MXPA00006065A - Carboxyl acid substituted heterocycles as metalloproteinase inhibitors - Google Patents

Abstract

The present invention relates to metalloproteinase inhibitors of formula (I) or a pharmaceutically acceptable salt thereof for prophylaxis and treatment of inflammation, tissue degradation, cancer, fibrosis and related diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of inflammation, tissue degradation and related diseases. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.

Description

HETEROCICLES SUBSTITUTED WITH CARBOXYLIC ACID AS INHIBITORS OF THE ME TALOPROTE INASA FIELD OF THE INVENTION The present invention relates to inhibitors of the meth alloprotein and, more particularly, to novel compounds, compositions and methods for the treatment and prophylaxis of inflammation, tissue degradation and the like. The invention in particular relates to novel substituted heterocyclic carboxylic acid compounds, compositions containing such compounds and methods of using such compounds. The object of the invention also relates to processes for making such compounds, as well as to intermediates used in such processes.

BACKGROUND OF THE INVENTION Enzymes of metallopro teins, such REF: 121049 as colegenasas, stromelisinas and gelatinasas can contribute to the beginning or etiology of, or states of exacerbated ailments, which are related to, the degradation of connective tissue and the like. For example, matrix metallopro teinases, such as collagenases, stromelysins, and gelatinases, are thought to be involved in tissue disruption seen in rehumatoid arthritis; osteoarthritis; osteopenia (for example, osteoporosis); per iodont itis; gingivitis; corneal ulceration, epidermal gastric; and tumor metastasis, invasion and growth; in neuroinflammatory disorders such as myelin degradation (eg, multiple sclerosis); and in the conditions dependent on angiogenesis, such as arthritic conditions; Cancer; solid tumor growth; psoriasis; proliferative retinopathies; neovascular glaucoma; oculi tumors; angiofibromas; hemangiomas; nephritis; pulmonary inflammation; and restenosis.

WO 96/33172 discloses hydroxamic acid derivatives heterocycles of rings of 6-element N-arylsul fonyl and N-heα-arylsylsulfonyl substituted, such as N-arylsulfonylo and N-heteroarylsulfonyl-piperidinyl-2-hydroxamic acid compounds, and its preparation and use as inhibitors of matrix metallopro teinases and the production of TNF.

EP 606046 discloses hydroxamic acid derivatives heterocycles of substituted 5-6-membered N-het eroarylsul fonyl rings, such as N-arylsulphonyl and N-heteroarylsulphyl-piperidinyl-2-hydroxamic acid compounds and acid compounds N-arylsulfonyl and N-heteroarylsulfonyl-1, 2773, 4-tetrahydroisoquinolinyl-2-hydroxamic, preparation and use as inhibitors of the matrix meoproproteinases.

WO 97/18194 discloses certain cyclohexane and cyclic carboxylic acids and N-subsituted heterocyclic acids and their preparation and use as inhibitors of matrix metallopro teinases.

