Anthelmintic compounds comprising a thienopyridine structure
The present invention relates to new anthelmintic compounds. These compounds can for example be used in the treatment of the kind of worm disease caused by helminths such as Dirofilaria , in particular Dirofilaria immitis.
1 . Compound of Formula (I)
wherein
R 1 is independently selected from the group consisting of
hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-10 -cycloalkyl, 5- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 1-6 -alkoxy, C 1-6 -alkylmercapto, halogen, cyano, nitro, hydroxy, mercapto, NR 2 R 3 , COOH, C(═O)OR 4 , SR 4 , SOR 4 , SO 2 R 4 , SO 2 NR 5 R 6 and C(═O)NR 5 R 6 ,
wherein each C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-10 -cycloalkyl, 5- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 1-6 -alkoxy or C 1-6 -alkylmercapto, is optionally substituted with one or more substituent(s) independently selected from the group consisting of
C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-10 -cycloalkyl, 5- to 10-membered heterocyclyl, C 6-10 -aryl, 5- to 10-membered heteroaryl, C 1-6 -alkoxy, C 1-6 -alkylmercapto, halogen, cyano, nitro, hydroxy, mercapto, NR 2′ R 3′ , C(═O)OR 4′ , SR 4′ , SOR 4′ , SO 2 R 4′ , SO 2 NR 5′ R 6′ and C(═O)NR 5′ R 6′ ,
R 2 and R 3 are independently selected from the group consisting of
hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-10 -cycloalkyl, 5- to 10-membered heterocyclyl, C 6-10 -aryl, 5- to 10-membered heteroaryl, C 1-6 -alkoxy-C 1-6 -alkyl, C 1-6 -alkyl substituted with C 3-10 -cycloalkyl, C 1-6 -alkyl substituted with 5- to 10-membered heterocyclyl, C 1-6 -alkyl substituted with C 6-10 -aryl and C 1-6 -alkyl substituted with 5- to 10-membered heteroaryl, or
R 2 and R 3 together with the N atom to which they are attached form a saturated or unsaturated heterocyclic ring having 3 to 12 ring atoms, wherein 0, 1, 2, or 3 further ring atoms are selected from N, S and O,
wherein each C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-10 -cycloalkyl, 5- to 10-membered heterocyclyl, C 6-10 -aryl, 5- to 10-membered heteroaryl, C 1-6 -alkoxy-C 1-6 -alkyl, C 1-6 -alkyl substituted with C 3-10 -cycloalkyl, C 1-6 -alkyl substituted with 5- to 10-membered heterocyclyl, C 1-6 -alkyl substituted with C 6-10 -aryl or C 1-6 -alkyl substituted with 5- to 10-membered heteroaryl or the heterocyclic ring formed by R 2 and R 3 together with the N atom to which they are attached is optionally substituted with one or more substituent(s) independently selected from the group consisting of
C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-10 -cycloalkyl, 5- to 10-membered heterocyclyl, C 6-10 -aryl, 5- to 10-membered heteroaryl, C 1-6 -alkoxy, carbonyl, halogen, cyano, hydroxy, mercapto, NR 2″ R 3″ , C(═O)OR 4″ , SR 4″ , SOR 4 , SO 2 R 4″ , SO 2 NR 5″ R 6″ and C(═O)NR 5″ R 6″ ,
R 4 , R 5 and R 6 are independently selected from hydrogen and C 1-6 -alkyl,
R 2′ , R 3′ , R 4′ , R 5′ and R 6′ are independently selected from hydrogen and C 1-6 -alkyl,
R 2″ , R 3″ , R 4″ , R 5″ and R 6″ are independently selected from hydrogen and C 1-6 -alkyl,
R 7 is independently selected from the group consisting of
hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-10 -cycloalkyl, 4- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 1-6 -alkoxy, C 1-6 -alkylmercapto, halogen, cyano, nitro, hydroxy, mercapto, NR 8 R 9 , COOH, C(═O)OR 10 , SR 10 , SOR 10 , SO 2 R 10 , SO 2 NR 11 R 12 and C(═O)NR 11 R 12 ,
wherein each C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-10 -cycloalkyl, 4- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 1-6 -alkoxy or C 1-6 -alkylmercapto, is optionally substituted with one or more substituent(s) independently selected from the group consisting of
