Carbazole-containing sulfonamides as cryptochrome modulators

1. A compound of formula I

or a pharmaceutically acceptable salt or hydrate thereof, wherein

each of A, B, C′, D, E, F, G, and H′ is independently C;

each of R 1 and R 2 , is independently selected from the group consisting of H, halo, cyano, nitro, —CF 3 , —CHF 2 , —CH 2 F, trifluoromethoxy, azido, hydroxyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(C═O)—R 8 , —(C═O)—O—R 8 , —O—(C═O)—R 8 , —NR 8 (C═O)—R 10 , —(C═O)—NR 8 R 9 , —NR 8 R 9 , —NR 8 OR 9 , —S(O) c NR 8 R 9 , —S(O) d (C 1 -C 8 )alkyl, —O—SO 2 —R 8 , —(CR 8 R 9 ) d (3-10)-membered cycloalkyl, —(CR 8 R 9 ) e (C 6 -C 10 )aryl, —(CR 8 R 9 ) e (4-10)-membered heterocyclyl, —(CR 8 R 9 ) f (C═O)(CR 8 R 9 ) e (C 6 -C 10 )aryl, —(CR 8 R 9 ) f (C═O)(CR 8 R 9 ) e (4-10)-membered heterocyclyl, —(CR 8 R 9 ) e O(CR 8 R 9 ) f (C 6 -C 10 )aryl, —(CR 8 R 9 ) e O(CR 8 R 9 ) f (4-10)-membered heterocyclyl, —(CR 8 R 9 ) f S(O) d (CR 8 R 9 ) e (C 6 -C 10 )aryl, and —(CR 8 R 9 ) f S(O) d (CR 8 R 9 ) e (4-10)-membered heterocyclyl;

each of R 3 and each of R 5 is independently selected from the group consisting of H, cyano, —CF 3 , —CHF 2 , —CH 2 F, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(C═O)—R 8 , —(C═O)—O—R 8 , —(C═O)—NR 8 R 9 , —S(O) c NR 8 R 9 , —S(O) d (C 1 -C 8 )alkyl, —(CR 8 R 9 ) d (3-10)-membered cycloalkyl, —(CR 8 R 9 ) e (C 6 -C 10 )aryl, —(CR 8 R 9 ) e (4-10)-membered heterocyclyl, —(CR 8 R 9 ) f (C═O)(CR 8 R 9 ) e (C 6 -C 10 )aryl, —(CR 8 R 9 ) f (C═O)(CR 8 R 9 ) e (4-10)-membered heterocyclyl, —(CR 8 R 9 ) e O(CR 8 R 9 ) f (C 6 -C 10 )aryl, —(CR 8 R 9 ) e O(CR 8 R 9 ) f (4-10)-membered heterocyclyl, —(CR 8 R 9 ) f S(O) d (CR 8 R 9 ) e (C 6 -C 10 )aryl, and —(CR 8 R 9 ) f S(O) d (CR 8 R 9 ) e (4-10)-membered heterocyclyl;

wherein each of the R 3 groups are optionally linked to each other as a 4-12 membered mono- or bicyclic ring;

wherein each of the R 5 groups are optionally linked to each other as a 4-12 membered mono- or bicyclic ring;

R 4 is selected from the group consisting of H, —CF 3 , —CHF 2 , —CH 2 F, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(C═O)—R 8 , —(C═O)—O—R 8 , —(C═O)—NR 8 R 9 , —(CR 8 R 9 ) d (3-10)-membered cycloalkyl, —(CR 8 R 9 ) e (C 6 -C 10 )aryl, —(CR 8 R 9 ) e (4-10)-membered heterocyclyl, —(CR 8 R 9 ) f (C═O)(CR 8 R 9 ) e (C 6 -C 10 )aryl, —(CR 8 R 9 ) f (C═O)(CR 8 R 9 ) e (4-10)-membered heterocyclyl, —(CR 8 R 9 ) e O(CR 8 R 9 ) f (C 6 -C 10 )aryl, —(CR 8 R 9 ) e O(CR 8 R 9 ) f (4-10)-membered heterocyclyl, —CR 8 R 9 ) f S(O) d (CR 8 R 9 ) e (C 6 -C 10 )aryl, and —(CR 8 R 9 ) f S(O) d (CR 8 R 9 ) e (4-10)-membered heterocyclyl;

