Oxoacridinyl acetic acid derivatives and methods of use
Compounds of Formula I or pharmaceutically acceptable salts or esters thereof capable of binding to and modulating the activity of a stimulator of interferon genes (STING) protein are provided. Methods involving compounds of Formula I as effective modulators of STING are also provided.
1. A compound of Formula I:
or a pharmaceutically acceptable salt or ester thereof, wherein
X is C(R X ) 2 , O, S, CH═CH, or a bond;
each R X is independently H, CH 3 , CF 3 , CF 2 H, or F, or two R X together form ═O, ═CH 2 , or ═CF 2 , or two R X , together with the carbon atom to which they are bonded, form a cyclopropyl;
Z 1 is (C(R Z ) 2 ) p -T 1 ;
p is 1, 2, 3, 4, 5, or 6;
each R Z is independently H, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with one or more halogen, or halogen;
T 1 is C(O)R 1 , C(O)OR 1 , C(O)N(R 1 ) 2 , NR 1 C(O)R 1 , C(S)R 1 , C(S)N(R 1 ) 2 , NR 1 C(S)R 1 , C(O)NHS(O) 2 R 5 , C(O)NHCOR 1 , C(O)NHOH, or C(O)NHCN;
R S is R 1 , C 3 -C 8 cycloalkyl, heterocyclyl comprising one 5- or 6-membered rings and 1-2 heteroatoms selected from N, O, and S, or C 6 -C 10 aryl, wherein the cycloalkyl, heterocyclyl, or aryl is optionally substituted with one or more groups independently selected from C 1 -C 4 alkyl;
each R 1 is independently H, C 1 -C 4 alkyl, or C 1 -C 4 alkyl substituted with one or more halogen;
m is 0, 1, or 2;
each Y is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, CN, OH, O—(C 1 -C 6 alkyl), S—(C 1 -C 6 alkyl), O—(C 2 -C 4 alkenyl), O—(C 2 -C 4 alkynyl), NH 2 , NH—C 1 -C 6 alkyl, N—(C 1 -C 6 alkyl) 2 , S(O)—(C 1 -C 6 alkyl), S(O) 2 —(C 1 -C 6 alkyl), or Q-T, wherein the alkyl, alkenyl, or alkynyl moiety is optionally substituted with one or more groups independently selected from OH, NH 2 , N 3 , halogen, O—(C 1 -C 6 alkyl), S—(C 1 -C 6 alkyl), NH—C 1 -C 6 alkyl, and N—(C 1 -C 6 alkyl) 2 , or two Y, together with the two adjacent carbon atoms to which they are bonded, form a 5- to 7-membered carbocycle or phenyl;
n is 2, 3, or 4;
each Z is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, OH, O—(C 1 -C 6 alkyl), S—(C 1 -C 6 alkyl), O—(C 2 -C 4 alkenyl), O—(C 2 -C 4 alkynyl), NH 2 , NH—C 1 -C 6 alkyl, N—(C 1 -C 6 alkyl) 2 , S(O)—(C 1 -C 6 alkyl), S(O) 2 —(C 1 -C 6 alkyl), or Q-T, wherein the alkyl, alkenyl, or alkynyl moiety is optionally substituted with one or more groups independently selected from OH, NH 2 , N 3 , halogen, O—(C 1 -C 6 alkyl), S—(C 1 -C 6 alkyl), NH—C 1 -C 6 alkyl, and N—(C 1 -C 6 alkyl) 2 ;
each Q is independently a bond, NH, N(C 1 -C 3 alkyl), O, S, S(O), S(O) 2 , Q′, NH-Q′, N(C 1 -C 3 alkyl)-Q′, O-Q′, S-Q′, S(O)-Q′, or S(O) 2 -Q′;
each Q′ is independently a carbon linker comprising one or more C(R Q ) 2 , C(R Q ) 2 —C(R Q ) 2 , CR Q =CR Q , or C≡C;
each R Q is independently H or C 1 -C 3 alkyl;
each T is independently C(O)—C 1 -C 6 alkyl, C(O)O—C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, heterocyclyl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, C 6 -C 10 aryl, or heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R T ;
each R T is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, OH, CN, halogen, O—(C 1 -C 6 alkyl), O—(C 1 -C 6 haloalkyl), S—(C 1 -C 6 alkyl), NH 2 , NH—C 1 -C 6 alkyl, N—(C 1 -C 6 alkyl) 2 , NHS(O) 2 —(C 1 -C 6 alkyl), (CH 2 ) q —C 3 -C 8 cycloalkyl, (CH 2 ) q -heterocyclyl, (CH 2 ) q -phenyl, or (CH 2 ) q -heteroaryl, wherein the heterocyclyl or heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S; and
q is 0, 1, 2, or 3,
and
wherein the compound of Formula I is substituted with Z at least at the 3-position and the 4-position.