C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-10 -cycloalkyl, 5- to 10-membered heterocyclyl, C 6-10 -aryl, 5- to 10-membered heteroaryl, C 1-6 -alkoxy, C 1-6 -alkylmercapto, halogen, cyano, nitro, hydroxy, mercapto, oxo, NR 8′ R 9′ , C(═O)OR 10′ , SR 10′ , SOR 10′ , SO 2 R 10′ , SO 2 NR 11′ R 12′ and C(═O)NR 11′ R 12′ ,
R 8 and R 9 are independently selected from the group consisting of
hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-10 -cycloalkyl, 5- to 10-membered heterocyclyl, C 6-10 -aryl, 5- to 10-membered heteroaryl, C 1-6 -alkoxy-C 1-6 -alkyl, C 1-6 -alkyl substituted with C 3-10 -cycloalkyl, C 1-6 -alkyl substituted with 5- to 10-membered heterocyclyl, C 1-6 -alkyl substituted with C 6-10 -aryl and C 1-6 -alkyl substituted with 5- to 10-membered heteroaryl, or
R 8 and R 9 together with the N atom to which they are attached form a saturated or unsaturated heterocyclic ring having 3 to 12 ring atoms, wherein 0, 1, 2, or 3 further ring atoms are selected from N, S and O,
wherein each C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-10 -cycloalkyl, 5- to 10-membered heterocyclyl, C 6-10 -aryl, 5- to 10-membered heteroaryl, C 1-6 -alkoxy-C 1-6 -alkyl, C 1-6 -alkyl substituted with C 3-10 -cycloalkyl, C 1-6 -alkyl substituted with 5- to 10-membered heterocyclyl, C 1-6 -alkyl substituted with C 6-10 -aryl or C 1-6 -alkyl substituted with 5- to 10-membered heteroaryl or the heterocyclic ring formed by R 8 and R 9 together with the N atom to which they are attached is optionally substituted with one or more substituent(s) independently selected from the group consisting of
C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-10 -cycloalkyl, 5- to 10-membered heterocyclyl, C 6-10 -aryl, 5- to 10-membered heteroaryl, C 1-6 -alkoxy, carbonyl, halogen, cyano, hydroxy, mercapto, NR 8″ R 9″ , C(═O)OR 10″ , SR 10″ , SOR 10″ , SO 2 R 10″ , SO 2 NR 11″ R 12″ and C(═O)NR 11″ R 12″ ,
R 10 , R 11 and R 12 are independently selected from hydrogen and C 1-6 -alkyl,
R 8′ , R 9′ , R 10′ , R 11′ and R 12′ are independently selected from hydrogen and C 1-6 -alkyl,
R 8″ , R 9″ , R 10″ , R 11″ and R 12″ are independently selected from hydrogen and C 1-6 -alkyl,
R 13 is hydrogen or C 1-3 alkyl,
R 14 is hydrogen, C 1-3 alkyl, C 1-3 alkoxy, NR 14′ R 14″ , wherein R 14′ and R 14″ are independently C 1-3 -alkyl or
R 13 and R 14 together with the atoms to which they are attached form a 5 or 6-carbon atoms containing saturated ring, wherein the saturated ring is optionally substituted with one or more C 1-3 -alkyl or ═O, and/or wherein one or more of the ring-forming carbon atoms are optionally replaced by —NH—, —O—, —S(O)—, —S(O) 2 — or —S—, or
R 13 and R 14 together with the atoms to which they are attached form a 5 or 6-carbon atoms containing unsaturated ring, wherein the unsaturated ring is optionally substituted with one or more C 1-3 -alkyl, and/or wherein one or more of the ring-forming carbon atoms are optionally replaced by —NH—, —N═, ═N—, —O— or —S—,
A1 is N or CR 15 , wherein R 15 is independently hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy, or NR 15′ R 15″ , wherein R 15′ and R 15″ are independently C 1-3 -alkyl,
A2 is N or CR 16 , wherein R 16 is independently hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy, or NR 16′ R 16″ , wherein R 16′ and R 16″ are independently C 1-3 -alkyl,
A3 is N or CR 17 , wherein R 17 is independently hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy, or NR 17′ R 17″ , wherein R 17 and R 17″ are independently C 1-3 -alkyl,
