Small molecule inhibitors of TRPA1

Abstract

The present invention relates to the use of compounds which are capable of attenuating skin irritation when they are applied to the skin. Skin irritation can be caused, inter alia, by ingredients of cosmetic or pharmaceutical compositions and/or environmental irritants. In particular, the present invention relates to compounds having the property of antagonizing the activation of the transient receptor potential (TRP) ankyrin 1 (TRPA1) ion channel and the use of said compounds as soothing agents. Such compounds can be used in many fields, particularly in personal-care products, cosmetics, textile and packaging products, pharmaceutical compositions, medical devices, and foodstuffs. The present invention further relates to products and/or pharmaceutical compositions containing said compounds. The present invention also relates to the use of the compounds described herein for the modulation of the taste of a food product.

Claims

1. A method of soothing skin irritation in a human in need thereof, comprising administering to the human an effective amount of a compound of Formula V.2: ##STR00147## or a pharmaceutically acceptable derivative thereof, wherein: R.sub.1 is (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, (C.sub.2-C.sub.4)alkynyl, or (C.sub.1-C.sub.4)alkoxy, each of which is unsubstituted or substituted with 1 or 2 independently selected R.sub.5 groups; R.sub.2 is H or CH.sub.3; R.sub.2 is H or CH.sub.3; each R.sub.3 is independently: (a) OT.sub.3, or OC(O)T.sub.3; or (b) C(O)T.sub.3, C(O)OT.sub.3, or C(O)N(T.sub.1)(T.sub.2); or (c) (C.sub.1-C.sub.3)alkyl, (C.sub.2-C.sub.3)alkenyl, (C.sub.2-C.sub.3)alkynyl, or (C.sub.1-C.sub.3)alkoxy; each R.sub.4 is independently: (a) -halo, CN, or NO.sub.2; or (b) -OT.sub.3, or OC(O)T.sub.3; or (c) C(O)T.sub.3, or C(O)OT.sub.3; or (d) ST.sub.3, S(O)T.sub.3, S(O).sub.2T.sub.3, or S(O).sub.2OT.sub.3; or (e) (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, (C.sub.2-C.sub.4)alkynyl, or (C.sub.1-C.sub.4)alkoxy; each R.sub.5 is independently H, (C.sub.1-C.sub.2)alkyl, (C.sub.2)alkenyl, (C.sub.2)alkynyl, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, -halo, N.sub.3, NO.sub.2, N(R.sub.7).sub.2, N(R.sub.7)OH, C(O)R.sub.7, C(O)OR.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7; b is 1 or 2; c is 0 or 1; each R.sub.7 is independently H, or CH.sub.3; each T.sub.1, T.sub.2, and T.sub.3 is independently H or CH.sub.3; and each halo is independently F, Cl, Br, or I, to sooth skin irritation by inhibiting a transient receptor potential ankyrin 1 (TRPA1) receptor in the human.

2. The method of claim 1, wherein the compound of Formula V.2 is: ##STR00148## or a pharmaceutically acceptable derivative thereof.

3. The method of claim 1, wherein the compound or a pharmaceutically acceptable derivative thereof is administered to the human in a personal-care product.

4. The method of claim 3, wherein the personal-care product is a cosmetic product or a wound dressing.

5. The method of claim 4, wherein the personal-care product is a cosmetic product, and wherein the cosmetic product is an oral hygiene composition, a skin care composition, or a hair care composition.

6. The method of claim 4, wherein the personal-care product is a cosmetic product, and wherein the cosmetic product is an insect repellent, a lotion, a shaving cream, a post-shaving preparation, a shampoo, a conditioner, a facial cleanser, a soap, a bath oil, a bath foam, an antiperspirant, a deodorant, a toothpaste, a mouthwash, a dental floss, a chewing gum, or a breath freshener.

7. The method of claim 3, wherein the personal-care product comprises a personal-care agent, wherein the personal-care agent is an emulsifier, a detergent, a preservative, an anti-aging compound, a depilation agent, or a peeling agent.

8. The method of claim 1, wherein the compound exhibits an antagonist activity at TRPA1 which is at least three times greater than the antagonist activity of the compound at a different ion channel or receptor.

9. The method of claim 8, wherein the different ion channel or receptor is TRPM8.

10. The method of claim 1, wherein the compound exhibits an antagonist activity at TRPA1 which is at least five times greater than the antagonist activity of the compound at a different ion channel or receptor.

11. The method of claim 10, wherein the different ion channel or receptor is TRPM8.

12. The method of claim 1, wherein the compound exhibits an antagonist activity at TRPA1 which is at least ten times greater than the antagonist activity of the compound at a different ion channel or receptor.

13. The method of claim 12, wherein the different ion channel or receptor is TRPM8.

14. The method of claim 1, wherein the skin irritation is caused by a cosmetic composition or a pharmaceutical composition.

15. The method of claim 1, wherein the skin irritation is caused by a personal-care product, a textile product, a medical device, a packaging product, or a food product.

16. The method of claim 1, wherein the skin irritation is caused by an environmental irritant.

17. The method of claim 1, wherein soothing skin irritation comprises alleviating stinging, burning, or itching.

18. The method of claim 2, wherein the compound or a pharmaceutically acceptable derivative thereof is administered to the human in a personal-care product.

19. The method of claim 18, wherein the personal-care product is a cosmetic product or a wound dressing.

20. The method of claim 19, wherein the personal-care product is a cosmetic product, and wherein the cosmetic product is an oral hygiene composition, a skin care composition, or a hair care composition.

21. The method of claim 19, wherein the personal-care product is a cosmetic product, and wherein the cosmetic product is an insect repellent, a lotion, a shaving cream, a post-shaving preparation, a shampoo, a conditioner, a facial cleanser, a soap, a bath oil, a bath foam, an antiperspirant, a deodorant, a toothpaste, a mouthwash, a dental floss, a chewing gum, or a breath freshener.

22. The method of claim 18, wherein the personal-care product comprises a personal-care agent, wherein the personal-care agent is an emulsifier, a detergent, a preservative, an anti-aging compound, a depilation agent, or a peeling agent.

23. The method of claim 2, wherein the skin irritation is caused by a cosmetic composition or a pharmaceutical composition.

24. The method of claim 2, wherein the skin irritation is caused by a personal-care product, a textile product, a medical device, a packaging product, or a food product.

25. The method of claim 2, wherein the skin irritation is caused by an environmental irritant.

26. The method of claim 2, wherein soothing skin irritation comprises alleviating stinging, burning, or itching.

Description

FIGURE LEGENDS

(1) The accompanying drawings, which are incorporated and form part of the specification, merely illustrate certain embodiments of the present invention. They are meant to serve to explain specific modes of the present invention to those of skilled in the art. In the drawings:

(2) FIG. 1: Dose-response curves of TRPA1 agonists (calcium assay).

(3) Exemplary dose-response curves are shown. Agonistic efficacy of menthol (EC.sub.80=35 M), propylparaben (EC.sub.80=80 M), and retinol (EC.sub.80=150 M) was measured in a cell-based calcium assay system.

(4) A: Agonistic activity of menthol at TRPA1.

(5) B: Agonistic activity of propylparaben and retinol at TRPA1.

(6) FIG. 2: Dose-response curves of TRPA1 antagonists (calcium assay).

(7) Exemplary dose-response curves are shown. Antagonistic efficacy of compound I.3 and II.3 against propylparaben and retinol (at their corresponding EC.sub.80 concentrations) was measured in a cell-based calcium assay system.

(8) A: Antagonistic activity of compound I.3 at TRPA1 against retinol and propylparaben.

(9) B: Antagonistic activity of compound II.3 at TRPA1 against retinol and propylparaben.

(10) FIG. 3: Dose-response curve of a TRPA1 agonist (impedance assay).

(11) An exemplary dose-response curve is shown. Agonistic efficacy of propylparaben (EC.sub.80=200 M) was measured in a cell-based impedance assay system. FIG. 3 depicts the agonistic activity of propylparaben at TRPA1.

(12) FIG. 4: Dose-response curves of TRPA1 antagonists (impedance assay).

(13) Exemplary dose-response curves are shown. Antagonistic efficacy of compound I.3 and II.3 against retinol and propylparaben (at their corresponding EC.sub.80 concentrations) was measured in a cell-based impedance assay system.

(14) A: Antagonistic activity of compound I.3 at TRPA1 against retinol.

(15) B: Antagonistic activity of compound II.3 at TRPA1 against propylparaben.

(16) FIGS. 5-9: Dose-response curves of compound I.3-V.3 at TRPA1 and TRPM8 (calcium assay) against menthol, which is known to trigger both TRPA1 as well as TRPM8. The antagonistic activity of compounds I.3, II.3, III.3, IV.3 and V.3 at TRPA1 (open circles, continuous line) as well as the antagonistic activity of said compounds at TRPM8 (filled squares, dotted line) was measured and compared. Activation of the two ion channels was triggered by addition of menthol, which is known to trigger both TRPA1 as well as TRPM8 (EC.sub.80[TRPA1]=35 M and EC.sub.80[TRPM8]=12 M). The receptor signals were normalized to the pure menthol signal in each case. FIG. 5: Antagonistic activity of Compound I.3 at TRPA1 (open circles, continuous line) and TRPM8 (filled squares, dotted line) against menthol. FIG. 6: Antagonistic activity of Compound II.3 at TRPA1 (open circles, continuous line) and TRPM8 (filled squares, dotted line) against menthol. FIG. 7: Antagonistic activity of Compound III.3 at TRPA1 (open circles, continuous line) and TRPM8 (filled squares, dotted line) against menthol. FIG. 8: Antagonistic activity of Compound IV.3 at TRPA1 (open circles, continuous line) and TRPM8 (filled squares, dotted line) against menthol. FIG. 9: Antagonistic activity of Compound V.3 at TRPA1 (open circles, continuous line) and TRPM8 (filled squares, dotted line) against menthol.

(17) FIG. 10: Results of the blinded study on the lid-check junction of 16 persons performed according to example 7 showing the in vivo activity of compound I.3 according to the invention.

DETAILED DESCRIPTION OF THE INVENTION

(18) The present invention illustratively described in the following may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein.

(19) The present invention will be described with respect to particular embodiments and with reference to certain drawings but the invention is not limited thereto but only by the claims. The drawings described are only schematic and are non-limiting. In the drawings, the size of some of the elements may be exaggerated and not drawn on scale for illustrative purposes.

(20) Where the term comprising is used in the present description and claims, it does not exclude other elements or steps. For the purposes of the present invention, the term consisting of is considered to be a preferred embodiment of the term comprising of. If hereinafter a group is defined to comprise at least a certain number of embodiments, this is also to be understood to disclose a group which optionally consists only of these embodiments.

(21) Where an indefinite or definite article is used when referring to a singular noun e.g. a or an, the, this includes a plural of that noun unless something else is specifically stated.

(22) The term about in the context of the present invention denotes an interval of accuracy that the person skilled in the art will understand to still ensure the technical effect of the feature in question. The term typically indicates deviation from the indicated numerical value of 10%, and optionally 5%.

(23) Furthermore, the terms first, second, third and the like in the description and in the claims, are used for distinguishing between similar elements and not necessarily for describing a sequential or chronological order. It is to be understood that the terms so used are interchangeable under appropriate circumstances and that the embodiments of the invention described herein are capable of operation in other sequences than described or illustrated herein.

(24) Further definitions of term will be given in the following in the context of which the terms are used.

(25) Compounds

(26) In one embodiment, the present invention relates to a compound having the following general formula (I):

(27) ##STR00006##
or a pharmaceutically acceptable derivative thereof wherein:
E is selected from O, C(O), C(O)O, C(O)NH, OC(O)NH, OC(O)O, S, S(O), S(O).sub.2, S(O).sub.2O, S(O).sub.2NH, S(O)O, S(O)NH, or NH;
R.sub.1 is selected from (C.sub.3-C.sub.20)cycloalkyl, (C.sub.6-C.sub.14)bicycloalkyl, (C.sub.8-C.sub.20)tricycloalkyl, (C.sub.5-C.sub.20)cycloalkenyl, (C.sub.7-C.sub.14)bicycloalkenyl, (C.sub.8-C.sub.20)tricycloalkenyl, -(5- or 6-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R.sub.4 groups;
R.sub.2 and R.sub.3 are each independently selected from: (a) -hydrogen; or (b) -halo, CN, NO.sub.2; or (c) OT.sub.3, OC(O)T.sub.3, OC(O)N(T.sub.1)(T.sub.2), OC(O)OT.sub.3; or (d) C(O)T.sub.3, C(O)OT.sub.3, C(O)N(T.sub.1)(T.sub.2); or (e) ST.sub.3, S(O)T.sub.3, S(O).sub.2T.sub.3, S(O).sub.2OT.sub.3, S(O).sub.2N(T.sub.1)(T.sub.2), S(O)OT.sub.3, S(O)N(T.sub.1)(T.sub.2); or (f) N(T.sub.1)(T.sub.2), N(T.sub.3)N(T.sub.1)(T.sub.2), N(T.sub.3)C(O)T.sub.3, N(T.sub.3)C(O)OT.sub.3, N(T)C(O)N(T.sub.1)(T.sub.2), N(T.sub.3)S(O).sub.2T.sub.3, N(T.sub.3)S(O).sub.2N(T.sub.1)(T.sub.2), N(T.sub.3)S(O)T.sub.3, N(T.sub.3)S(O)N(T.sub.1)(T.sub.2); or (g) (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.6-C.sub.14)bicycloalkyl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.5 groups; or (h) -phenyl or -(5- or 6-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.6 groups; with the proviso that R.sub.2 and R.sub.3 are not both hydrogen;
R.sub.4 and R.sub.5 are each independently selected from (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, -(5- or 6-membered)heteroaryl, -phenyl, (C.sub.1-C.sub.6)alkylCOOR.sub.7, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, O, S, -halo, N.sub.3, NO.sub.2, CHN(R.sub.7), NR.sub.7(C.sub.1-C.sub.6)alkylCOOR.sub.7, N(R.sub.7).sub.2, N(R.sub.7)OH, N(R.sub.7)S(O)R.sub.R, N(R.sub.7)S(O).sub.2R.sub.8, N(R.sub.7)C(O)R.sub.8, N(R.sub.7)C(O)N(R.sub.7).sub.2, N(R.sub.7)C(O)OR.sub.8, C(O)R.sub.7, C(O)C(O)OR.sub.7, C(O)N(R.sub.7).sub.2, C(O)OR.sub.7, OC(O)R.sub.7, OC(O)N(R.sub.7).sub.2, OC(O)OR.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7;
each R.sub.6 is independently selected from (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, -halo, N.sub.3, NO.sub.2, CHN(R.sub.7), N(R.sub.7).sub.2, N(R.sub.7)OH, N(R.sub.7)S(O)R.sub.8, N(R.sub.7)S(O).sub.2R.sub.8, N(R.sub.7)C(O)R.sub.8, N(R.sub.7)C(O)N(R.sub.7).sub.2, N(R.sub.7)C(O)OR.sub.8, C(O)R.sub.7, C(O)N(R.sub.7).sub.2, C(O)OR.sub.7. OC(O)R.sub.7, OC(O)N(R.sub.7).sub.2, OC(O)OR.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7;
each R.sub.7 is independently selected from H, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.8)cycloalkyl, (C.sub.5-C.sub.8)cycloalkenyl, -phenyl, -benzyl, -(3- to 6-membered)heterocycle, -(5- to 10-membered)heteroaryl, C(halo).sub.3, CH(halo).sub.2, or CH.sub.2(halo);
each R.sub.8 is independently selected from H or (C.sub.1-C.sub.4)alkyl;
each T.sub.1, T.sub.2, and T.sub.3 is independently H or (C.sub.1-C.sub.10)alkyl which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.5 groups: and
each halo is independently selected from F, Cl, Br, or I.

(28) In a further embodiment, the present invention relates to a compound having the following general formula (I.1):

(29) ##STR00007##
or a pharmaceutically acceptable derivative thereof wherein:
E is selected from O and N(T.sub.3);
n is an integer selected from 0 or 1;
R.sub.11, R.sub.12, R.sub.13, R.sub.14, and R.sub.15 are each independently selected from H, (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkylCOOR.sub.7, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, -halo, N.sub.3, NO.sub.2, CHN(R.sub.7), N(R.sub.7).sub.2, N(R.sub.7)OH, C(O)R.sub.7, C(O)C(O)OR.sub.7, C(O)N(R.sub.7).sub.2, C(O)OR.sub.7, OC(O)R.sub.7, OC(O)N(R.sub.7).sub.2, OC(O)OR.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7;
the dashed lines between R.sub.13 and R.sub.14, and between R.sub.14 and R.sub.15 each denote the presence or absence of a bond, wherein: (a) R.sub.13, R.sub.14 and R.sub.15 are each present if both bonds are absent; or (b) R.sub.13 and R.sub.14 are each absent and R.sub.15 is present if the bond between R.sub.13 and R.sub.14 is present and the bond between R.sub.14 and R.sub.15 is absent; or (c) R.sub.13 is present and R.sub.14 and R.sub.15 are absent if the bond between R.sub.13 and R.sub.14 is absent and the bond between R.sub.14 and R.sub.15 is present;
R.sub.11, R.sub.12, R.sub.13, R.sub.14, and R.sub.15, if present, are each independently selected from: (a) H, or (C.sub.1-C.sub.4)alkyl; or (b) R.sub.12, R.sub.13 are each independently selected from H, or (C.sub.1-C.sub.4)alkyl, and R.sub.11 and R.sub.14 together form a (C.sub.1-C.sub.2) bridge which is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from OH, (C.sub.1-C.sub.4)alkyl, -halo, and C(halo).sub.3; or (c) R.sub.11 and R.sub.14 are each independently selected from H, or (C.sub.1-C.sub.4)alkyl, and R.sub.12 and R.sub.13 together form a (C.sub.3-C.sub.7)cycloalkyl, (C.sub.6-C.sub.14)bicycloalkyl, (C.sub.5-C.sub.10)cycloalkenyl, (C.sub.7-C.sub.14)bicycloalkenyl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.5 groups, and wherein the bond indicated by the dashed line between R.sub.12 and R.sub.13 can be present or absent; or (d) R.sub.13, R.sub.14 are each independently selected from H, or (C.sub.1-C.sub.4)alkyl, and R.sub.11 and R.sub.12 together form a (C.sub.3-C.sub.7)cycloalkyl, (C.sub.6-C.sub.14)bicycloalkyl, (C.sub.5-C.sub.10)cycloalkenyl, or (C.sub.7-C.sub.14)bicycloalkenyl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.5 groups;
R.sub.2 and R.sub.3 are each independently selected from: (a) -halo, CN, NO.sub.2; or (b) OT.sub.3, OC(O)T.sub.3; or (c) C(O)T.sub.3, C(O)OT.sub.3, C(O)N(T.sub.1)(T.sub.2); or (d) (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, (C.sub.2-C.sub.4)alkylnyl, (C.sub.1-C.sub.4)alkoxy, each of which is unsubstituted or substituted with 1 or 2 independently selected R.sub.5 groups;
each R.sub.5 is independently selected from (C.sub.1-C.sub.3)alkyl, (C.sub.2-C.sub.3)alkenyl, (C.sub.2-C.sub.3)alkynyl, (C.sub.1-C.sub.3)alkylCOOR.sub.7, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, O, S, -halo, N.sub.3, NO.sub.2, N(R.sub.7).sub.2, N(R.sub.7)OH, C(O)R.sub.7, C(O)OR.sub.7, OC(O)R.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7;
each R.sub.7 is independently selected from H, CH.sub.3, or CH.sub.2CH.sub.3;
each T.sub.1, T.sub.2, and T.sub.3 is independently H or (C.sub.1-C.sub.5)alkyl which is unsubstituted or substituted with 1 or 2 independently selected R.sub.5 groups; and
each halo is independently selected from F, Cl, Br, or I.

