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Patent Application
App. No. 18/341,950

CARBAZOLE-CONTAINING AMIDES, CARBAMATES, AND UREAS AS CRYPTOCHROME MODULATORS

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Patent No.
US None
App. No.
18/341,950
Abstract

The subject matter herein is directed to carbazole-containing amide, carbamate, and urea derivatives and pharmaceutically acceptable salts or hydrates thereof of structural formula I wherein the variable R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , A, D, E, G, J, L, M, Q, a, and b are accordingly described. Also provided are pharmaceutical compositions containing the compounds of formula I to treat a Cry-mediated disease or disorder, such as diabetes, complications associated with diabetes, Cushing's syndrome, NASH, NAFLD, asthma, and COPD.

Claims (41)

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 independently N or C;

each of R 1 and R 2 , when A, D, E, G, J, L, M, or Q is C, is independently selected from 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 , 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 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 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 R 6 and R 7 are 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 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 8 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 are independently optionally substituted with 1 to 3 R 14 substituents each independently selected from 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 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 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.

2 .- 5 . (canceled)

6 . A compound selected from the group consisting of:

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

2-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)-2-azabicyclo[2.2.1]heptan-3-one

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

(1R,4S)-2-((R)-3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)-2-azabicyclo[2.2.1]heptan-3-one

(R)-1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)imidazolidin-2-one

(R)-1-((R)-3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)-3-fluoropyrrolidin-2-one

(S)-1-((S)-3-(9H-carbazol-9-yl)-2-hydroxy-2-methylpropyl)-3-fluoropyrrolidin-2-one

(R)-1-((R)-3-(9H-carbazol-9-yl)-2-hydroxypropyl)-4-methylimidazolidin-2-one;

or a pharmaceutically acceptable salt or hydrate thereof.

7 . The compound according to claim 6 which is 1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)-3-fluoropyrrolidin-2-one; or a pharmaceutically acceptable salt thereof.

8 . The compound according to claim 6 which is 2-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)-2-azabicyclo[2.2.1]heptan-3-one; or a pharmaceutically acceptable salt or hydrate thereof.

9 . The compound according to claim 6 which is 1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)imidazolidin-2-one; or a pharmaceutically acceptable salt or hydrate thereof.

10 . The compound according to claim 6 which is (1R,4S)-2-((R)-3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)-2-azabicyclo[2.2.1]heptan-3-one; or a pharmaceutically acceptable salt or hydrate thereof.

11 . The compound according to claim 6 which is (R)-1-(3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)imidazolidin-2-one; or a pharmaceutically acceptable salt or hydrate thereof.

12 . The compound according to claim 6 which is (R)-1-((R)-3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxypropyl)-3-fluoropyrrolidin-2-one; or a pharmaceutically acceptable salt or hydrate thereof.

13 . The compound according to claim 6 which is (S)-1-((S)-3-(9H-carbazol-9-yl)-2-hydroxy-2-methylpropyl)-3-fluoropyrrolidin-2-one; or a pharmaceutically acceptable salt or hydrate thereof.

14 . The compound according to claim 6 which is (R)-1-((R)-3-(9H-carbazol-9-yl)-2-hydroxypropyl)-4-methylimidazolidin-2-one; or a pharmaceutically acceptable salt or hydrate thereof.

15 .- 21 . (canceled)

22 . A method of treating a Cry-mediated disease or disorder in a subject, comprising administering to the subject a therapeutically effective amount of the compound according to claim 1 .

23 .- 55 . (canceled)