirs and spend the night.Product is with ethyl acetate extracting (3 * 50ml).Separated organic layer to dried over sodium sulfate.Evaporation organic solvent, provides 140mg5-[2-(the fluoro-1-hydroxyl-ethyl of 2,2,2-tri-)-phenyl]-pyridine-2-nitrile, yield: 95%.
5-[2-(2,2, the fluoro-1-hydroxyl-ethyl of 2-tri-)-phenyl]-pyridine-2-nitrile (46mg, 0.165mmol), (S)-3-[4-(the chloro-pyrimidine-4-yl of 2-amino-6-)-phenyl]-2-tert-butoxycarbonyl amino-propionic acid (59mg, 0.15mmol), cesium carbonate (195mg, 0.6mmol) and Isosorbide-5-Nitrae-bis- heated overnight at 110 ℃, the mixture of alkane (1ml).Reaction mixture is cooled to room temperature, then pours into 5ml water.Add 1N HCl to regulate pH to 4.5, water is with ethyl acetate extracting (3 * 10ml).The organic layer salt water washing merging, 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, the fluoro-oxyethyl group of 2-tri-}-pyrimidine-4-yl)-phenyl]-2-tert-butoxycarbonyl amino-propionic acid, yield: 84%.
By 80mg (S)-3-[4-(2-amino-6-{1-[2-(6-cyanopyridine-3-yl)-phenyl]-2, the fluoro-oxyethyl group of 2,2-tri-}-pyrimidine-4-yl)-phenyl]-2-tert-butoxycarbonyl amino-propionic acid is dissolved in the solution of methylene dichloride (5ml) of 30% trifluoroacetic acid.Under this mixture room temperature, stir 1 hour.Evaporating solvent, residue is through 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, the fluoro-oxyethyl group of 2-tri-}-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, the fluoro-1-of 2,2-tri-(2-imidazoles-1-base-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid
THF solution (8ml) to 2-imidazoles-1-base-phenyl aldehyde (0.344g, 2mmol) adds trifluoromethyl trimethyl silane (0.341g, 2.4mmol).Reaction mixture is cooled to 0-5 ℃ (ice-water bath), adds four-n-butyl Neutral ammonium fluoride (1M, in THF for 0.035ml, 0.035mmol).Shift out ice bath, under this mixture room temperature, stir 6 hours.Add 2N HCl (5ml), under this reaction mixture room temperature, further stir 3 hours.By centrifugal distiller, reduce pressure down and 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, the fluoro-1-of 2-tri-(2-imidazoles-1-base-phenyl)-ethanol (0.45g, 93%), is directly used in next step.
By ADCP (0.107g, 0.65mmol), 2,2, under the fluoro-1-of 2-tri-(2-imidazoles-1-base-phenyl)-ethanol (0.157g, 0.65mmol) and NaH (0.03g, 0.78mmol) nitrogen, be added into anhydrous THF (10ml).At 40-45 ℃ of this reaction, stir 6 hours, be then cooled to room temperature, and water (0.2ml) cancellation.This reaction mixture is concentrated, provides the chloro-6-[2 of rough 4-, the fluoro-1-of 2,2-tri-(2-imidazoles-1-base-phenyl)-oxyethyl group]-pyrimidine-2-base amine (0.24g, LCMS records purity >90%), be directly used in next step.
By above-mentioned rough intermediate (0.24g), the p-borono--phenylalanine (0.140g of L-, 0.67mmol), sodium carbonate (0.14g, 1.32mmol) and two (the triphenylphosphine)-palladiums (II) (15mg, 0.021mmol) of dichloro in microwave bottle, be dissolved in MeCN (2.0ml) and H 2the mixture of O (2.0ml).Seal this reaction mixture, and at 150 ℃, stir 6 minutes in microwave reactor.This mixture filters, and filtrate is concentrated.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, the fluoro-1-of 2,2-tri-(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, the fluoro-1-of 2,2-tri-(2-pyrazol-1-yl-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid
In the THF solution (8ml) of 2-pyrazol-1-yl-phenyl aldehyde (0.344g, 2mmol), add trifluoromethyl trimethyl silane (0.341g, 2.4mmol).Mixture is cooled to 0-5 ℃ (ice-water bath), adds four-n-butyl Neutral ammonium fluoride (1M, in THF for 0.035ml, 0.035mmol).Shift out ice bath, under this mixture room temperature, stir 6 hours.Add 2N HCl (5ml), under this reaction mixture room temperature, further stir 3 hours.By centrifugal distiller, reduce pressure down and 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 the fluoro-1-of 2-tri-(2-pyrazol-1-yl-phenyl)-ethanol (0.45g, 93%), is directly used in experiment below.
By 4,6-dichloro pyrimidine (0.082g, 0.55mmol), 2,2, the fluoro-1-of 2-tri-(2-pyrazol-1-yl-phenyl)-ethanol (0.121g, 0.50mmol), NaH (0.03g, 0.78mmol) are added in anhydrous THF (10ml) under nitrogen atmosphere.At 40-45 ℃ of this reaction, stir 6 hours, be then cooled to room temperature, and water (0.2ml) cancellation.This reaction mixture is concentrated, provides the chloro-6-[2 of rough 4-, the fluoro-1-of 2,2-tri-(2-pyrazol-1-yl-phenyl)-oxyethyl group]-pyrimidine (0.20g, LCMS records purity >90%), be directly used in next step.
By this rough intermediate (0.20g), the p-borono--phenylalanine (0.105g of L-, 0.50mmol), sodium carbonate (0.105g, 1mmol), two (the triphenylphosphine)-palladiums (II) (15mg, 0.021mmol) of dichloro are dissolved in MeCN (2.0ml) and H in microwave bottle 2the mixture of O (2.0ml).Seal this microwave bottle, allow this reaction mixture at 150 ℃, heat 6 minutes in microwave reactor.This mixture filters, and filtrate is concentrated.Residue is dissolved in MeOH and H 2o (1:1), then utilizes MeOH/H by preparation HPLC 2o/TFA is as solvent systems and purifying, provide (S)-2-amino-3-(4-[6-[2, the fluoro-1-of 2,2-tri-(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, the fluoro-1-[2-of 2,2-tri-(3-trifluoromethyl-pyrazol-1-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid
By the fluoro-1-of 2,2,2-tri-(the iodo-phenyl of 2-)-ethanol (0.331g, 1.1mmol), 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-1,2-diamines (0.028g, 0.2mmol) and toluene (10ml) merge in 20ml penstock.130 ℃ of (oil bath temperature) lower heating of this mixture 12 hours.Reaction mixture dilutes by ethyl acetate, uses H 2o (2 * 20ml), salt water washing, and to dried over sodium sulfate.After removing solvent, provide crude product, by ISCO column chromatography, utilize the hexane solution of 5-10% ethyl acetate to carry out purifying as solvent, obtain 140mg2, the fluoro-1-[2-of 2,2-tri-(3-trifluoromethyl-pyrazol-1-yl)-phenyl]-ethanol.
By 2-amino-4,6-dichloro pyrimidine (0.074g, 0.45mmol), 2,2, the fluoro-1-[2-of 2-tri-(3-trifluoromethyl-pyrazol-1-yl)-phenyl]-ethanol (0.140g, 0.45mmol) and NaH (0.022g, 0.59mmol) under nitrogen atmosphere, be added into anhydrous THF (10ml).At 40-45 ℃ of this reaction, stir 6 hours, be then cooled to room temperature, and water (0.2ml) cancellation.This reaction mixture is concentrated, provide the chloro-6-[2 of rough 4-, the fluoro-1-[2-of 2,2-tri-(3-trifluoromethyl-pyrazol-1-yl) phenyl]-oxyethyl group]-pyrimidine-2-base amine (0.21g, LCMS measures purity >90%), be directly used in next step.
By this rough intermediate (0.21g), the p-borono--phenylalanine (0.1g of L-, 0.48mmol), sodium carbonate (0.1g, 0.94mmol) and two (the triphenylphosphine)-palladiums (II) (15mg, 0.021mmol) of dichloro in microwave bottle, be dissolved in MeCN (2.0ml) and H 2in the mixture of O (2.0ml).Seal this bottle, allow reaction mixture at 150 ℃, heat 6 minutes in microwave reactor.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, the fluoro-1-of 2,2-tri-(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, the fluoro-oxyethyl group of 2-tri-}-pyrimidine-4-yl)-phenyl]-propionic acid
By the fluoro-1-of 2,2,2-tri-(the iodo-phenyl of 2-)-ethanol (0.331g, 1.1mmol), 3，5-dimethylpyrazole (0.096g, 1.0mmol), CuI (0.019g, 0.1mmol), K 2cO 3(0.290g, 2.1mmol), (1R, 2R)-N, N '-dimethyl-hexanaphthene-1,2-diamines (0.028g, 0.2mmol) and toluene (10ml) merge in 20ml penstock, 130 ℃ of (oil bath temperature) lower heating of this mixture 12 hours.Reaction mixture dilutes by ethyl acetate, uses H 2o (2 * 20ml), salt water washing, and to dried over sodium sulfate.Remove solvent and provide crude product, by ISCO column chromatography, utilize the hexane solution of 5-10% ethyl acetate to carry out purifying as solvent, obtain 1-[2-(3,5-dimethyl-pyrazol-1-yl)-phenyl]-2,2, the fluoro-ethanol of 2-tri-(120mg).
By 2-amino-4,6-dichloro pyrimidine (0.074g, 0.45mmol), 1-[2-(3,5-dimethyl-pyrazol-1-yl)-phenyl]-2,2, the fluoro-ethanol of 2-tri-(0.120g, 0.45mmol), NaH (0.022g, 0.59mmol) are added into anhydrous THF (10ml) under nitrogen atmosphere.At 40-45 ℃ of this reaction, stir 6 hours, be then cooled to room temperature, and water (0.2ml) cancellation.This reaction mixture is concentrated, provides the chloro-6-{1-[2-of rough 4-(3,5-dimethyl-pyrazol-1-yl)-phenyl]-2,2, the fluoro-oxyethyl group of 2-tri-]-pyrimidine-2-base amine (0.195g, LCMS measures purity >90%), be directly used in next step.
By this rough intermediate (0.195g), the p-borono--phenylalanine (0.10g of L-, 0.48mmol), sodium carbonate (0.10g, 0.95mmol) and two (the triphenylphosphine)-palladiums (II) (15mg, 0.021mmol) of dichloro in microwave bottle, be dissolved in MeCN (2.0ml) and H 2the mixture of O (2.0ml).Seal this bottle, allow this reaction mixture at 150 ℃, heat 6 minutes in microwave reactor.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, the fluoro-oxyethyl group of 2-tri-}-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, the fluoro-1-[2-of 2,2-tri-(3-phenyl-pyrazole-1-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid
By the fluoro-1-of 2,2,2-tri-(the iodo-phenyl of 2-)-ethanol (0.331g, 1.1mmol), 3-phenylpyrazole (0.144g, 1.0mmol), CuI (0.019g, 0.1mmol), K 2cO 3(0.290g, 2.1mmol), (1R, 2R)-N, N '-dimethyl-hexanaphthene-1,2-diamines (0.028g, 0.2mmol) and toluene (10ml) are placed in 20ml penstock, 130 ℃ of (oil bath temperature) lower heating of this mixture 12 hours.Mixture dilutes by ethyl acetate, uses H 2o (2 * 20ml), salt water washing, and to dried over sodium sulfate.Remove solvent and provide crude product, by ISCO column chromatography, utilize the hexane solution of 5-10% ethyl acetate to carry out purifying as solvent, obtain the fluoro-1-[2-of 2,2,2-tri-(3-phenyl-pyrazole-1-yl)-phenyl]-ethanol (75mg).
