Anti-mucus drugs and uses therefor
Disclosed are methods of identifying, generating and synthesizing compounds that inhibit MAPK13 activity. In various embodiments, compounds, salts thereof and prodrugs thereof of the present teachings can be useful for the treatment of diseases and disorders that involve excess mucus production.
1. A compound, or a pharmaceutically acceptable salt thereof, of Formula I
wherein R 1 is selected from the group consisting of H, lower alkyl and aryl;
R 2 and R 3 together are a 4-6 member heterocylic ring with 1 or 2 heteroatoms, each heteroatom selected from the group consisting of N, O and S.
X is selected from the group consisting of Ch 2 , NH, O, and S;
ring A is a 6-membered aliphatic, aromatic, or heteroaromatic ring, wherein each R 4 and R 5 is independently selected from the group consisting of H, a halogen, lower alkyl, —CF 3 , —OR 8 and —SR 9 ;
each of R 8 and R 9 is independently selected from the group consisting of H, lower alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, and arylaklyl;
Z is selected from the group consisting of CH 2 , NH, O and S; and
R 6 is selected from the group consisting of H, amine, lower alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyloalkyl, aryl, arylalkyl, —OR 12 ,—SR 13 , —NR 14 R 15 , —C(O)NR 16 R 17 , —NR 18 C(O)R 19 , —C(O)OR 20 , —NR 21 C(O)OR 22 , and —NR 23 C(O)NR 24 R 25 ;
wherein each of R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 and R 25 is independently selected from the group consisting of H, lower alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, and arylaklyt;
and wherein lower alkyl is C 1 -C 10 linear alkyl, C 3 -C 10 cyclic alkyl and 0, 1, 2 or 3 carbons of a lower alkyl are replaced with a heteroatom, each heteroatom selected from the group consisting of N, O, and S.
2. A compound or a pharmaceutically acceptable salt thereof in accordance with claim 1 , wherein the compound is selected from the group consisting of
3. A compound or a pharmaceutically acceptable salt thereof in accordance
with claim 1 , of structure
4. A compound Or a pharmaceutically acceptable salt thereof in accordance
with claim 1 , of structure.
5. A compound or a pharmaceutically acceptable salt thereof in accordance with claim 1 , wherein the compound is selected from the group consisting of
6. A compound, or a <pharmaceutically acceptable salt thereof, of Formula II
wherein R 1 is selected from the group consisting of H, lower alkyl, and aryl:,
J is selected from the group consisting of CH 2 , O, and S;
X is selected from the group consisting of CH 2 , HN, O, and S;
ring A is a 6-membered aliphatic, aromatic, or heteroaromatic ring, wherein each R 4 and R 5 is independently selected from the group consisting of H, a halogen, lower alkyl, —CF 3 , —OR 8 and —SR 9 ;
each of R 8 and R 9 is selected from the group consisting of H, lower alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, and arylaklyl;
Z is selected from the group consisting of CH 2 , NH, O, and S; and
R 6 is selected from the group consisting of H, amine, lower alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyloalkyl, aryl, aylalkyl, —OR 12 , —SR 13 , —NR 14 R 15 , —C(O)NR 16 R 17 , —NR 18 C(O)R 19 , —C(O)OR 20 , —NR 21 C(O)OR 22 , and —NR 23 C(O)NR 24 R 25 ;
wherein each of R 12 , R 13 , R 14 , R 15 , R 16 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 and R 25 is independently selected from the group consisting of H, lower alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, and alylaklyl; and
wherein lower alkyl is C 1 -C 10 linear alkyl, C 3 -C 10 branched alkyl, or C 3 -C 10 cyclic alkyl and 0, 1, 2 or 3 carbons of a lower alkyl are replaced with a heteroatom, each heteroatom selected from the group consisting of N, O, and S.
7. A compound or a pharmaceutically acceptable salt thereof in accordance with claim 6 , wherein the compound is selected from the group consisting, of
8. A compound or a pharmaceutically acceptable salt thereof in accordance with claim 6 , wherein the compound is selected from the group consisting of
9. A compound, or a pharmaceutically acceptable salt thereof, of Formula VI:
wherein R 1 is selected from the group consisting of H, lower alkyl, and aryl;
R 2 and R 3 are each independently selected form the group consisting of H or lower alkyl, or together are a 4-6 member aliphatic, carbocyclic, or heterocyclic ring with 0, 1, or 2 heteroatoms, each heteroatom selected from the group consisting of N, O, and S;
Q is selected from the group consisting of O and S;
X is selected from the group consisting of CH 2 and NH;
R 9 is selected from the group consisting of H, lower alkyl, cycloalkyl, cycloalkylalkyl, heterocycyl, hetemcycylalkyl, aryl, arylalkyl, —NHC(O)R 8 , —NHC(O)NR 10 R 11 , —CH 2 NHC(O)R 12 , —CH 2NHC(O)NR 13 R 14 , —C(O)NR 15 R 16 , and —C(O)OR 17 ;
wherein each of R 8 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 is independently selected from the group consisting of H, lower alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, and arylaklyl; and
wherein lower alkyl is C 1 -C 10 linear alkyl, C 3 -C 10 branched alkyl, or C 3 -C 10 cyclic alkyl and 0, 1, 2 or 3 carbons of a lower alkyl are replaced with a heteroatom, each heteroatom selected from the group consisting of N, O, and S.
10. A compound or a pharmaceutically acceptable salt thereof in accordance with claim 9 , wherein X is NH.
11. A compound or a pharmaceutically acceptable salt thereof in accordance with claim 10 , wherein the compound is
12. A compound or a pharmaceutically acceptable salt thereof in accordance with claim 9 , wherein X is CH 2 .
13. A compound or a pharmaceutically acceptable salt thereof in accordance with claim 12 , wherein the compound is
14. A compound, or a pharmaceutically acceptable salt thereof, of Formula VII
wherein R 1 is selected from the group consisting of H, lower alkyl, and aryl;
J is selected from the group consisting of CH 2 , O, and S;
X is selected from the group consisting of CH 2 and NH;
Q is selected from the group consisting of O and S; and
R 9 is selected from the group consisting of H, lower alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, —C(O)NR 18 R 9 , and —C(O)OR 20 ;
wherein each R 18 , R 19 and R 20 is independently selected from the group consisting of H, lower alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyeloalkyl, aryl, and arylalkyl; and
wherein lower alkyl is linear alkyl, C 1 -C 10 branched alkyl, or C 3 -C 10 cyclic alkyl and 0, 1, 2 or 3 carbons of a lower alkyl are replaced with a heteroatom, each heteroatom selected from the group consisting of N, O, and S.
15. A compound or a pharmaceutically acceptable salt thereof in accordance with claim 14 , wherein the compound is selected from the group consisting of