(30) In a further embodiment, the present invention relates to a compound having the following general formula (I.1.1):

(31) ##STR00008##
or a pharmaceutically acceptable derivative thereof wherein:
E is selected from O and N(T.sub.3);
R.sub.1 is selected from the following general formulae:

(32) ##STR00009##
wherein R.sub.11, R.sub.12, R.sub.13 and R.sub.14 are each independently selected from H, (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkylCOOR.sub.7, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, -halo, N.sub.3, NO.sub.2, CHN(R.sub.7), N(R.sub.7).sub.2, N(R.sub.7)OH, C(O)R.sub.7, C(O)C(O)OR.sub.7, C(O)N(R.sub.7).sub.2, C(O)OR.sub.7, OC(O)R.sub.7, OC(O)N(R.sub.7).sub.2, OC(O)OR.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7; the dashed lines between R.sub.13 and R.sub.14 and R.sub.14 and R.sub.15 each denote the presence or absence of a bond, wherein: (a) R.sub.13, R.sub.14 and R.sub.15 are each present if both bonds are absent; or (b) R.sub.13 and R.sub.14 are each absent and R.sub.15 is present if the bond between R.sub.13 and R.sub.14 is present and the bond between R.sub.14 and R.sub.15 is absent; or (c) R.sub.13 is present and R.sub.14 and R.sub.15 are absent if the bond between R.sub.13 and R.sub.14 is absent and the bond between R.sub.14 and R.sub.15 is present; and R.sub.11, R.sub.12, R.sub.13, R.sub.14, and R.sub.15, if present, are each independently selected from H, or (C.sub.1-C.sub.4)alkyl, wherein R.sub.11 and R.sub.14 together can form a (C.sub.1-C.sub.2) bridge which is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from OH, (C.sub.1-C.sub.4)alkyl, -halo, and C(halo).sub.3; or

(33) ##STR00010##
wherein R.sub.11, R.sub.12, R.sub.13 and R.sub.14 are each independently selected from H, (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkylCOOR.sub.7, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, -halo, N.sub.3, NO.sub.2, CHN(R.sub.7), N(R.sub.7).sub.2, N(R.sub.7)OH, C(O)R.sub.7, C(O)C(O)OR.sub.7, C(O)N(R.sub.7).sub.2, C(O)OR.sub.7, OC(O)R.sub.7, OC(O)N(R.sub.7).sub.2, OC(O)OR.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7; the dashed line between R.sub.14 and R.sub.15 denotes the presence or absence of a bond, wherein: (a) R.sub.14 and R.sub.15 are present if the bond is absent; or (b) R.sub.14 and R.sub.15 are absent if the bond is present; R.sub.11, R.sub.14, and R.sub.15, if present, are each independently selected from H, or (C.sub.1-C.sub.4)alkyl; and a is an integer selected from 1, 2, or 3; wherein: (a) if a=1, the ring denoted as Q is (C.sub.5)cycloalkyl, or (C.sub.5)cycloalkenyl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.5 groups; (b) if a=2, the ring denoted as Q is (C.sub.6)cycloalkyl, or (C.sub.6)cycloalkenyl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.5 groups; (c) if a=3, the ring denoted as Q is (C.sub.7)cycloalkyl, or (C.sub.7)cycloalkenyl, each of which is unsubstituted or substituted with 1, 2, 3 or 4 independently selected R.sub.5 groups; or

(34) ##STR00011##
wherein R.sub.11, R.sub.12, R.sub.13 and R.sub.14 are each independently selected from H, (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkylCOOR.sub.7, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo). CN, -halo, N.sub.3, NO.sub.2, CHN(R.sub.7), N(R.sub.7).sub.2, N(R.sub.7)OH, C(O)R.sub.7, C(O)C(O)OR.sub.7, C(O)N(R.sub.7).sub.2, C(O)OR.sub.7, OC(O)R.sub.7, OC(O)N(R.sub.7).sub.2, OC(O)OR.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7; the dashed line between R.sub.14 and R.sub.15 denotes the presence or absence of a bond, wherein: (a) R.sub.14 and R.sub.15 are present if the bond is absent; or (b) R.sub.14 and R.sub.15 are absent if the bond is present; the dashed line between R.sub.12 and R.sub.13 denotes the absence of a bond; the dashed lines together with the solid lines in the ring denoted as Q each independently denote the presence or absence of a double bond, wherein R.sub.12 is absent if the carbon atom carrying R.sub.12 is unsaturated, and wherein R.sub.13 is absent if the carbon atom carrying R.sub.13 is unsaturated; R.sub.11, R.sub.12, R.sub.13, R.sub.14, and R.sub.15, if present, are each independently selected from H, or (C.sub.1-C.sub.4)alkyl; and a is an integer selected from 1, 2, or 3; wherein: (a) if a=1, the ring denoted as Q is (C.sub.5)cycloalkyl, or (C.sub.5)cycloalkenyl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.5 groups; (b) if a=2, the ring denoted as Q is (C.sub.6)cycloalkyl, or (C.sub.6)cycloalkenyl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.5 groups; (c) if a=3, the ring denoted as Q is (C.sub.7)cycloalkyl, or (C.sub.7)cycloalkenyl, each of which is unsubstituted or substituted with 1, 2, 3 or 4 independently selected R.sub.5 groups; or

(35) ##STR00012##
wherein R.sub.11, R.sub.12, R.sub.13 and R.sub.14 are each independently selected from H, (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkylCOOR.sub.7, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, -halo, N.sub.3, NO.sub.2, CHN(R.sub.7), N(R.sub.7).sub.2, N(R.sub.7)OH, C(O)R.sub.7, C(O)C(O)OR.sub.7, C(O)N(R.sub.7).sub.2, C(O)OR.sub.7, OC(O)R.sub.7, OC(O)N(R.sub.7).sub.2, OC(O)OR.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7; the dashed lines between R.sub.13 and R.sub.14 and R.sub.14 and R.sub.15 each denote the presence or absence of a bond, wherein: (a) R.sub.13, R.sub.14 and R.sub.15 are each present if both bonds are absent; or (b) R.sub.13 and R.sub.14 are each absent and R.sub.15 is present if the bond between R.sub.13 and R.sub.14 is present and the bond between R.sub.14 and R.sub.15 is absent; or (c) R.sub.13 is present and R.sub.14 and R.sub.15 are absent if the bond between R.sub.13 and R.sub.14 is absent and the bond between R.sub.14 and R.sub.15 is present; R.sub.11, R.sub.12, R.sub.13, R.sub.14, and R.sub.15, if present, are each independently selected from H, or (C.sub.1-C.sub.4)alkyl; and a is an integer selected from 1, 2, or 3; wherein: (a) if a=1, the ring denoted as Q is (C.sub.5)cycloalkyl, or (C.sub.5)cycloalkenyl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.5 groups; (b) if a=2, the ring denoted as Q is (C.sub.6)cycloalkyl, or (C.sub.6)cycloalkenyl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.5 groups; (c) if a=3, the ring denoted as Q is (C.sub.7)cycloalkyl, or (C.sub.7)cycloalkenyl, each of which is unsubstituted or substituted with 1, 2, 3 or 4 independently selected R.sub.5 groups;
R.sub.2 and R.sub.3 are each independently selected from: (a) -halo, CN, NO.sub.2; or (b) OT.sub.3, OC(O)T.sub.3; or (c) C(O)T.sub.3, C(O)OT.sub.3, C(O)N(T.sub.1)(T.sub.2); or (d) (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, (C.sub.2-C.sub.4)alkynyl, (C.sub.1-C.sub.4)alkoxy, each of which is unsubstituted or substituted with 1 or 2 independently selected R.sub.5 groups;
each R.sub.5 is independently selected from (C.sub.1-C.sub.3)alkyl, (C.sub.2-C.sub.3)alkenyl, (C.sub.2-C.sub.3)alkynyl, (C.sub.1-C.sub.3)alkylCOOR.sub.7, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, O, S, -halo, N.sub.3, NO.sub.2, N(R.sub.7).sub.2, N(R.sub.7)OH, C(O)R.sub.7, C(O)OR.sub.7, OC(O)R.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7;
each R.sub.6 is independently selected from (C.sub.1-C.sub.3)alkyl, (C.sub.2-C.sub.3)alkenyl, (C.sub.2-C.sub.3)alkynyl, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, -halo, N.sub.3, NO.sub.2, N(R.sub.7).sub.2, N(R.sub.7)OH, C(O)R.sub.7, C(O)OR.sub.7, OC(O)R.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7;
each R.sub.7 is independently selected from H, CH.sub.3, or CH.sub.2CH.sub.3;
each T.sub.1, T.sub.2, and T.sub.3 is independently H or (C.sub.1-C.sub.5)alkyl which is unsubstituted or substituted with 1 or 2 independently selected R.sub.5 groups; and
each halo is independently selected from F, Cl, Br, or I.

(36) In a further embodiment, the present invention relates to a compound having the following general formula (I.2):

(37) ##STR00013##
or a pharmaceutically acceptable derivative thereof wherein:
E is selected from O and N(T.sub.3);
n is an integer selected from 0 or 1;
R.sub.11, R.sub.12, R.sub.13, and R.sub.14 are each independently selected from H, (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, (C.sub.2-C.sub.4)alkynyl, OR.sub.7, SR.sub.7, C(halo), CH(halo), CH.sub.2(halo), CN, -halo, N.sub.3, NO.sub.2, N(R.sub.7).sub.2, N(R.sub.7)OH, C(O)R.sub.7, C(O)N(R.sub.7).sub.2, C(O)OR.sub.7, OC(O)R.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7;
the dashed line between R.sub.14 and R.sub.15 denotes the presence or absence of a bond, wherein: (a) R.sub.14 and R.sub.15 are present if the bond is absent; or (b) R.sub.14 and R.sub.15 are absent if the bond is present;
R.sub.11, R.sub.12, R.sub.13, R.sub.14, and R.sub.15, if present, are each independently selected from: (a) H, or (C.sub.1-C.sub.3)alkyl; or (b) R.sub.12, R.sub.13 are each independently selected from H, or (C.sub.1-C.sub.3)alkyl, and R.sub.11 and R.sub.14 together form a (C.sub.1-C.sub.2) bridge which is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from OH, (C.sub.1-C.sub.2)alkyl, -halo, and C(halo).sub.3; or (c) if n=0, R.sub.11 and R.sub.14 are each independently selected from H, or (C.sub.1-C.sub.3)alkyl, and R.sub.12 and R.sub.13 together form a (C.sub.5-C.sub.7)cycloalkyl or (C.sub.5-C.sub.7)cycloalkenyl, each of which is unsubstituted or substituted with 1, 2, 3 or 4 independently selected R.sub.5 groups, and wherein the bond indicated by the dashed line between R.sub.12 and R.sub.13 can be present or absent; or (d) if n=1, R.sub.13, R.sub.14 are each independently selected from H, or (C.sub.1-C.sub.4)alkyl, and R.sub.11 and R.sub.12 together form a (C.sub.5-C.sub.7)cycloalkyl or (C.sub.5-C.sub.7)cycloalkenyl, each of which is unsubstituted or substituted with 1, 2, 3 or 4 independently selected R.sub.5 groups;
R.sub.2 and R.sub.3 are each independently selected from: (a) -halo, CN, NO.sub.2; or (b) OT.sub.3, OC(O)T.sub.3; or (c) C(O)T.sub.3, C(O)OT.sub.3, C(O)N(T.sub.1)(T.sub.2); or (d) (C.sub.1-C.sub.3)alkyl, (C.sub.2-C.sub.3)alkenyl, (C.sub.2-C.sub.3)alkynyl, (C.sub.1-C.sub.3)alkoxy, each of which is unsubstituted or substituted with 1 or 2 independently selected R.sub.5 groups;
each R.sub.5 is independently selected from H, (C.sub.1-C.sub.3)alkyl, (C.sub.3)alkenyl, (C.sub.3)alkynyl, OR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, -halo, N.sub.3, NO.sub.2, N(R.sub.7).sub.2, N(R.sub.7)OH, C(O)R.sub.7, or C(O)OR.sub.7;
each R.sub.7 is independently selected from H, or CH.sub.3;
each T.sub.1, T.sub.2, and T.sub.3 is independently H or CH.sub.3; and
each halo is independently selected from F, Cl, Br, or I.

(38) In a further embodiment, the present invention relates to a compound having the following general formula (I.2.1):

(39) ##STR00014##
or a pharmaceutically acceptable derivative thereof wherein:
E is selected from O and N(T.sub.3);
R.sub.1 is selected from the following general formulae:

(40) ##STR00015##
wherein R.sub.11, R.sub.12, R.sub.13, and R.sub.14 are each independently selected from H, (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, (C.sub.2-C.sub.4)alkynyl, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, -halo, N.sub.3, NO.sub.2, N(R.sub.7).sub.2, N(R.sub.7)OH, C(O)R.sub.7, C(O)N(R.sub.7).sub.2, C(O)OR.sub.7, OC(O)R.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7; R.sub.11, R.sub.12, R.sub.13, R.sub.14, and R.sub.15, if present, are each independently selected from H, or (C.sub.1-C.sub.3)alkyl; and R.sub.16 and R.sub.17 are each independently selected from H, OH, (C.sub.1-C.sub.2)alkyl, -halo, and C(halo).sub.3; or

(41) ##STR00016##
wherein R.sub.11, R.sub.12, R.sub.13, and R.sub.14 are each independently selected from H, (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, (C.sub.2-C.sub.4)alkynyl, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, -halo, N.sub.3, NO.sub.2, N(R.sub.7).sub.2, N(R.sub.7)OH, C(O)R.sub.7, C(O)N(R.sub.7).sub.2, C(O)OR.sub.7, OC(O)R.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7; the dashed line between R.sub.14 and R.sub.15 denotes the presence or absence of a bond, wherein: (a) R.sub.14 and R.sub.15 are present if the bond is absent; or (b) R.sub.14 and R.sub.15 are absent if the bond is present; R.sub.11, R.sub.14, and R.sub.15, if present, are each independently selected from H, or (C.sub.1-C.sub.3)alkyl; and a is an integer selected from 2 or 3; wherein: (a) if a=2, the ring denoted as Q is (C.sub.6)cycloalkyl, or (C.sub.6)cycloalkenyl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.5 groups; (b) if a=3, the ring denoted as Q is (C.sub.7)cycloalkyl, or (C.sub.7)cycloalkenyl, each of which is unsubstituted or substituted with 1, 2, 3 or 4 independently selected R.sub.5 groups; or

(42) ##STR00017##
wherein R.sub.11, R.sub.12, R.sub.13, and R.sub.14 are each independently selected from H, (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, (C.sub.2-C.sub.4)alkynyl, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, -halo, N.sub.3, NO.sub.2, N(R.sub.7).sub.2, N(R.sub.7)OH, C(O)R.sub.7, C(O)N(R.sub.7).sub.2, C(O)OR.sub.7. OC(O)R.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7; the dashed line between R.sub.14 and R.sub.15 denotes the presence or absence of a bond, wherein: (a) R.sub.14 and R.sub.15 are present if the bond is absent; or (b) R.sub.14 and R.sub.15 are absent if the bond is present; R.sub.11, R.sub.14, and R.sub.15, if present, are each independently selected from H, or (C.sub.1-C.sub.3)alkyl; and a is an integer selected from 1, 2 or 3; or

(43) ##STR00018##
wherein R.sub.11, R.sub.12, R.sub.13, and R.sub.14 are each independently selected from H, (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, (C.sub.2-C.sub.4)alkynyl, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, -halo, N.sub.3, NO.sub.2, N(R.sub.7).sub.2, N(R.sub.7)OH, C(O)R.sub.7, C(O)N(R.sub.7).sub.2, C(O)OR.sub.7, OC(O)R.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7; the dashed lines between R.sub.13 and R.sub.14 and R.sub.14 and R.sub.15 each denote the presence or absence of a bond, wherein: (a) R.sub.13, R.sub.14 and R.sub.15 are each present if both bonds are absent; or (b) R.sub.13 and R.sub.14 are each absent and R.sub.15 is present if the bond between R.sub.13 and R.sub.14 is present and the bond between R.sub.14 and R.sub.15 is absent; or (c) R.sub.13 is present and R.sub.14 and R.sub.15 are absent if the bond between R.sub.13 and R.sub.14 is absent and the bond between R.sub.14 and R.sub.15 is present; R.sub.11, R.sub.12, R.sub.13, R.sub.14, and R.sub.15, if present, are each independently selected from H, or (C.sub.1-C.sub.3)alkyl; and a is an integer selected from 1 or 2; wherein: (a) if a=1, the ring denoted as Q is (C.sub.5)cycloalkyl, or (C.sub.5)cycloalkenyl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.5 groups; (b) if a=2, the ring denoted as Q is (C.sub.6)cycloalkyl, or (C.sub.6)cycloalkenyl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.5 groups;
R.sub.2 and R.sub.3 are each independently selected from: (a) -halo, CN, NO.sub.2; or (b) OT.sub.3, OC(O)T.sub.3; or (c) C(O)T.sub.3, C(O)OT.sub.3, C(O)N(T.sub.1)(T.sub.2); or (d) (C.sub.1-C.sub.3)alkyl, (C.sub.2-C.sub.3)alkenyl, (C.sub.2-C.sub.3)alkynyl, (C.sub.1-C.sub.3)alkoxy, each of which is unsubstituted or substituted with 1 or 2 independently selected R.sub.5 groups;
each R.sub.5 is independently selected from H, (C.sub.1-C.sub.3)alkyl, (C.sub.3)alkenyl, (C.sub.3)alkynyl, OR.sub.7, C(halo), CH(halo), CH.sub.2(halo), CN, -halo, N.sub.3, NO.sub.2, N(R.sub.7).sub.2, N(R.sub.7)OH, C(O)R.sub.7, or C(O)OR.sub.7;
each R.sub.7 is independently selected from H, or CH.sub.3;
each T.sub.1, T.sub.2, and T.sub.3 is independently H or CH.sub.3; and
each halo is independently selected from F, Cl, Br, or I.

(44) In an optional embodiment, the present invention relates to a compound having the general formula (I.2) or (I.2.1) or a pharmaceutically acceptable derivative thereof, wherein E is O.

(45) In an optional embodiment, the present invention relates to a compound having the general formula (I.2) or (I.2.1) or a pharmaceutically acceptable derivative thereof, wherein R.sub.2 and R.sub.3 are each independently selected from OH, OCH.sub.3, OC(O)H, OC(O)CH.sub.3, C(O)H, C(O)CH.sub.3, C(O)OH, or C(O)OCH.sub.3.

(46) In an optional embodiment, the present invention relates to a compound having the general formula (I.2) or (I.2.1) or a pharmaceutically acceptable derivative thereof, wherein R.sub.2 is selected from OH or OCH.sub.3, and R.sub.3 is selected from OH, OCH.sub.3, OC(O)H or OC(O)CH.sub.3.

(47) In an optional embodiment, the present invention relates to a compound having the general formula (I.2) or (I.2.1) or a pharmaceutically acceptable derivative thereof, wherein R.sub.11, R.sub.12, R.sub.13, R.sub.14, and R.sub.15 are each independently selected from H, (C.sub.1-C.sub.3)alkyl, OH, or OCH.sub.3.

(48) In an optional embodiment, the present invention relates to a compound having the general formula (I.2.1) or a pharmaceutically acceptable derivative thereof, wherein R.sub.1 is:

(49) ##STR00019##
wherein R.sub.11, R.sub.12, R.sub.13, and R.sub.14 are each independently selected from H, (C.sub.1-C.sub.3)alkyl, OH, or OCH.sub.3; R.sub.11, R.sub.12, R.sub.13, R.sub.14, and R.sub.15, if present, are each independently selected from H, or (C.sub.1-C.sub.3)alkyl; and R.sub.16 and R.sub.17 are each independently selected from H, and (C.sub.1-C.sub.2)alkyl.

(50) In an optional embodiment, the present invention relates to a compound having the general formula (I.2.1) or a pharmaceutically acceptable derivative thereof, wherein R.sub.1 is:

(51) ##STR00020##
wherein R.sub.11, R.sub.12, R.sub.13, and R.sub.14 are each independently selected from H, (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, (C.sub.2-C.sub.4)alkynyl, OR.sub.7, SR, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, -halo, N.sub.3, NO.sub.2, N(R.sub.7).sub.2, N(R.sub.7)OH, C(O)R.sub.7, C(O)N(R.sub.7).sub.2, C(O)OR.sub.7, OC(O)R.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7; R.sub.11, R.sub.12, R.sub.13, R.sub.14, and R.sub.15, if present, are each independently selected from H, or (C.sub.1-C.sub.3)alkyl; and R.sub.16 and R.sub.17 are each independently selected from H, OH, (C.sub.1-C.sub.2)alkyl, -halo, and C(halo).sub.3.

(52) In an optional embodiment, the present invention relates to a compound having the general formula (I.2.1) or a pharmaceutically acceptable derivative thereof, wherein R.sub.1 is:

(53) ##STR00021##
wherein R.sub.11, R.sub.12, R.sub.13, and R.sub.14 are each independently selected from H, (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, (C.sub.2-C.sub.4)alkynyl, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, -halo, N.sub.3, NO.sub.2, N(R.sub.7).sub.2, N(R.sub.7)OH, C(O)R.sub.7, C(O)N(R.sub.7).sub.2, C(O)OR.sub.7, OC(O)R.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7; R.sub.11, R.sub.12, R.sub.13, R.sub.14, and R.sub.15, if present, are each independently selected from H, or (C.sub.1-C.sub.3)alkyl; and R.sub.16 and R.sub.17 are each independently selected from H, OH, (C.sub.1-C.sub.2)alkyl, -halo, and C(halo).sub.3.