2. The compound of claim 1 , wherein X is C(R X ) 2 .
3. The compound of claim 1 , wherein each R X is H.
4. The compound of claim 1 , wherein two R X together form ═O, ═CH 2 , or ═CF 2 .
5. The compound of claim 1 , wherein two R X together form ═O.
6. The compound of claim 1 , wherein each R Z is H, C 1 -C 4 alkyl, or halogen.
7. The compound of claim 1 , wherein T 1 is C(O)R 1 , C(O)OR 1 , C(O)N(R 1 ) 2 , or NR 1 C(O)R 1 .
8. The compound of claim 1 , wherein T 1 is C(O)OR 1 , C(O)N(R 1 ) 2 , C(O)NHS(O) 2 R 5 , C(O)NHCOR 1 , C(O)NHOH, or C(O)NHCN.
9. The compound of claim 1 , wherein each R 1 is H.
10. The compound of claim 1 , wherein m is 0 or 1.
11. The compound of claim 1 , wherein at least one Y is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, OH, O—(C 1 -C 6 alkyl), O—(C 2 -C 4 alkenyl), O—(C 2 -C 4 alkynyl), S—(C 1 -C 6 alkyl), S(O)—(C 1 -C 6 alkyl), S(O) 2 —(C 1 -C 6 alkyl), NH 2 , NH—C 1 -C 6 alkyl, N—(C 1 -C 6 alkyl) 2 , or Q-T, wherein the alkyl, alkenyl, or alkynyl is optionally substituted with one or more groups independently selected from OH, NH 2 , N 3 , halogen, O—(C 1 -C 6 alkyl), S—(C 1 -C 6 alkyl), NH—C 1 -C 6 alkyl, and N—(C 1 -C 6 alkyl) 2 .
12. The compound of claim 1 , wherein two Y, together with the two adjacent carbon atoms to which they are bonded, form a cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclopentynyl, cyclohexynyl, or cycloheptynyl.
13. The compound of claim 1 , wherein at least one Z is Q-T, C 1 -C 6 alkyl, halogen, OH, O—(C 1 -C 6 alkyl), O—(C 2 -C 4 alkenyl), O—(C 2 -C 4 alkynyl), S—(C 1 -C 6 alkyl), S(O)—(C 1 -C 6 alkyl), S(O) 2 —(C 1 -C 6 alkyl), NH 2 , NH—C 1 -C 6 alkyl, or N—(C 1 -C 6 alkyl) 2 .
14. The compound of claim 1 , wherein at least one Z is halogen.
15. The compound of claim 1 , wherein Q is NH, O, S, Q′, NH-Q′, N(C 1 -C 3 alkyl)-Q′, O-Q′, S-Q′, S(O)-Q′, or S(O) 2 -Q′.
16. The compound of claim 1 , wherein Q′ is a carbon linker comprising one or more C(R Q ) 2 —C(R Q ) 2 , C(R Q ) 2 , and CR Q =CR Q .
17. The compound of claim 1 , wherein T is cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, or cyclooctenyl, each of which is optionally substituted with one or more R T .
18. The compound of claim 1 , wherein T is heterocyclyl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S or heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, each optionally substituted with one or more R T .
19. The compound of claim 1 , wherein T is C 6 -C 10 aryl optionally substituted with one or more R T .
20. The compound of claim 1 , of Formula I5a1, I5b1, I5c1, or I5d1:
or a pharmaceutically acceptable salt or ester thereof, wherein R′ is H or methyl.
21. The compound of claim 1 , selected from the following:
or a pharmaceutically acceptable salt or ester thereof.
22. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier.
23. A method of modulating a stimulator of interferon genes (STING) protein, comprising administering to a subject in need thereof an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt or ester thereof.