Methionine metabolic pathway inhibitors

Abstract

The present invention provides novel inhibitors of cystathionin gamma synthase (CGS), their use as selective and non-selective herbicides, agricultural and non-agricultural herbicides, herbicides in integrated pest management, herbicides for gardening, clearing waste ground, clearing industrial or constructions sites, clearing railways and railway embankments, pesticide, fungicide, agricultural plant stimulant or antimicrobial agent. Also provided is a method for the control of undesired vegetation or clearing areas from the undesired vegetation comprising applying to the locus of said undesired vegetation, to the undesired plants or to a habitat thereof, a herbicidally effective amount of the compound of the present invention.

1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein R 1  is an aromatic or heteroaromatic radical of Formula (A), Formula (B), Formula (C), Formula (D), or Formula (E): 
       
       
         
           
           
               
               
           
         
         wherein Q in Formula (A) is C—R 7 , C·, or N; 
         R 4 , R 6  and R 7  are independently selected from hydrogen, halogen, amino, cyano, nitro, (C 1 -C 3 )-alkyl, (C 1 -C 3 )-haloalkyl, hydroxy, (C 1 -C 3 )-alkoxy, (C 1 -C 3 )-haloalkoxy, mono-(C 1 -C 3 )-alkylamino, di-(C 1 -C 3 )-alkylamino, amino-(C 1 -C 3 )-alkyl, mono-(C 1 -C 3 )-alkylamino-(C 1 -C 3 )-alkyl and di-(C 1 -C 3 )-alkylamino-(C 1 -C 3 )-alkyl group; and 
         R 5  is hydrogen, halogen, cyano, (C 1 -C 3 )-alkyl, (C 1 -C 3 )-haloalkyl, (C 1 -C 3 )-alkoxy, hydroxy, (C 1 -C 3 )-haloalkoxy, amino, mono-(C 1 -C 3 )-alkylamino, di-(C 1 -C 3 )-alkylamino, amino-(C 1 -C 3 )-alkyl, mono-(C 1 -C 3 )-alkylamino-(C 1 -C 3 )-alkyl, di-(C 1 -C 3 )-alkylamino-(C 1 -C 3 )-alkyl, nitro or 3,5-dimethyl-1H-pyrazol-1-yl group; or 
         R 5  and R 6  taken together with two carbon atoms to which they are attached form a five-membered heterocyclic radical 2,5-dihydrofuranyl of the following formula: 
       
       
         
           
           
               
               
           
         
         X and Y in Formula (D) are independently CH or N; 
         Z is C—R 8  or N; 
         R 8  is hydrogen, halogen, nitro, (C 1 -C 3 )-alkyl, (C 1 -C 3 )-haloalkyl, (C 1 -C 3 )-alkoxy, hydroxy, carboxylate, (C 1 -C 3 )-alkylcarboxylate, carboxylic acid, (C 1 -C 3 )-alkylcarboxylic acid, carboxamide, (C 1 -C 3 )-alkylcarboxamide, cyano, pyridinyl, phenyl, benzyl or phenylamino, wherein said pyridinyl, phenyl, benzyl or phenylamino are optionally substituted with one to three same or different substituents at any available heteroaromatic or aromatic ring carbon atom, said substituents are selected from halogen, (C 1 -C 3 )-alkyl, (C 3 -C 6 )-cycloalkyl, (C 1 -C 3 )-haloalkyl, hydroxy, (C 1 -C 3 )-alkoxy, cyano, amino, carboxylic acid, or nitro group; 
         L is N—R 9 , O or S; and 
         R 9  is hydrogen, (C 1 -C 3 )-alkyl, (C 1 -C 3 )-haloalkyl, carboxymethyl, benzyl, pyridinyl or phenyl, wherein said benzyl, pyridinyl or phenyl are optionally substituted with one to three same or different substituents at any available aromatic ring carbon atom, said substituents are selected from halogen, cyano, (C 1 -C 3 )-alkyl, (C 1 -C 3 )-haloalkyl, hydroxy, (C 1 -C 3 )-alkoxy, amino, or nitro group; 
         two dashed arrows in Formula (E) point to two carbon atoms of the phenyl ring, to which the carbonyl can be attached; 
         A is CH—R 10  or N—R 11 ; 
         E is C—R 12  or N; 
         J is C—R 13  or N; and 
         R 10 , R 11 , R 12  and R 13 , are independently selected from hydrogen, (C 1 -C 3 )-alkyl and (C 1 -C 3 )-haloalkyl; 
       
