Compound for the treatment of bovine or swine respiratory disease

Abstract

The present invention provides compounds for use in the treatment of respiratory diseases of animals, especially Bovine or Swine Respiratory disease (BRD and SRD).

1 - 29 . (canceled) 
     
     
         30 . A Method of treatment of bovine respiratory disease or swine respiratory disease comprising administering to an animal a compound according to the formula (I): 
       
         
           
           
               
               
           
         
         or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, or prodrug thereof, wherein A is selected from the group consisting of
 NR A1 R A2 , and NO 2 , 
 wherein
 R A1 , R A2  are independently selected from the group consisting of 
 H, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-10 -cycloalkyl, aryl, heterocyclyl, heteroaryl, C 1-6 -alkyloxy-C 1 -C 6 , C 1 -C 6 -alkyl substituted with aryl, C 1 -C 6 -alkyl substituted with heteroaryl, C 1 -C 6 -alkyl substituted with heterocyclyl, or 
 R A1 , R A2  together with the N atom to which they are attached can form a saturated or unsaturated heterocyclic ring having 3 to 12 ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3 further ring atoms are selected from N, S, and O; 
 
 wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkyloxy or the heterocyclic ring formed by R A1 , R A2  together with the N atom to which they are attached is optionally substituted with a substituent selected from the group consisting of
 C 1-6 -alkyl, C 3-8 -cycloalky, C 1-6 -alkyloxy, —NR A3 R A4 —, carbonyl, —C(═O)—OR A5 —, halogen atom, C 1-6 -alkyl substituted with halo, C 1-6 -alkyloxy-C 1 -C 6 —, aryl, heteroaryl, C 1 -C 6 -alkyl substituted with aryl, cyano, hydroxy, —SR A5 —, —SO 2 R A5 —, SO 2 NR A3 R A4 , —C(═O)NR A3 R A4 —, C 1-6 -alkyl substituted with hydroxy; 
 
 wherein
 R A3 , R A4 , R A5  are independently chosen from 
 H, or C 1-6 -alkyl; 
 
 
         L is absent or selected from the group consisting of
 C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-10 -cycloalkyl, aryl, heterocyclyl, heteroaryl, —(NR L3 ) 0-1 —(CH 2 ) 0-4 —NR L3 —(CH 2 ) 0-4 —, —(NR L3 ) 0-1 —(CR L1 R L2 ) 0-4 —NR L3 —(CR L1 R L2 )—, —(CR L1 R L2 ) 0-4 —O—(CR L1 R L2 )—, —(CH 2 ) 0-4 —NR L3 —(CR L1 R L2 )—C(═O)NH—(CH 2 ) 0-4 —, —C(═O)—(CR L1 R L2 )—NR L3 C(═O)—, —C(═O)NR L3 —, —NR L3 C(═O)—, —NR L3 —, —SO 2 NR L3 —, NR L3 —C(═O)—NR L3 — 
 wherein
 R L1 , R L2 , R L3 , are independently selected from the group consisting of 
 H, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1 -C 6 -alkyl substituted with aryl, C 1 -C 6 -alkyl substituted with heteroaryl, C 1 -C 6 -alkyl substituted with heterocyclyl; or 
 R L1 , R L3  together with the atoms to which they are attached can form a saturated or unsaturated heterocyclic ring having 3 to 8 ring atoms, wherein 1, 2, or 3, ring atoms are selected from N, S, and O; 
 
