New indole derivatives as factor xa inhibitors

Abstract

The present invention relates to compounds of formula I, in which R 0 ; R 1 ; R 2 ; R 3 ; R 4 ; R 5 ; R 6 ; R 7 ; Q; V, G and M have the meanings indicated in the claims. The compounds of formula I are valuable pharmacologically active compounds. They exhibit a strong antithrombotic effect and are suitable, for example, for the therapy and prophylaxis of cardiovascular disorders like thromboembolic diseases or restenoses. They are reversible inhibitors of the blood clotting enzymes factor Xa (FXa) and/or factor VIIa (FVIIa), and can in general be applied in conditions in which an undesired activity of factor Xa and/or factor VIIa is present or for the cure or prevention of which an inhibition of factor Xa and/or factor VIIa is indicated. The invention furthermore relates to processes for the preparation of compounds of formula I, their use, in particular as pharmaceuticals for treating the foregoing conditions, and pharmaceutical preparations comprising them.

1 . A compound of formula I, 
     
       
         
         
             
             
         
       
       wherein 
       R 0  is selected from the group consisting of:
 monocyclic and bicyclic 6- to 14-membered aryl carbon rings, said aryl rings being substituted with one to three R 8  groups independently selected from those substituents defined below, with the stipulation that at least one R 8  group is halogen, —C(O)—NH 2  or —O—(C 1 -C 8 )-alkyl; 
 
       R 8  is selected from the group consisting of:
 halogen, —NO 2 ; —CN; —C(O)—NH 2 ; —OH; —NH 2 ; —OCF 3 ; monocyclic and bicyclic 4- to 14-membered aryl radicals, said aryl radicals being substituted with one, two, or three groups independently selected from halogen, —O—(C 1 -C 8 )-alkyl; and —(C 1 -C 8 )-alkyl which are both unsubstituted or substituted with up to three groups independently selected from halogen, NH 2 , —OH and methoxy; 
 
       Q is selected from the group consisting of
 —C(O)—; —(C 0 -C 2 )-alkylene-C(O)—NR 10 —; —NR 10 —C(O)—NR 10 —; —NR 10 —C(O)—; —SO 2 — and —(C 1 -C 6 )-alkylene, wherein alkylene is unsubstituted or substituted with up to three substituents independently selected from halogen, 
 —NH 2  and —OH; and (C 3 -C 6 )-cycloalkylene, wherein cycloalkylene is unsubstituted or substituted with up to three groups independently selected from halogen, —NH 2  and —OH; 
 
       R 1  is selected from the group consisting of
 hydrogen; —(C 1 -C 4 )-alkyl radicals, said alkyl radicals being unsubstituted or substituted with one to three substituents independently selected from the R 13  substituents defined below; and monocyclic or bicyclic 4- to 14-membered heteroaryl radicals said heteroaryl radical is unsubstituted or substituted with one to three substituents independently selected from the R 14  substituents defined below; 
 
       R 2  is a bond or —(C 1 -C 4 )-alkylene;
 R 14  is selected from the group consisting of
 halogen, —OH, —(C 1 -C 8 )-alkyl, —(C 1 -C 4 )-alkoxy, —NO 2 , —C(O)—OH, —CN, —NH 2 , —C(O)—O—(C 1 -C 4 )-alkyl, —(C 1 -C 8 )-alkylsulfonyl, —SO 2 , —C(O)—NH—(C 1 -C 8 )-alkyl, —C(O)—N—[(C 1 -C 8 )-alkyl] 2 , —NR 10 —C(O)—NH—(C 1 -C 8 )-alkyl, —C(O)—NH 2 , —SR 10 , and —NR 10 —C(O)—NH—[(C 1 -C 8 )-alkyl] 2 , said R 10  being selected from hydrogen, —(C 1 -C 3 )-perfluoroalkyl and —(C 1 -C 6 )-alkyl; 
 
 V is a monocyclic or bicyclic 4 to 14-member heteroaryl group in which one or more of the 5 to 14 ring carbon atoms are replaced by heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur. 
 