EP 803505 describes' N-fused aryl heterocycles optionally substituted and their preparation and use as inhibitors of metallopro-teinases.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to inhibitor compounds of the selected metalloproteinases, analogs and pharmaceutically acceptable salts and prodrugs thereof. The objective compounds are characterized as substituted heterocyclic carboxylic acid compounds. The compounds are used in the prophylaxis and treatment of inflammation, tissue degradation and related conditions. Therefore, the invention also encompasses pharmaceutical compositions and methods for the prophylaxis treatment of inflammation, tissue degradation and related conditions. The subject of the invention also relates to processes for the preparation of such compounds, as well as to intermediates employed in such processes. ~ DETAILED DESCRIPTION OF THE INVENTION In accordance with the present invention, a compound of the following formula I is provided (I) or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2; and n is 0, 1 or 2; R is (1) an alkyl, alkenyl, cycloalkyl or heterocyclyl radical optionally substituted by 1-3 radicals of -OH, OR3, -SR3, -S (0) R3, -S (0) 2R3 / -NR3R4, aryl , heteroaryl, cycloalkyl or heterocyclyl; or (2) an aryl radical optionally substituted by an optionally substituted heteroaryl or heterocyclyl radical of 5-6 elements in the ring which is optionally substituted by a phenyl radical or a monocyclic heteroaryl radical of 5-6 elements in the ring; or (3) a heteroaryl radical optionally substituted by an optionally substituted phenyl radical or a heteroaryl or monocyclic heterocyclic radical of 5-6 elements in the ring which is optionally substituted by a phenyl radical or a monocyclic heteroaryl radical of 5-6 elements in the ring; wherein the phenyl, aryl, heteroaryl, cycloalkyl and heterocyclyl radicals of (1), (2) and (3) are optionally substituted by 1-3 hydroxy radicals, OR3, -SR3, -S (0) R3, S ( 0) 2R 3 / -C (0) R 3, -NR R 4, amino, acanoi 1 amino, alkylsulphonylamino, alkoxy carboylamino, alkoxycarbonyl, cyano, halo, azido, alkyl or haloacyl; preferably, R1 is (1) a C C-C ?2 alkyl / C2-Ci2 alkenyl radical C2-Ci2 alkynyl, cycloalkyl or heterocyclyl optionally substituted by 1-3 radicals of -OH, OR3, -SR3, -S (0) R3, -S (0) 2R3, -C (0) R3, -NR3R4, aryl, heteroaryl, cycloalkyl, or heterocyclyl; or (2) an aryl radical optionally substituted by a heterocyclyl radical or an optionally substituted monocyclic heteroaryl of 5-6 elements in the ring which is optionally substituted by a phenyl radical or a monocyclic heteroaryl radical of 5-6 elements in the ring; or (3) a heteroaryl radical optionally substituted by an optionally substituted phenyl or a heterocyclyl radical or a 5-6-element monocyclic heteroaryl on the ring which is optionally substituted by a phenyl radical or a 5-6 element monocyclic heteroaryl radical at the ring; wherein the phenyl, aryl, heteroaryl, cycloalkenyl and heterocyclyl radicals of (1) (2) and (3) are optionally substituted by 1-3 radicals of -hydroxy, OR3, -SR3, -S (0) R3, -S (0) 2R3, -C (0) R ?, -NR3R4, amino, alkanoylamino Ci-Ce, to which 1 ful foní 1 amino C? ~ Cs, alkoxycarbonylamino Ci-Cs, alkoxycarbonyl Ci-Cs, cyano, halo, azido , Ci-Cß alkyl or Ci'-Cß haloalkyl of 1-3 halo radicals; more preferably R1 is (1) a C? -C? 2 alkyl / C ^ -C ^ alkenyl; C2-C2 alkynyl, cycloalkyl or heterocyclyl radicals optionally substituted by 1-3 radicals of -OH, -OR3, "-SR3, -S (0) R3, -S (0) 2R3, -C (0) R? , -NR3R4, aryl, heteroaryl, cycloalkyl or heterocyclyl, or (2) and an aryl radical optionally substituted by an optionally substituted monocyclic heteroaryl or heterocyclyl radical of 5-6 elements in the ring which is optionally substituted by a phenyl radical or a 5-6 ring monocyclic radical heteroaryl, or (3) a heteroaryl radical optionally substituted by an optionally substituted phenyl or a heteroaryl or monocyclic heterocyclyl radical 5-6 ring elements which is optionally substituted by a phenyl radical or a 5-6 ring monocyclic heteroaryl radical wherein the phenyl, aryl, heteroaryl, cycloalkyl and heterocyclyl radicals of (1), (2) and (3) are optionally substituted by 1-3 hydroxy-OR3 radicals , SR3, -S (0) R3, -S (0) 2R3, -C (0) R3, -NR3 R4, amino, C? -C alkanoylamide, C? -C4 alkylsulfonylamino, C2-C4 alkoxycarbonylamino, C4-4-alkoxycarbonyl, cyano, halo, azido, C? -C3 alkyl or C? -C haloalkyl radicals 1-3 halo; more preferably, R1 is (1) a C? -C? 2 alkyl radical optionally substituted by 1-3 radicals of -OH, -OR3, -SR3, -S (0) R3, -S (0) 2R3, -C (0) R3, NR3R4, aryl, heteroaryl, cycloalkyl or heterocyclyl; or (2) an aryl radical optionally substituted by an optionally substituted heteroaryl or heterocyclyl radical of 5-6 elements in the ring which is optionally substituted by a phenyl radical or a monocyclic heteroaryl radical of 5-6 elements in the ring; or (3) a heteroaryl radical optionally substituted by an optionally substituted phenyl or a 5-6-membered heterocyclic or heterocyclic radical in the ring, which is optionally substituted by a phenyl radical or a "monocyclic heteroaryl radical" of 5-6. elements in the ring, wherein the phenyl, aryl, heteroaryl, cycloalkyl and heterocyclyl radicals of (1), (2), and (3) are optionally substituted by ^ 1-3 hydroxy radicals, -OR3, -SR3, - S (0) R 3, -S ^ (0) _R 3, - C (0) R 3, -NR 3 R 4, amino, acetylamino, methylsulfonylamino, C 1 -C 4 alkoxycarbonylamino, C 1 -C 4 alkoxycarbonyl, cyano, halo, C 1 -C 6 alkyl or radicals -CF3; more preferably, R1 is (1) an alkyl radical C1-C12 optionally substituted by 1-3 radicals of -OH, -OR3, -SR3, -S (0) 2R3, -NR3R4, aryl, heteroaryl, cycloalkyl or heterocyclyl; or (2) an aryl radical optionally substituted by a heteroaryl or monocyclic heterocyclyl radical of 5-6 elements in the ring, which is optionally substituted by a phenyl or a radical. monocyclic heteroaryl radical of 5-6 elements in the ring; or (3) a heteroaryl radical optionally substituted by a phenyl radical or a monocyclic or heterocyclyl heteroaryl of 5-6 elements in the ring which is optionally substituted by a phenyl radical or a monocyclic heteroaryl radical of 5-6 elements in the ring; wherein the phenyl, aryl, heteroaryl, cycloalkyl and heterocyclyl radicals of (1), (2) and (3) are optionally substituted by 1-3 hydroxy radicals, -OR3, -SR3, -S (0) R3, - NR 3 R 4, amino, acetylamino, methylsulphonylamino, C 1 -C 4 alkoxycarbonylamino, C 1 -C 4 alkoxycarbonyl, cyano, halo, C 1 -C 6 alkyl or C 3 radicals; more preferably, R 1 is (1) a C 1 -C 4 alkyl radical substituted by 1-2 radicals of -OH, -OR 3, -NR 3 R 4, aryl or heteroaryl; or (2) an aryl radical optionally substituted by a monocyclic heteroaryl radical of 5-6"ring elements, or (3) a heteroaryl radical optionally substituted by a phenyl radical, wherein the phenyl, aryl and heteroaryl radicals of (1) ), (2) and (3) are optionally substituted by 1-2 hydroxy radicals, -OR3, -SR3, -S (0) R5, NR3R4, amino, acetylamino, methylsulphonylamino, alkoxycarbonylamino C? -C4 / C 1 -C 4 alkoxycarbonyl, halo, Ci-Cβ alkyl or -CF 3 radicals; more preferably, R1 are aryl or heteroaryl radicals optionally substituted by radicals 1-2 of hydroxy, -OR3, -SR3, -S (0) 2R3, RJR, amino, acetylamino, methylsulphonylamino, alkoxycarbonylamino C? -C4, alkoxycarbonylC? -C4, halo, C? -C3 alkyl or radicals -CF3; and ~ " more preferably, R1 is an aryl radical optionally substituted by hydroxy radicals 1-2, -OR3, -S (0) 2R3, -NR3R4, amino, acetylamino, methylsulfonylamino, halo, C? -C alkyl or -CF3 radicals; more preferably, R is a phenyl or biphenyl radical optionally substituted by 1-2 hydroxy radicals, -OR3, -S (0) 2R3 / -NR3R4, amino, acetylamino, methylsulphonylamino, halo, C? -C4 alkyl or radicals -CF3; more preferably, R1 is a phenyl or biphenyl radical optionally substituted by 1-2 hydroxy radicals, -OR3, halo, methyl or -CF3 radicals; Y provided that the total number of phenyl, aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in R1 is preferably 0-3, more preferably 0-2, most preferably 1-2; wherein each R is independently an alkyl, haloalkyl, aryl, heteroaryl, arylalkyl or heteroaryl 1-alkylating radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 'radicals of hydroxy, alkoxy, alkylthiol, amino, alkanoylamino, alkylsul phonylamino, alkyl sui finyl, alkyl sui fonyl, alkoxycarbonylamino, alkoxycarbonyl, cyano, halo, azido, alkyl, haloalkyl or haloalkoxy; preferably, each R is independently a C alkyl? -Ce, C? -C8 haloalkyl of 1-3 halo radicals, aryl radical, heteroaryl, arylC? -C4 alkyl or heteroarylC? ~ C4 alkyl, wherein the aryl and heteroaryl radicals are optionally substituted by radicals 1- 3-hydroxy, C 1 -C-alkoxy / C 1 -C 4 -alkyl, amino, C 1 -C 8 -alkanoylamino, alkylsulfonylamino C 1 -C > -, C 1 -C 4 alkylsulphonyl C 1 -C 0 alkoxycarbonylamino Ci-Ce, C 1 -C 6 alkoxycarbonyl, cyano, halo, azido, Ci-Cs alkyl, Ci-Cß haloalkyl of 1-3 halo radicals or Ci-Cs haloalkoxy of halo radicals 1-3; more preferably, each R is independently a C 1 -C 4 alkyl, C 1 -C 4 haloalkyl of 1-3 halo radicals, an aryl radical, heteroaryl, aryl C 1 -C 4 alkyl or heteroaryl C 1 -C 4 alkyl, wherein Aryl and heteroaryl radicals are optionally substituted by 1-3 hydroxyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, amino, C 1 -C 4 alkanoylamino, C 1 -C 4 alkylsulfonylamino, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkoxycarbonylamino C4, C 1 -C 4 alkoxycarbonyl, cyano, halo, azido, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl of l-3 halo or C 1 -C haloalkoxy radicals of 1-3 halo radicals; more preferably, each R3 is independently a C? ~C, -CF 3, aryl, heteroaryl, aryl-C?-C 4 alkyl or heteroaryl-C 1 -C 4 alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by radicals 1 -3-hydroxy, C1-C4 alkoxy, C1-C4 alkyldial, amino, acetylamino, me t-ilsul phonylamino, Cs-C4 alkylsulfonyl, C1-C4 alkoxycarbonylamino, C1-C4 alkoxycarbonyl, cyano, halo, C1.-C4 alkyl, - CF3, or -OCF3; more preferably, each R is independently un-adical C3-C4 alkyl, -CF, aryl, heteroaryl, aryl-C?-C2 alkyl or heteroaryl-C?-C2 alkyl, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, C1-C4 alkoxy, C1-C4 alkylthiol, amino, acetylamino, methylsulphonylamino, alkylsulfonyl Ci-C, alkoxycarbonylamino C1-C4, alkoxycarbonyl C1-C4, cyano, halo, alkoxy C? -C4, -CF3 or -OCFj, - more preferably, each R "is independently a" C 1 -C 4 alkyl radical, -CF 3, aryl, heteroaryl, aryl-C 1 -C 2 alkyl or heteroaryl C 1 -C 2 alkyl, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 hydroxy, alkoxy C radicals? -C2, alkylthiol C? -C, amino, acetylamino, me tilsul phylamino, alkylsulfonylamino C? ~ C, alkoxycarbonylamino C1-C4, alkoxycarbonyl C? -C4, halo alkyl C? -C2, _-CF3 or -OCF3; more preferably, each R ~ is independently a C1-C4 alkyl, -CF3, aryl, heteroaryl, arylmethyl or heteroarylmethyl radical; more preferably, each R3 is independently a C1-C4 alkyl, -CF3, phenyl, heteroaryl, phenylmethyl or heteroarylmethyl radical; most preferably, each R3 is independently a methyl radical, -CF3, phenyl, heteroaryl, phenethylmethyl or heteroarylmethyl; Y each R4 is independently a hydrogen or alkyl radical; preferably, each R4 is independently a hydrogen or Ci-Ce alkyl radical; more preferably, each R4 is independently a hydrogen or alkyl radical C? -C4; most preferably, each -R 'is independently a hydrogen methyl radical; Y RJ is a radical • C (0) -R31, -C (0) -OR30, • C (0) NR3ZR31 S (0) -RJU or -S (0) 2NR3-R3J1 preferably R, 11 is a -C radical (0) -R 3J11 or -S (0) 2 -R3? or -S (0): NRJ "R; wherein R5 and R6 are each independently a hydrogen or alkyl radical; preferably, R5 and R6 are each independently a hydrogen radical or C? -C4 alkyl; and more preferably, R5 and R6 with each a hydrogen radical; or CR5-CR6 is C = C (double bond carbon atoms); wherein R9 and R10 are each independently -B-A, provided that that combined total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in R-R 10 and R 11 is 0-3, preferably Q-2; wherein each B is independently a (1) link; (2) alkyl, alkenyl or alkynyl radical. optionally substituted by (a) 1-3 amino, alkylamino, dialkylamino, campylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano or halo radicals, and / or (b) 1-2 heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, halo, alkyl, haloalkyl or haloalkoxy radicals; (3) heterocyclyl radical optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio cyano, alkyl, haloalkyl or haloalkoxy radicals; or (4) aryl or heteroaryl radical optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, halo, alkyl, haloalkyl or haloalkoxy radicals; preferably, each B is independently one (1) bond; (2) C 1 -C 8 alkyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl radical, optionally substituted by (a) 1-3 amino, C 1 -C 4 alkylamino, di (C 1 -C 4) amino, alkanoylamino C1 radicals -C5, carbonylamino (C1-C4 alkoxy), alkylsulfonylamino C? ~. C, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano or halo, and / or (b) 1-2 heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 amino, C 1 -C 4 alkylamino radicals, di (C 1 -C 4 alkyl) amino, C 1 -C 5 alkanoylamino, carbonylamino (C 1 -C 4 alkoxy), C 2 -C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy / C 1 -C 4 alkylthio, cyano, halo, C 1 -C 6 alkyl C4, C1-C4 haloalkyl radicals 1-3 halo or C1-C4 haloalkoxy of halo radicals 1 -; 3 (heterocyclyl radical optionally substituted by 1-3 amino, C 1 -C 4 alkylamino, di (C 1 -C 4) alkyl, amino, C 1 -C 5 alkanoylamino, carbonylamino (C 1 -C 4) alkoxy, alkylsulfonylamino C x -C, radicals hydroxy, C 1 -C 4 alkoxy, C 3 -C 4 alkylthio, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl of 1-3 halo radicals or C 1 -C 4 haloalkoxy of 1-3 halo radicals, or (4) aryl radical or heteroaryl optionally substituted by 1-3 amino, alkylamino radicals C1-C4, di (C1-C4 alkyl) amino, C1-C5 alkanoylamino, carbonylamino (C1-C4 alkoxy), alkylsulfonylamino C? C4, hydroxy, C1-C4 alkoxy, C? -C4 alkylthio, cyano, halo, C1.-C4 alkyl, C? -C8 haloalkyl radical 1-3 halo or C 1 -C 8 haloalkoxy of 1-3 halo radicals; more preferably, each B is independently one (1) bond; (2) C 1 -C 8 alkyl radical optionally substituted by (a) an amino radical, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, C 1 -C 5 alkanoylamino, carboni lamino (C 1 -C 4 alkoxy), C 1 -C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano and / or (b) 1-3 halo radicals, and / or (c) 1-2 heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 amino, C1-C4 alkylamino, di (C? -C4) alkyl amino radicals , C 1 -C 5 alkanoylamino, carbonylamino (C 1 -C 4 alkoxy), C 1 -C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl radical 1 3 halo or C1-C4 haloalkoxy radicals 1-3 halo; (3) heterocyclyl radical; or (4) aryl or heteroaryl radical optionally substituted by 1-3 moieties of amino, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, C 1 -C 5 alkanoylamino, carbonylamino (C 1 -C 4 alkoxy), alkylsulfonylamino C 1 - C 4 / hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, C 1 -C 4 alkyl / C 1 -C 4 haloalkyl of 1-3 halo radicals or C 1 -C 4 haloalkoxy of 1-3 halo radicals; more preferably, each B is independently one (1) bond; (2) C 1-6 alkyl radical optionally substituted by (a) an amino radical, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, C 1 -C 5 alkanoylamino, carbonylamino (C 1 -C 4 alkoxy), Alkylsulfonylamino C? ~ C4 / hydroxy, C1-C4 alkyl, C1-C4 alkylthio, cyano and / or (b) 1-3 radicals of halo, and / or (c) 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by amino radicals 1-3, alkylamino C? -C, di (C? - C4 alkyl) amino, C1-C5 alkanoylamino, carbonylamino (C1-C4 alkoxy), alkylsulfonylamino C? ~ radicals. C4, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl, -CF3 or -0CF3; (3) heterocyclyl radical; or (4) aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino radicals, di (Ci-C4 alkyl) amino, Ci-Cs alkanoylamino / carbonylamino (C1-C4), C1-C4 alkylsulfonylamino , hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl, -3CF3 or 0CF3; more preferably, each B is independently one (1) bond; (2) C 1 -C 4 alkyl radical optionally substituted by (a) an amino radical, C 1 -C 2 alkylamino, di (C 1 -C 2 alkyl) amino, C 1 -C 2 alkanoylamino / carbonylamino (C 1 -C 4 alkoxy), hydroxy , C?-C2 alkoxy and / or (b) halo 1-2 radicals, and / or (c) a heterocyclyl, aryl or heteroaryl radical optionally substituted by 1-2 amino radicals, alkylamino C?-C2 radicals, di alkyl (C? -C2) alkylamino, alkanoylamino C? ~ C2, carbonylamino (C1-C4) alkylsulfonylamino Ci-C2, hydroxy, C? -C, alkylthio C? ~ C2, halo, C1-C4 -CF3 or -OCF3; (3) heterocyclyl radical; or (4) aryl or heteroaryl radical optionally substituted by 1-2 radicals amino, alkylamino radicals C? -C2, di (alkyl Cyclamen, alkanoylamino d.-C2 / carbonylamino (C1-C4) alkylsulfonylamino C? -C2 / hydroxy, C? -C2 alkoxy, C? -C2 alkylthio, halo, C? -C4 alkyl, -CF3 or -0CF3; more preferably, each B is independently a (1) bond or C 1 -C 4 alkyl radical; or (2) aryl or heteroaryl radical optionally substituted by a radical of amino, alkylamino radicals C? -C2, di (alkyl C? ~ C2) alkylamino, alkanoylamino C? -C2 / carbonylamino (C1-C4) alkylsulfonylamino Ci- C2, hydroxy, C? -C2 alkoxy / C2-alkylthio, halo, C1-C4 alkyl, -CF3 or -OCF3; Y more preferably, each B is independently a bond, C 1 -C 4 alkyl, aryl or heteroaryl radical; wherein each A is independently a 1) hydrogen radical; radical halo, cyano 30 nitro; (3) radical -C < 0) -R, -C (0) -OR, -C (0) -R R O -C (NR) -NR R; (4) radical -O 31, -0-C. { 0) -NR32R31 OR -0-C (O) -NR33-S (O) 2-R3 ° (5) rad ± cal -SR31, -S (0) -R3 °, -S (0.}. 2 -R3 °, -S { 0) 2- 32 31, -SiO > 2-NR33-C < 0) -R31, -S (0) 2-NR33-C (0) -OR30 OR -S (0) 2-NR33- 32 31, 32 3J 33 31 33 C (0) -NR R; or radical (6) -MR R, -KR -C (0) -R, -NR-30 33,, 32 31 33 32 32 31 33 C < 0) -0R, -NR -C (0) -NR R, -NR -C. { NR) -NR R, -NR - 30 33 32 31 S (0) -R or -NR -S (0) 2-NR R preferably, each A is independently one (1) hydrogen radical; (2) radical halo, cyano or y-, and-. 30 nitro; (3) radical ~ C (0) -R, 31 32 31 32, 32 31 -C (0) -0R, -C (0) -NR R O -C < NR) -NR R; (4) radical -OR31, -0-C (0) -R31, -0-C (0) -NR32R31 O -O-C (O) -NR33 ~ S (0) 2- 30 31 30 30 R; (5) radical -S, -S (O) -R, -S (0) 2-R, -S (0) 2- 32 31 33 31 33 30 NR R, -S (0> 2-KR - C (0) -R, -S (0) 2-NR -C (0) -OR or -33 32 31, _ "32 31 33 S (0) 2-NR -C (0) -NR R; radical (6) -NR R, -NR - 31 33 30 33 _,, 32 31 33 32 C { 0) -R, -NR-CÍO) -OR, -NR -C (0) -NR R, -NR -C. { NR > - 32 31 33 30 33 32 31 NR R, -NR -5 (0.}. 2-R O -NR -S (0) 2-NR R, - more preferably, each A is independently a hydrogen, halo, cyano, nitro, radical -C (O) -R30, • C (0) • OR31, -C (O) -NR32R31, -. , ~ 32, 32 31 31, 31 32 31 31 -C (NR) -NR R, -OR, -0-C (0) -R, -0-C. { 0) -NR R, -SR X 30 32 31 32 31 -S (0) -R3 °, -S (0) 2-R "-S { 0) 2-NR R, -NR R, -NR33 -C { 0) - 31 33, 30 33 32 31 33 32 R, -NR -C (0) -OR f -NR -C (0) -NR R, -NR -C (NR) - 32 31 33, 30 33 32 31 NR R, -NR -S (0) 2-R O. -NR -S <0) 2-NR R; more preferably, each A is independently a hydrogen radical, halo, -C (0) -R30, -C (O) -OR 3'1 • C (O: -NR32R31 -C (NR32) • NR3 R31 31 31 30", 32 31 32 31 33 -OR, -SR, -S (0) 2-R, -S < 0) 2-NR R, -NR R, -NR- 31 33 30 33 _, 32 31 33 CÍO) -R, -NR -C < 0) -OR, -NR -C (0) -NR R, -NR -S. { 0) 2- 30 33 32 32 R O -NR -S. { 0 > 2-NR R; more preferably, each A is independently a hydrogen radical, halo, -C (0) -R30, -C (O) -NR3IR31, -C (NR32) -NR3 R31, -OR31, • SR31, • S (0) 2-R3p, • S (O) 2-NR3 R31, -NR32R31, -NR33-C (O) -R31-NR33-S (0) 2_R 0; and more preferably, each A is independently a hydrogen, halo, -C (0) -R30 or -C (0) -NR32R31 radical; wherein each R3tI is independently (1) alkyl, alkenyl or alkynyl radical optionally substituted by 1-3 radicals of -C02R34, amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonyl, N- (alkoxycarbonyl] -N- (alkyl) amino radicals, aminocarbonyl, alkylsulfonyl amino, hydroxy, alkoxy, alkylthio, alkylsulphonyl, alkylsulfonyl, cyano, halo or aralkoxy, arylalkyl, arylalkylsulfonyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl radicals are optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamido, alkanoyl, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl, haloalkyl or haloalkoxy radicals; (2) heterocyclyl radical optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonyl radicals no, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, cyano, alkyl, haloalkyl or haloalkoxy; or (3) optionally substituted aryl or heteroaryl radicals by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxy carbonylamino, alkylsulfonylamino, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, cyano, halo, azido, alkyl, haloalkyl or haloalkoxy radicals; preferably, each R30 is independently (1) a C? -C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl radical optionally substituted by 1-3 radicals of -C02R34, amino, alkylamino C? -C, di (alkyl) radicals C? -C) amino, C1-C5 alkanoylamino, carbonylamino (C1-C4 alkoxy), N- ((C1-C4 alkoxy) carbonyl) -N- (C1-C4 alkyl) amino, aminocarbonylamino, alkylsulfonylamino CJ.-C, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, cyano, halo, aryl-C 1 -C 4 alkoxy, ary lo-C 1 -C 4 alkyl, aryl-alkylsulfonyl C 1 -C 4 , C3-C8 cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl radicals are optionally substituted by 1-3 amino, C1-C4 alkylamino, di (C1-C4 alkyl) amino, C1-alkanoylamino radicals -C5, carbonylamino (C1-C4 alkoxy), alkylsulfonylamino Ci-C4, C1-C5 alkanoyl, carbonyl (C1-C4 alkoxy), hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, alkylsulfonyl C1-C4, cyano, halo, C 1 -C 4 -alkyl C 1 -C 4 alkyl, 1-3 halo radicals or C 1 -C 4 haloalkoxy of 1-3 halo radicals; (2) heterocyclyl radical optionally substituted by 1-3 moieties of amino, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, C 1 -C 5 alkanoylamino, carbonylamino (C 1 -C 4 alkoxy), C 1 -C 4 alkylsulfonylamino, carbonyl ( C 1 -C 4 alkoxy), hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl of 1-3 halo radicals; or (3) aryl or heteroaryl radical optionally substituted by 1-3 moieties of amino, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, C 1 -C 5 alkanoylamino, carbonylamino (C 1 -C 4 alkoxy), alkylsulfonylamino Ci-C 4, carbonyl (C 1 -C 4 alkoxy), hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, azido, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl of 1-3 halo radicals or C 1 -C 4 haloalkoxy of radicals 1 -3 halo; more preferably, each R30 is independently (1) C? -C6 alkyl radical optionally substituted by 1-3 radicals of -C02R3 '!, free radicals, C1-C4 alkylamino, di (C1-C4 alkyl) amino, C1-C5 alkanoylamino, carboni lamino (C1-C4 alkoxy), N- ((C1-C alkoxy) carbonyl) -N- (C-alkyl) ~ C4) amino, aminocarbonyl-amino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylaryl, cyano, halo, aryl-C1-C4 alkoxy -C4, aryl-alkylthio Cj.-C4, aryl-C1-C4alkylsulfonyl, C3-C8cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl radicals are optionally substituted by radicals 1-3 of amino, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, C 1 -C 5 alkanoylamino, carbonylamino (C 1 -C 4 alkoxy), C 1 -C 4 alkylsulfonylamino, C 1 -C 5 alkanoyl, carbonyl (to C 1 -C 4 coxi) , hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, cyano, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl radical 1-3 halo or C1-C haloalkoxy of 1-3 halo radicals; (2) heterocyclyl radical optionally substituted by 1-3 amino, C1-C4 alkylamino, di (C1-C4 alkyl) amino, C1-C5 alkanoylamino, carbonylamino (C1-C4 alkoxy), alkylsulfonylamino Ci-C4, carbonyl (alkoxy) radicals C? -C4), hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals or haloalkoxy-C1-C4 of 1-3 halo radicals; or (3) aryl or heteroaryl radical optionally substituted by 1-3 moieties of amino, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, C 1 -C 5 alkanoylamino, carbonylamino (C 4 -C 4 alkoxy), alkylsulfonylamino C? -C4, carbonyl (C1-C4 alkoxy), hydroxy, C? -C4 alkoxy, C? -C4 alkylthio, cyano, halo, azido, C1-C4 alkyl, C? -C4 haloalkyl of 1-3 halo radicals or C1-C4 haloalkoxy of 1-3 halo radicals; more preferably, each R30 is independently (1) C? -Cd alkyl radical optionally substituted by 1-3 radicals of -C02R34, amino, C? -C4 alkylamino, di (C? -C4) amino, alkanoylamino C? Cs, carbonylamino (C? -C4 alkoxy), N- ((C? -C) alkoxycarbonyl) -N- (C? -C4 alkyl) amino, aminocarbonyl-amino, alkylsulfonylamino C? -C4, hydroxy, alkoxy C? -C, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 4 -C 4 alkylsulfonyl, cyano, halo, aryl-C 1 -C alkoxy, aryl-alkyl thio C 4 -C 4, aryl-C 1 -C 4 alkylsulphon, cycloalkyl C3-C8, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl radicals are optionally substituted by 1-3 amino radicals, alkylamino C? -C4, di (C? -C) alkyl amino radicals, C? -C5 alkanoylamino, carbonylamino (C? -C4 alkoxy), C? -C4 alkylsulfonylamino, C-Cs alkanoyl, carbonyl (C? -C4 coxy), hydroxy, C? -C alkoxy, C? -C4 alkylthio, C 1 -C alkylsulfinyl, C 1 -C 4 alkylsulfonyl, cyano, halo, al C1-C4, -CF3 or -0CF3; (2) heterocyclyl radical optionally substituted by 1-3 moieties of amino, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, C 1 -C 4 alkanoylamino, carbonylamino (C 1 -C 4 alkoxy), C 1 -C 4 alkylsulfonylamino , carbonyl (C? -C alkoxy), hydroxy, C? -C4 alkoxy, C? -C4 alkylthio, cyano, C? -C4 alkyl, C? 4 haloalkyl of 1-3 halo radicals or -OCF3; or (3) aryl or heteroaryl radical optionally substituted by 1-3 amino radicals, C 1 -C 4 alkylamino radicals, di (C 1 -C) alkyl amino, C 1 -C 5 alkanoylamino, carbonylamino (C 1 -C 6 alkoxy), C 1 -C 4 alkylsulfonylamino, carbonyl (C 4 -C 4 alkoxy), hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, C 1 -C 4 alkyl, -CF 3 or -OCF 3; more preferably, each R30 is independently (1) a -CF3 radical or C? -C4 alkyl optionally substituted by 1-2 radicals of -C02R34, amino, alkylamino C? -C2, di (C? -C2) alkyl amino, C alca-C2 alkanoylamino, carbonylamino (C?-C) alkoxy, N - ((C?-C4 alkoxy) carbonyl) -N- (C?-C) alkyl, hydroxy, C?-C 4 alkoxy, or aryl- C 1 -C 2 alkoxy / heterocyclyl, aryl or heteroaryl, wherein the heterocyclyl, aryl and heteroaryl radicals are optionally substituted by 1-3 amino radicals, C 1 -C 2 alkylamino radicals, di (C 1 -C 2 alkyl) amino, alkanoylamino C -C2, carbonylamino (C?-C4 alkoxy), C? -Cs alkanoyl, carbonyl (C?-C) alkoxy, hydroxy, C?-C / halo alkoxy, C?-C 4 alkyl, -CF 3 or -0CF 3; (2) heterocyclyl radical optionally substituted by 1-2 carbonyl radicals (C 1 -C 4 alkoxy) hydroxy or C 1 -C 4 alkyl; or (3) aryl or heteroaryl radicals optionally substituent by amino 1-2 radicals, C 1 -C 2 alkylamino radicals, di (C 2 -C 2 alkyl) amino, C 1 -C 2 alkanoylamino, hydroxy, C 2 -C 2 alkoxy, halo , C 1 -C 4 alkyl, -CF 3 or -OCF 3; more preferably, each R 30 is independently (1) heterocyclyl radical optionally substituted by 1-2 carbonyl radicals (C 4 -C 4 alkoxy), hydroxy or C 1 -C 4 alkyl; or (2) heteroaryl radicals optionally substituted by amino 1-2 radicals, C -C2 alkylamino radicals, di (C? -C2 alkyl) amino, C? -C2 alkanoylamino, hydroxy, C? -C2 alkoxy, halo, C-alkyl -C, -CF3 or -0CF3; and more preferably, each R 30 is independently a heterocyclyl radical optionally substituted by C 1 -C 4 alkyl; wherein each R31 is independently hydrogen radical or (1) alkyl, alkenyl or alkynyl radical optionally substituted by 1-3 radicals of -C02R34, amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, N- (alkoxycarbonyl) -N- (alkyl) radicals amino, aminocarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo or aralkoxy, arialkyl thio, arylalkylsulfoyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl radicals are optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsul phonylamine, alkanoyl, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl, haloalkyl or haloalkoxy radicals; (2) heterocyclic radical optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsul fonylamino alkoxycarbonyl, hydroxy, alkoxy, alkylthio, cyano, alkyl, haloalkyl or haloalkoxy radicals; or (3) aryl or heteroaryl radical optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, cyano, halo, azido, alkyl, haloalkyl or haloalkoxy radicals; preferably, each R31 is independently hydrogen radical or (1) C? -Ca alkyl radical, C2-C8 alkenyl or C2-C8 alkynyl optionally substituted by 1-3 radicals of -CQ2R34, amino, alkylamino C? -C4 / di radicals ( C?-C 4 alkyl) amino, C?-C alca alkanoylamino, carbonylamino (C?-C) alkoxy, N- ((C?-C) alkoxycarbonyl) -N- (C 1 -C 4 alkyl) amino, aminocarbonylamino, alkylsulfonylamino C ? -C, hydroxy, C? -C4 alkoxy, C? -C alkylthio, C? -C alkylsulfinyl, C? -C4 alkylsulfonyl, cyano, halo, aryl-C? -C4 alkoxy / aryl-alkyl? T? C? -C4, aryl-alkylsul fonyl C? -C, C3-C8 cycloalkyl / heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl radicals are optionally substituted by 1-3 amino, alkylamino C? -C radicals , di (C 1 -C 4 alkyl) amino, C 1 -C 4 alkanoylamino, carbonylamino (C 1 -C 4 alkoxy), C 1 -C 4 alkylsulfonylamino, C 1 -C 4 alkanoyl, carbonyl (to C 1 -C coxy), hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C alkylsulfinyl 4, C 1 -C 4 alkylsulfonyl, cyano, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl of 1-3 halo radicals or C 1 -C 4 haloalkoxy of 1-3 halo radicals; (2) heterocyclyl radical optionally substituted by 1-3 moieties of amino, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, C 1 -C 5 alkanoylamino, carbonylamino (C 1 -C 4 alkoxy), C 1 -C 4 alkylsulfonylamino , carbonyl (C 1 -C 4 alkoxy), hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl of 1-3 halo radicals or C 1 -C haloalkoxy radicals; or (3) aryl or heteroaryl radical optionally substituted by 1-3 moieties of amino, C? -C alkylamino, di (C? -C4 alkyl) amino, C? -C5 alkanoylamino, carbonylamino (C? -C4 alkoxy), alkylsulfonylamino C 1 -C 4 carbonyl (C 1 -C 6 alkoxy), hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio cyano, halo, azido, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl radical 1-3 halo or C 1 -C 4 haloalkoxy of 1-3 halo radicals; more preferably, each R is independently hydrogen radical or (1) C? -C6 alkyl radical optionally substituted by 1-3 radicals of -C02R34, amino, alkylamino C -C, di (C? -C4) amino, alkanoylamino- C? -C5, carbonylamino (C? -C alkoxy), N- ((C? -C4 alkoxy) carbonyl) -N- (C? -C4 alkyl) amino, aminocarbonyl, alkylsulfonylamino C? -C, hydroxy, alkoxy C C 4, C 1 -C 4 alkylthio, C 4 -C alkylsulfinyl, C 1 -C 4 alkylsulfonyl, cyano, halo, aryl C 1 -C 4 alkoxy, arylalkyl 1 t C 1 -C 4, aryloalkyl 1 fonilo C? ~ C4, C3-Ca cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl radicals are optionally substituted by 1-3 amino, C? -C4 alkylamino, di (C) alkyl radicals ? -C) amino, C? -C5 alkanoylamino, carbonylamino (C? -C4 alkoxy), C? -C4 alkylsulfonylamino, C? -C5 alkanoyl, carbonyl (C? -C4 alkoxy), hydroxy, C? -C alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 4 -C 4 alkylsulfonyl, cyano, halo, C? -C alkyl, C? -C haloalkyl of halo radicals of 1-3 or haloalkoxy C? -C4 of radicals 1-3 halo; (2) heterocyclyl radical optionally substituted by 1-3 moieties of amino, alkylamino C? -C, di (C? -C) alkyl amino, alkanoylamino C? -Cs, carbonylamino (C? -C4 alkoxy), alkylsulfonylamino C? C4, carbonyl (C? -C4 alkoxy), hydroxy, C? -C4 alkoxy, C? -C4 alkylthio, cyano, C? -C alkyl, C? -C4 haloalkyl of 1-3 halo radicals or haloalkoxy C? of radicals 1-3 halo; or (3) aryl or heteroaryl radical optionally substituted by 1-3 moiety of amino, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, C 1 -C 5 alkanoylamino, carbonylamino (C 1 -C 4 alkoxy), alkylsulfonylamino C? -C4, carbonyl (CX-C4 alkoxy) A hydroxy, C? -C4 alkoxy, C? -C4 alkylthio, cyano, halo, azido, C? -C4 alkyl, haloalkyl C? 4 radicals 1-3 halo or C1-C4 haloalkoxy of 1-3 halo radicals; more preferably, each R31 is independently hydrogen radical or (1) C? -C6 alkyl radical optionally substituted by 1-3 radicals of -C02R34, amino, C? -C4 alkylamino, di (C? -C4) amino, alkanoylamino C? -C5, carbonylamino (C1-C4 alkoxy), N- ((d-C4 alkoxy) carbonyl) -N- (C? -C4 alkyl) amino, aminocarbonylamino, alkylsulfonylamino C? -C4, hydroxy, C? Alkoxy? C 4 / alkylthio d -d, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, cyano, halo, aryl-C 1 -C 4 alkoxy, arylo-alkyl thio C 1 -C, aryl-alkylsulfoyl C C4, C3-C8 cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl radicals are optionally substituted by 1-3 amino radicals, C? -C4 alkylamino radicals, di (C? -C4 alkyl) amino, C?-C5 alkanoylamino, carbonylamino (C -C4 alkoxy), C alqu-C alkylsulfonylamino, C 1 -C 5 alkanoyl, carbonyl (C?-C) alkoxy, hydroxy, C -C4 alkoxy, Cilt-C 4 alkylthio, C 1 -C 4 alkylsulfinyl / alkylsulfonyl C? -C4, cyano halo, C? -C4 alkyl, -CF3 or -OCF3; (2) heterocyclyl radical optionally substituted by 1-3"radicals of amino, C? -C4 alkylamino, di (C? -C) alkyl amino, C? -C5 alkanoylamino, carbonylamino (C? -C4 alkoxy), alkylsulfonylamino C? - C4, carbonyl (C? -C alkoxy), hydroxy, C? -C4 alkoxy, C? -C4 alkylthio, cyano, C? -C4 alkyl, haloalkyl C? -C2 of 1-3 halo radicals or OCF, or (3) aryl or heteroaryl radical optionally substituted by 1-3 amino radicals, C 1 -C alkylamino radicals, di (C 1 -C 4 alkyl) amino, C 1 -C 5 alkanoylamino, carbonylamino (C 1 -C alkoxy) ), C 1 -C 4 alkylsulfonylamino, carbonyl (C 1 -C 4 alkoxy), hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, C 1 -C 4 alkyl, -CF 3 or -OCF 3; more preferably, R * 1 is independently hydrogen radical or (1) -CF3 radical or C? -C4 alkyl optionally substituted by 1-2 hydroxy, C? -C2 alkoxy or aryl C? -C2 alkoxy radicals, aryl radicals or heteroaryl, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 amino radicals, C 1 -C 2 alkylamino radicals, di (C 1 -C 2 alkyl) amino, C 1 -C 2 alkanoylamino, carbonylamino (C 1 -C 4 alkoxy) ), C? -C5 alkanoyl, carbonyl (C? -C4 alkoxy), hydroxy, C? -C4 alkoxy, halo, C? -C4 alkyl, -CF3 or -OCF?; or (2) aryl or heteroaryl radical optionally substituted by amino 1-2 radicals, C 1 -C 2 alkylamino radicals, di (C 1 -C 2) alkyl amino, C 1 -C 2 alkanoylamino, hydroxy, C 2 alkoxy, halo, C 1 -C 4 alkyl, -CF 3 or -OCF 3; Y more preferably, each R31 is independently a hydrogen radical or (1) -CF radical, or C? -C4 alkyl optionally substituted by 1-2 aryl radicals or heteroaryl radicals; or (2) aryl or heteroaryl radical; wherein each R 32"is independently (1) a hydrogen radical, (2) alkyl, alkenyl or alkynyl radical optionally substituted by 1-3 amino radicals, alkylamino, dialkylamino, hydroxy, alkoxy, alkylthio, cyano or halo radicals; 3) aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or cycloalkylalkyl optionally substituted by 1-3 amino, alkylamino, dialkylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl, haloalkyl or haloalkoxy radicals; more preferably, each R32 is independently (1) hydrogen radical; (2) C 1 -C 8 alkyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl optionally substituted by 1-3 amino radicals, C 1 -C 4 alkylamino radical, di (C 1 -C 4 alkyl) amino, hydroxy, C alkoxy ? -C, alkylthio C? -C4, cyano or halo; or (3) aryl, heteroaryl, aryl-C-alkyl, heteroarylalkyl C? -C4, heterocyclyl, heterocyclyl-C? -C-cycloalkyl, C3-Ca cycloalkyl or C3-Cs-cycloalkyl-C? -C4 alkyl optionally susbstituted by 1-3 amino, alkylamino C? -d, di (C? -C4) amino, hydroxy, C? -C4 alkoxy, C? -C4 alkylthio, cyano, C? -C4 alkyl, C? -C haloalkyl radicals of radicals 1-3 halo or C 1 -C 4 haloalkoxy of 1-3 halo radicals; more preferably, each R 32 is independently a hydrogen or C 1 -C 4 alkyl radical; and more preferably, each R32 is independently a hydrogen or methyl radical; wherein each R33 is independently one (1) hydrogen radical; (2) alkyl radical optionally substituted by a heterocyclyl, aryl or heteroaryl radical which is optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkyl sui phonylamino, "~ hydroxy, alkoxy, alkylthio, alkylsulfinyl radicals , alkylsulfonyl, cyano, halo, alkyl, haloalkyl or haloalkoxy, or (3) heterocyclyl, aryl or heteroaryl radical optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl radicals , alkylsulfonyl, cyano, halo, alkyl, haloalkyl or haloalkoxy; preferably, each R is independently (1) hydrogen radical; (2) C 1 -C 4 alkyl radical optionally substituted by a heterocyclic, aryl or heteroaryl radical which is optionally substituted by 1-3 amino, C 1 -C 4 alkylamino, di (C 1 -C 4) amino, radicals, C 1 -C 5 alkanoylaminocarbonylamino (C 1 -C alkoxy), C 1 -C 4 alkylsulfonylamino, hydroxy, C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, cyano, halo, C alkyl ? -C4, C? -C4 haloalkyl of 1-3 halo radicals or C? -C4 haloalkoxy of 1-3 halo radicals; or (3) heterocyclyl, aryl or heteroaryl radical optionally substituted by 1-3 amino, C 1 -C 4 alkylamino, di (C 1 -C 4) amino, alkanoylamino Ci-Cs, carbonylamino (C 1 -C 4) alkoxy, alkylsulfonylamino C radicals ? C, hydroxy, C? -C4 alkoxy, C? -C4 alkylthio, C? -C4 alkylsulfinyl, C? -C4 alkylsulfonyl, cyano, halo, C? -C4 alkyl, C? -C haloalkyl radicals 1-3 halo or C 1 -C 4 haloalkoxy of 1-3 halo radicals; more preferably, each R33 is independently a hydrogen or C? -C4 alkyl radical; and most preferably, each R33 is independently a hydrogen or methyl radical; Y wherein each R34 is independently hydrogen, alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl radical, wherein the aryl and heteroaryl radicals are optionally "susbtied by 1-3 amino, alkylamino, dialkylamm, alkanoylamino, alkoxy carbonylamino, alkylsulfonylamino, radicals, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl, haloalkyl or haloalkoxy; preferably, each R34 is independently a hydrogen radical or C? -C4 alkyl, aryl, heteroaryl, arylC? -C4 alkyl or heteroarylC? -C4 alkyl, wherein the aryl and heteroaryl radicals are optionally substituted by radicals 1- 3 of amino, alkylamino C -C 4, di (C 1 -C 4 alkyl) amino, 1-C 5 alkanoylamino, carbonylamino (C 1 -C 4 alkoxy), C 1 -C 4 alkylsulfonylamino, hydroxy, C 1 -C alkoxy, C 1 alkylthio -C, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, cyano, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl of 1-3 halo radicals or C 1 -C 4 haloalkoxy of 1-3 halo radicals; more preferably, each R34 is independently a hydrogen or C? -C4 alkyl radical; and most preferably, each R34 is independently a hydrogen or methyl radical.