 
         M is selected from the group consisting of
 C 3-10 -cycloalkyl, aryl, heterocyclyl, heteroaryl, C 2-4 alkenyl, C 2-4 alkynyl, —C(R M1 )═C(R M1 )—C≡C—, —C(R M1 )═C(R M1 )—, 
 wherein each cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with a substituent selected from the group consisting of
 C 1-6 -alkyl, C 3-8 -cycloalky, C 1-6 -alkyloxy, NR M2 R M3 , carbonyl, —C(═O)—OR M2 , halo, halo-C 1-6 -alkyl, C 1-6 -alkyloxy-C 1 -C 6 , aryl, heteroaryl, C 1 -C 6 -alkyl substituted with aryl, cyano, hydroxy, —SR M2 , —SO 2 R M4 , —OSO 2 R M4 , —SO 2 NR M2 R M3 , —C(═O)NR M2 R M3 —, hydroxy-C 1-6 -alkyl; 
 
 wherein R M1  is selected from the group consisting of H, C 1-6 -alkyl, halo, hydroxyl, and amino; 
 wherein R M2 , R M3  are independently selected from the group consisting of H, and C 1-6 -alkyl; 
 wherein R M4  is selected from the group consisting of H, C 1-6 -alkyl, and amino; 
 
         G is selected from the group consisting of
 —(C(R G2 R G3 ) 0-4 —O—(C(R G2 R G3 ) 0-4 —, —(C(R G2 R G3 ) 0-4 —S—(C(R G2 R G3 ) 0-4 —, —(C(R G2 R G3 ) 0-4 —NR R1 —(C(R G2 R G3 ) 0-4 —, —C(═O)—, —NR G1  C(═O)—, —C(═O)—, —C(═O)NR G1 —, —(C(R G2 R G3 ) 0-4 —NR G1  —C(R G2 R G3 )—C(═O)NR G1 —, —CR G2 ═CR G2 —, —CR G2 ═CR G2 —CR G2 ═CR G2 —, —C≡C—, —C≡C—C≡C—, —CR G2 ═CR G2 —C≡C—, —C≡C—CR G2 ═CR G2 , —C(═O)—C≡C—, —C≡C—C(═O)— —SO 2 —, —S(═O)—, —S(═O)C(R G2 R G3 )—. —C(R G2 R G3 )S(═O)—, —C(R G2 R G3 )—SO 2 —, —SO 2 C(R G2 R G3 )—; 
 wherein
 R G1  is H or C 1-6 -alkyl 
 each R G2 , R G3  is independently selected from the group consisting of 
 H, halogen atom, or C 1-6 -alkyl; 
 
 
         Y is selected from the group consisting of
 C 3-10 -cycloalkyl, aryl, heterocyclyl, heteroaryl, 
 wherein each cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with a substituent selected from the group consisting of
 C 1-6 -alkyl, C 3-8 -cycloalky, C 1-6 -alkyloxy, NR Y1 R Y2 , carbonyl, —C(═O)—OR Y1 , halo, halo-C 1-6 -alkyl, C 1-6 -alkyloxy-C 1 -C 6 , aryl, heteroaryl, C 1 -C 6 -alkyl substituted with aryl, cyano, hydroxy, —SR Y2 , —SO 2 R Y3 , —OSO 2 R Y3 , —SO 2 NR Y1 R Y2 , —C(═O)NR Y2 R Y3 —, hydroxy-C 1-6 -alkyl; 
 
 wherein R Y1 , R Y2  are independently selected from the group consisting of H, and C 1-6 -alkyl; 
 wherein R Y3  is selected from the group consisting of H, C 1-6 -alkyl, and amino; 
 
         X is absent or selected from the group consisting of
 —C(═O)—, —C 1-6 -alkyl-C(═O)—, —C 2-6 -alkenyl-C(═O)—, —C 2-6 -alkynyl-C(═O)—, and —(C(R X1 ) 2 —, —S(═O)—, —SO 2 —; 
 wherein
 R X1 . is selected from the group consisting of 
 H, halogen atom, substituted C 1-6 -alkyl, or un-substituted C 1-6 -alkyl; 
 wherein the substituents on the substituted C 1-6 -alkyl may be selected from the group consisting of halogen, hydroxyl, alkoxy, aryloxy, thiol, C 1-6 -alkyl, carbonyl, —SR X3 , —SO 2 R X5 , —C(═O)NR X3 R X4 , cyano, —NR X3 R X4 , —C(═O)—OR X3 , aryl, heteroaryl, heterocycle, C 3-8 -cycloalkyl; 
 wherein R X3 , R X4  are independently selected from the group consisting of H, or C 1-6 -alkyl; 
 wherein RX 5  is selected from the group consisting of H, C 1-6 -alkyl, and amine; 
 
