US patent application 12/668,550 — Benzenesulfonyl-chromane, thiochromane, tetrahydronaphthalene and related gamma secretase inhibitors

›REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No. 60/950,160 filed Jul. 17, 2007.

›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 · 1 of 2

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

or a pharmaceutically acceptable salt, solvate, or ester thereof, wherein L 1 , n, X, Ar, Y, Z, Q, and Q 1 are 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).

›SUMMARY OF THE INVENTION · 2 of 2

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 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 a compound 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 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 a compound 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 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 a compound 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 · 1 of 78

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

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

L 1 , n, X, Y, Z, Q, Q 1 and Ar are each independently selected;

X is selected from the group consisting of —C(R 1 ) 2 —, —O—, —S—, —S(O 2 )—, —NR 1 —, and —N(C(O)R 1 )—;

The dotted line ( ) 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 A 1 and Q 1 , wherein Y and Z are as defined above and the remaining Q ring members are —CH 2 — 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;

Q 1 is a 5 to 7 membered ring (including Y and Z) fused to Ring Q, said Q 1 ring 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 ; or

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

Each R 1 is independently selected from the group consisting of H and alkyl;

R 2 is selected from the group consisting of: H, and alkyl (e.g., C 1 to C 6 alkyl, such as, for example, methyl, ethyl and isopropyl);

Each R 3 substituent is independently selected from the group consisting of:

