CN1747955A - Nitrogen-substituted hexahydropyrazino[1,2-a]pyrimidine-4,7-dione derivatives, method for the production and use thereof as medicaments - Google Patents
Nitrogen-substituted hexahydropyrazino[1,2-a]pyrimidine-4,7-dione derivatives, method for the production and use thereof as medicaments Download PDFInfo
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- CN1747955A CN1747955A CNA2004800039186A CN200480003918A CN1747955A CN 1747955 A CN1747955 A CN 1747955A CN A2004800039186 A CNA2004800039186 A CN A2004800039186A CN 200480003918 A CN200480003918 A CN 200480003918A CN 1747955 A CN1747955 A CN 1747955A
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- A61P3/04—Anorexiants; Antiobesity agents
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- 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
- A61P3/06—Antihyperlipidemics
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Abstract
The invention relates to nitrogen-substituted hexahydropyrazino[1,2-a]pyrimidine-4,7-dione derivatives, in addition to the physiologically compatible salts thereof and physiologically functional derivatives. The invention also relates to compounds of formula (I), wherein the radicals have the cited meanings, the physiologically compatible salts thereof and methods for the production thereof. Said compounds can be used, for example, as anorectics.
Description
The hexahydropyrazine that the present invention relates to replace is [1,2-a] pyrimidine-4 also, the salt that can tolerate on 7-derovatives and their physiology.
Can to alleviate weight of mammal and be suitable for preventing the compound with treatment of obesity be target to provide in the present invention.Therefore, the present invention relates to the salt that can tolerate on formula I compound and their physiology,
Wherein
A be comprise the heteroatomic 3-12 unit of one or more N of being selected from, O and S single-, two-or spiral shell two rings, and described 3-12 unit ring can further be replaced by following groups: for example F, Cl, Br, NO
2, CF
3, OCF
3, CN, (C
1-C
6)-alkyl, aryl, CON (R11) (R12), N (R13) (R14), OH, O-(C
1-C
6)-alkyl, S-(C
1-C
6)-alkyl, N (R15) CO (C
1-C
6)-alkyl or COO-(C
1-C
6)-alkyl;
R11, R12, R13, R14, R15 are H, (C independently of one another
1-C
6)-alkyl or heterocycle;
N is 0 or 1;
M is 0,1,2,3,4,5 or 6;
R1 is R8, (C
1-C
6)-alkylidene group-R8, (C
2-C
6)-alkylene group-R9, (SO
2)-R8, (SO
2)-(C
1-C
6)-alkylidene group-R8, (SO
2)-(C
2-C
6)-alkylene group-R9, (C=O)-R8, (C=O)-(C
1-C
6)-alkylidene group-R8, (C=O) NH-R8, (C=O)-(C
2-C
6)-alkylene group-R9, (C=O)-NH-(C
1-C
6)-alkylidene group-R8, (C=O)-NH-(C
2-C
6)-alkylene group-R9, COO-R8, COO-(C
1-C
6)-alkylidene group-R8, COO-(C
2-C
6)-alkylene group-R9, alkynylene-R9, (C
1-C
4-alkyl)-and heterocycle, wherein alkylene moiety can be replaced by F;
R8, R9 are H, F, Cl, Br, I, OH, CF independently of one another
3, aryl, heterocycle, (C
3-C
8)-cycloalkyl, wherein said ring and ring system can be by following groups to polysubstituted 3 times: F, Cl, Br, I, OH, CF
3, NO
2, CN, OCF
3, O-(C
1-C
6)-alkyl, (C
1-C
6)-alkyl, NH
2, CON (R11) (R12), N (R13) (R14), SO
2-CH
3, COOH, COO-(C
1-C
6)-alkyl, CONH
2
R2 is NH
2, NO
2, N (R13) (R14), NH-SO
2-CH
3, NH-SO
2-R12, NR11-SO
2-R12, N (CO) R11, nitrogen heterocyclic ring (described heterocycle connects by nitrogen-atoms), NHCONR11, N (C
1-C
6-alkyl) N
+(C
1-C
4-alkyl)
3
R3, R4, R5 are H, F, Cl, Br, I, OH, CF independently of one another
3, NO
2, CN, OCF
3, O-(C
1-C
6)-alkyl, O-(C
1-C
4)-alkoxyl group-(C
1-C
4)-alkyl, S-(C
1-C
6)-alkyl, (C
1-C
6)-alkyl, (C
2-C
6)-alkenyl, (C
3-C
8)-cycloalkyl, O-(C
3-C
8)-cycloalkyl, (C
3-C
8)-cycloalkenyl group, O-(C
3-C
8)-cycloalkenyl group, (C
2-C
6)-alkynyl, aryl, O-aryl (C
1-C
8)-alkylidene group-aryl, O-(C
1-C
8)-alkylidene group-aryl, S-aryl, N ((C
1-C
6)-alkyl)
2, SO
2-CH
3, COOH, COO-(C
1-C
6)-alkyl, CO-N ((C
1-C
6)-alkyl)
2
R6 is H, F, Cl, Br, I, OH, CF
3, NO
2, CN, OCF
3, O-(C
1-C
6)-alkyl, O-(C
1-C
4)-alkoxyl group-(C
1-C
4)-alkyl, S-(C
1-C
6)-alkyl, (C
1-C
6)-alkyl, (C
2-C
6)-alkenyl, (C
3-C
8)-cycloalkyl, O-(C
3-C
8)-cycloalkyl, (C
3-C
8)-cycloalkenyl group, O-(C
3-C
8)-cycloalkenyl group, (C
2-C
6)-alkynyl, (C
0-C
8)-alkylidene group-aryl, O-(C
0-C
8)-alkylidene group-aryl, S-aryl, N ((C
1-C
6)-alkyl)
2, SO
2-CH
3, COOH, COO-(C
1-C
6)-alkyl, CO-N ((C
1-C
6)-alkyl)
2
Preferably have the salt that can tolerate on the formula I compound of Ia structure and their physiology:
Wherein
A be comprise the heteroatomic 3-12 unit of one or more N of being selected from, O and S single-, two-or spiral shell two rings, and described 3-12 unit ring can further be replaced by following groups: for example F, Cl, Br, NO
2, CF
3, OCF
3, CN, (C
1-C
6)-alkyl, aryl, CON (R11) (R12), N (R13) (R14), OH, O-(C
1-C
6)-alkyl, S-(C
1-C
6)-alkyl, N (R15) CO (C
1-C
6)-alkyl or COO-(C
1-C
6)-alkyl;
R11, R12, R13, R14, R15 are H, (C independently of one another
1-C
6)-alkyl or heterocycle;
M is 0,1,2,3,4,5 or 6;
R1 is R8, (C
1-C
6)-alkylidene group-R8, (C
2-C
6)-alkylene group-R9, (SO
2)-R8, (SO
2)-(C
1-C
6)-alkylidene group-R8, (SO
2)-(C
2-C
6)-alkylene group-R9, (C=O)-R8, (C=O)-(C
1-C
6)-alkylidene group-R8, (C=O) NH-R8, (C=O)-(C
2-C
6)-alkylene group-R9, (C=O)-NH-(C
1-C
6)-alkylidene group-R8, (C=O)-NH-(C
2-C
6)-alkylene group-R9, COO-R8, COO-(C
1-C
6)-alkylidene group-R8, COO-(C
2-C
6)-alkylene group-R9, alkynylene-R9 or (C
1-C
4-alkyl)-heterocycle;
R8, R9 are H, F, Cl, Br, I, OH, CF independently of one another
3, aryl, heterocycle, (C
3-C
8)-cycloalkyl, wherein said ring and ring system can be by following groups to polysubstituted 3 times: F, Cl, Br, I, OH, CF
3, NO
2, CN, OCF
3, O-(C
1-C
6)-alkyl, (C
1-C
6)-alkyl, NH
2, CON (R11) (R12), N (R13) (R14), SO
2-CH
3, COOH, COO-(C
1-C
6)-alkyl, CONH
2
R2 is NH
2, NO
2, N (R13) (R14), NH-SO
2-CH
3, NH-SO
2-R12, NR11-SO
2-R12, N (CO) R11, nitrogen heterocyclic ring (wherein said heterocycle connects by nitrogen-atoms), NHCONR11, N (C
1-C
6-alkyl) N
+(C
1-C
4-alkyl)
3
R3, R4, R5 are H, F, Cl, Br, I, OH, CF independently of one another
3, NO
2, CN, OCF
3, O-(C
1-C
6)-alkyl, O-(C
1-C
4)-alkoxyl group-(C
1-C
4)-alkyl, S-(C
1-C
6)-alkyl, (C
1-C
6)-alkyl, (C
2-C
6)-alkenyl, (C
3-C
8)-cycloalkyl, O-(C
3-C
8)-cycloalkyl, (C
3-C
8)-cycloalkenyl group, O-(C
3-C
8)-cycloalkenyl group, (C
2-C
6)-alkynyl, aryl, O-aryl (C
0-C
8)-alkylidene group-aryl, O-(C
0-C
8)-alkylidene group-aryl, S-aryl, N ((C
1-C
6)-alkyl)
2, SO
2-CH
3, COOH, COO-(C
1-C
6)-alkyl, CO-N ((C
1-C
6)-alkyl)
2
R6 is H, F, Cl, Br, I, OH, CF
3, NO
2, CN, OCF
3, O-(C
1-C
6)-alkyl, O-(C
1-C
4)-alkoxyl group-(C
1-C
4)-alkyl, S-(C
1-C
6)-alkyl, (C
1-C
6)-alkyl, (C
2-C
6)-alkenyl, (C
3-C
8)-cycloalkyl, O-(C
3-C
8)-cycloalkyl, (C
3-C
8)-cycloalkenyl group, O-(C
3-C
8)-cycloalkenyl group, (C
2-C
6)-alkynyl, aryl, O-aryl, (C
1-C
8)-alkylidene group-aryl, O-(C
1-C
8)-alkylidene group-aryl, S-aryl, N ((C
1-C
6)-alkyl)
2, SO
2-CH
3, COOH, COO-(C
1-C
6)-alkyl, CO-N ((C
1-C
6)-alkyl)
2
The salt that can tolerate on preferred so especially formula Ia compound and their physiology,
Wherein
A is an aryl, and wherein said aromatic ring can be chosen wantonly by following groups and replace: F, Cl, Br, NO
2, CF
3, OCF
3, CN, (C
1-C
6)-alkyl, aryl, CON (R11) (R12), N (R13) (R14), OH, O-(C
1-C
6)-alkyl, S-(C
1-C
6)-alkyl, N (R15) CO (C
1-C
6)-alkyl or COO-(C
1-C
6)-alkyl;
R11, R12, R13, R14, R15 are H, (C independently of one another
1-C
6)-alkyl or heterocycle;
M is 1;
R1 is R8, (C
1-C
6)-alkylidene group-R8, (C
2-C
6)-alkylene group-R9, (SO
2)-R8, (SO
2)-(C
1-C
6)-alkylidene group-R8, (SO
2)-(C
2-C
6)-alkylene group-R9, (C=O)-R8, (C=O)-(C
1-C
6)-alkylidene group-R8, (C=O) NH-R8, (C=O)-(C
2-C
6)-alkylene group-R9, (C=O)-NH-(C
1-C
6)-alkylidene group-R8, (C=O)-NH-(C
2-C
6)-alkylene group-R9, COO-R8, COO-(C
1-C
6)-alkylidene group-R8, COO-(C
2-C
6)-alkylene group-R9, alkynylene-R9, (C
1-C
4-alkyl)-heterocycle;
R8, R9 are H, F, Cl, Br, I, OH, CF independently of one another
3, aryl, heterocycle, (C
3-C
8)-cycloalkyl, wherein said ring and ring system can be by following groups to polysubstituted 3 times: F, Cl, Br, I, OH, CF
3, NO
2, CN, OCF
3, O-(C
1-C
6)-alkyl, (C
1-C
6)-alkyl, NH
2, CON (R11) (R12), N (R13) (R14), SO
2-CH
3, COOH, COO-(C
1-C
6)-alkyl, CONH
2
R2 is NH
2, NO
2, N (R13) (R14), NH-SO
2-CH
3, NH-SO
2-R12, NR11-SO
2-R12, N (CO) R11, nitrogen heterocyclic ring (wherein said heterocycle connects by nitrogen-atoms), NHCONR11, N (C
1-C
6-alkyl) N
+(C
1-C
4-alkyl)
3
R3 is H;
R4, R5 are H, F, Cl, Br, OH, CF independently of one another
3, OCF
3, O-(C
1-C
6)-alkyl, (C
1-C
6)-alkyl;
R6 is H.
The salt that can tolerate on more special preferred formula Ia compound and their physiology,
Wherein
A is an aryl, and wherein said aryl rings is optional to be replaced by following groups: F, Cl, Br, NO
2, CF
3, OCF
3, CN, (C
1-C
6)-alkyl, aryl, CON (R11) (R12), N (R13) (R14), OH, O-(C
1-C
6)-alkyl, S-(C
1-C
6)-alkyl, N (R15) CO (C
1-C
6)-alkyl or COO-(C
1-C
6)-alkyl;
R11, R12, R13, R14, R15 are H, (C independently of one another
1-C
6)-alkyl or heterocycle;
M is 1;
R1 is (C
1-C
6)-alkyl, (C
1-C
6)-alkylidene group-R8;
R8, R9 are F, Cl, Br, I, OH, CF independently of one another
3
R2 is NH
2, NO
2, CN, N (R13) (R14), NH-SO
2-CH
3, NH-SO
2-R12, NR11-SO
2-R12, N (CO) R11, nitrogen heterocyclic ring (wherein said heterocycle connects by nitrogen-atoms), NHCONR11, N (C
1-C
6-alkyl) N
+(C
1-C
4-alkyl)
3
R3 is H;
R4 is F, Cl, Br, OH, CF
3, OCF
3, O-(C
1-C
6)-alkyl, (C
1-C
6)-alkyl;
R5 is H, F, Cl, Br, OH, CF
3, OCF
3, O-(C
1-C
6)-alkyl, (C
1-C
6)-alkyl;
R6 is H.
If group or substituting group not only occur once in formula I compound, for example CON (R11) (R12), they each all can be independent mutually, have described definition, and can be identical or different.
The present invention relates to the formula I compound of racemoid, enantiomorph enrichment mixture and pure enantiomeric form, and their diastereomer and mixture.
Alkyl among substituent A, R1, R2, R3, R4, R5, R6, R8, R9, R10, R11, R12, R13, R14, the R15, alkenyl and alkynyl group can be straight chain, side chain or optional halo.
Term " aryl " means the phenyl or naphthyl group.
Heterocycle or heterocyclic group mean ring system, except carbon, also comprise heteroatoms for example nitrogen, oxygen or sulphur.This definition also comprises ring system, and wherein heterocycle or heterocyclic group and benzene nucleus condense.
Suitable " heterocycle " or " heterocyclic group " is acridyl, the azocine base, benzimidazolyl-, benzofuryl, benzothienyl benzoxazolyl, benzothiazolyl, the benzotriazole base, the benzo tetrazyl, the benzoisoxazole base, the benzisothiazole base, benzimidazoline base (imidazalinyl), carbazyl, the 4aH-carbazyl, carbolinyl, quinazolyl, quinolyl, the 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, benzopyranyl, the cinnolines base, decahydroquinolyl, 2H, 6H-1,5,2-dithiazine base, dihydrofuran also [2,3-b]-tetrahydrofuran (THF), furyl, the furazan base, imidazolidyl, imidazolinyl, imidazolyl, the 1H-indazolyl, indolinyl, the indolizine base, indyl, the 3H-indyl, isobenzofuran-base, the isochroman base, iso indazolyl, iso-dihydro-indole-group, pseudoindoyl, isoquinolyl (benzimidazolyl-), isothiazolyl isoxazolyl, morpholinyl, phthalazinyl, octahydro isoquinolyl oxadiazole base, 1,2,3-oxadiazole base, 1,2,4-oxadiazole base, 1,2,5-oxadiazole base, 1,3,4-oxadiazole base oxazolidinyl oxazolyl oxazolidinyl, pyrimidyl, phenanthridinyl, the phenanthroline base, phenazinyl, phenothiazinyl, phenoxathiinyl phenoxazinyl, 2, the 3-phthalazinyl, piperazinyl, piperidyl, pteridyl, purine radicals, pyranyl, pyrazinyl, pyrazolidyl, pyrazolinyl, pyrazolyl, pyridazinyl, Bi Ding Bing oxazolyl, the pyridine-imidazole base, the pyrido thiazolyl, pyridyl, pyrimidyl, pyrrolidyl, pyrrolinyl, the 2H-pyrryl, pyrryl, tetrahydrofuran base, tetrahydro isoquinolyl, tetrahydric quinoline group, 6H-1,2,5-thiadiazine base, thiazolyl, 1,2, the 3-thiadiazolyl group, 1,2, the 4-thiadiazolyl group, 1,2, the 5-thiadiazolyl group, 1,3, the 4-thiadiazolyl group, thienyl, triazolyl, tetrazyl and xanthenyl.
Pyridyl can be 2-, 3-and 4-pyridyl.Thienyl can be 2-and 3-thienyl.Furyl can be 2-and 3-furyl.
Corresponding N-the oxide compound that also comprises these compounds, that is, for example 1-oxygen-2-, 3-or 4-pyridyl.
Comprise that also these heterocyclic are by the derivative of benzo-fused one or many
Heterocycle or heterocyclic group can be replaced one or many by suitable group, for example, and F, Cl, Br, I, CF
3, NO
2, N
3, CN, COOH, COO (C
1-C
6) alkyl, CONH
2, CONH (C
1-C
6) alkyl, CON[(C
1-C
6) alkyl]
2, (C
1-C
6)-alkyl, (C
2-C
6)-alkenyl, (C
2-C
6)-alkynyl, O-(C
1-C
6)-alkyl, wherein one or more or all hydrogen in the alkyl group can be replaced by fluorine; PO
3H
2, SO
3H, SO
2-NH
2, SO
2NH (C
1-C
6)-alkyl, SO
2N[(C
1-C
6)-alkyl]
2, S-(C
1-C
6)-alkyl, S-(CH
2)
n-phenyl, SO-(C
1-C
6)-alkyl, SO-(CH
2)
n-phenyl, SO
2-(C
1-C
6)-alkyl, SO
2-(CH
2)
n-phenyl, wherein n can be 0-6, and phenyl group can be by twice replacement of following groups as many as: F, Cl, Br, OH, CF
3, NO
2, CN, OCF
3, O-(C
1-C
6)-alkyl, (C
1-C
6)-alkyl, NH
2C (NH) (NH
2), NH
2, NH-(C
1-C
6)-alkyl, N ((C
1-C
6)-alkyl)
2, NH (C
1-C
7)-acyl group, phenyl, O-(CH
2)
n-phenyl, wherein n can be 0-6, and wherein phenyl ring can be replaced 1-3 time by following groups: F, Cl, Br, I, OH, CF
3, NO
2, CN, OCF
3, O-(C
1-C
6)-alkyl, (C
1-C
6)-alkyl, NH
2, NH (C
1-C
6)-alkyl, N ((C
1-C
6)-alkyl)
2, SO
2-CH
3, COOH, COO-(C
1-C
6)-alkyl, CONH
2
Pharmacy acceptable salt is particularly suitable for medicinal application, is basic cpd because they water-soluble is higher than initial.These salt must have pharmaceutically acceptable negatively charged ion or positively charged ion.The suitable pharmaceutically-acceptable acid addition of The compounds of this invention is inorganic acid salt example hydrochloric acid salt, hydrobromate, phosphoric acid salt, metaphosphate, nitrate, sulfamate and vitriol, and organic acid salt such as acetate, benzene sulfonate, benzoate, Citrate trianion, esilate, fumarate, gluconate, glycollate, isethionate, lactic acid salt, Lactobionate, maleate, malate, mesylate, succinate, p-tosylate, tartrate and trifluoroacetate.Especially preferably hydrochloride is used as medicine.Suitable pharmaceutically acceptable basic salt is ammonium salt, an alkali metal salt (as sodium and sylvite) and alkaline earth salt (as magnesium and calcium salt).
Have pharmaceutically unacceptable anionic salt equally also in scope of invention of the present invention, can and/or be used for non-treatment, for example external application as the intermediate of preparation or purifying pharmacy acceptable salt.
The term of Shi Yonging " physiological function derivative " means the derivative that can tolerate on any physiology of formula I compound of the present invention herein, ester for example, these compounds can form (directly or indirectly) formula I compound or their active metabolite after giving the Mammals such as the mankind.
Physiological function derivative also comprises the prodrug of The compounds of this invention.Such prodrug metabolism in vivo is a The compounds of this invention.These prodrugs itself can be active, also can be inactive.
The compounds of this invention also can exist with various polymorphics, for example amorphous and crystal polymorphic.The polymorphic of all The compounds of this invention all is contained in the present invention, is another aspect of the present invention.
All " formula (I) compounds " of hereinafter mentioning mean formula mentioned above (I) compound and salt, solvate and their physiological function derivative described herein.
The amount that can reach formula (I) compound of required physiologic effect depends on many factors, for example selected specific compound, purposes, administering mode and patient's clinical manifestation.Usually, the per daily dose scope is per kilogram of body weight 0.3mg-100mg (being generally 3mg-50mg), for example 3-10mg/kg/ days.Vein dosage can be for example 0.3mg-1.0mg/kg, and the dosage range of optimal infusion administration is per kilogram per minute 10ng-100ng.The suitable infusion solution that is used for this purpose can comprise for every milliliter, and for example 0.1ng-10mg is generally 1ng-10mg.Single dose can comprise, for example the 1mg-10g activeconstituents.Therefore the injection ampoule can comprise, 1mg-100mg for example, and single dose preparation that can the oral administration administration, for example tablet or capsule comprise, and for example 1.0-1000mg is generally 10-600mg.If pharmacy acceptable salt, the aforementioned weight data of mentioning is based on the weight of the free cpds of salt.When preventing or treat above-mentioned disorder, formula (I) compound can use with compound itself, but they preferably use with the medicinal compositions form that contains acceptable carrier.Certainly, carrier must be acceptable, compatible with other composition of composition, and healthy harmless to patient.Carrier can all have for solid or liquid or the two, and preferably is formulated as the preparation of single dose with compound, and described single dose for example tablet can contain the activeconstituents of 0.05%-95% weight.The pharmaceutically active substance that can also comprise other comprises other formula (I) compound.Medicinal compositions of the present invention can be by known pharmaceutical methods preparation, and described method mainly comprises this composition and pharmaceutically acceptable carrier and/or mixed with excipients.
Medicinal compositions of the present invention is those compositions that are suitable for oral, rectum, part, per os (for example hypogloeeis) and parenteral (for example subcutaneous, muscle, intracutaneous or vein) administration, although depend on the character of employed formula (I) compound under the character of the disorder of being treated and seriousness and the every kind of situation in the optimal mode of the administration on each particular individual.Coated preparation and coated slow release agent are equally also within the scope of the invention.The preparation of preferred antiacid and gastric juice.The dressing of suitable anti-gastric juice comprises the anionic polymer of rhodia phthalic acid ester, Vinyl Acetate Copolymer phthalic acid ester, hydroxypropylmethyl phthalic acid Mierocrystalline cellulose and methacrylic acid and methyl methylacrylic acid.
The suitable medicinal compound that is used for oral administration can exist as capsule, cachet, can inhale tablet or tablet with the individual form, and each all comprises formula (I) compound of specified quantitative; As powder or granule; Solution or suspension as the aqueous solution or non-aqueous solution; Or oil-in-water or water-in-oil emulsion.As mentioned above, these compositions can comprise activeconstituents and carrier (can comprise one or more other compositions) blended step by any suitable medicinal method preparation.Usually, composition can evenly mix by the solid carrier with activeconstituents and liquid and/or segmentation and produce, then if desired with the product moulding.Therefore, for example tablet can add one or more other composition production by the powder or the particle of compacting or molding compounds in the time of suitably.Compressed tablets can be by with the compound of free-flowing form for example powder or particle, in the time of suitably and the film-making production in suitable machine of a kind of tackiness agent, lubricant, inert diluent and/or one or more surfactant/dispersant.The molding tablet can be by producing the compound of powder type in suitable machine with the wetting post moulding of inert liquid diluent.
The medicinal compositions that is suitable for per os (hypogloeeis) administration comprises can inhale tablet and lozenge, described tablet comprises formula (I) compound and correctives, normally sucrose and Sudan Gum-arabic or tragacanth, described lozenge is included in the compound in inert base such as gelatin and glycerine or sucrose and the Sudan Gum-arabic.
The medicinal compositions of suitable parenteral admin preferably comprises the aseptic aqueous solution preparation of formula (I) compound, and described preparation preferably oozes with blood of treatment acceptor etc.Although these preparations also can preferably pass through intravenously administrable by subcutaneous, muscle or intradermal injection administration.These preparations preferably prepare by compound being mixed with water and the sterile solution that obtains and blood etc. being oozed.Composition for injection of the present invention is by containing the active compound of 0.1-5% weight.
The medicinal compositions of suitable rectal administration preferably exists with the suppository form of single dose.These compositions can by with formula (I) compound and one or more conventional solid carriers for example theobroma oil mix, and the mixture molding that obtains is prepared.
The preferred form of the medicinal compositions of suitable local skin medication is: forms such as ointment, emulsion, washing lotion, paste, sprays, aerosol or oily matter exist.Can adopt following carrier: paraffin wax, lanolin, polyoxyethylene glycol, alcohol and two or more these mixture of ingredients.The concentration of activeconstituents is generally the 0.1-15% of composition weight, for example 0.5-2%.
Also can percutaneous dosing.The suitable medicinal compositions that uses through skin can exist with the form of single plaster, and this form is fit to closely contact with patient's epidermis for a long time.This class plaster is fit to comprise activeconstituents, and described activeconstituents can dissolve and/or be scattered in tackiness agent or be scattered in polymkeric substance in the optional buffered aqueous solution.The concentration of suitable activeconstituents is about 1%-35%, preferably about 3%-15%.As a kind of special case, activeconstituents can discharge by electromigration or iontophoresis, Pharmaceutical Research for example, 2 (6): described in 318 (1986).
The metabolism that is characterized as lipoid cpd of formula I compound has useful effect, and they weight of mammal is alleviated and the body weight after the back that loses weight keeps alleviating effective especially, can be used as anorectic medicaments.The characteristics of this compounds are their hypotoxicity and less side effect.
This compounds can be separately or is lost weight or subtract the appetite active component with other and unite use.This this compounds other subtracts the appetite activeconstituents as at Rote Liste, the 01st chapter loses weight and addresses in the medicine/appetite inhibiting part, and can comprise that also increasing the organism Conversion of energy reaches the activeconstituents of the purpose that loses weight then or pass through the organic common metabolism of influence, does not cause fatty reserves increase and normal calorie absorption can reach the activeconstituents of the purpose that reduces the fatty reserves of organism though the calorie absorption is increased.This compounds is suitable for prevention and particularly treats overweight or fat.Metabolism normalizing and treatment hypertension that this compounds is further adapted for prevention and particularly treats type ii diabetes, atherosclerosis and make lipoid cpd.This compounds can be used as the novel melanocortin receptor antagonist, also is suitable for treating healthy unbalance and other psychotic symptoms for example depression, anxiety state, anxiety neurosis, schizophrenia and disorder and the drug habit relevant with circadian rhythm.
This compounds also is suitable for treating cancer, sacroiliitis, somnopathy, sleep apnea, women and male sexual dysfunction, inflammation, acne, cutaneous pigmentation, metabolism syndrome, steroid metabolism disorder, dermatosis, psoriatic, mycosis, neurodegenerative disease and Alzheimer in addition.
The present invention on the other hand, formula I compound can with the active compound combined administration of one or more other medicines, described activeconstituents is antidiabetic drug, anti-obesity medicine, hypotensive activeconstituents, fat-reducing medicament and treat and/or prevent diabetes or the activeconstituents of the complication that diabetes are relevant for example.
Suitable antidiabetic drug comprises the derivative of Regular Insulin, islet amyloid polypeptide, GLP-1 and GLP-2, as is disclosed among the WO 98/08871 of Novo Nordisk A/S those, and the Orally active blood-sugar decreasing active.
The Orally active blood-sugar decreasing active preferably comprises sulfonylurea, biguanides, meglitinide class; oxadiazole alkane two ketones, thiazolidinediones, alpha-glucosidase inhibitors, glucagon receptor antagonist, the GLP-1 agonist, potassium channel openers, as be disclosed in the WO 97/26265 of Novo Nordisk A/S and among the WO 99/03861 those, insulin sensitizer, the insulin receptor kinase activator, the liver enzyme inhibitor that participation gluconeogenesis and/or glycogen decomposition stimulate is the glycogen phosphorglase inhibitor for example, glucose uptake and the agent of glucose regulation of secretion, change metabolic compound of lipoid cpd such as reducing blood-fat active component and fall for example HMGCoA reductase inhibitor of lipid activeconstituents, cholesterol transport/cholesterol uptake inhibitor, resorbent inhibitor of bile acide or microsomal triglyceride transfer protein (MTP) inhibitor, reduce the compound of ingestion of food, PPAR and rxr agonist and the activeconstituents that acts on β cell ATP-dependency potassium channel.
In one embodiment of the invention, The compounds of this invention can with the insulin combination administration.
In further embodiment, The compounds of this invention can with sulfonylurea such as tolbutamide, U26452, glimepiride, Glipizide, gliquidone, glisoxepide, glibornuride or gliclazide Combined Preparation.
In another embodiment, The compounds of this invention can with biguanides such as N1,N1-Dimethylbiguanide Combined Preparation.
In another embodiment, The compounds of this invention can with meglitinide such as repaglinide Combined Preparation.
In another embodiment, The compounds of this invention can with the thiazolidinedione Combined Preparation, as troglitazone, ciglitazone, pioglitazone, rosiglitazone or be disclosed in compound among the WO 97/41097 of Dr.Reddy ' s ResearchFoundation, 5-[[4-[(3 particularly, 4-dihydro-3-methyl-4-oxo-2-quinazolyl methoxyl group) phenyl] methyl]-2, the 4-thiazolidinedione.
In further embodiment, The compounds of this invention can with alpha-glucosidase inhibitor such as miglitol or acarbose Combined Preparation.
In another embodiment, The compounds of this invention can with the activeconstituents Combined Preparation that acts on β cell ATP-dependency potassium channel, described activeconstituents is tolbutamide, U26452, glimepiride, Glipizide, gliclazide or repaglinide for example.
In another embodiment, The compounds of this invention can with reducing blood-fat active component or anti-lipid activeconstituents Combined Preparation, described activeconstituents for example QUESTRAN, colestipol, chlorine Bei Te, fenofibrate, gemfibrozil, lovastatin, Pravastatin, Simvastatin, Zarator, happiness cut down his spit of fland, fluvastatin, probucol, according to Ezetimibe or dextrothyroxine.
In further embodiment, The compounds of this invention can with multiple compound Combined Preparation mentioned above, as with Combined Preparation such as sulfonylurea and N1,N1-Dimethylbiguanide, sulfonylurea and acarbose, repaglinide and N1,N1-Dimethylbiguanide, Regular Insulin and sulfonylurea, Regular Insulin and N1,N1-Dimethylbiguanide, Regular Insulin and troglitazone, Regular Insulin and lovastatin.
The compounds of this invention also can with one or more anti-obesity medicines or appetite-adjusting activeconstituents Combined Preparation.