R 6 is selected from the group consisting of H, —CF 3 , —CHF 2 , —CH 2 F, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(C═O)—R 8 , —(C═O)—O—R 8 , —(C═O)—NR 8 R 9 , —(CR 8 R 9 ) d (3-10)-membered cycloalkyl, —(CR 8 R 9 ) e (C 6 -C 10 )aryl, —(CR 8 R 9 ) e (4-10)-membered heterocyclyl, —(CR 8 R 9 ) f (C═O)(CR 8 R 9 ) e (C 6 -C 10 )aryl, —(CR 8 R 9 ) f (C═O)(CR 8 R 9 ) e (4-10)-membered heterocyclyl, —(CR 8 R 9 ) e O(CR 8 R 9 ) f (C 6 -C 10 )aryl, —(CR 8 R 9 ) e O(CR 8 R 9 ) f (4-10)-membered heterocyclyl, —(CR 8 R 9 ) f S(O) d (CR 8 R 9 ) e (C 6 -C 10 )aryl, and —(CR 8 R 9 ) f S(O) d (CR 8 R 9 ) e (4-10)-membered heterocyclyl;

wherein one R 5 group and R 6 are optionally linked to each other as a 4-12 membered mono- or bicyclic ring;

R 7 is selected from the group consisting of —CF 3 , —CHF 2 , —CH 2 F, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(C═O)—R 8 , —(C═O)—O—R 8 , —NR 8 (C═O)—R 10 , —(C═O)—NR 8 R 9 , —NR 8 R 9 , —NR 8 OR 9 , —(CR 8 R 9 ) d (3-10)-membered cycloalkyl, —(CR 8 R 9 ) e (4-10)-membered heterocyclyl, —(CR 8 R 9 ) f (C═O)(CR 8 R 9 ) e (C 6 -C 10 )aryl, —(CR 8 R 9 ) f (C═O)(CR 8 R 9 ) e (4-10)-membered heterocyclyl, —(CR 8 R 9 ) e O(CR 8 R 9 ) f (C 6 -C 10 )aryl, —(CR 8 R 9 ) e O(CR 8 R 9 ) f (4-10)-membered heterocyclyl, —(CR 8 R 9 ) f S(O) d (CR 8 R 9 ) e (C 6 -C 10 )aryl, and —(CR 8 R 9 ) f S(O) d (CR 8 R 9 ) e (4-10)-membered heterocyclyl;

R 6 and R 7 can be linked to each other as a 4-12 membered mono- or bicyclic ring;

each of R 8 , R 9 and R 10 are independently selected from the group consisting of H, (C 1 -C 6 )alkyl, —(CR 11 R 12 ) e (3-10)-membered cycloalkyl, —(CR 11 R 12 ) g (C 6 -C 10 )aryl, and —(CR 11 R 12 ) g (4-10)-membered heterocyclyl;

any carbon atoms of the (C 1 -C 6 )alkyl, the (3-10)-membered cycloalkyl, the (C 6 -C 10 )aryl and the (4-10)-membered heterocyclyl of the foregoing R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 15 , and R 16 are independently optionally substituted with 1 to 3 R 14 substituents each independently selected from the group consisting of halo, cyano, nitro, —CF 3 , —CHF 2 , —CH 2 F, trifluoromethoxy, azido, hydroxyl, —O—R 15 , (C 1 -C 6 )alkoxy, —(CR 8 R 9 ) e (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(C═O)—R 11 , —(C═O)—R 15 , —(C═O)—O—R 11 , —(C═O)—O—R 15 , —O—(C═O)—R 11 , —O—(C═O)—R 15 , —NR11(C═O)—R 13 , —(C═O)—NR 11 R 12 , —(C═O)—NR 11 R 15 , —NR 11 R 12 , —NR 11 R 15 , —NR 11 OR 12 , —NR 11 OR 15 , —S(O) c NR 11 R 12 , —S(O) c NR 11 R 15 , —S(O) d (C 1 -C 6 )alkyl, —S(O) d R 15 , —O—SO 2 —R 11 , —O—SO 2 —R 15 , —(CR 11 R 12 ) e (3-10)-membered cycloalkyl, —(CR 11 R 12 ) e (C 6 -C 10 )aryl, —(CR 11 R 12 ) e (4-10)-membered heterocyclyl, —(CR 11 R 12 ) f (C═O)(CR 11 R 12 ) e (C 6 -C 10 )aryl, —(CR 11 R 12 ) f (C═O)(CR 11 R 12 ) e (4-10)-membered heterocyclyl, —(CR 11 R 12 ) e O(CR 11 R 12 ) f (C 6 -C 10 )aryl, —(CR 11 R 12 ) e O(CR 11 R 12 ) f (4-10)-membered heterocyclyl, —(CR 11 R 12 ) f S(O) d (CR 11 R 12 ) e (C 6 -C 10 )aryl, and —(CR 11 R 12 ) f S(O) d (CR 11 R 12 ) e (4-10)-membered heterocyclyl;

