Novel Compounds and Compositions as Cathepsin Inhibitors

Abstract

The present invention relates to novel cathepsin S inhibitors, the pharmaceutically acceptable salts and N-oxides thereof, their uses as therapeutic agents and the methods of their making.

1 . A compound of Formula I:  
     
       
         
         
             
             
         
       
     
     in which: 
 X 1  and X 2  are both methylene or X 1  is ethylene and X 2  is a bond;  
 R 3  is —CR 5 ═CHR 6 , —CR 5 (CR 6   3 ) 2  or —CR 7 ═NR 8 , wherein R 5  is hydrogen and R 6  is hydrogen or (C 1-4 )alkyl or R 5  and R 6  together with the atoms to which R 5  and R 6  are attached form (C 3-12 )cycloalkenyl, hetero(C 5-12 )cycloalkenyl, (C 6-12 )aryl, hetero(C 6-12 )aryl, (C 9-12 )bicycloaryl or hetero(C 8-12 )bicycloaryl and R 7  and R 8  together with the atoms to which R 7  and R 8  are attached form hetero(C 5-12 )cycloalkenyl, hetero(C 6-12 )aryl or hetero(C 8-12 )bicycloaryl, wherein R 3  optionally is substituted by 1 to 5 radicals independently selected from a group consisting of (C 1-4 )alkyl, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, —X 4 NR 9 R 9 , —X 4 OR 9 , —X 4 SR 9 , —X 4 C(O)NR 9 R 9 , —X 4 C(O)OR 9 , —X 4 S(O)R 10 , —X 4 S(O) 2 R 10  and —X 4 C(O)R 10 , wherein X 4  is a bond or (C 1-2 )alkylene, R 9  at each occurrence independently is hydrogen, (C 1-3 )alkyl or halo-substituted (C 1-3 )alkyl and R 10  is (C 1-3 )alkyl or halo-substituted (C 1-3 )alkyl; and  
 R 4  is —C(O)X 5 R 11  or —S(O) 2 X 5 R 11 , wherein X 5  is a bond, —O— or —NR 12 —, wherein R 12  is hydrogen or (C 1-6 )alkyl, and R 11  is (i) (C 1-6 )alkyl optionally substituted by —OR 13 , —SR 13 , —S(O)R 13 , —S(O) 2 R 13 , —C(O)R 13 , —C(O)OR 13 , —C(O)NR 13 R 14 , —NR 13 R 14 , —NR 14 C(O)R 13 , —NR 14 C(O)OR 13 , —NR 14 C(O)NR 13 R 14  or —NR 14 C(NR 14 )NR 13 R 14 , wherein R 13  is (C 3-12 )cycloalkyl(C 0-3 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-3 )alkyl, (C 6-12 )aryl(C 0-3 )alkyl, hetero(C 5-12 )aryl(C 0-3 )alkyl, (C 9-12 )bicycloaryl(C 0-3 )alkyl or hetero(C 8-12 )bicycloaryl(C 0-3 )alkyl and R 14  at each occurrence independently is hydrogen or (C 1-6 )alkyl, or (ii) (C 3-12 )cycloalkyl(C 0-3 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-3 )alkyl, (C 6-12 )aryl(C 0-3 )alkyl, hetero(C 5-12 )aryl(C 0-3 )alkyl, (C 9-12 )bicycloaryl(C 0-3 )alkyl or hetero(C 8-12 )bicycloaryl(C 0-3 )alkyl or (iii) (C 3-6 )cycloalkyl(C 0-3 )alkyl, hetero(C 5-6 )cycloalkyl(C 0-3 )alkyl, phenyl(C 0-3 )alkyl or hetero(C 5-6 )aryl(C 0-3 )alkyl substituted by —X 6 OR 15 , —X 6 SR 15 , —X 6 S(O)R 15 , —X 6 S(O) 2 R 15 , —X 6 C(O)R 15 , —X 6 C(O)OR 15 , —X 6 C(O)NR 15 R 16 , —X 6 NR 15 R 16 , —X 6 NR 16 C(O)R 15 , —X 6 NR 16 C(O)OR 15 , —X 6 NR 16 C(O)NR 15 R 16 , —X 6 NR 16 C(O)OR 16 , —X 6 NR 16 C(NR 16 )NR 15 R 16 , wherein X 6  is a bond or methylene, R 15  is (C 3-6 )cycloalkyl(C 0-3 )alkyl, hetero(C 5-6 )cycloalkyl(C 0-3 )alkyl, phenyl(C 0-3 )alkyl or hetero(C 5-6 )aryl(C 0-3 )alkyl and R 16  is hydrogen or (C 1-6 )alkyl; wherein R 4  optionally further contains 1 to 5 substituents which when occurring within an alicyclic or aromatic ring system are radicals independently selected from a group consisting of (C 1-6 )alkyl, (C 1-6 )alkylidene, cyano, halo, nitro, halo-substituted (C 1-3 )alkyl, —X 6 NR 17 R 17 , —X 6 NR 17 C(O)OR 17 , —X 6 NR 17 C(O)NR 17 R 17 , —X 6 NR 17 C(NR 17 )NR 17 R 17 , —X 6 OR 17 , —X 6 SR 17 , — 6 C(O)OR 17 , —X 6 C(O)NR 17 R 17 , —X 6 S(O) 2 NR 17 R 17 , —X 6 P(O)(OR 18 )OR 17 , —X 6 OP(O)(OR 18 )OR 17 , —X 6 NR 17 C(O)R 18 , —X 6 S(O)R 18 , —X 6 S(O) 2 R 18  and —X 6 C(O)R 18  and when occurring within an aliphatic moiety are radicals independently selected from a group consisting of cyano, halo, nitro, —NR 17 R 17 , —NR 17 C(O)OR 17 , —NRC 17 C(O)NR 17 R 17 , —NR 17 C(NR 17 )NR 17 R 17 , —OR 17 , —SR 17 , —C(O)OR 17 , —C(O)NR 17 R 17 , —S(O) 2 NR 17 R 17 , —P(O)(OR 17 )OR 17 , —OP(O)(OR 17 )OR 17 , —NR 17 C(O)R 18 , —S(O)R 18 , —S(O) 2 R 18  and —C(O)R 18 , wherein X 6  is a bond or (C 1-6 )alkylene, R 17  at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl and R 18  is (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl;  
 X 3  is a group of Formula (b) or (c):  
                     
