Compounds for the treatment of inflammatory diseases
View Patent ↗This invention relates to compounds of the Formula (I)-(IX):, as defined herein, or a pharmaceutically acceptable salt, solvate or ester thereof, which can be useful for the treatment of diseases or conditions mediated by MMPs, ADAMs, TACE, aggrecanase, TNF-α combinations thereof.
1. A compound represented by Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
ring A is aryl or heteroaryl, wherein said aryl or heteroaryl is unsubstituted or substituted with R 2 or —OR 3 , wherein R 2 is H or halo, and R 3 is H or alkyl;
T is aryl or heteroaryl, substituted with an R 4 , R 5 , and R 6 as shown;
X is selected from the group consisting of —S—,—O—, —S(O) 2 —, —S(O)—, —(CR 8 2 ) p — and —N(R′)—;
p is 1 to 3;
R′ is selected from the group consisting of H, alkyl, and aryl;
R is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, —C(═O)alkyl, —C(═O)cycloalkyl, —C(═O)heterocyclyl, —C(═O)aryl, —C(═O)heteroaryl, —C(═O)O-alkyl, —C(═O)O-cycloalkyl, —C(═O)O-heterocyclyl, —C(═O)O-aryl, and —C(═O)O-heteroaryl;
R 1 is selected from the group consisting of H and —C(R 7 ) 2 -(Q) n R 9 ;
R 4 is selected from the group consisting of H, alkyl, and halogen;
R 5 and R 6 are substituents on adjacent carbon atoms, wherein R 5 and R 6 together with the carbon atoms to which they are attached form a first five-to eight-membered cycloalkyl, cycloalkenyl, heterocyclyl, or heterocyclenyl; wherein said first five-to eight-membered cycloalkyl, cycloalkenyl, heterocyclyl, or heterocyclenyl contains two radicals on the same carbon atom, and said radicals taken together with the carbon atom to which they are attached form a second five-to eight-membered cycloalkyl, cycloalkenyl, heterocyclyl, or heterocyclenyl; wherein said first five-to eight-membered cycloalkyl, cycloalkenyl, heterocyclyl, or heterocyclenyl, optionally with said second five-to eight-membered cycloalkyl, cycloalkenyl, heterocyclyl, or heterocyclenyl is unsubstituted or substituted with one to four R 10 moieties;
each R 7 independently is selected from the group consisting of H, alkyl, and aryl;
each R 8 independently is selected from the group consisting of H, alkyl, and aryl;
R 9 is selected from the group consisting of H, alkyl, heterocyclyl, aryl, heteroaryl, —C(═O)N(R 12 ) 2 , —C(═O)-alkyl, C(═O)-cycloalkyl, C(═O)-heterocyclyl, —C(═O)-aryl, —C(═O)-heteroaryl, —C(═O)—O-alkyl, —C(═O)—O-cycloalkyl, —C(═O)—O-heterocyclyl, —C(═O)—O-aryl, —C(═O)—O-heteroaryl, —P(═O)(—OH) 2 , —P(═O)(—O-alkyl) 2 , wherein when each of said “cycloalkyl”, “heterocyclyl”, “aryl”, or “heteroaryl” in any of the aforementioned R 9 groups contains two radicals on adjacent carbon atoms, said radicals may optionally be taken together with the carbon atoms to which they are attached to form a five-or six-membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring;
each R 10 is independently selected from the group consisting of cyano, nitro, —OC(O)R 11 , —C(R 11 )═N—OR 11 , —OR 11 , —SR 11 , —N(R 11 ) 2 , —S(O)R 11 , —S(O) 2 R 11 , —N(R 11 )S(O) 2 R 11 , —N(R 11 )—C(O)—R 11 , —N(R 11 )—C(O)—N(R 11 ) 2 , —N(R 11 )—C(O)—OR 11 , —OC(O)N(R 11 ) 2 , —C(O)N(R 11 )—S(O) 2 R 11 , —S(O) 2 N(R 11 )—C(O)—R 11 , —C(O)N(R 11 )C(O)R 11 , —C(O)N(R 11 )C(O)NR 11 , —S(O) 2 N(R 11 ) 2 , —N(R 11 )—C(═NR 11 )—N(R 11 ) 2 , —N(R 11 )—C(═N—CN)—N(R 11 ) 2 , -haloalkoxy, —C(O)OR 11 , —C(O)R 11 , —C(O)N(R 11 ) 2 , halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclenyl, cycloalkenyl, and cycloalkyl, with the proviso that there are no adjacent heteroatoms in any of said R 10 ;
each R 11 independently is selected from the group consisting of H, alkyl, cycloalkyl, haloalkyl, hydroxy, heterocyclyl, aryl, and heteroaryl;
Q is selected from the group consisting of —NR 12 —, —O—, —S—, —S(O)—, and —S(O) 2 —;
each R 12 is independently selected from the group consisting of H and alkyl; and
n is 0 or 1.
