CN1431904A - Protease inhitors - Google Patents

Protease inhitors Download PDF

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Publication number
CN1431904A
CN1431904A CN01808290A CN01808290A CN1431904A CN 1431904 A CN1431904 A CN 1431904A CN 01808290 A CN01808290 A CN 01808290A CN 01808290 A CN01808290 A CN 01808290A CN 1431904 A CN1431904 A CN 1431904A
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base
pyridine
alkyl
azepan
carboxylic acid
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Inventor
马克斯韦尔·D·卡明斯
小罗伯特·W·马奎斯
汝玉
斯科特·K·汤普森
丹尼尔·F·维伯
丹尼斯·S·雅马什塔
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Abstract

The present invention provides methods which use 4-amino-azepan-3-one protease inhibitors of cathepsin S in the treatment of diseases in which cathepsin S is implicated, especially treatment or prevention of autoimmune disease; treatment or prevention of a disease state caused by the formation of atherosclerotic lesions and complications arising therefrom; and diseases requiring inhibition, for therapy, of a class II MHC-restricted immune response, inhibition of an asthmatic response, inhibition of an allergic response, inhibition of immune response against a transplanted organ or tissue, or inhibition of elastase activity in atheroma, and novel compounds for use therewith.

Description

Protease inhibitor
Invention field
The present invention relates generally to 4-amino-azepan-3-ketone protease inhibitors, especially cathepsin S inhibitor, in treatment and cathepsin S diseases associated, especially treats or the prevention autoimmune disease; Treatment or prevention form caused disease and its complication that causes by the atheroma damage; Disease with treating the immunne response that needs inhibition II class MHC-limitation suppresses asthmatic and reacts, and suppresses anaphylactic reaction, and inhibition is transplanted the immunoreation that causes by organ or tissue, or is suppressed at the purposes of elasticity protease activities in the sebaceous cyst; Noval chemical compound with this application.
Background of invention
Cathepsin is the gang's protease as the part of the papain superfamily of cysteine proteinase.Cathepsin K, B, H, L, N and S described in the literature.
Cathepsin comprises the degraded of human body internal protein animal, for example brings into play function in the normal physiological processes of connective tissue degradation.But the level of these enzymes raises and may cause producing the pathological conditions of disease in vivo.Therefore, cathepsin includes but not limited to by Pneumocystis carinii in various diseases, the short film insect infection of Oswaldocruzia and fusiformis; And in schistosomicide, malaria, neoplasm metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy is counted as causative agent in waiting.Referring on March 3rd, 1994 disclosed WO94/04172 and the list of references wherein quoted.Also referring to European patent application EP 0603873A1 and the list of references wherein quoted.Two of the isolated gingipains of being called kinds of antibacterial cysteine proteinases have been counted as the cause of disease of gingivitis from P.gingivall.Potempa, J. etc. (1994) Perspectives in Drug Discovery and Design, 2,445-458.Cathepsin K has been considered to the effect of the cause of disease in the disease of excessive bone or cartilage loss.Referring on May 9th, 1997 disclosed WO97/16433 and the list of references wherein quoted.
The pathology level of cathepsin S is related with various diseases.For example, the mice with inhibitor for treating shows that the antibody response that weakens shows that the selectivity of cathepsin S suppresses can provide the treatment countermeasure to asthma and autoimmune disease.Riese, RichardJ. etc., J.Clin Invest.1998 101 (11), 2351-2363. therefore, the selectivity of cathepsin S suppresses to provide effective treatment to the disease of needs treatment or prevention: suppress the immunne response of II class MHC-limitation, treat and/or prevent autoimmune disease such as rheumatoid arthritis, multiple sclerosis, juvenile diabetes, systemic lupus erythematosus (sle), discoid lupus erythematosus, pemphigus vulgaris, pemphigoid, grave disease, myasthenia gravis, chronic lymphocytic thyroiditis, scleroderma, dermatomyositis, bronzed disease, pernicious anemia, constitutional solid edema, thyrotoxicosis, the autoimmune atrophic gastritis, stiff person's syndrome, Goodpasture syndrome, sympathetic ophthalmia, phacoantigenic uveitis, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, the special property sent out leukopenia, primary biliary cirrhosis, active chronic hepatitis, latent source property hepatitis interstitialis chronica, ulcerative colitis, xerodermosteosis, and mixed connective tissue disease; Suppress asthma reaction; Suppress anaphylaxis; The immunoreation that inhibition is caused by organ or tissue's transplanting (referring to L.Roitt, J.Brostoff, D.Male, Immunology, Fifth Edition, 1998, p.368; R.J.Riese etc., Immunity, 1996,4,357-366; GP Shi etc., Immunity 1999,10,197-206; T.Nakagawa etc., Immunity 1999,10,207-217; And WO97/40066); The activity that suppresses the sebaceous cyst elastoser; Treatment or prevention form caused disease and its complication that causes (G.K.Sukhova etc., J.Clin.Invest.1998,102,576) by the atheroma damage.
A few class cystatins are known.Palmer etc. (1995), J.Med.Chem., 38,3193, disclose some and irreversibly suppressed cysteine proteinase, as cathepsin B, L, S, the vinyl sulfone of O2 and cruzain.The chemical compound of other types such as aldehydes, nitrile, α-ketone carbonyl compound, the halogenated methyl ketone, azo methyl ketone, (acyloxy) methyl ketone, ketone group methyl sulfonium salt and epoxy succinic acyl compounds also have been in the news can suppress cysteine proteinase.Referring to Palmer, the same and list of references wherein quoted.
US-4,518,528 disclose the irreversible inhibitor of peptidyl methyl fluoride ketone as cysteine proteinase.Disclosed International Patent Application WO 94/04172 and European patent application EP 0525420A1, EP0603873A1, and EP0611756A2 has described and can suppress cysteine proteinase cathepsin B, the alkoxy methyl of H and L and mercapto methyl ketone.International Patent Application PCT/US94/08868 and European patent application EP 0623592A1 have described the alkoxy methyl and the mercapto methyl ketone that can suppress cysteine proteinase IL-1 'beta ' converting emzyme.Alkoxy methyl and mercapto methyl ketone have been described to the inhibitor (International Patent Application PCT/GB91/01479) of serine protease kininogenase.
Be designed to nitrogen aminoacid is transported to the serine protease site, and the nitrogen peptide with good leaving group is disclosed Flmore etc., Biochem.J., 1968,107,103, garker etc., Biochem.J., 1974,139,555, gray etc., Tetrahedron, 1977,33,837, gupton etc., J.Biol.Chem., 1984,259,4279, Powers etc., J.Biol.Chem., 1984,259,4288, and knownly can suppress serine protease.In addition, J.Med.Chem., 1992,35,4279, some nitrogen peptide as cystatin is disclosed.
Protease inhibitor and leupeptin be at McConnell etc., and J.Med.Chem. is described to the reversible inhibitor of cysteine proteinase in 33,86; At Umezawa etc., among 45 Meth.Enzymol.678, also be disclosed as the inhibitor of serine protease.E64 and its synthetic analogues also are the cystatin known (Barrett, Biochem.J., 201,189, and Grinde, Biochem.Biophys.Acta, 701,328).
1,3-diamides base-acetone class is at US-4, has been described to analgesic in 749,792 and 4,638,010.
Various cysteine and serine protease, especially cathepsin K inhibitor disclose among the open WO97/16433 in the disclosed world on May 9th, 1997.
We have had now found that 4-amino-azepan-3-ketonic compound of some inhibition of histone enzyme S, and can be used for treatment and cathepsin S diseases associated.
Brief summary of the invention
A target of the present invention provides with the 4-amino-azepan-3-ketone carbonyl protease inhibitor of the cathepsin S that can be used for treating formula I that can the disease that therapeutic is improved by the activity that changes cathepsin S and treats the method for disease.
Aspect concrete, method of the present invention is particularly useful for treatment or prevention autoimmune disease; Treatment or prevention form caused disease and its complication that causes by the atheroma damage; Treatment needs the disease of the immunne response of inhibition II class MHC-limitation, suppresses the asthmatic reaction, suppresses anaphylactic reaction, and inhibition is transplanted the immunoreation that causes by organ or tissue, or is suppressed at elasticity protease activities in the sebaceous cyst.
Another target of the present invention provides the noval chemical compound that is used for the inventive method.
Detailed Description Of The Invention
The invention provides the method for inhibition of histone enzyme S, comprise that the animal to needs, particularly mammal, the most particularly people use the formula I chemical compound of effective dose: Wherein:
R 1Be selected from as next group:
Figure A0180829000272
With
Figure A0180829000273
R 2Be selected from as next group: H, C 1-6Alkyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl, Het-C 0-6Alkyl, R 9C (O)-, R 9C (S)-, R 9SO 2-, R 9OC (O)-,
R 9R 11NC (O)-, R 9R 11NC (S)-, R 9(R 11) NSO 2- With
Figure A0180829000275
R 3Be selected from as next group: H, C 1-6Alkyl, C 3-6Cycloalkyl-C 0-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, HetC 0-6Alkyl, ArC 0-6Alkyl, Ar-ArC 0-6Alkyl, Ar-HetC 0-6Alkyl, Het-ArC 0-6Alkyl, and Het-HetC 0-6Alkyl;
R 3And R ' can be connected to form pyrrolidine, piperidines or morpholine ring;
R 4Be selected from as next group: H, C 1-6Alkyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl, Het-C 0-6Alkyl, R 5C (O)-, R 5C (S)-, R 5SO 2-, R 5OC (O)-, R 5R 13NC (O)-, and R 5R 13NC (S)-;
R 5Be selected from as next group: H, C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl and Het-C 0-6Alkyl;
R 6Be selected from as next group: H, C 1-6Alkyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl, and Het-C 0-6Alkyl;
R 7Be selected from as next group: H, C 1-6Alkyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl, Het-C 0-6Alkyl, R 10C (O)-, R 10C (S)-, R 10SO 2-, R 10OC (O)-, R 10R 14NC (O)-, and R 10R 14NC (S)-;
R 8Be selected from as next group: H, C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, HetC 0-6Alkyl and ArC 0-6Alkyl;
R 9Be selected from as next group: C 1-6Alkyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl and Het-C 0-6Alkyl;
R 10Be selected from as next group: C 1-6Alkyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl and Het-C 0-6Alkyl;
R 11Be selected from as next group: H, C 1-6Alkyl, Ar-C 0-6Alkyl, and Het-C 0-6Alkyl;
R 12Be selected from as next group: H, C 1-6Alkyl, Ar-C 0-6Alkyl, and Het-C 0-6Alkyl;
R 13Be selected from as next group: H, C 1-6Alkyl, Ar-C 0-6Alkyl, and Het-C 0-6Alkyl;
R 14Be selected from as next group: H, C 1-6Alkyl, Ar-C 0-6Alkyl, and Het-C 0-6Alkyl;
R ＇ is selected from as next group: H, C 1-6Alkyl, Ar-C 0-6Alkyl, and Het-C 0-6Alkyl;
R " is selected from as next group: H, C 1-6Alkyl, Ar-C 0-6Alkyl, or Het-C 0-6Alkyl;
R is selected from as next group: H, C 1-6Alkyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl, and Het-C 0-6Alkyl;
X is selected from as next group: CH 2, S, and O;
Z is selected from as next group: C (O) and CH 2
With its pharmaceutical salts, hydrate and solvate.
In formula I chemical compound, R 1Preferably In this compounds:
R 3Be selected from as next group: H, C 1-6Alkyl, C 3-6Cycloalkyl-C 0-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, Het-C 0-6Alkyl and Ar-C 0-6Alkyl, preferably C 3-6Cycloalkyl-C 0-6Alkyl and C 1-6Alkyl is selected from particularly as next group: cyclohexyl methyl and 2, the 2-dimethyl propyl more preferably is C 3-6Cycloalkyl-C 0-6Alkyl most preferably is a cyclohexyl methyl;
R 4Be selected from as next group: H, C 1-6Alkyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl, Het-C 0-6Alkyl, R 5C (O)-, R 5C (S)-, R 5SO 2-, R 5OC (O)-, R 5R 13NC (O)-, and R 5R 13NC (S)-, R preferably 5C (O)-.
R 5Be selected from as next group: C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl. R preferably 5Be selected from as next group: C 1-6Alkyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl and Het-C 0-6Alkyl.More preferably be R 5Be selected from as next group:
Furyl, furan-2-base and furan-3-base particularly, the furyl that replaces of aryl more specifically, also basic and 5-(3-trifluoromethyl-phenyl)-furan-2-base of 5-(4-chloro-phenyl)-furan-2-more specifically;
Benzofuranyl, benzofuran-2-base, more specifically C particularly 1-6The benzofuranyl that alkoxyl replaces, particularly 5,6-dimethoxy-benzofuran-2-base and 5-(2-morpholine-4-base-ethyoxyl) benzofuran-2-base;
Thienyl, thiene-3-yl-and thiophene-2-base, more specifically Het-C particularly 0-6Alkyl-thienyl; 5-pyridine-2-base-thiophene-2-base, more specifically C particularly 1-6Alkyl-thienyl, particularly 5-methyl-thiophene-2-base and 3-methyl-thiophene-2-base; C more specifically 1-6Alkoxyl-thienyl, particularly 3-ethyoxyl-thiophene-2-base;
Furo [3,2-b]-pyridine-2-base, C particularly 1-6Alkyl-furo [3,2-b]-pyridine-2-base, more specifically 3-methyl-furo [3,2-b]-pyridine-2-base;
Thiazolyl, thiazole-5-base, more specifically Het-C particularly 0-6Alkyl-thiazolyl, particularly 4-methyl-2-pyridine-2-base-thiazole-5-base;
Phenyl, the phenyl, particularly bromophenyl of halogen replacement, more especially 4-bromophenyl particularly;
Cyclobutyl;
Cyclopenta;
Tetrahydrofuran base, oxolane-2-base;
Selenophen base, selenophen-2-base particularly; With
Thieno [3,2-b] thienyl, thieno [3,2-b] thiophene-2-base particularly.
R ＇ is selected from as next group: H, C 1-6Alkyl, Ar-C 0-6Alkyl, and Het-C 0-6Alkyl, preferably H.
R " is selected from as next group: H, C 1-6Alkyl, Ar-C 0-6Alkyl, and Het-C 0-6Alkyl, preferably H.
In formula I chemical compound, R 2Be selected from as next group: H, C 1-6Alkyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl, Het-C 0-6Alkyl, R 9C (O)-, R 9C (S)-, R 9SO 2-, R 9OC (O)-, R 9R 11NC (O)-, R 9R 11NC (S)-, R 9R 11NSO 2-.
Figure A0180829000301
With
Figure A0180829000302
R preferably 2Be selected from as next group: R 9SO 2And C 1-6Alkyl.Work as R 2Be C 1-6During alkyl, C 1-6Alkyl is propyl group preferably.R 2Most preferably be R 9SO 2
R 9Be selected from as next group: C 1-6Alkyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl, and Het-C 0-6Alkyl, preferably Het-C 0-6Alkyl more preferably is pyridine radicals and 1-oxygen base-pyridine radicals.Work as R 2Be R 9SO 2The time, R 9Also more preferably be to be selected from: pyridine-2-base and 1-oxygen base-pyridine-2-base as next group.Most preferably be R 9It is pyridine-2-base.
Preferred formula I chemical compound is wherein:
R 1Be
R 2Be R 9SO 2
R 3Be C 3-6Cycloalkyl-C 0-6Alkyl;
R 4Be R 5C (O);
R 5Be Het-C 0-6Alkyl;
R 9Be Het-C 0-6Alkyl;
R ＇ is H
R " is H; With
R is C 1-6Alkyl.
Also preferred formula I chemical compound is wherein:
R 1Be
R 2Be R 9SO 2
R 3It is cyclohexyl methyl;
R 4Be R 5C (O);
R 5Be selected from as next group: furyl, furan-2-base particularly, and thienyl, thiene-3-yl-particularly;
R 9Be selected from as next group: pyridine-2-base and 1-oxygen base-pyridine-2-base, preferably pyridine-2-base;
R ＇ is H
R " is H; With
R is selected from as next group: H and C 1-6Alkyl.When R is C 1-6During alkyl, R is:
Be selected from particularly as next group: methyl, ethyl, propyl group, butyl, amyl group and hexyl, more specifically methyl;
Preferably be selected from as next group: 5-6-or 7-C 1-6Alkyl is selected from particularly as next group: 5-, 6-or 7-methyl ,-ethyl ,-propyl group ,-butyl ,-amyl group and-hexyl, more specifically be selected from as next group: 5-6-or 7-methyl;
More preferably be to be selected from: 6-or 7-C as next group 1-6Alkyl is selected from particularly as next group: 6-or 7-methyl ,-ethyl ,-propyl group ,-butyl ,-amyl group and-hexyl, more specifically be selected from as next group: 6-or 7-methyl;
Also more preferably be suc as formula the cis-7-C shown in the Ia 1-6Alkyl: Wherein R is C 1-6Alkyl is selected from particularly as next group: methyl, ethyl, propyl group, butyl, amyl group and hexyl;
Most preferably be wherein R be methyl suc as formula the cis shown in the Ia-7-methyl.