The symbols used previously have the following meanings: R -NR- i. -S. { 0) 2- V For example -NR33-C (NR32) -NR32R31 = -0-C (0) -NR33-S. { 0) 2-R30 = An aryl radical optionally substituted by a monocyclic or heterocyclic heteroaryl radical or optionally substituted by 5-6 elements in the ring which is optionally substituted by a phenyl radical or a 5-6-membered monocyclic heteroaryl radical in the ring means a radical aryl which is optionally substituted by (a) a menarocyclic heteroaryl radical of 5-6 ring elements optionally substituted by a phenyl radical or a monocyclic heteroaryl radical of 5-6 elements in the ring, or (b) a monocyclic heterocyclyl radical of 5-6 elements in the ring optionally substituted by a phenyl radical or a monocyclic heteroaryl radical of 5-6 elements in the ring.

A heteroaryl radical optionally substituted by a phenyl radical or a monocyclic or heterocyclyl heteroaryl of 5-6 elements in the ring which is optionally substituted by a phenyl radical or a monocyclic heteroaryl radical of 5-6 elements in the ring means a heteroaryl radical in the which is optionally substituted by (a) a phenyl radical optionally substituted by a fyl radical or a monocyclic heteroaryl radical of 5-6 elements in the ring; (b) a monocyclic heteroaryl radical of 5-6 elements in the ring optionally substituted by a phenyl radical or a monocyclic heteroaryl radical of 5-6 elements in the ring; or (c) a monocyclic heterocyclyl radical of 5-6 ring elements optionally substituted by a phenyl radical or a monocyclic heteroaryl radical of 5-6 elements in the ring.

The compounds of this invention generally have different asymmetric centers and are presented in the form of racemic mixtures. This invention is proposed to encompass racemic mixtures, partially racemic mixtures and separate enantiomers and diastereomers. Preferably, the absolute configuration of the carboxylic acid group is (R). Preferably, the relative configuration of the carboxylic acid group and -NRX1R33 is cis, ie, the carboxylic acid and -NR11R33 are the same face of the ring system. The compounds of interest include the following: 3- (Phenylmethylsulfonylamino) -1- (4-methoxyphenylsulphyl) azepane-2-carboxylic acid 3- ((2-Amino-phenyl-1) -methyl-sulfonylamino) -1- (4-methoxyphenylsulphyl) to z-2-carboxylic acid Cis-1- (4-methoxy-benzenesul fonyl) -3- (phenylmethanesulfonylamino) -heptamethyleneimino-2-carboxylic acid Trans-1- (4-methoxy-benzenesul fonyl) -3- (phenylmethanesulfonylamino) -1- (4-methoxy-b-encensul fonil) -lH-azepane-2-carboxylic acid 3-Amino-l- (4-methoxyphenylsulfonyl) -2, 3, 4, 7-tetrahydro-lH-azepine-2-carboxylic acid 3- (Methylsulfonylamino) -1- (-methoxyphenylsulphyl) -2, 3, 4, 7- terahydroyl-H-azepine-2-carboxylic acid 3- (Phenylmethylsulfonylamino) -1- (A-methoxyphenylsulfonyl) -2, 3, 4, 7-tetrahydro-lH-azepine-2-carboxylic acid 3- (Napht-2-ylsulfonylamino) -1- (4'-methoxyphenylsulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid 3- (naphth-1-ylsulphonylamino) - 1- (4-methoxyphenylsulphyl) -2, 3, 4, 7- tetrahydro-l-azepine-2-carboxylic 3- (Phenylmethylsulfonylamino) -1- (4-methoxyphenylsulfonyl) -2, 3, 4, 7-tetrahydro-lH-azepine-2-carboxylic acid 3- ((2-Nitrophenyl) methylsulfonylamino) -1- (4-methoxyphenylsulfonyl) -2, 3,, 7-tetrahydro-H-azepine-2-carboxylic acid 3- ((2-phenylethyl) sulfonylamino) -1- (4-methoxy phenylsul foni.1) -2, 3,4, 7- 1-tetrahydro-1H-az epin-2-carboxylic acid 3- ((Iodophenyl) sulfonylamino) -1- (4-methoxyphenylsulfonyl) -2, 3, 4, 7-tetrahydro-lH-azepine-2-carboxylic acid 3- (4- (4-chlorophenyl) phenyl) sui-fonylamino) -1- (4'-methoxy-phenylsulfonyl) -2, 3, 4,7-tetrahydro-l-azepine-2-carboxylic acid 3- (phenylmethoxycarbonyl) - 1- (4-methoxyphenylsulfonyl) -2,3,4,7-tetrahydro-lH-azepine-2-carboxylic acid 3- ((4-trifluoromethylphenyl) ethoxycarbonylamino) -1- (4-methoxyphenylsulfonyl) -2, 3, 4, 7-tetrahydro-lH-azepine-2-carboxylic acid 3- ((4-Chlorophenyl) methoxycarbonylamino) -1- (4-methoxyphenylsulfonyl) -2, 3, 4, 7-tetrahydro-lH-azepine-2-carboxylic acid 3- ((3,5-Dichlorophenyl) methoxycarbonylamino) -1- (4-methoxyphenylsulfonyl) -2, 3, 4, 7-tetrahydro-lH-azepine-2-carboxylic acid 1- (4-methoxy-benzenesulfonyl) -3- (4-chlorophenyl-phenylsulfonylamino) -2, 3, 4, 7-tetrahydro-lH-azepine-2-carboxylic acid 1- (4-methoxy-benzenesulfonyl) -3- (4-chlorophenyl-ethanesulfonylamino) -2, 3, 4, 7-tetrahydro-lH-azepln-2-carboxylic acid 1- (4-methoxy-benzenesulfonyl) -3 (R) (phenylmethanesulfonylamino) -heptamethyleneimide-2 (S) -carboxylic acid Trans-1- (4-methoxy-benzenesulfonyl) -3 (R) - (phenylmethanesulfonylamino) -heptamethyleneimide-2 (R) -carboxylic acid As used here, the following terms will have the following meanings: "Alkyl" alone or in combination means a straight or straight chain or branched chain alkyl radical, preferably containing 1-15 carbon atoms (C? -C? S) more preferably 1-8 carbon atoms (C1-? C8), still more preferably 1-6 carbon atoms (Cl-C6), still more preferably 1-4 carbon atoms (Cl-C4), still more preferably 1-3 carbon atoms (Cl-C3), and more preferably 1-2 carbon atom (C1-C2). Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamino, hexyl, octyl and the like.

"Alkenyl", alone or in combination, means a straight or straight chain or branched chain hydrocarbon radical, having one or more double bonds, preferably 1-2 double bonds and more preferably a double bond, and preferably contains 2-15 carbon atoms (C2-C15), more preferably 2-8 carbon atoms (C2-C8), even more preferably 2-6 atoms carbon (C2-C5), still more preferably 2-4 carbon atoms (C -C), and still more preferably 2-3 carbon atoms C2-C3) • Examples of such alkenyl radicals include, ethenyl, propenyl , 2-methylpropenyl, 1,4-butadienyl and the like.

"Alkynyl", alone or in combination, means a straight or branched chain straight hydrocarbon radical having one or more triple bonds, preferably 1-2 triple bonds and more preferably a triple bond, and preferably containing 2-15 atoms of carbon (C2-C5), more preferably 2-8 carbon atoms (C2-C8), even more preferably 2-6 carbon atoms (C2-C6), still more preferably 2-4 carbon atoms (C2-C4), and still more preferably 2-3 carbon atoms (C2-C3). Examples of such alkynyl radicals include ethynyl, propynyl (propargyl), butynyl and the like.

'Alkoxy', alone or in combination means a radical of the type "R-0-" wherein "R" is an alkyl radical as defined above and "O" is an oxygen atom Examples of such alkoxy radicals include, methoxy , ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.

"Alkoxycarbonyl", alone or in combination, means a radical of the type "R-O-C (0) -", wherein "R-0-" is an alkoxy radical as defined above and "C (O)" is a carbomyl radical.

"Alkoxycarbonylamino", alone or in combination, means a radical of the type "ROC (0) -NH", wherein "ROC (O)" is an alkoxycarbonyl radical as defined above, wherein the amino radical may be optionally substituted, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, and the like; "Alkylthio", alone or in combination, means a radical of the type "R-S-" where "R" is an alkyl radical as defined above and is a sulfur atom. Examples of such alkylthio radicals include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio and the like.

"Alkylsulfinyl", alone or in combination, means a radical of the type "R-S (O) -" wherein "R" is an alkyl radical as defined above and "S (O)" is a mono-oxygenated sulfur atom. Examples of such alkylsulfinyl radicals include, methylsulphyl, ethylsulfinyl, n-propylsulphyl, isopropylsulfinyl, n-butylsulfinyl, iso-butylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl and the like.

"Alkylsulfonyl" alone or in combination means a radical of the type "R-S (0) 2-" where "R" is an alkyl radical as defined above and "S (0) 2" is a dioxygen sulfur atom. Examples of such alkylsulfonyl radicals -include, I tilsul fonilo, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-but i 1 sulfonyl, 'isobuti 1 sui foni it, sec-butylsulfonyl, t erc-butilsul fonilo and the like.

"Alkylsulfonylamino", alone or in combination, means a radical of the type "RS £ 0) _- NE" where "RS (0) 2" is an alkylsulfonyl radical as defined above wherein the amino radical can be optionally substituted, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl and the like.

"Aryl", alone or in combination, means a phenyl, biphenyl or naphthyl, which is optionally substituted with one or more substituents selected from alkyl, alkoxy, halogen, hydroxy, amino, azido, nitro, cyano, haloalkyl, carboxy , alkoxycarbonyl, cycloalkyl, heterocycle, alkanoylamino, amido, amidino, alkoxycarbonylamino, N-alkylamidoino, alkylamino, dialkylamino, N-alkylamido, N, N-dialqui lido, aralkoxycarbonylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, and the like. Examples of aryl radicals are phenyl, p-tolyl, 4-methoxy enyl, 4- (tert-butoxy) phenyl, 3-methyl-4-methoxy phenyl, 4 -CF3- phenyl, 4 - fluorophenyl, '4-chlorophenyl, 3 - or trofenyl, 3-aminophenyl, 3-acetamido phenyl, 4-acetamidophenyl, 2-methyl, 3-acetamidophenyl, 2-me thi-3-amino phenylT. 3-methyl-4-aminophenyl, 2-amino-3-methyl phenyl, 2, 4 -dimet yl-3-aminophenyl, 4-hydroxyphenyl, 3-methyl-4-hydroxy pheny I, 4 - (4-methoxy pheny 1 ) phenyl, l-naphthyl, 2-naphthyl, 3-amino- l-naphthyl, 2-methyl-3-amino- 1-naphthyl, 6-amino-2-naphthyl, 4, 6-dimethoxy-2-naphth yl, piperazine 1 phenyl and the like.

"Aryl-alkyl" alone or in combination means an alkyl radical as defined above, in which at least one hydrogen atom, preferably 1-2, is replaced by an aryl radical as defined above, such as benzyl , 1, 2-phenylene, dibenzylmethyl, hydroxy phenyl, methyl phenyl, diphenylmethyl, dichlorophenylmethyl, 2-naphthylmethyl, 4-methoxyphenylmethyl and the like.

"Aryl-alkoxy" alone or in combination, means an alkoxy radical as defined above in which, at least one hydrogen atom, preferably 1-2, is replaced by an aryl radical as defined above, such as benzyloxy, , 2-phenylethoxy, dibenzylmethoxy, hydroxyphenylmethoxy, methylphenylmethoxy, dichlorophenylmethoxy, -metoxyphenylmethoxy and the like.

"Aryloxy", alone or in combination, means a radical of the.-Type "R-0-" wherein "R" is an aryl radical as defined above.

"Aroyl" alone or in combination means a radical of the type "R-C (O) -" wherein "R" is an aryl radical as defined above and "-C (O) -" is a carbonyl.

"Alkanoyl" alone or in combination means a radical of the type "RC (0) -" _ where "R" is an alkyl radical as defined above and "-C (O) - is a carbonyl radical. Alkanoyl radicals include acetyl, tri-fluoroacetyl, hydroxyacetyl, propionyl, butyryl, valeryl, 4-ethylvaleryl and the like.

"Alkanoylamino", alone or in. combination, means a radical of the type "RC (0) -NH" in "where" RC (O) - "is an alkanoyl radical as defined above, wherein the amino radical may optionally be substituted, such as with alkyl, aryl , aralkyl, cycloalkyl, cycloalkylalkyl and the like.

"Aminocarbonylamino", alone or in combination, means a substituted aminocarbonyl radical, substituted on a second amino (ureido) radical, wherein each amino radical may optionally be mono- or di-subsided, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkanoyl, alkoxycarbonyl, aralkoxycarbonyl and the like.

"Benzo", alone or in combination, means the divalent radical C6H4 = derivative delencene.

"B i cyclic" as used herein is intended to include both fused ring systems, such as naphthyl, and β-carbolinyl, and substituted ring systems such as biphenyl, phenylpyridyl, naphtyl, and di-phenylpiperazyl.

"Cycloalkyl", alone or in combination, means a monocyclic, bicyclic or tricyclic alkyl radical, preferably a double bond, saturated or partially saturated, preferably monocyclic containing preferably 3-10 carbon atoms (C3-C10), more preferably 3- 8 carbon atoms (C3-C8), even more preferably 3-6 carbon atoms (C3-C6), which is optionally benzo fused and which is optionally substituted as defined herein, with respect to the definition of aryl. Examples of such cycloalkyl radicals include, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, dihydroxycyclohexyl, cycloheptyl, octahydronaphthyl, tetrahydronaphthyl, dimethoxytetrahydronaphthyl, 2,3-dihydro-H-indenyl, and the like.

"Cycloalkylalkyl" alone or in combination means an alkyl radical as defined above, which is substituted by a cycloalkyl radical as defined above. Examples of such cycloalkylalkyl radicals include, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1-cyclopentylethyl, 1-cyclohexylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, hydroxycyclopentylpropyl, tetrahydronaphthylpropyl, cyclohexylbutyl, and the like.

"Heteroatoms" mean heteroatoms of nitrogen, oxygen and sulfur.