This active component can be selected from following: CART agonist, NPY antagonist, MCH antagonist, increase food factor antagonist, H
3Antagonist; the TNF agonist; the CRF agonist; CRF BP antagonist; agonist can be decided in excellent Lip river; β 3 agonists; MSH (melanophorin) agonist; the CCK agonist; serotonin reuptake inhibitor; the blended serotonin-and NRI; the 5HT conditioning agent; the MAO inhibitor; to the bombesin agonist; the sweet third plain antagonist; tethelin; tethelin-release compound; the TRH agonist; move back coupling protein 2 or 3 conditioning agents; the leptin agonist; dopamine agonist (bromocriptine, Doprexin); lipase/amylase inhibitor; hemp ester acceptor 1 antagonist; short acylated protein (ASP) conditioning agent; the PPAR conditioning agent; the RXR conditioning agent; hCNTF agonist or TR-beta-agonists.
In one embodiment of the invention, the anti-obesity medicine is the leptin of leptin or modification.
In another embodiment, the anti-obesity medicine is dextroamphetamine or amphetamines.
In another embodiment, the anti-obesity medicine is Phenfluoramine or dexfenfluramine.
In another embodiment, the anti-obesity medicine is list-and two demethylation active metabolites of sibutramine or sibutramine.
In further embodiment, the anti-obesity medicine is Ao Liesita.
In another embodiment, the anti-obesity medicine is Mazindol, Diethylpropion or Phentermine.
The compounds of this invention and one or more antihypertensive active composition drug combinations in addition.The example of antihypertensive active composition has beta-blocker such as H-56/28, atenolol USP 23, timolol, Visken, Propranololum and metoprolol, ACE (Zinc metallopeptidase Zace1) inhibitor such as Zinadril Briem, captopril, Enalapril, fosinopril, lisinopril, quinapril and Ramipril, calcium channel blocker such as nifedipine, felodipine, nicardipine, Isrodipine, nimodipine, diltiazem and verapamil, and alpha blocker such as Doxazosin, urapidil, Prazosin and terazosin.Can be further with reference to Remington:The Science and Practice of Pharmacy, the 19th edition, Gennaro, editor, Mack Publishing Co., Easton, PA, 1995.
The compounds of this invention and one or more aforesaid compounds and choose any one kind of them or each suitable combination of multiple other medicines activeconstituents all is regarded as being included in the scope that the present invention protects.
The curative effect of compound can be measured by following method: the biological assay model:
On female NMRI mouse, measure the apocleisis effect.Stop behind the feeding 24 hours, gavage gives the compound that tries.Place this animal separately, freely drink water, and give dense milk after 30 minutes in administration.In 7 hours after the administration, measure the consumption of dense milk per half an hour, and observe the healthy state of animal.With milk consumption of measuring and the control animals of using vehicle treated relatively.
Table 1: measure with the minimizing of the accumulation milk consumption of control animals comparison and to subtract the appetite effect.
| Embodiment | Oral dosage [mg/kg] | Size of animal/the animal of trying accumulation milk consumption N/[ml] | Size of animal/control animals accumulation milk consumption N/[ml] | The minimizing of accumulation milk consumption accounts for the % of control group reduction |
| 5 | 50 | 5/2.4 | 5/3.40 | 31 |
| 9 | 50 | 5/2.06 | 5/3.86 | 47 |
By in the table obviously as can be seen, formula I compound exhibits good apocleisis effect and therefore be suitable as very much the anti-obesity medicine.
Hereinafter embodiment of Xiang Ximiaoshuing and preparation method be used for the explanation but be not to be used to limit the present invention.
Universal method
Used starting raw material can derive from chemical supplier for example Aldrich, Acros, Sigma, Fluka, Nova Biochem, Advanced Chemtech, Bachem, Lancaster and other company in synthetic.
In synthetic, the protected radical protection of the functional group of used amino acid derivative is to avoid the side reaction in the coupling step.The example such as the The Peptides of suitable blocking group and their purposes, supra, 1981, the 9th volume was described in the Udenfriend and Meienhofer (editor) 1987 (being incorporated herein by reference).
The compounds of this invention can adopt the universal method preparation that consolidate-is combined to.These class methods are described in for example synthetic (Freeman of Solid Phase Peptide of Steward and Young; Co., SanFrancisco 1969) in (being incorporated herein by reference).
Unless specialize, compound can adopt method described in the TentaGel HL12019 Resin (RappPolymere, T ü bingen) synthetic.The polymkeric substance that this commerce obtains comprises the bromoacetal linking agent.This type of coupling can be passed through Vojkovsky, T. etc., J.Org.Chem.1998,63,3162-3163, and Patek, M., Contribution to Combinatorial Chemistry 2000, London, method described in the 11.-14.7.2000 (being incorporated herein by reference) is introduced all types hydroxyl-TG.
In first synthesis step (referring to the flow process 1 of total synthetic flow process), under the temperature that raises, in DMSO, adopt the bromine in the amine replacement bromoacetal linking agent.The amino acid of Fmoc-protection be coupled to generation on the secondary amine on the polymkeric substance.Coupling in DMF, is undertaken by DIC/HOAt or HATU/DIEA usually.Coupling at room temperature (RT) is carried out carrying out under 16 hours or 55 ℃ 4-5 hour.The protection of Fmoc group can adopt 50% piperidines to remove (5+15 minute) in DMF.Thereby can by remove volume that the optical density of protection back measuring solution in 302nm place measures the amount of the Fmoc that discharges, washings and synthetic in the weight mensuration replacement situation of used polymkeric substance; this can be according to Krchnak, and V. etc. carry out in method described in the Collect.Czech.Chem.Commun.53 (1988) 2542 (being incorporated herein by reference).
To be connected to the free ammonia group and Fmoc-Beta-alanine (or beta-amino acids of Fmoc-a-amino acid or the replacement) coupling of the structure of solid phase then.Coupling can be passed through N, and N '-DIC (DIC) in the presence of HOBt, carries out in DMF usually.Finishing by ninhydrin test of coupling monitored.
The protection of Fmoc group can be removed through reaction in 5+15 minute in DMF with 50% piperidines.The amount of the Fmoc that discharges can by measure the volume of the optical density of the solution after removing protection, used washings in 302nm place and synthesize in used polymkeric substance determine.
The free amine group that will be connected to the structure of solid phase then carry out alkylsulfonylization with 2 normal sulphonyl ammonia/DIEA at the most in DCM or acetonitrile.
Finishing by ninhydrin test of alkylsulfonylization monitored.
The precursor of ol cpds is used DMF and DCM or THF washing and vacuum-drying in turn with solid phase after the combination on the polymkeric substance is finished.
Under room temperature with formic acid with required compound cyclative cracking 18-24 hour, unite use in 50 ℃ of 6 hours or two kinds of conditions.Leach polymkeric substance and with the washing of DCM or formic acid.Washing lotion is introduced formic acid solution.Evaporating solns, the mixture of the water-soluble and acetonitrile of residue, and freeze-drying.
The exsiccant compound is through the HPLC purifying, with water and acetonitrile (ACN) wash-out of the 0.1%TFA of suitable gradient.After collection contains the peak of required synthetic product, with this compound solution freeze-drying.For determining to have synthesized correct compound, compound analyzed through electrospray ionization mass spectrum (LC/MS) and/or NMR carry out qualitative test.
Analyze for carrying out HPLC, compound sample is adopted YMC ODS-AM 4.6 * 250mm post (S-5 (5 μ m) through Beckman HPLC system (the data station Controlling System that comprises solvent plenum system 126, programming monitoring modular 166 and self-actuated sampler 507e and have GoldNouveau software), YMC, Inc.Wilmington, NC USA) analyzes in the 230nm place.By this setting, adopt flow velocity 1ml/min and gradient water/0.1%TFA damping fluid and ACN (HPL quality) as elutriant.
Flow process 1:
This compound also can prepare (flow process 2) with being similar to described resin synthetic method in solution.Replaced functionalized resins, in the first step, made 2-bromo-1,1-diethoxyethane and primary amine reaction.
Flow process 2:
To be similar to the method for solid phase synthesis, to make product and the amino acid reaction that obtains.Replace FMOC as amino acid whose amido protecting group with allyloxy carbonyl blocking group (Aloc), and introduce (Aloc-Cl, triethylamine) and remove (Pd (PPh according to method in the document
3)
4, dimethyl barbituric acid).
In the presence of triethylamine, make the aminocarboxylic acid and the SULPHURYL CHLORIDE reaction that have radicals R 4.By the carbodiimide method (EDC, HOBt) or adopt urea salt (HATU HOAt) makes the free carboxy acid and removes the unhindered amina coupling that the Aloc group obtains.
Cyclization process is carried out under acidic conditions, uses HBr, removes benzyloxycarbonyl (Cbz) group in ice acid.Functionalized process subsequently is similar to method mentioned above.
Sample by the TFA aqueous solution and the mixture in 10-50% acetonitrile or the acetate with 0.1% intensity launch freeze dried crude product material makes product purification.Usually with the solution of this compound by being connected to ACRODISC 13 CR PTFE 0.45 μ m strainer (Gelman Sciences; Ann Arbor, MI, syringe USA) filters.With the filtering solution of the compound of proper volume be injected to semipreparative C18 post (YMC ODS-AM, S-5 (5 μ m), 20 * 150mm, YMC, Inc., Wilmington, NC, USA).Water/0.1%TFA damping fluid and ACN (HPL level) pass through Beckman SYSTEM GOLD HPLC (System Gold as the gradient flow velocity of elutriant, programmable solvent module 126 and programmable monitoring modular 166 are by SYSTEM GOLD software control) mode keeps.In 230 or 280nm, detect the wash-out of monitoring compound by UV.Determined the peak of synthetic compound by LC/MS after, collect compound, freeze-drying is also carried out biological assay.
Behind the purifying, the compound that has basic group obtains with the trifluoroacetic acid salt form.The hydrochloride of these compounds can easily prepare by with excessive HCl/ diox the trifluoroacetate of compound being handled.Behind the evaporating solvent, with the hydrochloride and the filtering separation of ether sedimentation compound.
Can adopt PE Sciex API 150EX and Sciex MassChrom software to carry out LC/MS in the ES+ mode, Gilson 215 liquid processors, two Shimadzu LC-10AD liquid modules, a Shimadzu SPD-10A monitor, Keystone Betasil C-18 post (a 2 * 30mm wherein are housed, 3 μ m, acetonitrile/water/0.1%TFA gradient flow velocity is 0.7ml/min).
Analyze for carrying out NMR, sample is at DMSO-d
6(Aldrich) in, measure with Bruker AvanceDPX300.
Flow process 3:
Synthetic can carrying out shown in the flow process 3 to be similar to another solution synthetic mode.In this case, the acid amides coupling all can be carried out as coupler with DMTMM.In addition, Fmoc can be used as the blocking group of solid state chemistry, and removes with diethylamine.Sulphonamide is not introduced with second acid amides coupling, but adopt diethylamine as alkali after formation.In acetonitrile, remove the Cbz group with TMSI.All further functionalizations all can be similar to method mentioned above to carry out.
Reactant and synthetic in the structural unit used can obtain by various suppliers such as Aldrich, Acros, Sigma, Fluka, Nova Biochem, Advanced Chemtech, Bachem, Lancaster, Rapp Polymere etc.
Unless specialize, adopt following method to carry out chemical analysis:
Liquid chromatography/mass spectrometry is analyzed (LC/MS): the Agilent 1100LC that mass detector is housed.Can adopt following equipment: Waters (YMC) Combiscreen Pro C184.6 * 33.5 μ, 120A, 3 minutes, 10% acetonitrile (0.1% trifluoroacetic acid) and 90% water (0.1% trifluoroacetic acid) were to 0% acetonitrile (0.1% trifluoroacetic acid) and 100% water (0.1% trifluoroacetic acid).1 minute flushing time, balance was initial condition in 1 minute subsequently.
Electrospray ionization mass spectrum, anode (unless specializing).
Preparation LC: semipreparative phase chromatography-use Gilson 215 liquid processors (being suitable for analyzing and semipreparative equipment) record.Moving phase: water (0.1%TFA) and acetonitrile (0.1%TFA).Sample can carry out initial analysis by analytical procedure.Can adopt half suitable preparation method then.The 5%-100% acetonitrile, 12 minutes (unless specializing).Waters (YMC) Combiscreen post is used for analyzing, and adopts 4.6 * 50per C18,5 μ, 120A.Waters Combiscreen 20 * 50.5 μ, the 120A semipreparative column.
Adopt glass to strengthen 60F-254 silica-gel plate (thickness 0.25mm) register layer chromatography (TLC).
Flash chromatography: this process can adopt Still, and W.C., Kahn, M. and Mitra, A. are at J.Org.Chem.1978, and the commercial system that obtains of method described in 43,2923 or employing such as BiotageHorizon, Isco Opix or Companion carry out.The solvent systems that in this case, can adopt in the experimental example to be mentioned.
Microwave is synthetic: unless specialize, microwave reaction can be made instrument in individualized length of schooling, optimize in instrument or the synthesizer (personal chemistry creator, Optimizer or synthesizer) and carry out.
All calculated amount all refer to single isotropic substance of planting.
Abbreviation
Unless specialize, hereinafter the abbreviation among the embodiment has following definition:
The ACN=acetonitrile
The Aloc=allyloxy carbonyl
The DIC=DIC
EDC=1-(3-dimethylaminopropyl)-3-ethyl carbodiimide
FMOC=9-fluorenyl methoxy carbonyl
DCE=1, the 2-ethylene dichloride
The DEA=diethylamine
The DIEA=diisopropylethylamine
NaBH
3The CN=sodium cyanoborohydride
DMAP=N, the N-dimethyl aminopyridine
DMF=N, dinethylformamide
The THF=tetrahydrofuran (THF)
The DIC=DIC
The DMSO=dimethyl sulfoxide (DMSO)
DCM=methylene dichloride (being also referred to as METHYLENE CHLORIDE)
DMTMM=4-(4,6-dimethoxy [1,3,5] triazine-2-yl)-4-methylmorpholine muriate
The HOBt=1-hydroxybenzotriazole
HOAt=1-hydroxyl-7-azepine benzotriazole
HATU=dimethylamino ([1,2,3] triazolo [4,5-b] pyridin-3-yl oxygen base) methylene radical Dimethyl Ammonium phosphofluoric acid
The EtOAc=ethyl acetate
HOAc=acetate
Et
3The N=triethylamine
HCl=hydrochloric acid
The HBr=Hydrogen bromide
The HPLC=high performance liquid chromatography
The TEA=triethylamine
TMSI=trimethyl silyl iodine
The following example is to be used for more at large illustrating the present invention, but not limits the invention to product described in the embodiment and embodiment.
Embodiment 1
3-amino-6-(4-benzyl chloride base)-1-(5-chloro-2-anisole alkylsulfonyl)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
With DMSO washing 0.35g TentaGel HL12019 (bromoacetal linking agent, S=0.5mmol/g, Rapp Polymere, T ü bingen).The DMSO solution that adds 20 equivalent 2M isopropylamine, and mixture was placed encloses container 15 hours in 60 ℃.Polymkeric substance washs 7 times with DMF.
Adopt the DMF of HOAt (3 equivalent) and DIC (3 equivalent), with Fmoc-(S)-4-chlorophenylalanine (3 equivalent) and the secondary amine coupling on polymkeric substance.Ultimate density is 0.2-0.3M.Reaction mixture places under the room temperature and spends the night.Polymkeric substance washs 6 times with DMF.DMF with 50% piperidines removes Fmoc protecting group (5+15 minute).
Adopt HOBt (3 equivalent) and DIC (3 equivalent) DMF (ultimate density: about 0.2M), through at least 4 hours with Z-Dap (Fmoc) (3 equivalent) coupling.DMF with 50% piperidines removes Fmoc protecting group (5+15 minute).
Polymkeric substance successively with DMF washing 5 times, with DCM washing 4 times, and with the DCM solution (ultimate density: 0.1-0.15M) mixes, under room temperature, reacted 5 hours of 1.5 equivalent 2-methoxyl group-5-chlorobenzene sulfonyl chlorides and 3 equivalent DIEA.Then successively with DMF washing 5 times, with DCM washing 5 times, and vacuum-drying.
Carry out the cyclative cracking, with exsiccant polymkeric substance and 10ml formic acid mix be incorporated in shake under the room temperature 16 hours, shook 6 hours in 50-55 ℃.Remove by filter polymkeric substance and wash with DCM.The filtrate vacuum-evaporation that merges.Under room temperature, residue was handled 2 hours and vacuum-evaporation with 5ml 37%HBr/HOAc.Add the diethyl ether precipitation and leach the product hydrobromate.Behind the HPLC purifying, separate pure target compound.Adopt " universal method " described system and method down herein.MW=554.12 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 555.3.
Embodiment 2
3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
With DMSO washing 0.7g TentaGel HL12019 (bromoacetal linking agent, S=0.5mmol/g, Rapp Polymere, T ü bingen).The DMSO solution that adds 20 equivalent 2M isopropylamine, and mixture was placed encloses container 15 hours in 60 ℃.Polymkeric substance washs 7 times with DMF.
Adopt the DMF of HOAt (3 equivalent) and DIC (3 equivalent), with Fmoc-4-chlorophenylalanine (3 equivalent) and the secondary amine coupling on polymkeric substance.Ultimate density is 0.2-0.3M.Reaction mixture places under the room temperature and spends the night.Polymkeric substance washs 6 times with DMF.DMF with 50% piperidines removes Fmoc protecting group (5+15 minute).
Adopt then HOBt (3 equivalent) and DIC (3 equivalent) DMF (ultimate density: about 0.2M), through at least 4 hours coupling Cbz-Dap (Fmoc) (3 equivalent).DMF with 50% piperidines removes Fmoc protecting group (5+15 minute).
Polymkeric substance is with DMF washing 5 times, with DCM washing 4 times, with the DCM solution (ultimate density: 0.1-0.15M) mix, and reacted 5 hours under room temperature of 1.5 equivalent 2,4 dichloro benzene SULPHURYL CHLORIDE and 3 equivalent DIEA.Then with DMF washing 5 times, with DCM washing 5 times and vacuum-drying.
Carry out the cyclative cracking, with exsiccant polymkeric substance and 15ml formic acid mix be incorporated in shake under the room temperature 16 hours, shook 6 hours in 50-55 ℃.Remove by filter polymkeric substance and wash with DCM.The filtrate that vacuum-evaporation merges.Under room temperature, residue was handled 2 hours and vacuum-evaporation with 10ml 37%HBr/HOAc.The adding diethyl ether is settled out the product hydrobromate and leaches.Behind the HPLC purifying, separate pure target compound.Adopt " universal method " described system and method down herein.MW=558.07 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 559.3.
Embodiment 3
6-(4-benzyl chloride base)-1-(5-chloro-2-anisole alkylsulfonyl)-3-diethylamino-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
With 50mg 6-(4-benzyl chloride base)-1-(2-methoxyl group-5-chlorobenzene alkylsulfonyl)-3-amino-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, 7-dione hydrochloride (embodiment 1) is dissolved in 3ml methyl alcohol, and adds 100 μ l acetate.The THF solution of 100 μ l acetaldehyde and 1ml 1M sodium cyanoborohydride is added to this solution.After 2 hours, evaporation reaction mixture is suspended in 5%Et
3The ethyl acetate of N is also filtered through little silicagel column.Evaporation eluent, crude product material are dissolved in the mixture of acetonitrile and water and freeze-drying.Behind the HPLC purifying, separate pure target compound.Adopt " universal method " described system and method down herein.MW=610.18 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 611.4.
Embodiment 4
The amino hexahydropyrazine of 6-(4-benzyl chloride base)-1-(5-chloro-2-anisole alkylsulfonyl)-8-sec.-propyl-3-sec.-propyl is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
With 50mg 6-(4-benzyl chloride base)-1-(2-methoxyl group-5-chlorobenzene alkylsulfonyl)-3-amino-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, 7-diketone (embodiment 1) is dissolved in the 5ml methyl alcohol, and adds 200 μ l acetate.The THF of 400 μ l acetone and 1ml 1M sodium cyanoborohydride solution is added to this solution.After 3 hours, evaporation reaction mixture is suspended in 5%Et
3Filter in the ethyl acetate of N and through little silicagel column.The evaporation eluent, the crude product material is dissolved in the mixture and the freeze-drying of acetonitrile and water.Behind the HPLC purifying, remove pure target compound.Adopt " universal method " described system and method down herein.MW=596.16 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 597.3.
Embodiment 5
6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-3-dimethylamino-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
With 200mg 6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-3-amino-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, 7-diketone hydrobromate (embodiment 2) is dissolved in 15ml methyl alcohol, and adds 600 μ l acetate.The THF solution that 0.5ml is contained 37% intensity formalin and 3ml 1M sodium cyanoborohydride adds to this solution.After 2 hours, evaporation reaction mixture is suspended in 5%Et
3The ethyl acetate of N is also filtered through little silicagel column.Evaporation eluent, crude product material are dissolved in the mixture of acetonitrile and water and freeze-drying.Behind the HPLC purifying, separate pure target compound.Adopt " universal method " described system and method down herein.MW=586.10 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 587.3.
Embodiment 6
6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-3-pyrroles-1-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
With 64mg 6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-3-amino-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, 7-diketone hydrobromate (embodiment 2) is suspended in the 1ml water, and adds 1mlDCE.With mixture and 2 equivalents 2, the 5-dimethoxy-tetrahydrofuran mixes and is incorporated in 80 ℃ of stirrings 1 hour.Remove the DCE layer and extract the liquid layer secondary with DCE.The extract that evaporation merges, crude product material are dissolved in the mixture of acetonitrile and water and freeze-drying.Behind the HPLC purifying, separate pure target compound.Adopt " universal method " described system and method down herein.MW=608.08 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 609.4.
Embodiment 7
3-azetidine-1-base-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl six hydrogen-pyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
With 32mg 6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-3-amino-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, 7-diketone hydrobromate (embodiment 2) is suspended in the 1ml water, and adds 2ml 1-butanols.With 1mmol salt of wormwood and 200 μ l 1, the 3-dibromopropane adds in the mixture.Stir Et in 90 ℃
3N mixed reaction mixture 16 hours and evaporation.Residue is suspended in 5%Et
3The N/ ethyl acetate is filtered and evaporation.Behind the HPLC purifying, separate pure target compound.Adopt " universal method " described system and method down herein.MW=598.10 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 599.3.
Embodiment 8
6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-3-tetramethyleneimine-1-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7--diketone
Structure:
With 32mg 6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-3-amino-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, 7-diketone hydrobromate (embodiment 2) is suspended in the 1ml water, and adds 2ml 1-butanols.With 1mmol salt of wormwood and 200 μ l 1, the 4-dibromobutane adds in the mixture.In 90 ℃ of stirred reaction mixtures 16 hours and evaporation.Residue is suspended in 5%Et
3The N/ ethyl acetate is filtered and evaporation.Behind the HPLC purifying, separate pure target compound.Adopt " universal method " described system and method down herein.MW=612.11 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 613.4.
Embodiment 9
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] Toluidrin
Structure:
With 64mg 6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-3-amino-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, 7-diketone hydrobromate (embodiment 2) is dissolved in 3ml DCM.0.5mmol triethylamine and 1.5 equivalent methylsulfonyl chlorides are added to this solution.After 2 hours, add the THF of 0.5ml dimethyl amine, and vacuum evaporating solvent.Behind the HPLC purifying, separate pure target compound.Adopt " universal method " described system and method down herein.MW=636.04 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 637.4.
Embodiment 10
6-(4-benzyl chloride base)-1-(5-chloro-2-anisole alkylsulfonyl)-3-dimethylamino-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Through synthetic embodiment 10 compounds of embodiment 5 described methods, adopt also [1,2-a] pyrimidine-4 of 6-(4-benzyl chloride base)-1-(2-methoxyl group-5-chlorobenzene alkylsulfonyl)-3-amino-8-sec.-propyl hexahydropyrazine, 7-diketone (embodiment 1) is as raw material.
MW=582.15 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 583.3.
Embodiment 11
3-(bicyclo-propyl methylamino)-6-(4-benzyl chloride base)-1-(5-chloro-2-anisole alkylsulfonyl)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Through embodiment 3 described methods, adopt 10 equivalent cyclopanecarboxaldehydes to synthesize embodiment 11 compounds.
MW=662.21 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 663.4.
Embodiment 12
6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-3-isobutylamino-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Through embodiment 4 described methods, adopt 4 equivalent isobutyric aldehydes to synthesize embodiment 12 compounds.
MW=614.13 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 615.4.
Embodiment 13
6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-3-diisobutyl amino-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Through embodiment 3 described methods, adopt 20 equivalent isobutyric aldehydes to synthesize embodiment 13 compounds.
MW=670.19 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 671.3.
Embodiment 14
6-(4-benzyl chloride base)-3-(cyclopropyl methylamino)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Through embodiment 4 described methods, adopt 5 equivalent cyclopanecarboxaldehydes to synthesize embodiment 14 compounds.
MW=612.11 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 613.4.
Embodiment 15
6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-3-diethylamino-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Through synthetic embodiment 15 compounds of embodiment 3 described methods, adopt also [1,2-a] pyrimidine-4 of 6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-3-amino-8-sec.-propyl hexahydropyrazine, 7-diketone (embodiment 2) is as raw material.
MW=614.13 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 615.3.
Embodiment 16
The amino hexahydropyrazine of 6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-3-sec.-propyl is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Through synthetic embodiment 16 compounds of embodiment 4 described methods, adopt also [1,2-a] pyrimidine-4 of 6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-3-amino-8-sec.-propyl hexahydropyrazine, 7-diketone (embodiment 2) is as raw material.
MW=600.11 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 601.3.
Embodiment 17
6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-3-(isopropyl methyl amino) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Through synthetic embodiment 17 compounds of embodiment 5 described methods, adopt also [1,2-a] pyrimidine-4 of the amino hexahydropyrazine of 6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-3-sec.-propyl, 7-diketone (embodiment 16) is as raw material.
MW=614.13 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 615.4.
Embodiment 18
6-(4-benzyl chloride base)-1-(5-chloro-2-anisole alkylsulfonyl)-8-sec.-propyl-3-tetramethyleneimine-1-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Through synthetic embodiment 18 compounds of embodiment 8 described methods, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(5-chloro-2-anisole alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, 7-diketone (embodiment 1) is as raw material.
MW=608.16 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 609.4.
Embodiment 19
4-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl amino also] and butyl } three second ammoniums
Structure:
With 200 μ l triethylamines and 100 μ l 1, the 4-dibromobutane is handled also [1,2-a] pyrimidine-4 of 32mg 6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-3-amino-8-sec.-propyl hexahydropyrazine, the 1ml ethylene dichloride of 7-diketone hydrobromate (embodiment 2).With reaction mixture remain in 60 ℃ 60 hours.Remove by filter throw out, and vacuum-evaporation filtrate.Behind the filtering residue of HPLC purifying, separate pure target compound trifluoroacetate.Adopt " universal method " described system and method down herein.
MW=714.24 (calculated value, single isotropic substance of planting); Measured value (M): 714.4.
Embodiment 20
3-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl amino also] and propyl group } three second ammoniums
Structure:
With 200 μ l triethylamines and 100 μ l 1, the 3-dibromopropane is handled also [1,2-a] pyrimidine-4 of 32mg 6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-3-amino-8-sec.-propyl hexahydropyrazine, the 1ml ethylene dichloride of 7-diketone hydrobromate (embodiment 2).In 60 ℃ reaction mixture was kept 60 hours.Remove by filter throw out, and vacuum-evaporation filtrate.Behind the filtering residue of HPLC purifying, separate pure target compound trifluoroacetate.Adopt " universal method " described system and method down herein.
MW=700.23 (calculated value, single isotropic substance of planting); Measured value (M): 700.4.
Embodiment 21
N-[6-(4-benzyl chloride base)-1-(5-chloro-2-anisole alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] ethanamide
Structure:
A) 2-allyloxy carbonyl ammonia base-3-(4-chloro-phenyl-) propionic acid
According to document currently known methods (ET
3N, methyl alcohol) obtain product, adopt 10g 4-chlorophenylalanine and 8ml allyl chlorocarbonate as raw material.
MW=283.71 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 284.1.
B) 2-(4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) and the sec.-propyl formamyl] ethyl } allyl carbamate
7.8ml DIC is dropped in the 30ml DMF solution of 5.7g 2-allyloxy carbonyl ammonia base-3-(4-chloro-phenyl-) propionic acid, 3.5g (2,2-diethoxy ethyl) isopropylamine, 6.8g HOAt, and stirred the mixture 12 hours.Concentrating under reduced pressure reaction soln and through the flash chromatography on silica gel purifying, eluent: ethyl acetate/n-heptane=1/3.Obtain target product, MW=440.97 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 441.15
C) 2-amino-3-(4-chloro-phenyl-)-N-(2,2-diethoxy ethyl)-N-sec.-propyl propionic acid amide
Under the protectiveness argon atmospher; 10mg four triphenyl phosphine palladiums are added to 13.2g{2-(4-chloro-phenyl-)-1-[(2; 2-diethoxy ethyl) sec.-propyl formamyl] ethyl } in the 140ml dichloromethane solution of allyl carbamate, 18.9g dimethyl barbituric acid, and stirred the mixture 12 hours.The concentrating under reduced pressure reaction soln also [bubble (lacuna)] through silica gel (eluent: methylene dichloride, 1%Et
3N, 0-10% methyl alcohol) flash chromatography.Obtain target product, MW=356.90 (calculated value, single isotropic substance of planting); Measured value (M-C
2H
6O+H)
+: 311.10
D) 2-benzyloxycarbonyl amino-3-(5-chloro-2-anisole sulfuryl amino)-propionic acid
The 5ml dioxane solution of 3.8g 5-chloro-2-anisole SULPHURYL CHLORIDE is dropped in the 20ml 1N NaOH solution of 2.3g 3-amino-2-benzyloxycarbonyl amino-propionic acid.Control pH value (pH＞7) stirred the mixture 12 hours, made the pH value less than 7 through adding citric acid, used the dichloromethane extraction reaction soln then.Organic layer is through dried over mgso, and concentrating under reduced pressure also is used for next reactions steps without being further purified.
Product: MW=442.06 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 442.95
E) (2-(5-chloro-2-anisole sulfuryl amino)-1-{2-(4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical } ethyl) the carboxylamine benzyl ester
52mg EDC, 45mg HOBt and 100 μ l N-ethylmorpholines are added in the 1ml DMF solution of 124mg2-benzyloxycarbonyl amino-3-(5-chloro-2-anisole sulfuryl amino) propionic acid.Drip the 1mlDMF solution of 100mg 2-amino-3-(4-chloro-phenyl-)-N-(2,2-diethoxy ethyl)-N-sec.-propyl propionic acid amide again, and mixture was stirred 12 hours.Reaction soln and ethyl acetate hybrid filtering are then with 5% sodium hydrogen carbonate solution and sodium chloride solution extraction.With the dry organic layer of Chromabond XTR, concentrating under reduced pressure then, residue separates through HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20 → 10/90).Obtain target product, MW=780.24 (calculated value); Measured value (M-C
2H
6O+H)
+: 735.1
F) [6-(4-benzyl chloride base)-1-(5-chloro-2-anisole alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester
Under room temperature; with 218mg (2-(5-chloro-2-anisole sulfuryl amino)-1-{2-(4-chloro-phenyl-)-1-[(2; 2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical } ethyl) the 3ml formic acid solution of carboxylamine benzyl ester stirred 12 hours, and stirred 5 hours in 55 ℃ then.The concentrating under reduced pressure reaction soln, residue separates through HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20 → 10/90).Obtain target product, MW=688.15 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 689.41
G) 3-amino-6-(4-benzyl chloride base)-1-(5-chloro-2-anisole alkylsulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
With 79mg[6-(4-benzyl chloride base)-1-(5-chloro-2-anisole alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] glacial acetic acid solution of the 2ml 33%HBr of carboxylamine benzyl ester stirred 2 hours.Reaction soln mixes with aqueous sodium carbonate and uses ethyl acetate extraction.Organic layer is dry and concentrating under reduced pressure through magnesiumcarbonate, and residue separates through HPLC (KnauerEurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20 → 10/90).Obtain target product, MW=554.12 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 555.12
H) N-[6-(4-benzyl chloride base)-1-(5-chloro-2-anisole alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] ethanamide
With 7mg 3-amino-6-(4-benzyl chloride base)-1-(5-chloro-2-anisole alkylsulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 1.5ml pyridine solution of 7-diketone, 2.4 μ l diacetyl oxides, 0.5mg DMAP stirred 12 hours.Concentrated reaction solution and through the flash chromatography on silica gel purifying, eluent: methylene dichloride, gradient: 0-10% methyl alcohol.