       (i) when R 1  is the radical of the Formula (A), then:
 R 3  is pyridinyl or phenyl substituted at any available aromatic ring carbon atom with one or two groups, wherein the first group is optional and selected from carboxylmethyl and carboxyl group, and the second group is selected from the following radicals: 
 
       
         
           
           
               
               
           
         
         
           wherein X and Y are independently CH or N;
 Z is C—R 8  or N; 
 R 8  is hydrogen, halogen, nitro, (C 1 -C 3 )-alkyl, (C 1 -C 3 )-haloalkyl, (C 1 -C 3 )-alkoxy, hydroxy, carboxylate, (C 1 -C 3 )-alkylcarboxylate, carboxylic acid, (C 1 -C 3 )-alkylcarboxylic acid, carboxamide, (C 1 -C 3 )-alkylcarboxamide, cyano, pyridinyl, phenyl, benzyl or phenylamino, wherein said pyridinyl, phenyl, benzyl or phenylamino are optionally substituted with one to three same or different substituents at any available heteroaromatic or aromatic ring carbon atom, said substituents are selected from halogen, (C 1 -C 3 )-alkyl, (C 3 -C 6 )-cycloalkyl, (C 1 -C 3 )-haloalkyl, hydroxy, (C 1 -C 3 )-alkoxy, cyano, amino, carboxylic acid, or nitro group; 
 L is N—R 9 , O or S; and 
 R 9  is hydrogen, (C 1 -C 3 )-alkyl, (C 1 -C 3 )-haloalkyl, carboxymethyl, benzyl, pyridinyl or phenyl, wherein said benzyl, pyridinyl or phenyl are optionally substituted with one to three same or different substituents at any available aromatic ring carbon atom, said substituents are selected from halogen, cyano, (C 1 -C 3 )-alkyl, (C 1 -C 3 )-haloalkyl, hydroxy, (C 1 -C 3 )-alkoxy, amino, or nitro group; and 
 R 2  is either hydrogen or carbonyl ( C═O), and
 when R 2  is carbonyl, Q is C· and R 2  and Q form a bond. 
 
 
         
       
       (ii) when R 1  is the radical of the Formula (B), then:
 R 2  is hydrogen, and 
 R 3  is [1,2,4]-triazolo[4,3-a]pyridinyl of the formula: 
 
       
         
           
           
               
               
           
         
       
       (iii) when R 1  is the radical of the Formula (C), then:
 R 2  is hydrogen, and 
 R 3  is phenyl; 
 
       (iv) when R 1  is the radical of the Formula (D), then:
 R 2  and R 3  taken together form around the nitrogen atom, to which they are attached, an indolyl radical of the formula: 
 
       
         
           
           
               
               
           
         
         wherein R 15  and R 16  are independently selected from hydrogen, halogen, nitro, (C 1 -C 3 )-alkyl, (C 1 -C 3 )-haloalkyl, (C 1 -C 3 )-alkoxy, hydroxy, cyano, carboxylic acid, carboxylate, (C 1 -C 3 )-alkylcarboxylate, carboxamide, (C 1 -C 3 )-alkylcarboxylic acid, (C 1 -C 3 )-alkylcarboxamide, or amino group; and 
       
       (v) when R 1  is the radical of the Formula (E), then
 R 2  is hydrogen or (C 1 -C 3 )-alkyl, and 
 R 3  is a radical of the formula: 
 
       
         
           
           
               
               
           
         
         wherein R 14  is one to three same or different substituents attached to any available carbon atom of the phenyl ring and independently selected from hydrogen, amino, (C 1 -C 3 )-alkyl, (C 1 -C 3 )-haloalkyl, (C 1 -C 3 )-alkoxy, (C 1 -C 3 )-alkylcarboxylic acid, carboxylic acid, (C 1 -C 3 )-alkylcarboxylate, carboxylate, (C 1 -C 3 )-alkylcarboxamide, carboxamide, halogen, cyano, hydroxy, nitro and acetylamino group; and either: 
            is a double bond, and G is O; or 
            is a single bond, and G taken together with the two adjacent carbon atoms and with the nitrogen atom to which the second carbon atom is attached forms a five- or six-membered heterocyclic ring. 
       
