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HK1034964B - Carboxyl acid substituted heterocycles as metalloproteinase inhibitors - Google Patents

Carboxyl acid substituted heterocycles as metalloproteinase inhibitors Download PDF

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Publication number
HK1034964B
HK1034964B HK01105515.4A HK01105515A HK1034964B HK 1034964 B HK1034964 B HK 1034964B HK 01105515 A HK01105515 A HK 01105515A HK 1034964 B HK1034964 B HK 1034964B
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Hong Kong
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alkyl
alkoxy
amino
aryl
group
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HK01105515.4A
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Chinese (zh)
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HK1034964A1 (en
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K‧科克
A‧特明
J‧A‧乔西
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安姆根有限公司
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Priority claimed from US09/213,031 external-priority patent/US6335329B1/en
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Publication of HK1034964A1 publication Critical patent/HK1034964A1/en
Publication of HK1034964B publication Critical patent/HK1034964B/en

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Description

Carboxylic acid substituted heterocycles as metalloproteinase inhibitors
Background
The present invention relates to metalloproteinase inhibitors, and in particular, to novel compounds, compositions, and methods for preventing and treating inflammation, tissue degeneration, and the like. The invention relates, inter alia, to novel carboxylic acid-substituted heterocyclic compounds, compositions containing such compounds, and uses of such compounds. The invention also relates to a method for preparing the compound and an intermediate used in the method.
Metalloproteinases, such as collagenase, stromelysin and gelatinase, can cause the onset, occurrence or worsening of diseases associated with connective tissue degradation and the like. For example, matrix metalloproteinases, such as collagenase, stromelysin and gelatinase, are thought to be associated with tissue damage observed in the following conditions: rheumatoid arthritis, osteoarthritis, osteopenia (e.g., osteoporosis), periodontitis, gingivitis, corneal, epidermal and gastric ulceration, tumor metastasis, onset and growth, neuritis, such as myelin degradation (e.g., multiple sclerosis), and angiogenesis dependent disorders, such as arthritis, cancer, solid tumor growth, psoriasis, retinal hyperplasia, neovascular glaucoma, ocular tumors, angiofibromas, hemangiomas, nephritis, pneumonia and restenosis.
WO 96/33172 discloses N-alkylsulfonyl and N-heteroarylsulfonyl substituted 6-membered heterocyclic hydroxamic acid derivatives, e.g., N-arylsulfonyl-and N-heteroarylsulfonyl-piperidinyl-2-hydroxamic acid compounds, methods for their preparation and the use of such compounds as matrix metalloproteinase inhibitors and the preparation of tumor necrosis factor.
EP 606046 discloses N-arylsulfonyl-and N-heteroarylsulfonyl-substituted 5-to 6-membered heterocyclic hydroxamic acid derivatives, e.g., N-arylsulfonyl-and N-heteroarylsulfonyl-piperidinyl-2-hydroxamic acid compounds and N-arylsulfonyl-and N-heteroarylsulfonyl-1, 2, 3, 4-tetrahydroisoquinolinyl-2-hydroxamic acid compounds, and methods for their preparation and use as matrix metalloproteinase inhibitors.
WO 97/18194 discloses certain cyclic and heterocyclic N-substituted alpha-substituted iminohydroxamic acids and carboxylic acids, methods for their preparation and use as matrix metalloproteinase inhibitors.
EP 803505 discloses optionally substituted aryl fused N-heterocyclic compounds, processes for their preparation and their use as metalloproteinase inhibitors.
Summary of The Invention
The present invention relates to selected metalloprotease inhibitor compounds, analogs thereof, and pharmaceutically acceptable salts and prodrugs thereof. The compounds of the present invention are characterized as carboxylic acid substituted heterocyclic compounds. The compounds are useful for the prevention and treatment of inflammation, tissue degeneration and related diseases. Accordingly, the invention also includes pharmaceutical compositions and methods for preventing and treating inflammation, tissue degeneration and related disorders. The invention also relates to a method for preparing the compound and an intermediate used by the method.
Detailed Description
The present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof,
wherein m is 1 or 2, n is 0, 1 or 2;
R1is (1) optionally substituted by 1-3 substituents selected from-OH, -OR3、-SR3、-S(O)R3、-S(O)2R3、-C(O)R3、-NR3R4Alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl substituted with a substituent of aryl, heteroaryl, cycloalkyl or heterocyclyl (heterocyclyl); or (2) aryl optionally substituted with an optionally substituted monocyclic heteroaryl or a 5-6 membered heterocyclyl optionally substituted with phenyl or a 5-6 membered monocyclic heteroaryl; or (3) heteroaryl optionally substituted with optionally substituted phenyl or monocyclic heteroaryl or 5-6 membered heterocyclyl optionally substituted with phenyl or 5-6 membered monocyclic heteroaryl; wherein the phenyl, aryl, heteroaryl, cycloalkyl and heterocyclyl groups in (1), (2) and (3) are optionally substituted by 1 to 3 groups selected from-OH, -OR3、-SR3、-S(O)R3、-S(O)2R3、-C(O)R3、-NR3R4Substituted with a substituent of amino, alkanoylamino, alkylsulfonylamino, alkoxycarbonylamino, alkoxycarbonyl, cyano, halogen, azido, alkyl or haloalkyl;
R1preferably (1) is optionally substituted by 1-3 groups selected from-OH, -OR3、-SR3、-S(O)R3、-S(O)2R3、-C(O)R3、-NR3R4C substituted by substituents of aryl, heteroaryl, cycloalkyl or heterocyclyl1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, cycloalkyl or heterocyclyl; or (2) aryl optionally substituted with an optionally substituted monocyclic heteroaryl or a 5-6 membered heterocyclyl optionally substituted with phenyl or a 5-6 membered monocyclic heteroaryl; or (3) heteroaryl optionally substituted with optionally substituted phenyl or monocyclic heteroaryl or 5-6 membered heterocyclyl optionally substituted with phenyl or 5-6 membered monocyclic heteroaryl; wherein the phenyl, aryl, heteroaryl, cycloalkyl and heterocyclyl groups in (1), (2) and (3) are optionally substituted by 1 to 3 groups selected from-OH, -OR3、-SR3、-S(O)R3、-S(O)2R3、-C(O)R3、-NR3R4Amino group, C1-8Alkanoylamino group, C1-8Alkylsulfonylamino group, C1-8Alkoxycarbonylamino group, C1-8Alkoxycarbonyl, cyano, halogenAzido group, C1-8Alkyl or C with 1-3 halogens1-8Substituted with a haloalkyl;
R1more preferably (1) optionally substituted by 1-3 groups selected from-OH, -OR3、-SR3、-S(O)R3、-S(O)2R3、-C(O)R3、-NR3R4C substituted by substituents of aryl, heteroaryl, cycloalkyl or heterocyclyl1-12Alkyl radical, C2-12Alkenyl radical, C2-12Alkynyl, cycloalkyl or heterocyclyl; or (2) aryl optionally substituted with an optionally substituted monocyclic heteroaryl or a 5-6 membered heterocyclyl optionally substituted with phenyl or a 5-6 membered monocyclic heteroaryl; or (3) heteroaryl optionally substituted with optionally substituted phenyl or monocyclic heteroaryl or 5-6 membered heterocyclyl optionally substituted with phenyl or 5-6 membered monocyclic heteroaryl; wherein the phenyl, aryl, heteroaryl, cycloalkyl and heterocyclyl groups in (1), (2) and (3) are optionally substituted by 1 to 3 groups selected from-OH, -OR3、-SR3、-S(O)R3、-S(O)2R3、-C(O)R3、-NR3R4Amino group, C1-4Alkanoylamino group, C1-4Alkylsulfonylamino group, C1-4Alkoxycarbonylamino group, C1-4Alkoxycarbonyl, cyano, halogen, azido, C1-6Alkyl or C with 1-3 halogens1-4Substituted with a haloalkyl;
R1more preferably (1) optionally substituted by 1-3 groups selected from-OH, -OR3、-SR3、-S(O)R3、-S(O)2R3、-C(O)R3、-NR3R4C substituted by substituents of aryl, heteroaryl, cycloalkyl or heterocyclyl1-12An alkyl group; or (2) aryl optionally substituted with an optionally substituted monocyclic heteroaryl or a 5-6 membered heterocyclyl optionally substituted with phenyl or a 5-6 membered monocyclic heteroaryl; or (3) heteroaryl optionally substituted with optionally substituted phenyl or monocyclic heteroaryl or 5-6 membered heterocyclyl optionally substituted with phenyl or 5-6 membered monocyclic heteroaryl; wherein the phenyl, aryl, heteroaryl, cycloalkyl and heterocyclyl groups in (1), (2) and (3) are optionally substituted by 1 to 3 substituents selected from the group consisting of-OH, C,-OR3、-SR3、-S(O)R3、-S(O)2R3、-C(O)R3、-NR3R4amino, acetylamino, methylsulfonylamino, C1-4Alkoxycarbonylamino group, C1-4Alkoxycarbonyl, cyano, halogen, C1 -6Alkyl or-CF3Substituted with the substituent(s);
R1more preferably (1) optionally substituted by 1-3 groups selected from-OH, -OR3、-SR3、-S(O)2R3、-NR3R4C substituted by substituents of aryl, heteroaryl, cycloalkyl or heterocyclyl1-12An alkyl group; or (2) aryl optionally substituted with an optionally substituted monocyclic heteroaryl or a 5-6 membered heterocyclyl optionally substituted with phenyl or a 5-6 membered monocyclic heteroaryl; or (3) heteroaryl optionally substituted with optionally substituted phenyl or monocyclic heteroaryl or 5-6 membered heterocyclyl optionally substituted with phenyl or 5-6 membered monocyclic heteroaryl; wherein the phenyl, aryl, heteroaryl, cycloalkyl and heterocyclyl groups in (1), (2) and (3) are optionally substituted by 1 to 3 groups selected from-OH, -OR3、-SR3、-S(O)2R3、-NR3R4Amino, acetylamino, methylsulfonylamino, C1-4Alkoxycarbonylamino group, C1-4Alkoxycarbonyl, cyano, halogen, C1-6Alkyl or-CF3Substituted with the substituent(s);
R1more preferably (1) optionally substituted by 1-2 groups selected from-OH, -OR3、-NR3R4Aryl or heteroaryl substituted C1-4An alkyl group; or (2) aryl optionally substituted with 5-6 membered monocyclic heteroaryl; or (3) heteroaryl optionally substituted with phenyl; wherein the phenyl, aryl and heteroaryl groups in (1), (2) and (3) are optionally substituted by 1-2 groups selected from-OH, -OR3、-S(O)2R3、-NR3R4Amino, acetylamino, methylsulfonylamino, C1-4Alkoxycarbonylamino group, C1-4Alkoxycarbonyl, halogen, C1-6Alkyl or-CF3Substituted with the substituent(s);
R1more preferably optionally substituted by 1-2 groups selected from-OH, -OR3、-SR3、-S(O)2R3、-NR3R4Amino, acetylamino, methylsulfonylamino, C1-4Alkoxycarbonylamino group, C1-4Alkoxycarbonyl, halogen, C1-6Alkyl or-CF3Aryl or heteroaryl substituted with the substituents of (1);
R1more preferably optionally substituted by 1-2 groups selected from-OH, -OR3、-S(O)2R3、-NR3R4Amino, acetylamino, methylsulfonylamino, halogen, C1-4Alkyl or-CF3Aryl substituted with the substituent of (1);
R1more preferably optionally substituted by 1-2 groups selected from-OH, -OR3、-S(O)2R3、-NR3R4Amino, acetylamino, methylsulfonylamino, halogen, C1-4Alkyl or-CF3Phenyl or biphenyl substituted with the substituents of (1);
R1most preferably optionally substituted by 1-2 substituents selected from-OH, -OR3Halogen, methyl or-CF3Phenyl or biphenyl substituted with the substituents of (1);
provided that R is1The total number of phenyl, aryl, heteroaryl, cycloalkyl and heterocyclyl groups in (a) is preferably 0 to 3, more preferably 0 to 2, most preferably 1 to 2;
wherein each R is3Each is alkyl, haloalkyl, aryl, heteroaryl, aryl-alkyl or heteroaryl-alkyl, wherein aryl and heteroaryl are optionally substituted with 1 to 3 substituents selected from hydroxy, alkoxy, alkylthio, amino, alkanoylamino, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, alkoxycarbonylamino, alkoxycarbonyl, cyano, halogen, azido, alkyl, haloalkyl or haloalkoxy;
each R is3Preferably C is each1-8Alkyl, C with 1-3 halogens1-8Haloalkyl, aryl, heteroaryl, aryl-C1-4Alkyl or heteroaryl-C1-4Alkyl, wherein aryl and heteroaryl are optionally substituted by 1-3 substituents selected from hydroxy, C1-4Alkoxy radical, C1-4Alkylthio, amino, C1-8Alkanoylamino group, C1-8Alkylsulfonylamino group, C1-4Alkylsulfinyl radical, C1-4Alkylsulfonyl radical, C1-8Alkoxycarbonylamino group, C1-8Alkoxycarbonyl, cyano, halogen, azido, C1-8Alkyl, C with 1-3 halogens1-8Haloalkyl or C having 1-3 halogens1-8Substituted with a halo alkoxy group;
each R is3More preferably each is C1-4Alkyl, C with 1-3 halogens1-4Haloalkyl, aryl, heteroaryl, aryl-C1-4Alkyl or heteroaryl-C1-4Alkyl, wherein aryl and heteroaryl are optionally substituted by 1-3 substituents selected from hydroxy, C1-4Alkoxy radical, C1-4Alkylthio, amino, C1-4Alkanoylamino group, C1-4Alkylsulfonylamino group, C1-4Alkylsulfinyl radical, C1-4Alkylsulfonyl radical, C1-4Alkoxycarbonylamino group, C1-4Alkoxycarbonyl, cyano, halogen, azido, C1-4Alkyl, C with 1-3 halogens1-4Haloalkyl or C having 1-3 halogens1-4Substituted with a halo alkoxy group;
each R is3More preferably each is C1-4Alkyl, -CF3Aryl, heteroaryl, aryl-C1-4Alkyl or heteroaryl-C1-4Alkyl, wherein aryl and heteroaryl are optionally substituted by 1-3 substituents selected from hydroxy, C1-4Alkoxy radical, C1-4Alkylthio, amino, acetylamino, methylsulfonylamino, C1-4Alkylsulfonyl radical, C1-4Alkoxycarbonylamino group, C1-4Alkoxycarbonyl, cyano, halogen, C1-4Alkyl, -CF3or-OCF3Substituted with the substituent(s);
each R is3More preferably each is C1-4Alkyl, -CF3Aryl, heteroarylaryl-C1-2Alkyl or heteroaryl-C1-2Alkyl, wherein aryl and heteroaryl are optionally substituted by 1-2 substituents selected from hydroxy, C1-4Alkoxy radical, C1-4Alkylthio, amino, acetylamino, methylsulfonylamino, C1-4Alkylsulfonyl radical, C1-4Alkoxycarbonylamino group, C1-4Alkoxycarbonyl, cyano, halogen, C1-4Alkyl, -CF3or-OCF3Substituted with the substituent(s);
each R is3More preferably each is C1-4Alkyl, -CF3Aryl, heteroaryl, aryl-C1-2Alkyl or heteroaryl-C1-2Alkyl, wherein aryl and heteroaryl are optionally substituted by 1-2 substituents selected from hydroxy, C1-2Alkoxy radical, C1-2Alkylthio, amino, acetylamino, methylsulfonylamino, C1-2Alkylsulfonyl radical, C1-4Alkoxycarbonylamino group, C1-4Alkoxycarbonyl, halogen, C1-2Alkyl, -CF3or-OCF3Substituted with the substituent(s);
each R is3More preferably each is C1-4Alkyl, -CF3Aryl, heteroaryl, arylmethyl or heteroarylmethyl;
each R is3More preferably each is C1-4Alkyl, -CF3Phenyl, heteroaryl, phenylmethyl, or heteroarylmethyl;
each R is3Most preferably methyl, -CF, respectively3Phenyl, heteroaryl, phenylmethyl, or heteroarylmethyl;
each R is4Are each hydrogen or alkyl, preferably each hydrogen or C1-8Alkyl, more preferably hydrogen or C, respectively1-4Alkyl, most preferably hydrogen or methyl, respectively;
R11is-C (O) -R31、-C(O)-OR30、-C(O)-NR32R31、-S(O)2-R30or-S (O)2-NR32R31Preferably is-C (O) -R31、-S(O)2-R30or-S (O)2-NR32R31。
Wherein R is5And R6Each independently hydrogen or alkyl, preferably hydrogen or C1-4Alkyl, more preferably hydrogen, or CR5-CR6Is C ═ C (double-bonded carbon atom).
