CN1437581A - Glucagon antagonists/inverse agonists - Google Patents

Glucagon antagonists/inverse agonists Download PDF

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Publication number
CN1437581A
CN1437581A CN01811591A CN01811591A CN1437581A CN 1437581 A CN1437581 A CN 1437581A CN 01811591 A CN01811591 A CN 01811591A CN 01811591 A CN01811591 A CN 01811591A CN 1437581 A CN1437581 A CN 1437581A
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China
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compound
alkyl
hydrogen
group
methyl
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CN01811591A
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Inventor
A·S·卓根森
I·T·克里斯滕森
J·T·克德拉
P·玛德森
C·拜赫伦斯
C·萨姆斯
J·劳
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Novo Nordisk AS
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Novo Nordisk AS
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Publication of CN1437581A publication Critical patent/CN1437581A/en
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
    • C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C275/24—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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    • C07C275/30—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
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    • C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
    • C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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    • C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
    • C07C317/38—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atom of at least one amino group being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfones
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    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
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Abstract

A novel class of compounds, which act to antagonize the action of the glucagon hormone on the glucagon receptor. Owing to their antagonizing effect of the glucagon receptor the compounds may be suitable for the treatment and/or prevention of any diseases and disorders, wherein a glucagon antagonistic action is beneficial, such as hyperglycemia, Type 1 diabetes, Type 2 diabetes, disorders of the lipid metabolism and obesity.

Description

Glucagon antagonist/inverse agonist
Invention field
The present invention relates to the promoting agent of antagonism hyperglycemic-glycogenolytic factor peptide hormone to the effect of glucagon receptor.More particularly, the present invention relates to glucagon antagonist or inverse agonist.
Background of invention
Hyperglycemic-glycogenolytic factor is the important hormone class material that works with the Regular Insulin cooperation, the homeostasis adjusting of glucose amount in its mediation blood.When glucose level descended, hyperglycemic-glycogenolytic factor mainly worked by stimulating some cells (mainly being liver cell) to discharge glucose.The effect of hyperglycemic-glycogenolytic factor is opposite with the effect of Regular Insulin, irritation cell picked-up and storage glucose when Regular Insulin increases in glucose level.Hyperglycemic-glycogenolytic factor and Regular Insulin all are peptide hormones.
Hyperglycemic-glycogenolytic factor is to produce in the α of pancreas islet cells, and Regular Insulin produces in the β islet cells.Diabetes are common glucose metabolism obstacles.The feature of this disease is a hyperglycemia, and can be divided into the type 1 diabetes of insulin-dependent and the diabetes B of non-insulin-depending type.The type 1 diabetes patient shows hyperglycemia and low insulinemia, and the conventional treatment of this type disease is provided Regular Insulin.Yet in some 1 type or diabetes B, absolute or high relatively hyperglycemic-glycogenolytic factor level causes hyperglycemia.In the control animal and 1 type or diabetes B animal model of health, with selectivity and specific antibody remove the round-robin hyperglycemic-glycogenolytic factor can cause glucose level descend (people such as Brand, Diabetologia 37,985 (1994); Diabetes 43, [suppl 1], 172A (1994); Am.J.Physio.269, E469-E477 (1995); Diabetes 44[suppl 1], 134A (1995); Diabetes45,1076 (1996)).These studies show that the effect of glucagon suppression or antagonism hyperglycemic-glycogenolytic factor can be used as the assisting therapy of the conventional hyperglycemia treatment of diabetes.Can be by antagonist or inverse agonist be provided, i.e. the effect that the material of the reaction that inhibition or prevention hyperglycemic-glycogenolytic factor cause comes glucagon suppression.Antagonist can be peptide class or non-peptide matters.
Natural hyperglycemic-glycogenolytic factor is to have 29 amino acid whose peptides, and its sequence is as follows: His-Ser-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-NH 2.
Hyperglycemic-glycogenolytic factor by in conjunction with and activate its acceptor and implement its effect, its acceptor is the 7-hyperglycemic-glycogenolytic factor-secretin branch of striding film g protein coupled receptor family people such as (, Science 259,1614, (1993)) Jelinek.Acceptor comes functionating by activating the adenylyl cyclase second messenger system, and the result improves the cAMP level.
Several pieces of publications disclose the peptide that plays the glucagon antagonist effect.General feature is determined to such an extent that the antagonist of fullest is DesHis 1[Glu 9]-hyperglycemic-glycogenolytic factor acid amides (people such as Unson, Peptides 10,1171 (1989); People such as Post, Proc.Natl.Acad.Sci.USA90,1662 (1993)).Other antagonists are DesHis 1, Phe 6[Glu 9]-hyperglycemic-glycogenolytic factor acid amides (people such as Azizh, Bioorganic ﹠amp; Medicinal Chem.Lett.16,1849 (1995)) and NLeu 9, Ala 11,16-hyperglycemic-glycogenolytic factor acid amides (people such as Unson, J.Biol.Chem.269 (17), 12548 (1994)).
The peptide antagonists of peptide hormone often is very effective.Yet, known because they are not orally active usually by the physiology enzyme liberating, and it is not good to distribute in the body.Therefore, the orally active non-peptide antagonist of peptide hormone generally is preferred.In the middle of non-peptide glucagon-like antagonist, the discovery quinoxaline derivatives (2-styryl-3-[3-(dimethylamino) propyl group methylamino]-6, the 7-dichloro-quinoxaline is replaced (Collins with hyperglycemic-glycogenolytic factor from the rat liver acceptor, J.L. wait the people, Bioorganic and Medicinal Chemistry Letters2 (9): 915-918 (1992)).WO 94/14426 discloses skyrin as glucagon antagonist-comprise 9 of a pair of connection, a kind of natural product and the synthetic analogues thereof of 10-amerantrone base.US patent 4,359,474 discloses the hyperglycemic-glycogenolytic factor antagonistic properties of 1-phenylpyrazole derivatives.US patent 4,374,130 discloses the silicoethane hexanaphthene (disilacyclohexanes) as the replacement of glucagon antagonist.WO98/04528 (BayerCorporation) discloses pyridine and the biphenyl as the replacement of glucagon antagonist.US patent 5,776,954 (Merck ﹠amp; Co., Inc.) Pyridylpyrrole as the replacement of glucagon antagonist is disclosed, WO98/21957, WO98/22108, WO98/22109 and US 5,880,139 (Merck ﹠amp; Co., Inc.) disclose as 2 of glucagon antagonist, 4-diaryl-5-Pyridinylimidazoles.In addition, WO97/16442 and US patent 5,837,719 (Merck ﹠amp; Co., the aryl-pyrrolidine that 5-replaces Inc.) is disclosed as 2 of glucagon antagonist.WO98/24780, WO98/24782, WO99/24404 and WO99/32448 (Amgen Inc.) disclose the pyrimidone of the replacement with hyperglycemic-glycogenolytic factor antagonistic activity and the pyrimidine compound of pyridinone compounds and replacement.People such as Madsen (J.Med.Chem.1998 (41) 5151-7) disclose a series of 2-(benzimidazolyl-2 radicals-Ji sulfenyl)-1-(3, the 4-dihydroxy phenyl)-1-ethyl ketones as competitive human glucagon receptor antagonist.
WO99/01423 and WO00/39088 (Novo Nordisk A/S) disclose the alkylidene group hydrazides as the different series of glucagon antagonist/inverse agonist.
These known glucagon antagonists are structurally different with The compounds of this invention.Definition
Be the specific definition that is used to describe the term of The compounds of this invention below:
" halogen " is meant and is selected from F, Cl, Br and I.
Term " C used herein 1-6-alkyl " be meant saturated straight chain or branched hydrocarbyl with 1-6 carbon atom.Representative example includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, tert-pentyl, n-hexyl, isohexyl etc.
Term " C used herein 2-6-alkenyl " be meant straight or branched alkyl with the two keys of 2-6 carbon atom and at least one.Such examples of groups includes but not limited to vinyl, 1-propenyl, 2-propenyl, pseudoallyl, 1,3-butadienyl, 1-butylene base, crotyl, 3-butenyl, 2-methyl isophthalic acid-propenyl, 1-pentenyl, pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butene base, 1-hexenyl, 2-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl etc.
Term " C used herein 2-6-alkynyl " be meant to have 2-6 carbon atom and at least one triple-linked straight or branched alkyl.Such examples of groups includes but not limited to ethynyl, 1-proyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 3-butynyl, 1-pentynyl, valerylene base, 3-pentynyl, 4-pentynyl, 1-hexin base, 2-hexin base, 3-hexin base, 4-hexin base, 5-hexin base, 2,4-hexadiyne base etc.
Term " C used herein 1-6-alkoxyl group " be meant group-O-C 1-6-alkyl, wherein C 1-6-alkyl as defined above.Representative example is methoxyl group, oxyethyl group, positive propoxy, isopropoxy, butoxy, sec-butoxy, tert.-butoxy, pentyloxy, isopentyloxy, hexyloxy, different hexyloxy etc.
Term " C used herein 1-6-alkanoyl " be meant group-C (O) H or-C (O)-C 1-5-alkyl.Representative example is formyl radical, ethanoyl, propionyl, butyryl radicals, pentanoyl, caproyl etc.
Term " C used herein 3-8-cycloalkyl " be meant saturated carbon ring group with 3-8 carbon atom.Representative example is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group etc.
Term " C used herein 4-8-cycloalkenyl group " be meant the non-aromatics carbon ring group that has 4-8 carbon atom, contains 1 or 2 two key.Representative example is 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2-cyclooctene base, 1,4-cyclooctadiene base etc.
Term used herein " heterocyclic radical " representative contains one or more heteroatomss that are selected from nitrogen, oxygen and sulphur, and the optional first ring of non-aromatics 3-10 that contains one or two pair key.Representative example is pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, ethylenimine base, tetrahydrofuran base etc.
Term used herein " aryl " comprises aromatic carbocyclic system, for example phenyl, xenyl, naphthyl, anthryl, phenanthryl, fluorenyl, indenyl, pentalenyl (pentalenyl), Azulene base etc.Aryl also comprises the partial hydrogenation derivative that above-mentioned carbocyclic ring is.The limiting examples of such partial hydrogenation derivative has 1,2,3,4-tetralyl, 1,4-dihydro naphthyl etc.
Term used herein " arylidene " comprises divalent aromatic carbocyclic ring system, for example phenylene, biphenylene, naphthylidene, anthrylene, phenanthrylene, fluorenylidene, sub indenyl, inferior pentalenyl, inferior Azulene base etc.Arylidene also comprises the partial hydrogenation derivative that above-mentioned carbocyclic ring is.The limiting examples of such partial hydrogenation derivative has 1,2,3,4-tetrahydrochysene naphthylidene, 1,4-dihydro naphthylidene etc.
Term used herein " aryloxy " is meant group-O-aryl, and wherein aryl as defined above.
Term used herein " aroyl " is meant group-C (O)-aryl, and wherein aryl as defined above.
Term used herein " heteroaryl " comprises and contains one or more nitrogen that are selected from, the heteroatomic hetero-aromatic ring of oxygen and sulphur is, furyl for example, thienyl, pyrryl oxazolyl, thiazolyl, imidazolyl isoxazolyl, isothiazolyl, 1,2, the 3-triazolyl, 1,2, the 4-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, 1,2, the 3-triazinyl, 1,2, the 4-triazinyl, 1,3, the 5-triazinyl, 1,2,3-oxadiazole base, 1,2,4-oxadiazole base, 1,2,5-oxadiazole base, 1,3,4-oxadiazole base, 1,2, the 3-thiadiazolyl group, 1,2, the 4-thiadiazolyl group, 1,2, the 5-thiadiazolyl group, 1,3, the 4-thiadiazolyl group, tetrazyl, the thiadiazine base, indyl, pseudoindoyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl-, benzothiazolyl, benzisothiazole base benzoxazolyl, the benzoisoxazole base, purine radicals, quinazolyl, quinolizinyl, quinolyl, isoquinolyl, quinoxalinyl, naphthyridinyl (naphthyridinyl), pteridyl, carbazyl, azepine _ base, diaza _ base, acridyl etc.Heteroaryl also comprises the partial hydrogenation derivative that above-mentioned heterocycle is.The limiting examples of such partial hydrogenation derivative has 2,3-dihydro benzo furyl, pyrrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxa-azepine _ base (oxazepinyl) etc.
" aryl-C 1-6-alkyl ", " heteroaryl-C 1-6-alkyl ", " aryl-C 2-6Alkenyl " etc. be meant the C that is replaced by aryl or heteroaryl as defined above 1-6-alkyl or C 2-6-alkenyl, for example:
Term used herein " optional replacement " is meant that group does not replace or is replaced by one or more specified substituent.When described group was replaced by an above substituting group, substituting group can be identical or different.
More than the term of some above-mentioned definition may occur once in structural formula, when occurring, each term should be independent of each other.
In addition, when using term " independently for " and " being independently selected from ", should be appreciated that described group can be identical or different.Invention is described
The present invention is based on following beyond thought discovery: the effect of following public general formula (I) compound antagonism hyperglycemic-glycogenolytic factor.
The favourable part of these compounds is, and is selective to glucagon receptor, and structurally relevant GIP (gastrin inhibitory polypeptide) acceptor of the binding affinity comparison that glucagon receptor is shown and the binding affinity height of GLP-1 acceptor.
Therefore, the present invention relates to general formula (I) compound:R wherein1、R 2、R 3、R 4And R5Be hydrogen or C independently1-6-alkyl, A be-C (O)-,-CH (OR6)-or-CHF-, wherein R6Hydrogen or C1-6-alkyl, Z are arlydene or derived from containing 1 or 2 divalent group that is selected from 5 or 6 yuan of hetero-aromatic rings of nitrogen, oxygen and sulphur, its can choose wantonly by 1 or 2 be selected from halogen ,-CN ,-CF3、-OCF 3、-NO 2、 -OR 9、-NR 9R 10And C1-6The R of-alkyl7And R8Replace, wherein R9And R10Be hydrogen or C independently1-6-alkyl, X are-(CH2) q-(CR 12R 13) r-(CH 2) s-，
Figure A0181159100242
Figure A0181159100243
Or
Figure A0181159100245
Wherein r be 0 or 1, q and s be 0,1,2 or 3, R independently11、R 12、R 13And R14Be hydrogen, C independently1-6-alkyl or C3-8Cycloalkyl, D isR wherein15、R 16、R 17And R18Be independently hydrogen, halogen ,-CN ,-CHF2，-CF 3，-OCF 3，-OCHF 2，-OCH 2CF 3，-OCF 2CHF 2， -S(O) 2CF 3，-SCF 3，-NO 2，-OR 21，-NR 21R 22，-SR 21，-NR 21S(O) 2R 22，-S(O) 2NR 21R 22， -S(O)NR 21R 22，-S(O)R 21，-S(O) 2R 21，-C(O)NR 21R 22，-OC(O)NR 21R 22，-NR 21C(O)R 22， -CH 2C(O)NR 21R 22，-OCH 2C(O)NR 21R 22，-OC(O)R 21，-C(O)R 21Or-C (O) OR21， ·C 1-6-alkyl, C2-6-alkenyl or C2-6Alkynyl, described group can choose wantonly by one or more be selected from halogen ,-CN ,-CF3、-OCF 3、-NO 2、-OR 21、-NR 21R 22And C1-6The substituting group of-alkyl replaces, C3-8Cycloalkyl, C4-8Cycloalkenyl group, heterocyclic radical, C3-8Cycloalkyl-C1-6-alkyl, C3-8-cycloalkyl-C1-6-alkoxyl, C3-8Cycloalkyloxy, C3-8Cycloalkyl-C1-6Alkylthio group, C3-8-cycloalkylthio, C3-8Cycloalkyl-C2-6Alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl group-C1-6Alkyl, C4-8-cycloalkenyl group-C2-6-alkenyl, C4-8-cycloalkenyl group-C2-6-alkynyl, heterocyclic radical-C1-6Alkyl, heterocyclic radical-C2-6-alkenyl, heterocyclic radical-C2-6-alkynyl, aryl, aryloxy group, aryloxycarbonyl, aroyl, aryl-C1-6-alkoxyl, aryl-C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-C1-6-alkyl, heteroaryl-C2-6-alkenyl or heteroaryl-C2-6-alkynyl, wherein said loop section can choose wantonly by one or more be selected from halogen ,-C (O) OR21、-CN、-CF 3、 -OCF 3、-NO 2、-OR 21、-NR 21R 22And C1-6The substituting group of-alkyl replaces, wherein R21And R22Be hydrogen, C independently1-6-alkyl, aryl-C1-6-alkyl or aryl, in the time of perhaps on being connected to same nitrogen-atoms, R21And R22With described nitrogen-atoms can together with form optional 1 or 2 other hetero atom that is selected from nitrogen, oxygen and sulphur, and the optional 3-8 unit heterocycle that contains 1 or 2 two key of containing, perhaps when being in adjacent position, R16-R 18In two groups can form together abutment group-(CR23R 24) a-O-(CR 25R 26) c-O-, wherein a be 0,1 or 2, c be 1 or 2, R23、R 24、R 25And R26Be hydrogen, C independently1-6-alkyl or fluorine, R19And R20Be hydrogen, C independently1-6-alkyl, C3-8-cycloalkyl or C3-8-cycloalkyl-C1-6-alkyl, E is OrR wherein27And R28Be independently hydrogen, halogen ,-CN ,-CF3、-OR 32、-NR 32R 33、C 1-6-alkyl, C3-8-cycloalkyl, C4-8-cycloalkenyl group or aryl, wherein said aryl can choose wantonly by one or more be selected from halogen ,-CN ,-CF3、-NO 2、-OR 32、 -NR 32R and C1-6The substituting group of-alkyl replaces, wherein R32And R33Be hydrogen or C independently1-6-alkyl, in the time of perhaps on being connected to same nitrogen-atoms, R32And R33With described nitrogen-atoms can together with form optional 1 or 2 other hetero atom that is selected from nitrogen, oxygen and sulphur, and the optional 3-8 unit heterocycle that contains 1 or 2 two key, the R of containing29、R 30And R31Be independently ■ hydrogen, halogen ,-CHF2，-CF 3，-OCF 3，-OCHF 2，-OCH 2CF 3，-OCF 2CHF 2，-SCF 3， -OR 34，-NR 34R 35，-SR 34，-S(O)R 34，-S(O) 2R 34，-C(O)NR 34R 35，-OC(O)NR 34R 35， -NR 34C(O)R 35，-OCH 2C(O)NR 34R 35，-C(O)R 34Or-C (O) OR34， ■C 1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl, described group can choose wantonly by one or more be selected from halogen ,-CN ,-CF3、-OCF 3、-NO 2、-OR 34、 -NR 34R 35And C1-6The substituting group of-alkyl replaces, ■ C3-8-cycloalkyl, C4-8Cycloalkenyl group, heterocyclic radical, C3-8-cycloalkyl-C1-6-alkyl, C3-8Cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl group-C1-6Alkyl, C4-8-cycloalkenyl group-C2-6-alkenyl, C4-8-cycloalkenyl group-C2-6-alkynyl, heterocyclic radical-C1-6-alkyl, heterocyclic radical-C2-6-alkenyl, heterocyclic radical-C2-6-alkynyl, aryl, aryloxy group, aroyl, aryl-C1-6-alkoxyl, aryl-C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-C1-6-alkyl, heteroaryl-C2-6-alkenyl or heteroaryl-C2-6-alkynyl, wherein said loop section can choose wantonly by one or more be selected from halogen ,-CN ,-CF3、-OCF 3、-NO 2、 -OR 34、-NR 34R 35And C1-6The substituting group of-alkyl replaces, wherein R34And R35Be hydrogen, C independently1-6-alkyl or aryl, in the time of perhaps on being connected to same nitrogen-atoms, R34And R35With described nitrogen-atoms can together with form optional 1 or 2 other hetero atom that is selected from nitrogen, oxygen and sulphur, and the optional 3-8 unit heterocycle that contains 1 or 2 two key of containing, in the time of perhaps on being connected to same ring carbon atom or different ring carbon atom, R29、R 30And R31Two central groups can form group-O-(CH together2) t-CR 36R 37-(CH 2) l-O-、 -(CH 2) t-CR 36R 37(CH 2) l-or-S-(CH2) t-CR 36R 37-(CH 2) l-S-, wherein t and l are 0,1,2,3,4 or 5, R independently36And R37Be hydrogen or C independently1-6-alkyl, and optically-active or geometric isomer or the tautomeric form of general formula (I) compound, comprise the mixture of these isomers or tautomeric form or their officinal salt.
On the other hand, the present invention relates to general formula (I ') compoundR wherein1、R 2、R 3、R 4And R5Be hydrogen or C independently1-6-alkyl, A be-C (O)-,-CH (OR6)-or-CHF-, wherein R6Hydrogen or C1-6-alkyl, Z are arlydene or derived from containing 1 or 2 divalent group that is selected from heteroatomic 5 or 6 yuan of hetero-aromatic rings of nitrogen, oxygen and sulphur, its can choose wantonly by 1 or 2 be selected from halogen ,-CN ,-CF3、-OCF 3、 -NO 2、-OR 9、-NR 9R 10And C1-6The R of-alkyl7And R8Replace, wherein R9And R10Be hydrogen or C independently1-6-alkyl, X are-(CH2) q-(CR 12R 13) r-(CH 2) s-  ，
Figure A0181159100282
OrWherein r be 0 or 1, q and s be 0,1,2 or 3, R independently11、R 12、R 13And R14Be hydrogen, C independently1-6-alkyl or C3-8Cycloalkyl, D is
Figure A0181159100291
Or
Figure A0181159100293
R wherein15、R 16、R 17And R18Be independently hydrogen, halogen ,-CN ,-CH2CN，-CHF 2，-CF 3，-OCF 3，-OCHF 2，-OCH 2CF 3， -OCF 2CHF 2，-S(O) 2CF 3，-SCF 3，-NO 2，-OR 21，-NR 21R 22，-SR 21，-NR 21S(O) 2R 22， -S(O) 2NR 21R 22，-S(O)NR 21R 22，-S(O)R 21，-S(O) 2R 21，-C(O)NR 21R 22，-OC(O)NR 21R 22-NR 21C(O)R 22，-CH 2C(O)NR 21R 22，-OCH 2C(O)NR 21R 22，-CH 2OR 21，-CH 2NR 21R 22， -OC(O)R 21，-C(O)R 21Or-C (O) OR21， ·C 1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl, described group can choose wantonly by one or more be selected from halogen ,-CN ,-CF3、-OCF 3、-NO 2、-OR 21、-NR 21R 22And C1-6The substituting group of-alkyl replaces, C3-8Cycloalkyl, C4-8-cycloalkenyl group, heterocyclic radical, C3-8Cycloalkyl-C1-6-alkyl, C3-8-cycloalkyl-C1-6-alkoxyl, C3-8Cycloalkyloxy, C3-8-cycloalkyl-C1-6-alkylthio group, C3-8-cycloalkylthio, C3-8-cycloalkyl-C2-6-alkenyl, C3-8Cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl group-C1-6-alkyl, C4-8-cycloalkenyl group-C2-6-alkenyl, C4-8-cycloalkenyl group-C2-6-alkynyl, heterocyclic radical-C1-6-alkyl, heterocyclic radical-C2-6-alkenyl, heterocyclic radical-C2-6-alkynyl, aryl, aryloxy group, aryloxycarbonyl, aroyl, aryl-C1-6-alkoxyl, aryl-C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-C1-6-alkyl, heteroaryl-C2-6-alkenyl or heteroaryl-C2-6-alkynyl, wherein said loop section can choose wantonly by one or more be selected from halogen ,-C (O) OR21、-CN、-CF 3、 -OCF 3、-NO 2、-OR 21、-NR 21R 22And C1-6The substituting group of-alkyl replaces, wherein R21And R22Be hydrogen, C independently1-6-alkyl, aryl-C1-6-alkyl or aryl, in the time of perhaps on being connected to same nitrogen-atoms, R21And R22With described nitrogen-atoms can together with form optional 1 or 2 other hetero atom that is selected from nitrogen, oxygen and sulphur, and the optional 3-8 unit heterocycle that contains 1 or 2 two key of containing, perhaps when being in adjacent position, R15-R 18In two groups can form together abutment group-(CR23R 24) a-O-(CR 25R 26) c-O-, wherein a be 0,1 or 2, c be 1 or 2, R23、R 24、R 25And R26Be hydrogen, C independently1-6-alkyl or fluorine, R19And R20Be hydrogen, C independently1-6-alkyl, C3-8-cycloalkyl or C3-8-cycloalkyl-C1-6-alkyl, E is
Figure A0181159100301
Figure A0181159100302
OrR wherein27And R28Be independently hydrogen, halogen ,-CN ,-CF3、-OR 32、-NR 32R 33、C 1-6-alkyl, C3-8-cycloalkyl, C4-8-cycloalkenyl group or aryl, wherein said aryl can choose wantonly by one or more be selected from halogen ,-CN ,-CF3、-NO 2、-OR 32、 -NR 32R 33And C1-6The substituting group of-alkyl replaces, wherein R32And R33Be hydrogen or C independently1-6-alkyl, in the time of perhaps on being connected to same nitrogen-atoms, R32And R33With described nitrogen-atoms can together with form optional 1 or 2 other hetero atom that is selected from nitrogen, oxygen and sulphur, and the optional 3-8 unit heterocycle that contains 1 or 2 two key, the R of containing29、R 30And R31Be independently ■ hydrogen, halogen ,-CHF2，-CF 3，-OCF 3，-OCHF 2，-OCH 2CF 3，-OCF 2CHF 2，-SCF 3， -OR 34，-NR 34R 35，-SR 34，-S(O)R 34，-S(O) 2R 34，-C(O)NR 34R 35，-OC(O)NR 34R 35， -NR 34C(O)R 35，-OCH 2C(O)NR 34R 35，-C(O)R 34Or-C (O) OR34， ■C 1-6-alkyl, C2-6Alkenyl or C2-6-alkynyl, described group can choose wantonly by one or more be selected from halogen ,-CN ,-CF3、-OCF 3、-NO 2、-OR 34、 -NR 34R 35And C1-6The substituting group of-alkyl replaces, ■ C3-8-cycloalkyl, C4-8-cycloalkenyl group, heterocyclic radical, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl group-C1-6-alkyl, C4-8-cycloalkenyl group-C2-6-alkenyl, C4-8-cycloalkenyl group-C2-6-alkynyl, heterocyclic radical-C1-6-alkyl, heterocyclic radical-C2-6-alkenyl, heterocyclic radical-C2-6-alkynyl, aryl, aryloxy group, aroyl, aryl-C1-6-alkoxyl, aryl-C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-C1-6-alkyl, heteroaryl-C2-6-alkenyl or heteroaryl-C2-6-alkynyl, wherein said loop section can choose wantonly by one or more be selected from halogen ,-CN ,-CF3、-OCF 3、-NO 2、 -OR 34、-NR 34R 35And C1-6The substituting group of-alkyl replaces, wherein R34And R35Be hydrogen, C independently1-6-alkyl or aryl, in the time of perhaps on being connected to same nitrogen-atoms, R34And R35With described nitrogen-atoms can together with form optional 1 or 2 other hetero atom that is selected from nitrogen, oxygen and sulphur, and the optional 3-8 unit heterocycle that contains 1 or 2 two key of containing, in the time of perhaps on being connected to same ring carbon atom or different ring carbon atom, R29、R 30And R31Two central groups can form group-O-(CH together2) t-CR 36R 37-(CH 2) l-O-、 -(CH 2) t-CR 36R 37-(CH 2) l-or-S-(CH2) t-CR 36R 37-(CH 2) l-S-, wherein t and l are 0,1,2,3,4 or 5, R independently36And R37Be hydrogen or C independently1-6-alkyl, and optically-active or geometric isomer or the tautomeric form of general formula (I ') compound, comprise the mixture of these isomers or tautomeric form or their officinal salt.
On the other hand, the present invention relates to general formula (I ") compoundR wherein1、R 2、R 3、R 4And R5Be hydrogen or C independently1-6-alkyl, A be-C (O)-,-CH (OR6)-or-CHF-, wherein R6Hydrogen, C1-6-alkyl or halogen, Z are arlydene or derived from containing 1 or 2 divalent group that is selected from heteroatomic 5 or 6 yuan of hetero-aromatic rings of nitrogen, oxygen and sulphur, its can choose wantonly by 1 or 2 be selected from halogen ,-CN ,-CF3、-OCF 3、 -NO 2、-OR 9、-NR 9R 10And C1-6The R of-alkyl7And R8Replace, wherein R9And R10Be hydrogen or C independently1-6-alkyl, X are-(CH2) q-(CR 12R 13) r-(CH 2) s-，
Figure A0181159100323
OrWherein r be 0 or 1, q and s be 0,1,2 or 3, R independently11、R 12、R 13And R14Be hydrogen or C independently1-6-alkyl, D is
Figure A0181159100334
Or
Figure A0181159100336
R wherein15、R 16、R 17And R18Be independently hydrogen, halogen ,-CN ,-CH2CN，-CHF 2，-CF 3，-OCF 3，-OCHF 2，-OCH 2CF 3， -OCF 2CHF 2，-OS(O) 2CF 3，-SCF 3，-NO 2，-OR 21，-NR 21R 22，-SR 21，-NR 21S(O) 2R 22， -S(O) 2NR 21R 22，-S(O)NR 21R 22，-S(O)R 21，-S(O) 2R 21，-OS(O) 2R 21，-C(O)NR 21R 22， -OC(O)NR 21R 22，-NR 21C(O)R 22，-CH 2C(O)NR 21R 22，-OCH 2C(O)NR 21R 22，-CH 2OR 21， -CH 2NR 21R 22，-OC(O)R 21，-C(O)R 21Or-C (O) OR21， ·C 1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl, described group can choose wantonly by one or more be selected from halogen ,-CN ,-CF3、-OCF 3、-NO 2、-OR 21、 -NR 21R 22And C1-6The substituting group of-alkyl replaces, C3-8-cycloalkyl, C4-8-cycloalkenyl group, heterocyclic radical, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cycloalkyl-C1-6-alkoxyl, C3-8Cycloalkyloxy, C3-8Cycloalkyl-C1-6-alkylthio group, C3-8-cycloalkylthio, C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl group-C1-6-alkyl, C4-8-cycloalkenyl group-C2-6Alkenyl, C4-8-cycloalkenyl group-C2-6-alkynyl, heterocyclic radical-C1-6-alkyl, heterocyclic radical-C2-6-alkenyl, heterocyclic radical-C2-6-alkynyl, aryl, aryloxy group, aryloxycarbonyl, aroyl, aryl-C1-6-alkoxyl, aryl-C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-C1-6-alkyl, heteroaryl-C2-6-alkenyl or heteroaryl-C2-6-alkynyl, wherein said loop section can choose wantonly by one or more be selected from halogen ,-CN ,-CF3、-OCF 3、-NO 2、 -OR 21、-NR 21R 22And C1-6The substituting group of-alkyl replaces, wherein R21And R22Be hydrogen, C independently1-6-alkyl or aryl, in the time of perhaps on being connected to same nitrogen-atoms, R21And R22With described nitrogen-atoms can together with form optional 1 or 2 other hetero atom that is selected from nitrogen, oxygen and sulphur, and the optional 3-8 unit heterocycle that contains 1 or 2 two key of containing, perhaps when being in adjacent position, R15-R 18In two groups can form together abutment group-(CR23R 24) a-O-(CR 25R 26) c-O-, wherein a be 0,1 or 2, c be 1 or 2, R23、R 24、R 25And R26Be hydrogen, C independently1-6-alkyl or fluorine, R19And R20Be hydrogen, C independently1-6-alkyl, C3-8-cycloalkyl or C3-8-cycloalkyl-C1-6-alkyl, E is
Figure A0181159100341
Figure A0181159100351
Or
Figure A0181159100352
R wherein27And R28Be independently hydrogen, halogen ,-CN ,-CF3、-OR 32、-NR 32R 33、C 1-6-alkyl, C3-8-cycloalkyl, C4-8-cycloalkenyl group or aryl, wherein said aryl can choose wantonly by one or more be selected from halogen ,-CN ,-CF3、-NO 2、-OR 32、 -NR 32R 33And C1-6The substituting group of-alkyl replaces, wherein R32And R33Be hydrogen or C independently1-6-alkyl, in the time of perhaps on being connected to same nitrogen-atoms, R32And R33With described nitrogen-atoms can together with form optional 1 or 2 other hetero atom that is selected from nitrogen, oxygen and sulphur, and the optional 3-8 unit heterocycle that contains 1 or 2 two key, the R of containing29、R 30And R31Be independently ■ hydrogen ,-CHF2，-CF 3，-OCF 3，-OCHF 2，-OCH 2CF 3，-OCF 2CHF 2，-SCF 3，-OR 34， -NR 34R 35，-SR 34，-S(O)R 34，-S(O) 2R 34，-C(O)NR 34R 35，-OC(O)NR 34R 35，-NR 34C(O)R 35， -OCH 2C(O)NR 34R 35，-C(O)R 34Or-C (O) OR34， ■C 1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl, described group can choose wantonly by one or more be selected from halogen ,-CN ,-CF3、-OCF 3、-NO 2、-OR 34、 -NR 34R 35And C1-6The substituting group of-alkyl replaces, ■ C3-8-cycloalkyl, C4-8-cycloalkenyl group, heterocyclic radical, C3-8Cycloalkyl-C1-6-alkyl, C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl group-C1-6-alkyl, C4-8-cycloalkenyl group-C2-6-alkenyl, C4-8-cycloalkenyl group-C2-6-alkynyl, heterocyclic radical-C1-6-alkyl, heterocyclic radical-C2-6-alkenyl, heterocyclic radical-C2-6-alkynyl, aryl, aryloxy group, aroyl, aryl-C1-6-alkoxyl, aryl-C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-C1-6-alkyl, heteroaryl-C2-6-alkenyl or heteroaryl-C2-6-alkynyl, wherein said loop section can choose wantonly by one or more be selected from halogen ,-CN ,-CF3、-OCF 3、-NO 2、 -OR 34、-NR 34R 35And C1-6The substituting group of-alkyl replaces, wherein R34And R35Be hydrogen, C independently1-6-alkyl or aryl, in the time of perhaps on being connected to same nitrogen-atoms, R34And R35With described nitrogen-atoms can together with form optional 1 or 2 other hetero atom that is selected from nitrogen, oxygen and sulphur, and the optional 3-8 unit heterocycle that contains 1 or 2 two key of containing, in the time of perhaps on being connected to same ring carbon atom or different ring carbon atom, R29、R 30And R31Two central groups can form group-O-(CH together2) t-CR 36R 37-(CH 2) l-O-、 -(CH 2) t-CR 36R 37(CH 2) l-or-S-(CH2) t-CR 36R 37-(CH 2) l-S-, wherein t and l are 0,1,2,3,4 or 5, R independently36And R37Be hydrogen or C independently1-6-alkyl, and general formula (optically-active or geometric isomer or the tautomeric form of I ") compound comprise the mixture of these isomers or tautomeric form or their officinal salt.
