Carbazole-containing amides, carbamates, and ureas as cryptochrome modulators
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C07D-401/06
C07D-413/02
C07D-403/02
C07D-209/52
C12Q-001/6883
A61K-031/5377
C07D-413/06
A61K-031/403
A61K-031/513
C07D-403/06
A61K-045/06
A61K-031/454
출원번호
US-0985168
(2018-05-21)
등록번호
US-10214507
(2019-02-26)
발명자
/ 주소
Bersot, Ross
Humphries, Paul
출원인 / 주소
Reset Therapeutics, Inc.
대리인 / 주소
Cooley LLP
인용정보
피인용 횟수 :
0인용 특허 :
86
초록▼
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 R1, R2, R3, R4, R5, R6, R7, A, D, E, G, J, L, M, Q, a, and b are accordingly described. Also pro
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 R1, R2, R3, R4, R5, R6, R7, 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.
대표청구항▼
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 R1 and R2 is independently selected from the group consisting of hydrogen, halo, cyano, nitro, —CF3, —CHF2, —CH2F, trifluoromethoxy, azido, hydroxyl, (C1-
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 R1 and R2 is independently selected from the group consisting of hydrogen, halo, cyano, nitro, —CF3, —CHF2, —CH2F, trifluoromethoxy, azido, hydroxyl, (C1-C6)alkoxy, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, —(C═O)—R8, —(C═O)—O—R8, —O—(C═O)—R8, —NR8(C═O)—R10, —(C═O)—NR8R9, —NR8R9, —NR8OR9, —S(O)cNR8R9, —S(O)d(C1-C6)alkyl, —O—SO2—R8, NR8—S(O)c, —(CR8R9)d(3-10)-membered cycloalkyl, —(CR8R9)e(C6-C10)aryl, —(CR8R9)e(4-10)-membered heterocyclyl, —(CR8R9)f(C═O)(CR8R9)e(C6-C10)aryl, —(CR8R9)f(C═O)(CR8R9)e(4-10)-membered heterocyclyl, —(CR8R9)eO(CR8R9)f(C6-C10)aryl, —(CR8R9)eO(CR8R9)f(4-10)-membered heterocyclyl, —(CR8R9)fS(O)d(CR8R9)e(C6-C10)aryl, and —(CR8R9)fS(O)d(CR8R9)e(4-10)-membered heterocyclyl;each of R3 and R5 is independently selected from the group consisting of hydrogen, cyano, —CF3, —CHF2, —CH2F, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, —(C═O)—R8, —(C═O)—O-R8, —(C═O)—NR8R9, —S(O)cNR8R9, —S(O)d(C1-C8)alkyl, —(CR8R9)d(3-10)-membered cycloalkyl, —(CR8R9)e(C6-C10)aryl, —(CR8R9)e(4-10)-membered heterocyclyl, —(CR8R9)f(C═O)(CR8R9)e(C6-C10)aryl, —(CR8R9)f(C═O)(CR8R9)e(4-10)-membered heterocyclyl, —(CR8R9)eO(CR8R9)f(C6-C10)aryl, —(CR8R9)eO(CR8R9)f(4-10)-membered heterocyclyl, —(CR8R9)fS(O)d(CR8R9)e(C6-C10)aryl, and —(CR8R9)fS(O)d(CR8R9)e(4-10)-membered heterocyclyl;wherein each of the R3 groups are optionally linked to each other as a 4-12 membered mono- or bicyclic ring;wherein each of the R5 groups are optionally linked to each other as a 4-12 membered mono- or bicyclic ring;R4 is selected from the group consisting of hydrogen, —CF3, —CHF2, —CH2F, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, —(C═O)—R8, —(C═O)—O—R8, —(C═O)—NR8R9, —(CR8R9)d(3-10)-membered cycloalkyl, —(CR8R9)e(C6-C10)aryl, —(CR8R9)e(4-10)-membered heterocyclyl, —(CR8R9)f(C═O)(CR8R9)e(C6-C10)aryl, —(CR8R9)f(C═O)(CR8R9)e(4-10)-membered heterocyclyl, —(CR8R9)eO(CR8R9)f(C6-C10)aryl, —(CR8R9)eO(CR8R9)f(4-10)-membered heterocyclyl, (CR8R9)fS(O)d(CR8R9)e(C6-C10)aryl, and —(CR8R9)fS(O)d(CR8R9)e(4-10)-membered heterocyclyl;wherein R6 and R7 are linked to each other as a piperidinone ring, optionally substituted with one or more halo, (C1-C6)alkyl, (C3-C10)cycloalkyl, or (C6-C10)aryl;each of R8, R9 and R10 are independently selected from the group consisting of hydrogen, (C1-C6)alkyl, —(CR11R12)e(3-10)-membered cycloalkyl, —(CR11R12)g(C6-C10)aryl, and —(CR11R12)g(4-10)-membered heterocyclyl;any carbon atoms of the (C1-C6)alkyl, the (3-10)-membered cycloalkyl, the (C6-C10)aryl and the (4-10)-membered heterocyclyl of the foregoing