Wherein R is9And R10Each independently is-B-A, provided that R9、R10And R11The total number of aryl, heteroaryl, cycloalkyl and heterocyclyl groups in (a) is 0 to 3, preferably 0 to 2;
wherein each B is independently a bond (1); (2) alkyl, alkenyl or alkynyl optionally substituted by the following (a) and/or (b): (a)1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano or halogen, and/or (b)1-2 heterocyclyl, aryl or heteroaryl optionally substituted with 1-3 substituents selected from amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, halogen, alkyl, haloalkyl or haloalkoxy; (3) heterocyclyl optionally substituted with 1-3 substituents selected from amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl, haloalkyl or haloalkoxy; or (4) aryl or heteroaryl optionally substituted with 1 to 3 substituents selected from amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, halogen, alkyl, haloalkyl or haloalkoxy;
b is preferably each independently a bond (1); (2) c optionally substituted by the following (a) and/or (b)1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl: (a)1-3 amino groups, C1-C4Alkylamino, di- (C)1-C4) Alkylamino radical, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C4Alkylsulfonylamino, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio, cyano or halogen, (b)1-2 optionally substituted by 1-3 groups selected from amino, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C4Alkylsulfonylamino, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio, cyano, halogen, C1-C4Alkyl, C with 1-3 halogens1-C4Haloalkyl or C having 1-3 halogens1-C4Heterocyclyl, aryl or heteroaryl substituted with a substituent of haloalkoxy; (3) optionally substituted by 1-3 groups selected from amino, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C4Alkylsulfonylamino, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio, cyano, C1-C4Alkyl, C with 1-3 halogens1-C4Haloalkyl or C having 1-3 halogens1-C4A heterocyclic group substituted with a substituent of a haloalkoxy group; or (4) optionally substituted by 1-3 groups selected from amino, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C4Alkylsulfonylamino, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio, cyano, halogen, C1-C4Alkyl, C with 1-3 halogens1-C8Haloalkyl or C having 1-3 halogens1-C8Aryl or heteroaryl substituted with a substituent of haloalkoxy;
b is more preferably each independently a bond (1); (2) c optionally substituted by (a) and/or (b) and/or (C) below1-C8Alkyl groups: (a) amino group, C1-C4Alkylamino, di- (C)1-C4) Alkylamino radical, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C4Alkylsulfonylamino, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio, cyano, (b)1-3 halogens, (C)1-2 optionally substituted by 1-3 groups selected from amino, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C4Alkylsulfonylamino, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio, cyano, halogen, C1-C4Alkyl, C with 1-3 halogens1-C4Haloalkyl or C having 1-3 halogens1-C4Heterocyclyl, aryl or heteroaryl substituted with a substituent of haloalkoxy; (3) a heterocyclic group; or (4) optionally substituted by 1-3 groups selected from amino, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C4Alkylsulfonylamino, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio, cyano, halogen, C1-C4Alkyl, C with 1-3 halogens1-C4Haloalkyl or C having 1-3 halogens1-C4Aryl or heteroaryl substituted with a substituent of haloalkoxy;
b is more preferably each independently a bond (1); (2) c optionally substituted by (a) and/or (b) and/or (C) below1-C8Alkyl groups: (a) amino group, C1-C4Alkylamino, di- (C)1-C4) Alkylamino radical, C1-C5Alkanoylamino, (C)1-C4Alkoxy radical) Carbonylamino group, C1-C4Alkylsulfonylamino, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio, cyano, (b)1-3 halogens, (C)1-2 optionally substituted by 1-3 groups selected from amino, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C4Alkylsulfonylamino, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio, cyano, halogen, C1-C4Alkyl, -CF3or-OCF3Heterocyclyl, aryl or heteroaryl substituted with the substituents of (a); (3) a heterocyclic group; or (4) optionally substituted by 1-3 groups selected from amino, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C4Alkylsulfonylamino, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio, cyano, halogen, C1-C4 alkyl, -CF3or-OCF3Aryl or heteroaryl substituted with the substituents of (1);
b is more preferably each independently a bond (1); (2) c optionally substituted by (a) and/or (b) and/or (C) below1-C4Alkyl groups: (a) amino group, C1-C2Alkylamino, di- (C)1-C2) Alkylamino radical, C1-C2Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, hydroxy, C1-C2Alkoxy, (b)1-2 halogens, (C) optionally substituted by 1-2 groups selected from amino, C1-C2Alkylamino, di- (C)1-C2Alkyl) amino, C1-C2Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C2Alkylsulfonylamino, hydroxy, C1-C2Alkoxy radical, C1-C2Alkylthio, halogen, C1-C4Alkyl, -CF3Or-OCF3Heterocyclyl, aryl or heteroaryl substituted with the substituents of (a); (3) a heterocyclic group; or (4) optionally substituted by 1-2 groups selected from amino, C1-C2Alkylamino, di- (C)1-C2Alkyl) amino, C1-C2Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C2Alkylsulfonylamino, hydroxy, C1-C2Alkoxy radical, C1-C2Alkylthio, halogen, C1-C4Alkyl, -CF3or-OCF3Aryl or heteroaryl substituted with the substituents of (1);
b is more preferably each independently a bond (1) or C1-C4An alkyl group; or (2) is optionally selected from amino, C1-C2Alkylamino, di- (C)1-C2) Alkylamino radical, C1-C2Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C2Alkylsulfonylamino, hydroxy, C1-C2Alkoxy radical, C1-C2Alkylthio, halogen, C1-C4Alkyl, -CF3or-OCF3Aryl or heteroaryl substituted with the substituents of (1);
and B are most preferably each independently a bond, C1-C4Alkyl, aryl or heteroaryl;
wherein each A is independently (1) hydrogen; (2) halogen, cyano or nitro; (3) -C (O) R30、-C(O)OR31、-C(O)-NR32R31or-C (NR)32)-NR32R31；(4)-OR31、-O-C(O)-R31、-O-C(O)-NR32R31or-O-C (O) -NR33-S(O)2-R30；(5)-SR31、-S(O)R30、-S(O)2R30、-S(O)2NR32R31、-S(O)2-NR33-C(O)-R31、-S(O)2-NR33-C(O)-OR30or-S (O)2-NR33-C(O)NR32R31(ii) a Or (6) -NR32R31、-NR33-C(O)-R31、-NR33-C(O)-OR30、-NR33-C(O)-NR32R31、-NR33-C(NR32)-NR32R31、-NR33-S(O)2-R30or-NR33-S(O)2-NR32R31；
A is preferably each independently (1) hydrogen; (2) halogen, cyano or nitro; (3) -C (O) R30、-C(O)OR31、-C(O)-NR32R31or-C (NR)32)-NR32R31；(4)-OR31、-O-C(O)-R31、-O-C(O)-NR32R31or-O-C (O) -NR33-S(O)2-R30；(5)-SR31、-S(O)-R30、-S(O)2-R30、-S(O)2NR32R31、-S(O)2-NR33-C(O)-R31、-S(O)2-NR33-C(O)-OR30or-S (O)2-NR33-C(O)NR32R31(ii) a Or (6) -NR32R31、-NR33-C(O)-R31、-NR33-C(O)-OR30、-NR33-C(O)-NR32R31、-NR33-C(NR32)-NR32R31、-NR33-S(O)2-R30or-NR33-S(O)2-NR32R31；
More preferably, A is each independently hydrogen, halogen, cyano, nitro, -C (O) R30、-C(O)OR31、-C(O)-NR32R31、-C(NR32)-NR32R31、-OR31、-O-C(O)-R31、-O-C(O)-NR32R31、-SR31、-S(O)-R30、-S(O)2-R30、-S(O)2NR32R31、-NR32R31、-NR33-C(O)-R31、-NR33-C(O)-OR30、-NR33-C(O)-NR32R31、-NR33-C(NR32)-NR32R31、-NR33-S(O)2-R30or-NR33-S(O)2-NR32R31；
More preferably, A is each independently hydrogen, halogen, -C (O) R30、-C(O)OR31、-C(O)-NR32R31、-C(NR32)-NR32R31、-OR31、-SR31、-S(O)2-R30、-S(O)2NR32R31、-NR32R31、-NR33-C(O)-R31、-NR33-C(O)-OR30、-NR33-C(O)-NR32R31、-NR33-S(O)2-R30or-NR33-S(O)2-NR32R31；
More preferably, A is each independently hydrogen, halogen, -C (O) R30、-C(O)-NR32R31、-C(NR32)-NR32R31、-OR31、-SR31、-S(O)2-R30、-S(O)2NR32R31、-NR32R31、-NR33-C(O)-R31or-NR33-S(O)2-R30(ii) a And A is most preferably each independently hydrogen, halogen, -C (O) R30or-C (O) -NR32R31；
Wherein R is30Each independently is (1) alkyl, alkenyl or alkynyl optionally substituted with 1 to 3 of: -CO2R34Amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, N- (alkoxycarbonyl) -N- (alkyl) amino, aminocarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halogen or arylalkoxy, arylalkylthio, arylalkylsulfonyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by 1 to 3 substituents selected from the group consisting of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylaminoSubstituted with a substituent of alkylamino, alkylsulfonylamino, alkanoyl, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halogen, alkyl, haloalkyl or haloalkoxy; (2) heterocyclyl optionally substituted with 1-3 substituents selected from amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, cyano, alkyl, haloalkyl or haloalkoxy; or (3) aryl or heteroaryl optionally substituted with 1 to 3 substituents selected from amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, cyano, halogen, azido, alkyl, haloalkyl or haloalkoxy;
R30preferably each independently (1) C optionally substituted with 1 to 3 substituents1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl: -CO2R34Amino group, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, N- ((C)1-C4Alkoxy) carbonyl) -N- (C1-C4Alkyl) amino, aminocarbonylamino, C1-C4Alkylsulfonylamino, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl, cyano, halogen or aryl C1-C4Alkoxy, aryl C1-C4Alkylthio, aryl C1-C4Alkylsulfonyl radical, C3-C8Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by 1-3 substituents selected from amino, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C4Alkylsulfonylamino group, C1-C5Alkanoyl, (C)1-C4Alkoxy) carbonyl, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl, cyano, halogen, C1-C4Alkyl, C with 1-3 halogens1-C4Haloalkyl or C having 1-3 halogens1-C4Substituted with a halo alkoxy group; (2) optionally substituted by 1-3 groups selected from amino, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C4Alkylsulfonylamino group, (C)1-C4Alkoxy) carbonyl, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio, cyano, C1-C4Alkyl, C with 1-3 halogens1-C4Haloalkyl or C having 1-3 halogens1-C4A heterocyclic group substituted with a substituent of a haloalkoxy group; or (3) optionally substituted by 1-3 groups selected from amino, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C4Alkylsulfonylamino group, (C)1-C4Alkoxy) carbonyl, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio, cyano, halogen, azido, C1-C4Alkyl, C with 1-3 halogens1-C4Haloalkyl or C having 1-3 halogens1-C4Aryl or heteroaryl substituted with a substituent of haloalkoxy;
R30more preferably each independently (1) C optionally substituted with 1 to 3 substituents described below1-C6Alkyl groups: -CO2R34Amino group, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, N- ((C)1-C4Alkoxy) carbonyl) -N- (C1-C4Alkyl) amino, aminocarbonylamino, C1-C4Alkylsulfonylamino, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl, cyano, halogen, aryl-C1-C4Alkoxy, aryl-C1-C4Alkylthio, aryl-C1-C4Alkylsulfonyl radical, C3-C8Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by 1-3 substituents selected from amino, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C4Alkylsulfonylamino group, C1-C5Alkanoyl, (C)1-C4Alkoxy) carbonyl, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl, cyano, halogen, C1-C4Alkyl, C with 1-3 halogens1-C4Haloalkyl or C having 1-3 halogens1-C4Substituted with a halo alkoxy group; (2) optionally substituted by 1-3 groups selected from amino, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C4Alkylsulfonylamino group, (C)1-C4Alkoxy) carbonyl, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio, cyano, C1-C4Alkyl, C with 1-3 halogens1-C4Haloalkyl groupOr C with 1-3 halogens1-C4A heterocyclic group substituted with a substituent of a haloalkoxy group; or (3) optionally substituted by 1-3 groups selected from amino, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C4Alkylsulfonylamino group, (C)1-C4Alkoxy) carbonyl, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio, cyano, halogen, azido, C1-C4Alkyl, C with 1-3 halogens1-C4Haloalkyl or C having 1-3 halogens1-C4Aryl or heteroaryl substituted with a substituent of haloalkoxy;
R30more preferably each independently (1) C optionally substituted with 1 to 3 substituents described below1-C6Alkyl groups: -CO2R34Amino group, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, N- ((C)1-C4Alkoxy) carbonyl) -N- (C1-C4Alkyl) amino, aminocarbonylamino, C1-C4Alkylsulfonylamino, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl, cyano, halogen, aryl-C1-C4Alkoxy, aryl-C1-C4Alkylthio, aryl-C1-C4Alkylsulfonyl radical, C3-C8Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by 1-3 substituents selected from amino, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C4Alkylsulfonylamino group, C1-C5Alkanoyl, (C)1-C4Alkoxy) carbonyl, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl, cyano, halogen, C1-C4Alkyl, -CF3or-OCF3Substituted with the substituent(s); (2) optionally substituted by 1-3 groups selected from amino, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C4Alkylsulfonylamino group, (C)1-C4Alkoxy) carbonyl, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio, cyano, C1-C4Alkyl, C with 1-3 halogens1-C2Haloalkyl or-OCF3A heterocyclic group substituted with the substituent(s) of (1); or (3) optionally substituted by 1-3 groups selected from amino, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C4Alkylsulfonylamino group, (C)1-C4Alkoxy) carbonyl, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio, cyano, halogen, C1-C4Alkyl, -CF3or-OCF3Aryl or heteroaryl substituted with the substituents of (1);
R30more preferably each independently is (1) -CF3Or C optionally substituted with 1 to 2 substituents1-C4Alkyl groups: -CO2R34Amino group, C1-C2Alkylamino, di- (C)1-C2Alkyl) amino, C1-C2Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, N- ((C)1-C4Alkoxy) carbonyl) -N- (C1-C4Alkyl) amino, hydroxy, C1-C4Alkoxy or aryl-C1-C2Alkoxy, heterocyclyl, aryl or heteroaryl, wherein heterocyclyl, aryl and heteroaryl are optionally substituted by 1 to 3 substituents selected from amino, C1-C2Alkylamino, di- (C)1-C2Alkyl) amino, C1-C2Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C5Alkanoyl, (C)1-C4Alkoxy) carbonyl, hydroxy, C1-C4Alkoxy, halogen, C1-C4Alkyl, -CF3or-OCF3Substituted with the substituent(s); (2) optionally 1-2 selected from (C)1-C4Alkoxy) carbonyl, hydroxy or C1-C4A heterocyclic group substituted with a substituent of an alkyl group; or (3) optionally substituted by 1-2 groups selected from amino, C1-C2Alkylamino, di- (C)1-C2Alkyl) amino, C1-C2Alkanoylamino, hydroxy, C1-C2Alkoxy, halogen, C1-C4Alkyl, -CF3or-OCF3Aryl or heteroaryl substituted with the substituents of (1);
R30more preferably each independently is (1) optionally substituted by 1-2 (C)1-C4Alkoxy) carbonyl, hydroxy or C1-C4A heterocyclic group substituted with an alkyl substituent; or (2) optionally substituted by 1-2 amino groups, C1-C2Alkylamino, di- (C)1-C2Alkyl) amino, C1-C2Alkanoylamino, hydroxy, C1-C2Alkoxy, halogen, C1-C4Alkyl, -CF3or-OCF3Heteroaryl substituted with the substituent of (1); and
R30most preferably each independently is optionally substituted C1-C4An alkyl-substituted heterocyclic group;