A4 is N or CR 18 , wherein R 18 is independently hydrogen, halogen C 1-3 alkyl, C 1-3 alkoxy, or NR 18′ R 18″ , wherein R 18′ and R 18″ are independently C 1-3 -alkyl,
R 19 is independently selected from the group consisting of C 6-10 -aryl and 5- to 10-membered heteroaryl,
wherein each C 6-10 -aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more substituent(s) independently selected from the group consisting of
C 1-6 -alkyl, C 2-6 -alkenyl, C 3-10 -cycloalkyl, 5- to 10-membered heterocyclyl, C 6-10 -aryl, 5- to 10-membered heteroaryl, C 1-6 -alkoxy, C 1-6 -alkylmercapto, halogen, cyano, nitro, hydroxy, mercapto, NR 20 R 21 , C(═O)OR 22 , SR 22 , SOR 22 , SO 2 R 22 , SO 2 NR 23 R 24 and C(═O)NR 23 R 24 ,
R 20 and R 21 are independently selected from the group consisting of
hydrogen, C 1-6 -alkyl, C 3-10 -cycloalkyl, C 6-10 -aryl, 5- to 10-membered heteroaryl, C 1-6 -alkoxy-C 1-6 -alkyl, C 1 -C 6 -alkyl substituted with C 6-10 -aryl, C 1-6 -alkyl substituted with 5- to 10-membered heteroaryl, or
R 20 and R 21 together with the N atom to which they are attached form a saturated or unsaturated heterocyclic ring having 3 to 12 ring atoms, wherein 0, 1, 2, or 3 further ring atoms are selected from N, S and O,
wherein each C 1-6 -alkyl, C 2-6 -alkenyl, C 3-10 -cycloalkyl, 5- to 10-membered heterocyclyl, C 6-10 -aryl, 5- to 10-membered heteroaryl, C 1-6 -alkoxy or C 1-6 -alkylmercapto or the heterocyclic ring formed by R 20 and R 21 together with the N atom to which they are attached is optionally substituted with one or more substituents independently selected from the group consisting of
C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-10 -cycloalkyl, 5- to 10-membered heterocyclyl, C 6-10 -aryl, 5- to 10-membered heteroaryl, C 1-6 -alkoxy, carbonyl, halogen, cyano, hydroxy, mercapto, NR 20′ R 21′ , C(═O)OR 22′ , SR 22′ , SOR 22′ , SO 2 R 22′ , SO 2 NR 23′ R 24′ and C(═O)NR 23′ R 24′ ,
R 22 , R 23 and R 24 are independently selected from hydrogen and C 1-6 -alkyl,
R 20′ , R 21′ , R 22′ , R 23′ and R 24′ are independently selected from hydrogen and C 1-6 -alkyl,
R 25 is independently selected from hydrogen and C 1-6 -alkyl,
or a stereoisomer, physiologically acceptable salt, ester, solvate, polymorph, prodrug and mixtures thereof.
2 . The compound according to claim 1 , wherein R 1 is independently selected from the group consisting of
hydrogen, C 1-6 -alkyl, C 1-6 -alkoxy, halogen, cyano, nitro, hydroxy, NR 2 R 3 , C(═O)OR 4 and C(═O)NR 5 R 6 ,
wherein each C 1-6 -alkyl or C 1-6 -alkoxy is optionally substituted with one or more substituents independently selected from the group consisting of
C 1-6 -alkyl, C 1-6 -alkoxy, halogen, cyano, nitro, hydroxy and NR 2′ R 3′ ,
R 2 and R 3 are independently selected from the group consisting of
hydrogen, C 1-6 -alkyl, C 3-10 -cycloalkyl, C 6-10 -aryl and 5 to 10-membered heteroaryl, or
R 2 and R 3 together with the N atom to which they are attached form a saturated or unsaturated heterocyclic ring having 3 to 12 ring atoms, wherein 0, 1, 2, or 3 further ring atoms are selected from N, S and O,
wherein each C 1-6 -alkyl, C 3-10 -cycloalkyl, C 6-10 -aryl or 5 to 10-membered heteroaryl or the heterocyclic ring formed by R 2 and R 3 together with the N atom to which they are attached is optionally substituted with one or more substituent(s) independently selected from the group consisting of
C 1-6 -alkyl, C 3-10 -cycloalkyl and C 1-6 -alkoxy,
R 4 , R 5 and R 6 are independently selected from hydrogen and C 1-6 -alkyl,
R 2′ and R 3′ are independently selected from hydrogen and C 1-6 -alkyl.