Being selected from following one group formula I chemical compound is to be used for particularly preferred chemical compound of the present invention:
Figure A0180829000312
Benzofuran-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
5-(3-trifluoromethyl-phenyl)-furan-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
5-(4-chloro-phenyl)-furan-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000323
5-(4-chloro-phenyl)-furan-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000324
5-(3-trifluoromethyl-phenyl)-furan-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000325
5,6-dimethoxy-benzofuran-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Furan-2-carboxylic acid (S)-and 2-cyclohexyl-1-[(4S, 7R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000332
Benzofuran-2-carboxylic acid (S)-and 2-cyclohexyl-1-[(4S, 7R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000333
Thiophene-3-carboxylic acid (S)-and 2-cyclohexyl-1-[(4S, 7R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000334
3-methyl-furo [3,2-b]-pyridine-2-carboxylic acids (S)-and 2-cyclohexyl-1-[(4S, 7R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
5-(2-morpholine-4-base-ethyoxyl)-benzofuran-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
4-methyl-2-pyridine-2-base-thiazole-5-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000343
5-pyridine-2-base-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000344
Furan-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000352
Thiophene-3-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000353
5-methyl-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000354
3-methyl-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
3-ethyoxyl-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000362
4-bromo-N-{ (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-Benzoylamide;
Cyclobutylcarboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Cyclopentane carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000371
(S)-tetrahydrochysene-furan-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
(R)-tetrahydrochysene-furan-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000373
Furan-3-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
5-pyridine-2-base-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
4-methyl-2-pyridine-2-base-thiazole-5-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000382
5-(2-morpholine-4-base-ethyoxyl)-benzofuran-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000383
Furan-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000384
Furan-3-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Thiophene-3-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000392
Thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000393
5-methyl-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000394
3-methyl-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000395
3-ethyoxyl-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Selenophen-2-carboxylic acid (S)-and the 2-cyclohexyl-1-[(R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Furan-2-carboxylic acid [(S)-2-cyclohexyl-1-((4S, 7R)-7-methyl-3-oxo-1-propyl group-azepan-4-base carbamoyl)-ethyl]-amide;
Figure A0180829000403
Thiophene-3-carboxylic acid [(S)-2-cyclohexyl-1-((4S, 7R)-7-methyl-3-oxo-1-propyl group-azepan-4-base carbamoyl)-ethyl]-amide;
Benzofuran-2-carboxylic acid [(S)-2-cyclohexyl-1-((4S, 7R)-7-methyl-3-oxo-1-propyl group-azepan-4-base carbamoyl)-ethyl]-amide;
2,2,4-three deuterium generation-furan-2-carboxylic acid (S)-and 2-cyclohexyl-1-[(4S, 7R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000412
Thiophene-3-carboxylic acid (S)-3,3-dimethyl-1-[(4S, 7R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-butyl }-amide;
Figure A0180829000413
Furan-2-carboxylic acid (S)-3,3-dimethyl-1-[(4S, 7R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-butyl }-amide; With
Thieno [3,2-b] thiophene-2-carboxylic acid (S)-3,3-dimethyl-1-[(4S, 7R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-butyl }-amide.
The formula I chemical compound that is selected from as next group is the more particularly preferred chemical compound of the present invention that is used for:
Furan-2-carboxylic acid (S)-and 2-cyclohexyl-1-[(4S, 7R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide; With
Figure A0180829000422
Thiophene-3-carboxylic acid (S)-and 2-cyclohexyl-1-[(4S, 7R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide.
Following compounds is the most preferred formula I chemical compound of the present invention that is used for:
Figure A0180829000423
Furan-2-carboxylic acid (S)-and 2-cyclohexyl-1-[(4S, 7R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide.
The invention provides following noval chemical compound:
Figure A0180829000431
5-(2-morpholine-4-base-ethyoxyl)-benzofuran-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000432
4-methyl-2-pyridine-2-base-thiazole-5-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000433
5-pyridine-2-base-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Furan-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Thiophene-3-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000442
5-methyl-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
3-methyl-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
3-ethyoxyl-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
4-bromo-N-{ (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-Benzoylamide;
Figure A0180829000452
Cyclobutylcarboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000453
Cyclopentane carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000454
(S)-tetrahydrochysene-furan-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000455
(R)-tetrahydrochysene-furan-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000461
Furan-3-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
5-pyridine-2-base-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000463
4-methyl-2-pyridine-2-base-thiazole-5-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
5-(2-morpholine-4-base-ethyoxyl)-benzofuran-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000471
Furan-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000472
Furan-3-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Thiophene-3-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
5-methyl-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000481
3-methyl-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000482
3-ethyoxyl-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000483
Selenophen-2-carboxylic acid (S)-and the 2-cyclohexyl-1-[(R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide; With
Figure A0180829000484
2,2,4-three deuterium generation-furan-2-carboxylic acid (S)-and 2-cyclohexyl-1-[(4S, 7R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide.
The concrete representative compounds that is used for the present invention provides in embodiment 1-44.
Compare with 6 Yuans cycle compounds with corresponding 5,7 Yuans cycle compounds that are used for the present invention are more stable in configuration in the carbon center of the α position of ketone.
The present invention also uses the deuterium of The compounds of this invention for analog.This class deuterium provides in embodiment 7 and 41 for the representative example of chemical compound.Deuterium of the present invention for the representative route of synthesis of chemical compound below route 3 and embodiment 7 and 41 in provide.Compare with its proton isomer, the deuterium that uses among the present invention goes out good chirality stability for compound exhibits.
Definition
The chemical compound that uses among the present invention comprises all hydrates, solvate, coordination compound and prodrug.Prodrug is the covalent bond chemical compound of the active parent drug of release type I in vivo.If have chiral centre or other forms of isomery center in the chemical compound that the present invention uses, then this class isomer of form of ownership comprises enantiomer and diastereomer, is all covered by this paper.The chemical compound that contains chiral centre that uses among the present invention can be with racemic mixture, and the mixture of enantiomer enrichment uses, maybe can be with any known technology separation of racemic mixture and the single enantiomer that can use separately.Chemical compound has under the situation of unsaturated carbon-to-carbon double bond therein, and cis (Z) and trans (E) isomer are all within the scope of the present invention.Chemical compound can be with tautomeric form therein, under the situation that ketone-pure tautomerism exists, no matter it is with poised state, or in the highest flight a kind of, each tautomeric form all is included within the scope of the invention.
Unless stated otherwise, any substituent meaning of any position is independent of itself meaning of any other position in formula I or its any inferior formula, or any other substituent meaning.
Being usually used in the abbreviation of peptide and chemical field and symbol is used to the present invention and describes The compounds of this invention.In general, amino acid whose abbreviation is according to Eur.J.Biochem., and the IUPAC-IUB Joint Commission on Biochemical Nomenclature described in 158,9 (1984) names.
" protease " is peptide and the proteinic amido link cracking of can catalysis being undertaken by the nucleophilic displacement of fluorine of amido link, finally causes the enzyme of hydrolysis.This albuminoid enzyme comprises: cysteine proteinase, serine protease, aspartic protease, and metalloproteases.The compounds of this invention combines with enzyme more strongly than substrate, and generally not cracking after enzymatic nucleopilic reagent attack.Thereby they can prevent protease identification and hydrolysis natural substrate competitively, thereby play inhibitor.
Term used herein " aminoacid " refers to alanine, arginine, agedoite, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, the D-of tyrosine and valine or L-isomer.
" hydrogen " or " H " comprises its all possible isotope, comprise " deuterium " or " D " or " 2H "; With " tritium " or " T " or " 3H ".
" C used herein 1-6Alkyl " comprise replacement and unsubstituted methyl, ethyl, just-and propyl group, isopropyl, just-and butyl, isobutyl group and tert-butyl, amyl group, just-and amyl group, isopentyl, neopentyl and hexyl and its simple aliphatic isomer.C 1-6Alkyl can the non-imposed replacement of selected next group group freely: OR 14, C (O) R 14, SR 14, S (O) R 14, NR 14 2, R 14NC (O) or 5, CO 2R 14, CO 2NR 14 2, N (C=NH) NH 2, Het, C 3-6Cycloalkyl, and Ar; R wherein 5Be selected from as next group: H, C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl and Het-C 0-6Alkyl; And R 14Be selected from as next group: H, C 1-6Alkyl, Ar-C 0-6Alkyl, and Het-C 0-6Alkyl;
" C used herein 3-6Cycloalkyl " comprise replacement with unsubstituted cyclopropane, Tetramethylene., Pentamethylene. and cyclohexane extraction.
" C used herein 2-6Thiazolinyl " refers to that wherein the carbon-to-carbon singly-bound is by displaced 2 to the 6 carbon alkyl of carbon-to-carbon double bond.C 2-6Thiazolinyl comprises ethylene, 1-propylene, 2-propylene, 1-butylene, 2-butylene, the amylene of isobutene. and several isomeries and hexene.Cis and transisomer are all included.
" C 2-6Alkynyl " refers to that one of them carbon-to-carbon singly-bound is by displaced 2 to the 6 carbon alkyl of carbon-to-carbon three key.C 2-6Alkynyl comprises acetylene, 1-propine, 2-propine, ethyl acetylene, 2-butyne, the simple isomer of 3-butine and pentyne and hexin.
" halogen " refers to F, Cl, Br, and I.
" Ar " or " aryl " refers to phenyl or naphthyl, non-imposedly by one or more Ph-C 0-6Alkyl; Het-C 0-6Alkyl; C 1-6Alkoxyl; Ph-C 0-6Alkoxyl; Het-C 0-6Alkoxyl; OH, (CH 2) 1-6NR 15R 16O (CH 2) 1-6NR 15R 16C 1-6Alkyl, OR 17, N (R 17) 2, SR 17, CF 3, NO 2, CN, CO 2R 17, CON (R 17), F, Cl, Br or I replace; R wherein 15And R 16Be H, C 1-6Alkyl, Ph-C 0-6Alkyl, naphthyl-C 0-6Alkyl or Het-C 0-6Alkyl; And R 17Be phenyl, naphthyl, or C 1-6Alkyl.
Stable 5-to the 7-member monocycle of " Het " used herein or " heterocycle " expression, stable 7-to 10-member dicyclo, or stable 11-to 18-member tricyclic heterocyclic, they are saturated or unsaturated, and be selected from N by carbon atom and one to three, and the hetero atom of O and S is formed, and wherein nitrogen and sulfur heteroatom can be oxidized, and nitrogen heteroatom can be non-imposedly by quaternized, and comprise arbitrarily the condensed bicyclic radicals of heterocycle and phenyl ring as defined above.This heterocycle can connect on any hetero atom that causes rock-steady structure to produce or carbon atom, and can be selected from C by one or two non-imposedly 0-6Ar, C 1-6Alkyl, OR 17, N (R 17) 2, SR 17, CF 3, NO 2, CN, CO 2R 17, CON (R 17), F, Cl, the group of Br and I replaces, wherein R 17Be phenyl, naphthyl, or C 1-6Alkyl. the heterocyclic example of this class comprises can obtain and stable piperidyl piperazinyl, 2-oxo-piperazinyl by the chemosynthesis approach, 2-oxo-piperidyl, 2-oxo-pyrrolidinyl, 2-oxo-azepines base, the azepines base, pyrrole radicals, 4-piperidone base, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazole radicals, pyridine radicals, 1-oxo--pyridine radicals, pyrazinyl ， oxazolidinyl ， oxazolinyl oxazolyl ， isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl, quininuclidinyl, indyl, quinolyl, quinoxalinyl, isoquinolyl, benzimidazolyl, benzopyranyl, benzoxazolyl, furyl, benzofuranyl, thienyl, benzo [b] thienyl, thieno [3,2-b] thienyl, benzo [1,3] dioxa cyclopentenyl, 1, the 8-phthalazinyl, pyranose, tetrahydrofuran base, THP trtrahydropyranyl, thienyl, benzoxazolyl, thio-morpholinyl sulfoxide, thio-morpholinyl sulfone ， is with the oxadiazole base, and triazolyl, thiadiazolyl group ， oxadiazole base, isothiazolyl, imidazole radicals, pyridazinyl, pyrimidine radicals, triazine radical and tetrazine base.Term hetero atom used herein refers to oxygen, nitrogen and sulfur.
The term C that the application is used in full 0The substituent group that refers on it to be followed does not exist; For example, at ArC 0-6In the alkyl, when C was 0, substituent group was Ar, for example, and phenyl.On the contrary, work as ArC 0-6Alkyl and concrete aryl for example, when phenyl was identical, the numerical value that should be appreciated that C was 0.
Some groups are abridged at this paper.T-Bu refers to the tert-butyl group, and Boc refers to the t-butoxy carbonyl, and Fmoc refers to the fluorenyl methoxy carbonyl, and Ph refers to phenyl, and Cbz refers to benzyloxycarbonyl.
Some reagent are abridged at this paper, m-CPBA refers to the 3-chloroperoxybenzoic acid, EDC refers to N-ethyl-N ＇ (dimethylaminopropyl)-carbodiimide, P-EDC refers to the EDC of polymer carrying, and DMF refers to dimethyl formamide, and DMSO refers to dimethyl sulfoxine, NMM refers to N-methylmorpholine, TEA refers to triethylamine, the TFA trifluoroacetic acid, and THF refers to oxolane.
Preparation method
The chemical compound of general formula I can be used in generalized similarity method preparation in the route 1 to 5.N-allyl amino formic acid benzyl ester (1) provides diene 2 (route 1) with alkali such as sodium hydride and the alkylation of 5-bromo-1-amylene.Two (tricyclohexyl phosphine) benzal chloride ruthenium (IV) olefin metathesis catalyst with the Grubbs exploitation handles 2, provides tetrahydroazepine 3.Oxidant such as the m-CPBA commonly used with this specialty make 3 epoxidations provide epoxide 4.Can make nucleophilic epoxide open loop with reagent, provide azido alcohol 5 such as Hydrazoic acid,sodium salt, with it under the commonly used condition of this specialty, as in methanol 1,3-dimercaptopropane and triethylamine, perhaps the triphenylphosphine in THF and water is reduced to amino alcohol 6.The amine of chemical compound 6 can provide N-Boc derivant 7 (route 2) with coke acid di-t-butyl ester (di-tert-butyldicarbonate) protection.Can provide amine 8 by in the presence of catalyst such as 10%Pd/C, sloughing the benzyloxycarbonyl group protecting group with hydrogen treat 7.In the presence of alkali such as N-methylmorpholine or triethylamine, handle amine 8 with sulfonic acid chloride such as 2-pyridine sulfonic acid chloride and provide sulfamide derivative 9.Slough the tertbutyloxycarbonyl protecting group with sour example hydrochloric acid and provide intermediate 10.10 provide alcohol intermediate 11 with the coupling in the presence of the EDC that coupling agent that this specialty is used always such as HBTU or polymer carry of acid as N-Boc-phenylalanine.Under acid condition, remove the tertbutyloxycarbonyl protecting group and provide amine 12.12 and sour as the coupling in the presence of the EDC of coupling agent such as HBTU or polymer carrying of benzofuran-2-carboxylic acid, provide alcohol 13.The oxidant that alcohol 13 can be used always with this specialty provides ketone 14 as pyridine sulfur trioxide complex or the high iodine alkoxide of Dess-Martin at DMSO and triethylamine.
Route 1
Reagent and condition: (a) NaH, 5-bromo-1-amylene, NaH; (b) two (tricyclohexyl phosphine) benzal chloride ruthenium (IV), CH 2Cl 2, reflux; (c) m-CPBA, CH 2Cl 2(d) NaN 3, NH 4Cl, CH 3OH, H 2O; (e) TEA, 1,3-dimercaptopropane, CH 3OH.
Route 2
Reagent and condition: (a) coke acid two-tert-butyl group, THF; (b) H 2, 10%Pd/C, EtOAc; (c) 2-pyridine radicals sulfonic acid chloride, TEA, DMF; (d) HCl, EtOAc; (e) N-Boc-Cyclohexylalanine, P-EDC, CH 2Cl 2(f) HCl, CH 2Cl 2(g) benzofuran-2-carboxylic acid, P-EDC, CH 2Cl 2(h) the high iodine alkane of Dess-Martin, dichloromethane.
The deuterium of embodiment 7 can pass through easily for chemical compound Route 3Preparation.Those skilled in the art will be appreciated that from embodiment 7 and route 3 deuterium how to make any The compounds of this invention is for chemical compound.
Benzofuran-2-carboxylic acid { (S)-3-methyl isophthalic acid-[(2,2 ＇, 4-three deuteriums generation)-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-butyl } amide 16 and each diastereomer of 17 can as Route 3In the preparation of generalized method.
Route 3
Reagent and condition: a.) CD 3OD; D 2O (10: 1), TEA; B.) HPLC separates.
With triethylamine at CD 3OD: D 2Under refluxing, handle diastereomer ketone 15 among the O and provide deuterium as non-enantiomer mixture, separate obtaining deuterium again by HPLC for chemical compound 16 and 17 for homologue.