wherein R is31Each independently hydrogen or (1) alkyl, alkenyl or alkynyl optionally substituted with 1 to 3 of: -CO2R34Amino group, alkylamino group, dialkylamino group, alkanoylamino group, alkoxycarbonylamino group, N- (alkoxycarbonyl group)) -N- (alkyl) amino, aminocarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halogen or arylalkoxy, arylalkylthio, arylalkylsulfonyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, alkanoyl, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halogen, alkyl, haloalkyl or haloalkoxy; (2) heterocyclyl optionally substituted with 1-3 substituents selected from amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, cyano, alkyl, haloalkyl or haloalkoxy; or (3) aryl or heteroaryl optionally substituted with 1 to 3 substituents selected from amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, cyano, halogen, azido, alkyl, haloalkyl or haloalkoxy;
R31preferably each independently hydrogen or (1) C optionally substituted with 1 to 3 groups1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl: -CO2R34Amino group, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, N- ((C)1-C4Alkoxy) carbonyl) -N- (C1-C4Alkyl) amino, aminocarbonylamino, C1-C4Alkylsulfonylamino, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl, cyano, halogen, aryl-C1-C4Alkoxy, aryl-C1-C4Alkylthio, aryl-C1-C4Alkylsulfonyl radical, C3-C8Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by 1-3 substituents selected from amino, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C4Alkylsulfonylamino group, C1-C5Alkanoyl, (C)1-C4Alkoxy) carbonyl, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl, cyano, halogen, C1-C4Alkyl, C with 1-3 halogens1-C4Haloalkyl or C having 1-3 halogens1-C4Substituted with a halo alkoxy group; (2) optionally substituted by 1-3 groups selected from amino, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C4Alkylsulfonylamino group, (C)1-C4Alkoxy) carbonyl, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio, cyano, C1-C4Alkyl, C with 1-3 halogens1-C4Haloalkyl or C having 1-3 halogens1-C4A heterocyclic group substituted with a substituent of a haloalkoxy group; or (3) optionally substituted by 1-3 groups selected from amino, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C4Alkylsulfonylamino group, (C)1-C4Alkoxy) carbonyl, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio, cyano, halogen, azido, C1-C4Alkyl, C with 1-3 halogens1-C4Haloalkyl or C having 1-3 halogens1-C4Aryl or heteroaryl substituted with a substituent of haloalkoxy;
R31more preferably each independently hydrogen or (1) C optionally substituted with 1 to 3 groups1-C6Alkyl groups: -CO2R34Amino group, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, N- ((C)1-C4Alkoxy) carbonyl) -N- (C1-C4Alkyl) amino, aminocarbonylamino, C1-C4Alkylsulfonylamino, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl, cyano, halogen, aryl-C1-C4Alkoxy, aryl-C1-C4-alkylthio, aryl-C1-C4-alkylsulfonyl, C3-C8Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by 1-3 substituents selected from amino, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C4Alkylsulfonylamino group, C1-C5Alkanoyl, (C)1-C4Alkoxy) carbonyl, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl, cyano, halogen, C1-C4Alkyl, C with 1-3 halogens1-C4Haloalkyl or C having 1-3 halogens1-C4Substituted with a halo alkoxy group; (2) optionally substituted by 1-3 groups selected from amino, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C4Alkylsulfonylamino group, (C)1-C4Alkoxy) carbonyl, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio, cyano, C1-C4Alkyl, C with 1-3 halogens1-C4Haloalkyl or C having 1-3 halogens1-C4A heterocyclic group substituted with a substituent of a haloalkoxy group; or (3) optionally substituted by 1-3 groups selected from amino, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C4Alkylsulfonylamino group, (C)1-C4Alkoxy) carbonyl, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio, cyano, halogen, azido, C1-C4Alkyl, C with 1-3 halogens1-C4Haloalkyl or C having 1-3 halogens1-C4Aryl or heteroaryl substituted with a substituent of haloalkoxy;
R31more preferably each independently hydrogen or (1) C optionally substituted with 1 to 3 groups1-C6Alkyl groups: -CO2R34Amino group, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, N- ((C)1-C4) Alkoxycarbonyl) -N- (C)1-C4Alkyl) amino, aminocarbonylamino, C1-C4Alkylsulfonylamino, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl, cyano, halogen, aryl-C1-C4Alkoxy, aryl-C1-C4Alkylthio, aryl-C1-C4Alkyl radicalSulfonyl radical, C3-C8Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by 1-3 substituents selected from amino, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C4Alkylsulfonylamino group, C1-C5Alkanoyl, (C)1-C4Alkoxy) carbonyl, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl, cyano, halogen, C1-C4Alkyl, -CF3or-OCF3Substituted with the substituent(s); (2) optionally substituted by 1-3 groups selected from amino, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C4Alkylsulfonylamino group, (C)1-C4Alkoxy) carbonyl, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio, cyano, C1-C4Alkyl, C having 1-3 halo groups1-C2Haloalkyl or-OCF3A heterocyclic group substituted with the substituent(s) of (1); or (3) optionally substituted by 1-3 groups selected from amino, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C4Alkylsulfonylamino group, (C)1-C4Alkoxy) carbonyl, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio, cyano, halogen, C1-C4Alkyl, -CF3or-OCF3Aryl or heteroaryl substituted with the substituents of (1);
R31more preferably each independently of the other is hydrogen or (1) -CF3Or optionally substituted by 1-2 hydroxy groups, C1-C2Alkoxy or aryl-C1-C2Alkoxy, aryl or heteroaryl substituted C1-C4Alkyl, wherein aryl and heteroaryl are optionally substituted by 1-2 substituents selected from amino, C1-C2Alkylamino, di- (C)1-C2Alkyl) amino, C1-C2Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C5Alkanoyl, (C)1-C4Alkoxy) carbonyl, hydroxy, C1-C4Alkoxy, halogen, C1-C4Alkyl, -CF3or-OCF3Substituted with the substituent(s); or (2) optionally substituted by 1-2 groups selected from amino, C1-C2Alkylamino, di- (C)1-C2Alkyl) amino, C1-C2Alkanoylamino, hydroxy, C1-C2Alkoxy, halogen, C1-C4Alkyl, CF3or-OCF3Aryl or heteroaryl substituted with the substituents of (1); and
R31most preferably each independently hydrogen or (1) -CF3Or C optionally substituted by 1-2 aryl or heteroaryl groups1-C4An alkyl group; or (2) aryl or heteroaryl;
wherein R is32Each independently is (1) hydrogen; (2) alkyl, alkenyl or alkynyl optionally substituted with 1 to 3 of: amino, alkylamino, dialkylamino, hydroxy, alkoxy, alkylthio, cyano or halogen; or (3) aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or cycloalkylalkyl optionally substituted with 1-3 substituents selected from amino, alkylamino, dialkylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl, haloalkyl, or haloalkoxy;
R32preferably each independently is (1) hydrogen; (2) c optionally substituted by 1 to 3 groups1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl: amino group, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio, cyano or halogen; or (3) optionally substituted by 1-3 groups selected from amino, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio, cyano, C1-C4Alkyl, C with 1-3 halogens1-C4Haloalkyl or C having 1-3 halogens1-C4Aryl, heteroaryl, aryl-C substituted by substituents of haloalkoxy1-C4Alkyl, heteroaryl-C1-C4Alkyl, heterocyclyl-C1-C4Alkyl radical, C3-C8Cycloalkyl or C3-C8cycloalkyl-C1-C4An alkyl group;
R32more preferably each independently hydrogen or C1-C4An alkyl group; and R32Most preferably each independently hydrogen or methyl;
wherein R is33Each independently is (1) hydrogen; (2) alkyl optionally substituted with heterocyclyl, aryl or heteroaryl, said heterocyclyl, aryl or heteroaryl being optionally substituted with 1 to 3 of the following groups: selected from amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halogen, alkyl, haloalkyl or haloalkoxy; or (3) heterocyclyl, aryl or heteroaryl optionally substituted with 1 to 3 substituents selected from amino, alkylamino, dialkylamino, alkanoylamino, alkylcarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halogen, alkyl, haloalkyl or haloalkoxy;
R33preferably each independently is (1) hydrogen; (2) c optionally substituted by heterocyclyl, aryl or heteroaryl1-C4Alkyl, said heterocyclyl, aryl or heteroaryl being optionally substituted with 1 to 3 of the following groups:amino group, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C4Alkylsulfonylamino, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl, cyano, halogen, C1-C4Alkyl, C with 1-3 halogens1-C4Haloalkyl or C having 1-3 halogens1-C4A haloalkoxy group; or (3) optionally substituted by 1-3 groups selected from amino, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C4Alkylsulfonylamino, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl, cyano, halogen, C1-C4Alkyl, C with 1-3 halogens1-C4Haloalkyl or C having 1-3 halogens1-C4Heterocyclyl, aryl or heteroaryl substituted with a substituent of haloalkoxy;
R33more preferably each independently hydrogen or C1-C4An alkyl group; and R33Most preferably each independently hydrogen or methyl; and
wherein R is34Each independently hydrogen, alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein aryl and heteroaryl are optionally substituted with 1 to 3 of the following groups: amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halogen, alkyl, haloalkyl or haloalkoxy;
R34preferably each independently of the others is hydrogen orC1-C4Alkyl, aryl, heteroaryl, aryl-C1-C4Alkyl or heteroaryl-C1-C4Alkyl, wherein aryl and heteroaryl are optionally substituted with 1-3 of the following groups: amino group, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Acylamino group, (C)1-C4Alkoxy) carbonylamino, C1-C4Alkylsulfonylamino, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl, cyano, halogen, C1-C4Alkyl, C with 1-3 halogens1-C4Haloalkyl or C having 1-3 halogens1-C4A haloalkoxy group;
R34more preferably each independently hydrogen or C1-C4An alkyl group; r34Most preferably each independently is hydrogen or methyl.
The meanings of the symbols used above are as follows:for example:
the aryl group optionally substituted with an optionally substituted 5-6 membered monocyclic heteroaryl or heterocyclic group means an aryl group optionally substituted with the following (a) or (b), wherein the optionally substituted 5-6 membered monocyclic heteroaryl or heterocyclic group is optionally substituted with phenyl or 5-6 membered monocyclic heteroaryl: (a) a 5-6 membered monocyclic heteroaryl optionally substituted with phenyl or a 5-6 membered monocyclic heteroaryl; or (b) a 5-6 membered monocyclic heterocyclyl optionally substituted with phenyl or 5-6 membered monocyclic heteroaryl.
Heteroaryl optionally substituted by optionally substituted phenyl or 5-6 membered monocyclic heteroaryl or heterocyclyl means heteroaryl optionally substituted by (a), (b) or (c) below, wherein said optionally substituted phenyl or 5-6 membered monocyclic heteroaryl or heterocyclyl is optionally substituted by phenyl or 5-6 membered monocyclic heteroaryl: (a) phenyl optionally substituted with phenyl or 5-6 membered monocyclic heteroaryl; (b) a 5-6 membered monocyclic heteroaryl optionally substituted with phenyl or a 5-6 membered monocyclic heteroaryl; or (c) a 5-6 membered monocyclic heterocyclyl optionally substituted with phenyl or 5-6 membered monocyclic heteroaryl.
The compounds of the invention generally have several asymmetric centers and are described herein as racemic mixtures thereof. The present invention includes racemic mixtures, partially racemic mixtures, as well as individual enantiomers and diastereomers. The absolute configuration of the carboxylic acid groups is preferably the (R) configuration, the carboxylic acid groups and the-NR11R33Is preferably in the cis configuration, i.e., carboxylic acid group and-NR11R33Located on the same side of the ring system.
Desirable compounds include the following:
3-amino-1- (4-methoxyphenylsulfonyl) -azepane (azepane) -2-carboxylic acid,
3- (phenylmethylsulfonylamino) -1- (4-methoxyphenylsulfonyl) -azepane (azepane) -2-carboxylic acid,
3- ((2-aminophenyl) methylsulfonylamino) -1- (4-methoxyphenylsulfonyl) -azepane (azepane) -2-carboxylic acid,
Cis-1- (4-methoxyphenylsulfonyl) -3- (phenylmethylsulfonylamino) -heptylideneimine-2-carboxylic acid,
Trans-1- (4-methoxyphenylsulfonyl) -3- (phenylmethylsulfonylamino) -heptylideneimine-2-carboxylic acid,
3-benzyloxycarbonylamino-1- (4-methoxy-benzenesulfonyl) -1H-azepane (azepane) -2-carboxylic acid,
3-amino-1- (4-methoxyphenylsulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid,
3- (methylsulfonylamino) -1- (4-methoxyphenylsulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid,
3- (phenylsulfonylamino) -1- (4-methoxyphenylsulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid,
3- (naphthalen-2-ylsulfonylamino) -1- (4-methoxyphenylsulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid,
3- (naphthalen-1-ylsulfonylamino) -1- (4-methoxyphenylsulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid,
3- (phenylmethylsulfonylamino) -1- (4-methoxyphenylsulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid,
3- ((2-Nitrophenyl) methylsulfonylamino) -1- (4-methoxyphenylsulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid,
3- ((2-phenylethyl) sulfonylamino) -1- (4-methoxyphenylsulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid,
3- ((4-iodophenyl) sulfonylamino) -1- (4-methoxyphenylsulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid,
3- (4- ((4-chlorophenyl) phenyl) sulfonylamino) -1- (4-methoxyphenylsulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid,
3- (Phenylmethoxycarbonylamino) -1- (4-methoxybenzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid,
3- ((4-trifluoromethylphenyl) methoxycarbonylamino) -1- (4-methoxyphenylsulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid,
3- ((4-chlorophenyl) methoxycarbonylamino) -1- (4-methoxybenzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid,
3- ((3, 5-dichlorophenyl) methoxycarbonylamino) -1- (4-methoxyphenylsulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid,
1- (4-Methoxybenzenesulfonyl) -3- (4-chlorophenylsulfonylamino) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid,
1- (4-Methoxyphenylsulfonyl) -3- (4-chlorophenyl-methylsulfonylamino) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid,
1- (4-Methoxyphenylsulfonyl) -3(R) - (phenylmethylsulfonylamino) -heptylideneimine-2 (S) -carboxylic acid,
Trans-1- (4-methoxyphenylsulfonyl) -3(R) - (phenylmethylsulfonylamino) -heptylideneimine-2 (R) -carboxylic acid.
The following terms used in the present invention have the following meanings:
"alkyl", alone or in combination, means preferably containing from 1 to 15 carbon atoms (C)1-C15) More preferably having 1 to 8 carbon atoms (C)1-C8) More preferably 1 to 6 carbon atoms (C)1-C6) More preferably 1 to 4 carbon atoms (C)1-C4) More preferably 1 to 3 carbon atoms (C)1-C3) Most preferably 1-2 carbon atoms (C)1-C2). Examples of the alkyl group include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and octyl, and the like.
"alkenyl", alone or in combination, means having 1 or more double bonds, preferably 1 to 2 double bonds, more preferably 1 double bond and preferably 2 to 15 carbon atoms (C)2-C15) More preferably containing 2 to 8 carbon atoms (C)2-C8) More preferably 2 to 6 carbon atoms (C)2-C6) More preferably 2 to 4 carbon atoms (C)2-C4) More preferably 2 to 3 carbon atoms (C)2-C3) Specific examples of the alkenyl group include: vinyl, propenyl, 2-methylpropenyl, and 1, 4-butadienyl, and the like.