In one embodiment, R 1, R 2, R 3, R 4And R 5Be hydrogen.
In one embodiment, A is-CHF-.
In another embodiment, A is-CH (OR 6)-, be R wherein 6Definition cotype (I) described in, for example be-CH (OH)-.
In one embodiment, Z is R wherein 7And R 8Definition cotype (I) described in, for example be
Figure A0181159100362
In one embodiment, X is
Figure A0181159100363
-(CH 2) s-,
Figure A0181159100371
Or Wherein q is 0 or 1, and r is 0 or 1, and s is 0,1 or 2, and R 12And R 13Be hydrogen or C independently 1-6-alkyl.
In another embodiment, X be-C (O) NH-,-C (O) NHCH 2-,-C (O) NHCH (CH 3)-,-C (O) NHC (CH 3) 2-,-C (O) NHCH 2CH 2-,-C (O) CH 2-,-C (O) CH 2CH 2-,-C (O) CH=CH-,-(CH 2) s-,-C (O)-,-C (O) O-or-NHC (O)-, wherein s is 0 or 1.
In another embodiment, X be-C (O) NH-,-C (O) NHCH 2-,-C (O) NHCH (CH 3)-,-C (O) NHCH 2CH 2-,-C (O) CH 2-,-C (O) CH=CH-,-(CH 2) s-,-C (O)-,-C (O) O-or-NHC (O)-, wherein s is 0 or 1
In another embodiment, X be-C (O) NH-,-C (O) NHCH 2-,-C (O) NHCH (CH 3)-,-C (O) NHCH 2CH 2-,-C (O) CH 2-,-CH 2-,-C (O)-or-NHC (O)-.
In another embodiment, X be-C (O) NH-,-C (O) NHCH 2-,-C (O) NHCH (CH 3)-,-C (O) CH 2-or-C (O)-, for example-C (O) NH-.
In one embodiment, D is
Figure A0181159100373
Or
Figure A0181159100375
R wherein 15, R 16, R 17, R 18, R 19And R 20Definition cotype (I) described in.
In another embodiment, D is
Figure A0181159100381
R wherein 15, R 16And R 17Definition cotype (I) described in.
In one embodiment, R 15, R 16And R 17Be independently hydrogen, halogen ,-CN ,-NO 2,-CF 3,-OCF 3-,-SCF 3, C 1-6-alkyl, C 1-6-alkoxyl group ,-S-C 1-6-alkyl ,-C (O) OR 21,-C (O) R 21,-CH 2OR 21,-C (O) NR 21R 22,-S (O) R 21,-S (O) 2R 21,-S (O) 2CF 3,-S (O) 2NR 21R 22, C 3-8-cycloalkyl, C 3-8-cycloalkyl-C 1-6-alkoxyl group or C 3-8-cycloalkyl-C 1-6-alkylthio, or aryl, heteroaryl or aryloxy, it can be chosen wantonly by-CF 3,-OCF 3, C 1-6-alkyl, halogen or-C (O) OR 21Replace, perhaps when being in the consecutive position, R 15, R 16And R 17Two central groups can form abutment group-(CR together 23R 24) a-O-(CR 25R 26) c-O-, wherein R 21And R 22Be hydrogen or C independently 1-6-alkyl, and a, c, R 23, R 24, R 25And R 26Definition cotype (I) described in.
In another embodiment, R 15, R 16And R 17Be independently hydrogen, halogen ,-CN ,-CF 3,-OCF 3Or C 1-6-alkoxyl group, perhaps R 15And R 16Form abutment group-CF together 2-O-CF 2-O-, and R 17Be hydrogen.
In another embodiment, R 15, R 16And R 17Be independently hydrogen, halogen ,-CN ,-CF 3,-OCF 3Or C 1-6-alkoxyl group.
In another embodiment, D is
Figure A0181159100382
Or
Figure A0181159100383
R wherein 15, R 16, R 19And R 20Definition cotype (I) described in.
In another embodiment, D is
Figure A0181159100384
R wherein 15And R 16All be hydrogen, and R 19Be C 1-6Alkyl, C 3-8-cycloalkyl or C 3-8-cycloalkyl-C 1-6-alkyl.
In another embodiment, D is
Figure A0181159100391
R wherein 15And R 16All be hydrogen, and R 19And R 20All be C 1-6-alkyl.
In one embodiment, E
Figure A0181159100392
Or R wherein 27, R 28, R 29, R 30And R 31Definition cotype (I) described in.
In another embodiment, E is R wherein 27And R 28Definition cotype (I) described in.
In another embodiment, E is
Figure A0181159100396
R wherein 27And R 28Definition cotype (I) described in.
In one embodiment, R 27And R 28Be hydrogen, C independently 1-6-alkyl, C 3-8-cycloalkyl, C 4-8-cycloalkenyl group or phenyl, wherein said phenyl can be chosen wantonly described in (I) and be substituted.
In another embodiment, R 27And R 28Be hydrogen, C independently 1-6-alkyl, C 3-8-cycloalkyl or C 4-8-cycloalkenyl group.
In another embodiment, R 27Be hydrogen, and R 28Be C 1-6-alkyl or C 3-8-cycloalkyl, for example tertiary butyl, cyclohexyl or cyclohexenyl.
In another embodiment, E is
Figure A0181159100401
R wherein 29, R 30And R 31Definition cotype (I) described in.
In another embodiment, E is
Figure A0181159100402
R wherein 29, R 30And R 31Definition cotype (I) described in.
In one embodiment, R 29, R 30And R 31Be independently ■ hydrogen ,-CHF 2,-CF 3,-OCF 3,-OCHF 2,-OCH 2CF 3,-OCF 2CHF 2,-SCF 3,-OR 34,-NR 34R 35,-SR 34,-S (O) R 34,-S (O) 2R 34,-C (O) NR 34R 35,-OC (O) NR 34R 35,-NR 34C (O) R 35,-OCH 2C (O) NR 34R 35,-C (O) R 34Or-C (O) OR 34, ■ C 1-6-alkyl, C 2-6-alkenyl or C 2-6-alkynyl, wherein said group can choose wantonly by one or more be selected from halogen ,-CN ,-CF 3,-OCF 3,-NO 2,-OR 34,-NR 34R 35And C 1-6The substituting group of-alkyl replaces, ■ C 3-8-cycloalkyl or C 4-8-cycloalkenyl group, wherein said group can choose wantonly by one or more be selected from halogen ,-CN ,-CF 3,-OCF 3,-NO 2,-OR 34,-NR 34R 35And C 1-6The group of-alkyl replaces, wherein R 34And R 35Be hydrogen, C independently 1-6-alkyl or aryl, in the time of perhaps on being connected same nitrogen-atoms, R 34And R 35Can form optional 1 or 2 other heteroatoms that is selected from nitrogen, oxygen and sulphur, and the optional 3-8 unit heterocycle that contains 1 or 2 two key of containing with described nitrogen-atoms.
In another embodiment, R 29, R 30And R 31Be hydrogen, C independently 1-6-alkoxyl group, halogen ,-CF 3,-OCF 3Or-NR 34R 35, R wherein 34And R 35Definition cotype (I) described in, or C 1-6-alkyl, C 3-8-cycloalkyl or C 4-8-cycloalkenyl group, wherein said group can be chosen wantonly described in (I) and be substituted.
In another embodiment, R 29, R 30And R 31Be hydrogen or C independently 1-6-alkyl, C 3-8-cycloalkyl or C 4-8-cycloalkenyl group, wherein said group can be chosen wantonly described in (I) and be substituted.
In another embodiment, R 29, R 30And R 31Be hydrogen or C independently 1-6-alkyl, C 3-8-cycloalkyl or C 4-8-cycloalkenyl group, the described group of ■ can choose wantonly by one or more be selected from halogen ,-CN ,-CF 3,-OCF 3,-NO 2,-OR 34,-NR 34R 35And C 1-6The substituting group of-alkyl replaces, and ■ is R wherein 34And R 35Be hydrogen, C independently 1-6-alkyl or aryl, ■ or on being connected same nitrogen-atoms time the, R 34And R 35Can form optional 1 or 2 other heteroatoms that is selected from nitrogen, oxygen and sulphur, and the optional 3-8 unit heterocycle that contains 1 or 2 two key of containing with described nitrogen-atoms.
In another embodiment, R 29And R 31All be hydrogen, and R 30Not hydrogen.
In another embodiment, R 29And R 31All be hydrogen, and R 30Be C 3-8-cycloalkyl or C 4-8-cycloalkenyl group, the described group of ■ can choose wantonly by one or more be selected from halogen ,-CN ,-CF 3,-OCF 3,-NO 2,-OR 34,-NR 34R 35And C 1-6The substituting group of-alkyl replaces, and ■ is R wherein 34And R 35Be hydrogen, C independently 1-6Alkyl or aryl, ■ or on being connected same nitrogen-atoms time the, R 34And R 35Can form optional 1 or 2 other heteroatoms that is selected from nitrogen, oxygen and sulphur, and the optional 3-8 unit heterocycle that contains 1 or 2 two key of containing with described nitrogen-atoms.
In another embodiment, R 29And R 31All be hydrogen, and R 30Be C 4-8-cycloalkenyl group, the described group of ■ can choose wantonly by one or more be selected from halogen ,-CN ,-CF 3,-OCF 3,-NO 2,-OR 34,-NR 34R 35And C 1-6The substituting group of-alkyl replaces, and ■ is R wherein 34And R 35Be hydrogen, C independently 1-6-alkyl or aryl, ■ or on being connected same nitrogen-atoms time the, R 34And R 35Can form optional 1 or 2 other heteroatoms that is selected from nitrogen, oxygen and sulphur, and the optional 3-8 unit heterocycle that contains 1 or 2 two key of containing with described nitrogen-atoms.
In another embodiment, R 29And R 31All be hydrogen, and R 30Be cyclohexenyl, the described group of ■ can choose wantonly by one or more be selected from halogen ,-CN ,-CF 3,-OCF 3,-NO 2,-OR 34,-NR 34R 35And C 1-6The substituting group of-alkyl replaces, and ■ is R wherein 34And R 35Be hydrogen, C independently 1-6-alkyl or aryl, ■ or on being connected same nitrogen-atoms time the, R 34And R 35Can form optional 1 or 2 other heteroatoms that is selected from nitrogen, oxygen and sulphur, and the optional 3-8 unit heterocycle that contains 1 or 2 two key of containing with described nitrogen-atoms.
In another embodiment, R 30By a C 1-6-alkyl substituent is the tertiary butyl or methyl substituted for example.
In another embodiment, R 29, R 30And R 31Be hydrogen, C independently 1-6-alkyl, C 3-8-cycloalkyl or C 4-8-cycloalkenyl group.
In another embodiment, R 29And R 31All be hydrogen, and R 30Be C 1-6-alkyl, C 3-8-cycloalkyl or C 4-8-cycloalkenyl group, for example tertiary butyl, cyclohexyl or cyclohexenyl.
In one embodiment, the invention provides formula (I 1) compound:
Figure A0181159100421
R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, X, D and E definition cotype (I) or arbitrary above-mentioned embodiment described in.In one embodiment, the present invention relates to formula (I 2) compound:
Figure A0181159100431
R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, D and E definition cotype (I) or arbitrary above-mentioned embodiment described in.
In one embodiment, the present invention relates to formula (I 3) compound:
Figure A0181159100432
R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 15, R 16, R 17, R 29, R 30, and R 31Definition cotype (I) or arbitrary above-mentioned embodiment described in.
At formula (I 1), (I 2) and (I 3) an embodiment in, R 1, R 2, R 3, R 4, R 5, R 6, R 7And R 8Be hydrogen.
In one embodiment, the present invention relates to formula (I 4) compound:
Figure A0181159100433
R wherein 1, R 2, R 3, R 4, R 5, R 7, R 8, X, D and E definition cotype (I) or arbitrary above-mentioned embodiment described in.
In one embodiment, the present invention relates to formula (I 5) compound:
Figure A0181159100441
R wherein 1, R 2, R 3, R 4, R 5, R 7, R 8, D and E definition cotype (I) or arbitrary above-mentioned embodiment described in.
At formula (I 4) and (I 5) an embodiment in, R 1, R 2, R 3, R 4, R 5, R 7And R 8Be hydrogen.
The compounds of this invention can have one or more asymmetric centers, its any optically active isomer, no matter be isolating, pure or partially purified optically active isomer, or its racemic mixture, all be included in the scope of the present invention.
In addition, when having two keys or unsaturated entirely or the unsaturated ring system of part in the molecule, can form geometrical isomer.Any geometrical isomer, no matter be isolating, pure or partially purified geometrical isomer, or its mixture, all be included in the scope of the present invention.Equally, have its molecule that rotates restricted key and also can form geometrical isomer.They are also included within the scope of the invention.
In addition, some The compounds of this invention can exist with different tautomeric forms, and The compounds of this invention any tautomeric form that can form all be included in the scope of the present invention.
The present invention also comprises the pharmacologically acceptable salt of The compounds of this invention.Such salt comprises pharmaceutically acceptable acid additive salt, pharmaceutically acceptable metal-salt, ammonium salt and alkylated ammonium.Acid salt comprises mineral acid and organic acid salt.The representative example of suitable mineral acid comprises hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, phosphoric acid, sulfuric acid, nitric acid etc.The representative example of appropriate organic comprises formic acid, acetate, trichoroacetic acid(TCA), trifluoroacetic acid, propionic acid, phenylformic acid, styracin, citric acid, fumaric acid, oxyacetic acid, lactic acid, toxilic acid, oxysuccinic acid, propanedioic acid, amygdalic acid, oxalic acid, picric acid, pyruvic acid, Whitfield's ointment, succsinic acid, methylsulfonic acid, ethyl sulfonic acid, tartrate, xitix, pounce on acid (pamoic acid), the dimethylene Whitfield's ointment, ethionic acid, gluconic acid, citraconic acid, aspartic acid, stearic acid, palmitinic acid, EDTA, oxyacetic acid, para-amino benzoic acid, L-glutamic acid, Phenylsulfonic acid, tosic acid etc.Other example of pharmaceutically acceptable mineral acid or organic acid addition salt is included in J.Pharm.Sci.1977, the pharmacologically acceptable salt of listing in 66,2, and the document is introduced the present invention with for referencial use.The example of metal-salt comprises lithium salts, sodium salt, sylvite, magnesium salts etc.The example of ammonium salt and alkylated ammonium comprises ammonium salt, methyl ammonium salt, dimethyl ammonium, leptodactyline, ethyl ammonium salt, hydroxyethyl ammonium salt, diethyl ammonium salt, normal-butyl ammonium salt, sec-butyl ammonium salt, tertiary butyl ammonium salt, tetramethyl ammonium etc.
Also as the pharmaceutically acceptable acid additive salt be included in the scope of the present invention be The compounds of this invention the hydrate that can form.
In addition, pharmacologically acceptable salt comprises alkaline amino acid salt for example lysine salt, arginic acid salt and ornithine salt.
Acid salt can be used as the synthetic product of direct compound and obtains.Perhaps, free alkali can be dissolved in the suitable solvent that contains suitable acid, and isolate salt by coming with solvent evaporation or with salt and separated from solvent.
Use the well-known method of those skilled in the art, The compounds of this invention can form solvate with the standard low molecular weight solvent.Such solvate is also included within the scope of the invention.
The present invention also comprises the prodrug of The compounds of this invention, by metabolic process generation chemical conversion, forms pharmacological active substance after its administration.Generally speaking, such prodrug is the functional derivatives of general formula (I) compound, and it is easy to change into required formula (I) compound in vivo." prodrug design ", ed.H.Bundgaard, Elsevier has described the ordinary method of selecting and prepare suitable prodrug derivant in 1985.
The present invention also comprises the active metabolite of The compounds of this invention.
Therefore the effect of The compounds of this invention energy antagonism hyperglycemic-glycogenolytic factor can be used for treating and/or preventing illness and the disease of benefiting from such antagonistic action.
Therefore, The compounds of this invention can be used for treating and/or preventing hyperglycemia, IGT (impaired glucose tolerance), insulin resistance syndrome, syndrome X, type 1 diabetes, diabetes B, hyperlipidaemia, unusual lipidemia, hypertriglyceridemia, hyperlipoproteinemia, hypercholesterolemia, the arteriosclerosis that comprises atherosclerosis, glucagonoma of pancreas, acute pancreatitis, cardiovascular disorder, hypertension, megalocardia, gastrointestinal tract disorder, obesity, as the unusual lipidemia of diabetes, diabetic of obesity consequence.
In addition, The compounds of this invention can be used as the patient's who determines to have the glucagon receptor defective diagnostic reagent, as improving gastric acid secretion and reversing owing to using the insufficient therapeutical agent of intestines mobility that hyperglycemic-glycogenolytic factor causes.
Therefore, on the other hand, the present invention relates to The compounds of this invention as medicine.
The invention still further relates to pharmaceutical composition, wherein comprise at least a The compounds of this invention as active ingredient and one or more pharmaceutically acceptable carrier or vehicle.
Pharmaceutical composition preferably is unit dosage, wherein comprises the about 1000mg of about 0.05mg-, the preferably about 500mg of about 0.1mg-, the especially preferred about 200mg The compounds of this invention of about 0.5mg-.
In addition, the invention still further relates to The compounds of this invention is used for the treatment of and/or prevents to benefit from application in the pharmaceutical composition of the illness of hyperglycemic-glycogenolytic factor antagonistic action or disease in preparation.
The invention still further relates to and treat and/or prevent the illness that can benefit from the hyperglycemic-glycogenolytic factor antagonistic action or the method for disease, described method comprises the The compounds of this invention of using significant quantity to the individuality that these needs are arranged.
In preferred embodiment of the present invention, The compounds of this invention can be used for preparing the illness that treats and/or prevents any hyperglycemic-glycogenolytic factor mediation and the medicine of disease.
In preferred embodiment of the present invention, The compounds of this invention can be used for preparing the medicine that treats and/or prevents hyperglycemia.
In preferred embodiment of the present invention, The compounds of this invention can be used for preparing the medicine that reduces Mammals blood sugar.
In another preferred embodiment of the present invention, The compounds of this invention can be used for preparing the pharmaceutical composition that treats and/or prevents IGT.
In another preferred embodiment of the present invention, The compounds of this invention can be used for preparing and/or preventing the pharmaceutical composition of diabetes B.
In another preferred embodiment of the present invention, The compounds of this invention can be used for preparing delay or prevents the pharmaceutical composition to the process of diabetes B conversion from IGT.
In another preferred embodiment of the present invention, The compounds of this invention can be used for preparing delay or prevents from the pharmaceutical composition of non-insulin desirability diabetes B to the process of insulin requirement diabetes B conversion.
In another preferred embodiment of the present invention, The compounds of this invention can be used for preparing the pharmaceutical composition that treats and/or prevents type 1 diabetes.Insulinize is followed in treating and/or preventing so usually.
In another preferred embodiment of the present invention, The compounds of this invention can be used for preparing the pharmaceutical composition that treats and/or prevents obesity.
In another preferred embodiment of the present invention, The compounds of this invention can be used for preparing the pharmaceutical composition that treats and/or prevents for example unusual lipidemia of lipidosis.
In another preferred embodiment of the present invention, The compounds of this invention can be used for preparing the pharmaceutical composition that treats and/or prevents appetite stimulator or energy expenditure disorder.
In another aspect of this invention, employing is united in The compounds of this invention and diet and/or exercise.
In another aspect of this invention, The compounds of this invention and one or more other active substances are co-administered with the ratio of any appropriate.Other promoting agent like this be selected from that antidiabetic, the agent of hyperlipidemia disease, antiobesity agent, hypotensive agent and treatment diabetes cause or with the promoting agent of diabetes complications associated with arterial system.
Suitable antidiabetic comprises Regular Insulin, insulin analog and derivative, for example those disclosed, for example N in EP 792 290 (Novo Nordisk A/S) ε B29-tetradecanoyl des (B30) insulin human, those disclosed, for example Asp in EP 214 826 and EP 705 275 (Novo NordiskA/S) B28The insulin human, at US 5,504, those disclosed, for example Lys among 188 (EliLilly) B28Pro B29The insulin human, those disclosed in EP 368 187 (Aventis), Lantus for example, all these documents are all introduced the present invention with for referencial use, the GLP-1 derivative, those disclosed in WO98/08871 (Novo Nordisk A/S) for example, the document are introduced the present invention with for referencial use, and the Hypoylycemic agents of Orally active.
The Hypoylycemic agents of Orally active preferably includes the imidazolines medicine, sulfonylureas, biguanides, meglitinide class medicine (meglitinides); oxadiazole alkane two ketone medicines, the thiazolidinediones medicine, glucosidase inhibitor, glucagon antagonist, the GLP-1 agonist, the promoting agent that acts on beta cell ATP dependency potassium channel for example potassium channel is opened agent, as at WO97/26265, those disclosed among WO99/03861 and the WO00/37474 (Novo Nordisk A/S), these documents are introduced the present invention with for referencial use, or nateglinide (nateglinide) or potassium channel blocker BTS-67582 for example, insulin sensitizer, DPP-IV (dipeptidyl peptidase-IV) inhibitor, the PTP enzyme inhibitors, relate to the inhibitor that stimulates glyconeogenesis and/or glycogenolytic liver enzyme, the glucose uptake conditioning agent, GSK-3 (glycogen synthase kinase-3) inhibitor, regulate for example agent of hyperlipidemia disease and the agent of lipotropism mass formed by blood stasis of compound of lipid metabolism, reduce the compound of ingestion of food, PPAR (Pexoxisome proliferator activated receptor) and RXR (retinoid X receptor) agonist be ALRT-268 for example, LG-1268 or LG-1069.
In an embodiment of the present invention, with The compounds of this invention and Regular Insulin or insulin analog or derivative N for example ε B29-tetradecanoyl des (B30) insulin human, Asp B28Insulin human, Lys B28Pro B29Insulin human, Lantus or comprise the mixed preparation Combined Preparation of one or more these promoting agents.
In another embodiment of the present invention, with The compounds of this invention and sulfonylureas for example tolbutamide, P-607, tolazamide, Glyburide, glyburide, Glipizide or gliclazide Combined Preparation.
In another embodiment of the present invention, with The compounds of this invention and biguanides metformin Combined Preparation for example.
In another embodiment of the present invention, with The compounds of this invention and meglitinide class medicine (meglitinide) for example repaglinide or Lie Gelienai Combined Preparation.
In another embodiment of the present invention, with The compounds of this invention and thiazolidinediones insulin sensitizer for example troglitazone, ciglitazone, pioglitazone, rosiglitazone, isaglitazone, darglitazone, englitazone, CS-011/CI-1037 or T174, or in WO97/41097, WO97/41119, WO97/41120, WO00/41121 and WO98/45292 (Dr.Reddy ' s Research Foundation) disclosed compound Combined Preparation.
In another embodiment of the present invention, with The compounds of this invention and insulin sensitizer Gl 262570 for example, YM-440, MCC-555, JTT-501, AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516 or in following document disclosed compound Combined Preparation: WO99/19313, WO00/50414, WO00/63191, WO00/63192, WO00/63193 (Dr.Reddy ' s Research Foundation) and WO00/23425, WO00/23415, WO00/23451, WO00/23445, WO00/23417, WO00/23416, WO00/63153, WO00/63196, WO00/63209, WO00/63190 and WO00/63189 (Novo Nordisk A/S).
In another embodiment of the present invention, with The compounds of this invention and alpha-glucosidase inhibitor for example voglibose, emiglitate, miglitol or acarbose Combined Preparation.
In another embodiment of the present invention, with The compounds of this invention and the promoting agent that acts on beta cell ATP dependency potassium channel for example tolbutamide, P-607, tolazamide, Glyburide, glyburide, Glipizide, gliclazide, BTS67582, repaglinide or nateglinide Combined Preparation.
In another embodiment of the present invention, with The compounds of this invention and the agent of hyperlipidemia disease or the agent of lipotropism mass formed by blood stasis for example Colestyramine, colestipol, chlorine Bei Te, gemfibrozil, lovastatin, Pravastatin, Simvastatin, probucol or dextrothyroxine Combined Preparation.
In another aspect of this invention, with The compounds of this invention and more than one above-claimed cpd Combined Preparation, for example with the following compound Combined Preparation of respectively organizing: metformin and sulfonylureas be Glyburide or glyburide for example; Sulfonylureas and acarbose; Metformin and meglitinide be repaglinide for example; Acarbose and metformin; Sulfonylureas, metformin and troglitazone; Sulfonylureas, metformin and pioglitazone; Sulfonylureas, metformin and insulin sensitizer be those disclosed in WO00/63189 or WO97/41097 for example; Meglitinide is repaglinide, metformin and troglitazone for example; Meglitinide is repaglinide, metformin and pioglitazone for example; Meglitinide is repaglinide, metformin and insulin sensitizer those disclosed in WO00/63189 or WO97/41097 for example for example; Regular Insulin and sulfonylureas; Regular Insulin and meglitinide be repaglinide for example; Regular Insulin and metformin; Regular Insulin, metformin and meglitinide be repaglinide for example; Regular Insulin, metformin and sulfonylureas; Regular Insulin and troglitazone; Regular Insulin and pioglitazone; Regular Insulin and insulin sensitizer be those disclosed in WO00/63189 or WO97/41097 for example; Regular Insulin and lovastatin; Insulin analog or derivative, metformin and meglitinide be repaglinide for example; Insulin analog or derivative, metformin and sulfonylureas; Insulin analog or derivative and troglitazone; Insulin analog or derivative and pioglitazone; Insulin analog or derivative and insulin sensitizer be those disclosed in WO00/63189 or WO97/41097 for example; Insulin analog or derivative and lovastatin etc.
In addition, can be with The compounds of this invention and one or more antiobesity agents or appetite stimulator Combined Preparation.
Such promoting agent can be selected from CART (transcribing of Cocaine amphetamine adjusting) agonist, NPY (neuropeptide tyrosine) antagonist, MC4 (melanocortin 4) agonist, the aricine antagonist, TNF (tumour necrosis factor) conditioning agent, CRF (corticotropin releasing factor) agonist, CRF BP (corticotropin releasing factor is conjugated protein) antagonist, the urocortin agonist, 'beta '3 adrenergic agonists is CL-316243 for example, AJ-9677, GW-0604, LY362884, LY377267 or AZ-40140, MSH (melanotropin) agonist, MCH (melanophore concentrates hormone) antagonist, CCK (cholecystokinin) agonist, serotonin reuptake inhibitors is fluoxetine for example, seroxat (seroxat) or citalopram, thrombotonin and NRI, 5HT (thrombotonin) agonist, the bombesin agonist, alpinin (galanin) antagonist, tethelin, growth hormone releasing compounds, TRH (thyrotrophin-releasing hormone) agonist, UCP 2 or 3 (uncoupling protein 2 or 3) conditioning agent, the leptin agonist, DA (Dopamine HCL) agonist (bromocriptine, doprexin), lipase/amylase inhibitor, the PPAR inhibitor, RXR conditioning agent or TR beta-agonists.
In an embodiment of the present invention, antiobesity agent is leptin.
In another embodiment of the present invention, antiobesity agent is Dextroamphetamine or amphetamine.
In another embodiment of the present invention, antiobesity agent is Phenfluoramine or dexfenfluramine.
In another embodiment of the present invention, antiobesity agent is a sibutramine.
In another embodiment of the present invention, antiobesity agent is an orlistat.
In another embodiment of the present invention, antiobesity agent is Mazindol or phentermine.
In addition, The compounds of this invention can with one or more hypotensive agent Combined Preparation.The example of hypotensive agent has beta blocker, for example alprenolol, atenolol USP 23, timolol, pindolol, Proprasylyte and metoprolol, ACE (angiotensin-converting enzyme) inhibitor is benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and Ramipril for example, calcium channel blocker is nifedipine, felodipine, nicardipine, Isrodipine, nimodipine, diltiazem _ and verapamil for example, and alpha block agent for example Doxazosin, urapidil, Prazosin and terazosin.Other reference can be referring to Remington:TheScience and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
Should be appreciated that The compounds of this invention and diet and/or exercise, one or more above-claimed cpds and choose any one kind of them or the random suitable combination of multiple other active substance all within the scope of the present invention.
Pharmaceutical composition
The compounds of this invention can be individually dosed, perhaps with pharmaceutically acceptable carrier or vehicle Combined Preparation, and can be with single dose or a plurality of dosed administration.Pharmaceutical composition of the present invention can be with pharmaceutically acceptable carrier or thinner and other known auxiliary agent and vehicle according to for example disclosed technology preparation in following document of routine techniques: Remington:The Science and Practice of Pharmacy, 19 Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
Specifically the compounding pharmaceutical composition is with the administration by any appropriate, suitable route of administration for example has per os, rectum, intranasal, in lung, part (comprising cheek and hypogloeeis), transdermal, brain pond, intraperitoneal, vagina and parenteral route (comprise in subcutaneous, intramuscular, the sheath, intravenously and intradermal) approach, the per os approach is preferred.Should be appreciated that preferred route of administration depend on the general situation of the patient's body for the treatment of and age, the sanatory character of institute and selected active ingredient.
Peroral administration pharmaceutical composition comprises solid dosage for example capsule, tablet, dragee, pill, lozenge, pulvis and granula.If suitably, can provide for example enteric coating of dressing, perhaps the release of their preparations with the control active ingredient is for example continued to discharge or postpone to discharge according to method well-known in the art to them.
Peroral administration liquid dosage form comprises solution, emulsion, suspension, syrup and elixir.
The pharmaceutical composition of parenteral administration comprises sterile aqueous and non-aqueous Injectable solution, dispersion liquid, suspension or emulsion, and the sterilized powder that is mixed with sterile injectable emulsion or dispersion liquid before using again.The drug storehouse storage injection also within the scope of the present invention.
Other suitable form of medication comprises suppository, sprays, paste, creme, gelifying agent, inhalation, skin patch, implant etc.
General oral dosage is the about 100mg/kg body weight/day of about 0.001-, is preferably the about 50mg/kg body weight/day of about 0.01-, and the about 10mg/kg body weight/day of more preferably about 0.05-is divided into a or for example 1-3 doses administration of many doses every day.Precise dosage will depend on administration frequency and mode, the patient's that treats the general situation of sex, age, body weight and health, the illness for the treatment of and any disease accompanied character and severity, and the other factors that it will be apparent to those skilled in the art that.
For the purpose of convenient, can preparation be made unit dosage by method known to those skilled in the art.Be used for every day the oral administration one or many for example 1-3 time typical flat formulation can contain the about 1000mg of 0.05-, the preferably about 500mg of about 0.1-, the about 200mg of 0.5mg-more preferably from about.
For the parenteral administration approach for example in intravenously, the sheath, intramuscular and similar administration, the dosage that is adopted generally is half of about oral administration dosage.
The compounds of this invention generally is to use as material itself or as its pharmacologically acceptable salt.An example is the base addition salt with compound of free acid.When formula (I) when compound contains free acid, such salt is to make by solution or suspension with the pharmaceutically acceptable alkaline purification formula of equivalent (I) free acid according to ordinary method.Representative example as mentioned above.
For parenteral administration, can use the solution of formula (I) new compound in aseptic aqueous solution, aqueous propylene glycol, the vitamin-E aqueous solution or sesame oil or peanut oil.If necessary, such aqueous solution suitably can be cushioned, and at first liquid diluent etc. is oozed with the salt solution or the glucose of capacity.The aqueous solution is particularly suitable for intravenously, intramuscular, subcutaneous and intraperitoneal administration.Used aseptic aqueous medium all is easy to obtain by standard technique well known by persons skilled in the art.
Suitable pharmaceutical carrier comprises inert solid diluent or weighting agent, aseptic aqueous solution and various organic solvent.The example of solid carrier has lactose, terra alba, sucrose, cyclodextrin, talcum powder, gelatin, agar, pectin, gum arabic, Magnesium Stearate, stearic acid and cellulosic lower alkyl ether.The example of liquid vehicle has syrup, peanut oil, sweet oil, phosphatide, lipid acid, fatty acid amine, polyoxyethylene and water.Similarly, carrier or thinner can comprise that any slow-release material known in the art for example uses separately or with wax blended monostearin or Stearic diglyceride.By formula (I) new compound and pharmaceutically acceptable carrier being mixed the different dosage form easily administration of pharmaceutical composition that forms to be suitable for disclosed route of administration.For the purpose of convenient, can preparation be made unit dosage by method known to those skilled in the art.
Be suitable for peroral administration preparation of the present invention and can be made into and respectively contain the predetermined amount active ingredient, and the discrete unit that can contain suitable vehicle for example capsule or tablet.In addition, oral preparations can be powder or particle, solution in water or on-aqueous liquid or suspension, or the form of oil-in-water or water-in-oil emulsion.
If use solid carrier to carry out oral administration, preparation can be the small pieces that place hard gelatin capsule with powder or piller form, and perhaps it can be the form of lozenge or dragee.The amount of solid carrier can great changes have taken place, but it typically is the about 1g of about 25mg-.If use liquid vehicle, preparation can be the form of syrup, emulsion, soft gelatin capsule or aseptic parenteral solution style such as water or on-aqueous liquid suspension or solution.
Can contain by the typical tablet that conventional tabletting technology makes: nuclear: the about 0.9mg*Polacrillin potassium of active compound (compound itself or its salt) 5.0mg lactose Ph.Eur. 67.8mg Microcrystalline Cellulose (Avicel) 31.4mgAmberiite_IRP88* 1.0mg Magnesium Stearate Ph.Eur. an amount of dressing Vltra tears about 9mgMywacett 9-40 T** NF, tablet disintegrant, Rohm and Haas.* is as the monoglyceride of the acidylate of film dressing softening agent.
If necessary, pharmaceutical composition of the present invention can contain formula (I) compound and the other for example above-mentioned active substance of pharmacological active substance.
Embodiment
Following embodiment and general method have been mentioned midbody compound and the end product of identifying in specification sheets and synthetic schemes.Use following embodiment to describe The compounds of this invention in more detail, but described chemical reaction is disclosed according to the general applicability of its preparation glucagon antagonist of the present invention.Sometimes reaction may be able to not be applicable to all compounds that are included in the scope disclosed in this invention.Those skilled in the art can be easy to recognize such compound.In these cases, by doing some conventional changes well known by persons skilled in the art, promptly by saturated interference group suitably, change other conventional reagent into or reaction conditions done some conventional changes, can successfully carry out these reactions.Perhaps, other reaction disclosed herein or popular response can be suitable for preparing corresponding The compounds of this invention.In ownership system Preparation Method, all raw materials all are known, perhaps can be easy to be made by known raw material.Except as otherwise noted, all temperature all are degree centigrade providing, and when mentioning productive rate, all umbers and per-cent all are by weight, and when mentioning solvent and thinner, all umbers all are by volume.