any carbon atoms of the (C 1 -C 6 )alkyl, the (3-10)-membered cycloalkyl, the (C 6 -C 10 )aryl and the (4-10)-membered heterocyclyl of the foregoing R 14 are independently optionally substituted with 1 to 3 R 16 substituents each independently selected from the group consisting of halo, cyano, nitro, —CF 3 , —CHF 2 , —CH 2 F, trifluoromethoxy, azido, (CH 2 ) e OH, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(C═O)—R 11 , —(C═O)—R 15 , —(C═O)—O—R 11 , —(C═O)—O—R 15 , —O—(C═O)—R 11 , —O—(C═O)—R 15 , —NR 11 (C═O)—R 13 , —(C═O)—NR 11 R 12 , —NR 11 R 12 , and —NR 11 R 15 ;

any nitrogen atoms of the (4-10)-membered heterocyclyl of the foregoing R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 14 , and R 15 are independently optionally substituted with (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(C═O)—R 11 , —(C═O)—O—R 11 , —(C═O)—NR 11 R 12 , —(CR 11 R 12 ) e (3-10)- membered cycloalkyl, —(CR 11 R 12 ) e (C 6 -C 10 )aryl, —(CR 11 R 12 ) e (4-10)-membered heterocyclyl, —(CR 11 R 12 ) f (C═O)(CR 11 R 12 ) e (C 6 -C 10 )aryl, or —(CR 11 R 12 ) f (C═O)(CR 11 R 12 ) e (4-10)-membered heterocyclyl;

each R 11 , R 12 , and R 13 are independently H or (C 1 -C 6 )alkyl;

R 15 is —(CR 11 R 12 ) e (3-10)-membered cycloalkyl, —(CR 11 R 12 ) e (C 6 -C 10 )aryl, or —(CR 11 R 12 ) e (4-10)-membered heterocyclyl;

a and b are each independently 1, 2, 3, or 4;

c is 1 or 2;

d is 0, 1, or 2; and

e, f, and g are each independently 0, 1, 2, 3, 4, or 5,

and wherein when R 7 is (C 1 -C 6 )alkyl, R 6 is selected from the group consisting of —CF 3 , —CHF 2 , —CH 2 F, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(C═O)—R 8 , —(C═O)—O—R 8 , —(C═O)—NR 8 R 9 , —(CR 8 R 9 ) d (3-10)-membered cycloalkyl, —(CR 8 R 9 ) e (4-10)-membered non-aromatic heterocyclyl, —(CR 8 R 9 ) f (C═O)(CR 8 R 9 ) e (C 6 -C 10 )aryl, —(CR 8 R 9 ) f (C═O)(CR 8 R 9 ) e (4-10)-membered heterocyclyl, —(CR 8 R 9 ) e O(CR 8 R 9 ) f (C 6 -C 10 )aryl, —(CR 8 R 9 ) e O(CR 8 R 9 ) f (4-10)-membered heterocyclyl, —(CR 8 R 9 ) f S(O) d (CR 8 R 9 ) e (C 6 -C 10 )aryl, and —(CR 8 R 9 ) f S(O) d (CR 8 R 9 ) e (4-10)-membered heterocyclyl.