(1) alkyl (e.g., C 1 to C 6 alkyl, such as, for example, methyl, ethyl, and isopropyl), (2) alkoxyalkyl- (such as, for example, —(C 1 to C 6 )alkoxy-(C 1 to C 6 )alkyl-, such as, for example, —(C 1 to C 4 )alkoxy-(C 1 to C 4 )alkyl-, such as, for example, —(C 1 to C 2 )alkoxy-(C 1 to C 2 )alkyl-, such as, for example, —CH 2 OCH 3 ), (3) hydroxyalkyl (such as, for example, hydroxy(C 1 to C 6 )alkyl-, such as, for example, hydroxy(C 1 to C 4 )alkyl-, such as, for example, hydroxy(C 1 to C 2 )alkyl-, such as, for example, —CH 2 CH 2 OH, and in another example, —CH 2 CH 2 CH 2 OH), (4) —OR 2 (e.g., —OH, —OCH 3 , —OC 2 H 5 , and —OCH(CH 3 ) 2 ), (5) arylalkyl- (e.g., aryl(C 1 to C 6 )alkyl-, such as, for example, benzyl and —(CH 2 ) 3 -phenyl), (6) ═O, (7) substituted arylalkyl- (e.g., substituted aryl(C 1 to C 6 )alkyl-, such as substituted benzyl) substituted with 1 to 3 substituents each independently selected from the group consisting of: —OR 2 (e.g., p-methoxybenzyl), (8) alkenyl (e.g., C 2 to C 6 alkenyl, such as, for example, C 2 to C 4 alkenyl), and wherein examples of said alkenyl include —CH 2 CH═CH 2 and —CH 2 CH═CHCH 3 , (9) heterocycloalkylalkyl- (e.g., a (C 5 to C 7 )heterocycloalkyl-(C 1 to C 6 )alkyl-, such as a (C 5 to C 7 )heterocycloalkyl-(C 1 to C 4 )alkyl-, such as a (C 5 to C 7 )heterocycloalkyl-(C 1 to C 2 )alkyl-, such as for example, pyrrolidinyl-(C 1 to C 2 )alkyl-, such as for example, pyrrolidinyl-CH 2 —CH 2 —, and in another example, morphlinyl-(C 1 to C 2 )alkyl-, such as, for example, morpholinyl-CH 2 —CH 2 —), (10) -alkyl-C(O)OH (e.g., —(C 1 to C 6 )alkyl-C(O)OH, such as, for example, —(C 1 to C 4 )alkyl-C(O)OH, such as, for example, —(C 1 to C 2 )alkyl-C(O)OH, such as, for example, —CH 2 CH 2 —C(O)OH, and in another example —CH 2 —C(O)OH), (11) -alkyl-NR 5 R 6 (e.g., —(C 1 to C 6 )alkyl-NR 5 R 6 , such as, for example, —(C 1 to C 4 )alkyl-NR 5 R 6 , such as, for example, —(C 1 to C 2 )alkyl NR 5 R 6 ), wherein R 5 and R 6 are each independently selected from the group consisting of: H and alkyl (e.g., C 1 to C 6 alkyl, such as, for example, C 1 to C 4 alkyl, such as, for example, methyl, ethyl, and isopropyl), and wherein examples of said -alkyl-NR 5 R 6 group include, for example, —CH 2 CH 2 CH 2 N(CH 3 ) 2 , (12) -alkyl-C(O)NR 5 R 6 (e.g., —(C 1 to C 6 )alkyl-C(O)NR 5 R 6 , such as, for example, —(C 1 to C 4 )alkyl-C(O)NR 5 R 6 , such as, for example, —(C 1 to C 2 )alkyl-C(O) NR 5 R 6 , wherein R 5 and R 6 are as defined in (11) above, and wherein in one example said -alkyl-C(O)NR 5 R 6 group is —CH 2 —C(O)NH 2 , (13) arylalkenyl- (e.g., aryl(C 2 to C 6 )alkenyl-, such as, for example, aryl(C 2 to C 4 )alkenyl-, such as, for example, phenyl(C 2 to C 6 )alkenyl-, such as, for example, phenyl(C 2 to C 4 )alkenyl-, such as, for example, —CH 2 CH═CH-phenyl), (14) -alkyl-C(O)OR 7 wherein R 7 is a C 1 to C 6 alkyl group (and in one example, R 7 is a C 1 to C 4 alkyl group, and in another example R 7 is a C 1 to C 2 alkyl group), and wherein in one example said -alkyl-C(O)OR 7 moiety is —(C 1 to C 6 )alkyl-C(O)O—(C 1 to C 6 )alkyl, and in another example said -alkyl-C(O)OR 7 moiety is —(C 1 to C 4 )alkyl-C(O)O—(C 1 to C 4 )alkyl, and in another example said -alkyl-C(O)OR 7 moiety is —(C 1 to C 2 )alkyl-C(O)O—(C 1 to C 2 )alkyl, and (15) substituted arylalkenyl- (e.g., substituted aryl(C 2 to C 6 )alkenyl-, such as, for example, substituted aryl(C 2 to C 4 )alkenyl-, such as, for example, substituted phenyl(C 2 to C 6 )alkenyl-, such as, for example, substituted phenyl(C 2 to C 4 )alkenyl-, such as, for example, substituted —CH 2 CH═CH-phenyl), wherein said substituted arylalkenyl- is substituted with 1 to 3 substituents independently selected from the group consisting of: —OR 5 , —NR 5 R 6 , —CF 3 , —CN, —C(O) 2 R 5 , and —C(O)NR 5 R 6 , and wherein R 5 and R 6 are as defined in (11) above; or

›DETAILED DESCRIPTION OF THE INVENTION · 2 of 78

two R 3 groups bound to the same carbon, taken together with the carbon to which they are bound, form a cycloalkyl ring (e.g., a C 5 to C 7 cycloalkyl ring, such as, for example, cyclopentyl) or form a cycloalkenyl ring (e.g., a C 5 to C 7 cycloalkenyl ring, such as, for example, cyclopentenyl);

Ar is selected from the group consisting of: (a) unsubstituted aryl, (b) aryl substituted with one or more L 1 groups, (c) unsubstituted heteroaryl (e.g., pyridyl), and (d) substituted heteroaryl (e.g., substituted pyridyl) substituted with one or more L 1 groups;

each L 1 is independently selected from the group consisting of: halogen, alkyl (e.g., C 1 -C 6 alkyl), —CN, —CF 3 , —O—(C 1 -C 6 )alkyl (e.g., —OCH 3 ), —O-(halo(C 1 -C 6 )alkyl) (e.g., —OCF 3 ), —C(O)—O—(C 1 -C 6 )alkyl (e.g., —C(O)OCH 3 ), -alkylene-OH (e.g., —CH 2 OH), halo(C 1 -C 6 )alkyl (e.g., —CF 3 ), hydroxyalkoxy- (e.g., HOCH 2 CH 2 O—), and alkoxyalkoxy- (e.g., CH 3 OCH 2 CH 2 O—); 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):