By 2-amino-4,6-dichloro pyrimidine (0.041g, 0.25mmol), 2,2, the fluoro-1-[2-of 2-tri-(3-phenyl-pyrazole-1-yl)-phenyl]-ethanol (0.070g, 0.22mmol) and NaH (0.012g, 0.31mmol) under nitrogen atmosphere, be added into anhydrous THF (7ml).At 40-45 ℃ of this reaction, stir 6 hours, be then cooled to room temperature, and water (0.04ml) cancellation.This reaction mixture is concentrated, provide the chloro-6-{2 of rough 4-, the fluoro-1-[2-of 2,2-tri-(3-phenyl-pyrazole-1-yl)-phenyl]-oxyethyl group]-pyrimidine-2-base amine (0.110g, LCMS measures purity >90%), be directly used in next step.
By this rough intermediate (0.110g), the p-borono--phenylalanine (0.050g of L-, 0.24mmol), sodium carbonate (0.050g, 0.48mmol) and two (the triphenylphosphine)-palladiums (II) (8mg, 0.010mmol) of dichloro in microwave bottle, be dissolved in MeCN (2.0ml) and H 2the mixture of O (2.0ml).Seal this bottle, allow reaction mixture at 150 ℃, heat 6 minutes in microwave reactor.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, provides (S)-2-amino-3-[4-(2-amino-6-{2, the fluoro-1-[2-of 2,2-tri-(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, the fluoro-1-[5-methoxyl group-2-of 2,2-tri-(4-methyl-pyrazol-1-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid
By 1-(the bromo-5-methoxyl group-phenyl of 2-)-2,2, the fluoro-ethanol of 2-tri-(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-1,2-diamines (0.071g, 0.5mmol) and toluene (10ml) are incorporated in 20ml penstock, 130 ℃ of (oil bath temperature) lower heating of this mixture 12 hours.Mixture dilutes by ethyl acetate, uses H 2o (2 * 20ml), salt water washing, and to dried over sodium sulfate.Remove solvent and provide crude product, by ISCO column chromatography, utilize the hexane solution of 5-10% ethyl acetate to carry out purifying as solvent, obtain the fluoro-1-[5-methoxyl group-2-of 2,2,2-tri-(4-methyl-pyrazol-1-yl)-phenyl]-ethanol (90mg).
By 2,2, the fluoro-1-[5-methoxyl group-2-of 2-tri-(4-methyl-pyrazol-1-yl)-phenyl]-ethanol (0.090g, 0.31mmol), (S)-3-[4-(the chloro-pyrimidine-4-yl of 2-amino-6-)-phenyl]-2-tert-butoxycarbonyl amino-propionic acid (0.122g, 0.31mmol), Isosorbide-5-Nitrae-bis- alkane (2ml), Cs 2cO 3(0.503g, 1.55mmol) is incorporated in microwave bottle, is heated to 180 ℃, lasts 45 minutes.This mixture filters and is concentrated.The DCM (50ml) that adds 5% methyl alcohol to residue.Filter this mixture.Concentrated filtrate provides crude product, and this crude product is placed in the DCM solution (30ml) of 20%TFA, stirs 30 minutes under room temperature.LCMS indicates the reaction of required product to complete.This reaction mixture is concentrated, provides crude product, and this crude product is dissolved in to MeOH and H 2o (1:1), utilizes MeOH/H by preparation HPLC 2o/TFA carries out purifying as solvent systems, obtains (S)-2-amino-3-[4-(2-amino-6-{2, the fluoro-1-[5-methoxyl group-2-of 2,2-tri-(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, the fluoro-1-[2-of 2-tri-(3-methyl-pyrazol-1-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid
By R-1-(the bromo-phenyl of 2-)-2,2, the fluoro-ethanol of 2-tri-(1.53g, 6mmol), 3-methylpyrazole (0.492g, 6mmol), CuI (0.456g, 2.4mmol), K 2cO 3(2.07g, 15mmol), (1R, 2R)-N, N '-dimethyl-hexanaphthene-1,2-diamines (0.170g, 1.2mmol) and toluene (10ml) are incorporated in 20ml penstock, 130 ℃ of (oil bath temperature) lower heating of this mixture 12 hours.Reaction mixture dilutes by ethyl acetate, uses H 2o (2 * 20ml), salt water washing, and to dried over sodium sulfate.Remove solvent and provide crude product, by ISCO column chromatography, utilize the hexane solution of 5-10% ethyl acetate to carry out purifying as solvent, obtain R-2, the fluoro-1-[2-of 2,2-tri-(3-methyl-pyrazol-1-yl)-phenyl]-ethanol (1.8g).
By ADCP (1.2g, 7.4mmol), R-2,2, the fluoro-1-[2-of 2-tri-(3-methyl-pyrazol-1-yl)-phenyl]-ethanol (1.8g, 7.03mmol) and NaH (0.380g, 10mmol) be added into anhydrous THF (40ml) under nitrogen atmosphere.At 40-45 ℃ of this reaction, stir 6 hours, be then cooled to room temperature, and water (0.1ml) cancellation.This reaction mixture is concentrated, provides the chloro-6-{R-2 of 4-, the fluoro-1-[2-of 2,2-tri-(3-methyl-pyrazol-1-yl)-phenyl]-oxyethyl group]-pyrimidine-2-base amine (3.0g, LCMS measures purity >90%), be directly used in next step.
By this rough intermediate (0.750g), the p-borono--phenylalanine (0.420g of L-, 2.0mmol), sodium carbonate (0.430g, 4.0mmol) and two (the triphenylphosphine)-palladiums (II) (30mg, 0.043mmol) of dichloro in microwave bottle, be dissolved in MeCN (7.0ml) and H 2the mixture of O (7.0ml).Seal this bottle, allow this reaction mixture at 150 ℃, heat 7 minutes in microwave reactor.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, provides (S)-2-amino-3-[4-(2-amino-6-{R-2, the fluoro-1-[2-of 2,2-tri-(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-(the chloro-2-of 2-amino-6-{1-[4-(3-methyl-pyrazol-1-yl)-phenyl]-2,2, the fluoro-oxyethyl group of 2-tri-}-pyrimidine-4-yl)-phenyl]-propionic acid
By 1-(the iodo-phenyl of the chloro-2-of 4-)-2,2, the fluoro-ethanol of 2-tri-(0.840g, 2.5mmol), 3-methylpyrazole (0.230g, 2.8mmol), CuI (0.190g, 1.0mmol), K 2cO 3(0.863g, 6.25mmol), (1R, 2R)-N, N '-dimethyl-hexanaphthene-1,2-diamines (0.071g, 0.5mmol) and toluene (10ml) are incorporated in 20ml penstock, 130 ℃ of (oil bath temperature) lower heating of this mixture 12 hours.Mixture dilutes by ethyl acetate, uses H 2o (2 * 20ml), salt water washing, and to dried over sodium sulfate.Remove solvent and provide crude product, by ISCO column chromatography, utilize the hexane of 5-10% ethyl acetate to carry out purifying as solvent, obtain the chloro-2-of 1-[4-(3-methyl-pyrazol-1-yl)-phenyl]-2,2, the fluoro-ethanol of 2-tri-(240mg).
By the chloro-2-of 1-[4-(3-methyl-pyrazol-1-yl)-phenyl]-2,2, fluoro-ethanol (the 0.120g of 2-tri-, 0.41mmol), (S)-3-[4-(the chloro-pyrimidine-4-yl of 2-amino-6-)-phenyl]-2-tert-butoxycarbonyl amino-propionic acid (0.176g, 0.45mmol), Isosorbide-5-Nitrae-bis- alkane (4ml) and Cs 2cO 3(0.533g, 1.64mmol) is incorporated in 20ml sealed tube, at 100 ℃, this mixture, heats 12 hours.Concentrated this mixture.To residue, add the DCM solution (50ml) of 10% methyl alcohol, and filter this mixture.Filtrate is concentrated, provides crude product, and this crude product is placed in THF/3N HCl (30ml/15ml), at 40-45 ℃, gained mixture, stirs 12 hours.LCMS indicates the reaction of required product to complete.This mixture is concentrated, provides crude product, and this crude product is dissolved in to 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-(the chloro-2-of 2-amino-6-{1-[4-(3-methyl-pyrazol-1-yl)-phenyl]-2,2, the fluoro-oxyethyl group of 2-tri-}-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-(the chloro-2-of 2-amino-6-{R-1-[4-(3-methyl-pyrazol-1-yl)-phenyl]-2,2, the fluoro-oxyethyl group of 2-tri-}-pyrimidine-4-yl)-phenyl]-ethyl propionate
Title compound progressively preparation as described below:
step 1: synthetic 1-(the chloro-phenyl of the bromo-4-of 2-)-2,2, the fluoro-ethyl ketone of 2-tri-.Lower to 10 minutes dropping thionyl chloride (29.2ml, 400mmol) to 0-5 ℃ (ice-water bath) in the 500ml2 neck RB flask that contains anhydrous methanol (300ml).Shift out ice-water bath, add the 2-chloro-phenylformic acid of bromo-4-(25g, 106mmol).This mixture is heated to gentle reflux 12 hours.Reaction progress is monitored by TLC and LCMS.After having reacted, concentrated reaction mixture.Crude product is 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 the chloro-methyl benzoate of the bromo-4-of 2-(26g, 99%), is directly used in next step.