       G is selected from the group consisting of a bond, —(CH 2 ) m —NR 10 —SO 2 —NR 10 —(CH 2 ) n —, —(CH 2 ) m —CH(OH)—(CH 2 ) n -1-(CH 2 ) m -1-(CH 2 ) m —O—(CH 2 ) n —, —(CH 2 ) m —C(O)—NR 10 —(CH 2 ) n —, —(CH 2 )—SO 2 —(CH 2 ) n —, —(CH 2 ) m —NR 10 —C(O)—NR 10 —(CH 2 )—, —(CH 2 ) m —NR 10 —C(O)—(CH 2 ) n —(CH 2 ) m —C(O)—(CH 2 ) n —, —(CH 2 )—S—(CH 2 ) n —, —(CH 2 ) m —SO 2 —NR 10 —(CH 2 ) n —, —(CH 2 ) m —NR 10 SO 2 —(CH 2 ) n —, —(CH 2 ) m —NR 10 —(CH 2 ) m —O—C(O)—NR 10 —(CH 2 ) n — and —(CH 2 ) m —NR 10 —C(O)—O—(CH 2 ) n —,
 n and m are independently selected from zero and the integers 1, 2, 3, 4, 5 and 6, 
 R 10  is hydrogen, —(C 1 -C 3 )-perfluoroalkyl or —C 1 -C 6 )-alkyl, 
 M is selected from the group consisting of:
 hydrogen; —(C 1 -C 8 )-alkyl, said alkyl being unsubstituted or substituted with one to three groups independently selected from the R 14  substituents defined above; —C(O)—NR 11 R 12 ; —(CH 2 ) m —NR 10 ; —(C 6 -C 14 )-aryl, said aryl being unsubstituted or substituted with one to three groups independently selected from the R 14  substituents defined above; —(C 4 -C 14 )-heteroaryl, said heteroaryl being unsubstituted or substituted with one to three groups independently selected from the R 14  substituents defined above; (C 3 -C 7 )-cycloalkyl, said cycloalkyl being unsubstituted or substituted with one to three groups independently selected from the R 14  substituents defined above; a 3- to 7-membered cyclic residue, optionally containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen, said cyclic residue being unsubstituted or substituted with one to three groups independently selected from the R 14  substituents defined above; 
 
 R 11  and R 12  are independently selected from the group consisting of:
 hydrogen; —(C 1 -C 6 )-alkyl, said alkyl being unsubstituted or substituted with from one to three groups independently selected from the R 13  substituents defined below; —(C 6 -C 14 )-aryl-(C 1 -C 4 )-alkyl-, wherein said alkyl and said aryl are each independently unsubstituted or substituted with one to three groups independently selected from the R 13  substituents defined below; —(C 6 -C 14 )-aryl-, said aryl being unsubstituted or substituted with one to three groups independently selected from the R 13  substituents defined below; 
 —(C 4 -C 14 )-heteroaryl, said heteroaryl being unsubstituted or substituted with one to three substituents independently selected from the R 13  substituents defined below; —(C 4 -C 14 )-heteroaryl-(C 1 -C 4 )-alkyl-, wherein said alkyl and said heteroaryl are each independently unsubstituted or substituted with one to three substituents independently selected from the R 13  substituents defined below; or, alternatively, 
 
 R 11  and R 12 , together with the nitrogen atom to which they are bonded, form a saturated 5- to 7-membered monocyclic heterocyclic ring which, in addition to said nitrogen atom, may contain one or two identical or different ring heteroatoms selected from oxygen, sulfur and nitrogen; said heterocyclic ring being unsubstituted or substituted with one to three substituents independently selected from the R 13  substituents defined below; 
 R 13  is selected from the group consisting of:
 halogen; —NO 2 ; —CN; ═O; —OH; —(C 1 -C 8 )-alkyl; —(C 1 -C 8 )-alkoxy; —CF 3 ; phenyl; phenyloxy-; —C(O)—O—R 11 ; phenyl-(C 1 -C 4 )-alkoxy-; —C(O)—N—R 11 R 12 ; —NR 11 R 12 ; —NR 10 —SO 2 —R 10 ; —S—R 10 ; —SO n —R 10 ; wherein n is 1 or 2; —SO 2 —NR 11 R 12 ; —C(O)—R 10 ; —(C 0 -C 4 )-alkyl-C(O)—O—C(R 15 R 16 )—O—C(O)—R 17 ; —(C 0 -C 4 )-alkyl-C(O)—O—C(R 15 R 16 )—O—C(O)O—R 17  and a residue of formula Va, 
 