Route 4
Figure A0180829000551
Route 4, benzyloxycarbonyl group-D-third amino alcohol (Cbz-D-third amino alcohol) at first is converted into iodide, then with pi-allyl Grignard reagent that has copper (I) catalyst or similarly pi-allyl organometallic reagent reaction.This amine is used the allyl iodide alkylation then.Form azepine with the Grubbs catalyst by the closed loop transposition then.This alkene is then separated diastereomer by epoxidation, makes the submember open loop with Hydrazoic acid,sodium salt then, provides intermediate azido alcohol.The reduction azide then with the aminoacid such as the Boc-Cyclohexylalanine acylated amine of protection, makes the Cbz deprotection then, provides intermediate secondary amine, uses sulfonic acid chloride such as pyridine sulfonic acid chloride sulfonylation then.Make the Boc deprotection, then with acylating agent such as pyromucic acid, HBTU, the NMM acidylate is oxidized to ketone with secondary alcohol at last, provides required product.
Route 5
Figure A0180829000561
As route 4 described intermediate (S)-3-cyclohexyl-N-((3S, 4S, 7R)-3-hydroxyl-7-methyl-azepan-4-yl)-2-methyl-propionic acid amide. and aldehydes or ketones such as propionic aldehyde carry out reductive amination, handle with Reducing agent such as sodium borohydride then.Make Boc base deprotection, then with acylating agent such as pyromucic acid, HBTU, the NMM acidylate is oxidized to ketone with secondary alcohol at last, provides required product.
Raw material used herein is the aminoacid that can buy on the market or known by this area professional and technical personnel, and can be at canonical reference book such as COMPENDIUM OF ORGANIC SYNTHETICMETHODS, the method preparation of finding among the Vol.I-VI (Wiley-Interscience publication).
The couling process of the formation amido link of this paper is that this specialty is known.By Bodansky etc., THEPRACTICE OF PEPTIDE SYNTHESIS, Springer-Verlag, Berlin, 1984; E.gross and J.Meienhofer, THE PEPTIDES, Vol.1,1-284 (1979); With J.M.Stewart and J.D.Young, SOLID PHASE PEPTIDE SYNTHESIS, 2d Ed., Pierce ChemicalCo., Rockford, Ill., 1984. the synthetic method of the peptide that provides generally is used to illustrate this technology, and draws and make this paper list of references.
The synthetic method of preparation The compounds of this invention protecting group commonly used is come the active functional group of protective reaction, and unwanted side reaction is minimized.This class protecting group is at Green, T.W, PROTECTIVEgROUPS IN ORGANIC SYNTHESIS, John Wiley﹠amp; Describe among the Sons, NewYork (1981).Term " amino protecting group " is often referred to Boc, acetyl group, benzoyl, Fmoc and Cbz base and the known derivant of its this specialty.The method that protection and deprotection and amino protecting group are replaced by other groups is known.
The acid-addition salts of formula I chemical compound with standard method by being suitable for parent compound and excessive acid, example hydrochloric acid, hydrobromic acid, Fluohydric acid., sulphuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid or methanesulfonic acid prepare in solvent.Acceptable inner salt of some compound formation or amphion salt.Cationic salts is by use excess base reagent, as contains suitable cationic hydroxide, carbonate or alkoxide, or with suitable organic amine processing parent compound and prepare.Cation such as Li +, Na +, K +, Ca ++, Mg ++And NH 4 +It is the cationic object lesson that in pharmaceutical salts, exists.Halogenide, sulfate, phosphate, alkane carboxylate (as the acetate trifluoroacetate), benzoate, and sulfonate (as mesylate) is the anionic example that is present in the officinal salt.
Method of the present invention can comprise one or more formulas I chemical compound and pharmaceutically suitable carrier by use, the pharmaceutical composition of diluent or excipient and realizing.Therefore, formula I chemical compound can be used for producing medicine.The pharmaceutical composition of Zhi Bei formula I chemical compound can be configured to solution or the freeze dried powder that is used for parenteral as previously mentioned.Powder can add suitable diluent or other pharmaceutical carriers before use and recombinate.Liquid preparation can be the isoosmotic aqueous solution of buffering.The example of suitable diluent has common grade to ooze saline solution, standard 5% D/W or buffered sodium acetate or Spirit of Mindererus..This class preparation is particularly suitable for parenteral, but also can be used for oral administration, or is contained in metered dose inhaler or the aerosol apparatus that is used for insufflation.May need to add excipient such as polyvinyl pyrrolidone, gelatin, hydroxylated cellulose, arabic gum, Polyethylene Glycol, mannitol, sodium chloride or sodium citrate.
In addition, these chemical compounds can be made into to be used for oral capsule, tablet, or be made into Emulsion or syrup.Medicinal solid or liquid-carrier can be added into and be used for strengthening or stable composition, or promote preparation of compositions.Solid carrier comprises starch, lactose, calcium sulfate dihydrate, hargil, magnesium stearate or stearic acid, Talcum, pectin, arabic gum, agar or gelatin.Liquid-carrier comprises syrup, Oleum Arachidis hypogaeae semen, olive oil, saline and water.Carrier also can comprise and prolongs releasable material such as independent glyceryl monostearate or glycerol distearate or with wax.The amount of solid carrier can change, but preferably at the about 20mg of every dosage unit between about 1g.Pharmaceutical preparation is according to the preparation of the routine techniques of pharmacy, comprises levigately, mix, granulating, but when needing for tablet tabletting, or levigate in addition for the gelatine capsule form, mix, fill.When using liquid-carrier, preparation will be syrup, the agent of speeding, Emulsion or water slurry or non-aqueous suspension.This class I liquid I preparation directly per os uses, or is filled in the soft capsule.
For rectally, The compounds of this invention also can with excipient such as cocoa butter, glycerol, gelatin or Polyethylene Glycol mix and also are molded as suppository.
Purposes of the present invention
Formula I chemical compound can be used as the inhibitor of cathepsin S.The invention provides the method for the disease that treatment causes by cathepsin S pathology level, this method comprises the animal to needs, especially mammal, the people uses the cathepsin S inhibitor of treatment effective dose the most specifically, comprises one or more The compounds of this invention.
The present invention provides the method for the treatment following disease relevant with cathepsin S especially:
Treat and/or prevent autoimmune disease such as rheumatoid arthritis, multiple sclerosis, juvenile diabetes, systemic lupus erythematosus (sle), discoid lupus erythematosus, pemphigus vulgaris, pemphigoid, grave disease, myasthenia gravis, chronic lymphocytic thyroiditis, scleroderma, dermatomyositis, bronzed disease, pernicious anemia, constitutional solid edema, thyrotoxicosis, autoimmune atrophic gastritis, stiff person's syndrome, Goodpasture syndrome, sympathetic ophthalmia, phacoantigenic uveitis, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, the special property sent out leukopenia, primary biliary cirrhosis, active chronic hepatitis, latent source property hepatitis interstitialis chronica, ulcerative colitis, xerodermosteosis, and mixed connective tissue disease; Treat and/or prevent by the atheroma damage and form caused disease and its complication that causes; Disease with the needs treatment: suppress the disease of the immunne response of II class MHC-limitation, suppress the asthmatic reaction, suppress anaphylactic reaction, suppress to transplant the immunoreation that causes, or be suppressed at elasticity protease activities in the sebaceous cyst by organ or tissue.
Method of the present invention can be by being used alone or multiple formula I chemical compound, perhaps uses with other medicable compound and realize.
For acute treatment, the parenteral of formula I chemical compound is preferred.Chemical compound in 5% D/W or generic physiological saline, or the venous perfusion of the similar formulations of other suitable excipient is arranged is the most effective, although intramuscular injection also is useful.Typically, parenteral dosage is about 0.01 to about 100mg/kg; Preferably 0.1 and 20mg/kg between, keep the concentration of medicine in blood plasma inhibition of histone enzyme S effectively.Chemical compound administration every day 1 to 4 time is about 0.4 to about 400mg/kg/ day to reach total daily dose.The best route of administration for the treatment of the accurate amount of effective The compounds of this invention and chemical compound be easy to by the haemoconcentration of those skilled in the art by medicament relatively with have the needed concentration of therapeutic effect and measure.
The compounds of this invention also can make drug concentrations reach is enough to suppress bone resorption, or the mode that realizes other treatment index disclosed herein is to patient's oral administration.Typically, the pharmaceutical composition that contains described chemical compound according to patient's situation with the oral dose between about 0.1 to about 50mg/kg and administration.Preferably, oral dose is about 0.5 to about 20mg/kg.
When formula I chemical compound during administration, is not observed unacceptable toxic action according to the present invention.
Biologic test
The chemical compound that uses in the inventive method is tested in one of several biologic tests with mensuration and is reached definite needed compound concentrations of pharmacological action.
The mensuration of cathepsin S protease catalytic activity
The mensuration of the cathepsin S that the is useful on recombinase of all choosing carries out.The standard test conditions of measuring kinetic constant uses the fluorescence peptide substrates, typically is Cbz-Val-Val-Arg-AMC, and in the 100mM sodium acetate that contains 20mM cysteine and 5mM EDTA, measures at pH5.5.The deposit substrate solution with 10 or the concentration of 20mM in DMSO, prepare, final in test concentration of substrate is 20uM.All tests all contain 10%DMSO.All tests are all at room temperature carried out.The fluorescence of product (excites at 360nM; The 460nM emission) with the monitoring of Perceptive Biosystems Cytofluor II fluorescent screen reader.Product progress curve forms the back at the AMC product and produced in 20 to 30 minutes.
Suppress research
Potential inhibitor is assessed with the progress curve method.Test is carried out in the presence of the test compound of various concentration.Reaction causes by add enzyme in the buffer solution of inhibitor and substrate.Outward appearance according to progress curve in the presence of inhibitor is carried out data analysis with one or both methods.For its progress curve is linear chemical compound, its apparent inhibition constant (K I, app) calculate (Brandt etc., Biochemitsry, 1989,28,140) according to formula 1:
V=V mA/[K a(1+I/K I, app)+A] (1) wherein v be response speed, and maximal rate is V m, A is a concentration of substrate, and Ka is the Michaelis constant, and I is an inhibitor concentration.
During for its progress reclinate time of curve display-inhibition feature, analyze, provide k from the data based formula 2 of single test gained Obs:
[AMC]=v SsT+ (v 0-v Ss) [l-exp (k ObsT)]/k Obs(2) wherein the concentration of [AMC] product of when data t, forming, v 0Be initial action speed, and v SsBe the speed of final plateau.k ObsValue is analyzed as the linear function of inhibitor concentration then, produces the apparent second speed constant (k in proper order of description time-inhibitions Obs/ inhibitor concentration or k Obs/ [I]).The complete discussion of this dynamics process has a detailed description (Morrison etc., Adv.Enzymol.Relat.Areas Mol.Biol., 1988,61,201).
General remark
Nuclear magnetic resoance spectrum uses Bruker AM 250 or Bruker AC 400 spectrogrphs 250 or the 400MHz record respectively.CDCl 3Be deuterochloroform, DMSO-d 6Six deuterated dimethyl sulfoxides, and CD 3OD is four deuterated methanols.Chemical shift is with the report of the ppm from interior mark tetramethylsilane toward downfield.The abbreviation of NMR data is as follows: s=is unimodal, the d=doublet, and the t=triplet, the q=quartet, the m=multiplet, two doublets of dd=, two triplets of dt=, app=is apparent, and br=broad peak .J represents the NMR coupling constant with hertz mensuration.Continuous wave infrared (IR) spectrum record on Perkin-Elmer 683 infrared spectrometers, and Fourier transform infrared (FTIR) spectrum record on Nicolet Impact 400 D infrared spectrometers.IR and FTIR spectrum are with the transmission mode record, and band position is with head sea number (cm -1) report.Mass spectrum is at VG 70FE, PE Syx API III, or carry out on the VG ZAB HF instrument, with fast atom bombardment (FAB) or electron spray (ES) ionization techniques.Elementary analysis carries out with Perkin-Elmer 240C elemental analyser.Fusing point is measured on Thomas-Hoover fusing point instrument, and not calibrated.All temperature are all with a degree centigrade report.
Analtech silica gel G F and E.Merck silica gel 60 F-254 lamellaes are used to thin layer chromatography.Quick and gravity chromatograph is all carried out on E.Merck Kieselgel 60 (230-400 order) silica gel.
As pointing out, some materials are from Aldrich Chemical Co., Milwaukee, Wisconsin, Chemical Dynamics Corp., South Plainfield, New Jersey, and AdvancedChemtech, Louisville, KentuckY buys.
Embodiment
In following synthetic embodiment, temperature be degree centigrade (℃).Unless otherwise indicated, all raw materials are all bought from the market.Do not need to be described in further detail, believe that those skilled in the art can use above-mentioned explanation to use the present invention to send out to greatest extent.These embodiment are used to illustrate the present invention, and do not limit its scope.Be the given reference of the artificial claim of invention below.
Embodiment 1
Preparation benzofuran-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepine Cycloheptane-4-base carbamoyl]-ethyl }-amide.
A) pi-allyl-penta-4-thiazolinyl-carbamic acid benzyl ester
Dropping benzyl pi-allyl-carbamic acid benzyl ester in the past DMF suspension of NaH (1.83g, 76.33mmol 90%NaH) (7.3g, 38.2mmol).Mixture about 10 minutes in stirring at room, then Dropwise 5-bromo-1-amylene (6.78mL, 57.24mmol).Reactant be heated to 40 ℃ about 4 hours, then with reactant distribution between dichloromethane and water.Organic layer water (2x), salt water washing, dry (MgSO 4), filter and concentrate.Residue column chromatography purification (10% ethyl acetate: hexane) provide 10.3 gram title compound grease: MS (EI) 260 (M+H +).
B) 2,3,4,7-tetrahydrochysene-azepines-1-carboxylic acid benzyl ester
Dichloromethane solution toward embodiment 1a chemical compound (50g) adds two (tricyclohexyl phosphine) benzal chloride ruthenium (IV) (5.0g).Reactant is heated backflow, the analysis showed that to react until TLC and finishes.With the reactant vacuum concentration.Residue column chromatography purification (50% dichloromethane: hexane) provide 35g title compound: MS (EI) 232 (M+H +).
C) 8-oxa--3-aza-bicyclo [5.1.0] octane-3-carboxyl acid benzyl ester
Toward embodiment 1b chemical compound (35g, CH 1.5mol) 2Cl 2Solution adding m-CPBA (78g, 0.45mol).Mixture leaches solid then in stirred overnight at room temperature.Filtrate water and saturated NaHCO 3Washing (several times).Organic layer (the MgSO that is dried 4), filter and concentrate, provide the 35g title compound, its purity is enough to be used in the step down: MS (EI) 248 (M+H +), 270 (M+Na +).
D) 4-azido-3-hydroxyl-azepan-1-carboxylic acid benzyl ester
(2.0g, 8.1mmol) at methanol: the solution in the water (8: 1 solution) adds NH to the epoxide of past embodiment 1c 4Cl (1.29g, 24.3mmol) and Hydrazoic acid,sodium salt (1.58g, 24.30mmol).Reactant is heated to 40 ℃, analyzes until TLC to show the full consumption of raw material epoxide.Vacuum is removed most of solvent, and residual solution is dispensed between ethyl acetate and the pH4 buffer.The saturated NaHCO of organic layer 3, water, salt water washing, dry (MgSO 4), filter and concentrate.Residue column chromatography purification (20% ethyl acetate: hexane) provide 1.3g title compound: MS (EI) 291 (M+H +) add 0.14g trans-4-hydroxyl-3-azido-hexahydro-1 H-azepines.
E) 4-amino-3-hydroxyl-azepan-1-carboxylic acid benzyl ester
The azido alcohol of past embodiment 1d (1.1g, and methanol solution adding triethylamine 3.79mmol) (1.5mL, 11.37mmol) with 1, the 3-dimercaptopropane (1.1mL, 11.37mL).Reactant is stirred until TLC and analyzes the full consumption of demonstration raw material, then with the reactant vacuum concentration.Residue column chromatography purification (20% methanol: dichloromethane) provide 0.72g title compound: MS (EI) 265 (M+H +).
F) 4-t-butoxycarbonyl amino-3-hydroxyl-azepan-1-carboxylic acid benzyl ester
(embodiment 1e, 1.04g, THF solution 3.92mmol) add coke acid di-t-butyl ester (0.864g) toward 4-amino-3-hydroxyl-azepan-1-carboxylic acid benzyl ester.After the stirring at room 30 minutes, reactant mixture dilutes with ether, and uses saturated NaHCO 3Extraction, the organic layer anhydrous Na 2SO 4Drying is filtered, and concentrates, and by the silicagel column purification, provides title compound yellow oil (0.963g, 2.64mmol, 67%) .MS (ESI): 365.03 (M+H +).