The toluene of the chloro-methyl benzoate of the bromo-4-of 2-(12.4g, 50mmol) (200ml) is cooled to-70 ℃, and adds trifluoromethyl trimethyl silane (13ml, 70mmol).Drip tetrabutyl ammonium fluoride (1M, 2.5ml), and make this mixture be warmed to room temperature with 4 hours, under room temperature, stir thereafter 10 hours.Concentrated this reaction mixture, provides rough [1-(the chloro-phenyl of the bromo-4-of 2-)-2,2, the fluoro-1-methoxyl group-oxyethyl group of 2-tri-]-trimethylammonium-silane.This rough intermediate is dissolved in to methyl alcohol (100ml), and adds 6N HCl (100ml).This mixture maintains at 45-50 ℃ 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 ISCO column chromatography, obtain 1-(the chloro-phenyl of the bromo-4-of 2-)-2,2, the fluoro-ethyl ketone of 2-tri-(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-(the chloro-phenyl of the bromo-4-of 2-)-2,2, the fluoro-ethanol of 2-tri-.Under nitrogen, to the catecholborane in 2L3-neck RB flask, (1M, in THF280ml, 280mmol) adds S-2-methyl-CBS azoles borine (7.76g, 28mmol), stirs 20 minutes under gained mixture room temperature.Reaction mixture is cooled to-78 ℃ (dry ice/acetone batch), and with within 2 hours, dripping 1-(the chloro-phenyl of the bromo-4-of 2-)-2,2, the THF solution (400ml) of the fluoro-ethyl ketone of 2-tri-(40g, 139mmol).Make reaction mixture be warmed to-36 ℃, at this temperature, stir 24 hours, and further at-32 ℃, stir other 24 hours.Add 3N NaOH (250ml), cooling bath is replaced with ice-water bath.Then with the aqueous solution (250ml) that drips 30% hydrogen peroxide for 30 minutes.Shift out ice-water bath, under this mixture room temperature, stir 4 hours.Separated organic layer, the concentrated ether (200ml) that is also again dissolved in.Water layer is with ether extracting (2 * 200ml).The 1N NaOH aqueous solution (4 * 100ml), the salt water washing for organic layer that merge, 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 alcohol 36.2g (90%, e.e.>95%).Alcohol (36.2g), from hexane (80ml) crystallization, obtains R-1-(the chloro-phenyl of the bromo-4-of 2-)-2,2, the fluoro-ethanol 28.2g (70% of 2-tri-; 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: the synthetic chloro-2-of R-1-[4-(3-methyl-pyrazol-1-yl)-phenyl]-2,2, the fluoro-second of 2-tri- alcohol.By R-1-(the chloro-phenyl of the bromo-4-of 2-)-2,2, the fluoro-ethanol of 2-tri-(15.65g, 54.06mmol), 3-methylpyrazole (5.33g, 65mmol), CuI (2.06g, 10.8mmol), K 2cO 3(15.7g, 113.5mmol), (1R, 2R)-N, N '-dimethyl-hexanaphthene-1,2-diamines (1.54g, 10.8mmol) and toluene (80ml) are incorporated in 250ml penstock, and be heated to 130 ℃ (oil bath temperatures), last 12 hours.Reaction mixture dilutes by ethyl acetate, uses H 2o (4 * 100ml), salt water washing, and to dried over sodium sulfate.After removing solvent, obtain crude product, this crude product utilizes the hexane solution of 5-10% ethyl acetate to carry out purifying as solvent by ISCO column chromatography, obtain the chloro-2-of R-1-[4-(3-methyl-pyrazol-1-yl)-phenyl]-2,2, the fluoro-ethanol (13.5g of 2-tri-; 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-(the chloro-2-of 2-amino-6-{R-1-[4-(3-methyl-pyrazoles -1-yl)-phenyl]-2,2, the fluoro-oxyethyl group of 2-tri-}-pyrimidine-4-yl)-phenyl]-ethyl propionate.The chloro-2-of R-1-[4-(3-methyl-pyrazol-1-yl)-phenyl]-2,2, fluoro-ethanol (the 17.78g of 2-tri-, 61.17mmol), (S)-3-[4-(the chloro-pyrimidine-4-yl of 2-amino-6-)-phenyl]-2-tert-butoxycarbonyl amino-propionic acid (20.03g, 51mmol), Isosorbide-5-Nitrae-bis- alkane (250ml) and Cs 2cO 3(79.5g, 244mmol) is incorporated in 3-neck 500ml RB flask and is heated to 100 ℃ (oil bath temperatures), lasts 12-24 hour.Reaction progress is monitored by LCMS.After having reacted, this mixture is cooled to 60 ℃, adds (250ml) and THF (400ml).Separated organic layer, and wash with salt solution (150ml).Remove the product that solvent provides rough BOC protection, this product is placed in THF (400ml), 3N HCl (200ml).At mixture 35-40 ℃, heat 12 hours.Vacuum is removed THF.Residue is isopropyl acetate (2 * 100ml) washing for water layer, concentrated separately, reclaims unreacted alcohol (3.5g).From moisture fraction, under vacuum, remove the residue organic solvent of trace.
To being equipped with in the 1L beaker of temperature controller and pH meter, add H 3pO 4(40ml, 85% the aqueous solution) and water (300ml), then add the aqueous solution of 50%NaOH, regulates pH to 6.15.Temperature is increased to 58 ℃, in damping fluid, drips above-mentioned acidic aqueous solution, adds the aqueous solution of 50%NaOH simultaneously, and pH is maintained between 6.1-6.3.After having added, the solid of filtering-depositing, with hot water (50-60 ℃) (2 * 200ml), wash, dry obtain rough (S)-2-amino-3-[4-(the chloro-2-of 2-amino-6-{R-1-[4-(3-methyl-pyrazol-1-yl)-phenyl]-2, the fluoro-oxyethyl group of 2,2-tri-}-pyrimidine-4-yl)-phenyl }-propionic acid (26.8g; 95%).LCMS and HPLC analyze and show, compound purity is about 96-97%.
At 0-5 ℃, in dehydrated alcohol (400ml), drip SOCl 2(22ml, 306mmol).The crude acid (26.8g) that adds above-mentioned reaction.Shift out ice-water bath, heat 6-12 hour at reaction mixture 40-45 ℃.After having reacted, vacuum is removed ethanol.To residue, add frozen water (300ml), and with isopropyl acetate (2 * 100ml) extracting.The saturated Na of this aqueous solution 2cO 3neutralization, regulates pH to 6.5.This is ethyl acetate (2 * 300ml) extracting for solution.The ethyl acetate layer salt water washing merging, the concentrated rough ester of 24g (HPLC purity 96-97%) that obtains.Then, rough ester utilizes the DCM solution of 5% ethanol to carry out purifying as solvent by ISCO column chromatography, obtain (S)-2-amino-3-[4-(the chloro-2-of 2-amino-6-{R-1-[4-(3-methyl-pyrazol-1-yl)-phenyl]-2, the fluoro-oxyethyl group of 2,2-tri-}-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-(the chloro-2-of 4-(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-(the chloro-2-of 2-amino-6-{R-1-[4-(3-methyl-pyrazol-1-yl)-phenyl]-2,2, the fluoro-oxyethyl group of 2-tri-}-pyrimidine-4-yl)-phenyl }-ethyl propionate (22.2g, 38.6mmol) is dissolved in THF (220ml) and water (50ml).Add lithium hydroxide monohydrate (5.56g, 132mmol).Under reaction mixture room temperature, stir 12 hours.Remove THF, water (100ml) is added in residue, obtain settled solution.
To the 1L beaker that temperature controller and pH meter are housed, add H 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 ℃, and the Li-salt brine solution to dripping this compound in damping fluid adds 3N HCl simultaneously, makes pH maintain 6.1-6.2.After having added, the solid of filtering-depositing, with hot water (50-60 ℃) (2 * 200ml), wash, and dry, obtain (S)-2-amino-3-[4-(the chloro-2-of 2-amino-6-{R-1-[4-(3-methyl-pyrazol-1-yl)-phenyl]-2, the fluoro-oxyethyl group of 2,2-tri-}-pyrimidine-4-yl)-phenyl }-propionic acid (19.39g; 92%).LCMS and HPLC analyze and show, 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, the fluoro-1-of 2,2-tri-(2-thiazol-2-yl-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid
In 40ml microwave reactor, add 1.04g2-formylphenyl boric acid (6.9mmol) 1.14g2-bromo thiazole (6.9mmol), 240mg bi triphenyl-phosphine dichloride palladium (Pd (PPh 3) 2cl 2, 0.34mmol).Then, to this mixture, add 13.8ml1M Na 2cO 3(13.8mmol) with 10ml CH 3cN.Sealed reactor, reaction under microwave 160 ℃ operation 5 minutes.LCMS shows that the reaction of required product completes.Then, this reaction mixture is poured into separatory funnel.Add 200ml methylene dichloride and 100ml water, 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 hexane/ethyl acetate mixture (5/1 to 2/1) wash-out, obtains pure 2-thiazol-2-yl-phenyl aldehyde (0.5g, yield: 38%).
To 50ml round-bottomed flask, add 184mg2-thiazol-2-yl-phenyl aldehyde (0.97mmol) and 10ml anhydrous tetrahydro furan (THF).Then, the THF solution (0.02mmol) that adds 145.4mg trifluoromethyl trimethyl silane (1.02mmol) and 20 μ l1M tert-butyl Neutral ammonium fluorides to this solution.Under this mixture room temperature, stir and spend the night, add thereafter 10ml1N HCl, under reaction mixture room temperature, stir 15 minutes.Vacuum is removed THF, this methylene dichloride extracting (3 * 50ml) for mixture.The CH merging 2cl 2layer is to MgSO 4dry.Remove solvent and provide 262mg crude product, purity approximately 95%, and for next step, without being further purified.
In 50ml sealed tube, by 2,2, the fluoro-1-of 2-tri-(2-thiazol-2-yl-phenyl)-ethanol (260mg, 1mmol), (S)-3-[4-(the chloro-pyrimidine-4-yl of 2-amino-6-)-phenyl]-2-tert-butoxycarbonyl amino-propionic acid (390mg, 1mmol), cesium carbonate (1.3g, 4mmol) and 10ml1,4-bis- alkane mixes.At 100 ℃ of reaction mixtures, heat 3 days.Add water (20ml), then slowly add the 1N HCl aqueous solution, regulate pH to 4, then vacuum is removed Isosorbide-5-Nitrae-bis- alkane, methylene dichloride extracting (3 * 50ml) for gained mixture.The dichloromethane layer merging is to MgSO 4dry.Remove solvent and provide crude product, this crude product is placed in next step reaction, without being further purified.
Above-mentioned crude product is dissolved in 5ml methylene dichloride, adds 0.4ml trifluoroacetic acid.Under mixture room temperature, stir and spend the night.Then vacuum is removed trifluoroacetic acid, provides crude product, and this crude product, by preparation HPLC purifying, provides 63mg pure products.HPLC; YMC Pack ODS-A3 * 50mm, 7um; Solvent orange 2 A=containing the water of 0.1%TFA; Solvent B=is containing 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)δ8.06ppm(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, the fluoro-1-[2-of 2,2-tri-(pyridin-3-yl oxygen base)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid; (S)-2-amino-3-[4-(2-amino-6-{2, the fluoro-1-[4-of 2,2-tri-(pyridin-3-yl oxygen base)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid; (S)-2-amino-3-[4-(6-{2, the fluoro-1-[4-of 2,2-tri-(pyridin-3-yl oxygen base)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid; (S)-2-amino-3-(4-{2-amino-6-[2, the fluoro-1-of 2,2-tri-(4-thiophene-2-base-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid; (S)-2-amino-3-(4-{6-[2, the fluoro-1-of 2,2-tri-(4-imidazoles-1-base-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid; (S)-2-amino-3-(4-{2-amino-6-[2, and the fluoro-1-of 2,2-tri-(4-[1,2,4] triazol-1-yl-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid
Utilize following general approach to prepare title compound:
In this approach, in the mixture of the THF solution of the phenyl aldehyde (1 equivalent) replacing and trifluoromethyl trimethyl silane (1.2 equivalent), add four-n-butyl Neutral ammonium fluoride (0.05 equivalent) at 0 ℃.Then allow temperature be warmed to room temperature.Under this mixture room temperature, stir 5 hours, then with ethyl acetate dilution, water, salt water washing, and use MgSO 4dry.Decompression goes down to desolventize, and provides trifluoro-ol crude product, and this crude product is for next step, without being further purified.
The alcohol of above-mentioned preparation (1 equivalent) is dissolved in anhydrous Isosorbide-5-Nitrae-bis- alkane.Add immediately sodium hydride (60% mineral oil solution, 1.2 equivalents), under this mixture room temperature, stir 30 minutes.Add ADCP (1 equivalent), at 80 ℃, gained mixture, stir 2 hours.Remove solvent, residue is suspended in ethyl acetate, washes with water, to MgSO 4dry, then concentrate and provide required monochloride product, this product is for next step, without being further purified.
To containing 4-borono--L-Phe (1 equivalent), Na 2cO 3in the 5ml microwave bottle of two (the triphenylphosphine)-palladiums (0.05 equivalent) of (2 equivalent), acetonitrile (2ml), water (2ml) and dichloro, add above-mentioned crude product (1 equivalent).This bottle adds cap, at 150 ℃, this mixture with microwave irradiation heating 5 minutes.This mixture is cooling, by injection filter, filters, and then by anti-phase preparative-HPLC, utilizes YMC-Pack ODS100 * 30mm ID post (MeOH/H 2o/TFA solvent systems) separation.Pure fraction merges, vacuum concentration.Then this product is suspended in to 5ml water, freezing and freeze-drying, provides trifluoroacetic acid (TFA) salt of product.