Obtain target product, MW=596.13 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 597.13
Embodiment 22
N-[6-(4-benzyl chloride base)-1-(5-chloro-2-anisole alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopropane carboxamide
11mg (0.105mmol) cyclopropanecarbonyl-acyl chlorides is added to 3-amino-6-(4-benzyl chloride base)-1-(5-chloro-2-anisole alkylsulfonyl)-8-sec.-propyl hexahydropyrazine also [1; 2-a] pyrimidine-4; (56mg is in 1ml methylene dichloride 0.10mmol) and 26mg (0.20mmol) the diisopropyl ethyl amine solution for the 7-diketone.After stirring 2 hours under the room temperature, reaction mixture is through 1g silica gel (eluent: EtOAc/DCM; Gradient: 0-20%) chromatography purification.Obtain the 42mg target product.MW=622 (calculated value, single isotropic substance of planting), measured value (M+H)
+=623.10
Embodiment 23
N-[6-(4-benzyl chloride base)-1-(5-chloro-2-anisole alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] the tetramethylene methane amide
Adopt the tetramethylene dicarbonyl chloride, synthetic with the method that is similar to embodiment 22.Obtain target product, MW=636.16 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 637.11
Embodiment 24
N-[6-(4-benzyl chloride base)-1-(5-chloro-2-anisole alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopentane formamide
Structure:
Adopt the pentamethylene dicarbonyl chloride, synthetic with the method that is similar to embodiment 22.Obtain target product, MW=650.17 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 651.12
Embodiment 25
4-dimethylamino-N-[6-(4-benzyl chloride base)-1-(5-chloro-2-anisole alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] benzamide
Structure:
Adopt 4-dimethylamino Benzoyl chloride, synthetic with the method that is similar to embodiment 22.Obtain target product, MW=701.18 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 702.12
Embodiment 26
N-[6-(4-benzyl chloride base)-1-(5-chloro-2-anisole alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] Toluidrin
Structure:
In 0 ℃, 1.8 μ l methylsulfonyl chlorides are dropped to also [1,2-a] pyrimidine-4 of 5mg 3-amino-6-(4-benzyl chloride base)-1-(5-chloro-2-anisole alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 1ml methylene dichloride of 7-diketone and 3 μ l Et
3In the N solution.Stirred the mixture 2 hours, and washed with sodium chloride solution then.Organic layer is through dried over mgso and concentrating under reduced pressure.
Obtain target product, be residue, MW=632.09 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 633.10
Embodiment 27
N-[6-(4-benzyl chloride base)-1-(5-chloro-2-anisole alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] the cyclopropane sulphonamide
Structure:
Adopt the cyclopropane SULPHURYL CHLORIDE, synthetic with the method that is similar to embodiment 26.Obtain target product, MW=658.11 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 659.10
Embodiment 28
The 1-tertiary butyl-3-[6-(4-benzyl chloride base)-1-(5-chloro-2-anisole alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] urea
Structure:
5.4mg tertiary butyl isocyanic acid tertiary butyl ester is added to also [1,2-a] pyrimidine-4 of 30mg 3-amino-6-(4-benzyl chloride base)-1-(5-chloro-2-anisole alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, 7-diketone and 7.6 μ lEt
3In the 500 μ l dioxane solutions of N.In 50 ℃, with solution heating 6 hours.Solvent removed in vacuo.Residue is through HPLC (Waters-Xterra
TMMS C18,5 μ m, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20 → 10/90) separate.
Obtain target product, MW=653.18 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 654.13
Embodiment 29
Structure:
Method A:
A) 2-benzyloxycarbonyl amino-3-(2,4 dichloro benzene sulfuryl amino) propionic acid
To be similar to embodiment 21d) method synthetic, adopt the 2,4 dichloro benzene SULPHURYL CHLORIDE as raw material.Obtain target product, MW=446.01 (calculated value, single isotropic substance of planting); Measured value (M+H-CO
2)
+: 403.00.
B) N-{2-(4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl] ethyl }-the amino propionic acid amide of 3-(2,4 dichloro benzene sulfuryl amino)-2-methylsulfonyl
To be similar to embodiment 21e) method synthetic, adopt 2-benzyloxycarbonyl amino-3-(2,4 dichloro benzene sulfuryl amino) propionic acid as raw material.Obtain target product, MW=784.186 (calculated value, single isotropic substance of planting); Measured value (M-CO
2+ H)
+: 741.10
C) [6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester
To be similar to embodiment 21f) method synthetic, adopt N-{2-(4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl] ethyl-the amino propionic acid amide of 3-(2,4 dichloro benzene sulfuryl amino)-2-methylsulfonyl is as raw material.Obtain target product, MW=692.10 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 693.05
D) 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
To be similar to embodiment 21g) method synthetic, adopt [6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester as raw material.Obtain target product, MW=558.07 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 559.10
E) N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopropane carboxamide.
With 15mg 3-amino-6-(4-benzyl chloride base)-1-(2; 4-dichlorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine also [1; 2-a] pyrimidine-4,110 μ l DMF solution of 7-diketone, 3.2mg cyclopropane-carboxylic acid are cooled to 0 ℃, and add 11.2mg HATU, 4.1mg HOAt and 11.6 μ l Et
3N.In 0 ℃,, under room temperature, stirred 4 hours then solution stirring 10 minutes.Solvent removed in vacuo.Use ethyl acetate and water dissolution residue then.With acetic acid ethyl acetate extract layer secondary.The organic layer that merges is through Na
2SO
4Dry also solvent removed in vacuo.The crude product product is through HPLC (Waters-Xterra
TMMS C18,5 μ m, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20 → 10/90) separate.
Obtain target product, MW=626.09 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 627.13
Method B:
A) 2-(4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) and the sec.-propyl formamyl] ethyl } carboxylamine 9H-fluorenes-9-ylmethyl ester
210mg (1.2mmol) (2,2-diethoxy ethyl) isopropylamine and 376mg (1.20mmol) DMTMM are added in the 2ml DMF solution of 505mg (1.2mmol) N-Fmoc-4-Cl-Phe-OH.Under room temperature, stirred reaction mixture spends the night.Also use the 10ml water washing with the 40ml extracted with diethyl ether then.The organic layer that merges is through MgSO
4Dry also vacuum concentration.The crude product product is through 10g SiO
2(eluent: DCM is 20%EtOAc/DCM then) chromatography purification.Obtain the 530mg target product, be oily matter.MW=578.26 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 579
B) 2-amino-3-(4-chloro-phenyl-)-N-(2,2-diethoxy ethyl)-N-sec.-propyl propionic acid amide
Under room temperature, the 15ml 20% diethylamide DCM solution that stirs 530mg (0.915mmol) 3-(4-fluorophenyl)-N-(2,2-diethoxy ethyl)-N-sec.-propyl-2-methyl propanamide spends the night.Vacuum concentration reaction mixture and through 5g SiO
2(eluent: DCM 20%EtOAc/DCM 20%MeOH/DCM) then then chromatography purification.Obtain the 320mg target product, be oily matter.MW=356.19 (calculated value, single isotropic substance of planting); Measured value (M+H)
+=357
C) (2-benzyloxycarbonyl amino-2-{2-(4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical } ethyl) carboxylamine 9H-fluorenes-9-ylmethyl ester
As under a) described the same terms, Z-Dap-Fmoc-OH and 2-amino-3-(4-chloro-phenyl-)-N-(2,2-diethoxy ethyl)-N-sec.-propyl propionic acid amide coupling.Obtain target product, MW=798.34 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+=821.43
D) (2-amino-1-{2-(4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical } ethyl) the carboxylamine benzyl ester
Adopt diethylamide and adopt as b) as described in method; from (2-benzyloxycarbonyl amino-2-{2-(4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical } ethyl) carboxylamine 9H-fluorenes-9-ylmethyl ester removal Fmoc protecting group.Obtain target product, MW=576.27 (calculated value, single isotropic substance of planting); Measured value (M+H)
+=577.22
E) [1-{2-(4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl] the ethylamino formyl radical }-2-(2,4 dichloro benzene sulfuryl amino) ethyl] the carboxylamine benzyl ester
With 1.94ml (11.09mmol) DIEA and 1.5g (6.1mmol) 2; 4-chloro-phenyl-SULPHURYL CHLORIDE adds to 3.2g (5.54mmol) (2-amino-1-{2-(4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical } ethyl) the 75ml DCM solution of carboxylamine benzyl ester.Under room temperature, stirred solution spends the night.Vacuum concentrated solution then, residue is through 100g SiO
2(eluent: DCM is 20%EtOAc/DCM then) column chromatography purification.Obtain the 2.78g target product, be colourless foam.MW=784.19 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+=807.24
F) [6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester
In 60 ℃; with 2.74g (3.49mmol) [1-{2-(4-chloro-phenyl-)-1-[(2; 2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical }-2-(2,4 dichloro benzene sulfuryl amino) ethyl] the 45ml formic acid solution heating 6 hours of carboxylamine benzyl ester.Vacuum concentration reaction mixture then, residue is through 40g SiO
2(eluent: DCM is 20%EtOAc/DCM then) chromatography purification.Obtain the 2.25g crystalline compounds, be colorless solid.
LC/MSMW=692.1 (calculated value, single isotropic substance of planting); Measured value (M+H)
+=693
G) 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
In 0 ℃; 206ml (1.44mmol) trimethyl silyl iodine (TMSI) is added to 250mg (0.36mmol) [6-(4-benzyl chloride base)-1-(2; 4-dichlorobenzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] the 10ml CH of carboxylamine benzyl ester
3In the CN solution.Conditioned reaction solution stirred 2 hours to room temperature and under this temperature.5ml MeOH is added to reaction soln, then vacuum concentrated solution.(eluent: MeOH is 3N NH then through 5g SCX post for residue
3/ MeOH) purifying.Obtain the 185mg target compound, be white powder.LC/MS 558.07 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 559.10
G) N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopropane carboxamide
Synthetic with the method that is similar to embodiment 22.
Embodiment 30
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] the tetramethylene methane amide
Structure:
Adopt also [1,2-a] pyrimidine-4 of tetramethylene dicarbonyl chloride and 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone, synthetic with the method that is similar to embodiment 22.Obtain target product, MW=640.11 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 641.09
Embodiment 31
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopentane formamide
Structure:
Adopt also [1,2-a] pyrimidine-4 of pentamethylene dicarbonyl chloride and 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone, synthetic with the method that is similar to embodiment 22.Obtain target product, MW=654.12 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 655.1
Embodiment 32
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclohexane carboxamide
Structure:
Adopt also [1,2-a] pyrimidine-4 of hexanaphthene dicarbonyl chloride and 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone, synthetic with the method that is similar to embodiment 22.Obtain target product, MW=668.14 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 669.11
Embodiment 33
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also]-2,2, the 2-trifluoroacetamide
With 40mg (0.071mmol) 3-amino-6-(4-benzyl chloride base)-1-(2; 4-dichlorobenzene alkylsulfonyl)-and 8-is different-propyl group hexahydropyrazine also [1; 2-a] pyrimidine-4, the 7-diketone is dissolved among the 1.5ml DCM, and adds 0.024ml (0.17mmol) trifluoroacetic anhydride and 0.075ml (0.43mmol) DIEA.In 50 ℃, stirred reaction mixture 1 hour.After adding 1ml water, separate organic layer, dry (MgSO
4) and vacuum concentration.Through 4g SiO
2(eluent: MeOH/DCM, gradient: 0-4%) flash chromatography purifying produces the 21mg material.MW (calculated value, single isotropic substance of planting)=654.05; MW (measured value)=655.06.
Embodiment 34
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also]-N-sec.-propyl cyclopropane carboxamide
With 0.2g (0.36mmol) 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone is dissolved among the 12ml MeOH, and adds 1.6ml acetone, 0.8ml CH then
3COOH and 4ml NaCNBH
3(THF of 1.0M).After 1 hour,, mix with 5ml EtOAc and use the 5ml water washing the mixture vacuum concentration.Separate organic layer, dry (MgSO
4) and vacuum concentration.The crude product material is through 20g SiO
2(eluent: EtOAc/DCM, gradient: 0-50%) flash chromatography, produce the 182mg intermediate, be oily matter, be used for coupling step subsequently.30mg (0.05mmol) intermediate mixes with 0.026ml (0.149mmol) DIEA and 0.0055ml (0.0598mmol) cyclopropanecarbonyl-acyl chlorides in 1ml DCM, and stirs under room temperature and spend the night.After adding 2ml water, separate organic layer, dry (MgSO
4) and vacuum concentration.The crude product material is through 4g SiO
2(eluent: MeOH/DCM, gradient: 0-5%) chromatography.Obtain the 21.4mg target compound.MW (calculated value, single isotropic substance of planting)=668.14; MW (measured value) (M
+H)=669.
Embodiment 35
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also]-N-cyclohexyl cyclopentane formamide
Adopt pimelinketone at reduction amination, be similar to embodiment 34 synthetic embodiment 35.The pentamethylene dicarbonyl chloride is used for the acid amides coupling.Obtain target product, MW=736.20 (calculated value, single isotropic substance of planting), measured value: (M+H)
+=737.15
Embodiment 36
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also]-1-methyl piperidine-4-methane amide
Adopt 1-methyl piperidine-4-formate hydrochlorate, synthetic with the method that is similar to embodiment 29e.Obtain target product, MW=683.15 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 684.38
Embodiment 37
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] piperidines-4-methane amide
Under room temperature; with 100mg (0.179mmol) 3-amino-6-(4-benzyl chloride base)-1-(2; 4-dichlorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine also [1; 2-a] pyrimidine-4; 7-diketone, 2ml DCM, the mixture of 23mg (0.178mmol) DIEA and 51mg (0.181mmol) 4-(chloroformyl) tetrahydrochysene-1 (2H)-pyridine carboxylic acid benzyl ester stirred 1 hour.Mixture is through 2g SiO
2(eluent: EtOAc/DCM, gradient: 0-20%) flash chromatography.Obtain 119mg intermediate 4-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl formamyl also] piperidines-1-formic acid benzyl ester.At LC/MS (single isotropic substance MW=803, measured value (M of planting of expectation
+H)=804 the result who obtains) is consistent with this structure.
Under room temperature; while stirring 103mg (0.517mmol) iodo trimethyl silane is added to 104mg (0.129mmol) 4-[6-(4-benzyl chloride base)-1-(2; 4-dichlorobenzene alkylsulfonyl)-8-sec.-propyl-4; 7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl formamyl also] in the 2.5ml acetonitrile solution of piperidines-1-formic acid benzyl ester.After 2 hours, enriched mixture.Residue is through Varian Bond-Elut SCX ion exchange column (eluent: methyl alcohol, 3N-NH then
3Methyl alcohol) purifying.Purifying amine is changed into hydrochloride.Obtain the 75mg target compound.LC/MS (single isotropic substance MW=669.13 that plants of expectation; Measured value (M
+H)=670)
Embodiment 38
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] morpholine-4-methane amide
47 μ l (0.268mmol) H ü nig ' s alkali are added to 50mg (0.089mmol) amine 3-amino-6-(4-benzyl chloride base)-1-(2; 4-dichlorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine also [1; 2-a] pyrimidine-4, in 1.8ml DCM/THF (1: the 1) solution of 7-diketone.Then 80mg (0.268mmol) triphosgene is slowly added in the reaction mixture.Under room temperature, stir the mixture and spend the night.Then reaction mixture is diluted with EtOAc, use H
2The O washing is through MgSO
4Dry also vacuum concentration.Intermediate is dissolved in 1ml THF, and adds 31 μ l (0.178mmol) H ü nig ' s alkali and 12mg (0.134mmol) morpholines.Under room temperature, stirred reaction mixture spends the night, and with the EtOAc dilution, uses H
2The O washing is through MgSO
4Dry and concentrated.Residue is through 4g SiO
2(eluent: MeOH/DCM, gradient: 1-8%) chromatography.Obtain the 36mg target substance, be colorless solid.LC/MS (the MW=671.11 of expectation; Measured value (M
+H)=672).
Embodiment 39
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] piperidines-2-methane amide
With 24.7mg (0.089mmol) 4-(4,6-dimethoxy [1,3,5] triazine-2-yl)-4-methylmorpholine muriate * H
2O (DMTMM), 31.3mg (0.089mmol) Fmoc-Pip-OH adds to 0.05g (0.089mmol) 3-amino-6-(4-benzyl chloride base)-1-(2 then; 4-dichlorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine also [1; 2-a] pyrimidine-4, in the 2ml DMF solution of 7-diketone.Under room temperature, stirred reaction mixture spends the night.Add 8ml ether and 5ml water then.Separate organic layer, use the 5ml water washing again, dry (MgSO
4) and vacuum concentration.Through 4g SiO
2(eluent: MeOH/DCM, gradient: 0-2%) flash chromatography purifying, produce 82mg Fmoc-protection intermediate, be the white solid form.Can prove that product is the target intermediate through LC/MS.Under room temperature, the DCM solution that stirs the 2ml 10% concentration diethylamide of 70mg (0.078mmol) Fmoc intermediate spends the night.Vacuum concentration reaction mixture and at Gilson C18 device (CH
3CN (0.1%TFA)/H
2O (0.1%TFA), gradient: 5-100%) through preparation property HPLC purifying.The vacuum concentration target fraction.Obtain the tfa salt of the target compound of 33.9mg correspondence.LC/MS MW (calculated value, single isotropic substance of planting)=669.13; Measured value (M
+H)=670.11.
Embodiment 40
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] tetramethyleneimine-2-methane amide
Under room temperature; stir 50mg (0.089mmol) 3-amino-6-(4-benzyl chloride base)-1-(2; 4-dichlorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine also [1; 2-a] pyrimidine-4, the mixture of 7-diketone, 1ml DCM, 23mg (0.178mmol) DIEA and 32mg (0.090mmol) Fmoc-Pro-Cl 1 hour.Mixture is through 2g SiO
2(eluent: EtOAc/DCM, gradient: 0-20%) chromatography purification.Obtain 72mg intermediate 2-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl formamyl also] tetramethyleneimine-1-formic acid 9H-fluorenes-9-ylmethyl ester.The LC/MS:(calculated value, single isotropic substance MW=877, measured value (M of planting
+H)=878)
Under room temperature; stir 60mg (0.068mmol) 2-[6-(4-benzyl chloride base)-1-(2; 4-dichlorobenzene alkylsulfonyl)-8-sec.-propyl-4; 7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl formamyl also] mixture overnight of the DCM of tetramethyleneimine-1-formic acid 9H-fluorenes-9-ylmethyl ester and 2ml 15% concentration diethylamide.Mixture concentrates and through 2g SiO
2(eluent: DCM, EtOAc, the flash chromatography purifying of 10% methyl alcohol/EtOAc) then.Amine is changed into hydrochloride.Obtain the 30mg solid.Anti-phase (RP) HPLC is further purified through preparation property.Obtain the 17mg target compound.LC/MS (calculated value, single isotropic substance MW=655.12 that plants; Measured value (M
+H)=656)
Embodiment 41
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also]-1-methylpyrrolidin-2-methane amide
0.3ml (5.2mmol) acetate, 0.25ml (3.33mmol) formaldehyde (in 37% water) and 1.5ml (1.5mmol) sodium cyanoborohydride (1M is in THF) are added in the 7.5ml methanol solution of amine that 93mg (0.142mmol) derives from embodiment 40.Under room temperature, stirred reaction mixture 2 hours and vacuum concentration.Residue is used 7N-NH with 10ml DCM dilution
3Methyl alcohol alkalization, filter also and concentrate.Residue is through preparation property RP-HPLC purifying.Obtain the 50mg target compound.LC/MS (calculated value, single isotropic substance MW=669 that plants; Measured value (M
+H)=670)
Embodiment 42
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] azetidine-3-methane amide
With 49.5mg (0.179mmol) 4-(4,6-dimethoxy [1,3,5] triazine-2-yl)-4-methylmorpholine muriate xH
2O (DMTMM), 58mg (0.179mmol) 1-Fmoc-azetidine-3-formic acid adds to 0.1g (0.179mmol) amine 3-amino-6-(4-benzyl chloride base)-1-(2 then; 4-dichlorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine also [1; 2-a] pyrimidine-4, in the 5ml DMF solution of 7-diketone.Under room temperature, stirred reaction mixture spends the night.Add 50ml diethyl ether and 50ml water then.Separate organic layer, use 50ml water washing secondary at every turn, dry (MgSO
4) and vacuum concentration.Through 20g SiO
2(eluent: MeOH/DCM, gradient: 0-10%) flash chromatography purifying, produce 117mg Fmoc-protection intermediate, be the white solid form.Be used for next step.Under room temperature, the DCM solution that stirs the 1.5ml 10% concentration diethylamide of 50mg (0.058mmol) Fmoc intermediate spends the night.Vacuum concentration reaction mixture and at Gilson C18 device (CH
3CN (0.1%TFA)/H
2O (0.1%TFA)) in through preparation property HPLC purifying.The vacuum concentration cut.Obtain the tfa salt of 21.6mg target product.MW (calculated value, single isotropic substance of planting)=641.11; Measured value (M
+H)=641.99.
Embodiment 43
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also]-N ', N '-dimethyl succinic diamide
Adopt N, N-dimethyl succinamic acid, synthetic with the method that is similar to embodiment 29e.Obtain target product, MW=685.13 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 686.30
Embodiment 44
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also]-N-normenthane methane amide
Structure:
Adopt the hexanaphthene dicarbonyl chloride in acid amides coupling step, be similar to embodiment 34 synthetic embodiment 44.Obtain target product, MW=710.19 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 711.18
Embodiment 45
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also]-N-sec.-propyl cyclopentane formamide
Structure:
Adopt the pentamethylene dicarbonyl chloride in acid amides coupling step, be similar to embodiment 34 synthetic embodiment 45.Obtain target product, MW=696.17 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 697.17
Embodiment 46
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also]-N-sec.-propyl piperidines-4-methane amide
Structure:
In embodiment 46, synthesize through 34 described methods.Adopt 4-piperidine carbonyl chloride-1-formic acid benzyl ester in the coupling step, produce Cbz-protection compound.In 0 ℃, through adding 0.0283ml (0.199mmol) TMSI and 2ml CH
3CN removes the Cbz protecting group.Stirred reaction mixture 3 days, vacuum concentration and through fill with 1g SCX and with the wetting post wash-out of MeOH.Impurity is through the MeOH wash-out.Through 2N-NH
3The MeOH wash-out, obtain targeted amine.Vacuum concentration and add the diethyl ether of 0.1ml1.0M HCl then.Be settled out the salt of generation like this, at every turn with 2ml diethyl ether washing 4 times and dry.Obtain the 0.025g target compound.
LC/MS:MW (calculated value, single isotropic substance of planting)=711.18; Measured value (M
+H)=712.11.
Embodiment 47
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also]-4-dimethylamino yl-benzamide
Structure:
Adopt the 4-dimethylaminobenzoic acid, synthetic with the method that is similar to embodiment 29e.Obtain target product, MW=705.13 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 706.21
Embodiment 48
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also]-2-pyridin-3-yl ethanamide
Adopt 3-pyridyl acetate, synthetic with the method that is similar to embodiment 29e.Obtain target product, MW=677.10 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 678.07
Embodiment 49
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] pyridine-2-carboxamide
Adopt pyridine carboxylic acid, synthetic with the method that is similar to embodiment 29e.Obtain target product, MW=663.09 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 664.22
Embodiment 50
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] niacinamide
Structure:
Adopt also [1,2-a] pyrimidine-4 of nicotinoyl chlorine * HCl and 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-hexahydropyrazine, the 7-diketone, synthetic with the method that is similar to embodiment 22.Obtain target product, MW=663.09 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 664.11
Embodiment 51
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also]-6-trifluoromethyl niacinamide
Structure:
Adopt also [1,2-a] pyrimidine-4 of 6-(trifluoromethyl) nicotinoyl chlorine and 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-hexahydropyrazine, the 7-diketone, synthetic with the method that is similar to embodiment 22.Obtain target product, MW=731.08 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 732.01
Embodiment 52
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also]-4-trifluoromethyl niacinamide
Structure:
Adopt also [1,2-a] pyrimidine-4 of 4-(trifluoromethyl) nicotinic acid and 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-hexahydropyrazine, the 7-diketone, synthetic with the method that is similar to embodiment 29e.Obtain target product, MW=731.08 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 732.07
Embodiment 53
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also]-5-methylpyrazine-2-methane amide
Structure:
Adopt also [1,2-a] pyrimidine-4 of 5-methylpyrazine-2-formic acid and 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone, synthetic with the method that is similar to embodiment 29e.Obtain target product, MW=678.10 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 679.06
Embodiment 54
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] pyrazine-2-methane amide
Structure:
Adopt also [1,2-a] pyrimidine-4 of pyrazine-2-dicarbonyl chloride and 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone, synthetic with the method that is similar to embodiment 22.Obtain target product, MW=664.08 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 665.05
Embodiment 55
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] quinoline-3-methane amide
Structure:
Adopt also [1,2-a] pyrimidine-4 of 3-quinolinecarboxylic acid and 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-hexahydropyrazine, the 7-diketone, synthetic with the method that is similar to embodiment 29e.Obtain target product, MW=713.10 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 714
Embodiment 56
The 1-tertiary butyl-3-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] urea
Structure:
Synthetic with the method that is similar to embodiment 28, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=657.13 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 658.26
Embodiment 57
1-ethyl-3-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] urea
Adopt the isocyanic acid ethyl ester, synthetic with the method that is similar to embodiment 56.Obtain target product, MW=629.10 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 630.13
Embodiment 58
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] the cyclopropane sulphonamide
Structure:
Synthetic with the method that is similar to embodiment 27, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=662.06 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 663.05.
Embodiment 59
6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-3-piperidines-1-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
In 175 ℃, in microwave oven with 50mg (0.089mmol) 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, 7-diketone, 2.0ml acetonitrile, 0.2ml (0.2mmol) 1M (H
2O)-NaHCO
3And 83mg (0.361mmol) 1, the mixture stirring heating of 5-dibromopropane 800 seconds.After the cooling, enriched mixture.Residue is through 2g SiO
2(eluent: EtOAc/DCM, gradient: 0-20%) flash chromatography.Purifying amine is changed into hydrochloride.Obtain the 38mg target compound.The LC/MS:(MW calculated value, single isotropic substance=626.13 of planting; Measured value (M
+H)=627.15)
Embodiment 60
6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-3-morpholine-4-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
With 149mg (0.64mmol, 4.0 equivalents) 2-bromine ether, then with 0.2ml 1N NaHCO
3Solution adds to also [1,2-a] pyrimidine-4 of 90mg (0.16mmol) amine 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 2ml CH of 7-diketone
3In the CN solution.In 200 ℃, in microwave oven (Smith Creator) heated 120 seconds with reaction mixture.Cooling is then with DCM dilution and use 1N NaHCO
3Washing.Organic layer is through MgSO
4Dry and concentrated.Residue is through 12g SiO
2(eluent: MeOH/DCM, gradient: 0-10%) chromatography.Obtain the 48mg target substance, be white solid.LC/MS (calculated value, single isotropic substance MW=628.18 that plants; Measured value (M
+H)=629.1) conform to structure.
Embodiment 61
6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-3-(4-methylpiperazine-1-yl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
With 50mg 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, 7-diketone, 14.4mg Nitrogranulogen, 13mg NaHCO
3Be dissolved in just enough ethylene glycol and obtain solution.1.6mg NaI is added to this solution, and in 110 ℃, heated solution 6 hours.After the cooling, solution mixes the also each 40ml of using ethyl acetate extraction three times with water.The organic layer that merges is through Na
2SO
4Drying, and solvent removed in vacuo.Residue is through HPLC (Waters-Xterra
TMMS C18,5 μ m, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20-＞10/90) separate.
Obtain target product, MW=641.14 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 642.25
Embodiment 62
3-(1-benzyl piepridine-4-base is amino)-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
With 115mg (0.61mmol) 1-benzyl-4-piperidone, then 130mg (4.1mmol/g) (polystyrene ylmethyl) trimethyl ammonium cyano group hydroborate is added to 100mg (0.18mmol) 3-amino-6-(4-benzyl chloride base)-1-(2; 4-dichlorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine also [1; 2-a] pyrimidine-4, the 1.2ml 5%HOAc/CH of 7-diketone
3In CN and the 3 MeOH solution.Under room temperature, shook reaction mixture 18 hours, filter and concentrate.Obtain the light brown oily matter of 160mg.Through (eluent: 5%MeOH/EtOAc) the post flash chromatography of filling separates the crude product product with 4g silica gel.Concentrate suitable cut and produce 110mg (85%) above-claimed cpd, be clarification oily matter form.LC/MS (expectation, single isotropic substance of planting) MW=731.19; Measured value (M
+H)=732.20)
Embodiment 63
6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-3-(2-oxo-pyrrolidine-1-yl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Under room temperature; stir 50mg (0.089mmol) 3-amino-6-(4-benzyl chloride base)-1-(2; 4-dichlorobenzene alkylsulfonyl)-and 8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 2ml DCM solution of 7-diketone, 0.012ml (0.107mmol) 4-chlorobutanoylchloride and 0.031ml DIEA spends the night.Add 2ml water then, separate organic layer, with the water washing of 2ml salt, dry (MgSO
4) and vacuum concentration.The crude product material is through 4g SiO
2(eluent: MeOH/DCM, gradient: 0-6%) chromatography.Enriched fraction produces 45.8mg chloro butyramide intermediate, for the white solid form, is used for next step.With 60mg (0.36mmol) potassiumiodide and 277mg (2mmol) K
2CO
3Add in 45mg (0.068mmol) the chloroamides intermediate that is dissolved in 2ml acetone.In 130 ℃, in microwave oven with mixture heating up 600 seconds, vacuum concentration and through 4g SiO then
2(eluent: MeOH/DCM, gradient: 0-5%) flash chromatography purifying.Obtain the 16.2mg white solid.LC/MS conforms to object construction.MW (calculated value, single isotropic substance of planting)=626.09; Measured value (M
+H)=627.1.
Embodiment 64
6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-3-(2-oxo-piperidine-1-yl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Adopt 5-chlorine valeryl chloride in acid amides coupling step, be similar to embodiment 63 synthetic embodiment 64.Obtain target product, MW=640.11 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 641.1
Embodiment 65
6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-3-(2-oxo azepan-1-yl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Be similar to embodiment 63 synthetic embodiment 65, adopt 6-chlorine caproyl chloride in acid amides coupling step.Obtain target product, MW=654.12 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 655.11.