"alkynyl", alone or in combination, means having 1 or more threeA bond, preferably having 1-2 triple bonds, more preferably having 1 triple bond and preferably containing 2-15 carbon atoms (C)2-C15) More preferably containing 2 to 8 carbon atoms (C)2-C8) More preferably 2 to 6 carbon atoms (C)2-C6) More preferably 2 to 4 carbon atoms (C)2-C4) More preferably 2 to 3 carbon atoms (C)2-C3) Specific examples of the alkynyl group include: ethynyl, propynyl (propargyl), and butynyl, and the like.
"alkoxy", alone or in combination, means a group of the type "R-O-", wherein "R" is an alkyl group as defined above and "O" is an oxygen atom. Specific examples of the alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
"alkoxycarbonyl", alone or in combination, means a group of the type "R-O-C (O) -", wherein "R-O-" is alkoxy as defined above and "C (O) -" is carbonyl.
"Alkoxycarbonylamino", alone or in combination, means a group of the type "R-O-C (O) -NH-", wherein "R-O-C (O)" is alkoxycarbonyl as defined above, wherein amino may be optionally substituted by groups such as alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl and the like.
"alkylthio", alone or in combination, refers to a group of the type "R-S-", wherein "R" is an alkyl group as defined above and "S" is a sulfur atom. Specific examples of the alkylthio group include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio and the like.
"Alkylsulfinyl", alone or in combination, refers to a group of the type "R-S (O) -", wherein "R" is an alkyl group as defined above and "S (O)" is a mono-oxidized sulfur atom. Specific examples of the alkylsulfinyl group include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl and the like.
"Alkylacyl", alone or in combination, means having the meaning of "R-S (O)2- "type of radical, in which" R "is alkyl as defined above," S (O)2"is a sulfur atom of dioxide. Specific examples of the alkylsulfonyl group include methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, isopropylsulfonyl group, n-butylsulfonyl group, isobutylsulfonyl group, sec-butylsulfonyl group, tert-butylsulfonyl group and the like.
"Alkylsulfonylamino", alone or in combination, means "R-S (O)2-NH- "type groups, in which" R-S (O)2- "is an alkylsulfonyl group as defined above, the amino group being optionally substituted by groups such as alkyl, aryl, aralkyl, cycloalkyl and cycloalkylalkyl, etc.
"aryl", alone or in combination, means phenyl, biphenyl, or naphthyl, wherein said phenyl, biphenyl, and naphthyl are optionally substituted with 1 or more groups selected from: alkyl, alkoxy, halogen, hydroxy, amino, azido, nitro, cyano, haloalkyl, carbonyl, alkoxycarbonyl, cycloalkyl, heterocyclyl, alkanoylamino, amido, amidino, alkoxycarbonylamino, N-alkylamidino, alkylamino, dialkylamino, N-alkylamino, N-dialkylamino, aralkyloxycarbonylamino, alkylthio, alkylsulfinyl, alkylsulfonyl and the like. Specific examples of the aryl group include a phenyl group, a p-tolyl group, a 4-methoxyphenyl group, a 4- (tert-butoxy) phenyl group, a 3-methyl-4-methoxyphenyl group, a 4-trifluoromethyl-phenyl group, a 4-fluorophenyl group, a 4-chlorophenyl group, a 3-nitrophenyl group, a 3-aminophenyl group, a 3-acetamidophenyl group, a 4-acetamidophenyl group, a 2-methyl-3-aminophenyl group, a 3-methyl-4-aminophenyl group, a 2-amino-3-methylphenyl group, a 2, 4-dimethyl-3-aminophenyl group, a 4-hydroxyphenyl group, a 3-methyl-4-hydroxyphenyl group, a 4- (4-methoxyphenyl) phenyl group, a, 1-naphthyl, 2-naphthyl, 3-amino-1-naphthyl, 2-methyl-3-amino-1-naphthyl, 6-amino-2-naphthyl, 4, 6-dimethoxy-2-naphthyl and piperazinylphenyl, and the like.
"arylalkyl", alone or in combination, means an alkyl group as defined hereinabove having at least 1 hydrogen atom, and preferably from 1 to 2 hydrogen atoms, replaced by an aryl group as defined hereinabove, such as benzyl, 1-, 2-naphthyl, dibenzylmethyl, hydroxyphenylmethyl, methylphenylmethyl, diphenylmethyl, dichlorophenylmethyl, 2-naphthylmethyl, and 4-methoxyphenylmethyl, and the like.
"arylalkoxy", alone or in combination, means an alkoxy group defined hereinabove having at least 1 hydrogen atom, and preferably from 1 to 2 hydrogen atoms, of the alkoxy group substituted by an aryl group defined hereinabove, such as benzyloxy, 1-, 2-phenylethoxy, dibenzylmethoxy, hydroxyphenylmethoxy, methylphenylmethoxy, dichlorophenylmethoxy, 4-methoxyphenylmethoxy, and the like.
"aryloxy", alone or in combination, refers to a group of the type "R-O-", wherein "R" is an aryl group as defined above.
"aroyl", alone or in combination, refers to a group of the type "R-C (O) -", wherein "R" is aryl as defined above and "-C (O) -" is carbonyl.
"alkanoyl", alone or in combination, means a group of the type "R-C (O) -", wherein "R" is alkyl as defined above and "-C (O) -" is carbonyl. Specific examples of alkanoyl groups include acetyl, trifluoroacetyl, hydroxyacetyl, propionyl, butyryl, valeryl, and 4-methylpentanoyl, and the like.
"Alkanoylamino", alone or in combination, means a group of the type "R-C (O) -NH-", wherein "R-C (O) -is an alkanoyl group as defined above, wherein the amino group may optionally be substituted by a group such as alkyl, aryl, aralkyl, cycloalkyl or cycloalkylalkyl, and the like.
"aminocarbonylamino", alone or in combination, means a group in which the second amino group is substituted with a carbonyl group substituted with an amino group (ureido), wherein each amino group may be optionally mono-or di-substituted with groups such as alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkanoyl, alkoxycarbonyl, or aralkoxycarbonyl, and the like.
"benzo", used alone or in admixture, refers to a divalent C derived from benzene6H4A group.
"bicyclic", alone or in combination, includes fused ring systems such as naphthyl and β -carbolinyl and substituted ring systems such as biphenyl, phenylpyridyl, naphthyl and diphenylpiperazinyl.
"cycloalkyl", alone or in mixture, means a saturated or partially saturated, preferably monocyclic, bicyclic or tricyclic alkyl radical, preferably a monocyclic alkyl radical, having 1 double bond, said cycloalkyl radical preferably containing from 3 to 10 carbon atoms (C)3-C10) More preferably 3 to 8 carbon atoms (C)3-C8) More preferably 3 to 6 carbon atoms (C)3-C6) Said cycloalkyl is optionally benzo-fused and optionally substituted as described above for aryl. Examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, dihydroxycyclohexyl, cycloheptyl, octahydronaphthyl, tetrahydronaphthyl, dimethoxytetrahydronaphthyl, and 2, 3-dihydro-1H-indenyl groups and the like.
"cycloalkylalkyl", alone or in combination, means an alkyl group as defined above substituted with a cycloalkyl group as defined above. Examples of cycloalkylalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1-cyclopentylethyl, 1-cyclohexylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, hydroxycyclopentylpropyl, tetrahydronaphthylpropyl, and cyclohexylbutyl, and the like.
"heteroatoms" are nitrogen atoms, oxygen atoms and sulfur atoms.
"Heterocyclyl", alone or in combination, means a saturated or partially saturated monocyclic or bicyclic heterocyclyl group, preferably a monocyclic or bicyclic heterocyclyl group having 1 double bond, preferably a monocyclic heterocyclyl group, containing at least 1, preferably 1 to 4, more preferably 1 to 3, even more preferably 1 to 2N, O or S ring heteroatoms in the heterocyclyl ring, each ring preferably being a 3 to 8 membered ring, more preferably a 5 to 6 membered ring. "Heterocyclyl" includes derivatives of sulfones and sulfoxides in which the ring heteroatom is sulfur, N-oxides in which the ring heteroatom is a tertiary nitrogen, and carbocyclic and benzo fused ring systems, preferably having from 3 to 6 ring carbon atoms, more preferably having from 5 to 6 ring carbon atoms. The "heterocyclic group" is optionally substituted on at least 1 carbon atom, preferably 1 to 4 carbon atoms, more preferably 1 to 3 carbon atoms, even more preferably 1 to 2 carbon atoms, with halogen, alkyl, alkoxy, hydroxy, oxo, thio, aryl, aralkyl, heteroaryl, heteroaralkyl, amidino, N-alkylamidino, alkoxycarbonylamino, alkylsulfonylamino or the like, and/or on a secondary nitrogen atom with hydroxy, alkyl, aralkoxycarbonyl, alkanoyl, alkoxycarbonyl, heterocycloaralkyl, aryl or aralkyl. "Heterocyclyl", alone or in mixture, more preferably a monocyclic or bicyclic saturated heterocyclyl having 5 to 8 ring atoms per ring and wherein 1 to 3 ring atoms are O, N or an S heteroatom, is an optionally partially unsaturated or benzo-fused heterocyclyl optionally substituted with 1 to 2 oxo or thioxo groups. Specific examples of the heterocyclic group include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thio (thia) morpholinyl, 4-benzyl-piperazin-1-yl, pyrimidinyl, tetrahydrofuranyl, pyrazolidinonyl, pyrazolinyl, pyridazinonyl, pyrrolidinonyl, tetrahydrothienyl, and sulfoxide or sulfone derivatives thereof, 2, 3-dihydroindolyl, tetrahydroquinolinyl, 1, 2, 3, 4-tetrahydroisoquinolinyl, 1, 2, 3, 4-tetrahydro-1-oxoisoquinolinyl, 2, 3-dihydrobenzofuranyl, benzopyranyl, methylenedioxyphenyl, ethylenedioxyphenyl, and the like.
"Heterocyclylalkyl", alone or in combination, refers to an alkyl group having at least 1 hydrogen atom, preferably 1 to 2 hydrogen atoms, of the alkyl group defined above substituted with a heterocyclyl group as defined above such as pyrrolidinylmethyl, tetrahydrothienylmethyl, piperidinylethyl and the like.
"heteroaryl", used alone or in combination, refers to a monocyclic or bicyclic ringAn aromatic heterocyclic group, preferably a monocyclic aromatic heterocyclic group, said heteroaryl group having at least 1, preferably 1 to 4, more preferably 1 to 3, even more preferably 1 to 2N, O or S ring heteroatoms in the ring, and preferably 5 to 6 ring members in each ring, said heteroaryl group being optionally benzo-fused or optionally saturated carbon-fused, preferably with 3 to 4 carbon atoms (C)3-C4) Form a 5-6 membered ring, which heteroaryl may be optionally substituted as defined above for aryl and heterocyclyl. "heteroaryl", alone or in mixture, more preferably a monocyclic or bicyclic aromatic heterocyclic group having 5 to 6 ring atoms per ring and 1 to 3O, S or N ring heteroatoms in it, said heteroaryl being optionally benzo-fused or optionally saturated C3-C4The carbocyclic rings are fused. Specific examples of the heteroaryl group include an imidazolyl group, a 1-benzyloxycarbonylimidazol-4-yl group, a pyrrolyl group, a pyrazolyl group, a pyridyl group, a 2- (1-piperidyl) pyridyl group, a 2- (4-benzylpiperazin-1-yl) -1-pyridyl group, a pyrazinyl group, a triazolyl group, a furyl group, a thienyl group, an oxazolyl group, a thiazolyl group, an indolyl group, a quinolyl group, a 1-epoxy-2-quinolyl group, an isoquinolyl group, a 5, 6, 7, 8-tetrahydroquinolyl group, a 5, 6, 7, 8-tetrahydroisoquinolyl group, a quinoxalyl group, a benzothiazolyl group, a β -carbolinyl group, a benzofuranyl group, a benzimidazolyl group, a benzoxazolyl group and.
"Heteroaroyl", alone or in combination, means a group of the type "R-C (O) -", wherein "R" is heteroaryl as defined above and "-C (O) -" is carbonyl.
"heteroarylalkyl", alone or in combination, means a radical in which at least 1 hydrogen atom, preferably 1 to 2 hydrogen atoms, of an alkyl group as defined above has been replaced by a heteroaryl group as defined above, such as 3-furylpropyl, 2-pyrrolylpropyl, chloroquinolinylmethyl, 2-thienylethyl, pyridylmethyl, 1-imidazolylethyl and the like.
"halogen" and "halo", used alone or in combination, are fluorine, chlorine, bromine or iodine.
"haloalkyl", alone or in combination, means a group as defined above wherein at least 1 hydrogen atom, preferably 1 to 3 hydrogen atoms, of the alkyl group is replaced by halogen, more preferably by fluorine or chlorine. Examples of haloalkyl groups include 1, 1, 1-trifluoroethyl, chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and bis (trifluoromethyl) methyl, and the like.
"haloalkoxy", alone or in combination, means a group in which at least 1 hydrogen atom, preferably 1 to 3 hydrogen atoms, of an alkoxy group as defined above has been replaced by halogen, more preferably by fluorine or chlorine. Examples of haloalkoxy groups include 2, 2, 2-trifluoroethoxy, chloromethoxy, 2-bromoethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and bis (trifluoromethyl) methoxy, and the like.
"Sulfinyl", alone or in combination, means a radical of the type "-S (O) -", in which "S (O)" is a monooxysulfur atom and "sulfonyl", alone or in combination, means "-S (O)2- "type divalent radical, in which" S (O)2"is a dioxo sulfur atom.
"leaving group", generally refers to a group susceptible to displacement by a nucleophile such as an amine, thiol, or alcohol, which leaving group is known in the art. Examples of such leaving groups include, but are not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates, and tosylates, and the like. Preferred leaving groups will be noted where appropriate herein.
"protecting group" generally refers to protecting groups known in the art for preventing selected reactive groups, such as carboxyl, amino, hydroxyl, and thiol groups, from undesired reactions, such as nucleophilic reactions, electrophilic reactions, oxidation reactions, reduction reactions, and the like. Preferred protecting groups will be indicated where appropriate herein. Examples of amino protecting groups include, but are not limited to, aralkyl, substituted aralkyl, cycloalkenylalkyl and substituted cycloalkenylalkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, arylalkoxycarbonyl, and silyl groups, and the like. Examples of the aralkyl group include, but are not limited to, benzyl, o-methylbenzyl, trityl and benzhydryl, which may be optionally substituted with halogen, alkyl, alkoxy, hydroxyl, nitro, amido and acyl groups, and the like, and salts such as phosphonium salts and ammonium salts. Examples of aryl groups include phenyl, naphthyl, 2, 3-indanyl, anthracenyl, 9- (9-phenylfluorenyl), phenanthrenyl, durenyl, and the like. Preferred cycloalkenylalkyl or substituted cycloalkenylalkyl groups containing 6 to 10 carbon atoms include, but are not limited to, cyclohexenylmethyl and the like. Suitable acyl, alkoxycarbonyl and arylalkoxycarbonyl groups include benzyloxycarbonyl, tert-butoxycarbonyl, isobutoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl, trifluoroacetyl, trichloroacetyl, phthaloyl and the like. The same amino group can be protected with mixed protecting groups, for example primary amino groups can be protected with both aralkyl and arylalkoxycarbonyl groups. The amino-protecting group may also form a heterocyclic ring together with the nitrogen atom to which it is attached, and may form, for example, 1, 2-bis (methylene) benzene, phthalimido, succinimidyl, maleimido, and the like, and the heterocyclic group formed herein may also include adjoining aromatic and cycloalkyl rings. In addition, the heterocyclic group may be a mono-, di-or tri-substituted heterocyclic group, such as a nitrophthalimido group. The amino group can also be protected from undesired reactions, such as oxidation, by forming addition salts, such as hydrochloride, tosylate or trifluoroacetate salts. Many amino protecting groups, such as aralkyl, are also suitable for protecting carboxyl, hydroxyl and thiol groups. Alkyl groups, such as tert-butyl, are also suitable for protecting hydroxyl and thiol groups.