G) 3-hydroxyl-azepan-4-base-carbamic acid tertiary butyl ester
(ethyl acetate 2.64mmol) (16mL) solution adds 10%Pd/C (500mg) for embodiment 1f, 0.963g toward 4-t-butoxycarbonyl amino-3-hydroxyl-azepan-1-carboxylic acid benzyl ester.In stirring at room after 48 hours, mixture is by filtration over celite with solution.Filtrate concentrating provided title compound (0.529g, 2.29mmol, 87%) .MS (ESI): 231.92 (M+H +).
H) 3-hydroxyl-1-(pyridine-2-sulfuryl base)-azepan-4-base-carbamic acid tertiary butyl ester
Past 3-hydroxyl-azepan-4-base-carbamic acid tertiary butyl ester (embodiment 1g, 0.529, DCM 2.29mmol) (20mL) solution adding triethylamine (232mg) and pyridine-2-sulfuryl chlorine (410mg, 2.32mmol).After the stirring at room 30 minutes, the saturated NaHCO of mixture 3Washing, organic layer is dried, and filters, concentrate and on silicagel column purification provide title compound solid (0.583g, 1.57mmol, 68%).
MS(ESI)：372.95(M+H +)。
I) 4-amino-1-(pyridine-2-sulfuryl base)-azepan-3-alcohol
(ethyl acetate 1.57mmol) (0.5mL) solution adds HCl (4M dioxane solution) (3.9mL) for embodiment 1h, 0.583g to stir down past 3-hydroxyl-1-(pyridine-2-sulfuryl base)-azepan-4-base-carbamic acid tertiary butyl ester.Behind the stirring at room reactant mixture 30 minutes, mixture is concentrated and provides white solid.This solid is handled with NaOH, uses ethyl acetate extraction then.Organic layer is dried, filters, and the concentrated yellow solid (0.347g, 1.28mmol, 81%) that provides.
MS(ESI)272.93(M+H +)。
J) (S)-2-cyclohexyl-1-[3-hydroxyl-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-the carbamic acid tertiary butyl ester
Toward 4-amino-1-(pyridine-2-sulfuryl base)-azepan-3-alcohol (EXAMPLE l i, 19mg, CH 0.070mmol) 2Cl 2Solution adding N-Boc-Cyclohexylalanine (28.5mg, 0.106mmol), I-hydroxybenzotriazole (16.1mg, 0.12mmol), and P-EDC (140mg, CH 0.14mmol) 2Cl 2Solution.After the room temperature vibration was spent the night, mixture was handled with PS-Trisamine.After vibrating 2 hours again, mixture is filtered and concentrates and provides the title compound solid.MS(ESI)525(M+H +)。
K) (S)-2-amino-3-cyclohexyl-N-[3-hydroxyl-1-(pyridine-2-sulfuryl base)-azepan-4-yl]-propionic acid amide.
Past under stirring (S)-2-cyclohexyl-1-[3-hydroxyl-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-carbamic acid tertiary butyl ester (embodiment 1j, 34mg, CH 0.07mmol) 2Cl 2(0.50mL) solution adds HCl (4M dioxane solution) (0.165mL).After the stirring at room 30 minutes, mixture is concentrated, and provides white solid.This white solid and methylbenzene azeotropic use the methanol solution of MP-carbonic ester (0.35mmol) to handle then.Vibrate after 4 hours, mixture is filtered and concentrates and provides the title compound solid.MS(ESI)425.03(M+H +)。
L) benzofuran-2-carboxylic acid (S)-2-cyclohexyl-1-[3-hydroxyl-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl-amide
Toward (S)-2-amino-3-cyclohexyl-N-[3-hydroxyl-1-(pyridine-2-sulfuryl base)-azepan-4-yl]-propionic acid amide. (embodiment 1k, 27mg, CH 0.070mmol) 2Cl 2Solution adding benzofuran-2-carboxylic acid (17.0mg, 0.106mmol), I-hydroxybenzotriazole (16.1mg, 0.12mmol), and P-EDC (140mg, CH 0.14mmol) 2Cl 2Solution.After the room temperature vibration was spent the night, mixture was handled with PS-Trisamine.After vibrating 2 hours again, mixture is filtered and concentrates and provides the title compound solid.MS(ESI)568.79(M+H) +。
M) benzofuran-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl-amide
Past benzofuran-2-carboxylic acid under stirring (S)-2-cyclohexyl-1-[3-hydroxyl-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide (embodiment 1l, 37mg, CH 0.70mmol) 2Cl 2(0.5mL) solution add Dess-Martin reagent (45mg, 0.105mmol).Stir after 30 minutes, add simultaneously in the reactant mixture hypo solution (10% aqueous solution, 0.50mL) and saturated sodium bicarbonate aqueous solution (0.50mL).Mixture is used dichloromethane extraction (2 times) then.Organic layer is dried, and filters, and concentrates.Residue is at preparation property R, by the HPLC purification, provides two kinds of non-enantiomer mixture solids (eluting: 4.5mg, the eluting for the second time for the first time: 4.5mg) .MS (ESI) 566.87 (M+H of title compound on the R-Whelk-O post +); 1H NMR (400Hz, CDCl 3): δ 8.67 (m), 7.95 (m), 7.63 (m), 7.50 (m), 7.02 (m), 6.83 (m), 5.25 (m), 4.76 (m), 4.14 (t), 3.88 (d), 2.74 (m), 2.16 (m), 1.88 (m), 1.66-0.94 (m).
Embodiment 2
Preparation 5-(3-trifluoromethyl-phenyl)-furan-2-carboxylic acid (S)-and the 2-cyclohexyl-1-[(R)-3-oxo-1-(pyrrole Pyridine-2-sulfonyl)-azepan-4-base carbamoyl]-ethyl }-amide
Figure A0180829000641
Method according to embodiment 1 (l)-1 (m) just replaces benzofuran-2-carboxylic acid with 5-(3-trifluoromethyl)-furan-2-carboxylic acid in step 1 (l), title compound is purified and provides two kinds of diastereomer solids:
1H-NMR(400Hz，CDCl 3)：δ8.67(m)，7.93(m)，7.58(m)，7.24(m)，6.83(m)，5.18(m)，4.76(m)，4.27(t)，3.85(d)，2.78(m)，2.16(m)，1.85(m)，1.52-1.02(m)。
Embodiment 3
Preparation 5-(4-chloro-phenyl)-furan-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl Base)-azepan-4-base carbamoyl]-ethyl }-amide
According to the method for embodiment 1 (l)-1 (m), just in step 1 (l), replace the 2-benzofurancarboxylic acid with 5-(4-chloro-phenyl)-furan-2-carboxylic acid, title compound is purified and provides two kinds of diastereomer solids: 1H-NMR (400Hz, CDCl 3): δ 8.62 (m), 7.93 (m), 7.65 (d), 7.47 (m), 7.38 (t), 7.20 (m), 6.92 (m), 6.72 (d), 5.18 (m), 4.77 (m), 4.09 (t), 3.84 (d), 2.73 (m), 2.33-1.02 (m).
Embodiment 4
Preparation 5-(4-chloro-phenyl)-furan-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine- The 2-sulfonyl)-azepan-4-base carbamoyl]-ethyl }-amide
Method according to embodiment 1 (h)-1 (m), just in step 1 (l), replace benzofuran-2-carboxylic acid with 5-(4-chloro-phenyl)-furan-2-carboxylic acid, and in step 1 (h), replace pyridine-2-sulfuryl chlorine with 2-pyridine-N-oxides sulfonic acid chloride, title compound is purified and provides two kinds of diastereomer solids: 1H-NMR (400Hz, CDCl 3): δ 8.26 (m), 8.12 (t), 7.73-7.21 (m), 6.76 (t), 5.09 (m), 4.82 (m), 4.10 (d), 3.88 (dd), 3.54 (s), 2.79 (m), 2.19-1.02 (m).
Embodiment 5
Preparation 5-(3-trifluoromethyl-phenyl)-furan-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen Base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide
Figure A0180829000651
Method according to embodiment 1 (h)-1 (m), just replace the 2-benzofurancarboxylic acid with 5-(3-trifluoromethyl-phenyl)-furan-2-carboxylic acid in step 1 (l), and in step 1 (h), replace pyridine-2-sulfuryl chlorine with 2-pyridine-N-oxides sulfonic acid chloride, title compound is purified and provides two kinds of diastereomer solids: 1H-NMR (400Hz, CDCl 3): δ 8.26 (m), 8.11 (t), 8.02-7.23 (m), 6.86 (t), 5.11 (m), 4.82 (m), 4.14 (t), 3.90-3.85 (d), 3.16 (s), 3.88 (m), 2.25-1.02 (m).
Embodiment 6
Preparation 56-dimethoxy-benzofuran-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base- The pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide
Figure A0180829000652
Method according to embodiment 1 (h)-1 (m), be with 5 in step 1 (l), 6-dimethoxy-benzofuran-2-carboxylic acid and replace pyridine-2-sulfuryl chlorine with 2-pyridine-N-oxides sulfonic acid chloride in step 1 (h), title compound is purified and provides two kinds of diastereomer solids: 1H-NMR (400Hz, CDCl 3): δ 8.25-7.37 (m), 7.07 (d), 5.02 (m), 4.88 (m), 4.12 (d), 3.96 (s), 3.94 (s), 3.84 (d), 3.73 (s), 2.86 (t), 2.20 (m), 1.94-1.02 (m).
Embodiment 7
Preparation benzofuran-2-carboxylic acid (S)-3-methyl isophthalic acid-[(2,2 ', 4-three deuteriums generation)-3-oxo-1-(pyridine-2- Sulfonyl)-azepan-4-base carbamoyl]-butyl } amide
A) 4-((S)-2-t-butoxycarbonyl amino-4-methyl-valeryl amino)-3-hydroxyl-azepan-1-carboxylic acid benzyl ester
4-amino-3-hydroxyl-azepan-1-carboxylic acid benzyl ester (720mg, CH 2.72mmol) toward embodiment 1e 2Cl 2Solution adds EDC (521mg), HOBt (368mg) and N-Boc-leucine (630mg).Reactant keeps in room temperature, until the TLC analysis and observation to the raw material full consumption.Reactant dilutes with ethyl acetate, and uses 1NHCl, saturated K 2CO 3, water, salt water washing, dry (MgSO 4), filter and concentrate.Residue column chromatography purification (3% methanol: dichloromethane) provide 1.0g title compound: MS (EI) 478 (M+H +).
B) [(S)-1-(3-hydroxyl-azepan-4-base carbamoyl)-3-methyl-butyl]-the carbamic acid tertiary butyl ester
Ethyl acetate toward chemical compound (1.0g) and the 10%Pd/C (catalytic amount) of embodiment 7a: methanol (2: 1 solution) solution adds the hydrogen in the balloon.Reactant is stirred, until the TLC analysis and observation to the raw material full consumption.Reactant is filtered removing catalyst, and the filtrate vacuum concentration is provided 0.82g title compound: MS (EI) 344 (M+H +).
C) (S)-1-[3-hydroxyl-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-3-methyl-butyl }-the carbamic acid tertiary butyl ester
The preparation of 2-pyridine sulfonic acid chloride: 2-mercaptopyridine solution (2.23g is in 33ml 9N HCl) is cooled to 0 ℃.Chlorine was fed this solution 90 minutes, and keeping temperature carefully is 0 ℃.Add ice-cold ethyl acetate, then slowly add ice-cold saturated NaHCO 3PH value until water layer is approximately 9.Organic layer is used salt water washing, MgSO then 4Dry.The evaporation of acetic acid ethyl ester provides the thick 2-pyridine of 3.5g sulfonic acid chloride yellow liquid.
Past embodiment 7b [(S)-1-(3-hydroxyl-azepan-4-base carbamoyl)-3-methyl-butyl]-carbamic acid tertiary butyl ester (12g; 34.93mmol) dichloromethane solution add triethylamine (5.8mL; 41.92mmol); then drip 2-pyridine sulfonic acid chloride (7.45g, 41.92mmol).Reactant is stirred, and reacts completely until the TLC assay determination.Mixture is used saturated NaHCO then 3, water, salt water washing, dry (Na 2SO 4), filter and concentrate.Residue column chromatography purification (75% ethyl acetate: hexane to 100% ethyl acetate) provide 15g title compound: MS 484 (M +)
D) (S)-2-amino-4-methyl-valeric acid-[3-hydroxyl-1-(pyridine-2-sulfuryl base)-azepan-4-yl]-amide
Toward embodiment 7c (S)-1-[3-hydroxyl-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-3-methyl-butyl-methanol solution of carbamic acid tertiary butyl ester (14.3g) adds the dioxane solution of 4M HCl.Reactant at room temperature is stirred, and reacts completely until the TLC assay determination, concentrates then and provides 14g title compound: MS (EI) 385 (M+H +).
E) benzofuran-2-carboxylic acid { (S)-3-methyl isophthalic acid-[3-hydroxyl-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-butyl } amide
The dichloromethane solution of (S)-2-amino-4-methyl-valeric acid [3-hydroxyl-1-(pyridine-2-sulfuryl base)-azepan-4-yl]-amide (0.15g) of past embodiment 7d adds TEA (0.11mL); HOBt (49mg), EDC (69mg) and benzofuran-2-carboxylic acid (58mg).Reactant is stirred until reacting completely.Handle and column chromatography purification (5% methanol: ethyl acetate) provide title compound: MS (EI), 529 (M+H +).
F) benzofuran-2-carboxylic acid { (S)-3-methyl isophthalic acid-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-butyl } amide
The DMSO solution of the alcohol (0.11g) of past embodiment 7e adds TEA (0.17mL) and pyridine sulfur trioxide complex (99mg).Reactant about 2 hours in stirring at room is distributed between ethyl acetate and the water then.Organic layer salt water washing, drying is filtered and is concentrated.Residue column chromatography purification (10%CH 3OH: EtOAc) provide 75mg title compound non-enantiomer mixture: 1H NMR (CDCl 3): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (dd, 1H) .4.0 (m, 1H), 4.7 (m, 2H), 5.0 (m, 1H), 7.2-7.3 (m, 3H), 7.4 (m, 4H), 7.6 (m, 1H), 8.0 (m, 2H), 8.7 (m, 1H); MS (EI): 527 (M+H +, 40%).
G) benzofuran-2-carboxylic acid { (S)-3-methyl isophthalic acid-[(2,2 ', 4-three deuteriums generation)-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-butyl } amide
D toward benzofuran-2-carboxylic acid of embodiment 7f { (S)-3-methyl isophthalic acid-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-butyl } amide (0.03g) 2O: CD 3(0.4: 4mL) solution adds triethylamine (0.04mL) to OD.Reactant is heated and refluxed 2 hours, then vacuum concentration and dry.Residue is dissolved in identical mixture again, and reflux is spent the night.Reactant is concentrated, residue by the column chromatography purification (5% methanol: dichloromethane) provide title compound (0.02g): 1HNMR: δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.7 (m, 1H), 4.1 (m, 1H), 4.7 (m, 2H), 7.4-8.0 (m, 8H), 8.7 (m, 1H); MS (EI): 529 (M +, 45%).
Non-enantiomer mixture separates the diastereomer that provides very fast eluting by HPLC: MS (EI): 530 (M+H +, 100%) and the diastereomer of slow eluting: MS (EI): 530 (M+H +, 100%).
Embodiment 8
Furan-2-carboxylic acid (S)-and 2-cyclohexyl-1-[(4S, 7R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide
A. ((R)-2-iodo-1-methyl-ethyl)-carbamic acid benzyl ester
(24g 91.8mmol) adds imidazoles (12.5g, CH 184mmol) with triphenyl phasphine 2Cl 2(231ml) solution is cooled to 0C then.(23.3g 91.8mmol) is added in the suspension iodine.It is yellow, little then brown that reactant mixture changes.After 5 minutes, (9.59g 45.9mmol) adds, and reactant mixture is warmed to room temperature, stirs then 3 hours with ((R)-2-hydroxyl-1-methyl-ethyl)-carbamic acid benzyl ester.Then with H 2O (7ml) adds, and reactant mixture is dispensed on CH 2Cl 2(300ml) and H 2Between the O (600ml).Water layer reuse CH 2Cl 2(200ml) extraction.The organic layer that merges is used 1: 9 saturated Na then 2S 2O 3Aqueous solution: H 2O (140ml), saline (400ml) washing then.The organic layer dried over mgso that merges is filtered, and vacuum concentration filters silica filler then, with 15%EtOAc/ hexane (1.5 liter) washing.With solution for vacuum concentration, then with the solid hexane wash, the white solid of generation just is used for the next step (11g, 75%) without being further purified.
B. ((R)-1-methyl-penta-4-thiazolinyl)-carbamic acid benzyl ester
(1.93g 9.4mmol) is dissolved in distilled THF (24ml) to copper bromide (I)-dimethyl sulfide, is cooled to then-78C.(Aldrich) solution is then with solution stirring 30 minutes for 9.4ml, the THF solution of 2M to drip allylmgcl.(1.5g, 4.7mmol) solution in distilled THF (3ml) is warmed to reactant-40C then, and stirs 2.5h to drip ((R)-2-iodo-1-methyl-ethyl)-carbamic acid benzyl ester.Reactant mixture is at the saturated NH of a 40C 4Cl aqueous solution (4ml) cancellation is warmed to room temperature, and gray reactant mixture transfers sky blue to.Vacuum is removed THF.Add Et then 2O, reactant mixture are filtered to remove precipitated solid.With solid reuse Et 2The O washing.The organic layer 10%NH that merges 4OH (3x), salt water washing then.The organic layer dried over mgso that merges is filtered, and vacuum concentration filters silica filler then, with 20%EtOAc/ hexane (100ml) washing.With solution for vacuum concentration, then the colorless oil that produces just is used for the next step (0.8g, 73%) without being further purified.