(54) In an optional embodiment, the present invention relates to a compound having the general formula (I.2.1) or a pharmaceutically acceptable derivative thereof, wherein R.sub.1 is:

(55) ##STR00022##
wherein R.sub.11, R.sub.12, R.sub.13, and R.sub.14 are each independently selected from H, (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, (C.sub.2-C.sub.4)alkynyl, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, -halo, N.sub.1, NO.sub.7, N(R.sub.7).sub.2, N(R.sub.7)OH, C(O)R.sub.7, C(O)N(R.sub.7).sub.2, C(O)OR.sub.7, OC(O)R.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7; R.sub.11, R.sub.12, R.sub.13, R.sub.14, and R.sub.15, if present, are each independently selected from H, or (C.sub.1-C.sub.3)alkyl; and R.sub.16 and R.sub.17 are each independently selected from H, OH, (C.sub.1-C.sub.2)alkyl, -halo, and C(halo).sub.3.

(56) In an optional embodiment, the present invention relates to a compound having the general formula (I.2.1) or a pharmaceutically acceptable derivative thereof, wherein R.sub.1 is:

(57) ##STR00023##
wherein R.sub.11, R.sub.12, R.sub.13, and R.sub.14 are each independently selected from H, (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, (C.sub.2-C.sub.4)alkynyl, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, -halo, N.sub.3, NO.sub.2, N(R.sub.7).sub.2, N(R.sub.7)OH, C(O)R.sub.7, C(O)N(R.sub.7).sub.2, C(O)OR.sub.7, OC(O)R.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7; R.sub.11, R.sub.12, R.sub.13, R.sub.14, and R.sub.15, if present, are each independently selected from H, or (C.sub.1-C.sub.3)alkyl; and R.sub.16 and R.sub.17 are each independently selected from H, OH, (C.sub.1-C.sub.2)alkyl, -halo, and C(halo).sub.3.

(58) In an optional embodiment, the present invention relates to a compound having the general formula (I.2.1) or a pharmaceutically acceptable derivative thereof, wherein R.sub.1 is:

(59) ##STR00024##
wherein R.sub.11, R.sub.12, R.sub.13, and R.sub.14 are each independently selected from H, (C.sub.1-C.sub.3)alkyl, OH, or OCH; R.sub.11, R.sub.12, R.sub.13, R.sub.14, and R.sub.15, if present, are each independently selected from H, or (C.sub.1-C.sub.3)alkyl; and R.sub.16 and R.sub.17 are each independently selected from H, and (C.sub.1-C.sub.2)alkyl.

(60) In an optional embodiment, the present invention relates to a compound having the general formula (I.2.1) or a pharmaceutically acceptable derivative thereof, wherein R.sub.1 is:

(61) ##STR00025##
wherein R.sub.11, R.sub.12, R.sub.13, and R.sub.14 are each independently selected from H, (C.sub.1-C.sub.3)alkyl, OH, or OCH.sub.3; R.sub.11, R.sub.12, R.sub.13, R.sub.14, and R.sub.15, if present, are each independently selected from H, or (C.sub.1-C.sub.3)alkyl; and R.sub.16 and R.sub.17 are each independently selected from H, and (C.sub.1-C.sub.2)alkyl.

(62) In an optional embodiment, the present invention relates to a compound having the general formula (I.2.1) or a pharmaceutically acceptable derivative thereof, wherein R.sub.1 is:

(63) ##STR00026##
wherein R.sub.11, R.sub.12, R.sub.13, and R.sub.14 are each independently selected from H, (C.sub.1-C.sub.3)alkyl, OH, or OCH.sub.3; R.sub.11, R.sub.12, R.sub.13, R.sub.14, and R.sub.15, if present, are each independently selected from H, or (C.sub.1-C.sub.3)alkyl; and R.sub.16 and R.sub.17 are each independently selected from H, and (C.sub.1-C.sub.2)alkyl.

(64) In an optional embodiment, the present invention relates to a compound having the general formula (I.2.1) or a pharmaceutically acceptable derivative thereof, wherein R.sub.1 is:

(65) ##STR00027##
wherein R.sub.11, R.sub.12, R.sub.13, and R.sub.14 are each independently selected from H, (C.sub.1-C.sub.3)alkyl, OH, or OCH.sub.3; R.sub.11, R.sub.12, R.sub.13, R.sub.14, and R.sub.15, if present, are each independently selected from H, or (C.sub.1-C.sub.3)alkyl; and R.sub.16 and R.sub.17 are each independently selected from H, and (C.sub.1-C.sub.2)alkyl.

(66) In an optional embodiment, the present invention relates to a compound having the general formula (I.2.1) or a pharmaceutically acceptable derivative thereof, wherein R.sub.1 is selected from (+)-borneole, ()-borneole, (+)-isoborneole, or ()-isoborneole.

(67) In an optional embodiment, the present invention relates to a compound having the general formula (I.2.1) or a pharmaceutically acceptable derivative thereof, wherein R.sub.1 is:

(68) ##STR00028##
wherein R.sub.11, R.sub.12, R.sub.13, and R.sub.14 are each independently selected-H, (C.sub.1-C.sub.3)alkyl, OH, or OCH.sub.3; the dashed line between R.sub.14 and R.sub.15 denotes the presence or absence of a bond, wherein: (a) R.sub.14 and R.sub.15 are present if the bond is absent; or (b) R.sub.14 and R.sub.15 are absent if the bond is present; R.sub.11, R.sub.14, and R.sub.15, if present, are each independently selected from H, or (C.sub.1-C.sub.2)alkyl; b is an integer selected from 2, 3 or 4; and each R.sub.5 is independently selected from H, (C.sub.1-C.sub.3)alkyl, OH, or OCH.sub.3.

(69) In an optional embodiment, the present invention relates to a compound having the general formula (I.2.1) or a pharmaceutically acceptable derivative thereof, wherein R.sub.1 is:

(70) ##STR00029##
wherein R.sub.11, R.sub.12, R.sub.13, and R.sub.14 are each independently selected-H, (C.sub.1-C.sub.3)alkyl, OH, or OCH.sub.3; the dashed line between R.sub.14 and R.sub.15 denotes the presence or absence of a bond, wherein: (a) R.sub.14 and R.sub.15 are present if the bond is absent; or (b) R.sub.14 and R.sub.15 are absent if the bond is present; R.sub.11, R.sub.14, and R.sub.15, if present, are each independently selected from H, or (C.sub.1-C.sub.2)alkyl; a is an integer selected from 0, 1, 2 or 3; and each R.sub.5 is independently selected from H, (C.sub.1-C.sub.3)alkyl, OH, or OCH.sub.3.

(71) In an optional embodiment, the present invention relates to a compound having the general formula (I.2.1) or a pharmaceutically acceptable derivative thereof, wherein R.sub.1 is:

(72) ##STR00030##
wherein R.sub.11, R.sub.12, R.sub.13, and R.sub.14 are each independently selected-H, (C.sub.1-C.sub.3)alkyl, OH, or OCH.sub.3; the dashed line between R.sub.14 and R.sub.15 denotes the presence or absence of a bond, wherein: (a) R.sub.14 and R.sub.15 are present if the bond is absent; or (b) R.sub.14 and R.sub.15 are absent if the bond is present; R.sub.11, R.sub.14, and R.sub.15, if present, are each independently selected from H, or (C.sub.1-C.sub.2)alkyl; b is an integer selected from 1, 2 or 3; and each R.sub.5 is independently selected from H, (C.sub.1-C.sub.3)alkyl, OH, or OCH.sub.3.

(73) In an optional embodiment, the present invention relates to a compound having the following general formula (I.2A):

(74) ##STR00031##
or a pharmaceutically acceptable derivative thereof wherein:
E is selected from O and NH, optionally O; and
R.sub.2 and R.sub.3 are each independently selected from OH, OCH.sub.3, OC(O)H, OC(O)CH.sub.3, C(O)H, C(O)CH.sub.3, C(O)OH, or C(O)OCH.sub.3.

(75) In an optional embodiment, the present invention relates to a compound having the following general formula (I.2B):

(76) ##STR00032##
or a pharmaceutically acceptable derivative thereof wherein:
E is selected from O and NH, optionally O; and
R.sub.2 and R.sub.3 are each independently selected from OH, OCH.sub.3, OC(O)H, OC(O)CH.sub.3, C(O)H, C(O)CH.sub.3, C(O)OH, or C(O)OCH.sub.3.

(77) In an optional embodiment, the present invention relates to a compound having the following general formula (I.2C):

(78) ##STR00033##
or a pharmaceutically acceptable derivative thereof wherein:
E is selected from O and NH, optionally O; and
R.sub.2 and R.sub.3 are each independently selected from OH, OCH.sub.3, OC(O)H, OC(O)CH.sub.3, C(O)H, C(O)CH.sub.3, C(O)OH, or C(O)OCH.sub.3.

(79) In an optional embodiment, the present invention relates to a compound having the following general formula (I.2D):

(80) ##STR00034##
or a pharmaceutically acceptable derivative thereof wherein:
E is selected from O and NH, optionally O; and
R.sub.2 and R.sub.3 are each independently selected from OH, OCH.sub.3, OC(O)H, OC(O)CH.sub.3, C(O)H, C(O)CH.sub.3, C(O)OH, or C(O)OCH.sub.3.

(81) In an optional embodiment, the present invention relates to a compound having the following general formula (I.2E):

(82) ##STR00035##
or a pharmaceutically acceptable derivative thereof wherein:
E is selected from O and NH, optionally O; and
R.sub.2 and R.sub.3 are each independently selected from OH, OCH.sub.3, OC(O)H, OC(O)CH.sub.3, C(O)H, C(O)CH.sub.3, C(O)OH, or C(O)OCH.sub.3.

(83) In an optional embodiment, the present invention relates to a compound having the following general formula (I.2F):

(84) ##STR00036##
or a pharmaceutically acceptable derivative thereof wherein:
E is selected from O and NH, optionally O; and
R.sub.2 and R.sub.3 are each independently selected from OH, OCH, OC(O)H, OC(O)CH.sub.3, C(O)H, C(O)CH.sub.3, C(O)OH, or C(O)OCH.sub.3.

(85) In an optional embodiment, the present invention relates to a compound having the following general formula (I.2G):

(86) ##STR00037##
or a pharmaceutically acceptable derivative thereof wherein:
E is selected from O and NH, optionally O; and
R.sub.2 and R.sub.3 are each independently selected from OH, OCH.sub.3, OC(O)H, OC(O)CH.sub.3, C(O)H, C(O)CH.sub.3, C(O)OH, or C(O)OCH.sub.3.

(87) In an optional embodiment, the present invention relates to a compound having the following formula (I.2H):

(88) ##STR00038##

(89) In an optional embodiment, the present invention relates to a compound having the following formula (I.2I):

(90) ##STR00039##

(91) In an optional embodiment, the present invention relates to a compound having the following formula (I.2J):

(92) ##STR00040##

(93) In an optional embodiment, the present invention relates to a compound having the following formula (I.2K):

(94) ##STR00041##

(95) In an optional embodiment, the present invention relates to a compound having the following formula (I.2L):

(96) ##STR00042##

(97) In an optional embodiment, the present invention relates to a compound having the following formula (I.2M):

(98) ##STR00043##

(99) In an optional embodiment, the present invention relates to a compound having the following formula (I.2N):

(100) ##STR00044##

(101) In an optional embodiment, the present invention relates to a compound having the following formula (I.2O):

(102) ##STR00045##

(103) In an optional embodiment, the present invention relates to a compound having the following formula (I.2P):

(104) ##STR00046##

(105) In a further embodiment, the present invention relates to a compound having the following general formula (II):

(106) ##STR00047##
or a pharmaceutically acceptable derivative thereof wherein:
E is selected from O, C(O), C(O)O, C(O)NH, OC(O)NH, OC(O)O, S, S(O), S(O).sub.2, S(O).sub.2O, S(O).sub.2NH, S(O)O, S(O)NH, or NH;
R.sub.1 is selected from (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.6-C.sub.14)bicycloalkyl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.5 groups;
R.sub.2 and R.sub.3 are each independently selected from H, (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, -halo, N.sub.3, NO.sub.2, CHN(R.sub.7), N(R.sub.7).sub.2, N(R.sub.7)OH, N(R.sub.7)S(O)R.sub.8, N(R.sub.7)S(O).sub.2R.sub.8, N(R.sub.7)C(O)R.sub.8, N(R.sub.7)C(O)N(R.sub.7).sub.2, N(R.sub.7)C(O)OR.sub.5, C(O)R.sub.7, C(O)N(R.sub.7).sub.2, C(O)OR.sub.7, OC(O)R.sub.7, OC(O)N(R.sub.7).sub.2, OC(O)OR.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7;
with the proviso that R.sub.2 and R.sub.3 are not both hydrogen;
R.sub.4 is selected from: (a) (C.sub.3-C.sub.7)cycloalkyl, (C.sub.6-C.sub.14)bicycloalkyl, (C.sub.8-C.sub.20)tricycloalkyl, (C.sub.5-C.sub.10)cycloalkenyl, (C.sub.7-C.sub.14)bicycloalkenyl, (C.sub.8-C.sub.20)tricycloalkenyl, -(5- or 6-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.5 groups; or (b) -phenyl, or -(5- or 6-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.6 groups;
each R.sub.5 is independently selected from (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, -(5- or 6-membered)heteroaryl, -phenyl, (C.sub.1-C.sub.6)alkylCOOR.sub.7, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, O, S, -halo, N.sub.3, NO.sub.2, CHN(R.sub.7), NR.sub.7(C.sub.1-C.sub.6)alkylCOOR.sub.7, N(R.sub.7).sub.2, N(R.sub.7)OH, N(R.sub.7)S(O)R.sub.8, N(R.sub.7)S(O).sub.2R.sub.8, N(R.sub.7)C(O)R.sub.8, N(R.sub.7)C(O)N(R.sub.7).sub.2, N(R.sub.7)C(O)OR.sub.8, C(O)R.sub.7, C(O)C(O)OR.sub.7, C(O)N(R.sub.7).sub.2, C(O)OR.sub.7, OC(O)R.sub.7, OC(O)N(R.sub.7).sub.2, OC(O)OR.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7;
each R.sub.6 is independently selected from (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, -halo, N.sub.3, NO.sub.2. CHN(R.sub.7), N(R.sub.7).sub.2, N(R.sub.7)OH, N(R.sub.7)S(O)R.sub.8, N(R.sub.7)S(O).sub.2R.sub.8, N(R.sub.7)C(O)R.sub.8, N(R.sub.7)C(O)N(R.sub.7).sub.2, N(R.sub.7)C(O)OR.sub.8, C(O)R.sub.7, C(O)N(R.sub.7).sub.2, C(O)OR.sub.7, OC(O)R.sub.7, OC(O)N(R.sub.7).sub.2, OC(O)OR.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7;
each R.sub.7 is independently selected from H, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.8)cycloalkyl, (C.sub.5-C.sub.8)cycloalkenyl, -phenyl, -benzyl, -(3- to 6-membered)heterocycle, -(5- to 10-membered)heteroaryl, C(halo).sub.3, CH(halo).sub.2, or CH.sub.2(halo);
each R.sub.5 is independently selected from H or (C.sub.1-C.sub.4)alkyl;
each T.sub.1, T.sub.2, and T.sub.3 is independently H or (C.sub.1-C.sub.10)alkyl which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.5 groups; and
each halo is independently selected from F, Cl, Br, or I.

(107) In a further embodiment, the present invention relates to a compound having the following general formula (II.1):

(108) ##STR00048##
or a pharmaceutically acceptable derivative thereof wherein:
E is O or N(T.sub.3);
R.sub.1 is selected from (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, or (C.sub.2-C.sub.4)alkynyl, each of which is unsubstituted or substituted with 1 or 2 independently selected R.sub.5 groups;
R.sub.2 and R.sub.3 are each independently selected from H, (C.sub.1-C.sub.3)alkyl, (C.sub.2-C.sub.3)alkenyl, (C.sub.2-C.sub.3)alkynyl, OR.sub.7, SR.sub.7, N.sub.3, NO.sub.2, CHN(R.sub.7), N(R.sub.7).sub.2, N(R.sub.7)OH, N(R.sub.7)S(O)R.sub.8, N(R.sub.7)S(O).sub.2R.sub.8, N(R.sub.7)C(O)R.sub.8, N(R.sub.7)C(O)N(R.sub.7).sub.2, CN, C(O)R.sub.7, C(O)OR.sub.7, OC(O)R.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7; with the proviso that R.sub.2 and R.sub.3 are not both hydrogen;
R.sub.4 is selected from -phenyl, or -(5- or 6-membered)heteroaryl containing at least one nitrogen atom, each of which is unsubstituted or substituted with 1 or 2 independently selected R.sub.6 groups;
each R.sub.5 is independently selected from (C.sub.1-C.sub.3)alkyl, (C.sub.2-C.sub.3)alkenyl, (C.sub.2-C.sub.3)alkynyl, (C.sub.1-C.sub.3)alkylCOOR.sub.7, OR.sub.7, SR.sub.7, C(halo).sub.2, CH(halo).sub.2, CH.sub.2(halo), CN, O, S, -halo, N.sub.3, NO.sub.2, N(R.sub.7).sub.2, N(R.sub.7)OH, C(O)R.sub.7, C(O)OR.sub.7, OC(O)R.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7;
each R.sub.6 is independently selected from (C.sub.1-C.sub.3)alkyl, (C.sub.2-C.sub.3)alkenyl, (C.sub.2-C.sub.3)alkynyl, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, -halo, N.sub.3, NO.sub.2, N(R.sub.7).sub.2, N(R.sub.7)OH, C(O)R.sub.7, C(O)OR.sub.7, OC(O)R.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7;
each R.sub.7 is independently selected from H, CH.sub.3, or CH.sub.2CH.sub.3;
each T.sub.3 is independently H or (C.sub.1-C.sub.5)alkyl which is unsubstituted or substituted with 1 or 2 independently selected R.sub.5 groups; and
each halo is independently selected from F, Cl, Br, or I.

(109) In a further embodiment, the present invention relates to a compound having the following general formula (II.2):

(110) ##STR00049##
or a pharmaceutically acceptable derivative thereof wherein:
E is O or N(T.sub.3);
R.sub.1 is (C.sub.1-C.sub.3)alkyl which is unsubstituted or substituted with 1 or 2 independently selected R.sub.5 groups;
R.sub.2 and R.sub.3 are each independently selected from CN, -halo, N.sub.3, NO.sub.2, N(R.sub.7).sub.2, N(R.sub.7)OH;
R.sub.4 is selected from -phenyl or -(5- or 6-membered)heteroaryl selected from the group consisting of diazole, triazole, pyridine, pyrazine, pyridazine and pyrimidine;
each R.sub.5 is independently selected from H, (C.sub.1-C.sub.2)alkyl, (C.sub.2)alkenyl, (C.sub.2)alkynyl, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, -halo, N.sub.3, NO.sub.2, N(R.sub.7).sub.2, N(R.sub.7)OH, C(O)R.sub.7, C(O)OR.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7;
each R.sub.7 is independently selected from H, or CH.sub.3; and
each T.sub.3 is independently selected from H or CH.sub.3; and
each halo is independently selected from F, Cl, Br, or I.

(111) In an optional embodiment, the present invention relates to a compound having the general formula (II.2) or a pharmaceutically acceptable derivative thereof, wherein E is O.

(112) In an optional embodiment, the present invention relates to a compound having the general formula (II.2) or a pharmaceutically acceptable derivative thereof, wherein R.sub.1 is CH.sub.3 or CH.sub.2CH.sub.3.

(113) In an optional embodiment, the present invention relates to a compound having the general formula (II.2) or a pharmaceutically acceptable derivative thereof, wherein R.sub.2 and R.sub.3 are each independently selected from NO.sub.2, or NH.sub.2, optionally NO.sub.2.

(114) In an optional embodiment, the present invention relates to a compound having the general formula (II.2) or a pharmaceutically acceptable derivative thereof, wherein R.sub.4 is a diazole or a triazole ring.

