BENZENESULFONYL-CHROMANE, THIOCHROMANE, TETRAHYDRONAPHTHALENE AND RELATED GAMMA SECRETASE INHIBITORS

BACKGROUND

WO 00/50391, published Aug. 13, 2000, discloses compounds having a sulfonamide moiety that are useful for the treatment and prevention of Alzheimer's Disease and other diseases relating to the deposition of amyloid protein.

McCombie et al., Tetrahedron Letters, Vol. 34, No. 50, pp. 8033-8036 (1993) describe methods of preparing chromans and thiochromans. However, the chromans and thiochromans described therein are quite different from the compounds of the present invention.

In view of the present interest in the treatment or prevention of neurodegenerative diseases, such as Alzheimer's Disease, a welcome contribution to the art would be compounds for use in such treatment or prevention. This invention provides such a contribution.

SUMMARY OF THE INVENTION

This invention provides compounds that are inhibitors (e.g., antagonists) of gamma-secretase (also termed “γ-secretase”) and have the Formula (1.0):

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or a pharmaceutically acceptable salt, solvate, or ester thereof, wherein L¹, n, X, Ar, Y, Z, Q, and Q¹are as defined below.

This invention also provides the compounds of formula (1.0) in pure and isolated form.

This invention also provides the compounds of formula (1.0) in pure form.

This invention also provides the compounds of formula (1.0) in isolated form.

This invention also provides compounds of formula selected from the group consisting of: Compounds 4a, 4b, 5a, 5a1, 5b, 5b2, 5b3, 5b4, 5b5, 5c, 5d, 5e, 6a, 6b, 7a, 7b, 7d, 7e, 7f, 7g, 8a, 8a1, 8b, 8b1, 8c, 8c1, 8d, 8d1, 8d2, 8e, 8e1, 8f, 8g, 8h, 10b, 11b1, 11b2, 11b3, 12b1, 12b2, 12b3, 13b1, 13b2, 13b3, 14b1, 14b2, 14b3, 16b, 17b, 20b, 28, 29, 30, 31, 33, 36, 36a, 36b, 36c, 36d, 36e, 36f, 37, 38, 40, 41, 42, 42a, 42b, 43, 44, 45, 46, 47, 48, 49, 50, and 51.

This invention also provides a compound of formula (1.0) selected from the group consisting of the compounds of formulas: 1.1, 2.1, 1.1A, 2.1A, 1.2, 1.2A, 1.3, 2.3, 1.3A, 2.3A, 1.4, 1.4A, 1.5, 2.5, 1.5A, 2.5A, 1.6, 1.6A, 1.7, 2.7, 1.7A, 2.7A, 1.8, 2.8, 1.8A, 2.8A, 1.9, 1.9A, 1.9^A1, 1.9^A2, 1.10, 1.10^A1, 1.10^A2, 2.10, 2.10^A1, 2.10^A2, 3.10, 1.10A, 2.10A, 3.10A, 3.10^A1, 3.10^A2, 1.11, 1.11^A1, 1.11^A2, 2.11, 2.11^A1, 2.11^A2, 3.11, 3.11^A1, 3.11^A2, 1.11A, 2.11A, 3.11A, 1.12 to 1.18, 2.13, 3.13, 2.14, 3.14, 2.16, 3.16, 2.17, 3.17, 1.18A, 1.18B, 1.18C, 1.19, 1.19A, 1.19B, 1.19C, 1.20, 1.20A, 1.20B, 1.20C, 1.21, 1.21A, 1.21B, 1.21C, 1.22, 1.22A, 1.22B, 1.22C, 1.23, 1.23A, 1.23B, 1.23C, 1.24, 1.24A, 1.24B, 1.24C, 1.25, 1.25A, 1.25B, 1.25C, 1.26, 1.26a, 1.27, 1.27A, 1.28, 1.28A, 1.29, 1.29A, 1.30, 1.30A, 1.31, 1.31A, 1.32, 1.32A, 1.33, 1.33A, 1.34, 1.34A, 1.35, 1.35A, 1.35C, 1.35D, 1.35E, 1.36, 1.36A, 1.36C, 1.36D, 1.36E, 1.37, 1.37A, 1.37C, 1.37D, 1.37E, 1.38, 1.38A, 1.38C, 1.38D, 1.38E, 1.39, 1.39A, 1.39C, 1.39D, 1.39E, 1.40, 1.40A, 1.40C, 1.41, 1.41A, 1.41C, 1.42, 1.42A, 1.42C, 1.43, 1.43A, 1.43C, 1.44, 1.44A, 1.44C, 1.45, 1.45A, and 1.45C, and wherein all substituents are as defined for formula (1.0).

This invention also provides a pharmaceutically acceptable salt of the compound of formula (1.0) selected from the group consisting of the pharmaceutically acceptable salts of the compounds of formulas: 1.1, 2.1, 1.1A, 2.1A, 1.2, 1.2A, 1.3, 2.3, 1.3A, 2.3A, 1.4, 1.4A, 1.5, 2.5, 1.5A, 2.5A, 1.6, 1.6A, 1.7, 2.7, 1.7A, 2.7A, 1.8, 2.8, 1.8A, 2.8A, 1.9, 1.9A, 1.9^A1, 1.9^A2, 1.10, 1.10^A1, 1.10^A2, 2.10, 2.10^A1, 2.10^A2, 3.10, 1.10A, 2.10A, 3.10A, 3.10^A1, 3.10^A2, 1.11, 1.11^A1, 1.11^A2, 2.11, 2.11^A1, 2.11^A2, 3.11, 3.11^A1, 3.11^A2, 1.11A, 2.11A, 3.11A, 1.12 to 1.18, 2.13, 3.13, 2.14, 3.14, 2.16, 3.16, 2.17, 3.17, 1.18A, 1.18B, 1.18C, 1.19, 1.19A, 1.19B, 1.19C, 1.20, 1.20A, 1.20B, 1.20C, 1.21, 1.21A, 1.21B, 1.21C, 1.22, 1.22A, 1.22B, 1.22C, 1.23, 1.23A, 1.23B, 1.23C, 1.24, 1.24A, 1.24B, 1.24C, 1.25, 1.25A, 1.25B, 1.25C, 1.26, 1.26a, 1.27, 1.27A, 1.28, 1.28A, 1.29, 1.29A, 1.30, 1.30A, 1.31, 1.31A, 1.32, 1.32A, 1.33, 1.33A, 1.34, 1.34A, 1.35, 1.35A, 1.35C, 1.35D, 1.35E, 1.36, 1.36A, 1.36C, 1.36D, 1.36E, 1.37, 1.37A, 1.37C, 1.37D, 1.37E, 1.38, 1.38A, 1.38C, 1.38D, 1.38E, 1.39, 1.39A, 1.39C, 1.39D, 1.39E, 1.40, 1.40A, 1.40C, 1.41, 1.41A, 1.41C, 1.42, 1.42A, 1.42C, 1.43, 1.43A, 1.43C, 1.44, 1.44A, 1.44C, 1.45, 1.45A, and 1.45C, and wherein all substituents are as defined for formula (1.0).