 n is 0, 1 or 2;  
 R 20  is selected from the group consisting of hydrogen, (C 1-6 )alkyl, (C 3-12 )cycloalkyl(C 0-6 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-6 )alkyl, (C 6-12 )aryl(C 0-6 )alkyl and hetero(C 5-12 )aryl(C 0-6 )alcyl;  
 R 23  is selected from (C 1-6 )alkyl, (C 4-6 )alkenyl, (C 3-12 )cycloalkyl(C 0-6 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-6 )alkyl, (C 6-12 )aryl(C 0-6 )alkyl or hetero(C 5-12 )aryl(C 0-6 )alkyl optionally substituted with amino, —NHC(O)R 15  or —R 15  wherein R 15  is as described above;  
 R 25  is selected from hydrogen, (C 1-6 )alkyl, (C 3-12 )cycloalkyl(C 0-6 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-6 )alkyl, (C 6-12 )aryl(C 0-6 )alkyl, hetero(C 5-13 )aryl(C 0-6 )alkyl, —X 4 NHR 15 , —X 4 S(O) 2 R 26  or —X 4 C(O)R 17 NR 17 C(O)R 17  wherein R 15 , R 17  and X 4  are as described above;  
 R 26  is selected from the group consisting of hydrogen, (C 1-6 )alkyl, (C 3-12 )cycloalkyl(C 0-6 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-6 )alkyl, (C 6-12 )aryl(C 0-6 )alkyl, hetero(C 5-12 )aryl(C 0-6 )allyl, (C 9-12 )bicycloaryl(C 0-3 )alkyl or hetero(C 8-12 )-bicycloaryl(C 0-3 )alkyl;  
 R 27  is hydrogen, (C 1-6 )alkyl, (C 3-12 )cycloalkyl(C 0-6 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-6 )alkyl, (C 6-12 )aryl(C 0-6 )alkyl or hetero(C 5-12 )aryl(C 0-6 )alkyl;  
 wherein X 3  optionally further contains 1 to 5 substituents which when occurring within an alicyclic or aromatic ring system are radicals independently selected from a group consisting of (C 1-6 )alkyl, (C 1-6 )alkylidene, cyano, halo, nitro, halo-substituted (C 1-3 )alkyl, —X 6 NR 17 R 17 , —X 6 NR 17 C(O)OR 17 , —X 6 NR 17 C(O)NR 17 R 17 , —X 6 NR 17 C(NR 17 )NR 17 R 17 , —X 6 OR 17 , —X 6 C(O)R 17 , —X 6 OR 15 , —X 6 SR 17 , —X 6 C(O)OR 17 , —X 6 C(O)NR 17 R 17 , —X 6 S(O) 2 NR 17 R 17 , —X 6 P(O)(OR 8 )OR 17 , —X 6 OP(O)(OR 8 )OR 17 , —X 6 NR 17 C(O)R 18 , —X 6 S(O)R 18 , —X 6 S(O) 2 R 18  and —X 6 C(O)R 18  and when occurring within an aliphatic moiety are radicals independently selected from a group consisting of cyano, halo, nitro, —NR 17 R 17 , —NR 17 C(O)OR 17 , —NR 17 C(O)NR 17 R 17 , —NR 17 C(NR 17 )NR 17 R 17 , —OR 17 , —SR 17 , —C(O)OR 17 , —C(O)NR 17 R 17 , —S(O) 2 NR 17 R 17 , —P(O)(OR 17 )OR 17 , —OP(O)(OR 17 )OR 17 , —NR 17 C(O)R 18 , —S(O)R 18 , —S(O) 2 R 18  and —C(O)R 18 , wherein R 15 , R 17 , R 18  and X 6  are as described above; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.  
 
   
   
       2 . The compound of  claim 1  in which X 1  and X 2  are both methylene or X 1  is ethylene and X 2  is a bond; R 3  is —CR 5 ═CHR 6 , —CR 5 (CR 6   3 ) 2  or —CR 7 ═NR 8 , wherein R 5  is hydrogen and R 6  is hydrogen or (C 1-4 )alkyl or R 5  and R 6  together with the atoms to which R 5  and R 6  are attached form (C 3-12 )cycloalkenyl, (C 6-12 )aryl, hetero(C 6-12 )aryl or (C 9-12 )bicycloaryl and R 7  and R 8  together with the atoms to which R 7  and R 8  are attached form hetero(C 5-12 )cycloalkenyl or hetero(C 6-12 )aryl, wherein R 3  optionally is substituted by 1 to 5 radicals independently selected from a group consisting of (C 1-4 )alkyl, cyano, halo, halo-substituted (C 1-4 )alkyl, —X 4 R 9  and —X 4 C(O)OR 9 , wherein X 4  is a bond or (C 1-2 )alkylene, R 9  at each occurrence independently is (C 1-3 )alkyl or halo-substituted (C 1-3 )alkyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof, and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.  
   