Embodiment 66
N-[6-(4-benzyl chloride base)-1-(5-fluoro-2-anisole alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also) ethanamide
A) [6-(4-benzyl chloride base)-1-(5-fluoro-2-anisole alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester
The solid phase approach:
In 60 ℃, in solid phase reactor, 26ml DMSO and 6ml (70.44mmol) isopropylamine with 7g (3.64mmol) Tentagel HL 12019 (Rapp Polymer GmbH is loaded with the bromoacetal linking agent) heated overnight.With resin washing four times, use DMSO, MeOH, DCM and ether (30ml is each) respectively, vacuum-drying then.Add DIEA (5.7ml, 32.76mmol) and HATU (4.15g, 30ml DMF 10.92mmol), with Fmoc (4-ClPhe) OH (4.6g, 10.92mmol) coupling.In 55 ℃, with reaction mixture heating 3 hours.Be similar to the first step washing resin.Treated resin secondary is removed the Fmoc group, uses the DMF, each 20 minutes of 30ml 20% piperidines at every turn, washs as mentioned above then.Under room temperature, with resin and Fmoc-ZDap (OH) (5.02g, 10.92mmol), DIC (1.71ml, 10.92mmol) and HOBt (1.47g, 30ml DMF 10.92mmol) further reaction spend the night.Being similar to aforesaid method washs.0.613g (2.73mmol) 5-fluoro-2-anisole SULPHURYL CHLORIDE (Butt Park 49/07-57), 0.95ml (5.46mmol) DIEA and 30ml DCM are added in half resin (1.82mmol).Shaking reaction soln under room temperature spends the night.Washing resin as mentioned above then.Then the HCOOH of resin and 30ml 99% is mixed and be incorporated in shaken over night under the room temperature.Decant is removed resin and each with 20ml HCOOH washing secondary.In 60 ℃, the filtrate that merges was heated 3 hours.The vacuum concentration reaction soln, the crude product product is through chromatography purification (100g SiO
2, eluent: EtOAc/DCM (gradient: 0-50%)).Obtain the 0.778g target product, be white solid, MW=672.18 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 673.1
B) 3-amino-6-(4-benzyl chloride base)-1-(5-fluoro-2-anisole alkylsulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
Synthetic with the method that is similar to embodiment 22g (method B), adopt [6-(4-benzyl chloride base)-1-(5-fluoro-2-anisole alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester as raw material.
Obtain target product, MW=538.14 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 539.14
C) N-[6-(4-benzyl chloride base)-1-(5-fluoro-2-anisole alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] ethanamide.
Synthetic with the method that is similar to embodiment 21h, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(5-fluoro-2-anisole alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=580.16 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 581.13
Embodiment 67
N-[6-(4-benzyl chloride base)-1-(5-fluoro-2-anisole alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopropane carboxamide
Structure:
Synthetic with the method that is similar to embodiment 22, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(5-fluoro-2-anisole alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=606.17 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 607.14
Embodiment 68
N-[6-(4-benzyl chloride base)-1-(5-fluoro-2-anisole alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] the tetramethylene methane amide
Structure:
Synthetic with the method that is similar to embodiment 30, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(5-fluoro-2-anisole alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=620.19 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 621.16
Embodiment 69
N-[6-(4-benzyl chloride base)-1-(5-fluoro-2-anisole alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopentane formamide
Structure:
Synthetic with the method that is similar to embodiment 31, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(5-fluoro-2-anisole alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=634.20 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 635.17
Embodiment 70
The 1-tertiary butyl-3-[6-(4-benzyl chloride base)-1-(5-fluoro-2-anisole alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] urea
Structure:
Synthetic with the method that is similar to embodiment 28, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(5-fluoro-2-anisole alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=637.31 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 660.17
Embodiment 71
N-[6-(4-benzyl chloride base)-1-(5-fluoro-2-anisole alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] Toluidrin
Structure:
Synthetic with the method that is similar to embodiment 26, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(5-fluoro-2-anisole alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=616.12 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 617.14.
Embodiment 72
6-(4-benzyl chloride base)-3-dimethylamino-1-(5-fluoro-2-anisole alkylsulfonyl)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
With 35mg (0.065mmol) 3-amino-6-(4-benzyl chloride base)-1-(5-fluoro-2-anisole alkylsulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone is dissolved in 3.5ml MeOH.Add 0.1mlCH
3COOH, 0.1ml formaldehyde (in 37% water) and 0.7ml NaCNBH
3(1.0M is in THF) stirs under room temperature then and spends the night.With the mixture vacuum concentration, mix and the each 1ml of using EtOAc extraction secondary then with 1ml water.Separate organic layer, dry (MgSO
4) and concentrate.Further through 4gSiO
2(eluent: MeOH/DCM, gradient: 0-5%MeOH) the flash chromatography purifying produces amine.The ether that adds 0.2ml 1.0M HCl behind the grinding amine.Each 1ml ether of using is with solids wash 4 times and vacuum-drying.Obtain the hydrochloride of 16.1mg target compound.LC/MS:MW (calculated value, single isotropic substance of planting)=567.08; Measured value (M
+H)=567.14.
Embodiment 73
3-azetidine-1-base-6-(4-benzyl chloride base)-1-(5-fluoro-2-anisole alkylsulfonyl)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
With 50mg (0.093mmol) 3-amino-6-(4-benzyl chloride base)-1-(5-fluoro-2-anisole alkylsulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone is inserted in the 2-5ml microwave heating container and is dissolved in 2ml CH
3CN.With 0.25ml NaHCO
3(1.0M is in the water) and 0.0375ml dibromopropane add to this solution.In 180 ℃, (the high absorption mode of churning time at the beginning of 30 seconds) reacting by heating mixture is 1000 seconds in Personal Chemistry Smith Synthesizer microwave oven.Then with the mixture vacuum concentration, mix with 2ml EtOAc and use the 2ml water washing.Separate organic layer, dry (MgSO
4) and vacuum concentration.Through preparation property RP HPLC (CH in the GILSON device
3CN (0.1%TFA)/H
2O (0.1%TFA), gradient: 5-100%) carry out purifying.Obtain the tfa salt of 6.9mg target compound.LC/MS:MW (calculated value, single isotropic substance of planting)=578.18; Measured value (M
+H)=579.17.
Embodiment 74
6-(4-benzyl chloride base)-1-(5-fluoro-2-anisole alkylsulfonyl)-8-sec.-propyl-3-tetramethyleneimine-1-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
With 40mg (0.074mmol) 3-amino-6-(4-benzyl chloride base)-1-(5-fluoro-2-anisole alkylsulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone is inserted in the 2-5ml microwave heating container and is dissolved in 2ml CH
3Among the CN.With 0.2ml NaHCO
3(1.0M is in the water) and 0.036ml dibromobutane add to this solution.In 190 ℃ of (the high absorption mode of churning time at the beginning of 30 seconds) reacting by heating mixtures 800 seconds in Personal Chemistry Smith Synthesizer microwave oven.Then with the mixture vacuum concentration, mix with 1ml EtOAc and use the 1ml water washing.Separate organic layer, dry (MgSO
4) and vacuum concentration.Through 4g SiO
2(MeOH/DCM, gradient: 0-5%) flash chromatography carries out purifying.Ether through adding 0.2ml 1.0M HCl changes into hydrochloride with condensed matter.Be settled out solid, with ether washing 4 times and vacuum-drying.Obtain the hydrochloride of 22.7mg target compound.LC/MS:MW (calculated value, single isotropic substance of planting)=592.19; Measured value (M
+H)=593.18.
Embodiment 75
6-(4-benzyl chloride base)-1-(5-fluoro-2-anisole alkylsulfonyl)-8-sec.-propyl-3-piperidines-1-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 59, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(5-fluoro-2-anisole alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=606.21 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 607.19
Embodiment 76
6-(4-benzyl chloride base)-1-(5-fluoro-2-anisole alkylsulfonyl)-8-sec.-propyl-3-morpholine-4-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 60, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(5-fluoro-2-anisole alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=608.19 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 609.16
Embodiment 77
A) [6-(4-benzyl chloride base)-1-(5-chloro-2-fluorobenzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester
Adopt 5-chloro-2-fluorobenzene SULPHURYL CHLORIDE, to be similar to embodiment 66a) method synthetic.Obtain target product, MW=676.13 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 677.1
B) 3-amino-6-(4-benzyl chloride base)-1-(5-chloro-2-fluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
To be similar to embodiment 66b) method synthetic, adopt [6-(4-benzyl chloride base)-1-(5-chloro-2-fluorobenzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester as raw material.Obtain target product, MW=542.1 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 543.1
C) N-[6-(4-benzyl chloride base)-1-(5-chloro-2-fluorobenzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] ethanamide.
To be similar to embodiment 66c) method synthetic, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(5-chloro-2-fluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=584.11 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 585.08
Embodiment 78
N-[6-(4-benzyl chloride base)-1-(5-chloro-2-fluorobenzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopropane carboxamide
Structure:
Synthetic with the method that is similar to embodiment 22, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(5-chloro-2-fluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=610.12 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 611.09
Embodiment 79
N-[6-(4-benzyl chloride base)-1-(5-chloro-2-fluorobenzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] the tetramethylene methane amide
Structure:
Synthetic with the method that is similar to embodiment 30, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(5-chloro-2-fluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=624.14 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 625.10
Embodiment 80
N-[6-(4-benzyl chloride base)-1-(5-chloro-2-fluorobenzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopentane formamide
Structure:
Synthetic with the method that is similar to embodiment 31, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(5-chloro-2-fluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=638.15 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 639.12
Embodiment 81
The 1-tertiary butyl-3-[6-(4-benzyl chloride base)-1-(5-chloro-2-fluorobenzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] urea
Synthetic with the method that is similar to embodiment 28, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(5-chloro-2-fluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=641.16 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 664.12
Embodiment 82
6-(4-benzyl chloride base)-1-(5-chloro-2-fluorobenzene alkylsulfonyl)-3-dimethylamino-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 72, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(5-chloro-2-fluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=570.13 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 571.09.
Embodiment 83
3-azetidine-1-base-6-(4-benzyl chloride base)-1-(5-chloro-2-fluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 73, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(5-chloro-2-fluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=582.13 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 583.11.
Embodiment 84
6-(4-benzyl chloride base)-1-(5-chloro-2-fluorobenzene alkylsulfonyl)-8-sec.-propyl-3-tetramethyleneimine-1-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 74, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(5-chloro-2-fluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=596.14 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 597.14.
Embodiment 85
6-(4-benzyl chloride base)-1-(5-chloro-2-fluorobenzene alkylsulfonyl)-8-sec.-propyl-3-piperidines-1-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 59, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(5-chloro-2-fluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=610.16 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 611.15
Embodiment 86
6-(4-benzyl chloride base)-1-(5-chloro-2-fluorobenzene alkylsulfonyl)-8-sec.-propyl-3-morpholine-1-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 60, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(5-chloro-2-fluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=612.14 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 613.13.
Embodiment 87
A) 2-chloro-5-fluorobenzene SULPHURYL CHLORIDE
In 0 ℃, 5g (34.3mmol) 2-chloro-5-fluoroaniline is slowly added in the solution of 17ml concentrating hydrochloric acid solution and 11ml water.In 0 ℃, stirred reaction mixture 1 hour.Add 2.49g (36.1mmol) NaNO
26ml H
2O stirred the mixture 15 minutes in 0 ℃ then, added to then in the 10ml acetic acid solution of 692mg (5.15mmol) sulfurous gas and cupric chloride (II).In 0 ℃, reactant was stirred 15 minutes, then restir 15 minutes under room temperature.With EtOAc extractive reaction mixture.Organic layer is concentrated, be dissolved in EtOAc, use 1N NaHCO
3Solution washing is through MgSO
4Dry and concentrated.Obtain 7.86g target SULPHURYL CHLORIDE, be yellow oil.
B) (2-(2-chloro-5-fluorobenzene sulfuryl amino)-1-{2-(4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical } ethyl) the carboxylamine benzyl ester
With Et
3N adds to 800mg (1.39mmol) amine (2-amino-1-{2-(4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical } ethyl) in the 4ml DCM solution of carboxylamine benzyl ester.Then under room temperature, add preparation as mentioned above the chloride solution in 3ml DCM (476mg, 2.08mmol).Under room temperature, stirred reaction mixture 1 hour is also used 1N NaHCO
3Washing.Organic layer is through MgSO
4Dry and concentrated.Residue is through 40gSiO
2(heptane of eluent: 30-70%EtOAc) chromatography.Obtain the 860mg target substance, be white solid.LC/MS:MW (calculated value, single isotropic substance of planting)=769.72; Measured value (M
+Na)=791.
C) [6-(4-benzyl chloride base)-1-(2-chloro-5-fluorobenzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester
To be similar to embodiment 29f) method of (method B) is synthetic; adopt N-{2-(4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl] ethyl }-the amino propionic acid amide of 3-(2-chloro-5-fluorobenzene sulfuryl amino)-2-methylsulfonyl is as raw material.Obtain target product, MW=676.13 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 677.16
D) 3-amino-6-(4-benzyl chloride base)-1-(2-chloro-5-fluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
To be similar to embodiment 29g) method of (method B) is synthetic, adopts [6-(4-benzyl chloride base)-1-(2-chloro-5-fluorobenzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester as raw material.Obtain target product, MW=542.1 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 543.10
E) N-[6-(4-benzyl chloride base)-1-(2-chloro-5-fluorobenzene alkylsulfonyl)-8-sec.-propyl-4,7--dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] ethanamide.
To be similar to embodiment 21h) method synthetic, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2-chloro-5-fluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=584.11 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 585.10
Embodiment 88
N-[6-(4-benzyl chloride base)-1-(2-chloro-5-fluorobenzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopropane carboxamide
Structure:
Synthetic with the method that is similar to embodiment 22, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2-chloro-5-fluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=610.12 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 611.14
Embodiment 89
N-[6-(4-benzyl chloride base)-1-(2-chloro-5-fluorobenzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] the tetramethylene methane amide
Structure:
Synthetic with the method that is similar to embodiment 30, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2-chloro-5-fluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=624.14 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 625.14
Embodiment 90
The 1-tertiary butyl-3-[6-(4-benzyl chloride base)-1-(2-chloro-5-fluorobenzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] urea
Structure:
Synthetic with the method that is similar to embodiment 28, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2-chloro-5-fluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=641.16 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 664.15
Embodiment 91
N-[6-(4-benzyl chloride base)-1-(2-chloro-5-fluorobenzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] Toluidrin
Synthetic with the method that is similar to embodiment 26, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2-chloro-5-fluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=620.07 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 621.0
Embodiment 92
A) 2-chloro-4-trifluoromethoxy benzene sulfonyl chloride
Warp and embodiment 87a) same procedure, make the reaction of 2-chloro-4-trifluoro-methoxyaniline produce corresponding SULPHURYL CHLORIDE.
B) [1-{2-(4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl] the ethylamino formyl radical }-2-(2-chloro-4-Trifluoromethyl phenyl ether sulfuryl amino) ethyl] the carboxylamine benzyl ester
To be similar to embodiment 87b) method synthetic, adopt 2-chloro-4-trifluoromethoxy benzene sulfonyl chloride as raw material.Obtain target product, MW=834.21 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 857.0
C) [6-(4-benzyl chloride base)-1-(2-chloro-4-trifluoromethoxy benzenesulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester
To be similar to embodiment 29f) method of (method B) is synthetic; adopt N-{2-(4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl] ethyl }-the amino propionic acid amide of 3-(2-chloro-4-Trifluoromethyl phenyl ether sulfuryl amino)-2-methylsulfonyl is as raw material.Obtain target product, MW=742.12 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 743.14
D) 3-amino-6-(4-benzyl chloride base)-1-(2-chloro-5-trifluoromethoxy benzenesulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
To be similar to embodiment 29g) method of (method B) is synthetic, adopts [6-(4-benzyl chloride base)-1-(2-chloro-4-trifluoromethoxy benzenesulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester as raw material.Obtain target product, MW=608.09 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 609.07
E) N-[6-(4-benzyl chloride base)-1-(2-chloro-4-trifluoromethoxy benzenesulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] ethanamide.
To be similar to embodiment 21h) method synthetic, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2-chloro-4-trifluoromethoxy benzenesulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=650.1 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 651.09
Embodiment 93
N-[6-(4-benzyl chloride base)-1-(2-chloro-4-trifluoromethoxy benzenesulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopropane carboxamide
Structure:
Synthetic with the method that is similar to embodiment 22, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2-chloro-4-trifluoromethoxy benzenesulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=676.11 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 677.13
Embodiment 94
N-[6-(4-benzyl chloride base)-1-(2-chloro-4-trifluoromethoxy benzenesulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] the tetramethylene methane amide
Structure:
Synthetic with the method that is similar to embodiment 30, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2-chloro-4-trifluoromethoxy benzenesulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=690.13 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 691.13
Embodiment 95
The 1-tertiary butyl-3-[6-(4-benzyl chloride base)-1-(2-chloro-4-trifluoromethoxy benzenesulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] urea
Structure:
Synthetic with the method that is similar to embodiment 28, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2-chloro-4-trifluoromethoxy benzenesulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=707.16 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 730.14
Embodiment 96
N-[6-(4-benzyl chloride base)-1-(2-chloro-4-trifluoromethoxy benzenesulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] Toluidrin
Structure:
Synthetic with the method that is similar to embodiment 26, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2-chloro-4-trifluoromethoxy benzenesulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=686.07 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 687.0
Embodiment 97
A) [1-{2-(4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl] the ethylamino formyl radical }-2-(4-chloro-2-fluorobenzene sulfuryl amino) ethyl] the carboxylamine benzyl ester
To be similar to embodiment 87b) method synthetic, adopt 4-chloro-2-fluorobenzene SULPHURYL CHLORIDE as raw material.Obtain target product, MW=768.22 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 791.0
B) [6-(4-benzyl chloride base)-1-(4-chloro-2-fluorobenzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester
To be similar to embodiment 29f) method of (method B) is synthetic; adopt N-{2-(4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl] ethyl }-the amino propionic acid amide of 3-(4-chloro-2-fluorobenzene sulfuryl amino)-2-methylsulfonyl is as raw material.Obtain target product, MW=676.13 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 677.14
C) 3-amino-6-(4-benzyl chloride base)-1-(4-chloro-2-fluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
To be similar to embodiment 29g) method of (method B) is synthetic, adopts [6-(4-benzyl chloride base)-1-(4-chloro-2-fluorobenzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester as raw material.Obtain target product, MW=542.1 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 543.1
D) N-[6-(4-benzyl chloride base)-1-(4-chloro-2-fluorobenzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] ethanamide.
To be similar to embodiment 21h) method synthetic, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(4-chloro-2-fluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=584.11 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 585.1
Embodiment 98
N-[6-(4-benzyl chloride base)-1-(4-chloro-2-fluorobenzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopropane carboxamide
Structure:
To be similar to embodiment 29e) method synthetic, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(4-chloro-2-fluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=610.12 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 611.14
Embodiment 99
N-[6-(4-benzyl chloride base)-1-(4-chloro-2-fluorobenzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] the tetramethylene methane amide
Structure:
Synthetic with the method that is similar to embodiment 30, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(4-chloro-2-fluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=624.12 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 625.14
Embodiment 100
The 1-tertiary butyl-3-[6-(4-benzyl chloride base)-1-(4-chloro-2-fluorobenzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] urea
Structure:
Synthetic with the method that is similar to embodiment 28, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(4-chloro-2-fluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=641.16 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 664.14
Embodiment 101
N-[6-(4-benzyl chloride base)-1-(4-chloro-2-fluorobenzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] Toluidrin
Structure:
Synthetic with the method that is similar to embodiment 26, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(4-chloro-2-fluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=620.07 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 621.0
Embodiment 102
N-[6-(4-benzyl chloride base)-1-(2,5-dimethoxy benzenesulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] Toluidrin
Structure:
A) 2-benzyloxycarbonyl amino-3-(2,5-dimethoxy benzene sulfuryl amino) propionic acid
To be similar to embodiment 21d) method synthetic, adopt 2,5-dimethoxy benzene sulfonyl chloride is as raw material.Obtain target product, MW=438.46 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 439.1
B) N-{2-(4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl] ethyl }-the amino propionic acid amide of 3-(2,5-dimethoxy benzene sulfuryl amino)-2-methylsulfonyl
To be similar to embodiment 21e) method synthetic, adopt 2-benzyloxycarbonyl amino-3-(2,5-dimethoxy benzene sulfuryl amino) propionic acid as raw material.Obtain target product, MW=777.34 (calculated value, single isotropic substance of planting); Measured value (M-C
2H
6O+H)
+: 731.9
C) [6-(4-benzyl chloride base)-1-(2,5-dimethoxy benzenesulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester
To be similar to embodiment 21f) method synthetic, adopt N-{2-(4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl] ethyl-the amino propionic acid amide of 3-(2,5-dimethoxy benzene sulfuryl amino)-2-methylsulfonyl is as raw material.Obtain target product, MW=684 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 685.38
D) 3-amino-6-(4-benzyl chloride base)-1-(2,5-dimethoxy benzenesulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
To be similar to embodiment 21g) method synthetic, adopt [6-(4-benzyl chloride base)-1-(2,5-dimethoxy benzenesulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester as raw material.Obtain target product, MW=550 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 551.15
E) 3-amino-6-(4-benzyl chloride base)-1-(2,5-dimethoxy benzenesulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
Synthetic with the method that is similar to embodiment 26, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2,5-dimethoxy benzenesulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=628.14 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 629.15
Embodiment 103
N-[6-(4-benzyl chloride base)-1-(3-fluorobenzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] Toluidrin
Structure:
A) 2-benzyloxycarbonyl amino-3-(3-fluorobenzene sulfuryl amino) propionic acid
To be similar to embodiment 21d) method synthetic, adopt 3-fluorobenzene SULPHURYL CHLORIDE as raw material.Obtain target product, MW=396.40 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 397.10
B) N-{2-(4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl] ethyl }-the amino propionic acid amide of 3-(3-fluorobenzene sulfuryl amino)-2-methylsulfonyl
To be similar to embodiment 21e) method synthetic, adopt 2-benzyloxycarbonyl amino-3-(3-fluorobenzene sulfuryl amino) propionic acid as raw material.Obtain target product, MW=735.28 (calculated value, single isotropic substance of planting); Measured value (M-C
2H
6O+H)
+: 689.8
C) [6-(4-benzyl chloride base)-1-(3-fluorobenzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester
To be similar to embodiment 21f) method synthetic, adopt N-{2-(4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl] ethyl-the amino propionic acid amide of 3-(3-fluorobenzene sulfuryl amino)-2-methylsulfonyl is as raw material.Obtain target product, MW=642 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 643.31
D) 3-amino-6-(4-benzyl chloride base)-1-(3-fluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
To be similar to embodiment 21g) method synthetic, adopt [6-(4-benzyl chloride base)-1-(3-fluorobenzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester as raw material.Obtain target product, MW=508 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 509.15
E) 3-amino-6-(4-benzyl chloride base)-1-(3-fluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
Synthetic with the method that is similar to embodiment 26, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(3-fluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=586.11 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 587.41
Embodiment 104
N-[1-benzenesulfonyl-6-(4-benzyl chloride base)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] Toluidrin
Structure:
A) 2-benzyloxycarbonyl amino-3-(benzenesulfonyl amino) propionic acid
To be similar to embodiment 21d) method synthetic, adopt benzene sulfonyl chloride as raw material.Obtain target product, MW=378.41 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 397.10
B) N-{2-(4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl] ethyl }-the amino propionic acid amide of 3-(benzenesulfonyl amino)-2-methylsulfonyl
To be similar to embodiment 21e) method synthetic, adopt 2-benzyloxycarbonyl amino-3-(benzenesulfonyl amino) propionic acid as raw material.Obtain target product, MW=717.29 (calculated value, single isotropic substance of planting); Measured value (M-C
2H
6O+H)
+: 671.7
C) [6-(4-benzyl chloride base)-1-(benzenesulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester
To be similar to embodiment 21f) method synthetic, adopt N-{2-(4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl] ethyl-the amino propionic acid amide of 3-(benzenesulfonyl amino)-2-methylsulfonyl is as raw material.Obtain target product, MW=642 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 625.33
D) 3-amino-6-(4-benzyl chloride base)-1-(benzenesulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
To be similar to embodiment 21g) method synthetic, adopt [6-(4-benzyl chloride base)-1-(benzenesulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester as raw material.Obtain target product, MW=490 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 491.10
E) 3-amino-6-(4-benzyl chloride base)-1-(benzenesulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
Synthetic with the method that is similar to embodiment 26, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(benzenesulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=568.12 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 569.13
Embodiment 105
N-[6-(4-benzyl chloride base)-1-(2-fluorobenzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] Toluidrin
Structure:
A) 2-benzyloxycarbonyl amino-3-(2-fluorobenzene sulfuryl amino) propionic acid
To be similar to embodiment 21d) method synthetic, adopt 2-fluorobenzene SULPHURYL CHLORIDE as raw material.Obtain target product, MW=396.40 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 397.10
B) N-{2-(4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl] ethyl }-the amino propionic acid amide of 3-(2-fluorobenzene sulfuryl amino)-2-methylsulfonyl
To be similar to embodiment 21e) method synthetic, adopt 2-benzyloxycarbonyl amino-3-(2-fluorobenzene sulfuryl amino) propionic acid as raw material.Obtain target product, MW=735.28 (calculated value, single isotropic substance of planting); Measured value (M-C
2H
6O+H)
+: 689.7
C) [6-(4-benzyl chloride base)-1-(2-fluorobenzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester
To be similar to embodiment 21f) method synthetic, adopt N-{2-(4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl] ethyl-the amino propionic acid amide of 3-(2-fluorobenzene sulfuryl amino)-2-methylsulfonyl is as raw material.Obtain target product, MW=642 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 643.31
D) 3-amino-6-(4-benzyl chloride base)-1-(2-fluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
To be similar to embodiment 21g) method synthetic, adopt [6-(4-benzyl chloride base)-1-(2-fluorobenzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester as raw material.Obtain target product, MW=508 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 509.15
E) 3-amino-6-(4-benzyl chloride base)-1-(2-fluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
Synthetic with the method that is similar to embodiment 26, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2-fluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=586.11 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 587.12
Embodiment 106
N-[6-(4-benzyl chloride base)-1-(2,4 difluorobenzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] Toluidrin
Structure:
A) 2-benzyloxycarbonyl amino-3-(2,4 difluorobenzene sulfuryl amino) propionic acid
To be similar to embodiment 21d) method synthetic, adopt the 2,4 difluorobenzene SULPHURYL CHLORIDE as raw material.Obtain target product, MW=414.40 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 415.10
B) N-{2-(4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl] ethyl }-the amino propionic acid amide of 3-(2,4 difluorobenzene sulfuryl amino)-2-methylsulfonyl
To be similar to embodiment 21e) method synthetic, adopt 2-benzyloxycarbonyl amino-3-(2,4 difluorobenzene sulfuryl amino) propionic acid as raw material.Obtain target product, MW=753.27 (calculated value, single isotropic substance of planting); Measured value (M-C
2H
6O+H)
+: 707.7
C) [6-(4-benzyl chloride base)-1-(2,4 difluorobenzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester
To be similar to embodiment 21f) method synthetic, adopt N-{2-(4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl] ethyl-the amino propionic acid amide of 3-(2,4 difluorobenzene sulfuryl amino)-2-methylsulfonyl is as raw material.Obtain target product, MW=660 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 661.32
D) 3-amino-6-(4-benzyl chloride base)-1-(2,4 difluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
To be similar to embodiment 21g) method synthetic, adopt [6-(4-benzyl chloride base)-1-(2,4 difluorobenzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester as raw material.Obtain target product, MW=526 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 527.10
E) 3-amino-6-(4-benzyl chloride base)-1-(2,4 difluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
Synthetic with the method that is similar to embodiment 26, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2,4 difluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=604.1 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 605.11
Embodiment 107
N-[6-(4-benzyl chloride base)-1-(3,4-difluoro benzenesulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] Toluidrin
Structure:
A) 2-benzyloxycarbonyl amino-3-(3,4-difluoro benzenesulfonyl amino) propionic acid
To be similar to embodiment 21d) method synthetic, adopt 3, the 4-difluoro chloride is as raw material.Obtain target product, MW=414.40 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 415.10
B) N-{2-(4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl] ethyl }-the amino propionic acid amide of 3-(3,4-difluoro benzenesulfonyl amino)-2-methylsulfonyl
To be similar to embodiment 21e) method synthetic, adopt 2-benzyloxycarbonyl amino-3-(3,4-difluoro benzenesulfonyl amino) propionic acid as raw material.Obtain target product, MW=753.27 (calculated value, single isotropic substance of planting); Measured value (M-C
2H
6O+H)
+: 707.7
C) [6-(4-benzyl chloride base)-1-(3,4-difluoro benzenesulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester
To be similar to embodiment 21f) method synthetic, adopt N-{2-(4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl] ethyl-the amino propionic acid amide of 3-(3,4-difluoro benzenesulfonyl amino)-2-methylsulfonyl is as raw material.Obtain target product, MW=660 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 661.31
D) 3-amino-6-(4-benzyl chloride base)-1-(3,4-difluoro benzenesulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
To be similar to embodiment 21g) method synthetic, adopt [6-(4-benzyl chloride base)-1-(3,4-difluoro benzenesulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester as raw material.Obtain target product, MW=526 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 527.10
E) 3-amino-6-(4-benzyl chloride base)-1-(3,4-difluoro benzenesulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
Synthetic with the method that is similar to embodiment 26, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(3,4-difluoro benzenesulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=604.1 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 605.11
Embodiment 108
A) [1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl]-2-(4-fluoroform phenyl) ethyl] carboxylamine 9H-fluorenes-9-ylmethyl ester
To be similar to embodiment 29a) method of (method B) is synthetic, adopts N-Fmoc-4-CF
3-Phe-OH is as raw material.Obtain target product, MW=612.28 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 635.28
B) 2-amino-3-(4-fluoroform phenyl)-N-(2,2-diethoxy ethyl)-N-sec.-propyl propionic acid amide
To be similar to embodiment 29b) method of (method B) is synthetic, adopt [1-[(2,2-diethoxy ethyl) sec.-propyl formamyl]-2-(4-fluoroform phenyl) ethyl] carboxylamine 9H-fluorenes-9-ylmethyl ester is as raw material.Obtain target product, MW=390.21 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 413.22
C) (2-benzyloxycarbonyl amino-2-{2-(4-fluoroform phenyl)-1-[(2,2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical } ethyl) carboxylamine 9H-fluorenes-9-ylmethyl ester
To be similar to embodiment 29c) method of (method B) is synthetic, adopts 2-amino-3-(4-fluoroform phenyl)-N-(2,2-diethoxy ethyl)-N-sec.-propyl propionic acid amide as raw material.Obtain target product, MW=832.37 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 855.0
D) (2-amino-1-{2-(4-fluoroform phenyl)-1-[(2,2-diethoxy ethyl) sec.-propyl formamyl]-the ethylamino formyl radical } ethyl) the carboxylamine benzyl ester
To be similar to embodiment 29d) method of (method B) is synthetic; adopt (2-benzyloxycarbonyl amino-2-{2-(4-fluoroform phenyl)-1-[(2,2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical } ethyl) carboxylamine 9H-fluorenes-9-ylmethyl ester is as raw material.Obtain target product, MW=610.30 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 611.33
E) [1-{2-(4-fluoroform phenyl)-1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl] the ethylamino formyl radical }-2-(2,4 dichloro benzene sulfuryl amino) ethyl] the carboxylamine benzyl ester
To be similar to embodiment 29e) method of (method B) is synthetic, adopts (2-amino-1-{2-(4-fluoroform phenyl)-1-[(2,2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical } ethyl) the carboxylamine benzyl ester is as raw material.Obtain target product, MW=818.21 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 841.2.
