Carbazole-containing amides, carbamates, and ureas as cryptochrome modulators

1. A compound of formula I

or a pharmaceutically acceptable salt or hydrate thereof, wherein each of A, D, E, G, J, L, M, and Q is carbon;

each of R 1 and R 2 is independently selected from the group consisting of hydrogen, 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 6 )alkyl, —O—SO 2 —R 8 , NR 8 —S(O) c , —(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 R 5 is independently selected from the group consisting of hydrogen, 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 hydrogen, —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 R 6 and R 7 are linked to each other as a piperidinone ring, optionally substituted with one or more halo, (C 1 -C 6 )alkyl, (C 3 -C 10 )cycloalkyl, or (C 6 -C 10 )aryl;

each of R 8 , R 9 and R 10 are independently selected from the group consisting of hydrogen, (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, (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 , —(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 , —NR 11 —S(O) c , —NR 15 —S(O) c , —(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 8 , 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 hydrogen 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.

2. The compound of claim 1 , wherein each of R 1 and R 2 is hydrogen or halo.

3. The compound of claim 1 , wherein each of R 3 and R 5 is independently selected from the group consisting of hydrogen or methyl.

4. The compound of claim 1 , wherein R 4 is hydrogen or methyl.

5. The compound of claim 1 , wherein the compound is selected from the group consisting of:

1-(3-(9H-carbazol-9-yl)-2-hydroxypropyl)piperidin-2-one (1);

1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)piperidin-2-one (4);

1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxy-2-methylpropyl)piperidin-2-one (5);

1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)-3-fluoropiperidin-2-one (11);

1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxy-2-methylpropyl)-3-fluoropiperidin-2-one (12);

1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)-3,3-difluoropiperidin-2-one (13);

1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxy-2-methylpropyl)-3,3-difluoropiperidin-2-one (14);

1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)-3,3-dimethylpiperidin-2-one (16);

1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)-3-phenylpiperidin-2-one (19);

3-cyclohexyl-1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)piperidin-2-one (20);

3-cyclohexyl-1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxy-2-methylpropyl)piperidin-2-one (21);

3-cyclopentyl-1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)piperidin-2-one (23);

1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)-3-ethylpiperidin-2-one (24);

1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)-3-isopropylpiperidin-2-one (25);

1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxy-2-methylpropyl)-3-isopropylpiperidin-2-one (26);

1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)-3-methylpiperidin-2-one (27);

1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxy-2-methylpropyl)-3-methylpiperidin-2-one (28);

1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxy-2-methylpropyl)-4-methylpiperidin-2-one (36);

1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)-5-methylpiperidin-2-one (37);

1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxy-2-methylpropyl)-5-methylpiperidin-2-one (38);

1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)-6-methylpiperidin-2-one (39);

1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxy-2-methylpropyl)-6-methylpiperidin-2-one (40);

1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)-4-methylpiperidin-2-one (49);

3-cyclobutyl-1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)piperidin-2-one (51);

3-cyclobutyl-1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxy-2-methylpropyl)piperidin-2-one (52);

1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)-3-methoxypiperidin-2-one (57);

1-(3-(9H-carbazol-9-yl)-2-hydroxypropyl)-3-methoxypiperidin-2-one (60);

1-(3-(9H-carbazol-9-yl)-2-hydroxypropyl)-4-methylpiperidin-2-one (61);

1-(3-(9H-carbazol-9-yl)-2-hydroxypropyl)-5-methylpiperidin-2-one (62);

1-(3-(9H-carbazol-9-yl)-2-hydroxypropyl)-6-methylpiperidin-2-one (63);

1-(3-(9H-carbazol-9-yl)-2-hydroxypropyl)-3-methylpiperidin-2-one (64);

1-(3-(9H-carbazol-9-yl)-2-hydroxy-2-methylpropyl)piperidin-2-one (66);

1-(3-(9H-carbazol-9-yl)-2-hydroxypropyl)-3,3-difluoropiperidin-2-one (69);

1-(3-(9H-carbazol-9-yl)-2-hydroxypropyl)-3-fluoropiperidin-2-one (70);

(S)-1-((R)-3-(9H-carbazol-9-yl)-2-hydroxypropyl)-5-methylpiperidin-2-one (129);