   
       3 . The compound of  claim 2  in which R 4  is —C(O)X 5 R 11  or —S(O) 2 X 5 R 11 , wherein X 5  is a bond, —O— or —NR 12 —, wherein R 12  is hydrogen or (C 1-6 )alkyl, and R 11  is (i) (C 1-6 )alkyl or (ii) hetero(C 5-12 )cycloalkyl(C 0-3 )alkyl, (C 6-12 )aryl(C 0-3 )alkyl, hetero(C 5-12 )aryl(C 0-3 )alkyl, (C 9-12 )bicycloaryl(C 0-3 )alkyl or hetero(C 8-12 )bicycloaryl(C 0-3 )alkyl or (iii) hetero(C 5-6 )cycloalkyl(C 0-3 )alkyl or phenyl(C 0-3 )alkyl substituted by —X 6 OR 15 , —X 6 C(O)R 15  or —X 6 NR 16 C(O)OR 16 , wherein X 6  is a bond or methylene, R 15  is phenyl(C 0-3 )alkyl or hetero(C 5-6 )aryl(C 0-3 )alkyl and R 16  is hydrogen or (C 1-6 )alkyl; wherein R 4  optionally further contains 1 to 5 substituents which when occurring within an alicyclic or aromatic ring system are radicals independently selected from a group consisting of (C 1-6 )alkyl, halo, —X 6 NR 17 R 17 , —X 6 OR 17 , —X 6 C(O)OR 17 , —X 6 NC(O)R 16  and —X 6 C(O)R 18 , R 17  at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl and R 18  is (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.  
   
   
       4 . The compound of  claim 3  in which X 3  is a group of Formula (b) or (c):  
     
       
         
         
             
             
         
       
       n is 0, 1 or 2;  
       R 20  is selected from the group consisting of hydrogen and (C 1-6 )alkyl;  
       R 23  is selected from (C 1-6 )alkyl optionally substituted with amino, —NHC(O)R 15  or —R 15  wherein R 15  is as described above;  
       R 25  is selected from (C 1-6 )alkyl, (C 6-12 )aryl(C 0-6 )alkyl, —X 4 S(O) 2 R 26  or —X 4 C(O)R 17 NR 17 C(O)R 17  wherein R 17  and X 4  are as described above and R 26  is as described below;  
       R 26  is selected from the group consisting of (C 1-6 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-6 )alkyl, (C 6-12 )aryl(C 0-6 )alkyl, hetero(C 5-12 )aryl(C 0-6 )alkyl and (C 9-12 )bicycloaryl(C 0-3 )alkyl;  
       R 27  is (C 1-6 )alkyl;  
       wherein X 3  optionally further contains 1 to 5 substituents which when occurring within an alicyclic or aromatic ring system are radicals independently selected from a group consisting of (C 1-6 )alkyl, cyano, halo, —X 6 OR 17 , —X 6 C(O)R 17  and —X 6 OR 15 ; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.  
     
   
   
       5 . The compound of  claim 4  in which R 3  is selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, vinyl, 2-difluoromethoxyphenyl, 1-oxy-pyridin-2-yl, 4-methoxyphenyl, 4-methylphenyl, 2-methylphenyl, 4-chlorophenyl, 3,5-dimethylphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 2-bromophenyl, naphthalen-2-yl, 3,4-dichlorophenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 2,3,4,5,6-pentafluoro-phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-cyano-phenyl, 2-trifluoromethylphenyl, 4-tert-butyl-phenyl, 3-chlorophenyl, 4-bromophenyl, 2-fluoro-3-chloro-phenyl, 2-fluoro-3-methyl-phenyl, 3-fluorophenyl, 2,5-difluorophenyl, 3-bromophenyl, 2,5-dichlorophenyl, 2,6-difluorophenyl, 3-cyano-phenyl, 4-cyano-phenyl, 2-trifluoromethoxyphenyl, 2,3-difluorophenyl, biphenyl, 2-bromo-5-fluoro-phenyl, 4-fluorophenyl, 3,4-difluorophenyl, 2,4-difluorophenyl, 2,4,6-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,4-trifluorophenyl, 2-chloro-5-trifluoromethylphenyl, 2,4-bis-trifluoromethylphenyl, 2,5,6-trifluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 2-fluoro-5-trifluoromethylphenyl, 2,3,5-trifluorophenyl, 2-fluoro-5-trifluoromethylphenyl, 5-fluoro-2-trifluoromethylphenyl, 4-fluoro-3-trifluoromethylphenyl, 2-methoxyphenyl, 3,5-bis-trifluoromethylphenyl, 4-difluoromethoxyphenyl, 3-difluoromethoxyphenyl, 2,6-dichlorophenyl, 4-carboxyphenyl, cyclohexyl, cyclopropyl, isopropyl, thiophen-2-yl, 5-chloro-thiophen-2-yl and 3,5-dimethyl-isoxazol-4-yl.  
   