"Heterocyclyl" alone or in combination means a heterocyclic, monocyclic or bicyclic, preferably monocyclic, preferably a double, saturated or partially saturated radical containing at least one, preferably 1 to 4, more preferably 1 to 3., still more preferably 1-2 ring elements of nitrogen, oxygen or sulfur atoms, and preferably having 3-8 ring elements in each ring, preferably 5-8 ring elements in each ring and even more preferably, -6 ring elements in each ring. "Heterocyclyl" is proposed to include sulfone and sulfoxide derivatives of sulfur ring elements and N-oxides of tertiary nitrogen, and fused carbocyclic ring elements, preferably 3-6 carbon atoms in the ring and more preferably 5-6 carbon atoms in the ring, and benzo fused ring systems. The "heterocyclic" radicals can be optionally substituted in at least one, preferably 1-4, more preferably 1-3, even more preferably 1-2, carbon atoms by halogen, alkyl, alkoxy, hydroxy, oxo, thioxo, aryl, aralkyl, heteroaryl, heteroarylalkyl, amidino, N-alkylamidino, alkoxycarbonylamino, alkylsulfonylamino and the like, and / or at a secondary nitrogen atom by hydroxy, alkyl, aralkoxycarbonyl, alkanoyl, alkoxycarbonyl, heteroaralkyl, aryl or aralkyl radicals. More preferably, "heterocyclyl" alone or in combination, is a radical of a monocyclic or bicyclic-saturated ring system having 5-8 ring elements per ring, wherein 1-3 ring elements are oxygen, sulfur or oxygen heteroatoms. : ~~ nitrogen, which are optionally partially unsaturated or benzofused and optionally substituted by 1-2 oxo or thioxo radicals. Examples of such heterocyclyl radicals include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorphyl inyl, 4-benzyl-piperazin-1-yl, pyrimidinyl, tetrahydrofuryl, pyrazole idonyl, pyrazolinyl, pyridazinonyl, pyrrolidonyl, tetrahydrothienyl-and-their sulfoxide and sulfone derivatives, 2, 3-dihydroindolyl, tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1, 2, 3, 4-tetrahydro-1-oxo-isoquinol inyl, 2,3-dihydrozofuryl, benzopyranyl, methylenedioxy phenyl, ethylenedioxy phenyl and Similar.

"Heterocyclylalkyl", alone or in combination, means an alkyl radical as defined above - in which at least one hydrogen atom, preferably 1-2, is replaced by a heterocyclyl radical as defined above, such as pyrrolidinylmethyl, tetrahydro tieni lmet ilo, piperidinyle, and the like.

"Heteroaryl", alone or in combination, means a heterocyclo-, monocyclic or radical. bicyclic, preferably monocyclic, aromatic, having at least one, preferably 1 to 4, more preferably 1 to 3, even more preferably 1-2, ring elements of nitrogen or sulfur atoms and preferably having 5-6 elements in the ring in each ring, which is optionally benzo fused or saturated carbocyclic fused, preferably 3-4 carbon atoms (C3-C) to form rings of 5-6 elements in the ring and which is optionally substituted- as defined above with respect to the definitions of aryl and heterocyclyl. More preferably, "heteroaryl", alone or in combination, is a radical of a bicyclic monocyclic aromatic heterocyclic ring system having 5-6 ring elements per ring, wherein 1-3 elements in the ring are ring heteroatoms. oxygen, sulfur or nitrogen, which are optionally fused benzo or saturated C3-C4 carbocyclic fused. Examples of such heteroaryl groups include imidazolyl, 1-benzyloxycarbonyl, lidozol-4-yl, pyrrolyl, pyrazolyl, pyridyl, 2- (1-piperidinyl) pyridyl, 2- (4-benzyl-piperazin-1-yl) -1. pyridinyl, pyrazinyl, triazolyl, furyl, thienyl, oxazolyl, thiazolyl, indolyl, quinolinyl, l-oxido-2-quinol inyl, isoquinolinyl, 5,6,7,8-tetrahydroquinolyl, , 6, 7, 8 -1 e trahi droisoquinol ini lo, quinoxalinilo, benzotiazolilo, ß-carbolinilo, benzofurilo, benzimidazolilo, benzoxazol i lo and the like.

"Heteroaryl", alone or in combination, means a radical of the type "R-C (OJ -" _ where "R" is a heteroaryl radical as defined above and "-C (O) is a carbonyl "Heteroaryl-alkyl", alone or in combination, means an alkyl radical as defined above in which, at least one hydrogen atom, preferably 1-2, is replaced by a heteroaryl radical as defined above, such as 3- furylpropyl, 2-pyrrolylpropi lo chloroquinol, inylmethyl, 2-thienylethyl, pyridylmethyl, 1-imidazole, and the like.

"Halogen" and "halo", alone or in combination, mean fluorine, chlorine, bromine or iodine radicals.

"Haloalkyl", alone or in combination, means an alkyl radical as defined above in which at least one hydrogen atom, preferably 1-3, is replaced by a halogen radical, more preferably fluorine or chlorine radicals. Examples of such haloalkyl radicals include 1, 1, 1 -trifluoroethyl, chloromethyl, 1-bromoethyl, fluoromethyl, di-luomomethyl, trifluoromethyl, bis (trifluoromethyl) methyl, and the like.

"Haloalkoxy", alone or in combination, means an alkoxy radical, as defined above in which at least one hydrogen atom, preferably 1-3, is replaced by a halogen radical, more preferably fluorine or chlorine radicals. Examples of such haloalkoxy radicals include 2,2,2-trifluoroethoxy, chloromethoxy, 2-bromoethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, bis (trifluoromethyl) metoxy and the like.

"Sulfinyl", alone or in combination, means a diradical of the type "-S0-" wherein, "S (O)" is a mono-oxygenated sulfur atom.

"Sulfonyl", alone or in combination, means a diradical of the type "-S (0) 2", wherein "S (0) 2" is a di-oxygenated sulfur atom. - _ _. _ _ _ "Residual group", generally refers to groups easily displaceable by a nucleophile, such as a nucleophile amine, thiol or alcohol.

Such residual groups are well known in the art. Examples of such residual groups include, but are not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates, tosylates, and the like. Preferred residual groups are indicated here as appropriate.

"Protective Group" generally refers to groups well known in the art, which are used to prevent selected reactive groups such as carboxy, amino, hydroxy, mercapto and the like, from the unwanted reactions subjected, such as nucleophilic , electrophillic, oxidation, reduction and the like. Preferred protecting groups are indicated herein as appropriate. Examples of protective amino groups include, but are not limited to, aralkyl, substituted aralkyl, cycloalkenylalkyl and substituted cycloalkenylalkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, silyl, and the like. Examples of aralkyl include, but are not limited to, benzyl, ortho-methylbenzyl, trifly and benzhydryl, which may be optionally substituted with halogen, alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts, such as salts of phosphonium and ammonium. Examples of aryl groups include phenyl, naphthyl, indanyl, anthracenyl, 9- (9-phenylfluorenyl), phenanthrenyl, durenyl and the like. Examples of cycloalkynyl alkyl or substituted cycloalkenylalkyl radicals, preferably have 6-10 carbon atoms, include, but are not limited to, cyclohexenyl, methyl and the like. Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups include benzyloxycarbonyl, t-butoxycarbonyl, isobutoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl, tri-fluoroacetyl, tri-chloroacetyl, phthaloyl and the like. A mixture of protecting groups can be used to protect the same amino group, such as a primary amino group can be protected by both an aralkyl group and an aralkoxycarbonyl group. The amino protecting groups can also form a heterocyclic ring-with the nitrogen to which they are attached, for example, 1,2-bis (meth i len) benzene, phthalimidyl, succinimidyl, maleimidyl and the like wherein these heterocyclic groups can further include rings aryl and cycloalkyl. In addition, the heterocyclic groups can be mono, di or tri-substituted, such as nitroftalimidil. Amino groups can also be protected against undesired reactions, such as oxidation, through the formation of an addition salt, such as hydrochloride, toluensulonic acid, trifluoroacetic acid, and the like. Many of the amino protecting groups may also be suitable for protecting carboxy, hydroxy and mercapto groups. For example, aralkyl groups. Alkyl groups are also suitable groups to protect hydroxy and mercapto groups, such as tert-butyl.

Silyl protecting groups are silica atoms optionally substituted by one or more alkyl, aryl and aralkyl groups. Suitable silyl protecting groups include, but are not limited to, trimethyl silyl, triethylsilyl, tri-isopropylsilyl, erc-butyldimethyl silyl, dimethyl phenyl silyl, 1,2-bis (dimethylsilyl) benzene, 1,2-bis (dimethylsilyl) ethane and di-fylmethyl-1-yl. Silylation of the amino groups provides mono- or di-silylamino groups. The silylation of the aminoalcohol compounds can lead to a N, N, O-tri-si lyl derivative. The removal of silyl function from a silyl ether function is easily accompanied by treatment with, for example, a metal hydroxide or an ammonium fluoride reagent, either as a discrete reaction step or in situ during a reaction with the alcohol group. Suitable silylating agents are, for example, trimethylsilyl chloride, tert-butyldimethylsilyl chloride, phenyldimethylsilyl chloride, diphenylmethylsilyl chloride or their combination products with imidazole or DMF. Methods for silylating de-amines and removal of silyl protecting groups are well known to those skilled in the art. The methods of preparation of these amine derivatives of the corresponding amino acids, amino acid amides or amino acid ester are well known to those skilled in the art of organic chemistry, including amino acid / amino acid ester or aminoalcohol chemistry.

Protective groups are removed under conditions which will not affect the remaining portion of the molecule. These methods are well known in the art and include acide hydrolysis, hydrogenolysis and the like. A preferred method involves the removal of a protecting group, such as a removal of a benzyloxycarbonyl group by hydrogenolysis using palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or a mixture thereof. A t-butoxycarbonyl protecting group can be removed using an organic or inorganic acid, such as HCl, or trifluoroacetic acid, in a suitable solvent system, such as dioxane or methylene chloride. The resulting amino salt can easily be neutralized to provide the free amine. The carboxy protecting group, such as methyl, ethyl, benzyl, tert-butyl, 4-meloxyphenylmethyl, and the like, can be removed under hydrolysis and hydrogenolysis conditions well known to those skilled in the art.

X The procedures for the preparation of the compounds of this invention are set forth below. It should be noted that the general procedures are shown to refer to the preparation of the compounds having unspecified stereochemistry. However, such procedures are generally applicable to those compounds of a specific thermochemistry, for example, wherein the thermochemistry of about one group is (S) or (R). In addition, compounds having a stereochemistry (e.g., (R)) can often be used to produce those that have opposite stereochemistry (ie, (S)), using methods well known in the art, for example, by investment.

Preparation of the Compounds of Formula (I) The compounds of the present invention represented by formula I above can be prepared using various synthetic techniques, many of which are included by reference. In particular, the compounds of the present invention are to be prepared following the general procedures discussed below. A general synthesis employed for the preparation of the novel compounds of this invention is illustrated in Scheme I, which employs a route convergent to the azepine ring and large ring systems. According to this method, the readily available Horner-Emmons reagent is reacted under standard conditions (see Wadsworth, Org Reactions, 1977, 25, 73), with an aldehyde variably substituted by a silyl ether also as an additional substitution in the alkyl chain (R5, R6, R9, RIO) to provide the unsaturated α, β ester. Deprotection of the silyl group, alcohol activation provides a residual group and a catalyzed intramolecular base to provide a key intermediate. Subsequent deprotection of the t-BOC group with HCl / ethyl acetate (Gibson, J. Org. Chem., 1994, 59, 3216) or with TFA and SCHEME I sui phylation with a sulfonyl halide in the presence of a base, preferably an obstructed amine base such as triethylamine in a chlorinated solvent, provides the substituted sulfonamide. The R group is a group that can be converted to an amine group using methods well known to those skilled in the art, such as benzylamine, protected silyl benzylamine, phthalimide or other readily available nucleophilic amine equivalents. The protected primary amine is deprotected to the primary amine substituted by methods well known in the art for example hydrogenation in the presence of a metal catalyst. The primary amine is then functionalized to provide the ester derivatives of the final product. Functionalization methods include sulfonating as described above, treatment with isocyanates to prepare ureas, treatment with mixed acid chlorides or anhydrides to provide amides, reductive aminations to provide amines, and chloroformates to provide carbamates (See, Compendium of Synthetic Organic Methods, Wiley). These adducts are treated with aqueous alkali bases such as LiOH to provide the free acid products, when the methyl or ethyl esters are used or TFA when the t-butyl ether is used as the ester component.

A second general synthesis employed for the preparation of the novel compounds of this invention is illustrated in Scheme II, which employs a route convergent to the azepine ring.

The readily available glutamic or aspartic acid derivative is protected and subjected to allylation as previously described for an analogue (see Bald in, Tetrahedron, 1989, 45, 6309 and references cited herein). The Mitsunobu reaction of the resulting sulfonamides (see Mitsunobu, Synthesis, 1981, 1), provides the bis olefin. Treatment of the resulting olefin with a metathesis reagent (see Schster, Angew.Chem.Inter.Ed.Eng.Eng.97, 36, 2036) provides the cyclized olefin. Saponification as known to one skilled in the art, followed by the Curtius rearrangement of the resulting acid under known conditions (Tetrahedron, 1974, 30, 2151) provides the desired carbamates. The carbamates protected from t-butyl acid can be deprotected with concentrated trifluoroacetic acid (TFA) to provide the final products. Additionally, by the selection of the alcohol entrapped agent suitable for the Curtius rearrangement for example, 4-methoxybenzyl alcohol, the carbamate may be differentially "deprotected to the amine with diluted TFA (3%) in a chlorinated solvent to provide the acid t- protected butyl, amine salt, sui-phylation, as previously described, or treatment with the appropriate alkylating or acylating agent as is known to one skilled in the art and deprotection of t-butyl ester-as described , provide the compounds.The large rings can be formed using homologues of allyl or hydroxyalyl iodide, such as 4-iodo-1-butene, 4-hydroxy-1-butene, 5-iodo-1-pentene, 5-hydroxy- 1-pentene, 4-iodo-2-butene, 4-hydroxy-2-butene and the like.

E SQUEMA I I The intermediates of Scheme II can be used as initiator materials for substituents R5, R6, R9, and R10. For example, the aspartic acid derivative can be alkylated with a variety of polysubstituted allyl iodides or triflates, such as CH2 = CH CHR7R1 ° I, followed by the Mitzunubu reaction with homoallyl alcohols and allyls to provide the intermediates for the metathesis reaction. The claimed compounds can also be prepared by the functionalization of the olefinic intermediates after metathesis. For example, the olefin can be hydrogenated under standard conditions, preferably, Pd / C under an atmosphere of hydrogen in a solvent such as an alcohol or ethyl acetate. The olefin can be hydroborated with a borane reagent (see Brown, Borane Reagents, Academic Press, NY, 1988) preferably, BH3-DMS, and the subsequent borane complex oxidized with H20 to provide the alcohol or with chromium agents under standard conditions ( see Hudlic and, Oxidations in Organic Chemistry, ACS monograph 186, 1990), provides the ketone. The ketone can serve as an electrophile with intentional agents, organometallic agents or can be reacted with aldehydes under basic or acidic conditions to "subject it to aldol condensations." Olefins can be subjected to ring oxidation with chromium or preferably selenium reagents (see Rabjohn, Org. Reaction, 1976, 24, 261) as is known in the art to provide allylic alcohols which are activated as with a residual group and sulfur nucleophiles with or without lewis or palladium acid catalysts. treatment of the olefin with an aryl or alkenylhalide or triflate in the presence of a palladium catalyst to subject it to a Heck reaction (for an extensive review of linkage formation using palladium catalysts, see "Tsu i, Palladium Reagents and Catalysis, Wiley, 1995). The olefin formed can be functionalized as described above to provide additional substitution. The olefin may be epoxidized with MCPBA or a peroxide related to the epoxide which may be substituted in the presence or absence or a Lewis acid with a reactive Carbon, nitrogen, oxygen or nucleophilic sulfide, as is known in the art.

Alternatively, the substituted urea derivatives can be prepared by reacting the isocyanate intermediate formed in the Curtius rearrangement using an amine (HNR 31Rt-, ° 32) instead of alcohol (R "-0H) (Scheme (III) SCHEME III SCHEME IV In addition, the carbamate formed in Scheme II can be hydrolyzed in acid to the free amine (Scheme IV) which can then be derivatized, such as by alkylation, reductive alkylation, sulfonylation, aminosullation, acylation and the like, as in the scheme V.

E SQUEMA V It is apparent from the above description, that a single general synthesis can not be used in the preparation of all the new compounds of this invention, because some of the radicals, well known to those skilled in the art, will be they may have the potential to interfere with, compete with or inhibit some of the reactions involved in the trajectory, however, one skilled in the art is fully aware of the appropriate point in the synthetic trajectory when a radical can be introduced and when they can be used. by protective groups.

- The sulfonyl halides can be prepared by the reaction of a suitable alkyl, aryl, heteroaryl, heterocyclyl, and Grignard or lithium-like reagents, with sulfuryl chloride, or sulfur dioxide, followed by oxidation with a halogen, preferably chlorine. Alkyl, heteroaryl, heterocyclyl, aryl and Grignard or lithium-like reagents can be prepared from the corresponding halide compounds (such as chlorine or bromine) which are commercially available or readily prepared from their commercially available starting materials using methods known in the art. Alternatively, mercaptans can be oxidized to sulfonyl chlorides, using chlorine in the presence of water, under carefully controlled conditions. Additionally, sulphonic acids can be converted to sulfonyl halides using reagents such as PC15, S0C12, C1C (0) C (0) C1 and the like, and also to anhydrides using suitable dehydration reagents.Sulfonic acids are either commercially available or can be prepared using procedures well known in the art from commercially available starting materials In place of sulfonyl halides, sulfinyl halides or sulfenyl halides can be used to prepare compounds wherein the sulfonyl moiety is replaced by a sulfinyl or thio portion, respectively. The arylsulfonic acids, benzo fused heterocyclyl sulfonic acids or heteroaryl sulfonic acids can be prepared by the sulfonation of the aromatic ring by methods well known in the art, such as by reaction with sulfuric acid, S03, S03 complexes, such as DMF (S03) , pyridine (S03), N, N-dimethyl acetamide (S03), and the like. Preferably, each of the sulfonyl halides is prepared from such aromatic compounds by reaction with DMF (SO;,) and S0C12 or C1C (O) C (O) Cl. The reactions can be carried out in the form of stages or in a single container.

The additional substitution Rl can be obtained by the additional reactions in the sulfonamide after the reaction of the sulfonyl halide with the related amine. For example, the substituted nitro aryl, or the heteroarylsulfonamides can be reduced to the aniline and substituted or converted to the diazonium salt and further reacted, to provide the compounds described by the methods known to one skilled in the art. Additional Rl substitutions may be obtained by the reaction of fluorine, halogen, or aryl or heteroaryl chlorides or alkyl sulphonyl trifluoromethanesulfonyloxy substituted with the related amine followed by substitution of the reactive intermediate with oxygen, nitrogen, sulfur or carbon nucleophile. in the presence or absence of a transition metal catalyst such as palladium, to provide the desired compounds. (For a monograph on the topic, see Miller, Aromatic Nucleophilic Substrate, Elsevier, NY, 1968).

Phosphonic alkylsulphonic acids, arylsulfonic acids, tertiary-cyclic sulphonic acids, heteroarylsulfonic acids, alkylmercaptans, arylmercaptans, heterocyclylmercaptans, heteroaryl mercaptans, alkylhalides, arylhalides, heterocyclylhalides, heteroarylhalides, and the like, are commercially available or can be readily prepared from - the commercially available initiator materials, using standard methods well known in the art.

The thioether derivatives can be converted to the corresponding sulfone or sulfoxide by oxidation of the thioether derivative with a suitable oxidation agent in a suitable solvent. Oxidation agents include, for example, hydrogen peroxide, sodium meta-perborate, oxone (sodium peroxy monosulfate), meta-chloroperoxybenzoic acid, periodic acid and the like, including mixtures thereof. Suitable solvents include acetic acid (for sodium ta-perborate) and, for other perished, ethers such as THF and dioxane, and acetonitrile, DMF and the like, including mixtures thereof.

The compounds of the invention can be produced in racemic or optically pure form.

When a single enantiomer is prepared, it can be synthesized by starting with optically pure starter materials, by resolution of a basic or racemic acidic intermediate with the appropriate chiral acid or base respectively, as is known to one skilled in the art, or by addition of a chiral protecting group to the racemic intermediate or final product, wherein the teriomeric couple can be separated by chromatography or crystallization.

The chemical reactions described above are generally described in terms of their broader application to the preparation of the compounds of this invention.

Occasionally, the reactions may not be applicable as described for each of the compounds included within the scope described. The compounds for which this occurs will be readily recognized by those skilled in the art. In all cases, any of the reactions can be successfully performed by conventional modifications known to those skilled in the art, for example, by the appropriate protection of interfering groups, by switching to alternating conventional reagents, by modifications derutin of the reaction conditions and the like, or other reactions described herein, or otherwise conventional, will be applicable to the preparation of the corresponding compounds of this invention. In all preparative methods, all initiating materials will be known or_. easily prepared from the initiating materials.

