MAP kinase modulators and uses thereof
The invention provides for novel MAP kinase inhibitors and compositions comprising the same. In some embodiments, the MAP kinase inhibitors are p38α MAP kinase inhibitors. The invention further provides for methods for treatment of diseases comprising administration of MAP kinase inhibitors or compositions comprising MAP kinase inhibitors. In some embodiments, the disease is Alzheimer's Disease, ALS, Huntington's Disease or Parkinson's Disease.
1. A method of treating a tauopathy in a subject comprising administration of a therapeutically effective amount of a compound of formula (I), or a composition comprising a compound of formula (I),
wherein
X 1 is N and X 2 is CH, or X 1 is CH and X 2 is N;
R 1 is —N(R 4 ) 2 , cyclopropyl, or R 5 -piperidin-4-yl;
R 2 is independently D or halogen;
R 3 is naphthyl, quinolinyl, or isoquinolinyl, wherein said naphthyl, quinolinyl, or isoquinolinyl is optionally independently substituted with at least one D, halogen, (C 1 -C 3 )-alkoxy, or (C 1 -C 3 )-alkoxy substituted with at least one D;
R 4 is independently H, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkyl substituted with at least one D, (C 3 -C 5 )-cycloalkyl, or each R 4 together with the nitrogen to which they are attached form a 3-7 membered heterocyclic ring, wherein one of the carbon atoms is optionally replaced with NR 6 , O or S, and wherein the 3-7 membered heterocyclic ring is optionally substituted with a (C 1 -C 3 )-alkyl;
R 5 is H or (C 1 -C 3 )-alkyl, or (C 1 -C 3 )-alkyl substituted with at least one D;
R 6 is H, (C 1 -C 3 )-alkyl, (C 1 -C 3 )-alkyl substituted with at least one D, or pyrimidin-2-yl; and
n is an integer from 0-4; or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein
R 4 is independently H, (C 1 -C 3 )-alkyl, (C 1 -C 3 )-alkyl substituted with at least one D, (C 3 -C 5 )-cycloalkyl, or each R 4 together with the nitrogen to which they are attached form a 3-7 membered heterocyclic ring, wherein one of the carbon atoms is optionally replaced with NR 6 , O or S; and
R 6 is H, (C 1 -C 3 )-alkyl, or (C 1 -C 3 )-alkyl substituted with at least one D.
3. The method of claim 1 , wherein
R 3 is naphthyl, quinolinyl, or isoquinolinyl, wherein said naphthyl, quinolinyl, or isoquinolinyl is optionally independently substituted with at least one D, halogen, (C 1 -C 3 )-alkoxy, or (C 1 -C 3 )-alkoxy substituted with at least one D.
4. The method of claim 1 , wherein the compound is selected from
or a pharmaceutically acceptable salt thereof.
5. The method of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
6. The method of claim 1 , wherein the tauopathy is Parkinson's disease.
7. The method of claim 1 , wherein the tauopathy is Alzheimer's disease.
8. The method of claim 5 , wherein the tauopathy is Parkinson's disease.
9. The method of claim 5 , wherein the tauopathy is Alzheimer's disease.
10. The method of claim 1 , wherein the tauopathy is ASD.
11. The method of claim 5 , wherein the tauopathy is ASD.