C. pi-allyl-((R)-1-methyl-penta-4-thiazolinyl)-carbamic acid benzyl ester
(790mg 3.39mmol) is dissolved in DMF (8ml) and be cooled to 0C with ((R)-1-methyl-penta-4-thiazolinyl)-carbamic acid benzyl ester.(6.78mmol), reactant is stirred 15 minutes for 60% dispersion thing, 271mg to add sodium hydride.(10.17mmol), reactant mixture stirred 3 hours at 0C for 1.23g, 0.88ml to add allyl bromide, bromoallylene.Add H 2O (10ml) drips 2N HCl then and regulates pH to 1.Reactant mixture Et 2O (2 * 50ml) extractions.The organic layer that merges 2N HCl aqueous solution, NaHCO then 3Aqueous solution, salt water washing then.The organic layer MgSO that merges 4Drying is filtered, vacuum concentration, and silica gel chromatography purification (5%EtOAc/ hexane) provides title compound colorless oil (883mg, 95%) then.
D.2-methyl-2,3,4,7-tetrahydrochysene-azepines-1-carboxylic acid benzyl ester
With pi-allyl-(0.872g 3.19mmol) is dissolved in CH to (1-methyl-penta-4-thiazolinyl)-carbamic acid benzyl ester 2Cl 2(10ml), and with argon fed reactant mixture 10 minutes.Add then two (tricyclohexyl phosphine) benzyl subunit ruthenous chloride (IV) (Strem Chemicals, the Grubbs catalyst, 19mg, 0.0227mmol), reactant mixture was refluxed 2 hours.(mg, 0.0108mmol), reactant mixture refluxed 1.5 hours again to add two (tricyclohexyl phosphine) benzyl subunit ruthenous chloride (IV) again.Reactant is cooled to ambient temperature overnight in argon, by the rotary evaporation vacuum concentration, chromatogram purification (silica gel, 5%EtOAc/ hexane) provides title compound (0.72g then then, 92%): 1H NMR:7.35-7.20 (m, 5H), 5.65 (1H, m), 5.13 (2H, AB), 4.45-4.05 (m, 2H), 3.56 (1H, d), 2.25-2.10 (m, 2H), 1.90-1.60 (m, 2H), 1.12 (3H, d); Liquid chromatograph/Electrospray Mass Spectrometry: M+H +=246.2
E. (1S, 4R, 7R)-4-methyl-8-oxa--3-aza-bicyclo [5.1.0] octane-3-carboxyl acid benzyl ester
Between-chloro-benzylhydroperoxide (1.10g, 57-86% purity) is added into 2-methyl-2,3,4 at 0C, 7-tetrahydrochysene-azepines-1-carboxylic acid benzyl ester (0.72g, CH 2.94mmol) 2Cl 2Solution.Reactant mixture is stirred half an hour, is warmed to room temperature then.Between adding again-and chloro-benzylhydroperoxide (0.660g, 57-86% is pure), reactant is stirred 2h.Reactant mixture adds 9: 1 hexane/EtOAc of 80ml then by the rotary evaporation vacuum concentration, and reactant mixture is filtered.Filtrate is by rotary evaporation vacuum concentration, chromatogram purification (silica gel, 20%EtOAc: hexane) provide (1S, 4R then, 7S)-4-methyl-8-oxa--3-aza-bicyclo [5.1.0] octane-3-carboxyl acid benzyl ester (0.450g, 75%) and title compound (0.15g, 25% productive rate): 1H NMR:7.42-7.22 (m, 5H), 5.13 (2H, s), 4.50-4.15 (m, 2H), 3.27 (1H, d), 3.12-2.95 (1H, m), 2.15-1.70 (m, 2H), 1.47 (m, 2H), 1.12 (3H, d); Liquid chromatograph/Electrospray Mass Spectrometry: M+H +=262.0.
F. (2R, 5S, 6S)-5-azido-6-hydroxy-2-methyl-azepan-1-carboxylic acid benzyl ester
With Hydrazoic acid,sodium salt (0.139g, 2.14mmol) add (1S, 4R, 7R)-4-methyl-8-oxa--3-aza-bicyclo [5.1.0] octane-3-carboxyl acid benzyl ester (0.186g, 0.71mmol) and ammonium chloride (0.114g, MeOH 2.14mmol) (1.5ml) and H 2O (0.15ml) solution, 6h then refluxes.Reactant mixture is by the rotary evaporation vacuum concentration, and water (5ml) dilutes then, and extracts with EtOAc (10ml).Organic layer is water then, and MgSO is used in the salt water washing 4Drying is filtered, by the rotary evaporation vacuum concentration, and chromatogram purification (silica gel, 20%EtOAc/ hexane) provides title compound (0.192g, 89%): 7.39-7.30 (m, 5H), 5.15 (2H, s), 4.10-3.67 (m, 2H), 3.10 (1H, d), and 1.85-1.53 (m, 4H), 1.09 (3H, d); Liquid chromatograph/Electrospray Mass Spectrometry: M+H +=305.2.
G. (2R, 5S, 6S)-5-Amide-6-hydroxy-2--methyl-heterocycle heptane-1-carboxylic acid benzyl ester
Triphenylphosphine (0.25g, 0.952mmol) be added into (2R, 5S, 6S)-5-azido-6-hydroxy-2-methyl-azepan-1-carboxylic acid benzyl ester (0.193g, THF 0.635mmol) (10ml) and H 2O (0.04ml) solution is heated to 45C then and spends the night.Reactant mixture is used toluene (100ml * 2) dilution then, and passes through rotary evaporation vacuum azeotropic twice.The grease that produces is dissolved in the Et of MeOH and HCl 2O solution filters and collects the salt that produces, and just is used for the next step (0.27g, 90%) without being further purified.
H. (2R, 5 S, 6S)-5-((S)-2-t-butoxycarbonyl amino-3-cyclohexyl-propiono amino)-2-methyl-3-hydroxyl-azepan-1-carboxylic acid benzyl ester
With 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (1.0g, 5.36mmol) adding Boc-Cyclohexylalanine (1.2g, 4.45mmol), 4-methyl morpholine (1.35g, 1.50ml, 13.4mmol), hydroxybenzotriazole (0.72g, 5.36mmol), (2R, 5S, 6S)-5-Amide-6-hydroxy-2--methyl-azepan-1-carboxylic acid benzyl ester (1.4g, DMF 4.45mmol) (20ml) solution.Reactant is used EtOAc (100ml) dilution then in stirred overnight at room temperature, uses H 2O (50ml), saline (50ml washing), dried over mgso is filtered, and by the rotary evaporation vacuum concentration, and chromatogram purification (silica gel, 50%EtOAc/ hexane) provides title compound (1.70g, 72%): Electrospray Mass Spectrometry: M+H +=532.4
I.[(S)-2-cyclohexyl-1-((3S, 4S, 7R)-7-methyl-3-hydroxyl-azepan-4-base carbamoyl)-ethyl]-the carbamic acid tertiary butyl ester
Will (2R, 5S, 6S)-(1.70g 3.20mmol) is dissolved in ethanol (30ml) to 5-((S)-2-t-butoxycarbonyl amino-3-cyclohexyl-propiono amino)-2-methyl-6-hydroxyl-azepan-1-carboxylic acid benzyl ester.(0.34g, 0.32mmol), reactant stirs under the situation that hydrogen balloon connects and spends the night to add 10%Pd/C then.Reactant mixture by the rotary evaporation vacuum concentration, just is used for the next step (1.2g) without being further purified: Electrospray Mass Spectrometry: M+H by filtration over celite +=398.4.
J.{ (S)-2-cyclohexyl-1-[(3S, 4S, 7R)-7-methyl-3-hydroxyl-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-the carbamic acid tertiary butyl ester
2-pyridine sulfonic acid chloride (0.53g, 3.30mmol) be added into [(S)-2-cyclohexyl-1-((3S, 4S; 7R)-7-methyl-3-hydroxyl-azepan-4-base carbamoyl)-ethyl]-carbamic acid tertiary butyl ester (1.2g; 3.00mmol), triethylamine (1.02g, CH 10.0mmol) 2Cl 2(20ml) solution, and stirring at room 30 minutes.Reactant mixture is used H with EtOAc (100ml) dilution 2O, the salt water washing, dried over mgso is filtered, by the rotary evaporation vacuum concentration, and chromatogram purification (silica gel, 1: 1 hexane/EtOAc) provide title compound (1.3g, 80%): Electrospray Mass Spectrometry: M+H +=539.2.
K. (S)-2-amino-3-cyclohexyl-N-[(3S, 4S, 7R)-7-methyl-3-hydroxyl-1-(pyridine-2-sulfuryl base)-azepan-4-yl]-propionic acid amide.
Stir following dioxane solution (4.0M with HCl; 15.0ml) add (S)-2-cyclohexyl-1-[(3S; 4S; 7R)-7-methyl-3-hydroxyl-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-carbamic acid tertiary butyl ester (1.30g, MeOH 2.40mmol) (5.0ml) solution.Reactant mixture by the rotary evaporation vacuum concentration, just is used for the next step (1.2g) without being further purified then stirring at room 2 hours.
L. furan-2-carboxylic acid (S)-2-cyclohexyl-1-[(3S, 4S, 7R)-7-methyl-3-hydroxyl-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl-amide
With 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (0.069g; 0.36mmol) adding furan-2-carboxylic acid (0.040g; 0.36mmol); (S)-2-amino-3-cyclohexyl-N-[(3S; 4S; 7R)-7-methyl-3-hydroxyl-1-(pyridine-2-sulfuryl base)-azepan-4-yl]-propionic acid amide. (0.15g; 0.30mmol); diisopropyl ethyl amine (0.15g; 0.20ml, 1.2mmol), hydroxybenzotriazole (0.049g; 0.36mmol) DMF (2.0ml) solution, and in stirred overnight at room temperature.Reactant mixture is warmed to room temperature and stirs and spend the night.Reactant mixture is used H with EtOAc (30ml) dilution 2O, the salt water washing, dried over mgso is filtered, by the rotary evaporation vacuum concentration, and chromatogram purification (silica gel, 2.5%MeOH/CH 2Cl 2) provide title compound (0.15g, 95%): Electrospray Mass Spectrometry: M+H +=533.2.
M. furan-2-carboxylic acid (S)-2-cyclohexyl-1-[(4S, 7R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl-amide
With the high iodine alkane of Dess-Martin (0.15g; 0.35mmol) adding furan-2-carboxylic acid (S)-2-cyclohexyl-1-[(3S; 4S, 7R)-7-methyl-3-hydroxyl-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide (0.15g, CH 0.28mmol) 2Cl 2(2.0ml) solution, and stirring at room 1 hour.This solution 10%Na 2S 2O 3Aqueous solution, saturated then NaHCO 3Aqueous solution, salt water washing then.By column chromatography (3%MeOH/CH 2Cl 2) provide title compound (0.12g, 80%): 1H NMR:8.73 (d, 1H), 7.62 (m, 2H), 7.53 (m, 2H), 7.13 (s, 1H), 6.94 (d, 1H), 6.77 (d, 1H), 6.51 (m, 1H), 5.18 (m, 1H), 4.77 (d, 1H), 4.63 (m, 1H), 4.25 (m, 1H), 3.86 (d, 1H), 2.10 (m, 2H), 1.87-0.93 (m, 18H); Electrospray Mass Spectrometry: M+H +=531.2.
Embodiment 9
Preparation benzofuran-2-carboxylic acid (S)-and 2-cyclohexyl-1-[(4S, 7R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide
Figure A0180829000721
According to the method for embodiment 8 (a-m), just provide title compound with " benzofuran-2-carboxylic acid " replacement " furan-2-carboxylic acid ": 1H NMR:8.74 (d, 1H), 7.96 (m, 3H), 7.55 (m, 1H), 7.42 (m, 2H), 7.28 (m, 2H), 6.77 (d, 1H), 6.51 (m, 1H), 5.14 (m, 1H), 4.77 (d, 1H), 4.69 (m, 1H), 4.43 (m, 1H), 3.85 (d, 1H), 2.18 (m, 2H), 1.85-0.98 (m, 18H); Electrospray Mass Spectrometry: M+H +=581.3.
Embodiment 10
Preparation thiophene-3-carboxylic acid (S)-and 2-cyclohexyl-1-[(4S, 7R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide
Figure A0180829000722
According to the method for embodiment 8 (a-m), just provide title compound with " thiophene-3-carboxylic acid " replacement " furan-2-carboxylic acid ": 1H NMR:8.74 (d, 1H), 8.00 (m, 2H), 7.66 (d, 1H), 7.46 (m, 3H), 7.28 (d, 1H), 6.90 (d, 1H), 5.14 (m, 1H), 4.43 (m, 1H), 3.82 (d, 1H), 2.16 (m, 2H), and 1.90-0.96 (m, 18H); Electrospray Mass Spectrometry: M+H +=547.2.
Embodiment 11
Preparation 3-methyl-furo [3,2-b]-pyridine-2-carboxylic acids (S)-and 2-cyclohexyl-1-[(4S, 7R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide
According to the method 8 (a-m) of embodiment, just provide title compound with " 3-methyl-furo [3,2-b]-pyridine-2-carboxylic acids " replacement " furan-2-carboxylic acid ": 1H NMR:8.75 (d, 1H), 7.98 (m, 2H), 7.55 (m, 1H), 7.40 (m, 2H), 7.33 (m, 1H), 6.75 (d, 1H), 6.50 (m, 1H), 5.09 (m, 1H), 4.79 (d, 1H), 4.68 (m, 1H), 4.47 (m, 1H), 3.87 (d, 1H), 2.55 (s, 3H), 2.17 (m, 1H), 1.93-0.93 (m, 19H); Electrospray Mass Spectrometry: M+H +=596.4.
Embodiment 12
Preparation 5-(2-morpholine-4-base-ethyoxyl)-benzofuran-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide
According to the method for embodiment 8 (i-m), just use " (3S, 4S)-4-amino-3-hydroxyl-azepan-1-carboxylic acid benzyl ester (as Marquis; Robert W. etc., described in the J.Med.Chem.44 2001) replacement " (2R, 5S, 6S)-5-Amide-6-hydroxy-2--methyl-azepan-1-carboxylic acid benzyl ester " and with " 5-(2-morpholine-4-base-ethyoxyl)-benzofuran-2-carboxylic acid " replacement " furan-2-carboxylic acid " provide title compound: 1HNMR:8.54 (s; 1H), 8.00 (m, 2H); 7.55-7.05 (m; 7H), 5.16 (m, 1H); 4.81-3.52 (m; 15H), 3.14 (br, 2H), 2.71 (t, 1H), and 2.21-0.95 (m, 16H); Electrospray Mass Spectrometry: M+H +=712.4.
Embodiment 13
Preparation 4-methyl-2-pyridine-2-base-thiazole-5-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide
According to the method for embodiment 8 (i-m), just use " (3S, 4S)-4-amino-3-hydroxyl-azepan-1-carboxylic acid benzyl ester " replacement " (2R, 5S; 6S)-5-Amide-6-hydroxy-2--methyl-azepan-1-carboxylic acid benzyl ester " and " 4-methyl-2-pyridine-2-base-thiazole-5-carboxylic acid " replacement " furan-2-carboxylic acid " provides title compound: 1H NMR:8.66 (d, 1H), 8.55 (d, 1H), 7.98 (m, 2H), 7.65 (m, 2H), 7.50 (m, 2H), 7.44 (m, 1H), 7.31 (t, 1H), 7.06 (d, 1H), 5.17 (m, 1H), 4.79 (m, 1H), 4.65 (d, 2H), 4.00 (d, 1H), 3.83 (d, 1H), 2.75 (t, 1H), 2.59 (s, 3H), 2.40 (m, 2H), and 1.84-0.90 (m, 15H); Electrospray Mass Spectrometry: M+H +=625.4.
Embodiment 14
Preparation 5-pyridine-2-base-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide
Figure A0180829000742
According to the method for embodiment 8 (i-m), just with " (3S, 4S)-4-amino-3-hydroxyl-azepan-1-carboxylic acid benzyl ester " replacements " (2R; 5S, 6S)-5-Amide-6-hydroxy-2--methyl-azepan-1-carboxylic acid benzyl ester " also with " 5-pyridine-2-base-thiophene-2-carboxylic acid " replacement " furan-2-carboxylic acid " provide title compound: 1HNMR:8.68 (d, 1H), 8.54 (d, 1H), 7.93 (m, 2H), 7.71 (m, 2H), 7.53 (m, 2H), 7.48 (m, 1H), 7.31 (t, 1H), 7.03 (d, 1H), 5.16 (m, 1H), 4.78 (m, 1H), 4.65 (d, 2H), 4.10 (d, 1H), 3.82 (d, 1H), 2.76 (t, 1H), 2.40 (m, 2H), and 1.88-0.89 (m, 15H); Electrospray Mass Spectrometry: M+H +=610.2.