Prodrugs of the compounds of this invention are also contemplated by this invention. A prodrug is an active or inactive compound that is chemically modified through a physiological action in vivo, such as hydrolysis, metabolism and the like, in a compound of this invention after administration of the prodrug to a patient. The suitability and techniques involved in the manufacture and use of the prodrugs are well known to those skilled in the art. For a general discussion of prodrugs involving esters, see Svensson and Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examples of a masked carboxylate anion include a variety of esters, such as alkyl (e.g., methyl, ethyl), cycloalkyl (e.g., cyclohexyl), aralkyl (e.g., benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (e.g. , pivaloyloxymethyl). The amines have been masked as substituted arylcarbonyloxymethyl derivatives, which are split by esterases in vivo releasing formaldehyde and free drug (Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, such as imidazole, imido, indole, and the like, have been masked with N-acyloxymethyl groups (Bungaard Design of _Prodrugs; Elsevier (1985)). The hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloan and Littel, 11/4/81) describe prodrugs of Mannich-based hydroxamic acid, 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 full extent. The following preferred specific embodiments are, therefore, constructed as merely illustrative and not limitative of the remaining description, in any way.

All reagents were used as received without purification. All proton and carbon NMR spectra were obtained on a Bruker nuclear magnetic resonance spectrometer.

The following Examples illustrate the preparation of the compounds of the present invention and intermediates employed in the preparation of the compounds of the present invention Example 1 Preparation of 1- (4-methoxy-benzenesul-fonyl) -273, 7-tetrahydro-1H-azepine-2,3-dicarboxylic acid 3- tert-butyl ester Stage A. 1-Ester-butyl ester of the 4-benzylic ester of 2-aminosuccinic acid β-benzyl ester of D-aspartic acid (9g, 40.3 mmol) was suspended in 75 ml of Dioxane and 7.5 ml of Sulfuric Acid and cooled to -15 ° C. 2-Methylpropene (75 ml) was added and the reaction mixture was sealed and stirred for 4 hours at room temperature. The reaction mixture was then cooled to 0 ° C and poured into 600 ml of diethyl ether and 325 ml of 1M NaOH. The organic phase was separated and the aqueous phase was extracted twice with 200 ml of Diethyl ether. The combined organic fractions were dried with MgSO 4 for 30 minutes and filtered. Diethyl ether was evaporated and the remaining oil was dried under high vacuum for 24 hours; Calculated 280.2, Found (M) + 280.

Stage B. 1- (4-benzyl ester) 2- (4-methoxy-benzenesul fonilamino) -succinic acid ester 1- erc-butyl ester 1-tert-butyl ester 4-benzyl ester of 2-aminosuccinic acid (9.57 g, 33.4 mmol), triethylamine (9.3 ml, 66.8 mmol) and 4-methoxybenzenesul fonyl chloride (6.9, 33.4 mmol) were dissolved in 50 ml of Dichloromethane (DCM) and stirred at room temperature for 1 hour. The reaction mixture was diluted with 50 ml of DCM. 200 ml of water were added and the organic phase was separated. The aqueous phase was extracted twice with DCM. The combined organic extracts were dried with MgSO 4 and filtered. The solvent was evaporated and the remaining residue was recrystallized from diethyl ether / ethylacetate as white needles: XH NMR (CDCl 3), ppm: 8.2 Hz, (d, ÍH), 7.7 Hz (d, 2H), 7.3 Hz (m, 5H), 7.1 Hz (d, 2H), 5.05 Hz, (d, 2H), 4.08 Hz (dd, ÍH), 3.09 Hz, (s, 3H), 2.72 -Hz (dd, ÍH), 2.59 Hz (dd) , ÍH), 1.21 Hz (s, 9H).

Stage C. 1-Benzyl 4-tert-butyl ester of 2-A1Í1-3-4- (4-methoxy-benzenesulfonylamino) -succic acid 100 ml of dry Tetrahydrofuran (THF), cooled to -78 °, added 1M TEF-solution of lithium bis (trimethylsilyl) amide (47.35 ml, 47.35 mmol), while maintaining the temperature. 1- (4-benzyl) tert-butyl ester of 2- (4-methoxy-benzenesulphonylamino) -succinic acid was dissolved (10.1 g, 22.5 mmol) in 45 ml of THF and added as drops to the reaction solution. The reaction mixture was allowed to stir for 1 hour and then warmed briefly to -40 ° C. After re-cooling to -78 ° C, allyl iodide (3.1 ml, 33.8 mmol) dissolved in 30 ml of THF was added as drops. The reaction mixture was allowed to warm to -40 ° C and quenched with a solution of NH 4 Cl. The organic phase was separated, dried over MgSO4 and filtered. The solvent was evaporated and the product was purified with a short flash column. Hexane / ethyl acetate (9: 1): Calculated. 489.6 Found, (M) + 490.

Step D. Ester 4-erc-butyl-1-ester of the 1-benzyl ester of 2-allyl-3- [allyl- (4-methoxy-benzenesul-fonyl) amino] -succinic acid Triphenylphosphine (1 g, 3.9 mmol) was dissolved in 60 ml of tetrahydrofuran JTHF) and cooled to 0 ° C. Diazopropyl dicarboxylate was added (DIAD) (0.77 ml, 3.9 mmol) via a syringe and the reaction mixture was stirred for 30 minutes. Allyl alcohol (16 μl, 0.23 mmol) was added to the yellow suspension, then, after 10 minutes, the 4-e-butyl ester of the 1-benzyl ester of 2-allyl-3- (methoxy) was added. -benzenesulfonylamino) -succinic acid (1.4 g, 2.6 mmol).

The reaction mixture was stirred for 30 minutes at 0 ° C and then allowed to warm to room temperature.

After evaporation of most of the THF, and flash chromatography with Hexane / ethyl acetate (2: 1), the desired product is obtained: XH NMR (CDCl 3, 400 MHz), 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, ÍH), 2.50 ( ddd, ÍH), 2.35 (ddd, ÍH), 1.40 (s, 9H).

Step E. Ester 2-erc-butyl ico of 3-benzis ter of l- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-lH-azepin-2,3-di carboxylic acid __ 4-Silyl-1-benzyl ester of 2-allyl-3- [allyl- (4-methoxy-benzenesulfonyl) -amino] -succinic acid ester (5.5 g, 10.4 mmol) was dissolved in 40 ml of dichloromethane and deoxygenated and filled with Argon three times. The catalyst was added (RuCl2 (PCy3) 2 = -Ph) (100 mg, 0.12 mmol), and the reaction was deoxygenated and filled with argon for a further time.The reaction solution was stirred for 7 hours at room temperature.Other (90 mg, 0.11 mmol) of the Ruthenium catalyst were added and the reaction was stirred overnight, evaporation of the solvent followed by flash chromatography afforded the product Hexane / ethyl acetate. (3: 1): 1 H NMR (CDCl 3 400 Mhz), ppm: 7.81 (d, 2 H), 7.37 (m, 5 H), 6.93 (d, 2 H), 5.60 (m, 2 H), 5.10 (m, 3 H) 4.18 (dd, ÍH), 4.05 (dd, 1H), 3.88 (s, 3H), 3.20 (ddd, ÍH), 2.68 (m, 2H), 1.32 (s, 9H).

E jmplo 2 Preparation of 1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-lH-azepin-2, 3-dicarboxylic acid, 2- ester erc-butyl ester Ester 2-erc-butyl ester of 1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2,3-dicarboxylic acid (6 g, 12 mmol) It was dissolved in a mixture of 120 ml of tetrahydrofuran and 78 ml of water. LiOH "H20 (1 g, 24 mmol) was added. After 45 minutes, more water (15 ml) was added and the reaction solution was stirred at room temperature for 24 hours. The solvent was evaporated and the remaining solid redissolved in Water / Diethyl ether. The aucose layer was acidified to pH 1. The organic phase was separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic fractions were dried with MgSO 4 and filtered. The solvent was evaporated to provide the product: Cal. 412.5, found (M) + 412.1 Example 3 Preparation of 2- (2- (4-methoxy-benzenesulfonyl) -azepan-2, 3-dicarboxylic acid 2-erc-butyl ester Ester of 3-benzyl ester of 1- (4-methoxy-benzenesulfonyl) acid -2, 3,, t-tetrahydro-lH-azepine-2,3-dicarboxylic acid (2.28 g, 4.5 mmol) was dissolved in 40 ml of Dioxane / Methanol (3: 1). Palladium on carbon (10%) (170 mg, 0.16 mmol) was added under a flow of argon. The flask is evacuated or emptied and filled three times with hydrogen. The reaction was stirred at room temperature for 6 hours. Filtration through Celite and evaporation of the solvents gave the product: 1E NMR (DMSO, 400 MHz), ppm: 7.81 (d, 2H), 6.95 (d, 2H), 5.40 (Id, ÍH), 3.68 ( s, 3H), 3.65 (m, ÍH), 3.25 (m, ÍH), 2.92 (m, ÍH), 2.15 (m, ÍH), 1.95 (, ÍH), 1.78 (m, 2H), 1.25 (s, 9H).

Example 4 Preparation of l- (4-methoxy-benzenesulfonyl) -3- (4-methoxy-benzyloxycarbonyl-amino) -2, 3, 4, 7- t-tetrahydro-lH-azepine-2-carboxylic acid tert-butyl ester 1 ico The reaction was carried out under an Argon atmosphere and light exclusion. 1- (4-Methoxy-benzenesulfonyl) -2,3,4,7-tetrahydro-l-azepin-2,3-dicarboxylic acid tert-butyl ester (550 mg, 1.34 mmol) was dissolved in 7 ml of tetrahydrofuran dry (THF). Tripropylamine (TPA) (280 μl) was added, 1.47 mmol), and the reaction was stirred for 30 minutes at room temperature. The di-phenylphosphoryl azide (318 μl, 1.47 mmol) was added and the reaction was gradually heated to 40 ° C for 3 hours. The reaction temperature was then increased to reflux conditions for 6 hours. The reaction mixture was allowed to cool to room temperature and 4-methoxybenzyl alcohol (184 μL, 1.47 mmol) was added. The reaction was heated to reflux overnight. The solvent was evaporated. Flash chromatography hexane / ethyl acetate (2: 1) provided the product: Cal. 383.5 Found (M) + 383.0.

E j emp l o 5 Preparation of 3-benzyloxycarbonylamino-l (4-methoxy-benzenesulfonyl) -2, 3,, 7-tetrahydro-1H-azepine-2-carboxylic acid Stage A: 3-benzyloxycarbonylamino- 1- (4-methoxy-benzenesul fonyl) -2, 3, 4, 7-tetrahydro-lH-aze in-2-carboxylic acid tert-butyl ester The reaction was carried out under an argon atmosphere. 2- (4-Methoxy-benzenesulfonyl) -2,3,4,7-tetrahydro-1H-azepin-2,3-dicarboxylic acid tert-butyl ester (300 mg, "0773 mmol) It was dissolved in 4 ml of Dioxane (dry), Tripropylamine (TPA) (98 μl, 0.73 mmol) was added, and the reaction was stirred for 15 minutes at room temperature.Di phenyl fos oryl azide (175 μl, 0.73 mmol) The reaction was allowed to cool to room temperature, Benzyl alcohol (235 μL, 2.2 mmol) was added and the reaction solution was heated at 60 ° C overnight. The reaction solution was diluted with ethyl acetate and washed with 2M citric acid and water, the organic phase was separated, dried with MgSO, and filtered, the solvent was evaporated and the remaining oil was purified by flash chromatography. , "hexane / ethyl acetate (2: 1): Calculated 516.5, Found (M) + 517.

Stage B_. 3-benzylloxycarbonyl amino-1-methoxy-benzenesul fonyl) -2, 3, 4, 7-trahydro-1H-azepine-2-carboxylic acid The 3-benzyloxycarbonylamino- 1- (4-methoxy-benzenesul foni 1) -2, 3, 4, 7- tet rahydro-H-azepine-2-carboxylic acid tert-butyl ester (28 mg, 0.54) was dissolved. mmol) in 4 ml of dichloromethane / trifluoroacetic acid; 3: 1 and stirred for 5 hours at room temperature. The solvent / reagent was evaporated and the remaining oil co-evaporated from toluene twice. Flash chromatography, hexane / ethyl acetate, 1: 1 provided the desired product: Calculated, 460.51, found (M) "460.9.

Example 6 Preparation of 3- (3, 3-dibenzylureido) -1- (4-methoxy-benzenesulfonyl) -2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid Step A. 3- (3,3-Dibenzylureido) -1- (4-methoxy-benzenesulfonyl) -2,3,4,7,7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester The reaction was carried out under a blanket of argon. Ester 2- (1- 4-methox -beneensui fonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2,3-dicarboxylic acid erc-butylic acid (204 mg, 0.5 mmol), in 10 ml of dry Dioxane. Tripropylamine (94 μl, 0.5 mmol) and then di-phenylphosphoryl azide (DPPA) were added. The reaction was heated to 75 ° C for 5 hours. After cooling to room temperature. Dibenzylamine (190.6 μL, 1 mmol) was added via syringe. The reaction was heated to 70 ° C and stirred overnight. Evaporation of the solvents and flash chromatography, hexane / ethyl acetate (1: 1) gave the product: Calculated. 606.8, Found (M) + 606.2.

Step B. 3- (3, 3-dibenzylureido) -1- (4-methyl-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-lH-azepine-2-carboxylic acid 3- (3,3-dibenzylureido) -1- (4-me-toxy-benzenesulfonyl) -2,3,4,7,7-tetrahydro-1H-azepine-2,3-dicarboxylic acid tert-butyl ester (200 mg, 0.33 mmol), was reacted in the same manner as the tert-butyl ester of 3-benzyloxycarbonylamino- 1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7- t -hydrohydroxy- azepine-2-carboxylic acid and purified by flash chromatography, dichloromethane / methanol (9: 1) to give the free acid: Calculated 550.6, Found (M) + = 550.

E j emp l o 7 Preparation of 3-amino-1- (4-methoxy-benzenesul-fonyl) -2-, 3,4,7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester The tert-butyl ester of 1- (4-methoxy-benzenesul-fonyl) -3- (4-methoxybenzyloxycarbonyl-amino) -2,3,4-7-tetrahydro-1H-azepine-2-carboxylic acid (370) was dissolved mg, 0.71 mMol) in dichloromethane (15 ml) containing 3% trifluoroacetic acid. The reaction was stirred for 1 hour at room temperature. The solvents were evaporated and the remaining oil was co-evaporated twice with toluene. Flash chromatography, dichloromethane / methanol (7: 1) gave the free amine: Calculated. 546.6, Found (M) + = 547.

Example Preparation of 1- (4-methoxy-benzenesulfonyl) -3- (phenylmethanesulfonylamino) -2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid _-_ Step A. Tetrabutyl ester of 1- (4-methoxy-benzenesul fonyl) -3- (phenylmet anosul phonylamino) -2,3,4,7- etrahydrohydroxy-2-carboxylic acid The tert-butyl ester of 3-amino-1-l- (4-methoxy-be-sulphonyl) -2, 3, 4, 7-tetrahydro-H-azepin-2-carboxylic acid (38 mg, 0.1 mmol) was dissolved in 3 ml of dry dichloromethane. The Hünigs base (42 μl, 0.24 mmol) was added and then alpha-toluenesulfonyl chloride (28.4 mg, 0.15 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. The solvent was evaporated and the remaining oil was purified by flash chromatography Hexane / ethyl acetate (2: 1): 1H NMR (CDC13, 400 Mhz), ppm: 7.75 (d, 2H), 7.50 (m, 2H), 7.4 (m, 3H), 6.99 (d, 2H), 5.70 (m, 2H), 5.70 (m, 2H), 4.85 (d, ÍH), 4.56 (d, ÍH), 4.35 (dd, 2H), 4.22 (d, 1H), 4.02 (mm, ÍH), 3.90 (m, 3H), 3.83 (m, 1H), 2.50 (m, 1H), 2.30 (m, 1H), 1.30 (s, 9H).

Step B: 1- (4-Methoxy-benzenesulfonyl) -3- (phenylmethanesulphonylamino) -2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester of l- (4-) methoxy-becensul fonil) -3- (phenylmethanesulphonylamino) -2, 3, 4, 7-1 and rahydro-lH-azepine-2-carboxylic acid (29 mg, 0.054 mmol) was reacted in the same manner as the 3-benzyloxycarbonylamino-1- (4-methoxy-benzenesul fonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester: Calculated 479.5, Found (MH) "478.6, Calculated 498.6, Found (MNH4) + 498.1; XH NMR (DMSO, 400 MHz), 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, ÍH), 3.90 (dd, ÍH), 3.83 (s, 3H), 2.18 (m, 2H).

Example 9 * ~ xf \ - Preparation of 1- (4-methoxy-benzenesul-fonyl) -3- (3-phenylpropionylamino) -2, 3, 4, 7-tetrahydro-lH-azepine-2-carboxylic acid Step A. 1- (4-Methoxy-benzenesul-fonyl) -3- (phenylpropionylamino) -2-, 3,4,7-tetrahydro-2H-azepine-2-carboxylic acid tert-butyl ester ___ " The tert-butyl ester of 3-amino-1- (-me toxy-be-sulphonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid (31 mg, 0.08 mmol) was dissolved in 4 ml of dichloromethane and was cooled to 0 ° C. The Hünigs base (34 μL, 0.2 mmol) was added and then hydrocinnamyl chloride (18 μL, 0.12 mmol) was added. The reaction mixture was stirred for 1 hour at 0 ° C and then allowed to warm to room temperature. The solvents were evaporated and the remaining oil was purified by flash chromatography dichloromethane / methanol (9: 1) to give the product: Calculated 513.6, Found (M + H) + = 514.9 Step B: 1- (4-Methoxy-be-sulphonyl) -3- (3-phenylpropionilamino) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid _- The 1- (4-methoxy-be-sulphonyl) -3- (3-phenylpropionylamino) -2, 3,, 7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester (22 mg, 0.04 mmol) was reacted ), in the same manner as the tert-butyl ester of 3-benzyloxycarbonylamino- 1- (4-methoxy-benzenesulphonyl) -2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid, and purified by flash chromatography, Dichloromethane / methanol (9: 1) to provide the acid: Calculated 457.5, Found (MH) + 456.6; XH NMR (DMSO, 400 MHz), ppm: 7.78 (d, 2H), 7.28 (m, 2H), 7.20 (m, 3H), 7.01 (d, 2H), 5.6 (m, ÍH), 5.5 (m, ÍH) , 4.3 (m, 3H), 4.0 (m, ÍH), 3.82 (s, 3H), 2.8 (t, 2H), 2.35 (m, 2H), 2.05 (m, 2H).

Example 10 Preparation of 3- (3-benzylureido) -1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-te trahydro-1H-azepine-2-carboxylic acid _ ___ Step A. 3- (3-benzylureido) -1- (-me toxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-α-zepine-2-carboxylic acid tert-butyl ester The tert-butyl ester of 3-amino-1- (4-methoxy-becensul phonyl) -2, 3, 7-tetrahydro-1H-azepine-2-carboxylic acid (33 mg, 0.09 mmol) was dissolved in 3 times. ml of dry dioxane. Benzyl isocyanate (10.6 μL, 0.086 mmol) was added and the reaction was stirred at room temperature for 1 hour. Evaporation of the solvent and flash chromatography dichloromethane / methanol (7: 1) gave the product: Calculated. 515.6, Found (M) + 515.9.

Stage Acid 3- (3-benzylurethane) -1- [4-ethoxybenzenesulfonyl] -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid The 3- (3-benzylureido) -1- (4-methoxy-be-sulphonyl) -2, 3, 4, 7-tetrahydro-H-azepine-2-carboxylic acid tert-butyl ester (25 mg, 0.05) was reacted. mmol) in the same manner as the tert-butyl ester of 3-benzyloxycarbonylamino- 1- (4-methoxy-benzenesul fonyl) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid and purified by flash chromatography, dichloromethane / methane (9: 1): Calculated 459.5, Found (MH) + 458.2; X H NMR (DMSO, 400 Mhz), ppm: 7.79 (d, 2 H), 7.30 (, 2 H), 7.20 (m, 3 H), 7.02 (d, 2 H), 5.60 (, 1 H), 5.50 (m, 1 H) , 4.3 (m, 3H), 4.00 (m, ÍH), 3.93 (m, 3H), 2.81 (t, 2H), 2.35 (m, 2H), 2.05 (m, 2H).