F) [6-(4-trifluoromethyl benzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester
To be similar to embodiment 29f) method of (method B) is synthetic; adopt [1-{2-(4-fluoroform phenyl)-1-[(2; 2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical }-2-(2,4 dichloro benzene sulfuryl amino) ethyl] the carboxylamine benzyl ester is as raw material.Obtain target product, MW=726.13 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 727.14
G) 3-amino-6-(4-trifluoromethyl benzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
To be similar to embodiment 29g) method of (method B) is synthetic, adopts [6-(4-trifluoromethyl benzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester as raw material.Obtain target product, MW=592.09 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 593.09
H) N-[6-(4-trifluoromethyl benzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] ethanamide
To be similar to embodiment 21h) method synthetic, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-trifluoromethyl benzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=634.10 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 635.12
Embodiment 109
N-[1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo-6-(4-trifluoromethyl benzyl) octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopropane carboxamide
Structure:
Synthetic with the method that is similar to embodiment 22, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-trifluoromethyl benzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=660.12 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 661.13
Embodiment 110
N-[1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo-6-(4-trifluoromethyl benzyl) octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] the tetramethylene methane amide
Structure:
Synthetic with the method that is similar to embodiment 30, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-trifluoromethyl benzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=674.13 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 675.15
Embodiment 111
N-[1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo-6-(4-trifluoromethyl benzyl) octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopentane formamide
Structure:
Synthetic with the method that is similar to embodiment 31, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-trifluoromethyl benzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=688.15 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 689.16
Embodiment 112
N-[1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo-6-(4-trifluoromethyl benzyl) octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] tetramethyleneimine-2-methane amide
Structure:
Synthetic with the method that is similar to embodiment 40, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-trifluoromethyl benzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=689.15 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 690.10.
Embodiment 113
N-[1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo-6-(4-trifluoromethyl benzyl) octahydro pyrazine is [1,2-a] pyrimidin-3-yl also]-4-dimethylamino yl-benzamide
Structure:
Synthetic with the method that is similar to embodiment 25, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-trifluoromethyl benzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=739.16 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 740.15
Embodiment 114
The 1-tertiary butyl-3-[1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo-6-(4-trifluoromethyl benzyl) octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] urea
Structure:
Synthetic with the method that is similar to embodiment 28, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-trifluoromethyl benzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=691.16 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 692.18
Embodiment 115
N-[1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo-6-(4-trifluoromethyl benzyl) octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] Toluidrin
Structure:
Synthetic with the method that is similar to embodiment 26, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-trifluoromethyl benzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=670.07 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 671.08
Embodiment 116
N-[1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo-6-(4-trifluoromethyl benzyl) octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopropane carboxamide
Structure:
Synthetic with the method that is similar to embodiment 27, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-trifluoromethyl benzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=696.09 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 697.0
Embodiment 117
1-(2,4 dichloro benzene alkylsulfonyl)-3-dimethylamino-8-sec.-propyl-6-(4-trifluoromethyl benzyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 72, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-trifluoromethyl benzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=620.12 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 621.09
Embodiment 118
3-azetidine-1-base-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-(4-trifluoromethyl benzyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 73, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-trifluoromethyl benzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=632.12 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 633.0
Embodiment 119
1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-3-tetramethyleneimine-1-base-6-(4-trifluoromethyl benzyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 74, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-trifluoromethyl benzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=646.14 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 647.14
Embodiment 120
1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-3-piperidines-1-base-6-(4-trifluoromethyl benzyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 59, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-trifluoromethyl benzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=660.16 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 661.13
Embodiment 121
1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-3-morpholine-4-base-6-(4-trifluoromethyl benzyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 60, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-trifluoromethyl benzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=662.13 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 663.07
Embodiment 122
A) [1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl]-2-(3-chloro-phenyl-) ethyl] carboxylamine 9H-fluorenes-9-ylmethyl ester
To be similar to embodiment 29a) method of (method B) is synthetic, adopts N-Fmoc-3-Cl-Phe-OH as raw material.Obtain target product, MW=578.25 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 579.27
B) 2-amino-3-(3-chloro-phenyl-)-N-(2,2-diethoxy ethyl)-N-sec.-propyl propionic acid amide
To be similar to embodiment 29b) method of (method B) is synthetic, adopt [1-[(2,2-diethoxy ethyl) sec.-propyl formamyl]-2-(3-chloro-phenyl-) ethyl] carboxylamine 9H-fluorenes-9-ylmethyl ester is as raw material.Obtain target product, MW=356.19 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 379.18
C) (2-benzyloxycarbonyl amino-2-{2-(3-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical } ethyl) carboxylamine 9H-fluorenes-9-ylmethyl ester
To be similar to embodiment 29c) method of (method B) is synthetic, adopts 2-amino-3-(3-chloro-phenyl-)-N-(2,2-diethoxy ethyl)-N-sec.-propyl propionic acid amide as raw material.Obtain target product, MW=798.34 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 799.35
D) (2-amino-1-{2-(3-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical } ethyl) the carboxylamine benzyl ester
To be similar to embodiment 29d) method of (method B) is synthetic; adopt (2-benzyloxycarbonyl amino-2-{2-(3-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical } ethyl) carboxylamine 9H-fluorenes-9-ylmethyl ester is as raw material.Obtain target product, MW=576.27 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 577.22
E) [1-{2-(3-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl] the ethylamino formyl radical }-2-(2,4 dichloro benzene sulfuryl amino) ethyl] the carboxylamine benzyl ester
To be similar to embodiment 29e) method of (method B) is synthetic, adopts (2-amino-1-{2-(3-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical } ethyl) the carboxylamine benzyl ester is as raw material.Obtain target product, MW=784.19 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 785.18
F) [6-(3-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester
To be similar to embodiment 29f) method of (method B) is synthetic; adopt [1-{2-(3-chloro-phenyl-)-1-[(2; 2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical }-2-(2,4 dichloro benzene sulfuryl amino) ethyl] the carboxylamine benzyl ester is as raw material.Obtain target product, MW=692.10 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 693.08
G) 3-amino-6-(3-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
To be similar to embodiment 29g) method of (method B) is synthetic, adopts [6-(3-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester as raw material.Obtain target product, MW=558.07 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 559.07
H) N-[6-(3-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] ethanamide
To be similar to embodiment 21h) method synthetic, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=600.08 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 601.07
Embodiment 123
N-[6-(3-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopropane carboxamide
Structure:
Synthetic with the method that is similar to embodiment 22, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=626.09 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 627.08
Embodiment 124
N-[6-(3-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] the tetramethylene methane amide
Structure:
Synthetic with the method that is similar to embodiment 30, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=640.11 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 641.08
Embodiment 125
N-[6-(3-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopentane formamide
Structure:
Synthetic with the method that is similar to embodiment 31, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=654.12 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 655.09
Embodiment 126
N-[6-(3-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also]-4-dimethylamino yl-benzamide
Structure:
Synthetic with the method that is similar to embodiment 25, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=705.13 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 706.10
Embodiment 127
The 1-tertiary butyl-3-[6-(3-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] urea
Structure:
Synthetic with the method that is similar to embodiment 28, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=657.13 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 658.11
Embodiment 128
N-[6-(3-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] Toluidrin
Structure:
Synthetic with the method that is similar to embodiment 26, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=636.04 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 637.03
Embodiment 129
6-(3-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-3-dimethylamino-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 72, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=586.10 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 587.09
Embodiment 130
6-(3-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-3-tetramethyleneimine-1-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 74, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=612.11 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 613.10
Embodiment 131
6-(3-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-3-piperidines-1-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 59, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=626.13 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 627.13
Embodiment 132
6-(3-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-3-morpholine-4-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 60, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=628.11 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 629.09
Embodiment 133
A) [1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl]-2-(4-fluorophenyl) ethyl] carboxylamine 9H-fluorenes-9-ylmethyl ester
To be similar to embodiment 29a) method of (method B) is synthetic, adopts N-Fmoc-4-F-Phe-OH as raw material.Obtain target product, MW=562.28 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 563.27
B) 2-amino-3-(4-fluorophenyl)-N-(2,2-diethoxy ethyl)-N-sec.-propyl propionic acid amide
To be similar to embodiment 29b) method of (method B) is synthetic, adopt [1-[(2,2-diethoxy ethyl) sec.-propyl formamyl]-2-(4-fluorophenyl) ethyl] carboxylamine 9H-fluorenes-9-ylmethyl ester is as raw material.Obtain target product, MW=340.22 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 341.20
C) (2-benzyloxycarbonyl amino-2-{2-(4-fluorophenyl)-1-[(2,2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical } ethyl) carboxylamine 9H-fluorenes-9-ylmethyl ester
To be similar to embodiment 29c) method of (method B) is synthetic, adopts 2-amino-3-(4-fluorophenyl)-N-(2,2-diethoxy ethyl)-N-sec.-propyl propionic acid amide as raw material.Obtain target product, MW=782.37 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 805.37
D) (2-amino-1-{2-(4-fluorophenyl)-1-[(2,2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical } ethyl) the carboxylamine benzyl ester
To be similar to embodiment 29d) method of (method B) is synthetic; adopt (2-benzyloxycarbonyl amino-2-{2-(4-fluorophenyl)-1-[(2,2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical } ethyl) carboxylamine 9H-fluorenes-9-ylmethyl ester is as raw material.Obtain target product, MW=560.30 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 561.31
E) [1-{2-(4-fluorophenyl)-1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl] the ethylamino formyl radical }-2-(2,4 dichloro benzene sulfuryl amino) ethyl] the carboxylamine benzyl ester
To be similar to embodiment 29e) method of (method B) is synthetic, adopts (2-amino-1-{2-(4-fluorophenyl)-1-[(2,2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical } ethyl) the carboxylamine benzyl ester is as raw material.Obtain target product, MW=768.22 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 791.23
F) [6-(4-luorobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester
To be similar to embodiment 29f) method of (method B) is synthetic; adopt [1-{2-(4-fluorophenyl)-1-[(2; 2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical }-2-(2,4 dichloro benzene sulfuryl amino) ethyl] the carboxylamine benzyl ester is as raw material.Obtain target product, MW=676.13 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 677.1
G) 3-amino-6-(4-luorobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
To be similar to embodiment 29g) method of (method B) is synthetic, adopts [6-(4-luorobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester as raw material.Obtain target product, MW=542.1 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 543.12
H) N-[6-(4-luorobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] ethanamide
To be similar to embodiment 21h) method synthetic, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-luorobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=584.11 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 585.08
Embodiment 134
N-[1-(2,4 dichloro benzene alkylsulfonyl)-6-(4-luorobenzyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopropane carboxamide
Structure:
Synthetic with the method that is similar to embodiment 22, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-luorobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=610.12 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 611.09
Embodiment 135
N-[1-(2,4 dichloro benzene alkylsulfonyl)-6-(4-luorobenzyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] the tetramethylene methane amide
Structure:
Synthetic with the method that is similar to embodiment 30, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-luorobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=624.14 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 625.13
Embodiment 136
N-[1-(2,4 dichloro benzene alkylsulfonyl)-6-(4-luorobenzyl)-8-sec.-propyl-4,7-oxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopentane formamide
Structure:
Synthetic with the method that is similar to embodiment 31, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-luorobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=638.15 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 639.14
Embodiment 137
N-[1-(2,4 dichloro benzene alkylsulfonyl)-6-(4-luorobenzyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also]-4-dimethylamino yl-benzamide
Structure:
Synthetic with the method that is similar to embodiment 25, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-luorobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=689.16 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 690.10
Embodiment 138
N-[1-(2,4 dichloro benzene alkylsulfonyl)-6-(4-luorobenzyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] Toluidrin
Structure:
Synthetic with the method that is similar to embodiment 26, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-luorobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=620.07 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 621.04
Embodiment 139
1-(2,4 dichloro benzene alkylsulfonyl)-3-dimethylamino-6-(4-luorobenzyl)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 72, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-luorobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=570.13 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 571.09
Embodiment 140
3-azetidine-1-base-1-(2,4 dichloro benzene alkylsulfonyl)-6-(4-luorobenzyl)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 73, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-luorobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=582.13 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 583.04
Embodiment 141
1-(2,4 dichloro benzene alkylsulfonyl)-6-(4-luorobenzyl)-8-sec.-propyl-3-tetramethyleneimine-1-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 74, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-luorobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=596.14 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 597.12
Embodiment 142
1-(2,4 dichloro benzene alkylsulfonyl)-6-(4-luorobenzyl)-8-sec.-propyl-3-piperidines-1-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 59, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-luorobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=610.16 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 611.16
Embodiment 143
1-(2,4 dichloro benzene alkylsulfonyl)-6-(4-luorobenzyl)-8-sec.-propyl-3-morpholine-4-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 60, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-luorobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=612.14 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 613.13
Embodiment 144
A) [1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl]-2-(4-bromophenyl) ethyl] carboxylamine 9H-fluorenes-9-ylmethyl ester
To be similar to embodiment 29a) method of (method B) is synthetic, adopts N-Fmoc-4-Br-Phe-OH as raw material.Obtain target product, MW=622.20 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 645.30
B) 2-amino-3-(4-bromophenyl)-N-(2,2-diethoxy ethyl)-N-sec.-propyl propionic acid amide
To be similar to embodiment 29b) method of (method B) is synthetic, adopt [1-[(2,2-diethoxy ethyl) sec.-propyl formamyl]-2-(4-bromophenyl) ethyl] carboxylamine 9H-fluorenes-9-ylmethyl ester is as raw material.Obtain target product, MW=400.14 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 401.10
C) (2-benzyloxycarbonyl amino-2-{2-(4-bromophenyl)-1-[(2,2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical } ethyl) carboxylamine 9H-fluorenes-9-ylmethyl ester
To be similar to embodiment 29c) method of (method B) is synthetic, adopts 2-amino-3-(4-bromophenyl)-N-(2,2-diethoxy ethyl)-N-sec.-propyl propionic acid amide as raw material.Obtain target product, MW=842.29 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 865.4
D) (2-amino-1-{2-(4-bromophenyl)-1-[(2,2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical } ethyl) the carboxylamine benzyl ester
To be similar to embodiment 29d) method of (method B) is synthetic; adopt (2-benzyloxycarbonyl amino-2-{2-(4-bromophenyl)-1-[(2,2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical } ethyl) carboxylamine 9H-fluorenes-9-ylmethyl ester is as raw material.Obtain target product, MW=620.22 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 621.20
E) [1-{2-(4-bromophenyl)-1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl] the ethylamino formyl radical }-2-(2,4 dichloro benzene sulfuryl amino) ethyl] the carboxylamine benzyl ester
To be similar to embodiment 29e) method of (method B) is synthetic, adopts (2-amino-1-{2-(4-bromophenyl)-1-[(2,2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical } ethyl) the carboxylamine benzyl ester is as raw material.Obtain target product, MW=828.14 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 829.11
F) [6-(4-bromobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester
To be similar to embodiment 29f) method of (method B) is synthetic; adopt [1-{2-(4-bromophenyl)-1-[(2; 2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical }-2-(2,4 dichloro benzene sulfuryl amino) ethyl] the carboxylamine benzyl ester is as raw material.Obtain target product, MW=736.05 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 737.1
G) 3-amino-6-(4-bromobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
To be similar to embodiment 29g) method of (method B) is synthetic, adopts [6-(4-bromobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester as raw material.Obtain target product, MW=602.02 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 603.01
H) N-[6-(4-bromobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] ethanamide
To be similar to embodiment 21h) method synthetic, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=644.03 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 645.0
Embodiment 145
N-[6-(4-bromobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopropane carboxamide
Structure:
Synthetic with the method that is similar to embodiment 22, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=670.04 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 671.06
Embodiment 146
N-[6-(4-bromobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] the tetramethylene methane amide
Structure:
Synthetic with the method that is similar to embodiment 30, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=684.06 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 685.04
Embodiment 147
N-[6-(4-bromobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopentane formamide
Structure:
Synthetic with the method that is similar to embodiment 31, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=698.07 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 699.1
Embodiment 148
N-[6-(4-bromobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] tetramethyleneimine-2-methane amide
Structure:
Synthetic with the method that is similar to embodiment 40, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=699.07 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 700.2
Embodiment 149
N-[6-(4-bromobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also]-4-dimethylamino yl-benzamide
Structure:
Synthetic with the method that is similar to embodiment 25, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=749.08 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 750.10
Embodiment 150
N-[6-(4-bromobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] niacinamide
Structure:
Synthetic with the method that is similar to embodiment 50, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=707.04 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 708.07
Embodiment 151
1-[6-(4-bromobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also]-the 3-tert butyl urea
Structure:
Synthetic with the method that is similar to embodiment 28, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=701.08 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 702.0
Embodiment 152
N-[6-(4-bromobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] Toluidrin
Structure:
Synthetic with the method that is similar to embodiment 26, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=679.99 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 681.0
Embodiment 153
N-[6-(4-bromobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] the cyclopropane sulphonamide
Structure:
Synthetic with the method that is similar to embodiment 27, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=706.01 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 707.01
Embodiment 154
6-(4-bromobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-3-tetramethyleneimine-1-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 74, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=656.06 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 657.06
Embodiment 155
A) [1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl]-2-(3, the 4-chloro-phenyl-) ethyl] carboxylamine 9H-fluorenes-9-ylmethyl ester
To be similar to embodiment 29a) method of (method B) is synthetic, adopts N-Fmoc-3,4-Cl
2-Phe-OH is as raw material.Obtain target product, MW=612.22 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 635.2
B) 2-amino-3-(3, the 4-chloro-phenyl-)-N-(2,2-diethoxy ethyl)-N-sec.-propyl propionic acid amide
To be similar to embodiment 29b) method of (method B) is synthetic, adopt [1-[(2,2-diethoxy ethyl) sec.-propyl formamyl]-2-(3, the 4-chloro-phenyl-) ethyl] carboxylamine 9H-fluorenes-9-ylmethyl ester is as raw material.Obtain target product, MW=390.34 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 391.16
C) (2-benzyloxycarbonyl amino-2-{2-(3, the 4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical } ethyl) carboxylamine 9H-fluorenes-9-ylmethyl ester
To be similar to embodiment 29c) method of (method B) is synthetic, adopts 2-amino-3-(3, the 4-chloro-phenyl-)-N-(2,2-diethoxy ethyl)-N-sec.-propyl propionic acid amide as raw material.Obtain target product, MW=832.30 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 833.30
D) (2-amino-1-{2-(3, the 4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical } ethyl) the carboxylamine benzyl ester
To be similar to embodiment 29d) method of (method B) is synthetic; adopt (2-benzyloxycarbonyl amino-2-{2-(3; the 4-chloro-phenyl-)-and 1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl] the ethylamino formyl radical } ethyl) carboxylamine 9H-fluorenes-9-ylmethyl ester is as raw material.Obtain target product, MW=610.23 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 611.27
E) [1-{2-(3, the 4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl] the ethylamino formyl radical }-2-(2,4 dichloro benzene sulfuryl amino) ethyl] the carboxylamine benzyl ester
To be similar to embodiment 29e) method of (method B) is synthetic, adopts (2-amino-1-{2-(3, the 4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical } ethyl) the carboxylamine benzyl ester is as raw material.Obtain target product, MW=818.15 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 819.20
F) [6-(3, the 4-dichloro benzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester
To be similar to embodiment 29f) method of (method B) is synthetic; [1-{2-(3 in employing; the 4-chloro-phenyl-)-and 1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl] the ethylamino formyl radical }-2-(2,4 dichloro benzene sulfuryl amino) ethyl] the carboxylamine benzyl ester is as raw material.Obtain target product, MW=726.06 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 727.1
G) 3-amino-6-(3, the 4-dichloro benzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
To be similar to embodiment 29g) method of (method B) is synthetic, adopts [6-(3, the 4-dichloro benzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester as raw material.Obtain target product, MW=592.03 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 593.00
H) N-[6-(3, the 4-dichloro benzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] ethanamide
To be similar to embodiment 21h) method synthetic, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3, the 4-dichloro benzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=634.04 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 635.0
Embodiment 156
N-[1-(2,4 dichloro benzene alkylsulfonyl)-6-(3, the 4-dichloro benzyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopropane carboxamide
Structure:
Synthetic with the method that is similar to embodiment 22, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3, the 4-dichloro benzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=660.05 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 661.0
Embodiment 157
N-[1-(2,4 dichloro benzene alkylsulfonyl)-6-(3, the 4-dichloro benzyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] the tetramethylene methane amide
Structure:
Synthetic with the method that is similar to embodiment 30, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3, the 4-dichloro benzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=674.07 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 675.05
Embodiment 158
N-[1-(2,4 dichloro benzene alkylsulfonyl)-6-(3, the 4-dichloro benzyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopentane formamide
Structure:
Synthetic with the method that is similar to embodiment 31, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3, the 4-dichloro benzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=688.08 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 689.09
Embodiment 159
N-[1-(2,4 dichloro benzene alkylsulfonyl)-6-(3, the 4-dichloro benzyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also]-4-dimethylamino yl-benzamide
Structure:
Synthetic with the method that is similar to embodiment 25, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3, the 4-dichloro benzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=739.10 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 740.0
Embodiment 160
The 1-tertiary butyl-3-[1-(2,4 dichloro benzene alkylsulfonyl)-6-(3, the 4-dichloro benzyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] urea
Structure:
Synthetic with the method that is similar to embodiment 28, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3, the 4-dichloro benzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=691.10 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 692.0
Embodiment 161
N-[1-(2,4 dichloro benzene alkylsulfonyl)-6-(3, the 4-dichloro benzyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] Toluidrin
Structure:
Synthetic with the method that is similar to embodiment 26, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3, the 4-dichloro benzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=670.0 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 670.98
Embodiment 162
1-(2,4 dichloro benzene alkylsulfonyl)-6-(3, the 4-dichloro benzyl)-8-sec.-propyl-3-tetramethyleneimine-1-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 74, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3, the 4-dichloro benzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=646.07 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 647.05
Embodiment 163
1-(2,4 dichloro benzene alkylsulfonyl)-6-(3, the 4-dichloro benzyl)-8-sec.-propyl-3-morpholine-4-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 60, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3, the 4-dichloro benzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=662.07 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 663.06
Embodiment 164
A) [1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl]-2-(3, the 4-difluorophenyl) ethyl] carboxylamine 9H-fluorenes-9-ylmethyl ester
To be similar to embodiment 29a) method of (method B) is synthetic, adopts N-Fmoc-3,4-F
2-Phe-OH is as raw material.Obtain target product, MW=580.27 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 603.25
B) 2-amino-3-(3, the 4-difluorophenyl)-N-(2,2-diethoxy ethyl)-N-sec.-propyl propionic acid amide
To be similar to embodiment 29b) method of (method B) is synthetic, adopt [1-[(2,2-diethoxy ethyl) sec.-propyl formamyl]-2-(3, the 4-difluorophenyl) ethyl] carboxylamine 9H-fluorenes-9-ylmethyl ester is as raw material.Obtain target product, MW=358.21 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 359.2
C) (2-benzyloxycarbonyl amino-2-{2-(3, the 4-difluorophenyl)-1-[(2,2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical } ethyl) carboxylamine 9H-fluorenes-9-ylmethyl ester
To be similar to embodiment 29c) method of (method B) is synthetic, adopts 2-amino-3-(3, the 4-difluorophenyl)-N-(2,2-diethoxy ethyl)-N-sec.-propyl propionic acid amide as raw material.Obtain target product, MW=800.36 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 801.35
D) (2-amino-1-{2-(3, the 4-difluorophenyl)-1-[(2,2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical } ethyl) the carboxylamine benzyl ester
To be similar to embodiment 29d) method of (method B) is synthetic; adopt (2-benzyloxycarbonyl amino-2-{2-(3; the 4-difluorophenyl)-and 1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl] the ethylamino formyl radical } ethyl) carboxylamine 9H-fluorenes-9-ylmethyl ester is as raw material.Obtain target product, MW=578.29 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 579.31
E) [1-{2-(3, the 4-difluorophenyl)-1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl] the ethylamino formyl radical }-2-(2,4 dichloro benzene sulfuryl amino) ethyl] the carboxylamine benzyl ester
To be similar to embodiment 29e) method of (method B) is synthetic, adopts (2-amino-1-{2-(3, the 4-difluorophenyl)-1-[(2,2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical } ethyl) the carboxylamine benzyl ester is as raw material.Obtain target product, MW=786.21 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 809.19
F) [6-(3, the 4-difluorobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester
To be similar to embodiment 29f) method of (method B) is synthetic; [1-{2-(3 in employing; the 4-difluorophenyl)-and 1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl] the ethylamino formyl radical }-2-(2,4 dichloro benzene sulfuryl amino) ethyl] the carboxylamine benzyl ester is as raw material.Obtain target product, MW=694.12 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 695.10
G) 3-amino-6-(3, the 4-difluorobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
To be similar to embodiment 29g) method of (method B) is synthetic, adopts [6-(3, the 4-difluorobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester as raw material.Obtain target product, MW=560.09 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 561.13
H) N-[1-(2,4 dichloro benzene alkylsulfonyl)-6-(3, the 4-difluorobenzyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopropane carboxamide
Synthetic with the method that is similar to embodiment 22, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3, the 4-difluorobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=628.11 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 629.18
Embodiment 165
N-[1-(2,4 dichloro benzene alkylsulfonyl)-6-(3, the 4-difluorobenzyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] the tetramethylene methane amide
Structure:
Synthetic with the method that is similar to embodiment 30, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3, the 4-difluorobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=642.13 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 643.21
Embodiment 166
N-[1-(2,4 dichloro benzene alkylsulfonyl)-6-(3, the 4-difluorobenzyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopentane formamide
Structure:
Synthetic with the method that is similar to embodiment 31, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3, the 4-difluorobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=656.14 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 657.21
Embodiment 167
N-[1-(2,4 dichloro benzene alkylsulfonyl)-6-(3, the 4-difluorobenzyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclohexane carboxamide
Structure:
Synthetic with the method that is similar to embodiment 32, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3, the 4-difluorobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=670.16 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 671.24
Embodiment 168
N-[1-(2,4 dichloro benzene alkylsulfonyl)-6-(3, the 4-difluorobenzyl)-8-sec.-propyl-4,7-dioxo-octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] Toluidrin
Structure:
Synthetic with the method that is similar to embodiment 26, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3, the 4-difluorobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=638.06 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 639.02
Embodiment 169
1-(2,4 dichloro benzene alkylsulfonyl)-6-(3, the 4-difluorobenzyl)-3-dimethylamino-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 72, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3, the 4-difluorobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=588.12 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 589.10
Embodiment 170
1-(2,4 dichloro benzene alkylsulfonyl)-6-(3, the 4-difluorobenzyl)-8-sec.-propyl-3-tetramethyleneimine-1-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 74, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3, the 4-difluorobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=614.13 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 615.10
Embodiment 171
1-(2,4 dichloro benzene alkylsulfonyl)-6-(3, the 4-difluorobenzyl)-8-sec.-propyl-3-piperidines-1-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 59, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3, the 4-difluorobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=628.15 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 629.22
Embodiment 172
1-(2,4 dichloro benzene alkylsulfonyl)-6-(3, the 4-difluorobenzyl)-8-sec.-propyl-3-morpholine-4-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 60, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3, the 4-difluorobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=630.13 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 631.10
Embodiment 173
A) 2-allyloxy carbonyl ammonia base-3-(2,4 difluorobenzene base) propionic acid
To be similar to embodiment 21a) method synthetic, adopt 2-amino-3-(2,4 difluorobenzene base) propionic acid as raw material.Obtain target product, MW=285.08 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 286.05
B) 2-(2,4 difluorobenzene base)-1-[(2,2-diethoxy ethyl) and the sec.-propyl formamyl] ethyl } the carboxylamine allyl ester.
To be similar to embodiment 21b) method synthetic, adopt 2-allyloxy carbonyl ammonia base-3-(2,4 difluorobenzene base) propionic acid as raw material.Obtain target product, MW=442.23 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 443.2
C) 2-amino-3-(2,4 difluorobenzene base)-N-(2,2-diethoxy ethyl)-N-sec.-propyl propionic acid amide
To be similar to embodiment 21c) method synthetic, adopt { 2-(2,4 difluorobenzene base)-1-[(2,2-diethoxy ethyl) sec.-propyl formamyl] ethyl } carboxylamine allyl ester as raw material.Obtain target product, MW=358.21 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 359.2
D) (2-(2,4 dichloro benzene sulfuryl amino)-1-{2-(2,4 difluorobenzene base)-1-[(2,2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical } ethyl) the carboxylamine benzyl ester
To be similar to embodiment 29b) method synthetic, adopt 2-amino-3-(2,4 difluorobenzene base)-N-(2,2-diethoxy ethyl)-N-sec.-propyl propionic acid amide as raw material.Obtain target product, MW=786.21 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 787.30
E) [6-(2, the 4-difluorobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester
To be similar to embodiment 21f) method synthetic; (2-(2 in employing; 4-dichlorobenzene sulfuryl amino)-and 1-{2-(2,4 difluorobenzene base)-1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl] the ethylamino formyl radical } ethyl) the carboxylamine benzyl ester is as raw material.Obtain target product, MW=694.12 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 695.05
F) 3-amino-6-(2, the 4-difluorobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
To be similar to embodiment 21g) method synthetic; (2-(2 in employing; 4-dichlorobenzene sulfuryl amino)-and 1-{2-(2,4 difluorobenzene base)-1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl] the ethylamino formyl radical } ethyl) the carboxylamine benzyl ester is as raw material.Obtain target product, MW=560.09 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 561.0
G) N-[1-(2,4 dichloro benzene alkylsulfonyl)-6-(2, the 4-difluorobenzyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopropane carboxamide
To be similar to embodiment 29e) method of (method A) is synthetic, adopts also [1,2-a] pyrimidine-4 of 3-amino-6-(2, the 4-difluorobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, and the 7-diketone is as raw material.Obtain target product, MW=628.11 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 629.31
Embodiment 174
1-(2,4 dichloro benzene alkylsulfonyl)-6-(2, the 4-difluorobenzyl)-3-dimethylamino-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 72, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(2, the 4-difluorobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=588.12 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 589.07
Embodiment 175
3-azetidine-1-base-1-(2,4 dichloro benzene alkylsulfonyl)-6-(2, the 4-difluorobenzyl)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 73, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(2, the 4-difluorobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=600.12 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 600.81
Embodiment 176
A) [1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl]-2-pentafluorophenyl group ethyl] carboxylamine 9H-fluorenes-9-ylmethyl ester
To be similar to embodiment 29a) method of (method B) is synthetic, adopts N-Fmoc-2, and 3,4,5,6-F
5-Phe-OH is as raw material.Obtain target product, MW=634.25 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 657.17
B) 2-amino-3-pentafluorophenyl group-N-(2,2-diethoxy ethyl)-N-sec.-propyl propionic acid amide
To be similar to embodiment 29b) method of (method B) is synthetic, adopt [1-[(2,2-diethoxy ethyl) sec.-propyl formamyl]-2-pentafluorophenyl group ethyl] carboxylamine 9H-fluorenes-9-ylmethyl ester is as raw material.Obtain target product, MW=412.18 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 435.17
C) (2-benzyloxycarbonyl amino-2-{2-(pentafluorophenyl group)-1-[(2,2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical } ethyl) carboxylamine 9H-fluorenes-9-ylmethyl ester
To be similar to embodiment 29c) method of (method B) is synthetic, adopts 2-amino-3-pentafluorophenyl group-N-(2,2-diethoxy ethyl)-N-sec.-propyl propionic acid amide as raw material.Obtain target product, MW=854.33 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 877.41
D) (2-amino-1-{2-pentafluorophenyl group-1-[(2,2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical } ethyl) the carboxylamine benzyl ester
To be similar to embodiment 29d) method of (method B) is synthetic; adopt (2-benzyloxycarbonyl amino-2-{2-pentafluorophenyl group-1-[(2,2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical } ethyl) carboxylamine 9H-fluorenes-9-ylmethyl ester is as raw material.Obtain target product, MW=632.26 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 655.24
E) [1-{2-pentafluorophenyl group-1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl] the ethylamino formyl radical }-2-(2,4 dichloro benzene sulfuryl amino) ethyl] the carboxylamine benzyl ester
To be similar to embodiment 29e) method of (method B) is synthetic, adopts (2-amino-1-{2-pentafluorophenyl group-1-[(2,2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical } ethyl) the carboxylamine benzyl ester is as raw material.Obtain target product, MW=840.18 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 863.18.