(S)-1-((R)-3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)-5-methylpiperidin-2-one (130);

(R)-1-((R)-3-(9H-carbazol-9-yl)-2-hydroxypropyl)-5-methylpiperidin-2-one (131);

(S)-1-((S)-3-(9H-carbazol-9-yl)-2-hydroxypropyl)-5-methylpiperidin-2-one (132);

(R)-1-((S)-3-(9H-carbazol-9-yl)-2-hydroxypropyl)-5-methylpiperidin-2-one (133); and

(R)-1-((R)-3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)-5-methylpiperidin-2-one (134); or a pharmaceutically acceptable salt or hydrate thereof.

6. A compound of formula I

or a pharmaceutically acceptable salt or hydrate thereof, wherein

each of A, D, E, G, J, L, M, and Q is carbon;

each of R 1 and R 2 is fluoro;

each of R 3 and R 5 is independently selected from the group consisting of hydrogen, 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 hydrogen, —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;

a wherein R 6 and R 7 are linked to each other as saturated pyrimidinone ring, optionally substituted with one or more halo, (C 1 -C 6 )alkyl, (C 3 -C 10 )cycloalkyl, or (C 6 -C 10 )aryl;

each of R 8 , R 9 and R 10 are independently selected from the group consisting of hydrogen, (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, (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 , —(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 , —NR 11 —S(O) c , —NR 15 —S(O) c , —(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 8 , 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 hydrogen 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.

7. The compound of claim 6 , wherein each of R 3 and R 5 is independently selected from the group consisting of hydrogen and methyl.

8. The compound of claim 6 , wherein R 4 is hydrogen or methyl.

9. The compound of claim 6 , wherein the compound is selected from the group consisting of:

1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)-3-methyltetrahydropyrimidin-2(1H)-one (6);

1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)tetrahydropyrimidin-2(1H)-one (71);

1-cyclohexyl-3-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)tetrahydropyrimidin-2(1H)-one (74);

1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)-3-phenyltetrahydropyrimidin-2(1H)-one (75);

1-cyclopentyl-3-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)tetrahydropyrimidin-2(1H)-one (76);

1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)-3-isopropyltetrahydropyrimidin-2(1H)-one (77);

1-cyclobutyl-3-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)tetrahydropyrimidin-2(1H)-one (78);

1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxy-2-methylpropyl)-3-phenyltetrahydropyrimidin-2(1H)-one (79);

1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxy-2-methylpropyl)-3-isopropyltetrahydropyrimidin-2(1H)-one (80);

1-cyclobutyl-3-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxy-2-methylpropyl)tetrahydropyrimidin-2(1H)-one (81);

1-cyclohexyl-3-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxy-2-methylpropyl)tetrahydropyrimidin-2(1H)-one (82);

1-cyclopropyl-3-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)tetrahydropyrimidin-2(1H)-one (83);

1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)-3-ethyltetrahydropyrimidin-2(1H)-one (86);

1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxy-2-methylpropyl)-3-ethyltetrahydropyrimidin-2(1H)-one (87);

1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)-3,5-dimethyltetrahydropyrimidin-2(1H)-one (94); and

1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)-3,4-dimethyltetrahydropyrimidin-2(1H)-one (101); or a pharmaceutically acceptable salt or hydrate thereof.

10. A compound selected from the group consisting of:

1-(3-(9H-carbazol-9-yl)-2-hydroxypropyl)-3-methyltetrahydropyrimidin-2(1H)-one (2);

1-(3-(9H-carbazol-9-yl)-2-hydroxypropyl)tetrahydropyrimidin-2(1H)-one (3);

4-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)morpholin-3-one (55);

4-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxy-2-methylpropyl)morpholin-3-one (56);

1-(3-(9H-carbazol-9-yl)-2-hydroxypropyl)-3-ethyltetrahydropyrimidin-2(1H)-one (95);

1-(3-(9H-carbazol-9-yl)-2-hydroxypropyl)-3-cyclopropyltetrahydropyrimidin-2(1H)-one (99); and

1-(3-(9H-carbazol-9-yl)-2-hydroxypropyl)-3-cyclobutyltetrahydropyrimidin-2(1H)-one (100); or a pharmaceutically acceptable salt or hydrate thereof.