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

X is selected from the group consisting of —C(R 1 ) 2 —, —O—, —S—, —S(O 2 )—, —NR 1 —, and —N(C(O)R 1 )—;

The dotted line ( ) 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);

Q represents a 5 to 8 membered ring fused to Rings A 1 and Q 1 , wherein Y and Z are as defined above and the remaining Q ring members are —CH 2 — 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;

Q 1 is a 5 to 7 membered ring (including Y and Z) fused to Ring Q, said Q 1 ring 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 ; or

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

Each R 1 is independently selected from the group consisting of H and alkyl;

R 2 is selected from the group consisting of: H, and alkyl (e.g., C 1 to C 6 alkyl, such as, for example, methyl, ethyl and isopropyl);

Each R 3 substituent is independently selected from the group consisting of: (1) alkyl (e.g., C 1 to C 6 alkyl, such as, for example, methyl and ethyl), (2) alkoxyalkyl-, (3) hydroxyalkyl, (4) —OR 2 (e.g., —OH, —OCH 3 , —OC 2 H 5 , and —OCH(CH 3 ) 2 ), (5) arylalkyl- (e.g., aryl(C 1 to C 6 )alkyl-, such as benzyl), (6) ═O, and (7) substituted arylalkyl- (e.g., substituted aryl(C 1 to C 6 )alkyl-, such as substituted benzyl) substituted with 1 to 3 substituents each independently selected from the group consisting of: —OR 2 (e.g., p-methoxybenzyl);

Ar is selected from the group consisting of: (a) unsubstituted aryl, (b) aryl substituted with one or more L 1 groups, (c) unsubstituted heteroaryl (e.g., pyridyl), and (d) substituted heteroaryl (e.g., substituted pyridyl) substituted with one or more L 1 groups;

each L 1 is independently selected from the group consisting of: halogen, alkyl (e.g., C 1 -C 6 alkyl), —CN, —CF 3 , —O—(C 1 -C 6 )alkyl (e.g., —OCH 3 ), —O-(halo(C 1 -C 6 )alkyl) (e.g., —OCF 3 ), —C(O)—O—(C 1 -C 6 )alkyl (e.g., —C(O)OCH 3 ), -alkylene-OH (e.g., —CH 2 OH), halo(C 1 -C 6 )alkyl (e.g., —CF 3 ), hydroxyalkoxy- (e.g., HOCH 2 CH 2 O—), and alkoxyalkoxy- (e.g., CH 3 OCH 2 CH 2 O—); and

n is 0, 1, 2 or 3.

In one embodiment of this invention two R 3 groups 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 R 3 groups 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 Q 1 is a 6 membered ring comprising a —N—SO 2 — moiety in the ring, and two R 3 groups bound to the carbon adjacent to the —SO 2 — moiety are taken together with the carbon atom to which they are bound to form a cycloalkyl ring (e.g., a cyclopentyl ring).