Example 11 Using the procedures of the general description and Examples 1-10 above, the following compounds were prepared: 1- (4-methoxy-benzenesul fonyl) -3- (phenylanesulphonylamino) -IH- to z-2-carboxylic acid: Calculated 496.6, Found (M) + 407; 1- (4-methoxy-benzenesulfonyl) -3- (2-amino-phenylamino-sui phonylamino) -lH-azepane-2-carboxylic acid: Calculated 497.6, Found (M) + 498; 1- (4-methoxy-benzenesulfonyl) -3- (phenylmethane sui foni lamino) -IH-azepane-2-carboxylic acid: Calculated 482.6, Found (M) + 483; Cis-1- (4-methoxy-benzenesulfonyl) -3- (phenylmet anosul phonylamino) -heptamethyleneimino-2-carboxylic acid: Calculated 496.6, Found (M-H) + 495; Trans-1- (4-methoxy-benzenesul fonyl) -3- (phenylmet anosul phonylamino) -heptamethyleneimino-2-carboxylic acid: Calculated 496.6, Found (M-H) + 495; 3-Benzyloxycarbonylamino- 1- (4-methoxy-benzenesul fonyl) -lH-azepane-2-carboxylic acid: Calculated 462.52, Found (M-H) + 461.2; 1- (methoxy-benzenesul fonyl) -3- (methansulfonylamino) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid: Calculated 404.5, Found '(M) + 405; 1- (4-methoxy-benzenesulfonyl) -3- (phenylsulphonylamino) -2, 3, 4, 7-tetrahydro-l-azepine-2-carboxylic acid: Calculated 466.6, Found (M) + 467; 1- (4-Methoxy-benzenesul fonyl) -3- (2-naphthylsulphonylamino) -2, 3, 4, 7-tetrahydro-l-azepine-2-carboxylic acid: Calculated 516.6, Found (M) + 517; 1- (4-methoxy-benzenesulfonyl) -3- (1-naphthylsulphonylamino) -2,3,4,7,7-tetrahydro-1H-az-epin-2-carboxylic acid: Calculated 516.6, Found (M) + 517; 1- (4-Chlorophenyl-phenylsulfonyl) -3- (phenylmethanesulphonylamino) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid: Calculated 560.6, Found (M) + 561; 1- (4-Methoxy-benzenesul-fonyl) -3- (4-chlorophenyl-phenylsulphonylamino) -2,3,4,7,7-tetrahydro-1H-azepine-2-carboxylic acid: Calculated 577.1, Found (M) + 577; 1- (4-Methoxy-benzenesul-fonyl) -3- (2-nitrophenyl-methanesulfonylamino) -2, 3, 4, 1-tetrahydro-1H-azepine-2-carboxylic acid: Calculated 525.6, Found (M) + 526; 1- (4-Methoxy-benzenesulfonyl) -3- (phenylacrylsul phonylamino) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid: Calculated 492.6, Found (M) + 493; 1- (4-Methoxy-benzenesul-fonyl) -3- (-iodopheni-1-sui-fonyl-amino) -2, 3,, 7-tetrahydro-1H-azepine-2-carboxylic acid: Calculated 592.7, Found (MH) + 593; 1- (4-methoxy-benzenesulfonyl) -3- (acetylamino) -2,3,4,7-ehydro-1H-azepine-2-carboxylic acid: Calculated 368.4, Found (M) + 369; 1- (4-Methoxy-benzenesul-fonyl) -3- (2-thiophene-2-acetylamino) -2, 3, 4, 7-tetrahydro-H-azepine-2-carboxylic acid: Calculated 450.5, Found (M) + 451; 3- (3-Phenethylureido) -1- (4-methoxy-benzenesul-fonyl) -2, 3, 4, 7- tet-hydroxy-l-azepine-2-carboxylic acid: Calculated 473.5, Found (M) ~ 474; 3- (3-Met i lureido) -1- (4-methox? -benzenesulfonyl) -2, 3, 4, 7- tet rahydro-lH-azepin-2-carboxylic acid: Calculated 383.4, Found (M) + 384; 3- (3-phenylimide) -1- (4-methoxybenzenesulfonyl) -2,3,4,7,7-tetrahydro-1H-azepine-2-carboxylic acid: Calculated 445.5, Found (M) + 446; 3- (3,3-benzylmethylurea) -1- (4-methoxy-benzenesul-fonyl) -2,3,4,7-tetrahydro-lH-a-zepin-2-carboxylic acid: Calculated 473.5, Found (M) + 474; 3- (3, 3-Benzyl phenylureido) -1- (4-methoxy-benzenesulfonyl) -2,3,4,7,7-tetrahydro-1H-azepine-2-carboxylic acid: Calculated 535.6, Found (M) + 536; 3-Methoxycarbonylamino- 1- (4-methoxy-benzenesul fonyl) -2, 3, 4, 7-tert-rahydro-1H-azepine-2-carboxylic acid: Calculated 384.41, Found (M) + 385; 3- (Trifluoromethyl-4-benzyloxycarbonylamino) -1- (4-methoxy-benzenesul-fonyl) -2, 3, 4, 7-tet -hydro-1H-azepine-2-carboxylic acid: Calculated 528.5, Found (M) + 529; 3- (-chlorobenzyloxycarbonylamino) -1- (4-methoxy-benzenesul fonyl) -2, 3,, 7-tetrahydro-1H-azepine-2-carboxylic acid: Calculated 494.9, Found (M) + 495; 3- (3,5-dichlorobenzyloxycarbonylamino) -1- (4-methoxy-benzenesul fonyl) -2,3,4-7-trahydro-1H-azepine-2-carboxylic acid: Calculated 529.4, Found (M) + 530; Example 12 Using the procedures of the above general description, and the above examples, the compounds of Table I can be prepared to Bl a m Hit 4-ClPh-Ph H 0 1 PhCH2S02 4-ClPh-Ph OH 0 1 PhCH2S02 4-ClPh-Ph OMe or • 2 PhCH2? CO 4-ClPh-Ph Ph 1 1 PhCH20C0 4-ClP -Ph PirCH2 0 1 PhCH2S02 4-MeOPh-Ph H 0 1 P? 1CH2S02 4-Me? Ph-Ph OH 0 1 PhCH2S02 4-MeO h-Ph OMe 0 2 P1XCH 0CO 4-MeOPh-Ph Ph 1 1 PliCH20CO 4-MeOPh-Pi? P ± rCH2 0 1 PhCH2S02 4 - . 4 -Ph- 4 -piper i din - H 0 1 PhCH2S? 2 4-Ph -Pli- -piperidin-OH 0 1 PhCH2S? 2 4-P -Ph- 4 -pipe idin-OMe 0 2 P? 1CH20CO 4- Ph 4-Ph-4-piperidin - Ph 1 1 PhCH20CO 4-Ph 4-Ph-4-piperidi ?? - PirCH2 0 1 PhCH2S02 4-Ph 4 -benzoamidoPh H 0 1 PhCH2S02 4 -benzoamidoPh. OH 0 1 PhCK2S02 4 ^ be? ZoamidoPh OMe 0 2 PhCH2OC0 4-benzoamidoPii Ph 1 1 PhCH2? C0 -benz-oamidoPh PitCH2 0 1 PhCH2S02 4- iridil-ox, iPh H 0 1 FhCH2S02 4-p ± ridil-o? IPh OH 0 1 PhCH2S02 4-p ± ridil-oxypi? OMe 0 2 PhCH2? CO -pyridyloxy h Ph 1 1 PhCH20C0 4-pyridyl-oxyPh T? ± tCH2 0 1 PhCH2S? 2 Example 13 The following assays are in vitro assays, which were used to characterize the ability of the compounds of this invention to inhibit collagenase and is thromelysin: Human Neutrophil Collagenase Assay and Estromeli sine Test of Human Fibroblast.

Human Neutrophil Collagenase Assay The activity of human peutrophilic collagenase (HNC) is determined by the use of a fluorogenic peptide substrate Dnp-Pro-b-Cyclohexyl-Ala-Gly-Cys (Me) -His-Al a-Lys- (N-methylanthrani acid 1) ico) -NH2. The N-terminus Dnp group and the C-terminus N-methyl-anthranilyl portion (Nma) are fluorescent by rapid self-cooling, until the peptide is cleaved to the Gly-Cys (me) bond. The fluorescence of the cleavage products is measured in a fluorescent microplate reader Bio-Tek Instrument FL500 (excitation at 360 nm, emission at 460 nm). The assay was carried out in a 96-well plate (in duplicate), and Km = 52 nM for the substrate, and Ki = 722 nM for Actinonin were determined. The test compounds (at 100, 33 &10 nM) are compared by their inhibition of NHC activity on the substrate against the activity of Actinonin and Ki, were determined in the selected compounds.

Essay of Es romelisina of the Human Fibroblast The activity of the human fibroblast tromelis ina (HFS) is determined by the use of a fluorogenic peptide substrate Dnp-Pro-b-Cyclohexyl-Ala-Gly-Cys (Me) -His-Ala-Lys- (N- acid) methylanthranic acid) -NH2. The N-terminus Dnp group and the C-terminus N-methyl-anthranilyl portion (Nma) are rapidly self-cooling fluorescents, until the peptide is cleaved to the Gly-Cys (me) bond. The fluorescence of the cleavage products is measured in a fluorescent microplate reader Bio-Tek Instrument FL500 (excitation at 360 nm, emission at 460 nm). The assay was performed in a 96-well plate (in duplicate), and Km = 51 nM for the substrate was determined, and Ki = 722 nM for Actinonin (an inhibitor of enzymatic activity; Sigma Chemical, St. Louis, MO; A6671) as the standard control. The test compounds (at 100, 33 &10 nM) are compared by their inhibition of NHC activity on the substrate against Actinonin and Ki activity determined in the selected compounds.

The following compounds have an HNC and / or an inhibition of HFS IC50 activity of less than 10 μnM: 1- (4-methoxy-benzenesulfonyl) -3- (2-amino-phenylmethanesulfonic acid) -1 H-azepane-2-carboxylic acid; 1- (4-methoxy-benzenesul fonyl) -3- (phenylmethine sui phonylamino) -lH-azepane-2-carboxylic acid; - - - 1- (4-Chlorophenyl-phenylsulfonyl) -3- (phenylmet anosul fonilamino) -2, 3, 4, 7-tetrahydro-1H-azepine-2-carboxylic acid; 1- (4-Methoxy-benzenesul-fonyl) -3- (2-nitrophenyl-methanesulphonylamino) -2,3,4,7,7-tetrahydro-1H-azepine-2-carboxylic acid; 1- (4-methoxy-benzenesul fonyl) -3- (phenylacroi sulfonylamino) -2, 3, 4, 7-tetrahydro-lH-azepine-2-carboxylic acid; 3- (4-Chlorobenzyloxycarbonylamino) -1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-trahydro-1H-azepine-2-carboxylic acid; 3- (3,5-Dichlorobenzyloxycarbonylamino) -1- (4- (methoxy-benzenesul-fonyl) -2,3,4,7,7-tetrahydro-1H-azepine-2-carboxylic acid.

Treatment Methods All compounds of this invention are employed in the prophylaxis and treatment of conditions of conditions in which HNC and / or HFS and / or gelatinases may play a role. Preferably, the compounds of this invention are employed in the prophylaxis and treatment of rehu atoid arthritis; os teorarthritis; osteopenia (for example, osteoporosis); periodonti tis; gingivitis; corneal, epidemial and gastric ulceration; and tumor metastasis, invasion and growth; in neuroinflammatory disorders, such as myelin degradation (eg, multiple sclerosis); and in conditions dependent on angiogenesis, such as arthritic conditions; Cancer; solid tumor growth; psoriasis, proliferative retinopathies; neurovascular glaucoma; ocular tumors; angiofibromas; hemangiomas; nephritis; pulmonary inflammation; and restenosis.

The present invention provides a method of treating a condition of suffering in which the levels of HCN or HFS and / or gelatinases are high, which comprises administering an effective amount of a compound of this invention. The compounds of this invention are for use in the prophylaxis and acute or chronic therapy of any condition of suffering in a human or other mammal, which may contribute to the onset or etiology of, its exacerbated by or mediated by HCN and / or HFS and / or gelatinases elevated or not regulated by mammalian cells. More preferably, this invention relates to a method for decreasing the activity levels of HCN or HFS and / or gelatinases in a mammal in need thereof, which comprises administering an effective dose of a compound of this invention or a pharmaceutical composition of the invention. same.

A compound of this invention or a pharmaceutical composition thereof is employed in the treatment or prophylaxis of a number of disease conditions including rehumatoid arthritis; osteoarthritis; osteopenia (for example, osteoporosis); periodonti tis; gingivitis; corneal, epidermal and gastric ulceration; and tumor metastasis, invasion and growth; in "neuroinflammatory disorders, such as myelin degradation (e.g., multiple sclerosis), and in angiogenesis-dependent conditions, such as arthritic conditions, cancer, solid tumor growth, psoriasis, proliferative retinopathies, neurovascular glaucoma, ocular tumors; angiofibro ace, hemangiomas, nephritis, pulmonary inflammation, and restenosis.

Pharmaceutical Compositions This invention further relates to the use of a compound of this invention in the manufacture of a medicament for the prophylaxis and treatment, either acutely or chronically, of conditions of conditions in which the HNC and / or HSF and / or gelatinases they play a role This invention also relates to a pharmaceutical composition comprising a compound of this invention and a pharmaceutically acceptable carrier, if desired, other active ingredients. The compounds of this invention are administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in an effective dose for the proposed treatment. Therapeutically effective doses of the compounds of the present invention required to arrest the progress or prevent tissue damage associated with the conditions are easily ascertained by one skilled in the art.

For the prophylaxis and treatment of disease states, the compounds of the present invention can be administered orally, parenterally or by inhalation by atomization, rectally, or topically in unit dosage formulations containing conventional pharmaceutically acceptable carriers, adjuvants and vehicles. The term "parenteral," as used herein, includes intrasternal, intramuscular, intravenous, subcutaneous, or intraperitoneal infusion techniques.

The amount of effective ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration.

The dosage regimen for treating a condition of suffering with the compounds of this invention and / or compositions of this invention is based on a variety of factors, including the type of condition, 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, efficacy, pharmacokinetic and toxicological profiles of the particular compound employed, whether a drug delivery system is used and whether the compound is administered as part of a combination of drugs. Thus, the dosage regimen can vary widely. Dosage levels in the range of about 0.01 mg to 80 mg per kilogram of body weight per day, preferably from about 0.5 mg to 30 mg / kg, more preferably from about 1 mg to 15 mg / kg are used for all methods of treatment. use described here. The pharmaceutically active compounds of this invention can be processed in accordance with conventional pharmacy methods to produce medicinal agents for administration to patients, mammals including humans.

For oral administration, the pharmaceutical composition can be in the form of, for example, a capsule, tablet, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a given amount of the active ingredient. For example, these may contain an amount of active ingredient of about 1 to 250 mg, preferably about 25 to 150 mg. A suitable daily dose for a human or other mammal can vary widely depending on the condition of the patient and other factors.

The compounds of this invention can also be administered by injection as a composition with suitable carriers including saline, dextrose or water. The daily parenteral dosing regimen will be from about 0.1 to about 80 mg / kg of body weight, preferably from about 0.5 to about 30 mg / kg, and more preferably from about 1 mg to 15 mg / kg.

Injectable preparations, for example, sterile or oily injectable aqueous suspensions, can be formulated according to the known art using suitable dispersing agents or humectants. The sterile injectable preparation can 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. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspension medium. For this purpose any soft fixed oil may be employed including synthetic mono or di-glycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

Suppositories for rectal administration of drugs can be prepared by mixing the drug with a suitable non-irritating excipient such as cocoa butter and polyethylene glycols, which are solid at ordinary temperatures but liquid at rectal temperature and will therefore be fused in-the rectum and will release the drug.

A suitable topical dose of the compounds of this invention is from 0.1 mg to 150 mg administered one to four, preferably two or three times daily. For topical administration, the active ingredient may comprise from 0.001% to 10% w / w, for example, from 1% to 2% by weight of the formulation, although it may comprise as much as 10% w / w, but preferably no more of 5% w / w, and more preferably from 0.1% to 1% of the formulation. Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for preparation through the skin, such as liniments or ointments, lotions, ointments, creams or pastes, and drugs suitable for administration to the eye, ear, or nose.

For administration, the compounds of this invention are ordinarily combined with one or more adjuvants appropriate for the indicated route of administration. The compounds can be mixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, stearic acid, talc, magnesium stearate, sodium, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, acacia, gelatin , sodium alginate, polyvinylpyrrolidine, and / or polyvinyl alcohol, and in the form of tablets or encapsulated for conventional administration. Alternatively, the compounds of this invention can be dissolved in 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 well known in the pharmaceutical art. The carrier or diluent may include material released over time, such as glyceryl monostearate or glyceryl distearate alone or in combination with a wax, or other materials well known in the art.

The pharmaceutical compositions can be worked up into a solid form including granules, powders or suppositories or in a liquid form such as solutions, suspensions, or emulsions. The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and / or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc.

Solid dosage forms for oral administration may include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as in normal practice, additional substances, instead of inert diluents, for example, lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can be additionally prepared with enteric coatings or coatings.

Liquid dosage forms for oral administration may include pharmaceutically acceptable solutions, suspensions and elixiris emulsions containing inert diluents - commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweeteners, flavors and perfuming agents.

The compounds of the present invention may possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers, also as in the form of racemic or non-racemic mixtures thereof. The optical isomers can be obtained by resolution of the racemic mixtures in accordance with conventional processes, for example, by the formation of tereosisomeric salts by treatment with an optically active acid or base. Examples of suitable acids are tartaric acid, diacetyltartaric, dibenzoyl tartaric, ditoluoyl tartaric and camphorsulfonic and then, the separation of the mixture of diastereomers by crystallization, followed by the release of the optically active bases of these salts. A different process for the separation of optical isomers involves the use of an optimally selected chiral column chromatography to minimize the separation of the enantiomers. Yet other available methods involve the synthesis of covalent diastereomeric molecule molecules by reacting compounds of Formula I with an optically pure acid in an activated form or an optically pure isocyanate. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation and then hydrolyzed to release the enant ionically pure compound. The optically pure compounds of Formula I can likewise be obtained by the use of optically active initiator materials. These isomers may be in the form of a free acid, a free base, an ester or a salt.

The compounds of the present invention can be used in the form of salts derived from organic and inorganic acids. These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorrate, camphor sulfate, digluconate, cyclopentanepropionate, dodecyl sulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, me tanosul fonate, nicotinate, 2-naphthalenesulphonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate , tartrate, thiocyanate, tosylate, mesylate and undecanoate. Also, groups containing basic nitrogen can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl and butyl chloride, bromides and iodides; dialkylsulfates such as dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides, such as benzyl and phenethyl bromides, and others. With this, soluble or dispersible products are obtained in oil or water.

Examples of acids which can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid organic acids such as oxalic acid, maleic acid, succinic acid and citric acid. Other examples include salts with alkali metals or ferrous alkali metals, such as sodium, potassium, calcium or magnesium or with organic bases.