   
       6 . The compound of  claim 5  in which R 4  is benzoyl, morpholine-4-carbonyl, acetyl, furan-3-carbonyl, 2-methoxy-benzoyl, 3-methoxy-benzoyl, naphthalene-2-carbonyl, benzo[1,3]dioxole-5-carbonyl, 3-pyridin-3-yl-acryloyl, benzofuran-2-carbonyl, furan-2-carbonyl, tert-butoxy-carbonyl, biphenyl-4-carbonyl, quinoline-2-carbonyl, quinoline-3-carbonyl, 3-acetyl-benzoyl, 4-phenoxy-benzoyl, 3-hydroxy-benzoyl, 4-hydroxy-benzoyl, pyridine-3-carbonyl, 3-(tert-butoxycarbonylamino-methyl)-benzoyl, 4-carbonyl-piperazine-1-carboxylic acid tert-butyl ester, 4-carbonyl-piperazine-1-carboxylic acid ethyl ester, 4-(furan-2-carbonyl)-piperazine-1-carbonyl, pyridine-4-carbonyl, 1-oxy-pyridine-4-carbonyl, 1-oxy-pyridine-3-carbonyl, thiophene-2-carbonyl, thiophene-3-carbonyl, 4-benzoyl-benzoyl, 5-methyl-thiophene-2-carbonyl, 3-chloro-thiophene-2-carbonyl, 3-bromo-thiophene-2-carbonyl, 4-chloro-benzoyl, 3-flouro-4-methoxy-benzoyl, 4-methoxy-benzoyl, 4-triflouromethoxy-benzoyl, 3,4-diflouro-benzoyl, 4-fluoro-benzoyl, 3,4-dimethoxy-benzoyl, 3-methyl-benzoyl, 4-bromo-benzoyl, 4-triflouromethyl-benzoyl, 3-benzoyl-benzoyl, cyclopentane-carbonyl, benzo[b]thiophene-2-carbonyl, 3-chloro-benzo[b]thiophene-2-carbonyl, benzenesulfonyl, naphthalene-2-sulfonyl, 5-methyl-thiophene-2-sulfonyl, thiophene-2-sulfonyl, formamyl-methyl ester, 4-methyl-pentanoyl, formamyl-isobutyl ester, formamyl-monoallyl ester, formamyl-isopropyl ester, N,N-dimethyl-formamyl, N-isopropyl-formamyl, N-pyridin-4-yl-formamyl, N-pyridin-3-yl-formamyl, 3-phenyl-acryloyl, 1H-indole-5-carbonyl, pyridine-2-carbonyl, pyrazine-2-carbonyl, 3-hydroxy-pyridine-2-carbonyl, 2-amino-pyridine-3-carbonyl, 2-hydroxy-pyridine-3-carbonyl, 6-amino-pyridine-3-carbonyl, 6-hydroxy-pyridine-3-carbonyl, pyridazine-4-carbonyl, 3-phenoxy-benzoyl and 1-oxo-1,3-dihydro-isoindole-2-carbonyl.  
   
   
       7 . The compound of  claim 6  in which X 3  is selected from a group consisting of 1-ethyl-2-oxo-3-(toluene-4-sulfonylamino)-butylamino, 1-ethyl-2-oxo-3-(4-phenoxy-benzenesulfonylamino)-propylamino, 1-ethyl-2-oxo-3-[4-(pyridin-3-yloxy)-benzenesulfonylamino]-propylamino, 3-(dibenzofuran-2-sulfonylamino)-1-ethyl-2-oxo-butylamino, 1-ethyl-3-[4-methyl-2-(4-methyl-pentanoylamino)-pentanoylamino]-2-oxo-propylamino, 5-amino-1-[(4-methoxy-phenylsulfamoyl)-methyl]-pentylamino, 5-benzyloxycarbonylamino-1-[(4-methoxy-phenylsulfamoyl)-methyl]-pentylamino, 1-[(4-methoxy-phenylsulfamoyl)-methyl]-3-phenyl-propylamino, 1-{[4-(1-hydroxy-ethyl)-phenylsulfamoyl]-methyl}-3-phenyl-propylamino, 1-[(4-acetyl-phenylsulfamoyl)-methyl]-3-phenyl-propylamino, 1-[(4-hydroxy-phenylsulfamoyl)-methyl]-3-phenyl-propylamino and 3-phenyl-1-[(2-phenylamino-ethylsulfamoyl)-methyl]-propylamino.  
   
   
       8 . The compound of  claim 7  selected from the group consisting of morpholine-4-carboxylic acid (1-{5-amino-1-[(4-methoxy-phenylsulfamoyl)-methyl]-pentylcarbamoyl}-2-phenylmethanesulfonyl-ethyl)-amide, (6-(4-methoxy-phenylsulfamoyl)-5-{2-[(morpholine-4-carbonyl)-amino]-3-phenylmethane-sulfonyl-propionylamino}-hexyl)-carbamic acid benzyl ester, morpholine-4-carboxylic acid (1-{1-[(4-methoxy-phenylsulfamoyl)-methyl]-3-phenyl-propylcarbamoyl}-2-phenylmethanesulfonyl-ethyl)-amide and morpholine-4-carboxylic acid [1-(3-benzenesulfonylamino-2-oxo-propylcarbamoyl)-2-phenyhethanesulfonyl-ethyl]-amide.  
   
   
       9 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  in combination with a pharmaceutically acceptable excipient.  
   
   
       10 . A method for treating a disease in an animal in which inhibition of Cathepsin S can prevent, inhibit or ameliorate the pathology and/or symptomology of the disease, which method comprises administering to the animal a therapeutically effective amount of compound of  claim 1  or a N-oxide derivative or individual isomer or mixture of isomers thereof; or a pharmaceutically acceptable salt or solvate of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.  
   
   
       11 . A process for preparing a compound of Formula I:  
     
       
         
         
             
             
         
       
     