F) [1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo-6-pentafluorophenyl group methyl octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester
To be similar to embodiment 29f) method synthetic, adopt (2-(2,4 dichloro benzene sulfuryl amino)-1-{1-[(2,2-diethoxy ethyl) sec.-propyl formamyl]-2-pentafluorophenyl group ethylamino formyl radical ethyl) the carboxylamine benzyl ester is as raw material.Obtain target product, MW=748.09 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 749.15
G) 3-amino-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-pentafluorophenyl group methyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
To be similar to embodiment 29g) method synthetic, adopt [1-(2,4-two chloro-benzenesulfonyls)-8-sec.-propyl-4,7-dioxo-6-pentafluorophenyl group methyl octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester as raw material.Obtain target product, MW=614.06 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 615.05
H) N-[1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo-6-pentafluorophenyl group methyl octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] tetramethyleneimine-2-methane amide
Synthetic with the method that is similar to embodiment 40, adopt also [1,2-a] pyrimidine-4 of 3-amino-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-pentafluorophenyl group methyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=711.11 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 712.06
Embodiment 177
1-(2,4 dichloro benzene alkylsulfonyl)-3-dimethylamino-8-sec.-propyl-6-pentafluorophenyl group methyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 72, adopt also [1,2-a] pyrimidine-4 of 3-amino-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-pentafluorophenyl group methyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=620.12 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 621.09
Embodiment 178
3-azetidine-1-base-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-pentafluorophenyl group methyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 73, adopt also [1,2-a] pyrimidine-4 of 3-amino-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-pentafluorophenyl group methyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=654.09 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 655.1
Embodiment 179
1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-pentafluorophenyl group methyl-3-tetramethyleneimine-1-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 74, adopt also [1,2-a] pyrimidine-4 of 3-amino-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-pentafluorophenyl group methyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=668.11 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 669.11
Embodiment 180
1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-pentafluorophenyl group methyl-3-piperidines-1-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 59, adopt also [1,2-a] pyrimidine-4 of 3-amino-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-pentafluorophenyl group methyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=682.12 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 683.09
Embodiment 181
1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-3-morpholine-4-base-6-pentafluorophenyl group methyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 60, adopt also [1,2-a] pyrimidine-4 of 3-amino-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-pentafluorophenyl group methyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=684.10 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 685.01
Embodiment 182
A) 1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl]-2-pyridin-3-yl ethyl } carboxylamine 9H-fluorenes-9-ylmethyl ester
To be similar to embodiment 29a) method of (method B) is synthetic, adopts Fmoc-3-pyridyl L-Ala as raw material.Obtain target product, MW=545.29 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 546.24
B) 2-amino-N-(2,2-diethoxy ethyl)-N-sec.-propyl-3-pyridin-3-yl propionic acid amide
To be similar to embodiment 29b) method of (method B) is synthetic, adopt 1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl]-2-pyridin-3-yl ethyl } carboxylamine 9H-fluorenes-9-ylmethyl ester is as raw material.Obtain target product, MW=323.22 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 324.22
C) [1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl]-2-pyridin-3-yl ethylamino formyl radical]-2-(9H-fluorenes-9-ylmethoxy carbonylamino) ethyl] the carboxylamine benzyl ester
To be similar to embodiment 29c) method of (method B) is synthetic, adopts 2-amino-N-(2,2-diethoxy ethyl)-N-sec.-propyl-3-pyridin-3-yl propionic acid amide as raw material.Obtain target product, MW=765.37 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 766.31
D) (2-amino-and 1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl]-2-pyridin-3-yl ethylamino formyl radical } ethyl) the carboxylamine benzyl ester
To be similar to embodiment 29d) method of (method B) is synthetic; adopt [1-[(2,2-diethoxy ethyl) sec.-propyl formamyl]-2-pyridin-3-yl ethylamino formyl radical]-2-(9H-fluorenes-9-ylmethoxy carbonylamino) ethyl] the carboxylamine benzyl ester is as raw material.Obtain target product, MW=543.31 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 544.4
E) (2-(2,4 dichloro benzene sulfuryl amino)-1-{1-[(2,2-diethoxy ethyl) sec.-propyl formamyl]-2-pyridin-3-yl ethylamino formyl radical } ethyl) the carboxylamine benzyl ester
To be similar to embodiment 29e) method of (method B) is synthetic, adopts (2-amino-{ 1-[(2,2-diethoxy ethyl) sec.-propyl formamyl]-2-pyridin-3-yl ethylamino formyl radical } ethyl) the carboxylamine benzyl ester is as raw material.Obtain target product, MW=751.22 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 752.19.
F) [1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo-6-pyridin-3-yl methyl octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester
To be similar to embodiment 29f) method synthetic; (2-(2 in employing; 4-two chloro-benzenesulfonyl amino)-and 1-{1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl]-2-pyridin-3-yl ethylamino formyl radical } ethyl) the carboxylamine benzyl ester is as raw material.Obtain target product, MW=659.14 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 660.10
G) 3-amino-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-pyridin-3-yl methyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
To be similar to embodiment 29g) method synthetic, adopt [1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo-6-pyridin-3-yl methyl octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester as raw material.Obtain target product, MW=525.10 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 526.1
H) N-[1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo-6-pyridin-3-yl methyl octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] ethanamide
To be similar to embodiment 21h) method synthetic, adopt also [1,2-a] pyrimidine-4 of 3-amino-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-pyridin-3-yl methyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=567.11 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 568.11
Embodiment 183
N-[1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo-6-pyridin-3-yl methyl octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopropane carboxamide
Structure:
Synthetic with the method that is similar to embodiment 22, adopt also [1,2-a] pyrimidine-4 of 3-amino-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-pyridin-3-yl methyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=593.13 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 594.13
Embodiment 184
N-[1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo-6-pyridin-3-yl methyl octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] the tetramethylene methane amide
Structure:
Synthetic with the method that is similar to embodiment 30, adopt also [1,2-a] pyrimidine-4 of 3-amino-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-pyridin-3-yl methyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=607.14 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 608.15
Embodiment 185
N-[1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo-6-pyridin-3-yl methyl octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopentane formamide
Structure:
Synthetic with the method that is similar to embodiment 31, adopt also [1,2-a] pyrimidine-4 of 3-amino-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-pyridin-3-yl methyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=621.16 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 622.17
Embodiment 186
N-[1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo-6-pyridin-3-yl methyl octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] tetramethyleneimine-2-methane amide
Structure:
Synthetic with the method that is similar to embodiment 40, adopt also [1,2-a] pyrimidine-4 of 3-amino-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-pyridin-3-yl methyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=622.15 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 623.14
Embodiment 187
N-[1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo-6-pyridin-3-yl methyl octahydro pyrazine is [1,2-a] pyrimidin-3-yl also]-4-dimethylamino yl-benzamide
Structure:
Synthetic with the method that is similar to embodiment 25, adopt also [1,2-a] pyrimidine-4 of 3-amino-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-pyridin-3-yl methyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=672.17 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 673.18
Embodiment 188
N-[1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo-6-pyridin-3-yl methyl octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] niacinamide
Structure:
Synthetic with the method that is similar to embodiment 50, adopt also [1,2-a] pyrimidine-4 of 3-amino-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-pyridin-3-yl methyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=630.12 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 631.16
Embodiment 189
The 1-tertiary butyl-3-[1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo-6-pyridin-3-yl methyl octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] urea
Structure:
Synthetic with the method that is similar to embodiment 28, adopt also [1,2-a] pyrimidine-4 of 3-amino-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-pyridin-3-yl methyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=624.17 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 625.1
Embodiment 190
N-[1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo-6-pyridin-3-yl methyl octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] Toluidrin
Structure:
Synthetic with the method that is similar to embodiment 26, adopt also [1,2-a] pyrimidine-4 of 3-amino-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-pyridin-3-yl methyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=603.08 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 604.06
Embodiment 191
N-[1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo-6-pyridin-3-yl methyl octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] the cyclopropane sulphonamide
Structure:
Synthetic with the method that is similar to embodiment 27, adopt also [1,2-a] pyrimidine-4 of 3-amino-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-pyridin-3-yl methyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=629.09 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 630.09
Embodiment 192
1-(2,4 dichloro benzene alkylsulfonyl)-3-dimethylamino-8-sec.-propyl-6-pyridin-3-yl methyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 72, adopt also [1,2-a] pyrimidine-4 of 3-amino-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-pyridin-3-yl methyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=553.13 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 554.08
Embodiment 193
A) 1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl]-2-pyridin-4-yl ethyl } carboxylamine 9H-fluorenes-9-ylmethyl ester
To be similar to embodiment 29a) method of (method B) is synthetic, adopts Fmoc-4-pyridyl L-Ala as raw material.Obtain target product, MW=545.29 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 546.26
B) 2-amino-N-(2,2-diethoxy ethyl)-N-sec.-propyl-3-pyridin-4-yl propionic acid amide
To be similar to embodiment 29b) method of (method B) is synthetic, adopt 1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl]-2-pyridin-4-yl ethyl } carboxylamine 9H-fluorenes-9-ylmethyl ester is as raw material.Obtain target product, MW=323.22 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 324.22
C) [1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl]-2-pyridin-4-yl ethylamino formyl radical]-2-(9H-fluorenes-9-ylmethoxy carbonylamino) ethyl] the carboxylamine benzyl ester
To be similar to embodiment 29c) method of (method B) is synthetic, adopts 2-amino-N-(2,2-diethoxy ethyl)-N-sec.-propyl-3-pyridin-4-yl propionic acid amide as raw material.Obtain target product, MW=809.36 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 832.3
D) (2-amino-and 1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl]-2-pyridin-4-yl ethylamino formyl radical } ethyl) the carboxylamine benzyl ester
To be similar to embodiment 29d) method of (method B) is synthetic; adopt [1-[(2,2-diethoxy ethyl) sec.-propyl formamyl]-2-pyridin-4-yl ethylamino formyl radical]-2-(9H-fluorenes-9-ylmethoxy carbonylamino) ethyl] the carboxylamine benzyl ester is as raw material.Obtain target product, MW=543.31 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 544.4
E) (2-(2,4 dichloro benzene sulfuryl amino)-1-{1-[(2,2-diethoxy ethyl) sec.-propyl formamyl]-2-pyridin-4-yl ethylamino formyl radical } ethyl) the carboxylamine benzyl ester
To be similar to embodiment 29e) method of (method B) is synthetic, adopts (2-amino-{ 1-[(2,2-diethoxy ethyl) sec.-propyl formamyl]-2-pyridin-4-yl ethylamino formyl radical } ethyl) the carboxylamine benzyl ester is as raw material.Obtain target product, MW=751.22 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 752.19.
F) [1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo-6-pyridin-4-yl methyl octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester
To be similar to embodiment 29f) method of (method B) is synthetic; (2-(2 in employing; 4-two chloro-benzenesulfonyl amino)-and 1-{1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl]-2-pyridin-4-yl ethylamino formyl radical } ethyl) the carboxylamine benzyl ester is as raw material.Obtain target product, MW=659.14 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 660.17
G) 3-amino-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-pyridin-4-yl methyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
To be similar to embodiment 29g) method of (method B) is synthetic, adopts [1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo-6-pyridin-4-yl methyl octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester as raw material.Obtain target product, MW=525.10 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 526.10
H) N-[1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo-6-pyridin-4-yl methyl octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] ethanamide
To be similar to embodiment 21h) method synthetic, adopt also [1,2-a] pyrimidine-4 of 3-amino-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-pyridin-4-yl methyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=567.11 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 568.13
Embodiment 194
N-[1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo-6-pyridin-4-yl methyl octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopropane carboxamide
Structure:
Synthetic with the method that is similar to embodiment 22, adopt also [1,2-a] pyrimidine-4 of 3-amino-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-pyridin-4-yl methyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=593.13 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 594.13
Embodiment 195
N-[1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo-6-pyridin-4-yl methyl octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopentane formamide
Structure:
Synthetic with the method that is similar to embodiment 31, adopt also [1,2-a] pyrimidine-4 of 3-amino-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-pyridin-4-yl methyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=621.16 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 622.17
Embodiment 196
N-[1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo-6-pyridin-4-yl methyl octahydro pyrazine is [1,2-a] pyrimidin-3-yl also]-4-dimethylamino yl-benzamide
Structure:
Synthetic with the method that is similar to embodiment 25, adopt also [1,2-a] pyrimidine-4 of 3-amino-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-pyridin-4-yl methyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=672.17 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 673.2
Embodiment 197
The 1-tertiary butyl-3-[1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo-6-pyridin-4-yl methyl octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] urea
Structure:
Synthetic with the method that is similar to embodiment 28, adopt also [1,2-a] pyrimidine-4 of 3-amino-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-pyridin-4-yl methyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=624.17 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 625.2
Embodiment 198
N-[1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo-6-pyridin-4-yl methyl octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] Toluidrin
Structure:
Synthetic with the method that is similar to embodiment 26, adopt also [1,2-a] pyrimidine-4 of 3-amino-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-pyridin-4-yl methyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=603.08 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 604.08
Embodiment 199
N-[1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo-6-pyridin-4-yl methyl octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] the cyclopropane sulphonamide
Structure:
Synthetic with the method that is similar to embodiment 27, adopt also [1,2-a] pyrimidine-4 of 3-amino-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-pyridin-4-yl methyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=629.09 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 630.06
Embodiment 200
A) [1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl]-2-(4-nitrophenyl) ethyl] carboxylamine 9H-fluorenes-9-ylmethyl ester
To be similar to embodiment 29a) method of (method B) is synthetic, adopts N-Fmoc-4-nitro-Phe-OH as raw material.Obtain target product, MW=589.28 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 590.3
B) 2-amino-N-(2,2-diethoxy ethyl)-N-sec.-propyl-3-(4-nitrophenyl) propionic acid amide
To be similar to embodiment 29b) method of (method B) is synthetic, adopt [1-[(2,2-diethoxy ethyl) sec.-propyl formamyl]-2-(4-nitrophenyl) ethyl] carboxylamine 9H-fluorenes-9-ylmethyl ester is as raw material.
C) [1-[1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl]-2-(4-nitrophenyl) ethylamino formyl radical]-2-(9H-fluorenes-9-ylmethoxy carbonylamino) ethyl] the carboxylamine benzyl ester
To be similar to embodiment 29c) method of (method B) is synthetic, adopts 2-amino-N-(2,2-diethoxy ethyl)-N-sec.-propyl-3-(4-nitrophenyl) propionic acid amide as raw material.Obtain target product, MW=765.37 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 766.31
D) 2-amino-1-[1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl]-2-(4-nitrophenyl) ethylamino formyl radical] ethyl } the carboxylamine benzyl ester
To be similar to embodiment 29d) method of (method B) is synthetic; adopt 1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl]-2-pyridin-4-yl ethylamino formyl radical }-2-(9H-fluorenes-9-ylmethoxy carbonylamino) ethyl] the carboxylamine benzyl ester is as raw material.Obtain target product, MW=587.68 (calculated value, single isotropic substance of planting); Measured value (M-OEt): 542.
E) 2-(2,4 dichloro benzene sulfuryl amino)-1-[1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl]-2-(4-nitrophenyl) ethylamino formyl radical] ethyl } the carboxylamine benzyl ester
To be similar to embodiment 29e) method of (method B) is synthetic, adopt 2-amino-1-[1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl]-2-(4-nitrophenyl) ethylamino formyl radical] ethyl } the carboxylamine benzyl ester is as raw material.Obtain target product, MW=795.21 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 818.21
F) [1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-(4-nitrobenzyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester
To be similar to embodiment 29f) method of (method B) is synthetic; { 2-(2 in employing; 4-dichlorobenzene sulfuryl amino)-and 1-[1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl]-2-(4-nitrophenyl) ethylamino formyl radical] ethyl } the carboxylamine benzyl ester is as raw material.Obtain target product, MW=703.13 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 704.1
G) 3-amino-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-(4-nitrobenzyl) hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
To be similar to embodiment 29g) method of (method B) is synthetic, adopts [1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-(4-nitrobenzyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester as raw material.Obtain target product, MW=525.10 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 526.10
H) 1-(2,4 dichloro benzene alkylsulfonyl)-3-dimethylamino-8-sec.-propyl-6-(4-nitrobenzyl) hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
With 0.15ml acetate, 0.15ml formaldehyde (37% H then
2O solution) and 1ml sodium cyanoborohydride (the THF solution of 1M) add to also [1,2-a] pyrimidine-4 of 100mg (0.17mmol) 3-amino-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-(4-nitrobenzyl) hexahydropyrazine, in the 5ml methanol solution of 7-diketone.Under room temperature, stirred the mixture 1 hour, vacuum concentration is with ethyl acetate dilution and water and salt water washing.Dry then (MgSO
4) and vacuum concentration.Residue is through 12g SiO
2(eluent: ethyl acetate/methanol, gradient: chromatography 0-5% methyl alcohol).Obtain the 25mg dimethyl amine.Ether with 1ml 1MHCl is handled amine.With the mixture vacuum concentration.Obtain 35mg dimethyl amine HCl salt, be white solid.LC/MS MW=597.12 (calculated value, single isotropic substance of planting) measured value (M
+H)=598.12
Embodiment 201
N-[6-(4-aminobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopentane formamide
Be similar to embodiment 31,3-amino-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-(4-nitrobenzyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, and 7-two reactive ketones produce cyclopentane formamide.The latter further reacts with following method:
71mg (0.3mmol) tin chloride (II) is added to 50mg (0.07mmol) N-[1-(2; 4-dichlorobenzene alkylsulfonyl)-8-sec.-propyl-6-(4-nitrobenzyl)-4; 7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] in the 3ml ethanolic soln of cyclopentane formamide (embodiment 200).In 100 ℃, in microwave oven internal heating mixture 5 minutes and vacuum concentration.Residue dilutes with ethyl acetate, through diatomite filtration and vacuum concentration.Then through 4g SiO
2(eluent: ethyl acetate/heptane, gradient: the 0-100% ethyl acetate) chromatography.Obtain 25mg target aniline, be oily matter.LC/MS MW (calculated value, single isotropic substance of planting)=635.17 and measured value (M
+H)=636.14.
Embodiment 202
6-(4-aminobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-3-dimethylamino-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Be similar to embodiment 201 reduction embodiment 202, adopt also [1,2-a] pyrimidine-4 of compound 1-(2,4 dichloro benzene alkylsulfonyl)-3-dimethylamino-8-sec.-propyl-6-(4-nitrobenzyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=567.15 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 568.1
Embodiment 203
6-(4-aminobenzyl)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-3-piperidines-1-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Synthetic with the method that is similar to embodiment 59, adopt also [1,2-a] pyrimidine-4 of 3-amino-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-6-(4-nitrobenzyl) hexahydropyrazine, the 7-diketone produces corresponding piperidine derivative as raw material.Then as reduction nitryl group as described in the embodiment 201.Obtain target product, MW=607.18 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 608.2
Embodiment 204
4-chloro-N-{4-[3-(pentamethylene carbonylamino)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidine-6-ylmethyl also] phenyl } benzamide
With 5mg (0.04mmol) diisopropyl ethyl amine, 7mg (0.04mmol) 4-chloro-benzoyl chloride adds to 25mg (0.03mmol) [6-(4-aminobenzyl)-1-(2 then; 4-dichlorobenzene alkylsulfonyl)-8-sec.-propyl-4; 7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] in the 1ml dichloromethane solution of carboxylamine benzyl ester.Under room temperature, stir the mixture and spend the night, with methylene dichloride dilution and use the salt water washing.Separate organic layer, dry (MgSO
4) and vacuum concentration.Residue is through 8g SiO
2(eluent: ethyl acetate/heptane, gradient: the 0-100% ethyl acetate) chromatography.Obtain the 28.5mg acid amides, be oily matter.This compound is directly used in next step.
In the 2ml acetonitrile solution of 0 ℃ of Cbz-carbamate that 28mg (0.14mmol) TMSI is added to 28.5mg (0.03mmol) ubi supra.Mixture places under the room temperature and spends the night, and vacuum concentration filters with methyl alcohol dilution and through SCX (5g) post (eluent: 5ml methyl alcohol, the methanol solution of 15ml 7N ammonia then).Obtain the 18mg targeted amine, be brown oil.This compound is used for next step without being further purified.
With 3mg (0.02mmol) DIEA, 2.7mg (0.02mmol) pentamethylene dicarbonyl chloride adds in the 1ml DCM solution of compound of 18mg (0.02mmol) deprotection then.Under room temperature, stir the mixture and spend the night and vacuum concentration.Residue is dissolved in the 2ml ethyl acetate, washes with water, dry (MgSO
4) and vacuum concentration.Then through 4g SiO
2(eluent: ethyl acetate/heptane, gradient: the 0-100% ethyl acetate) chromatography.Obtain 11mg target acid amides, be oily matter.LC/MS MW=773.16 (calculated value, single isotropic substance of planting); Measured value (M
+H)=774.12
Embodiment 205
A) cyclopropyl (2,2-diethoxy ethyl) amine
In 120 ℃, in encloses container, 2.36g (12mmol) 2-bromoacetaldehyde diethyl acetal and 4.94g (86.6mmol) cyclopropylamine solution were heated 2 hours.Reaction mixture is cooled to room temperature and with the dilution of 75ml ether and with the 5%NaOH aqueous solution, water and saturated nacl aqueous solution wash then.Organic layer drying (MgSO
4) and vacuum concentration.Residue vacuum (130 ℃-140 ℃) distillation.Obtain the 2.01g target compound.LC/MS M+H＝173
B) [1-[cyclopropyl (2,2-diethoxy ethyl) formamyl]-2-(4-bromophenyl) ethyl] carboxylamine 9H-fluorenes-9-ylmethyl ester
To be similar to embodiment 29a) method of (method B) is synthetic, adopts N-Fmoc-4-Br-Phe-OH and cyclopropyl (2,2-diethoxy ethyl) amine as raw material.Obtain target product, MW=629.19 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 643.16
C) 2-amino-3-(4-bromophenyl)-N-cyclopropyl-N-(2,2-diethoxy ethyl) propionic acid amide
To be similar to embodiment 29b) method of (method B) is synthetic, adopts [1-[cyclopropyl (2,2-diethoxy ethyl) formamyl]-2-(4-bromophenyl) ethyl] carboxylamine 9H-fluorenes-9-ylmethyl ester is as raw material.Obtain target product, MW=398.12 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 399.11
D) [1-{2-(4-bromophenyl)-1-[cyclopropyl (2,2-diethoxy ethyl) formamyl] ethylamino formyl radical }-2-(9H-fluorenes-9-ylmethoxy carbonylamino) ethyl] the carboxylamine benzyl ester
To be similar to embodiment 29c) method of (method B) is synthetic, adopts 2-amino-3-(4-bromophenyl)-N-cyclopropyl-N-(2,2-diethoxy ethyl) propionic acid amide as raw material.Obtain target product, MW=840.27 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 863.23
E) (2-amino-1-{2-(4-bromophenyl)-1-[cyclopropyl (2,2-diethoxy ethyl) formamyl] the ethylamino formyl radical } ethyl) the carboxylamine benzyl ester.
To be similar to embodiment 29d) method of (method B) is synthetic; adopt [1-{2-(4-bromophenyl)-1-[cyclopropyl (2,2-diethoxy ethyl) formamyl] ethylamino formyl radical }-2-(9H-fluorenes-9-ylmethoxy carbonylamino) ethyl] the carboxylamine benzyl ester is as raw material.Obtain target product, MW=618.21 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 619.2
F) [1-{2-(4-bromophenyl)-1-[cyclopropyl (2,2-diethoxy ethyl) formamyl] ethylamino formyl radical }-2-(2,4 dichloro benzene sulfuryl amino) ethyl] the carboxylamine benzyl ester
To be similar to embodiment 29e) method of (method B) is synthetic, adopts (2-amino-1-{2-(4-bromophenyl)-1-[cyclopropyl (2,2-diethoxy ethyl) formamyl] ethylamino formyl radical } ethyl) carboxylamine benzyl ester as raw material.Obtain target product, MW=826.12 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 849.14.
G) [6-(4-bromobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester.