This invention also provides a solvate of the compound of formula (1.0) selected from the group consisting of the solvates of the compounds of formulas: 1.1, 2.1, 1.1A, 2.1A, 1.2, 1.2A, 1.3, 2.3, 1.3A, 2.3A, 1.4, 1.4A, 1.5, 2.5, 1.5A, 2.5A, 1.6, 1.6A, 1.7, 2.7, 1.7A, 2.7A, 1.8, 2.8, 1.8A, 2.8A, 1.9, 1.9A, 1.9^A1, 1.9^A2, 1.10, 1.10^A1, 1.10^A2, 2.10, 2.10^A1, 2.10^A2, 3.10, 1.10A, 2.10A, 3.10A, 3.10^A1, 3.10^A2, 1.11, 1.11^A1, 1.11^A2, 2.11, 2.11^A1, 2.11^A2, 3.11, 3.11^A1, 3.11^A2, 1.11A, 2.11A, 3.11A, 1.12 to 1.18, 2.13, 3.13, 2.14, 3.14, 2.16, 3.16, 2.17, 3.17, 1.18A, 1.18B, 1.18C, 1.19, 1.19A, 1.19B, 1.19C, 1.20, 1.20A, 1.20B, 1.20C, 1.21, 1.21A, 1.21B, 1.21C, 1.22, 1.22A, 1.22B, 1.22C, 1.23, 1.23A, 1.23B, 1.23C, 1.24, 1.24A, 1.24B, 1.24C, 1.25, 1.25A, 1.25B, 1.25C, 1.26, 1.26a, 1.27, 1.27A, 1.28, 1.28A, 1.29, 1.29A, 1.30, 1.30A, 1.31, 1.31A, 1.32, 1.32A, 1.33, 1.33A, 1.34, 1.34A, 1.35, 1.35A, 1.35C, 1.35D, 1.35E, 1.36, 1.36A, 1.36C, 1.36D, 1.36E, 1.37, 1.37A, 1.37C, 1.37D, 1.37E, 1.38, 1.38A, 1.38C, 1.38D, 1.38E, 1.39, 1.39A, 1.39C, 1.39D, 1.39E, 1.40, 1.40A, 1.40C, 1.41, 1.41A, 1.41C, 1.42, 1.42A, 1.42C, 1.43, 1.43A, 1.43C, 1.44, 1.44A, 1.44C, 1.45, 1.45A, and 1.45C, and wherein all substituents are as defined for formula (1.0).

This invention also provides a pharmaceutically acceptable ester of the compound of formula (1.0) selected from the group consisting of the pharmaceutically acceptable esters of the compounds of formulas: 1.1, 2.1, 1.1A, 2.1A, 1.2, 1.2A, 1.3, 2.3, 1.3A, 2.3A, 1.4, 1.4A, 1.5, 2.5, 1.5A, 2.5A, 1.6, 1.6A, 1.7, 2.7, 1.7A, 2.7A, 1.8, 2.8, 1.8A, 2.8A, 1.9, 1.9A, 1.9^A1, 1.9^A2, 1.10, 1.10^A1, 1.10^A2, 2.10, 2.10^A1, 2.10^A2, 3.10, 1.10A, 2.10A, 3.10A, 3.10^A1, 3.10^A2, 1.11, 1.11^A1, 1.11^A2, 2.11, 2.11^A1, 2.11^A2, 3.11, 3.11^A1, 3.11^A2, 1.11A, 2.11A, 3.11A, 1.12 to 1.18, 2.13, 3.13, 2.14, 3.14, 2.16, 3.16, 2.17, 3.17, 1.18A, 1.18B, 1.18C, 1.19, 1.19A, 1.19B, 1.19C, 1.20, 1.20A, 1.20B, 1.20C, 1.21, 1.21A, 1.21B, 1.21C, 1.22, 1.22A, 1.22B, 1.22C, 1.23, 1.23A, 1.23B, 1.23C, 1.24, 1.24A, 1.24B, 1.24C, 1.25, 1.25A, 1.25B, 1.25C, 1.26, 1.26a, 1.27, 1.27A, 1.28, 1.28A, 1.29, 1.29A, 1.30, 1.30A, 1.31, 1.31A, 1.32, 1.32A, 1.33, 1.33A, 1.34, 1.34A, 1.35, 1.35A, 1.35C, 1.35D, 1.35E, 1.36, 1.36A, 1.36C, 1.36D, 1.36E, 1.37, 1.37A, 1.37C, 1.37D, 1.37E, 1.38, 1.38A, 1.38C, 1.38D, 1.38E, 1.39, 1.39A, 1.39C, 1.39D, 1.39E, 1.40, 1.40A, 1.40C, 1.41, 1.41A, 1.41C, 1.42, 1.42A, 1.42C, 1.43, 1.43A, 1.43C, 1.44, 1.44A, 1.44C, 1.45, 1.45A, and 1.45C, and wherein all substituents are as defined for formula (1.0).

This invention also provides a pharmaceutical composition comprising an effective amount of one or more (e.g., 1, 2 or 3, or 1 or 2, or 1) compounds of Formula (1.0) and at least one pharmaceutically acceptable carrier.

This invention also provides a pharmaceutical composition comprising an effective amount a compound of Formula (1.0) and at least one pharmaceutically acceptable carrier.

This invention also provides a pharmaceutically acceptable salt of a compound of formula (1.0).