Embodiment 15
Preparation furan-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide
According to the method for embodiment 8 (i-m), just with " (3S, 4S)-4-amino-3-hydroxyl-azepan-1-carboxylic acid benzyl ester " replacement " (2R; 5S, 6S)-5-Amide-6-hydroxy-2--methyl-azepan-1-carboxylic acid benzyl ester " provide title compound: 1H NMR:8.70-8.68 (d, 1H), 7.98 (m, 2H), 7.53 (m, 2H), and 7.16-7.12 (m, 2H), 6.81-6.75 (m, 1H), 6.53 (s, 1H), and 5.31-5.10 (m, 1H), 4.81-4.68 (m, 2H), 4.13-4.09 (d, 1H), and 3.93-3.80 (d, 1H), 2.77-2.69 (m, 1H), and 2.26-0.90 (m, 17H); Electrospray Mass Spectrometry: M+H +=517.4.
Embodiment 16
The preparation thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide
Figure A0180829000752
According to the method for embodiment 8 (i-m), just use " (3S, 4S)-4-amino-3-hydroxyl-azepan-1-carboxylic acid benzyl ester " replacement " (2R; 5S, 6S)-5-Amide-6-hydroxy-2--methyl-azepan-1-carboxylic acid benzyl ester " and with " thiophene-2-carboxylic acid " replacement " furan-2-carboxylic acid " provides title compound: and 1H NMR:8.70-8.69 (d, 1H), 7.99-7.82 (m, 2H), 7.60-7.51 (m, 3H), and 7.12-7.10 (m, 2H), 6.55-6.53 (d, 1H), and 5.14-5.11 (m, 1H), 4.78-4.67 (m, 2H), and 4.10-4.07 (d, 1H), 3.89-3.84 (d, 1H), and 2.81-2.74 (m, 1H), 2.26-2.16 (m, 2H), and 1.86-0.90 (m, 15H); Electrospray Mass Spectrometry: M+H +=533.2.
Embodiment 17
Preparation thiophene-3-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide
According to the method for embodiment 8 (i-m), just use " (3S, 4S)-4-amino-3-hydroxyl-azepan-1-carboxylic acid benzyl ester " replacement " (2R; 5S, 6S)-5-Amide-6-hydroxy-2--methyl-azepan-1-carboxylic acid benzyl ester " and with " thiophene-3-carboxylic acid " replacement " furan-2-carboxylic acid " provides title compound: and 1H NMR:8.72-8.71 (d, 1H), 8.15-8.00 (m, 3H), 7.56-7.30 (m, 3H), and 7.15-7.12 (br, 1H), 6.70 (br, 1H), 5.20 (m, 1H), and 4.90-4.70 (m, 2H), 4.15 (m, 1H), 3.90 (d, 1H), 2.90-2.70 (m, 1H), and 2.28-0.97 (m, 17H); Electrospray Mass Spectrometry: M+H +=533.4.
Embodiment 18
Preparation 5-methyl-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide
Figure A0180829000762
According to the method for embodiment 8 (i-m), just use " (3S, 4S)-4-amino-3-hydroxyl-azepan-1-carboxylic acid benzyl ester " replacement " (2R; 5S, 6S)-5-Amide-6-hydroxy-2--methyl-azepan-1-carboxylic acid benzyl ester " and with " 5-methyl-thiophene-2-carboxylic acid " replacement " furan-2-carboxylic acid " provides title compound: and 1H NMR:8.69-8.67 (d, 1H), 7.97-7.90 (m, 2H), 7.52-7.28 (m, 3H), and 6.74-6.49 (m, 2H), 5.18-5.08 (m, 1H), 4.77-4.63 (m, 2H), and 4.28-4.26 (d, 1H), 3.87-3.80 (d, 1H), and 2.78-2.66 (m, 1H), 2.51 (s, 3H), and 2.25-0.88 (m, 17H); Electrospray Mass Spectrometry: M+H +=547.2.
Embodiment 19
Preparation 3-methyl-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide
Figure A0180829000771
According to the method for embodiment 8 (i-m), just use " (3S, 4S)-4-amino-3-hydroxyl-azepan-1-carboxylic acid benzyl ester " replacement " (2R; 5S, 6S)-5-Amide-6-hydroxy-2--methyl-azepan-1-carboxylic acid benzyl ester " and with " 3-methyl-thiophene-2-carboxylic acid " replacement " furan-2-carboxylic acid " provides title compound: and 1H NMR:8.69-8.68 (d, 1H), 7.97-7.89 (m, 2H), 7.53-7.50 (m, 1H), and 7.32-7.17 (m, 2H), 6.91-6.84 (d, 1H), 6.34-6.32 (d, 1H), and 5.16-5.11 (m, 1H), 4.79-4.70 (m, 2H), and 4.31-4.10 (d, 1H), 3.85-3.81 (d, 1H), and 2.76-2.69 (m, 1H), 2.55 (s, 3H), and 2.26-0.89 (m, 17H); Electrospray Mass Spectrometry: M+H +=547.2.
Embodiment 20
Preparation 3-ethyoxyl-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide
Figure A0180829000772
According to the method for embodiment 8 (i-m), just with " (3S, 4S)-4-amino-3-hydroxyl-azepan-1-carboxylic acid benzyl ester " replacements " (2R; 5S, 6S)-5-Amide-6-hydroxy-2--methyl-azepan-1-carboxylic acid benzyl ester " also with " 3-ethyoxyl-thiophene-2-carboxylic acid " replacement " furan-2-carboxylic acid " provide title compound: 1HNMR:8.69-8.67 (d, 1H), 7.96-7.90 (m, 2H), 7.60-7.28 (m, 4H), and 6.92-6.83 (d, 1H), 5.15-5.10 (m, 1H), and 4.74-4.56 (m, 2H), 4.30-4.08 (m, 3H), and 3.84-3.77 (d, 1H), 2.72-2.66 (m, 1H), and 2.25-0.89 (m, 20H); Electrospray Mass Spectrometry: M+H +=577.2.
Embodiment 21
Preparation 4-bromo-N-{ (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-Benzoylamide
Figure A0180829000781
According to the method for embodiment 8 (i-m), just use " (3S, 4S)-4-amino-3-hydroxyl-azepan-1-carboxylic acid benzyl ester " replacement " (2R; 5S, 6S)-5-Amide-6-hydroxy-2--methyl-azepan-1-carboxylic acid benzyl ester " and with " 4-bromo-benzoic acid " replacement " furan-2-carboxylic acid " provides title compound: and 1H NMR:8.71 (d, 1H), 8.00 (m, 2H), 7.69 (d, 2H), 7.52 (m, 3H), 7.26 (d, 1H), 6.91 (d, 1H), 5.22 (m, 1H), 4.77 (m, 2H), 4.14 (d, 1H), 3.85 (d, 1H), 2.71 (t, 1H), 2.31 (m, 2H), and 1.86-0.91 (m, 15H); Electrospray Mass Spectrometry: M+H +=605.2.
Embodiment 22
The preparation Cyclobutylcarboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide
Figure A0180829000782
According to the method for embodiment 8 (i-m), just use " (3S, 4S)-4-amino-3-hydroxyl-azepan-1-carboxylic acid benzyl ester " replacement " (2R; 5S, 6S)-5-Amide-6-hydroxy-2--methyl-azepan-1-carboxylic acid benzyl ester " and with " Cyclobutylcarboxylic acid " replacement " furan-2-carboxylic acid " provides title compound: and 1H NMR:8.68 (d, 1H), 7.97-7.90 (m, 2H), 7.71-7.48 (m, 1H), and 7.19-7.12 (d, 1H), 6.81-6.79 (d, 1H), 5.08 (m, 1H), and 4.72-4.48 (m, 2H), 4.05-4.01 (d, 1H), 3.86-3.79 (d, 1H), and 3.11-3.05 (m, 1H), 2.80-2.70 (m, 1H), and 2.32-0.80 (m, 23H); Electrospray Mass Spectrometry: M+H +=505.4.
Embodiment 23
The preparation Cyclopentane carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide
Figure A0180829000791
According to the method for embodiment 8 (i-m), just use " (3S, 4S)-4-amino-3-hydroxyl-azepan-1-carboxylic acid benzyl ester " replacement " (2R; 5S, 6S)-5-Amide-6-hydroxy-2--methyl-azepan-1-carboxylic acid benzyl ester " and with " Cyclopentane carboxylic acid " replacement " furan-2-carboxylic acid " provides title compound: and 1H NMR:8.70-8.69 (d, 1H), 7.99-7.92 (m, 2H), 7.55-7.51 (m, 1H), and 7.09-7.08 (d, 1H), 5.89-5.87 (d, 1H), 5.10 (m, 1H), and 4.71-4.70 (d, 1H), 4.65 (m, 1H), and 4.07-4.03 (d, 1H), 3.89-3.84 (d, 1H), and 2.82-2.58 (m, 2H), 2.15 (m, 2H), and 1.90-0.89 (m, 23H); Electrospray Mass Spectrometry: M+H +=519.4.
Embodiment 24
Preparation (S)-tetrahydrochysene-furan-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide
Figure A0180829000792
According to the method for embodiment 8 (i-m), just with " (3S, 4S)-4-amino-3-hydroxyl-azepan-1-carboxylic acid benzyl ester " replacements " (2R; 5S, 6S)-5-Amide-6-hydroxy-2--methyl-azepan-1-carboxylic acid benzyl ester " also with " (S)-tetrahydrochysene-furan-2-carboxylic acid " replacement " furan-2-carboxylic acid " provide title compound: 1HNMR:8.67 (d, 1H), 7.96 (m, 2H), 7.53 (m, 1H), 6.96 (m, 2H), 5.13 (m, 1H), 4.75 (m, 1H), 4.41 (m, 2H), and 4.07-3.91 (m, 4H), 2.68 (m, 1H), and 2.35-0.92 (m, 21H); Electrospray Mass Spectrometry: M+H +=521.4.
Embodiment 25
Preparation (R)-tetrahydrochysene-furan-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide
Figure A0180829000801
According to the method for embodiment 8 (i-m), just with " (3S, 4S)-4-amino-3-hydroxyl-azepan-1-carboxylic acid benzyl ester " replacements " (2R; 5S, 6S)-5-Amide-6-hydroxy-2--methyl-azepan-1-carboxylic acid benzyl ester " also with " (R)-tetrahydrochysene-furan-2-carboxylic acid " replacement " furan-2-carboxylic acid " provide title compound: 1HNMR:8.71 (d, 1H), 7.96 (m, 2H), 7.53 (m, 1H), 7.12 (m, 2H), 5.10 (m, 1H), 4.72 (m, 1H), 4.46 (m, 2H), and 4.11-3.95 (m, 4H), 2.74 (m, 1H), and 2.35-0.92 (m, 21H); Electrospray Mass Spectrometry: M+H +=521.4.
Embodiment 26
Preparation furan-3-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide
Figure A0180829000802
According to the method for embodiment 8 (i-m), just use " (3S, 4S)-4-amino-3-hydroxyl-azepan-1-carboxylic acid benzyl ester " replacement " (2R; 5S, 6S)-5-Amide-6-hydroxy-2--methyl-azepan-1-carboxylic acid benzyl ester " and with " furan-3-carboxylic acid " replacement " furan-2-carboxylic acid " provides title compound: and 1H NMR:8.70-8.68 (d, 1H), 7.99-7.92 (m, 3H), 7.54-7.44 (m, 2H), and 7.19-7.18 (d, 1H), 6.59-6.57 (m, 2H), 5.14-5.09 (m, 1H), and 4.79-4.63 (m, 2H), 4.07-4.04 (d, 1H), and 3.89-3.84 (d, 1H), 2.83-2.76 (m, 1H), and 2.23-0.91 (m, 17H); Electrospray Mass Spectrometry: M+H +=517.4.
Embodiment 27
Preparation 5-pyridine-2-base-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide
Figure A0180829000803
According to the method for embodiment 8 (i-m), just use " (3S, 4S)-4-amino-3-hydroxyl-azepan-1-carboxylic acid benzyl ester " replacement " (2R; 5S, 6S)-5-Amide-6-hydroxy-2--methyl-azepan-1-carboxylic acid benzyl ester " and with " 5-pyridine-2-base-thiophene-2-carboxylic acid " replacement " furan-2-carboxylic acid " and " oxygen base-pyridine-2-sulfuryl chlorine " replacement " 2-pyridine sulfonic acid chloride " provide title compound: and 1H NMR:8.55 (d, 1H), 8.05 (d, 1H), 8.03 (d, 1H), and 7.73-7.09 (m, 9H), 5.06 (m, 1H), 4.80 (m, 2H), 4.11 (d, 1H), 3.84 (d, 1H), 2.90 (t, 1H), 2.22 (m, 1H), and 2.10-0.88 (m, 15H); Electrospray Mass Spectrometry: M+H +=626.4.
Embodiment 28
Preparation 4-methyl-2-pyridine-2-base-thiazole-5-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide
Figure A0180829000811
According to the method for embodiment 8 (i-m), just use " (3S, 4S)-4-amino-3-hydroxyl-azepan-1-carboxylic acid benzyl ester " replacement " (2R; 5S, 6S)-5-Amide-6-hydroxy-2--methyl-azepan-1-carboxylic acid benzyl ester " and with " 4-methyl-2-pyridine-2-base-thiazole-5-carboxylic acid " replacement " furan-2-carboxylic acid ", and " oxygen base-pyridine-2-sulfuryl chlorine " replacement " 2-pyridine sulfonic acid chloride " provides title compound: 1H NMR:8.53 (d, 1H), 8.08 (d, 1H), 8.03 (d, 1H), 7.77-7.05 (m, 9H), 5.03 (m, 1H), 4.75 (m, 2H), 4.13 (d, 1H), 3.80 (d, 1H), 2.88 (t, 1H), 2.67 (s, 3H), 2.22 (m, 1H), 2.10-0.88 (m, 15H); Electrospray Mass Spectrometry: M+H +=641.4.
Embodiment 29
Preparation 5-(2-morpholine-4-base-ethyoxyl)-benzofuran-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide
According to the method for embodiment 8 (i-m), just with " (3S, 4S)-4-amino-3-hydroxyl-azepan-1-carboxylic acid benzyl ester " replacements " (2R; 5S, 6S)-5-Amide-6-hydroxy-2--methyl-azepan-1-carboxylic acid benzyl ester " also with " 5-(2-morpholine-4-base-ethyoxyl)-benzofuran-2-carboxylic acid " replacement " furan-2-carboxylic acid " and " oxygen base-pyridine-2-sulfuryl chlorine " replacement " 2-pyridine sulfonic acid chloride " provides title compound: 1H NMR:8.23 (br, 1H), 8.06 (d, 2H), and 7.48-7.00 (m, 8H), 5.03 (m, 1H), 4.80 (m, 2H), 4.59 (m, 2H), 4.27 (m, 2H), 4.09-3.33 (m, 9H), 3.29 (m, 2H), 2.80 (m, 2H), and 2.27-0.88 (m, 14H); Electrospray Mass Spectrometry: M+H +=712.4.
Embodiment 30
Preparation furan-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide
According to the method for embodiment 8 (i-m), just use " (3S, 4S)-4-amino-3-hydroxyl-azepan-1-carboxylic acid benzyl ester " replacement " (2R; 5S, 6S)-5-Amide-6-hydroxy-2--methyl-azepan-1-carboxylic acid benzyl ester " and with " furan-2-carboxylic acid " replacement " furan-2-carboxylic acid ", and " oxygen base-pyridine-2-sulfuryl chlorine " replacement " 2-pyridine sulfonic acid chloride " provides title compound: 1H NMR:8.24-8.23 (d, 1H), and 8.14-8.11 (m, 1H), 7.50-7.39 (m, 3H), 7.14 (d, 1H), and 7.01-6.99 (d, 1H), 6.78-6.76 (d, 1H), 6.52-6.51 (d, 1H), and 5.04-4.91 (m, 2H), 4.72-4.66 (d, 1H), and 4.14-4.10 (d, 1H), 3.93-3.88 (d, 1H), and 2.85-2.79 (m, 1H), 2.25-0.94 (m, 17H); Electrospray Mass Spectrometry: M+H +=533.4.