(115) In an optional embodiment, the present invention relates to a compound having the general formula (II.2) or a pharmaceutically acceptable derivative thereof, wherein R.sub.4 is

(116) ##STR00050##

(117) In a further embodiment, the present invention relates to a compound having the following general formula (III):

(118) ##STR00051##
or a pharmaceutically acceptable derivative thereof wherein:
R.sub.1 is selected from: (a) (C.sub.3-C.sub.7)cycloalkyl, (C.sub.6-C.sub.14)bicycloalkyl, (C.sub.8-C.sub.20)tricycloalkyl, (C.sub.5-C.sub.10)cycloalkenyl, (C.sub.7-C.sub.14)bicycloalkenyl, (C.sub.8-C.sub.20)tricycloalkenyl, -(5- or 6-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.4 groups; or (b) -phenyl, -naphthalenyl, (C.sub.14)aryl, or -(5- or 6-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.4 groups;
R.sub.2 is selected from: (a) H; or (b) -halo, CN, NO.sub.2; or (c) O, OT.sub.3, OC(O)T.sub.3, OC(O)N(T.sub.1)(T.sub.2), OC(O)OT.sub.3; or (d) C(O)T.sub.3, C(O)OT.sub.3, C(O)N(T.sub.1)(T.sub.2); or (e) S, ST.sub.3, S(O)T.sub.3, S(O).sub.2T.sub.3, S(O).sub.2OT.sub.3, S(O).sub.2N(T.sub.1)(T.sub.2), S(O)OT.sub.3, S(O)N(T.sub.1)(T.sub.2); or (f) NT.sub.3, N(T.sub.1)(T.sub.2), N(T.sub.3)N(T.sub.1)(T.sub.2), N(T.sub.3)C(O)T.sub.3, N(T.sub.3)C(O)OT.sub.3, N(T.sub.3)C(O)N(T.sub.1)(T.sub.2), N(T.sub.3)S(O).sub.2T.sub.3, N(T.sub.3)S(O).sub.2N(T.sub.1)(T.sub.2), N(T.sub.3)S(O)T.sub.3, N(T.sub.3)S(O)N(T.sub.1)(T.sub.2); or (g) (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.6-C.sub.14)bicycloalkyl, (C.sub.8-C.sub.20)tricycloalkyl, (C.sub.5-C.sub.10)cycloalkenyl, (C.sub.7-C.sub.14)bicycloalkenyl, (C.sub.8-C.sub.20)tricycloalkenyl, -(5- or 6-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.5 groups; or (h) -phenyl or -(5- or 6-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.6 groups;
Y is O, S, or N(T.sub.3);
E is O, S, or N(T.sub.3);
R.sub.3 is selected from: (a) (C.sub.3-C.sub.7)cycloalkyl, (C.sub.6-C.sub.14)bicycloalkyl, (C.sub.8-C.sub.20)tricycloalkyl, (C.sub.5-C.sub.10)cycloalkenyl, (C.sub.7-C.sub.14)bicycloalkenyl, (C.sub.8-C.sub.20)tricycloalkenyl, -(5- or 6-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.6 groups; or (b) -phenyl, -naphthalenyl, (C.sub.14)aryl, or -(5- or 6-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.6 groups;
each R.sub.4 is independently selected from (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, -halo, N.sub.3, NO.sub.2, CHN(R.sub.7), N(R.sub.7).sub.2, N(R.sub.7)OH, N(R.sub.7)S(O)R.sub.8, N(R.sub.7)S(O).sub.2R.sub.8, N(R.sub.7)C(O)R.sub.8, N(R.sub.7)C(O)N(R.sub.7).sub.2, N(R.sub.7)C(O)OR, C(O)R.sub.7, C(O)N(R.sub.7).sub.2, C(O)OR.sub.7, OC(O)R.sub.7, OC(O)N(R.sub.7).sub.2, OC(O)OR.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7;
each R.sub.5 is independently selected from (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, -(5- or 6-membered)heteroaryl, -phenyl, (C.sub.1-C.sub.6)alkylCOOR.sub.7, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, O, S, -halo, N.sub.1, NO.sub.2, CHN(R.sub.7), NR.sub.7(C.sub.1-C.sub.6)alkylCOOR.sub.7, N(R.sub.7).sub.2, N(R.sub.7)OH, N(R.sub.7)S(O)R.sub.8, N(R.sub.7)S(O).sub.2R.sub.8, N(R.sub.7)C(O)R.sub.8, N(R.sub.7)C(O)N(R.sub.7).sub.2, N(R.sub.7)C(O)OR.sub.8, C(O)R.sub.7, C(O)C(O)OR.sub.7, C(O)N(R.sub.7), C(O)OR.sub.7, OC(O)R.sub.7, OC(O)N(R.sub.7).sub.2, OC(O)OR.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7;
each R.sub.6 is independently selected from (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, -halo, N.sub.3, NO.sub.2, CHN(R.sub.7), N(R.sub.7).sub.2, N(R.sub.7)OH, N(R.sub.7)S(O)Rx, N(R.sub.7)S(O).sub.2R.sub.8, N(R.sub.7)C(O)R.sub.8, N(R.sub.7)C(O)N(R.sub.7).sub.2, N(R.sub.7)C(O)OR.sub.8, C(O)R.sub.7, C(O)N(R.sub.7).sub.2, C(O)OR.sub.7, OC(O)R.sub.7, OC(O)N(R.sub.7).sub.2, OC(O)OR.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7;
each R.sub.7 is independently selected from H, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.8)cycloalkyl, (C.sub.5-C.sub.8)cycloalkenyl, -phenyl, -benzyl, -(3- to 6-membered)heterocycle, -(5- to 10-membered)heteroaryl, C(halo).sub.3, CH(halo).sub.2, or CH.sub.2(halo);
each R.sub.8 is independently selected from H or (C.sub.1-C.sub.4)alkyl;
each T.sub.1, T.sub.2, and T.sub.3 is independently H or (C.sub.1-C.sub.10)alkyl which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.5 groups:
the dashed line denotes the presence or absence of a bond; and
each halo is independently selected from F, Cl, Br, or I.

(119) In a further embodiment, the present invention relates to a compound having the following general formula (III.1):

(120) ##STR00052##
or a pharmaceutically acceptable derivative thereof wherein:
R.sub.1 is selected from -phenyl or -(5- or 6-membered)heteroaryl, each of which is unsubstituted or substituted with 1 or 2 independently selected R.sub.4 groups;
R.sub.2 is selected from: (a) H; or (b) -halo, CN, NO.sub.2; or (c) OT.sub.3, OC(O)T.sub.3; or (d) C(O)T.sub.3, C(O)OT.sub.3, C(O)N(T)(T.sub.2); or (e) NT.sub.3, N(T.sub.1)(T.sub.2), N(T.sub.3)N(T.sub.1)(T.sub.2), N(T.sub.3)C(O)T.sub.3, N(T.sub.3)C(O)OT.sub.3, N(T.sub.3)C(O)N(T.sub.1)(T.sub.2); or (f) (C.sub.1-C.sub.5)alkyl, (C.sub.2-C.sub.5)alkenyl, (C.sub.2-C.sub.5)alkynyl, (C.sub.1-C.sub.5)alkoxy, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.5-C.sub.10)cycloalkenyl, or -(5- or 6-membered)heterocycle, each of which is unsubstituted or substituted with 1 or 2 independently selected R.sub.5 groups;
E is selected from O or NT.sub.3;
R.sub.3 is selected from -phenyl or -(5- or 6-membered)heteroaryl, each of which is unsubstituted or substituted with 1 or 2 independently selected R.sub.6 groups;
each R.sub.4 is independently selected from (C.sub.1-C.sub.3)alkyl, (C.sub.2-C.sub.3)alkenyl, (C.sub.2-C.sub.3)alkynyl, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, -halo, N.sub.3, NO.sub.2, N(R.sub.7).sub.2, N(R.sub.7)OH, C(O)R.sub.7, C(O)OR.sub.7, C(O)N(R.sub.7).sub.2, OC(O)R.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7;
each R.sub.5 is independently selected from (C.sub.1-C.sub.3)alkyl, (C.sub.2-C.sub.3)alkenyl, (C.sub.2-C.sub.3)alkynyl, (C.sub.1-C.sub.3)alkylCOOR.sub.7, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, O, S, -halo, N.sub.3, NO.sub.2, N(R.sub.7).sub.2, N(R.sub.7)OH, C(O)R.sub.7, C(O)OR.sub.7, OC(O)R.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7;
each R.sub.6 is independently selected from (C.sub.1-C.sub.3)alkyl, (C.sub.2-C.sub.3)alkenyl, (C.sub.2-C.sub.3)alkynyl, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, -halo, N.sub.3, NO.sub.2, N(R.sub.7).sub.2, N(R.sub.7)OH, C(O)R.sub.7, C(O)OR.sub.7, OC(O)R.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7;
each R.sub.7 is independently selected from H, CH.sub.3, or CH.sub.2CH.sub.3;
each T.sub.1, T.sub.2, and T.sub.3 is independently H or (C.sub.1-C.sub.5)alkyl which is unsubstituted or substituted with 1 or 2 independently selected R.sub.5 groups; and
each halo is independently selected from F, Cl, Br, or I.

(121) In a further embodiment, the present invention relates to a compound having the following general formula (III.2):

(122) ##STR00053##
or a pharmaceutically acceptable derivative thereof wherein:
E is O or NH;
R.sub.2 is selected from (C.sub.1-C.sub.2)alkyl, (C.sub.2)alkenyl, (C.sub.2)alkynyl, OR.sub.7, CN, N.sub.3, NO.sub.2, N(R.sub.7).sub.2, N(R.sub.7)OH, C(O)R.sub.7, C(O)OR.sub.7;
R.sub.4 is selected from OR.sub.7, SR.sub.7, C(O)R.sub.7, C(O)N(R.sub.7).sub.2, C(O)OR.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7;
each R.sub.6 is independently selected from C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), or -halo;
a is an integer selected from 1 or 2:
each R.sub.6 is independently selected from H, or CH.sub.3; and
each halo is independently selected from F, Cl, Br, or I.

(123) In an optional embodiment, the present invention relates to a compound having the general formula (III.2) or a pharmaceutically acceptable derivative thereof, wherein a is 1 and the phenyl group comprising (R.sub.6) is substituted as follows:

(124) ##STR00054##
wherein R.sub.6 is defined as above.

(125) In an optional embodiment, the present invention relates to a compound having the general formula (III.2) or a pharmaceutically acceptable derivative thereof, wherein a is 1 and the phenyl group comprising (R.sub.6).sub.a is substituted as follows:

(126) ##STR00055##
wherein R.sub.6 is defined as above.

(127) In an optional embodiment, the present invention relates to a compound having the general formula (III.2) or a pharmaceutically acceptable derivative thereof, wherein a is 1 and the phenyl group comprising (R.sub.6).sub.a is substituted as follows:

(128) wherein R.sub.6 is defined as above.

(129) ##STR00056##

(130) In an optional embodiment, the present invention relates to a compound having the general formula (III.2) or a pharmaceutically acceptable derivative thereof, wherein a is 1 and Hal is F.

(131) In an optional embodiment, the present invention relates to a compound having the general formula (III.2) or a pharmaceutically acceptable derivative thereof, wherein a is 1 and the phenyl group comprising (R.sub.6).sub.a is substituted as follows:

(132) wherein R.sub.6 is -Hal, optionally F.

(133) ##STR00057##

(134) In an optional embodiment, the present invention relates to a compound having the general formula (III.2) or a pharmaceutically acceptable derivative thereof, wherein the phenyl group comprising R.sub.4 is substituted as follows:

(135) ##STR00058##
wherein R.sub.4 is defined as above.

(136) In an optional embodiment, the present invention relates to a compound having the general formula (III.2) or a pharmaceutically acceptable derivative thereof, wherein the phenyl group comprising R.sub.4 is substituted as follows:

(137) ##STR00059##
wherein R.sub.4 is defined as above.

(138) In an optional embodiment, the present invention relates to a compound having the general formula (III.2) or a pharmaceutically acceptable derivative thereof, wherein the phenyl group comprising R.sub.4 is substituted as follows:

(139) ##STR00060##
wherein R.sub.4 is defined as above.

(140) In an optional embodiment, the present invention relates to a compound having the general formula (III.2) or a pharmaceutically acceptable derivative thereof, wherein the phenyl group comprising R.sub.4 is substituted as follows:

(141) ##STR00061##
wherein R.sub.4 is C(O)OH, C(O)OCH.sub.3, C(O)NH.sub.2, or C(O)N(CH.sub.3).sub.2, optionally C(O)OCH.sub.3.

(142) In an optional embodiment, the present invention relates to a compound having the general formula (III.2) or a pharmaceutically acceptable derivative thereof, wherein a is 1 and the phenyl group comprising (R.sub.6).sub.a is substituted as follows:

(143) ##STR00062##
wherein R.sub.6 is defined as above; and wherein the phenyl group comprising R.sub.4 is substituted as follows:

(144) ##STR00063##
wherein R.sub.1 is defined as above.

(145) In an optional embodiment, the present invention relates to a compound having the general formula (III.2) or a pharmaceutically acceptable derivative thereof, wherein a is 1 and the phenyl group comprising (R.sub.6).sub.a is substituted as follows:

(146) ##STR00064##
wherein R.sub.6 is -Hal, optionally F; and wherein the phenyl group comprising R.sub.4 is substituted as follows:

(147) ##STR00065##
wherein R.sub.4 is C(O)OH or C(O)OCH.sub.3.

(148) In an optional embodiment, the present invention relates to a compound having the general formula (III.2) or a pharmaceutically acceptable derivative thereof, wherein E is O.

(149) In an optional embodiment, the present invention relates to a compound having the general formula (III.2) or a pharmaceutically acceptable derivative thereof, wherein R.sub.2 is selected from (C.sub.2)alkenyl, (C.sub.2)alkynyl, or CN.

(150) In an optional embodiment, the present invention relates to a compound having the general formula (III.2) or a pharmaceutically acceptable derivative thereof, wherein R.sub.2 is CN.

(151) In a further embodiment, the present invention relates to a compound having the following general formula (IV):

(152) ##STR00066##
or a pharmaceutically acceptable derivative thereof wherein:
R.sub.1 is selected from: (a) (C.sub.3-C.sub.7)cycloalkyl, (C.sub.6-C.sub.14)bicycloalkyl, (C.sub.5-C.sub.10)cycloalkenyl, (C.sub.7-C.sub.14)bicycloalkenyl, -(5- or 6-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.5 groups; or (b) -phenyl or -(5- or 6-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.6 groups;
R.sub.2 is selected from: (a) (C.sub.3-C.sub.7)cycloalkyl, (C.sub.6-C.sub.14)bicycloalkyl, (C.sub.5-C.sub.10)cycloalkenyl, (C.sub.7-C.sub.14)bicycloalkenyl, -(5- or 6-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.3 groups; or (b) -phenyl or -(5- or 6-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.3 groups;
each R.sub.3 is independently selected from: (a) -halo, CN, NO.sub.2; or (b) OT.sub.3, OC(O)T.sub.3, OC(O)N(T.sub.1)(T.sub.2), OC(O)OT.sub.3; or (c) C(O)T.sub.3, C(O)OT.sub.3, C(O)N(T.sub.1)T.sub.2); or (d) ST.sub.3, S(O)T.sub.3, S(O).sub.2T.sub.3, S(O).sub.2OT.sub.3, S(O).sub.2N(T.sub.1)(T.sub.2), S(O)OT.sub.3, S(O)N(T.sub.1)(T.sub.2); or (e) N(T.sub.1)(T.sub.2), N(T.sub.3)N(T.sub.1)(T.sub.2), N(T.sub.3)C(O)T.sub.3, N(T.sub.3)C(O)OT.sub.3, N(T.sub.3)C(O)N(T.sub.1)(T.sub.2), N(T.sub.3)S(O).sub.2T.sub.3, N(T.sub.3)S(O).sub.2N(T.sub.1)(T.sub.2), N(T.sub.3)S(O)T.sub.3, N(T.sub.3)S(O)N(T.sub.1)(T.sub.2); or (f) (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.6-C.sub.14)bicycloalkyl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.5 groups; or (g) -phenyl or -(5- or 6-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.6 groups;
E.sub.1 is selected from O, C(O), C(O)O, C(O)NH, OC(O)NH, OC(O)O, S, S(O), S(O).sub.2, S(O).sub.2O, S(O).sub.2NH, S(O)O, S(O)NH, or NH;
E.sub.2 is selected from C(T.sub.3) or N;
E.sub.3 and E.sub.4 are each independently selected from C(T.sub.3).sub.2, O, S or NT.sub.3;
the dashed lines each denote the presence or absence of a bond, wherein E.sub.5 is selected from C(T.sub.3).sub.2, O, S or NT.sub.3 if the bond is absent, and E.sub.5 is selected from CT.sub.3, or N if the bond is present;
Q is selected from fused benzo or (5- or 6-membered)heterocycle;
n is an integer selected from 0, 1, 2, or 3;
each R.sub.5 is independently selected from (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, -(5- or 6-membered)heteroaryl, -phenyl, (C.sub.1-C.sub.6)alkylCOOR.sub.7, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, O, S, -halo, N.sub.3, NO.sub.2, CHN(R.sub.7), NR.sub.7(C.sub.1-C.sub.6)alkylCOOR.sub.7, N(R.sub.7).sub.2, N(R.sub.7)OH, N(R.sub.7)S(O)R.sub.8, N(R.sub.7)S(O).sub.2R.sub.8, N(R.sub.7)C(O)R.sub.8, N(R.sub.7)C(O)N(R.sub.7).sub.2, N(R.sub.7)C(O)OR.sub.8, C(O)R.sub.7, C(O)C(O)OR.sub.7, C(O)N(R.sub.7).sub.2, C(O)OR.sub.7, OC(O)R.sub.7, OC(O)N(R.sub.7).sub.2, OC(O)OR.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7;
each R.sub.6 is independently selected from (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, -halo, N.sub.3, NO.sub.2, CHN(R.sub.7), N(R.sub.7).sub.2, N(R.sub.7)OH, N(R.sub.7)S(O)R.sub.8, N(R.sub.7)S(O).sub.2R.sub.8, N(R.sub.7)C(O)R.sub.8, N(R.sub.7)C(O)N(R.sub.7).sub.2, N(R.sub.7)C(O)OR.sub.8, C(O)R.sub.7, C(O)N(R.sub.7).sub.2, C(O)OR.sub.7, OC(O)R.sub.7, OC(O)N(R.sub.7).sub.2, OC(O)OR.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7;
each R.sub.7 is independently selected from H, (C.sub.1-C.sub.5)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.8)cycloalkyl, (C.sub.5-C.sub.5)cycloalkenyl, -phenyl, -benzyl, -(3- to 6-membered)heterocycle, -(5- to 10-membered)heteroaryl, C(halo).sub.3, CH(halo).sub.2, or CH.sub.2(halo);
each R.sub.8 is independently selected from H or (C.sub.1-C.sub.4)alkyl;
each T.sub.1, T.sub.2, and T.sub.3 is independently H or (C.sub.1-C.sub.10)alkyl which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.5 groups; and
each halo is independently selected from F, Cl, Br, or I.