(S)-2-amino-3-[4-(2-amino-6-{2, the fluoro-1-[2-of 2,2-tri-(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, the fluoro-1-[4-of 2,2-tri-(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, the fluoro-1-[4-of 2,2-tri-(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, the fluoro-1-of 2,2-tri-(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, the fluoro-1-of 2,2-tri-(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, and the fluoro-1-of 2,2-tri-(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, the fluoro-1-of 2,2-tri-(the fluoro-2-thiene-3-yl--phenyl of 4-) oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid; (S)-2-amino-3-[4-(2-amino-6-{2, the fluoro-2-of the fluoro-1-[4-of 2,2-tri-(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-different azoles-4-yl) the fluoro-phenyl of-4-]-2,2, the fluoro-oxyethyl group of 2-tri-}-pyrimidine-4-yl)-phenyl]-propionic acid
Utilize following general approach to prepare title compound:
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 at 150 ℃, stirs 6 minutes with microwave irradiation.Reaction mixture is cooling, by injection filter, filters, and then by ethyl acetate, dilutes.Wash with water.Then add silica gel to prepare plug, and with hexane and eluent ethyl acetate, carry out purifying by chromatogram.
Then, identical reaction described in the aldehyde of above-mentioned preparation experience embodiment 22.
(S)-2-amino-3-(4-{2-amino-6-[2, the fluoro-1-of 2,2-tri-(the fluoro-2-thiene-3-yl--phenyl of 4-)-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, and the fluoro-1-of 2,2-tri-(the fluoro-2-of 4-(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-different azoles-4-yl) the fluoro-phenyl of-4-]-2,2, the fluoro-oxyethyl group of 2-tri-}-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, the fluoro-2-of the fluoro-1-[5-of 2,2-tri-(3-methyl-pyrazol-1-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid
The fluoro-methyl benzoate of the bromo-5-of 2-(1g, 4.292mmol), NaBH 4under the mixture room temperature of the THF/EtOH solution (20ml/10ml) of (0.423g, 11.159mmol) and LiCl (0.474g, 11.159mmol), stir and spend the night.Add the HCl aqueous solution (10ml, 2N), stir about 10 minutes.Then rough vacuum is gone down except organic solvent.Residue dilute with water, and with ethyl acetate extracting.Organic layer NaHCO 3the aqueous solution (10%), water and salt water washing, then dry (MgSO 4), and concentrated obtain 852mg (96.8% thick yield) crude product, and (the fluoro-phenyl of the bromo-5-of 2-) methyl alcohol of white solid, use is without being further purified.
Solution to the DCM (15ml) of (the fluoro-phenyl of the bromo-5-of 2-) methyl alcohol (0.852g, 4.156mmol) adds MnO 2(4.254g, 85%, 41.56mmol).Under this mixture room temperature, stir two days, then filter and wash with DCM.The concentrated fluoro-phenyl aldehyde of the bromo-5-of 777mg2-(92% yield) that obtains of filtrate.Then freshly prepd aldehyde (0.777g, 3.828mmol) is dissolved in to anhydrous THF (10ml), and is cooled to 0 ℃.Add trifluoromethyl trimethyl silane (1.13ml, 7.656mmol), then add tetrabutyl ammonium fluoride (0.020g, 0.076mmol).Allow temperature be warmed to room temperature.Under this mixture room temperature, stir 5 hours, then with ethyl acetate dilution, water, salt water washing, and through MgSO 4dry.Decompression goes down to desolventize, and obtains crude product (the fluoro-phenyl of the bromo-5-of 2-) 2,2, the fluoro-ethanol of 2-tri-, and 1.1g (90% purity), for next step, without being further purified.
By (the fluoro-phenyl of the bromo-5-of 2-) 2,2, the fluoro-ethanol of 2-tri-(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-1,2-diamines (0.110g, 0.653mmol) and toluene (10ml) are incorporated in 20ml microwave bottle, and then sealing is heated 40 minutes at 180 ℃.This mixture filters, and washs by ethyl acetate.Filtrate water washing 3 times, then adds silica gel to prepare plug.This compound, by ISCO column chromatography, utilizes the hexane solution of 5-10% ethyl acetate to carry out purifying as solvent, obtains 1-(the fluoro-2-of 5-(3-methyl-pyrazol-1-yl)-phenyl)-2,2, the fluoro-ethanol 75mg of 2-tri-. 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 (0.075g, 0.273mmol) of above-mentioned preparation is dissolved in anhydrous Isosorbide-5-Nitrae-bis- alkane (3ml).Add immediately sodium hydride (0.013g, 0.328mmol, 60% mineral oil solution), under this mixture room temperature, stir 30 minutes.Add 2-amino-4, the chloro-pyrimidine of 6-bis-(0.045g, 0.273mmol).At 80 ℃, this mixture, stir about is 2 hours.Remove solvent, residue is suspended in ethyl acetate, wash with water, and to MgSO 4dry, then concentrate and provide required monochloride product 100mg (0.249mmol), this product is added into and contains 4-borono--L-Phe (0.052g, 0.249mmol), Na 2cO 3in the 5ml microwave bottle of two (the triphenylphosphine)-palladiums (5mg, 0.007mmol) of (0.053g, 0.498mmol), acetonitrile (2ml)/water (2ml) and dichloro.This bottle adds cap, and under microwave irradiation 150 ℃ stir 5 minutes.Reaction mixture is cooling, by injection filter, filters, and then by anti-phase preparative-HPLC, utilizes YMC-Pack ODS100 * 30mmID post (MeOH/H 2o/TFA solvent systems) separation.The pure fraction of vacuum concentration.Then this product is suspended in 5ml water, freezing and freeze-drying, provide (S)-2-amino-3-[4-(the fluoro-2-of 2-amino-6-{ (R)-1-[5-(3-methyl-pyrazol-1-yl)-phenyl]-2,2, the fluoro-oxyethyl group of 2-tri-}-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, the chloro-2-of the fluoro-1-[5-of 2,2-tri-(3-methyl-pyrazol-1-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid
Title compound preparation is from the chloro-2-of R-1-[5-(3-methyl-pyrazol-1-yl)-phenyl]-2, the fluoro-ethanol of 2,2-tri-is to utilize the chloro-2-of R-1-[4-(3-methyl-pyrazol-1-yl)-phenyl]-2, prepared by the above-mentioned identical approach of 2,2-, tri-fluoro-ethanol.Particularly, the chloro-2-of R-1-[5-(3-methyl-pyrazol-1-yl)-phenyl]-2,2, the fluoro-ethanol of 2-tri-(0.959g, 3.318mmol) is dissolved in anhydrous Isosorbide-5-Nitrae-bis- in alkane (8ml).Add immediately sodium hydride (0.159g, 3.982mmol, 60% mineral oil solution), under this mixture room temperature, stir 30 minutes.Add 2-amino-4, the chloro-pyrimidine of 6-bis-(0.544g, 3.318mmol).At 80 ℃, mixture, stir about is 2 hours.Remove solvent, residue is suspended in ethyl acetate, washes with water, to MgSO 4dry, then concentrated, provide required monochloride product 1.38g, directly use, without being further purified.
The monochloride (0.460g, 1.104mmol) of above-mentioned preparation is added into 20ml microwave bottle, and this bottle contains 4-borono--L-Phe (0.277g, 1.325mmol), Na 2cO 3two (the triphenylphosphine)-palladiums (0.039g, 0.055mmol) of (0.234g, 2.208mmol), acetonitrile (8ml)/water (8ml) and dichloro.This bottle adds cap, and mixture stirs 10 minutes with microwave irradiation at 150 ℃.Mixture is cooling, by injection filter, filters, and then by anti-phase preparative-HPLC, utilizes YMC-Pack ODS100 * 30mm ID post (MeOH/H 2o/TFA solvent systems) separation.The pure fraction of vacuum concentration.Then this product is suspended in 5ml water, freezing and freeze-drying, provide 580mg (S)-2-amino-3-[4-(the chloro-2-of 2-amino-6-{R-1-[5-(3-methyl-pyrazol-1-yl)-phenyl]-2,2, the fluoro-oxyethyl group of 2-tri-}-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, the fluoro-1-[4-of 2,2-tri-(2-oxo-pyrrolidin-1-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid
THF (20ml) solution of 4-(2-oxygen-pyrrolidin-1-yl)-phenyl aldehyde (500mg, 2.64mmol) is cooled to 0 ℃, and adds trifluoromethyl trimethyl silane (375mg, 2.64mmol).Drip tetrabutyl ammonium fluoride (1M, 0.1ml), allow this mixture be warmed to room temperature with 1 hour, under room temperature, further stirring is spent the night.After having reacted, add 3N HCl (5ml), this reaction mixture stirs 2 hours.Concentrated this mixture.Add water (20ml), this mixture, with EtOAc extracting (2 * 20ml), is used NaHCO 3(20ml), salt solution (20ml) washing, and to dried over sodium sulfate, the concentrated required product of 590mg that obtains, this product is for next step, without being further purified (yield: 86%).
4, the chloro-pyrimidine-2-base amine of 6-bis-(700mg, 2.69mmol), NaH (194mg, 8.07mmol, 60%) and 1-(4-(2, the fluoro-1-hydroxyl-ethyl of 2,2-tri-)-phenyl) under anhydrous THF (10ml) the solution room temperature of-pyrrolidin-2-one (441mg, 2.69mmol), stir and spend the night.After having reacted, the lower THF that removes of decompression.Add water (10ml), this mixture is cooled to 0 ℃ simultaneously.Then this methylene dichloride extracting (2 * 40ml) for mixture.The organic solution merging is to Na 2sO 4dry.Remove solvent and obtain the required product of 498mg, purity 92%, this product is for next step, without being further purified (yield 498mg, 48%).
Microwave (20ml) is equipped with 1-(4-(the chloro-pyrimidine-4-yl oxygen of 2-amino-6-base)-2 with Emrys processing bottle (Emrys process vial), 2, the fluoro-ethyl of 2-tri-)-phenyl)-pyrrolidin-2-one (200mg, 0.51mmol), 4-borono--L-Phe (108mg, 0.51mmol) and 5ml acetonitrile.To above-mentioned solution, add 5ml aqueous sodium carbonate (1M), 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 cooling, evaporation reaction mixture is to dry.Residue is dissolved in 4ml methyl alcohol, and purifies with Prep-LC, 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, the fluoro-2-of the fluoro-1-[5-of 2-tri-(3-methyl-pyrazol-1-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid
By R-1-(the fluoro-phenyl of the bromo-5-of 2-)-2,2, the fluoro-ethanol of 2-tri-(4.0g, 14.65mmol), 3-methylpyrazole (1.56g, 19.04mmol), CuI (0.557g, 2.93mmol), K 2cO 3(4.25g, 30.76mmol), (1R, 2R)-N, N '-dimethyl-hexanaphthene-1,2-diamines (0.416g, 2.93mmol) and toluene (15ml) are placed in 50ml sealed tube, 130 ℃ of (oil bath temperature) heating of gained mixture two days.Mixture dilutes by ethyl acetate, uses H 2o (4 * 30ml), salt water washing, and to dried over sodium sulfate.Remove solvent and provide crude product, this crude product, by ISCO column chromatography, utilizes the hexane solution of 5-10% ethyl acetate to carry out purifying as solvent, obtains 1.75g R-2, the fluoro-2-of the fluoro-1-[5-of 2,2-tri-(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)。
By 4, the chloro-pyrimidine-2-base amine of 6-bis-(938mg, 5.72mmol), NaH (188mg, 1.5 equivalent 8.17mmol, 60%) and R-2, the fluoro-2-of the fluoro-1-[5-of 2,2-tri-(3-methyl-pyrazol-1-yl)-phenyl]-ethanol (1.5g, 1 equivalent 5.45mmol) under anhydrous THF (10ml) solution room temperature, stir 10 minutes, then stir at 50 ℃ and spend the night.After having reacted, the lower THF that removes of decompression.Add this reaction of water (10ml) cancellation.Then this mixture is with methylene dichloride (2 * 40ml) extracting.The organic solution merging is to Na 2sO 4dry.Remove solvent and provide required product, purity 92%, this product is used for next step (yield: 85%) without purifying.