Biao Shi some NMR data only are selected data in the following embodiments.
In embodiment and pharmacology method, following term has following meanings: DCM: methylene dichloride DMF:N, dinethylformamide DMSO: methyl-sulphoxide M.p.: fusing point TFA: trifluoroacetic acid THF: tetrahydrofuran (THF) EDAC:1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride HOBt:1-hydroxybenzotriazole HOAt:3-hydroxyl-3H-[1,2,3] triazolo [4,5-b] pyridine, also be called 1-hydroxyl-7-azepine benzotriazole EGTA: ethylene glycol bisthioglycolate (beta-amino ether) N, N, N ' N '-tetraacethyl BSA:N, O-two (trimethyl silyl) acetimide hydrochlorate IBMX: isobutyl methylxanthine HPLC-MS (method A) uses following instrumentation: Sciex API 100 Singles four phase mass spectrograph Perkin Elmer Series 200 Quard pump Perkin Elmer Series 200 self-actuated sampler Applied Biosystems 785A UV detector Sedex 55 light scattering detector Valco posts, and with passing through from the time-controlled Valco driver switch of pump.
The Sciex Sample control software that use moves on Macintosh PowerPC 7200 computers is carried out instrument control and is obtained data.
The HPLC pump links to each other with 4 eluent storages that contain following component: A: acetonitrile B: water C:0.5%TFA aqueous solution D:0.02 M ammonium acetate
Being them to the requirement of sample for example contains the compound (the strong eluting solvent of high density will disturb the chromatogram of carrying out under low acetonitrile concentration) of about 500 μ g/mL preanalysis in methyl alcohol, ethanol, acetonitrile, THF, water and composition thereof in acceptable solvent.
Analysis is by carrying out in room temperature at on-column injection 20 μ L sample solutions, with the gradient solution wash-out post of acetonitrile in 0.05%TFA or 0.002M ammonium acetate.Use different elution requirements according to analytical procedure.
Allow the eluent stream that flows down from post through shunting T-junctor, it flow on the API interface of API 100 spectrometers via about 1m.75 μ quartz glass capillary about 20 μ L/ minutes.
Flowed through in remaining 1.48mL/ minute UV detector and arrive the ELS detector.
During LC analyzes, obtain to detect data from mass spectrograph, UV detector and ELS detector concurrently.
The LC condition, detector setting and the mass spectrograph setting that are used for different methods are listed in following table.
Post YMC?ODS-A?120_s-5μ3mm×50mmid
Gradient The mixture of 5%-90% acetonitrile in 0.05%TFA increased so that 1.5mL/ minute speed is linear in 7.5 minutes
Detect UV：214nm ELS：40℃
MS Experiment: beginning: 100 amu stop: 800 amu spacings: 0.2 amu stops: 0.571 msec
Method: scan 284 times=9.5 minutes
HPLC-MS (method B)
Use following instrumentation: Hewlett Packard series 1100 G1312A Bin PumpHewlett Packard series 1100 Column compartment Hewlett Packard series 1100 G13 15A DAD diode-array detector Hewlett Packard series 1100 MSD
By HP Chemstation software control instrument.
The HPLC pump links to each other with 2 eluent storages that contain following component: the solution of A:0.01%TFA aqueous solution B:0.01%TFA in acetonitrile
Analysis is to be expelled on the post by the sample (preferred 1 μ L) with proper volume and to carry out at 40 ℃, carries out gradient elution with acetonitrile.
Used HPLC condition, detector setting and mass spectrograph setting are listed in the following table.
Post Waters?Xterra?MS?C-18×3mmid
Gradient The 10-100% acetonitrile increased so that 1.0mL/ minute speed is linear in 7.5 minutes
Detect UV:210nm (from the similar output of DAD)
MS Ionization pattern: API-ES scanning 100-1000 amu, spacing 0.1amu
HPLC-MS (method C)
Use following instrumentation: Hewlett Packard series 1100 G1312A Bin PumpHewlett Packard series 1100 G13 15A DAD diode-array detector Sciex 300 34 phase mass spectrograph Gilson 215 micro-syringe Sedex 55 light scattering detectors
Pump and detector are by the MassChrom1.1.1 software control that moves on Macintosh G3 computer.Gilson Unipoint Version 1.90 control automatic injectors.
The HPLC pump links to each other with 2 eluent storages that contain following component: the solution of A:0.01%TFA aqueous solution B:0.01%TFA in acetonitrile
Analysis is to be expelled on the post by the sample (preferred 1 μ L) with proper volume and to carry out in room temperature, carries out gradient elution with acetonitrile.
Used HPLC condition, detector setting and mass spectrograph setting are listed in the following table.
Post YMC?ODS-A120_s-5μ3mm×50mmid
Gradient The 5-90% acetonitrile increased so that 1.5mL/ minute speed is linear in 7.5 minutes
Detect 210nm (from the similar output of DAD)
MS Ionization pattern: API-ES scans 100-1000amu, spacing 0.1amu
Preparation is used for the member member 1:(RS of following embodiment)-the isoserine carbethoxy hydrochloride
(40mL) cools off on ice bath with thick dehydrated alcohol, and thionyl chloride (4mL) remains on temperature below 5 ℃ simultaneously.(2.5g 23.79mmol), and continues to stir until obtaining homogeneous solution to add (RS)-isoserine in this cold soln.Remove ice bath, continue stirring at room 17 hours.With this solution for vacuum concentration, obtained 4.0g (100%) (RS)-the isoserine carbethoxy hydrochloride, be oily matter. 1H-NMR (DMSO-d 6): δ 1.22 (t, 3H), 3.00 (dm, 2H), 4.15 (q, 2H), 4.40 (dd, 1H), 6.30 (brs, 1H), 8.32 (brs, 2H). 13C-NMR (DMSO-d 6): δ 14.7 (q), 42.4 (t), 61.7 (t), 67.7 (d), 171 (s). member 2:(R)-isoserine carbethoxy hydrochloride steps A: (R)-(2,2-dimethyl-5-oxo-[1,3] dioxolane-4-yl) acetate
To D-(+)-oxysuccinic acid (15.0g 0.1119mol) adds 2 in the suspension in dry toluene (150mL), the 2-Propanal dimethyl acetal (50mL, 0.392mmol).This mixture was refluxed 2 hours at 100 ℃, and vacuum-evaporation.Resistates is dissolved in the ether (150mL),, uses ether as eluent (200mL) by the flash column chromatography purifying.Merge pure fraction, vacuum-evaporation is stirred resistates in normal hexane.Collecting precipitation with normal hexane washing and dry, has obtained (R)-(2,2-dimethyl-5-oxo-[1,3] dioxolane-4-yl) acetate of 15.7g (81%), is solid. 1H-NMR (acetone-d 6): δ 1.57 (ds, 6H), 2.85 (m, 2H), 4.80 (dd, 1H), 11.0 (brs, 1H). 13C-NMR (Acetone-d 6): δ 25.9 (q), 26.8 (q), 36.2 (t), 71.5 (d), 111.2 (s), 170.7 (s), 172.7 (s). ultimate analysis: C 7H 10C 5Calculated value: C, 48.28%; H, 5.79%. measured value: C, 48.31%; H, 6.09%. step B:(R)-(2,2-dimethyl-5-oxo-[1,3] dioxolane-4-ylmethyl) benzyl carbamate
With (R)-(2; 2-dimethyl-5-oxo-[1; 3] acetate (10.0g dioxolane-4-yl); 57.41mmol), triethylamine (10mL; 68.89mmol) and diphenyl phosphoryl azide (14mL, 63.15mmol) mixture in dry toluene (100mL) is in 85 ℃ of heating with stir.After stopping to discharge gas, continue to stir 1 hour.(6.3mL 63.15mmol), and continues heating 17 hours to add dry-out benzene methyl alcohol.After the vacuum-evaporation, resistates is distributed between methylene dichloride, water and salt solution., the organic phase that merges is washed 2 times water extraction 2 times with methylene dichloride with saturated sodium bicarbonate.Behind organic phase drying (sal epsom), filtration and vacuum concentration,, use the methylene dichloride wash-out by flash column chromatography purifying resistates.Obtain (R)-(2,2-dimethyl-5-oxo-[1,3] dioxolane-4-ylmethyl) benzyl carbamate of 6.4g (40%), be oily matter. 1H-NMR (acetone-d 6): δ 1.56 (s, 6H), 3.61 (m, 2H), 4.64 (dd, 1H), 5.08 (dd, 2H), 6.51 (br s, 1H), 7.29-7.38 (m, 5H). step C:(R)-3-benzyloxycarbonyl amino-2 hydroxy propanoic acid
To (R)-(2,2-dimethyl-5-oxo-[1,3] dioxolane-4-ylmethyl) benzyl carbamate (6.0g, 25.08mmol) add in the solution in acetonitrile (100mL) hydrochloric acid (1N, 100mL).This mixture was stirred 3 hours at 40 ℃, and vacuum concentration is to half original volume.By solid collected by filtration, and wash with water.Crude product was stirred 5 minutes in acetone (100mL), and filter.Toluene is added in clarification and the colourless filtrate, and vacuum concentration is until obtaining precipitation.By filtering collecting precipitation, drying, obtained 4.45g (87%) (R)-3-benzyloxycarbonyl amino-2 hydroxy propanoic acid. 1H-NMR (acetone-d 6): δ 3.45 (ddd, 1H), 3.58 (ddd, 1H), 4.29 (dd, 1H), 5.08 (s, 2H), 6.41 (br s, 1H), 7.29-7.38 (m, 5H). 13C-NMR (acetone-d 6): δ 45.1 (t), 66.4 (t), 70.4 (d), 128.3 (d), 128.9 (d), 138.0 (d), 157.2 (s), 173.8 (s); HPLC-MS (method C): m/z=262 (M+Na +); R t=2.20min. M.p.131-132 ℃. ultimate analysis: C 11H 13NO 5Calculated value: C, 55.23%; H, 5.48%; N, 5.85%. measured value: C, 55.35%; H, 5.72%; N, 5.82%. step D:(R)-isoserine
(4.4g 18.39mmol) is dissolved in the dehydrated alcohol (150mL) with (R)-3-benzyloxycarbonyl amino-2 hydroxy propanoic acid.Under nitrogen atmosphere, add palladium carbon (10%, 0.5g), with the hydrogenation 17 hours under 1 normal atmosphere of this mixture.Filter out catalyzer, and wash with water.By vacuum-evaporation filtrate and the washings that merges is concentrated into about 20mL.Obtained precipitation by dripping methyl alcohol (100mL).Filter out precipitation, with methanol wash and dry, obtained 1.78g (92%) (R)-isoserine, be solid. 1H-NMR (D 2O): δ 3.07 (dd, 1H), 3.30 (dd, 1H), 4.19 (dd, 1H). 13C-NMR (D 2O): δ 43.0 (t), 68.9 (d) .M.p.200-201 ℃ of 177.5 (s). step e: (R)-the isoserine carbethoxy hydrochloride
This compound is to make according to the method that is similar to above-mentioned preparation (RS)-isoserine carbethoxy hydrochloride. 1H-NMR (DMSO-d 6): δ 1.22 (t, 3H), 2.88 (dd, 1H), 3.10 (dd, 1H), 4.14 (q, 2H), 4.40 (m, 1H), 6.32 (d, 1H), 8.28 (br s, 2H). 13C-NMR (DMSO-d 6): 13.9 (q), 41.4 (t), 60.7 (t), 66.9 (d), 170.9 (s). member 3:(S)-2,2-dimethyl-5-oxo-[1,3] dioxolane-4-ylmethyl trifluoroacetic acid ammonium steps A: (S)-(2,2-dimethyl-5-oxo-[1,3] dioxolane-4-yl) acetate
To L MALIC ACID (3g 22.4mmol) adds 2 in the suspension in toluene (25mL), the 2-Propanal dimethyl acetal (8.5g, 81mmol).With this suspension reflux 20 minutes., obtained (S)-(2,2-dimethyl-5-oxo-[1,3]-4-yl)-acetate except that desolvating by vacuum-evaporation. 1H-NMR (DMSO-d 6): δ 1.52 (6H, d), 2.75 (2H, t), 4.78 (1H, t) .12.52 (1H, brs). step B:(S)-(2,2-dimethyl-5-oxo-[1,3] dioxolane-4-ylmethyl) benzyl carbamate
To (S)-(2 in toluene (20mL), 2-dimethyl-5-oxo-[1,3] acetate (1g dioxolane-4-yl), 5.7mmol) and triethylamine (0.66 g, 6.5mmol) middle adding diphenyl phosphate azide (phosphorazidic acid diphenyl ester) (1.7g, 6.2mmol).With this vlil 1 hour.(0.54g 5mmol), and continues to reflux 6 hours to add phenylcarbinol.After the cooling, (2 * 50mL) (distribute between 10%, 2 * 50mL) with sodium bicarbonate aqueous solution in ethyl acetate with this solution.Merge organic layer, dry (sodium sulfate), and remove by vacuum-evaporation and to desolvate, obtained 976 mg (S)-(2,2-dimethyl-5-oxo-[1,3] dioxolane-4-ylmethyl) benzyl carbamate crude product, be oily matter. 1H-NMR (DMSO-d 6): δ 1.53 (6H, d), 3.34 (1H, m), 3.50 (1H, m), 4.50 (1H, d), 4.64 (1H, t), 5.03 (2H, d), 7.32 (5H, m) step C:(S)-2,2-dimethyl-5-oxo-[1,3] dioxolane-4-ylmethyl trifluoroacetic acid ammonium
With rough (S)-(2,2-dimethyl-5-oxo-[1,3] benzyl carbamate (976 mg dioxolane-4-ylmethyl), 3.5mmol) be dissolved in the ethanol (14mL), (10% palladium carbon is 300mg) with 1 to add palladium, 3-cyclohexadiene (2.8g, 35mmol), this was reflected at stirring at room 1 hour, and 40 ℃ of heating 10 minutes.After the filtration, (0.4g 3.5mmol), and by evaporating except that desolvating, has obtained (S)-2, and 2-dimethyl-5-oxo-[1,3] dioxolane-4-ylmethyl trifluoroacetic acid ammonium is oily matter to add TFA. 1H-NMR (CDCl 3): δ 1.46 (6H, d), 3.40-3.70 (2H, m), 4.38 (1H, m), 7.25 (＞4H, brs); HPLC-MS (method B): m/z=146 (M +); R t=0.38min. member 4:3-amino-2-fluorine methyl propionate
Anhydrous methanol (5.3mL) is cooled to-15 ℃ on ice bath, thionyl chloride (2.5mL) remains on temperature below 5 ℃ simultaneously.(0.27g 2.52mmol), and continues to stir until obtaining homogeneous solution to add (RS)-3-amino-2-fluorine propionic acid in this cold solution.Remove ice bath, and continue stirring at room 17 hours.This solution for vacuum concentration is further with anhydrous methanol coevaporation 3 times.Filter out resistates,, obtained 0.13g (33%) 3-amino-2-fluorine methyl propionate hydrochloride, be solid with DCM washing and dry. 1H-NMR (DMSO-d 6): δ 3.36 (m, 2H), 3.76 (s, 3H), 5.51 (d, 2H), 8.59 (brs, 3H). member 5:3-amino-2 (R)-methoxypropionic acid methyl ester hydrochloride step (A): (R)-2-hydroxy succinic acid dimethyl ester
In the ice-cold solution of (250mL), add Acetyl Chloride 98Min. (12.5mL), this solution was stirred 1 hour at 0 ℃.Add (R)-oxysuccinic acid (20.0g), and with this solution stirring at room 16 hours.Except that desolvating, obtained (R)-2-hydroxy succinic acid dimethyl ester by vacuum-evaporation, be oily matter with quantitative yield. 1H-NMR (CDCl 3): δ 4.52 (dd, 1H), 3.80 (s, 3H), 3.71 (s, 3H), 3.55 (bs, 1H), 2.88 (dd, 1H), 2.80 (dd, 1H) step (B): (R)-2-methoxyl group Succinic acid dimethylester
Above-mentioned (R)-2-hydroxy succinic acid dimethyl ester is dissolved in the methyl-iodide (100mL) again, adds freshly prepd silver suboxide (30.2g), and with this mixture stirring at room 24 hours.With this reaction mixture with acetonitrile (200mL) dilution, via diatomite filtration to remove silver salt and excessive hydrogen silver suboxide.With the filtrate drying, obtained (R)-2-methoxyl group Succinic acid dimethylester, be oily matter (23.2g, 88%). 1H-NMR (CDCl 3): δ 4.20 (dd, 1H), 3.78 (s, 3H), 3.71 (s, 3H), 3.48 (s, 3H), 2.80 (dd, 2H). step (C): (R)-2-methoxyl group succsinic acid 1-methyl esters
Above-mentioned (R)-2-methoxyl group Succinic acid dimethylester is suspended in the 2N hydrochloric acid, and reflux 30 minutes has obtained settled solution.With solvent vacuum-evaporation, obtained 2 (R)-methoxyl group succsinic acids with quantitative yield, be oily matter.This oily matter is dissolved in the diacetyl oxide (120mL) again, and 110 ℃ of heating 2 hours.Except that desolvating, obtained oily matter by rotary evaporation.Add ice-cold methyl alcohol (150mL), this mixture was stirred 3 hours at 0 ℃, then stirring at room 16 hours.Remove and desolvate, obtained (R)-2-methoxyl group succsinic acid 1-methyl esters. 1H-NMR (CDCl 3): δ 10.30 (bs, 1H), 4.19 (dd, 1H), 3.80 (s, 3H), 3.50 (s, 3H), 2.86 (dd, 1H), 2.78 (dd, 1H). step (D): 3-tert-butoxycarbonyl amino-2 (R)-methoxypropionic acid methyl esters
Need not be further purified, (5.0g 30.8mmol) is dissolved in the thionyl chloride (16mL), and reflux 2 hours is removed thionyl chloride and minor component by rotary evaporation, then with the acetonitrile coevaporation with above-mentioned (R)-2-methoxyl group succsinic acid 1-methyl esters. 1H-NMR(CDCl 3)：δ3.27(dd，1H)，3.48(dd，1H)，3.51(s，3H)，3.80(s，3H)，4.22(dd，1H).
Purified chloride of acid is dissolved in the toluene (50mL).Add the trimethyl silyl trinitride (5.0mL, 38.2mmol), and with this mixture 100 ℃ of heated overnight.Add the trimethyl carbinol (30mL), continue heating 16 hours.With this reaction mixture cooling, by removing by filter insolubles.With organic phase water (100mL), saturated sodium bicarbonate solution (100mL), 10% citric acid solution (100mL), water (100mL) and saturated nacl aqueous solution (100mL) washing, use anhydrous sodium sulfate drying then.Remove by rotary evaporation and to desolvate.By the oily matter of column chromatography purifying remnants, with 20% ethyl acetate/heptane wash-out.Merge pure fraction (the TLC plate being dyeed) with ammonium molybdate/cerous sulfate/sulfuric acid, and dry.Final 3-tert.-butoxy-carbonylamino-2 (the R)-methoxypropionic acid methyl esters that obtains is 600mg (9%).
1H-NMR(CDCl 3)：δ6.93(t，1H)，3.83(t，1H)，3.64(s，3H)，3.25(s，3H)，3.18(dd，2H)，1.36(s，
9H). step (E): 3-amino-2 (R)-methoxypropionic acid methyl ester hydrochloride
With 3-tert-butoxycarbonyl amino-2-methoxypropionic acid methyl esters (500mg 2mmol) is dissolved in the solution (20mL) of 10%TFA in DCM, with this reaction mixture stirring at room 30 minutes.Remove and to desolvate, with the diethyl ether solution coevaporation of resistates and 30mL1N hydrogenchloride 2 times.Output: 320mg (88%). 1H-NMR (CDCl 3): δ 8.25 (s, 3H), 4.21 (dd, 1H), 3.71 (s, 3H), 3.40 (s, 3H), 3.15 (m, 1H), 2.98 (m, 1H). member 6:(R)-3-(9H-fluorenes-9-ylmethoxy carbonylamino)-2 hydroxy propanoic acid ((R)-Fmoc-isoserine
To (R)-(2,2-dimethyl-5-oxo-[1,3] dioxolane-4-yl) acetate (5.88g, add in 33.8mmol) toluene (100mL), triethylamine (4.7mL, 33.8mmol) and two phenoxy group phosphoryl trinitride (8.0mL, 37.2mmol).This reaction mixture is heated to 100 ℃, and under nitrogen atmosphere, stirred 1.5 hours in 100 ℃.Add the 9-Lumefantrine (5.1g, 26mmol), and with this reaction mixture refluxed 6 hours.After being cooled to room temperature, this mixture is transferred in the separating funnel, and water (2 * 50mL) washings.Solvent removed in vacuo, and with acetonitrile (100mL) coevaporation.The light brown oily thing of remnants is dissolved among the DCM (20mL), and purifying on silicagel column uses DCM as eluent.Remove DCM by evaporation, obtained light yellow oil, it is dissolved in the acetonitrile (150mL) again, and adding hydrochloric acid (1N, 75mL).With this yellow reaction mixture stirring at room 3 hours.Solvent removed in vacuo adds toluene (100mL), and with this suspension reflux, is cooled to room temperature.By filtering to isolate (R)-Fmoc-isoserine (3.1g, 28%), be powder.Mp：165-166℃。 1H-NMR (DMSO-d 6): δ 12.5 (brs, 1H), 7.90 (m, 2H), 7.70 (m, 2 H), 7.50-7.30 (m, 4H), 5.45 (brs, 1H), 4.23 (m, 3H), 4.05 (m, 1H), 3.17 (m, 1H); HPLC-MS (method B): m/z=350 (M+Na); R t=3.20min. member 7:3-(t-butyldimethylsilyloxy ylmethyl)-4-Trifluoromethoxyphen-l amine ( 3-(tert-Butyldimethylsilanyloxymethyl)-4-trifluoromethoxyphenyl amine) steps A: 5-nitro-2-trifluoro-methoxy-benzoic acid methyl esters
In being equipped with three neck round-bottomed flasks of thermometer and separating funnel, with HNO 3(5mL nitrosonitric acid, 100%) cools off in ice bath.(5g 22.7mmol) was added in the refrigerative nitric acid lentamente, simultaneously temperature is remained on below 15 ℃ with 2-(trifluoromethoxy) methyl benzoate with 0.5 hour.Then this is reflected at 60 ℃ and stirred 1 hour, stirring at room 2 hours.This reaction mixture is added in the frozen water, isolates oily matter.This oily resistates is added in the water (50mL),, uses ethyl acetate (25mL) extraction then with the sodium bicarbonate aqueous solution neutralization.Use ethyl acetate (15mL) once again with the water extraction.(2 * 15mL) washings, dry (sal epsom), and vacuum concentration have obtained 5.69g5-nitro-2-trifluoro-methoxy-benzoic acid methyl esters with saturated sodium-chloride with the organic phase that merges. 1H-NMR (DMSO-d 6): δ 3.93 (3H, s), 7.82 (1H, d), 8.58 (1H, d), 8.67 (1H, s). step B:5-amino-2-trifluoro-methoxy-benzoic acid methyl esters
With 5-nitro-2-trifluoro-methoxy-benzoic acid methyl esters (5.69 g 21.5mmol) are dissolved in 99.9% ethanol (80mL), add tin protochloride (II) dihydrate (24.2g, 107mmol).This suspension was stirred 2 hours at 75 ℃, then vacuum concentration.Resistates is added in ethyl acetate (100mL) and the water (50mL), and with 4N sodium hydroxide (50mL) with pH regulator to 8.Liquid is inclined to from the thin precipitation that generates, and with the ethyl acetate washing precipitation and incline to, this operation is carried out 2 times.Organic phase water with merging: saturated sodium-chloride (1: 1) solution (2 * 100mL) washings, dry (sal epsom), and vacuum concentration.By column chromatography (120g silicon-dioxide) purifying resistates, use ethyl acetate: heptane (1: 1) wash-out has obtained 3.8g5-amino-2-trifluoro-methoxy-benzoic acid methyl esters. 1H-NMR (DMSO-d 6): δ 3.82 (3H, s), 5.63 (2H, s), 6.79 (1H, d), 7.07 (1H, s), 7.11 (1H, d). step C:(5-amino-2-Trifluoromethoxyphen-l) methyl alcohol
In the three-necked flask that is equipped with thermometer and separating funnel, (3.0g 12.8mmol) is dissolved among the THF (20mL) with 5-amino-2-trifluoro-methoxy-benzoic acid methyl esters under nitrogen atmosphere.Under agitation with dripped in 10 minutes ice-cold lithium aluminium hydride (1MTHF solution, 15mL).Continuation is stirring at room 1 hour, with this reaction mixture vacuum concentration.Resistates is suspended in DCM (150mL) and the water (50mL), and via diatomite filtration.Filtrate is distributed between DCM and water.(2 * 20mL) washings, dry (sal epsom), and vacuum concentration have obtained 2.47g (5-amino-2-Trifluoromethoxyphen-l) methyl alcohol with the organic phase water that merges. 1H-NMR (DMSO-d 6): δ 3.92 (2H, d), 5.18 (1H, t), 5.28 (2H, s), 6.45 (1H, d), 6.91 (1H, d). step (D): 3-(t-butyldimethylsilyloxy ylmethyl)-4-Trifluoromethoxyphen-l aniline
With (5-amino-2-Trifluoromethoxyphen-l) methyl alcohol (1.2g 5.8mmol) is dissolved among the DMF (5mL), add imidazoles (0.48g, 7.1mmol) and tert-butyldimethylsilyl chloride (0.99g, 6.6mmol), and with this mixture stirring 16 hours.Extract this reaction mixture with ethyl acetate (50mL) and water (20mL).(20mL) extracts water once again with ethyl acetate.With organic phase water (10mL), aqueous citric acid solution (10mL, 10%) and water (2 * 10mL) washings, dry (sal epsom) and the vacuum concentration that merges.By column chromatography (110g, silica gel) purifying resistates, use ethyl acetate and heptane (1: 3) as eluent, obtained 1.2g3-(t-butyldimethylsilyloxy ylmethyl)-4-Trifluoromethoxyphen-l aniline. 1H-NMR (DMSO-d 6): δ 0.82 (9H, s), 3.25 (6H, s), 4.52 (2H, s), 5.23 (2H, s), 6.41 (1H, d), 6.61 (1H, s), 6.86 (1H, d). member 8:4-hexamethylene-1-thiazolinyl aniline
This compound is according to being similar to people such as J.v.Braun, J.Liebigs Ann.Chem., 472 (1929), the method of describing among the 1-89 makes, be about to aniline (2 equivalent), pimelinketone (1 equivalent) in ethanol and 37% hydrochloric acid backflow 4-5 days, add ethyl acetate, water and sodium hydroxide then, neutralize with 85% phosphoric acid, be separated, and organic phase is distilled.The sulfuric acid that in resistates, adds catalytic amount, and distillation (180 ℃, the 5-7 millibar).With resistates distillation (120 ℃, 3 millibars), obtained (in resistates) required 4-hexamethylene-1-thiazolinyl aniline again. 1HNMR (DMSO-d 6): δ 1.50-1.60 (m, 2H), 1.60-1.70 (m, 2H), 2.10-2.15 (m, 2H), 2.20-2.30 (brds, 2H), 5.00 (s, 2H), 5.90 (t, 1H), 6.50 (d, 2H), 7.10 (d, 2H). member 9:4-cyclohexyl aniline
This compound is commercially available (for example deriving from Lancaster or Avocado).Member 10:4-cyclohexyl ring hexyl amine
The preparation of this compound is described in the literature, referring to people such as H.Booth, and J.Chem.Soc. (B), 1971,1047-1050.Member 11:4-(2-methyl cyclohexane-1-thiazolinyl) aniline and (R, S)-4-(6-methyl cyclohexane-1-thiazolinyl) aniline
Figure A0181159100651
With the 2-methylcyclohexanone (112g, 1,0mol), aniline (186g, 2mol) and the mixture of ethanol (26mL) in stirring at room, with adding 12M hydrochloric acid (167mL) in 30 minutes.This deep yellow solution was refluxed 7 days at 85 ℃.This solution is cooled off, and dilute with ethyl acetate.This mixture is stirred in ice bath, and, temperature is remained on below 30 ℃ with 27% sodium hydroxide solution alkalization (pH=9).Isolate organic layer,, use dried over mgso, concentrate, obtained brown oil (131g) with salt water washing (3 *).Excessive aniline is removed in decompression.The 12M hydrochloric acid (1mL) that adds catalytic amount is with the fractionation under high vacuum of this resistates.Be collected in the fraction that 145-175 ℃ (0.2mmHg) distills, the circumstances in which people get things ready for a trip of going forward side by side spectrum purifying (silica gel), with 30% ethyl acetate/toluene wash-out, obtained 4-(2-methyl cyclohexane-1-thiazolinyl) aniline and (R, S)-9: 1 mixtures (8.7g) of 4-(6-methyl cyclohexane-1-thiazolinyl) aniline.4-(2-methyl cyclohexane-1-thiazolinyl) aniline: 1HNMR (DMSO-d 6): δ 1,53 (s, 3H), 1,61 (m, 4H), 2,00 (bs, 2H), 2,13 (bs, 2H), 4,92 (s, 2H), 6,50 (d, 2H), 6,79 (d, 2H); HPLC-MS (method B): m/z=188 (M +); R t=2,96min. (R, S)-4-(6-methyl cyclohexane-1-thiazolinyl) aniline: 1HNMR (DMSO-d 6): δ 0,88 (d, 3H), 1,61 (m, 4H), 2,00 (bs, 2H), 2,13 (bs, 2H), 2,74 (m, 1H), 4,92 (s, 2H), 5,68 (t, 1H), 6,50 (d, 2H), 6,79 (d, 2H). member 12:4-(4-tertiary butyl hexamethylene-1-thiazolinyl) aniline
Figure A0181159100661
4-(4-tertiary butyl hexamethylene-1-thiazolinyl) aniline is the method for preparing member 11 according to being similar to, and uses 4-tertiary butyl pimelinketone (0.59mol) and aniline to make. 1H NMR (DMSO-d 6): δ 0,88 (s, 9H), 1,21 (m, 2H), 1,90 (m, 2H), 2,10-2,50 (m, 3H), 4,97 (s, 2H), 5,90 (m, 1H), 6,50 (d, 2H), 7,06 (d, 2H); HPLC-MS (method B): m/z=230 (M +); R t=4,07min. member 13:(R, S)-4-(5-methyl cyclohexane-1-thiazolinyl) aniline and (R, S)-4-(3-methyl cyclohexane-1-thiazolinyl) aniline
Figure A0181159100671
Will (R, S)-the 3-methylcyclohexanone (123mL, 1.0mol), aniline (182mL, 2.0mol), 12M hydrochloric acid (167mL, 2.0mol) and the mixture of ethanol (26mL) refluxed 10 days at 90 ℃.This solution is cooled off, and dilute with ethyl acetate.With the 6M sodium hydroxide solution with water layer alkalization (pH=10).Isolate organic layer,, use dried over mgso, concentrate, obtained brown oil with salt water washing (3 *).Excessive aniline is removed in decompression.The 12M hydrochloric acid (1mL) that adds catalytic amount is with resistates fractionation under high vacuum.Be collected in the fraction that 123-128 ℃ (0.15-0.20mmHg) distills, obtained 21.0g oily matter. 1H-NMR show and exist (R, S)-4-(5-methyl cyclohexane-1-thiazolinyl) aniline and (R, S)-3: 2 mixtures of 4-(3-methyl cyclohexane-1-thiazolinyl) aniline.(R, S)-4-(5-methyl cyclohexane-1-thiazolinyl) aniline: 1HNMR (DMSO-d 6): δ 1.00 (d, 3H), 1.45-1.95 (m, 3H), 2.10-2.45 (m, 3H), 5.04 (s, 2H), 5.86 (t, 1H), 6.48 (d, 2H), 7.06 (d, 2H). (R, S)-4-(3-methyl cyclohexane-1-thiazolinyl) aniline: 1HNMR (DMSO-d 6): δ 1.00 (d, 3H), 1.45-1.95 (m, 3H), 2.10-2.45 (m, 3H), 5.04 (s, 2H), 5.75 (d, 1H), 6.48 (d, 2H), 7.06 (d, 2H). be used for synthetic general formula (Ia) of liquid phase and (Ib) general method of compound (A): R wherein 2, R 3, R 7, R 8, A, E and D definition cotype (I) described in.
The compound that is generated by general method (A) can make via ester approach or carboxylic acid approach.Unique difference of these two approach is phenylformic acid is protected as ester.With ester deprotection (step 2a), obtained to be equal to the intermediate of carboxylic acid approach.
Embodiment 1 and 2 illustrated the method for ester basis approach, embodiment 3 illustrated according to the method for carboxylic acid approach.Embodiment 1 (general method (A)) (R)-3-{4-[1-(4-cyclohexyl phenyl)-3-(3-methoxyl group-5-trifluoromethyl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid Step 1:4-((4-cyclohexyl phenyl amino) methyl) methyl benzoate
(6.65g 40.5mmol) is dissolved in the methyl alcohol (175mL) of heat with the 4-acyl radical methyl benzoate.Adding 4-cyclohexyl aniline in this mixture (7.1g, 40.5mmol).In gained suspension, add methyl alcohol (75mL), and this mixture heating up was refluxed 1 hour.Be cooled to after 0 ℃, this mixture filtered, with solid with ice-cold methanol wash, and 40 ℃ of vacuum-dryings 16 hours, obtained 10.95g4-[(4-cyclohexyl phenyl imino-)-methyl] methyl benzoate.With this compound (10.93g 34mmol) is suspended in the methyl alcohol (200mL), adds Glacial acetic acid (27mL), then with a small amount of mode repeatedly add sodium cyanoborohydride (1.9g, 30mmol).With this mixture stirring at room 1 hour, and vacuum concentration.Resistates is dissolved among the DCM (200mL), with 5% aqueous sodium carbonate (5 * 80mL) washings, dry (sal epsom), and vacuum concentration.In resistates, add ethyl acetate (100mL) and normal heptane (200mL), and vacuum concentration is to half of original volume.Filter out solid,,, obtained 9.52g (87%) 4-((4-cyclohexyl phenyl amino) methyl) methyl benzoate 40 ℃ of vacuum-dryings 16 hours with the normal heptane washing.