     in which: 
 X 1  and X 2  are both methylene or X 1  is ethylene and X 2  is a bond;  
 R 3  is —CR 5 ═CHR 6 , —CR 5 (CR 6   3 ) 2  or —CR 7 ═NR 8 , wherein R 5  is hydrogen and R 6  is hydrogen or (C 1-4 )alkyl or R 5  and R 6  together with the atoms to which R 5  and R 6  are attached form (C 3-12 )cycloalkenyl, hetero(C 5-12 )cycloalkenyl, (C 6-12 )aryl, hetero(C 6-12 )aryl, (C 9-12 )bicycloaryl or hetero(C 8-12 )bicycloaryl and R 7  and R 8  together with the atoms to which R 7  and R 8  are attached form hetero(C 5-12 )cycloalkenyl, hetero(C 6-12 )aryl or hetero(C 8-12 )bicycloaryl, wherein R 3  optionally is substituted by 1 to 5 radicals independently selected from a group consisting of (C 1-4 )alkyl, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, —X 4 NR 9 R 9 , —X 4 OR 9 , —X 4 SR 9 , —X 4 C(O)NR 9 R 9 , —X 4 C(O)OR 9 , —X 4 S(O)R 10 , —X 4 S(O) 2 R 10  and —X 4 C(O)R 10 , wherein X 4  is a bond or (C 1-2 )alkylene, R 9  at each occurrence independently is hydrogen, (C 1-3 )alkyl or halo-substituted (C 1-3 )alkyl and R 10  is (C 1-3 )alkyl or halo-substituted (C 1-3 )alkyl; and  
 R 4  is —C(O)X 5  R 11  or —S(O) 2 X 5 R 11 , wherein X 5  is a bond, —O— or —NR 12 —, wherein R 12  is hydrogen or (C 1-6 )alkyl, and R 11  is (i) (C 1-6 )alkyl optionally substituted by —OR 17 , —SR 13 , —S(O)R 13 , —S(O) 2 R 13 , —C(O)R 13 , —C(O)OR 13 , —C(O)NR 13 R 14 , —NR 13 R 14 , —NR 14 C(O)R 13 , —NR 14 C(O)OR 13 , —NR 14 C(O)NR 13 R 14  or —NR 14 C(NR 14 )NR 13 R 14 , wherein R 13  is (C 3-12 )cycloalkyl(C 0-3 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-3 )alklyl, (C 6-12 )aryl(C 0-3 )alkyl, hetero(C 5-12 )aryl(C 0-3 )alkyl, (C 9-12 )bicycloaryl(C 0-3 )alkyl or hetero(C 8-12 )bicycloaryl(C 0-3 )alkyl and R 14  at each occurrence independently is hydrogen or (C 1-6 )alkyl, or (ii) (C 3-12 )cycloalkyl(C 0-3 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-3 )alkyl, (C 6-12 )aryl(C 0-3 )alkyl, hetero(C 5-12 )aryl(C 0-3 )alkyl, (C 9-12 )bicycloaryl(C 0-3 )alkyl or hetero(C 8-12 )bicycloaryl(C 0-3 )alkyl or (iii) (C 3-6 )cycloalkyl(C 0-3 )alkyl, hetero(C 5-6 )cycloalkyl(C 0-3 )alkyl, phenyl(C 0-3 )alkyl or hetero(C 5-6 )aryl(C 0-3 )alkyl substituted by —X 6 OR 15 , —X 6 SR 15 , —X 6 S(O)R 15 , —X 6 S(O) 2 R 15 , —X 6 C(O)R 15 , —X 6 C(O)OR 15 , —X 6 C(O)NR 15 R 16 , —X 6 NR 15 R 16 , —X 6 NR 16 C(O)R 15 , —X 6 NR 16 C(O)OR 15 , —X 6 NR 16 C(O)NR 15 R 16 , —X 6 NR 16 C(O)OR 16 , —X 6 NR 16 C(NR 16 )NR 15 R 17 , wherein X 6  is a bond or methylene, R 15  is (C 3-6 )cycloalkyl(C 0-3 )alkyl, hetero(C 5-6 )cycloalkyl(C 0-3 )alkyl, phenyl(C 0-3 )alkyl or hetero(C 5-6 )aryl(C 0-3 )alkyl and R 16  is hydrogen or (C 1-6 )alkyl; wherein R 4  optionally further contains 1 to 5 substituents which when occurring within an alicyclic or aromatic ring system are radicals independently selected from a group consisting of (C 1-6 )alkyl, (C 1-6 )alkylidene, cyano, halo, nitro, halo-substituted (C 1-3 )alkyl, —X 6 NR 17 R 17 , —X 6 NR 17 C(O)OR 17 , —X 6 NR 17 C(O)NR 17 R 17 , —X 6 NR 17 C(NR 17 )NR 17 R 17 , —X 6 OR 17 , —X 6 SR 17 , —X 6 C(O)OR 17 , —X 6 C(O)NR 17 R 17 , —X 6 S(O) 2 NR 17 R 17 , —X 6 P(O)(OR 18 )OR 17 , —X 6 OP(O)(OR 18 )OR 17 , —X 6 NR 17 C(O)R 18 , —X 6 S(O)R 18 , —X 6 S(O) 2 R 18  and —X 6 C(O)R 18  and when occurring within an aliphatic moiety are radicals independently selected from a group consisting of cyano, halo, nitro, —NR 17 R 17 , —NR 17 C(O)OR 17 , —NR 17 C(O)NR 17 R 17 , —NR 17 C(NR 17 )NR 17 R 17 , —OR 17 , —SR 17 , —C(O)OR 17 , —C(O)NR 17 R 17 , —S(O) 2 NR 17 R 17 , —P(O)(OR 17 )OR 17 , —OP(O)(OR 17 )OR 17 , —NR 17 C(O)R 18 , —S(O)R 18 , —S(O) 2 R 18  and —C(O)R 18 , wherein X 6  is a bond or (C 1-6 )alkylene, R 17  at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl and R 18  is (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl;  
 X 3  is a group of Formula (b) or (c):  
                     