Microwave is equipped with chloro-6-R-2 with Emrys processing bottle (20ml), 2, the fluoro-1-of 2-tri-(the fluoro-2-of 5-(3-methyl-pyrazol-1-yl)-phenyl)-oxyethyl group)-pyrimidine-2-base amine (2.18g, 5.45mmol), 4-borono--L-Phe (1.13g, 5.45mmol), to above-mentioned solution, add sodium carbonate (1M10.90ml, 2 equivalents), then add two (the triphenylphosphine)-palladiums (II) (191mg, 0.27mmol) of 5mol% dichloro and 5ml acetonitrile and 5ml H 2o.Sealed reaction vessel, at 160 ℃, this mixture with microwave irradiation heating 10 minutes.After cooling, reaction mixture is evaporated to dry.Residue is dissolved in H 2o (10ml) with ether extracting.Discard ether layer.Then vacuum is removed the most of water in water, 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, the fluoro-1-[4-of 2,2-tri-(6-methoxyl group-pyridine-2-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid
To 4-(6-methoxyl group-pyridine-2-yl)-phenyl aldehyde (213mg, 1mmol) with trifluoromethyl trimethyl silane (0.2ml, in 10ml THF solution 1.2mmol), at 0 ℃, add tetrabutyl ammonium fluoride (TBAF) (0.1ml, the THF solution of 1M).Warm until the room temperature of this mixture, and stir 4 hours.Then, this reaction mixture is processed and is stirred and spend the night with 12ml1M HCl.This ethyl acetate extracting (3 * 20ml) for product.Separated organic layer, and to dried over sodium sulfate.Evaporation organic solvent, provides 0.25g1-[4-(6-methoxyl group-pyridine-2-yl)-phenyl]-2,2, the fluoro-ethanol of 2-tri-, is directly used in next step, without purifying.Yield: 90%.
To 1-[4-(6-methoxyl group-pyridine-2-yl)-phenyl]-2,2, anhydrous Isosorbide-5-Nitrae-bis-of 10ml of the fluoro-ethanol of 2-tri-(67mg, 0.2mmol) in alkane solution, add Cs 2cO 3(375mg, 1mmol).This mixture stirs 5 minutes, then adds (S)-3-[4-(the chloro-pyrimidine-4-yl of 2-amino-6-)-phenyl]-2-tert-butoxycarbonyl amino-propionic acid (78mg, 0.2mmol), heated overnight at 110 ℃, this mixture.After cooling, add 5ml water, ethyl acetate (20ml) is for extract product.Organic layer is to dried over sodium sulfate.By centrifugal distiller, remove solvent, provide 112mg (S)-3-[4-(2-amino-6-{2, the fluoro-1-[4-of 2,2-tri-(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 5ml30%TFA/DCM solution.After having reacted, evaporating solvent, provide crude product, this crude product is by preparation HPLC purifying, provide 5mg (S)-2-amino-3-[4-(2-amino-6-{2, the fluoro-1-[4-of 2,2-tri-(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＝8.1Hz1H)，4.37(t，1H)，4.03(s，3H)，3.5(m，2H)。
29. synthetic (S)-2-amino-3-[4-(2-amino-6-{2, the fluoro-4-of the fluoro-1-[2-of 2,2-tri-(5-methoxyl group-pyridin-3-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid
By at 0 ℃ of TBAF (0.1ml), be added into the 4-fluoro-phenyl aldehyde of bromo-2-(2.03g, 10mmol) and TMSCF 3the 10ml THF solution of (20ml, 12mmol).Warm until the room temperature of the mixture that forms, and stir 4 hours.Then this reaction mixture is processed with 12ml3M HCl, and stirs and spend the night.This is ethyl acetate (3 * 20ml) extracting for product.Separated organic layer, and to dried over sodium sulfate.Evaporation organic solvent, provides 2.4g1-(the fluoro-phenyl of the bromo-2-of 4-)-2,2, the fluoro-ethanol of 2-tri-(yield: 90%).
To 1-(the fluoro-phenyl of the bromo-2-of 4-)-2,2, anhydrous Isosorbide-5-Nitrae-bis-of 10ml of the fluoro-ethanol of 2-tri-(1.4g, 5.2mmol) alkane solution adds Cs 2cO 3(8.45g, 26mmol), this mixture stirs 5 minutes, then adds (S)-3-[4-(the chloro-pyrimidine-4-yl of 2-amino-6-)-phenyl]-2-tert-butoxycarbonyl amino-propionic acid (2.0g, 5mmol), heated overnight at 110 ℃, gained mixture.After cooling, add 5ml water, ethyl acetate (20ml) is for extract product.Organic layer is to dried over sodium sulfate.By centrifugal distiller, remove solvent, provide 2.6g (S)-3-(4-{2-amino-6-[1-(the fluoro-phenyl of the bromo-2-of 4-)-2, the fluoro-oxyethyl group of 2,2-tri-]-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-(the fluoro-phenyl of the bromo-2-of 4-)-2,2, the fluoro-oxyethyl group of 2-tri-]-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)-pyridine (70mg, 0.3mmol), 1ml acetonitrile and 0.7ml water.To this mixture, add 0.4ml aqueous sodium carbonate (1M), 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 cooling, this reaction mixture is evaporated to dry, residue is dissolved in 2.5ml methyl alcohol, and carry out purifying by Prep HPLC, provide 51mg (S)-3-[4-(2-amino-6-{2, the fluoro-4-of the fluoro-1-[2-of 2,2-tri-(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 5ml30%TFA/DCM solution.Under this mixture room temperature, stir 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, the fluoro-4-of the fluoro-1-[2-of 2,2-tri-(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, the fluoro-1-[4-of 2-tri-(the fluoro-pyridin-4-yl of 2-)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid
To (S)-1-(the bromo-phenyl of 4-)-2,2, anhydrous Isosorbide-5-Nitrae-bis-of 10ml of the fluoro-ethanol of 2-tri-(2.55g, 11.0mmol) alkane solution adds Cs 2cO 3(16.25g, 50mmol), this mixture stirs 5 minutes, then adds (S)-3-[4-(the chloro-pyrimidine-4-yl of 2-amino-6-)-phenyl]-2-tert-butoxycarbonyl amino-propionic acid (3.92g, 10mmol).Heated overnight at 110 ℃, gained mixture.After cooling, add 5ml water, ethyl acetate (20ml) is for extract product.Organic layer is to dried over sodium sulfate.By centrifugal distiller, remove solvent, provide 5.2g (S)-3-(4-{2-amino-6-[(S)-1-(the bromo-phenyl of 4-)-2, the fluoro-oxyethyl group of 2,2-tri-]-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-(the bromo-phenyl of 4-)-2,2, the fluoro-oxyethyl group of 2-tri-]-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.To this mixture, add 0.4ml aqueous sodium carbonate (1M), 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 cooling, this reaction mixture is evaporated to dry, 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, the fluoro-1-[4-of 2,2-tri-(the fluoro-pyridin-4-yl of 2-)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-2-tert-butoxycarbonyl amino-propionic acid.
Above-mentioned product (70mg) is dissolved in the DCM solution of 5ml30%TFA.Under this reaction mixture room temperature, stir 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, the fluoro-1-[4-of 2-tri-(the fluoro-pyridin-4-yl of 2-)-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, the fluoro-1-[4-of 2-tri-(5-methoxyl group-pyridin-3-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid
Microwave bottle (2ml) is equipped with (S)-3-(4-{2-amino-6-[(S)-1-(the bromo-phenyl of 4-)-2,2, the fluoro-oxyethyl group of 2-tri-]-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.To this mixture, add 0.4ml aqueous sodium carbonate (1M), 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 cooling, this reaction mixture is evaporated to dry, 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, the fluoro-1-[4-of 2,2-tri-(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 5ml30%TFA.Under this reaction mixture room temperature, stir 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, the fluoro-1-[4-of 2,2-tri-(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, the fluoro-1-[4-of 2-tri-(4-trifluoromethyl-pyridin-3-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid
Microwave bottle (2ml) is equipped with (S)-3-(4-{2-amino-6-[(S)-1-(the bromo-phenyl of 4-)-2,2, the fluoro-oxyethyl group of 2-tri-]-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.To this mixture, add 0.4ml aqueous sodium carbonate (1M), 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 cooling, this reaction mixture is evaporated to dry, 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, the fluoro-1-[4-of 2,2-tri-(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 5ml30%TFA.Under this reaction mixture room temperature, stir 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, the fluoro-1-[4-of 2,2-tri-(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, (4-is different for the fluoro-1-of 2-tri- azoles-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-(the bromo-phenyl of 4-)-2,2, the fluoro-oxyethyl group of 2-tri-]-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)-different azoles (57.5mg, 0.3mmol), 1ml acetonitrile and 0.7ml water.To this mixture, add 0.4ml aqueous sodium carbonate (1M), 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 cooling, this reaction mixture is evaporated to dry, and residue is dissolved in 2.5ml methyl alcohol and carries out purifying by preparation HPLC, provides 20mg (S)-3-(4-{2-amino-6-[(S)-2,2, and (4-is different for the fluoro-1-of 2-tri- azoles-4-base-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-2-tert-butoxycarbonyl alanine.
Above-mentioned product (20mg) is dissolved in the DCM solution of 5ml30%TFA.Under this mixture room temperature, stir and spend the night.Remove solvent and provide crude product, this crude product carries out purifying by preparation HPLC, provides 10mg (S)-2-amino-3-(4-{2-amino-6-[(S)-2,2, and (4-is different for the fluoro-1-of 2-tri- azoles-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, the fluoro-1-of 2,2-tri-(2-pyrimidine-5-base-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid
Microwave bottle (20ml) is equipped with 2-formylphenyl boric acid (290mg, 2.0mmol), the bromo-pyrimidine of 5-(316mg, 2.0mmol) and 8ml acetonitrile.To this mixture, add 4ml aqueous sodium carbonate (1M), then add two (the triphenylphosphine)-palladiums (II) of 100mg dichloro.Sealed reaction vessel, and at 150 ℃, heat 5 minutes with microwave irradiation.After cooling, this reaction mixture is with ethyl acetate extracting.Evaporation organic layer, provides roughage, and this roughage carries out purifying by ISCO, provides 220mg2-pyrimidine-5-base-phenyl aldehyde.
By at 0 ℃ of tetrabutyl ammonium fluoride (TBAF, 0.1ml, the THF solution of 1M), be added into 2-pyrimidine-5-base-phenyl aldehyde (184mg, 1mmol) and trifluoromethyl trimethyl silane (TMSCF 3, 0.2ml, 1.2mmol) 10ml THF solution.Warm until the room temperature of mixture, and stir 4 hours.Then this mixture is processed with 3ml1M HCl, and stirs and spend the night.This is ethyl acetate (3 * 20ml) extracting for product.Separated organic layer, and to dried over sodium sulfate.Evaporation organic solvent, provides 0.21g2, the fluoro-1-of 2,2-tri-(2-pyrimidine-5-base-phenyl)-ethanol (yield: 84%), be directly used in next step without purifying.