›DETAILED DESCRIPTION OF THE INVENTION · 3 of 78

In another embodiment of this invention Q 1 is a 6 membered ring comprising a —N—SO 2 — moiety in the ring, and two R 3 groups bound to the carbon adjacent to the —SO 2 — moiety 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 Q is a 6 membered ring, Q 1 is a 6 membered ring comprising a —N—SO 2 — moiety in the ring, and two R 3 groups bound to the carbon adjacent to the —SO 2 — 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, Q 1 is a 6 membered ring comprising a —N—SO 2 — moiety in the ring, and two R 3 groups bound to the carbon adjacent to the —SO 2 — moiety 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 Y is CH, Z is CH, Q 1 is a 6 membered ring comprising a —N—SO 2 — moiety in the ring, and two R 3 groups bound to the carbon adjacent to the —SO 2 — 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 1 is a 6 membered ring comprising a —N—SO 2 — moiety in the ring, and two R 3 groups bound to the carbon adjacent to the —SO 2 — moiety 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 Y is CH, Z is CH, Q is a 6 membered ring, Q 1 is a 6 membered ring comprising a —N—SO 2 — moiety in the ring, and two R 3 groups bound to the carbon adjacent to the —SO 2 — 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, Q 1 is a 6 membered ring comprising a —N—SO 2 — moiety in the ring, and two R 3 groups bound to the carbon adjacent to the —SO 2 — moiety are taken together with the carbon atom to which they are bound to form a cycloalkenyl ring (e.g., a cyclopentenyl ring).

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

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

In another embodiment of this invention Y is CH, Z is CH, Q 1 is 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 Q 1 is a 5 membered ring comprising an oxygen atom.

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

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

In another embodiment of this invention Y is CH, Z is CH, and Q 1 is 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 Q 1 is a 5 membered ring comprising a nitrogen atom.

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

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

In another embodiment of this invention Y is CH, Z is CH, and Q 1 is 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 Q 1 is a 6 membered ring comprising a nitrogen atom.

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

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

In another embodiment of this invention Y is N, Z is CH, and Q 1 is 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 Q 1 is a 6 membered ring comprising a nitrogen atom in addition to the nitrogen atom at Y.

›DETAILED DESCRIPTION OF THE INVENTION · 4 of 78

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

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

In another embodiment of this invention each R 3 is independently selected from the group consisting of: C 1 to C 4 alkyl, (C 1 to C 2 )alkoxy-(C 1 to C 2 )alkyl-, hydroxy(C 1 to C 4 )alkyl-, —OR 2 , phenyl(C 1 to C 4 )alkyl-, ═O, phenyl(C 1 to C 2 )alkyl-, C 2 to C 4 alkenyl, (C 5 to C 7 )heterocycloalkyl-(C 1 to C 2 )alkyl-, —(C 1 to C 2 )alkyl-C(O)OH, —(C 1 to C 4 )alkyl-NR 5 R 6 , —(C 1 to C 4 )alkyl-C(O)NR 5 R 6 , phenyl(C 2 to C 4 )alkenyl-, —(C 1 to C 4 )alkyl-C(O)O—(C 1 to C 4 )alkyl, and substituted phenyl(C 2 to C 4 )alkenyl-.

In another embodiment of this invention each R 3 is independently selected from the group consisting of: methyl, ethyl, isopropyl, —CH 2 CH 2 OH, —CH 2 CH 2 CH 2 OH, —OH, —OCH 3 , —OC 2 H 5 , —OCH(CH 3 ) 2 , benzyl, —(CH 2 ) 3 -phenyl, ═O, p-methoxybenzyl, —CH 2 CH═CH 2 , —CH 2 CH═CHCH 3 , pyrrolidinyl-CH 2 —CH 2 —, morpholinyl-CH 2 —CH 2 —, —CH 2 CH 2 —C(O)OH, —CH 2 —C(O)OH, —CH 2 CH 2 CH 2 N(CH 3 ) 2 , —CH 2 —C(O)NH 2 and —CH 2 CH═CH-phenyl.

In another embodiment of this invention R 3 is alkyl.

In another embodiment of this invention R 3 is C 1 to C 4 alkyl.

In another embodiment of this invention R 3 is selected from the group consisting of: methyl, ethyl, and isopropyl.

In another embodiment of this invention R 3 is methyl.

In another embodiment of this invention R 3 is alkoxyalkyl-.

In another embodiment of this invention R 3 is (C 1 to C 2 )alkoxy-(C 1 to C 2 )alkyl-

In another embodiment of this invention R 3 is —CH 2 OCH 3 .

In another embodiment of this invention R 3 is hydroxyalkyl-.