Embodiment 31
Preparation furan-3-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide
According to the method for embodiment 8 (i-m), just with " (3S, 4S)-4-amino-3-hydroxyl-azepan-1-carboxylic acid benzyl ester " replacement " (2R; 5S, 6S)-5-Amide-6-hydroxy-2--methyl-azepan-1-carboxylic acid benzyl ester ", and with " furan-3-carboxylic acid " replacement " furan-2-carboxylic acid ", and " oxygen base-pyridine-2-sulfuryl chlorine " replacement " 2-pyridine sulfonic acid chloride " provides title compound: and 1H NMR:8.25-8.23 (d, 1H), 8.14-8.11 (m, 1H), 7.97 (s, 1H), 7.51-7.39 (m, 3H), 7.04-7.03 (d, 1H), 6.67 (s, 1H), 6.50-6.48 (d, 1H), 5.06-4.88 (m, 2H), and 4.74-4.68 (m, 1H), 4.13-4.09 (d, 1H), and 3.93-3.88 (d, 1H), 2.86-2.79 (m, 1H), and 2.23-0.93 (m, 17H); Electrospray Mass Spectrometry: M+H +=533.4.
Embodiment 32
Preparation thiophene-3-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide
Figure A0180829000831
According to the method for embodiment 8 (i-m), just use " (3S, 4S)-4-amino-3-hydroxyl-azepan-1-carboxylic acid benzyl ester " replacement " (2R; 5S, 6S)-5-Amide-6-hydroxy-2--methyl-azepan-1-carboxylic acid benzyl ester " and with " thiophene-3-carboxylic acid " replacement " furan-2-carboxylic acid ", and " oxygen base-pyridine-2-sulfuryl chlorine " replacement " 2-pyridine sulfonic acid chloride " provides title compound: 1H NMR:8.24-8.22 (d, 1H), and 8.12-8.09 (m, 1H), 7.95 (s, 1H), and 7.49-7.19 (m, 5H), 6.59-6.57 (d, 1H), and 5.05-5.01 (m, 1H), 4.83-4.74 (m, 2H), and 4.10-4.06 (d, 1H), 3.92-3.87 (d, 1H), and 2.91-2.85 (m, 1H), 2.26-0.92 (m, 17H); Electrospray Mass Spectrometry: M+H +=549.4.
Embodiment 33
The preparation thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide
According to the method for embodiment 8 (i-m), just use " (3S, 4S)-4-amino-3-hydroxyl-azepan-1-carboxylic acid benzyl ester " replacement " (2R; 5S; 6S)-5-Amide-6-hydroxy-2--methyl-azepan-1-carboxylic acid benzyl ester " and with " thiophene-2-carboxylic acid " replacement " furan-2-carboxylic acid ", and " oxygen base-pyridine-2-sulfuryl chlorine " replacement " 2-pyridine sulfonic acid chloride " provides title compound: 1H NMR:8.24-8.23 (d, 1H), 8.13-8.10 (m, 1H), and 7.58-7.38 (m, 4H), 7.11-7.07 (m, 2H), and 6.79-6.77 (d, 1H), 5.04-4.69 (m, 3H), and 4.12-4.08 (d, 1H), 3.92-3.87 (d, 1H), and 2.85-2.79 (m, 1H), 2.21-0.90 (m, 17H); Electrospray Mass Spectrometry: M+H +=549.4.
Embodiment 34
Preparation 5-methyl-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide
According to the method for embodiment 8 (i-m), just with " (3S, 4S)-4-amino-3-hydroxyl-azepan-1-carboxylic acid benzyl ester " replacement " (2R; 5S, 6S)-5-Amide-6-hydroxy-2--methyl-azepan-1-carboxylic acid benzyl ester ", and with " 5-methyl-thiophene-2-carboxylic acid " replacement " furan-2-carboxylic acid ", and " oxygen base-pyridine-2-sulfuryl chlorine " replacement " 2-pyridine sulfonic acid chloride " provides title compound: and 1H NMR:8.23-8.22 (d, 1H), 8.11-8.08 (d, 1H), and 7.49-7.24 (m, 4H), 6.75-6.74 (s, 1H), and 6.62-6.60 (d, 1H), 5.03-4.71 (m, 3H), and 4.09-4.05 (d, 1H), 3.90-3.85 (d, 1H), and 2.88-2.83 (m, 1H), 2.67 (s, 3H), and 2.35-0.88 (m, 17H); Electrospray Mass Spectrometry: M+H +=563.2.
Embodiment 35
Preparation 3-methyl-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide
Figure A0180829000842
According to the method for embodiment 8 (i-m), just with " (3S, 4S)-4-amino-3-hydroxyl-azepan-1-carboxylic acid benzyl ester " replacement " (2R; 5S, 6S)-5-Amide-6-hydroxy-2--methyl-azepan-1-carboxylic acid benzyl ester ", and with " 3-methyl-thiophene-2-carboxylic acid " replacement " furan-2-carboxylic acid ", and " oxygen base-pyridine-2-sulfuryl chlorine " replacement " 2-pyridine sulfonic acid chloride " provides title compound: and 1H NMR:8.23-8.22 (d, 1H), 8.11-8.09 (d, 1H), and 7.49-7.17 (m, 4H), 6.93-6.91 (s, 1H), 6.27 (m, 1H), 5.06-4.70 (m, 3H), and 4.14-4.11 (d, 1H), 3.91-3.86 (d, 1H), and 2.87-2.81 (m, 1H), 2.56 (s, 3H), and 2.28-0.93 (m, 17H); Electrospray Mass Spectrometry: M+H +=563.2.
Embodiment 36
Preparation 3-ethyoxyl-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide
Figure A0180829000851
According to the method for embodiment 8 (i-m), just with " (3S, 4S)-4-amino-3-hydroxyl-azepan-1-carboxylic acid benzyl ester " replacement " (2R; 5S, 6S)-5-Amide-6-hydroxy-2--methyl-azepan-1-carboxylic acid benzyl ester ", and with " 3-ethyoxyl-thiophene-2-carboxylic acid " replacement " furan-2-carboxylic acid ", and " oxygen base-pyridine-2-sulfuryl chlorine " replacement " 2-pyridine sulfonic acid chloride " provides title compound: 1HNMR:8.24-8.22 (d, 1H), and 8.11-8.09 (d, 1H), 7.60-7.31 (m, 5H), and 6.88-6.87 (d, 1H), 5.06-4.65 (m, 3H), and 4.37-4.27 (m, 1H), 4.12-4.08 (d, 1H), and 3.88-3.83 (d, 1H), 2.84-2.77 (m, 1H), and 2.28-0.92 (m, 21H); Electrospray Mass Spectrometry: M+H +=593.2.
Embodiment 37
Preparation selenophen-2-carboxylic acid (S)-and the 2-cyclohexyl-1-[(R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide
Figure A0180829000852
According to the method 8 (i-m) of embodiment, just provide title compound with " selenophen-2-carboxylic acid " replacement " furan-2-carboxylic acid ": 1H NMR:8.64 (d, 1H), 8.14 (d, 1H), 7.84 (m, 2H), 7.64 (d, 1H), 7.42 (m, 1H), 7.22 (m, 1H), 6.88 (d, 1H), 6.60 (d, 1H), 5.01 (m, 1H), 4.71 (d, 1H), 4.50 (m, 1H), 4.34 (m, 1H), 3.77 (d, 1H), 2.05 (m, 2H), 1.78-0.82 (m, 18H); Electrospray Mass Spectrometry: M+H +=593.2.
Embodiment 38
Preparation furan-2-carboxylic acid [(S)-2-cyclohexyl-1-((4S, 7R)-7-methyl-3-oxo-1-propyl group-azepan-4-base carbamoyl)-ethyl]-amide
Figure A0180829000861
A.[(S)-2-cyclohexyl-1-((3S, 4S, 7R)-3-hydroxyl-7-methyl isophthalic acid-propyl group-azepan-4-base carbamoyl)-ethyl]-the carbamic acid tertiary butyl ester
[(S)-2-cyclohexyl-1-((3S, 4S, 7R)-3-hydroxyl-7-methyl-azepan-4-base carbamoyl)-ethyl]-(embodiment 1a-I, 1.5g 3.78mmol) are dissolved in CH to the carbamic acid tertiary butyl ester 2Cl 2(30ml), add then propionic aldehyde (0.41ml, 5.67mmol).(1.6g, 7.56mmol), reactant mixture was stirring at room 1 hour to add sodium borohydride again.Reactant mixture by the rotary evaporation vacuum concentration, is filtered (silica gel, 1-4%MeOH/CH then 2Cl 2) obtain the title compound white solid (84%, 1.4g): Electrospray Mass Spectrometry: M+H +=440.4.
B. (S)-2-amino-3-cyclohexyl-N-((3S, 4S, 7R)-3-hydroxyl-7-methyl isophthalic acid-propyl group-azepan-4-yl)-propionic acid amide.
Stir down; dioxane (the 4.0M of HCl; 15ml) solution be added into [(S)-2-cyclohexyl-1-((3S; 4S; 7R)-3-hydroxyl-7-methyl isophthalic acid-propyl group-azepan-4-base carbamoyl)-ethyl]-carbamic acid tertiary butyl ester (1.4g, MeOH 3.0mmol) (5ml) solution.Reactant mixture by the rotary evaporation vacuum concentration, just is used for the next step (1.4g) without being further purified then stirring at room 2 hours.
C. furan-2-carboxylic acid [(S)-2-cyclohexyl-1-((3S, 4S, 7R)-3-hydroxyl-7-methyl isophthalic acid-propyl group-azepan-4-base carbamoyl)-ethyl]-amide
1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (0.10g, 0.53mmol) be added into furan-2-carboxylic acid (0.059g, 0.53mmol), (S)-2-amino-3-cyclohexyl-N-((3S, 4S, 7R)-3-hydroxyl-7-methyl isophthalic acid-propyl group-azepan-4-yl)-propionic acid amide. (0.15g, 0.36mmol), 4-methyl morpholine (0.14g, 0.16ml, 1.44mmol), hydroxybenzotriazole (0.071g, 0.53mmol) DMF (2.0ml) solution, and in stirred overnight at room temperature.Reactant mixture is warmed to room temperature then and stirs and spend the night.Reactant mixture is used H with EtOAc (30ml) dilution 2O, the salt water washing, dried over mgso is filtered, by the rotary evaporation vacuum concentration, chromatogram purification (silica gel, 2.5%MeOH/CH 2Cl 2) provide title compound (0.12g, 76%): Electrospray Mass Spectrometry: M+H +=434.2.
D. furan-2-carboxylic acid [(S)-2-cyclohexyl-1-((4S, 7R)-7-methyl-3-oxo-1-propyl group-azepan-4-base carbamoyl)-ethyl]-amide
Sulfur trioxide-pyridine complex (0.0.35g; 2.2mmol) be added into furan-2-carboxylic acid [(S)-2-cyclohexyl-1-((3S; 4S; 7R)-3-hydroxyl-7-methyl isophthalic acid-propyl group-azepan-4-base carbamoyl)-ethyl]-amide (0.19g; 0.44mmol) DMSO (4.0ml) and triethylamine (0.61ml; 4.4mmol) solution, and at stirring at room 1h.The reactant mixture dilute with water extracts with EtOAc then.Organic layer extracts with saline.The organic layer that merges is dry with magnesium sulfate, filters, and vacuum concentration, and provide title compound (0.15mg, 79%) by column chromatography purification (3% ethanol/methylene): 1H NMR:7.44 (s, 1H), 7.11 (d, 1H), 7.04 (d, 1H), 6.92 (d, 1H), 6.49 (d, 1H), 5.29 (m, 1H), 4.69 (m, 1H), 3.40 (d, 1H), 3.08 (m, 2H), 2.51 (m, 2H), 1.88-0.81 (m, 29H); Electrospray Mass Spectrometry: M+H +=432.2.
Embodiment 39
Preparation thiophene-3-carboxylic acid [(S)-2-cyclohexyl-1-((4S, 7R)-7-methyl-3-oxo-1-propyl group-azepan-4-base carbamoyl)-ethyl]-amide
Figure A0180829000871
According to the method for embodiment 38 (a-c), just provide title compound with " thiophene-3-carboxylic acid " replacement " furan-2-carboxylic acid ": 1H NMR:7.62 (d, 1H), 7.40 (d, 1H), 7.04 (d, 1H), 6.80 (d, 1H), 6.45 (d, 1H), 5.27 (m, 1H), 4.66 (m, 1H), 3.44 (d, 1H), 3.09 (m, 2H), 2.54 (m, 2H), and 1.87-0.87 (m, 29H); Electrospray Mass Spectrometry: M+H +=448.4.
Embodiment 40
Preparation benzofuran-2-carboxylic acid [(S)-2-cyclohexyl-1-((4S, 7R)-7-methyl-3-oxo-1-propyl group-azepan-4-base carbamoyl)-ethyl]-amide
Figure A0180829000872
According to the method for embodiment 38 (a-c), just provide title compound with " benzofuran-2-carboxylic acid " replacement " furan-2-carboxylic acid ": 1H NMR:7.98 (d, 1H), 7.45 (m, 2H), 7.27 (s, 2H), 6.90 (d, 1H), 6.50 (d, 1H), 5.28 (m, 1H), 4.67 (m, 1H), 3.40 (d, 1H), 3.06 (m, 2H), 2.56 (m, 2H), and 1.88-0.80 (m, 29H); Electrospray Mass Spectrometry: M+H +=482.4.
Embodiment 41
Preparation 2,2,4-three deuterium generation-furan-2-carboxylic acid (S)-and 2-cyclohexyl-1-[(4S, 7R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide
A. furan-2-carboxylic acid (S)-2-cyclohexyl-1-[(4S, 7R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl-amide is dissolved in d4-methanol (CD 3OD) and D 2O (10: 1) adds triethylamine then, and reactant mixture is stirred 3 days.By vacuum concentration and methylbenzene azeotropic, provide title compound.
Embodiment 42
Preparation thiophene-3-carboxylic acid (S)-3,3-dimethyl-1-[(4S, 7R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-butyl }-amide
Figure A0180829000882
According to the method for embodiment 8 (a-m), just with " N-Boc-tert-butyl group alanine " replacement " Boc-L-Cyclohexylalanine " also with " thiophene-3-carboxylic acid " replacement " furan-2-carboxylic acid " provide title compound: 1HNMR:8.72 (m, 1H), 7.96 (m, 2H), 7.48 (m, 2H), 7.00 (m, 3H), 6.60 (m, 2H), 5.18 (m, 1H), 4.67 (m, 2H), 4.42 (m, 1H), 3.88 (m, 1H), 2.87 (m, 2H), 2.22 (m, 2H), 1.95 (m, 1H), 1.70 (m, 2H), 1.01 (m, 12H); Electrospray Mass Spectrometry: M+H +=521.4.
Embodiment 43
Preparation furan-2-carboxylic acid (S)-3,3-dimethyl-1-[(4S, 7R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-butyl }-amide
Figure A0180829000891
According to the method for embodiment 8 (a-m), just provide title compound with " N-Boc-tert-butyl group alanine " replacement " Boc-L-Cyclohexylalanine ": 1H NMR:8.73 (d, 1H), 7.95 (m, 3H), 7.54 (m, 1H), 7.41 (m, 1H), 7.32 (m, 1H), 7.26 (s, 1H), 7.01 (d, 1H), 6.56 (d, 1H), 5.08 (m, 1H), 4.73 (m, 2H), 4.43 (m, 1H), 3.88 (d, 1H), 2.18 (m, 2H), 1.70 (m, 3H), 1.04 (s, 9H), 0.98 (d, 3H); Electrospray Mass Spectrometry: M+H +=505.4.
Embodiment 44
Preparation thieno [3,2-b] thiophene-2-carboxylic acid (S)-3,3-dimethyl-1-[(4S, 7R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-butyl }-amide
Figure A0180829000892
According to the method for embodiment 8 (a-m), just with " N-Boc-tert-butyl group alanine " replacement " Boc-L-Cyclohexylalanine " and with " " replacement " furan-2-carboxylic acid " provides title compound to thieno [3,2-b] thiophene-2-carboxylic acid: 1H NMR:8.73 (d, 1H), 7.92 (m, 3H), 7.52 (m, 2H), 7.27 (m, 1H), 7.09 (br, 1H), 6.80 (br, 1H), 5.10 (m, 1H), 4.77 (m, 2H), 4.40 (m, 1H), 3.87 (d, 1H), 1.90 (m, 5H), 1.05 (s, 9H), 0.95 (d, 3H); Electrospray Mass Spectrometry: M+H +=577.2.
Above explanation and embodiment fully disclose and how to prepare and use chemical compound of the present invention.Yet the present invention is not limited to above-mentioned particular, and comprises all improvement in claims scope.At the various periodicals that this paper quoted, patent and other public publications have comprised this professional present situation, and draw in full and make this paper list of references.