This invention also provides a solvate of a compound of formula (1.0).

This invention also provides a pharmaceutically acceptable ester of a compound of formula (1.0).

This invention also provides a method for inhibiting gamma-secretase in a patient in need of such treatment, said method comprising administering to said patient an effective amount (i.e., a therapeutically effective amount) of one or more (e.g., 1, 2 or 3, or 1 or 2, or 1) compounds of formula (1.0).

This invention also provides a method of treating one or more neurodegenerative diseases in a patient in need of such treatment, said method comprising administering to said patient an effective amount (i.e., a therapeutically effective amount) of one or more (e.g., 1, 2 or 3, or 1 or 2, or 1) compounds of formula (1.0).

This invention also provides a method of inhibiting the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain) in a patient in need of such treatment, said method comprising administering to said patient an effective amount (i.e., a therapeutically effective amount) of one or more (e.g., 1, 2 or 3, or 1 or 2, or 1) compounds of formula (1.0).

This invention also provides a method of treating Alzheimer's disease in a patient in need of such treatment, said method comprising administering to said patient an effective amount (i.e., a therapeutically effective amount) of one or more (e.g., 1, 2 or 3, or 1 or 2, or 1) compounds of formula (1.0).

This invention also provides combination therapies for (1) inhibiting gamma-secretase, or (2) treating one or more neurodegenerative diseases, or (3) inhibiting the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain), or (4) treating Alzheimer's disease. The combination therapies are directed to methods comprising the administration of one or more (e.g. one) compounds of formula (1.0) and the administration of one or more (e.g., one) other pharmaceutical active ingredients (e.g., drugs). The compounds of formula (1.0) and the other drugs can be administered separately (i.e., each is in its own separate dosage form), or the compounds of formula (1.0) can be combined with the other drugs in the same dosage form.

This invention provides any of the above methods wherein the compound of formula (1.0) is a pharmaceutically acceptable salt of the compound of formula (1.0).

This invention provides any of the above methods wherein the compound of formula (1.0) is a solvate of the compound of formula (1.0).

This invention provides any of the above methods wherein the compound of formula (1.0) is a pharmaceutically acceptable ester of the compound of formula (1.0).

This invention also provides any of the above methods wherein the compound of formula (1.0) is selected from the group consisting of the compounds of formulas: 1.1, 2.1, 1.1A, 2.1A, 1.2, 1.2A, 1.3, 2.3, 1.3A, 2.3A, 1.4, 1.4A, 1.5, 2.5, 1.5A, 2.5A, 1.6, 1.6A, 1.7, 2.7, 1.7A, 2.7A, 1.8, 2.8, 1.8A, 2.8A, 1.9, 1.9A, 1.9^A1, 1.9^A2, 1.10, 1.10^A1, 1.10^A2, 2.10, 2.10^A1, 2.10^A2, 3.10, 1.10A, 2.10A, 3.10A, 3.10^A1, 3.10^A2, 1.11, 1.11^A1, 1.11^A2, 2.11, 2.11^A1, 2.11^A2, 3.11, 3.11^A1, 3.11^A2, 1.11A, 2.11A, 3.11A, 1.12 to 1.18, 2.13, 3.13, 2.14, 3.14, 2.16, 3.16, 2.17, 3.17, 1.18A, 1.18B, 1.18C, 1.19, 1.19A, 1.19B, 1.19C, 1.20, 1.20A, 1.20B, 1.20C, 1.21, 1.21A, 1.21B, 1.21C, 1.22, 1.22A, 1.22B, 1.22C, 1.23, 1.23A, 1.23B, 1.23C, 1.24, 1.24A, 1.24B, 1.24C, 1.25, 1.25A, 1.25B, 1.25C, 1.26, 1.26a, 1.27, 1.27A, 1.28, 1.28A, 1.29, 1.29A, 1.30, 1.30A, 1.31, 1.31A, 1.32, 1.32A, 1.33, 1.33A, 1.34, 1.34A, 1.35, 1.35A, 1.35C, 1.35D, 1.35E, 1.36, 1.36A, 1.36C, 1.36D, 1.36E, 1.37, 1.37A, 1.37C, 1.37D, 1.37E, 1.38, 1.38A, 1.38C, 1.38D, 1.38E, 1.39, 1.39A, 1.39C, 1.39D, 1.39E, 1.40, 1.40A, 1.40C, 1.41, 1.41A, 1.41C, 1.42, 1.42A, 1.42C, 1.43, 1.43A, 1.43C, 1.44, 1.44A, 1.44C, 1.45, 1.45A, and 1.45C, and wherein all substituents are as defined for formula (1.0).

This invention also provides any one of the above methods wherein the compound of formula (1.0) is selected from the group consisting of: Compounds 4a, 4b, 5a, 5b, 5b2, 5b3, 5b4, 5b5, 5c, 6a, 6b, 7a, 7b, 7d, 7e, 7f, 7g, 8a, 8a1, 8b, 8b1, 8c1, 8d, 10b, 11b1, 11b2, 11b3, 12b1, 12b2, 12b3, 13b1, 13b2, 13b3, 14b1, 14b2, 14b3, 16b, 17b, 20b, 28, 29, 30, 31, 33, 36, 36a, 36b, 36c, 36d, 36e, 36f, 37, 38, 40, 41, 42, 42b, 43, 44, 45, 46, 47, 48, 49, 50, and 51.