2. The compound according to claim 1 , wherein each of R 1 and R 2 is independently selected from H or halo; R 4 is H or (C 1 -C 6 )alkyl; R 3 and R 5 are H; R 6 is —CF 3 , —CHF 2 , —CH 2 F, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(CR 8 R 9 ) d (3-10)-membered cycloalkyl, —(CR 8 R 9 ) e (C 6 -C 10 )aryl, —(CR 8 R 9 ) e (4-10)-membered heterocyclyl, —(CR 8 R 9 ) e O(CR 8 R 9 ) f (C 6 -C 10 )aryl, —(CR 8 R 9 ) e O(CR 8 R 9 ) f (4-10)-membered heterocyclyl, —(CR 8 R 9 ) f S(O) d (CR 8 R 9 ) e (C 6 -C 10 )aryl, or —(CR 8 R 9 ) f S(O) d (CR 8 R 9 ) e (4-10)-membered heterocyclyl; R 7 is —CF 3 , —CHF 2 , —CH 2 F, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(CR 8 R 9 ) d (3-10)-membered cycloalkyl, —(CR 8 R 9 ) e (4-10)-membered heterocyclyl, —(CR 8 R 9 ) e O(CR 8 R 9 ) f (C 6 -C 10 )aryl, —(CR 8 R 9 ) e O(CR 8 R 9 ) f (4-10)-membered heterocyclyl, —(CR 8 R 9 ) f S(O) d (CR 8 R 9 ) e (C 6 -C 10 )aryl, or —(CR 8 R 9 ) f S(O) d (CR 8 R 9 ) e (4-10)-membered heterocyclyl.

3. The compound according to claim 1 , wherein each of R 1 and R 2 is independently selected from H or halo; R 4 is H or (C 1 -C 6 )alkyl; R 3 and R 5 are H; R 6 and R 7 are linked to each other as a 4-12 membered mono- or bicyclic ring.

4. The compound according to claim 1 , wherein each of R 1 and R 2 is independently selected from H or halo; R 4 is H or (C 1 -C 6 )alkyl; R 3 and one R 5 are H; one R 5 and R 6 are linked to each other as a 4-12 membered mono- or bicyclic ring; R 7 is —CF 3 , —CHF 2 , —CH 2 F, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(CR 8 R 9 ) d (3-10)-membered cycloalkyl, —(CR 8 R 9 ) e (4-10)-membered heterocyclyl, —(CR 8 R 9 ) e O(CR 8 R 9 ) f (C 6 -C 10 )aryl, —(CR 8 R 9 ) e O(CR 8 R 9 ) f (4-10)-membered heterocyclyl, —(CR 8 R 9 ) f S(O) d (CR 8 R 9 ) e (C 6 -C 10 )aryl, or —(CR 8 R 9 ) f S(O) d (CR 8 R 9 ) e (4-10)-membered heterocyclyl.

5. The compound according to claim 1 , wherein the compound is the single enantiomer bearing an (S)-configuration at C-3; each of R 1 and R 2 is independently selected from H or halo; R 4 is H or (C 1 -C 6 )alkyl, R 3 and R 5 are H; R 6 is —CF 3 , —CHF 2 , —CH 2 F, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(CR 8 R 9 ) d (3-10)-membered cycloalkyl, —(CR 8 R 9 ) e (C 6 -C 10 )aryl, —(CR 8 R 9 ) e (4-10)-membered heterocyclyl, —(CR 8 R 9 ) e O(CR 8 R 9 ) f (C 6 -C 10 )aryl, —(CR 8 R 9 ) e O(CR 8 R 9 ) f (4-10)-membered heterocyclyl, —(CR 8 R 9 ) f S(O) d (CR 8 R 9 ) e (C 6 -C 10 )aryl, or —(CR 8 R 9 ) f S(O) d (CR 8 R 9 ) e (4-10)-membered heterocyclyl; R 7 is —CF 3 , —CHF 2 , —CH 2 F, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(CR 8 R 9 ) d (3-10)-membered cycloalkyl, —(CR 8 R 9 ) e (4-10)-membered heterocyclyl, —(CR 8 R 9 ) e O(CR 8 R 9 ) f (C 6 -C 10 )aryl, —(CR 8 R 9 ) e O(CR 8 R 9 ) f (4-10)-membered heterocyclyl, —(CR 8 R 9 ) f S(O) d (CR 8 R 9 ) e (C 6 -C 10 )aryl, or —(CR 8 R 9 ) f S(O) d (CR 8 R 9 ) e (4-10)-membered heterocyclyl.

6. The compound according to claim 1 , wherein the compound is the single enantiomer bearing an (S)-configuration at C-3; each of R 1 and R 2 is independently selected from H or halo; R 4 is H or (C 1 -C 6 )alkyl; R 3 and R 5 are H; R 6 and R 7 are linked to each other as a 4-12 membered mono- or bicyclic ring.