 
     
     
       
         
         
             
             
         
       
       
         
           wherein R 10 , R 11  and R 12  are as defined above and R 15 , R 16  or R 17  are as defined below; 
         
         R 15  and R 16  are independently selected from the group consisting of hydrogen, and —(C 1 -C 6 )-alkyl, or they alternatively, together with the carbon atom to which they are bonded, form a 3- to 6 membered carbocyclic ring, said carbocyclic ring being unsubstituted or substituted with one to three groups independently selected from the group consisting of the R 10  substituents defined above; 
         R 17  is selected from the group consisting of —(C 1 -C 6 )-alkyl, —(C 1 -C 8 )-cycloalkyl, and —(C 1 -C 6 )-alkyl-(C 1 -C 8 )-cycloalkyl, each said cycloalkyl ring being unsubstituted or substituted with one to three groups independently selected from the R 10  substituents defined above; 
         R 3 , R 4 , R 5 , R 6  and R 7  are each independently selected from the group consisting of: hydrogen; halogen and —(C 1 -C 4 )-alkyl, said alkyl being unsubstituted or substituted with one to three groups independently selected from the group consisting of the R 13  substituents defined above; —(C 1 -C 3 )-perfluoroalkyl and phenyl, said phenyl being unsubstituted or substituted with one to three groups independently selected from the group consisting of the R 13  substituents defined above; —O—(C 1 -C 4 )-alkyl, said alkyl being unsubstituted or substituted with one to three groups independently selected from the R 13  substituents defined above; —NO 2 ; —CN; —OH and phenyloxy-, said phenyloxy being unsubstituted or substituted with one to three groups independently selected from the R 13  substituents defined above; benzyloxy-, said benzyloxy being unsubstituted or substituted with one to three groups independently selected from the R 13  substituents defined above; —C(O)—O—R 11 , wherein R 11  is as defined above; —C(O)—N—R 11 R 12 , wherein R 11  and R 12  are as defined above; —NR 11 R 12 , wherein R 11  and R 12  are as defined above; —NR 10 —SO 2 —R 10 , wherein R 10  is as defined above; —SR 10 , wherein R 10  is as defined above; —SO n —R 10 , wherein n is 1 or 2 and R 10  is as defined above; —SO 2 —NR 11 R 12 , wherein R 11  and
 R 12  are as defined above; —C(O)—R 10 , wherein R 10  is as defined above; —C(O)—O—C(R 15 R 16 )—O—C(O)—R 17 , wherein R 15 , R 16  and R 17  are as defined above; —C(O)—O—C(R 15 R 16 )—O—C(O)O—R 17 , wherein R 15 , R 16  and R 17  are as defined above; a residue of formula Va, 
 
       
     
     
       
         
         
             
             
         
       
       
         
           wherein R 10  is as defined above, and a residue of formula Vb or Vc, 
         
       
     
     
       
         
         
             
             
         
       
       
         —NR 10 —(C 1 -C 4 )-alkyl, said alkyl being unsubstituted or substituted with one to three groups independently selected from the R 13  substituents defined above; —O—CF 3 ; and a residue selected from the group consisting of: 
       
     
     
       
         
         
             
             
         
       
       
         wherein R 10 , R 11 , R 12  and R 13  are as defined above; 
         its stereoisomers, salts and mixtures thereof 
       
     
   
   
       2 . The compound of formula I, as claimed in  claim 1 , wherein
 R 0  is selected from the group consisting of:
 monocyclic and bicyclic 6- to 14-membered aryl carbon rings, said aryl rings being substituted with one to three R 8  groups independently selected from those substituents previously defined above, with the stipulation that at least one R 8  group is halogen, —C(O)—NH 2  or —O—(C 1 -C 8 )-alkyl; 
   Q is selected from the group consisting of:
 —C(O)—; —SO 2 —; —(C 1 -C 6 )-alkylene; and —(C 0 -C 2 )-alkylene-C(O)—NR 10 —; 
 R 1  is hydrogen or —(C 1 -C 2 )-alkyl; 
 R 2  is a direct bond or —(C 1 -C 2 )-alkylene; 
 R 14  is halogen, —(C 1 -C 4 )-alkyl or —NH 2 ;
 V is a monocyclic or bicyclic 4 to 14-member heteroaryl group in which one or more of the 5 to 14 ring carbon atoms are replaced by heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur, G is a bond, —(CH 2 ) m —, or —(CH 2 ) m —NR 10 —; 
 