DETAILED DESCRIPTION OF THE INVENTION

This invention provides compounds that are inhibitors (e.g., antagonists) of gamma-secretase (also termed “γ-secretase”) and have the Formula (1.0):

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or a pharmaceutically acceptable salt, solvate, or ester thereof, wherein:

L¹, n, X, Y, Z, Q, Q¹and Ar are each independently selected;

X is selected from the group consisting of —C(R¹)₂—, —O—, —S—, —S(O₂)—, —NR¹—, and —N(C(O)R¹)—;

The dotted line ( custom-character ) represents an optional bond between Y and Z;

Y is selected from the group consisting of N and CH and C, and when Y is N the optional bond is absent, when Y is CH the optional bond is absent, and when Y is C the optional bond is present;

Z is selected from the group consisting of: CH, C, and N, provided that both Y and Z are not N (i.e., only one of Y and Z can be N), and when Z is N the optional bond is absent, when Z is CH the optional bond is absent, and when Z is C the optional bond is present (those skilled in the art will appreciate that when Y is N then Z is CH, and when Z is N then Y is CH);

Q represents a 5 to 8 membered ring fused to Rings A¹and Q¹, wherein Y and Z are as defined above and the remaining Q ring members are —CH₂— groups, and in one example Q is a 5 to 7 membered ring, and in another example Q is a 5 to 6 membered ring, and in another example Q is a 5 membered ring, and in another example Q is a 6 membered ring, and preferably Q is a 6 membered ring;

Q¹is a 5 to 7 membered ring (including Y and Z) fused to Ring Q, said Q¹ring comprising at least one heteroatom (e.g., 1 to 3, or 1 to 2, or 1) selected from the group consisting of N, O, S, S(O), and S(O)₂; and said Q¹ring being substituted with 1 to 3 substituents independently selected from the group consisting of: R³substitutents (wherein each R³can be bound to any substitutable atom in the Q¹ring, such as any substitutable carbon atom and/or any substitutable nitrogen atom, and (a) in one example at least one carbon atom of said Q¹ring is substituted with one R³group, and (b) in another example one carbon atom of said Q¹ring is substituted with one R³group, and (c) in another example one carbon atom of said Q¹ring is substituted with two independently selected R³groups and the remaining carbon atoms of said Q¹ring are unsubstituted, and (d) in another example one carbon atom of said Q¹ring is substituted with two independently selected R³groups, and one or more of the remaining carbon atoms are substituted with one R³group wherein each R³group is independently selected when more than one remaining carbon atom is substituted with an R³group, and (e) in other examples the Q¹ring is as described in any one of the examples described in (a) to (d) wherein said Q¹ring comprises at least one nitrogen atom that is substituted with an R³group, and wherein each R³group is independently selected for each nitrogen atom when more than one nitrogen is substituted with an R³group);

Each R¹is independently selected from the group consisting of H and alkyl;

R²is selected from the group consisting of: H, and alkyl (e.g., C₁to C₆alkyl, such as, for example, methyl, ethyl and isopropyl);

Each R³substitutent is independently selected from the group consisting of:

- (1) alkyl (e.g., C₁to C₆alkyl, such as, for example, methyl, ethyl, and isopropyl),
- (2) alkoxyalkyl- (such as, for example, —(C₁to C₆)alkoxy-(C₁to C₆)alkyl-, such as, for example, —(C₁to C₄)alkoxy-(C₁to C₄)alkyl-, such as, for example, —(C₁to C₂)alkoxy-(C₁to C₂)alkyl-, such as, for example, —CH₂OCH₃),
- (3) hydroxyalkyl (such as, for example, hydroxy(C₁to C₆)alkyl-, such as, for example, hydroxy(C₁to C₄)alkyl-, such as, for example, hydroxy(C₁to C₂)alkyl-, such as, for example, —CH₂CH₂OH, and in another example, —CH₂CH₂CH₂OH),
- (4) —OR²(e.g., —OH, —OCH₃, —OC₂H₅, and —OCH(CH₃)₂),
- (5) arylalkyl- (e.g., aryl(C₁to C₆)alkyl-, such as, for example, benzyl and —(CH₂)₃-phenyl),
- (6) ═O,
- (7) substituted arylalkyl- (e.g., substituted aryl(C₁to C₆)alkyl-, such as substituted benzyl) substituted with 1 to 3 substitutents each independently selected from the group consisting of: —OR²(e.g., p-methoxybenzyl),
- (8) alkenyl (e.g., C₂to C₆alkenyl, such as, for example, C₂to C₄alkenyl), and wherein examples of said alkenyl include —CH₂CH═CH₂and —CH₂CH═CHCH₃,
- (9) heterocycloalkylalkyl- (e.g., a (C₅to C₇)heterocycloalkyl-(C₁to C₆)alkyl-, such as a (C₅to C₇)heterocycloalkyl-(C₁to C₄)alkyl-, such as a (C₅to C₇)heterocycloalkyl-(C₁to C₂)alkyl-, such as for example, pyrrolidinyl-(C₁to C₂)alkyl-, such as for example, pyrrolidinyl-CH₂—CH₂-, and in another example, morphlinyl-(C₁to C₂)alkyl-, such as, for example, morpholinyl-CH₂—CH₂—),
- (10) -alkyl-C(O)OH (e.g., —(C₁to C₆)alkyl-C(O)OH, such as, for example, —(C₁to C₄)alkyl-C(O)OH, such as, for example, —(C₁to C₂)alkyl-C(O)OH, such as, for example, —CH₂CH₂—C(O)OH, and in another example —CH₂—C(O)OH),
- (11) -alkyl-NR⁵R⁶(e.g., —(C₁to C₆)alkyl-NR⁵R⁶, such as, for example, —(C₁to C₄)alkyl-NR⁵R⁶, such as, for example, —(C₁to C₂)alkyl NR⁵R⁶), wherein R⁵and R⁶are each independently selected from the group consisting of: H and alkyl (e.g., C₁to C₆alkyl, such as, for example, C₁to C₄alkyl, such as, for example, methyl, ethyl, and isopropyl), and wherein examples of said -alkyl-NR⁵R⁶group include, for example, —CH₂CH₂CH₂N(CH₃)₂,
- (12) -alkyl-C(O)NR⁵R⁶(e.g., —(C₁to C₆)alkyl-C(O)NR⁵R⁶, such as, for example, —(C₁to C₄)alkyl-C(O)NR⁵R⁶, such as, for example, —(C₁to C₂)alkyl-C(O) NR⁵R⁶, wherein R⁵and R⁶are as defined in (11) above, and wherein in one example said -alkyl-C(O)NR⁵R⁶group is —CH₂—C(O)NH₂,
- (13) arylalkenyl- (e.g., aryl(C₂to C₆)alkenyl-, such as, for example, aryl(C₂to C₄)alkenyl-, such as, for example, phenyl(C₂to C₆)alkenyl-, such as, for example, phenyl(C₂to C₄)alkenyl-, such as, for example, —CH₂CH═CH-phenyl),
- (14) -alkyl-C(O)OR⁷wherein R⁷is a C₁to C₆alkyl group (and in one example, R⁷is a C₁to C₄alkyl group, and in another example R⁷is a C₁to C₂alkyl group), and wherein in one example said -alkyl-C(O)OR⁷moiety is —(C₁to C₆)alkyl-C(O)O—(C₁to C₆)alkyl, and in another example said -alkyl-C(O)OR⁷moiety is —(C₁to C₄)alkyl-C(O)O—(C₁to C₄)alkyl, and in another example said -alkyl-C(O)OR⁷moiety is —(C₁to C₂)alkyl-C(O)O—(C₁to C₂)alkyl, and

