Sulfonamides for the modulation of PKM2
The invention relates to sulfonamide compounds and methods for activating PKM2. The compounds and methods are useful in treating or preventing a disease or disorder selected from cancer, cell proliferative disorder, inflammatory disorder, metabolic disorder, and immune system disorder.
1. A compound of Formula IA:
or a salt, solvate, hydrate, or prodrug thereof, wherein:
Z is SO 2 ;
W is absent;
T is selected from the group consisting of NR 2 COR 1 and NR 2 S(O) 2 R 1 ;
R 1 is selected from the group consisting of a linear or branched C 1 -C 6 alkyl, linear or branched C 2 -C 6 alkenyl, linear or branched C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, heterocycloalkyl, aryl and heteroaryl,
wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with one or more R c ,
R c is independently at each occurrence selected from the group consisting of linear or branched C 1 -C 6 alkyl, linear or branched C 2 -C 6 alkenyl, linear or branched C 2 -C 6 alkynyl, linear or branched C 1 -C 6 haloalkyl, linear or branched C 1 -C 6 alkoxy, aryloxy, linear or branched C 1 -C 6 haloalkoxy, linear or branched C 1 -C 6 alkylsulfonyl, linear or branched C 1 -C 6 thioalkyl, thioaryl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, aryl, heteroaryl, heterocycloalkyl, hydroxyl, cyano, nitro, halogen, COR d , COOR d , CONR d R e , NHCOR d , and NR d R e ;
R d and R e are, each independently selected from the group consisting of linear or branched, C 1 -C 6 alkyl, linear or branched C 2 -C 6 alkenyl, linear or branched C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, heterocycloalkyl, aryl, and heteroaryl;
R 2 and R 3 , together with the atoms to which they are attached, form a five to seven membered heterocycloalkyl or heteroaryl ring containing one nitrogen atom, wherein said ring is unsubstituted or substituted with one or more R m ,
R m is selected from the group consisting of halogen, linear or branched C 1 -C 6 alkyl, linear or branched C 2 -C 6 alkenyl, linear or branched C 2 -C 6 alkynyl, linear or branched C 1 -C 6 alkoxy, linear or branched C 1 -C 6 haloalkyl, benzyloxy, NR d R e , NHCOR d , and SO 2 R d ;
R 4 is selected from the group consisting of halogen, linear or branched C 1 -C 6 alkyl, linear or branched C 2 -C 6 alkenyl, linear or branched C 2 -C 6 alkynyl, and heteroalkyl,
wherein said alkyl, alkenyl, alkynyl, and heteroalkyl are unsubstituted or substituted with one or more R f ,
R f is independently at each occurrence selected from the group consisting of linear or branched C 1 -C 6 alkyl, linear or branched C 2 -C 6 alkenyl, linear or branched C 2 -C 6 alkynyl, linear or branched C 1 -C 6 haloalkyl, linear or branched C 1 -C 6 alkoxy, aryloxy, linear or branched C 1 -C 6 haloalkoxy, linear or branched C 1 -C 6 alkylsulfonyl, linear or branched, C 1 -C 6 thioalkyl, thioaryl, C 3 -C 8 cycloalkyl, C 3 -C 8 alkenyl, aryl, heteroaryl, heterocycloalkyl, hydroxyl, cyano, amino, nitro, halogen, COR g , COOR g , CONR g R h , NHCOR g , and NR g R h ;
R g and R h are, each independently selected from a group consisting of hydrogen, linear or branched C 1 -C 6 alkyl, linear or branched C 2 -C 6 alkenyl, linear or branched C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, heterocycloalkyl, aryl and heteroaryl;
t is 0, 1, 2 or 3;
R 5′ , R 8′ and R 9′ are, each independently, selected from hydrogen, linear or branched C 1 -C 6 alkyl, linear or branched C 2 -C 6 alkenyl, linear or branched C 2 -C 6 alkynyl, linear or branched C 1 -C 6 haloalkyl, linear or branched C 1 -C 6 alkoxy, benzyloxy, aryloxy, linear or branched C 1 -C 6 haloalkoxy, linear or branched C 1 -C 6 alkylsulfonyl, linear or branched C 1 -C 6 thioalkyl or thioaryl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, aryl, heteroaryl, heterocycloalkyl, hydroxyl, cyano, amino, nitro, halogen, COR i , COOR i , CONR i R j , NHCOR i , and NR i R j ;
