4H-THIENO[3,2-C]CHROMENE-BASED INHIBITORS OF NOTUM PECTINACETYLESTERASE AND METHODS OF THEIR USE
Compounds that may be used to inhibit Notum Pectinacetylesterase are described, as well as compositions comprising them, and methods of their use to treat diseases and disorders affecting bone.
1 . A compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein:
X is C(R 4 ) 2 , C(R 4 ), O, 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, carbonyl, cyano, halo, hydroxyl, nitro, sulfanyl, sulfinyl, sulfonyl, or thio;
each R 2C is independently hydrogen, alkyl, aryl, heteroalkyl, or 5- or 6-membered heterocycle;
one of R 3 is C 1-2 -alkyl or cycloalkyl, and the other R 3 is H or C 1-2 -alkyl;
m is 0-2; and
each R 4 is independently H, fluoro or C 1-2 -alkyl;
wherein the bond between X and C 4 is a double bond if X is C(R 4 );
provided that:
when X is CH 2 , n is 0, m is 0, and R 2 is —C(O)R 2A , R 2A is not —OR 2C or —N(R 2C ) 2 ;
when X is 0, n is 0, m is 0, and R 2 is —C(O)R 2A , R 2A is not —O-alkyl;
when X is 0, n is 1, R 1 is fluoro, m is 0, and R 2 is —C(O)R 2A , R 2A is not —O-alkyl; and
when X is 0 and n is 0, R 3 is not methyl.
2 . The compound of claim 1 , wherein X is C(R 4 ) 2 .
3 . The compound of claim 2 , wherein at least one R 4 is H.
4 . The compound of claim 1 , wherein the bond between X and C 4 is a single bond.
5 . The compound of claim 1 , wherein X is 0.
6 . The compound of claim 1 , wherein X is S, S(O), or S(O) 2 .
7 . The compound of claim 1 , wherein at least one R 1 is R 1A .
8 . The compound of claim 1 , wherein R 1A is halo.
9 . The compound of claim 1 , wherein R 1A is cyano.
10 . The compound of claim 1 , wherein R 1A is nitro.
11 . The compound of claim 1 , wherein R 2 is C(O)OH.
12 . The compound of claim 1 , wherein R 2 is optionally substituted 5- or 6-membered heterocycle.
13 . 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.
14 . The compound of claim 1 , wherein R 2A is optionally substituted 5- or 6-membered heterocycle.
15 . The compound of claim 1 , wherein n is 2.
16 . The compound of claim 1 , wherein n is 3.
17 . The compound of claim 1 , wherein m is 0.
18 . The compound of claim 1 , wherein m is 1 and R 3 is methyl.
19 . A formulation comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
20 - 27 . (canceled)