3 . The compound according to claim 1 , wherein R 1 is independently selected from the group consisting of
hydrogen, C 1-6 -alkyl, C 1-6 -alkoxy and halogen,
wherein each C 1-6 -alkyl or C 1-6 -alkoxy is optionally substituted with one or more substituent(s) independently selected from the group consisting of
C 1-6 -alkyl, C 1-6 -alkoxy, halogen, cyano, hydroxy and NR 2′ R 3′ ,
wherein R 2′ and R 3′ are independently selected from hydrogen and C 1-3 -alkyl.
4 . The compound according to claim 1 , wherein R 1 is independently selected from the group consisting of
hydrogen, methyl, trifluoromethyl, ethyl, methoxy, ethoxy, fluoride and chloride.
5 . The compound according to claim 1 , wherein R 7 is independently selected from the group consisting of
hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 3-10 -cycloalkyl, 4- to 10 membered heterocyclyl, C 1-6 -alkoxy, halogen, cyano, hydroxy, NR 8 R 9 , C(═O)OR 10 , SR 10 , SOR 10 , SO 2 R 10 and C(═O)NR 11 R 12 ,
wherein each C 1-6 -alkyl, C 2-6 -alkenyl, C 3-10 -cycloalkyl, 4- to 10 membered heterocyclyl or C 1-6 -alkoxy is optionally substituted with one or more substituent(s) independently selected from the group consisting of
C 1-6 -alkyl, C 3-10 -cycloalkyl, 5- to 10 membered heterocyclyl, C 1-6 -alkoxy, halogen, cyano, hydroxy, oxo, NR 8′ R 9′ , C(═O)OR 10′ , and C(═O)NR 11′ R 12′ ,
R 8 and R 9 are independently selected from the group consisting of
hydrogen, C 1-6 -alkyl, C 3-10 -cycloalkyl, C 6-10 -aryl, 5- to 10 membered heterocyclyl and 5- to 10 membered heteroaryl, or
R 8 and R 9 together with the N atom to which they are attached form a saturated or unsaturated heterocyclic ring having 3 to 12 ring atoms, wherein 0, 1, 2, or 3 further ring atoms are selected from N, S and O,
wherein each C 1-6 -alkyl, C 3-10 -cycloalkyl, C 6-10 -aryl, 5- to 10 membered heterocyclyl, and 5- to 10 membered heteroaryl or the heterocyclic ring formed by
R 8 and R 9 together with the N atom to which they are attached is optionally substituted with one or more substituent(s) independently selected from the group consisting of
C 1-6 -alkyl, C 1-6 -alkoxy, halogen, cyano, hydroxy, NR 8″ R 9″ , C(═O)—OR 10″ and C(═O)NR 11″ R 12″ ;
R 10 , R 11 and R 12 are independently selected from hydrogen and C 1-6 -alkyl,
R 8′ , R 9′ , R 10′ , R 11′ and R 12′ are independently selected from hydrogen and C 1-6 -alkyl,
R 8″ , R 9″ , R 10″ , R 11″ and R 12″ are independently selected from hydrogen and C 1-6 -alkyl.