11. A pharmaceutical composition comprising a compound according to claim 5 , or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier, adjuvant, or diluent.

12. The pharmaceutical composition according to claim 11 , further comprising one or more additional therapeutic agents selected from the group consisting of DPP-IV inhibitors, SGLT2 inhibitors, metformin, sulfonylureas, Signifor®, ketoconazole, metyrapone, mitotane, etomidate, Korlym®, epidermal growth factor receptor inhibitors, the aldosterone synthase/11β-hydroxylase inhibitor LCI699, and levoketoconazole (COR-003).

13. A method of treating or alleviating a subject suffering from a Cry-mediated disease or disorder, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to claim 11 , wherein the Cry-mediated disease or disorder is selected from the group consisting of diabetes, a diabetic complication, nonalcoholic steatohepatitis (NASH); non-alcoholic fatty liver disease (NAFLD); asthma; chronic obstructive pulmonary disease (COPD); metabolic syndrome; insulin resistance syndrome; obesity; glaucoma; Cushing's syndrome; psychotic depression; Alzheimer's disease; neuropathic pain; drug abuse; osteoporosis; cancer; macular degeneration; and myopathy, wherein the subject suffers from a Cry-mediated disease or disorder.

14. The method of claim 13 , wherein the diabetic complication is selected from the group consisting of diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, cataract formation, glaucoma, diabetic angiopathy, and atherosclerosis.

15. A pharmaceutical composition comprising a compound according to claim 6 , or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier, adjuvant, or diluent.

16. The pharmaceutical composition according to claim 15 , further comprising one or more additional therapeutic agents selected from the group consisting of DPP-IV inhibitors, SGLT2 inhibitors, metformin, sulfonylureas, Signifor®, ketoconazole, metyrapone, mitotane, etomidate, Korlym®, epidermal growth factor receptor inhibitors, the aldosterone synthase/11β-hydroxylase inhibitor LCI699, and levoketoconazole (COR-003).

17. A method of treating or alleviating a subject suffering from a Cry-mediated disease or disorder, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to claim 15 , wherein the Cry-mediated disease or disorder is selected from the group consisting of diabetes, a diabetic complication, nonalcoholic steatohepatitis (NASH); non-alcoholic fatty liver disease (NAFLD); asthma; chronic obstructive pulmonary disease (COPD); metabolic syndrome; insulin resistance syndrome; obesity; glaucoma; Cushing's syndrome; psychotic depression; Alzheimer's disease; neuropathic pain; drug abuse; osteoporosis; cancer; macular degeneration; and myopathy, wherein the subject suffers from a Cry-mediated disease or disorder.

18. The method of claim 17 , wherein the diabetic complication is selected from the group consisting of diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, cataract formation, glaucoma, diabetic angiopathy, and atherosclerosis.

19. A pharmaceutical composition comprising a compound according to claim 10 , or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier, adjuvant, or diluent.

20. The pharmaceutical composition according to claim 19 , further comprising one or more additional therapeutic agents selected from the group consisting of DPP-IV inhibitors, SGLT2 inhibitors, metformin, sulfonylureas, Signifor®, ketoconazole, metyrapone, mitotane, etomidate, Korlym®, epidermal growth factor receptor inhibitors, the aldosterone synthase/11β-hydroxylase inhibitor LCI699, and levoketoconazole (COR-003).

21. A method of treating or alleviating a subject suffering from a Cry-mediated disease or disorder, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to claim 19 , wherein the Cry-mediated disease or disorder is selected from the group consisting of diabetes, a diabetic complication, nonalcoholic steatohepatitis (NASH); non-alcoholic fatty liver disease (NAFLD); asthma; chronic obstructive pulmonary disease (COPD); metabolic syndrome; insulin resistance syndrome; obesity; glaucoma; Cushing's syndrome; psychotic depression; Alzheimer's disease; neuropathic pain; drug abuse; osteoporosis; cancer; macular degeneration; and myopathy, wherein the subject suffers from a Cry-mediated disease or disorder.

22. The method of claim 21 , wherein the diabetic complication is selected from the group consisting of diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, cataract formation, glaucoma, diabetic angiopathy, and atherosclerosis.