The silyl protecting group is a silicon atom optionally substituted with 1 or more alkyl, aryl and aralkyl groups. Suitable silyl protecting groups include, but are not limited to, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl, 1, 2-bis (dimethylsilyl) benzene, 1, 2-bis (dimethylsilyl) ethane, and diphenylmethylsilyl. Silylation of the amino group provides a mono-or disilylamino group. Silanization of aminoalcohol compounds provides N, O-tri-silyl derivatives. Silyl groups can be readily removed from silyl ethers by treatment with, for example, a metal hydroxide or ammonium fluoride reagent, or with an alcohol group as a separate reaction step or in situ during the reaction. Suitable silylating agents are, for example, trimethylsilyl chloride, tert-butyl-dimethylsilane chloride, phenyldimethylsilane chloride and diphenylmethylsilane chloride or mixtures thereof with imidazole or DMF. Methods for amine silylation and methods for removing silyl protecting groups are known to those skilled in the art. Methods for preparing these amine derivatives from the corresponding amino acids, amino acid amides or amino acid esters are known to those skilled in the art of organic chemistry including amino acid/amino acid ester or amino alcohol chemistry.
The protecting group is removed under conditions that do not affect the remainder of the molecule. Such methods are known in the art and include acid hydrolysis and hydrogenolysis, among others. The process is preferably carried out by removing, for example, benzyloxycarbonyl protecting groups by hydrogenolysis using palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, or the like, or mixtures thereof. The tert-butoxycarbonyl protecting group may be removed using an inorganic or organic acid such as HCl or trifluoroacetic acid in a suitable solvent system such as 1, 4-dioxane or dichloromethane. The amine salts are readily neutralized to give the free amines. The carboxyl protecting groups such as methyl, ethyl, benzyl, t-butyl, and 4-methoxyphenylmethyl may be removed under hydrolysis and hydrogenolysis conditions known to those skilled in the art.
The process for preparing the compounds of the invention is as follows. It must be noted that said process represents a general preparation process of the compound without particular indication of stereochemical configuration. However, the process can also be used to prepare compounds which have the indicated stereochemical configuration, for example compounds of the (S) or (R) configuration. In addition, compounds having one stereochemical configuration (e.g., (R-form)) may be prepared from compounds having one stereochemical configuration (e.g., (S-form)) using known methods, e.g., by inversion.
Process for the preparation of compounds of formula (I)
The compounds of the invention represented by formula (I) above may be prepared using a variety of synthetic techniques, many of which are incorporated herein by reference. The compounds of the present invention can be prepared, inter alia, by the following conventional methods.
Scheme I describes a general synthetic procedure for the preparation of the novel compounds of the present invention, which employs a convergent route to the formation of azepine rings and macrocyclic systems. According to this method, a readily available Horner-Emmons reagent is reacted under standard conditions with an aldehyde whose alkyl chain (R5, R6, R9 and R10) is substituted with silyl ethers and other substituents (see Wadsworth, org. reactions, 1977, 25, 73) to give an α, β unsaturated ester. Removing the silyl protecting group, activating alcohol to obtain a leaving group, and carrying out intramolecular base catalytic ring closure to obtain a key intermediate. Subsequent removal of the t-BOC protecting group with either anhydrous HCl/ethyl acetate (Gibson, J.org.Chem., 1994, 59, 3216) or anhydrous TFA
And sulfonylation with sulfuryl chloride in a chlorinated solvent under basic conditions, preferably a hindered amine base such as triethylamine, to give the substituted sulfonamide. The R group can be converted to an amino group using methods known to those skilled in the art, for example, using benzylamine, silyl protected benzylamine, phthalimide, or other readily available nucleophilic amine equivalents. The protected primary amine may be deprotected to an unsubstituted primary amine using methods known in the art, for example, hydrogenation in the presence of a metal catalyst. The primary amine is then functionalized to provide the ester derivative of the final product. The functionalization process involves sulfonylation as described above, treatment with isocyanates to give ureas, treatment with acid chlorides or mixed anhydrides to give amides, reductive amination to give amines, and esterification with chloroformic acid to give carbamates (see complex of Synthetic organic methods, Wiley). The above adduct is treated with an aqueous base such as LiOH to give the free acid product when the ester compound is a methyl or ethyl ester, or TFA to give the free product when the ester compound is a tert-butyl ester.
Reaction scheme II depicts another conventional synthetic method for preparing the novel compounds of the present invention, which employs a convergent route for the formation of an azepine ring.
Readily available aspartic acid or glutamic acid derivatives were protected and allylated, mimicking the above method (see Baldwin, Tetrahedron, 1989, 45, 6309). The resulting sulfonamides were subjected to a Mitsunobu reaction (see Mitsunobu, Synthesis, 1981, 1) to give dienes. The resulting olefin is treated with a metathesis reagent (see Schustre, angelw. chem. int. ed. engl.1997, 36, 2036) to yield a cyclic olefin. Saponification is carried out, as known to the person skilled in the art, followed by a Curtius rearrangement of the resulting acid under known conditions (Tetrahedron, 1974, 30, 2151) to give the desired carbamate. The tert-butyric acid protected carbamate was selectively deprotected with concentrated trifluoroacetic acid (TFA) to give the final product. Alternatively, for the Curtius rearrangement, a suitable alcohol trapping reagent such as 4-methoxybenzyl alcohol can be selected to selectively deprotect the carbamate with dilute (3%) TFA in a chlorinated solvent to give the amine salt of the tert-butyl protected acid. Sulfonylation as described above or treatment with a suitable alkylating or acylating agent known to those skilled in the art and removal of the tert-butyl ester protecting group as described above gives the product. Macrocycles can be formed using allyl iodide or homologs of allyl alcohol, e.g., using 4-iodo-1-butene, 4-hydroxy-1-butene, 5-iodo-1-pentene, 5-hydroxy-1-pentene, 4-iodo-2-butene, or 4-hydroxy-2-butene, and the like.
Intermediates from reaction scheme II are useful as substituents R5、R6、R9And RDThe raw materials of (1). For example, with various polysubstituted allyl iodides or substituents such as CH2＝CH2CHR7R10The Triflate (Triflate) of I alkylates the aspartic acid derivative, followed by Mitsunobu reaction with allyl alcohol or homoallyl alcohol, to give the intermediate for the metathesis reaction. The olefin intermediate after the metathesis reaction may also be functionalized to prepare the claimed compounds.For example, the hydrogenation of olefins with Pd/C in solvents such as alcohols or ethyl acetate under standard conditions, preferably in a hydrogen atmosphere. The olefin may be hydroborated with a Borane reagent (see Brown, Borane Reagents, Academic Press, NY, 1998), preferably with BH3-DMS, followed by H2O2The borane complexes are oxidized to give alcohols or the borane complexes are oxidized with chromium (chromium) reagents under standard conditions to give ketones (see Hudlicky, Oxidation in organic chemistry, ACS mongraph186, 1990). The ketones may be aldolized as wittig reagents, electrophiles to organometallic reagents, or by reaction with aldehydes under basic or acidic conditions. Allylic oxidation of olefins with chromium reagents or preferably with selenium reagents (see Rabjohn, org. reactions, 1976, 24, 261) as known in the art, gives allyl alcohols activated as leaving groups, substitution of olefins with carbon, oxygen, nitrogen or sulfur electrophiles under neutral or basic conditions with or without palladium or lewis acid catalysts as known in the art. Other compounds can be prepared by Heck reaction of an olefin treated with an aryl halide or haloolefin or Triflate (Triflate) in the presence of a Palladium catalyst (see Tsuji, paladium Reagents and catalysts, Wiley, 1995, for an extended release of bond formation using Palladium catalyst). The olefins formed can be functionalized by the methods described above to give other substituted products. Olefins may be epoxidized with MCPBA or related peroxides to provide epoxides, and the resulting epoxides may be substituted with activated carbon, oxygen, nitrogen, or sulfur electrophiles known in the art, in the presence or absence of lewis acids.
Alternatively, with amines (HNR)31R32) In place of alcohol (R)30-OH) by reacting the isocyanate intermediate formed in the Curtius rearrangement reaction to prepare substituted urea derivatives (scheme III)
Furthermore, the carbamates formed in reaction scheme II may be hydrolyzed in acid to form free amines (reaction scheme IV) which may be reacted by reacting the resulting free amines with a carboxylic acidE.g., alkylation, reductive alkylation, sulfonylation, sulfamidation, and acylation, and the like, as in reaction scheme V.
From the above description, it is apparent that no single conventional synthetic method can be used to prepare all of the novel compounds of the present invention, since one skilled in the art would know that certain groups will or may influence, compete with, or inhibit certain reactions in the synthetic pathway. However, it is well known to those skilled in the art when groups can be introduced at appropriate steps in the synthetic route and when protecting groups can be used.
The sulfonyl halides can be prepared by reaction of a Grignard or lithium reagent such as an appropriate alkyl, aryl, heteroaryl, heterocyclic group, or the like with sulfuryl chloride or sulfur dioxide followed by oxidation with a halogen, preferably with chlorine. Grignard or lithium reagents such as alkyl, heteroaryl, heterocyclyl, and aryl groups can be prepared from their corresponding halides (e.g., chloride or bromide), which are commercially available or readily prepared from commercially available starting materials according to methods known in the art. Alternatively, the thiol may be oxidised with chlorine in the presence of water under carefully controlled reaction conditions to give the sulphuryl chloride. In addition, use is made of, for example, PCl5、SOCl2Reagents such as ClC (O) C (O) Cl which convert sulfonic acids to sulfonyl halides and also to anhydrides using suitable dehydrating agents. The sulfonic acid is either commercially available or prepared according to methods known in the art from commercially available starting materials. The compounds may be prepared using thionyl halide or thio halide instead of sulfonyl halide, wherein sulfonyl is replaced by sulfinyl or thio, respectively. By sulphonation of the aromatic ring by methods known in the art, e.g. by reaction with sulphuric acid, SO3Or such as DMF (SO)3) Pyridine (SO)3) And N, N-dimethylacetamide (SO)3) Etc. SO of3The complex is reacted to produce an arylsulfonic acid, a benzo-fused heterocyclyl sulfonic acid, or a heteroaryl sulfonic acid. Preferably with the above aromatic compound and DMF (SO)3) And SOCl2Or ClC (O) C (O) ClThe above sulfonyl halides are prepared. The reaction may be carried out batchwise or in separate reactors.
Further R1 substitution can be obtained by further reaction on the sulfonamide after reaction of the sulfonyl halide with the associated amine. For example, nitro substituted aryl or heteroaryl sulfonamides may be reduced to anilines and substituted or converted to diazonium salts and further reacted to give the compounds according to methods known in the art. The desired compound can be obtained by reaction of aryl or heteroaryl or alkyl sulfonyl chlorides substituted with fluorine, halogen or trifluoromethylsulfonyloxy with the relevant amine, followed by Substitution of the activated intermediate with oxygen, nitrogen, sulfur or carbon nucleophiles in the presence or absence of a transition metal catalyst such as palladium to give a further R1 Substitution (see Miller, aromatic nuclear fashion Substistion, Elsevier, N.Y., 1968, subject matter monograph).
Alkyl sulfonic acids, aryl sulfonic acids, heterocyclyl sulfonic acids, heteroaryl sulfonic acids, alkyl thiols, aryl thiols, heterocyclyl thiols, heteroaryl thiols, alkyl halides, aryl halides, heterocyclyl halides, and heteroaryl halides and the like are commercially available or are readily prepared according to standard procedures known in the art using commercially available starting materials.
Thioether derivatives can be converted to the corresponding sulfones or sulfoxides by oxidation of the thioether derivative in a suitable solvent using a suitable oxidizing agent. Suitable oxidizing agents include, for example, hydrogen peroxide, sodium metaborate, oxone (potassium peroxymonosulfate), chloroperbenzoic acid, periodic acid, and the like, and mixtures thereof. Suitable solvents include acetic acid (for sodium metaborate) and ethers such as THT and 1, 4-dioxane for other peracids, acetonitrile and DMF and the like and mixtures thereof.
The compounds of the invention can be prepared as racemic mixtures or as optically pure compounds. When preparing single enantiomers, the diastereomer pairs can be separated by chromatography or crystallization starting from optically pure starting materials by resolution of acidic or basic racemic intermediates with a suitable chiral acid or base or addition of a chiral protecting group to the racemic intermediate or the final product, respectively, according to methods known to those skilled in the art.
The chemical reactions described above are generally described in terms of their broadest application in the preparation of the compounds of the present invention. The reaction is sometimes not useful for preparing every compound within the scope of the present invention. It will be apparent to those skilled in the art that this occurs. In all such cases, or by subjecting the reaction to conventional modifications known to those skilled in the art, e.g., by appropriate protection of interfering groups, by use of additional conventional reagents, and by conventional modification of reaction conditions, etc., the above-described reactions can be successfully carried out, or the corresponding compounds of the invention can often be prepared by other reactions disclosed in this invention or other information. In all preparation methods, all starting materials are known or can be readily prepared from known starting materials.
The invention also includes prodrugs of the compounds of the invention. A prodrug is an active or inactive compound that is converted to the compound of the present invention by in vivo physiological effects, such as chemical modifications by hydrolysis and metabolism, after administration to a patient. Adaptations and techniques relating to the preparation and use of prodrugs are known to those skilled in the art. A general description of Prodrugs including esters is given in Svensson and Tunek, Durg Metabolism Reviews 165(1988) and Bundgaarddesign of produgs, Elsevier (1985). Examples of masked carboxylate anions include various esters, for example, alkyl (e.g., methyl and ethyl) esters, cycloalkyl (e.g., cyclohexyl) esters, aralkyl (e.g., benzyl, p-methoxybenzyl) esters, and alkylcarbonyloxyalkyl (e.g., pivaloyloxymethyl) esters. Amines are concealed as derivatives substituted with arylcarbonyloxyalkyl, which are cleaved in vivo by esterases to release the free drug and formaldehyde (see Bundgaard, j.med. chem.2503 (1989)).
Drugs containing acidic NH groups such as imidazoles, imines, indoles and the like may also be masked with N-acyloxymethyl groups (see Bundgaard Design of products, Elsevier (1985)). The hydroxyl groups can be masked as esters and ethers. EP039051(Sloan and Little, 4/11/81) discloses mannich base hydroxamic acid prodrugs and their preparation and use.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
All resulting reagents can be used directly without purification. All hydrogen and carbon NMR spectra were obtained from Bruker NMR.
The following examples are presented to describe the preparation of the compounds of the present invention and the intermediates used to prepare the compounds of the present invention.