1H-NMR(DMSO-d 6)：δ1.2-1.4(5H，m)，1.65(5H，m)，2.30(1H，t)，3.84(3H，s)，4.30(2H，d)，
6.18 (1H, t), 6.50 (2H, d), 6.87 (2H, d), 7.49 (2H, d), 7.92 (2H, d); HPLC-MS (method B): m/z
=324 (M+1); R t=7.18min step 2:4-[1-(cyclohexyl phenyl)-3-(3-methoxyl group-5-trifluoromethyl) urea groups methyl] methyl benzoate
(2.0g 10.5mmol) is dissolved in the ethyl acetate (10mL), adds the solution of anhydrous HCl in ethyl acetate (15mL), and solvent removed in vacuo with 5-methoxyl group-3-(trifluoromethyl) aniline.With this solid and toluene (3 * 15mL) coevaporations.Add toluene (75mL) and trichloromethylchloroformate (13mL), this reaction mixture was refluxed 2.5 hours under nitrogen atmosphere.Vacuum is removed excessive trichloromethylchloroformate, with clarifying oily matter and toluene coevaporation.The isocyanic ester that obtains need not be further purified direct use.
Above-mentioned isocyanic ester is dissolved among the DCM (75mL), and adding 4-((4-cyclohexyl phenyl amino)-methyl) methyl benzoate (2.3g, 7.1mmol).In stirred overnight at room temperature, solvent removed in vacuo is by the oily matter of silica gel chromatography remnants, with the mixture wash-out of heptane and ethyl acetate (7: 3) with this reaction mixture.Obtained 3g4-[1-(cyclohexyl phenyl)-3-(3-methoxyl group-5-three fluoro-aminomethyl phenyls) urea groups methyl] methyl benzoate, be oily matter. 1H-NMR (DMSO-d 6): δ 1.22 (broad peak, 1H), 1.37 (broad peak, 4H), 1.7 (broad peaks, 1H), 1.79 (broad peak, 4H), 3.77 (s, 3H), 3.83 (s, 3H), 4.98 (s, 2H), 6.81 (s, 1H), 7.18 (d, 2H), 7.23 (d, 2H), 7.42 (m, 3H), 7.51 (s, 1H), 7.90 (d, 2H), 8.53 (s, 1H), 10.01 (s, 1H); HPLC-MS (method A): m/z=541 (M+1); R t=8.98min. step 2a:4-[1-(cyclohexyl phenyl)-3-(3-methoxyl group-5-trifluoromethyl) urea groups methyl] phenylformic acid
With 4-[1-(cyclohexyl phenyl)-3-(3-methoxyl group-5-trifluoromethyl) urea groups methyl] methyl benzoate (3.0g) is dissolved in the dehydrated alcohol (50mL), add sodium hydroxide (4N, 15mL), with this reaction mixture stirring at room 16 hours.Vacuum is removed organic solvent, adds entry (50mL), and usefulness hydrochloric acid (4N) to acid-reaction, adds ethyl acetate (200mL) with pH regulator then.(5 * 50mL) washings, dry (sal epsom) filters and vacuum-evaporation with the organic phase water.With resistates recrystallization from acetonitrile (25mL), obtained 4-[1-(cyclohexyl phenyl)-3-(3-methoxyl group-5-trifluoromethyl) urea groups methyl] phenylformic acid (1.83g), be crystal. 1H-NMR (DMSO-d 6): δ 1.22 (m, 1H), 1.37 (m, 4H), 1.70 (m, 1H), 1.79 (m, 4H), 3.77 (s, 3H), 4.95 (s, 2H), 6.81 (s, 1H), 7.18 (d, 2H), 7.23 (d, 2H), 7.40 (d, 2H), 7.42 (s, 1H), 7.51 (s, 1H), 7.89 (d, 2H), 8.55 (s, 1H), 12.90 (s, 1H); HPLC-MS (method A): m/z=527 (M+1); R t=8.23 min; M.p.148-150 ℃. ultimate analysis: C 29H 29N 2F 3O 4Calculated value: C, 66.15%; H5.55%; N5.32%. measured value: C, 66.65%; H5.70%; N5.33%. step 3:(R)-and 3-{4-[1-(4-cyclohexyl phenyl)-3-(3-methoxyl group-5-trifluoromethyl) urea groups methyl] benzoyl-amido }-the 2 hydroxy propanoic acid ethyl ester
With 4-[1-(cyclohexyl phenyl)-3-(3-methoxyl group-5-trifluoromethyl) urea groups methyl] phenylformic acid (420mg 0.8mmol) is dissolved among the DMF (10mL), add then HOBt (160mg, 1.2mmol) and EDAC (230mg, 1.2mmol).With this reaction mixture sat 30 minutes, add then (R)-isoserine ethyl ester of being dissolved among the DMF (5mL) (260mg, 1.2mmol) and diisopropyl ethyl amine (210mL, 1.2mmol), and with this reaction mixture stirring at room 16 hours.Add entry (50mL) and ethyl acetate (100mL), (5 * 50mL) washings, dry (sal epsom) filters and vacuum-evaporation with the organic phase water.By the silica gel chromatography resistates; mixture (1: 3) wash-out with heptane and ethyl acetate; obtained 510mg (R)-3-{4-[1-(4-cyclohexyl phenyl)-3-(3-methoxyl group-5-trifluoromethyl) urea groups methyl] benzoyl-amido }-the 2 hydroxy propanoic acid ethyl ester, be amorphous solid. 1H-NMR (DMSO-d 6): δ 1.12 (t, 3H), 1.22 (m, 1H), 1.37 (m, 4H), 1.70 (m, 1H), 1.79 (broad peak, 4H), 3.41 (m, 1H), 3.52 (m, 1H), 3.77 (s, 3H), 4.06 (q, 2H), 4.21 (q, 1H), 4.95 (s, 2H), 5.68 (d, 1H), 6.81 (s, 1H), 7.18 (d, 2H), 7.23 (d, 2H), 7.33 (d, 2H), 7.42 (s, 1H), 7.51 (s, 1H), 7.77 (d, 2H), 8.47 (t, 1H), 8.53 (s, 1H); HPLC-MS (method A): m/z=658 (M+1); R t=8.17min. step 4:
With (R)-3-{4-[1-(4-cyclohexyl phenyl)-3-(3-methoxyl group-5-trifluoromethyl) urea groups methyl] benzoyl-amino-the 2 hydroxy propanoic acid ethyl ester is dissolved in the ethanol (15mL), and add sodium hydroxide (2N, 2mL).With this reaction mixture stirring at room 60 minutes.Vacuum is removed ethanol then, adds entry (50mL), with 4N hydrochloric acid with pH regulator to acid-reaction.(5 * 5mL) washings, vacuum-drying has obtained this title compound of 460mg, is solid crystal for filtration and water. 1H-NMR (DMSO-d 6): δ 1.22 (m, 1H), 1.37 (m, 4H), 1.70 (m, 1H), 1.79 (broad peak, 4H), 3.37 (m, 1H), 3.51 (m, 1H), 3.77 (s, 3H), 4.09 (t, 1H), 4.95 (s, 2H), 6.80 (s, 1H), 7.18 (d, 2H), 7.23 (d, 2H), 7.33 (d, 2H), 7.42 (s, 1H), 7.51 (s, 1H), 7.77 (d, 2H), 8.47 (t, 1H), 8.53 (s, 1H); HPLC-MS (method A.): m/z=614 (M+1); R t=7.67min. ultimate analysis: C 32H 34N 3F 3O 6(+1.25H 2O): C, 60.42%; H, 5.78%; N, 6.61%. measured value: C, 60.25%; H, 5.55%; N, 6.50%. embodiment 2 (general method (A)) (R)-3-{4-[3-(3,5-two (trifluoromethyl) phenyl)-1-(4-cyclohexyl phenyl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid
Figure A0181159100721
Step 2:4-[3-(3,5-two (trifluoromethyl) phenyl)-1-(4-cyclohexyl phenyl) urea groups methyl] methyl benzoate
With 4-((4-cyclohexyl phenyl amino) methyl) methyl benzoate (2.38g 7.36mmol) is dissolved among the DCM (150mL), adds isocyanic acid 3,5-two (trifluoromethyl) phenylester (1.36mL, 8.10mmol), and with this mixture stirring at room 16 hours.With this reaction mixture Zhou Shui (3 * 15mL) washings, dry (sal epsom) and vacuum concentration have obtained 4.3g4-[3-(3,5-two (trifluoromethyl) phenyl)-1-(4-cyclohexyl phenyl) urea groups methyl] methyl benzoate. 1H-NMR (DMSO-d 6): δ 1.17-1.44 (m, 5H), 1.66-1.82 (m, 5H), 3.83 (s, 3H), 4.98 (s, 2H, 7.20-7.28 (m, 4H), 7.44 (d, 2H), 7.62 (s, 1H), 7.93 (d, 2H), 8.24 (s, 2H), 8.94 (s, 1H); HPLC-MS (method A): m/z=579 (M+1); R t=9.50min step 2a:4-[3-(3,5-two (trifluoromethyl) phenyl)-1-(4-cyclohexyl phenyl) urea groups methyl] phenylformic acid
With 4-[3-(3,5-two (trifluoromethyl) phenyl)-1-(4-cyclohexyl phenyl) urea groups methyl] methyl benzoate (4.2g 7.36mmol) is suspended in the ethanol (80mL), add sodium hydroxide (4N, 11mL), and stirring at room 16 hours.This reaction mixture vacuum concentration to doing, is added entry (50mL) in resistates, with hydrochloric acid (4N, 12mL) acidifying.With ethyl acetate water is extracted 2 times (75mL and 25mL), and wash the organic phase that merges with water (3 * 15mL), dry (sal epsom) and vacuum concentration have obtained 4-[3-(3,5-two (trifluoromethyl) phenyl)-1-(4-cyclohexyl phenyl) urea groups methyl] phenylformic acid. 1H-NMR (DMSO-d 6): δ 1.32-1.43 (m, 5H), 1.7 (m, 1H), 1.75-1.85 (5H), 4.98 (s, 2H), 7.20-7.28 (m, 4H), 7.4 (d, 2H), 7.61 (d, 1H), 7.88 (d, 2H), 8.25 (s, 2H), 8.93 (s, 1H), 12.90 (s, 1H); HPLC-MS (method B): m/z=565 (M+1); R t=8.65min; M.p.148.5-149.5 ℃. ultimate analysis: C 29H 26F 6N 2O 3Calculated value: C, 61.70%; H, 4.64%; N, 4.96%. measured value: C, 61.54%; H, 4.71%; N, 4.92%. step 3:(R)-3-{4-[3-(3,5-two (trifluoromethyl) phenyl)-1-(4-cyclohexyl phenyl) urea groups methyl] benzoyl-amido }-the 2 hydroxy propanoic acid ethyl ester
With 4-[3-(3,5-two (trifluoromethyl) phenyl)-and 1-(4-cyclohexyl phenyl) urea groups methyl] (0.22 g 0.39mmol) is dissolved among the DMF (3mL) phenylformic acid, and adds 1-hydroxyl-7-azepine benzotriazole (0.06g, 0.47mmol) and EDAC (0.09g, 1.2mmol).This mixture was stirred 1.5 hours, be added in (R)-isoserine ethyl ester among the DMF (2mL) (0.10g, 0.59mmol) and diisopropyl ethyl amine (0.10mL, 0.59mmol).With this mixture stirring at room 16 hours.This reaction mixture water (10mL) is diluted, and extract with ethyl acetate (25mL).With ethyl acetate (10mL) aqueous phase extracted.With the organic phase that merges with hydrochloric acid (0.2N, 3 * 10mL) and water: saturated sodium-chloride (1: 1) washing, dry (sal epsom) and vacuum concentration.By column chromatography (35g silica gel) purifying resistates; with ethyl acetate and normal heptane (6: 4) wash-out; obtained 0.27g (R)-3-{4-[3-(3,5-two (trifluoromethyl) phenyl)-1-(4-cyclohexyl phenyl) urea groups methyl] benzoyl-amido }-the 2 hydroxy propanoic acid ethyl ester. 1H-NMR (DMSO-d 6): δ 1.14 (t, 3H), 1.19-1.42 (m, 5H), 1.67-1.85 (m, 5H), 3.38-3.48 (m, 1H), 3.49-3.57 (m, 1H), 4.08 (q, 2H), 4.20 (m, 1H), 4.97 (s, 2H), 5.67 (d, 1H), 7.20-7.27 (m, 4H), 7.36 (d, 2H), 7.62 (s, 1H), 7.75 (d, 2H), 8.24 (s, 2H), 8.48 (t, 1H), 8.90 (s, 1H); HPLC-MS (method A): m/z=680 (M+1); R t=8.42min. step 4:
With (R)-3-{4-[3-(3,5-two (trifluoromethyl) phenyl)-1-(4-cyclohexyl phenyl) urea groups methyl] benzoyl-amido }-(0.26g 0.38mmol) is dissolved in ethanol (96% to the 2 hydroxy propanoic acid ethyl ester; 15mL); adding sodium hydroxide (4N, 0.57mL, 2.3mmol).25 ℃ stir 1 hour after, with this mixture vacuum-evaporation, in resistates, add entry (30mL), and with hydrochloric acid (4N, 0.62mL) acidifying.With water with ethyl acetate extraction 2 times (25mL and 10mL), and with the organic phase saturated sodium-chloride that merges: water (1: 1) washing, drying (sal epsom) and vacuum concentration have obtained this title compound of 0.21g. 1H-NMR (DMSO-d 6): δ 1.21-1.45 (m, 5H), 1.66-1.86 (m, 5H), 3.37-3.44 (m, 1H), 3.53-3.60 (m, 1H), 4.18 (t, 1H), 4.95 (s, 2H), 7.18-7.27 (m, 4H), 7.45 (d, 2H), 7.60 (s, 1H), 7.78 (d, 2H), 8.24 (s, 2H), 8.44 (t, 1H), 8.90 (s, 1H); HPLC-MS (method B): m/z=652 (M+1); R t=7.93min. embodiment 3 (general method (A)) (R)-3-{4-[3-(3-bromophenyl)-1-(4-cyclohexyl phenyl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid
Figure A0181159100741
Step 1:4-[(4-cyclohexyl phenyl amino) methyl] phenylformic acid
(8.0g 53mmol) is dissolved in the methyl alcohol (200mL), and add 4-formyl radical phenylformic acid (9.4g, the 53mmol) suspension in Glacial acetic acid (12mL) heat the gained mixture 1.5 hours at reflux temperature in batches with 4-cyclohexyl aniline.After being cooled to room temperature, add in batches sodium cyanoborohydride (5.0g, the 80mmol) mixture in methyl alcohol (100mL), and with the gained mixture stirring at room 16 hours.This mixture is filtered, and the water thorough washing 50 ℃ of vacuum-dryings 3 days, has obtained 12.8g (78%) 4-[(4-cyclohexyl phenyl amino) methyl] phenylformic acid. 1H-NMR (DMSO-d 6): δ 1.1-1.35 (5H, m), 1.65-1.75 (5H, m), 2.29 (1H, m), 4.31 (2H, s), 6.15 (1H, bs), 6.45 (2H, d), 6.89 (2H, d), 7.46 (2H, d), 7.88 (2H, d). step 2:4-[3-(3-bromophenyl)-1-(4-cyclohexyl phenyl) urea groups methyl] phenylformic acid
(1.4g 8.1mmol) is dissolved in the ether (50mL), adds the mixture of the anhydrous HCl of 3.5M in ethyl acetate (2.3mL) with the 3-bromaniline.With this mixture vacuum concentration.In resistates, add toluene (100mL) and vacuum concentration.(8.1g 41mmol), and refluxes the gained mixture 1.5 hours to add toluene (100mL) and trichloromethylchloroformate in resistates.After the cooling, with this mixture vacuum concentration.Be dissolved in the toluene (100mL) resistates and vacuum concentration.Resistates is dissolved among the DMF (30mL), adds 4-[(4-cyclohexyl phenyl amino) methyl] phenylformic acid (1.3g, 4.1mmol).With this mixture stirring at room 16 hours.In this mixture, add ethyl acetate (150mL), and water: salt solution (1: 1) (2 * 100mL) washings.With the organic phase dried over sodium sulfate, and vacuum concentration.By the silica gel chromatography resistates, at first use ethyl acetate: normal heptane: the mixture of triethylamine (7: 2: 1) wash-out, use eluent ethyl acetate then, use methanol-eluted fractions at last, obtained 1.95g (94%) 4-[3-(3-bromophenyl)-1-(4-cyclohexyl phenyl) urea groups methyl] phenylformic acid. 1H-NMR (CDCl 3): δ 1.2-1.4 (5H, m), 1.7-1.8 (5H, m), 4.94 (2H, s), 7.1-7.25 (6H, m), 7.30 (2H, d), 7.44 (1H, d), 7.78 (1H, t), 7.83 (2H, d), 8.38 (1H, s); HPLC-MS (method B): m/z=507 (M+1); R 1=5.52min. step 3:(R)-and 3-{4-[3-(3-bromophenyl)-1-(4-cyclohexyl phenyl) urea groups methyl] benzoyl-amido }-the 2 hydroxy propanoic acid ethyl ester
With 4-[3-(3-bromophenyl)-1-(4-cyclohexyl phenyl) urea groups methyl] phenylformic acid (0.20g, 0.39mmol) be dissolved among the DMF (2.5mL), add EDAC (0.12g, 0.6mmol) and HOBt (0.089mg, 0.6mmol), and with this mixture stirring at room 10 minutes.Add (the R)-isoserine carbethoxy hydrochloride be dissolved among the DMF (2.5mL) (0.10g, 0.6mmol) and N, N-diisopropyl ethyl amine (130 μ L), and with the gained mixture stirring at room 16 hours.In this mixture, add ethyl acetate (70mL), water (2 * 100mL) washings, with sodium sulfate with the organic phase drying, and vacuum concentration.By the silica gel chromatography resistates, use the ethyl acetate that contains 10% acetate: normal heptane mixture (1: 2) wash-out.Obtained 100mg (R)-3-{4-[3-(3-bromophenyl)-1-(4-cyclohexyl phenyl) urea groups methyl] benzoyl-amido }-the 2 hydroxy propanoic acid ethyl ester.HPLC-MS (method B): m/z=624 (M+1); R t=5.33 minutes.Step 4:(R)-and 3-{4-[3-(3-bromophenyl)-1-(4-cyclohexyl phenyl) urea groups methyl] benzoyl-amido }-2 hydroxy-propionic acids
With (R)-3-{4-[3-(3-bromophenyl)-1-(4-cyclohexyl phenyl) urea groups methyl] benzoyl-amido }-2-hydroxyl-ethyl propionate (100mg) is dissolved in the ethanol (10mL); add 1N sodium hydroxide (480 μ L), and with the gained mixture stirring at room 1 hour.Add 1N hydrochloric acid (480 μ L), and with this mixture vacuum concentration.Be suspended in the water (50mL) resistates and filtration, obtained this title compound of 38mg. 1H-NMR (CDCl 3): δ 1.2-1.4 (5H, m), 1.7-1.85 (5H, m) .2.45 (1H, s), 3.7 (2H, m), 4.30 (1H, m), 4.78 (2H, s), 6.23 (1H, s), 6.95-7.3 (8H, m), 7.42 (1H, s), 7.60 (2H, d); HPLC-MS (method A): m/z=595 (M+1); R t=7.48min. embodiment 4 (general method (A)) (R)-3-{4-[1-(4-cyclohexyl phenyl)-3-(4-trifluoromethyl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid
Figure A0181159100761
1H-NMR (DMSO-d 6): δ 1.2-1.4 (5H, m), 1.7-1.8 (5H, m), 3.40 (1H, m), 3.56 (1H, dt), 4.18 (1H, t), 4.97 (2H, s), 5.5 (1H, brd) 7.14-7.25, (6H, m), 7.34 (2H, d), 7.55 (2H, d), 7.79 (2H, d), 8.38 (1H, s), 8.44 (1H, t); HPLC-MS (method A): m/z=600 (M+1); R t=7.38min. embodiment 5 (general method (A)) (R)-3-{4-[1-(4-cyclohexyl phenyl)-3-(3-trifluoromethyl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid 1H-NMR (400 MHz, DMSO-d 6): δ 1.15-1-45 (m, 5H), 1.60-1.90 (m, 5H), 4.95 (s, 2H), 7.12 (d, 2H), 7.19 (d, 2H), 7.24 (d, 1H), 7.45 (t, 1H), 7.72 (d, 2H), 7.75 (sbr, 1H), 7.90 (s, 1H), 8.55 (s, 1H), 8.58 (s br, 1H); HPLC-MS (method B): m/z=584 (M+1); R t=4.99min. embodiment 6 (general method (A)) (R)-3-{4-[1-(4-cyclohexyl phenyl)-3-(3-fluoro-5-trifluoromethyl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid
Figure A0181159100772
1H-NMR (200MHz, DMSO-d 6): δ 1.15-1-45 (m, 5H), 1.60-1.85 (m, 5H), 3.25-3.65 (m, 3H), 4.13 (t, 1H), 4.95 (s, 2H), 7.10-7.22 (m, 5H), 7.30 (d, 2H), 7.75 (m, 3H), 8.45 (t, 1H), 8.78 (s, 1H); HPLC-MS (method A): m/z=602 (M+1); R t=7.83min. embodiment 7 (general method (A)) (R)-3-{4-[3-(3-cyano group-5-trifluoromethyl)-1-(4-hexamethylene-1-thiazolinyl phenyl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid 1H-NMR (200MHz, DMSO-d 6): δ 1.15-1.70 (m, 4H), 2.12 (s, 2H), 2.35 (s, 2H), 5.00 (s, 2H), 6.15 (s, 1H), 7.10-7.40 (m, 6H), 7.78 (m, 3H), 8.20 (d, 2H), 8.90 (s, 1H); HPLC-MS (method A): m/z=607 (M+1); R t=7.42min. embodiment 8 (general method (A)) (R)-3-{4-[3-(3-cyano group-5-trifluoromethyl)-1-(4-cyclohexyl phenyl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid 1H-NMR (400MHz, DMSO-d 6): δ 1.15-1.45 (m, 5H), 1.60-1.85 (m, 5), 3.45-3.60 (m, 3H), 4.15 (t, and 1H) 4.95 (s, 2H), 7.20 (dd, 4H), 7.35 (d, 2H), 7.76 (d, 2H), 7.88 (s, 1H), 8.18 (s, 1H), 8.21 (s, 1H), 8.45 (t, 1H), 8.95 (s, 1H); HPLC-MS (method A): m/z=609 (M+1); R t=7.58 min. embodiment 9 (general method (A)) (R)-3-{4-[3-(3-bromo-5-trifluoromethyl)-1-(4-hexamethylene-1-thiazolinyl phenyl) urea groups methyl] benzoyl-amido)-2 hydroxy propanoic acid 1H-NMR (DMSO-d 6): δ 1.50-1.76 (m, 4H), 2.15 (m, 2H); 2.33 (m, 2H), 3.37 (m, 2H); 3.54 (m, 1H), 4.14 (dd, 1H); 4.95 (s, 2H), 6.17 (t, 1H); 7.17 (d, 2H), 7.33 (d; 2H), 7.40 (d, 2H); 7.46 (s, 1H), 7.75 (d; 2H), 7.91 (s, 1H); 8.07 (s, 1H), 8.44 (t; 1H), 8.66 (s, 1H). embodiment 10 (general method (A)) (R)-3-{4-[1-(4-hexamethylene-1-thiazolinyl phenyl)-3-(3-methoxyl group-5-trifluoromethyl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid 1H-NMR (DMSO-d 6): δ 1.51-1.76 (m, 4H), 2.15 (m, 2H); 2.34 (m, 2H), 3.37 (m, 2H); 3.54 (m, 1H), 3.75 (s, 3H); 4.14 (dd, 1H), 4.95 (s, 2H); 6.16 (t, 3H), 6.78 (s; 1H), 7.16 (d, 2H); 7.32 (d, 2H), 7.38 (d; 2H), 7.43 (s, 1H); 7.76 (d, 2H), 8.44 (t; 1H), 8.51 (s, 1H). embodiment 11 (general method (A)) (R)-3-{4-[3-(3-bromophenyl)-1-(4-hexamethylene-1-thiazolinyl phenyl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid
Figure A0181159100793
This title compound is according to general method (A), and change step 2 as described below makes: step 2:4-[3-(3-bromophenyl)-1-(4-hexamethylene-1-thiazolinyl phenyl) urea groups methyl] methyl benzoate
To the 3-bromo-benzoic acid in toluene (20mL) (1.2g, add in 5.7mmol) triethylamine (0.91mL, 6.5mmol) and two phenoxy group phosphoryl trinitride (1.3mL, 6.2mmol), and under agitation with this mixture heating up to 100 ℃.After 1 hour, add 4-[(4-hexamethylene-1-thiazolinyl phenyl amino) methyl]-(1.6g 5mmol), and continues heating 1.5 hours to methyl benzoate (according to being similar to embodiment 1, the method for step 1 makes).After being cooled to room temperature, this mixture and ethyl acetate (50mL) are transferred in the separating funnel.(2 * 50mL) washings are with ethyl acetate (50mL) back scrubbing with saturated sodium bicarbonate aqueous solution with organic mixture.Collected organic layer, dry (sodium sulfate), solvent removed in vacuo has obtained brown oil, by the silicagel column purifying, uses the DCM wash-out, has obtained 700mg4-[3-(3-bromophenyl)-1-(4-hexamethylene-1-thiazolinyl phenyl) urea groups methyl] methyl benzoate.HPLC-MS (method B): m/z=521 (M+1); R t=6.1 minutes.The data of this title compound: 1H-NMR (CDCl 3): δ 1.54 (s, 2H), 1.65 (s, 2H); 2.15 (s, 2H), 2.36 (s, 2H), 3.56 (br s, 2H), 4.19 (brs, 1H), 4.71 (s, 2H), 6.09 (s, 1H), 6.42 (s, 1H), 6.90-7.18 (m, 6H), 7.30.7.70 (m, 6H); HPLC-MS (method B): m/z=592.5 (M+1); R t=4.73min. embodiment 12 (general method (A)) (R)-3-{4-[3-(3-bromo-5-trifluoromethyl)-1-(4-cyclohexyl phenyl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid
Figure A0181159100801
1H-NMR (DMSO-d 6): δ 1.14-1.43 (m, 5H), 1.64-1.83 (m, 5H), 3.40-3.45 (m, 1H), 3.45-3.53 (m, 1H), 4.00 (t, 1H), 4.95 (s, 2H), 7.13-7.27 (m, 4H), 7.33 (d, 2H), 7.48 (s, 1H), 7.77 (d, 2H), 7.92 (s, 1H), 8.07 (s, 1H), 8.43 (t, 1H), 8.71 (s, 1H); HPLC-MS (method A): m/z=662 (M+1); R t=8.17min. embodiment 13 (general method (A)) (S)-trans-3-{4-[3-(3,5-two (trifluoromethyl) phenyl)-1-(4-tert-butylcyclohexyl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid
Figure A0181159100811
Step 1: trans-4-[(4-tert-butylcyclohexyl amino) methyl] methyl benzoate
Figure A0181159100812
(10.6g 64.4mmol) is dissolved in the methyl alcohol (200mL) with the 4-acyl radical methyl benzoate.(10.0g, 64.4mmol Aldrich), have been settled out white crystal to 17: 83 cis/trans mixtures of adding 4-tert-butylcyclohexyl amine immediately.This mixture heating up is refluxed 30 minutes to be completed into imines, on ice bath, be cooled to 0 ℃ then.Collect pure trans-4-[(4-tert-butylcyclohexyl imino-by filtering) methyl] the methyl benzoate crystal, and vacuum-drying is spent the night.Output: 15.3g (78%). 1HNMR (CDCl 3), 300MHz: δ 8.37 (s, 1H); 8.06 (d, 2H); 7.77 (d, 2H); 3.92 (s, 3H); 3.17 (m, 1H); 1.83 (m, 4H); 1.60 (m, 2H), 1.09 (m, 3H); 0.87 (s, 9H). ultimate analysis: C 19H 27NO 2Calculated value: C, 75.71%; H, 9.03%; N, 4.65%. measured value: C, 75.60%; H, 9.37%; N, 4.68%.
With the mother liquor drying, obtained 4.2g (22%) white solid, confirm that according to NMR it mainly is made up of the imino-cis-isomeride. 1HNMR(CDCl 3)，300MHz：δ8.36(s，1H)；8.07(d，2H)；7.81(d，2H)；3.92(s，3H)；3.54(m，1H)；1.55-1.92(m，8H)；1.14(m，1H)；0.90(s，9H).
Figure A0181159100821
With trans-4-[(4-tert-butylcyclohexyl imino-) methyl] (21.0g 69.2mmol) is suspended in the methyl alcohol (300mL) methyl benzoate, adds acetate (50mL).In the gained settled solution, add sodium cyanoborohydride (3.5g, 55.5mmol), with this mixture stirring at room 30 minutes.By rotary evaporation the volume of reaction mixture is reduced to 1/3rd then, add ethyl acetate (500mL).(5%, 500mL) the washing organic phase and is used dried over sodium sulfate with sodium carbonate solution.Except that desolvating, obtained this title compound by rotary evaporation, be white crystalline solid, its purity is enough to carry out later reaction.Output: 21.1g (100%). 1HNMR (CDCl 3), 300MHz: δ 7.98 (d, 2H); 7.38 (d, 2H); 3.90 (s, 3H); 3.86 (s, 2H); 2.39 (m, 1H); 2.01 (m, 2H); 1.77 (m, 2H); 1.51 (bs, 1H); 0.93-1.18 (m, 5H); 0.82 (s, 9H); HPLC-MS (method B:R t=4.87m/z=304 (M+1). step 2: trans-4-[1-(3,5-two (trifluoromethyl) phenyl)-3-(4-tert-butylcyclohexyl) urea groups methyl] methyl benzoate
With trans-4-[(4-tert-butylcyclohexyl amino) methyl] methyl benzoate (1.0g, 3.3mmol) be dissolved in the acetonitrile (40mL), add isocyanic acid 3,5-two (trifluoromethyl) phenylester (0.9g, 3.6mmol), and with this reaction mixture in stirred overnight at room temperature.With the solvent vacuum concentration to 5-10mL, by filtering to isolate crystallization, obtained 1.45g (81%) trans-4-[1-(3,5-two (trifluoromethyl) phenyl)-3-(4-tert-butylcyclohexyl) urea groups methyl] methyl benzoate: 1H-NMR (DMSO-d 8): δ 9.08 (s, 1H); 8.25 (s, 2H); 7.91 (d, 2H); 7.60 (s, 1H); 7.40 (d, 2H); 4.65 (s, 2H); 4.07 (broad peak, 1H); 3.83 (s, 3H); 1.71 (broad peak, 4H); 1.42 (broad peak, 2H); 1.11 (broad peak, 2H); 0.93 (broad peak, 1H); HPLC-MS (method B): m/z=559 (M+1); R t=9.40min; M.p.188-190 ℃ of (CH 3CN). ultimate analysis: C 28H 32N 2F 6O 3Calculated value: C, 60.21%; H, 5.77%; N, 5.02%. measured value: C, 60.46%; H, 5.94%; N, 5.00%. step 2a: trans-4-[1-(3,5-two (trifluoromethyl) phenyl)-3-(4-tert-butylcyclohexyl) urea groups methyl] phenylformic acid
With trans-4-[1-(3,5-two (trifluoromethyl) phenyl)-and 3-(4-tert-butylcyclohexyl) urea groups methyl] methyl benzoate (1.4g) is suspended in the dehydrated alcohol (20mL), adding sodium hydroxide (2N, 11mL), and with the slight backflow of this reaction mixture 2 hours.Vacuum is removed ethanol, adds entry (40mL), and usefulness hydrochloric acid (4N) to acid-reaction, adds ethyl acetate (200mL) with pH regulator then.Isolate organic phase, water (dried over mgso use in 4 * 50mL) washings, filters also vacuum-evaporation, obtained 1.1g (85%) trans-4-[1-(3,5-two (trifluoromethyl) phenyl)-3-(4-tert-butylcyclohexyl) urea groups methyl] phenylformic acid, be solid.
1H-NMR(DMSO-d 6)：δ12.85(s，1H)；9.08(s，1H)；8.25(s，2H)；7.89(d，2H)；7.61(s，1H)；
7.38(d，2H)；4.65(s，2H)；4.07(m，1H)；1.73(m，4H)；1.43(m，2H)；1.11(m，2H)；0.93(m，
1H); 0.82 (s, 9H); M.p.239-241 ℃ (MeCN). ultimate analysis: C 27H 30N 2F 6O 3Calculated value: C, 59.55%; H, 5.55%; N, 5.14%. measured value: C, 59.58%; H, 5.65%; N, 5.11%.