6 . The compound according to claim 1 , wherein R 7 is independently selected from the group consisting of
hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, 4- to 10 membered heterocyclyl, C 1-6 -alkoxy, hydroxy, NR 8 R 9 , C(═O)OR 10 , SR 10 , SOR 10 , SO 2 R 10 and C(═O)NR 11 R 12 ,
wherein each C 1-6 -alkyl, C 2-6 -alkenyl, 4- to 10 membered heterocyclyl or C 1-6 -alkoxy is optionally substituted with one or more substituent(s) independently selected from the group consisting of
C 1-6 -alkyl, 5- to 10 membered heterocyclyl, C 1-6 -alkoxy, halogen, cyano, hydroxy, oxo, NR 8′ R 9′ , C(═O)OR 10′ and C(═O)NR 11′ R 12′ ,
R 8 and R 9 are independently selected from the group consisting of
hydrogen, C 1-6 -alkyl, C 3-6 -cycloalkyl, C 6-10 -aryl, and 5- to 10 membered heteroaryl, or
R 8 and R 9 together with the N atom to which they are attached form a saturated or unsaturated heterocyclic ring having 3 to 12 ring atoms, wherein 0, 1, 2, or 3 further ring atoms are selected from N, S and O,
wherein the C 1-6 -alkyl, C 6-10 -aryl, and 5- to 10 membered heteroaryl or the heterocyclic ring formed by R 8 and R 9 together with the N atom to which they are attached is optionally substituted with one or more substituent(s) independently selected from the group consisting of
C 1-6 -alkyl, C 1-6 -alkoxy, hydroxy and NR 8″ R 9″ ,
R 10 , R 11 and R 12 are independently selected from hydrogen or C 1-6 -alkyl,
R 8′ , R 9′ , R 10′ , R 11′ and R 12′ are independently selected from hydrogen or C 1-6 -alkyl,
R 8″ are R 9″ are independently selected from hydrogen or C 1-6 -alkyl.
7 . The compound according to claim 1 , wherein R 7 is independently selected from the group consisting of
hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, 4- to 10 membered heterocyclyl, C 1-6 -alkoxy, NR 8 R 9 ,
wherein each C 1-6 -alkyl, C 2-6 -alkenyl, 4- to 10 membered heterocyclyl or C 1-6 -alkoxy is optionally substituted with one or more substituent(s) independently selected from the group consisting of
C 1-6 -alkyl, C 1-6 -alkoxy, and halogen,
R 8 and R 9 are independently selected from the group consisting of
hydrogen, C 1-6 -alkyl, C 3-6 -cycloalkyl,
wherein the C 1-6 -alkyl, or C 3-6 -cycloalkyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of
C 1-6 -alkyl, C 1-6 -alkoxy, and hydroxy.
8 . The compound according to claim 1 , wherein
R 13 and R 14 together with the atoms to which they are attached form a 5 or 6-carbon atoms containing saturated ring, wherein the saturated ring is optionally substituted with one or more C 1-3 -alkyl or ═O, and/or wherein one or more of the ring-forming carbon atoms are optionally replaced by —NH—, —O—, —S(O)—, —S(O) 2 — or —S—, or
R 13 and R 14 together with the atoms to which they are attached form a 5 or 6-carbon atoms containing unsaturated ring, wherein the unsaturated ring is optionally substituted with one or more C 1-3 -alkyl, and/or wherein one or more of the ring-forming carbon atoms are optionally replaced by —NH—, —N═, ═N—, —O— or —S—,
A1 is N or CR 15 , wherein R 15 is independently hydrogen, halogen C 1-3 alkyl, C 1-3 alkoxy or NR 15′ R 15″ , wherein R 15′ and R 15″ are independently C 1-3 -alkyl,
A2 is N or CR 16 , wherein R 16 is independently hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy or NR 16′ R 16″ , wherein R 16′ and R 16″ are independently C 1-3 -alkyl,
A3 is N or CR 17 , wherein R 17 is independently hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy or NR 15′ R 15″ , wherein R 15′ and R 15″ are independently C 1-3 -alkyl,
A4 is N or CR 18 , wherein R 18 is independently hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy or NR 15′ R 15″ , wherein R 15′ and R 15″ are independently C 1-3 -alkyl.