(15) substituted arylalkenyl- (e.g., substituted aryl(C₂to C₆)alkenyl-, such as, for example, substituted aryl(C₂to C₄)alkenyl-, such as, for example, substituted phenyl(C₂to C₆)alkenyl-, such as, for example, substituted phenyl(C₂to C₄)alkenyl-, such as, for example, substituted —CH₂CH═CH-phenyl), wherein said substituted arylalkenyl- is substituted with 1 to 3 substitutents independently selected from the group consisting of: —OR⁵, —NR⁵R⁶, —CF₃, —CN, —C(O)₂R⁵, and —C(O)NR⁵R⁶, and wherein R⁵and R⁶are as defined in (11) above; or

two R³groups bound to the same carbon, taken together with the carbon to which they are bound, form a cycloalkyl ring (e.g., a C₅to C₇cycloalkyl ring, such as, for example, cyclopentyl) or form a cycloalkenyl ring (e.g., a C₅to C₇cycloalkenyl ring, such as, for example, cyclopentenyl);

Ar is selected from the group consisting of: (a) unsubstituted aryl, (b) aryl substituted with one or more L¹groups, (c) unsubstituted heteroaryl (e.g., pyridyl), and (d) substituted heteroaryl (e.g., substituted pyridyl) substituted with one or more L¹groups;

each L¹is independently selected from the group consisting of: halogen, alkyl (e.g., C₁-C₆alkyl), —CN, —CF₃, —O—(C₁-C₆)alkyl (e.g., —OCH₃), —O-(halo(C₁-C₆)alkyl) (e.g., —OCF₃), —C(O)—O—(C₁-C₆)alkyl (e.g., —C(O)OCH₃), -alkylene-OH (e.g., —CH₂OH), halo(C₁-C₆)alkyl (e.g., —CF₃), hydroxyalkoxy- (e.g., HOCH₂CH₂O—), and alkoxyalkoxy- (e.g., CH₃OCH₂CH₂O—); and

n is 0, 1, 2 or 3.

In one embodiment this invention provides compounds that are inhibitors (e.g., antagonists) of gamma-secretase (also termed “γ-secretase”) and have the Formula (1.0):

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or a pharmaceutically acceptable salt, solvate, or ester thereof, wherein:

X is selected from the group consisting of —C(R¹)₂—, —O—, —S—, —S(O₂)—, —NR¹—, and —N(C(O)R¹)—;

The dotted line ( custom-character ) represents an optional bond between Y and Z;

Y is selected from the group consisting of N and CH and C, and when Y is N the optional bond is absent, when Y is CH the optional bond is absent, and when Y is C the optional bond is present;

Z is selected from the group consisting of: CH, C, and N, provided that both Y and Z are not N (i.e., only one of Y and Z can be N), and when Y is N the optional bond is absent, when Z is CH the optional bond is absent, and when Z is C the optional bond is present (those skilled in the art will appreciate that when Y is N then Z is CH, and when Z is N then Y is CH);

Each R¹is independently selected from the group consisting of H and alkyl;

R²is selected from the group consisting of: H, and alkyl (e.g., C₁to C₆alkyl, such as, for example, methyl, ethyl and isopropyl);

Each R³substitutent is independently selected from the group consisting of: (1) alkyl (e.g., C₁to C₆alkyl, such as, for example, methyl and ethyl), (2) alkoxyalkyl-, (3) hydroxyalkyl, (4) —OR²(e.g., —OH, —OCH₃, —OC₂H₅, and —OCH(CH₃)₂), (5) arylalkyl- (e.g., aryl(C₁to C₆)alkyl-, such as benzyl), (6) ═O, and (7) substituted arylalkyl- (e.g., substituted aryl(C₁to C₆)alkyl-, such as substituted benzyl) substituted with 1 to 3 substitutents each independently selected from the group consisting of: —OR²(e.g., p-methoxybenzyl);

n is 0, 1, 2 or 3.

In one embodiment of this invention two R³groups bound to the same carbon atom are taken together with the carbon atom to which they are bound to form a cycloalkyl ring (e.g., a cyclopentyl ring).

In another embodiment of this invention two R³groups bound to the same carbon atom are taken together with the carbon atom to which they are bound to form a cycloalkenyl ring (e.g., a cyclopentenyl ring).

In another embodiment of this invention Q¹is a 6 membered ring comprising a —N—SO₂— moiety in the ring, and two R³groups bound to the carbon adjacent to the —SO₂— moiety are taken together with the carbon atom to which they are bound to form a cycloalkyl ring (e.g., a cyclopentyl ring).

In another embodiment of this invention Q is a 6 membered ring, Q¹is a 6 membered ring comprising a —N—SO₂— moiety in the ring, and two R³groups bound to the carbon adjacent to the —SO₂— moiety are taken together with the carbon atom to which they are bound to form a cycloalkyl ring (e.g., a cyclopentyl ring).

In another embodiment of this invention Y is CH, Z is CH, Q¹is a 6 membered ring comprising a —N—SO₂— moiety in the ring, and two R³groups bound to the carbon adjacent to the —SO₂— moiety are taken together with the carbon atom to which they are bound to form a cycloalkyl ring (e.g., a cyclopentyl ring).

In another embodiment of this invention Y is CH, Z is CH, Q is a 6 membered ring, Q¹is a 6 membered ring comprising a —N—SO₂— moiety in the ring, and two R³groups bound to the carbon adjacent to the —SO₂— moiety are taken together with the carbon atom to which they are bound to form a cycloalkyl ring (e.g., a cyclopentyl ring).

In one embodiment of this invention Y is CH, Z is CH, and Q¹is a 6 membered ring comprising a nitrogen atom and a —S(O)₂— group.