(153) In a further embodiment, the present invention relates to a compound having the following general formula (IV.1):

(154) ##STR00067##
or a pharmaceutically acceptable derivative thereof wherein:
R.sub.1 is (C.sub.3-C.sub.7)cycloalkyl, (C.sub.5-C.sub.10)cycloalkenyl, or -(5- or 6-membered)heterocycle, each of which is unsubstituted or substituted with 1 or 2 independently selected R.sub.5 groups;
each R.sub.3 is independently selected from: (a) -halo, CN, NO.sub.2; or (b) OT.sub.3, OC(O)T.sub.3, OC(O)N(T.sub.1)(T.sub.2), OC(O)OT.sub.3 or (c) C(O)T.sub.3, C(O)OT.sub.3, C(O)N(T.sub.1)(T.sub.2); or (d) ST.sub.3, S(O)T.sub.3, S(O).sub.2T.sub.3, S(O).sub.2OT.sub.3, S(O).sub.2N(T.sub.1)(T.sub.2), S(O)OT.sub.3, S(O)N(T.sub.1)(T.sub.2); or (e) N(T.sub.1)(T.sub.2), N(T.sub.3)N(T.sub.1)(T.sub.2), N(T.sub.3)C(O)T.sub.3, N(T.sub.3)C(O)OT.sub.3, N(T)C(O)N(T.sub.1)(T.sub.2), N(T.sub.3)S(O).sub.2T.sub.3, N(T.sub.3)S(O).sub.2N(T.sub.1)(T.sub.2), N(T)S(O)T.sub.3, N(T.sub.3)S(O)N(T.sub.1)(T.sub.2); or (f) (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.6-C.sub.14)bicycloalkyl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.5 groups; or (g) -phenyl or -(5- or 6-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.6 groups;
E.sub.1 is selected from C(O), C(O)O, C(O)NH, S(O), S(O).sub.2, S(O)O, or S(O)NH;
E.sub.2 is selected from C(T.sub.3) or N;
E.sub.3 and E.sub.4 are each independently selected from C(T.sub.3).sub.2, O, S or NT.sub.3;
E.sub.5 is selected from CT.sub.3, or N;
the dashed lines each denote the presence or absence of a bond, wherein E.sub.6 is selected from C(T.sub.3).sub.2, O, S or NT.sub.3 if the bond is absent, and E.sub.6 is selected from CT.sub.3, or N if the bond is present;
E.sub.7 is selected from C(T.sub.3).sub.2, O, S or NT.sub.3;
n is an integer selected from 0, 1, or 2;
m is an integer selected from 1 or 2; wherein: (a) if m=1, the ring denoted as Q is -(5-membered)heteroaryl containing 1 or 2 nitrogen atoms in place of a ring carbon atom; and (b) if m=2, the ring denoted as Q is -phenyl or -(6-membered)heteroaryl containing 1 or 2 nitrogen atoms in place of a ring carbon atom;
a is an integer selected from 1, 2, or 3;
each R.sub.5 is independently selected from (C.sub.1-C.sub.3)alkyl, (C.sub.2-C.sub.3)alkenyl, (C.sub.2-C.sub.3)alkynyl, (C.sub.1-C.sub.3)alkylCOOR.sub.7, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, O, S, -halo, N.sub.3, NO.sub.2, N(R.sub.7).sub.2, N(R.sub.7)OH, C(O)R.sub.7, C(O)OR.sub.7, OC(O)R.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7;
each R.sub.6 is independently selected from (C.sub.1-C.sub.3)alkyl, (C.sub.2-C.sub.3)alkenyl, (C.sub.2-C.sub.3)alkynyl, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, -halo, N.sub.3, NO.sub.2, N(R.sub.7).sub.2, N(R.sub.7)OH, C(O)R.sub.7, C(O)OR.sub.7, OC(O)R.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7;
each R.sub.7 is independently selected from H, CH.sub.3, or CH.sub.2CH.sub.3;
each T.sub.1, T.sub.2, and T.sub.3 is independently H or (C.sub.1-C.sub.5)alkyl which is unsubstituted or substituted with 1 or 2 independently selected R.sub.5 groups; and
each halo is independently selected from F, Cl, Br, or I.

(155) In a further embodiment, the present invention relates to a compound having the following general formula (IV.2):

(156) ##STR00068##
or a pharmaceutically acceptable derivative thereof wherein:
R.sub.1 is -(5- or 6-membered)heterocycle containing at least one nitrogen atom, each of which is unsubstituted or substituted with 1 or 2 independently selected R.sub.5 groups;
each R.sub.3 is independently selected from (C.sub.1-C.sub.3)alkyl, (C.sub.2-C.sub.3)alkenyl, (C.sub.2-C.sub.3)alkynyl, or (C.sub.1-C.sub.3)alkoxy;
each R.sub.6 is independently selected from C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), or -halo;
a is an integer selected from 1 or 2;
E.sub.1 is selected from C(O), C(O)O, C(O)NH, S(O), or S(O).sub.2;
E.sub.3 and E.sub.4 are each independently selected from O, S or NT.sub.3;
E.sub.7 is selected from CH.sub.2, O or S;
the 5-membered ring denoted as Q is a -(5-membered)heteroaryl containing at least one nitrogen atom at the position as depicted in formula (IV.2);
R.sub.5 is selected from H, (C.sub.1-C.sub.2)alkyl, (C.sub.2)alkenyl, (C.sub.2)alkynyl, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, -halo, N.sub.3, NO.sub.2, N(R.sub.7).sub.2, N(R.sub.7)OH, C(O)R.sub.7, C(O)OR.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7;
each R.sub.7 is independently selected from H, or CH.sub.3;
each T.sub.3 is independently selected from H or CH.sub.3; and
each halo is independently selected from F, Cl, Br, or I.

(157) In an optional embodiment, the present invention relates to a compound having the general formula (IV.2) or a pharmaceutically acceptable derivative thereof, wherein R.sub.1 is:

(158) ##STR00069##
wherein R.sub.5 is defined as above.

(159) In an optional embodiment, the present invention relates to a compound having the general formula (IV.2) or a pharmaceutically acceptable derivative thereof, wherein R.sub.1 is:

(160) ##STR00070##

(161) In an optional embodiment, the present invention relates to a compound having the general formula (IV.2) or a pharmaceutically acceptable derivative thereof, wherein E.sub.1 is C(O).

(162) In an optional embodiment, the present invention relates to a compound having the general formula (IV.2) or a pharmaceutically acceptable derivative thereof, wherein E.sub.3 is NT.sub.3, wherein T.sub.3 is selected from H or CH.sub.3.

(163) In an optional embodiment, the present invention relates to a compound having the general formula (IV.2) or a pharmaceutically acceptable derivative thereof, wherein E.sub.3 is NH.

(164) In an optional embodiment, the present invention relates to a compound having the general formula (IV.2) or a pharmaceutically acceptable derivative thereof, wherein E.sub.4 is O.

(165) In an optional embodiment, the present invention relates to a compound having the general formula (IV.2) or a pharmaceutically acceptable derivative thereof, wherein E.sub.7 is S.

(166) In an optional embodiment, the present invention relates to a compound having the general formula (IV.2) or a pharmaceutically acceptable derivative thereof, wherein E.sub.1 is C(O), E.sub.3 is NH, E.sub.4 is O and E.sub.7 is S.

(167) In an optional embodiment, the present invention relates to a compound having the general formula (IV.2) or a pharmaceutically acceptable derivative thereof, wherein each R.sub.3 is independently selected from (C.sub.1-C.sub.3)alkyl, optionally CH.sub.3.

(168) In an optional embodiment, the present invention relates to a compound having the general formula (IV.2) or a pharmaceutically acceptable derivative thereof, wherein a=2.

(169) In an optional embodiment, the present invention relates to a compound having the general formula (IV.2) or a pharmaceutically acceptable derivative thereof, wherein the 5-membered ring denoted as Q is:

(170) ##STR00071##
wherein R.sub.3 and R.sub.6 are defined as above.

(171) In an optional embodiment, the present invention relates to a compound having the general formula (IV.2) or a pharmaceutically acceptable derivative thereof, wherein the 5-membered ring denoted as Q is:

(172) ##STR00072##
wherein R.sub.3 and R.sub.6 are defined as above.

(173) In an optional embodiment, the present invention relates to a compound having the general formula (IV.2) or a pharmaceutically acceptable derivative thereof, wherein the 5-membered ring denoted as Q is:

(174) ##STR00073##
wherein R.sub.3 and R.sub.6 are defined as above.

(175) In an optional embodiment, the present invention relates to a compound having the general formula (IV.2) or a pharmaceutically acceptable derivative thereof, wherein the 5-membered ring denoted as Q is:

(176) ##STR00074##
wherein R.sub.3 and R.sub.6 are defined as above.

(177) In an optional embodiment, the present invention relates to a compound having the general formula (IV.2) or a pharmaceutically acceptable derivative thereof, wherein the 5-membered ring denoted as Q is:

(178) ##STR00075##
wherein each R.sub.3 is CH.sub.3 and R.sub.6 is defined as above.

(179) In an optional embodiment, the present invention relates to a compound having the general formula (IV.2) or a pharmaceutically acceptable derivative thereof, wherein halo is Cl.

(180) In an optional embodiment, the present invention relates to a compound having the general formula (IV.2) or a pharmaceutically acceptable derivative thereof, wherein the phenyl group comprising R.sub.6 is substituted as follows:

(181) ##STR00076##
wherein R.sub.6 is defined as above.

(182) In an optional embodiment, the present invention relates to a compound having the general formula (IV.2) or a pharmaceutically acceptable derivative thereof, wherein the phenyl group comprising R.sub.6 is substituted as follows:

(183) ##STR00077##
wherein R.sub.6 is defined as above.

(184) In an optional embodiment, the present invention relates to a compound having the general formula (IV.2) or a pharmaceutically acceptable derivative thereof, wherein the phenyl group comprising R.sub.6 is substituted as follows:

(185) ##STR00078##
wherein R.sub.6 is defined as above.

(186) In an optional embodiment, the present invention relates to a compound having the general formula (IV.2) or a pharmaceutically acceptable derivative thereof, wherein the phenyl group comprising R.sub.6 is substituted as follows:

(187) ##STR00079##
wherein R.sub.6 is Cl.

(188) In an optional embodiment, the present invention relates to a compound having the general formula (IV.2) or a pharmaceutically acceptable derivative thereof, wherein the 5-membered ring denoted as Q is:

(189) ##STR00080##
wherein R.sub.3 and R.sub.6 are defined as above.

(190) In an optional embodiment, the present invention relates to a compound having the general formula (IV.2) or a pharmaceutically acceptable derivative thereof, wherein the 5-membered ring denoted as Q is:

(191) ##STR00081##
wherein R.sub.3 is CH.sub.3 and R.sub.6 is Cl.

(192) In one embodiment, the present invention relates to a compound having the following general formula (V):

(193) ##STR00082##
or a pharmaceutically acceptable derivative thereof wherein:
Q is selected from fused benzo or (5- or 6-membered)heteroaryl;
each R.sub.1, R.sub.3 and R.sub.4 are each independently selected from: (a) -halo, CN, NO.sub.2; or (b) OT.sub.3, OC(O)T.sub.3, OC(O)N(T.sub.1)(T.sub.2), OC(O)OT.sub.3; or (c) C(O)T.sub.3, C(O)OT.sub.3, C(O)N(T.sub.1)(T.sub.2); or (d) ST.sub.3, S(O)T.sub.3, S(O).sub.2T.sub.3, S(O).sub.2OT.sub.3, S(O).sub.2N(T.sub.1)(T.sub.2), S(O)OT.sub.3, S(O)N(T.sub.1)(T.sub.2); or (e) N(T.sub.1)(T.sub.2), N(T.sub.3)N(T.sub.1)(T.sub.2), N(T.sub.3)C(O)T.sub.3, N(T.sub.3)C(O)OT.sub.3, N(T.sub.3)C(O)N(T,)(T.sub.2), N(T.sub.3)S(O).sub.2T.sub.3, N(T.sub.3)S(O).sub.2N(T.sub.1)(T.sub.2), N(T.sub.3)S(O)T.sub.3, N(T.sub.3)S(O)N(T.sub.1)(T.sub.2); or (f) (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.6-C.sub.14)bicycloalkyl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.5 groups; or (g) -phenyl or -(5- or 6-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.6 groups;
a is an integer selected from 1, 2 or 3;
b is an integer selected from 1, 2 or 3;
c is an integer selected from 0, 1, 2 or 3;
R.sub.2 is selected from H and CH.sub.3;
R.sub.2 is selected from H and CH.sub.3;
n is an integer selected from 0 or 1;
each R.sub.5 is independently selected from (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, -(5- or 6-membered)heteroaryl, -phenyl, (C.sub.1-C.sub.6)alkylCOOR.sub.7, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, O, S, -halo, N.sub.3, NO.sub.2, CHN(R.sub.7), NR.sub.7(C.sub.1-C.sub.6)alkylCOOR.sub.7, N(R.sub.7).sub.2, N(R.sub.7)OH, N(R.sub.7)S(O)R.sub.8, N(R.sub.7)S(O).sub.2R.sub.8, N(R.sub.7)C(O)R.sub.8, N(R.sub.7)C(O)N(R.sub.7).sub.2, N(R.sub.7)C(O)OR.sub.8, C(O)R.sub.7, C(O)C(O)OR.sub.7, C(O)N(R.sub.7).sub.2, C(O)OR.sub.7, OC(O)R.sub.7, OC(O)N(R.sub.7).sub.2, OC(O)OR.sub.7, S(O)R.sub.7, or S(O).sub.1R.sub.7;
each R.sub.6 is independently selected from (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, -halo, N.sub.3, NO.sub.2, CHN(R.sub.7), N(R.sub.7).sub.2, N(R.sub.7)OH, N(R.sub.7)S(O)R.sub.8, N(R.sub.7)S(O).sub.2R.sub.8, N(R.sub.7)C(O)R.sub.8, N(R.sub.7)C(O)N(R.sub.7).sub.2, N(R.sub.7)C(O)OR.sub.3, C(O)R.sub.7, C(O)N(R.sub.7).sub.2, C(O)OR.sub.7, OC(O)R.sub.7, OC(O)N(R.sub.7).sub.2, OC(O)OR.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7;
each R.sub.7 is independently selected from H, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.8)cycloalkyl, (C.sub.5-C.sub.8)cycloalkenyl, -phenyl, -benzyl, -(3- to 6-membered)heterocycle, -(5- to 10-membered)heteroaryl, C(halo).sub.3, CH(halo).sub.2, or CH.sub.2(halo);
each R.sub.8 is independently selected from H or (C.sub.1-C.sub.4)alkyl:
each T.sub.1, T.sub.2, and T.sub.3 is independently H or (C.sub.1-C.sub.10)alkyl which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.5 groups;
each halo is independently selected from F, Cl, Br, or I.

(194) In a further embodiment, the present invention relates to a compound having the following general formula (V.1):

(195) ##STR00083##
or a pharmaceutically acceptable derivative thereof wherein:
Q is selected from fused benzo or 6-membered heteroaryl;
each R.sub.1 is independently selected from: (a) -halo, CN, NO.sub.2; or (b) OT.sub.3, OC(O)T.sub.3; or (c) C(O)T.sub.3, C(O)OT.sub.3, C(O)N(T.sub.1)(T.sub.2); or (d) ST.sub.3, S(O)T.sub.3, S(O).sub.2T.sub.3, S(O).sub.2OT.sub.3; or (e) (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, (C.sub.2-C.sub.4)alkynyl, (C.sub.1-C.sub.4)alkoxy, each of which is unsubstituted or substituted with 1 or 2 independently selected R.sub.5 groups;
each R.sub.3 is independently selected from: (a) -halo, CN, NO.sub.2; or (b) OT.sub.3, OC(O)T.sub.3; or (c) C(O)T.sub.3, C(O)OT.sub.3, C(O)N(T.sub.1)(T.sub.2); or (d) ST.sub.3, S(O)T.sub.3, S(O).sub.2T.sub.3, S(O).sub.2OT.sub.3; or (e) (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, (C.sub.2-C.sub.4)alkynyl, (C.sub.1-C.sub.4)alkoxy, each of which is unsubstituted or substituted with 1 or 2 independently selected R.sub.5 groups;
each R.sub.4 is independently selected from: (a) -halo, CN, NO.sub.2; or (b) OT.sub.3, OC(O)T.sub.3; or (c) C(O)T.sub.3, C(O)OT.sub.3, C(O)N(T.sub.1)(T.sub.2); or (d) ST.sub.3, S(O)T.sub.3, S(O).sub.2T.sub.3, S(O).sub.2OT.sub.3; or (e) (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, (C.sub.2-C.sub.4)alkynyl, (C.sub.1-C.sub.4)alkoxy, each of which is unsubstituted or substituted with 1 or 2 independently selected R.sub.5 groups;
a is an integer selected from 1 or 2;
b is an integer selected from 1 or 2;
c is an integer selected from 0 or 1;
R.sub.2 is selected from H and CH.sub.3;
R.sub.2 is selected from H and CH.sub.3;
each R.sub.5 is independently selected from (C.sub.1-C.sub.3)alkyl, (C.sub.2-C.sub.3)alkenyl, (C.sub.2-C.sub.3)alkynyl, (C.sub.1-C.sub.3)alkylCOOR.sub.7, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, O, S, -halo, N.sub.3, NO.sub.2, N(R.sub.7).sub.2, N(R.sub.7)OH, C(O)R.sub.7, C(O)OR.sub.7, OC(O)R.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7;
each R.sub.6 is independently selected from (C.sub.1-C.sub.3)alkyl, (C.sub.2-C.sub.3)alkenyl, (C.sub.2-C.sub.3)alkynyl, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2, CH.sub.2(halo), CN, -halo, N.sub.3, NO.sub.2, N(R.sub.7).sub.2, N(R.sub.7)OH, C(O)R.sub.7, C(O)OR.sub.7, OC(O)R.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7;
each R.sub.7 is independently selected from H, CH.sub.3, or CH.sub.2CH.sub.3;
each T.sub.1, T.sub.2, and T.sub.3 is independently H or (C.sub.1-C.sub.5)alkyl which is unsubstituted or substituted with 1 or 2 independently selected R.sub.5 groups; and
each halo is independently selected from F, Cl, Br, or I.

(196) In a further embodiment, the present invention relates to a compound having the following general formula (V.2):

(197) ##STR00084##
or a pharmaceutically acceptable derivative thereof wherein:
R.sub.1 is selected from (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, (C.sub.2-C.sub.4)alkynyl, (C.sub.1-C.sub.4)alkoxy, each of which is unsubstituted or substituted with 1 or 2 independently selected R.sub.5 groups;
R.sub.2 is selected from H and CH.sub.3;
R.sub.2 is selected from H and CH.sub.3;
each R.sub.3 is independently selected from: (a) OT.sub.3, OC(O)T.sub.3; or (b) C(O)T.sub.3, C(O)OT.sub.3, C(O)N(T.sub.1)(T.sub.2); or (c) (C.sub.1-C.sub.3)alkyl, (C.sub.2-C.sub.3)alkenyl, (C.sub.2-C.sub.3)alkynyl, (C.sub.1-C.sub.3)alkoxy;
each R.sub.4 is independently selected from: (a) -halo, CN, NO.sub.2; or (b) OT.sub.3, OC(O)T.sub.3; or (c) C(O)T.sub.3, C(O)OT.sub.3; or (d) ST.sub.3, S(O)T.sub.3, S(O).sub.2T.sub.3, S(O).sub.2OT.sub.3; or (e) (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, (C.sub.2-C.sub.4)alkynyl, (C.sub.1-C.sub.4)alkoxy, each R.sub.5 is independently selected from H, (C.sub.1-C.sub.2)alkyl, (C.sub.7)alkenyl, (C.sub.2)alkynyl, OR.sub.7, SR.sub.7, C(halo).sub.3, CH(halo).sub.2. CH.sub.2(halo), CN, -halo, N.sub.3, NO.sub.2, N(R.sub.7).sub.2, N(R.sub.7)OH, C(O)R.sub.7, C(O)OR.sub.7, S(O)R.sub.7, or S(O).sub.2R.sub.7;
b is an integer selected from 1 or 2;
c is an integer selected from 0 or 1;
each R.sub.7 is independently selected from H, or CH.sub.3;
each T.sub.1, T.sub.2, and T.sub.3 is independently selected from H or CH.sub.3; and
each halo is independently selected from F, Cl, Br, or I.

(198) In an optional embodiment, the present invention relates to a compound having the general formula (V.2) or a pharmaceutically acceptable derivative thereof, wherein the fused benzo is substituted as follows:

(199) ##STR00085##
wherein R.sub.1 is defined as above.

(200) In an optional embodiment, the present invention relates to a compound having the general formula (V.2) or a pharmaceutically acceptable derivative thereof, wherein the fused benzo is substituted as follows:

(201) ##STR00086##
wherein R.sub.1 is defined as above.

(202) In an optional embodiment, the present invention relates to a compound having the general formula (V.2) or a pharmaceutically acceptable derivative thereof, wherein the fused benzo is substituted as follows:

(203) ##STR00087##
wherein R.sub.1 is (C.sub.1-C.sub.4)alkyl, optionally isopropyl.

(204) In an optional embodiment, the present invention relates to a compound having the general formula (V.2) or a pharmaceutically acceptable derivative thereof, wherein R.sub.1 is (C.sub.1-C.sub.4)alkyl, optionally isopropyl.

(205) In an optional embodiment, the present invention relates to a compound having the general formula (V.2) or a pharmaceutically acceptable derivative thereof, wherein the octahydrophenanthrene ring is substituted as follows:

(206) ##STR00088##
wherein R.sub.3, R.sub.2, R.sub.2 and b are defined as above.

(207) In an optional embodiment, the present invention relates to a compound having the general formula (V.2) or a pharmaceutically acceptable derivative thereof, wherein the octahydrophenanthrene ring is substituted as follows:

(208) ##STR00089##
wherein R.sub.3 and b are defined as above.

(209) In an optional embodiment, the present invention relates to a compound having the general formula (V.2) or a pharmaceutically acceptable derivative thereof, wherein the octahydrophenanthrene ring is substituted as follows:

(210) ##STR00090##
wherein R.sub.3 and b=2.

(211) In an optional embodiment, the present invention relates to a compound having the general formula (V.2) or a pharmaceutically acceptable derivative thereof, wherein b=2.

