4H-thieno[3,2-C]chromene-based inhibitors of Notum Pectinacetylesterase and methods of their use

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:

X is S, S(O), or S(O) 2 ;

each R 1 is independently R 1A or alkyl or heteroalkyl optionally substituted with one or more R 1A ;

each R 1A is independently alkoxyl, amido, amino, carbamide, carboxyl, cyano, halo, hydroxyl, nitro, sulfanyl, sulfinyl, sulfonyl, or thio;

n is 0-4;

R 2 is —C(O)R 2A or 5- or 6-membered cycloalkyl or heterocycle optionally substituted with one or more R 2B ;

R 2A is —OR 2C , —N(R 2C ) 2 , —C(R 2C ) 2 NO 2 , —C(R 2C ) 2 OR 2C , —C(R 2C ) 2 CN, or aryl or 5- or 6-membered heterocycle optionally substituted with one or more R 2B ;

each R 2B is independently alkoxyl, amido, amino, carboxamide, carboxyl, cyano, halo, hydroxyl, nitro, sulfanyl, sulfinyl, sulfonyl, or thio;

each R 2C is independently hydrogen, alkyl, aryl, heteroalkyl, or 5- or 6-membered heterocycle;

m is 0-2;

when m is 1, R 3 is H or C 1-2 -alkyl;

when m is 2, one of R 3 is C 1-2 -alkyl or cycloalkyl, and the other R 3 is H or C 1-2 -alkyl; and

each R 4 is independently H, fluoro or C 1-2 -alkyl.

2. The compound of claim 1 , wherein at least one R 4 is H.

3. The compound of claim 1 , wherein at least one R 1 is R 1A .

4. The compound of claim 1 , wherein R 1A is halo.

5. The compound of claim 1 , wherein R 1A is cyano.

6. The compound of claim 1 , wherein R 1A is nitro.

7. The compound of claim 1 , wherein R 2 is C(O)OH.

8. The compound of claim 1 , wherein R 2A is —OR 2C , —N(R 2C ) 2 , —CH 2 NO 2 , —CH 2 OR 2C , or —CH 2 CN.

9. The compound of claim 1 , wherein n is 2.

10. The compound of claim 1 , wherein n is 3.

11. The compound of claim 1 , wherein m is 0.

12. The compound of claim 1 , wherein m is 1 and R 3 is methyl.

13. A formulation comprising a compound of claim 1 and a pharmaceutically acceptable excipient.