In another embodiment of this invention R 3 is hydroxy(C 1 to C 4 )alkyl-.

In another embodiment of this invention R 3 is selected from the group consisting of: —CH 2 CH 2 OH and —CH 2 CH 2 CH 2 OH.

In another embodiment of this invention R 3 is —OR 2 .

In another embodiment of this invention R 3 is —OR 2 wherein R 2 is H (i.e., R 3 is —OH).

In another embodiment of this invention R 3 is —OR 2 wherein R 2 is alkyl.

In another embodiment of this invention R 3 is —OR 2 wherein R 2 is C 1 to C 4 alkyl.

In another embodiment of this invention R 3 is —OR 2 wherein R 2 is selected from the group consisting of: —OCH 3 , —OC 2 H 5 , and —OCH(CH 3 ) 2 .

In another embodiment of this invention R 3 is arylalkyl-.

In another embodiment of this invention R 3 is aryl(C 1 to C 4 )alkyl-.

In another embodiment of this invention R 3 is phenylalkyl-.

In another embodiment of this invention R 3 is phenyl(C 1 to C 4 )alkyl-.

In another embodiment of this invention R 3 is selected from the group consisting of: benzyl and —(CH 2 ) 3 -phenyl.

In another embodiment of this invention R 3 is ═O.

In another embodiment of this invention R 3 is substituted arylalkyl-.

In another embodiment of this invention R 3 is substituted aryl(C 1 to C 2 )alkyl-

In another embodiment of this invention R 3 is substituted phenylalkyl-.

In another embodiment of this invention R 3 is substituted phenyl(C 1 to C 2 )alkyl-

In another embodiment of this invention R 3 is substituted arylalkyl-.

In another embodiment of this invention R 3 is phenyl(C 1 to C 2 )alkyl- substituted with —OR 2 .

In another embodiment of this invention R 3 is phenyl(C 1 to C 2 )alkyl- substituted with —OR 2 wherein R 2 is alkyl.

In another embodiment of this invention R 3 is benzyl substituted with —OR 2 wherein R 2 is alkyl.

In another embodiment of this invention R 3 is p-methoxybenzyl.

In another embodiment of this invention R 3 is alkenyl.

In another embodiment of this invention R 3 is C 2 to C 4 alkenyl.

In another embodiment of this invention R 3 is selected from the group consisting of: —CH 2 CH═CH 2 and —CH 2 CH═CHCH 2 .

In another embodiment of this invention R 3 is heterocycloalkylalkyl-.

In another embodiment of this invention R 3 is (C 5 to C 7 )heterocycloalkyl-(C 1 to C 2 )alkyl-.

In another embodiment of this invention R 3 is selected from the group consisting of: pyrrolidinyl-(C 1 to C 2 )alkyl- and morphlinyl-(C 1 to C 2 )alkyl-.

In another embodiment of this invention R 3 is selected from the group consisting of: pyrrolidinyl-CH 2 —CH 2 — and morpholinyl-CH 2 —CH 2 —.

In another embodiment of this invention R 3 is -alkyl-C(O)OH.

In another embodiment of this invention R 3 is —(C 1 to C 2 )alkyl-C(O)OH.

In another embodiment of this invention R 3 is selected from the group consisting of: —CH 2 CH 2 —C(O)OH and —CH 2 —C(O)OH.

In another embodiment of this invention R 3 is -alkyl-NR 5 R 6 .

In another embodiment of this invention R 3 is —(C 1 to C 4 )alkyl-NR 5 R 6 .

In another embodiment of this invention R 3 is —(C 1 to C 4 )alkyl-NR 5 R 6 wherein R 5 and R 6 are each independently selected from the group consisting of: H, methyl, ethyl, and isopropyl.

In another embodiment of this invention R 3 is —CH 2 CH 2 CH 2 N(CH 3 ) 2 .

In another embodiment of this invention R 3 is -alkyl-C(O)NR 5 R 6 .

In another embodiment of this invention R 3 is —(C 1 to C 4 )alkyl-C(O)NR 5 R 6 .