To be similar to embodiment 29f) method of (method B) is synthetic; adopt [1-{2-(4-bromophenyl)-1-[cyclopropyl (2; 2-diethoxy ethyl) formamyl] the ethylamino formyl radical }-2-(2,4 dichloro benzene sulfuryl amino) ethyl] the carboxylamine benzyl ester is as raw material.Obtain target product, MW=734.04 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 735.02
H) 3-amino-6-(4-bromobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
To be similar to embodiment 29g) method of (method B) is synthetic, adopts [6-(4-bromobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester as raw material.Obtain target product, MW=600.0 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 600.99
I) N-[6-(4-bromobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] ethanamide
To be similar to embodiment 21h) method synthetic, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=642.01 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 643.02
Embodiment 206
N-[6-(4-bromobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopropane carboxamide
Structure:
Synthetic with the method that is similar to embodiment 22, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=668.03 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 669.04
Embodiment 207
N-[6-(4-bromobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] the tetramethylene methane amide
Structure:
Synthetic with the method that is similar to embodiment 30, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=682.04 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 683.06
Embodiment 208
N-[6-(4-bromobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopentane formamide
Structure:
Synthetic with the method that is similar to embodiment 31, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=696.06 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 697.08
Embodiment 209
N-[6-(4-bromobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] tetramethyleneimine-2-methane amide
Structure:
Synthetic with the method that is similar to embodiment 40, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=697.05 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 698.02
Embodiment 210
N-[6-(4-bromobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also]-4-dimethylamino yl-benzamide
Structure:
Synthetic with the method that is similar to embodiment 47, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=747.07 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 748.08
Embodiment 211
N-[6-(4-bromobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] niacinamide
Structure:
Synthetic with the method that is similar to embodiment 50, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=705.02 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 706.06
Embodiment 212
1-[6-(4-bromobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also]-the 3-tert butyl urea
Structure:
Synthetic with the method that is similar to embodiment 28, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=699.07 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 700.09
Embodiment 213
N-[6-(4-bromobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] Toluidrin
Structure:
Synthetic with the method that is similar to embodiment 26, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=677.98 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 679.0
Embodiment 214
N-[6-(4-bromobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] the cyclopropane sulphonamide
Structure:
Synthetic with the method that is similar to embodiment 27, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=703.99 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 705.01
Embodiment 215
6-(4-bromobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-3-dimethylamino hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 72, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=628.03 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 629.04
Embodiment 216
3-azetidine-1-base-6-(4-bromobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 73, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=636.08 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 637.1
Embodiment 217
6-(4-bromobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-3-tetramethyleneimine-1-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 74, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=654.05 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 655.04
Embodiment 218
6-(4-bromobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-3-piperidines-1-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 59, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=668.06 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 669.08
Embodiment 219
6-(4-bromobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-3-morpholine-4-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 60, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=670.04 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 670.97
Embodiment 220
A) [1-{2-(4-bromophenyl)-1-[cyclopropyl (2,2-diethoxy ethyl) formamyl] ethylamino formyl radical }-2-(5-chloro-2-anisole sulfuryl amino) ethyl] the carboxylamine benzyl ester
To be similar to embodiment 29e) method of (method B) is synthetic, adopts (2-amino-1-{2-(4-bromophenyl)-1-[cyclopropyl (2,2-diethoxy ethyl) formamyl] ethylamino formyl radical } ethyl) carboxylamine benzyl ester as raw material.Obtain target product, MW=822.17 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 845.19
B) [6-(4-bromobenzyl)-1-(5-chloro-2-anisole alkylsulfonyl)-8-cyclopropyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester
To be similar to embodiment 29f) method of (method B) is synthetic; adopt [1-{2-(4-bromophenyl)-1-[cyclopropyl (2,2-diethoxy ethyl) formamyl] ethylamino formyl radical }-2-(5-chloro-2-anisole sulfuryl amino) ethyl] the carboxylamine benzyl ester is as raw material.Obtain target product, MW=730.09 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 731.09
C) 3-amino-6-(4-bromobenzyl)-1-(5-chloro-2-anisole alkylsulfonyl)-8-cyclopropyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
To be similar to embodiment 29g) method of (method B) is synthetic, adopts [6-(4-bromobenzyl)-1-(5-chloro-2-anisole alkylsulfonyl)-8-cyclopropyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester as raw material.Obtain target product, MW=596.05 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 597.04
D) N-[6-(4-bromobenzyl)-1-(5-chloro-2-anisole alkylsulfonyl)-8-cyclopropyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] ethanamide
To be similar to embodiment 21h) method synthesize, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-1-(5-chloro-2-anisole alkylsulfonyl)-8-cyclopropyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=638.06 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 639.11
Embodiment 221
N-[6-(4-bromobenzyl)-1-(5-chloro-2-anisole alkylsulfonyl)-8-cyclopropyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopropane carboxamide
Structure:
Synthetic with the method that is similar to embodiment 22, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-1-(5-chloro-2-anisole alkylsulfonyl)-8-cyclopropyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=664.08 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 665.13
Embodiment 222
N-[6-(4-bromobenzyl)-1-(5-chloro-2-anisole alkylsulfonyl)-8-cyclopropyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] the tetramethylene methane amide
Structure:
Synthetic with the method that is similar to embodiment 30, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-1-(5-chloro-2-anisole alkylsulfonyl)-8-cyclopropyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=678.09 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 679.15
Embodiment 223
N-[6-(4-bromobenzyl)-1-(5-chloro-2-anisole alkylsulfonyl)-8-cyclopropyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopentane formamide
Structure:
Synthetic with the method that is similar to embodiment 31, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-1-(5-chloro-2-anisole alkylsulfonyl)-8-cyclopropyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=692.11 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 693.16
Embodiment 224
N-[6-(4-bromobenzyl)-1-(5-chloro-2-anisole alkylsulfonyl)-8-cyclopropyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] tetramethyleneimine-2-methane amide
Structure:
Synthetic with the method that is similar to embodiment 40, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-1-(5-chloro-2-anisole alkylsulfonyl)-8-cyclopropyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=693.10 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 694.06
Embodiment 225
N-[6-(4-bromobenzyl)-1-(5-chloro-2-anisole alkylsulfonyl)-8-cyclopropyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also]-4-dimethylamino yl-benzamide
Structure:
Synthetic with the method that is similar to embodiment 25, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-1-(5-chloro-2-anisole alkylsulfonyl)-8-cyclopropyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=743.12 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 744.17
Embodiment 226
N-[6-(4-bromobenzyl)-1-(5-chloro-2-anisole alkylsulfonyl)-8-cyclopropyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] niacinamide
Structure:
Synthetic with the method that is similar to embodiment 50, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-1-(5-chloro-2-anisole alkylsulfonyl)-8-cyclopropyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=701.07 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 702.08
Embodiment 227
1-[6-(4-bromobenzyl)-1-(5-chloro-2-anisole alkylsulfonyl)-8-cyclopropyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also]-the 3-tert butyl urea
Structure:
Synthetic with the method that is similar to embodiment 28, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-1-(5-chloro-2-anisole alkylsulfonyl)-8-cyclopropyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=695.12 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 696.17
Embodiment 228
N-[6-(4-bromobenzyl)-1-(5-chloro-2-anisole alkylsulfonyl)-8-cyclopropyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] Toluidrin
Structure:
Synthetic with the method that is similar to embodiment 26, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-1-(5-chloro-2-anisole alkylsulfonyl)-8-cyclopropyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=674.03 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 675.08
Embodiment 229
N-[6-(4-bromobenzyl)-1-(5-chloro-2-anisole alkylsulfonyl)-8-cyclopropyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] the cyclopropane sulphonamide
Structure:
Synthetic with the method that is similar to embodiment 27, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-1-(5-chloro-2-anisole alkylsulfonyl)-8-cyclopropyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=700.04 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 701.1
Embodiment 230
6-(4-bromobenzyl)-1-(5-chloro-2-anisole alkylsulfonyl)-8-cyclopropyl-3-dimethylamino hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 72, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-1-(5-chloro-2-anisole alkylsulfonyl)-8-cyclopropyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=743.12 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 744.17
Embodiment 231
3-azetidine-1-base-6-(4-bromobenzyl)-1-(5-chloro-2-anisole alkylsulfonyl)-8-cyclopropyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 73, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-1-(5-chloro-2-anisole alkylsulfonyl)-8-cyclopropyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=640.03 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 641.0
Embodiment 232
6-(4-bromobenzyl)-1-(5-chloro-2-anisole alkylsulfonyl)-8-cyclopropyl-3-tetramethyleneimine-1-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 74, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-1-(5-chloro-2-anisole alkylsulfonyl)-8-cyclopropyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=650.10 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 651.07
Embodiment 233
6-(4-bromobenzyl)-1-(5-chloro-2-anisole alkylsulfonyl)-8-cyclopropyl-3-piperidines-1-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 59, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-1-(5-chloro-2-anisole alkylsulfonyl)-8-cyclopropyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=664.11 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 665.12
Embodiment 234
6-(4-bromobenzyl)-1-(5-chloro-2-anisole alkylsulfonyl)-8-cyclopropyl-3-morpholine-4-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 60, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-bromobenzyl)-1-(5-chloro-2-anisole alkylsulfonyl)-8-cyclopropyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=666.09 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 667.02
Embodiment 235
A) [6-(4-luorobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester
To be similar to embodiment 66a) method synthetic.Obtain target product, MW=689.16 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 690.10
B) 3-amino-6-(4-luorobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
To be similar to embodiment 66b) method synthetic, adopt [6-(4-luorobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester as raw material.Obtain target product, MW=540.08 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 541.06
C) N-[6-(4-luorobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] ethanamide
To be similar to embodiment 21b) method synthetic, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-luorobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=582.09 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 583.10
Embodiment 236
N-[8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-6-(4-luorobenzyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopropane carboxamide
Structure:
Synthetic with the method that is similar to embodiment 22, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-luorobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=608.11 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 609.11
Embodiment 237
N-[8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-6-(4-luorobenzyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] the tetramethylene methane amide
Structure:
Synthetic with the method that is similar to embodiment 30, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-luorobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=622.12 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 623.13
Embodiment 238
N-[8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-6-(4-luorobenzyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopentane formamide
Structure:
Synthetic with the method that is similar to embodiment 31, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-luorobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=636.14 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 637.14
Embodiment 239
N-[8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-6-(4-luorobenzyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also]-4-dimethylamino yl-benzamide
Structure:
Synthetic with the method that is similar to embodiment 25, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-luorobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=687.15 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 688.15
Embodiment 240
The 1-tertiary butyl-3-[8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-6-(4-luorobenzyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] urea
Structure:
Synthetic with the method that is similar to embodiment 28, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-luorobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=639.15 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 640.18
Embodiment 241
N-[8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-6-(4-luorobenzyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] Toluidrin
Structure:
Synthetic with the method that is similar to embodiment 26, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-luorobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=618.06 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 619.08
Embodiment 242
8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-3-dimethylamino-6-(4-luorobenzyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 72, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-luorobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=568.11 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 569.12
Embodiment 243
8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-6-(4-luorobenzyl)-3-piperidines-1-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 59, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-luorobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=608.14 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 609.14
Embodiment 244
8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-6-(4-luorobenzyl)-3-morpholine-4-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 60, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-luorobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=610.12 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 611.1
Embodiment 245
A) [6-(3-benzyl chloride base)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester
To be similar to embodiment 66a) method synthetic.Obtain target product, MW=690.09 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 691.0
B) 3-amino-6-(3-benzyl chloride base)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
To be similar to embodiment 66b) method synthetic, adopt [6-(3-benzyl chloride base)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester as raw material.Obtain target product, MW=556.05 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 557.04
C) N-[6-(3-benzyl chloride base)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] ethanamide
To be similar to embodiment 21h) method synthetic, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3-benzyl chloride base)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=598.06 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 599.0
Embodiment 246
N-[6-(3-benzyl chloride base)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopropane carboxamide
Structure:
Synthetic with the method that is similar to embodiment 22, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3-benzyl chloride base)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=624.08 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 625.0
Embodiment 247
N-[6-(3-benzyl chloride base)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] the tetramethylene methane amide
Structure:
Synthetic with the method that is similar to embodiment 30, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3-benzyl chloride base)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=638.09 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 639.08
Embodiment 248
N-[6-(3-benzyl chloride base)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopentane formamide
Structure:
Synthetic with the method that is similar to embodiment 31, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3-benzyl chloride base)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=652.11 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 653.0
Embodiment 249
N-[6-(3-benzyl chloride base)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also]-4-dimethylamino yl-benzamide
Structure:
Synthetic with the method that is similar to embodiment 25, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3-benzyl chloride base)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=703.12 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 704.0
Embodiment 250
The 1-tertiary butyl-3-[6-(3-benzyl chloride base)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] urea
Structure:
Synthetic with the method that is similar to embodiment 28, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3-benzyl chloride base)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=655.12 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 656.11
Embodiment 251
N-[6-(3-benzyl chloride base)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] Toluidrin
Structure:
Synthetic with the method that is similar to embodiment 26, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3-benzyl chloride base)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=634.03 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 635.0
Embodiment 252
6-(3-benzyl chloride base)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-3-dimethylamino hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 72, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3-benzyl chloride base)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=584.08 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 585.1
Embodiment 253
3-azetidine-1-base-6-(3-benzyl chloride base)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 73, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3-benzyl chloride base)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=596.08 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 597.07
Embodiment 254
6-(3-benzyl chloride base)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-3-tetramethyleneimine-1-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 74, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3-benzyl chloride base)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=610.10 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 611.09
Embodiment 255
6-(3-benzyl chloride base)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-3-piperidines-1-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 59, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3-benzyl chloride base)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=624.11 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 625.11
Embodiment 256
6-(3-benzyl chloride base)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-3-morpholine-4-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 60, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3-benzyl chloride base)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=626.09 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 627.09
Embodiment 257
A) [1-[cyclopropyl (2,2-diethoxy ethyl) formamyl]-2-(3, the 4-difluorophenyl) ethyl] carboxylamine 9H-fluorenes-9-ylmethyl ester
To be similar to embodiment 29a) method of (method B) is synthetic, adopts N-Fmoc-3,4-F
2-Phe-OH and cyclopropyl (2,2-diethoxy ethyl) amine is as raw material.Obtain target product, MW=578.26 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 579.3
B) 2-amino-3-(3, the 4-difluorophenyl)-N-cyclopropyl-N-(2,2-diethoxy ethyl) propionic acid amide
To be similar to embodiment 29b) method of (method B) is synthetic, adopts [1-[cyclopropyl (2,2-diethoxy ethyl) formamyl]-2-(3, the 4-difluorophenyl) ethyl] carboxylamine 9H-fluorenes-9-ylmethyl ester is as raw material.Obtain target product, MW=356.19 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 357.23
C) [1-{2-(3, the 4-difluorophenyl)-1-[cyclopropyl (2,2-diethoxy ethyl) formamyl] ethylamino formyl radical }-2-(9H-fluorenes-9-ylmethoxy carbonylamino) ethyl] the carboxylamine benzyl ester
To be similar to embodiment 29c) method of (method B) is synthetic, adopts 2-amino-3-(3, the 4-difluorophenyl)-N-cyclopropyl-N-(2,2-diethoxy ethyl) propionic acid amide as raw material.Obtain target product, MW=798.34 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 821.35
D) (2-amino-1-{2-(3, the 4-difluorophenyl)-1-[cyclopropyl (2,2-diethoxy ethyl) formamyl] the ethylamino formyl radical } ethyl) the carboxylamine benzyl ester.
To be similar to embodiment 29d) method of (method B) is synthetic; [1-{2-(3 in employing; the 4-difluorophenyl)-and 1-[cyclopropyl (2,2-diethoxy ethyl) formamyl] the ethylamino formyl radical }-2-(9H-fluorenes-9-ylmethoxy carbonylamino) ethyl] the carboxylamine benzyl ester is as raw material.Obtain target product, MW=576.28 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 599.27
F) [1-{2-(3, the 4-difluorophenyl)-1-[cyclopropyl (2,2-diethoxy ethyl) formamyl] ethylamino formyl radical }-2-(2,4 dichloro benzene sulfuryl amino) ethyl] the carboxylamine benzyl ester
To be similar to embodiment 29e) method of (method B) is synthetic, adopts (2-amino-1-{2-(3, the 4-difluorophenyl)-1-[cyclopropyl (2,2-diethoxy ethyl) formamyl] ethylamino formyl radical } ethyl) carboxylamine benzyl ester as raw material.Obtain target product, MW=784.19 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 807.18.
E) [6-(3, the 4-difluorobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester
To be similar to embodiment 29f) method of (method B) is synthetic; [1-{2-(3 in employing; the 4-difluorophenyl)-and 1-[cyclopropyl (2,2-diethoxy ethyl) formamyl] the ethylamino formyl radical }-2-(2,4 dichloro benzene sulfuryl amino) ethyl] the carboxylamine benzyl ester is as raw material.Obtain target product, MW=692.11 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 693.0
F) 3-amino-6-(3, the 4-difluorobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
To be similar to embodiment 29g) method of (method B) is synthetic, adopts [6-(3, the 4-difluorobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester as raw material.Obtain target product, MW=558.07 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 559.05
G) N-[8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-6-(3, the 4-difluorobenzyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopropane carboxamide
Synthetic with the method that is similar to embodiment 22, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3, the 4-difluorobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=626.10 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 627.18
Embodiment 258
N-[8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-6-(3, the 4-difluorobenzyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] the tetramethylene methane amide
Structure:
Synthetic with the method that is similar to embodiment 30, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3, the 4-difluorobenzyl)-8-cyclopropyl-1-(2,4--dichlorobenzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=640.11 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 641.1
Embodiment 259
N-[8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-6-(3, the 4-difluorobenzyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopentane formamide
Structure:
Synthetic with the method that is similar to embodiment 31, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3, the 4-difluorobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=654.13 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 655.21
Embodiment 260
N-[8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-6-(3, the 4-difluorobenzyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclohexane carboxamide
Structure:
Synthetic with the method that is similar to embodiment 32, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3, the 4-difluorobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=668.14 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 669.22
Embodiment 261
N-[8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-6-(3, the 4-difluorobenzyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] Toluidrin
Structure:
Synthetic with the method that is similar to embodiment 26, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3, the 4-difluorobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=636.05 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 637.07
Embodiment 262
8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-6-(3, the 4-difluorobenzyl)-3-dimethylamino hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 72, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(3, the 4-difluorobenzyl)-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7--diketone is as raw material.Obtain target product, MW=586.10 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 587.10
Embodiment 263
A) 1-[cyclopropyl (2,2-diethoxy ethyl) formamyl]-2-pyridin-3-yl-ethyl } carboxylamine 9H-fluorenes-9-ylmethyl ester
To be similar to embodiment 29a) method of (method B) is synthetic, adopts Fmoc-PAL-OH and cyclopropyl (2,2-diethoxy ethyl) amine as raw material.Obtain target product, MW=543.27 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 544.21
B) 2-amino-N-cyclopropyl-N-(2,2-diethoxy ethyl)-3-pyridin-3-yl propionic acid amide
To be similar to embodiment 29b) method of (method B) is synthetic, adopts { 1-[cyclopropyl (2,2-diethoxy ethyl) formamyl]-2-pyridin-3-yl-ethyl } carboxylamine 9H-fluorenes-9-ylmethyl ester as raw material.Obtain target product, MW=321.21 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 322.20
C) [1-{1-[cyclopropyl (2,2-diethoxy ethyl) formamyl]-2-pyridin-3-yl ethylamino formyl radical }-2-(9H-fluorenes-9-ylmethoxy carbonylamino) ethyl] the carboxylamine benzyl ester
To be similar to embodiment 29c) method of (method B) is synthetic, adopts 2-amino-N-cyclopropyl-N-(2,2-diethoxy ethyl)-3-pyridin-3-yl propionic acid amide as raw material.Obtain target product, MW=798.34 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 821.35
D) (2-amino-1-{1-[cyclopropyl (2,2-diethoxy ethyl) formamyl]-2-pyridin-3-yl ethylamino formyl radical } ethyl) the carboxylamine benzyl ester.
To be similar to embodiment 29d) method of (method B) is synthetic; adopt [1-{1-[cyclopropyl (2,2-diethoxy ethyl) formamyl]-2-pyridin-3-yl ethylamino formyl radical }-2-(9H-fluorenes-9-ylmethoxy carbonylamino) ethyl] the carboxylamine benzyl ester is as raw material.Obtain target product, MW=541.29 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 542.30
E) [1-{1-[cyclopropyl (2,2-diethoxy ethyl) formamyl]-2-pyridin-3-yl ethylamino formyl radical }-2-(2,4 dichloro benzene sulfuryl amino) ethyl] the carboxylamine benzyl ester
To be similar to embodiment 29e) method of (method B) is synthetic, adopt (2-amino-1-{1-[cyclopropyl (2,2-diethoxy ethyl) formamyl]-2-pyridin-3-yl ethylamino formyl radical } ethyl) the carboxylamine benzyl ester is as raw material.Obtain target product, MW=826.12 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 849.14.
F) [8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo-6-pyridin-3-yl methyl octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester
To be similar to embodiment 29f) method of (method B) is synthetic; adopt [1-{1-[cyclopropyl (2; 2-diethoxy ethyl) formamyl]-2-pyridin-3-yl ethylamino formyl radical }-2-(2,4 dichloro benzene sulfuryl amino) ethyl] the carboxylamine benzyl ester is as raw material.Obtain target product, MW=657.12 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 658.11
G) 3-amino-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-6-pyridin-3-yl methyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
To be similar to embodiment 29g) method of (method B) is synthetic, adopts [8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo-6-pyridin-3-yl methyl octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester as raw material.Obtain target product, MW=523.08 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 524.09
H) N-[8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo-6-pyridin-3-yl methyl octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] ethanamide
To be similar to embodiment 21h) method synthetic, adopt also [1,2-a] pyrimidine-4 of 3-amino-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-6-pyridin-3-yl methyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=565.10 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 566.10
Embodiment 264
N-[8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo-6-pyridin-3-yl methyl octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopropane carboxamide
Structure:
Synthetic with the method that is similar to embodiment 22, adopt also [1,2-a] pyrimidine-4 of 3-amino-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-6-pyridin-3-yl methyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=591.11 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 592.09
Embodiment 265
N-[8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo-6-pyridin-3-yl methyl octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] the tetramethylene methane amide
Structure:
Synthetic with the method that is similar to embodiment 30, adopt also [1,2-a] pyrimidine-4 of 3-amino-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-6-pyridin-3-yl methyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=605.13 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 606.12
Embodiment 266
N-[8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo-6-pyridin-3-yl methyl octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopentane formamide
Structure:
Synthetic with the method that is similar to embodiment 31, adopt also [1,2-a] pyrimidine-4 of 3-amino-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-6-pyridin-3-yl methyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=619.14 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 620.14
Embodiment 267
N-[8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo-6-pyridin-3-yl methyl octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] tetramethyleneimine-2-methane amide
Structure:
Synthetic with the method that is similar to embodiment 40, adopt also [1,2-a] pyrimidine-4 of 3-amino-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-6-pyridin-3-yl methyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=620.14 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 621.12
Embodiment 268
N-[8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo-6-pyridin-3-yl methyl octahydro pyrazine is [1,2-a] pyrimidin-3-yl also]-4-dimethylamino yl-benzamide
Structure:
Synthetic with the method that is similar to embodiment 25, adopt also [1,2-a] pyrimidine-4 of 3-amino-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-6-pyridin-3-yl methyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=670.15 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 671.16
Embodiment 269
N-[8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo-6-pyridin-3-yl methyl octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] pyridine-2-carboxamide
Structure:
Synthetic with the method that is similar to embodiment 49, adopt also [1,2-a] pyrimidine-4 of 3-amino-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-6-pyridin-3-yl methyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=628.11 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 629.14
Embodiment 270
The 1-tertiary butyl-3-[8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo-6-pyridin-3-yl methyl octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] urea
Structure:
Synthetic with the method that is similar to embodiment 28, adopt also [1,2-a] pyrimidine-4 of 3-amino-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-6-pyridin-3-yl methyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=622.15 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 623.16
Embodiment 271
N-[8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo-6-pyridin-3-yl methyl octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] Toluidrin
Structure:
Synthetic with the method that is similar to embodiment 26, adopt also [1,2-a] pyrimidine-4 of 3-amino-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-6-pyridin-3-yl methyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=601.06 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 602.06
Embodiment 272
N-[8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo-6-pyridin-3-yl methyl octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] the cyclopropane sulphonamide
Structure:
Synthetic with the method that is similar to embodiment 27, adopt also [1,2-a] pyrimidine-4 of 3-amino-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-6-pyridin-3-yl methyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=627.08 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 628.09
Embodiment 273
8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-3-dimethylamino-6-pyridin-3-yl methyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 72, adopt also [1,2-a] pyrimidine-4 of 3-amino-8-cyclopropyl-1-(2,4 dichloro benzene alkylsulfonyl)-6-pyridin-3-yl methyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=551.12 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 552.14
Embodiment 274
A) cyclobutyl (2,2-diethoxy ethyl) amine
In 80 ℃, in encloses container with 1.75ml (11.65mmol) 1-bromo-2,2-diethoxyethane and 2ml (23.3mmol) cyclobutyl amine aqueous solution heated overnight.Reaction mixture and 40%NaOH (H
2Among the O) mix and use extracted with diethyl ether.Separate organic layer, dry (MgSO
4) and vacuum concentration.Obtain the 2.39g material, be orange liquid.
B) 2-amino-3-(4-chloro-phenyl-)-N-cyclobutyl-N-(2,2-diethoxy ethyl) propionic acid amide
1.0g (2.37mmol) Fmoc-Phe (4-Cl)-OH and 489mg (2.61mmol) amine cyclobutyl (2,2-diethoxy ethyl) amine aqueous solution are dissolved in the 9.5ml dimethyl formamide.722mg (2.61mmol) DMTMM is added to this solution.Under room temperature, stir the mixture and spend the night, with ethyl acetate dilution and water and salt water washing.Separate organic layer, dry (MgSO
4) and vacuum concentration.Residue is through 40g SiO
2(eluent: EtOAc/ heptane, gradient: 10-70%) chromatography.Obtain the 890mg material, be white foam.LC/MS M
+=591, measured value (M
+Na)=613 and M-OEt=545 conform to target substance.The described substance solution of 890mg (1.5mmol) is dissolved in the 7.5ml dimethyl formamide, and adds the 0.8ml diethylamide.Stirred reaction mixture 10 minutes and vacuum concentration under room temperature.Residue is through 12g SiO
2(the DCM solution of eluent: MeOH, gradient: 1-10%) flash chromatography.Obtain 470mg targeted amine 2-amino-3-(4-chloro-phenyl-)-N-cyclobutyl-N-(2,2-diethoxy ethyl) propionic acid amide, be colorless oil.LC/MS M
+=368, measured value (M
+Na)=391 and M-OEt=323, conform to structure.
C) [1-{2-(4-chloro-phenyl-)-1-[cyclobutyl (2,2-diethoxy ethyl) formamyl] ethylamino formyl radical }-2-(2,4 dichloro benzene sulfuryl amino) ethyl] the carboxylamine benzyl ester
The 21ml 1N NaOH solution that stirs 2.5g (10.5mmol) Z-Dap-OH is up to evenly.With 2.83g (11.5mmol) 2, the 29ml dioxane solution of 4-chlorobenzene sulfonyl chloride slowly adds to Z-Dap-OH solution.Stirred the mixture then 2 hours.Reaction mixture extracts with the citric acid acidifying and with DCM.Organic layer drying (MgSO
4) and vacuum concentration.Obtain 4.08g target sulphonamide and be used for following steps without being further purified.755mg (2.73mmol) DMTMM is added in the 9ml DMF solution of 840mg (2.28mmol) 2-amino-3-(4-chloro-phenyl-)-N-cyclobutyl-N-(2,2-diethoxy ethyl) propionic acid amide and the described sulphonamide of 1.22g (2.73mmol).Under room temperature, stirred the mixture 2, with ethyl acetate dilution and water and salt water washing.Separate organic layer, dry (MgSO
4) and vacuum concentration.Obtain 1.9g crude product material, be white foam.Residue is through 40g SiO
2(eluent: EtOAc/ heptane, gradient: 10-80%) flash chromatography.Obtain 1.09g target substance [1-{2-(4-chloro-phenyl-)-1-[cyclobutyl-(2,2-diethoxy ethyl) formamyl] ethylamino formyl radical }-2-(2,4 dichloro benzene sulfuryl amino) ethyl] the carboxylamine benzyl ester, be white solid.LC/MS M
+798, measured value (M
+Na)=819 and M-OEt=753, conform to structure.
D) [6-(4-benzyl chloride base)-8-cyclobutyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester
To be similar to embodiment 29f) method of (method B) is synthetic; adopt [1-{2-(4-chloro-phenyl-)-1-[cyclobutyl (2; 2-diethoxy ethyl) formamyl] the ethylamino formyl radical }-2-(2,4 dichloro benzene sulfuryl amino) ethyl] the carboxylamine benzyl ester is as raw material.Obtain target product, MW=704.10 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 705.1
E) 3-amino-6-(4-benzyl chloride base)-8-cyclobutyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
To be similar to embodiment 29g) method of (method B) is synthetic, adopts [6-(4-benzyl chloride base)-8-cyclobutyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester as raw material.Obtain target product, MW=570.07 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 570.99
F) N-[6-(4-benzyl chloride base)-8-cyclobutyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] ethanamide
To be similar to embodiment 21h) method synthetic, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-8-cyclobutyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=612.08 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 613.07
Embodiment 275
N-[6-(4-benzyl chloride base)-8-cyclobutyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopropane carboxamide
Structure:
Synthetic with the method that is similar to embodiment 22, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-8-cyclobutyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=638.09 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 639.09
Embodiment 276
1-[6-(4-benzyl chloride base)-8-cyclobutyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also]-the 3-ethyl carbamide
Structure:
Synthetic with the method that is similar to embodiment 57, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-8-cyclobutyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=641.10 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 642.09
Embodiment 277
N-[6-(4-benzyl chloride base)-8-cyclobutyl-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] Toluidrin
Structure:
Synthetic with the method that is similar to embodiment 26, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-8-cyclobutyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=648.04 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 649.15
Embodiment 278
6-(4-benzyl chloride base)-8-cyclobutyl-1-(2,4 dichloro benzene alkylsulfonyl)-3-dimethylamino hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 72, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-8-cyclobutyl-1-(2,4 dichloro benzene alkylsulfonyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=598.10 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 599.07
Embodiment 279
A) (2,2-diethoxy ethyl)-(2-fluoro ethyl) amine
In 100 ℃, with 3.1ml (21.5mmol) 1-amino-2,2-diethoxyethane, 3.0g (23.6mmol) 1-bromo-2-fluoroethane and 5.56g (43mmol) diisopropyl ethyl amine solution heated 6 hours in encloses container.Reaction mixture is with ether dilution and with 1N NaOH and water washing.Organic layer drying (MgSO
4) and vacuum concentration.The vacuum distilling residue.Obtain the 1.3g material, be clarified liq.
B) 2-amino-3-(4-chloro-phenyl-)-N-(2,2-diethoxy ethyl)-N-(2-fluoro ethyl) propionic acid amide
To be similar to embodiment 274b) method synthetic.Obtain target product, MW=360.16 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 361.2
C) [1-{2-(4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl)-(2-fluoro ethyl) formamyl] the ethylamino formyl radical }-2-(2,4 dichloro benzene sulfuryl amino) ethyl] the carboxylamine benzyl ester
To be similar to embodiment 274c) method synthetic.Obtain target product, MW=788.16 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 811.19
D) [6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2-fluoro ethyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester
To be similar to embodiment 29f) method of (method B) is synthetic; adopt [1-{2-(4-chloro-phenyl-)-1-[(2; 2-diethoxy ethyl)-(2-fluoro ethyl) formamyl] the ethylamino formyl radical }-2-(2,4 dichloro benzene sulfuryl amino) ethyl] the carboxylamine benzyl ester is as raw material.Obtain target product, MW=696.08 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 697.04
E) 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2-fluoro ethyl) hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
To be similar to embodiment 29e) method of (method B) is synthetic, adopts [6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2-fluoro ethyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester as raw material.Obtain target product, MW=562.04 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 563.03
F) N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2-fluoro ethyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] ethanamide
To be similar to embodiment 21b) method synthetic, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2-fluoro ethyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=604.05 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 605.07
Embodiment 280
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2-fluoro ethyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopropane carboxamide
Structure:
Synthetic with the method that is similar to embodiment 22, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2-fluoro ethyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=630.07 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 631.06
Embodiment 281
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2-fluoro ethyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] the tetramethylene methane amide
Structure:
Synthetic with the method that is similar to embodiment 30, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2-fluoro ethyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=644.08 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 645.11
Embodiment 282
The 1-tertiary butyl-3-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2-fluoro ethyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] urea
Structure:
Synthetic with the method that is similar to embodiment 28, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2-fluoro ethyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=661.11 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 662.1
Embodiment 283
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2-fluoro ethyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] Toluidrin
Structure:
Synthetic with the method that is similar to embodiment 26, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2-fluoro ethyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=640.02 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 641.03
Embodiment 284
6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-3-dimethylamino-8-(2-fluoro ethyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
Synthetic with the method that is similar to embodiment 72, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2-fluoro ethyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=590.07 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 591.04
Embodiment 285
A) (2,2-diethoxy ethyl)-(2,2-two fluoro ethyls) amine
In 120 ℃, with 3g (22.5mmol) 1-amino-2, the 44ml toluene solution of 2-diethoxyethane, 3.1g (24.8mmol) difluoro acetaldehyde ethyl hemiacetal and 1 (pellet) solid NaOH heated 1.5 hours with the Dean-Stark trap.Mixture is placed to and is cooled to room temperature and vacuum concentration.Residue dilutes with 80ml methyl alcohol, and adds 3.4g (90mmol) sodium borohydride in a small amount.Stirred reaction mixture spends the night then, vacuum concentration and be allocated in ethyl acetate and water between.Separate organic layer, dry (MgSO
4) and vacuum concentration.Obtain 3.7g crude product material, be colorless oil.Residue is through 40g SiO
2(eluent: DCM/MeOH, gradient: 1-8%) flash chromatography.Obtain the 3.1g targeted amine, be colorless oil.
B) 2-amino-3-(4-chloro-phenyl-)-N-(2,2-diethoxy ethyl)-N-(2,2-two fluoro ethyls) propionic acid amide
To be similar to embodiment 274b) method synthetic.Obtain target product, MW=378.15 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 379.18
C) [1-{2-(4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl)-(2,2-two fluoro ethyls) formamyl] the ethylamino formyl radical }-2-(2,4 dichloro benzene sulfuryl amino) ethyl] the carboxylamine benzyl ester
To be similar to embodiment 274c) method synthetic.Obtain target product, MW=806.15 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 829.11
D) [6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2,2-two fluoro ethyls)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester
To be similar to embodiment 29f) method of (method B) is synthetic; adopt [1-{2-(4-chloro-phenyl-)-1-[(2; 2-diethoxy ethyl)-(2,2-two fluoro ethyls) formamyl] the ethylamino formyl radical }-2-(2,4 dichloro benzene sulfuryl amino) ethyl] the carboxylamine benzyl ester is as raw material.Obtain target product, MW=714.07 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 715.02
E) 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2,2-two fluoro ethyls) hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
To be similar to embodiment 29e) method of (method B) is synthetic, adopts [6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2,2-two fluoro ethyls)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester as raw material.Obtain target product, MW=580.03 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 580.99
F) N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2,2-two fluoro ethyls)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] ethanamide
To be similar to embodiment 21h) method synthetic, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2,2-two fluoro ethyls) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=622.04 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 623.03
Embodiment 286
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2,2-two fluoro ethyls)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopropane carboxamide
Structure:
Synthetic with the method that is similar to embodiment 22, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2,2-two fluoro ethyls) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=648.06 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 649.04
Embodiment 287
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2,2-two fluoro ethyls)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] the tetramethylene methane amide
Synthetic with the method that is similar to embodiment 30, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2,2-two fluoro ethyls) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=662.07 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 663.06
Embodiment 288
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2,2-two fluoro ethyls)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopentane formamide
Synthetic with the method that is similar to embodiment 31, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2,2-two fluoro ethyls) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=676.09 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 677.07
Embodiment 289
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2,2-two fluoro ethyls)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] tetramethyleneimine-2-methane amide
Synthetic with the method that is similar to embodiment 40, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2,2-two fluoro ethyls) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=677.08 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 678.08
Embodiment 290
6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2,2-two fluoro ethyls)-3-dimethylamino hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Synthetic with the method that is similar to embodiment 72, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2,2-two fluoro ethyls) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=608.06 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 609.05
Embodiment 291
6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2,2-two fluoro ethyls)-3-morpholine-4-base hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Synthetic with the method that is similar to embodiment 60, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2,2-two fluoro ethyls) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=650.07 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 651.07
Embodiment 292
A) (2,2-diethoxy ethyl)-(2,2, the 2-trifluoroethyl) amine
In 110 ℃, with 1g (7.5mmol) 1-amino-2, the 15ml toluene solution of 2-diethoxyethane, 1.26g (7.9mmol) trifluoro-acetaldehyde ethyl hemiacetal and 1 NaOH heated 3 hours with the Dean-Stark trap.In 125 ℃, reheat mixture 3 hours.Reaction mixture is placed to and is cooled to room temperature and vacuum concentration.Residue dilutes with 25ml methyl alcohol, and adds 1.13g (30mmol) sodium borohydride.Then reaction mixture is heated to 70 ℃ and stir and to spend the night, vacuum concentration and be allocated in water and ethyl acetate between.Separate organic layer, dry (MgSO
4) and vacuum concentration.Obtain the 740mg targeted amine, be clarification oily matter.