9 . The compound according to claim 1 , wherein
R 13 and R 14 together with the atoms to which they are attached form a 5 or 6-carbon atoms containing saturated ring, wherein one or more of the ring-forming carbon atoms are optionally replaced by —NH—, —O— or —S—, or
R 13 and R 14 together with the atoms to which they are attached form a 5 or 6-carbon atoms containing unsaturated ring, wherein one or more of the ring-forming carbon atoms are optionally replaced by —NH—, —N═, ═N—, —O— or —S—,
A1 is CR 15 , wherein R 15 is independently hydrogen, halogen C 1-3 alkyl, C 1-3 alkoxy or NR 15′ R 15″ wherein R 15′ and R 15″ are independently C 1-3 -alkyl,
A2 is CR 16 , wherein R 16 is independently hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy or NR 16′ R 16″ , wherein R 16′ and R 16″ are independently C 1-3 -alkyl,
A3 is CR 17 , wherein R 17 is hydrogen,
A4 is CR 18 , wherein R 18 is hydrogen.
10 . The compound according to claim 1 , wherein
R 13 and R 14 together with the atoms to which they are attached form a 5 or 6-carbon atoms containing saturated ring, wherein one or more of the ring-forming carbon atoms are optionally replaced by —NH—, —O— or —S—,
A1 is CR 15 , wherein R 15 is independently hydrogen, halogen C 1-3 alkyl, C 1-3 alkoxy or NR 15′ R 15″ , wherein R 15′ and R 15″ are independently C 1-3 -alkyl,
A2 is CR 16 , wherein R 16 is independently hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy or NR 16′ R 16″ , wherein R 16′ and R 16″ are independently C 1-3 -alkyl,
A3 is CR 17 , wherein R 17 is hydrogen,
A4 is CR 18 , wherein R 18 is hydrogen.
11 . The compound according to claim 1 , wherein none, one or two of residues A1, A2, A3 and A4 is N.
12 . The compound according to claim 1 , wherein
R 19 is independently selected from the group consisting of
C 6-10 -aryl and 5- to 10-membered heteroaryl,
wherein each C 6-10 -aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more substituent(s) independently selected from the group consisting of
C 1-6 -alkyl, C 3-10 -cycloalkyl, 5- to 10-membered heterocyclyl, C 6-10 -aryl, 5- to 10-membered heteroaryl, C 1-6 -alkoxy, halogen, cyano, nitro, hydroxy, NR 20 R 21 , C(═O)OR 22 and C(═O)NR 23 R 24 ,
R 20 and R 21 are independently selected from the group consisting of
hydrogen, C 1-6 -alkyl, C 3-10 -cycloalkyl and C 6-10 -aryl or
R 20 and R 21 together with the N atom to which they are attached form a saturated or unsaturated heterocyclic ring having 3 to 12 ring atoms, wherein 0, 1, 2, or 3 further ring atoms are selected from N, S and O;
wherein each C 1-6 -alkyl, C 3-10 -cycloalkyl, C 1-6 -alkoxy, or C 6-10 -aryl or the heterocyclic ring formed by R 20 and R 21 together with the N atom to which they are attached is optionally substituted with one or more substituents independently selected from the group consisting of
C 1-6 -alkyl, C 3-10 -cycloalkyl, 5- to 10-membered heterocyclyl, C 6-10 -aryl, 5- to 10-membered heteroaryl, C 1-6 -alkoxy, halogen, cyano, hydroxy, NR 20′ R 21′ , C(═O)OR 22′ and C(═O)NR 23′ R 24′
R 22 , R 23 and R 24 are independently selected from hydrogen and C 1-6 -alkyl,
R 20′ , R 21′ , R 22′ , R 23′ and R 24′ are independently selected from hydrogen and C 1-6 -alkyl.
13 . The compound according to claim 1 , wherein R 19 is independently selected from the group consisting of
C 6-10 -aryl and 5- to 10-membered heteroaryl
wherein each C 6-10 -aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more substituent(s) independently selected from the group consisting of
C 1-6 -alkyl, C 1-6 -alkoxy, halogen, cyano, nitro and hydroxy, wherein each C 1-6 -alkyl, C 1-6 -alkoxy, is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, or wherein each C 1-6 -alkyl, C 1-6 -alkoxy, is optionally substituted with one or more halogen.