Claims (54)

1. the method for inhibition of histone enzyme S comprises that patient to needs uses the formula I chemical compound of effective dose:
Wherein:
R 1Be selected from as next group:
Figure A0180829000022
With
Figure A0180829000023
R 2Be selected from as next group: H, C 1-6Alkyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl, Het-C 0-6Alkyl, R 9C (O)-, R 9C (S)-, R 9SO 2-, R 9OC (O)-,
R 9R 11NC (O)-, R 9R 11NC (S)-, R 9(R 11) NSO 2- With
R 3Be selected from as next group: H, C 1-6Alkyl, C 3-6Cycloalkyl-C 0-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, HetC 0-6Alkyl, ArC 0-6Alkyl, Ar-ArC 0-6Alkyl, Ar-HetC 0-6Alkyl, Het-ArC 0-6Alkyl, and Het-HetC 0-6Alkyl;
R 3Can be connected to form pyrrolidine with R ＇, piperidines or morpholine ring;
R 4Be selected from as next group: H, C 1-6Alkyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl, Het-C 0-6Alkyl, R 5C (O)-, R 5C (S)-, R 5SO 2-, R 5OC (O)-, R 5R 13NC (O)-, and R 5R 13NC (S)-;
R 5Be selected from as next group: H, C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl and Het-C 0-6Alkyl;
R 6Be selected from as next group: H, C 1-6Alkyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl, and Het-C 0-6Alkyl;
R 7Be selected from as next group: H, C 1-6Alkyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl, Het-C 0-6Alkyl, R 10C (O)-, R 10C (S)-, R 10SO 2-, R 10OC (O)-, R 10R 14NC (O)-, and R 10R 14NC (S)-;
R 8Be selected from as next group: H, C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, HetC 0-6Alkyl and ArC 0-6Alkyl;
R 9Be selected from as next group: C 1-6Alkyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl and Het-C 0-6Alkyl;
R 10Be selected from as next group: C 1-6Alkyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl and Het-C 0-6Alkyl;
R 11Be selected from as next group: H, C 1-6Alkyl, Ar-C 0-6Alkyl, and Het-C 0-6Alkyl;
R 12Be selected from as next group: H, C 1-6Alkyl, Ar-C 0-6Alkyl, and Het-C 0-6Alkyl;
R 13Be selected from as next group: H, C 1-6Alkyl, Ar-C 0-6Alkyl, and Het-C 0-6Alkyl;
R 14Be selected from as next group: H, C 1-6Alkyl, Ar-C 0-6Alkyl, and Het-C 0-6Alkyl;
R ＇ is selected from as next group: H, C 1-6Alkyl, Ar-C 0-6Alkyl, and Het-C 0-6Alkyl;
R " is selected from as next group: H, C 1-6Alkyl, Ar-C 0-6Alkyl, or Het-C 0-6Alkyl;
R is selected from as next group: H, C 1-6Alkyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl, and Het-C 0-6Alkyl;
X is selected from as next group: CH 2, S, and O;
Z is selected from as next group: C (O) and CH 2
With its pharmaceutical salts, hydrate and solvate.
2. according to the process of claim 1 wherein R in said chemical compound 1Be
3. according to the method for claim 2, R in said chemical compound wherein 3Be C 3-6Cycloalkyl-C 0-6Alkyl.
4. according to the method for claim 3, R in said chemical compound wherein 3It is cyclohexyl methyl.
5. according to the method for claim 2, R in said chemical compound wherein 4Be R 5C (O)-.
6. according to the method for claim 5, R in said chemical compound wherein 5Be selected from as next group: C 1-6Alkyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl and Het-C 0-6Alkyl.
7. according to the method for claim 6, R in said chemical compound wherein 5Be selected from as next group:
Furyl;
Benzofuranyl;
Thienyl;
Furo [3,2-b]-pyridine-2-base;
Thiazolyl;
Phenyl;
Cyclobutyl;
Cyclopenta;
Tetrahydrofuran base;
The selenophen base; With
Thieno [3,2-b] thienyl.
8. according to the method for claim 6, R in said chemical compound wherein 5Be selected from as next group:
Furan-2-base and furan-3-base;
Benzofuran-2-base;
Thiene-3-yl-and thiophene-2-base;
Furo [3,2-b]-pyridine-2-base;
Thiazole-5-base;
Oxolane-2-base;
Selenophen-2-base; With
Thieno [3,2-b] thiophene-2-base.
9. according to the method for claim 6, R in said chemical compound wherein 5Be selected from as next group;
The furyl that aryl replaces;
C 1-6The benzofuranyl that alkoxyl replaces;
Het-C 0-6Alkyl-thienyl, C 1-6Alkyl-thienyl and C 1-6Alkoxyl-thienyl,
C 1-6Alkyl-furo [3,2-b]-pyridine-2-base,
Het-C 0-6Alkyl-thiazolyl; With
The phenyl that halogen replaces.
10. according to the method for claim 6, R in said chemical compound wherein 5Be selected from as next group:
5-(3-trifluoromethyl-phenyl)-furan-2-base and 5-(4-chloro-phenyl)-furan-2-base;
5,6-dimethoxy-benzofuran-2-base and 5-(2-morpholine-4-base-ethyoxyl) benzofuran-2-base;
5-pyridine-2-base-thiophene-2-base, 5-methyl-thiophene-2-base, 3-methyl-thiophene-2-base; With 3-ethyoxyl-thiophene-2-base;
3-methyl-furo [3,2-b]-pyridine-2-base;
4-methyl-2-pyridine-2-base-thiazole-5-base; With
The 4-bromophenyl.
11. according to the process of claim 1 wherein that R ＇ is H in said chemical compound.
12. according to the process of claim 1 wherein that R in said chemical compound " is H.
13. according to the process of claim 1 wherein that R is selected from as next group in said chemical compound: H and C 1-6Alkyl.
14. according to the process of claim 1 wherein R in said chemical compound " is H and R is selected from as next group: H and C 1-6Alkyl.
15. according to the method for claim 13, wherein R is H in said chemical compound.
16. according to the method for claim 13, wherein R is C in said chemical compound 1-6Alkyl.
17. according to the chemical compound of claim 16, wherein C 1-6Alkyl is selected from as next group: 5-, 6-and 7-C 1-6Alkyl.
18. according to the chemical compound of claim 17, wherein 5-, 6-and 7-C 1-6Alkyl is selected from as next group: 5-, 6-or 7-methyl ,-ethyl ,-propyl group ,-butyl ,-amyl group and-hexyl.
19. according to the chemical compound of claim 18, wherein 5-, 6-and 7-C 1-6Alkyl is selected from as next group: 5-, 6-and 7-methyl.
20. according to the chemical compound of claim 16, wherein C 1-6Alkyl is selected from as next group: 6-and 7-C 1-6Alkyl.
21. according to the chemical compound of claim 20, wherein 6-and 7-C 1-6Alkyl is selected from as next group: 6-or 7-methyl ,-ethyl ,-propyl group ,-butyl ,-amyl group and-hexyl.
22. according to the chemical compound of claim 21, wherein 6-and 7-C 1-6Alkyl is selected from as next group: 6-and 7-methyl.
23. according to the chemical compound of claim 16, wherein C 1-6Alkyl is 7-C 1-6Alkyl.
24. according to the chemical compound of claim 23, wherein 7-C 1-6Alkyl is selected from as next group: the 7-methyl ,-ethyl ,-propyl group ,-butyl ,-amyl group and-hexyl.
25. according to the chemical compound of claim 24, wherein 7-C 1-6Alkyl is the 7-methyl.
26. formula Ia chemical compound according to claim 16:
Wherein R is cis-7-C 1-6Alkyl.
27. according to the chemical compound of claim 26, wherein R is cis-7-methyl.
28. according to the process of claim 1 wherein R in said chemical compound 2Be R 9SO 2
29. according to the method for claim 28, R in said chemical compound wherein 9Be Het-C 0-6Alkyl.
30. according to the method for claim 29, wherein Het-C 0-6Alkyl is selected from as next group: pyridine radicals and 1-oxygen base-pyridine radicals.
31. according to the method for claim 30, wherein R 9It is pyridine-2-base.
32. according to the process of claim 1 wherein in said chemical compound:
R 1Be
Figure A0180829000062
R 2Be R 9SO 2
R 3Be C 3-6Cycloalkyl-C 0-6Alkyl;
R 4Be R 5C (O);
R 5Be Het-C 0-6Alkyl;
R 9Be Het-C 0-6Alkyl;
R ＇ is H
R " is H; With
R is C 1-6Alkyl.
33. according to the process of claim 1 wherein in said chemical compound:
R 3It is cyclohexyl methyl;
R 5Be selected from as next group: furan-2-base and thiene-3-yl-;
R 9It is pyridine-2-base; With
R is the 7-methyl.
34. according to the process of claim 1 wherein that said chemical compound is selected from as next group:
Figure A0180829000071
Benzofuran-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
5-(3-trifluoromethyl-phenyl)-furan-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000073
5-(4-chloro-phenyl)-furan-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000074
5-(4-chloro-phenyl)-furan-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000075
5-(3-trifluoromethyl-phenyl)-furan-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000076
5,6-dimethoxy-benzofuran-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide; With
Figure A0180829000081
Furan-2-carboxylic acid (S)-and 2-cyclohexyl-1-[(4S, 7R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000082
Benzofuran-2-carboxylic acid (S)-and 2-cyclohexyl-1-[(4S, 7R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000083
Thiophene-3-carboxylic acid (S)-and 2-cyclohexyl-1-[(4S, 7R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
3-methyl-furo [3,2-b]-pyridine-2-carboxylic acids (S)-and 2-cyclohexyl-1-[(4S, 7R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
5-(2-morpholine-4-base-ethyoxyl)-benzofuran-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
4-methyl-2-pyridine-2-base-thiazole-5-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
5-pyridine-2-base-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Furan-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000101
Thiophene-3-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000102
5-methyl-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000103
3-methyl-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
3-ethyoxyl-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000105
4-bromo-N-{ (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-Benzoylamide;
Cyclobutylcarboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Cyclopentane carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
(S)-tetrahydrochysene-furan-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000114
(R)-tetrahydrochysene-furan-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Furan-3-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000121
5-pyridine-2-base-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000122
4-methyl-2-pyridine-2-base-thiazole-5-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
5-(2-morpholine-4-base-ethyoxyl)-benzofuran-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000124
Furan-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Furan-3-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000126
Thiophene-3-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000131
Thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
5-methyl-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
3-methyl-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
3-ethyoxyl-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000135
Selenophen-2-carboxylic acid (S)-and the 2-cyclohexyl-1-[(R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000136
Furan-2-carboxylic acid [(S)-2-cyclohexyl-1-((4S, 7R)-7-methyl-3-oxo-1-propyl group-azepan-4-base carbamoyl)-ethyl]-amide;
Figure A0180829000141
Thiophene-3-carboxylic acid [(S)-2-cyclohexyl-1-((4S, 7R)-7-methyl-3-oxo-1-propyl group-azepan-4-base carbamoyl)-ethyl]-amide;
Benzofuran-2-carboxylic acid [(S)-2-cyclohexyl-1-((4S, 7R)-7-methyl-3-oxo-1-propyl group-azepan-4-base carbamoyl)-ethyl]-amide;
2,2,4-three deuterium generation-furan-2-carboxylic acid (S)-and 2-cyclohexyl-1-[(4S, 7R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000144
Thiophene-3-carboxylic acid (S)-3,3-dimethyl-1-[(4S, 7R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-butyl }-amide;
Furan-2-carboxylic acid (S)-3,3-dimethyl-1-[(4S, 7R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-butyl }-amide; With
Figure A0180829000151
Thieno [3,2-b] thiophene-2-carboxylic acid (S)-3,3-dimethyl-1-[(4S, 7R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-butyl }-amide.
35., be selected from as next group according to the chemical compound of claim 34:
Furan-2-carboxylic acid (S)-and 2-cyclohexyl-1-[(4S, 7R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide; With
Thiophene-3-carboxylic acid (S)-and 2-cyclohexyl-1-[(4S, 7R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide.
36. the chemical compound according to claim 35 is:
Furan-2-carboxylic acid (S)-and 2-cyclohexyl-1-[(4S, 7R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide.
37. the method for treatment and prevention autoimmune disease comprises by the patient to needs and uses each the chemical compound of claim 1 to 36 of effective dose to come the overexpression of inhibition of histone enzyme S.
38. according to the method for claim 37, said disease is selected from as next group: rheumatoid arthritis, multiple sclerosis, juvenile diabetes, systemic lupus erythematosus (sle), discoid lupus erythematosus, pemphigus vulgaris, pemphigoid, grave disease, myasthenia gravis, chronic lymphocytic thyroiditis, scleroderma, dermatomyositis, bronzed disease, pernicious anemia, the constitutional solid edema, thyrotoxicosis, autoimmune atrophic gastritis, stiff person's syndrome, Goodpasture syndrome, sympathetic ophthalmia, phacoantigenic uveitis, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, the special property sent out leukopenia, primary biliary cirrhosis, active chronic hepatitis, latent source property hepatitis interstitialis chronica, ulcerative colitis, xerodermosteosis, and mixed connective tissue disease.
39. treatment or prevention form the method for caused disease and its complication by atherosclerotic lesions, comprise that each the chemical compound of claim 1 to 36 by the patient being used effective dose suppresses the formation of said damage or complication.
40. treatment need to suppress the method for disease of the immunne response of II class MHC-limitation, comprises that each the chemical compound of claim 1 to 36 by the patient being used effective dose suppresses the immunne response of said II class MHC-limitation.
41. treatment need to suppress the method for the disease of asthmatic reaction, comprises that each the chemical compound of claim 1 to 36 by the patient being used effective dose suppresses said asthmatic reaction.
42. treatment need to suppress the method for the disease of anaphylactic reaction, comprises that each the chemical compound of claim 1 to 36 by the patient being used effective dose suppresses said anaphylactic reaction.
43. treatment need to suppress to be transplanted by organ or tissue the method for the immunoreactive disease that causes, comprises that each the chemical compound of claim 1 to 36 by the patient being used effective dose suppresses to transplant the immunoreation that causes by organ or tissue.
44. treatment need be suppressed at the method for active disease of the elastoser in the sebaceous cyst, comprises by the patient to needs using each the chemical compound of claim 1 to 36 of effective dose to be suppressed at the activity of the said elastoser in the sebaceous cyst.
45. each chemical compound of claim 1 to 36 is used for the purposes of the medicine of inhibition of histone enzyme S in production.
46. each chemical compound of claim 1 to 36 is used for the treatment of and prevents purposes in the medicine of autoimmune disease in production.
47. according to the purposes of claim 46, wherein said disease is selected from as next group: rheumatoid arthritis, multiple sclerosis, juvenile diabetes, systemic lupus erythematosus (sle), discoid lupus erythematosus, pemphigus vulgaris, pemphigoid, grave disease, myasthenia gravis, chronic lymphocytic thyroiditis, scleroderma, dermatomyositis, bronzed disease, pernicious anemia, the constitutional solid edema, thyrotoxicosis, autoimmune atrophic gastritis, stiff person's syndrome, Goodpasture syndrome, sympathetic ophthalmia, phacoantigenic uveitis, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, the special property sent out leukopenia, primary biliary cirrhosis, active chronic hepatitis, latent source property hepatitis interstitialis chronica, ulcerative colitis, xerodermosteosis, and mixed connective tissue disease.
48. any one chemical compound of claim 1 to 36 is used for the treatment of or prevents to be formed by atherosclerotic lesions purposes in the medicine of caused disease and its complication in production.
49. any one chemical compound of claim 1 to 36 is used for the treatment of purposes in the medicine of disease of immunne response that needs suppress II class MHC-limitation in production.
50. any one chemical compound of claim 1 to 36 is used for suppressing the purposes of the medicine of asthma reaction in production.
51. any one chemical compound of claim 1 to 36 is used for suppressing the purposes of anaphylactoid medicine in production.
52. any one chemical compound of claim 1 to 36 is used for suppressing to be transplanted by organ or tissue the purposes of the immunoreactive medicine that causes in production.
53. any one chemical compound of claim 1 to 36 is used for being suppressed at purposes in the active medicine of elastoser of sebaceous cyst in production.
54. be selected from chemical compound as next group.
5-(2-morpholine-4-base-ethyoxyl)-benzofuran-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
4-methyl-2-pyridine-2-base-thiazole-5-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
5-pyridine-2-base-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000182
Furan-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000183
Thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000184
Thiophene-3-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000185
5-methyl-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000191
3-methyl-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
3-ethyoxyl-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
4-bromo-N-{ (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-Benzoylamide;
Figure A0180829000194
Cyclobutylcarboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Cyclopentane carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000202
(S)-tetrahydrochysene-furan-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000203
(R)-tetrahydrochysene-furan-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Furan-3-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000205
5-pyridine-2-base-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000211
4-methyl-2-pyridine-2-base-thiazole-5-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000212
5-(2-morpholine-4-base-ethyoxyl)-benzofuran-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000213
Furan-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Furan-3-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000215
Thiophene-3-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000221
Thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
5-methyl-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Figure A0180829000223
3-methyl-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
3-ethyoxyl-thiophene-2-carboxylic acid (S)-2-cyclohexyl-1-[3-oxo-1-(1-oxygen base-pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide;
Selenophen-2-carboxylic acid (S)-and the 2-cyclohexyl-1-[(R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide; With
2,2,4-three deuterium generation-furan-2-carboxylic acid (S)-and 2-cyclohexyl-1-[(4S, 7R)-7-methyl-3-oxo-1-(pyridine-2-sulfuryl base)-azepan-4-base carbamoyl]-ethyl }-amide.
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