2. The compound of claim 1 , selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
3. A compound represented by Formula (II)
or a pharmaceutically acceptable salt thereof, wherein:
T is aryl or heteroaryl, each of which is substituted with m R 5 substituents as shown;
X is selected from the group consisting of —S—,—O—, —S(O) 2 —, —S(O)—, —(CR 6 2 ) p -and —N(R′)—,
p is 1 to 3;
R′ is selected from the group consisting of H, alkyl, and aryl;
R is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, —C(═O)alkyl, —C(═O)cycloalkyl, —C(═O)heterocyclyl, —C(═O)aryl, —C(═O)heteroaryl, —C(═O)O-alkyl, —C(═O)O-cycloalkyl, —C(═O)O-heterocyclyl, —C(═O)O-aryl, and —C(═O)O-heteroaryl;
R 1 is selected from the group consisting of H and —C(R 6 ) 2 -(Q) n R 7 ;
R 2 is selected from the group consisting of H, alkyl, and halogen;
R 3 and R 4 are substituents on adjacent carbon atoms, wherein R 3 and R 4 together with the carbon atoms to which they are attached form a first five or six-membered heteroaryl, which is unsubstituted or substituted with one or two substituents independently selected from the group consisting of alkyl and cycloalkyl;
R 5 is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
each R 6 independently is selected from the group consisting of H, alkyl, and aryl;
R 7 is selected from the group consisting of H, alkyl, heterocyclyl, aryl, heteroaryl, —C(═O)N(R 8 ) 2 , —C(═O)-alkyl, C(═O)-cycloalkyl, C(═O)-heterocyclyl, —C(═O)-aryl, —C(═O)-heteroaryl, —C(═O)—O-alkyl, —C(═O)—O-cycloalkyl, —C(═O)—O-heterocyclyl, —C(═O)—O-aryl, —C(═O)—O-heteroaryl, —P(═O)(—OH) 2 , —P(═O)(—O-alkyl) 2 , wherein when each of said “cycloalkyl”, “heterocyclyl”, “aryl”, or “heteroaryl” in any of the aforementioned R 9 groups contains two radicals on adjacent carbon atoms, said radicals may optionally be taken together with the carbon atoms to which they are attached to form a five-or six-membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring;
each R 8 is independently selected from the group consisting of H and alkyl;
Q is selected from the group consisting of —NR 8 —, —O—, —S—, —S(O)—, and —S(O) 2 —;
n is 0 or 1; and
m is 0-3.