14 . The compound according to claim 1 , wherein R 19 is C 6-10 -aryl, wherein the C 6-10 -aryl is optionally substituted with one or more substituent(s) independently selected from the group consisting of
C 1-6 -alkyl, halogen, C 1-6 -alkoxy cyano and nitro wherein each C 1-6 -alkyl, C 1-6 -alkoxy is optionally substituted with one or more halogen.
15 . The compound according to claim 1 , wherein R 25 is hydrogen.
16 . Process for preparing the compound according to Formula (I)
comprising the step of
reacting a compound of Formula (A)
with a compound of Formula (B)
wherein R 1 , R 7 , R 13 , R 14 , A1, A2, A3, A4, R 19 and R 25 are defined as in claim 1 , to obtain the compound according to Formula (I).
17 . A Veterinary composition comprising
compound according to Formula (I) according to claim 1 , and
one or more physiologically acceptable excipient(s).
18 . A method of treating a disease caused by helminths which comprises administering to an animal a therapeutically effective amount of a compound according to Formula (I) according to claim 1 .
19 . A method of treating a disease according to claim 18 wherein the disease is a heartworm disease.
20 . A method of treating a disease caused by helminths which comprises administering to an animal, a therapeutically effective amount of the veterinary composition according to claim 17 .
21 . A method of treating a disease according to claim 20 wherein the disease is a heartworm disease.
22 . The compound according to claim 1 , wherein A1, A2, A3 and A4 are CH and is selected from compounds 3, 4, 6, 7, 10, 12, 13, 16, 32, 36, 39, 49, 53, 56, 62, 65, 68, 72, 102, 118, 128 as recited in the following table:
No
R 1
R 7
R 13
R 14
R 19
R 25
3
H
morpholin-4-yl
—CH 2 —CH 2 —
3,5-dichlorophenyl
H
4
H
morpholin-4-yl
—CH 2 —CH 2 —O—
2,3-dichlorophenyl
H
6
H
morpholin-4-yl
—CH 2 —CH 2 —
2,3-dichlorophenyl
H
7
H
dimethylamino
—CH 2 —CH 2 —O—
3,5-dichlorophenyl
H
10
H
dimethylamino
—CH 2 —CH 2 —O—
2,3-dichlorophenyl
H
12
H
dimethylamino
—CH 2 —CH 2 —
2,3-dichlorophenyl
H
13
H
morpholin-4-yl
—CH 2 —CH 2 —CH 2 —
2,3-dichlorophenyl
H
16
H
morpholin-4-yl
—CH 2 —CH 2 —
2,3,5-trifluorophenyl
H
32
H
morpholin-4-yl
—CH 2 —CH 2 —CH 2 —
3,5-dichlorophenyl
H
36
CH 3
dimethylamino
—CH 2 —CH 2 —O—
2,3-dichlorophenyl
H
39
H
3,3-difluoroazetidin-1-yl
—CH 2 —CH 2 —
2,3-dichlorophenyl
H
49
H
morpholin-4-yl
═CH—CH═CH—
3,5-dichlorophenyl
H
53
CH 3
dimethylamino
—CH 2 —CH 2 —O—
3,5-dichlorophenyl
H
56
CH 3
3,3-difluoroazetidin-1-yl
—CH 2 —CH 2 —O—
2,3-dichlorophenyl
H
62
CH 3
3-fluoroazetidin-1-yl
—CH 2 —CH 2 —O—
2,3-dichlorophenyl
H
65
CH 3
3-fluoroazetidin-1-yl
—CH 2 —CH 2 —O—
3,5-dichlorophenyl
H
68
CH 3
morpholin-4-yl
—CH 2 —CH 2 —O—
3,5-dichlorophenyl
H
72
CH 3
morpholin-4-yl
—CH 2 —CH 2 —O—
2,3-dichlorophenyl
H
102
CH 3
dimethylamino
—CH 2 —CH 2 —O—
2,3,5-trifluorophenyl
H
118
H
3-fluoroazetidin-1-yl
—CH 2 —CH 2 —
3,5-dichlorophenyl
H
128
H
morpholin-4-yl
—CH 2 —CH 2 —
3,5-difluorophenyl
H.