R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R15, and R16 are independently optionally substituted with 1 to 3 R14 substituents each independently selected from the group consisting of halo, cyano, nitro, —CF3, —CHF2, —CH2F, trifluoromethoxy, azido, hydroxyl, —O—R15, (C1-C6)alkoxy, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, —(C═O)—R11, —(C═O)—R15, —(C═O)—O—R11, —(C═O)—O—R15, —O—(C═O)—R11, —O—(C═O)—R15, —NR11(C═O)—R13, —(C═O)—NR11R12, —(C═O)—NR11R15, —NR11R12, —NR11R15, —NR11OR12, —NR11OR15, —S(O)cNR11R12, —S(O)cNR11R15, —S(O)d(C1-C6)alkyl, —S(O)dR15, —O—SO2—R11, —O—SO2—R15, —NR11—S(O)c, —NR15—S(O)c, —(CR11R12)e(3-10)-membered cycloalkyl, —(CR11R12)e(C6-C10)aryl, —(CR11R12)e(4-10)-membered heterocyclyl, —(CR11R12)f(C═O)(CR11R12)e(C6-C10)aryl, —(CR11R12)f(C═O)(CR11R12)e(4-10)-membered heterocyclyl, —(CR11R12)eO(CR11R12)f(C6-C10)aryl, —(CR11R12)eO(CR11R12)f(4-10)-membered heterocyclyl, —(CR11R12)fS(O)d(CR11R12)e(C6-C10)aryl, and —(CR11R12)fS(O)d(CR11R12)e(4-10)-membered heterocyclyl;any carbon atoms of the (C1-C6)alkyl, the (3-10)-membered cycloalkyl, the (C6-C10)aryl and the (4-10)-membered heterocyclyl of the foregoing R14 are independently optionally substituted with 1 to 3 R16 substituents each independently selected from the group consisting of halo, cyano, nitro, —CF3, —CHF2, —CH2F, trifluoromethoxy, azido, (CH2)eOH, (C1-C6)alkoxy, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, —(C═O)—R11, —(C═O)—R15, —(C═O)—O—R11, —(C═O)—O—R15, —O—(C═O)—R11, —O—(C═O)—R15, —NR11(C═O)—R13, —(C═O)—NR11R12, —NR11R12, and —NR11R15; any nitrogen atoms of the (4-10)-membered heterocyclyl of the foregoing R1, R2, R3, R4, R8, R6, R7, R8, R9, R10, R14, and R15 are independently optionally substituted with (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, —(C═O)—R11, —(C═O)—O—R11, —(C═O)—NR11R12, —(CR11R12)e(3-10)-membered cycloalkyl, —(CR11R12)e(C6-C10)aryl, —(CR11R12)e(4-10)-membered heterocyclyl, —(CR11R12)f(C═O)(CR11R12)e(C6-C10)aryl, or —(CR11R12)f(C═O)(CR11R12)e(4-10)-membered heterocyclyl;each R11, R12, and R13 are independently hydrogen or (C1-C6)alkyl;R15 is —(CR11R12)e(3-10)-membered cycloalkyl, —(CR11R12)e(C6-C10)aryl, or —(CR11R12)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; ande, f, and g are each independently 0, 1, 2, 3, 4, or 5. 2. The compound of claim 1, wherein each of R1 and R2 is hydrogen or halo. 3. The compound of claim 1, wherein each of R3 and R5 is independently selected from the group consisting of hydrogen or methyl. 4. The compound of claim 1, wherein R4 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 R1 and R2 is fluoro;each of R3 and R5 is independently selected from the group consisting of hydrogen, cyano, —CF3, —CHF2, —CH2F, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, —(C═O)—R8, —(C═O)—O—R8, —(C═O)—NR8R9, —S(O)cNR8R9, —S(O)d(C1-C8)alkyl, —(CR8R9)d(3-10)-membered cycloalkyl, —(CR8R9)e(C6-C10)aryl, —(CR8R9)e(4-10)-membered heterocyclyl, —(CR8R9)f(C═O)(CR8R9)e(C6-C10)aryl, —(CR8R9)f(C═O)(CR8R9)e(4-10)-membered heterocyclyl, —(CR8R9)eO(CR8R9)f(C6-C10)aryl, —(CR8R9)eO(CR8R9)f(4-10)-membered heterocyclyl, —(CR8R9)fS(O)d(CR8R9)e(C6-C10)aryl, and —(CR8R9)fS(O)d(CR8R9)e(4-10)-membered heterocyclyl;wherein each of the R3 groups are optionally linked to each other as a 4-12 membered mono- or bicyclic ring;wherein each of the R5 groups are optionally linked to each other as a 4-12 membered mono- or bicyclic ring;R4 is selected from the group consisting of hydrogen, —CF3, —CHF2, —CH2F, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, —(C═O)—R8, —(C═O)—O—R8, —(C═O)—NR8R9, —(CR8R9)d(3-10)-membered