 n is 0, 1 or 2;  
 R 20  is selected from the group consisting of hydrogen, (C 1-6 )alkyl, (C 3-12 )cycloalkyl(C 0-6 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-6 )alklyl, (C 6-12 )aryl(C 0-6 )alkyl and hetero(C 5-12 )aryl(C 0-6 )alkyl;  
 R 23  is selected from (C 1-6 )alkyl, (C 4-6 )alkenyl, (C 3-12 )cycloalkyl(C 0-6 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-6 )alkyl, (C 6-12 )aryl(C 0-6 )alkyl or hetero(C 5-12 )aryl(C 0-6 )alkyl optionally substituted with amino, —NHC(O)R 15  or —R 15  wherein R 15  is as described above;  
 R 25  is selected from hydrogen, (C 1-6 )alkyl, (C 3-12 )cycloalkyl(C 0-6 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-6 )alkyl, (C 6-12 )aryl(C 0-6 )alkyl, hetero(C 5-13 )aryl(C 0-6 )alkyl, —X 4 NHR 15 , —X 4 S(O) 2 R 26  or —X 4 C(O)R 17 NR 17 C(O)R 17  wherein R 15 , R 17  and X 4  are as described above;  
 R 26  is selected from the group consisting of hydrogen, (C 1-6 )alkyl, (C 3-12 )cycloalkyl(C 0-6 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-6 )alkyl, (C 6-12 )aryl(C 0-6 )alkyl, hetero(C 5-12 )aryl(C 0-6 )alkyl, (C 9-12 )bicycloaryl(C 0-3 )alkyl and hetero(C 8-12 )-bicycloaryl(C 0-3 )alkyl;  
 R 27  is hydrogen, (C 1-6 )alkyl, (C 3-12 )cycloalkyl(C 0-6 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-6 )alkyl, (C 6-12 )aryl(C 0-6 )alkyl or hetero(C 5-12 )aryl(C 0-6 )alkyl;  
 wherein X 3  optionally further contains 1 to 5 substituents which when occurring within an alicyclic or aromatic ring system are radicals independently selected from a group consisting of (C 1-6 )alkyl, (C 1-6 )alkylidene, cyano, halo, nitro, halo-substituted (C 1-3 )alkyl, —X 6 NR 17 R 17 , —X 6 NR 17 C(O)OR 17 , —X 6 NR 17 C(O)NR 17 R 17 , —X 6 NR 17 C(NR 17 )NR 17 R 17 , —X 6 OR 17 , —X 6 C(O)R 17 , —X 6 OR 15 , —X 6 SR 17 , —X 6 C(O)OR 17 , —X 6 C(O)NR 17 R 17 , —X 6 S(O) 2 NR 17 R 17 , —X 6 P(O)(OR 8 )OR 17 , —X 6 OP(O)(OR 8 )OR 17 , —X 6 NR 17 C(O)R 18 , —X 6 S(O)R 18 , —X 6 S(O) 2 R 18  and —X 6 C(O)R 18  and when occurring within an aliphatic moiety are radicals independently selected from a group consisting of cyano, halo, nitro, —NR 17 R 17 , —NR 17 C(O)OR 17 , —NR 17 C(O)NR 17 R 17 , —NR 17 C(NR 17 )NR 17 R 17 , —OR 17 , —SR 17 , —C(O)OR 17 , —C(O)NR 17 R 17 , —S(O) 2 NR 17 R 17 , —P(O)(OR 17 )OR 17 , —OP(O)(OR 17 )OR 17 , —NR 17 C(O)R 18 , —S(O)R 18 , —S(O) 2 R 18  and —C(O)R 18 , wherein R 15 , R 17 , R 18  and X 6  are as described above; said process comprising:  
 (A) reacting a compound of Formula 2 with a compound of the formula (b):  
                     
 in which R 20 , R 23  and R 25  are the same as defined above for Formula I; or  
 (B) reacting a compound of Formula 2 with a compound of the formula (c):  
                     
 in which R 20 , R 23  and R 25  are the same as defined above for Formula I; and  
 (C) optionally converting a compound of Formula I into a pharmaceutically acceptable salt; or  
 (D) optionally converting a salt form of a compound of Formula I to non-salt form; or  
 (E) optionally converting an unoxidized form of a compound of Formula I into a pharmaceutically acceptable N-oxide; or  
 (F) optionally converting an N-oxide form of a compound of Formula I into an unoxidized form; or  
 (G) optionally resolving an individual isomer of a compound of Formula I from a mixture of isomers; or  
 (H) optionally converting a non-derivatized compound of Formula I into a pharmaceutically prodrug derivative; or  
 (I) optionally converting a prodrug derivative of a compound of Formula 1 to its non-derivatized form.  
 
   
   
       12 . A compound of Formula Ix:  
     
       
         
         
             
             
         
       
     