 m is zero or an integer selected from 1, 2, 3 and 4; 
 R 10  is hydrogen, —(C 1 -C 3 )-perfluoroalkyl or —(C 1 -C 4 )-alkyl; 
 M is selected from the group consisting of
 hydrogen; —(C 6 -C 14 )-heteroaryl, said heteroaryl being a residue selected from the group consisting of the derivatives of piperidine, piperazine, pyridine, pyrimidine, pyrrolidine, pyrrolidinone, pyridonyl, imidazole, pyridazine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole, 1,2,4-triazole, tetrazine, tetrazole, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, azepine, ketopiperazine, oxazole, isoxazole, isoxazolidine, 2-isoxazoline, morpholine, thiazole, isothiazole, tetrahydropyran, thiadiazole and thiomorpholine, which are unsubstituted or substituted with one to three substituents independently selected from the R 14  substituents defined above; —(C 1 -C 6 )-alkyl, said alkyl being unsubstituted or substituted with one to three substituents independently selected from the R 14  substituents defined above; and (C 3 -C 6 )-cycloalkyl; 
 
 R 3 , R 4 , R 5 , R 6  and R 7  are independently selected from the group consisting of hydrogen; F; Cl; Br; —(C 1 -C 4 )-alkyl, said alkyl being unsubstituted or substituted by R 13  as defined below; —CF 3 ; phenyl, said phenyl being unsubstituted or substituted with one to three substituents independently selected from the R 13  substituents defined below; —O—(C 1 -C 4 )-alkyl, wherein alkyl is unsubstituted or substituted by R 13  as defined below; —NO 2 ; —CN; —OH; phenyloxy-, said phenyloxy being unsubstituted or substituted by R 13  as defined below; benzyloxy-, said benzyloxy being unsubstituted or substituted by R 13  as defined below; —C(O)—O—R 11 ; —C(O)—N—R 11 R 12 ; —NR 11 R 12 ; —NR 10 —SO 2 —R 10 ; —SO, —R 10 , wherein n is 1 or 2; —SO 2 —NR 11 R 12 ; —C(O)—R 10 ; —C(O)—O—C(R 15 R 16 )—O—C(O)—R 17 ; —C(O)—O—C(R 15 R 16 )—O—C(O)O—R 17 ; a residue of formula Va: 
   
     
       
         
         
             
             
         
       
       
         a residue of formula Vb or Vc, 
       
     
     
       
         
         
             
             
         
       
       
         —O—CF 3 ; and a residue selected from the group consisting of 
       
     
     
       
         
         
             
             
         
       
       
         R 13  is selected from the group consisting of
 halogen; —NO 2 ; —CN, ═O; —OH; —(C 1 -C 8 )-alkoxy; —CF 3 ; —C(O)—O—R 11 ; —C(O)—N—R 11 R 12 ; —NR 11 R 12 ; —NR 10 —SO 2 —R 10 ; —SO n —R 10 , wherein n is 1 or 2; —SO 2 —NR 11 R 12 ; —C(O)—R 10 ; —(C 0 -C 4 )-alkyl-C(O)—O—C(R 15 R 16 )—O—C(O)—R 17 ; —(C 0 -C 4 )-alkyl-C(O)—O—C(R 15 R 16 )—O—C(O)O—R 17 ; and a residue of formula Va, 
 
       
     
     
       
         
         
             
             
         
       
       and R 10 , R 11 , R 12 , R 15 , R 16  and R 17  are as defined in  claim 1  above, its' isomers, salts and mixtures thereof 
     
   
   