In another embodiment of this invention R 3 is —(C 1 to C 2 )alkyl-C(O)NR 5 R 6 .

In another embodiment of this invention R 3 is —(C 1 to C 4 )alkyl-C(O)NR 5 R 6 wherein R 5 and R 6 are each independently selected from the group consisting of: H, methyl, ethyl, and isopropyl.

In another embodiment of this invention R 3 is —(C 1 to C 2 )alkyl-C(O)NR 5 R 6 wherein R 5 and R 6 are each independently selected from the group consisting of: H, methyl, ethyl, and isopropyl.

In another embodiment of this invention R 3 is —CH 2 —C(O)NH 2 .

In another embodiment of this invention R 3 is arylalkenyl-.

In another embodiment of this invention R 3 is aryl(C 2 to C 4 )alkenyl-.

›DETAILED DESCRIPTION OF THE INVENTION · 5 of 78

In another embodiment of this invention R 3 is phenylalkenyl.

In another embodiment of this invention R 3 is phenyl(C 2 to C 4 )alkenyl-.

In another embodiment of this invention R 3 is —CH 2 CH═CH-phenyl.

In another embodiment of this invention R 3 is -alkyl-C(O)OR 7

In another embodiment of this invention R 3 is -alkyl-C(O)OR 7 wherein R 7 is a C 1 to C 4 alkyl group.

In another embodiment of this invention R 3 is -alkyl-C(O)OR 7 wherein R 7 is a C 1 to C 2 alkyl group.

In another embodiment of this invention R 3 is —(C 1 to C 4 )alkyl-C(O)O—(C 1 to C 4 )alkyl.

In another embodiment of this invention R 3 is —(C 1 to C 2 )alkyl-C(O)O—(C 1 to C 2 )alkyl.

In another embodiment of this invention R 3 is substituted arylalkenyl-.

In another embodiment of this invention R 3 is substituted aryl(C 2 to C 6 )alkenyl-.

In another embodiment of this invention R 3 is substituted aryl(C 2 to C 4 )alkenyl-.

In another embodiment of this invention R 3 is substituted phenyl(C 2 to C 6 )alkenyl-.

In another embodiment of this invention R 3 is substituted phenyl(C 2 to C 4 )alkenyl-.

In another embodiment of this invention R 3 is substituted —CH 2 CH═CH-phenyl.

In another embodiment of this invention X is O.

In another embodiment of this invention L 1 is halo.

In another embodiment of this invention n is 2 and each L 1 is the same or different halo.

In another embodiment of this invention n is 2 and L 1 is F.

In another embodiment n is 3.

In another embodiment n is 3 and each L 1 is the same or different halo.

In another embodiment n is 3 and each L 1 is independently selected from the group consisting of F and Cl.

In another embodiment n is 3, two L 1 moieties are F, and one L 1 is Cl.

In another embodiment n is 3, two L 1 moieties are F, one L 1 moiety is Cl, and the two F L 1 moieties 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 —CF 3 group.

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 L 1 is halo, and Ar is phenyl substituted with at least one —CF 3 .

In another embodiment of this invention X is O, n is 2, each L 1 is the same or different halo, and Ar is phenyl substituted with one —CF 3 .

In another embodiment of this invention X is O, n is 2, L 1 is F, and Ar is phenyl substituted with one —CF 3 .

In another embodiment of this invention X is O, each L 1 is halo, and Ar is phenyl substituted with at least one —CN.

In another embodiment of this invention X is O, n is 2, each L 1 is 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, L 1 is F, and Ar is phenyl substituted with one —CN.

In another embodiment of this invention X is O, each L 1 is halo, and Ar is phenyl substituted with at least one halo.

In another embodiment of this invention X is O, n is 2, each L 1 is 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, L 1 is 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 Q 1 , or describing Y, Z Q, and Q 1 , wherein X is O.

Another embodiment of this invention is directed to any one of the above embodiments describing Y, Z and Q 1 , or describing Y, Z Q, and Q 1 , wherein L 1 is halo.