(212) In an optional embodiment, the present invention relates to a compound having the general formula (V.2) or a pharmaceutically acceptable derivative thereof, wherein R.sub.2 is CH.sub.3.

(213) In an optional embodiment, the present invention relates to a compound having the general formula (V.2) or a pharmaceutically acceptable derivative thereof, wherein R.sub.2 is H.

(214) In an optional embodiment, the present invention relates to a compound having the general formula (V.2) or a pharmaceutically acceptable derivative thereof, wherein R.sub.2 is CH.sub.3 and R.sub.2 is H.

(215) In an optional embodiment, the present invention relates to a compound having the general formula (V.2) or a pharmaceutically acceptable derivative thereof, wherein b=2 and one R.sub.3 is C(O)OT.sub.3 or C(O)NH-T.sub.3 and the other R.sub.3 is (C.sub.1-C.sub.3)alkyl, and wherein T.sub.3 is H or CH.sub.3.

(216) In an optional embodiment, the present invention relates to a compound having the general formula (V.2) or a pharmaceutically acceptable derivative thereof, wherein c=0.

(217) In an optional embodiment, the present invention relates to a compound having the general formula (V.2) or a pharmaceutically acceptable derivative thereof, wherein the octahydrophenanthrene ring is substituted as follows:

(218) ##STR00091##

(219) In an optional embodiment, the present invention relates to a compound having the general formula (V.2) or a pharmaceutically acceptable derivative thereof, wherein the octahydrophenanthrene ring is substituted as follows:

(220) ##STR00092##

(221) In an optional embodiment, the present invention relates to a compound having the general formula (V.2) or a pharmaceutically acceptable derivative thereof, wherein the octahydrophenanthrene ring is substituted as follows:

(222) ##STR00093##

(223) In an optional embodiment, the present invention relates to a compound having the general formula (V.2) or a pharmaceutically acceptable derivative thereof, wherein the octahydrophenanthrene ring is substituted as follows:

(224) ##STR00094##

(225) In an optional embodiment, the present invention relates to a compound having the general formula (V.2) or a pharmaceutically acceptable derivative thereof, wherein the octahydrophenanthrene ring is substituted as follows:

(226) ##STR00095##
Exemplified Compounds

(227) In an optional embodiment, the present invention relates to the compounds depicted in Table 1 or a pharmaceutically acceptable derivative thereof.

(228) TABLE-US-00002 TABLE 1 Compound Chemical structure I.3 II.3 III.3 IV.3 V.3 00

(229) In an optional embodiment, the present invention relates to a compound having the general formula (I.2) or (I.2.1) or a pharmaceutically acceptable derivative thereof, where Compound (I.3) is excluded.

(230) In an optional embodiment, the present invention relates to a compound having the general formula (II.2) or a pharmaceutically acceptable derivative thereof, where Compound (II.3) is excluded.

(231) In an optional embodiment, the present invention relates to a compound having the general formula (III.2) or a pharmaceutically acceptable derivative thereof, where Compound (III.3) is excluded.

(232) In an optional embodiment, the present invention relates to a compound having the general formula (IV.2) or a pharmaceutically acceptable derivative thereof, where Compound (IV.3) is excluded.

(233) In an optional embodiment, the present invention relates to a compound having the general formula (V.2) or a pharmaceutically acceptable derivative thereof, where Compound (V.3) is excluded.

(234) Definitions

(235) As used in connection with the Compounds herein, the terms used herein having following meaning:

(236) When a first group is substituted with one or more second groups, one or more hydrogen atoms of the first group is replaced with a corresponding number of second groups. When the number of second groups is two or greater, each second group can be the same or different. In one embodiment, a first group is substituted with up to three second groups. In another embodiment, a first group is substituted with one or two second groups. In another embodiment, a first group is substituted with only one second group.

(237) (C.sub.1-C.sub.10)alkyl means a straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms. Representative straight chain (C.sub.1-C.sub.10)alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl, and -n-decyl. A branched alkyl means that one or more straight chain (C.sub.1-C.sub.8)alkyl groups, such as methyl, ethyl or propyl, replace one or both hydrogens in a CH.sub.2-group of a straight chain alkyl. A branched non-cyclic hydrocarbon means that one or more straight chain (C.sub.1-C.sub.10)alkyl groups, such as methyl, ethyl or propyl, replace one or both hydrogens in a CH.sub.2 group of a straight chain non-cyclic hydrocarbon. Representative branched (C.sub.1-C.sub.10)alkyls include -iso-propyl, -sec-butyl, -iso-butyl, -tert-butyl, -iso-pentyl, -neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,2-dimethylhexyl, 1,3-dimethylhexyl, 3,3-dimethylhexyl, 1,2-dimethylheptyl, 1,3-dimethylheptyl, and 3,3-dimethylheptyl.

(238) (C.sub.1-C.sub.6)alkyl means a straight chain or branched non-cyclic hydrocarbon having from 1 to 6 carbon atoms. Representative straight chain (C.sub.1-C.sub.5)alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl. Representative branched (C.sub.1-C.sub.6)alkyls include -iso-propyl, -sec-butyl, -iso-butyl, -tert-butyl, -iso-pentyl, -neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylbutyl.

(239) (C.sub.1-C.sub.4)alkyl means a straight chain or branched non-cyclic hydrocarbon having from 1 to 4 carbon atoms. Representative straight chain (C.sub.1-C.sub.4)alkyls include -methyl, -ethyl, -n-propyl, and -n-butyl. Representative branched (C.sub.1-C.sub.4)alkyls include -iso-propyl, -sec-butyl, -iso-butyl, and -tert-butyl.

(240) (C.sub.1-C.sub.3)alkyl means a straight chain or branched non-cyclic hydrocarbon having from 1 to 3 carbon atoms. Representative straight chain (C.sub.1-C.sub.3)alkyls include -methyl, -ethyl, and -n-propyl. Representative branched (C.sub.1-C.sub.3)alkyls include -iso-propyl.

(241) (C.sub.1-C.sub.2)alkyl means a straight chain non-cyclic hydrocarbon having 1 or 2 carbon atoms. Representative straight chain (C.sub.1-C.sub.2)alkyls include -methyl and -ethyl.

(242) (C.sub.2-C.sub.10)alkenyl means a straight chain or branched non-cyclic hydrocarbon having from 2 to 10 carbon atoms and including at least one carbon-carbon double bond. A branched alkenyl means that one or more straight chain (C.sub.1-C.sub.5)alkyl groups, such as methyl, ethyl or propyl, replace one or both hydrogens in a CH.sub.2 or CH group of a straight chain alkenyl. Representative straight chain and branched (C.sub.2-C.sub.10)alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl, -iso-butylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl, -3-hexenyl, -1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl, -2-octenyl, -3-octenyl, -1-nonenyl, -2-nonenyl, -3-nonenyl, -1-decenyl, -2-decenyl, -3-decenyl, and the like.

(243) (C.sub.2-C.sub.6)alkenyl means a straight chain or branched non-cyclic hydrocarbon having from 2 to 6 carbon atoms and including at least one carbon-carbon double bond. Representative straight chain and branched (C.sub.2-C.sub.6)alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl, -iso-butylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, 2-hexenyl, 3-hexenyl, and the like.

(244) (C.sub.2-C.sub.4)alkenyl means a straight chain or branched non-cyclic hydrocarbon having from 2 to 4 carbon atoms and including at least one carbon-carbon double bond. Representative (C.sub.2-C.sub.4)alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl, -iso-butylenyl, and the like.

(245) (C.sub.2-C.sub.3)alkenyl means a straight chain or branched non-cyclic hydrocarbon having from 2 to 3 carbon atoms and including at least one carbon-carbon double bond. Representative (C.sub.2-C.sub.3)alkenyls include -vinyl, -allyl, and the like.

(246) (C.sub.2)alkenyl means a straight chain non-cyclic hydrocarbon having 2 carbon atoms and including one carbon-carbon double bond.

(247) (C.sub.2-C.sub.10)alkynyl means a straight chain or branched non-cyclic hydrocarbon having from 2 to 10 carbon atoms and including at least one carbon-carbon triple bond. A branched alkynyl means that one or more straight chain (C.sub.1-C.sub.8)alkyl groups, such as methyl, ethyl or propyl, replace one or both hydrogens in a CH.sub.2 group of a straight chain alkynyl. Representative straight chain and branched (C.sub.2-C.sub.10)alkynyls include -acetylenyl, -propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl-1-butynyl, -4-pentynyl, -1-hexynyl, -2-hexynyl, -5-hexynyl, -1-heptynyl, -2-heptynyl, -6-heptynyl, -1-octynyl, -2-octynyl, -7-octynyl, -1-nonynyl, -2-nonynyl, -8-nonynyl, -1-decynyl, -2-decynyl, -9-decynyl, and the like.

(248) (C.sub.2-C.sub.6)alkynyl means a straight chain or branched non-cyclic hydrocarbon having from 2 to 6 carbon atoms and including at least one carbon-carbon triple bond. Representative straight chain and branched (C.sub.2-C.sub.6)alkynyls include -acetylenyl, -propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl-1-butynyl, -4-pentynyl, -1-hexynyl, -2-hexynyl, -5-hexynyl, and the like.

(249) (C.sub.2-C.sub.4)alkynyl means a straight chain or branched non-cyclic hydrocarbon having from 2 to 4 carbon atoms and including at least one carbon-carbon triple bond. Representative (C.sub.2-C.sub.4)alkynyls include -acetylenyl, -propynyl, -1-butynyl, -2-butynyl, and the like.

(250) (C.sub.2-C.sub.3)alkynyl means a straight chain or branched non-cyclic hydrocarbon having from 2 to 3 carbon atoms and including at least one carbon-carbon triple bond. Representative (C.sub.2-C.sub.3)alkynyls include -acetylenyl, -propynyl, and the like.

(251) (C.sub.2)alkynyl means a straight chain non-cyclic hydrocarbon having 2 carbon atoms and including one carbon-carbon triple bond.

(252) (C.sub.1-C.sub.6)alkoxy means a straight chain or branched non-cyclic hydrocarbon having one or more ether groups and from 1 to 6 carbon atoms. Representative straight chain and branched (C.sub.1-C.sub.6)alkoxys include -methoxy, -ethoxy, methoxymethyl, 2-methoxyethyl, -5-methoxypentyl, 3-ethoxybutyl and the like.

(253) (C.sub.1-C.sub.4)alkoxy means a straight chain or branched non-cyclic hydrocarbon having one or more ether groups and from 1 to 4 carbon atoms. Representative (C.sub.1-C.sub.4)alkoxys include -methoxy, -ethoxy, methoxymethyl, 2-methoxyethyl, and the like.

(254) (C.sub.1-C.sub.3)alkoxy means a straight chain or branched non-cyclic hydrocarbon having one or more ether groups and from 1 to 3 carbon atoms. Representative (C.sub.1-C.sub.3)alkoxys include -methoxy, -ethoxy, methoxymethyl, 2-methoxyethyl, and the like.

(255) (C.sub.3-C.sub.20)cycloalkyl means a saturated monocyclic hydrocarbon having from 3 to 20 carbon atoms. Representative (C.sub.3-C.sub.20)cycloalkyls are -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, -cyclooctyl, -cyclononyl, -cyclodecyl, cycloundecyl, and -cyclododecyl, and -cyclotetradecyl.

(256) (C.sub.3-C.sub.14)cycloalkyl means a saturated monocyclic hydrocarbon having from 3 to 14 carbon atoms. Representative (C.sub.3-C.sub.14)cycloalkyls are -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, -cyclooctyl, -cyclononyl, -cyclodecyl, cycloundecyl, and -cyclododecyl, and -cyclotetradecyl.

(257) (C.sub.3-C.sub.12)cycloalkyl means a saturated monocyclic hydrocarbon having from 3 to 12 carbon atoms. Representative (C.sub.3-C.sub.12)cycloalkyls are -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, -cyclooctyl, -cyclononyl, -cyclodecyl, cycloundecyl, and -cyclododecyl.

(258) (C.sub.6-C.sub.12)cycloalkyl means a saturated monocyclic hydrocarbon having from 6 to 12 carbon atoms. Representative (C.sub.6-C.sub.12)cycloalkyls are -cyclohexyl, -cycloheptyl, -cyclooctyl, -cyclononyl, -cyclodecyl, cycloundecyl, and -cyclododecyl.

(259) (C.sub.4-C.sub.5)cycloalkyl or 4- to 8-member cycloalkyl ring means a saturated monocyclic hydrocarbon having from 4 to 8 carbon atoms. Representative (C.sub.4-C.sub.8)cycloalkyls are -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, and -cyclooctyl.

(260) (C.sub.5)cycloalkyl or 5-member cycloalkyl ring means a saturated monocyclic hydrocarbon having 5 carbon atoms (i.e. -cyclopentyl).

(261) (C.sub.6)cycloalkyl or 6-member cycloalkyl ring means a saturated monocyclic hydrocarbon having 6 carbon atoms (i.e. -cyclohexyl).

(262) (C.sub.7)cycloalkyl or 7-member cycloalkyl ring means a saturated monocyclic hydrocarbon having 7 carbon atoms (i.e. -cycloheptyl).

(263) (C.sub.3-C.sub.8)cycloalkyl means a saturated monocyclic hydrocarbon having from 3 to 8 carbon atoms. Representative (C.sub.3-C.sub.8)cycloalkyls include -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, and -cyclooctyl.

(264) (C.sub.3-C.sub.7)cycloalkyl means a saturated monocyclic hydrocarbon having from 3 to 7 carbon atoms. Representative (C.sub.3-C.sub.7)cycloalkyls include cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -and cycloheptyl.

(265) (C.sub.6-C.sub.14)bicycloalkyl means a bi-cyclic hydrocarbon ring system having from 6 to 14 carbon atoms and at least one saturated cyclic alkyl ring. Representative (C.sub.6-C.sub.14)bicycloalkyls include -indanyl, -norbornyl, -1,2,3,4-tetrahydronaphthalenyl, -5,6,7,8-tetrahydronaphthalenyl, -perhydronaphthalenyl, bicyclo[2.2.1]hexyl, bicyclo[2.2.1.]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, bicyclo[4.2.2]decyl, bicyclo[4.3.2]undecyl, bicyclo[4.3.1]decyl, and the like.

(266) (C.sub.8-C.sub.20)tricycloalkyl means a tri-cyclic hydrocarbon ring system having from 8 to 20 carbon atoms and at least one saturated cyclic alkyl ring. Representative (C.sub.8-C.sub.20)tricycloalkyls include -pyrenyl, -adamantyl, noradamantyl, -1,2,3,4-tetrahydroanthracenyl, -perhydroanthracenyl -aceanthrenyl, -1,2,3,4-tetrahydropenanthrenyl, -5,6,7,8-tetrahydrophenanthrenyl, -perhydrophenanthrenyl, tetradecahydro-1H-cyclohepta[a]naphthalenyl, tetradecahydro-1H-cycloocta[e]indenyl, tetradecahydro-1H-cyclohepta[e]azulenyl, hexadccahydrocycloocta[b]naphthalenyl, hexadccahydrocyclohcpta[a]heptalenyl, tricyclo-pentadecanyl, tricyclo-octadecanyl, tricyclo-nonadecanyl, tricyclo-icosanyl, and the like.

(267) (C.sub.3-C.sub.20)cycloalkenyl means a cyclic non-aromatic hydrocarbon having at least one carbon-carbon double bond in the cyclic system and from 3 to 20 carbon atoms. Representative (C.sub.3-C.sub.20)cycloalkenyls include -cyclopropenyl, -cyclobutenyl, -cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl, -cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl, - cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl, -cyclononenyl, -cyclononadienyl, -cyclodecenyl, -cyclodecadienyl, -cyclotetradecenyl, -cyclododecadienyl, and the like.

(268) (C.sub.3-C.sub.14)cycloalkenyl means a cyclic non-aromatic hydrocarbon having at least one carbon-carbon double bond in the cyclic system and from 3 to 14 carbon atoms. Representative (C.sub.3-C.sub.14)cycloalkenyls include -cyclopropenyl, -cyclobutenyl, -cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl, -cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl, - cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl, -cyclononenyl, -cyclononadienyl, -cyclodccenyl, -cyclodccadienyl, -cyclotctradccenyl, -cyclododccadienyl, and the like.

(269) (C.sub.5-C.sub.14)cycloalkenyl means a cyclic non-aromatic hydrocarbon having at least one carbon-carbon double bond in the cyclic system and from 5 to 14 carbon atoms. Representative (C.sub.5-C.sub.14)cycloalkenyls include -cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl, -cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl, -cyclooctadienyl, - cyclooctatrienyl, -cyclooctatetraenyl, -cyclononenyl, -cyclononadienyl, -cyclodecenyl, -cyclodecadienyl, -cyclotetradecenyl, -cyclododecadienyl, and the like.

(270) (C.sub.6-C.sub.12)cycloalkenyl means a cyclic non-aromatic hydrocarbon having at least one carbon-carbon double bond in the cyclic system and from 6 to 12 carbon atoms. Representative (C.sub.6-C.sub.12)cycloalkenyls include -cyclohexenyl, -cyclohexadienyl, -cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl, -cyclooctadienyl, -cyclooctatrienyl, -cyclooctatctraenyl, - cyclononenyl, -cyclononadienyl, -cyclodecenyl, -cyclodecadienyl, -cyclododecadienyl, and the like.

(271) (C.sub.5-C.sub.10)cycloalkenyl means a cyclic non-aromatic hydrocarbon having at least one carbon-carbon double bond in the cyclic system and from 5 to 10 carbon atoms. Representative (C.sub.5-C.sub.10)cycloalkenyls include -cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl, -cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl, -cyclooctadienyl, - cyclooctatrienyl, -cyclooctatetraenyl, -cyclononenyl, -cyclononadienyl, -cyclodeccenyl, -cyclodecadienyl, and the like.

(272) (C.sub.5-C.sub.8)cycloalkenyl means a cyclic non-aromatic hydrocarbon having at least one carbon-carbon double bond in the cyclic system and from 5 to 8 carbon atoms. Representative (C.sub.5-C.sub.8)cycloalkenyls include -cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl, -cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl, -cyclooctadienyl, - cyclooctatrienyl, -cyclooctatetraenyl, and the like.

(273) (C.sub.5)cycloalkenyl means a cyclic non-aromatic hydrocarbon having at least one carbon-carbon double bond in the cyclic system and 5 carbon atoms. Representative (C.sub.5)cycloalkenyls include -cyclopentenyl, -cyclopentadienyl, and the like.

(274) (C.sub.6)cycloalkenyl means a cyclic non-aromatic hydrocarbon having at least one carbon-carbon double bond in the cyclic system and 6 carbon atoms. Representative (C.sub.6)cycloalkenyls include -cyclohexenyl, -cyclohexadienyl, and the like.

(275) (C.sub.7)cycloalkenyl means a cyclic non-aromatic hydrocarbon having at least one carbon-carbon double bond in the cyclic system and 7 carbon atoms. Representative (C.sub.7)cycloalkenyls include -cycloheptenyl, -cycloheptadienyl, and the like.

(276) (C.sub.7-C.sub.14)bicycloalkenyl means a bi-cyclic hydrocarbon ring system having at least one carbon-carbon double bond in each ring and from 7 to 14 carbon atoms. Representative (C.sub.7-C.sub.14)bicycloalkenyls include -bicyclo[3.2.0]hept-2-enyl, -indenyl, -pentalenyl, -naphthalenyl, -azulenyl, -heptalenyl, -1,2,7,8-tetrahydronaphthalenyl, norbornenyl, and the like.

(277) (C.sub.8-C.sub.20)tricycloalkenyl means a tri-cyclic hydrocarbon ring system having at least one carbon-carbon double bond in each ring and from 8 to 20 carbon atoms. Representative (C.sub.8-C.sub.20)tricycloalkenyls include -anthracenyl, -phenanthrenyl, -phenalenyl, -acenaphthalenyl, as-indacenyl, s-indacenyl, 2,3,6,7,8,9,10,11-octahydro-1H-cycloocta[e]indenyl, 2,3,4,7,8,9,10,11-octahydro-1H-cyclohepta[a]naphthalenyl, 8,9,10,11-tetrahydro-7H-cyclohepta[a]naphthalenyl, 2,3,4,5,6,7,8,9,10,11,12,13-dodecahydro-1H-cyclohepta[a]heptalenyl, 1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-dicyclohepta[a,c]cyclooctenyl, 2,3,4,5,6,7,8,9,10,11,12,13-dodecahydm-1H-dibenzo[a,d]cyclononenyl, and the like.