After step 3 and 4, obtained this title compound. 1H-NMR (DMSO-d 6): δ 0.83 (s, 9H), 0.90-0.99 (m, 1H), 1.06-1.15 (m, 2H), 1.37-1.50 (m, 2H), 1.64-1.80 (m, 4H), 3.35-3.43 (m, 1H), 3.52-3.61 (m, 1H), 4.01-4.11 (m, 1H), 4.18 (t, 1H), 4.63 (s, 2H), 7.35 (d, 2H), 7.61 (s, 1H), 7.81 (d, 2H), 8.27 (s, 2H), 8.43 (t, 1H), 9.07 (s, 1H), 12.46 (broad peak, 1H); HPLC-MS (method A): m/z=632 (M+1); R t=8.00min; M.p.185-187 ℃. ultimate analysis: C 30H 35F 6N 3O 5Calculated value: C, 57.05%; H, 5.59%; N, 6.65%. measured value: C, 57.32%; H, 5.70%; N, 6.27%. embodiment 14 (general method (A)) (R)-trans-3-{4-[3-(3,5-two (trifluoromethyl) phenyl)-1-(4-tert-butylcyclohexyl) urea groups methyl benzoyl amino-2 hydroxy propanoic acid
1H-NMR(DMSO-d 6)：δ0.82(s，9H)，0.93(m，1H)，1.11(m，2H)，1.43(m，2H)，1.71(m，4H)，
3.38(m，1H)，3.56(m，1H)，4.05(m，1H)，4.16(t，1H)，4.63(s，2H)，7.33(d，2H)，7.61(s，1H)，
7.80 (d, 2H), 8.26 (s, 2H), 8.43 (t, 1H); HPLC-MS (method A): m/z=632 (M+1); R t=8.17
Min; M.p.184-187 ℃. ultimate analysis: C 30H 35N 3F 6O 5The calculated value of (+0.5 ethyl acetate): C, 56.88%; H, 5.82%; N, 6.22%. measured value: C, 56.63%; H, 5.66%; N, 6.47%. embodiment 15 (general method (A)) is trans-(R)-and 3-{4-[3-(3-methyl-5-trifluoromethyl)-1-(4-tert-butylcyclohexyl) urea groups methyl] benzoyl-amido }-2 hydroxy propanoic acid 1H-NMR (DMSO-d 6): δ 0.82 (s, 9H), 0.93 (m, 1H), 1.11 (m, 2H), 1.43 (m, 2H), 1.71 (m, 4H), 2.33 (s, 3H), 3.38 (m, 1H), 3.56 (m, 1H), 4.05 (m, 1H), 4.16 (t, 1H), 4.63 (s, 2H), 7.10 (s, 1H), 7.33 (d, 2H), 7.73 (s, 1H), 7.80 (d, 2H), 8.43 (t, 1H), 8.62 (s, 1H); HPLC-MS (method A): m/z=578 (M+1); R t=7.45min. embodiment 16 (general method (A)) (RS)-3-{4-[1-(4-tert-butyl-phenyl)-3-(4-Trifluoromethoxyphen-l) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid
Figure A0181159100852
Step 1:4-[1-(4-tert-butyl-phenyl)-3-(4-Trifluoromethoxyphen-l) urea groups methyl] phenylformic acid
(10.6g 64mmol) is dissolved in the methyl alcohol (200mL) with the 4-acyl radical methyl benzoate.Add 4-tertiary butyl aniline (9.61g, 64mmol), and with gained suspension returning 15 minutes.After being cooled to room temperature, add TFA (5.18mL, 68mmol), add then in batches sodium cyanoborohydride (3.26g, 52mmol).With the gained mixture stirring at room 2 hours, and vacuum concentration.Resistates is distributed between ethyl acetate (200mL) and 1N aqueous sodium hydroxide solution (150 and 100mL).With organic phase drying (sal epsom) and vacuum-evaporation, obtained 19.0g (99%) 4-[(4-tert-butyl-phenyl amino) methyl] methyl benzoate, be solid. 1H-NMR (CDCl 3): δ 1.28 (9H, s), 3.92 (3H, s), 4.39 (2H, s), 6.57 (2H, d), 7.20 (2H, d), 7.44 (2H, d), 8.00 (2H, d). step 2:
With above-mentioned methyl benzoate (0.73g 2.44mmol) is dissolved in the acetonitrile (7mL), add isocyanic acid 4-Trifluoromethoxyphen-l ester (405 μ L, 2.68mmol).The gained mixture stirring at room 3 hours, was refluxed 1.5 hours then.Behind cooling and the vacuum concentration, by the silica gel chromatography resistates, at first use mixture (1: the 6) wash-out of ethyl acetate and heptane, use mixture (1: the 3) wash-out of ethyl acetate and heptane then, obtained 1.14g (94%) 4-[1-(4-tert-butyl-phenyl)-3-(4-three fluoro-p-methoxy-phenyls) urea groups methyl] methyl benzoate, be oily matter. 1H-NMR (CDCl 3): δ 1.35 (9H, s), 3.91 (3H, s), 4.97 (2H, s), 6.30 (1H, s), 7.1 (4H, m), 7.32-7.43 (6H, m), 7.96 (2H, d) .TLC:Rf=0.11 (SiO 2Ethyl acetate/heptane (1: 6)); HPLC-MS (method B): m/z=501 (M+1); R t=9.05min step 2a:
(1.14g 2.28mmol) is dissolved in 1, in the 4-dioxane (25 mL), and adds 1N aqueous sodium hydroxide solution (5mL) with above-mentioned urea groups methyl-toluate.With the gained mixture stirring at room 1 hour.Add ethanol (15mL) and 1N aqueous sodium hydroxide solution (5mL), and with the gained mixture stirring at room 16 hours.With this mixture vacuum concentration, (distribute between 2 * 50mL) at 1N hydrochloric acid (100mL) and ethyl acetate.Organic phase drying (sal epsom) and vacuum concentration with merging have obtained 847mg (76%) 4-[1-(4-tert-butyl-phenyl)-3-(4-Trifluoromethoxyphen-l) urea groups methyl] phenylformic acid, be solid. 1H-NMR (CDCl 3): δ 1.33 (9H, s), 3.91 (3H; s), 4.97 (2H, s); 6.30 (1H, s), 7.1 (4H; m), 7.33 (2H, d); 7.43 (4H; m), 8.03 (2H, d). step 3:(RS)-3-[4-[1-(4-tert-butyl-phenyl)-3-(4-Trifluoromethoxyphen-l) urea groups methyl] benzoyl-amido }-the 2 hydroxy propanoic acid ethyl ester
To [1-(4-tert-butyl-phenyl)-3-(4-Trifluoromethoxyphen-l) urea groups methyl] phenylformic acid (1.0g, 2.06mmol) add in the solution in DMF (1mL) and DCM (10mL) 1-hydroxyl-7-azepine benzotriazole (0.33g, 2.47mmol).Stirring at room 1 hour, add successively then EDAC (0.47g, 2.47mmol), (RS)-isoserine carbethoxy hydrochloride (0.52g, 3.09mmol) and diisopropyl ethyl amine (1.1mL, 6.18mmol)., after 17 hours this reaction mixture is distributed between water, salt solution and ethyl acetate in stirring at room.Use the ethyl acetate extraction water again.With organic phase water and the salt water washing that merges.After dry (sal epsom), and filter, with organic phase vacuum-evaporation.By the silica gel chromatography resistates, with mixture (6: the 4) wash-out of toluene and ethyl acetate.Obtained 1.2g (97%) (RS)-3-4-[1-(4-tert-butyl-phenyl)-3-(4-Trifluoromethoxyphen-l) urea groups methyl]-benzoyl-amido-the 2 hydroxy propanoic acid ethyl ester, be oily matter. 1H-NMR (DMSO-d 6): δ 1.12 (t, 3H), 1.27 (s, 9H), 3.45 (m, 2H), 4.05 (q, 2H), 4.21 (dd, 1H), 4.98 (s, 2H), 5.67 (d, 1H), 7.20 (dd, 4H), 7.35 (dd, 4H), 7.55 (d, 2H), 5.77 (d, 2H), 8.42 (s, 1H), 8.48 (t, 1H); HPLC-MS (method B): m/z=602 (M+1); R t=3.38min. step 4:
With 3-4-[1-(4-tert-butyl-phenyl)-3-(4-Trifluoromethoxyphen-l) urea groups methyl] benzoyl-amino }-solution stirring of 2 hydroxy propanoic acid ethyl ester in dehydrated alcohol (20mL), and add 1M sodium hydroxide (6mL).Continue to stir 17 hours, with hydrochloric acid with this solution acidifying.Inclining solvent, by heating remaining oily matter is dissolved in the acetonitrile (20mL).Under vigorous stirring, drip water (20mL), this mixture is cooled to room temperature.Filter out precipitation, wash with water, drying has obtained this title compound of 0.51g (43%), is solid. 1H-NMR (DMSO-d 6): δ 1.25 (s, 9H), 3.50 (ddd, 2H), 4.18 (dd, 1H), 4.95 (s, 2H), 7.20 (dd, 4H), 7.39 (dd, 4H), 7.52 (d, 2H), 7.78 (d, 2H), 8.32 (s, 1H), 8.46 (t, 1H); HPLC-MS (method B): m/z=574 (M+1); R t=3.07min. ultimate analysis: C 29H 30F 3N 3O 6Calculated value: C, 60.73%; H, 5.27%; N, 7.33%. measured value: C, 60.77%; H, 5.37; N%, 7.26%. embodiment 17 (general method (A)) (RS)-3-{4-[1-(4-hexamethylene-1-thiazolinyl phenyl)-3-(3, the 5-dichlorophenyl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid Step 3:(RS)-and 3-{4-[1-(4-hexamethylene-1-thiazolinyl phenyl)-3-(3, the 5-dichlorophenyl) urea groups methyl] benzoyl-amino }-2 hydroxy propanoic acid ethyl ester output: 0.33g (89%). 1H-NMR (CDCl 3): δ 1.30 (t, 3H), 1.68 (m, 2H); 1.79 (m, 2H), 2.23 (m, 2H); 2.38 (m, 2H), 3.41 (d, 1H); 3.83 (m, 2H), 4.27 (q, 2H); 4.37 (dd, 1H), 4.92 (s, 2H); 6.20 (m, 1H), 6.27 (s, 1H); 6.51 (t, 1H), 6.98 (s, 1H); 7.04 (d, 2H), 7.18 (d, 2H); 7.33 (d, 2H), 7.42 (d, 2H); 7.68 (d, 2H). step 4:(RS)-3-{4-[1-(4-hexamethylene-1-thiazolinyl phenyl)-3-(3, the 5-dichlorophenyl) urea groups methyl] benzoyl-amido }-2 hydroxy propanoic acid
With (RS)-3-{4-[1-(4-hexamethylene-1-thiazolinyl phenyl)-3-(3; the 5-dichlorophenyl) urea groups methyl]-benzoyl-amido }-2 hydroxy propanoic acid ethyl ester (0.99g; 1.61mmol) solution stirring in ethanol (15mL) and THF (15mL), and add 1M sodium hydroxide (6mL).This mixture was stirred 4 hours at 40 ℃, and use the 1N hcl acidifying.After the vacuum-evaporation, with preparation property HPLC (Gilson system) purifying resistates partly.Merge pure fraction, and vacuum-evaporation, obtained this title compound of 0.74g (79%), be solid. 1H-NMR (DMSO-d 6): δ 1.56 (m, 2H), 1.70 (m, 2H), 2.17 (s, 2H), 2.33 (s, 2H), 3.35 (m, 2H), 3.55 (m, 2H), 4.15 (dd, 1H), 4.95 (s, 2H), 6.20 (s.1H), 7.12 (s, 1H), 7.18 (d, 2H), 7.33 (d, 2H), 7.40 (d, 2H), 7.62 (s, 2H), 7.76 (d, 2H), 8.43 (t, 1H), 8.55 (s, 1H); HPLC-MS (method B): m/z=582 (M+1); R t=5.13min ultimate analysis: C 29H 30Cl 2N 3O 5Calculated value: C, 61.86%; H, 5.02%; N, 7.21%. measured value: C, 61.10%; H, 5.05%; N, 7.03%. embodiment 18 (S)-3-{4-[1-(4-hexamethylene-1-thiazolinyl phenyl)-3-(3, the 5-dichlorophenyl) urea groups methyl] benzoyl-amido }-2 hydroxy propanoic acid
With 4-[1-(4-hexamethylene-1-thiazolinyl phenyl)-3-(3, the 5-dichlorophenyl) urea groups methyl] (130mg 0.26mmol) is dissolved among the DMF (2mL) phenylformic acid, add EDAC (50mg then, 0.26mmol) and HOBt (43mg, 0.32mmol), and with this reaction mixture stirring at room 1 hour.With above-mentioned (S)-2,2-dimethyl-5-oxo-[1,3] dioxolane-4-ylmethyl trifluoroacetic acid ammonium crude product is dissolved among the DMF (1mL), and (450mg 3.5mmol) is added in this reaction mixture together with diisopropyl ethyl amine.With this mixture stirring at room 16 hours.This reaction mixture is transferred on the silicagel column, and use the DCM wash-out, obtained (S)-4-[1-(4-hexamethylene-1-thiazolinyl phenyl)-3-(3 after the evaporation, the 5-dichlorophenyl) urea groups methyl]-N-(2,2-dimethyl-5-oxo-[1,3] dioxolane-4-ylmethyl) the benzamide crude product is oily matter.This oily matter is dissolved in the acetonitrile (5mL) again, add hydrochloric acid (1N, 5mL), and with this mixture stirring at room 1.5 hours.Except that desolvating,, obtained this title compound by evaporation by partly preparing HPLC purifying crude product (acetonitrile/water gradient).HPLC-MS (method B): m/z=582 (M+1); R t=5.10 minutes.Embodiment 19 (general method (A)) (R)-3-{4-[1-(4-hexamethylene-1-thiazolinyl phenyl)-3-(3, the 5-dichlorophenyl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid
Figure A0181159100901
Step 3:(R)-and 3-{4-[1-(4-hexamethylene-1-thiazolinyl phenyl)-3-(3, the 5-dichlorophenyl) urea groups methyl] benzoyl-amido }-the 2 hydroxy propanoic acid ethyl ester 1H-NMR (acetone-d 6): δ 1.20 (t, 3H), 1.70 (dm, 4H), 2.31 (dm, 4H), 3.70 (m, 2H), 4.15 (q, 2H), 4.35 (dd, 1H), 5.02 (s, 2H), 6.22 (m, 1H), 7.00 (s, 1H), 7.0 (d, 2H), 7.40 (dd, 4H), 7.61 (ds, 2H), 7.80 (d, 3H), 7.89 (s, 1H). step 4:
With (R)-3-{4-[1-(4-hexamethylene-1-thiazolinyl phenyl)-3-(3; the 5-dichlorophenyl) urea groups methyl]-benzoyl-amido }-2 hydroxy propanoic acid ethyl ester (0.60g; 0.98mmol) solution stirring in ethanol (5mL) and THF (5mL); and adding 4N sodium hydroxide (0.76mL, 2.94mmol).This solution stirring at room 3 hours, is used the 1N hcl acidifying then.Vacuum-evaporation has obtained oily matter, and it is distributed between ethyl acetate, water and salt solution.Water is extracted 2 times the organic phase that water and salt water washing merge with ethyl acetate.Dry (sal epsom) filters, and vacuum-evaporation, has obtained this title compound of 0.43g (73%), is solid. 1H-NMR (DMSO-d 6): δ 1.50-1.80 (4H, m), 2.08-2.38 (4H, m), 3.36-3.65 (2H, m), 4.14-4.24 (1H, m), 4.96 (2H, m), 6.17 (1H, t), 7.14 (1H, t), 7.18 (2H, d), 7.35 (2H, d), 7.42 (2H, d), 7.63 (2H, d), 7.78 (2H, d), 8.48 (1H, t), 8.55 (1H, s); HPLC-MS (method B): m/z=582 (M+1); R t=5.11min. embodiment 20 (general method (A)) (R)-3-{4-[3-(3-chloro-phenyl-)-1-(4-hexamethylene-1-thiazolinyl phenyl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid 1H-NMR (DMSO-d 6): δ 1.56-1.71 (m, 4H), 2.15-2.33 (m, 4H), 3.37-3.51 (m, 2H), 4.14-4.17 (m, 1H), 4.96 (s, 1H), 6.17 (t, 1H), 7.12 (dd, 1H), 7.27-7.41 (m, 8H), 7.62 (t, 1H), 7.87 (d, 2H), 8.38-8.43 (m, 3H); HPLC-MS (method B): m/z=548 (M+1); R t=4.69min. embodiment 21 (general method (A)) (R)-3-{4-[1-(4-hexamethylene-1-thiazolinyl phenyl)-3-phenylurea ylmethyl] benzoyl-amido-2 hydroxy propanoic acid
Figure A0181159100912
1H-NMR (DMSO-d 6): δ 1.56-1.71 (m, 4H), 2.15-2.40 (m, 4H); 3.30-3.51 (m, 2H), 4.14-4.19 (m, 1H); 4.97 (s, 1H), 6.16 (t, 1H); 6.98 (t, 1H), 7.12-7.48 (m, 10H); 7.79 (d, 2H), 8.15 (s; 1H), 8.43 (t, 1H). embodiment 22 (general method (A)) (R)-3-{4-[3-benzyl-1-(4-hexamethylene-1-thiazolinyl phenyl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid 1H-NMR (DMSO-d 6): δ 1.50-1.75 (m, 4H), 1.86 (s, 2H), 2.08 (s; 2H), and 3.30-3.60 (m, 2H), 4.13-4.20 (m; 1H), 4.25 (d, 2H), 4.87 (s; 2H), 6.18 (t, 1H), 6.55 (t; 1H), and 7.08-7.42 (m, 11H), 7.77 (d; 2H), 8.48 (t, 1H). embodiment 23 (general method (A)) (RS)-3-{4-[1-(4-hexamethylene-1-thiazolinyl phenyl)-3-(3, the 5-dichlorophenyl) urea groups methyl] benzoyl-amido-2-fluorine propionic acid Step 1 and 2:4-[1-(4-hexamethylene-1-thiazolinyl phenyl)-3-(3, the 5-dichlorophenyl) urea groups methyl] phenylformic acid 1H-NMR (DMSO-d 6): δ 1.52-1.77 (m, 4H), 2.10-2.23 (m, 2H), 2.26-2.38 (m, 2H), 4.95 (s, 2H), 6.18 (t, 1H), 7.14 (t, 1H), 7.17 (d, 2H), 7.34 (d, 2H), 7.40 (d, 2H), 7.64 (dd, 2H), 7.85 (d, 2H), 8.55 (s, 1H). ultimate analysis: C 27H 24N 2O 3Cl 2Calculated value: C, 65.46%; H, 4.88%; N, 5.65%. measured value: C, 65.43%; H, 5.10%; N, 5.66%. step 3:(RS)-3-{4-[1-(4-hexamethylene-1-thiazolinyl phenyl)-3-(3, the 5-dichlorophenyl) urea groups methyl] benzoyl-amido }-2-fluorine methyl propionate 1H-NMR (DMSO-d 6): δ 1.52-1.75 (m, 4H), 2.10-2.40 (m, 4H), 3.60-3.81 (m, 5H), 4.95 (s, 2H), 5.04-5.35 (m, 1H), 6.18 (m, 1H), 7.10-7.80 (m, 11H), 8.55 (s, 1H), 8.75 (t, 1H), 13.45 (brs, 1H). step 4:
With (RS)-3-{4-[1-(4-hexamethylene-1-thiazolinyl phenyl)-3-(3, the 5-dichlorophenyl) urea groups methyl] benzoyl-amido }-hydrolysis in THF and methanol mixture of 2-fluorine methyl propionate, obtained this title compound.
1H-NMR(DMSO-d 6)：δ1.59-1.72(m，4H)，2.15-2.33(m，4H)，3.58-3.81(m，2H)，4.96(s，2H)，
5.17-5.23(m，1H)，6.18(m，1H)，7.13-7.80(m，11H)，8.54(s，1H)，8.73(t，1H)，13.45(brs，
1H). embodiment 24 (general method (A)) (R)-3-{4-[1-(4-cyclohexyl phenyl)-3-(4-trifluoromethylthio phenyl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid
Figure A0181159100931
Step 2:4-[1-(4-cyclohexyl phenyl)-3-(4-trifluoromethylthio phenyl) urea groups methyl] methyl benzoate
With 4-((4-cyclohexyl phenyl amino) methyl) methyl benzoate (0.32g 1mmol) is suspended in the acetonitrile (5mL), add isocyanic acid 4-(trifluoromethylthio) phenylester (0.24g, 1.1mmol).Add isocyanic ester (0.05g) after first day again, add a part of isocyanic ester (0.05g) after second day again.At the 3rd day stopped reaction, and vacuum concentration.By silica gel (30g) column chromatography purifying resistates, use ethyl acetate: normal heptane (400mL1: 4 and 100mL1: 1) wash-out has obtained 0.53g4-[1-(4-cyclohexyl phenyl)-3-(4-trifluoromethylthio phenyl) urea groups methyl] methyl benzoate. 1H-NMR (DMSO-d 6): δ 1.16-1.43 (m, 5H), 1.65-1.82 (m, 5H), 3.84 (s, 3H), 4.99 (s, 2H), 8.62 (s, 1H); HPLC-MS (method B): m/z=543 (M+1); R t=9.35min. step 2a:4-[1-(4-cyclohexyl phenyl)-3-(4-trifluoromethylthio phenyl) urea groups methyl] phenylformic acid
With 4-[1-(4-cyclohexyl phenyl)-3-(4-trifluoromethylthio phenyl) urea groups methyl] methyl benzoate (0.53g, 0.98mmol) be dissolved in ethanol (96%, 11mL) in, and add sodium hydroxide (4N, 1.47mL).This mixture stirring is spent the night.This reaction is concentrated into dried, adds entry (15mL), (4N 1.6mL) is acidified to pH2-3, and extracts with ethyl acetate (25mL) with hydrochloric acid.Water is used ethyl acetate (15mL) extraction once again, the organic phase water (10mL) that merges is washed 3 times, use dried over mgso, filter and vacuum concentration.From ethyl acetate: crystallization the normal heptane has obtained 0.34g4-[1-(4-cyclohexyl phenyl)-3-(4-three fluoro-methylthio phenyl bases) urea groups methyl] phenylformic acid. 1H-NMR (DMSO-d 6): δ 1.5-1.42 (m, 5H), 1.67-1.83 (m, 5H), 2.45 (m, 1H), 5.00 (s, 2H), 7.15-7.25 (dd, 4H), 7.40 (d, 2H), and 7.54-7.63 (dd, 4H), 7.88 (d, 2H), 7.62 (s, 1H), 12.90 (broad peak 1H), HPLC-MS (method B): m/z=529 (M+1); R t=8.55min; M.p.162.0-164.0 ℃. ultimate analysis: C 28H 27F 3N 2O 3The calculated value of S: C, 63.62%; H, 5.15%; N, 5.30%. measured value: C, 63.97%; H, 5.28%; N, 5.26%. step 3:(R)-3-{4-[1-(4-cyclohexyl phenyl)-3-(4-trifluoromethylthio phenyl) urea groups methyl] benzoyl-amido }-the 2 hydroxy propanoic acid methyl esters
With 4-[1-(4-cyclohexyl phenyl)-3-(4-trifluoromethylthio phenyl) urea groups methyl] phenylformic acid (0.32g 0.606mmol) is dissolved among the DMF (7mL), and add HOAt (0.10g, 0.727mmol) and EDAC (0.14g, 0.727mmol).This mixture was stirred 30 minutes.Add then (R)-3-amino-2 hydroxy propanoic acid methyl ester hydrochloride (0.14g) and diisopropyl ethyl amine (0.16mL, 0.909mmol).Should react to stir and spend the night.This reaction mixture and ethyl acetate (30mL) and water (15mL) are transferred in the separating funnel, and extraction.(15mL) extracts water once again with ethyl acetate, with the organic phase that merges with hydrochloric acid (0.2N, 3 * 10mL) and saturated sodium-chloride water solution (dried over mgso use in 3 * 10mL) washings, and filtration is vacuum concentration also.With resistates at post (silica gel; 30g) go up purifying; mixture (200mL with ethyl acetate and normal heptane; 40: 60 and 450mL1: 1) wash-out has obtained 0.33g (R)-3-{4-[1-(4-cyclohexyl phenyl)-3-(4-trifluoromethylthio phenyl)-urea groups methyl] benzoyl-amido }-the 2 hydroxy propanoic acid methyl esters. 1H-NMR (DMSO-d 6) δ 1.16-1.43 (m, 5H), 1.66-1.81 (m, 5H), 2.47 (m, 1H), 3.4 (m, 1H), 3.51 (m, 1H), 3.63 (s, 3H), 4.22 (q, 1H), 4.97 (s, 2H), 5.73 (d, 1H), 7.2 (dd, (4H), 7.35 (d, 2H), 7.60 (dd, 4H), 7.76 (d, 2H), 8.50 (t, 1H), 8.60 (s, 1H), HPLC-MS (method B): m/z=630 (M+1); R t=8.07min. step 4:
With (R)-3-{4-[1-(4-cyclohexyl phenyl)-3-(4-trifluoromethylthio phenyl) urea groups methyl] benzoyl-amino }-2 hydroxy propanoic acid methyl esters (0.32g; 0.508mmol) be dissolved in the ethanol (15mL); and adding sodium hydroxide (4N, 0.76mL, 3.05mmol).This reaction mixture was stirred 1.5 hours.With this reactive evaporation, add entry (15mL), with hydrochloric acid (4N, 0.8mL) acidifying.(20mL) extracts this mixture with ethyl acetate.Water is extracted once with ethyl acetate (15mL) again, and (organic phase that 3 * 10mL) washings merge is used dried over mgso to water, filters and concentrates, and has obtained this title compound (0.3g). 1H-NMR (DMSO-d 6): δ 1.12-1.42 (m, 5H), 1.66-1.82 (m, 5H), 2.45 (m, 1H), 3.38 (m, 1H), 3.54 (m, 1H), 4.17 (q, 1H), 4.96 (s, 2H), 5.45 (broad peak, 1H), 7.20 (dd, 4H), 7.34 (d, 2H), 7.60 (dd, 4H), 7.78 (d, 2H), 8.45 (t, 1H), 8.60 (s, 1H), 12.53 (broad peak, 1H), HPLC-MS (method B): m/z=616 (M+1); R t=7.68min. ultimate analysis: C 31H 32F 3N 3O 5The calculated value of S: C, 60.48%; H, 5.24%; N, 6.83%. measured value: C, 60.25%; H, 5.52%; N, 6.53%. embodiment 25 (general method (A)) (R)-3-{4-[1-(4-tetrahydrobenzene-1-base phenyl)-3-(3-methylsulfonyl-4-Trifluoromethoxyphen-l) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid The isocyanic acid 3-methyl sulphonyl that preparation is used in step 2-4-Trifluoromethoxyphen-l ester, intermediate D-N=C=O
To methyl-iodide (59.0g, 0.41mol) add in the solution in DMF (150mL) salt of wormwood (23.0g, 0.16mol).With added in 30 minutes in batches 2-(trifluoromethoxy) thiophenol (16.0g, 0.08mol).This reaction mixture vigorous stirring is spent the night.Add entry (250mL).(2 * 150mL) extract this reaction mixture with ethyl acetate.(4 * 100mL) washings, drying (sal epsom), and vacuum concentration have obtained 15.0g1-methylthio group-2-trifluoromethoxy with 50% saturated sodium-chloride water solution with the organic phase that merges.
With 1-methylthio group-2-Trifluoromethyl phenyl ether (15.0g 72mmol) is dissolved among the DCM (200mL), with 30 minutes with a small amount of mode repeatedly add metachloroperbenzoic acid (39.0g, 216mmol).Then this reaction mixture sat is spent the night.Add DCM (200mL), add lentamente then sodium hydroxide (2N, 200mL).Isolate organic phase, (dry (sal epsom) and vacuum concentration have obtained 15.8g1-methyl sulphonyl-2-Trifluoromethyl phenyl ether for 2N, 3 * 150mL) washings with sodium hydroxide. 1H-NMR (400 MHz, CDCl 3): δ 8.11 (d, 1H), 7.71 (t, 1H), 7.48 (m, 2H) 3.23 (s 1H); M.p.44-46 ℃. ultimate analysis: C 8H 7F 3O 3The calculated value of S: C, 40.00%; H, 2.94%. measured value: C, 40.22%; H, 2.92%.
(15.7g 65mmol) is dissolved in the vitriol oil (27mL), and this solution is heated to 40 ℃ with 1-methyl sulphonyl-2-Trifluoromethyl phenyl ether.With dripped in 45 minutes nitric acid (100%, 27mL).60 ℃ of standing over night, cooling is poured on the trash ice (300mL) then with this reaction mixture.By the filtering separation precipitated product, (10 * 50mL) washings, dry (sal epsom) has obtained 17.5g3-methyl sulphonyl-4-trifluoromethoxy oil of mirbane to water.
1H-NMR(400MHz，DMSO-d 6)：δ8.69(d，1H)，8.64(d，1H)，7.95(d，1H)3.45(s3H)；M.p.
102-104 ℃. ultimate analysis: C 8H 6F 3NO 5The calculated value of S: C, 33.69%; H, 2.12%; N, 4.91%. measured value: C, 33.91%; H, 2.08%; N, 4.92%.
3-methyl sulphonyl-4-trifluoromethoxy oil of mirbane (17.5g) is dissolved in the methyl alcohol (400mL), add then palladium carbon (10%, 50% water, 3.2g).With the hydrogenation 17 hours under 1atm hydrogen of this reaction mixture, filter and vacuum concentration, obtained 14.3g3-methyl sulphonyl-4-trifluoro-methoxyaniline. 1H-NMR (400MHz, DMSO-d 6): δ 7.26 (d, 1H), 7.14 (d, 1H), 6.85 (dd, 1H) 5.89 (s, and 2H) 3.21 (s, 3H); M.p.106-109 ℃. ultimate analysis: C 8H 8F 3NO 3The calculated value of S: 37.65%C, 3.16%H, 5.49%N. measured value: 37.65%C, 3.14%H, 5.45%N.