     
     
         2 . The compound of  claim 1  having Formula (IA-1): 
       
         
           
           
               
               
           
         
         wherein Q is C—R 7  or N; 
         R 3  is pyridinyl or phenyl substituted at any available aromatic ring carbon atom with one or two groups, wherein the first group is optional and selected from carboxymethyl and carboxyl group, and the second group is selected from the following radicals: 
       
       
         
           
           
               
               
           
         
         and R 5  is hydrogen, halogen, cyano, (C 1 -C 3 )-alkyl, (C 1 -C 3 )-haloalkyl, (C 1 -C 3 )-alkoxy, hydroxy, (C 1 -C 3 )-haloalkoxy, amino, mono-(C 1 -C 3 )-alkylamino, di-(C 1 -C 3 )-alkylamino, amino-(C 1 -C 3 )-alkyl, mono-(C 1 -C 3 )-alkylamino-(C 1 -C 3 )-alkyl, di-(C 1 -C 3 )-alkylamino-(C 1 -C 3 )-alkyl, nitro or 3,5-dimethyl-1H-pyrazol-1-yl group; or 
         R 5  and R 6  taken together with two carbon atoms to which they are attached form a five-membered heterocyclic radical 2,5-dihydrofuranyl of the following formula: 
       
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 2 , wherein Q is C—R 7 ;
 R 3  is pyridinyl or phenyl substituted at any available aromatic ring carbon atom with one or two groups, wherein the first group is optional and selected from carboxylmethyl and carboxyl group, and the second is the following radical: 
 
       
         
           
           
               
               
           
         
         and R 5  is hydrogen, halogen, cyano, (C 1 -C 3 )-alkyl, (C 1 -C 3 )-haloalkyl, (C 1 -C 3 )-alkoxy, hydroxy, (C 1 -C 3 )-haloalkoxy, amino, mono-(C 1 -C 3 )-alkylamino, di-(C 1 -C 3 )-alkylamino, amino-(C 1 -C 3 )-alkyl, mono-(C 1 -C 3 )-alkylamino-(C 1 -C 3 )-alkyl, di-(C 1 -C 3 )-alkylamino-(C 1 -C 3 )-alkyl, nitro or 3,5-dimethyl-1H-pyrazol-1-yl group. 
       
     
     
         4 . The compound of  claim 3 , wherein R 4 , R 5 , R 6  and R 7  are independently selected from hydrogen, halogen, hydroxy, methoxy or trifluoromethyl;
 R 8  is hydrogen, ethyl, cyclopentyl, trifluoromethyl, hydroxy, benzyl or phenylamino, wherein said benzyl or phenylamino are optionally substituted with one to three substituents independently selected from halogen, methyl, trufluoromethyl, hydroxy, methoxy or carboxylic acid group; and   R 9  is hydrogen, methyl, ethyl, carboxymethyl or benzyl group.   
     
     
         5 . The compound of  claim 4  selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 2 , wherein Q is N;
 R 3  is phenyl substituted at any available aromatic ring carbon atom with the follow radical:   
       
         
           
           
               
               
           
         
         and R 5  is hydrogen, halogen, cyano, (C 1 -C 3 )-alkyl, (C 1 -C 3 )-haloalkyl, (C 1 -C 3 )-alkoxy, hydroxy, (C 1 -C 3 )-haloalkoxy, amino, mono-(C 1 -C 3 )-alkylamino, di-(C 1 -C 3 )-alkylamino, amino-(C 1 -C 3 )-alkyl, mono-(C 1 -C 3 )-alkylamino-(C 1 -C 3 )-alkyl, di-(C 1 -C 3 )-alkylamino-(C 1 -C 3 )-alkyl, nitro or 3,5-dimethyl-1H-pyrazol-1-yl group. 
       
     
     
         7 . The compound of  claim 6 , wherein R 4 , R 5  and R 6  are independently selected from hydrogen, halogen, methoxy or trifluoromethyl;
 X and Y are independently CH or N;   Z is C—R 8  or N;   R 8  is hydrogen, ethyl, cyclopentyl, trifluoromethyl, hydroxy, benzyl or phenylamino, wherein said benzyl or phenylamino are optionally substituted with one to three substituents independently selected from halogen, methyl, trufluoromethyl, hydroxy, methoxy or carboxylic acid group;   L is N—R 9 , O or S; and   R 9  is hydrogen, methyl, or benzyl group.   
     