cycloalkyl, —(CR8R9)e(C6-C10)aryl, —(CR8R9)e(4-10)-membered heterocyclyl, —(CR8R9)f(C═O)(CR8R9)e(C6-C10)aryl, —(CR8R9)f(C═O)(CR8R9)e(4-10)-membered heterocyclyl, —(CR8R9)eO(CR8R9)f(C6-C10)aryl, —(CR8R9)eO(CR8R9)f(4-10)-membered heterocyclyl, (CR8R9)fS(O)d(CR8R9)e(C6-C10)aryl, and —(CR8R9)fS(O)d(CR8R9)e(4-10)-membered heterocyclyl;a wherein R6 and R7 are linked to each other as saturated pyrimidinone ring, optionally substituted with one or more halo, (C1-C6)alkyl, (C3-C10)cycloalkyl, or (C6-C10)aryl;each of R8, R9 and R10 are independently selected from the group consisting of hydrogen, (C1-C6)alkyl, —(CR11R12)e(3-10)-membered cycloalkyl, —(CR11R12)g(C6-C10)aryl, and —(CR11R12)g(4-10)-membered heterocyclyl;any carbon atoms of the (C1-C6)alkyl, the (3-10)-membered cycloalkyl, the (C6-C10)aryl and the (4-10)-membered heterocyclyl of the foregoing R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R15, and R16 are independently optionally substituted with 1 to 3 R14 substituents each independently selected from the group consisting of halo, cyano, nitro, —CF3, —CHF2, —CH2F, trifluoromethoxy, azido, hydroxyl, —O—R15, (C1-C6)alkoxy, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, —(C═O)—R11, —(C═O)—R15, —(C═O)—O—R11, —(C═O)—O—R15, —O—(C═O)—R11, —O—(C═O)—R15, —NR11(C═O)—R13, —(C═O)—NR11R12, —(C═O)—NR11R15, —NR11R12, —NR11R15, —NR11OR12, —NR11OR15, —S(O)cNR11R12, —S(O)cNR11R15, —S(O)d(C1-C6)alkyl, —S(O)dR15, —O—SO2—R11, —O—SO2—R15, —NR11—S(O)c, —NR15—S(O)c, —(CR11R12)e(3-10)-membered cycloalkyl, —(CR11R12)e(C6-C10)aryl, —(CR11R12)e(4-10)-membered heterocyclyl, —(CR11R12)f(C═O)(CR11R12)e(C6-C10)aryl, —(CR11R12)f(C═O)(CR11R12)e(4-10)-membered heterocyclyl, —(CR11R12)eO(CR11R12)f(C6-C10)aryl, —(CR11R12)eO(CR11R12)f(4-10)-membered heterocyclyl, —(CR11R12)fS(O)d(CR11R12)e(C6-C10)aryl, and —(CR11R12)fS(O)d(CR11R12)e(4-10)-membered heterocyclyl;any carbon atoms of the (C1-C6)alkyl, the (3-10)-membered cycloalkyl, the (C6-C10)aryl and the (4-10)-membered heterocyclyl of the foregoing R14 are independently optionally substituted with 1 to 3 R16 substituents each independently selected from the group consisting of halo, cyano, nitro, —CF3, —CHF2, —CH2F, trifluoromethoxy, azido, (CH2)eOH, (C1-C6)alkoxy, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, —(C═O)—R11, —(C═O)—R15, —(C═O)—O—R11, —(C═O)—O—R15, —O—(C═O)—R11, —O—(C═O)—R15, —NR11(C═O)—R13, —(C═O)—NR11R12, —NR11R12, and —NR11R15;any nitrogen atoms of the (4-10)-membered heterocyclyl of the foregoing R1, R2, R3, R4, R8, R6, R7, R8, R9, R10, R14, and R15 are independently optionally substituted with (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, —(C═O)—R11, —(C═O)—O—R11, —(C═O)—NR11R12, —(CR11R12)e(3-10)-membered cycloalkyl, —(CR11R12)e(C6-C10)aryl, —(CR11R12)e(4-10)-membered heterocyclyl, —(CR11R12)f(C═O)(CR11R12)e(C6-C10)aryl, or —(CR11R12)f(C═O)(CR11R12)e(4-10)-membered heterocyclyl;each R11, R12, and R13 are independently hydrogen or (C1-C6)alkyl;R15 is —(CR11R12)e(3-10)-membered cycloalkyl, —(CR11R12)e(C6-C10)aryl, or —(CR11R12)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; ande, f, and g are each independently 0, 1, 2, 3, 4, or 5. 7. The compound of claim 6, wherein each of R3 and R5 is independently selected from the group consisting of hydrogen and methyl. 8. The compound of claim 6, wherein R4 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); and1-(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); and1-(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.
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