(278) -(3- to 7-membered)heterocycle or -(3- to 7-membered)heterocyclo means a 3-10 to 7-membered monocyclic heterocyclic ring which is either saturated, unsaturated non-aromatic, or aromatic. A 3-membered heterocycle can contain up to 1 heteroatom, a 4-membered heterocycle can contain up to 2 heteroatoms, a 5-membered heterocycle can contain up to 4 heteroatoms, a 6-membered heterocycle can contain up to 4 heteroatoms, and a 7-membered heterocycle can contain up to 5 heteroatoms. Each heteroatom is independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone. The -(3- to 7-membered)heterocycle can be attached via a nitrogen or carbon atom. Representative -(3- to 7-membered)heterocycles include pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolidinyl, thiadiazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, triazinyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, 2,3-dihydrofuranyl, dihydropyranyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyridinyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

(279) -(5- or 6-membered)heterocycle or -(5- or 6-membered)heterocyclo means a 5- or 6-membered monocyclic heterocyclic ring which is either saturated, unsaturated non-aromatic, or aromatic. A 5-membered heterocycle can contain up to 4 heteroatoms and a 6-membered heterocycle can contain up to 4 heteroatoms. Each heteroatom is independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone. The -(5- or 6-membered)heterocycle can be attached via a nitrogen or carbon atom. Representative -(5- or 6-membered)heterocycles include pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolidinyl, thiadiazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, triazinyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, 2,3-dihydrofuranyl, dihydropyranyl, hydantoinyl, valerolactamyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyridinyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrazolyl, and the like.

(280) -(3- to 5-membered)heterocycle or -(3- to 5-membered)heterocyclo means a 3- to 5-membered monocyclic heterocyclic ring which is either saturated, unsaturated non-aromatic, or aromatic. A 3-membered heterocycle can contain up to 1 heteroatom, a 4-membered heterocycle can contain up to 2 heteroatoms, and a 5-membered heterocycle can contain up to 4 heteroatoms. Each heteroatom is independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone. The -(3- to 5-membered)heterocycle can be attached via a nitrogen or carbon atom. Representative -(3- to 5-membered)heterocycles include furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolidinyl, thiadiazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, triazinyl, pyrrolidinonyl, pyrrolidinyl, 2,3-dihydrofuranyl, hydantoinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl and the like.

(281) -(7- to 10-membered)bicycloheterocycle or -(7- to 10-membered)bicycloheterocyclo means a 7- to 10-membered bicyclic, heterocyclic ring which is either saturated, unsaturated non-aromatic, or aromatic. A -(7- to 10-membered)bicycloheterocycle contains from 1 to 4 heteroatoms independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone. The 47- to 10-membered)bicycloheterocycle can be attached via a nitrogen or carbon atom. Representative -(7- to 10-membered)bicycloheterocycles include -quinolinyl, -isoquinolinyl, -chromonyl, -coumarinyl, -indolyl, -indolizinyl, -benzo[b]furanyl, -benzo[b]thiophenyl, -indazolyl, -purinyl, -4H-quinolizinyl, -isoquinolyl, -quinolyl, -phthalazinyl, -naphthyridinyl, -carbazolyl, --carbolinyl, -indolinyl, -isoindolinyl, -1,2,3,4-tetrahydroquinolinyl, -1,2,3,4-tetrahydroisoquinolinyl, pyrrolopyrrolyl and the like.

(282) (C.sub.3-C.sub.12)cycloalkoxy means a saturated monocyclic hydrocarbon having from 3 to 12 carbon atoms where at least one of the carbon atoms is replaced by an oxygen atom. Representative (C.sub.3-C.sub.12)cycloalkoxy are -oxiranyl, -oxetanyl, -tetrahydrofuranyl, -tetrahydro-2H-pyranyl, -1,4-dioxanyl, -oxepanyl, -1,4-dioxepanyl, -oxocanyl, -1,5-dioxocanyl, -1,3,5-trioxocanyl, -oxonanyl, -1,5-dioxonanyl, -1,4,7-trioxonanyl, -oxacyclododecanyl, -1,7-dioxacyclododecanyl, and -1,5,9-trioxacyclododecanyl.

(283) (C.sub.3-C.sub.7)cycloalkoxy means a saturated monocyclic hydrocarbon having from 3 to 7 carbon atoms where at least one of the carbon atoms is replaced by an oxygen atom. Representative (C.sub.3-C.sub.7)cycloalkoxy are -oxiranyl, -oxetanyl, -tetrahydrofuranyl, -tetrahydro-2H-pyranyl, -1,4-dioxanyl, -oxepanyl, and -1,4-dioxepanyl.

(284) (C.sub.14)aryl means a 14-membered aromatic carbocyclic moiety such as -anthryl or -phenanthryl.

(285) -(5- to 10-membered)heteroaryl means an aromatic heterocycle ring of 5 to 10 members, including both mono- and bicyclic ring systems, where at least one carbon atom of one or both of the rings is replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur, or at least two carbon atoms of one or both of the rings are replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur. In one embodiment, one of the -(5- to 10-membered)heteroaryl's rings contain at least one carbon atom. In another embodiment, both of the -(5- to 10-membered)heteroaryl's rings contain at least one carbon atom. Representative -(5- to 10-membered)heteroaryl's include pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, isoquinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidyl, pyrimidinyl, pyrazinyl, thiadiazolyl, triazinyl, thienyl, cinnolinyl, phthalazinyl, and quinazolinyl.

(286) -(5- or 6-membered)heteroaryl means a monocyclic aromatic heterocycle ring of 5 or 6 members where at least one carbon atom is replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur. In one embodiment, one of the -(5- or 6-membered)heteroaryl's ring contains at least one carbon atom. Representative -(5- or 6-membered)heteroaryls include pyridyl, furyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidyl, pyrazinyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,5-triazinyl, and thiophenyl.

(287) CH.sub.2(halo) means a methyl group where one of the hydrogens of the methyl group has been replaced with a halogen. Representative CH.sub.2(halo) groups include CH.sub.2F, CH.sub.2Cl, CH.sub.2Br, and CH.sub.2I.

(288) CH(halo).sub.2 means a methyl group where two of the hydrogens of the methyl group have been replaced with a halogen. Representative CH(halo).sub.2 groups include CHF.sub.2, CHCl.sub.2, CHBr.sub.2, CHBrCl, CHCH, and CHI.sub.2.

(289) C(halo).sub.3 means a methyl group where each of the hydrogens of the methyl group has been replaced with a halogen. Representative C(halo).sub.3 groups include CF.sub.3, CCl.sub.3, CBr3, and Cl.sub.3.

(290) Halogen or -halo means F, Cl, Br, or I. Oxo, O, and the like as used herein mean an oxygen atom doubly bonded to carbon or another element.

(291) Thiooxo, thioxo, S, and the like as used herein mean a sulfur atom doubly bonded to carbon or another element.

(292) Imino, NT.sub.3, and the like as used herein mean a nitrogen atom doubly bonded to carbon or another element.

(293) As used herein in connection with Formula (I.1), when the dashed lines between R13 and R14, and between R14 and R15 each denote the presence or absence of a bond, then Formula (I.1) is understood to appear as follows:

(294) ##STR00101##

(295) As used herein in connection with Formula (I.1), when the bond indicated by the dashed line between R.sub.12 and R.sub.13 is absent and R.sub.12 and R.sub.13 together form a (C.sub.3-C.sub.7)cycloalkyl, (C.sub.6-C.sub.14)bicycloalkyl, (C.sub.5-C.sub.10)cycloalkenyl, (C.sub.7-C.sub.14)bicycloalkenyl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R.sub.5 groups, then Formula (I.1) is e.g. understood to appear as follows if R.sub.12 and R.sub.13 together form a (C.sub.6)cycloalkenyl:

(296) ##STR00102##

(297) As used herein in connection with Formula (I.1.1) and R.sub.1=(i), when the dashed lines between R.sub.13 and R.sub.14 and R.sub.14 and R.sub.15 each denote the presence or absence of a bond, then R.sub.1 of Formula (I.1.1) is understood to appear as follows:

(298) ##STR00103##

(299) As used herein in connection with Formula (I.1.1) and R.sub.1=(i), when R.sub.11 and R.sub.14 together form a (C.sub.1-C.sub.2) bridge which is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from OH, (C.sub.1-C.sub.4)alkyl, -halo, and C(halo).sub.3, then R.sub.1 of Formula (I.1.1) is understood to appear as follows:

(300) ##STR00104##

(301) As used herein in connection with Formula (I.1.1) or (I.2.1) and R.sub.1=(ii), when the dashed line between R.sub.14 and R.sub.15 denotes the presence or absence of a bond, then R.sub.1 of Formula (I.1.1) or (I.2.1) is understood to appear as follows:

(302) ##STR00105##
wherein Q is defined as above.

(303) As used herein in connection with Formula (I.1.1) and R.sub.1=(iii), when the dashed line between R.sub.14 and R.sub.15 denotes the presence or absence of a bond, then R.sub.1 of Formula (I.1.1) is understood to appear as follows:

(304) ##STR00106##
wherein Q is defined as above.

(305) As used herein in connection with Formula (I.1.1) and R.sub.1=(iii), when the dashed line between R.sub.12 and R.sub.13 denotes the absence of a bond, and the dashed lines together with the solid lines in the ring denoted as Q each independently denote the presence or absence of a double bond, wherein R.sub.12 is absent if the carbon atom carrying R.sub.12 is unsaturated, and wherein R.sub.13 is absent if the carbon atom carrying R.sub.13 is unsaturated, then R.sub.1 of Formula (I.1.1) is understood to appear as follows:

(306) ##STR00107##
wherein Q is defined as above.

(307) As used herein in connection with Formula (I.1.1) or (I.2.1) and R.sub.1=(iv), when the dashed lines between R.sub.13 and R.sub.14 and R.sub.14 and R.sub.15 each denote the presence or absence of a bond, then R.sub.1 of Formula (I.1.1) or (I.2.1) is understood to appear as follows:

(308) ##STR00108##
wherein Q is defined as above.

(309) As used herein in connection with Formula (I.2), when the dashed line between R.sub.14 and R.sub.15 denotes the presence or absence of a bond, then Formula (I.2) is understood to appear as follows:

(310) ##STR00109##

(311) As used herein in connection with Formula (I.2), when n=0 and R.sub.12 and R.sub.13 together form a (C.sub.5-C.sub.7)cycloalkyl or (C.sub.5-C.sub.7)cycloalkenyl, each of which is unsubstituted or substituted with 1, 2, 3 or 4 independently selected R.sub.5 groups, and wherein the bond indicated by the dashed line between R.sub.12 and R.sub.13 can be present or absent, then Formula (I.2) is understood to appear as follows:

(312) ##STR00110##

(313) As used herein in connection with Formula (I.2.1) and R.sub.1=(iii), when the dashed line between R.sub.14 and R.sub.15 denotes the presence or absence of a bond, then R.sub.1 of Formula (I.2.1) is understood to appear as follows:

(314) ##STR00111##

(315) As used herein in connection with Formula (III), when the dashed line denotes the presence or absence of a bond, then Formula (III) is understood to appear as follows:

(316) ##STR00112##

(317) As used herein in connection with Formula (IV), when the dashed lines each denote the presence or absence of a bond, then Formula (IV) is understood to appear as follows:

(318) ##STR00113##

(319) As used herein in connection with Formula (IV.1), when the dashed lines each denote the presence or absence of a bond, then Formula (IV.1) is understood to appear as follows:

(320) ##STR00114##

(321) (C.sub.2-C.sub.6)bridge as used in connection with the Formulas disclosed herein means a hydrocarbon chain containing 2 to 6 carbon atoms joining two indicated carbon atoms to form a cyclic ring system. Exemplary compounds of the invention include those with a (C.sub.2)bridge, CH.sub.2CH.sub.2, joining the two carbon atoms: a (C.sub.3)bridge, CH.sub.2CH.sub.2CH.sub.2, joining the two carbon atoms; a (C.sub.4)bridge, CH.sub.2CH.sub.2CH.sub.2CH.sub.2, joining the two carbon atoms: a (C.sub.5)bridge, CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2, joining the two carbon atoms; or a (C.sub.6)bridge, CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2, joining the two carbon atoms. Examples of a (C.sub.2-C.sub.6)bridge which optionally contains HCCH within the (C.sub.2-C.sub.6)bridge include HCCH, CH.sub.2HCCH, HCCHCH.sub.2, CH.sub.2HCCHCH.sub.2, and the like. Examples of a (C.sub.2-C.sub.6)bridge which optionally contains O within the (C.sub.2-C.sub.6)bridge include CH.sub.2OCH.sub.2 (containing 2 carbon atoms), CH.sub.2OCH.sub.2CH.sub.2 and CH.sub.2CH.sub.2OCH.sub.2 (each containing 3 carbon atoms), CH.sub.2CH.sub.2OCH.sub.2CH.sub.2, CH.sub.2OCH.sub.2CH.sub.2CH.sub.2 and CH.sub.2CH.sub.2CH.sub.2OCH.sub.2 (each containing 4 carbon atoms), and the like.

(322) The phrase benzo, benzo group and the like, when used in connection with the optionally-substituted fused Q group in Formula (IV), means

(323) ##STR00115##
where R.sub.1 and E.sub.1 and n are defined above for the compounds of Formula (IV).

(324) The phrase (5- or 6-membered)heteroaryl when used in connection with the optionally-substituted fused Q group in Formula (IV), means

(325) ##STR00116##
where at least one carbon atom is replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur and R.sub.1 and E.sub.1 and n are defined above for the compounds of Formula (IV). Representative -(5- or 6-membered)heteroaryls include pyridyl, furyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidyl, pyrazinyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,5-triazinyl, and thiophenyl.

(326) The phrase benzo, benzo group and the like, when used in connection with the optionally-substituted fused Q group in Formulas (V) and (V.1), means

(327) ##STR00117##
where R.sub.1 a are defined above for the compounds of Formulas (V) and (V.1).

(328) The phrase (5- or 6-membered)heteroaryl when used in connection with the optionally-substituted fused Q group in Formulas (V) and (V.1), means

(329) ##STR00118##
where at least one carbon atom is replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur and R.sub.1 and a are defined above for the compounds of Formulas (V) and (V.1). Representative -(5- or 6-membered)heteroaryls include pyridyl, furyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidyl, pyrazinyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,5-triazinyl, and thiophenyl.

(330) The phrase pyrrolino, pyrrolino group and the like, when used in connection with the optionally-substituted fused Q group, means optionally substituted

(331) ##STR00119##

(332) The phrase imidazolino, imidazolino group and the like, when used in connection with the optionally-substituted fused Q group, means optionally substituted

(333) ##STR00120##

(334) The phrase pyrazolino, pyrazolino group and the like, when used in connection with the optionally-substituted fused Q group, means optionally substituted

(335) ##STR00121##

(336) The phrase triazolino, triazolino group and the like, when used in connection with the optionally-substituted fused Q group, means optionally substituted

(337) ##STR00122##

(338) The phrase furano, furano group and the like, when used in connection with the optionally-substituted fused Q group, means optionally substituted

(339) ##STR00123##

(340) The phrase oxazolino, oxazolino group and the like, when used in connection with the optionally-substituted fused Q group, means optionally substituted

(341) ##STR00124##

(342) The phrase isoxazolino, isoxazolino group and the like, when used in connection with the optionally-substituted fused Q group, means optionally substituted

(343) ##STR00125##

(344) The phrase oxadiazolino, oxadiazolino group and the like, when used in connection with the optionally-substituted fused Q group, means optionally substituted

(345) ##STR00126##

(346) The phrase thiopheno, thiopheno group and the like, when used in connection with the optionally-substituted fused Q group, means optionally substituted

(347) ##STR00127##

(348) The phrase thiazolino. thiazolino group and the like, when used in connection with the optionally-substituted fused Q group, means optionally substituted

(349) ##STR00128##

(350) The phrase isothiazolino, isothiazolino group and the like, when used in connection with the optionally-substituted fused Q group, means optionally substituted

(351) ##STR00129##

(352) The phrase thiadiazolino, thiadiazolino group and the like, when used in connection with the optionally-substituted fused Q group, means optionally substituted

(353) ##STR00130##

(354) The phrase pyridine, pyridino group and the like, when used in connection with the optionally-substituted fused Q group means optionally substituted

(355) ##STR00131##

(356) The phrase pyrimidino, pyrimidino group and the like, when used in connection with the optionally-substituted fused Q group means optionally substituted

(357) ##STR00132##

(358) The phrase pyrazino, pyrazino group and the like, when used in connection with the optionally-substituted fused Q group means optionally substituted

(359) ##STR00133##

(360) The phrase pyridazino, pyridazino group and the like, when used in connection with the optionally-substituted fused Q group means optionally substituted

(361) ##STR00134##

(362) The phrase diazole, diazole group and the like, when used in connection with the formulas disclosed herein means pyrazolinyl, pyrazoline group and the like as well as imidazolyl, imidazoline group and the like.

(363) The phrase imidazolino. imidazolino group and the like, when used in connection with formula (II.2), means optionally substituted

(364) ##STR00135##

(365) The phrase pyrazolino, pyrazolino group and the like, when used in connection with formula (II.2), means optionally substituted

(366) ##STR00136##

(367) The phrase triazolino, triazolino group and the like, when used in connection with formula (II.2), means optionally substituted

(368) ##STR00137##

(369) The phrase pyridine, pyridino group and the like, when used in connection with the formulas disclosed herein means optionally substituted

(370) ##STR00138##

(371) The phrase pyrimidine, pyrimidino group and the like, when used in connection with the formulas disclosed herein means optionally substituted

(372) ##STR00139##

(373) The phrase pyrazine, pyrazino group and the like, when used in connection with the formulas disclosed herein means optionally substituted

(374) ##STR00140##

(375) The phrase pyridazine, pyridazino group and the like, when used in connection with the formulas disclosed herein means optionally substituted

(376) ##STR00141##

(377) The phrase (C.sub.6)cycloalkyl when used herein means optionally substituted

(378) ##STR00142##

(379) The phrase (C.sub.6)cycloalkenyl when used herein means optionally substituted

(380) ##STR00143##
where the cyclic non-aromatic hydrocarbon has at least one carbon-carbon double bond in the cyclic system.

(381) The phrase (6-membered)heterocycle when used herein means optionally substituted

(382) ##STR00144##
where at least one carbon atom in the ring is replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur.

(383) The phrase (6-membered)heteroaryl when used herein means optionally substituted

(384) ##STR00145##
where at least one carbon atom in the ring is replaced with a nitrogen.

(385) The term animal includes, but is not limited to, a human or a non-human animal, such as a companion animal or livestock, e.g., a cow, monkey, baboon, chimpanzee, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig.

(386) The phrase pharmaceutically acceptable derivative, as used herein, includes any pharmaceutically acceptable salt, solvate, prodrug, radiolabeled, stereoisomer, enantiomer, diastereomer, other stereoisomeric form, racemic mixture, geometric isomer, and/or tautomer, e.g., of a compound disclosed herein. In one embodiment, the pharmaceutically acceptable derivative is a pharmaceutically acceptable salt, solvate, radiolabeled, stereoisomer, enantiomer, diastereomer, other stereoisomeric form, racemic mixture, geometric isomer, and/or tautomer, e.g., of a compound disclosed herein. In another embodiment, the pharmaceutically acceptable derivative is a pharmaceutically acceptable salt, e.g., of a compound disclosed herein.

(387) The phrase pharmaceutically acceptable salt, as used herein, is any pharmaceutically acceptable salt that can be prepared from a compound disclosed herein including a salt formed from an acid and a basic functional group, such as a nitrogen group, of a compound disclosed herein. Illustrative salts include, but are not limited, to sulfate, citrate, acetate, trifluoroacetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucoronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term pharmaceutically acceptable salt also includes a salt prepared from a compound disclosed herein having an acidic functional group, such as a carboxylic acid functional group, and a pharmaceutically acceptable inorganic or organic base. Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, cesium, and lithium: hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine: pyridine; picoline; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-(C.sub.1-C.sub.3)alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine, N,N-di-[(C.sub.1-C.sub.3)alkyl]-N-(hydroxy-(C.sub.1-C.sub.3)alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and the like. One skilled in the art will recognize that, e.g., acid addition salts of a compound disclosed herein can be prepared by reaction of the compounds with the appropriate acid via a variety of known methods.

(388) A compound disclosed herein can contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. The invention is also meant to encompass all such possible forms as well as their racemic and resolved forms or any mixture thereof. When a compound disclosed herein contains an olefinic double bond or other center of geometric asymmetry, and unless specified otherwise, it is intended to include all geometric isomers, e.g., both E and Z geometric isomers. All tautomers, e.g., ketone-enol, amide-imidic acid, lactam-lactim, enamine-imine, amine-imine, and enamine-enamine tautomers, are intended to be encompassed by the invention as well.