     
         8 . The compound of  claim 7  selected from: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 2 , wherein Q is C—R 7 ;
 R 3  is phenyl substituted at any available aromatic ring carbon atom with one group selected from the following radicals: 
 
       
         
           
           
               
               
           
         
         R 4  and R 7  are H; and 
         R 5  and R 6  taken together with two carbon atoms to which they are attached form a five-membered heterocyclic radical 2,5-dihydrofuranyl of the following formula: 
       
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 9  having Formula (IA-13): 
       
         
           
           
               
               
           
         
         wherein R 3  is phenyl substituted at any available aromatic ring carbon atom with one group selected from the following radicals: 
       
       
         
           
           
               
               
           
         
         X and Y are independently CH or N; 
         Z is C—R 8  or N; 
         R 8  is hydrogen, ethyl, cyclopentyl, trifluoromethyl, hydroxy, benzyl or phenylamino, wherein said benzyl or phenylamino are optionally substituted with one to three substituents independently selected from halogen, methyl, trufluoromethyl, hydroxy, methoxy or carboxylic acid group; 
         L is N—R 9 , O or S; and 
         R 9  is hydrogen, methyl, or benzyl group. 
       
     
     
         11 . The compound of  claim 10  selected from: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound of  claim 1 , wherein Q is C—R 7 ;
 R 3  is phenyl substituted at any available aromatic ring carbon atom with one group selected from the following radicals: 
 
       
         
           
           
               
               
           
         
         and R 5  is hydrogen, halogen, cyano, (C 1 -C 3 )-alkyl, (C 1 -C 3 )-haloalkyl, (C 1 -C 3 )-alkoxy, hydroxy, (C 1 -C 3 )-haloalkoxy, amino, mono-(C 1 -C 3 )-alkylamino, di-(C 1 -C 3 )-alkylamino, amino-(C 1 -C 3 )-alkyl, mono-(C 1 -C 3 )-alkylamino-(C 1 -C 3 )-alkyl, di-(C 1 -C 3 )-alkylamino-(C 1 -C 3 )-alkyl, nitro or 3,5-dimethyl-1H-pyrazol-1-yl group. 
       
     
     
         13 . The compound of  claim 12 , wherein
 R 4 , R 6  and R 7  are independently selected from hydrogen, ethyl, halogen, hydroxy, methoxy, trifluoromethyl, difluoromethoxy, amino, dimethylamino and dimethylamino-methyl; and   R 5  is hydrogen, halogen, ethyl, trifluoromethyl, amino, dimethylamino, hydroxy, methoxy or 3,5-dimethyl-1H-pyrazol-1-yl group.   
     
     
         14 . The compound of  claim 13  selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         15 . The compound of  claim 2 , wherein Q is C—R 7  or N;
 R 3  is phenyl substituted at any available aromatic ring carbon atom with one group selected from the following radicals: 
 
       
         
           
           
               
               
           
         
         and R 5  is hydrogen, halogen, cyano, (C 1 -C 3 )-alkyl, (C 1 -C 3 )-haloalkyl, (C 1 -C 3 )-alkoxy, hydroxy, (C 1 -C 3 )-haloalkoxy, amino, mono-(C 1 -C 3 )-alkylamino, di-(C 1 -C 3 )-alkylamino, amino-(C 1 -C 3 )-alkyl, mono-(C 1 -C 3 )-alkylamino-(C 1 -C 3 )-alkyl, di-(C 1 -C 3 )-alkylamino-(C 1 -C 3 )-alkyl, nitro or 3,5-dimethyl-1H-pyrazol-1-yl group. 
       
     
     
         16 . The compound of  claim 15 , wherein Q is C—R 7 ; and R 4 , R 5 , R 6  and R 7  are independently selected from hydrogen, halogen, amino, hydroxy or methoxy. 
     
     
         17 . The compound of  claim 16  selected from: 
       
         
           
           
               
               
           
         
       
     
     
         18 . The compound of  claim 15 , wherein Q is N; and
 R 3  is phenyl substituted at any available aromatic ring carbon atom with the following radical:   
       
         
           
           
               
               
           
         
       
     
     
         19 . The compound of  claim 18 , wherein R 4 , R 5 , and R 6  are independently selected from hydrogen, methyl, hydroxy, methoxy or trifluoromethyl. 
     