3-methyl sulphonyl-4-trifluoro-methoxyaniline in being dissolved in ethyl acetate (6mL) (2.0mmol, 500mg) the middle solution (5mL) of 3N hydrogenchloride in ethyl acetate, the vacuum concentration then of adding.(3 * 5mL) handle, at every turn vacuum concentration all with toluene with resistates.(6mmol 0.73mL), and refluxed 2 hours this suspension is slight to add toluene (10mL) and trichloromethylchloroformate under nitrogen atmosphere in resistates.(6mmol 0.73mL), and continues to reflux and spends the night to add trichloromethylchloroformate again.With this reaction mixture vacuum concentration, obtained isocyanic acid 3-methyl sulphonyl-4-Trifluoromethoxyphen-l ester.Step 3:(R)-and 3-{4-[1-(4-tetrahydrobenzene-1-base phenyl)-3-(3-methylsulfonyl-4-Trifluoromethoxyphen-l) urea groups methyl] benzoyl-amido }-the 2 hydroxy propanoic acid methyl esters
This intermediate makes with general method (A) (step 1,2,2a and 3). 1H-NMR (DMSO-d 6): δ 1.60 (m, 2H), 1.72 (m, 2H), 2.18 (m, 2H), 2.36 (m, 2H), 3.27 (s, 3H), 3.41 (m, 1H), 3.51 (m, 1H), 3.61 (s, 3H), 4.23q, 1H), 4.96 (s, 2H), 5.70 (d, 1H), 6.18 (m, 1H), 7.19 (d, 2H), 7.33 (d, 2H), 7.39 (d, 2H), 7.53 (d, 1H), 7.75 (d, 2H), 8.00 (d, 1H), 8.18 (s, 1H), 8.50 (t, 1H), 8.85 (s, 1H); HPLC-MS (method B): m/z=690 (M+1): R t=6.92min. step 4:
With (R)-3-{4-[1-(4-tetrahydrobenzene-1-base phenyl)-3-(3-methylsulfonyl-4-Trifluoromethoxyphen-l) urea groups methyl] benzoyl-amido }-hydrolysis of 2 hydroxy propanoic acid methyl esters, obtained this title compound. 1H-NMR (DMSO-d 6): δ 1.60 (m, 2H), 1.72 (m, 2H), 2.18 (m, 2H), 2.36 (m, 2H), 3.27 (s, 3H), 3.41 (m, 1H), 3.51 (m, 1H), 4.17 (t, 1H), 4.96 (s, 2H), 5.50 (broad peak, 1H), 6.18 (m, 1H), 7.19 (d, 2H), 7.33 (d, 2H), 7.39 (d, 2H), 7.53 (d, 1H), 7.75 (d, 2H), 8.00 (d, 1H), 8.18 (s, 1H), 8.50 (t, 1H), 8.85 (s, 1H), 12.55 (broad peak, 1H); HPLC-MS (method B): m/z=676 (M+1); R t=6.50min. embodiment 26 (general method (A)) is trans-(R)-3-{4-[-3-(3,5-two (methyl) phenyl)-1-(4-tert-butylcyclohexyl) urea groups methyl] benzoyl-amido]-2 hydroxy propanoic acid
Figure A0181159100981
Step 1 and 2: trans-4-[3-(3,5-two (methyl) phenyl)-1-(tert-butylcyclohexyl) urea groups methyl] methyl benzoate 1H-NMR (DMSO-d 6): δ 0.82 (s, 9H), 0.93 (m, 1H), 1.11 (m, 2H), 1.41 (m, 2H), 1.71 (m, 4H), 2.23 (s, 6H), 3.83 (s, 3H), 4.09 (m, 1H), 4.61 (s, 2H), 6.60 (s, 1H), 7.08 (s, 2H), 7.38 (d, 2H), 7.90 (d, 2H), 8.20 (s, 1H); HPLC-MS (method B): m/z=451 (M+1); R t=8.93min. step 2a: trans-4-[3-(3,5-two (methyl) phenyl)-1-(tert-butylcyclohexyl) urea groups methyl] phenylformic acid
This compound is by with trans-4-[3-(3,5-two (methyl) phenyl)-1-(tertiary butyl-cyclohexyl) urea groups methyl] the methyl benzoate hydrolysis makes. 1H-NMR (DMSO-d 6): δ 0.82 (s, 9H), 0.93 (m, 1H), 1.11 (m, 2H), 1.41 (m, 2H), 1.71 (m, 4H), 2.23 (s, 6H), 4.09 (m, 1H), 4.61 (s, 2H), 6.60 (s, 1H), 7.08 (s, 2H), 7.38 (d, 2H), 7.90 (d, 2H), 8.20 (s, 1H), 12.82 (s, 1H); HPLC-MS (method B): m/z=437 (M+1); R t=8.00min. ultimate analysis: C 27H 36N 2O 3Calculated value: C, 74.28%; H, 8.31%; N, 6.42%. measured value: C, 74.31%; H, 8.40%; N, 6.35%.Step 3: trans-(R)-and 3-{4-[-3-(3,5-two (methyl) phenyl)-1-(4-tert-butylcyclohexyl) urea groups methyl] benzoyl-amido }-the 2 hydroxy propanoic acid methyl esters:
This compound is by trans-4-[3-(3,5-two (methyl) phenyl)-1-(tert-butylcyclohexyl) urea groups methyl] phenylformic acid makes. 1H-NMR (DMSO-d 6): δ 0.82 (s, 9H), 0.93 (m, 1H), 1.11 (m, 2H), 1.43 (m, 2H), 1.71 (m, 4H), 2.23 (s, 6H), 3.42 (m, 1H), 3.52 (m, 1H), 3.63 (s, 3H), 4.05 (m, 1H), 4.23 (q, 1H), 4.59 (s, 2H), 5.70 (d, 1H), 6.58 (s, 1H), 7.08 (s, 2H), 7.30 (d, 2H), 7.78 (d, 2H), 8.18 (s, 1H), 8.47 (t, 1H); HPLC-MS (method B): m/z=538 (M+1); R t=7.43min; M.p.159-160 ℃. ultimate analysis: C 31H 43N 3O 5Calculated value: C, 69.25%; H, 8.06%; N, 7.81%. measured value: C, 69.03%; H, 8.15%; N, 7.79%. step 4:
With trans-(R)-3-{4-[-3-(3,5-two (methyl) phenyl)-1-(4-tert-butylcyclohexyl) urea groups methyl] benzoyl-amido-hydrolysis of 2 hydroxy propanoic acid methyl esters, obtained this title compound. 1H-NMR (DMSO-d 6): δ 0.82 (s, 9H), 0.93 (m, 1H), 1.11 (m, 2H), 1.43 (m, 2H), 1.71 (m, 4H), 2.23 (s, 6H), 3.40 (m, 1H), 3.55 (m, 1H), 4.05 (m, 1H), 4.18 (t, 1H), 4.59 (s, 2H), 6.58 (s, 1H), 7.08 (s, 2H), 7.30 (d, 2H), 7.78 (d, 2H), 8.18 (s, 1H), 8.47 (t, 1H); HPLC-MS (method B): m/z=524 (M+1); R t=7.08min. ultimate analysis: C 30H 41N 3O 5, 1.5H 2The calculated value of O: C, 65.43%; H, 8.05%; N, 7.63%. measured value: C, 65.54%; H, 7.93%; N, 7.44%. embodiment 27 (general method (A)) (R)-3-{4-[1-(4-cyclohexyl phenyl)-3-(3, the 5-dichlorophenyl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid 1H-NMR (CDCl 3): δ 7.64 (d, 2H), 7.49 (br s, 1H), 7.25-7.15 (m, 6H), 7.03 (d, 2H), 6.90 (m, 1H), 6.40 (s, 1H), 4.75 (s, 2H), 4.30 (brs, 1H), 3.80-3.60 (m, 2H), 2.49 (m, 1H), 1.90-1.65 (m, 5H), 1.45-1.25 (m, 5H); HPLC-MS (method B): m/z=584 (M+1); R t=5.28min. embodiment 28 (general method (A)) (R)-(3-{4-[1-(4-hexamethylene-1-thiazolinyl phenyl)-3-(3-fluoro-5-trifluoromethyl) urea groups methyl] benzoyl-amido }-2 hydroxy propanoic acid 1H-NMR (DMSO-d 6): δ 8.75 (s, 1H), 8.42 (t, 1H), 7.75 (d, 4H), 7.45-7.30 (m, 4H), 7.20 (d, 3H), 6.20 (s, 1H), 4.96 (s, 2H), 4.15 (dd, 1H), 3.55 (m, 1H), 3.40 (m, 1H), 2.35 (brs, 2H), 2.15 (brs, 2H) .1.75-1.55 (m, 4H); HPLC-MS (method B): m/z=600 (M+1); R t=5.01min. embodiment 29 (general method (A)) (R)-3-{4-[1-(4-cyclohexyl phenyl)-3-(3-methylthio group phenyl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid
Figure A0181159101012
1H-NMR (DMSO-d 6): δ 12.2 (brs, 1H), 8.44 (t, 1H), 8.20 (s, 1H), 7.78 (m, 2H), 7.40 (s, 1H), 7.33 (m, 2H), 7.25-7.10 (m, 6H), 6.84 (d, 1H), 4.95 (s, 1H), 4.15 (dd, 1H), 3.55 (m, 1H), 3.38 (m, 1H) .2.42 (s, 3H) 1.85-1.65 (m, 5H), 1.40-1.15 (m, 5H); HPLC-MS (method B): m/z=562 (M+1); R t=4.77min. embodiment 30 (general method (A)) (R)-3-{4-[1-(4-hexamethylene-1-thiazolinyl phenyl)-3-(2,2,4,4-tetrafluoro-4H-benzo [1,3] dioxine-6-yl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid
Figure A0181159101021
1H-NMR (CDCl 3): δ 7.70-7.50 (m, 3H), 7.45-7.30 (m, 4H), 7.25-6.85 (m, 6H), 6.12 (s, 1H), 4.80 (s, 2H), 4.28 (m, 1H), 3.70 (m, 2H), 2.40-2.00 (m, 4H), 1.70-1.55 (m, 4H); HPLC-MS (method B): m/z=644 (M+1); R t=5.13min. embodiment 31 (general method (A)) 3-{4-[1-(4-hexamethylene-1-thiazolinyl phenyl)-3-(3, the 5-dichlorophenyl) urea groups methyl] benzoyl-amido }-2 (R)-methoxypropionic acid:
Figure A0181159101022
Step 3:
With 4-[1-(4-hexamethylene-1-thiazolinyl phenyl)-3-(3,5-two chloro-phenyl) urea groups methyl] phenylformic acid (500mg, 1.0mmol), HOBt (184mg, 1.2mmol) and EDAC (232mg; 1.2mrol) be dissolved in the mixture of DCM (4.0mL) and DMF (1.0mL).With settled solution stirring at room 1 hour.(257mg, the 1.5mmol) solution in DCM (2.0mL) and DMF (0.2mL) add diisopropyl ethyl amine (515 μ L) then to add 3-amino-2 (R)-methoxypropionic acid methyl ester hydrochloride.This mixture in stirred overnight at room temperature, is used DCM (40mL) dilution then, and wash once with the mixture (1: 2) of saturated sodium-chloride/water.Use the anhydrous sodium sulfate drying organic phase, and vacuum-drying.Step 4:
This oily matter is dissolved in the mixture of THF (4.0mL) and methyl alcohol (4.0mL).Add the 4N aqueous sodium hydroxide solution (625 μ L, 2.5mmol), and with this mixture stirring at room 2 hours., remove then and desolvate pH regulator to 3.0 with 1N hydrochloric acid.Product is dissolved in the ethyl acetate (20mL) again, and water (20mL) washing.Return aqueous phase extracted with ethyl acetate (10mL), with the organic extract liquid that merges with sodium-chlor (2 * 20mL) washings, and use anhydrous sodium sulfate drying.Except that after desolvating, obtained this pure title compound of 230mg (67%). 1H-NMR (DMSO-d 6): δ 12.90 (bs, 1H), 8.55 (s, 1H), 8.54 (t, 1H), 7.76 (d, 2H), 7.63 (s, 2H), 7.41 (d, 2H), 7.34 (d, 2H), 7.20 (d, 2H), 7.15 (s, 1H), 6.18 (s, 1H), 4.95 (s, 2H), 3.90 (dd, 1H), 3.57 (m, 1H), 3.42 (m, 1H), 3.29 (s, 3H), 2.34 (m, 2H), 2.16 (m, 2H), 170 (m, 2H), 1.59 (m, 2H); HPLC-MS (method B): m/z=596.2 (M+1); Rt=5.93min. (4-{3-(3 for 3-for embodiment 32 (general method (A)); the 5-dichlorophenyl)-and 1-[4-(2-methyl cyclohexane-1-thiazolinyl) phenyl] the urea groups methyl } benzoyl-amido)-2-(R)-hydroxy-propionic acid and (R; S)-3-(4-{3-(3, the 5-dichlorophenyl)-1-[4-(6-methyl cyclohexane-1-thiazolinyl) phenyl] the urea groups methyl) benzoyl-amido)-2-(R)-hydroxy-propionic acid
Figure A0181159101031
Use 4-(2-methyl cyclohexane-1-thiazolinyl) aniline and (R, S)-mixture of 4-(6-methyl cyclohexane-1-thiazolinyl) aniline (member 11) and (R)-3-amino-2 hydroxy propanoic acid methyl esters (member 5), (A) obtained this title compound according to general method.(R, S)-3-(4-{3-(3, the 5-dichlorophenyl)-1-[4-(6-methyl cyclohexane-1-thiazolinyl) phenyl] the urea groups methyl } benzoyl-amido)-2 (R)-hydroxy-propionic acids: 1H-NMR (DMSO-d 6): δ 1,55 (s, 3H), 1,63 (bs, 4H), 2,03 (bs, 2H), 2,19 (bs, 2H), 3,47 (dm, 2H) .4,16 (m, 1H), 4,96 (s, 2H), 5,49 (bs, 1H), 7,15 (m, 5H), 7,33 (d, 2H), 7,61 (s, 2H), 7,78 (d, 2H), 8,45 (t, 1H), 8,65 (s, 1H), 12,53 (bs, 1H); M.p.:105-107 ℃; HPLC-MS (method B): m/z=596 (M +); R t=5,34min. 3-(4-{3-(3, the 5-dichlorophenyl)-1-[4-(6-methyl cyclohexane-1-thiazolinyl) phenyl] the urea groups methyl } benzoyl-amino)-2 (R)-hydroxy-propionic acids: 1H-NMR (DMSO-d 6): δ 0,90 (ds, 3H), 1,63 (bs; 4H), 2,03 (bs, 2H), 2; 19 (bs, 2H), 3,47 (dm, 2H); 4,16 (m, 1H), 4,96 (s; 2H), 5,49 (bs, 1H), 5; 93 (t, 1H), 7,15 (m, 5H); 7,33 (d, 2H), 7,61 (s; 2H), 7,78 (d, 2H), 8; 45 (t, 1H), 8,62 (s, 1H); 12,53 (bs, 1H). embodiment 33 (general method (A)) 3-{4-[1-[4-(4-tertiary butyl hexamethylene-1-thiazolinyl) phenyl]-3-(3, the 5-dichlorophenyl) urea groups methyl] benzoyl-amido }-2-(R)-hydroxy-propionic acid
Use 4-(4-tertiary butyl hexamethylene-1-thiazolinyl) aniline (member 12) and (R)-3-amino-2 hydroxy propanoic acid methyl esters (member 5), (A) obtained this title compound according to general method. 1H-NMR (DMSO-d 6): δ 0,88 (s, 9H), 1,23 (m, 2H), 1,93 (m, 2H), 2,27 (m, 3H), 3,47 (dm, 2H), 4,16 (dd, 1H), 4,95 (s, 2H), 6,19 (m, 1H), 7,13 (m1H), 7,18 (d, 2H), 7,33 (d, 2H), 7,39 (d, 2H), 7,62 (s, 2H), 7,77 (d, 2H), 8,44 (t, 1H), 8,55 (s, 1H), 12,53 (bs, 1H); M.p.:151-155 ℃; HPLC-MS (method B): m/z=638 (M +); R t=6.04 embodiment 34 (general method (A)) (R; S)-((3-(3 for 4-for 3-; the 5-dichlorophenyl)-1-(4-(5-methyl cyclohexane-1-thiazolinyl) phenyl) urea groups methyl)-benzoyl-amido)-2 hydroxy propanoic acid and (R; S)-3-(4-(3-(3, the 5-dichlorophenyl)-1-(4-(3-methyl cyclohexane-1-thiazolinyl) phenyl) urea groups methyl) benzoyl-amido)-2 hydroxy propanoic acid
Figure A0181159101051
Use (R, S)-4-(5-methyl cyclohexane-1-thiazolinyl) aniline has been with (R S)-mixture of 4-(3-methyl cyclohexane-1-thiazolinyl) aniline (member 13), has obtained the mixture (6: 4) of this title compound according to general method (A).(R, S)-3-(4-(3-(3, the 5-dichlorophenyl)-1-(4-(5-methyl cyclohexane-1-thiazolinyl) phenyl) urea groups methyl)-benzoyl-amido)-2 hydroxy propanoic acid: 1H-NMR (200 MHz, DMSO-d 6): δ 1.02 (d, 3H), 1.15-1-24 (m, 1H); 1.61-1.96 (m, 3H), 2.14-2.44 (m, 3H); 3.40 (t, 2H), 3.47-3.62 (m, 1H); 4.10-4.19 (m, 1H), 4.95 (s, 2H); 6.16 (t, 1H), 7.14 (t, 1H); 7.17 (d, 2H), 7.34 (d, 2H); 7.39 (d, 2H), 7.61 (d, 2H); 7.76 (d, 2H), 8.44 (t, 1H); 8.56 (s, 1H), 12.08 (sbr; 1H). (R, S)-3-(4-(3-(3, the 5-dichlorophenyl)-1-(4-(3-methyl cyclohexane-1-thiazolinyl) phenyl) urea groups methyl)-benzoyl-amido)-2 hydroxy propanoic acid: 1H-NMR (200MHz, DMSO-d 6): δ 1.02 (d, 3H), 1.15-1-24 (m, 1H); 1.61-1.96 (m, 3H), 2.14-2.44 (m, 3H); 3.40 (t, 2H), 3.47-3.62 (m, 1H); 4.10-4.19 (m, 1H), 4.95 (s, 2H); 6.04 (d, 1H), 7.14 (t, 1H); 7.17 (d, 2H), 7.34 (d, 2H); 7.39 (d, 2H), 7.61 (d; 2H), 7.76 (d, 2H); 8.44 (t, 1H), 8.53 (s; 1H), 12.08 (sbr, 1H). embodiment 353-{4-[3-[1 (S)-(4-chloro-phenyl-) ethyl]-1-(4-cyclohexyl phenyl) urea groups methyl] benzoyl-amido }-2 (R)-hydroxy-propionic acids 4-[(4-cyclohexyl phenyl amino) methyl] methyl benzoate
(47g 285mmol) is dissolved in the methyl alcohol (400mL), adds 4-cyclohexyl aniline (50g, 0.285mmol) solution in methyl alcohol (200mL) under mechanical stirring lentamente with the 4-acyl radical methyl benzoate.Add methyl alcohol (1L) again, with this suspension stirring at room 3 days.Filter, washing and vacuum-drying have obtained 90.7g (99%) 4-[(4-cyclohexyl phenyl imino-) methyl] methyl benzoate.It is dissolved in N-Methyl pyrrolidone (855mL) and the methyl alcohol (45mL).Add the sodium borohydride piller under mechanical stirring (42.4g 1.12mol), remains on temperature below 40 ℃ in batches.Then with this mixture stirring at room 2 hours, stirred 16 hours at 40 ℃.This mixture is cooled to 5 ℃, adds entry (2L) lentamente.Add acetone (350mL) then, and this mixture was stirred 1 hour at 5 ℃.Filter water (2 * 500mL) washings, and vacuum-drying have obtained 78g (86%) 4-[(4-cyclohexyl phenyl amino) methyl] methyl benzoate, be solid. 1H-NMR (CDCl 3): δ 1.2-1.4 (5H, m), 1.7-1.85 (5H, m); 2.39 (1H, m), 3.97 (3H, s); 4.04 (1H, bs), 4.39 (2H; s), 6.55 (2H, d); 7.01 (2H, d), 7.44 (2H; d), 8.00 (2H, d) .N-chloro amido formyl radical-4-[(4-cyclohexyl phenyl amino) methyl] methyl benzoate
With 4-[(4-cyclohexyl phenyl amino) methyl] (75g 0.23mol) is dissolved among the THF (750mL) methyl benzoate.Add diisopropyl ethyl amine (56.0mL, 0.32mmol) and 4-dimethylaminopyridine (1.0g; 8.1mmol).This solution is cooled to 5 ℃.(28.0g 0.093mol), remains on internal reaction temperature below 10 ℃ simultaneously to add carbonic acid two (trichloromethyl) ester in a small amount of mode repeatedly.This mixture 10 ℃ of restir 2 hours, is transferred in the separating funnel then.Add ethyl acetate (800mL) and water (1000mL).After the mixing, isolate organic layer, use anhydrous sodium sulfate drying, and be concentrated into dried by rotary evaporation in vacuo.Obtain product with quantitative yield, be stable, hard crystallisate. 1H-NMR (CDCl 3): δ 7.92 (d, 2H); 7.40 (d, 2H); 7.25 (d, 2H); 7.17 (d, 2H); 4.98 (s, 2H); 3.83 (s, 3H); 2.5 (m, 1H); 1.65-1.80 (m, 5H); (1.15-1.40 m, 5H) .N-chloro amido formyl radical-4-[(4-cyclohexyl phenyl amino) methyl] methyl benzoate
With 4-[(4-cyclohexyl phenyl amino) methyl] (75g 0.23mol) is dissolved among the THF (750mL) methyl benzoate.Add diisopropyl ethyl amine (56.0mL, 0.32mmol) and 4-dimethylaminopyridine (1.0g; 8.1mmol).This solution is cooled to 5 ℃.(28.0g 0.093mol), remains on internal reaction temperature below 10 ℃ simultaneously to add carbonic acid two (trichloromethyl) ester in a small amount of mode repeatedly.This mixture 10 ℃ of restir 2 hours, is transferred in the separating funnel then.Add ethyl acetate (800mL) and water (1000mL).After the mixing, isolate organic layer, use anhydrous sodium sulfate drying, and be concentrated into dried by rotary evaporation in vacuo.Obtain product with quantitative yield, be stable, hard crystallisate. 1H-NMR (CDCl 3): δ 7.92 (d, 2H), 7.40 (d, 2H), 7.25 (d, 2H), 7.17 (d, 2H), 4.98 (s, 2H), 3.83 (s, 3H), 2.5 (m, 1H), 1.65-1.80 (m, 5H), 1.15-1.40 (m, 5H) .4-[3-[1 (S)-(4-chloro-phenyl-) ethyl]-1-(4-cyclohexyl phenyl) urea groups methyl] methyl benzoate
In the 2L reaction flask that is equipped with mechanical stirrer, add N-chloro amido formyl radical-4-[(4-cyclohexyl phenyl amino) methyl] methyl benzoate (and 94g, 0.244mol), N-N-methyl-2-2-pyrrolidone N-(1.0L) and triethylamine (68mL, 0.487mol).(38.0g 0.244mol), remains on internal reaction temperature below 30 ℃ to drip (S)-1-(4-chloro-phenyl-) ethylamine in this settled solution.Continue to stir 2 hours, then this reaction mixture is distributed between water (1.0L) and ethyl acetate (1.0L).Behind the thorough mixing, isolate organic layer,, use anhydrous sodium sulfate drying then with 5% aqueous citric acid solution (500mL) and saturated ammonium chloride (500mL) washing.Remove and to desolvate, the oily matter of resistates is evaporated once from acetonitrile.Degree of purity of production is enough to carry out subsequently synthetic.Output: 103g (84%). 1H-NMR(DMSO-d 6)：δ7.88(d，2H)，7.32(d，2H)，7.30(d，4H)，7.19(d，2H)，7.08(d，2H)，6.28(d，1H)，4.88(dd，2H)，4.76(m，1H)，?3.81(s，3H)，2.44(m，1H)，1.65-1.80(m，5H)，1.15-
1.40 (m, 5H); HPLC-MS (method B): m/z=505 (M+1); Rt=6.17min.4-[3-[1 (S)-(4-chloro-phenyl-) ethyl]-1-(4-cyclohexyl phenyl) urea groups methyl] phenylformic acid
With 4-[3-[1 (S)-(4-chloro-phenyl-) ethyl]-1-(4-cyclohexyl phenyl) urea groups methyl] (35.0g 69.3mmol) is dissolved in the ethanol (400mL) methyl benzoate.Add 4N aqueous sodium hydroxide solution (100mL), with this clear soln stirring at room 3 hours.With 4N hydrochloric acid (100mL) this solution that neutralizes, be placed on the ice bath to cause crystallization.Collect crystal, the water thorough washing, and vacuum-drying is spent the night.Output: 34.25g (100%). 1H-NMR (DMSO-d 6): δ 12.85 (bs, 1H), 7.85 (d, 2H), 7.32 (d, 2H), 7.30 (d, 4H), 7.19 (d, 2H), 7.08 (d, 2H), 6.27 (d, 1H), 4.85 (m, 3H), 2.45 (m, 1H), 1.65-1.80 (m, 5H), 1.15-1.40 (m, 5H); HPLC-MS (method B): m/z=491 (M+1); Rt=5.50min. 3-{4-[3-[1 (S)-(4-chloro-phenyl-) ethyl]-1-(4-cyclohexyl phenyl) urea groups methyl] benzoyl-amido }-2 (R)-hydroxy methyl propionates
With 4-[3-[1 (S)-(4-chloro-phenyl-) ethyl]-1-(4-cyclohexyl phenyl) urea groups methyl] phenylformic acid (200mg, 0.4mmol), HOBt (75mg, 0.5mmol) and EDAC (94mg 0.5mmol) is dissolved in the mixture of DMF (200 μ L) and DCM (2mL).With this settled solution stirring at room 90 minutes.Add R-isoserine methyl ester hydrochloride (95mg, the 0.6mmol) solution in the mixture of DCM (1.0mL) and DMF (0.4mL), and with this reaction mixture in stirred overnight at room temperature.This reaction mixture is distributed between DCM (20mL) and water (20mL).Isolate organic phase, and, use anhydrous sodium sulfate drying, and be evaporated to dried with salt solution and water (1: 2) washing.Then resistates is evaporated from acetonitrile, obtained this title compound with quantitative yield. 1H-NMR (DMSO-d 6): δ 8.48 (t, 1H), 7.73 (d, 2H); 7.34 (d, 2H), 7.30 (d, 2H); 7.24 (d, 2H), 7.18 (d, 2H); 7.08 (d, 2H), 6.27 (d; 1H), 5.70 (d, 1H); 4.34 (m, 1H), 4.32 (d; 2H), 4.22 (q, 1H); 3.62 (s, 3H), 3.52 (m; 1H), 3.40 (m, 1H); 1.65-1.80 (m, 5H) .1.10-1.40 (m, 9H) .3-{4-[3-[1 (S)-(4-chloro-phenyl-) ethyl]-1-(4-cyclohexyl phenyl) urea groups methyl] benzoyl-amido-2 (R)-hydroxy-propionic acids
With 3-{4-[3-[1 (S)-(4-chloro-phenyl-) ethyl]-1-(4-cyclohexyl phenyl) urea groups methyl] benzoyl-amido }-2 (R)-hydroxy methyl propionate (280mg; 0.473mmol) be dissolved in the mixture of THF (2.5mL) and methyl alcohol (2.5mL), and add 4N aqueous sodium hydroxide solution (0.355mL).With this reaction mixture stirring at room 2 hours.By adding 1N hydrochloric acid with pH regulator to 3.0., except that desolvating resistates is dissolved in the ethyl acetate (10mL) again by rotary evaporation in vacuo.Organic phase is washed with water 2 times, with the salt water washing once, then vacuum concentration as for, obtained this title compound, be powder.Output: 168mg (89%). 1H-NMR (DMSO-d 6): δ 8.46 (t, 1H), 7.75 (d, 2H), 7.35 (d, 2H), 7.31 (d, 2H), 7.25 (d, 2H), 7.19 (d, 2H), 7.08 (d, 2H), 6.28 (d, 2H), 4.85 (m, 1H), 4.80 (d, 2H), 4.15 (m, 1H), 3.55 (m, 1H), 3.40 (m, 1H), and 1.65-1.80 (m, 5H), 1.10-1.40 (m, 9H); HPLC-MS (method B): m/z=579 (M+1); Rt=5.27min. embodiment 363-{4-[3-biphenyl-2-ylmethyl-1-(4-cyclohexyl phenyl) urea groups methyl] benzoyl-amido }-2 (R)-hydroxy-propionic acids
Figure A0181159101091
This compound makes like this: according to the method that is similar to embodiment 35; with N-chloro amido formyl radical-4-[(4-cyclohexyl phenyl amino) methyl] methyl benzoate and biphenyl-2-ylmethyl amine reaction; then with this methyl benzoate hydrolysis, with the coupling of (R)-isoserine carbethoxy hydrochloride.Hydrolysis has obtained this title compound. 1H-NMR (DMSO-d 6): δ 12.6 (s, 1H), 8.45 (t, 1H), 7.78 (d, 2H), 7.45-7.20 (m, 14H), 7.05 (d, 2H), 6.10 (t, 1H), 5.50 (bs, 1H), 4.85 (s, 2H), 4.2 (m, 3H), 3.55 (m, 1H), 2.45 (m, 1H), 1.85-1.70 (m, 5H), 1.40-1.20 (m, 6H); HPLC-MS (method B): m/z=606 (M+1); Rt=5.08min.
Be used for synthetic general formula (Ia) of liquid phase and (Ib) general method of compound (B):
Figure A0181159101101
R wherein 2, R 3, R 7, R 8, A, E and D definition cotype (I) described in.
When A be-during CHOH-, use 1) BSA and 2) D-N=C=O carry out step 6.Otherwise only use D-N=C=O carry out step 6.
Further illustrate this method in the following embodiments.Embodiment 37 (general method (B)) (R)-3-{4-[3-(4-cyano group-3-trifluoromethyl)-1-(4-cyclohexyl phenyl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid
Figure A0181159101111
Step 1 is to use the method identical with general method (A) to carry out.Step 2:4-{[tert-butoxycarbonyl-(4-cyclohexyl phenyl) amino] methyl } methyl benzoate
With 4-((4-cyclohexyl phenyl amino) methyl) methyl benzoate (2.0g, 6.18mmol) be suspended in sodium hydroxide (1N, 6.18mL) in, drip tert-Butyl dicarbonate (1.67g, 7.42mmol) solution in THF (10mL).This reaction mixture stirring is spent the night, and vacuum concentration has obtained solid residue, and it is dissolved in the ether (50mL) again, washes (25mL) with water, and adding sodium hydroxide (1.3mL, 1N).With ether (25mL) in pH11-12 aqueous phase extracted once more.The organic phase that merges is used sodium pyrosulfate (30mL, 10%) and water, and (dried over mgso is used in 3 * 20mL) washings, and vacuum concentration.Crystallization from ethyl acetate and normal heptane has obtained 1.98g4-{[tert-butoxycarbonyl-(4-cyclohexyl phenyl) amino] methyl } methyl benzoate. 1H-NMR (DMSO-d 6): δ 1.13-1.44 (m, 14H), 1.63-1.81 (m, 5H), 2.46 (m, 1H), 3.83 (s, 3H), 4.88 (s, 2H), 7.12 (m, 4H), 7.48 (d, 2H), 7.92 (d, 2H); HPLC-MS (method B): m/z=424 (M+1); R t=9.10min; M.p.99.5-101.0 ℃. ultimate analysis: C 26H 33NO 4Calculated value: C, 73.73%; H, 7.85%; N, 3.3 1%. measured values: C, 73.30%; H, 8.07%; N, 3.26%. step 3:4-{[tert-butoxycarbonyl-(4-cyclohexyl phenyl) amino] methyl } phenylformic acid
With 4-{[tert-butoxycarbonyl-(4-cyclohexyl phenyl) amino] methyl methyl benzoate is suspended in the ethanol (30mL), and add sodium hydroxide (4N, 8.1mL).This reaction mixture stirring is spent the night.This mixture is concentrated into dried, is suspended in the water (100mL), with hydrochloric acid (8.5mL, 4N) acidifying, and extract with ethyl acetate (100mL).(30mL) extracts water once again with ethyl acetate, and (3 * 50mL) washings are with dried over mgso and vacuum concentration with the organic phase water that merges.With resistates crystallization from the mixture of ethyl acetate and normal heptane, obtained 1.75g4-{[tert-butoxycarbonyl-(4-cyclohexyl phenyl) amino] methyl } phenylformic acid. 1H-NMR (CDCl 3-d 6): δ 1.18-1.42 (m, 14H), 1.68-1.87 (m, 5H), 2.46 (m, 1H), 4.88 (s, 2H), 7.10 (m, 4H), 7.47 (d, 2H), 8.07 (d, 2H); HPLC-MS (method B): m/z=410 (M+1); R t=8.15min; M.p.192.5-194.5 ℃. ultimate analysis: C 25H 31NO 4Calculated value: C, 73.32%; H, 7.63%; N, 3.42%. measured value: C, 73.03%; H, 7.86%; N, 3.36%. step 4:(R)-3-(4-{[tert-butoxycarbonyl-(4-cyclohexyl phenyl) amino] methyl } benzoyl-amido)-the 2 hydroxy propanoic acid methyl esters
With 4-{[tert-butoxycarbonyl-(4-cyclohexyl phenyl) amino] methyl phenylformic acid is dissolved among the DMF (10mL), and add HOBt (0.40g, 2.93mmol) and EDAC (0.52g, 2.73mmol).This reaction mixture was stirred 45 minutes.Add (R)-3-amino-solution and the diisopropyl ethyl amine (0.46mL) of 2 hydroxy propanoic acid methyl esters in DMF (8mL) then.This mixture stirring is spent the night.This reaction mixture water (40mL) is diluted, and extract with ethyl acetate (75mL).Water is extracted with ethyl acetate (30mL).(0.2N, 3 * 30mL), water: (3 * 30mL) washings are with dried over mgso and vacuum concentration for saturated sodium-chloride with hydrochloric acid with the organic phase that merges.By silica gel (100g) column chromatography purifying resistates; use mixture (1L (1: 1) and 0.5L (7: the 3)) wash-out of ethyl acetate and normal heptane, obtained 0.77g (R)-3-(4-{[tert-butoxycarbonyl-(4-cyclohexyl phenyl) amino] methyl } benzoyl-amido)-2 hydroxy propanoic acid methyl esters. 1H-NMR (DMSO-d 6): δ 1.16-1.41 (m, 14H), 1.63-1.81 (m, 5H), 2.46 (m, 1H), 3.42 (m, 1H), 3.54 (m, 1H), 3.62 (s, 3H), 4.24 (m, 1H), 4.84 (s, 2H), 5.70 (d, 1H), 7.12 (m, 4H), 7.28 (d, 2H), 7.78 (d, 2H), 8.51 (t, 1H); HPLC-MS (method B): m/z=511 (M+1); R t=7.63min. step 5:(R)-and 3-{4-[(4-cyclohexyl phenyl amino) methyl] benzoyl-amido }-the 2 hydroxy propanoic acid methyl esters
(R)-3-(4-{[tert-butoxycarbonyl-(4-cyclohexyl phenyl) amino] methyl } benzoyl-amido)-2-hydroxyl-methyl propionate is dissolved in the ethyl acetate (10mL), add the solution of anhydrous hydrogen chloride in ethyl acetate (3M, 10mL).With this mixture stirring at room 2 hours, and vacuum concentration.Resistates is suspended in the ethyl acetate (15mL), and concentrates.This operation repeats 2 times.Resistates is suspended in the ethyl acetate (10mL) then, and spends the night 5 ℃ of placements.Filter out precipitation, with ice-cold ethyl acetate washing, and vacuum-drying, obtained 0.62g (R)-3-{4-[(4-cyclohexyl phenyl amino) methyl] benzoyl-amido }-the 2 hydroxy propanoic acid methyl esters. 1H-NMR (DMSO-d 6): δ 1.12-1.43 (m, 5H), 1.63-1.82 (m, 5H), 2.45 (m, 1H), 3.42 (m, 1H), 3.53 (m, 1H), 3.60 (s, 3H), 4.25 (t, 1H), 4.48 (s, 2H), 7.18 (m, 4H), 7.57 (d, 2H), 7.82 (d, 2H), 8.58 (t, 1H); HPLC-MS (method B): m/z=411 (M+1); R t=4.93min. step 6:(R)-and 3-{4-[3-(4-cyano group-3-trifluoromethyl)-1-(4-cyclohexyl phenyl) urea groups methyl] benzoyl-amido }-the 2 hydroxy propanoic acid methyl esters
With 5-amino-2-cyano-benzotrifluoride (0.07g 0.36mmol) is dissolved in the ethyl acetate (2mL), and add the solution of anhydrous hydrogen chloride in ethyl acetate (3.5M, 5.5mL).After 15 minutes, to doing, (coevaporation is 3 times 3 * 5mL) from toluene with this solution concentration.In resistates, add toluene (2.5mL), with nitrogen purging about 10 minutes, add trichloromethylchloroformate (0.43mL) then.With this mixture slight backflow 1 hour under nitrogen atmosphere.With the cooling of this mixture, vacuum concentration is to doing, and coevaporation 2 times has obtained isocyanic acid 4-cyano group-3 trifluoromethyl ester to remove excessive trichloromethylchloroformate from toluene then.
With (R)-3-{4-[(4-cyclohexyl phenyl amino) methyl] benzoyl-amido }-the 2 hydroxy propanoic acid methyl ester hydrochloride (0.13g 0.3mmol) is dissolved among the DCM (5mL), and adding BSA (0.22mL, 0.9mmol).This mixture was stirred 0.5 hour, and the adding diisopropyl ethyl amine (0.052mL, 0.3mmol).This reaction mixture is added in the above-mentioned isocyanic ester, and this mixture stirring is spent the night.This reaction mixture is transferred in the separating funnel, and water (10mL) washing 2 times, with dried over mgso and vacuum concentration.By column chromatography (30g) purifying resistates; use ethyl acetate/normal heptane (4: 6) (400mL) and ethyl acetate (200mL) wash-out successively, obtained 0.085g (R)-3-{4-[3-(4-cyano group-3-trifluoromethyl)-1-(4-cyclohexyl phenyl) urea groups methyl] benzoyl-amido }-the 2 hydroxy propanoic acid methyl esters. 1H-NMR (DMSO-d 6): δ 1.12-1.44 (m, 6H), 1.66-1.82 (m, 5H), 3.41 (m, 1H), 3.53 (m, 1H), 3.60 (s, 3H), 4.22 (m, 1H), 4.47 (s, 2H), 5.69 (s, 1H), 7.21 (m, 4H), 7.33 (d, 2H), 7.76 (d, 2H), 7.98 (s, 2H), 8.14 (s, 1H), 8.48 (t, 1H), 9.1 (s, 1H); HPLC-MS (method B): m/z=623 (M+1); R t=6.02min. step 7:
With (R)-3-{4-[3-(4-cyano group-3-trifluoromethyl)-1-(4-cyclohexyl phenyl) urea groups methyl] benzoyl-amino }-2 hydroxy propanoic acid methyl esters (0.07g; 0.124mmol) be suspended in the ethanol (3mL); and adding sodium hydroxide (4N, 0.19mL, 0.742mmol).This reaction mixture was stirred 1.5 hours, concentrate to remove ethanol.With resistates water (10mL) dilution, and with hydrochloric acid (4N, 0.21mL) acidifying.(2 * 10mL) extract this mixture, and (3 * 10mL) washings with dried over mgso and vacuum concentration, have obtained this title compound (0.68g) with the organic phase water that merges with ethyl acetate. 1H-NMR (DMSO-d 6): δ .1.16-1.42 (m, 6H), 1.66-1.82 (m, 5H), 3.40 (m, 1H), 3.54 (m, 1H), 4.16 (m, 1H), 4.48 (s, 2H), 7.20 (m, 4H), 7.34 (d, 2H), 7.78 (d, 2H), 7.99 (s, 2H), 8.16 (s, 1H), 8.44 (t, 1H), 9.1 (s, 1H); HPLC-MS (method B): m/z=609 (M+1); R t=7.27min. embodiment 38 (general method (B)) (R)-3-{4-[3-(3-tert-butyl-phenyl)-1-(4-cyclohexyl phenyl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid Step 6:(R)-and 3-{4-[3-(3-tert-butyl-phenyl)-1-(4-cyclohexyl phenyl) urea groups methyl] benzoyl-amido }-the 2 hydroxy propanoic acid methyl esters
With 3-(tertiary butyl) aniline (0.054g 0.36mmol) is dissolved in the ethyl acetate (2mL), and add solution in ethyl acetate of twice anhydrous hydrogen chloride (3.5M, 3mL+2.5mL).After 15 minutes, this mixture is concentrated into dried, (coevaporation is 3 times 3 * 5mL) from toluene.In resistates, add toluene (2.5mL), with nitrogen purging about 10 minutes, add trichloromethylchloroformate (0.43mL) then.With this mixture slight backflow 1 hour under nitrogen atmosphere.With this mixture cooling, vacuum concentration.This operation repeats 2 times to remove excessive trichloromethylchloroformate.This mixture is concentrated into dried, coevaporation 3 times from toluene (each 5mL).Resistates is concentrated into dried, and from toluene twice of coevaporation.Then it is dissolved in the toluene (2.5mL) again, with nitrogen purging about 10 minutes, adds trichloromethylchloroformate (0.43mL) then.With this mixture slight backflow 1 hour under nitrogen atmosphere.After the cooling, this mixture is concentrated, coevaporation 2 times has obtained isocyanic acid 3-tert-butyl-phenyl ester to remove excessive trichloromethylchloroformate from toluene.