 
         R 1  is selected from the group consisting of
 H, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-10 -cycloalkyl, C(═O)R 9 , C(═N—OR 8 )R 8 , aryl, heterocyclyl, heteroaryl, C 1 -C 6 -alkyl substituted with aryl, C 1 -C 6 -alkyl substituted with heteroaryl, C 1 -C 6 -alkyl substituted with heterocyclyl; 
 wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, is optionally substituted with a substituent selected from the group consisting of
 C 1-6 -alkyl, C 3-8 -cycloalky, C 1-6 -alkyloxy, NR 6 R 7 , carbonyl, nitro, C(═O)OR 9 , halogen, halo-C 1-6 -alkyl, C 1-6 -alkyloxy-C 1 -C 6 , cyano, hydroxy, —SR 8 , —SO 2 R 8 , SO 2 NR 6 R 7 , —C(═O)NR 6 R 7 —; 
 
 wherein R 6 , R 7 , R 8  are independently chosen from H, or C 1-6 -alkyl; 
 wherein R 9  is selected from the group consisting of H, hydroxyl, or C 1-6 -alkyl; 
 
         R 2 , R 3  are independently selected from the group consisting of
 H, substituted C 1-6 -alkyl, or un-substituted C 1-6 -alkyl;
 wherein the substituents on the substituted C 1-6 -alkyl may be selected from the group consisting of halogen, hydroxyl, alkoxy, aryloxy, thiol, C 1-6 -alkyl, carbonyl, —SR 8 , —SO 2 R 8 , SO 2 NR 6 R 7 , —C(═O)NR 6 R 7 , cyano, —NR 6 R 7 , —C(═O)—OR 6 , aryl, heteroaryl, heterocycle, C 3-8 -cycloalkyl; 
 
 
         q is 0, 1, 2, 3, or 4; 
         R 4  is selected from the group consisting of
 H, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-10 -cycloalkyl, —OR 8 , C(═O)OR 9 , C(═O)R 9 , aryl, heterocyclyl, heteroaryl, C 1 -C 6 -alkyl substituted with aryl, C 1 -C 6 -alkyl substituted with heteroaryl, C 1 -C 6 -alkyl substituted with heterocyclyl; 
 wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, is optionally substituted with a substituent selected from the group consisting of
 C 1-6 -alkyl, C 3-8 -cycloalky, C 1-6 -alkyloxy, NR 6 R 7 , carbonyl, nitro, C(═O)OR 9 , halogen, halo-C 1-6 -alkyl, C 1-6 -alkyloxy-C 1 -C 6 , cyano, hydroxy, —SR 8 , —SO 2 R 8 , SO 2 NR 6 R 7 , —C(═O)NR 5 R 6 ; 
 
 
         R 5  is selected from the group consisting of H, and C 1-6 -alkyl; 
         R 6 , R 7 , R 8  are independently selected from the group consisting of H, and C 1-6 -alkyl; 
         wherein R 9  is selected from the group consisting of H, hydroxyl, or C 1-6 -alkyl. 
       
     
     
         31 . The method of treatment according to  claim 30  wherein A is selected from the group consisting of
 NR A1 R A2 , and NO 2 , 
 wherein
 R A1 , R A2  are independently selected from the group consisting of 
 H, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-10 -cycloalkyl, C 1-6 -alkyloxy-C 1 -C 6 , C 1 -C 6 -alkyl substituted with aryl, C 1 -C 6 -alkyl substituted with heteroaryl, C 1 -C 6 -alkyl substituted with heterocyclyl, or 
 R A1 , R A2  together with the N atom to which they are attached can form a saturated or unsaturated heterocyclic ring having 3 to 12 ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3 further ring atoms are selected from N, S, and O; 
 
 wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkyloxy or the heterocyclic ring formed by R A1 , R A2  together with the N atom to which they are attached is optionally substituted with a substituent selected from the group consisting of
 C 1-6 -alkyl, C 3-8 -cycloalky, —NR A3 R A4 , carbonyl, halogen atom, C 1-6 -alkyl substituted with halo, aryl, heteroaryl, C 1 -C 6 -alkyl substituted with aryl, cyano, hydroxy, —SR A6 , —SO 2 R A6 , SO 2 NR A3 R A4 , —C(═O)NR A3 R A4 , C 1-6 -alkyl substituted with hydroxy; 
 
 wherein
 R A3 , R A4 , R A5  are independently chosen from 
 H, or C 1-6 -alkyl. 
 
 
     
     
         32 . The method of treatment according to  claim 30  wherein A is NR A1 R A2 . 
     
     
         33 . The method of treatment according to  claim 30 , wherein q is 0, or 1. 
     
     
         34 . The method of treatment according to  claim 30 , wherein L is selected from the group consisting of
 C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-10 -cycloalkyl, —(NR L3 ) 0-1 —(CH 2 ) 0-4 —NR L3 —(CH 2 ) 0-4 —, —(NR L3 ) 0-1 —(CR L1 R L2 ) 0-4 —NR L3 —(CR L1 R L2 )—, —(CR L1 R L2 ) 0-4 —O—(CR L1 R L2 )—, —(CH 2 ) 0-4 —NR L3 —(CR L1 R L2 )—C(═O)NH—(CH 2 ) 0-4 —, —C(═O)—(CR L1 RL 2 )—NR L3 C(═O)—, —C(═O)NR L3 —, —NR L3 C(═O)—, —NR L3 —, —SO 2 NR L3 —, NR L3 —C(═O)—NR l3 —;   wherein
 R L1 , R L2 , R L3 , are independently selected from the group consisting of 
 H, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1 -C 6 -alkyl substituted with aryl, C 1 -C 6 -alkyl substituted with heteroaryl, C 1 -C 6 -alkyl substituted with heterocyclyl; or 
 R L1 , R L3  together with the atoms to which they are attached can form a saturated or unsaturated heterocyclic ring having 3 to 8 ring atoms, wherein 1, 2, or 3, ring atoms are selected from N, S, and O. 
   
     
     
         35 . The method of treatment according to  claim 30 , wherein L is selected from the group consisting of
 C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-10 -cycloalkyl, —NR L3 —;   wherein
 R L3  is selected from the group consisting of 
 H, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1 -C 6 -alkyl substituted with aryl, C 1 -C 6 -alkyl substituted with heteroaryl, C 1 -C 6 -alkyl substituted with heterocyclyl. 
   
     
     
         36 . The method of treatment according to  claim 30 , wherein L is selected from the group consisting of —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, and —CH 2 CH 2 CH 2 CH 2 —. 
     
     
         37 . The method of treatment according to  claim 30 , wherein M is selected from the group consisting of
 C 3-10 -cycloalkyl, aryl, heterocyclyl, heteroaryl, C 2-4 alkenyl, C 2-4 alkynyl, —C(R M1 )═C(R M1 )—C≡C—, —C(R M1 )═C(R M1 )—.   
     
     
         38 . The method of treatment according to  claim 30 , wherein G is selected from the group consisting of
 —CR G2 ═CR G2 —, —CR G2 ═CR G2 —CR G2 ═CR G2 —, —C≡C—, —C≡C—C≡C—, —CR G2 ═CR G2 —C≡C—, —C≡C—CR G2 ═CR G2 , —C(═O)—C≡C—, —C≡C—C(═O)—;   wherein
 R G2  is selected from the group consisting of 
 H, halogen atom, or C 1-6 -alkyl. 
   
