STAT6 inhibitors
The present disclosure provides compounds that are useful for inhibiting the STAT6 pathway. Also provided are related pharmaceutical compositions and methods of using the compounds. In some embodiments, the compounds may be used to treat a disease such as, e.g., an allergic lung disease, allergic rhinitis, chronic pulmonary obstructive disease, or a cancer.
1. A compound of the formula:
wherein:
the bond between carbons 1 and 2 is a single or double bond;
R 1 is phosphate, —OP(O)(OR 10 )(OR 10′ ), -substituted or unsubstituted alkyl (C≦1-6) -P(O)(OR 10 )(OR 10′ ), or a substituted version of the R 10 of R 10′ ; wherein
R 10 and R 10′ are each independently hydrogen, alkyl (C1-6) , aryl (C6-8) , aralkyl (C7-12) , -alkyl (C1-6) -O—C(O)-alkyl (C1-6) , -alkyl (C1-6) -O—C(O)-aryl (C6-8) , or
wherein m=1-8; wherein X is —CH 2 —, —O—, —S—, or —NH—; provided that R 10 and R 10′ are not both hydrogen;
R 2 is hydrogen
R 3 , R 5 , and R 6 , are each independently hydrogen, unsubstituted alkyl (C1-6) , or substituted alkyl (C1-6) ,
R 4 is hydrogen or —N(R 11 )R 12 ; wherein:
R 11 is hydrogen, or a substituted or unsubstituted alkyl (C1-6) , a substituted or unsubstituted aryl (C6-8) , or substituted or unsubstituted acyl (C2-6) ;
R 12 is hydrogen, alkyl (C1-6) , or acyl (C1-6) ;
R 9 is hydrogen, unsubstituted alkyl (C1-6) , substituted alkyl (C1-6) , unsubstituted aryl (C6-8) , substituted aryl (C6-8) , a canonical amino acid, -alkanediyl (C1-6) -C(O)NX 1 X 2 , —CH 2 —C(O)NX 1 X 2 ,
wherein X 1 and X 2 are each independently substituted or unsubstituted alkyl (C1-6) , or substituted or unsubstituted aryl (C6-12) ;
wherein if an alkyl, aryl, aralkyl, or acyl group is substituted then one or more hydrogen atom on the alkyl, arly, aralkyl, or acyl group has been independently replaced by —OH, —F, —Cl, —Br, —I, —NH 2 , —NO 2 , —CO 2 H, —CO 2 CH 3 , —CN, —SH, —OCH 3 , —OCH 2 CH 3 , —C(O)CH 3 , —NHCH 3 , —NHCH 2 CH 3 , —N(CH 3 ) 2 , —C(O)NH 2 , —OC(O)CH 3 , or —S(O) 2 NH 2 ;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein the bond between carbons 1 and 2 is a double bond.
3. The compound of claim 1 , wherein R 1 is phosphate or —CF 2 —P(O)(OR 10 )(OR 10′ ).
4. The compound claim 3 , wherein R 10 or R 10′ is —CH 2 OC(O)C(CH 3 ) 3 .
5. The compound of claim 4 , wherein R 10 and R 10′ is —CH 2 OC(O)C(CH 3 ) 3 .
6. The compound of claim 1 , wherein R 2 is hydrogen.
7. The compound of claim 1 , wherein R 3 is hydrogen or alkyl (C1-6) .
8. The compound of claim 7 , wherein R 3 is methyl.
9. The compound of claim 1 , wherein R 4 is hydrogen or —N(R 11 )R 12 .
10. The compound of claim 9 , wherein R 11 is hydrogen or R 12 is hydrogen.
11. The compound of claim 9 , wherein R 12 is alkyl (C1-6) , aryl (C6) , or acyl (C1-6) .
12. The compound of claim 1 , wherein R 5 is hydrogen or alkyl (C1-6) .
13. The compound of claim 1 , wherein R 6 is hydrogen or alkyl (C1-6) .
14. The compound of claim 1 , wherein R 5 and R 6 are hydrogen or methyl.
15. The compound of claim 1 , wherein R 9 is alkyl (C1-6) or an amino acid.
16. The compound of claim 1 , wherein the R 9 is cis to the carbonyl.
17. The compound of claim 1 , further defined as:
or a pharmaceutically acceptable salt thereof;
wherein POM has the structure —CH 2 OC(O)C(CH 3 ) 3 .
18. The compound of claim 17 , wherein the compound is PM-43I or a pharmaceutically acceptable salt thereof.
19. A pharmaceutical composition comprising a compound comprising an effective amount of a compound according to claim 1 and a pharmaceutically acceptable excipient.
20. A method of treating an allergic or inflammatory lung disease in a subject comprising administering to the subject a therapeutically effective amount of a compound of claim 1 to the subject.
21. A method of inhibiting STAT6 in a subject in need of treatment comprising administering to the subject a compound of claim 1 in an amount an effective to inhibit STAT6, wherein the subject has lung inflammation.
22. The compound of claim 12 , wherein R 5 is hydrogen.
23. The method of claim 20 , wherein the disease is a lung disease.
24. The method of claim 23 , wherein the lung disease is asthma.
25. The method of claim 23 , wherein the lung disease is airway hyperresponsiveness.
26. The method of claim 23 , wherein the lung disease is an allergic disease, allergic rhinitis, emphysema, chronic obstructive pulmonary disease (COPD), reactive airway disease, or chronic rhinosinusitis.