With (R)-3-{4-[(4-cyclohexyl phenyl amino) methyl] benzoyl-amido }-the 2 hydroxy propanoic acid methyl ester hydrochloride (0.13g 0.3mmol) is dissolved among the DCM (5mL), and adding BSA (0.22mL, 0.9mmol).This mixture was stirred 0.5 hour, and the adding diisopropyl ethyl amine (0.052mL, 0.3mmol).This reaction mixture is added in the above-mentioned isocyanic ester, and stirs and spend the night.This reaction mixture is transferred in the separating funnel, and water (10mL) washing 2 times, with dried over mgso and vacuum concentration.By silica gel (30g) column chromatography purifying resistates; use successively ethyl acetate and normal heptane (6:4) (400mL) with ethyl acetate (100mL) wash-out, obtained 0.12g (R)-3-{4-[3-(3-tert-butyl-phenyl)-1-(4-cyclohexyl phenyl) urea groups methyl] benzoyl-amido-the 2 hydroxy propanoic acid methyl esters. 1H-NMR (DMSO-d 6): δ 1.23 (s, 11H), 1.28-1.42 (m, 3H), 1.65-1.80 (m, 5H), 2.47 (m, 1H), 3.40 (m, 1H), 3.51 (m, 1H), 4.22 (m, 1H), 4.94 (s, 2H), 5.71 (d, 1H), 6.99 (d, 1H), 7.12-7-24 (m, 5H), 7.28 (d, 1H), 7.36 (d, 2H), 7.42 (s, 1H), 7.77 (d, 2H), 8.08 (s, 1H), 8.50 (t, 1H); HPLC-MS (method B): m/z=(585+1); R t=8.30min step 7:
With (R)-3-{4-[3-(3-tert-butyl-phenyl)-1-(4-cyclohexyl phenyl) urea groups methyl] benzoyl-amido }-2 hydroxy propanoic acid methyl esters (0.11g; 0.188mmol) be dissolved in the ethanol (4mL); and adding sodium hydroxide (4N, 0.28mL, 1.128mmol).Should react and stir 1.5 hours, and vacuum concentration is to remove ethanol.With resistates water (10mL) dilution, with hydrochloric acid (4N, 0.3mL) acidifying, and with ethyl acetate (2 * 10mL) extract.(dried over mgso is used in 3 * 10mL) washings, and vacuum concentration, has obtained this title compound (0.10g) with the organic phase water that merges. 1H-NMR (DMSO-d 6): δ 1.23 (s, 9H), 1.28-1.42 (m, 4H), 1.65-1.81 (m, 5H), 2.47 (m, 1H), 3.38 (m, 1H), 3.55 (m, 1H), 4.16 (m, 1H), 4.94 (s, 2H), 7.00 (d, 1H), 7.11-7.24 (m, 6H), 7.28 (d, 1H), 7.35 (d, 1H), 7.41 (s, 1H), 7.80 (d, 2H), 8.10 (s, 1H), 8.46 (t, 1H); HPLC-MS (method B): m/z=572 (M+1); R t=7.78min. embodiment 39 (general method (B)) (R)-3-{4-[1-(4-cyclohexyl phenyl)-3-(3-hydroxymethyl-4-Trifluoromethoxyphen-l) urea groups methyl] benzoyl-amido]-2 hydroxy propanoic acid Preparation is used for 3-(t-butyldimethylsilyloxy the ylmethyl)-4-trifluoro-methoxyaniline of step 6:
(5mL) cools off on ice bath with nitrosonitric acid, and (5g 22.7mmol), remains on temperature below 15 ℃ simultaneously to add 2-(trifluoromethoxy) methyl benzoate lentamente with 30 minutes.Then this is reflected at 60 ℃ and stirred 1 hour, stirring at room 2 hours.This mixture is poured on ice, has isolated oily matter thus.Inclining moisture supernatant liquor, adds entry (50mL) in oily matter.With in the sodium bicarbonate and after, (25mL) extracts this mixture with ethyl acetate.(15mL) extracts water once again with ethyl acetate.(2 * 15mL) washings, dry (sal epsom), and vacuum concentration have obtained 5.69g5-nitro-2-trifluoro-methoxy-benzoic acid methyl esters with saturated sodium-chloride with the organic phase that merges. 1H NMR (DMSO-d 6): δ 3.93 (3H, s), 7.82 (1H, d), 8.58 (1H, d), 8.67 (1H, s); HPLC-MS (method B): m/z:266; R t=6.0min.
With 5-nitro-2-trifluoro-methoxy-benzoic acid methyl esters (5.69g 21.5mmol) is dissolved in the ethanol 99.9% (80mL), and add tin protochloride (II) dihydrate (24.2g, 107mmol).Suspension was stirred 2 hours in 75 ℃ of oil baths, and vacuum concentration.Add ethyl acetate (100mL) and water (50mL), use 4N sodium hydroxide (50mL) pH regulator to 8.Liquid in the precipitation is inclined to.With ethyl acetate with washing of precipitate 2 times.With ethyl acetate (60mL) water is extracted 2 times.With organic phase saturated nacl aqueous solution (2 * 100mL) washings, dry (sal epsom) and the vacuum concentration that merges.By column chromatography (120g silicon-dioxide) purifying, use ethyl acetate and heptane (1: 1) wash-out, obtained 3.8g5-amino-2-trifluoro-methoxy-benzoic acid methyl esters. 1HNMR (DMSO-d 6): δ 3.82 (3H, s), 5.63 (2H, s), 6.79 (1H, d), 7.07 (1H, s), 7.11 (1H, d); HPLC-MS (method B): m/z:236, R t=4.6min.
In the three-necked flask that is equipped with thermometer and addition funnel, (3.0g 12.8mmol) is dissolved among the THF (20mL) with 5-amino-2-trifluoro-methoxy-benzoic acid methyl esters under nitrogen atmosphere.Under agitation with dripped in 10 minutes ice-cold lithium aluminium hydride (1MTHF solution, 15mL).Continuation should be reacted vacuum concentration stirring at room 1 hour.Resistates is suspended in DCM (150mL) and the water (50mL), then via diatomite filtration, with DCM and water washing.Isolate filtrate, water is extracted once again with DCM (30mL).(2 * 20mL) washings, dry (sal epsom) and vacuum concentration have obtained 2.47g (5-amino-2-Trifluoromethoxyphen-l) methyl alcohol with the organic phase water that merges. 1HNMR (DMSO-d 6): δ 3.92 (2H.d), 5.18 (1H, t), 5.28 (2H, s), 6.45 (1H, d), 6.91 (1H, d); HPLC-MS (method B): m/z:208, Rt=7.2min.
With 5-amino-2-Trifluoromethoxyphen-l) methyl alcohol (1.2g 5.8mmol) is dissolved among the DMF (5mL), add imidazoles (0.48g, 7.1mmol) and tert-butyldimethylsilyl chloride (0.99g, 6.6mmol).This reaction mixture was stirred 16 hours, add entry (20mL).(2 * 50mL) extract this mixture, with organic phase water (10mL), citric acid (10mL, 10%) and water (2 * 10mL) washings, dry (sal epsom) and the vacuum concentration that merges with ethyl acetate.By column chromatography (110g, silicon-dioxide) purifying resistates, use ethyl acetate and heptane (1: 3) wash-out, obtained 1.2g3-(t-butyldimethylsilyloxy ylmethyl)-4-trifluoro-methoxyaniline. 1HNMR (DMSO-d 6): δ 0.82 (9H, s), 3.25 (6H, s), 4.52 (2H, s), 5.23 (2H, s), 6.41 (1H, d), 6.61 (1H, s), 6.86 (1H, d); HPLC-MS (method B): m/z:322; R t=7.17min. step 6:(R)-3-{4-[3-[3-(t-butyldimethylsilyloxy ylmethyl)-4-Trifluoromethoxyphen-l]-1-(4-cyclohexyl phenyl) urea groups methyl] benzoyl-amido }-the 2 hydroxy propanoic acid methyl esters
(0.09g 0.31mmol) is dissolved among the DCM (2mL), and cools off under nitrogen atmosphere in ice bath with carbonic acid two (trichloromethyl) ester (triphosgene).(0.3g 0.93mmol) evaporates 2 times to remove all moisture from toluene, be dissolved in then among the DCM (2mL), and add diisopropyl ethyl amine (0.32mL) with 3-(t-butyldimethylsilyloxy ylmethyl)-4-trifluoro-methoxyaniline.This solution is added in the refrigerative triphosgene solution, and this mixture was stirred 2.5 hours at 20 ℃.With (R)-3-{4-[(4-cyclohexyl phenyl amino) methyl] benzoyl-amido }-2-hydroxyl-methyl propionate hydrochloride (0.37g; 0.83mmol) from toluene, evaporate 2 times; be dissolved among the DMF (3mL), and the adding diisopropyl ethyl amine (0.141mL, 0.83mmol).Under agitation this solution is added in the above-mentioned isocyanic ester, under nitrogen atmosphere, heated 2 hours in 80 ℃.With this reaction mixture vacuum-evaporation, with DCM (80mL), aqueous citric acid solution (10%, 25mL) extracted residues.With DCM (30mL) aqueous phase extracted.(10%, 3 * 25mL) washing is with dried over mgso and vacuum-evaporation with aqueous citric acid solution with the organic phase that merges.By silica gel (58g) column chromatography purifying resistates; use ethyl acetate and normal heptane (940mL; 1: 1 and 300mL ethyl acetate) wash-out, obtained 0.03g (R)-3-{4-[3-[3-(t-butyldimethylsilyloxy ylmethyl)-4-Trifluoromethoxyphen-l]-1-(4-cyclohexyl phenyl) urea groups methyl] benzoyl-amido }-the 2 hydroxy propanoic acid methyl esters.HPLC-MS (method B): m/z=758 (M+1); R t=9.57 minutes.Step 7:
With (R)-3-{4-[3-[3-(t-butyldimethylsilyloxy ylmethyl)-4-Trifluoromethoxyphen-l]-1-(4-cyclohexyl-phenyl) urea groups methyl] benzoyl-amido }-2 hydroxy propanoic acid methyl esters (24mg; 0.032mmol) be dissolved in the ethanol (1mL); and adding sodium hydroxide (0.05mL, 019mmol).This reaction mixture was stirred 2 hours, concentrate to remove ethanol.With resistates water (10mL) dilution, with hydrochloric acid (4N, 0.3mL) acidifying, and with ethyl acetate (2 * 10mL) extract.With organic phase water (3 * 10mL) washings that merge; with dried over mgso and vacuum concentration, obtained 17mg (R)-3-{4-[3-[3-(t-butyldimethylsilyloxy ylmethyl)-4-Trifluoromethoxyphen-l]-1-(4-cyclohexyl phenyl) urea groups methyl] benzoyl-amido }-2 hydroxy propanoic acid.HPLC-MS (method B): m/z=744 (M+1); R t=9.35 minutes.
With (R)-3-{4-[3-[3-(t-butyldimethylsilyloxy ylmethyl)-4-Trifluoromethoxyphen-l]-1-(4-cyclohexyl-phenyl) urea groups methyl] benzoyl-amido }-2 hydroxy propanoic acid (17mg; 0.023mmol) be dissolved in acetonitrile: water (9: 1) (2mL) in; and the adding cesium fluoride (35mg, 0.35mmol).This reaction mixture was stirred 6 hours at 80 ℃, add cesium fluoride (35mg) again.This mixture is spent the night 60 ℃ of stirrings, and vacuum concentration is with ethyl acetate (10mL) and water (5mL) dilution.(3 * 5mL) washings are with dried over mgso and vacuum concentration with the organic phase water.By preparation HPLC purifying resistates, obtained this title compound. 1H-NMR (DMSO-d 6): δ 1.35 (m, 5H), 1.79 (m, 5H), 4.49 (s, 2H), 4.95 (s, 2H), 5.29 (s, 1H), 7.12-7.26 (m, 6H), 7.34 (d, 2H), 7.49 (dd, 1H), 7.63 (d, 1H), 7.77 (d, 2H), 8.42 (t, 1H); HPLC-Ms (method B): m/z=630 (M+1); R t=6.62min.
The general method (C) that is used for solid phase synthesis general formula (Ic) compound:
Figure A0181159101191
Figure A0181159101201
R wherein 2, R 3, R 4, R 5, A, Z, D and E definition with described in (I), X is-C (O) NH-or-C (O) NHCR 12R 13-R wherein 12And R 13Definition cotype (I) described in, and resin is the polystyrene resin with the load of 2-chlorine trityl linking group.When A be-during CHOH-, use 1) BSA and 2) D-N=C=O or D-CHR 13-N=C=O carry out step 4.Otherwise, only use D-N=C=O or D-CHR 13-N=C=O carry out step 4.
Illustrate this method in the following embodiments.Embodiment 40 (general method (C)) (R)-3-{4-[1-(4-tert-butyl-phenyl)-3-(3, the 4-dichlorophenyl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid Step 1: be combined in (the R)-Fmoc-isoserine on the resin
To connect group functionalized 50mg polystyrene resin and N-N-methyl-2-2-pyrrolidone N-(500 μ L) and 1,2-propylene dichloride (500 μ L) vortex 1 hour with 2-chlorine trityl chloride.With resin filter, and use the N-N-methyl-2-2-pyrrolidone N-: 1, the 2-propylene dichloride (1: 1,2 * 1mL) washings.Add N-N-methyl-2-2-pyrrolidone N-(500 μ L) and 1,2-propylene dichloride (500 μ L) adds 150 μ mol (R)-Fmoc-isoserine and 100 μ L diisopropyl ethyl amines then.This suspension 25 ℃ of joltings after 4 hours, by filtering to isolate resin, and is used DCM: methyl alcohol: diisopropyl ethyl amine 17: 2: 1 (2 * 1mL) and (2 * 1mL) washings of N-N-methyl-2-2-pyrrolidone N-.Step 2: be combined in (R)-3-(4-formyl radical the benzoyl-amido)-2 hydroxy propanoic acid on the resin
In above-mentioned (the R)-Fmoc-isoserine that is combined on the resin, add the solution of 500 μ L20% pyridines in DMF.After the jolting 30 minutes, give off resin, and (6 * 1mL) wash with the N-N-methyl-2-2-pyrrolidone N-.Then 200 μ mol 4-formyl radical phenylformic acid (30mg) and 200 μ molHOBt (31mg) are dissolved in the N-N-methyl-2-2-pyrrolidone N-(500 μ L); and be added in the resin, add the 200 μ mol DIC (25.2mg) that are dissolved in the acetonitrile (500 μ L) then.This mixture 25 ℃ of joltings 4 hours, is filtered then, and with N-N-methyl-2-2-pyrrolidone N-(3 * 1mL) washing resins.Step 3: be combined in (the R)-3-{4-[(4-tert-butyl-phenyl amino on the resin) methyl] benzoyl-amido }-2 hydroxy propanoic acid
Above-mentioned (R)-3-(4-formyl radical benzoyl-amido)-2 hydroxy propanoic acid that is combined on the resin is used 0.5M4-tertiary butyl aniline (0.25mmol), and (1: 1,0.5mL) solution in and Glacial acetic acid (50 μ L) were handled 1 hour in 25 ℃ at the mixture of N-N-methyl-2-2-pyrrolidone N-and trimethyl orthoformate.Add and to be dissolved in N-N-methyl-2-2-pyrrolidone N-and methyl alcohol (1: 1,0.25mL) in sodium cyanoborohydride (250 μ mol, 16mg), with this mixture 25 ℃ of vortexs 4 hours, filter then, and with N-N-methyl-2-2-pyrrolidone N-and methanol mixture (1: 1,2 * 1mL) 3 * 1mL N-N-methyl-2-2-pyrrolidone N-s (3 * 1mL) and 1, the mixture of 2-propylene dichloride and diisopropyl ethyl amine (7: 1,2 * 0.75mL) washings.Step 4: be combined in (R)-3-{4-[1-(4-tert-butyl-phenyl)-3-(3, the 4-dichlorophenyl) the urea groups methyl on the resin] benzoyl-amido }-2 hydroxy propanoic acid
To above-mentioned (the R)-3-{4-[(4-tert-butyl-phenyl amino that is combined on the resin) methyl] benzoyl-amido-add 1 in the 2 hydroxy propanoic acid, 2-propylene dichloride (500 μ L) and BSA (100 μ L), and with this mixture 25 ℃ of vortexs 1 hour.Add 200 μ mol isocyanic acids 3, the 4-Dichlorfop 25 ℃ of joltings 5 hours, filters then, with resin with 2 * 1mLDCM, 4 * 1mL N-N-methyl-2-2-pyrrolidone N-, 2 * 1mL H 2O, 3 * 1mL THF and 5 * 1mLDCM washing have obtained to be combined in this title compound on the resin.Step 5:(R)-and 3-{4-[1-(4-tert-butyl-phenyl)-3-(3, the 4-dichlorophenyl) urea groups methyl] benzoyl-amido }-2 hydroxy propanoic acid
With above-mentioned (R)-3-{4-[1-(4-tert-butyl-phenyl)-3-(3, the 4-dichlorophenyl) the urea groups methyl that is combined on the resin]-benzoyl-amido }-2 hydroxy propanoic acid handled 1 hour in 25 ℃ with the solution of 1mL 20%TFA in DCM.Filter out product, resin is washed with 1mL DCM.Extraction liquid vacuum concentration with merging has obtained this title compound. 1H-NMR (CDCl 3): δ 7.65 (d, 2H), 7.45-7.40 (m, 4H), 7.35-7.20 (m, 3H), 7.10-7.00 (m, 3H), 6.30 (s, 1H), 4.90 (s, 2H), 4.40 (m, 1H), 3.83 (m, 2H), 1.32 (s, 9H); HPLC-MS (method B): m/z=558 (M+1); R t=4.71min.
Following embodiment carries out as mentioned above.Embodiment 41 (general method (C)) (R)-3-{4-[1-(4-tert-butylcyclohexyl)-3-(3, the 4-dichlorophenyl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid HPLC-MS (method B): m/z=564 (M+1); R t=4.92 minutes/5.02 minutes.Embodiment 42 (general method (C)) (R)-3-{4-[1-(4-cyclohexyl phenyl)-3-(3, the 4-dichlorophenyl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid HPLC-MS (method B): m/z=584 (M+1); R t=5.12 minutes.Embodiment 43 (general method (C)) (R)-3-{4-[1-(4-cyclohexyl phenyl)-3-(2,2,4,4-tetrafluoro-4H-benzo [1,3] dioxine-6-yl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid
Figure A0181159101231
HPLC-MS (method B): m/z=646 (M+1); R t=5.24 minutes.Embodiment 44 (general method (C)) (R)-3-{4-[1-(4-tert-butyl-phenyl)-3-(2,2,4,4-tetrafluoro-4H-benzo [1,3] dioxine-6-yl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid HPLC-MS (method B): m/z=620 (M+1); R t=4.88 minutes.Embodiment 45 (general method (C)) (R)-3-{4-[1-(4-tert-butylcyclohexyl)-3-(2,2,4,4-tetrafluoro-4H-benzo [1,3] dioxine-6-yl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid HPLC-MS (method B): m/z=606 (M+1); R t=5.11 minutes/5.20 minutes.Embodiment 46 (as method (C)) (R)-3-{4-[1-(4-tert-butyl-phenyl)-3-(3, the 4-difluorophenyl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid
Figure A0181159101242
HPLC-MS (method B): m/z=526 (M+1); R t=4.24 minutes.Embodiment 47 (general method (C)) (R)-3-{4-[1-(4-cyclohexyl phenyl)-3-(3, the 4-difluorophenyl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid
Figure A0181159101243
HPLC-MS (method B): m/z=552 (M+1); R t=4.65 minutes.Embodiment 48 (general method (C)) (R)-3-{4-[1-(4-hexamethylene-1-thiazolinyl phenyl)-3-(3, the 4-difluorophenyl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid
Figure A0181159101251
HPLC-MS (method A): m/z=550 (M+1); R t=6.77 minutes.Embodiment 49 (general method (C)) (R)-3-{4-[3-(4-chloro-3-trifluoromethyl)-1-(4-cyclohexyl phenyl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid HPLC-MS (method A): m/z=618 (M+1); R t=7.58 minutes.Embodiment 50 (general method (C)) (R)-3-{4-[1-(4-cyclohexyl phenyl)-3-(4-fluoro-3-nitrophenyl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid HPLC-MS (method A): m/z=579 (M+1); R t=6.85 minutes.Embodiment 51 (general method (C)) (R)-3-{4-[1-(4-cyclohexyl phenyl)-3-(4-isopropyl phenyl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid HPLC-MS (method A): m/z=558 (M+1); R t=7.73 minutes.Embodiment 52 (general method (C)) (R)-3-{4-[1-(4-hexamethylene-1-thiazolinyl phenyl)-3-(3, the 4-dichlorophenyl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid HPLC-MS (method B): m/z=582 (M+1); R t=4.99 minutes.Embodiment 53 (general method (C)) (R)-3-{4-[3-(4-acetylphenyl)-1-(4-cyclohexyl phenyl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid HPLC-MS (method A): m/z=558 (M+1); R t=6.42 minutes.Embodiment 54 (general method (C)) 3-{4-[3-[1 (RS)-(4-bromophenyl) ethyl]-1-(4-cyclohexyl phenyl) urea groups methyl] benzoyl-amido }-2 (R)-hydroxy-propionic acids
Figure A0181159101271
HPLC-MS (method A): m/z=624 (M+1); R t=7.45 minutes.Embodiment 55 (general method (C)) (R)-3-{4-[1-(4-cyclohexyl phenyl)-3-(3, the 5-difluorophenyl) urea groups methyl] benzoyl-amido-2 hydroxy propanoic acid
Figure A0181159101272
HPLC-MS (method B): m/z=552 (M+1); R t=4.76 minutes.
The general method (D) that is used for solid phase synthesis general formula (Id) compound:
Figure A0181159101273
Figure A0181159101281
R wherein 2, R 3, R 4, R 5, A, Z, D and E definition cotype (I) described in, X is-C (O)-(CR 12R 13) r-(CH 2) s-wherein r, s, R 12And R 13Definition cotype (I) described in, and resin is the polystyrene resin with the load of 2-chlorine trityl linking group.When A be-during CHOH-, with 1) BSA and 2) D-C (O) OH or D-CHR 13-C (O) OH carry out step 4.Otherwise, only use D-C (O) OH or D-CHR 13-C (O) OH carry out step 4.Embodiment 56 (general method (D)) (R)-3-[4-({ (4-tert-butylcyclohexyl)-[2-(4-Trifluoromethoxyphen-l) ethanoyl] amino } methyl) benzoyl-amido]-2 hydroxy propanoic acid
Figure A0181159101282
Step 1: be combined in (the R)-Fmoc-isoserine on the resin
To connect group functionalized 50mg polystyrene resin and N-N-methyl-2-2-pyrrolidone N-(500 μ L) and 1,2-propylene dichloride (500 μ L) vortex 1 hour with 2-chlorine trityl chloride.With resin filter, and use the N-N-methyl-2-2-pyrrolidone N-: 1, the 2-propylene dichloride (1: 1,2 * 1mL) washings.Add N-N-methyl-2-2-pyrrolidone N-(500 μ L) and 1,2-propylene dichloride (500 μ L) adds 150 μ mol (R)-Fmoc-isoserine and 100 μ L diisopropyl ethyl amines then.This suspension 25 ℃ of joltings after 4 hours, by filtering to isolate resin, and is used DCM: methyl alcohol: diisopropyl ethyl amine 17: 2: 1 (2 * 1mL) and (2 * 1mL) washings of N-N-methyl-2-2-pyrrolidone N-.Step 2: be combined in (R)-3-(4-formyl radical the benzoyl-amido)-2 hydroxy propanoic acid on the resin
In above-mentioned (the R)-Fmoc-isoserine that is combined on the resin, add the solution of 500 μ L20% pyridines in DMF.After the jolting 30 minutes, give off resin, and (6 * 1mL) wash with the N-N-methyl-2-2-pyrrolidone N-.Then 200 μ mol4-formyl radical phenylformic acid (30mg) and 200 μ molHOBt (31mg) are dissolved in the N-N-methyl-2-2-pyrrolidone N-(500 μ L); and be added in the resin, add the 200 μ mol DIC (25.2mg) that are dissolved in the acetonitrile (500 μ L) then.This mixture 25 ℃ of joltings 4 hours, is filtered then, and with N-N-methyl-2-2-pyrrolidone N-(3 * 1mL) washing resins.Step 3: be combined in (the R)-3-{4-[(4-tert-butylcyclohexyl amino on the resin) methyl] benzoyl-amido }-2 hydroxy propanoic acid
Above-mentioned (R)-3-(4-formyl radical benzoyl-amido)-2 hydroxy propanoic acid that is combined on the resin is used 0.5M4-tert-butylcyclohexyl amine (0.25mmol), and (1: 1,0.5mL) solution in and Glacial acetic acid (50 μ L) were handled 1 hour in 25 ℃ at the mixture of N-N-methyl-2-2-pyrrolidone N-and trimethyl orthoformate.Add and to be dissolved in N-N-methyl-2-2-pyrrolidone N-and methyl alcohol (1: 1,0.25mL) in sodium cyanoborohydride (250 μ mol, 16mg), with this mixture 25 ℃ of vortexs 4 hours, filter then, and with N-N-methyl-2-2-pyrrolidone N-and methanol mixture (1: 1,2 * 1mL) 3 * 1mL N-N-methyl-2-2-pyrrolidone N-s (3 * 1mL) and 1, the mixture of 2-propylene dichloride and diisopropyl ethyl amine (7: 1,2 * 0.75mL) washings.Step 4: be combined in (R)-3-[4-on the resin ({ (4-tert-butylcyclohexyl)-2-(4-Trifluoromethoxyphen-l) ethanoyl] amino } methyl) benzoyl-amido]-2 hydroxy propanoic acid
To above-mentioned (the R)-3-{4-[(4-tert-butylcyclohexyl amino that is combined on the resin) methyl] benzoyl-amido }-adding 1 in the 2 hydroxy propanoic acid, 2-propylene dichloride (500 μ L) and BSA (100 μ L) 25 ℃ of vortexs 1 hour, filter this mixture then.In this resin, add 4-(trifluoromethoxy) phenylacetic acid (400 μ mol) at N-N-methyl-2-2-pyrrolidone N-, 1,2-propylene dichloride and diisopropyl ethyl amine (4.5: 4.5: 1, solution 1mL), (pyrrolidyl) Phosphonium hexafluorophosphate (400 μ mol) is 1, the solution in the 2-propylene dichloride (500 μ L) to add bromine three then.With this mixture 50 ℃ the reaction 3 hours, resin is cooled to 25 ℃, use simultaneously the N-N-methyl-2-2-pyrrolidone N-(4 * 1mL) and DCM (10 * 1mL) washing, obtained to be combined in this title compound on the resin.Step 5:(R)-3-[4-({ (4-tert-butylcyclohexyl)-[2-(4-Trifluoromethoxyphen-l) ethanoyl] amino } methyl) benzoyl-amido]-2 hydroxy propanoic acid
With above-mentioned (R)-3-{4-[1-(4-tert-butylcyclohexyl)-3-(4-the Trifluoromethoxyphen-l)-urea groups methyl that is combined on the resin] benzoyl-amido }-2 hydroxy propanoic acid handled 1 hour in 25 ℃ with the solution of 1mL 20%TFA in DCM.Filter out product, and with 1mL DCM washing resin.Extraction liquid vacuum concentration with merging has obtained this title compound.HPLC-MS (method A): m/z=579 (M+1); R t=7.20 minutes.
Following embodiment carries out as mentioned above.Embodiment 57 (general method (D)) (R)-3-[4-({ (4-tert-butylcyclohexyl)-[2-(3-fluoro-5-trifluoromethyl) ethanoyl] amino } methyl) benzoyl-amido]-2 hydroxy propanoic acid
Figure A0181159101301
HPLC-MS (method A): m/z=581 (M+1); R t=7.22 minutes.Embodiment 58 (general method (D)) (R)-3-[4-({ (2, the 2-diphenyl-ethyl)-[2-(3-fluoro-5-trifluoromethyl) ethanoyl] amino } methyl) benzoyl-amido]-2 hydroxy propanoic acid HPLC-MS (method A): m/z=623 (M+1); R t=6.87 minutes.Embodiment 59 (general method (D)) (R)-3-(the 4-{[5-chlorobenzene is [b] thiophene-3-carbonyl also)-(2, the 2-diphenyl-ethyl) amino] methyl benzoyl-amido)-2 hydroxy propanoic acid
Figure A0181159101311
HPLC-MS (method A): m/z=613 (M+1); R t=6.50 minutes.Embodiment 60 (general method (D)) (R)-3-[4-({ (2, the 2-diphenyl-ethyl)-[2-(4-Trifluoromethoxyphen-l) ethanoyl] amino } methyl) benzoyl-amido]-2 hydroxy propanoic acid HPLC-MS (method A): m/z=621 (M+1); R t=6.90 minutes.Embodiment 61 (as method (D)) (R)-3-(4-{[(4-tert-butylcyclohexyl)-(the 5-chlorobenzene is [b] thiophene-3-carbonyl also) amino] methyl benzoyl-amido)-2 hydroxy propanoic acid HPLC-MS (method A): m/z=571 (M+1); R t=7.15 minutes.Embodiment 62 (general method (D)) (R)-3-(4-{[(2,2-diphenyl-ethyl)-(5-trifluoromethoxy-1H-indole-2-carbonyl) amino] methyl benzoyl-amido)-2 hydroxy propanoic acid HPLC-MS (method A): m/z=646 (M+1); R t=6.93 minutes.Embodiment 63 (general method (D)) (R)-3-[4-({ (4-cyclohexyl phenyl)-[(4-Trifluoromethoxyphen-l) ethanoyl] amino } methyl) benzoyl-amido]-2 hydroxy propanoic acid
Figure A0181159101322
HPLC-MS (method B): m/z=599 (M+1); R t=5.19 minutes.Embodiment 64 (general method (D)) (R)-3-[4-({ (4-cyclohexyl phenyl)-[(3-Trifluoromethoxyphen-l) ethanoyl] amino } methyl) benzoyl-amido]-2 hydroxy propanoic acid
Figure A0181159101323
HPLC-MS (method B): m/z=599 (M+1); R t=5.1 7 minutes.Embodiment 65 (general method (D)) (R)-3-[4-({ (4-cyclohexyl phenyl)-[(3-fluoro-5-trifluoromethyl) ethanoyl] amino } methyl) benzoyl-amido]-2 hydroxy propanoic acid HPLC-MS (method B): m/z=601 (M+1); R t=5.19 minutes.Embodiment 66 (general method (D)) (R)-3-(4-{ ([(3,5-two (trifluoromethyl) phenyl) ethanoyl]-(4-cyclohexyl phenyl) amino) methyl } benzoyl-amido)-2 hydroxy propanoic acid HPLC-MS (method B): m/z=651 (M+1); R t=5.50 minutes.Embodiment 67 (general method (D)) (R)-3-[4-({ (4-cyclohexyl phenyl)-[(3-trifluoromethyl) ethanoyl] amino } methyl) benzoyl-amido]-2 hydroxy propanoic acid HPLC-MS (method B): m/z=583 (M+1); R t=5.08 minutes.Embodiment 68 (general method (D)) (R)-3-[4-({ (4-cyclohexyl phenyl)-[(3, the 4-dichlorophenyl) ethanoyl] amino } methyl) benzoyl-amido]-2 hydroxy propanoic acid
Figure A0181159101341
HPLC-MS (method B): m/z=583 (M+1); R t=5.26 minutes.Embodiment 69 (general method (D)) (R)-3-(4-{[[(3-bromophenyl) ethanoyl]-(4-cyclohexyl phenyl) amino] methyl benzoyl-amido)-2 hydroxy propanoic acid
Figure A0181159101342
HPLC-MS (method B): m/z=595 (M+1); R t=5.01 minutes.Embodiment 70 (general method (D)) (R)-3-(4-{[(biphenyl-4-base ethanoyl)-(4-cyclohexyl phenyl) amino] methyl benzoyl-amido)-2-hydroxyl-propionic acid
Figure A0181159101343
HPLC-MS (method B): m/z=591 (M+1); R t=5.38 minutes.Embodiment 71 (general method (D)) (R)-3-(4-{[(4-cyclohexyl phenyl)-(2-naphthyl ethanoyl) amino] methyl benzoyl-amido)-2 hydroxy propanoic acid HPLC-MS (method B): m/z=565 (M+1); R t=5.10 minutes.Embodiment 72 (general method (D)) (R)-3-(4-{[(3-(3,5-two (trifluoromethyl) phenyl) propionyl)-(4-cyclohexyl phenyl) amino] methyl benzoyl-amido)-2 hydroxy propanoic acid HPLC-MS (method B): m/z=665 (M+1); R t=5.51 minutes.Embodiment 73 (general method (D)) (R)-3-[4-({ (4-cyclohexyl phenyl)-[3-(3-nitrophenyl) propionyl] amino } methyl) benzoyl-amido]-2 hydroxy propanoic acid HPLC-MS (method B): m/z=665 (M+1); R t=5.51 minutes.
Following preferred compound and can make according to method disclosed herein within the scope of the present invention.Other preferred compound is
Figure A0181159101354
Wherein
Figure A0181159101371
Figure A0181159101391
Figure A0181159101411
In addition, following compounds and can make according to method disclosed herein within the scope of the present invention:
Figure A0181159101431
Figure A0181159101451
Figure A0181159101461
Figure A0181159101471
Figure A0181159101501
Figure A0181159101511
Figure A0181159101521
Figure A0181159101541
Figure A0181159101571
Figure A0181159101581
Figure A0181159101591
Figure A0181159101611
Figure A0181159101631
Figure A0181159101651
In addition, following preferred compound (pure (R) or (S) enantiomorph of configuration, or its mixture comprise racemic modification) and can make according to aforesaid method within the scope of the present invention:
Figure A0181159101671
Figure A0181159101691
Figure A0181159101701
Figure A0181159101721
Figure A0181159101741
Figure A0181159101751
Figure A0181159101761
Figure A0181159101781
The pharmacology method
Describe below and be used to estimate combination mensuration and the functional examination that The compounds of this invention is renderd a service.