4. The compound of claim 3 , selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
5. A compound represented by Formula (III)
or a pharmaceutically acceptable salt thereof, wherein:
ring B is aryl or heteroaryl, wherein said aryl or heteroaryl is unsubstituted or substituted with alkoxy;
at least one of T and V is present;
T is absent or present, and if present, is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heterocyclenyl, and heteroaryl;
V is absent or present, and if present, is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heterocyclenyl, and heteroaryl;
R is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, —C(═O)alkyl, —C(═O)cycloalkyl, —C(═O)heterocyclyl, —C(═O)aryl, —C(═O)heteroaryl, —C(═O)O-alkyl, —C(═O)O-cycloalkyl, —C(═O)O-heterocyclyl, —C(═O)O-aryl, and —C(═O)O-heteroaryl;
R 1 is selected from the group consisting of H and —C(R 3 ) 2 -(Q) n R 4 ;
each R 3 independently is selected from the group consisting of H, alkyl and aryl;
R 4 is selected from the group consisting of H, alkyl, heterocyclyl, aryl, heteroaryl, —C(═O)N(R 5 ) 2 , —C(═O)-alkyl, C(═O)-cycloalkyl, C(═O)-heterocyclyl, —C(═O)-aryl, —C(═O)-heteroaryl, —C(═O)—O-alkyl, —C(═O)—O-cycloalkyl, —C(═O)—O-heterocyclyl, —C(═O)—O-aryl, —C(═O)—O-heteroaryl, —P(═O)(—OH) 2 , —P(═O)(—O-alkyl) 2 , wherein when each of said “cycloalkyl”, “heterocyclyl”, “aryl”, or “heteroaryl” in any of the aforementioned R 9 groups contains two radicals on adjacent carbon atoms, said radicals may optionally be taken together with the carbon atoms to which they are attached to form a five-or six-membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring;
Q is selected from the group consisting of —NR 5 —, —O—, —S—, —S(O)—, and —S(O) 2 —;
each R 5 is independently selected from the group consisting of H and alkyl;
and n is 0 or 1.
6. The compound of claim 5 , selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
7. A compound represented by Formula (IV):
or a pharmaceutically acceptable salt thereof, wherein:
ring A is aryl or heteroaryl, substituted on adjacent ring atoms with R 2 , R 3 , and R 4 ;
at least one of T and V is present;
T is absent or present, and if present, is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heterocyclenyl, and heteroaryl;
V is absent or present, and if present, is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heterocyclenyl, and heteroaryl;
X is selected from the group consisting of —S—,—O—, —S(O) 2 —, —S(O)—, —(CR 5 2 ) p -and —N(R′)—;
p is 1 to 3;
R′ is selected from the group consisting of H, alkyl, and aryl;
R is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, —C(═O)alkyl, —C(═O)cycloalkyl, —C(═O)heterocyclyl, —C(═O)aryl, —C(═O)heteroaryl, —C(═O)O-alkyl, —C(═O)O-cycloalkyl, —C(═O)O-heterocyclyl, —C(═O)O-aryl, and —C(═O)O-heteroaryl;
R 1 is selected from the group consisting of H and —C(R 6 ) 2 -(Q) n R 7 ;
R 2 , R 3 , and R 4 are substituents on adjacent ring atoms, wherein each of R 2 , R 3 , and R 4 is independently selected from the group consisting of halo, alkyl, and alkoxy;
each R 5 independently is selected from the group consisting of H, alkyl, and aryl;
each R 6 independently is selected from the group consisting of H, alkyl, and aryl;
R 7 is selected from the group consisting of H, alkyl, heterocyclyl, aryl, heteroaryl, —C(═O)N(R 8 ) 2 , —C(═O)-alkyl, C(═O)-cycloalkyl, C(═O)-heterocyclyl, —C(═O)-aryl, —C(═O)-heteroaryl, —C(═O)—O-alkyl, —C(═O)—O-cycloalkyl, —C(═O)—O-heterocyclyl, —C(═O)—O-aryl, —C(═O)—O-heteroaryl, —P(═O)(—OH) 2 , —P(═O)(—O-alkyl) 2 , wherein when each of said “cycloalkyl”, “heterocyclyl”, “aryl”, or “heteroaryl” in any of the aforementioned R 9 groups contains two radicals on adjacent carbon atoms, said radicals may optionally be taken together with the carbon atoms to which they are attached to form a five-or six-membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring;
Q is selected from the group consisting of —NR 8 —, —O—, —S—, —S(O)—, and —S(O) 2 —;
each R 8 is independently selected from the group consisting of H and alkyl; and
n is 0 or 1.