Example 1
1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine- Preparation of 3-benzyl 2-tert-butyl 2, 3-dicarboxylate
Step A: 2-Aminosuccinic acid 4-benzyl ester 1-tert-butyl ester
D-aspartic acid beta-benzyl ester (9g, 40.3mmol) was suspended in 75ml of 1, 4-dioxane and 7.5ml of sulfuric acid and cooled to-15 ℃. 2-Methylpropene (75ml) was added and the reaction mixture was sealed and stirred at room temperature for 4 hours. The reaction mixture was then cooled to 0 ℃ and poured into 600ml of diethyl ether 325ml of 1M NaOH. The organic phase is separated and the aqueous phase is extracted twice with 200ml of diethyl ether. The combined organic phases were separated by MgSO4Dried for 30 minutes and filtered. The ether was evaporated and the residual oil was dried under high vacuum for 24 hours. Calculated value 280.2, found (M)+280。
And B: 2- (4-methoxy-benzenesulfonylamino) -succinic acid 4-benzyl ester 1-tert-butyl Esters of phenyl or naphthyl
4-benzyl 2-aminosuccinate 1-tert-butyl ester (9.57g, 33.4mmol), triethylamine (9.3ml, 66.8mmol) and 4-methoxybenzenesulfonyl chloride (6.9g, 33.4mmol) were dissolved in 50ml of Dichloromethane (DCM) and stirred at room temperature for 1 hour. The reaction mixture was diluted with 50ml of DCM, 200ml of water were added and the organic phase was separated. The aqueous phase was extracted twice with DCM. The combined organic phases were separated by MgSO4Dried and filtered. The solvent was evaporated and the residue was recrystallized from ether/ethyl acetate to give white needle crystals:
1H NMR(CDCl3)，ppm：8.2
Hz，(d，1H)，7.7Hz(d，2H)，7.3Hz(m，5H)，7.1Hz(d，
2H)，5.05Hz(d，2H)，4.08Hz(dd，1H)，3.9Hz(s，3H)，
2.72Hz(dd，1H)，2.59Hz(dd，1H)1.21Hz(s，9H).
and C:2-allyl-3- (4-methoxy-benzenesulfonylamino) -succinic acid 1- Benzyl 4-tert-butyl ester
100ml of anhydrous Tetrahydrofuran (THF) was cooled to-78 ℃. While maintaining the temperature, a 1M solution of lithium bis (trimethylsilyl) amide in THF (47.35ml.47.35mmol) was added. 4-benzyl 2- (4-methoxy-benzenesulfonylamino) -succinate 1-tert-butyl ester (10.1g, 22.5mmol) dissolved in 45ml of THF was added dropwise to the reaction solution. The reaction mixture was stirred for 1 hour and briefly warmed to-40 ℃. After the reaction mixture was cooled again to-78 ℃, allyl iodide (3.1ml, 33.8mmol) dissolved in 30ml of THF was added dropwise. Warm the reaction mixture to-40 ℃ with NH4The reaction was quenched with Cl solution. The separated organic phase is separated by MgSO4Dried and filtered. The solvent was evaporated and the product was purified by short column flash chromatography (hexane/ethyl acetate (9: 1)). Calculated 489.6, found (M)+490。
Step D: 2-allyl-3- [ allyl- (4-methoxy-benzenesulfonyl) -amino Base of]-succinic acid 1-benzyl ester 4-tert-butyl esterButyl ester
Triphenylphosphine (1g, 3.9mmol) was dissolved in 60ml Tetrahydrofuran (THF) and cooled to 0 deg.C. Diazopropyl dicarboxylate (DIAD) (0.77ml, 3.9mmol) was added via syringe and the reaction mixture was stirred for 30 min. To the yellow suspension was added allyl alcohol (16. mu.l, 0.23mmol) and after 10 minutes, 2-allyl-3- (4-methoxy-benzenesulfonylamino) -succinic acid 1-benzyl ester 4-tert-butyl ester (1.4g, 2.6mmol) was added. The reaction mixture was stirred at 0 ℃ for 30 minutes. Then warmed to room temperature. After evaporation of most of the THF, purification by flash chromatography (hexane/ethyl acetate (2: 1)) gave the product.
1H NMR(CDCl3 400MHz)，ppm：7.80(d，2H)，
7.38(m，5H)，6.95(d，2H)，5.75(m，2H)，5.10(m，6H)，
3.95(m，2H)，3.90(s，3H)，3.21(ddd，1H)，2.50(ddd，
1H)，2.35(ddd，1H)，1.40(s，9H).
Step E: 1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H- Azepine-2, 3-dicarboxylic acid 3-benzyl 2-tert-butyl ester
Reacting 2-allyl-3- [ allyl- (4-methoxy-benzenesulfonyl) -amino]1-benzyl 4-tert-butyl succinate (5.5g, 10.4mmol) was dissolved in 40ml dichloromethane, deoxygenated and purged with argon three times. Catalyst (RuCl) is added2(PCy3)2-Ph) (100mg, 0.12mmol) and deoxygenated the reaction, purged several times with argon. The reaction solution was stirred at room temperature for 7 hours. Another portion of ruthenium catalyst (90mg, 0.11mmol) was added and the reaction stirred overnight. Evaporation of the solvent followed by flash chromatography (hexane/ethyl acetate (3: 1)) gave the product:
1H NMR(CDCl3400 Mhz)，ppm：7.81
(d，2H)，7.37(m，5H)，6.93(d，2H)，5.60(m，2H)，5.10
(m，3H)，4.18(dd，1H)，4.05(dd，1H)，3.88(s，3H)，
3.20(ddd，1H)，2.68(m，2H)，1.32(s，9H).
example 2
1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine- Preparation of 2, 3-dicarboxylic acid 2-tert-butyl ester
1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2, 3-dicarboxylic acid 3-benzyl ester 2-tert-butyl ester (6g, 12mmol) was dissolved in a mixture of 120ml tetrahydrofuran and 78ml water. Adding LiOH H2O (1g, 24 mmol). After 45 minutes, water (15ml) was added thereto, and the reaction solution was stirred at room temperature for 24 hours. The solvent was evaporated and the residual solid was redissolved in water/ether. The aqueous layer was acidified to pH 1. The organic phase was separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were separated by MgSO4Dried and filtered. Evaporation of the solvent gave the product: calculated value 412.5, found value (M)+412.1。
Example 3
1- (4-methoxy-benzenesulfonyl) -azepane-2, 3-dicarboxylic acid 2-tert-butyl ester Preparation of butyl esters
1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2, 3-dicarboxylic acid 3-benzyl ester 2-tert-butyl ester (2.28g, 4.5mmol) was dissolved in 40ml1, 4-dioxane/methanol (3: 1), and palladium on carbon (10%) (170mg, 0.16mmol) was added under a stream of argon gas. The flask was evacuated, purged three times with hydrogen, and the reaction was stirred at room temperature for 6 hours. Filtration through celite and evaporation of the solvent gave the product:
1H NMR(DMSO，400
MHz)，ppm：7.81(d，2H)，6.95(d，2H)，5.40(d，1H)，
3.68(s，3H)，3.65(m，1H)，3.25(m，1H)，2.92(m，1H)，
2.15(m，1H)，1.95(m，1H)，1.78(m，2H)1.25(s，9H).
example 4
1- (4-methoxy-benzenesulfonyl) -3- (4-methoxy-benzyloxycarbonyl-ammonia Preparation of yl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester
The reaction was carried out under an argon atmosphere and protected from light. 1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2, 3-dicarboxylic acid 2-tert-butyl ester (550mg, 1.34mmol) was dissolved in 7ml of anhydrous Tetrahydrofuran (THF). Tripropylamine (TAP) (280. mu.l, 1.47mmol) was added, and the reaction was stirred at room temperature for 30 minutes. Phosphoryl diphenyl azide (318. mu.l, 1.47mmol) was added and the reaction was gradually heated to 40 ℃ and incubated for 3 hours. The reaction was then heated to reflux for 6 hours. The reaction mixture was cooled to an elevated temperature and 4-methoxybenzyl alcohol (184. mu.l, 1.47mmol) was added. The reaction was heated to reflux overnight. The solvent was evaporated and purified by flash chromatography (hexane/ethyl acetate (2: 1)) to give the product. Calculated value 383.5, found value (M)+383.0。
Example 5
3-benzyloxycarbonylamino-1- (4-methoxy-benzenesulfonyl) -amino)-2，3，4，7 Preparation of (E) -tetrahydro-1H-azepine-2-carboxylic acid
Step A: 3-benzyloxycarbonylamino-1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester
The reaction was carried out under an argon atmosphere. 1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2, 3-dicarboxylic acid 2-tert-butyl ester (300mg, 0.73mmol) was dissolved in 4ml1, 4-dioxane (anhydrous). Tripropylamine (TPA) (98. mu.l, 0.73mmol) was added and the reaction was stirred at room temperature for 15 minutes. Phosphoryl diphenyl azide (157. mu.l, 0.73mmol) was added and the reaction was gradually heated to 60 ℃ and incubated for 3 hours. The reaction was then cooled to room temperature, benzyl alcohol (235. mu.l, 2.2mmol) was added and the reaction solution was heated to 60 ℃ overnight. The reaction solution was diluted with ethyl acetate and washed with 2M citric acid and water. Separating the organic layer with MgSO4Dried and filtered. The solvent was evaporated and the residual oil was purified by flash chromatography (hexane/ethyl acetate (2: 1)): calculated value 516.6, found value (M)+517。
And B: 3-benzyloxycarbonylamino-1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid
Tert-butyl 3-phenoxycarbonylamino-1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylate (28mg, 0.054mmol) was dissolved in 4ml dichloromethane/trifluoroacetic acid (3: 1) and stirred at room temperature for 5 hours. The solvent/reagent was evaporated, the residual oil co-evaporated twice with toluene and purified by flash chromatography (hexane/ethyl acetate (1: 1)) to give the product: calculated value 460.51, found value (M)+460.9。
Example 6
3-（3，3-Tribenzylureido) -1- (4-oxy-benzenesulfonyl) -2, 3, preparation of 4, 7-tetrahydro-1H-azepine-2-carboxylic acid
Step A: 3- (3, 3-dibenzylureido) -1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester
The reaction was carried out under an argon atmosphere. Tert-butyl 1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2, 3-carboxylate (204mg, 0.5mmol) was dissolved in 10ml of anhydrous 1, 4-dioxane. Tripropylamine (94. mu.l, 0.5ml) was added followed by phosphoryl diphenyl ester azide (DPPA). The reaction was heated to 75 ℃ for 5 hours. After cooling to room temperature, dibenzylamine (190.6. mu.l, 1mmol) was added via syringe. The reaction was heated to 70 ℃ and stirred overnight. The solvent was evaporated and purified by flash chromatography (hexane/ethyl acetate (1: 1)) to give the product: calculated value 606.8, found value (M)+606.2。
And B: 3- (3, 3-dibenzylureido) -1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid
3- (3, 3-dibenzylureido) -1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester (200mg, 0.33mmol) was reacted in the same manner as 3-benzyloxycarbonylamino-1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester and purified by flash chromatography (dichloromethane/methanol (9: 1)) to give the product: calculation 550.6, found (M)+550。
Example 7
3-amino-1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H Preparation of tert-butyl (2-azepin-2-carboxylate)
1- (4-methoxy-benzenesulfonyl) -3- (4-methoxybenzyloxycarbonylamino) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester (370mg, 0.71mmol)
Dissolved in dichloromethane (15ml) containing 3% trifluoroacetic acid. The reaction was stirred at room temperature for 1 hour. The solvent was evaporated and the residual oil was co-evaporated twice with toluene and purified by flash chromatography (dichloromethane/methanol (7: 1)) to give the free amine: calculated value 546.6, found value (M)+547。
Example 8
1- (4-methoxy-benzenesulfonyl) -3- (phenylmethanesulfonylamino) -2, 3, 4, preparation of 7-tetrahydro-1H-azepine-2-carboxylic acid
Step A: 1- (4-methoxy-benzenesulfonyl) -3- (phenylmethanesulfonylamino) - 2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester
Tert-butyl 3-amino-1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylate (38mg, 0.1mmol) was dissolved in 3ml of anhydrous dichloromethane. Hunigs base (42. mu.l, 0.24mmol) was added followed by α -toluenesulfonyl chloride (28.4mg, 0.15 mmol). The reaction mixture was stirred at room temperature for 4 hours. The solvent was evaporated and the residual oil was purified by flash chromatography (hexane/ethyl acetate (2: 1)):
1H NMR(CDCl3 400MHz)，ppm：
7.75(d，2H)，7.50(m，2H)，7.4(m，3H)6.99(d，2H)，
5.70(m，2H)，4.85(d，1H)，4.56(d，1H)，4.35(dd，2H)，
4.22(dd，1H)，4.02(m，1H)，3.90(m，3H)，3.83(m，
1H)，2.50(m，1H)，2.30(m，1H)，1.30(s，9H).
and B: 1- (4-methoxy-benzenesulfonyl) -3- (phenylmethanesulfonylamino) - 2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid
1- (4-methoxy-benzenesulfonyl) -3- (4-phenylmethanesulfonylamino) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester (29mg, 0.054mmol) was reacted in the same manner as 3-benzyloxycarbonylamino-1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester: calcd 479.5, found (M)+478.6。
1H NMR(DMSO，
400MHz)，ppm：7.85(d，2H)，7.38(m，5H)7.01(d，2H)，
5.5(m，2H)4.45(d，2H)，4.30(d，2H)，4.15(m，2H)，
4.00(m，1H)，3.90(dd，1H)，3.83(s，3H)，2.18(m，2H).
Example 9
1- (4-methoxy-benzenesulfonyl) -3- (3-phenylpropionylamino) -2, 3, preparation of 4, 7-tetrahydro-1H-azepine-2-carboxylic acid
Step A: 1- (4-methoxy-benzenesulfonyl) -3- (3-phenylpropionylamino) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester
3-amino-1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester (31mg, 0.08mmol) was dissolved in 4ml of dichloromethane and cooled to 0 ℃. Hunigs base (34. mu.l, 0.2) was addedmmol) followed by addition of phenylpropyl chloride (18. mu.l, 0.12 mmol). The reaction was stirred at 0 ℃ for 1 hour and then warmed to room temperature. The solvent was evaporated and the residual oil was purified by flash chromatography (dichloromethane/methanol (9: 1)) to give the product: calculated value 513.6, found (M + H)+514.9。
And B: 1- (4-methoxy-benzenesulfonyl) -3- (3-phenylpropionylamino) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid
1- (4-methoxy-benzenesulfonyl) -3- (3-phenylpropionylamino) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester (22mg, 0.04mmol) was reacted in the same manner as 3-benzyloxycarbonylamino-1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester and purified by flash chromatography (dichloromethane/methanol (9: 1)) to give the acid: calcd 457.5, found (M-H)+456.6；
1H NMR
(DMSO，400MHz)，ppm：7.78(d，2H)，7.28(m，2H)，7.20
(m，3H)，7.01(d，2H)，5.6(m，1H)，5.5(m，1H)，4.3(m，
3H)，4.0(m，1H)，3.82(s，3H)，2.8(t，2H)，2.35(m，
2H)，2.05(m，2H).
Example 10
3- (3-benzylureido) -1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7 Preparation of (E) -tetrahydro-1H-azepine-2-carboxylic acid
Step A: 3- (3-benzylureido) -1- (4-methoxy-benzenesulfonyl) -2, 3，4, 7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester
3-amino-1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester (33mg, 0.09ml) was dissolved in 3ml of anhydrous 1, 4-dioxane. Benzyl isocyanate (10.6. mu.l, 0.086mmol) was added and the reaction stirred at room temperature for 1 hour. The solvent was evaporated and purified by flash chromatography (dichloromethane/methanol (7: 1)) to give the product: calcd 515.6 found (M)+515.9。
And B: 3- (3-benzylureido) -1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid
3- (3-Benzylhureido) -1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester (25mg, 0.05mmol) was reacted in the same manner as 3-benzyloxycarbonylamino-1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester and purified by flash chromatography (dichloromethane/methanol (9: 1)) to give the product: calculated value 459.5, found (M-H)+458.2：
1H NMR(DMSO，400MHz)，ppm：
7.79(d，2H)，7.30(m，2H)，7.20(m，3H)7.02(d，2H)，
5.60(m，1H)，5.50(m，1H)4.3(m，3H)，4.00(m，1H)，
3.93(m，3H)，2.81(t，2H)，2.35(m，2H)，2.05(m，2H).