Can in the competitive binding assay that uses the human cloning glucagon receptor, measure combining of compound and glucagon receptor.
Antagonistic action can be used as the amount of the cAMP that the compound inhibition forms in the presence of the 5nM hyperglycemic-glycogenolytic factor and determines.Hyperglycemic-glycogenolytic factor is in conjunction with measuring (I)
Use human cloning receptor determination receptors bind people such as (, Gene140,203-209 (1994)) Lok.In baby hamster kidney cell system (A3 BHK570-25), express the acceptor in the pLJ6 ' expression vector that is inserted into use EcoRI/SSt1 restriction site people such as () Lok.In the presence of 0.5mg/mL G-418, select the clone, and to be presented at more than 40 generations be stable.Through showing K dBe 0.1nM.
Plasma membrane is preparation like this: cell is grown to fusion, it is got off from surface isolation, cell is resuspended in cold damping fluid (10mM tris/HCl, pH7.4, contain 30mM NaCl, the 1mM dithiothreitol (DTT), 5mg/L leupeptin (Sigma), 5mg/L pepstatin (Sigma), the Trypsin inhibitor,Trasylol (NovoNordisk A/S) of 100mg/L bacitracin (Sigma) and 15 mg/L reorganization), use Poltron PT10-35 homogenizer (Kinematica) homogenate twice, each 10 seconds, and on one deck 41 w/v% sucrose with 95.000 * g centrifugal 75 minutes.To in buffer reagent, dilute centrifugal 45 minutes at the white band between two-layer with 40.000 * g.The precipitation that will contain plasma membrane is suspended in the damping fluid, and-80 ℃ of storages until use.
According to chloramine-t method (Hunter and Greenwood, Nature194,495 (1962)) with the hyperglycemic-glycogenolytic factor iodate, and with anion-exchange chromatography (people such as Jrgensen, Hormoneand Metab.Res.4,223-224 (1972) purifying.On iodate same day, specific activity is 460 μ Ci/ μ g.With tracer agent in the mode of aliquots containig-18 ℃ of storages, use immediately after the thawing.
(MADVN65 measures to carry out combination in triplicate in Millipore) at the filter microtiter plate.Damping fluid is 50mM HEPES, 5mM EGTA, 5mM MgCl 2, 0.005% polysorbas20, pH7.4.Hyperglycemic-glycogenolytic factor is dissolved among the 0.05MHCl, adds equivalent (w/w) human serum albumin, and lyophilize.On the same day using, it is dissolved in the water, and in damping fluid, is diluted to desired concn.
Test compounds is dissolved and in DMSO, dilute.In each hole, add 140 μ L damping fluids, 25 μ L hyperglycemic-glycogenolytic factors or damping fluid and 10 μ LDMSO or test compounds.(50.000cpm) dilutes in buffer reagent with tracer agent, and adds 25 μ L in each hole.The new plasmalemma protein that melts of the 1-4 μ g that in damping fluid, dilutes that in each hole, adds 25 μ L aliquots containigs then.Flat board was cultivated 2 hours at 30 ℃.With 10 -6The M hyperglycemic-glycogenolytic factor is measured non-specific binding.By vacuum filtration (Millipore vacuum manifold) the bonded tracer agent is separated with unconjugated tracer agent then.Dull and stereotyped with 2 * 100 μ L damping fluids/hole washing.With air-dry 2 hours of flat board, use Millipore Puncher that filter is taken off from flat board afterwards.Filter is counted in gamma counter.Functional examination (I)
(tissue culturing plate carries out functional examination in Nunc) at 96 hole microtiter plates.The damping fluid that uses in mensuration is 50mM tris/HCl, 1mM EGTA, 1.5mM MgSO 4, 1.7mM ATP, 20 μ MGTP, 2mM IBMX, 0.02% tween 20 and 0.1% human serum albumin.PH is 7.4.Add 35 μ L aliquots containigs at 50 mM tris/HCl, 1mMEGTA, 1.8mM MgSO 4, 0.0222% tween 20 and 0.111% human serum albumin, the hyperglycemic-glycogenolytic factor that dilutes among the pH7.4 and the antagonist of being tested.Add 20 μ L50mM tris/HCl, 1mM EGTA, 1.5mM MgSO 4, 11.8mM ATP, 0.14mM GTP, 14mM IBMX and 0.1% human serum albumin, pH7.4.Before facing mensuration, GTP is dissolved.
Be added in tris/HCl, EGTA, MgSO 4, the 50 μ L that contain 5 μ g plasmalemma proteins in the human serum albumin damping fluid (actual concentrations depends on the protein concentration in the plasma membrane of storage).
Total mensuration volume is 140 μ L.Flat board was being cultivated 2 hours in 37 ℃ under the jolting continuously.Come termination reaction by adding 25 μ L0.5NHCl.Use the approximate instrument (Amersham) of flicker to measure cAMP.Hyperglycemic-glycogenolytic factor is in conjunction with measuring (II)
With human glucagon receptor transfection BHK (baby hamster kidney cell system) cell, and the membrane prepare thing of preparation cell.Allow the SPA pearl (WGA pearl) of wheat germ agglutinin (the Wheat Germ Agglutinin) derivatize that contains scintillator (Amersham) combine with film. 125The I-hyperglycemic-glycogenolytic factor combines with human glucagon receptor in the film, and will be excited to slight emission at the scintillator in the WGA pearl.With the hyperglycemic-glycogenolytic factor of receptors bind or sample and 125The competition of I-hyperglycemic-glycogenolytic factor.
Membrane prepare all carry out in steps on ice or at 4 ℃.The results bhk cell is also centrifugal.Centrifugal group is resuspended in homogenate buffer (25mM HEPES, pH=7.4,2.5mMCaCl 2, 1.0mM MgCl 2, 250mg/L bacitracin, 0.1mM Pefabloc) in, use Poltron 10-35 homogenizer (Kinematica) homogenate 2 * 10 seconds, and add the resuspended homogenate buffer that is used for of same amount.After centrifugal (with centrifugal 15 minutes of 2000 * g), supernatant liquor is transferred in the cold centrifuge tube, and with 40.000 * g centrifugal 45 minutes.Centrifugal group is resuspended in the homogenate buffer, and homogenate 2 * 10 seconds (Polytron) adds homogenate buffer again.With this suspension centrifugal 45 minutes, centrifugal group is resuspended in resuspended damping fluid (25mMHEPES, pH=7.4,2.5mM CaCl with 40.000 * g 2, 1.0mM MgCl 2) in, and homogenate 2 * 10 seconds (Polytron).Protein concentration is generally about 1.75 mg/mL.Add flicker damping fluid (25mMHEPES, pH=7.4,2.5mM CaCl 2, 1.0mM MgCl 2, 1% bovine serum albumin, 500mg/L bacitracin, 2.5 M sucrose), and with the membrane prepare thing-80 ℃ of storages.
(the polystyrene microplate carries out hyperglycemic-glycogenolytic factor in conjunction with mensuration in Packard) at the opti plate.In each hole, add 50 μ L and measure damping fluid (25 mM HEPES, pH=7.5,2.5mM CaCl 2, 1.0mM MgCl 2, 0.003% tween 20,0.005% bacitracin, 0.05% sodiumazide) and 5 μ L hyperglycemic-glycogenolytic factors or test compounds (in DMSO).In the hole, add then 50 μ L tracer agents ( 125I-pig hyperglycemic-glycogenolytic factor is 50.000cpm) with the 50 μ L films (7.5 μ g) that contain human glucagon receptor.The 50 μ LWGA pearls that will contain 1 mg pearl are at last transferred in the hole.The opti plate was cultivated on wobbler 4 hours, left standstill then 8-48 hour.The opti plate is counted in Topcounter.Measure non-specific binding with the 500nM hyperglycemic-glycogenolytic factor.
The IC that the compound of embodiment shows 50Value is lower than 1500nM, and when at hyperglycemic-glycogenolytic factor in conjunction with measuring when testing in (II), have in the middle of them much to be lower than 250nM.GIP is in conjunction with mensuration
Personnel selection gip receptor transfection BHK (baby hamster kidney cell system) cell, and the membrane prepare thing of preparation cell.Allow the SPA pearl (WGA pearl) of the wheat germ agglutinin derivatize that contains scintillator (Amersham) combine with film.Allow 125I-GIP combines with people's gip receptor in the film, will be excited to slight emission at the scintillator in the WGA pearl.With the GIP of receptors bind or sample and 125The I-GIP competition.
Membrane prepare all carry out in steps on ice or at 4 ℃.The results bhk cell is also centrifugal.Centrifugal group is resuspended in homogenate buffer (25mM HEPES, pH=7.4,2.5mMCaCl 2, 1.0mM MgCl 2, 250mg/L bacitracin, 0.1mM Pefabloc) in, use Poltron 10-35 homogenizer (Kinematica) homogenate 2 * 10 seconds, and add the resuspended homogenate buffer that is used for of same amount.After centrifugal (with centrifugal 15 minutes of 2000 * g), supernatant liquor is transferred in the cold centrifuge tube, and with 40.000 * g centrifugal 45 minutes.Centrifugal group is resuspended in the homogenate buffer, and homogenate 2 * 10 seconds (Polytron) adds homogenate buffer again.With this suspension centrifugal 45 minutes, centrifugal group is resuspended in resuspended damping fluid (25mMHEPES, pH=7.4,2.5mM CaCl with 40.000 * g 2, 1.0mM MgCl 2) in, and homogenate 2 * 10 seconds (Polytron).Protein concentration is generally about 1.75mg/mL.Add stabilization damping fluid (25mMHEPES, pH=7.4,2.5mM CaCl 2, 1.0mM MgCl 2, 1% bovine serum albumin, 500mg/L bacitracin, 2.5M sucrose), and with the membrane prepare thing-80 ℃ of storages.
(the polystyrene microplate carries out GIP in conjunction with mensuration in Packard) at the opti plate.In each hole, add 50 and measure damping fluid (25 mM HEPES, pH=7.5,2.5mM CaCl 2, 1.0mM MgCl 2, 0.003% tween 20,0.005% bacitracin, 0.05% sodiumazide) and 5 μ LGIP or test compounds (in DMSO).In the hole, add then 50 μ L tracer agents ( 125I-pig GIP is 50.000cpm) with the 50 μ L films (20 μ g) that contain people's gip receptor.The 50 μ LWGA pearls that will contain the 1mg pearl are at last transferred in the hole.The opti plate was cultivated on wobbler 3.5 hours, left standstill then 8-48 hour.The opti plate is counted in Topcounter.Measure non-specific binding with 500nM GIP.

Claims (71)

1. general formula (I) compound:
R wherein 1, R 2, R 3, R 4And R 5Be hydrogen or C independently 1-6-alkyl,
A is-C (O)-,-CH (OR 6)-or-CHF-,
R wherein 6Be hydrogen or C 1-6-alkyl,
Z is an arylidene or derived from containing 1 or 2 divalent group that is selected from heteroatomic 5 or 6 yuan of hetero-aromatic rings of nitrogen, oxygen and sulphur, its can choose wantonly by 1 or 2 be selected from halogen ,-CN ,-CF 3,-OCF 3,-NO 2,-OR 9,-NR 9R 10And C 1-6The R of-alkyl 7And R 8Replace,
R wherein 9And R 10Be hydrogen or C independently 1-6-alkyl,
X is-(CH 2) q-(CR 12R 13) r-(CH 2) s-,
Figure A0181159100022
Figure A0181159100023
Figure A0181159100025
Or
Figure A0181159100026
Wherein r is 0 or 1, and q and s are 0,1,2 or 3 independently, R 11, R 12, R 13And R 14Be hydrogen, C independently 1-6-alkyl or C 3-8Cycloalkyl, D is Or R wherein 15, R 16, R 17And R 18Be independently hydrogen, halogen ,-CN ,-CHF 2,-CF 3,-OCF 3,-OCHF 2,-OCH 2CF 3,-OCF 2CHF 2,-S (O) 2CF 3,-SCF 3,-NO 2,-OR 21,-NR 21R 22,-SR 21,-NR 21S (O) 2R 22,-S (O) 2NR 21R 22,-S (O) NR 21R 22,-S (O) R 21,-S (O) 2R 21,-C (O) NR 21R 22,-OC (O) NR 21R 22,-NR 21C (O) R 22,-CH 2C (O) NR 21R 22,-OCH 2C (O) NR 21R 22-OC (O) R 21,-C (O) R 21Or-C (O) OR 21, or-C (O) OR 21,
C 1-6-alkyl, C 2-6-alkenyl or C 2-6Alkynyl, described group can choose wantonly by one or more be selected from halogen ,-CN ,-CF 3,-OCF 3,-NO 2,-OR 21,-NR 21R 22And C 1-6The substituting group of-alkyl replaces,
C 3-8Cycloalkyl, C 4-8-cycloalkenyl group, heterocyclic radical, C 3-8Cycloalkyl-C 1-6-alkyl, C 3-8-cycloalkyl-C 1-6-alkoxyl group, C 3-8Cycloalkyloxy, C 3-8Cycloalkyl-C 1-6-alkylthio, C 3-8-cycloalkylthio, C 3-8-cycloalkyl-C 2-6Alkenyl, C 3-8Cycloalkyl-C 2-6-alkynyl, C 4-8-cycloalkenyl group-C 1-6-alkyl, C 4-8-cycloalkenyl group-C 2-6-alkenyl, C 4-8-cycloalkenyl group-C 2-6Alkynyl, heterocyclic radical-C 1-6-alkyl, heterocyclic radical-C 2-6-alkenyl, heterocyclic radical-C 2-6-alkynyl, aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C 1-6-alkoxyl group, aryl-C 1-6-alkyl, aryl-C 2-6-alkenyl, aryl-C 2-6Alkynyl, heteroaryl, heteroaryl-C 1-6Alkyl, heteroaryl-C 2-6-alkenyl or heteroaryl-C 2-6-alkynyl,
Wherein said loop section can choose wantonly by one or more be selected from halogen ,-C (O) OR 21,-CN ,-CF 3,-OCF 3,-NO 2,-OR 21,-NR 21R 22And C 1-6The substituting group of-alkyl replaces,
R wherein 21And R 22Be hydrogen, C independently 1-6-alkyl, aryl-C 1-6-alkyl or aryl,
In the time of perhaps on being connected same nitrogen-atoms, R 21And R 22Can form optional 1 or 2 other heteroatoms that is selected from nitrogen, oxygen and sulphur, and the optional 3-8 unit heterocycle that contains 1 or 2 two key of containing with described nitrogen-atoms,
Perhaps when being in the consecutive position, R 15-R 18In two groups can form abutment group-(CR together 23R 24) a-O-(CR 25R 26) c-O-,
Wherein
A is 0,1 or 2,
C is 1 or 2,
R 23, R 24, R 25And R 26Be hydrogen, C independently 1-6-alkyl or fluorine,
R 19And R 20Be hydrogen, C independently 1-6-alkyl, C 3-8-cycloalkyl or C 3-8-cycloalkyl-C 1-6-alkyl,
E is
Figure A0181159100042
Or
R wherein 27And R 28Be independently hydrogen, halogen ,-CN ,-CF 3,-OR 32,-NR 32R 33, C 1-6-alkyl, C 3-8-cycloalkyl, C 4-8-cycloalkenyl group or aryl,
Wherein said aryl can choose wantonly by one or more be selected from halogen ,-CN ,-CF 3,-NO 2,-OR 32,-NR 32R 33And C 1-6The substituting group of-alkyl replaces,
R wherein 32And R 33Be hydrogen or C independently 1-6-alkyl,
In the time of perhaps on being connected same nitrogen-atoms, R 32And R 33Can form optional 1 or 2 other heteroatoms that is selected from nitrogen, oxygen and sulphur, and the optional 3-8 unit heterocycle that contains 1 or 2 two key of containing with described nitrogen-atoms,
R 29, R 30And R 31Be independently
■ hydrogen, halogen ,-CHF 2,-CF 3,-OCF 3,-OCHF 2,-OCH 2CF 3,-OCF 2CHF 2,-SCF 3,-OR 34,-NR 34R 35,-SR 34,-S (O) R 34,-S (O) 2R34 ,-C (O) NR 34R 35,-OC (O) NR 34R 35,-NR 34C (O) R 35,-OCH 2C (O) NR 34R 35,-C (O) R 34Or-C (O) OR 34,
■ C 1-6-alkyl, C 2-6-alkenyl or C 2-6-alkynyl,
Described group can choose wantonly by one or more be selected from halogen ,-CN ,-CF 3,-OCF 3,-NO 2,-OR 34,-NR 34R 35And C 1-6The substituting group of-alkyl replaces,
■ C 3-8-cycloalkyl, C 4-8-cycloalkenyl group, heterocyclic radical, C 3-8Cycloalkyl-C 1-6-alkyl, C 3-8-cycloalkyl-C 2-6-alkenyl, C 3-8-cycloalkyl-C 2-6-alkynyl, C 4-8-cycloalkenyl group-C 1-6-alkyl, C 4-8-cycloalkenyl group-C 2-6-alkenyl, C 4-8-cycloalkenyl group-C 2-6-alkynyl, heterocyclic radical-C 1-6-alkyl, heterocyclic radical-C 2-6-alkenyl, heterocyclic radical-C 2-6-alkynyl, aryl, aryloxy, aroyl, aryl-C 1-6-alkoxyl group, aryl-C 1-6-alkyl, aryl-C 2-6-alkenyl, aryl-C 2-6-alkynyl, heteroaryl, heteroaryl-C 1-6-alkyl, heteroaryl-C 2-6-alkenyl or heteroaryl-C 2-6-alkynyl,
Wherein said loop section can choose wantonly by one or more be selected from halogen ,-CN ,-CF 3,-OCF 3,-NO 2,-OR 34,-NR 34R 35And C 1-6The substituting group of-alkyl replaces,
R wherein 34And R 35Be hydrogen, C independently 1-6-alkyl or aryl,
In the time of perhaps on being connected same nitrogen-atoms, R 34And R 35Can form optional 1 or 2 other heteroatoms that is selected from nitrogen, oxygen and sulphur, and the optional 3-8 unit heterocycle that contains 1 or 2 two key of containing with described nitrogen-atoms,
In the time of perhaps on being connected same ring carbon atom or different ring carbon atom, R 29, R 30And R 31Two central groups can form group-O-(CH together 2) t-CR 36R 37-(CH 2) l-O-,-(CH 2) t-CR 36R 37-(CH 2) l-or-S-(CH 2) t-CR 36R 37-(CH 2) l-S-,
Wherein t and l are 0,1,2,3,4 or 5 independently,
R 36And R 37Be hydrogen or C independently 1-6-alkyl,
And optically-active or the geometrical isomer or the tautomeric form of general formula (I) compound, comprise the mixture of these isomer or tautomeric form or their pharmacologically acceptable salt.
2. the compound of claim 1, wherein R 1, R 2, R 3, R 4And R 5Be hydrogen.
3. claim 1 or 2 compound, wherein A is-CHF-.
4. claim 1 or 2 compound, wherein A is-CH (OR 6)-, be R wherein 6As defined in claim 1.
5. the compound of claim 4, wherein A be-CH (OH)-.
6. each compound of aforementioned claim, wherein Z is
Figure A0181159100061
R wherein 7And R 8As defined in claim 1.
7. the compound of claim 6, wherein Z is
8. each compound of aforementioned claim, wherein X is -(CH 2) s-,
Figure A0181159100073
Figure A0181159100074
Or
Wherein q is 0 or 1, and r is 0 or 1, and s is 0,1 or 2, and R 12And R 13Be hydrogen or C independently 1-6-alkyl.
9. the compound of claim 8, wherein X be-C (O) NH-,-C (O) NHCH 2-,-C (O) NHCH (CH 3)-,-C (O) NHC (CH 3) 2-,-C (O) NHCH 2CH 2-,-C (O) CH 2-,-C (O) CH 2CH 2-,-C (O) CH=CH-,-(CH 2) s-,-C (O)-,-C (O) O-or-NHC (O)-, wherein s is 0 or 1.
10. the compound of claim 9, wherein X be-C (O) NH-,-C (O) NHCH 2-,-C (O) NHCH (CH 3)-,-C (O) NHCH 2CH 2-,-C (O) CH 2-,-C (O) CH=CH-,-(CH 2) s-,-C (O)-,-C (O) O-or-NHC (O)-, wherein s is 0 or 1.
11. the compound of claim 10, wherein X be-C (O) NH-,-C (O) NHCH 2-,-C (O) NHCH (CH 3)-,-C (O) NHCH 2CH 2-,-C (O) CH 2-,-CH 2-,-C (O)-or-NHC (O)-.
12. the compound of claim 11, wherein X be-C (O) NH-,-C (O) NHCH 2-,-C (O) NHCH (CH 3)-,-C (O) CH 2-or-C (O)-.
13. the compound of claim 12, wherein X is-C (O) NH-.
14. each compound of aforementioned claim, wherein D is
Figure A0181159100081
Or R wherein 15, R 16, R 17, R 18, R 19And R 29As defined in claim 1.
15. the compound of claim 14, wherein D is R wherein 15, R 16And R 17As defined in claim 1.
16. the compound of claim 14 or 15, wherein R 15, R 16And R 17Be independently hydrogen, halogen ,-CN ,-NO 2,-CF 3,-OCF 3-,-SCF 3, C 1-6-alkyl, C 1-6-alkoxyl group ,-S-C 1-6-alkyl ,-C (O) OR 21,-C (O) R 21,-CH 2OR 21,-C (O) NR 21R 22,-S (O) R 21,-S (O) 2R 21,-S (O) 2CF 3,-S (O) 2NR 21R 22, C 3-8-cycloalkyl, C 3-8-cycloalkyl-C 1-6-alkoxyl group or C 3-8-cycloalkyl-C 1-6-alkylthio, or
Aryl, heteroaryl or aryloxy, wherein said group can be chosen wantonly by-CF 3,-OCF 3, C 1-6-alkyl, halogen or-C (O) OR 21Replace,
Perhaps when being in the consecutive position, R 15, R 16And R 17Two central groups can form abutment group-(CR together 23R 24) a-O-(CR 25R 26) c-O-,
R wherein 21And R 22Be hydrogen or C independently 1-6-alkyl, and a, c, R 23, R 24, R 25And R 26As defined in claim 1.
17. the compound of claim 16, wherein R 15, R 16And R 17Be independently hydrogen, halogen ,-CN ,-CF 3,-OCF 3Or C 1-6-alkoxyl group, perhaps R 15And R 16Form abutment group-CF together 2-O-CF 2-O-, and R 17Be hydrogen.
18. the compound of claim 17, wherein R 15, R 16And R 17Be independently hydrogen, halogen ,-CN ,-CF 3,-OCF 3Or C 1-6-alkoxyl group.
19. the compound of claim 14, wherein D is
Figure A0181159100091
Or R wherein 15, R 16, R 19And R 20As defined in claim 1.
20. the compound of claim 19, wherein D is
R wherein 15And R 16All be hydrogen, and R 19Be C 1-6-alkyl, C 3-8-cycloalkyl or C 3-8-cycloalkyl-C 1-6-alkyl.
21. the compound of claim 19, wherein D is R wherein 15And R 16All be hydrogen, and R 19And R 20All be C 1-6-alkyl.
22. each compound of aforementioned claim, wherein E
Figure A0181159100101
Or
Figure A0181159100103
R wherein 27, R 28, R 29, R 30And R 31As defined in claim 1.
23. the compound of claim 22, wherein E is R wherein 27And R 28As defined in claim 1.
24. the compound of claim 23, wherein E is R wherein 27And R 28As defined in claim 1.
25. the compound of claim 23 or 24, wherein R 27And R 28Be hydrogen, C independently 1-6-alkyl, C 3-8-cycloalkyl, C 4-8-cycloalkenyl group or phenyl, wherein phenyl is optional is substituted according to claim 1.
26. the compound of claim 25, wherein R 27And R 28Be hydrogen, C independently 1-6-alkyl, C 3-8-cycloalkyl or C 4-8-cycloalkenyl group.
27. the compound of claim 26, wherein R 27Be hydrogen, and R 28Be C 1-6-alkyl, C 3-8-cycloalkyl or C 4-8-cycloalkenyl group.
28. the compound of claim 27, wherein R 27Be hydrogen, and R 28Be C 1-6-alkyl or C 3-8-cycloalkyl.
29. the compound of claim 22, wherein E is R wherein 29, R 30And R 31As defined in claim 1.
30. the compound of claim 29, wherein E is R wherein 29, R 30And R 31As defined in claim 1.
31. the compound of claim 29 or 30, wherein R 29, R 30And R 31Be independently
■ hydrogen ,-CHF 2,-CF 3,-OCF 3,-OCHF 2,-OCH 2CF 3,-OCF 2CHF 2,-SCF 3,-OR 34,-NR 34R 35,-SR 34,-S (O) R 34,-S (O) 2R 34,-C (O) NR 34R 35,-OC (O) NR 34R 35,-NR 34C (O) R 35,-OCH 2C (O) NR 34R 35,-C (O) R 34Or-C (O) OR 34,
■ C 1-6-alkyl, C 2-6-alkenyl or C 2-6-alkynyl, wherein said group can choose wantonly by one or more be selected from halogen ,-CN ,-CF 3,-OCF 3,-NO 2,-OR 34,-NR 34R 35And C 1-6The substituting group of-alkyl replaces,
■ C 3-8Cycloalkyl or C 4-8-cycloalkenyl group, wherein said group can choose wantonly by one or more be selected from halogen ,-CN ,-CF 3,-OCF 3,-NO 2,-OR 34,-NR 34R 35And C 1-6The group of-alkyl replaces,
R wherein 34And R 35Be hydrogen, C independently 1-6-alkyl or aryl,
In the time of perhaps on being connected same nitrogen-atoms, R 34And R 35Can form optional 1 or 2 other heteroatoms that is selected from nitrogen, oxygen and sulphur, and the optional 3-8 unit heterocycle that contains 1 or 2 two key of containing with described nitrogen-atoms.
32. the compound of claim 31, wherein R 29, R 30And R 31Be hydrogen, C independently 1-6-alkoxyl group, halogen ,-CF 3,-OCF 3Or-NR 34R 35, R wherein 34And R 35As defined in claim 1, or
C 1-6-alkyl, C 3-8-cycloalkyl or C 4-8-cycloalkenyl group, described group is optional to be substituted according to claim 1.
33. the compound of claim 32, wherein R 29, R 30And R 31Be independently
Hydrogen or
C 1-6-alkyl, C 3-8-cycloalkyl or C 4-8-cycloalkenyl group, described group is optional to be substituted according to claim 1.
34. the compound of claim 32, wherein R 29, R 30And R 31Be independently
Hydrogen or
C 1-6-alkyl, C 3-8-cycloalkyl or C 4-8Cycloalkenyl group,
The described group of ■ can choose wantonly by one or more be selected from halogen ,-CN ,-CF 3,-OCF 3,-NO 2,-OR 34,-NR 34R 35And C 1-6The substituting group of-alkyl replaces,
■ is R wherein 34And R 35Be hydrogen, C independently 1-6Alkyl or aryl,
■ or on being connected same nitrogen-atoms the time, R 34And R 35Can form optional 1 or 2 other heteroatoms that is selected from nitrogen, oxygen and sulphur, and the optional 3-8 unit heterocycle that contains 1 or 2 two key of containing with described nitrogen-atoms.
35. the compound of claim 34, wherein R 29And R 31All be hydrogen, and R 30Not hydrogen.
36. the compound of claim 34, wherein R 29And R 31All be hydrogen, and R 30Be C 3-8-cycloalkyl or C 4-8-cycloalkenyl group,
The described group of ■ can choose wantonly by one or more be selected from halogen ,-CN ,-CF 3,-OCF 3,-NO 2,-OR 34,-NR 34R 35And C 1-6The substituting group of-alkyl replaces,
■ is R wherein 34And R 35Be hydrogen, C independently 1-6-alkyl or aryl,
■ or on being connected same nitrogen-atoms the time, R 34And R 35Can form optional 1 or 2 other heteroatoms that is selected from nitrogen, oxygen and sulphur, and the optional 3-8 unit heterocycle that contains 1 or 2 two key of containing with described nitrogen-atoms.
37. the compound of claim 36, wherein R 29And R 31All be hydrogen, and R 30Be C 4-8-cycloalkenyl group,
The described group of ■ can choose wantonly by one or more be selected from halogen ,-CN ,-CF 3,-OCF 3,-NO 2,-OR 34,-NR 34R 35And C 1-6The substituting group of-alkyl replaces,
■ is R wherein 34And R 35Be hydrogen, C independently 1-6-alkyl or aryl,
■ or on being connected same nitrogen-atoms the time, R 34And R 35Can form optional 1 or 2 other heteroatoms that is selected from nitrogen, oxygen and sulphur, and the optional 3-8 unit heterocycle that contains 1 or 2 two key of containing with described nitrogen-atoms.
38. the compound of claim 37, wherein R 29And R 31All be hydrogen, and R 30Be cyclohexenyl,
The described group of ■ can choose wantonly by one or more be selected from halogen ,-CN ,-CF 3,-OCF 3,-NO 2,-OR 34,-NR 34R 35And C 1-6The substituting group of-alkyl replaces,
■ is R wherein 34And R 35Be hydrogen, C independently 1-6-alkyl or aryl,
■ or on being connected same nitrogen-atoms the time, R 34And R 35Can form optional 1 or 2 other heteroatoms that is selected from nitrogen, oxygen and sulphur, and the optional 3-8 unit heterocycle that contains 1 or 2 two key of containing with described nitrogen-atoms.
39. the compound of claim 37 or 38, wherein R 30By a C 1-6-alkyl substituent replaces.
40. the compound of claim 33, wherein R 29, R 30And R 31Be hydrogen, C independently 1-6-alkyl, C 3-8-cycloalkyl or C 4-8-cycloalkenyl group.
41. the compound of claim 40, wherein R 29And R 31All be hydrogen, and R 30Be C 1-6-alkyl, C 3-8-cycloalkyl or C 4-8-cycloalkenyl group.
42. the compound of claim 1, it has general formula (I 1):
R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, X, D and E in claim 1 or the arbitrary aforementioned claim definition.
43. the general formula (I of claim 1 2) compound:
R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, D and E in claim 1 or the arbitrary aforementioned claim definition.
44. the compound of claim 1, it has general formula (I 3):
R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 15, R 16, R 17, R 29, R 30, and R 31Such as in claim 1 or the arbitrary aforementioned claim definition.
45. claim 42,43 or 44 compound, wherein R 1, R 2, R 3, R 4, R 5, R 6, R 7And R 8Be hydrogen.
46. the compound of claim 1, it has general formula (I 4):
R wherein 1, R 2, R 3, R 4, R 5, R 7, R 8, X, D and E in claim 1 or the arbitrary aforementioned claim definition.
47. the general formula (I of claim 1 5) compound:
R wherein 1, R 2, R 3, R 4, R 5, R 7, R 8, D and E in claim 1 or the arbitrary aforementioned claim definition.
48. the compound of claim 46 or 47, wherein R 1, R 2, R 3, R 4, R 5, R 7And R 8Be hydrogen.
49. each compound of aforementioned claim, the IC of wherein said compound 50Value is not higher than 5 μ M, and described value is measured in conjunction with measuring (II) in conjunction with measuring (I) or hyperglycemic-glycogenolytic factor by hyperglycemic-glycogenolytic factor disclosed herein.
50. the compound of claim 49, the IC of wherein said compound 50Value be lower than 1 μ M, preferably be lower than 500nM, more preferably less than 100nM, described value is measured in conjunction with measuring (II) in conjunction with measuring (I) or hyperglycemic-glycogenolytic factor by hyperglycemic-glycogenolytic factor disclosed herein.
51. each compound of aforementioned claim, wherein said compound are the materials that can be used for treating and/or preventing the indication that is selected from hyperglycemia, IGT, diabetes B, type 1 diabetes, unusual lipidemia and obesity.
52. as each compound of the claim 1-51 of medicine.
53. pharmaceutical composition wherein comprises each compound of at least a claim 1-51 as active ingredient and one or more pharmaceutically acceptable carrier or vehicle.
54. the composition of the claim 53 of unit dosage forms wherein comprises the about 1000mg of about 0.05mg-, the preferably about 500mg of about 0.1mg-, especially preferred each compound of the about 200mg claim of about 0.5mg-1-51.
55. each compound of claim 1-51 is used for the treatment of and/or prevents to benefit from application in the medicine of the illness of hyperglycemic-glycogenolytic factor antagonistic action or disease in preparation.
56. each compound of claim 1-51 is used for the treatment of and/or prevents application in the medicine of the illness of hyperglycemic-glycogenolytic factor mediation and disease in preparation.
57. each compound of claim 1-51 is used for the treatment of and/or prevents application in the medicine of hyperglycemia in preparation.
58. each compound of claim 1-51 is used for reducing the application of the medicine of Mammals blood sugar in preparation.
59. each compound of claim 1-51 is used for the treatment of and/or prevents application in the medicine of IGT in preparation.
60. each compound of claim 1-51 is used for the treatment of and/or prevents application in the medicine of diabetes B in preparation.
61. the application of claim 60, wherein said application are to be used for postponing or the application of the medicine of the process preventing to transform to diabetes B from IGT in preparation.
62. the application of claim 60, wherein said application are to be used for postponing or the application of the medicine of the process preventing to transform to the insulin requirement diabetes B from non-insulin desirability diabetes B in preparation.
63. each compound of claim 1-51 is used for the treatment of and/or prevents application in the medicine of type 1 diabetes in preparation.
64. claim 1-51 each compound preparation be used for the treatment of and/or the medicine of obesity prevention in application.
65. each compound of claim 1-51 is used for the treatment of and/or prevents application in the medicine of unusual lipidemia in preparation.
66. each application of claim 55-65, wherein said medicine and other antidiabetic are united and are used for the treatment of.
67. each application of claim 55-66, wherein said medicine and other antiobesity agent are united and are used for the treatment of.
68. each application of claim 55-67, wherein said medicine and other hyperlipidemia disease agent are united and are used for the treatment of.
69. each application of claim 55-68, wherein said medicine and other hypotensive agent are united and are used for the treatment of.
70. treat and/or prevent the illness that can benefit from the hyperglycemic-glycogenolytic factor antagonistic action or the method for disease, described method comprise to the individuality that these needs are arranged use significant quantity claim 1-51 each compound or the pharmaceutical composition of claim 53 or 54.
71. the method for claim 70, wherein the significant quantity of compound is the about 2000mg/ of about 0.05mg-days, preferably the about 1000mg/ of about 0.1mg-days, especially preferably the about 500mg/ of about 0.5mg-days.
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