8. The compound of claim 7 , selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
9. A compound represented by Formula (V):
or a pharmaceutically acceptable salt thereof, wherein:
ring A is aryl or heteroaryl, wherein said aryl or heteroaryl is unsubstituted or substituted with alkoxy or deuterium;
at least one of T and V is present, and at least one of T and V is substituted with 1-3 R 2 substituents;
T is absent or present, and if present is selected from the group consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heterocyclenyl, and heteroaryl;
V is absent or present, and if present is selected from the group consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heterocyclenyl, and heteroaryl;
X is selected from the group consisting of —S—,—O—, —S(O) 2 —, —S(O)—, —(CR 7 2 ) p -and —N(R′)—;
p is 1 to 3;
R′ is selected from the group consisting of H, alkyl, and aryl;
R is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, —C(═O)alkyl, —C(═O)cycloalkyl, —C(═O)heterocyclyl, —C(═O)aryl, —C(═O)heteroaryl, —C(═O)O-alkyl, —C(═O)O-cycloalkyl, —C(═O)O-heterocyclyl, —C(═O)O-aryl, and —C(═O)O-heteroaryl;
R 1 is selected from the group consisting of H and —C(R 6 ) 2 -(Q) n R 9 ;
Q is selected from the group consisting of —NR 6 -, —O—, —S—, —S(O)—, and —S(O) 2 —; and
n is 0 or 1;
R 2 is selected from the group consisting of deuterium, —C(═N—OH)—N(R 6 ) 2 , —C(═O)NR 6 S(═O) 2 N(R 6 ) 2 , —C(R 6 )((C═O)OR 6 )-heterocyclyl—C(═O)OR 6 , —C(R 6 )((C═O)N(R 6 ) 2 )-heterocyclyl—C(═O)Oalkyl, —C(═NR 6 )—N(R 6 )OR 6 , —C(═NR 6 )—N(R 6 )-heterocyclyl, —C(═NR 6 )—N(R 6 )-aryl, —C(═NR 6 )—N(R 6 )-heteroaryl, —C(═NR 6 )—N(R 6 ) 2 , and —NR 6 —C(═S)N(R 6 )-alkyl-heterocyclyl;
each R 6 independently is H or alkyl;
each R 7 independently is H, alkyl, or aryl;
R 9 is selected from the group consisting of H, alkyl, heterocyclyl, aryl, heteroaryl, —C(═O)N(R 6 ) 2 , —C(═O)-alkyl, C(═O)-cycloalkyl, C(═O)-heterocyclyl, —C(═O)-aryl, —C(═O)-heteroaryl, —C(═O)—O-alkyl, —C(═O)—O-cycloalkyl, —C(═O)—O-heterocyclyl, —C(═O)—O-aryl, —C(═O)—O-heteroaryl, —P(═O)(—OH) 2 , —P(═O)(—O-alkyl) 2 , wherein when each of said “cycloalkyl”, “heterocyclyl”, “aryl”, or “heteroaryl” in any of the aforementioned R 9 groups contains two radicals on adjacent carbon atoms, said radicals may optionally be taken together with the carbon atoms to which they are attached to form a five-or six-membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring.
10. The compound of claim 9 , selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
11. A compound represented by Formula (VI):
or a pharmaceutically acceptable salt thereof; wherein:
ring A is aryl or heteroaryl, where said aryl or heteroaryl is unsubstituted or is substituted with one or two substituents selected from the group consisting of halo and alkoxy;
X is selected from the group consisting of —S—, —O—, —S(O) 2 —, —S(O)—,—(CR 7 2 ) p — and —N(R′)—;
p is 1 to 3;
Y is O or S;
T is aryl or heteroaryl;
R′ is selected from the group consisting of H, alkyl, and aryl;
R is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, —C(═O)alkyl, —C(═O)cycloalkyl, —C(═O)heterocyclyl, —C(═O)aryl, —C(═O)heteroaryl, —C(═O)O-alkyl, —C(═O)O-cycloalkyl, —C(═O)O-heterocyclyl, —C(═O)O-aryl, and —C(═O)O-heteroaryl;
R 1 is selected from the group consisting of H and —C(R 6 ) 2 -(Q) n R 9 ,
Q is selected from the group consisting of —NR 6 —, —O—, —S—, —S(O)—, and —S(O) 2 —,
n is 0 or 1;
each of R 1 and R 2 is independently H or alkyl;
each of R 4 and R 5 is independently selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
or wherein R 4 and R 5 together with the nitrogen atom to which they are shown attached form a heterocyclyl or heteroaryl ring;
each R 6 independently is H or alkyl;
each R 7 independently is H, alkyl or aryl; and
R 9 is selected from the group consisting of H, alkyl, heterocyclyl, aryl, heteroaryl, —C(═O)N(R 6 ) 2 , —C(═O)-alkyl, C(═O)-cycloalkyl, C(═O)-heterocyclyl, —C(═O)-aryl,—C(═O)-heteroaryl, —C(═O)—O-alkyl, —C(═O)—O-cycloalkyl, —C(═O)—O-heterocyclyl,—C(═O)—O-aryl, —C(═O)—O-heteroaryl, —P(═O)(—OH) 2 , —P(═O)(—O-alkyl) 2 , wherein when each of said “cycloalkyl”, “heterocyclyl”, “aryl”, or “heteroaryl” in any of the aforementioned R 9 groups contains two radicals on adjacent carbon atoms, said radicals may optionally be taken together with the carbon atoms to which they are attached to form a five-or six-membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring.