10ml anhydrous THF solution to the fluoro-1-of 2,2,2-tri-(2-pyrimidine-5-base-phenyl)-ethanol (72mg, 0.28mmol) adds Cs 2cO 3(325mg, 1.0mmol).This mixture stirs 20 minutes, adds 2-amino-4, the chloro-pyrimidine of 6-bis-(36.7mg, 0.22mmol), and then heating at 110 ℃ of reaction mixtures, until reacted.Be cooled to after room temperature, add 5ml water, ethyl acetate (20ml) is for extract product.Organic layer is to dried over sodium sulfate.By centrifugal distiller, remove solvent, provide the chloro-6-[2 of the rough 4-of 76mg, the fluoro-1-of 2,2-tri-(2-pyrimidine-5-base-phenyl)-oxyethyl group]-pyrimidine-2-base amine (yield: 92%).
Microwave bottle (2ml) is equipped with above-mentioned rough intermediate (38mg, 0.1mmol), 4-borono--L-Phe (31mg, 0.15mmol), 1ml acetonitrile and 0.7ml water.To this mixture, add 0.3ml aqueous sodium carbonate (1M), 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 cooling, this reaction mixture is evaporated to dry, 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, the fluoro-1-of 2,2-tri-(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, the fluoro-1-of 2,2-tri-(2-thiene-3-yl--phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid
Microwave bottle (20ml) is equipped with 2-formylphenyl boric acid (290mg, 2.0mmol), the bromo-thiophene of 3-(326mg, 2.0mmol) and 8ml acetonitrile.To this mixture, add 4ml aqueous sodium carbonate (1M), then add two (the triphenylphosphine)-palladiums (II) of 50mg dichloro.Sealed reaction vessel, and at 150 ℃, heat 5 minutes with microwave irradiation.After cooling, the ethyl acetate extracting of this reaction mixture.Evaporation organic layer, provides roughage, and this roughage carries out purifying by ISCO, provides 211mg2-thiene-3-yl--phenyl aldehyde.
The 10ml THF solution of 2-thiene-3-yl--phenyl aldehyde (100mg, 0.53mmol) and trifluoromethyl trimethyl silane (0.1ml, 0.64mmol) will be added at 0 ℃ of tetrabutyl ammonium fluoride (TBAF, 0.1ml, the THF solution of 1M).Warm until the room temperature of mixture, and stir 4 hours.Then this reaction mixture is processed with 3ml1M HCl, and stirs and spend the night.This is ethyl acetate (3 * 20ml) extracting for product.Organic layer is separated, and to dried over sodium sulfate.Evaporation organic solvent, provides 0.12g2, and the fluoro-1-of 2,2-tri-(2-pyrimidine-5-base-phenyl)-ethanol, is directly used in next step without purifying (yield: 89%).
10ml anhydrous THF solution to the fluoro-1-of 2,2,2-tri-(2-thiene-3-yl--phenyl)-ethanol (72mg, 0.28mmol) adds Cs 2cO 3(325mg, 1.0mmol), this mixture stirs 20 minutes.Then add 2-amino-4, the chloro-pyrimidine of 6-bis-(36.7mg, 0.22mmol), heating at 110 ℃, mixture, until reacted.After cooling, add 5ml water, ethyl acetate (20ml) is for extract product.Organic layer is to dried over sodium sulfate.By centrifugal distiller, remove solvent, provide the chloro-6-[2 of 67mg4-, the fluoro-1-of 2,2-tri-(2-pyrimidine-5-base-phenyl)-oxyethyl group]-pyrimidine-2-base amine (yield: 78%).
Microwave bottle (2ml) is equipped with above-mentioned roughage (40mg, 0.1mmol), 4-borono--L-Phe (31mg, 0.15mmol), 1ml acetonitrile and 0.7ml water.To this mixture, add 0.3ml aqueous sodium carbonate (1M), 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 cooling, this reaction mixture is evaporated to dry.Residue is dissolved in 2.5ml methyl alcohol, then with preparation HPLC, carry out purifying, obtain 11.8mg (S)-2-amino-3-(4-{2-amino-6-[2, the fluoro-1-of 2,2-tri-(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, the fluoro-1-[2-of 2,2-tri-(1-methyl isophthalic acid H-pyrazoles-4-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid
Microwave bottle (20ml) is equipped with the bromo-phenyl aldehyde of 2-(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 8ml acetonitrile.To this mixture, add 2.4ml aqueous sodium carbonate (1M), then add two (the triphenylphosphine)-palladiums (II) of 50mg dichloro.Sealed reaction vessel, and at 150 ℃, heat 5 minutes with microwave irradiation.After cooling, the ethyl acetate extracting of this reaction mixture.Evaporation organic layer, provides roughage, and this roughage carries out purifying by ISCO, provides 181mg2-(1-methyl isophthalic acid H-pyrazoles-4-yl)-phenyl aldehyde (96% yield).
By tetrabutyl ammonium fluoride (0.1ml, the THF solution of 1M) be added into 2-(1-methyl isophthalic acid H-pyrazoles-4-yl)-phenyl aldehyde (100mg at 0 ℃, 0.53mmol) and the 10ml THF solution of trifluoromethyl trimethyl silane (0.12ml, 0.6mmol).Warm until the room temperature of mixture, and stir 4 hours.Then this mixture is processed with 3ml1M HCl, and stirs and spend the night.This is ethyl acetate (3 * 20ml) extracting for product.Separated organic layer, and to dried over sodium sulfate.Evaporation organic solvent, provides 0.12g2, and the fluoro-1-[2-of 2,2-tri-(1-methyl isophthalic acid H-pyrazoles-4-base-phenyl)-ethanol, is directly used in next step without purifying (yield: 89%).
To the fluoro-1-[2-of 2,2,2-tri-(1-methyl isophthalic acid H-pyrazoles-4-yl)-phenyl] the 10ml anhydrous THF solution of-ethanol (60mg, 0.2mmol) adds Cs 2cO 3(325mg, 1.0mmol), this mixture stirs 20 minutes.Add 2-amino-4, the chloro-pyrimidine of 6-bis-(32mg, 0.2mmol), then heating at 110 ℃ of reaction mixtures, until reacted.After cooling, add 5ml water, ethyl acetate (20ml) is for extract product.Organic layer is to dried over sodium sulfate.By centrifugal distiller, remove solvent, obtain the chloro-6-{2 of 70mg4-, the fluoro-1-[2-of 2,2-tri-(1-methyl isophthalic acid H-pyrazoles-4-yl)-phenyl]-oxyethyl group }-pyrimidine-2-base amine (yield: 92%).
Microwave bottle (2ml) is equipped with above-mentioned roughage (38mg, 0.1mmol), 4-borono--L-Phe (31mg, 0.15mmol), 1ml acetonitrile and 0.7ml water.To this mixture, add 0.3ml aqueous sodium carbonate (1M), 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 cooling, this mixture is evaporated to dry, 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, the fluoro-1-[2-of 2,2-tri-(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, the fluoro-1-of 2,2-tri-(2-furans-3-base-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid
Microwave bottle (20ml) is equipped with 2-formylphenyl boric acid (298mg, 2.0mmol), the bromo-furans of 3-(350mg, 2.4mmol) and 8ml acetonitrile.To this mixture, add 4ml aqueous sodium carbonate (1M), then add two (the triphenylphosphine)-palladiums (II) of 100mg dichloro.Sealed reaction vessel, and at 150 ℃, heat 5 minutes with microwave irradiation.After cooling, this reaction mixture is with ethyl acetate extracting.Evaporation organic layer, provides roughage, and this roughage carries out purifying by ISCO, provides 110mg2-furans-3-base-phenyl aldehyde (30% yield).
The 10ml THF solution of 2-furans-3-base-phenyl aldehyde (110mg, 0.64mmol) and trifluoromethyl trimethyl silane (109mg, 0.78mmol) will be added at 0 ℃ of tetrabutyl ammonium fluoride (0.1ml, under the THF of 1M).Warm until the room temperature of mixture, and stir 4 hours.Then this mixture is processed with 3ml1M HCl, and stirs and spend the night.Ethyl acetate for product (3 * 20ml) extracting.Separated organic layer, and to dried over sodium sulfate.Evaporation organic solvent, provides 0.130g2, and the fluoro-1-of 2,2-tri-(2-furans-3-base-phenyl)-ethanol, is directly used in next step, without purifying (yield: 90%).
60%NaH (12mg, 0.3mmol) is added into the 10ml anhydrous THF solution of the fluoro-1-of 2,2,2-tri-(2-furans-3-base-phenyl)-ethanol (54mg, 0.2mmol).This mixture stirs 20 minutes, adds thereafter the chloro-pyrimidine of 4,6-bis-(30mg, 0.2mmol).Then heating at 70 ℃, this mixture, until reacted.After cooling, add 5ml water, with cancellation reaction, ethyl acetate (20ml) is for extract product.Organic layer is to dried over sodium sulfate.By centrifugal distiller, remove solvent, obtain the chloro-6-[2 of 67mg4-, the fluoro-1-of 2,2-tri-(2-furans-3-base-phenyl)-oxyethyl group]-pyrimidine (yield: 94%).
Microwave bottle (2ml) is equipped with above-mentioned roughage (38mg, 0.1mmol), 4-borono--L-Phe (31mg, 0.15mmol), 1ml acetonitrile and 0.7ml water.To this mixture, add 0.3ml aqueous sodium carbonate (1M), 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 cooling, this reaction mixture is evaporated to dry, residue is dissolved in 2.5ml methyl alcohol, then by preparation HPLC, carry out purifying, obtain 6mg (S)-2-amino-3-(4-{6-[2, the fluoro-1-of 2,2-tri-(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, the fluoro-1-of 2,2-tri-(2-furans-2-base-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid
Microwave bottle (20ml) is equipped with 2-formylphenyl boric acid (298mg, 2.0mmol), the bromo-furans of 2-(350mg, 2.4mmol) and 8ml acetonitrile.To this mixture, add 4ml aqueous sodium carbonate (1M), then add two (the triphenylphosphine)-palladiums (II) of 100mg dichloro.Sealed reaction vessel, and at 150 ℃, heat 5 minutes with microwave irradiation.After cooling, the ethyl acetate extracting of this reaction mixture.Evaporation organic layer, provides roughage, and this roughage carries out purifying by ISCO, provides 123mg2-furans-2-base-phenyl aldehyde (34% yield).
The 10ml THF solution of 2-furans-2-base-phenyl aldehyde (123mg, 0.71mmol) and trifluoromethyl trimethyl silane (120mg, 0.86mmol) will be added at 0 ℃ of tetrabutyl ammonium fluoride (0.1ml, the THF solution of 1M).Warm until the room temperature of mixture, and stir 4 hours.Then this mixture is processed with 3ml1M HCl, and stirs and spend the night.This is ethyl acetate (3 * 20ml) extracting for product.Separated organic layer, and to dried over sodium sulfate.Evaporation organic solvent, provides 0.150g2, and the fluoro-1-of 2,2-tri-(2-furans-3-base-phenyl)-ethanol, is directly used in next step, without purifying (yield: 90%).
60%NaH (12mg, 0.3mmol) is added into the 10ml anhydrous THF solution of the fluoro-1-of 2,2,2-tri-(2-furans-2-base-phenyl)-ethanol (55mg, 0.2mmol).This mixture stirs 20 minutes, adds thereafter the chloro-pyrimidine of 4,6-bis-(29mg, 0.2mmol).The then heating at 110 ℃ of this mixture, until reacted.After cooling, add 5ml water, ethyl acetate (20ml) is for extract product.Organic layer is to dried over sodium sulfate.By centrifugal distiller, remove solvent, obtain the chloro-6-[2 of 60mg4-, the fluoro-1-of 2,2-tri-(2-furans-2-base-phenyl)-oxyethyl group]-pyrimidine (yield 80%).