     in which: 
 X 1  and X 2  are both methylene or X 1  is ethylene and X 2  is a bond;  
 R 3  is —CR 5 ═CHR 6 , —CR 5 (CR 6   3 ) 2  or —CR 7 ═NR 8 , wherein R 5  is hydrogen and R 6  is hydrogen or (C 1-4 )alkyl or R 5  and R 6  together with the atoms to which R 5  and R 6  are attached form (C 3-12 )cycloalkenyl, hetero(C 5-12 )cycloalkenyl, (C 6-12 )aryl, hetero(C 6-12 )aryl, (C 9-12 )bicycloaryl or hetero(C 8-12 )bicycloaryl and R 7  and R 8  together with the atoms to which R 7  and R 8  are attached form hetero(C 5-12 )cycloalkenyl, hetero(C 6-12 )aryl or hetero(C 8-12 )bicycloaryl, wherein R 3  optionally is substituted by 1 to 5 radicals independently selected from a group consisting of (C 1-4 )alkyl, cyano, halo, halo-substituted (C 1-4 )alkyl, nitro, —X 4 NR 9 R 9 , —X 4 OR 9 , —X 4 SR 9 , —X 4 C(O)NR 9 R 9 , —X 4 C(O)OR 9 , —X 4 S(O)R 10 , —X 4 S(O) 2 R 10  and —X 4 C(O)R 10 , wherein X 4  is a bond or (C 1-2 )alkylene, R 9  at each occurrence independently is hydrogen, (C 1-3 )alkyl or halo-substituted (C 1-3 )alkyl and R 10  is (C 1-3 )alkyl or halo-substituted (C 1-3 )alkyl; and  
 R 4  is —C(O)X 5 R 11  or —S(O) 2 X 5 R 11 , wherein X 5  is a bond, —O— or —NR 12 , wherein R 12  is hydrogen or (C 1-6 )alkyl, and R 11  is (i) (C 1-6 )alkyl optionally substituted by —OR 13 , —SR 13 , —S(O)R 13 , —S(O) 2 R 13 , —C(O)R 13 , —C(O)OR 13 , —C(O)NR 13 R 14 , —NR 13 R 14 , —NR 14 C(O)R 13 , —NR 14 C(O)OR 13 , —NR 14 C(O)NR 13 R 14  or —NR 14 C(NR 14 )NR 13 R 14 , wherein R 13  is (C 3-12 )cycloalkyl(C 0-3 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-3 )alkyl, (C 6-12 )aryl(C 0-3 )alkyl, hetero(C 5-12 )aryl(C 0-3 )alkyl, (C 9-12 )bicycloaryl(C 0-3 )alkyl or hetero(C 8-12 )bicycloaryl(C 0-3 )alkyl and R 14  at each occurrence independently is hydrogen or (C 1-6 )alkyl, or (ii) (C 3-12 )cycloalkyl(C 0-3 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-3 )alkyl, (C 6-12 )aryl(C 0-3 )alkyl, hetero(C 5-12 )aryl(C 0-3 )alkyl, (C 9-12 )bicycloaryl(C 0-3 )alkyl or hetero(C 8-12 )bicycloaryl(C 0-3 )alkyl or (iii) (C 3-6 )cycloalkyl(C 0-3 )alkyl, hetero(C 5-6 )cycloalkyl(C 0-3 )alkyl, phenyl(C 0-3 )alkyl or hetero(C 5-6 )aryl(C 0-3 )alkyl substituted by —X 6 OR 15 , —X 6 SR 15 , —X 6 S(O)R 15 , —X 6 S(O) 2 R 15 , —X 6 C(O)R 15 , —X 6 C(O)OR 15 , —X 6 C(O)NR 15 R 16 , —X 6 NR 15 R 16 , —X 6 NR 16 C(O)R 15 , —X 6 NR 16 C(O)OR 15 , —X 6 NR 16 C(O)NR 15 R 16 , —X 6 NR 16 C(O)OR 16 , —X 6 NR 16 C(NR 16 )NR 15 R 16 , wherein X 6  is a bond or methylene, R 15  is (C 3-6 )cycloalkyl(C 0-3 )alkyl, hetero(C 5-6 )cycloalkyl(C 0-3 )alkyl, phenyl(C 0-3 )alkyl or hetero(C 5-6 )aryl(C 0-3 )alkyl and R 16  is hydrogen or (C 1-6 )alkyl; wherein R 4  optionally further contains 1 to 5 substituents which when occurring within an alicyclic or aromatic ring system are radicals independently selected from a group consisting of (C 1-6 )alkyl, (C 1-6 )alkylidene, cyano, halo, nitro, halo-substituted (C 1-3 )alkyl, —X 6 NR 17 R 17 , —X 6 NR 17 C(O)OR 17 , —X 6 NR 17 C(O)NR 17 R 17 , —X 6 NR 17 C(NR 17 )NR 17 R 17 , —X 6 OR 17 , —X 6 SR 17 , —X 6 C(O)OR 17 , —X 6 C(O)NR 17 R 17 , —X 6 S(O) 2 NR 17 R 17 , —X 6 P(O)(OR 18 )OR 17 , —X 6 OP(O)(OR 18 )OR 17 , —X 6 NR 17 C(O)R 18 , —X 6 S(O)R 18 , —X 6 S(O) 2 R 18  and —X 6 C(O)R 18  and when occurring with aliphatic moiety are radicals independently selected from a group consisting of cyano, halo, nitro, —NR 17 R 17 , —NR 17 C(O)OR 17 , —NR 17 C(O)NR 17 R 17 , —NR 17 C(NR 17 )NR 17 R 17 , —OR 17 , —SR 17 , —C(O)OR 17 , —C(O)NR 17 R 17 , —S(O) 2 NR 17 R 17 , —P(O)(OR 17 )OR 17 , —OP(O)(OR 17 )OR 17 , —NR 17 C(O)R 18 , —S(O)R 18 , —S(O) 2 R 18  and —C(O)R 18 , wherein X 6  is a bond or (C 1-6 )alkylene, R 17  at each occurrence independently is hydrogen, (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl and R 18  is (C 1-6 )alkyl or halo-substituted (C 1-3 )alkyl;  
 X 3  is a group of Formula (b), (c), (d), (e), (f), (g) or (h):  
                     