     
         20 . The compound of  claim 19  selected from: 
       
         
           
           
               
               
           
         
       
     
     
         21 . The compound of  claim 1  having Formula (IA-2): 
       
         
           
           
               
               
           
         
         wherein R 3  is phenyl substituted at any available aromatic ring carbon atom with the following radical: 
       
       
         
           
           
               
               
           
         
       
     
     
         22 . The compound of  claim 21 , wherein
 X is CH, Y is N;   Z is C—R 8 ; and   R 8  is phenylamino group optionally substituted with one to three substituents independently selected from halogen, (C 1 -C 3 )-alkyl, (C 3 -C 6 )-cycloalkyl, (C 1 -C 3 )-haloalkyl, hydroxy, (C 1 -C 3 )-alkoxy, carboxylic acid, cyano, amino and nitro group.   
     
     
         23 . The compound of  claim 22  having the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         24 . The compound of  claim 1  selected from: 
       
         
           
           
               
               
           
         
       
     
     
         25 . The compound of  claim 1  having Formula (ID): 
       
         
           
           
               
               
           
         
         wherein R 15  and R 16  are independently selected from hydrogen, halogen, nitro, carboxylic acid, carboxylate, acetic acid, and acetate group; 
         X is CH, Y is N; 
         L is NH or O; 
         Z is C—R 8 ; and 
         R 8  is pyridinyl or phenyl, wherein said phenyl is optionally substituted with one to three same or different substituents at any available aromatic ring carbon atom, said substituents are selected from halogen, hydroxy and methoxy group. 
       
     
     
         26 . The compound of  claim 25  selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         27 . A compound having Formula (IE): 
       
         
           
           
               
               
           
         
         wherein two dashed arrows points to two carbon atoms of the phenyl ring, to which the carbonyl can be attached, 
         R 2  is hydrogen or (C 1 -C 3 )-alkyl; 
         R 14  is one to three same or different substituents attached to any available carbon atom of the phenyl ring and independently selected from hydrogen, amino, (C 1 -C 3 )-alkyl, (C 1 -C 3 )-haloalkyl, (C 1 -C 3 )-alkoxy, (C 1 -C 3 )-alkylcarboxylic acid, carboxylic acid, (C 1 -C 3 )-alkylcarboxylate, carboxylate, (C 1 -C 3 )-alkylcarboxamide, carboxamide, halogen, cyano, hydroxy, nitro and acetylamino group; 
         A is CH—R 10  or N—R 11 ; 
         E is C—R 12  or N; 
         J is C—R 13  or N; 
         R 10 , R 11 , R 12 , and R 13  are independently selected from hydrogen, (C 1 -C 3 )-alkyl and (C 1 -C 3 )-haloalkyl; and either: 
            is a double bond, and G is O; or 
            is a single bond, and G taken together with the two adjacent carbon atoms and with the nitrogen atom to which the second carbon atom is attached forms a five- or six-membered heterocyclic ring. 
       
     
     
         28 . The compound of  claim 27 , wherein R 14  is one substituent attached to any available carbon atom of the phenyl ring and selected from hydrogen, (C 1 -C 3 )-alkyl and acetylamino group;
 R 10 , R 11 , R 12 , and R 13  are independently selected from hydrogen and (C 1 -C 3 )-alkyl;      is a double bond; and G is O.   
     
     
         29 . The compound of  claim 28  selected from: 
       
         
           
           
               
               
           
         
       
     
     
         30 . The compound of  claim 27 , wherein R 14  is one substituent attached to any available carbon atom of the phenyl ring and selected from hydrogen, (C 1 -C 3 )-alkyl and acetylamino group;
 R 10 , R 11 , R 12 , and R 13  are independently selected from hydrogen and (C 1 -C 3 )-alkyl      is a single bond, and G taken together with the two adjacent carbon atoms and with the nitrogen atom to which the second carbon atom is attached forms a five- or six-membered heterocyclic ring.   
     
     
         31 . The compound of  claim 30  selected from: 
       
         
           
           
               
               
           
         
       
     
     
         32 . The compound of  claim 1  for use as a selective herbicide, non-selective herbicide, agricultural herbicide, non-agricultural herbicide, herbicide in integrated pest management, herbicide in gardening, herbicide in clearing waste ground, herbicide in clearing industrial or constructions sites, herbicide in clearing railways and railway embankments, pesticide, fungicide, agricultural plant stimulant or antimicrobial agent. 
     
     
         33 . A method for the control of undesired vegetation or clearing areas from the undesired vegetation comprising applying to the locus of said undesired vegetation, to the undesired plants or to a habitat thereof, a herbicidally effective amount of the compound of  claim 1 . 
     
     
         34 . The method of  claim 33 , wherein said locus is agricultural areas, crop fields, gardens, waste grounds, industrial or constructions sites, railways, or railway embankments.