Example 11
Using the methods described above and the methods of examples 1-10, the following compounds can be prepared:
1- (4-methoxy-benzenesulfonyl) -3- (phenethylsulfonylamino) -1H-azepane-2-carboxylic acid: calculated value 496.6, found value (M)+497；
1- (4-methoxy-benzenesulfonyl) -3- (2-amino-benzenesulfonylamino) -1H-azepane-2-carboxylic acid: calculated 497.6, found (M)+498；
1- (4-methoxy-benzenesulfonyl) -3- (phenylmethanesulfonylamino) -1H-azepane-2-carboxylic acid: calculated 482.6, found (M)+483；
Cis-1- (4-methoxy-benzenesulfonyl) -3- (phenylmethanesulfonylamino) -heptylideneimine-2-carboxylic acid: calculated value 496.6, found value (M-H)+495；
Trans-1- (4-methoxy-benzenesulfonyl) -3- (phenylmethanesulfonylamino) -heptylideneimine-2-carboxylic acid: calculated value 496.6, found value (M-H)+495；
3-benzyloxycarbonylamino-1- (4-methoxy-benzenesulfonyl) -1H-azepane-2-carboxylic acid: calculated value 462.52, found value (M-H)+461.2；
1- (4-methoxy-benzenesulfonyl) -3- (methylsulfonylamino) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid: calculated value 404.5, found value (M)+405；
1- (4-methoxy-benzenesulfonyl) -3- (benzenesulfonylamino) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid: calculated value 466.6, found value (M)+467；
1- (4-methoxy-benzenesulfonyl) -3- (2-naphthylsulfonylamino) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid: calculated value 516.6, found value (M)+517；
1- (4-methoxy-benzenesulfonyl) -3- (1-naphthylsulfonylamino) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid: calculated value 516.6, found value (M)+517；
1- (4-chlorophenyl-benzenesulfonyl) -3- (phenylmethanesulfonylamino) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid: calculated value 560.6, found value (M)+561；
1- (4-methoxy-benzenesulfonic acid)Acyl) -3- (4-chlorophenylbenzenesulfonylamino) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid: calculated value 577.1, found value (M)+577；
1- (4-methoxy-benzenesulfonyl) -3- (2-nitrophenylmethylsulfonylamino) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid: calculated value 525.6, found value (M)+526；
1- (4-methoxy-benzenesulfonyl) -3- (phenylacryloyl) sulfonylamino) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid: calculated value 492.6, found value (M)+493；
1- (4-methoxy-benzenesulfonyl) -3- (4-iodophenylsulfonylamino) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid: calculated value 592.7, found value (M)+593；
1- (4-methoxy-benzenesulfonyl) -3- (acetylamino) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid: calculated value 368.4, found value (M)+369；
1- (4-methoxy-benzenesulfonyl) -3- (2-thienyl-2-acetylamino) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid: calculated value 450.5, found (M)+451；
3- (3-phenethylureido) -1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid: calcd 473.5, found (M)+474；
3- (3-methylureido) -1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid: calculated value 383.4, found (M)+384；
3- (3-phenylureido) -1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid: calcd 445.5, found (M)+446；
3- (3, 3-benzylmethylureido) -1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid: calcd 473.5, found (M)+474；
3- (3, 3-benzylphenylureido) -1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid: calculated value 535.6, found value (M)+536；
3-methoxycarbonylamino-1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid: calculated value 384.41, found value (M)+385；
3- (4-trifluoromethylbenzyloxycarbonylamino) -1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid: calculated value 528.5, found value (M)+529；
3- (4-chlorobenzyloxycarbonylamino) -1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid: calculated value 494.9, found (M)+495；
3- (3, 5-dichlorobenzyloxycarbonylamino) -1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid: calculated value 529.4, found value (M)+530。
Example 12
Using the procedures described above and in the examples above, the compounds of Table I can be prepared
TABLE I
R 1 R 9 n m R 11
4-ClPh-Ph H 0 1 PhCH2SO2
4-ClPh-Ph OH 0 1 PhCH2SO2
4-ClPh-Ph OMe 0 2 PhCH2SO2
4-ClPh-Ph Ph 1 1 PhCH2SO2
4-ClPh-Ph pyridine CH 201 PhCH2SO2
4-MeOPh-Ph H 0 1 PhCH2SO2
4-MeOPh-Ph OH 0 1 PhCH2SO2
4-MeOPh-Ph OMe 0 2 PhCH2SO2
4-MeOPh-Ph Ph 1 1 PhCH2SO2
4-MeOPh-Ph pyridine CH 201 PhCH2SO2
4-Ph-4-piperidine-4-Ph H01 PhCH2SO2
4-Ph-4-piperidine-4-Ph OH 01 PhCH2SO2
4-Ph-4-piperidine-4-Ph OMe 02 PhCH2SO2
4-Ph-4-piperidine-4-Ph 11 PhCH2SO2
4-Ph-4-piperidine-4-Ph pyridine CH 201 PhCH2SO2
4-BenzamidoPh H01 PhCH2SO2
4-BenzoamidoPh PhOH 01 PhCH2SO2
4-BenzamidoPh PhOMe 02 PhCH2SO2
4-BenzamidoPh Ph 11 PhCH2SO2
4-BenzoamidoPh Ph pyridine CH 201 PhCH2SO2
4-pyridyl-oxo Ph H01 PhCH2SO2
4-pyridyl-oxo Ph OH 01 PhCH2SO2
4-pyridyl-oxo Ph OMe 02 PhCH2SO2
4-pyridyl-oxo Ph 11 PhCH2SO2
4-pyridyl-oxo Ph pyridine CH 201 PhCH2SO2
Example 13
The following in vitro experiments were used to characterize the ability of the compounds of the invention to inhibit collagenase and stromelysin: human neutrophil collagenase assay and human fibroblast stromelysin assay.
Human neutrophil collagenase assay
Using fluorescent peptide substrate Dnp-Pro-b-cyclohexyl-Ala-Gly-Cys (Me) -His-Ala-Lys- (N-methylanthranilic acid) -NH2The activity of Human Neutrophil Collagenase (HNC) was determined. Before cleaving the Gly-Cys (me) bond of the peptide, the N-terminal Dnp group andthe fluorescence of the C-terminal N-methyl-benzoylimino group (Nma) is self-quenched. The fluorescence of the cleavage products was determined on a microplate reader from Bio-TeK Instrument FL500 fluorescence (excitation: 360nm, emission 460 nm). Experiments were performed in duplicate in 96-well plates, and the substrates Km ═ 51nM and actinonin Ki ═ 722nM were determined. The inhibitory effect of the test compounds (100, 33 and 10mM) on HNC activity of the substrate was compared against the activity of actinonin, and the Ki of the selected compounds was determined.
Human fibroblast stromelysin assay
Using fluorescent peptide substrate Dnp-Pro-b-cyclohexyl-Ala-Gly-Cys (Me) -His-Ala-Lys- (N-methylanthranilic acid) -NH2Determining the activity of Human Fibroblast Stromelysin (HFS). The fluorescence of the N-terminal Dnp group and the C-terminal N-methyl-benzoylimino group (Nma) is self-quenched prior to cleavage of the Gly-to-cys (me) bond of the peptide. The fluorescence of the cleavage products was determined on a microplate reader from Bio-TeK Instrument FL500 fluorescence (excitation: 360nm, emission 460 nm). Experiments were performed in 96-well plates (in duplicate) and the substrate Km ═ 51nM, and actinonin (enzyme activity inhibitor; Sigma Chemical, st. louis, MO; a6671) Ki ═ 722nM as a standard reference. The inhibition of HFS activity of the substrates by the test compounds (100, 33 and 10mM) was compared against the activity of actinonin, and the Ki of the selected compounds was determined.
The following compounds have an IC of less than 10. mu.M50HNC and/or HFS inhibitory activity:
1- (4-methoxy-benzenesulfonyl) -3- (2-amino-benzenesulfonylamino) -1H-azepane-2-carboxylic acid;
1- (4-methoxy-benzenesulfonyl) -3- (phenylmethanesulfonylamino) -1H-azepane-2-carboxylic acid;
1- (4-chlorophenyl-benzenesulfonyl) -3- (phenylmethanesulfonylamino) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid;
1- (4-methoxy-benzenesulfonyl) -3- (2-nitrophenylmethanesulfonamido) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid;
1- (4-methoxy-benzenesulfonyl) -3- (phenylpropenoyl (acroyl) sulfonylamino) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid;
3- (4-chlorobenzyloxycarbonylamino) -1- (4-methoxybenzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid;
3- (3, 5-Dichlorobenzyloxycarbonylamino) -1- (4-methoxybenzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid.
Method of treatment
All compounds of the invention are useful for the prevention and treatment of diseases caused by HNC and/or HFS and/or gelatinases. The compounds of the invention are preferably used for the prevention and treatment of the following disorders: rheumatoid arthritis, osteoarthritis, osteopenia (e.g., osteoporosis), periodontitis, gingivitis, corneal, epidermal and gastric ulceration, tumor metastasis, onset and growth, neuritis such as myelin degradation (e.g., multiple sclerosis), and angiogenesis dependent disorders such as arthritis, cancer, solid tumor growth, psoriasis, retinal hyperplasia, neovascular glaucoma, ocular tumors, angiofibromas, hemangiomas, nephritis, pneumonia and restenosis.
The present invention provides methods for treating conditions caused by elevated concentrations of HNS and/or HFS and/or gelatinase comprising administering an effective amount of a compound of the invention. The compounds of the invention are useful for the prophylactic and acute or chronic treatment of the onset, occurrence and exacerbation of any disease in humans or other mammals caused by elevated or indeterminate levels of HNS and/or HFS and/or gelatinase in mammalian cells. The present invention relates, inter alia, to a method of reducing the concentration of HNS and/or HFS and/or gelatinase activity in a mammal (if desired) comprising administering an effective amount of a compound or pharmaceutical composition of the invention.
The compounds or pharmaceutical compositions of the invention are useful for the treatment or prevention of a variety of diseases, including:
rheumatoid arthritis, osteoarthritis, osteopenia (e.g., osteoporosis), periodontitis, gingivitis, corneal, epidermal and gastric ulceration, tumor metastasis, onset and growth, neuritis such as myelin degradation (e.g., multiple sclerosis), and angiogenesis dependent disorders such as arthritis, cancer, solid tumor growth, psoriasis, retinal hyperplasia, neovascular glaucoma, ocular tumors, angiofibromas, hemangiomas, nephritis, pneumonia and restenosis.
Pharmaceutical composition
The invention also relates to the use of the compounds according to the invention for the production of medicaments for the prophylaxis and acute or chronic treatment of diseases caused by HNS and/or HFS and/or gelatinase.
The invention also relates to pharmaceutical compositions comprising a compound of the invention, a pharmaceutically acceptable carrier and, if desired, other active ingredients. The compounds of the invention may be administered by any suitable route, preferably in a pharmaceutical composition suitable for the above route of administration at a therapeutically effective dose as required. Any person of ordinary skill in the art can readily determine the therapeutically effective dose of a compound of the present invention required to inhibit the progression of, or prevent tissue damage associated with, the aforementioned diseases.
For the prophylaxis and treatment of diseases, the compounds of the invention are administered orally, parenterally, or by inhalation spray, rectally, or topically in dosage unit formulations in dosage unit forms containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles. Parenteral administration as described herein includes subcutaneous, intravenous, intramuscular, intrasternal, infusion or intraperitoneal administration.
The amount of active ingredient that is combined with the carrier materials to form a single dosage form will vary depending upon the host treated and the particular mode of administration.
The dosage regimen for treating the above-mentioned diseases with the compounds of the present invention and/or the pharmaceutical compositions of the present invention is based on a variety of factors including the type of disease, the age, weight, sex and medical condition of the patient, the severity of the condition, the route of administration, pharmacological considerations such as the activity, potency, pharmacokinetics and toxicology of the particular compound employed, whether a drug delivery system is employed and whether the compound is administered as part of a combination drug. Thus, the dosage administered varies widely. For all methods described herein, the desired dose is from about 0.01mg to about 80mg per kg of body weight per day, preferably from about 0.5mg to about 30mg per kg of body weight per day, and more preferably from about 1mg to about 15mg per kg of body weight per day. The pharmacologically active compounds of the present invention may be processed according to conventional pharmaceutical methods to prepare medicaments for administration to patients or mammals, including humans.
For oral administration, the pharmaceutical composition may be in the form of, for example, capsules, tablets, suspensions or liquids. The pharmaceutical compositions of the present invention are preferably formulated in dosage unit dosage forms containing a given amount of active ingredient. For example, the dosage forms described above contain the active ingredient in an amount of about 25 to 250mg, preferably about 25 to 150 mg. The appropriate daily dosage for humans or other mammals varies widely depending on the condition of the patient and other factors.
The compounds of the invention may also be administered by injection in a composition comprising saline, dextrose or water in a suitable carrier. The daily parenteral dosage is about 0.1-80mg/kg of total body weight, preferably about 0.5-30mg/kg of total body weight, more preferably about 1-15mg/kg of total body weight.
Sterile aqueous injection solutions or oily suspensions for injection may be prepared, for example, by using suitable dispersing or wetting agents and suspending agents in accordance with techniques known in the art. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol. Acceptable excipients and solvents used are water, ringer's solution and isotonic sodium chloride solution. In addition, a conventional sterile fixed oil may be used as a solvent or dispersion medium. Thus, any mixed fixed oil including synthetic mono-or diglycerides can be used. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Suppositories for rectal administration of the drug can be prepared by mixing the drug with suitable, non-irritating excipients such as coconut oil and polyethylene glycol, which are solid at ordinary temperatures but liquid at the rectal temperature, so that the excipients melt in the rectum to release the drug.
Suitable topical dosages of the compounds of the invention are in the range of 0.1 to 150mg, administered 1 to 4 times per day, preferably 2 to 3 times per day. For topical administration, the active ingredient may be present in the formulation in an amount of 0.001% to 10% by weight of the formulation, for example 1% to 2% by weight of the formulation, although the active ingredient may be present in an amount up to 10% by weight of the formulation, preferably it is present in an amount not exceeding 5% by weight of the formulation, more preferably it is present in an amount of 0.1% to 1% by weight of the formulation. Suitable formulations for topical administration include suitable liquid or semi-liquid formulations for transdermal administration, for example liniments, lotions, ointments, creams or patches and drops suitable for administration to the eye, ear or nose.
For administration, the compounds of the present invention are typically administered in admixture with one or more adjuvants appropriate for the intended route of administration. For conventional administration, the compounds of the invention may be combined with the following adjuvants and formulated into tablets or capsules: lactose, sucrose, starch, cellulose alkanoates, stearic acid, talc, magnesium stearate, sodium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gum arabic, gelatin, sodium alginate, polyvinylpyrrolidone and/or polyvinyl alcohol. Alternatively, the compounds of the present invention are dissolved in the following solvents: saline, water, polyethylene glycol, propylene glycol, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil, benzyl alcohol, and/or various buffers. Other adjuvants and modes of administration are known in the pharmaceutical art. The carrier or diluent comprises a time delay material such as glyceryl monostearate or glyceryl distearate, or a mixture of glyceryl monostearate or glyceryl distearate with a paraffin or other material known in the art.
The pharmaceutical composition of the present invention may be formulated into solid preparations including granules, powders or suppositories or may be formulated into liquid preparations such as solutions, suspensions or emulsions. The pharmaceutical compositions may be treated with conventional pharmaceutical processing methods such as sterilization and/or may contain conventional adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, buffers and the like.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In the above solid dosage forms, the active compounds of the invention may be mixed with at least one inert diluent such as sucrose, lactose or starch. In conventional pharmaceutical practice, the solid dosage forms may also contain, in addition to inert diluents, other substances, for example, lubricants such as magnesium stearate. When the solid dosage form is a capsule, tablet or pill, the dosage form may also contain buffering agents. Additionally, tablets and pills can be prepared with enteric coatings.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. The compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
The compounds of the invention have one or more asymmetric carbon atoms and may therefore exist as optical isomers and as racemic or meso mixtures thereof. The racemic mixture is resolved to give optically active isomers according to conventional methods, for example, a method of treating the racemic mixture with an optically active acid or base to form diastereomeric salts. Specific examples of suitable acids are tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphorsulfonic acid, the diastereomeric mixture being separated by crystallization and the optically active base being released from the diastereomeric salt. Various methods of separating optical isomers include the selection of the optimal chiral chromatographic column to maximize the separation of enantiomers. Other suitable methods include the synthesis of covalent diastereomeric molecules by reacting an active compound of formula (I) with an activated form of an optically pure acid or an optically pure isocyanate. The synthesized diastereomers can be separated by conventional methods, e.g., by chromatography, distillation, crystallization, or sublimation methods, and then hydrolyzed to release enantiomerically pure compounds. Optically active compounds of formula (I) can be similarly obtained by using optically active starting materials. The isomers may be free acids, free bases, esters or salts.