12. The compound of claim 11 , selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
13. A compound represented by Formula (VII):
or a pharmaceutically acceptable salt thereof; wherein:
ring A is aryl, wherein said aryl is unsubstituted or substituted with alkoxy;
T is heteroaryl, wherein when said T heteroaryl contains two radicals on adjacent carbon atoms, said radicals may optionally be taken together with the carbon atoms to which they are attached to form a five-to eight membered heterocyclyl ring;
R is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, —C(═O)alkyl, —C(═O)cycloalkyl, —C(═O)heterocyclyl, —C(═O)aryl, —C(═O)heteroaryl, —C(═O)O-alkyl, —C(═O)O-cycloalkyl, —C(═O)O-heterocyclyl, —C(═O)O-aryl, and —C(═O)O-heteroaryl;
R 1 is selected from the group consisting of H and —C(R 6 ) 2 -(Q) n R 7 ;
each of R 2 , R 3 , R 4 , and R 5 independently is H or alkyl;
each R 6 independently is H or alkyl;
R 7 is selected from the group consisting of H, alkyl, heterocyclyl, aryl, heteroaryl, —C(═O)N(R 6 ) 2 , —C(═O)-alkyl, C(═O)-cycloalkyl, C(═O)-heterocyclyl, —C(═O)-aryl, —C(═O)-heteroaryl, —C(═O)—O-alkyl, —C(═O)—O-cycloalkyl, —C(═O)—O-heterocyclyl, —C(═O)—O-aryl, —C(═O)—O-heteroaryl, —P(═O)(—OH) 2 , —P(═O)(—O-alkyl) 2 , wherein when each of said “cycloalkyl”, “heterocyclyl”, “aryl”, or “heteroaryl” in any of the aforementioned R 7 groups contains two radicals on adjacent carbon atoms, said radicals may optionally be taken together with the carbon atoms to which they are attached to form a five-or six-membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring; and
Q is selected from the group consisting of —NR 6 —, —O—, —S—, —S(O)—, and —S(O) 2 ; and
n is 0 or 1.
14. The compound of claim 13 , selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
15. A compound represented by Formula (VIII)
or a pharmaceutically acceptable salt thereof; wherein:
X is selected from the group consisting of —S—, —O—, —S(O) 2 —, —S(O)—, —(CR 7 2 ) p -and —N(R′)—;
R′ is selected from the group consisting of H, alkyl, and aryl;
T is heteroaryl, wherein said heteroaryl is unsubstituted or substituted with a halo;
Y is selected from the group consisting of —OR 6 , —N(R 6 ) 2 , and —NR 6 —C(═O)N(R 6 ) 2 ;
each of R 1 and R 2 is independently H or alkyl;
R 3 is selected from the group consisting of H or halo;
each R 6 independently is H or alkyl;
each R 7 independently is H, alkyl or aryl;
and p is 1-3.
16. The compound of claim 15 , selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
17. A compound represented by Formula (IX):
or a pharmaceutically acceptable salt thereof.
18. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
19. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.