NOVEL ADAMANTANE DERIVATIVES AS INHIBITORS OF FOCAL ADHESION KINASE

20230049557

17/782117

December 02, 2020

The present invention provides novel adamantane derivatives as inhibitors of a focal adhesion kinase, pharmaceutically acceptable salts thereof, stereoisomers thereof, hydrates or solvates thereof, and a pharmaceutical composition comprising same.

1. Adamantane derivatives represented by formula 1 below, pharmaceutically acceptable salts thereof, stereoisomers thereof, hydrates or solvates thereof: [chemical expression included] wherein in above formula 1, L1 and L2 are each independently a single bond, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene, —N(Ra)—, —C(═O)—N(Ra)-, —N(Ra)—C(═O)—, —C(═O)—, —O—, —C(═O)—O—, —N(Ra)—C(═O)—O—, —N(Ra)—S(═O)—, —N(Ra)—S(═O)2—, —S(═O)(═N-Ra)-, or —S—; R1 and R2 are each independently C1-10 heterocycloalkylene, C3-10 cycloalkylene, C5-16 arylene or C4-10 heteroarylene; R3 is H, C1-10 alkyl, C2-10 alkenyl, —O—Ra, ═O, —NH—Ra, —NH(C═O)-Ra or C1-10 heterocycloalkyl; R4 is —O—Ra; R5 and R6 are each independently H or C1-10 alkyl; R7 is —CF3 or a halogen atom; Ra is H, —CF3 or C1-10 alkyl; and m, n, p and q are each independently 0 or 1.

2. The adamantane derivatives, pharmaceutically acceptable salts thereof, stereoisomers thereof, hydrates or solvates thereof according to claim 1: wherein in above formula 1, R1 and R2 are each independently [chemical expression included] R3 is H, C1-10 alkyl, C2-10 alkenyl, —O—Ra, ═O, —NH—Ra, —NH(C═O)-Ra or [chemical expression included] W1, W2 and W3 are each independently CH or N; W4 is CH2, NH or O; Ra is H, —CF3 or C1-10 alkyl; and a, b, c and d are each independently 1, 2 or 3.

3. The adamantane derivatives, pharmaceutically acceptable salts thereof, stereoisomers thereof, hydrates or solvates thereof according to claim 1: wherein in above formula 1, R1 and R2 are each independently [chemical expression included] R3 is H, C1-10 alkyl, C2-10 alkenyl, —O—Ra, ═O, —NH—Ra, —NH(C═O)-Ra or [chemical expression included] and Ra is H, —CF3 or C1-10 alkyl.

4. The adamantane derivatives, pharmaceutically acceptable salts thereof, stereoisomers thereof, hydrates or solvates thereof according to claim 1, wherein the compound represented by above formula 1 is a compound represented by formula 2 below: [chemical expression included] wherein in above formula 2, L1 is —N(Ra)—, —C(═O)—N(Ra)- or —O—; L2 is —N(Ra)—, —C(═O)—N(Ra)-, —N(Ra)—C(═O)—, —C(═O)— or —C(═O)—O—; R1 and R2 are each independently [chemical expression included] R3 is H, C1-10 alkyl, C2-10 alkenyl, —O—Ra, ═O, —NH—Ra, —NH(C═O)-Ra or morphoridinyl; R6 is H or C1-10 alkyl; R7 is —CF3 or Cl; Ra is H, —CF3 or C1-10 alkyl; and m, n, p and q are each independently 0 or 1.

5. The adamantane derivatives, pharmaceutically acceptable salts thereof, stereoisomers thereof, hydrates or solvates thereof according to claim 1, wherein the compound represented by above formula 1 is any one selected from the group consisting of compounds shown in a following table: [table included]

6. A pharmaceutical composition comprising the adamantane derivatives, pharmaceutically acceptable salts thereof, stereoisomers thereof, hydrates or solvates thereof according to one of claims 1 to 5 as active ingredients.

7. The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition is for preventing or treating FAK activity-associated diseases.

8. The pharmaceutical composition according to claim 7, wherein the FAK activity-associated disease is at least one selected from the group consisting of solid cancers comprising gastric cancer, lung cancer, liver cancer, colorectal cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, uterine cancer, cervical cancer, ovarian cancer, head and neck cancer, thyroid cancer, parathyroid cancer, kidney cancer, prostate cancer, urethral cancer, bladder cancer, mesothelioma, etc., and blood cancers comprising leukemia, multiple myeloma and lymphoma.

9. The pharmaceutical composition according to claim 6, wherein the adamantane derivatives, pharmaceutically acceptable salts thereof, stereoisomers thereof, hydrates or solvates thereof inhibit at least any one kinase of FAK and Pyk2(FAK2).

10. A method for preventing or treating FAK activity-associated diseases, comprising administering a therapeutically effective amount of the adamantane derivatives, pharmaceutically acceptable salts thereof, stereoisomers thereof, hydrates or solvates thereof according to one of claims 1 to 5 into an individual.

11. A use of the adamantane derivatives, pharmaceutically acceptable salts thereof, stereoisomers thereof, hydrates or solvates thereof according to one of claims 1 to 5 for preventing or treating FAK activity-associated diseases.

12. A use of the adamantane derivatives, pharmaceutically acceptable salts thereof, stereoisomers thereof, hydrates or solvates thereof according to one of claims 1 to 5 for manufacture of a medicament for preventing or treating FAK activity-associated diseases.

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