In another embodiment of this invention Y is CH, Z is CH, Q is a 6 membered ring, and Q¹is a 6 membered ring comprising a nitrogen atom and a —S(O)₂— group.

In one embodiment of this invention Y is CH, Z is CH, Q¹is a 6 membered ring comprising a nitrogen atom and a —S(O)₂— group, and said Q¹ring substituted with 1 to 3 substitutents as defined in formula 1.0.

In another embodiment of this invention Y is CH, Z is CH, Q is a 6 membered ring, Q¹is a 6 membered ring comprising a nitrogen atom and a —S(O)₂— group, and said Q¹ring substituted with 1 to 3 substitutents as defined in formula 1.0.

In another embodiment of this invention Y is CH, Z is CH, Q¹is a 5 membered ring comprising an oxygen atom.

In another embodiment of this invention Y is CH, Z is CH, Q is a 6 membered ring, and Q¹is a 5 membered ring comprising an oxygen atom.

In another embodiment of this invention Y is CH, Z is CH, Q¹is a 5 membered ring comprising an oxygen atom, and said Q¹ring substituted with 1 to 3 substitutents as defined in formula 1.0.

In another embodiment of this invention Y is CH, Z is CH, Q is a 6 membered ring, Q¹is a 5 membered ring comprising an oxygen atom, and said Q¹ring substituted with 1 to 3 substitutents as defined in formula 1.0.

In another embodiment of this invention Y is CH, Z is CH, and Q¹is a 5 membered ring comprising a nitrogen atom.

In another embodiment of this invention Y is CH, Z is CH, Q is a 6 membered ring, and Q¹is a 5 membered ring comprising a nitrogen atom.

In another embodiment of this invention Y is CH, Z is CH, Q¹is a 5 membered ring comprising a nitrogen atom, and said Q¹ring substituted with 1 to 3 substitutents as defined in formula 1.0.

In another embodiment of this invention Y is CH, Z is CH, Q is a 6 membered ring, Q¹is a 5 membered ring comprising a nitrogen atom, and said Q¹ring substituted with 1 to 3 substitutents as defined in formula 1.0.

In another embodiment of this invention Y is C, Z is C, the optional bond between Y and Z is present, and Q¹is a 5 membered ring comprising a nitrogen atom.

In another embodiment of this invention Y is C, Z is C, the optional bond between Y and Z is present, Q is a 6 membered ring, and Q¹is a 5 membered ring comprising a nitrogen atom.

In another embodiment of this invention Y is C, Z is C, the optional bond between Y and Z is present, Q¹is a 5 membered ring comprising a nitrogen atom, and said Q¹ring substituted with 1 to 3 substitutents as defined in formula 1.0.

In another embodiment of this invention Y is C, Z is C, the optional bond between Y and Z is present, Q is a 6 membered ring, Q¹is a 5 membered ring comprising a nitrogen atom, and said Q¹ring substituted with 1 to 3 substitutents as defined in formula 1.0.

In another embodiment of this invention Y is CH, Z is CH, and Q¹is a 6 membered ring comprising a nitrogen atom.

In another embodiment of this invention Y is CH, Z is CH, Q is a 6 membered ring, and Q¹is a 6 membered ring comprising a nitrogen atom.

In another embodiment of this invention Y is CH, Z is CH, Q¹is a 6 membered ring comprising a nitrogen atom, and said Q¹ring substituted with 1 to 3 substitutents as defined in formula 1.0.

In another embodiment of this invention Y is CH, Z is CH, Q is a 6 membered ring, Q¹is a 6 membered ring comprising a nitrogen atom, and said Q¹ring substituted with 1 to 3 substitutents as defined in formula 1.0.

In another embodiment of this invention Y is N, Z is CH, and Q¹is a 6 membered ring comprising a nitrogen atom in addition to the nitrogen atom at Y.

In another embodiment of this invention Y is N, Z is CH, Q is a 6 membered ring, and Q¹is a 6 membered ring comprising a nitrogen atom in addition to the nitrogen atom at Y.

In another embodiment of this invention Y is N, Z is CH, Q¹is a 6 membered ring comprising a nitrogen atom in addition to the nitrogen atom at Y, and said Q¹ring substituted with 1 to 3 substitutents as defined in formula 1.0.

In another embodiment of this invention Y is N, Z is CH, Q is a 6 membered ring, Q¹is a 6 membered ring comprising a nitrogen atom in addition to the nitrogen atom at Y, and said Q¹ring substituted with 1 to 3 substitutents as defined in formula 1.0.

In another embodiment of this invention each R³is independently selected from the group consisting of: C₁to C₄alkyl, (C₁to C₂)alkoxy-(C₁to C₂)alkyl-, hydroxy(C₁to C₄)alkyl-, —OR², phenyl(C₁to C₄)alkyl-, ═O, phenyl(C₁to C₂)alkyl-, C₂to C₄alkenyl, (C₅to C₇)heterocycloalkyl-(C₁to C₂)alkyl-, —(C₁to C₂)alkyl-C(O)OH, —(C₁to C₄)alkyl-NR⁵R⁶, —(C₁to C₄)alkyl-C(O)NR⁵R⁶, phenyl(C₂to C₄)alkenyl-, —(C₁to C₄)alkyl-C(O)O—(C₁to C₄)alkyl, and substituted phenyl(C₂to C₄)alkenyl-.

In another embodiment of this invention each R³is independently selected from the group consisting of: methyl, ethyl, isopropyl, —CH₂CH₂OH, —CH₂CH₂CH₂OH, —OH, —OCH₃, —OC₂H₅, —OCH(CH₃)₂, benzyl, —(CH₂)₃-phenyl, ═O, p-methoxybenzyl, —CH₂CH═CH₂, —CH₂CH═CHCH₃, pyrrolidinyl-CH₂—CH₂-, morpholinyl-CH₂—CH₂—, —CH₂CH₂—C(O)OH, —CH₂—C(O)OH, —CH₂CH₂CH₂N(CH₃)₂, —CH₂—C(O)NH₂and —CH₂CH═CH-phenyl.

In another embodiment of this invention R³is alkyl.

In another embodiment of this invention R³is C₁to C₄alkyl.