Microwave bottle (2ml) is equipped with above-mentioned roughage (60mg, 0.2mmol), 4-borono--L-Phe (62mg, 0.3mmol), 1ml acetonitrile and 0.6ml water.To this mixture, add 0.4ml aqueous sodium carbonate (1M), 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 cooling, this reaction mixture is evaporated to dry, residue is dissolved in 2.5ml methyl alcohol, and carry out purifying by preparation HPLC, obtain 6mg (S)-2-amino-3-(4-{6-[2, the fluoro-1-of 2,2-tri-(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 compounds that utilize method known in this field and/or described here to prepare are listed below:
Table 1
40. vitro inhibition analyses
People TPH1, TPH2, tyrosine hydroxylase (TH) and Phenylalanine hydroxylase (PH) all utilize the gene respectively with following accession number to generate: X52836, AY098914, X05290, and U49897.
The complete encoding sequence of people TPH1 is cloned in bacterial expression vector pET24 (Novagen, Madison, WI, USA).Single bacterium colony BL21 (DE3) cell that contains expression vector is seeded to 50ml L meat soup (LB)-kantlex substratum and spends the night at 37 ℃ of oscillating growths.Then half culture (25ml) is transferred to 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 (pH7.0), and at 37 ℃, supplement 40% oxygen, maintain pH7.0, with increase glucose, culture grows to OD 600=6.Utilize 15%D-lactose, at 25 ℃, with 10 hours, induce the expression of TPH1.Cell rotation sedimentation, and with phosphate buffered saline (PBS) (PBS) washing once.
Combination based on itself and pterin, TPH1 is by affinity chromatography purifying.Cell mass is resuspended to lysis buffer (100ml/20g), described lysis buffer contains 50mM Tris-Cl, pH7.6,0.5M NaCl, 0.1%Tween-20,2mM EDTA, 5mM DTT, protease inhibitor cocktail (Roche Applied Science, Indianapolis, IN, USA) and 1mM phenylmethylsulfonyl fluoride (PMSF), cell is with microjet nanometer clarifixator (microfluidizer) cracking.Lysate is centrifugal, and by supernatant liquor loading to the sepharose 4B post of pterin coupling, this post to be to contain 50mM Tris, pH8.0,2M NaCl, 0.1%Tween-20,0.5mM EDTA, and the damping fluid balance of 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, pH10.5,0.5M 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, pH7.0,0.5M NaCl, 20mM DTT, 0.5mMEDTA, and the neutralization of 10% glycerine, and be stored in-80 ℃.
Substantially express in the same manner and Purification of Human tryptophan hydroxylase II type (TPH2), tyrosine hydroxylase (TH) and Phenylalanine hydroxylase (PAH), except at growing period, TH cell being supplemented to tyrosine and PAH being supplemented phenylalanine.
The TPH1 measuring in reaction mixture and TPH2 are active, described mixture contains 50mM4-morpholine propanesulfonic acid (MOPS), pH7.0,60 μ M tryptophanes, 100mM ammonium sulfate, 100 μ M ferrous ammonium sulphates, 0.5mM tri-(2-propyloic) phosphine (TCEP), 0.3mM6-methyl tetrahydrochysene pterin, 0.05mg/ml catalase, and 0.9mM DTT.Add TPH1 to final concentration 7.5nM, start reaction.The change in fluorescence of locating by following 360nm (excitation wavelength=300nm), determines the original speed reacting.By measuring under different compound concentrations their activity, determine that TPH1 and TPH2 suppress, and utilize the effect of the given compound of following Equation for Calculating:
v = b + v 0 - b 1 + ( [ C ] [ I c 50 ] ) D
Wherein ν is the original speed of given compound concentration C, ν 0ν while being C=0, b is background signal, D approaches to equal 1 Hill slope, and I c50that compound suppresses half concentration of maximum enzyme activity.
By measuring, utilize respectively L-[3,4- 3h]-tyrosine and L-[4- 3h] generation of-phenylalanine 3h 2the amount of O, determines that people TH and PAH are active.First by enzyme (100nM) and its 0.1mM substrate incubation approximately 10 minutes, and being added into reaction mixture, described mixture contains 50mMMOPS, pH7.2,100mM ammonium sulfate, 0.05%Tween-20,1.5mM TCEP, 100 μ M ferrous ammonium sulphates, 0.1mM tyrosine or phenylalanine, 0.2mM6-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 by scintillation counting, determines the radioactivity of filtrate.Utilize the activity of this Analysis deterrmination compound to TH and PAH, and so that the TPH1 mode identical with TPH2 calculated.
41. inhibition analysiss based on cell
The clone of two types is rat hypertrophy cell oncocyte system for screening: RBL2H3, and it contains TPH1, and the spontaneous serotonin (5HT) of preparing; BON is human cancer cell line, and it contains TPH1, and prepares 5HTP (5HTP).CBA carries out with 96-well plate format.In HPLC, moving phase used contains 97%100mM sodium acetate, pH3.5 and 3% acetonitrile.Waters C18 post (4.6 * 50mm) is used together with Waters HPLC (model 2795).By setting 280nm as excitation wavelength, and 360nm is as emission wavelength, and hyperchannel photofluorometer (model 2475) is through-flow for monitoring.
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 the cell in the perfect medium without any compound.At 37 ℃, hatch collecting cell after 3 days.Cell >95% when there is no compound converges.In slave plate, remove substratum, cell is with isopyknic 0.1N NaOH cracking.Most cell lysate by with isopyknic 1M TCA combination treatment, then by glass fibre, filter.Filtrate loading is to reversed-phase HPLC, for analyzing 5HT concentration.The cell lysate of small portion is also removed, to measure the protein concentration of cell, and the cytotoxicity of this concentration reflection compound under working concentration.Utilize BCA method to measure protein concentration.
According to above-mentioned equation, in the cell without compound treatment, the mean level (ML) of 5HT is as IC 50maximum value in derivation.The minimum value of 5HT or be set as 0, or from the cell of the compound treatment with maximum concentration, if the compound of this concentration does not have cytotoxicity.
bON CBA: cell is grown 3-4 hour (20K cells/well) in isopyknic DMEM with 5% bovine serum and F12K, and adds the compound of 0.07 μ M-50 μ M concentration range.Cell is overnight incubation at 37 ℃.Then take out 50 μ M culture supernatants, for 5HTP, measure.Supernatant mixes with isopyknic 1M TCA, then by glass fibre, filters.By filtrate loading to reversed-phase HPLC, for 5HTP measurement of concetration.Utilize the Celltiter-Glo photogenic cell vigor analysis of Promega, by processing remaining cell, measure cell viability.Then, with RBL CBA in same way computerized compound effect.
42. in vitro effects
Utilize aforesaid method, the ability of test compounds vitro inhibition people TPH1.Data provide in following table 2:
Table 2
In 43. bodies, serotonin reduces
(S)-2-amino-3-(4-(2-amino-6-((R)-1-(the chloro-2-of 4-(3-methyl isophthalic acid H-pyrazol-1-yl) phenyl)-2,2,2-trifluoro ethoxy) pyrimidine-4-yl) phenyl) in the body of ethyl propionate effect by they be mixed with solution, then oral administration is determined.Generally speaking, 14-male C57 albinism mouse in age in week gavages 5-10ml/kg by mouth, and be administered once every day, continuous 4 days.After last potion 5 hours, put to death fast animal.Each animal, in order to isoflurane anesthesia, utilizes 1ml syringe and 255/8 pin, by cardiac puncture method, extracts blood, and 250 μ l blood are placed in the pipe that contains Capiject EDTA, maintains rotation gently.Then animal decaptitates, and takes out full brain, and quick-frozen, disposes fat and the chamber content of jejunum, ileum and colon, quick-frozen.5-HT is from blood or organize extracting, and measures through the high performance liquid chromatography (HPLC) of online fluorescence detector is housed.Gather blood sample, for exposure analysis.Utilize the rules of management of laboratory animal and the use council (The Institutional Animal Care and Use Committee) approval, carry out all zooscopies.
Fig. 1 shows the dose-dependently impact of compound on mouse 5-HT level.
44. on stomach transportation and emptying impact
Effective TPH1 inhibitor of the present invention, (S)-2-amino-3-(4-(2-amino-6-((R)-1-(the chloro-2-of 4-(3-methyl isophthalic acid H-pyrazol-1-yl) phenyl)-2,2,2-trifluoro ethoxy) pyrimidine-4-yl) phenyl) ethyl propionate is determined in Sprague-Dawley rat the impact of stomach and intestine (GI) haulage time and stomach emptying.Compound is with 50,125 and the dosed administration of 250mpk, oral, and one day four times, 14 days by a definite date.Respectively take medicine and organize with 9 rats.Also with 9 rats, make negative control group (only administration media), and separately have 6 as positive control (coromegine).
Rat is with 10ml/kg take medicine compound or medium.Coromegine only gave to positive controls 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 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 (having 5% charcoal in medium) is with 15ml/kg oral administration.Charcoal meal is taken medicine and within latter 25 minutes, is carried out ptomatopsia.The distance of walking downwards along small intestine by measuring charcoal meal, divided by small intestine overall length, determines GI haulage time by this distance.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 GI mobility in dose-dependently mode.As shown in Figure 3, it has also slowed down stomach emptying in dose-dependently mode.And as shown in Figure 4, this compound is relevant to the variation of 5-HT level in blood and nearly colon on the impact of GI transportation and stomach emptying.Brain 5-HT level is not subject to this compounds affect.
Above-mentioned all publications (for example, patent and patent application) are incorporated to and are hereby incorporated by reference in full with it.

Claims (17)

1. formula I compound:
Or its pharmacologically acceptable salt or solvate, wherein:
A 1it is the optional heterocycle replacing;
Each R 1halogen independently, hydrogen, C (O) R a, OR a, NR br c, S (O 2) R a, or C 1-4-alkyl;
R 2halogen independently, hydrogen, C (O) R a, OR a, NR br c, S (O 2) R a, or C 1-4-alkyl;
R 3hydrogen, C (O) R a, C (O) OR a, or C 1-4-alkyl;
R 4hydrogen or C 1-4-alkyl;
Each R ahydrogen or C independently 1-4-alkyl;
Each R bhydrogen or C independently 1-4-alkyl;
Each R chydrogen or C independently 1-4-alkyl; And
M is 1-4.
2. the compound of claim 1, it is the compound that is selected from following formula:
Wherein:
Each R 5halogen independently, hydrogen, C (O) R a, OR a, NR br c, S (O 2) R a, or C 1-4-alkyl; And
N is 1-3.
3. the compound of claim 2, its compound that is following formula:
4. the compound of claim 3, its compound that is following formula:
5. the compound of claim 1, its compound that is following formula:
Wherein:
Each R 5halogen independently, hydrogen, C (O) R a, OR a, NR br c, S (O 2) R a, or C 1-4-alkyl; And
P is 1-4.
6. the compound of claim 1, it is the compound that is selected from following formula:
Wherein:
Each R 5halogen independently, hydrogen, C (O) R a, OR a, NR br c, S (O 2) R a, or C 1-4-alkyl; And
Q is 1-2.