       3 . The compound of formula I as recited in  claim 1 , wherein
 R 0  is monocyclic and bicyclic 6- to 14-membered aryl carbon rings, said aryl rings being substituted with one to three R 8  groups independently selected from those substituents previously defined herein, with the stipulation that at least one R 8  group is halogen, —C(O)—NH 2  or —O—(C 1 -C 8 )-alkyl;   Q is —C(O)—, —SO 2 —, methylene or ethylene;   R 1  is hydrogen;   R 2  is a bond or methylene;   R 13  is selected from the group consisting of
 —C(O)—O—R 11 ; —C(O)—N—R 11 R 12 ; —NR 11 R 12 ; —NR 10 —SO 2 —R 10 ; and —SO n —R 10 , wherein n is 1 or 2; 
 —SO 2 —NR 11 R 12 ; —C(O)—R 10 ; —(C 0 -C 4 )-alkyl-C(O)—O—C(R 15 R 16 )—O—C(O)—R 17 ; —(C 0 -C 4 )-alkyl-C(O)—O—C(R 15 R 16 )—O—C(O)O—R 17 ; and a residue of formula Va, 
   
     
       
         
         
             
             
         
       
       
         wherein R 10 , R 11 , R 12 , R 15 , R 16  or R 17  are as defined in  claim 1  above; 
       
       R 14  is halogen, methyl, ethyl or —NH 2 ; 
       V is a monocyclic or bicyclic 4 to 14-member heteroaryl group in which one or more of the 5 to 14 ring carbon atoms are replaced by heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur; 
       G is a bond, (CH 2 ) m —, or —(CH 2 ) m —NR 10 —, wherein m is zero, 1 or 2, and R 10  is hydrogen or —(C 1 -C 4 )-alkyl; 
       M is selected from the group consisting of hydrogen, (C 2 -C 4 )-alkyl, imidazolyl, pyrazolyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, and (C 3 -C 6 )-cycloalkyl, which cyclic residues are unsubstituted or substituted with one or two substituents independently selected from the R 14  substituents defined above; and 
       R 3 , R 4 , R 5 , R 6  and R 7  are independently selected from the group consisting of hydrogen; F; Cl; —(C 1 -C 4 )-alkyl, wherein alkyl is unsubstituted or substituted by R 13 , as defined above; phenyl, which is unsubstituted or substituted with one to three substituents independently selected from the R 13  substituents defined above; —O—(C 1 -C 4 )-alkyl, wherein alkyl is unsubstituted or substituted by R 13 , as defined above; —C(O)—O—R 11 ; —C(O)—N—R 11 R 12 ; —NR 11 R 12 ; —NR 10 —SO 2 —R 10 ;
 —SO 2 —NR 11 R 12 ; —C(O)—R 10 ; —C(O)—O—C(R 15 R 16 )—O—C(O)—R 17 , wherein R 15 , R 16  and R 17  are as defined in  claim 1  above; —C(O)—O—C(R 15 R 16 )—O—C(O)O—R 17 , wherein R 15 , R 16  and R 17  are as defined in  claim 1  above; a residue of formula Va 
 
     
     
       
         
         
             
             
         
       
       
         a residue of formula Vb or Vc, 
       
     
     
       
         
         
             
             
         
       
       
         and a residue selected from the group consisting of: 
       
     
     
       
         
         
             
             
         
       
       its' isomers, salts and mixtures thereof 
     
   
   
       4 . The compound of formula I as recited in  claim 1  selected from the group consisting of: 
     1-(3-methoxy-benzyl)-1H-indole-2-carboxylic acid (3-pyridin-4-yl-4,5-dihydro-isoxazol-5-ylmethyl)-amide; 
     1-(3-methoxy-benzyl)-1H-indole-2-carboxylic acid (4-amino-quinazolin-7-ylmethyl)-amide; 
     1-(4-chloro-phenyl)-1H-indole-2-carboxylic acid ((4-amino-quinazolin-7-ylmethyl)-amide; 
     1-(4-chloro-benzyl)-1H-indole-2-carboxylic acid (3-pyridin-4-yl-4,5-dihydro-isoxazol-5-ylmethyl)-amide; 
     1-(2,4-dichloro-benzyl)-1H-indole-2-carboxylic acid (3-pyridin-4-yl-4,5-dihydro-isoxazol-5-ylmethyl)-amide; and 
     1-(2,4-dichloro-benzyl)-1H-indole-2-carboxylic acid ((4-amino-quinazolin-7-ylmethyl)-amide.