In another embodiment of this invention R³is selected from the group consisting of: methyl, ethyl, and isopropyl.

In another embodiment of this invention R³is methyl.

In another embodiment of this invention R³is alkoxyalkyl-.

In another embodiment of this invention R³is (C₁to C₂)alkoxy-(C₁to C₂)alkyl-

In another embodiment of this invention R³is —CH₂OCH₃.

In another embodiment of this invention R³is hydroxyalkyl-.

In another embodiment of this invention R³is hydroxy(C₁to C₄)alkyl-.

In another embodiment of this invention R³is selected from the group consisting of: —CH₂CH₂OH and —CH₂CH₂CH₂OH.

In another embodiment of this invention R³is —OR².

In another embodiment of this invention R³is —OR²wherein R²is H (i.e., R³is —OH).

In another embodiment of this invention R³is —OR²wherein R²is alkyl.

In another embodiment of this invention R³is —OR²wherein R²is C₁to C₄alkyl.

In another embodiment of this invention R³is —OR²wherein R²is selected from the group consisting of: —OCH₃, —OC₂H₅, and —OCH(CH₃)₂.

In another embodiment of this invention R³is arylalkyl-.

In another embodiment of this invention R³is aryl(C₁to C₄)alkyl-.

In another embodiment of this invention R³is phenylalkyl-.

In another embodiment of this invention R³is phenyl(C₁to C₄)alkyl-.

In another embodiment of this invention R³is selected from the group consisting of: benzyl and —(CH₂)₃-phenyl.

In another embodiment of this invention R³is ═O.

In another embodiment of this invention R³is substituted arylalkyl-.

In another embodiment of this invention R³is substituted aryl(C₁to C₂)alkyl-

In another embodiment of this invention R³is substituted phenylalkyl-.

In another embodiment of this invention R³is substituted phenyl(C₁to C₂)alkyl-

In another embodiment of this invention R³is substituted arylalkyl-.

In another embodiment of this invention R³is phenyl(C₁to C₂)alkyl- substituted with —OR².

In another embodiment of this invention R³is phenyl(C₁to C₂)alkyl- substituted with —OR²wherein R²is alkyl.

In another embodiment of this invention R³is benzyl substituted with —OR²wherein R²is alkyl.

In another embodiment of this invention R³is p-methoxybenzyl.

In another embodiment of this invention R³is alkenyl.

In another embodiment of this invention R³is C₂to C₄alkenyl.

In another embodiment of this invention R³is selected from the group consisting of: —CH₂CH═CH₂and —CH₂CH═CHCH₂.

In another embodiment of this invention R³is heterocycloalkylalkyl-.

In another embodiment of this invention R³is (C₅to C₇)heterocycloalkyl-(C₁to C₂)alkyl-.

In another embodiment of this invention R³is selected from the group consisting of: pyrrolidinyl-(C₁to C₂)alkyl- and morphlinyl-(C₁to C₂)alkyl-.

In another embodiment of this invention R³is selected from the group consisting of: pyrrolidinyl-CH₂—CH₂— and morpholinyl-CH₂—CH₂—.

In another embodiment of this invention R³is -alkyl-C(O)OH.

In another embodiment of this invention R³is —(C₁to C₂)alkyl-C(O)OH.

In another embodiment of this invention R³is selected from the group consisting of: —CH₂CH₂—C(O)OH and —CH₂—C(O)OH.

In another embodiment of this invention R³is -alkyl-NR⁵R⁶.

In another embodiment of this invention R³is —(C₁to C₄)alkyl-NR⁵R⁶.

In another embodiment of this invention R³is —(C₁to C₄)alkyl-NR⁵R⁶wherein R⁵and R⁶are each independently selected from the group consisting of: H, methyl, ethyl, and isopropyl.

In another embodiment of this invention R³is —CH₂CH₂CH₂N(CH₃)₂.

In another embodiment of this invention R³is -alkyl-C(O)NR⁵R⁶.

In another embodiment of this invention R³is —(C₁to C₄)alkyl-C(O)NR⁵R⁶.

In another embodiment of this invention R³is —(C₁to C₂)alkyl-C(O)NR⁵R⁶.

In another embodiment of this invention R³is —(C₁to C₄)alkyl-C(O)NR⁵R⁶wherein R⁵and R⁶are each independently selected from the group consisting of: H, methyl, ethyl, and isopropyl.

In another embodiment of this invention R³is —(C₁to C₂)alkyl-C(O)NR⁵R⁶wherein R⁵and R⁶are each independently selected from the group consisting of: H, methyl, ethyl, and isopropyl.

In another embodiment of this invention R³is —CH₂—C(O)NH₂.

In another embodiment of this invention R³is arylalkenyl-.

In another embodiment of this invention R³is aryl(C₂to C₄)alkenyl-.

In another embodiment of this invention R³is phenylalkenyl.

In another embodiment of this invention R³is phenyl(C₂to C₄)alkenyl-.

In another embodiment of this invention R³is —CH₂CH═CH-phenyl.

In another embodiment of this invention R³is -alkyl-C(O)OR⁷

In another embodiment of this invention R³is -alkyl-C(O)OR⁷wherein R⁷is a C₁to C₄alkyl group.

In another embodiment of this invention R³is -alkyl-C(O)OR⁷wherein R⁷is a C₁to C₂alkyl group.

In another embodiment of this invention R³is —(C₁to C₄)alkyl-C(O)O—(C₁to C₄)alkyl.

In another embodiment of this invention R³is —(C₁to C₂)alkyl-C(O)O—(C₁to C₂)alkyl.

In another embodiment of this invention R³is substituted arylalkenyl-.

In another embodiment of this invention R³is substituted aryl(C₂to C₆)alkenyl-.

In another embodiment of this invention R³is substituted aryl(C₂to C₄)alkenyl-.

In another embodiment of this invention R³is substituted phenyl(C₂to C₆)alkenyl-.

In another embodiment of this invention R³is substituted phenyl(C₂to C₄)alkenyl-.

In another embodiment of this invention R³is substituted —CH₂CH═CH-phenyl.

In another embodiment of this invention X is O.

In another embodiment of this invention L¹is halo.

In another embodiment of this invention n is 2 and each L¹is the same or different halo.

In another embodiment of this invention n is 2 and L¹is F.

