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 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 compound 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 compound of claim 2 , 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 compound of claim 3 , wherein
R 2 is independently halogen;
R 3 is naphthalen-1-yl, naphthalen-2-yl, quinolin-8-yl, or isoquinolin-5-yl, wherein said naphthalen-1-yl, naphthalen-2-yl, quinolin-8-yl, or isoquinolin-5-yl, is optionally independently substituted with at least one halogen or (C 1 -C 3 )-alkoxy;
R 4 is independently H, (C 1 -C 3 )-alkyl, (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;
R 5 is H or (C 1 -C 3 )-alkyl; and
R 6 is H or (C 1 -C 3 )-alkyl.
5. The compound of claim 4 , wherein
R 1 is-N(R 4 ) 2 or cyclopropyl;
R 2 is fluorine;
R 3 is naphthalen-1-yl or naphthalen-2-yl;
R 4 is independently H, (C 1 -C 3 )-alkyl, (C 3 -C 5 )-cycloalkyl, or each R 4 together with the nitrogen to which they are attached form
and
n is 0 or 1.
6. The compound of claim 2 , wherein
X 1 is N and X 2 is CH.
7. The compound of claim 6 , wherein
R 1 is-N(R 4 ) 2 or cyclopropyl;
R 2 is independently halogen;
R 3 is naphthalen-1-yl, naphthalen-2-yl, quinolin-8-yl, or isoquinolin-5-yl, wherein naphthalen-1-yl, naphthalen-2-yl, quinolin-8-yl, or isoquinolin-5-yl is optionally independently substituted with one or more fluorine atoms;
R 4 is independently H, (C 1 -C 3 )-alkyl, (C 3 -C 5 )-cycloalkyl, or each R 4 together with the nitrogen to which they are attached form NR 6 -piperazine, piperidine, pyrrolidine, azetidine, or morpholine;
R 6 is H, methyl or CD 3 ; and
n is an integer from 0-2.
8. The compound of claim 7 , wherein
R 1 is
R 3 is naphthalen-1-yl or naphthalen-2-yl; and
n is 0.
9. The compound of claim 8 , wherein the compound is
10. The compound of claim 7 , wherein the compound is selected from
11. The compound of claim 10 , wherein the compound is
12. The compound of claim 10 , wherein the compound is
13. The compound of claim 10 , wherein the compound is
14. The compound of claim 10 , wherein the compound is
15. The compound of claim 10 , wherein the compound is
16. The compound of claim 2 , wherein
X 1 is CH and X 2 is N;
R 1 is-N(CH 3 ) 2 , cyclopropyl, or
R 3 is naphthalen-1-yl or naphthalen-2-yl;
R 6 is H, methyl or CD 3 ; and
n is 0.
17. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.