While the compounds of the invention can be administered as the active pharmaceutical agent alone, they can also be used in combination with one or more other agents.When administered as a combination, the therapeutic agents can be formulated as separate compositions, which are given at the same time or different times, or the therapeutic agents can be given as an individual composition, The foregoing is merely illustrative of the invention and is not intended to limit the invention to the described compounds. which are obvious to one skilled in the art, are proposed to be within the scope and nature of the invention which is defined in the appended claims .. From the above description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, it can make several changes and modifications of the invention to adapt it to the various used and conditions. It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention. Having described the foregoing, the property contained in the following is claimed as property:

Claims (23)

1. A compound of the formula I (i) or a pharmaceutically acceptable salt thereof, characterized in that ~~~ m is 1 or 2; and n is 0, 1 or 2; R1 is (1) an alkyl, alkenyl, cycloalkyl or heterocyclyl radical optionally substituted by 1-3 radicals of -OH, OR3, -SR3, -S (0) R3, -S (0) 2R3, -C (0) R 3, -NR 3 R 4, aryl, heteroaryl, cycloalkyl or heterocyclyl; or (2) an aryl radical optionally substituted by an optionally substituted monocyclic heterocyclic or heterocyclic radical of 5-6 elements in the ring which is optionally substituted by a phenyl radical or a monocyclic heteroaryl radical of 5-6 elements in the ring; or (3) a heteroaryl radical optionally substituted by an optionally substituted phenyl radical or a heteroaryl radical or 5- or 5- membered monocyclic heterocyclic ring, which is optionally substituted by a phenyl radical or a 5-6 membered monocyclic heteroaryl radical. in the ring; wherein the phenyl, aryl, heteroaryl, cycloalkyl and heterocyclyl radicals of (1), (2) and (3) are optionally substituted by 1-3 hydroxy radicals, OR3, -SR3, -S (0) R3, S ( 0) 2R3, -C (0) R3, -NR3R4, amino, acanoylamino, alkylsulfonylamino, alkoxycarbonylamino, alkoxycarbonyl, cyano, halo; azido, alkyl or haloacyl; provided that the total number of phenyl, aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in R1 is 0-3; wherein each R3 is independently an alkyl, haloalkyl, aryl, heteroaryl, 'arylalkyl or heteroaryl-alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3-hydroxyl, alkoxy, alkylthiol, amino, alkanoyl amino radicals, alkylsul fonyl amino, alkylsulfinyl, alkylsul fonyl, alkoxycarbonylamino, alkoxycarbonyl, cyano, halo, azido, to which, haloalkyl haloalkoxy each R is independently a hydrogen or alkyl radical; R, 11 is a radical -C (0) -R31, -C (0) -0R30, -C (0) -NR32R31, -S (0) 2 -R30 or -S (O) 2NR3: R31; wherein R5 and R6 are each independently a hydrogen or alkyl radical; or CR5-CR6 is C = C; wherein R9 and R10 are each independently provided that that combined total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in X, R? n and R11 is 0-3; wherein each B is independently a (1) link; (2) alkyl, alkenyl or alkynyl radical optionally substituted by (a) I-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano or halo radicals, and / or (b) radicals 1-2 of hetrocyclyl, aryl or heteroaryl optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, halo, alkyl, haloalkyl or haloalkoxy radicals; (3) heterocyclyl radical optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio cyano, alkyl, haloalkyl or haloalkoxy radicals; or (4) aryl or heteroaryl radical optionally substituted by 1-3 amino, alkylamino, dialkylamino, α-alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, halo, alkyl, haloalkyl or haloalkoxy radicals; each A is independently one (1) hydrogen radical; (2) radical halo, cyano or 30 nitro; (3) radical -C (0) -R, -C (0) - _ 31,, 32 31 32 32 31 31 OR, -C. { 0) -NR R O -C (NR) -NR R; (4) radical -OR, 31 32 31 33 3 -0-C. { 0) -R, -0-C. { 0) -NR R O -0-C (0 > -NR -S (0 > 2-R 3 30 30 32 31 (5) radical -SR, -S (0) -R, -S (0.}. -R, -S (0) 2-NR R, -S (0) 2-NR33-C (0) -R31, -S (0) 2-NR33-C (O) -OR30 or -S (0) 2-NR33- 32 31 _ 32 31 33 31 31 C { 0) -NR R; or radical (6) -NR R, -NR -C < 0) -R, -NR -,, 30 33 32 31 33 32 32 31 33 C (0) -OR, -NR -C (0) -NR R, -NR -C. { NR) -NR R, -NR - 30 33 32 31 S (0) 2-R or -NR -S (0) 2-NR R wherein each R30 is independently (1) alkyl radical, alkenyl or alkynyl optionally substituted by 1-3 radicals of -CO2R34, amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonyl, N- (alkoxycarbonyl) -N- (alkyl) amino, - aminocarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio radicals , alkylsulfinyl, alkylsulfonyl, cyano, halo or aralkoxy, arylalkyl, aryl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl radicals are optionally substituted by radicals 1-3 of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, alkanoyl, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl, haloalkyl or haloalkoxy; (2) heterocyclyl radical optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulinylamino, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, cyano, alkyl, haloalkyl or haloalkoxy radicals; or (3) an aryl or heteroaryl radical optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonic acid, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, cyano, halo, azido, alkyl, haloalkyl radicals or -haloalkoxy; wherein each R31 is independently a hydrogen radical or R30; wherein each R 32 is independently (1) a hydrogen radical; (2) an alkyl, alkenyl or alkynyl radical optionally substituted by 1-3 amino radicals, alkylamino, dialkylamino, hydroxy, alkoxy, alkylthio, cyano or halo radicals; or (3) aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or cycloalkylalkyl optionally substituted by 1-3 amino, alkylamino, dialkylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl, haloalkyl or haloalkoxy radicals; Y each R33 is independently (1) a hydrogen radical; (2) an alkyl radical optionally substituted by a heterocyclyl, aryl or heteroaryl radical which is optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl, haloalkyl or haloalkoxy; or (3) heterocyclyl, aryl or heteroaryl radical optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl, haloalkyl or haloalkoxy radicals; Y each R34 is independently hydrogen, alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio radicals , alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl, haloalkyl or haloalkoxy;

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that R1 is (1) a C 1 -C 2 alkyl, C 2 -C 12 alkenyl, C 2 -C 2 alkynyl / cycloalkyl or heterocyclyl radical. optionally substituted by 1-3 radicals of -OH, OR3, -SR3, -S (0) R3, -S (0) 2R3, -C (0) R3, -NR3R4, aryl, heteroaryl, cycloalkyl, or heterocyclyl; 'or (2) an aryl radical optionally substituted by a heterocyclyl radical or an optionally substituted monocyclic heteroaryl of 5-6 elements in the ring which is optionally substituted by a phenyl radical or a 5-6 element monocyclic heteroaryl radical in the ring; or (3) a heteroaryl radical optionally substituted by an optionally substituted phenyl or a heterocyclyl radical or a 5-6 membered monocyclic heteroaryl in the ring which is optionally substituted by a phenyl radical or a 5-6 membered monocyclic heteroaryl radical in the ring; wherein the phenyl, aryl, heteroaryl, cycloalkyl and heterocyclyl radicals of (1) (2) and (3) are optionally substituted by 1-3 hydroxy radicals, OR3, SR3, -S (O) R3, -S (O ) 2R- "-C (O) R- -NR3R4 amino, C?-C8 alkanoylamino, C fulf-C8 alkylarynylamino, C?-C8 alkoxycarbonylamino, C?-C8 alkoxycarbonyl, cyano, halo, azido, C alquilo-alkyl C or C? -C8 haloalkyl of 1-3 halo radicals, provided that the total number of phenyl, aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in R1 is 0-3; more preferably, each R3 is independently a C? -C8 alkyl, C? -C8 haloalkyl of 1-3 halo radicals, an aryl radical, heteroaryl, aryl C? -C alkyl or heteroaryl C1-C4 alkyl, wherein Aryl and heteroaryl radicals are optionally substituted by hydroxy radicals 1-3, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, amino, C 1 -C 8 alkanoylamino, C 1 -C 8 alkylsulfonylamino, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl C 1 -C 8 alkoxycarbonylamino, C 1 -C 8 alkoxycarbonyl, cyano, halo, azido, C 1 -C 4 alkyl- haloalkyl C 1 -Ca of 1-3 halo radicals or C 1 -C 4 haloalkoxy of 1-3 halo radicals; and each R 4 is independently a hydrogen radical or C 1 -C β alkyl; 1- is a radical -C (0) -R, -C (0) -OR, • C (O) -NR3ZR31, -S (0) 2 -R30 or -S (O) 2NR32R31; R "and R are each independently a hydrogen or alkyl radical, or CR5-CR6 is C = C;. wherein R9 and R10 are each independently -B-A, provided that that combined total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in R9, R10 and R11 is 0-3; wherein each B is independently a (1) link; (2) "a Ci-Cs alkyl radical, C2-C8 alkenyl or C2-C8 alkynyl, optionally substituted by (a) 1-3 amino, C1-C4 alkylamino, di (C1-C4 alkyl) amino, alkanoylamino radicals C1-C5, carbonylamide (C1-C4 alkoxy), alkylsulfonylamino C? ~ C4, hydroxy, C1-C4 alkoxy, Ci-C4 alkylthio, cyano or halo, and / or (b) 1-2 heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 amino, C1-C4 alkylamino, di (C1-C4 alkyl) amino, C1-C5 alkanoylamino, carbonylamino (C1-C4 alkoxy), alkylsulfonylamino C? ~ C4, hydroxy, C1-C4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl of 1-3 halo radicals or C 1 -C 4 haloalkoxy of halo radicals 1-2; (3) heterocyclyl radical optionally substituted by 1-3 moieties of amino, C 1 -C 4 alkylamino, di (dC 4 alkyl) amino, C 1 -C 5 alkanoylamino, carbonylamino (C 1 -C 4 alkoxy), alkylsulfonylamino Ci-C 4, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl of 1-3 halo radicals or C 1 -C 4 haloalkoxy of 1-3 halo radicals; or (4) aryl or heteroaryl radical optionally substituted by 1-3 amino, C1-C4 alkylamino, di (C1-C4 alkyl) amino, C1-C5 alkanoylamino, carbonylamino (C1-C4 alkoxy), alkylsulfonylamino Cj.-C4 radicals, hydroxy, C1-C4 alkoxy, alkylthio-d-C4, cyano, halo, C1-C4 alkyl, C6-8 haloalkyl of radicals 1-3 halo or C6-8 haloalkoxy of 1-3 halo radicals; each A is independently one (1) hydrogen radical; (2) radical halo, cyano or nitro (3) radical -C (0) -C (0) - 31 32 31 32 32 31 OR, -C. { 0) -NR R O -C (NR) -NR R; (4) radical 31 -OR '1. 30 30 32 31 (5) radical -SR, -S (0) -R, -S (0.}. -R, -S (0) 2 ~ NR R, -S (0) 2-NR33-C (0) -R31 , -S < 0) 2-NR33-C (O) -OR30 or -S (0) 2-NR33- 32 31, 32 31 33 31 33 C (0) -NR R; or radical (6) -NR R, -NR -C (0) -R, -NR-. , 30 33 32 31 33 32 32 31 33 C < 0) -0R, -NR -C (0) -NR R, -NR -C. { NR) -NR R, -NR - 30 33 32 31 S (0) 2-R or -NR -S (0) 2-NR R wherein each R30 is independently (1) a C? -C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl optionally substituted by 1-3 radicals of -C02R34, amino, C3-C4 alkylamino, di (alkyl) radicals C1-C4) amino, C1-C5 alkanoylamino, carbonylamino (C1-C4 alkoxy), N- ((C1-C4 alkoxy) carbonyl) -N- (C1-C4 alkyl) amino, aminocarbonylamino, alkylsulfonylamino C? -C4, hydroxy , C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, cyano, halo, aryl-C1-C4 alkoxy, aryl-alkyl C1-C4 alkyl, aryl-alkylsul fonyl C1-C4, cycloalkyl C3 -C8, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl radicals are optionally substituted by 1-3 amino, C1-C4 alkylamino, di (C1-C4 alkyl) amino, alkanoylamino C1.-C5 radicals , carbonylamino (C 1 -C 4 alkoxy), C 1 -C 4 alkylsulfonylamino, C 1 -C 5 alkanoyl, carbonyl (C 3 -C 4 coxy), hydroxy, C 1 -C 4 alkoxy C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, cyano, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, 1-3 halo radicals or C 1 -C 4 haloalkoxy of 1-3 halo radicals; (2) heterocyclyl radical optionally substituted by 1-3 moieties of amino, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, C 1 -C 5 alkanoylamino, carbonylamino (C 1 -C 4 alkoxy), C 1 -C 4 alkylsulfonylamino, carbonyl (to the C1-C4 coxi), hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl, C 1 -C 4 haloalkyl of 1- to 3-halo radicals or C 1 -C-haloalkoxy of 1-3 radicals halo; or (3) aryl or heteroaryl radical optionally substituted by 1-3 moieties of amino, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, C 1 -C 5 alkanoylamino, carbonylamino (C 1 -C 4 alkoxy), C 1 -C 4 alkylsulfonylamino, carbonyl (C 1 -C 4 alkoxy), hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, azido, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl radical 1 to 1 halo or C 1 -C 4 haloalkoxy radical 1 -3 halo; each R is independently hydrogen radical or R30; wherein each R32 is independently (1) a hydrogen radical; (2) a C 1 -C 8 alkyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl optionally substituted by 1-3 amino radicals, C 1 -C 4 alkylamino radical, di (C 1 -C 4 alkyl) amino, hydroxy, C 1 -C 6 alkoxy C4, C 1 -C 4 alkylthio, cyano or halo; or (3) aryl, heteroaryl, aryl-C1-C4 alkyl, heteroaryl-C1-C4 alkyl, heterocyclyl, heterocyclyl-C1-C4 alkyl, C3-C8 cycloalkyl or C3-C8 cycloalkyl-C1-C4 alkyl optionally susbtituted by 1-3 amino radicals, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl radical 1 3 halo or C1-C haloalkoxy of 1-3 halo radicals; and each R33 is independently one (1) hydrogen radical; (2) C 1 -C 4 alkyl radical optionally substituted by a heterocyclyl, aryl or heteroaryl radical which is optionally substituted by 1-3 amino, C 1 -C 4 alkylamino, di (C 1 -C 4) amino, and C 1 -C 5 alkanoylamino radicals , carbonylamino (C 1 -C 4 alkoxy), C 1 -C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, cyano, halo, C 1 -C 4 alkyl, C 1 -C 9 haloalkyl C4 of 1-3 halo radicals or C1-C4 haloalkoxy of 1-3 halo radicals; or (3) heterocyclyl, aryl or heteroaryl radical optionally substituted by 1-3 amino, C? -C4 alkylamino, di (C1-C4 alkyl) amino, C1-C5 alkanoylamino, carbonylamino (C1-C4 alkoxy), alkylsulfonylamino C1- radicals C 4, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulphs, cyano, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl of 1-3 halo radicals or C 1 -C 4 haloalkoxy radicals 1-3 halo; Y each R34 is independently a hydrogen radical or C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C4 alkyl or heteroaryl-C1-C4 alkyl, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 amino, alkylamino radicals C? -C4, di (C? -C4 alkyl) amino, C1-C5 alkanoylamino, carbonylamino (C1-C4 alkoxy), alkylsulfonylamino C? -C4 hydroxy, C1-C4 alkoxy, Ci-C4 alkylthio, C1-C4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, cyano, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl of 1-3 halo radicals or C 1 -C 4 haloalkoxy of 1-3 halo radicals; Y wherein the cycloalkyl is a monocyclic, bicyclic or tricyclic carbocyclic alkyl radical of 3-10 elements in the ring, which is benzo fused or optionally partially unsaturated; heterocyclyl is a radical of a saturated monocyclic or bicyclic heterocyclyl ring system having 5-8 ring elements per ring, wherein 1-3 ring elements are oxygen, sulfur or nitrogen heteroatoms, which are optionally partially unsaturated or benzo fused optionally substituted by 1-2 oxo or thioxo radicals; aryl is a phenyl, bifido or naphthyl radical; and heteroaryl is a radical of a heterocyclic or aromatic bicyclic heterocyclic ring system having 5-6 ring elements per ring, wherein 1-3 ring elements are oxygen, sulfur or nitrogen heteroatoms, which are optionally benzofused or C-3-C4 carbocyclic fused saturated.

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, characterized in that R1 is (1) a C -Cj alkyl radical. C2-C12 alkenyl, C2-Ci2 alkynyl cycloalkyl or heterocyclyl optionally substituted by 1-3 radicals of -OH, OR3, -SR3, -S (0) R3, -S (0) 2R3, -C (0) R3, -NR3R4, aryl, heteroaryl, cycloalkyl, or heterocyclyl; or (2) an aryl radical optionally substituted by a heterocyclyl radical or an optionally substituted monocyclic heteroaryl of 5-6 elements in the ring which is optionally substituted by a phenyl radical or a 5-6-element monocyclic heteroaryl radical "in the ring or (3) a heteroaryl radical optionally substituted by an optionally substituted phenyl or a heterocyclyl radical or a 5-6-membered monocyclic heteroaryl on the ring which is optionally substituted by a phenyl radical or a 5-6 membered monocyclic heteroaryl radical in the ring; wherein the phenyl, aryl, heteroaryl, cycloalkenyl and hetrocyclyl radicals of (1) (2) and (3) are optionally substituted by 1-3 hydroxy radicals, OR3, -SR3, -S (0) R3, -S ( 0) 2R3, -C (0) R3, -NR3R4, amino, Ci-Cß alkanoylamino to C 1 -C 8 -cycloalkylcarbonylamino C 1 -C 8 alkoxycarbonyl, cyano, halo, azido, C?-C8 alkyl or C? -C8 haloalkyl of 1-3 halo radicals; provided that the total number of phenyl, aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in R1 is 0-3; each R is independently a C 1 -C 4 alkyl, C 1 -C 4 haloalkyl of 1-3 halo radicals, an aryl radical, heteroaryl, aryl C 1 -C 4 alkyl or heteroaryl C 1 -C 4 alkyl, wherein the aryl and heteroaryl radicals are optionally substituted by hydroxy radicals 1-3, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkanoylamino, C 1 -C 4 alkylsulfonylamino, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkoxycarbonylamino, alkoxycarbonyl C1-C4, cyano, halo, azido, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals or C1-C4 haloalkoxy of 1-3 halo radicals; and each R 4 is independently a hydrogen or C 1 -C 4 alkyl radical; wherein each B is independently a (1) link; (2) a C?-C8 alkyl radical, optionally substituted by (a) an amino radical, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, C 1 -C 5 alkanoylamino, carbonylamino (C 1 -C 4 alkoxy), alkylsulfonylamino C1-C4, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano or halo, and / or (b) 1-3 halo radicals, and / or (c) 1-2 heterocyclyl, aryl or optionally substituted heteroaryl radicals by amino 1-3 radicals, C1-C4 alkylamino, di (C1-C4 alkyl) amino, C1-C5 alkanoylamino, carbonylamino (C1-C4 alkoxy), alkylsulfonylamino Ci-C4, hydroxy, C1-C4 alkoxy, alkylthio C? -C4, cyano, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals or C1-C4 haloalkoxy of 1-3 halo radicals; (3) heterocyclyl radical; or (4) aryl or heteroaryl radical optionally substituted by 1-3 amino, C1-C4 alkylamino, di (C1-C4 alkyl) amino, alkanoylamino Cj-Cs, carbonylamino (C1-C4 alkoxy), alkylsulfonylamino C? ~ C4 radicals , hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl of 1-3 halo radicals or C 1 -C haloalkoxy of 1-3 halo radicals; wherein each R30 is independently (1) a C? -C6 alkyl radical optionally substituted by 1-3 radicals of -C02R34, amino, C1-C4 alkylamino, di (C? -C4 alkyl) amino, C1-C5 alkanoylamino radicals, carbonylamino (C 1 -C 4 alkoxy), N- ((C 1 -C 4 alkoxy) carbonyl) -N- (C 1 -C 4 alkyl) amino, aminocarbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, cyano, halo, aryl-C 1 -C 4 alkoxy, aryl-C 1 -C 4 alkyl, aryl-C 1 -C 4 alkylsulfonyl, C 3 -C 8 cycloalkyl, heterocyclyl, aplo or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl radicals are optionally substituted by 1-3 amino, C1-C4 alkylamino, di (C1-C4 alkyl) amino, C1-C5 alkanoylamino, carbonylamino (C1-C4 alkoxy), alkylsulfonylamino Cj radicals. C4, C 1 -C 5 alkanoyl, carbonyl (C 1 -C 4 alkoxy), hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, cyano, halo, C 1 -C alkyl, haloalkyl C1-C4, of 1-3 halo radicals or C1-C4 haloalkoxy of 1-3 halo radicals; (2) heterocyclyl radical optionally substituted by 1-3 moieties of amino, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, C 1 -C 5 alkanoylamino, carbonylamino (C 1 -C 4 alkoxy), C 1 -C 4 alkylsulfonylamino, carbonyl ( C 1 -C 4 alkoxy) / hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl of 1-3 halo radicals or C 1 -C 4 haloalkoxy; or (3) aryl or heteroaryl radical optionally substituted by 1-3 moieties of amino, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, C 1 -C 5 alkanoylamino, carbonylamino (C 1 -C 4 alkoxy), C 1 -C 4 alkylsulfonylamino, carbonyl (C1-C4 alkoxy), hydroxy, C1-C4 alkoxy / CrC4 alkylthio, cyano, halo, azido, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals or C1-C4 haloalkoXi of radicals 1-3 halo; each R31 is independently hydrogen radical or R30; wherein each R 32 is independently a hydrogen radical or C 1 -C 4 alkyl; each R33 is independently a hydrogen radical or a C? -C alkyl radical; Y each R34 is independently a hydrogen radical or C1-C4 alkyl.