In another embodiment n is 3.

In another embodiment n is 3 and each L¹is the same or different halo.

In another embodiment n is 3 and each L¹is independently selected from the group consisting of F and Cl.

In another embodiment n is 3, two L¹moieties are F, and one L¹is Cl.

In another embodiment n is 3, two L¹moieties are F, one L¹moiety is Cl, and the two F L¹moieties are para to each other.

In another embodiment of this invention Ar is phenyl.

In another embodiment of this invention Ar is phenyl substituted with halo.

In another embodiment of this invention Ar is phenyl substituted with one halo.

In another embodiment of this invention Ar is phenyl substituted with at least one Cl.

In another embodiment of this invention Ar is phenyl substituted with a —CF₃group.

In another embodiment of this invention Ar is phenyl substituted with a cyano group.

In another embodiment of this invention Ar is phenyl substituted with a Cl.

In another embodiment of this invention X is O, each L¹is halo, and Ar is phenyl substituted with at least one —CF₃.

In another embodiment of this invention X is O, n is 2, each L¹is the same or different halo, and Ar is phenyl substituted with one —CF₃.

In another embodiment of this invention X is O, n is 2, L¹is F, and Ar is phenyl substituted with one —CF₃.

In another embodiment of this invention X is O, each L¹is halo, and Ar is phenyl substituted with at least one —CN.

In another embodiment of this invention X is O, n is 2, each L¹is the same or different halo, and Ar is phenyl substituted with one —CN.

In another embodiment of this invention X is O, n is 2, L¹is F, and Ar is phenyl substituted with one —CN.

In another embodiment of this invention X is O, each L¹is halo, and Ar is phenyl substituted with at least one halo.

In another embodiment of this invention X is O, n is 2, each L¹is the same or different halo, and Ar is phenyl substituted with one halo.

In another embodiment of this invention X is O, n is 2, L¹is F, and Ar is phenyl substituted with one Cl.

Another embodiment of this invention is directed to any one of the above embodiments describing Y, Z and Q¹, or describing Y, Z Q, and Q¹, wherein X is O.

Another embodiment of this invention is directed to any one of the above embodiments describing Y, Z and Q¹, or describing Y, Z Q, and Q¹, wherein L¹is halo.

Another embodiment of this invention is directed to any one of the above embodiments describing Y, Z and Q¹, or describing Y, Z Q, and Q¹, wherein n is 2 and each L¹is the same or different halo.

Another embodiment of this invention is directed to any one of the above embodiments describing Y, Z and Q¹, or describing Y, Z Q, and Q¹, wherein n is 2 and L¹is F.

Another embodiment of this invention is directed to any one of the above embodiments describing Y, Z and Q¹, or describing Y, Z Q, and Q¹, wherein Ar is phenyl.

Another embodiment of this invention is directed to any one of the above embodiments describing Y, Z and Q¹, or describing Y, Z Q, and Q¹, wherein Ar is phenyl substituted with halo.

Another embodiment of this invention is directed to any one of the above embodiments describing Y, Z and Q¹, or describing Y, Z Q, and Q¹, wherein Ar is phenyl substituted with one halo.

Another embodiment of this invention is directed to any one of the above embodiments describing Y, Z and Q¹, or describing Y, Z Q, and Q¹, wherein Ar is phenyl substituted with at least one Cl.

Another embodiment of this invention is directed to any one of the above embodiments describing Y, Z and Q¹, or describing Y, Z Q, and Q¹, wherein Ar is phenyl substituted with a Cl.

Another embodiment of this invention is directed to any one of the above embodiments describing Y, Z and Q¹, or describing Y, Z Q, and Q¹, wherein X is O, each L¹is halo, and Ar is phenyl substituted with at least one halo.

Another embodiment of this invention is directed to any one of the above embodiments describing Y, Z and Q¹, or describing Y, Z Q, and Q¹, wherein X is O, n is 2, each L¹is the same or different halo, and Ar is phenyl substituted with one halo.

Another embodiment of this invention is directed to any one of the above embodiments describing Y, Z and Q¹, or describing Y, Z Q, and Q¹, wherein X is O, n is 2, L¹is F, and Ar is phenyl substituted with one Cl.

Another embodiment of this invention is directed to any one of the above embodiments describing Y, Z and Q¹, or describing Y, Z Q, and Q¹, wherein Ar is phenyl substituted with —CF₃.

Another embodiment of this invention is directed to any one of the above embodiments describing Y, Z and Q¹, or describing Y, Z Q, and Q¹, wherein Ar is phenyl substituted with one —CF₃.

Another embodiment of this invention is directed to any one of the above embodiments describing Y, Z and Q¹, or describing Y, Z Q, and Q¹, wherein Ar is phenyl substituted with at least one —CF₃.

Another embodiment of this invention is directed to any one of the above embodiments describing Y, Z and Q¹, or describing Y, Z Q, and Q¹, wherein Ar is phenyl substituted with a —CF₃.

Another embodiment of this invention is directed to any one of the above embodiments describing Y, Z and Q¹, or describing Y, Z Q, and Q¹, wherein Ar is phenyl substituted with —CN.

Another embodiment of this invention is directed to any one of the above embodiments describing Y, Z and Q¹, or describing Y, Z Q, and Q¹, wherein Ar is phenyl substituted with one —CN.

Another embodiment of this invention is directed to any one of the above embodiments describing Y, Z and Q¹, or describing Y, Z Q, and Q¹, wherein Ar is phenyl substituted with at least one —CN.

Another embodiment of this invention is directed to any one of the above embodiments describing Y, Z and Q¹, or describing Y, Z Q, and Q¹, wherein Ar is phenyl substituted with a —CN.

Another embodiment of this invention is directed to any one of the above embodiments wherein the —SO₂Ar moiety has the stereochemistry:

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Another embodiment of this invention is directed to any one of the above embodiments wherein the H on the carbon at the ring junction of Rings A¹and Q is cis to the —SO₂Ar moiety:

Another embodiment of this invention is directed to any one of the above embodiments wherein at least one carbon of ring Q¹is substituted with at least one R³group, and the carbon to R³bond has the stereochemistry:

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In one embodiment of this invention the compounds of formula 1.0 are compounds of the formula 1.1

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