7. A compound selected from the group consisting of:

(S)—N-(3-(9H-Carbazol-9-yl)-2-hydroxypropyl)-1,2-thiazinane-1,1-dioxide;

N-(3-(3,6-Difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)-isothiazolidine-1,1-dioxide;

(S)—N-(3-(9H-Carbazol-9-yl)-2-hydroxypropyl)isothiazolidine-1,1-dioxide;

2-(3-(9H-Carbazol-9-yl)-2-hydroxypropyl)-5-fluoro-isothiazolidine-1,1-dioxide;

2-(3-(3,6-Difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)-1,2,6-thiadiazinane-1,1-dioxide;

N-(3-(9H-Carbazol-9-yl)-2-hydroxypropyl)-N-(1-methylcyclopentyl)methanesulfonamide;

N-(3-(9H-Carbazol-9-yl)-2-hydroxypropyl)isothiazolidine-1,1-dioxide;

N-(3-(9H-Carbazol-9-yl)-2-hydroxypropyl)-2,3-dihydrobenzo[d]isothiazole-1,1-dioxide;

N-(3-(2,6-Difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)-1,2-thiazinane-1,1-dioxide; and

2-(3-(9H-Carbazol-9-yl)-2-hydroxypropyl)-1,2,6-thiadiazinane-1,1-dioxide;

or a pharmaceutically acceptable salt or hydrate thereof.

8. The compound according to claim 7 which is (S)—N-(3-(9H-Carbazol-9-yl)-2-hydroxypropyl)-1,2-thiazinane-1,1-dioxide; or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 7 which is N-(3-(3,6-Difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)-isothiazolidine-1,1-dioxide; or a pharmaceutically acceptable salt or hydrate thereof.

10. The compound according to claim 7 which is (S)—N-(3-(9H-Carbazol-9-yl)-2-hydroxypropyl)isothiazolidine-1,1-dioxide; or a pharmaceutically acceptable salt or hydrate thereof.

11. The compound according to claim 7 which is 2-(3-(9H-Carbazol-9-yl)-2-hydroxypropyl)-5-fluoro-isothiazolidine-1,1-dioxide; or a pharmaceutically acceptable salt or hydrate thereof.

12. The compound according to claim 7 which is 2-(3-(3,6-Difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)-1,2,6-thiadiazinane-1,1-dioxide; or a pharmaceutically acceptable salt or hydrate thereof.

13. The compound according to claim 7 which is N-(3-(9H-Carbazol-9-yl)-2-hydroxypropyl)-N-(1-methylcyclopentyl)methanesulfonamide; or a pharmaceutically acceptable salt or hydrate thereof.

14. The compound according to claim 7 which is N-(3-(9H-Carbazol-9-yl)-2-hydroxypropyl)isothiazolidine-1,1-dioxide; or a pharmaceutically acceptable salt or hydrate thereof.

15. The compound according to claim 7 which is N-(3-(9H-Carbazol-9-yl)-2-hydroxypropyl)-2,3-dihydrobenzo[d]isothiazole-1,1-dioxide; or a pharmaceutically acceptable salt or hydrate thereof.

16. The compound according to claim 7 which is N-(3-(2,6-Difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)-1,2-thiazinane-1,1-dioxide; or a pharmaceutically acceptable salt or hydrate thereof.

17. The compound according to claim 7 which is 2-(3-(9H-Carbazol-9-yl)-2-hydroxypropyl)-1,2,6-thiadiazinane-1,1-dioxide; or a pharmaceutically acceptable salt or hydrate thereof.

18. The compound according to claim 1 , wherein said compound modulates Cry1 or Cry2.

19. The compound according to claim 18 , wherein said modulation comprises any one of the following:

(i) binding to Cry1 or Cry2;

(ii) inhibiting modification of Cry1 or Cry2;

(iii) altering Cry1 or Cry2 localization;

(iv) increasing or decreasing Cry1 or Cry2 stabilization;

(v) increasing or decreasing the binding between Cry1 or Cry2 to a target;

(vi) increasing or decreasing Cry1 or Cry2 activity; and

(vii) increasing or decreasing activity of a Cry1 or Cry2 target.

20. The compound according to claim 19 , wherein said target is Per1, Per2, glucocorticoid receptor (GR), CLOCK, BMAL1, or a CLOCK-BMAL1 promoter sequence.

21. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier, adjuvant, or diluent.

22. The pharmaceutical composition according to claim 21 , further comprising one or more additional therapeutic agents.