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, characterized in that RJ is (1) a C1-C1 alkyl radical; optionally substituted by 1-3 radicals of -OH, OR3, -SR3, S (O) R3, -S (O) R3, • C (0) R3, -NR3R4, aryl, heteroaryl, cycloalkyl, or heterocyclyl; or (2) an aryl radical optionally substituted by a heterocyclyl radical or an optionally substituted monocyclic heteroaryl of 5-6 elements in the ring which is optionally substituted by a phenyl radical or a monocyclic heteroaryl radical of 5-6 elements in the ring; or (3) a heteroaryl radical optionally substituted by an optionally substituted phenyl or a heterocyclyl radical or a 5-6 membered monocyclic heteroaryl in the ring which is optionally substituted by a phenyl radical or a 5-6 membered monocyclic heteroaryl radical in the ring; wherein the phenyl, aryl, heteroaryl, cycloalkenyl and hetrocyclyl radicals of (1) (2) and (3) are optionally substituted by 1-3 hydroxy radicals, OR3, -SR3, -S (0) R3, -S ( 0) 2R 3, -C (0) R 3, -NR 3 R 4, amino, acetylamino, methylsulfonylamino, C 1 -C 4 alkoxycarbonylamino, C 1 -C 4 alkoxycarbonyl, halo, C 1 -C 6 alkyl or -JCF 3; provided that the total number of phenyl, aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in R1 is 0-3; wherein each R3 is independently a C1-C4 alkyl, -CF3, aryl, heteroaryl, arylalkyl or heteroaryl-C1-C4 alkyl, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 hydroxy radicals , C 1 -C 4 alkoxy, C 1 -C 4 alkylthiol, amino, acetylamino, methylsulfonylamino, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkoxycarbonylamino, C 1 -C 4 alkoxycarbonyl, cyano, halo, Ci-C alkyl, -CF 3 or -0CF 3; and each R4 is independently a hydrogen or methyl radical; wherein each B is independently a (1) link; (2) a C 1 -C 8 alkyl radical, optionally substituted by (a) an amino, C 1 -C 4 alkylamino, di (C 1 -C) amino, C 1 -C 5 alkanoylamino, carbonylamino (C 1 -C 4 alkoxy) radical. , C 1 -C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano or halo, and / or (b) 1-3 halo radicals, and / or (c) 1-2 heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 moieties of amino, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, C 1 -C 5 alkanoylamino, carbonylamino (C 1 -C 4 alkoxy), C 1 -C 4 alkylsulfonylamino, hydroxy, C 1 -C 6 alkoxy C 4, C 1 -C 4 alkylthio, cyano, halo, C 1 -C 4 alkyl, -CF 3 or -0CF 3; (3) heterocyclyl radical; or (4) aryl or heteroaryl radical, optionally substituted by 1-3 amino, C1-C4 alkylamino, di (C1-C4 alkyl) amino, alkanoylamino Ca-C5, carbonylamino (C1-C4 alkoxy), alkylsulfonylamino Cj.- radicals C4, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl, -CF3 or -0CF3; each A is independently a (I) hydrogen radical; 2) radical halo, cyano or nitro 3) radical -C (O) -R30, -C (0) -OR31, C (0) -NR32R31 -C (NR32) -NR32R31; (4; radical -OR 31 0-C (0) -R- O • 0-C (0) -NRJ 3"2R-T- 31 (5) radical SR31, -S (0) -R 30 -S (0) 2-R 30 -S (0) 2- NR32R31; or (6) radical -NR32R31, -NR33-C (0) -R31 NR 33 C (0) -OR 30 -NR33-C (0) NR3 R31 NR 3J3O-C (NR 3J2i) -NRJiRJ1, -NR, 3J3J-S (O) 2-R 30 -NR33-S (O) 2-NR32R31; wherein each R30 is independently (1) a C? -C6 alkyl radical, optionally substituted by 1-3 radicals of -C02R34, amino, C? -C4 alkylamino, di (C? -C) amino, alkanoylamino C? -C5 / carbonylamino (C? -C4 alkoxy), N- ((C? -C) alkoxycarbonyl) -N- (C1-C4 alkyl) amino, aminocarbonylamino, alkylsulfonylamino "" - C1-C4, hydroxy, C1-6 alkoxy C4, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, cyano, halo, aryl-C1-C4 alkoxy, aryl-alkyl C1-C4 alkyl, aryl-alkylsulfoyl C1-C4, C3-C8 cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl radicals are optionally substituted by 1-3 amino, alkylamino C? ~ C4, di (C 1 -C 4 alkyl) amino, C 1 -C 5 alkanoylamino, carbonylamino (C 1 -C 4 alkoxy), C 1 -C 4 alkylsulfonylamino, C 1 -C 5 alkanoyl, carbonyl (C 1 -C 4 alkoxy), hydroxy, C 1 -C 4 alkoxy C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, cyano, halo, C 1 -C 4 alkyl -CF 3 or -0CF 3; (2) heterocyclyl radical optionally substituted by 1-3 moieties of amino, C 1 -C 4 alkylamino, di- (C 1 -C 4 alkyl) amino, C 1 -C 5 alkanoylamino, carbonylamino (C 1 -C 4 alkoxy), C 1 -C 4 alkylsulfonylamino, carbonyl ( C 1 -C 4 alkoxy), hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl of 1-3 halo radicals or -0CF 3; or (3) aryl or heteroaryl radical optionally substituted by 1-3 amino, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, C 1 -C 5 alkanoylamino, carbonylamino (C 1 -C 4 alkoxy), C 1 -C 4 alkylsulfonylamino radicals , carbonyl (coxy C? -C4), hydroxy, C-C4 alkoxy, C1-C4 alkylthio, cyano, halo, azido, C? -C4 alkyl, -CF3 or -0CF3; each R31 is independently radical hydrogen or Y each R33 is independently a hydrogen or methyl radical.

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, characterized in that R is a radical -C (0) R, 31 O-S (0) 2-R, 30; provided that the combined total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in R9, R10 and R11 is 0-2.

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, characterized in that R1 is (1) a C? -C? 2 alkyl radical, optionally substituted by 1-3 radicals of -OH, OR3, -SR3, S (0) R3, -NR3R4, aryl, heteroaryl, cycloalkyl, or heterocyclyl; or ^ (2) an aryl radical optionally substituted by a heterocyclyl radical or an optionally substituted monocyclic heteroaryl of 5-6 elements in the ring which is optionally substituted by a phenyl radical or a 5-6 element monocyclic heteroaryl radical in the ring; or (3) a heteroaryl radical optionally substituted by an optionally substituted phenyl or a heterocyclyl radical or a 5-6-membered monocyclic heteroaryl in the ring which is optionally substituted by a phenyl radical or a 5-6 membered monocyclic heteroaryl radical in the ring; wherein the phenyl, aryl, heteroaryl, cycloalkenyl and hetrocyclyl radicals of (1) (2) and (3) are optionally substituted by 1-3 hydroxy radicals, OR3, -SR3, -S (0) 2R3, NR3R4, amino , acetylamino, methylsulfoni lamino, alkoxycarbonylamino C? -C4 / alkoxycarbonyl C? -C4, cyano, halo, C? -C6 alkyl or radicals -CF3; provided that the total number of phenyl, aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in R1 is 0-2; wherein each R is independently a C 1 -C 4 alkyl radical, -CF, aryl, heteroaryl, aryl C 1 -C 4 alkyl or heteroaryl C 1 -C 2 alkyl, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 hydroxy radicals, C 1 -C 4 alkoxy, C 1 -C 4 alkylthiol, amino, acetylamino, methylsulphonylamino, C 1 -C 4 alkylsul onyl, C 1 -C 8 alkoxycarbony, C 1 -C 8 alkoxycarbonyl, cyano, halo, C 1 -C 4 alkyl, -CF 3 or -OCF 3; wherein each B is independently a (1) link; (2) a C 1 -C 4 alkyl radical, optionally substituted by (a) an amino radical, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, C 1 -C 2 alkanoylamino, carbonylamino (C 1 -C 4 alkoxy), hydroxy, C 1 -C 2 alkoxy, and / or (b) 1-2 halo radicals, and / or (c) a heterocyclyl, aryl or heteroaryl radical optionally substituted by 1-2 amino radicals, C 1 -C 2 alkylamino, di (Cinylamino alkyl, C 1 -C 4 alkanoylamino, carbonylamino (C 1 -C 4 alkoxy), C 1 -C 2 alkylsulfonylamino, hydroxy, C 1 -C 2 alkoxy, C 1 -C 2 alkylthio, halo, C 1 -C 4 alkyl or C 3 -C 3 or (3) heterocyclyl radical, or (4) aryl or heteroaryl radical optionally substituted by 1-2 amino, C1-C2 alkylamino, di (C? -C) alkyl amino, C1-C2 alkanoylamino, carbonylamino (C1-6 alkoxy) radicals C4), alkylsulfonylamino d.-C2, hydroxy, C2-C2 alkoxy, C1-C2 alkylthio, halo, C1-C4 alkyl, -CF3 or -0CF3; each A is independently one (1) hydrogen radical; (2) radical halo, (3 radical -C (0) -R 30 • C (O) -OR 31 -C (O) -NRJ 3; "DR31 (4) radical -OR31; (5) radical -SR31, -S (0) 2-NR30 -S (O) 2 -NRJ 3i2R- 31. O (6) radical .NR32R3I • NR 33 • C (O) -R 31 NR 3-C (O) -OR30, -NR33-C (0) - NR32R31, -NR33-S (O) 2-R30 NR 3"3-S (O) - NR32R31 wherein each R30 is independently (1) -CF3, a C? -C4 alkyl radical / optionally substituted by 1-2 radicals of -C02R34, amino, C? -C2 alkylamino / di (C1-C4 alkyl) amino, alkanoylamino C? ? -C2, carbonylamino (C1-C4 alkoxy), N- ((C1-C4 alkoxy) carbonyl) -N- (C1-C4 alkyl) amino, hydroxy, C1-C4 alkoxy or aryl-C? -C2 heterocyclyl alkoxy, aryl or heteroaryl, wherein the heterocyclyl, aryl and heteroaryl radicals are optionally substituted by 1-3 amino, C 1 -C 2 alkylamino, di (C 1 -C 4) amino, C 1 -C 2 alkanoylamino, carbonylamino (C 1 -C 6) alkoxy radicals C4), C1-C5 alkanoyl, carbonyl (C1-C4 alkoxy), hydroxy, halo, C1-C4 alkyl-, CF3 or -OCF3; (2) heterocyclyl radical optionally substituted by 1-2 carboni 1 radicals (C 1 -C 4 alkoxy), hydroxy or C 1 -C 4 alkyl; or (3) aryl or heteroaryl radicals, optionally substituted by 1-2 amino radicals, C 1 -C 2 alkylamino, di- (C 1 -C 2 alkyl) amino, C 1 -C 2 alkanoylamino, hydroxy, C 1 -C 2 alkoxy, halo, C 1 -C 4 alkyl, -CF 3 or -OCF 3; each R31 is independently hydrogen radical or wherein the cycloalkyl is a carbocyclic, monocyclic, bicyclic or tricyclic alkyl radical of 3-10 elements in the ring, which is benzo fused or optionally partially unsaturated; and heterocyclyl is a radical of a saturated monocyclic or bicyclic heterocyclyl ring system having 5-8 ring elements per ring, wherein 1-3 ring elements are oxygen heteroatoms, nitrogen sulfur, which are optionally partially not saturated or benzo fused optionally substituted by 1-2 oxo or thioxo radicals;

7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, characterized in that: R1 is (1) a C?-C4 alkyl radical, optionally substituted by 1-2 radicals of -OH, OR3, -NR3Rd, aryl, heteroaryl; or (2) an aryl radical optionally substituted by a 5-6 element monocyclic heteroaryl radical; or (3) a heteroaryl radical optionally substituted by a phenyl radical; wherein the phenyl, aryl and heteroaryl radicals of (1) (2) and (3) are optionally substituted by hydroxy radicals 1-2, OR, -SR, -S (0) 2R, --NNRR3 ~ RR4 ^, amino, acetylamino, methylsulphonylamino, C 1 -C 4 alkoxycarbonylamino, C 1 -C 4 alkoxycarbonyl, halo, Ci-Cß alkyl or -CF 3 radicals; provided that the total number of phenyl, aryl and heteoaryl radicals, in R1 is 0-2; wherein each R3 is independently a C alquilo ~C, -CF 3, aryl, heteroaryl, arylalkyl C?-C2, or heteroaryl-C C-C2 alkyl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of hydroxy, C 1 -C 2 alkoxy, C 3 -C 2 alkylthiol, amino, acetylamino, methylsulphonylamino, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkoxycarbonylamino, C 1 -C 4 alkoxycarbonyl, halo, C 1 -C 4 alkyl, -CF 3 or - 0CF3; wherein each B is independently a (1) link; (2) a C 1 -C 4 alkyl radical; or (3) aryl or heteroaryl radical optionally substituted by an amino, alkylamino Ci-C2, di (C? -C2) amino, alkanoylamino Cj.-C2 / carbonylamino (C1-C4 alkoxy), alkylsulfonylamino Ci-C2 radical, hydroxy, C 1 -C 2 alkoxy / C 1 -C 2 alkylthio, halo, C 1 -C 4 alkyl, -CF 3 or -0CF 3; each A is independently one (1) hydrogen radical; (2) halo radical; (3) radical -C (0) -R30, -C (O) -NR32R31 -C (NR32) -NR32R31 (4) radical -OR, 31, • (5) radical -SR31, -S (0) 2- NR30 -S (O) 2-NR ^ '(6) radical -NR "R; -NR, 3J3J-C (or; -R 3; 1 or UR- • S (0) 2-R 30 wherein each R30 is independently (1) heterocyclyl radical optionally substituted by 1-2 carbonyl radicals (to C co-C4 coxy), hydroxy or C?-C4 alkyl, or (2) heteroaryl radicals optionally substituted by 1-2 amino radicals, alkylamino C? ~ C2 / di (C? -C2 alkyl) amino, C? -C2 alkanoylamino, hydroxy, C? -C2 alkoxy, halo, C? -C4 / -CF3 or -0CF3 alkyl; each R31 is independently hydrogen or radical. (1) -CF3 radical or C1-C4 alkyl optionally substituted by hydroxy 1-2 radicals, C? -C2 alkoxy or aryl-C? -C2 alkoxy, aryl or heteroaryl radicals, wherein the aryl and heteroaryl radicals are optionally substituted by amino radicals 1-2, alkylamino C? -C2 radicals, di (C? -C2 alkyl) amino, C? -C2 alkanoylamino, lamino carboni (C1-C4 alkoxy), C1-C5 alkanoyl, c-rbonyl (C1-alkoxy) -C4), hydroxy, C? -C4 alkoxy, halo, C? -C / -CF3 alkyl or -OCF3; or (2) aryl or heteroaryl radical optionally substituted by 1-2 amino radicals, C 1 -C 2 alkylamino radicals, di (C 1 -C 2 alkyl) amino, C 1 -C 2 alkanoylamino, hydroxy, C 1 -C 2 alkoxy, halo , to what the C? -C < • CF3 -OCF3;

8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, characterized in that R1 are aryl or heteroaryl radicals optionally substituted by 1-hydroxy radicals, -OR3, SR3, -S (0) 2R3, -NR3R4, amino, acetylamino, methylsulfonylamino, C1-C4 alkoxycarbonylamino, C1-C4 alkoxycarbonyl, halo, alkyl C? -C6 or radicals -CF3; provided that the total number of aryl and heteroaryl radicals in R1 is 1-2; more preferably, each R3 is independently a C1-C4 alkyl, -CF3, aryl, heteroaryl, arylmethyl or heteroarylmethyl radical; wherein each A is independently one (1) bond (2) a C 1 -C 4 alkyl radical; (3) an aryl or heteroaryl radical; each, 30 is independently a heterocyclyl radical optionally substituted by C 1 -C 4 alkyl; more preferably, Rjl is independently hydrogen radical or (1) -CF3 radical or C1-C4 alkyl optionally substituted by 1-2 aryl or heteroaryl radicals; or (2) an aryl or heteroaryl radical; Y wherein each R32 is independently a hydrogen or methyl radical.

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, characterized in that R1 is an aryl radical optionally substituted by radicals 1-2 of hydroxy, -OR3, -S (0) 2R3 ^ -NR3R4, amino, acetylamino, methylsulphonylamino, halo, C1-C4 alkyl or radicals -CF ^; and provided that the total number of aryl radicals, heteroaryl, in R1 is preferably 1-2; R5, R6, and R9 are each a hydrogen radical; or CR5-CR6 is C = C; Y wherein heterocyclyl is a radical of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, 4-benzyl-1-piperazin-1-yl, pyrimidinyl, tetrahydrofuryl, pyrazolidinyl, pyrazolinyl, pyridazinonyl, pyrrolidonyl, tetrahydrothienyl or their sulfide and sulfone derivatives, 2,3-dihydroindolyl, tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinolinyl, 1, 2, 3, 4-tetrahydro-1-oxo-isoquinolinyl, 2,3-dihydrozofuryl, benzopyranyl, methylenedioxy phenyl, ethylenedioxy phenyl; aryl is a phenyl, biphenyl or naphthyl radical; and heteroaryl is an imidazolyl, pyrrolyl, pyrazolyl, pyridyl, pyrazinyl, triazolyl, furyl, thienyl, oxazolyl, thiazolyl, indolyl, quinolinyl, isoquinolinyl, 5, 6, 7, 8-1-tetrahydroquinolyl, 5,6,7, 8-tetrahydroisoquinolinyl, quinoxalinyl, benzothiazolyl, β-carbolinyl, benzofuryl, benzimidazolyl or benzoxazole 1-yl.

10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, characterized in that R1 is a phenyl or biphenyl radical optionally substituted by radicals 1-2 of hydroxy, -OR3, S (0) 2R3 / -NR3R4, amino, acetylamino, methylsulphonylamino, halo, C1-C4 alkyl or -CF3 radicals; provided that the total number of aryl radicals, heteroaryl in R1 is 1-2; wherein each R 3 is independently a C 1 -C 4 alkyl radical -CF 3, phenyl, heteroaryl, phenylmethyl or heteroarylmethyl; Y wherein heterocyclyl is a pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, -benzyl-piperazin-1-yl or pyrimidinyl radical; and heteroaryl is an imidazolyl, pyrrolyl, pyrazolyl, pyridyl, pyrazinyl, indolyl, quinolinyl, isoquinolinyl, benzothiazolyl, bezofuryl, benzimidazolyl or benzoxazoyl radical.

11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, characterized in that R1 is a phenyl or biphenyl radical optionally substituted by radicals 1-2 of hydroxy, -OR3, halo, methyl or CF3; provided that the total number of aryl radicals, heteroaryl in R1 is 1-2; Y wherein each R3 is independently a methyl radical, -CF3, phenyl, heteroaryl, phenylmethyl or heteroarylmethyl.

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, characterized in that it is 1- (4-methoxy-benzenesul fonyl) -3- (2-amino-phenylmethanesulphoniclamino) -lH-azepane-2-carboxylic acid; 1- (4-methoxy-benzenesul fonyl) -3- (enylmethanesulphonylamino) -lH-azepane-2-carboxylic acid; 1- (4-chlorophenyl-phenylsulfonyl) -3- (phenylmethanesulphonylamino) -2, 3,, 7-tetrahydro-1H-azepine-2-carboxylic acid; 1- (4-Methoxy-benzenesul-fonyl) -3- (2-nitrophenyl-methanesulphonylamino) -2,3,4,7,7-tetrahydro-1H-azepine-2-carboxylic acid; 1- (4-Methoxy-benzenesul-fonyl) -3- (phenylacroylsul phonylamino) -2,3,4,7,7-tetrahydro-1H-azepine-2-carboxylic acid; 3- (4-Chlorobenzyloxycarbonylamino) -1- (4-methoxy-benzenesulfonyl) -2, 3, 4, 7-tetrahydro-1H-azépin-2-carboxylic acid; 3- (3,5-Dichlorobenzyloxycarbonylamino) -1- (4- (methoxy-benzenesulfonyl) -2,4,4,7-tetrahydro-1H-azepine-2-carboxylic acid.

13. A pharmaceutical composition characterized in that it comprises a compound of claims 1 to 12, and a pharmaceutically acceptable carrier.

14. A method for the treatment or prophylaxis of inflammation, characterized in that it comprises administering an effective amount of a compound of claims 1 to 12.

15. A method for the treatment or prophylaxis of inflammation, characterized in that it comprises administering an effective amount of a compound of claim 13.

16. A method for the treatment or prophylaxis of connective tissue degradation, characterized in that it comprises administering an effective amount of a compound of claims 1 to 12.

17. A method for the treatment or prophylaxis of connective tissue degradation, characterized in that it comprises administering an effective amount of a compound of claim 13.

18. A method of treating neuroinflammatory disorders or conditions that depend on angiogenesis characterized in that it comprises administering an effective amount of a compound of claims 1 to 12.

19. A method of treating neuroinflammatory disorders or conditions that depend on angiogenesis characterized in that it comprises administering an effective amount of a composition of claim 13.

20. A method of treating rehumatoid arthritis; osteoarthritis; osteopenia, periodont itis; gingivitis; corneal ulceration, epidermal gastric, tumor metastasis, tumor invasion, tumor growth, myelin degradation, cancer, psoriasis, proliferative retinopathies, neovascular glaucoma, oculi tumors, angiofibromas, hemangiomas, nephritis; pulmonary inflammation or -restenosis comprising administering an effective amount of a compound of claims 1 to 12.

21. A method of treating rehumatoid arthritis; osteoarthritis; osteopenia, periodontitis; gingivitis; corneal ulceration, epidermal gastric, tumor metastasis, tumor invasion, tumor growth, myelin degradation, cancer, psoriasis, proliferative retinopathies, neovascular glaucoma, oculi tumors, angiofibromas, hemangiomas, nephritis; pulmonary inflammation or restenosis comprising administering an effective amount of a composition of claim 13.

22. Use of a compound of claims 1 to 12 for the preparation of a composition for use in the treatment or prophylaxis of inflammation. 23. Use of a compound of claims 1 to 12 for the preparation of a composition for use in the treatment or prophylaxis of connective tissue degradation. 24. Use of a compound of claims 1 to 12 for the preparation of a composition for use in the treatment of neuroinflammatory disorders or disorders dependent on angiogenesis.

23. Use of a compound of claims 1 to 12 for the preparation of a composition for use in the treatment of rehumatoid arthritis; osteoarthritis; osteopenia, periodont itis; gingivitis; corneal ulceration, epidermal gastric, tumor metastasis, tumor invasion, tumor growth, myelin degradation, cancer, psoriasis, proliferative retinopathies, neovascular glaucoma, oculi tumors, angiofibromas, hemangiomas, nephritis; pulmonary inflammation or restenosis.