The compounds of the invention may be derived from salts of inorganic or organic acids. Such salts include, but are not limited to: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethylsulfonate, glucoheptonate, glycerophosphate, metabisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methylsulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate (palmoate), pectinate (pectinate), persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, methanesulfonate, and undecanoate. Meanwhile, there may be used, for example, lower alkyl halides such as chloro, bromo and iodo methane, ethane, propane and butane; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as chloro-, bromo-and iododecane, dodecane, tetradecane and octadecane; aralkyl halides, such as benzyl bromide and phenethyl bromide and others, quaternize the basic nitrogen-containing groups.
Specific examples of acids useful for forming pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric, phosphoric and sulfuric acids, and acids such as oxalic, maleic, succinic and citric acids, and organic acids. Other examples include salts with alkali metals or alkaline earth metals such as sodium, potassium, calcium or magnesium, or salts with organic bases.
Although the compounds of the present invention may be administered alone as the active agent, they can also be administered in admixture with one or more other agents. When administered in admixture with other drugs, the therapeutic agents may be formulated as separate compositions for simultaneous or non-simultaneous administration, or as a single composition.
The foregoing is merely illustrative of the present invention and is not intended to limit the invention to the disclosed compounds. Various modifications and changes may be made apparent to those skilled in the art within the scope and spirit of the invention as defined by the claims.
From the above description, one skilled in the art can easily ascertain the essential characteristics of the present invention, and without departing from the scope and spirit of the invention, can make various changes and modifications of the invention to adapt the invention to various usages and conditions.

Claims (14)

1. A compound of the formula or a pharmaceutically acceptable salt thereof,wherein m is 1 or 2, n is 0, 1 or 2;
R1is optionally selected from 1-2 of-OH, -OR3、-S(O)2R3、-NR3R4Amino, acetylamino, methylsulfonylamino, halogen, C1-4Alkyl or-CF3Aryl substituted with the substituent of (1); provided that at R1The total number of upper aryl and heteroaryl groups is 1 to 2;
R5、R6、R9and R10Each is hydrogen; or CR5-CR6Is C ═ C; and
each R is3Are respectively C1-4Alkyl, C with 1-3 halogens1-4Haloalkyl, aryl, heteroaryl, aryl-C1-4Alkyl or heteroaryl-C1-4Alkyl, wherein aryl and heteroaryl are optionally substituted by 1-3 substituents selected from hydroxy, C1-4Alkoxy radical, C1-4Alkylthio, amino, C1-4Alkanoylamino group, C1-4Alkylsulfonylamino group, C1-4Alkylsulfinyl radical, C1-4Alkylsulfonyl radical, C1-4Alkoxycarbonylamino group, C1-4Alkoxycarbonyl, cyano, halogen, azido, C1-4Alkyl, C with 1-3 halogens1-4Haloalkyl or C having 1-3 halogens1-4Substituted with a halo alkoxy group; and R4Is hydrogen or C1-4An alkyl group;
R11is-C (O) -R31、-C(O)-OR30、-C(O)-NR32R31、-S(O)2-R30or-S (O)2-NR32R31；
Wherein R is30Each independently is
(1) C optionally substituted by 1 to 3 substituents1-C6Alkyl groups: -CO2R34Amino group, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, N- ((C)1-C4Alkoxy) carbonyl) -N- (C1-C4Alkyl) amino, aminocarbonylamino, C1-C4Alkylsulfonylamino, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl, cyano, halogen, aryl C1-C4Alkoxy, aryl C1-C4Alkylthio, aryl C1-C4Alkylsulfonyl radical, C3-C8Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by 1-3 substituents selected from amino, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C4Alkylsulfonylamino group, C1-C5Alkanoyl, (C)1-C4Alkoxy) carbonyl, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl, cyano, halogen, C1-C4Alkyl, C with 1-3 halogens1-C4Haloalkyl or C having 1-3 halogens1-C4Substituted with a halo alkoxy group;
(2) optionally substituted by 1-3 groups selected from amino, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C4Alkylsulfonylamino group, (C)1-C4Alkoxy) carbonyl, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio, cyano, C1-C4Alkyl, C with 1-3 halogens1-C4Haloalkyl or C having 1-3 halogens1-C4A heterocyclic group substituted with a substituent of a haloalkoxy group; or
(3) Optionally substituted by 1-3 groups selected from amino, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C4Alkylsulfonylamino group, (C)1-C4Alkoxy) carbonyl, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio, cyano, halogen, azido, C1-C4Alkyl, C with 1-3 halogens1-C4Haloalkyl or C having 1-3 halogens1-C4Aryl or heteroaryl substituted with a substituent of haloalkoxy;
R31each independently is hydrogen or R30；
Wherein R is32Each independently is hydrogen or C1-C4An alkyl group;
R33is hydrogen or C1-C4An alkyl group;
R34is hydrogen or C1-C4An alkyl group;
wherein heterocyclyl is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 4-benzyl-piperazin-1-yl, pyrimidinyl, tetrahydrofuranyl, pyrazolidinonyl, pyrazolinyl, pyridazinonyl, pyrrolidinonyl, tetrahydrothienyl and sulfoxide or sulfone derivatives thereof, 2, 3-dihydroindolyl, tetrahydroquinolinyl, 1, 2, 3, 4-tetrahydroisoquinolinyl, 1, 2, 3, 4-tetrahydro-1-oxoisoquinolinyl, 2, 3-dihydrobenzofuranyl, benzopyranyl, methylenedioxophenyl or ethylenedioxyphenyl; aryl is phenyl, biphenyl or naphthyl; and heteroaryl is imidazolyl, pyrrolyl, pyrazolyl, pyridyl, pyrazinyl, triazolyl, furyl, thienyl, oxazolyl, thiazolyl, indolyl, quinolinyl, isoquinolinyl, 5, 6, 7, 8-tetrahydroquinolinyl, 5, 6, 7, 8-tetrahydroisoquinolinyl, quinoxalinyl, benzothiazolyl, β -carbolinyl, benzofuranyl, benzimidazolyl or benzoxazolyl.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein
Each R is3Are respectively C1-4Alkyl, -CF3Aryl, heteroaryl, aryl-C1-4Alkyl or heteroaryl-C1-4Alkyl, wherein aryl and heteroaryl are optionally substituted by 1-3 substituents selected from hydroxy, C1-4Alkoxy radical, C1-4Alkylthio, amino, acetylamino, methylsulfonylamino, C1-4Alkylsulfonyl radical, C1-4Alkoxycarbonylamino group, C1-4Alkoxycarbonyl, cyano, halogen, C1-4Alkyl, -CF3or-OCF3Substituted with the substituent(s); r4Is hydrogen or methyl;
R30each independently is
(1) C optionally substituted by 1 to 3 substituents1-C6Alkyl groups: -CO2R34Amino group, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, N- ((C)1-C4Alkoxy) carbonyl) -N- (C1-C4Alkyl) amino, aminocarbonylamino, C1-C4Alkylsulfonylamino, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl, cyano, halogen, aryl-C1-C4Alkoxy, aryl-C1-C4Alkylthio, aryl-C1-C4Alkylsulfonyl radical, C3-C8Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by 1-3 substituents selected from amino, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C4Alkylsulfonylamino group, C1-C5Alkanoyl, (C)1-C4Alkoxy) carbonyl, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl, cyano, halogen, C1-C4Alkyl, -CF3or-OCF3Substituted with the substituent(s);
(2) optionally substituted by 1-3 groups selected from amino, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C4Alkylsulfonylamino group、(C1-C4Alkoxy) carbonyl, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio, cyano, C1-C4Alkyl, C with 1-3 halogens1-C2Haloalkyl or-OCF3A heterocyclic group substituted with the substituent(s) of (1); or
(3) Optionally substituted by 1-3 groups selected from amino, C1-C4Alkylamino, di- (C)1-C4Alkyl) amino, C1-C5Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C4Alkylsulfonylamino group, (C)1-C4Alkoxy) carbonyl, hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio, cyano, halogen, C1-C4Alkyl, -CF3or-OCF3Aryl or heteroaryl substituted with the substituents of (1);
R31each independently is hydrogen or R30(ii) a And
R33is hydrogen or methyl.
3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R11is-C (O) -R31or-S (O)2-R30。
4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein
Each R is3Are respectively C1-4Alkyl, -CF3Aryl, heteroaryl, aryl-C1-2Alkyl or heteroaryl-C1-2Alkyl, wherein aryl and heteroaryl are optionally substituted by 1-2 substituents selected from hydroxy, C1-4Alkoxy radical, C1-4Alkylthio, amino, acetylamino, methylsulfonylamino, C1-4Alkylsulfonyl radical, C1-4Alkoxycarbonylamino group, C1-4Alkoxycarbonyl, cyano, halogen, C1-4Alkyl, -CF3or-OCF3Substituted with the substituent(s);
R30is composed of
(1)-CF3Or optionally is covered withC substituted by 1-2 substituents1-C4Alkyl groups: -CO2R34Amino group, C1-C2Alkylamino, di- (C)1-C2Alkyl) amino, C1-C2Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, N- ((C)1-C4Alkoxy) carbonyl) -N- (C1-C4Alkyl) amino, hydroxy, C1-C4Alkoxy or aryl radicals C1-C2Alkoxy, heterocyclyl, aryl or heteroaryl, wherein heterocyclyl, aryl and heteroaryl are optionally substituted by 1 to 3 substituents selected from amino, C1-C2Alkylamino, di- (C)1-C2Alkyl) amino, C1-C2Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C5Alkanoyl, (C)1-C4Alkoxy) carbonyl, hydroxy, C1-C4Alkoxy, halogen, C1-C4Alkyl, -CF3or-OCF3Substituted with the substituent(s);
(2) optionally 1-2 selected from (C)1-C4Alkoxy) carbonyl, hydroxy or C1-C4A heterocyclic group substituted with a substituent of an alkyl group; or
(3) Optionally substituted by 1-2 groups selected from amino, C1-C2Alkylamino, di- (C)1-C2Alkyl) amino, C1-C2Alkanoylamino, hydroxy, C1-C2Alkoxy, halogen, C1-C4Alkyl, -CF3or-OCF3Aryl or heteroaryl substituted with the substituents of (1);
R31is hydrogen or R30。
5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein
Each R is3Are respectively C1-4Alkyl, -CF3Aryl, heteroaryl, aryl-C1-2Alkyl or heteroaryl-C1-2Alkyl, wherein aryl and heteroaryl are optionally substituted by 1-2 substituents selected from hydroxy, C1-2Alkoxy radical, C1-2Alkylthio, amino, acetylamino, methylsulfonylamino, C1-2Alkylsulfonyl radical, C1-4Alkoxycarbonylamino group, C1-4Alkoxycarbonyl, halogen, C1-2Alkyl, -CF3or-OCF3Substituted with the substituent(s);
R30is composed of
(1) Optionally 1-2 selected from (C)1-C4Alkoxy) carbonyl, hydroxy or C1-C4A heterocyclic group substituted with a substituent of an alkyl group; or
(2) Optionally substituted by 1-2 groups selected from amino, C1-C2Alkylamino, di- (C)1-C2Alkyl) amino, C1-C2Alkanoylamino, hydroxy, C1-C2Alkoxy, halogen, C1-C4Alkyl, -CF3or-OCF3Heteroaryl substituted with the substituent of (1); and
R31is hydrogen or
(1)-CF3Or optionally substituted by 1-2 hydroxy groups, C1-C2Alkoxy or aryl-C1-C2Alkoxy, aryl or heteroaryl substituted C1-C4Alkyl, wherein aryl and heteroaryl are optionally substituted by 1-2 substituents selected from amino, C1-C2Alkylamino, di- (C)1-C2Alkyl) amino, C1-C2Alkanoylamino, (C)1-C4Alkoxy) carbonylamino, C1-C5Alkanoyl, (C)1-C4Alkoxy) carbonyl, hydroxy, C1-C4Alkoxy, halogen, C1-C4Alkyl, -CF3or-OCF3Substituted with the substituent(s);
(2) optionally substituted by 1-2 groups selected from amino, C1-C2Alkylamino, di- (C)1-C2Alkyl) amino, C1-C2Alkanoylamino, hydroxy, C1-C2Alkoxy, halogen, C1-C4Alkyl, -CF3or-OCF3Aryl or heteroaryl substituted with the substituents of (1).
6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein
Each R is3Are respectively C1-4Alkyl, -CF3Aryl, heteroaryl, arylmethyl or heteroarylmethyl;
R30is optionally substituted by C1-C4An alkyl-substituted heterocyclic group;
R31is hydrogen or
(1)-CF3Or C optionally substituted by 1-2 aryl or heteroaryl groups1-C4An alkyl group; or
(2) An aryl group or a heteroaryl group, or a pharmaceutically acceptable salt thereof,
7. the compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein
R1Is optionally selected from 1-2 of-OH, -OR3、-S(O)2R3、-NR3R4Amino, acetylamino, methylsulfonylamino, halogen, C1-4Alkyl or-CF3Phenyl or biphenyl substituted with the substituents of (1);
each R is3Are respectively C1-4Alkyl, -CF3Phenyl, heteroaryl, phenylmethyl, or heteroarylmethyl.
8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein
R1Is optionally selected from 1-2 of-OH, -OR3Halogen, methyl or-CF3Phenyl or biphenyl substituted with the substituents of (1); and
wherein R is3Is methyl, -CF3Phenyl, heteroaryl, phenylmethyl, or heteroarylmethyl.
9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is
1- (4-methoxy-benzenesulfonyl) -3- (2-amino-phenylmethanesulfonylamino) -1H-azepane-2-carboxylic acid;
1- (4-methoxy-benzenesulfonyl) -3- (phenylmethanesulfonylamino) -1H-azepane-2-carboxylic acid;
1- (4-chlorophenyl-benzenesulfonyl) -3- (phenylmethanesulfonylamino) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid;
1- (4-methoxy-benzenesulfonyl) -3- (2-nitrophenyl-methanesulfonylamino) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid;
1- (4-methoxy-benzenesulfonyl) -3- (phenylpropenoylsulfonylamino) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid;
3- (4-chlorobenzyloxycarbonylamino) -1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid; or
3- (3, 5-dichlorobenzyloxycarbonylamino) -1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid.
10. A pharmaceutical composition comprising a compound of claims 1-9 and a pharmaceutically acceptable carrier.
11. Use of a compound according to claims 1-9 for the preparation of a composition for the prevention or treatment of inflammation.
12. Use of a compound according to claims 1-9 for the preparation of a composition for the prevention or treatment of connective tissue degradation.
13. Use of a compound according to claims 1-9 for the preparation of a composition for the prevention or treatment of neuritis or angiogenesis dependence.
14. Use of a compound according to claims 1-9 for the preparation of a pharmaceutical composition for the prevention or treatment of the following diseases:
rheumatoid arthritis, osteoarthritis, osteopenia, periodontitis, gingivitis, corneal ulceration, epidermal ulceration, gastric ulceration, tumor metastasis, tumor onset, tumor growth, myelin degradation, cancer, psoriasis, retinal hyperplasia, neovascular glaucoma, ocular tumors, angiofibromas, hemangiomas, nephritis, pneumonia or restenosis.
HK01105515.4A 1997-12-19 1998-12-18 Carboxyl acid substituted heterocycles as metalloproteinase inhibitors HK1034964B (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US6820097P 1997-12-19 1997-12-19
US60/068,200 1997-12-19
US09/213,031 1998-12-16
US09/213,031 US6335329B1 (en) 1997-12-19 1998-12-16 Carboxylic acid substituted heterocycles, derivatives thereof and methods of use
PCT/US1998/027082 WO1999032452A1 (en) 1997-12-19 1998-12-18 Carboxyl acid substituted heterocycles as metalloproteinase inhibitors

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Publication Number Publication Date
HK1034964A1 HK1034964A1 (en) 2001-11-09
HK1034964B true HK1034964B (en) 2004-02-06

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