R i and R j are, each independently, hydrogen or a group selected from a linear or branched C 1 -C 6 alkyl, linear or branched C 2 -C 6 alkenyl, linear or branched C 2 -C 6 alkynyl, linear or branched C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, or heterocycloalkyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, and heteroaryl are unsubstituted or substituted with one or more R k ,
R k is selected from halogen or hydroxyl;
R 6′ and R 7′ together with the atoms to which they are attached, form a 6 membered heterocycloalkyl ring consisting of four carbon atoms and two oxygen atoms, wherein said heterocycloalkyl ring is unsubstituted or substituted with one or more R m1 selected from C 1 -C 6 alkyl and S(O) p (C 1 -C 6 alkyl);
w is 0 or 1, and
p is 0, 1, or 2.
2. The compound according to claim 1 of Formula IIA:
or a salt, solvate, hydrate or prodrug thereof, wherein:
m is 0, 1, 2, 3, or 4;
n is 0, 1, 2, 3 or 4, thereby forming a five to seven membered heteroaryl or a five to seven membered heterocycloalkyl ring, wherein the five to seven membered heteroaryl or heterocycloalkyl ring is unsubstituted or substituted with one or more R m ,
R m is linear or branched C 1 -C 6 alkyl.
3. The compound according to claim 1 of Formula IIB:
or a salt, solvate, hydrate, or prodrug thereof and wherein o is 0 or 1.
4. The compound according to claim 1 of Formula IID:
or a salt, solvate, hydrate, or prodrug thereof.
5. The compound according to claim 1 or a salt, solvate, hydrate, or prodrug thereof, wherein R 6′ and R 7′ together with the atoms to which they are attached form a 1,4-dioxane ring.
6. The compound according to claim 5 or a salt, solvate, hydrate, or prodrug thereof, wherein remaining R 8′ R 5′ and R 9′ are each hydrogen.
7. The compound according to claim 1 or a salt, solvate, hydrate, or prodrug thereof, wherein R 1 is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 8 cycloalkenyl.
8. The compound according to claim 7 or a salt, solvate, hydrate, or prodrug thereof, wherein R 1 is selected from C 1 -C 6 alkyl and aryl, wherein said aryl is unsubstituted or substituted with one or more R c .
9. The compound according to claim 1 or a salt, solvate, hydrate, or prodrug thereof, wherein t is 0.
10. A compound selected from
11. A pharmaceutical composition comprising a compound according to claim 1 or a salt, solvate, hydrate, or prodrug thereof and at least one pharmaceutically acceptable carrier or excipient.
12. The compound of claim 3 , wherein o is 0.
13. The compound of claim 3 , wherein o is 1 and R m is CH 3 .
14. The compound of claim 3 , wherein t is 0.
15. The compound of claim 3 , wherein R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, and C 3 -C 8 cycloalkyl.
16. The compound of claim 15 , wherein R 1 is selected from methyl, ethyl, propyl, isopropyl, butyl, and isobutyl.
17. The compound of claim 15 , wherein R 1 is aryl, wherein said aryl is unsubstituted or substituted with one or more R c selected from methyl, OCH 3 , F, Cl, and CF 3 .
18. The compound of claim 3 , wherein R 6′ and R 7′ together with the atoms to which they are attached form a 1,4-dioxane ring.
19. The compound of claim 18 , wherein R 5′ , R 8′ , and R 9′ are each hydrogen.
20. The compound of claim 2 , wherein R 6′ and R 7′ together with the atoms to which they are attached form a 1,4-dioxane ring.