     
     
         39 . The method of treatment according to  claim 30 , wherein the compound is a compound according to formula (IX) 
       
         
           
           
               
               
           
         
         or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, or prodrug thereof, wherein A, L, M, Y, X, q, R 1 , R 2 , R 3 , R 4 , and R 5 , are defined as in  claim 30 . 
       
     
     
         40 . The method of treatment according to  claim 30 , wherein Y is selected from aryl, or heteroaryl. 
     
     
         41 . The method of treatment according to  claim 30 , wherein the compound is a compound according to formula (XI) 
       
         
           
           
               
               
           
         
         or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, or prodrug thereof, wherein A, L, M, X, q, R 1 , R 2 , R 3 , R 4 , and R 5 , are defined as in  claim 30 . 
       
     
     
         42 . The method of treatment according to  claim 30 , wherein X is selected from the group consisting of —C(═O)—, and —S(═O). 
     
     
         43 . The method of treatment according to  claim 30 , wherein the compound is a compound according to formula (XVI) 
       
         
           
           
               
               
           
         
         or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, or prodrug thereof, wherein A, L, M, G, Y, q, R 1 , R 2 , R 3 , R 4 , and R 5 , are defined as in  claim 30 . 
       
     
     
         44 . The method of treatment according to  claim 30 , wherein R 2 , R 3  is independently selected from the group consisting of H, substituted C 1-6 -alkyl, or un-substituted C 1-6 -alkyl, wherein the substituent on the substituted C 1-6 -alkyl is selected from the group consisting of halogen, hydroxyl, C 1-6 -alkyl, carbonyl, —SR 8 , —SO 2 R 8 , SO 2 NR 6 R 7 , —C(═O)NR 6 R 7 , cyano, —NR 6 R 7 , —C(═O)—OR 6 . 
     
     
         45 . The method of treatment according to  claim 30 , wherein R 4  is selected from the group consisting of H, C 1-6 -alkyl, —OR 8 , —C(═O)OR 9 , C(═O)R 9 . 
     
     
         46 . The method of treatment according to  claim 30 , wherein R 1  is selected from the group consisting of C 1-6 -alkyl, C(═O)R 9 , C(═N—OR 8 )R 8 , wherein the alkyl is optionally substituted with a substituent selected from the group consisting of C 1-6 -alkyl, —NR 6 R 7 , carbonyl, nitro, C(═O)OR 9 , halogen, cyano, hydroxy, —SR 8 , —SO 2 R 8 , SO 2 NR 6 R 7 , —C(═O)NR 6 R 7 —. 
     
     
         47 . The method of treatment according to  claim 30 , wherein the compound is a compound according to formula 
       
         
           
           
               
               
           
         
         or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, or prodrug thereof, wherein A, L, M, G, Y, and X, are defined as in  claim 30 . 
       
     
     
         48 . The method of treatment according to  claim 30 , wherein the compound is a compound according to formula 
       
         
           
           
               
               
           
         
         or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, or prodrug thereof, wherein A, L, M, G, Y, and X, are defined as in  claim 30 . 
       
     
     
         49 . The method of treatment according to  claim 30 , wherein the compound is a compound according to formula 
       
         
           
           
               
               
           
         
         or a stereoisomer, pharmaceutically acceptable salt, ester, solvate, or prodrug thereof, wherein A, L, M, G, Y, and X, are defined as in  claim 30 . 
       
     
     
         50 . The method of treatment according to  claim 30  wherein the treatment is prevention of bovine respiratory disease. 
     
     
         51 . The method of treatment according to  claim 30  wherein the treatment is prevention of swine respiratory disease. 
     
     
         52 . The method of treatment according to  claim 30  wherein an effective dose is between about 0.01 to about 50 mg/kg bodyweight of the animal. 
     
     
         53 . The method of treatment according to  claim 30  wherein one or two doses of the compound in a pharmaceutically acceptable carrier are administered to the animal. 
     
     
         54 . The method of treatment according to  claim 30  wherein a composition comprising the compound and a veterinarily acceptable carrier is administered subcutaneously.