B) 2-amino-3-(4-chloro-phenyl-)-N-(2,2-diethoxy ethyl)-N-(2,2, the 2-trifluoroethyl) propionic acid amide
To be similar to embodiment 274b) method synthetic.Obtain target product, MW=378.15 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 379.18
C) [1-{2-(4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl)-(2,2, the 2-trifluoroethyl) formamyl] the ethylamino formyl radical }-2-(2,4 dichloro benzene sulfuryl amino) ethyl] the carboxylamine benzyl ester
To be similar to embodiment 274c) method synthetic.Obtain target product, MW=806.15 (calculated value, single isotropic substance of planting); Measured value (M+Na)
+: 829.11
D) [6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2,2, the 2-trifluoroethyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester
To be similar to embodiment 29f) method of (method B) is synthetic; adopt [1-{2-(4-chloro-phenyl-)-1-[(2; 2-diethoxy ethyl)-(2; 2; the 2-trifluoroethyl) formamyl] the ethylamino formyl radical }-2-(2,4 dichloro benzene sulfuryl amino) ethyl] the carboxylamine benzyl ester is as raw material.Obtain target product, MW=732.06 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 732.12
E) 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2,2, the 2-trifluoroethyl) hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
To be similar to embodiment 29e) method of (method B) is synthetic, adopts [6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2,2, the 2-trifluoroethyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester as raw material.Obtain target product, MW=598.02 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 599.06
F) N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2,2, the 2-trifluoroethyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] ethanamide
To be similar to embodiment 21h) method synthetic, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2,2, the 2-trifluoroethyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=640.03 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 641.06
Embodiment 293
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo-8-(2,2, the 2-trifluoroethyl) octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopropane carboxamide
Synthetic with the method that is similar to embodiment 22, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2,2, the 2-trifluoroethyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=666.05 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 667.07
Embodiment 294
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo-8-(2,2, the 2-trifluoroethyl) octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] the tetramethylene methane amide
Synthetic with the method that is similar to embodiment 30, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2,2, the 2-trifluoroethyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=680.06 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 681.02
Embodiment 295
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo-8-(2,2, the 2-trifluoroethyl) octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopentane formamide
Synthetic with the method that is similar to embodiment 31, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2,2, the 2-trifluoroethyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=694.08 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 695.10
Embodiment 296
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-4,7-dioxo-8-(2,2, the 2-trifluoroethyl) octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] piperidines-4-methane amide
Synthetic with the method that is similar to embodiment 37, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2,2, the 2-trifluoroethyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=709.09 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 710.09
Embodiment 297
6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-3-dimethylamino-8-(2,2, the 2-trifluoroethyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Synthetic with the method that is similar to embodiment 72, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2,2, the 2-trifluoroethyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=626.05 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 627.05
Embodiment 298
A) [6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2-hydroxyethyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester
With 3.13g (3.96mmol) [1-{2-(4-chloro-phenyl-)-1-[(2; 2-diethoxy ethyl)-(2-fluoro ethyl) formamyl] the ethylamino formyl radical }-2-(2,4 dichloro benzene sulfuryl amino) ethyl] the 20ml formic acid solution of carboxylamine benzyl ester is heated to 60 ℃ and stirred 6 hours.The vacuum concentration reaction mixture is with EtOAc dilution and use 1N NaHCO
3Solution and salt water washing.Separate organic layer, dry (MgSO
4) and vacuum concentration.The crude product material is through 120g SiO
2(eluent: EtOAc/ heptane, gradient: 50-100%) flash chromatography.Obtain 350mg material [6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2-fluoro ethyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester.Further column chromatography obtains the 980mg compound, is equivalent to [6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2-hydroxyethyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester by product.The single isotopic LC/MS MW=694 and measured value (M of planting of expectation
+H)=695, conform to structure.
B) 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2-hydroxyethyl) hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
To be similar to embodiment 29g) method of (method B) is synthetic, adopts [6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2-hydroxyethyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester as raw material.Obtain target product, MW=560.04 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 561.03
C) N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2-hydroxyethyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] the tetramethylene methane amide
Synthetic with the method that is similar to embodiment 30, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2-hydroxyethyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=642.09 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 643.11
Embodiment 299
N-[6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2-hydroxyethyl)-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopentane formamide
Synthetic with the method that is similar to embodiment 31, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-(2-hydroxyethyl) hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=656.10 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 657.12
Embodiment 300
A) 2-benzyloxycarbonyl amino-3-(2,5-dichlorobenzene sulfuryl amino) propionic acid
To be similar to embodiment 21d) method synthetic, adopt 2, the 5-two chloro phenylsulfonyl chloride is as raw material.Obtain target product, MW=446.01 (calculated value, single isotropic substance of planting); Measured value (M+H-CO
2)
+: 403.00.
B) N-{2-(4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl] ethyl }-the amino propionic acid amide of 3-(2,5-dichlorobenzene sulfuryl amino)-2-methylsulfonyl
To be similar to embodiment 21e) method synthetic, adopt 2-benzyloxycarbonyl amino-3-(2,6-dichlorobenzene sulfuryl amino) propionic acid as raw material.Obtain target product, MW=784.186 (calculated value, single isotropic substance of planting); Measured value (M-CO
2+ H)
+: 741.10
C) [6-(4-benzyl chloride base)-1-(2,5-dichlorobenzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester
To be similar to embodiment 21f) method synthetic, adopt N-{2-(4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl] ethyl-the amino propionic acid amide of 3-(2,5-dichlorobenzene sulfuryl amino)-2-methylsulfonyl is as raw material.Obtain target product, MW=692.10 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 693.05
D) 3-amino-6-(4-benzyl chloride base)-1-(2,5-dichlorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
To be similar to embodiment 21g) method synthetic, adopt [6-(4-benzyl chloride base)-1-(2,5-dichlorobenzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester as raw material.Obtain target product, MW=558.07 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 559.10
E) N-[6-(4-benzyl chloride base)-1-(2,5-dichlorobenzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] ethanamide
To be similar to embodiment 21h) method synthetic, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2,5-dichlorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=600.08 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 601.13.
Embodiment 301
N-[6-(4-benzyl chloride base)-1-(2,5-dichlorobenzene alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] Toluidrin
Synthetic with the method that is similar to embodiment 26, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2,5-dichlorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=636.04 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 637.02.
Embodiment 302
A) 2-benzyloxycarbonyl amino-3-hydroxy-2-methyl propionic acid methyl ester:
250mg (2.1mmol) 2-amino-3-methyl hydroxy-propionic acid is dissolved among the anhydrous MeOH of 9ml.Cooled reaction solution in ice bath, and slowly drip 0.153ml (2.1mmol) SOCl
2Make solution slowly to ambient temperature overnight.The vacuum concentration reaction soln is then with 1ml EtOAc and the saturated NaHCO of 5ml
3(aqueous solution) mixes, and is 0.285ml (1.995mmol) benzyl chloroformate then.Stirred solution spends the night under room temperature.Add 5ml EtOAc then, separate organic layer and wash secondary, use the saturated NaHCO of 2ml at every turn at every turn with 1ml 1N HCl (aqueous solution)
3(aqueous solution) washing secondary is through MgSO
4Dry also vacuum concentration.Through chromatography (40g SiO
2, eluent: MeOH/DCM (gradient: 0-10%)) carries out purifying.Obtain target product, colorless oil (0.130g), MW=267 (calculated value, single isotropic substance of planting), measured value: (M+Na)
+290.
B) 2-benzyloxycarbonyl amino-2-methyl-3-oxo propionic acid methyl ester:
The 1mlDCM solution of 97.7mg (0.23mmol) Dess Martin periodinane reagent (Aldrich) is slowly dropped in the 1ml DCM solution of 56mg (0.21mmol) 2-benzyloxycarbonyl amino-3-hydroxy-2-methyl propionic acid methyl ester, and under room temperature, stirred the mixture 30 minutes.Then with 5ml ether and the saturated NaHCO of 4ml
3And 0.36gNa
2S
2O
3.5H
2The mixture of O adds to this solution.Stir 15 minutes to the solid dissolving, use saturated NaHCO then
3With water washing ether layer, through MgSO
4Dry also vacuum concentration.The crude product product is through 4g SiO
2Chromatography purification is with EtOAc/ heptane (gradient: 0-50%) wash-out.Obtain 40mg target aldehyde.
C) 3-allyl amino-2-benzyloxycarbonyl amino-2-methyl propionic acid methyl ester:
With 1.237ml (16.5mmol) allyl amine and 0.9g (7.48mmol) MgSO
4Add in the 15ml DCM solution of 0.874g (3.3mmol) 2-benzyloxycarbonyl amino-2-methyl-3-oxo propionic acid methyl ester.Under room temperature, stir the mixture and spend the night.Filter reaction mixture and vacuum concentration then.With the anhydrous MeOH of 50ml, 6ml NaCNBH
3(the THF solution of 1.0M) and 1.8ml acetate add in the crude product product.Under room temperature, mixture was stirred 2 hours.The vacuum concentration reaction soln adds EtOAc and water then.Separate organic layer and through MgSO
4Drying, solvent removed in vacuo.Through chromatography (25g SiO
2, eluent: MeOH/DCM (gradient: 0-10%) purifying.Obtain the 1.035g target product, be oily matter.MW=306 (calculated value, single isotropic substance of planting), measured value: (M+H)
+307.
D) 3-amino-2-benzyloxycarbonyl amino-2-methyl propionic acid methyl ester:
In 35 ℃, with 0.22g (1.42mmol) N, N-dimethyl barbituric acid, 0.02g (0.017mmol) Pd (PPh
3)
4, 1.5ml DCM and 0.145g (0.47mmol) 3-allyl amino-heating of 2-benzyloxycarbonyl amino-2-methyl propionic acid methyl ester solution 2 hours.The vacuum concentration reaction soln adds the 20ml ether then subsequently, and solution is used the saturated Na of 20ml at every turn
2CO
3Wash 3 times.Be adjusted to pH value 2 through dripping 4N HCl.Separate water layer and with the 2mlEtOAc extraction, and solvent removed in vacuo.Obtain the 0.105g target product.MW (calculated value, single isotropic substance of planting)=266, measured value: (M+H)
+267.
E) 2-benzyloxycarbonyl amino-3-(2,4 dichloro benzene sulfuryl amino)-2 Methylpropionic acid methyl ester:
0.103g (0.341mmol) 3-amino-2-benzyloxycarbonyl amino-2-methyl propionic acid methyl ester, 0.109g (0.443mmol) 2,4 dichloro benzene SULPHURYL CHLORIDE and 0.237ml (1.36mmol) DIEA are dissolved among the 2ml DCM.Under room temperature, stir the mixture and spend the night.2ml is added in the reaction soln, separate organic layer then and through MgSO
4Drying, and solvent removed in vacuo.The crude product product is through 4g SiO
2Chromatography purification, eluent: EtOAc/DCM (gradient: 0-40%).Obtain the 0.081g target product, be oily matter.MW=474 (calculated value, single isotropic substance of planting), measured value: (M+H)
+475.
F) 2-benzyloxycarbonyl amino-3-(2,4 dichloro benzene sulfuryl amino)-2 Methylpropionic acid:
0.08g (0.168mmol) 2-benzyloxycarbonyl amino-3-(2,4 dichloro benzene sulfuryl amino)-2 Methylpropionic acid methyl ester and 0.093g (0.674mmol) salt of wormwood were stirred 90 minutes in 4.5ml MeOH and 0.5ml water mixture.Add the saturated NaHCO of 3ml then
3Solution, and stirred the mixture 2 hours in 60 ℃.Add 0.5ml water, 4N HCl (aqueous solution) is to pH value 2 then.Use 10mlEtOAc extraction solution 3 times, the organic layer of merging is through MgSO at every turn
4Drying, and solvent removed in vacuo.Obtain the 68mg target product.MW=460 (calculated value, single isotropic substance of planting), measured value: (M+H)
+461.
G) [1-{2-(4-chloro-phenyl-)-1-[(2,2-diethoxy ethyl) the sec.-propyl formamyl] ethylamino formyl radical-2-(2,4 dichloro benzene sulfuryl amino)-1-methylethyl } the carboxylamine benzyl ester:
With 52.6mg (0.15mmol) 2-amino-3-(4-chloro-phenyl-)-N-(2,2-diethoxy ethyl)-N-sec.-propyl propionic acid amide and 41mg 4-(4,6-dimethoxy [1,3,5] triazine-2-yl) 4-methylmorpholine muriate * H
2O (DMTMM) adds in the 3ml DMF solution of 68mg (0.15mmol) 2-benzyloxycarbonyl amino-3-(2,4 dichloro benzene sulfuryl amino)-2 Methylpropionic acid.Stirring reaction solution spends the night and adds the 10ml ether then under room temperature, separates organic layer and through MgSO
4Dry.Solvent removed in vacuo, the crude product product is through 4g SiO
2(eluent: MeOH/DCM, gradient: 0-1%) chromatography purification.Obtain the 83mg target product.MW=798 (calculated value, single isotropic substance of planting), measured value: (M+H)
+799.
H) [6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-3-methyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] carboxylamine benzyl ester:
In 60 ℃; with 80mg (0.1mmol) [1-{2-(4-chloro-phenyl-)-1-[(2; 2-diethoxy ethyl) sec.-propyl formamyl] the ethylamino formyl radical }-2-(2,4 dichloro benzene sulfuryl amino)-1-methylethyl] 1.5ml HCOOH (99%) solution stirring 24 hours of carboxylamine benzyl ester.The vacuum concentration reaction soln, the crude product product is through chromatography purification (4g SiO
2, eluent: EtOAc/ heptane (gradient: 0-50%)).Obtain the 30mg target product, be white solid.MW (calculated value, single isotropic substance of planting)=706, measured value: (M+H)
+=707
I) 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-3-methyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone:
Will [6-(4-benzyl chloride base)-1-(2 in ice bath; 4-dichlorobenzene alkylsulfonyl)-8-sec.-propyl-3-methyl-4; 7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] the 2ml acetonitrile solution of carboxylamine benzyl ester is cooled to 0 ℃, and adds 0.05ml (0.35mmol) TMSI.Under room temperature, with the solution stirring vacuum concentration then that spends the night, be dissolved in 1ml MeOH and place on the 1gSCX post, with 5ml MeOH flush away impurity, use 5ml 2N NH then
3MeOH with eluted product.Vacuum concentration obtains the 15mg target product.MW (calculated value, single isotropic substance of planting)=572, measured value: (M+H)
+573.
N-[1-benzenesulfonyl-6-(4-benzyl chloride base)-8-sec.-propyl-3-methyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidin-3-yl also] cyclopropane carboxamide:
Synthetic with the method that is similar to embodiment 22, adopt also [1,2-a] pyrimidine-4 of 3-amino-6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl-3-methyl hexahydropyrazine, the 7-diketone is as raw material.Obtain target product, MW=640 (calculated value, single isotropic substance of planting); Measured value (M+H)
+: 641.
Claims (17)
1. the salt that can tolerate on formula I compound and their physiology:
Wherein be defined as follows:
A be comprise the heteroatomic 3-12 unit of one or more N of being selected from, O and S single-, two-or spiral shell two rings, and described 3-12 unit ring can further be replaced by following groups: for example F, Cl, Br, NO
2, CF
3, OCF
3, CN, (C
1-C
6)-alkyl, aryl, CON (R11) (R12), N (R13) (R14), OH, O-(C
1-C
6)-alkyl, S-(C
1-C
6)-alkyl, N (R15) CO (C
1-C
6)-alkyl or COO-(C
1-C
6)-alkyl;
R11, R12, R13, R14, R15 are H, (C independently of one another
1-C
6)-alkyl or heterocycle;
N is 0 or 1;
M is 0,1,2,3,4,5 or 6;
R1 is R8, (C
1-C
6)-alkylidene group-R8, (C
2-C
6)-alkylene group-R9, (SO
2)-R8, (SO
2)-(C
1-C
6)-alkylidene group-R8, (SO
2)-(C
2-C
6)-alkylene group-R9, (C=O)-R8, (C=O)-(C
1-C
6)-alkylidene group-R8, (C=O) NH-R8, (C=O)-(C
2-C
6)-alkylene group-R9, (C=O)-NH-(C
1-C
6)-alkylidene group-R8, (C=O)-NH-(C
2-C
6)-alkylene group-R9, COO-R8, COO-(C
1-C
6)-alkylidene group-R8, COO-(C
2-C
6)-alkylene group-R9, alkynylene-R9, (C
1-C
4-alkyl)-and heterocycle, wherein alkylidene group can be replaced by F;
R8, R9 are H, F, Cl, Br, I, OH, CF independently of one another
3, aryl, heterocycle, (C
3-C
8)-cycloalkyl, wherein ring or ring system can be replaced 3 times by following groups at the most: F, Cl, Br, I, OH, CF
3, NO
2, CN, OCF
3, O-(C
1-C
6)-alkyl, (C
1-C
6)-alkyl, NH
2, CON (R11) (R12), N (R13) (R14), SO
2-CH
3, COOH, COO-(C
1-C
6)-alkyl, CONH
2
R2 is NH
2, NO
2, N (R13) (R14), NH-SO
2-CH
3, NH-SO
2-R12, NR11-SO
2-R12, N (CO) R11, nitrogen heterocyclic ring, described heterocycle is by nitrogen-atoms connection, NHCONR11, N (C
1-C
6-alkyl) N
+(C
1-C
4-alkyl)
3
R3, R4, R5 are H, F, Cl, Br, I, OH, CF independently of one another
3, NO
2, CN, OCF
3, O-(C
1-C
6)-alkyl, O-(C
1-C
4)-alkoxyl group-(C
1-C
4)-alkyl, S-(C
1-C
6)-alkyl, (C
1-C
6)-alkyl, (C
2-C
6)-alkenyl, (C
3-C
8)-cycloalkyl, O-(C
3-C
8)-cycloalkyl, (C
3-C
8)-cycloalkenyl group, O-(C
3-C
8)-cycloalkenyl group, (C
2-C
6)-alkynyl, aryl, O-aryl (C
0-C
8)-alkylidene group-aryl, O-(C
0-C
8)-alkylidene group-aryl, S-aryl, N ((C
1-C
6)-alkyl)
2, SO
2-CH
3, COOH, COO-(C
1-C
6)-alkyl, CO-N ((C
1-C
6)-alkyl)
2
R6 is H, F, Cl, Br, I, OH, CF
3, NO
2, CN, OCF
3, O-(C
1-C
6)-alkyl, O-(C
1-C
4)-alkoxyl group-(C
1-C
4)-alkyl, S-(C
1-C
6)-alkyl, (C
1-C
6)-alkyl, (C
2-C
6)-alkenyl, (C
3-C
8)-cycloalkyl, O-(C
3-C
8)-cycloalkyl, (C
3-C
8)-cycloalkenyl group, O-(C
3-C
8)-cycloalkenyl group, (C
2-C
6)-alkynyl, aryl, O-aryl, (C
1-C
8)-alkylidene group-aryl, O-(C
1-C
8)-alkylidene group-aryl, S-aryl, N ((C
1-C
6)-alkyl)
2, SO
2-CH
3, COOH, COO-(C
1-C
6)-alkyl, CO-N ((C
1-C
6)-alkyl)
2
2. the salt that can tolerate on the formula I compound of claim 1 and their physiology, wherein I has structure I a:
Wherein be defined as follows:
A be comprise the heteroatomic 3-12 unit of one or more N of being selected from, O and S single-, two-or spiral shell two rings, and described 3-12 unit ring can further be replaced by following groups: for example F, Cl, Br, NO
2, CF
3, OCF
3, CN, (C
1-C
6)-alkyl, aryl, CON (R11) (R12), N (R13) (R14), OH, O-(C
1-C
6)-alkyl, S-(C
1-C
6)-alkyl, N (R15) CO (C
1-C
6)-alkyl or COO-(C
1-C
6)-alkyl;
R11, R12, R13, R14, R15 are H, (C independently of one another
1-C
6)-alkyl or heterocycle;
M is 0,1,2,3,4,5 or 6;
R1 is R8, (C
1-C
6)-alkylidene group-R8, (C
2-C
6)-alkylene group-R9, (SO
2)-R8, (SO
2)-(C
1-C
6)-alkylidene group-R8, (SO
2)-(C
2-C
6)-alkylene group-R9, (C=O)-R8, (C=O)-(C
1-C
6)-alkylidene group-R8, (C=O) NH-R8, (C=O)-(C
2-C
6)-alkylene group-R9, (C=O)-NH-(C
1-C
6)-alkylidene group-R8, (C=O)-NH-(C
2-C
6)-alkylene group-R9, COO-R8, COO-(C
1-C
6)-alkylidene group-R8, COO-(C
2-C
6)-alkylene group-R9, alkynylene-R9, (C
1-C
4-alkyl)-heterocycle;
R8, R9 are H, F, Cl, Br, I, OH, CF independently of one another
3, aryl, heterocycle, (C
3-C
8)-cycloalkyl, wherein ring or ring system can be at the most by following replacements 3 times: F, Cl, Br, I, OH, CF
3, NO
2, CN, OCF
3, O-(C
1-C
6)-alkyl, (C
1-C
6)-alkyl, NH
2, CON (R11) (R12), N (R13) (R14), SO
2-CH
3, COOH, COO-(C
1-C
6)-alkyl, CONH
2
R2 is NH
2, NO
2, N (R13) (R14), NH-SO
2-CH
3, NH-SO
2-R12, NR11-SO
2-R12, N (CO) R11, nitrogen heterocyclic ring, described heterocycle is by nitrogen-atoms connection, NHCONR11, N (C
1-C
6-alkyl) N
+(C
1-C
4-alkyl)
3
R3, R4, R5 are H, F, Cl, Br, I, OH, CF independently of one another
3, NO
2, CN, OCF
3, O-(C
1-C
6)-alkyl, O-(C
1-C
4)-alkoxyl group-(C
1-C
4)-alkyl, S-(C
1-C
6)-alkyl, (C
1-C
6)-alkyl, (C
2-C
6)-alkenyl, (C
3-C
8)-cycloalkyl, O-(C
3-C
8)-cycloalkyl, (C
3-C
8)-cycloalkenyl group, O-(C
3-C
8)-cycloalkenyl group, (C
2-C
6)-alkynyl, aryl, O-aryl (C
0-C
8)-alkylidene group-aryl, O-(C
0-C
8)-alkylidene group-aryl, S-aryl, N ((C
1-C
6)-alkyl)
2, SO
2-CH
3, COOH, COO-(C
1-C
6)-alkyl, CO-N ((C
1-C
6)-alkyl)
2
R6 is H, F, Cl, Br, I, OH, CF
3, NO
2, CN, OCF
3, O-(C
1-C
6)-alkyl, O-(C
1-C
4)-alkoxyl group-(C
1-C
4)-alkyl, S-(C
1-C
6)-alkyl, (C
1-C
6)-alkyl, (C
2-C
6)-alkenyl, (C
3-C
8)-cycloalkyl, O-(C
3-C
8)-cycloalkyl, (C
3-C
8)-cycloalkenyl group, O-(C
3-C
8)-cycloalkenyl group, (C
2-C
6)-alkynyl, aryl, O-aryl, (C
1-C
8)-alkylidene group-aryl, O-(C
1-C
8)-alkylidene group-aryl, S-aryl, N ((C
1-C
6)-alkyl)
2, SO
2-CH
3, COOH, COO-(C
1-C
6)-alkyl, CO-N ((C
1-C
6)-alkyl)
2
3. the salt that can tolerate on claim 1 or 2 formula I compound and their physiology wherein is defined as:
A is an aryl, and wherein aromatic ring can be replaced by following groups: F, Cl, Br, NO
2, CF
3, OCF
3, CN, (C
1-C
6)-alkyl, aryl, CON (R11) (R12), N (R13) (R14), OH, O-(C
1-C
6)-alkyl, S-(C
1-C
6)-alkyl, N (R15) CO (C
1-C
6)-alkyl or COO-(C
1-C
6)-alkyl;
R11, R12, R13, R14, R15 are H, (C independently of one another
1-C
6)-alkyl or heterocycle;
M is 1;
R1 is R8, (C
1-C
6)-alkylidene group-R8, (C
2-C
6)-alkylene group-R9, (SO
2)-R8, (SO
2)-(C
1-C
6)-alkylidene group-R8, (SO
2)-(C
2-C
6)-alkylene group-R9, (C=O)-R8, (C=O)-(C
1-C
6)-alkylidene group-R8, (C=O) NH-R8, (C=O)-(C
2-C
6)-alkylene group-R9, (C=O)-NH-(C
1-C
6)-alkylidene group-R8, (C=O)-NH-(C
2-C
6)-alkylene group-R9, COO-R8, COO-(C
1-C
6)-alkylidene group-R8, COO-(C
2-C
6)-alkylene group-R9, alkynylene-R9, (C
1-C
4-alkyl)-heterocycle;
R8, R9 are H, F, Cl, Br, I, OH, CF independently of one another
3, aryl, heterocycle, (C
3-C
8)-cycloalkyl, wherein ring or ring system can be at the most replaced 3 times by following groups: F, Cl, Br, I, OH, CF
3, NO
2, CN, OCF
3, O-(C
1-C
6)-alkyl, (C
1-C
6)-alkyl, NH
2, CON (R11) (R12), N (R13) (R14), SO
2-CH
3, COOH, COO-(C
1-C
6)-alkyl, CONH
2
R2 is NH
2, NO
2, N (R13) (R14), NH-SO
2-CH
3, NH-SO
2-R12, NR11-SO
2-R12, N (CO) R11, nitrogen heterocyclic ring, described heterocycle is by nitrogen-atoms connection, NHCONR11, N (C
1-C
6-alkyl) N
+(C
1-C
4-alkyl)
3
R3 is H
R4, R5 are H, F, Cl, Br, OH, CF independently of one another
3, OCF
3, O-(C
1-C
6)-alkyl, (C
1-C
6)-alkyl;
R6 is H.
4. the salt that can tolerate on one or multinomial compound and their physiology among the claim 1-3 wherein is defined as follows:
A is an aryl, and wherein aromatic ring can be replaced by following groups: F, Cl, Br, NO
2, CF
3, OCF
3, CN, (C
1-C
6)-alkyl, aryl, CON (R11) (R12), N (R13) (R14), OH, O-(C
1-C
6)-alkyl, S-(C
1-C
6)-alkyl, N (R15) CO (C
1-C
6)-alkyl or COO-(C
1-C
6)-alkyl;
R11, R12, R13, R14, R15 are H, (C independently of one another
1-C
6)-alkyl or heterocycle;
M is 1;
R1 is (C
1-C
6)-alkyl or (C
1-C
6)-alkylidene group-R8;
R8, R9 are F, Cl, Br, I, OH, CF independently of one another
3
R2 is NH
2, NO
2, CN, N (R13) (R14), NH-SO
2-CH
3, NH-SO
2-R12, NR11-SO
2-R12, N (CO) R11, nitrogen heterocyclic ring, described heterocycle is by nitrogen-atoms connection, NHCONR11, N (C
1-C
6-alkyl) N
+(C
1-C
4-alkyl)
3
R3 is H;
R4 is F, Cl, Br, OH, CF
3, OCF
3, O-(C
1-C
6)-alkyl, (C
1-C
6)-alkyl;
R5 is H, F, Cl, Br, OH, CF
3, OCF
3, O-(C
1-C
6)-alkyl, (C
1-C
6)-alkyl;
R6 is H.
5. one or multinomial compound among the claim 1-4 are used as medicine.
6. medicine, this medicine contains one or multinomial compound among one or more claims 1-4.
7. medicine, this medicine contain among one or more claims 1-4 one or multinomial compound and one or more subtract the appetite activeconstituents.
8. medicine, this medicine contain among one or more claims 1-4 one or the multinomial compound and the medicine of one or more statin classes.
9. the medicine of claim 6, this medicine comprises one or more antidiabetic drugs as other activeconstituents, blood-sugar decreasing active, the HMGCoA reductase inhibitor, cholesterol absorption inhibitor, the PPAR gamma agonist, the PPAR alfa agonists, PPAR α/gamma agonist, fibrate, the MTP inhibitor, the bile acide absorption inhibitor, the CETP inhibitor, polymerization bile acide absorption agent, the ldl receptor inductor, the ACAT inhibitor, antioxidant, the lipoprotein lipase inhibitor, ATP-citrate lyase inhibitor, squalene synthetase inhibitor, lipoprotein (a) antagonist, lipase inhibitor, Regular Insulin, sulfonylureas, biguanides, meglitinide, thiazolidinedione, alpha-glucosidase inhibitor, act on the activeconstituents of β cell ATP-dependency potassium channel, the CART agonist, the NPY agonist, the MC4 agonist, increase food factor agonist, the H3 agonist, the TNF agonist, the CRF agonist, CRF BP antagonist, agonist can be decided in excellent Lip river, β 3 agonists, MSH (melanophorin) agonist, the CCK agonist, serotonin reuptake inhibitor, mix serotonin energy and norepinephrine energy compound, the 5HT agonist, to the bombesin agonist, the sweet third plain antagonist, tethelin, tethelin-release compound, the TRH agonist, move back coupling protein 2 or 3 conditioning agents, the leptin agonist, the DA antagonist (bromocriptine, Doprexin), lipase/amylase inhibitor, the PPAR conditioning agent, RXR conditioning agent or TR-beta antagonists or amphetamines.
With at least a other claim 1-4 that subtracts the associating of appetite activeconstituents in one or multinomial compound, as the medicine of prevention or treatment of obesity.
11. with one or multinomial compound among at least a other claim 1-4 that subtracts the associating of appetite activeconstituents, as the medicine of prevention or treatment type ii diabetes.
12. produce the method for the medicine comprise among one or more claims 1-4 one or multinomial compound, described method comprises mixes activeconstituents and mixture is converted into the form that is suitable for administration with appropriate carriers pharmaceutically.
13. one or multinomial compound are used for the purposes of the medicine that weight of mammal alleviates among the claim 1-4 in production.
14. one or multinomial compound are used for preventing or the purposes of the medicine of treatment of obesity in production among the claim 1-4.
15. one or multinomial compound are used for preventing or treating the purposes of the medicine of type ii diabetes among the claim 1-4 in production.
16. one or multinomial compound are used for preventing or treating the purposes of the medicine of metabolism syndrome among the claim 1-4 in production.
17. one or multinomial compound are used for the treatment of purposes in the medicine of women or male sexual dysfunction in production among the claim 1-4.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10305885.0 | 2003-02-13 | ||
| DE10305885A DE10305885A1 (en) | 2003-02-13 | 2003-02-13 | New pyrazinopyrimidine or pyrazinoimidazole derivatives useful for weight reduction in mammals, for preventing or treating obesity, type II diabetes or metabolic syndrome and for treating sexual disorders |
| DE10349671.8 | 2003-10-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1747955A true CN1747955A (en) | 2006-03-15 |
Family
ID=32747777
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2004800039186A Pending CN1747955A (en) | 2003-02-13 | 2004-01-29 | Nitrogen-substituted hexahydropyrazino[1,2-a]pyrimidine-4,7-dione derivatives, method for the production and use thereof as medicaments |
| CNB2004800042121A Expired - Fee Related CN100363364C (en) | 2003-02-13 | 2004-01-29 | Substituted hexahydropyrazino(1,2-a)pyrimidin-4,7-dion derivatives, method for the production and use thereof as medicaments |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004800042121A Expired - Fee Related CN100363364C (en) | 2003-02-13 | 2004-01-29 | Substituted hexahydropyrazino(1,2-a)pyrimidin-4,7-dion derivatives, method for the production and use thereof as medicaments |
Country Status (3)
| Country | Link |
|---|---|
| CN (2) | CN1747955A (en) |
| DE (1) | DE10305885A1 (en) |
| ZA (2) | ZA200505419B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102186853A (en) * | 2008-10-14 | 2011-09-14 | 株式会社棱镜生物实验室 | Alpha helix mimetics in the treatment of cancer |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6184223B1 (en) * | 1995-10-27 | 2001-02-06 | Molecumetics Ltd. | Reverse-turn mimetics and methods relating thereto |
| US6013458A (en) * | 1995-10-27 | 2000-01-11 | Molecumetics, Ltd. | Reverse-turn mimetics and methods relating thereto |
| US6294525B1 (en) * | 1999-09-01 | 2001-09-25 | Molecumetics Ltd. | Reverse-turn mimetics and methods relating thereto |
-
2003
- 2003-02-13 DE DE10305885A patent/DE10305885A1/en not_active Withdrawn
-
2004
- 2004-01-29 CN CNA2004800039186A patent/CN1747955A/en active Pending
- 2004-01-29 CN CNB2004800042121A patent/CN100363364C/en not_active Expired - Fee Related
-
2005
- 2005-07-05 ZA ZA200505419A patent/ZA200505419B/en unknown
- 2005-07-05 ZA ZA200505420A patent/ZA200505420B/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102186853A (en) * | 2008-10-14 | 2011-09-14 | 株式会社棱镜生物实验室 | Alpha helix mimetics in the treatment of cancer |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200505420B (en) | 2006-07-26 |
| DE10305885A1 (en) | 2004-08-26 |
| CN1751046A (en) | 2006-03-22 |
| ZA200505419B (en) | 2006-03-29 |
| CN100363364C (en) | 2008-01-23 |
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