Another embodiment of this invention is directed to any one of the above embodiments describing Y, Z and Q 1 , or describing Y, Z Q, and Q 1 , wherein n is 2 and each L 1 is the same or different halo.

Another embodiment of this invention is directed to any one of the above embodiments describing Y, Z and Q 1 , or describing Y, Z Q, and Q 1 , wherein n is 2 and L 1 is F.

Another embodiment of this invention is directed to any one of the above embodiments describing Y, Z and Q 1 , or describing Y, Z Q, and Q 1 , wherein Ar is phenyl.

Another embodiment of this invention is directed to any one of the above embodiments describing Y, Z and Q 1 , or describing Y, Z Q, and Q 1 , 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 Q 1 , or describing Y, Z Q, and Q 1 , 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 Q 1 , or describing Y, Z Q, and Q 1 , 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 Q 1 , or describing Y, Z Q, and Q 1 , 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 Q 1 , or describing Y, Z Q, and Q 1 , wherein X is O, each L 1 is 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 Q 1 , or describing Y, Z Q, and Q 1 , wherein X is O, n is 2, each L 1 is 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 Q 1 , or describing Y, Z Q, and Q 1 , wherein X is O, n is 2, L 1 is 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 Q 1 , or describing Y, Z Q, and Q 1 , wherein Ar is phenyl substituted with —CF 3 .

Another embodiment of this invention is directed to any one of the above embodiments describing Y, Z and Q 1 , or describing Y, Z Q, and Q 1 , wherein Ar is phenyl substituted with one —CF 3 .

›DETAILED DESCRIPTION OF THE INVENTION · 6 of 78

Another embodiment of this invention is directed to any one of the above embodiments describing Y, Z and Q 1 , or describing Y, Z Q, and Q 1 , wherein Ar is phenyl substituted with at least one —CF 3 .

Another embodiment of this invention is directed to any one of the above embodiments describing Y, Z and Q 1 , or describing Y, Z Q, and Q 1 , wherein Ar is phenyl substituted with a —CF 3 .

Another embodiment of this invention is directed to any one of the above embodiments describing Y, Z and Q 1 , or describing Y, Z Q, and Q 1 , wherein X is O, each L 1 is halo, and Ar is phenyl substituted with at least one —CF 3 .

Another embodiment of this invention is directed to any one of the above embodiments describing Y, Z and Q 1 , or describing Y, Z Q, and Q 1 , wherein X is O, n is 2, each L 1 is the same or different halo, and Ar is phenyl substituted with one —CF 3 .

Another embodiment of this invention is directed to any one of the above embodiments describing Y, Z and Q 1 , or describing Y, Z Q, and Q 1 , wherein X is O, n is 2, L 1 is F, and Ar is phenyl substituted with one —CF 3 .

Another embodiment of this invention is directed to any one of the above embodiments describing Y, Z and Q 1 , or describing Y, Z Q, and Q 1 , 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 Q 1 , or describing Y, Z Q, and Q 1 , 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 Q 1 , or describing Y, Z Q, and Q 1 , 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 Q 1 , or describing Y, Z Q, and Q 1 , wherein Ar is phenyl substituted with a —CN.

Another embodiment of this invention is directed to any one of the above embodiments describing Y, Z and Q 1 , or describing Y, Z Q, and Q 1 , wherein X is O, each L 1 is halo, and 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 Q 1 , or describing Y, Z Q, and Q 1 , wherein X is O, n is 2, each L 1 is the same or different halo, and 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 Q 1 , or describing Y, Z Q, and Q 1 , wherein X is O, n is 2, L 1 is F, and Ar is phenyl substituted with —CN.

Another embodiment of this invention is directed to any one of the above embodiments wherein the —SO 2 Ar moiety has the stereochemistry:

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 A 1 and Q is cis to the —SO 2 Ar moiety:

Another embodiment of this invention is directed to any one of the above embodiments wherein at least one carbon of ring Q 1 is substituted with at least one R 3 group, and the carbon to R 3 bond has the stereochemistry:

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