7. the compound of claim 6, it is the compound that is selected from following formula:
8. compound or pharmaceutically acceptable salt thereof or a solvate, wherein said compound is:
(S)-2-amino-3-(4-{2-amino-6-[2, the fluoro-1-of 2,2-tri-(4-pyridin-4-yl-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid;
(S)-2-amino-3-(4-{6-[2, the fluoro-1-of 2,2-tri-(2-pyridin-4-yl-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid;
(S)-2-amino-3-(4-{2-amino-6-[2, and the fluoro-1-of 2,2-tri-(2-(4-methyl-thiene-3-yl-)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-(4-{2-amino-6-[2, and the fluoro-1-of 2,2-tri-(2-(5-methyl-thiene-3-yl-)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-(4-{2-amino-6-[2, the fluoro-1-of 2,2-tri-(4-furans-3-base-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid;
(S)-2-amino-3-[4-{2-amino-6-{1-[2-(5-dimethylaminomethyl-furans-2-yl)-phenyl]-2,2, the fluoro-oxyethyl group of 2-tri-}-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, the fluoro-oxyethyl group of 2-tri-}-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-(4-{2-amino-6-[2, the fluoro-1-of 2,2-tri-(2-imidazoles-1-base-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid;
(S)-2-amino-3-(4-{6-[2, the fluoro-1-of 2,2-tri-(2-pyrazol-1-yl-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid;
(S)-2-amino-3-[4-(2-amino-6-{2, the fluoro-1-[2-of 2,2-tri-(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, the fluoro-oxyethyl group of 2-tri-}-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-[4-(2-amino-6-{2, the fluoro-1-[2-of 2,2-tri-(3-phenyl-pyrazole-1-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-[4-(2-amino-6-{2, the fluoro-1-[5-methoxyl group-2-of 2,2-tri-(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, the fluoro-1-[2-of 2-tri-(3-methyl-pyrazol-1-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-[4-(the chloro-2-of 2-amino-6-{1-[4-(3-methyl-pyrazol-1-yl)-phenyl]-2,2, the fluoro-oxyethyl group of 2-tri-}-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-[4-(the chloro-2-of 2-amino-6-{R-1-[4-(3-methyl-pyrazol-1-yl)-phenyl]-2,2, the fluoro-oxyethyl group of 2-tri-}-pyrimidine-4-yl)-phenyl]-ethyl propionate;
(S)-2-amino-3-(4-(2-amino-6-((R)-1-(the chloro-2-of 4-(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, the fluoro-1-of 2,2-tri-(2-thiazol-2-yl-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid;
(S)-2-amino-3-[4-(2-amino-6-{2, the fluoro-1-[2-of 2,2-tri-(pyridin-3-yl oxygen base)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-[4-(2-amino-6-{2, the fluoro-1-[4-of 2,2-tri-(pyridin-3-yl oxygen base)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-[4-(6-{2, the fluoro-1-[4-of 2,2-tri-(pyridin-3-yl oxygen base)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-(4-{2-amino-6-[2, the fluoro-1-of 2,2-tri-(4-thiophene-2-base-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid;
(S)-2-amino-3-(4-{6-[2, the fluoro-1-of 2,2-tri-(4-imidazoles-1-base-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid;
(S)-2-amino-3-(4-{2-amino-6-[2, and the fluoro-1-of 2,2-tri-(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, the fluoro-1-of 2,2-tri-(the fluoro-2-thiene-3-yl--phenyl of 4-) oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid;
(S)-2-amino-3-[4-(2-amino-6-{2, the fluoro-2-of the fluoro-1-[4-of 2,2-tri-(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-different azoles-4-yl) the fluoro-phenyl of-4-]-2,2, the fluoro-oxyethyl group of 2-tri-}-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-[4-(2-amino-6-{2, the fluoro-2-of the fluoro-1-[5-of 2,2-tri-(3-methyl-pyrazol-1-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-[4-(2-amino-6{2, the chloro-2-of the fluoro-1-[5-of 2,2-tri-(3-methyl-pyrazol-1-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-[4-(2-amino-6-{2, the fluoro-1-[4-of 2,2-tri-(2-oxo-pyrrolidin-1-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-[4-(2-amino-6-{ (R)-2,2, the fluoro-2-of the fluoro-1-[5-of 2-tri-(3-methyl-pyrazol-1-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-[4-(2-amino-6-{2, the fluoro-1-[4-of 2,2-tri-(6-methoxyl group-pyridine-2-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-[4-(2-amino-6-{2, the fluoro-4-of the fluoro-1-[2-of 2,2-tri-(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, the fluoro-1-[4-of 2-tri-(the fluoro-pyridin-4-yl of 2-)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-[4-(2-amino-6-{ (S)-2,2, the fluoro-1-[4-of 2-tri-(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, the fluoro-1-[4-of 2-tri-(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, (4-is different for the fluoro-1-of 2-tri- azoles-4-base-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid;
(S)-2-amino-3-(4-{2-amino-6-[2, the fluoro-1-of 2,2-tri-(2-pyrimidine-5-base-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid;
(S)-2-amino-3-(4-{2-amino-6-[2, the fluoro-1-of 2,2-tri-(2-thiene-3-yl--phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid;
(S)-2-amino-3-[4-(2-amino-6-{2, the fluoro-1-[2-of 2,2-tri-(1-methyl isophthalic acid H-pyrazoles-4-yl)-phenyl]-oxyethyl group }-pyrimidine-4-yl)-phenyl]-propionic acid;
(S)-2-amino-3-(4-{6-[2, the fluoro-1-of 2,2-tri-(2-furans-3-base-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid;
(S)-2-amino-3-(4-{6-[2, the fluoro-1-of 2,2-tri-(2-furans-2-base-phenyl)-oxyethyl group]-pyrimidine-4-yl }-phenyl)-propionic acid;
(2S)-2-amino-3-(4-(2-amino-6-(the fluoro-1-of 2,2,2-tri-(4-(pyridin-3-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid;
(2S)-2-amino-3-(4-(2-amino-6-(the fluoro-1-of 2,2,2-tri-(2-(2-picoline-4-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid;
(2S)-2-amino-3-(4-(2-amino-6-(the fluoro-1-of 2,2,2-tri-(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-(the fluoro-1-of 2,2,2-tri-(4-(furans-2-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid;
(2S)-2-amino-3-(4-(6-(the fluoro-1-of 2,2,2-tri-(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-(the fluoro-1-of 2,2,2-tri-(2-(furans-3-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid;
(2S)-2-amino-3-(4-(2-amino-6-(the fluoro-1-of 2,2,2-tri-(4-(furans-2-yl)-3-p-methoxy-phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid;
(2S)-2-amino-3-(4-(5-(the fluoro-1-of 2,2,2-tri-(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-(the fluoro-1-of 2,2,2-tri-(2-(2-methyl-1 H-imidazole-1-group) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid;
(2S)-2-amino-3-(4-(2-amino-6-(the fluoro-1-of 2,2,2-tri-(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-(the fluoro-1-of 2,2,2-tri-(the fluoro-2-of 4-(thiophene-2-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid;
(2S)-2-amino-3-(4-(6-(the fluoro-1-of 2,2,2-tri-(the fluoro-2-of 4-(thiophene-2-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid;
(2S)-2-amino-3-(4-(6-(the fluoro-1-of 2,2,2-tri-(the fluoro-2-of 4-(thiene-3-yl-) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid;
(2S)-2-amino-3-(4-(6-(the fluoro-1-of 2,2,2-tri-(the fluoro-2-of 4-(4-thiotolene-2-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid;
(S)-2-amino-3-(4-(2-amino-6-((R)-2,2, the fluoro-1-of 2-tri-(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-(the fluoro-1-of 2,2,2-tri-(4-(thiophene-2-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid;
(S)-2-amino-3-(4-(2-amino-6-((R)-2,2, the fluoro-1-of 2-tri-(4-(pyrimidine-5-yl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid;
(2S) (((((3,5-dimethyl is different for 2-for 1-for 6-for 4-for-2-amino-3- azoles-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, the fluoro-1-of 2-tri-(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-(the fluoro-1-of 2,2,2-tri-(4-(piperidin-1-yl methyl) phenyl) oxyethyl group) pyrimidine-4-yl) phenyl) propionic acid;
(2S)-2-amino-3-(4-(2-amino-6-(the fluoro-1-of 2,2,2-tri-(the fluoro-4-of 2-(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-(the fluoro-1-of 2,2,2-tri-(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-(the chloro-2-of 5-(3-methyl isophthalic acid H-pyrazol-1-yl) phenyl)-2,2,2-trifluoro ethoxy) pyrimidine-4-yl) phenyl) propionic acid.
9. the compound of claim 8, it is (S)-2-amino-3-(4-(2-amino-6-((R)-1-(the chloro-2-of 4-(3-methyl isophthalic acid H-pyrazol-1-yl) phenyl)-2,2,2-trifluoro ethoxy) pyrimidine-4-yl) phenyl) propionic acid.
10. the compound of claim 8, its be (S)-2-amino-3-[4-(the chloro-2-of 2-amino-6-{R-1-[4-(3-methyl-pyrazol-1-yl)-phenyl]-2,2, the fluoro-oxyethyl group of 2-tri-}-pyrimidine-4-yl)-phenyl]-ethyl propionate.
11. compounds, its be (S)-2-amino-3-[4-(the chloro-2-of 2-amino-6-{1-[4-(3-methyl-pyrazol-1-yl)-phenyl]-2,2, the fluoro-oxyethyl group of 2-tri-}-pyrimidine-4-yl)-phenyl]-propionic acid or its pharmaceutical salts.
12. compounds, its be (S)-2-amino-3-[4-(the chloro-2-of 2-amino-6-{R-1-[4-(3-methyl-pyrazol-1-yl)-phenyl]-2,2, the fluoro-oxyethyl group of 2-tri-}-pyrimidine-4-yl)-phenyl]-ethyl propionate or its pharmaceutical salts.
13. compositions, the compound that comprises any one in claim 1-12 and pharmaceutically acceptable vehicle or thinner.
14. single unit dosage, the composition that comprises claim 13.
The method of 15. vitro inhibition TPH1 activity, it comprises makes TPH1 contact with the compound of any one in claim 1-12.
The single unit dosage of the compound of any one or the composition of claim 13 or claim 14 in 16. claim 1-12, it is as medicine.
In 17. claim 1-12, the single unit dosage of the compound of any one or the composition of claim 13 or claim 14 is being used for the treatment of, is preventing or managing the application being selected from following disease or disorderly medicine: carcinoid crisis, carcinoid syndrome, Crohn disease, cardiovascular or pulmonary disorder or disorder, irritable bowel syndrome, scleroderma, serotonin syndrome, and ulcerative colitis.
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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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US9512122B2 (en) 2013-09-06 2016-12-06 Karos Pharmaceuticals, Inc. Spirocyclic compounds as tryptophan hydroxylase inhibitors
US9750740B2 (en) 2013-09-06 2017-09-05 Kanos Pharmaceuticals, Inc. Spirocyclic compounds as tryptophan hydroxylase inhibitors
US10045988B2 (en) 2013-09-06 2018-08-14 Roivant Sciences Gmbh Spirocyclic compounds as tryptophan hydroxylase inhibitors
US10350208B2 (en) 2013-09-06 2019-07-16 Roivant Sciences Gmbh Spirocyclic compounds as tryptophan hydroxylase inhibitors
US10660893B2 (en) 2013-09-06 2020-05-26 ROIVANT SCIENCES, GmbH Spirocyclic compounds as tryptophan hydroxylase inhibitors
US10946018B2 (en) 2013-09-06 2021-03-16 Roivant Sciences Gmbh Spirocyclic compounds as tryptophan hydroxylase inhibitors
US11759462B2 (en) 2013-09-06 2023-09-19 Altavant Sciences Gmbh Spirocyclic compounds as tryptophan hydroxylase inhibitors
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
US10710948B2 (en) 2015-03-05 2020-07-14 Roivant Sciences Gmbh 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
CN112921406A (en) * 2019-12-05 2021-06-08 成都先导药物开发股份有限公司 Method for synthesizing On-DNA 2-aminopyrimidine compound
CN112921406B (en) * 2019-12-05 2024-03-12 成都先导药物开发股份有限公司 Method for synthesizing On-DNA 2-aminopyrimidine compound

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