    represents a single bond, or a double bond;  
 X 7  represents aryl, heteroaryl or NR 20 R 25 ;  
 n is 0, 1 or 2;  
 R 20  is selected from the group consisting of hydrogen, (C 1-6 )alkyl, (C 3-12 )cycloalkyl(C 0-6 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-6 )alkyl, (C 6-12 )aryl(C 0-6 )alkyl and hetero(C 5-12 )aryl(C 0-6 )alkyl;  
 R 23  is selected from —H, (C 1-6 )alkyl, (C 4-6 )alkenyl, (C 3-12 )cycloalkyl(C 0-6 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-6 )alkyl, (C 6-12 )aryl(C 0-6 )alkyl or hetero(C 5-12 )aryl(C 0-6 )alkyl optionally substituted with amino, —NHC(O)R 15  or —R 15  wherein R 15  is as described above;  
 R 25  is selected from hydrogen, (C 1-6 )alkyl, (C 3-12 )cycloalkyl(C 0-6 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-6 )alkyl, (C 6-12 )aryl(C 0-6 )alkyl, hetero(C 5-13 )aryl(C 0-6 )alkyl, —X 4 NHR 15 , —X 4 S(O) 2 R 26  or —X 4 C(O)R 17 NR 17 C(O)R 17  wherein R 15 , R 17  and X 4  are as described above;  
 R 26  is selected from the group consisting of hydrogen, (C 1-6 )alkyl, (C 3-12 )cycloalkyl(C 0-6 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-6 )alkyl, (C 6-12 )aryl(C 0-6 )alkyl, hetero(C 5-12 )aryl(C 0-6 )alkyl, (C 9-12 )bicycloaryl(C 0-3 )alkyl and hetero(C 8-12 )-bicycloaryl(C 0-3 )alkyl;  
 R 27  is hydrogen, (C 1-6 )alkyl, (C 3-12 )cycloalkyl(C 0-6 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-6 )alkyl, (C 6-12 )aryl(C 0-6 )alkyl or hetero(C 5-12 )aryl(C 0-6 )alkyl;  
 R 28  is R 20  or —O—C(═O)—R 29 ;  
 R 29  is (C 1-6 )alkyl, (C 3-12 )cycloalkyl(C 0-3 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-3 )alkyl, (C 6-12 )aryl(C 0-3 )alkyl, hetero(C 5-12 )aryl(C 0-3 )alkyl, (C 9-12 )bicycloaryl(C 0-3 )alkyl or hetero(C 8-12 )bicycloaryl(C 0-3 )alkyl;  
 wherein X 3  optionally further contains 1 to 5 substituents which when occurring within an alicyclic or aromatic ring system are radicals independently selected from a group consisting of (C 1-6 )alkyl, (C 1-6 )alkylidene, cyano, halo, nitro, halo-substituted (C 1-3 )alkyl, —X 6 NR 17 R 17 , —X 6 NR 17 C(O)OR 17 , —X 6 NR 17 C(O)NR 17 R 17 , —X 6 NR 17 C(NR 17 )NR 17 R 17 , —X 6 OR 17 , —X 6 C(O)R 17 , —X 6 OR 15 , —X 6 SR 17 , —X 6 C(O)OR 17 , —X 6 C(O)NR 17 R 17 , —X 6 S(O) 2 NR 17 R 17 , —X 6 P(O)(OR 8 )OR 17 , —X 6 OP(O)(OR 8 )OR 17 , —X 6 NR 17 C(O)R 18 , —X 6 S(O)R 18 , —X 6 S(O) 2 R 18  and —X 6 C(O)R 18  and when occurring within an aliphatic moiety are radicals independently selected from a group consisting of cyano, halo, nitro, —NR 17 R 17 , —NR 17 C(O)OR 17 , —NR 17 C(O)NR 17 R 17 , —NR 17 C(NR 17 )NR 17 R 17 , —OR 17 , —SR 17 , —C(O)OR 17 , —C(O)NR 17 R 17 , —S(O) 2 NR 17 R 17 , —P(O)(OR 17 )OR 17 , —OP(O)(OR 17 )OR 17 , —NR 17 C(O)R 18 , —S(O) 2 R 18  and —C(O)R 18 , wherein R 15 , R 17 , R 18  and X 6  are as described above; or one of N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers of compounds of formula Ix; or one of pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers formula Ix.  
 
   
   
       13 . A compound of  claim 13 , wherein R 13  is selected from (C 1-6 )alkyl, (C 4-6 )alkenyl, (C 3-12 )cycloalkyl(C 0-6 )alkyl, hetero(C 5-12 )cycloalkyl(C 0-6 )alkyl, (C 6-12 )aryl(C 0-6 )alkyl or hetero(C 5-12 )aryl(C 0-6 )alkyl optionally substituted with amino, —NHC(O)R 15  or —R 15  wherein R 15  is as described above.  
   
   
       14 . A compound of  claim 13 , selected from the group consisting of: 
 Morpholine-4-carboxylic acid [1-(3-benzenesulfonylamino-2-oxo-propylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-amide; or    N-{1S-[1S-(4-Methoxyphenylsulfamoylmethyl)-3-phenylpropylcarbamoyl]2-benzylsulfonylethyl}-morpholine-4-carboxamide.    
   
   
       15 . A compound of  claim 13 , selected from the group consisting of: 
 Morpholine-4-carboxylic acid [(R)-1-(6-oxo-cyclohex-1-enylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-amide;    Morpholine-4-carboxylic acid [(R)-2-cyclopropylmethanesulfonyl-1-(6-oxo-cyclohex-1-enylcarbamoyl)-ethyl]-amide;    Morpholine-4-carboxylic acid [(R)-1-(3,4-dioxo-cyclopentylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-amide;    Morpholine-4-carboxylic acid [2-(2-difluoromethoxy-phenylmethanesulfonyl)-1-(2-oxo-cyclohexylcarba-moyl)-ethyl]-amide;    Morpholine-4-carboxylic acid [2-(2-difluoromethoxy-phen-ylmethanesulfonyl)-1-(2-oxo-cyclopentylcarbamoyl)-ethyl]-amide;    Morpholine-4-carboxylic acid [2-(2-difluoromethoxy-phenylmethanesulfonyl)-1-(2-oxo-cyclobutylcarbamoyl)-ethyl]-amide;    (Morpholine-4-carboxylic acid[1-(2-benzylcarbamoyl-2-oxo-ethylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-amide);    Acetic acid 3-{2-[(morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionylamino}-4-oxo-azetidin-2-yl ester;    Morpholine-4-carboxylic acid [1-(2-hydroxy-1,1-dimethyl-3-oxo-3-phenyl-propylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-amide;    Morpholine-4-carboxylic acid [1-(4-oxo-tetrahydro-furan-3-ylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-amide; or    Morpholine-4-carboxylic acid [2-(2-difluoromethoxy-phenylmethanesulfonyl)-1-(1,1-dimethyl-2,3-diox-o-3-phenyl-propylcarbamoyl)-ethyl]-amide.