(389) As used herein, the terms stereoisomer, stereoisomeric form, and the like are general terms for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).

(390) The term chiral center refers to a carbon atom to which four different groups are attached.

(391) The term enantiomer or enantiomeric refers to a molecule that is nonsuperimposeable on its mirror image and hence optically active where the enantiomer rotates the plane of polarized light in one direction and its mirror image rotates the plane of polarized light in the opposite direction.

(392) The term racemic refers to a mixture of equal parts of enantiomers which is optically inactive.

(393) The term resolution refers to the separation or concentration or depletion of one of the two enantiomeric forms of a molecule.

(394) Optical isomers of a compound disclosed herein can be obtained by known techniques such as chiral chromatography or formation of diastereomeric salts from an optically active acid or base.

(395) Accordingly, as used herein in connection with Formula (I.2.1) and R.sub.1=(i), R.sub.1 of Formula (I.2.1) is understood to appear as follows:

(396) ##STR00146##
wherein R.sub.11 to R.sub.17 are defined as above.

(397) The phrases treatment of, treating, and the like include the amelioration or cessation of a condition or a symptom thereof. In one embodiment, treating includes inhibiting, for example, decreasing the overall frequency of episodes of a condition or a symptom thereof. The phrases prevention of, preventing, and the like include the avoidance of the onset of a condition or a symptom thereof. A disorder includes, but is not limited to, the conditions defined above.

(398) The term half maximal effective concentration or EC.sub.50 refers to the concentration of a compound disclosed herein which induces a response on a channel halfway between the baseline and maximum after some specified exposure time. The EC.sub.50 of a graded dose response curve therefore represents the concentration of a compound where 50% of its maximal effect (which may be either agonistic or antagonistic) on the respective channel is observed.

(399) Throughout the literature several different synonyms are used for TRPA1: ANKTM1, p 120, transient receptor potential ankyrin 1, transient receptor potential cation channel subfamily A member 1. All these synonyms are all included in terms of the present invention. Included as well are all functional modifications of the ion channel and the analog receptors from different organisms like human, mouse and rat. The according sequence data is available to the skilled person.

(400) According to the present invention, an antagonist and/or a compound exhibiting antagonistic activity refers to a pharmaceutical and/or cosmetic active inhibitor of the TRPA1 related bioactivity (acting in vivo and/or in vitro). The antagonist can bind to the ion channel in a specific or unspecific, reversible or irreversible manner.

(401) According to the present invention, the term selective antagonistic activity describes the exclusive inhibition of the TRPA1 ion channel by the respective compound without substantial influence on other ion channels and/or receptor proteins.

(402) According to the present invention, the term partial antagonistic activity describes the partial inhibition of the TRPA1 ion channel by the respective compound. The compound reduces the response of the channel to a certain extend without complete inhibition of the TRPA1 related bioactivity.

(403) The term half maximal inhibitory concentration or IC.sub.50 refers to the concentration of a compound disclosed herein which reduces the response of a channel by half. The IC.sub.50 of a dose response curve therefore represents the concentration of an antagonist where 50% of its maximal effect on the respective channel is observed.

(404) The term EC.sub.80 refers to the concentration of an agonist disclosed herein which gives 80% of its maximal effect on the respective channel.

(405) Preparation of the Compounds

(406) The compounds disclosed herein are either commercially available or can be made using conventional organic synthesis which are known to the person skilled in the art.

(407) Screening Method

(408) As part of the invention, compound libraries can be employed comprising compounds to be tested for having modulating activity for one or more members of the transient receptor potential cation channel families. The methods of the invention can employ such compound libraries e.g. for identifying suitable modulators of TRPA1 and/or any further member of the transient receptor potential cation channel families.

(409) In the context of the present invention, the term chemical library means a collection of chemical compounds. A chemical library employed in the present invention will comprise at least 2 different compounds, rarely less than about 5 compounds, usually at least about 10 compounds, frequently will have about 50 compounds or more, usually more than about 500 compounds such as about 15,000 compounds or more.

(410) The activity of the compounds comprised by such compound libraries at TRPA1 or TRPM8 (or any further member of the transient receptor potential cation channel families) can be evaluated in a functional cell based assay. In such functional cell based assays a compound-channel interaction can lead to a functional response of the cell. The physiological response of the cell, initiated by a screening compound can be quantified by using recombinant reporter technology. It is known in the art that the TRP channels are a family of ion channel proteins that mediate ion influx of Na.sup.+ and Ca.sup.2+ and, in several cases, Mg.sup.2+. For instance, in the case of TRPA1 and TRPM8, assembly of the channel subunits as tetramers results in the formation of cation-selective channels that permeate calcium ions. This calcium influx can be used as read-out in functional cell based assays.

(411) Furthermore, a cell-based (label-free) impedance assay may be used to validate the antagonistic activity of the tested compounds at TRPA1. In particular, cellular changes (like alterations in cell adherence, shape, volume, and interaction) due to channel activation can be monitored using a label-free, non-invasive assay platform based on cellular dielectric spectroscopy (such as CellKey system, Molecular Devices).

(412) The sequences that encode the members of the transient receptor potential cation channel families are available to the person skilled in the art (cf. National Center for Biotechnology Information website: http://www.ncbi.nlm.nih.gov). The methods of amplifying and cloning such sequences (e.g., by PCR) are also commonly known in the art. According to an optional embodiment, TRPM8 (human) has the nucleic acid or amino acid sequence as disclosed in GenBank Accession Number NM_024080 or NP_076985.4 and TRPA1 (human) has the nucleic acid or amino acid sequence as disclosed in GenBank Accession Number NM_007332 or NP_015628.2.

(413) Methods of providing suitable test systems are known to the person skilled in the art. For example, a cell based test system can be based on stably transfected cell lines expressing human TRPM8 or TRPA1. Methods of producing suitable test systems are disclosed, inter alia, in Behrendt H J et al., Br. J. Pharmacol. 2004, 141:737-745, which is enclosed herein by reference. According to an optional embodiment, the functional cell based assay utilizes human HEK293 cells recombinantly expressing human TRPM8 or TRPA1. Agonistic or antagonistic action of a compound can be quantified via a Ca.sup.2+-sensitive dye (such as FURA. Fluo-4, etc.), wherein agonists produce an increase of intracellular calcium ions and antagonists inhibit an increase of intracellular calcium ions (e.g., triggered by endogenous ligands). Such assays are routine and well known to the person skilled in the art.

(414) According to an optional embodiment of the present invention, a compound library comprising suitable compounds is tested in a screening for antagonistic activity towards TRPA1 and/or other channels. Optionally, compounds can be selected as development candidates, which compounds are antagonists or partial antagonists of TRPA1 in cells expressing the channel. Optionally, the compounds can further be analyzed with regard to their IC.sub.50 values as well as their efficacy values and/or can be analyzed in a structure-action relationship. Such screening methods are routine and well known to the person skilled in the art.

(415) According to an embodiment, the present invention further encompasses compounds which are identified in such a screening as development candidates.

(416) Embodiments of the Invention

(417) The present invention relates to compounds which are capable of producing a soothing effect when they are brought into contact with the human body. Such compounds have applications in many fields, for example in oral and personal hygiene products and foodstuffs, but also in cosmetics, pharmaceutical composition products, textile products and packaging products.

(418) For instance, a known compound for producing a sensation of cold is menthol (2-isopropyl-5-methyl-cyclohexanol), which has been extensively applied as an additive in, for example, foodstuffs and oral hygiene products. It is used primarily because it elicits a sensation of coolness in the mouth, and because it has a pleasing mint flavour and odour. However, the use of menthol is limited by its strong minty smell which is undesirable for some applications and its relative volatility and burning sensations at high concentrations through unintentional activation of other TRPs/ion channels, such as TRPA1.

(419) It is believed that TRPA1 plays a role in the mechanisms of mechanical and cold hypersensitivity produced by skin irritation or inflammation. Furthermore, TRPA1 responds to a wide variety of stimuli and is activated by a multitude of exogenous and endogenous chemicals, i.e. it can serve as a sensor for reactive and therefore potentially harmful chemicals. As indicated above, certain substances cosmetic and/or pharmaceutical compositions can cause skin irritation if they are applied to the skin, especially the face. This may lead to unpleasant sensations like stinging, burning, and itching, especially in persons with sensitive skin. It is known to persons skilled in the art that these nociceptive sensations are at least to a certain extent mediated by TRPA1. Symptoms like stinging, burning, and itching may lead to dissatisfaction and thereby influence life quality and consumer preferences.

(420) The compounds and compositions disclosed in the present invention exhibit a certain antagonist activity at TRPA1 and have thus the ability to produce a soothing effect when in contact with the skin and/or mucosal membrane of a human or animal body. The term soothing effect, as used herein, is thus intended to mean any alleviation of unpleasant sensations like stinging, burning, and itching produced by compounds of e.g. cosmetic and/or pharmaceutical compositions.

(421) Such a soothing effect can be desirable in many different applications. For example, the compounds and compositions of the invention have applications in a number of products, such as personal-care products, pharmaceutical compositions, textile products, medical devices, packaging products, and food products.

(422) In an embodiment, the present invention relates to a product comprising a compound that, optionally selectively, exhibits antagonist activity at the TRPA1 channel (e.g. as evaluated in a functional cell based assay under standard conditions as described herein or as evaluated in a cell-based (label-free) impedance assay under standard conditions as described herein), and wherein the product is selected from the group consisting of a personal-care product, a pharmaceutical composition, a textile product, a medical device, a packaging product, and a food product. It is understood that such products can comprise any combination of compounds as described herein above, and optionally can also comprise further agents.

(423) In an embodiment, the present invention relates to a product comprising a compound that selectively exhibits antagonist activity at the TRPA1 channel (e.g. as evaluated in a functional cell based assay under standard conditions as described herein or as evaluated in a cell-based (label-free) impedance assay under standard conditions as described herein), and wherein the product is selected from the group consisting of a personal-care product, a pharmaceutical composition, a textile product, a medical device, a packaging product, and a food product. It is understood that such products can comprise any combination of compounds as described herein above, and optionally can also comprise further agents.

(424) In a further embodiment, the present invention relates to a product comprising a compound that acts as an, optionally selective, TRPA1 antagonist or partial antagonist (e.g. as evaluated in a functional cell based assay under standard conditions as described herein or as evaluated in a cell-based (label-free) impedance assay under standard conditions as described herein), and wherein the product is selected from the group consisting of a personal-care product, a pharmaceutical composition, a textile product, a medical device, a packaging product, and a food product.

(425) In a further embodiment, the present invention relates to a product comprising an effective amount of a compound that acts as an, optionally selective, TRPA1 antagonist or partial antagonist (e.g. as evaluated in a functional cell based assay under standard conditions as described herein or as evaluated in a cell-based (label-free) impedance assay under standard conditions as described herein), and wherein the product is selected from the group consisting of a personal-care product, a pharmaceutical composition, a textile product, a medical device, a packaging product, and a food product.

(426) In a further embodiment, the present invention relates to a product comprising a compound that exhibits antagonist activity at TRPA1, which activity is at least three times, at least five times, or even at least ten times, greater than the activity of the compound at a different ion channel or receptor, optionally at TRPM8 (e.g. as evaluated in a functional cell based assay under standard conditions as described herein), and wherein the product is selected from the group consisting of a personal-care product, a pharmaceutical composition, a medical device, a textile product, a packaging product, and a food product.

(427) In a further embodiment, the present invention relates to a product comprising a compound, wherein in a functional cell based assay the compound inhibits an increase in intracellular calcium concentration in human cells recombinantly expressing human TRPA1 at least three times, at least five times, or even at least ten times more efficient than that of human cells recombinantly expressing a different human ion channel and/or receptor, optionally TRPM8 (e.g. as evaluated in a functional cell based assay under standard conditions as described herein), and wherein the product is selected from the group consisting of a personal-care product, a pharmaceutical composition, a textile product, a medical device, a packaging product, and a food product.

(428) In a further embodiment, the present invention relates to a product selected from the group consisting of a personal-care product, a pharmaceutical composition, a textile product, a medical device, a packaging product, and a food product, which product comprises a compound selected from the group consisting of Compounds I, II, III, IV, V, I.1, I.1.1, II.1, III.1, IV.1, V.1, I.2, I.2.1, I.2A, I.2B, I.2C, I.2D, I.2E, I.2F, I.2G, I.2H, I.2I, I.2J, I.2K, I.2L, I.2M, I.2N, I.2O, II.2P, II.2, III.2, IV.2, V.2, I.3, II.3, III.3, IV.3, and V.3, wherein the Compounds have the chemical structures as defined herein above.

(429) In a further embodiment, the present invention relates to a product selected from the group consisting of a personal-care product, a pharmaceutical composition, a textile product, a medical device, a packaging product, and a food product, which product comprises a compound selected from the group consisting of Compounds I.1, I.1.1, II.1, III.1, IV.1, V.1, I.2, I.2.1, I.2A, I.2B, I.2C, I.2D, I.2E, I.2F, I.2G, I.2H, I.2I, I.2J, I.2K, I.2L, I.2M, I.2N, I.2O, I.2P, II.2, III.2, IV.2, V.2, I.3, II.3, III.3, IV.3, and V.3, wherein the Compounds have the chemical structures as defined herein above.

(430) In a further embodiment, the present invention relates to a product selected from the group consisting of a personal-care product, a pharmaceutical composition, a textile product, a medical device, a packaging product, and a food product, which product comprises a compound selected from the group consisting of Compounds I.2, I.2.1, I.2A, I.2B, II.2C, II.2D, I.2E, II.2F, I.2G. I.2H, I.2I, 1.2J, 1.2K, II.2L, II.2M, II.2N, I.2O, I.2P, II.2, II.2, IV.2, V.2, I.3. II.3, III.3, IV.3, and V.3, wherein the Compounds have the chemical structures as defined herein above.

(431) In a further embodiment, the present invention relates to a product selected from the group consisting of a personal-care product, a pharmaceutical composition, a textile product, a medical device, a packaging product, and a food product, which product comprises a compound selected from the group consisting of Compounds I.3, II.3, III.3, IV.3, and V.3, wherein the Compounds have the chemical structures as defined herein above.

(432) In a further embodiment, the present invention relates to a compound selected from the group consisting of Compounds I, II, III, IV, V, I.1, I.1.1, II.1, III.1, IV.1, V.1, I.2, I.2.1, I.2A, I.2B, II.2C, I.2D, I.2E, I.2F, I.2G, I.2H, I.2I, 1.2J, 1.2K, 1.2L, 1.2M, I.2N, I.2O, I.2P, II.2, III.2. IV.2, V.2, I.3, II.3. III.3, IV.3, and V.3, wherein the Compounds have the chemical structures as defined herein above. In a further embodiment, the present invention relates to a compound selected from the group consisting of Compounds I.1, I.1.1, II.1, III.1, IV.1, V.1, I.2, I.2.1, I.2A, I.2B, I.2C, I.2D, II.2E, I.2F, I.2G, I.2H, I.2I, I.2J, I.2K, I.2L, I.2M, 1.2N, I.2O, II.2P, II.2, III.2, IV.2, V.2, I.3, II.3, III.3, IV.3, and V.3, wherein the Compounds have the chemical structures as defined herein above. In a further embodiment, the present invention relates to a compound selected from the group consisting of Compounds I.2, I.2.1, I.2A, I.2B. I.2C, II.2D, I.2E, II.2F, I.2G, I.2H, I.2I, I.2J, II.2K, I.2L, II.2M, II.2N, I.2O, I.2P, II.2, III.2, IV.2, V.2, I.3, II.3, III.3, IV.3, and V.3, wherein the Compounds have the chemical structures as defined herein above. In a further embodiment, the present invention relates to a compound selected from the group consisting of Compounds I.2.1, I.2A, I.2B, I.2C, I.2D, I.2E, I.2F, I.2G, I.2H, I.2I, I.2J, I.2K, I.2L, I.2M, I.2N, I.2O, I.2P, II.2, III.2, IV.2, V.2, I.3, II.3, III.3, IV.3, and V.3, wherein the Compounds have the chemical structures as defined herein above. In a further embodiment, the present invention relates to a compound selected from the group consisting of Compounds I.3, II.3, III.3, IV.3, and V.3, wherein the Compounds have the chemical structures as defined herein above.

(433) Optionally, the compound exhibits an antagonist activity at TRPA1, which activity is at least three times, optionally at least four times, five times, seven times, ten times, 12 times, 15 times or 20 times, greater than the antagonist activity of the compound at TRPM8 (e.g. as evaluated in a functional cell based assay under standard conditions as described herein).

(434) According to an optional embodiment, the compound acts as a TRPA1 partial antagonist or antagonist (e.g. as evaluated in a functional cell based assay under standard conditions as described herein or as evaluated in a cell-based (label-free) impedance assay under standard conditions as described herein).

(435) According to an optional embodiment, the compound acts as a selective TRPA1 partial antagonist or antagonist (e.g. as evaluated in a functional cell based assay under standard conditions as described herein or as evaluated in a cell-based (label-free) impedance assay under standard conditions as described herein).

(436) According to a further optional embodiment, in a functional cell based assay the compound inhibits an increase in intracellular calcium concentration in human cells recombinantly expressing human TRPA1 at least four times, five times, seven times, ten times, 12 times, 15 times or 20 times more efficient than that of human cells recombinantly expressing human TRPM8 (e.g. as evaluated in a functional cell based assay under standard conditions as described herein).

(437) According to an optional embodiment of the present invention, the IC.sub.50 value of the compound with regard to TRPA1 (antagonistic activity against menthol) is less than 20 M, 15 M, 12 M, 10 M, 8 M, 6 M, 4 M, 2 M, 1 M or 0.5 M (as evaluated in a functional cell based assay under standard conditions as described herein). According to an optional embodiment of the present invention, the IC.sub.50 value of the compound with regard to TRPA1 (antagonistic activity against propylparaben) is less than 20 M, 15 M, 12 M, 10 M, 8 M, 6 M, 4 M, 2 M, 1 M or 0.5 M (as evaluated in a functional cell based assay under standard conditions as described herein). According to an optional embodiment of the present invention, the IC.sub.50 value of the compound with regard to TRPA1 (antagonistic activity against retinol) is less than 20 M, 15 M, 12 M, 10 M, 8 M, 6 M, 4 M, 2 M, 1 M or 0.5 M (as evaluated in a functional cell based assay under standard conditions as described herein). According to an optional embodiment of the present invention, the IC.sub.50 value of the compound with regard to TRPA1 (antagonistic activity against allyl isothiocyanate) is less than 20 M, 15 M, 12 M, 10 M, 8 M, 6 M, 4 M, 2 M, 1 M or 0.5 M (as evaluated in a functional cell based assay under standard conditions as described herein).

(438) Optionally, the compound is selected from the group consisting of Compounds I, II, III, IV, V, I.1, I.1.1, II.1, III.1, IV.1, V.1, I.2, I.2.1, I.2A, I.2B, I.2C, I.2D, I.2E, I.2F, I.2G, I.2H, I.2I, I.2J, 1.2K. I.2L, II.2M, II.2N, I.2O, I.2P, II.2, III.2, IV.2, V.2, I.3, II.3, III.3, IV.3, and V.3, wherein the Compounds have the chemical structures as defined herein above. Optionally, the compound is selected from the group consisting of Compounds I.1, I.1.1, II.1, III.1, IV.1, V.1, I.2, I.2.1, I.2A, I.2B, I.2C, I.2D, I.2E, I.2F, I.2G, I.2H, I.2I, I.2J, I.2K, I.2L, I.2M, I.2N, I.2O, II.2P, II.2, III.2, IV.2, V.2, I.3, II.3, III.3, IV.3, and V.3, wherein the Compounds have the chemical structures as defined herein above. Optionally, the compound is selected from the group consisting of Compounds I.2, I.2.1, I.2A, I.2B, I.2C, I.2D, I.2E, I.2F, I.2G, I.2H, I.2I, I.2J, I.2K, I.2L, I.2M, I.2N, I.2O. I.2P, II.2, III.2, IV.2, V.2, I.3, II.3, III.3, IV.3, and V.3, wherein the Compounds have the chemical structures as defined herein above. Optionally, the compound is selected from the group consisting of Compounds I.3, II.3, III.3. IV.3, and V.3, wherein the Compounds have the chemical structures as defined herein above.

(439) In one further embodiment, the present invention relates to the use of a compound as defined herein above in a product selected from the group consisting of a personal-care product, a pharmaceutical composition, a textile product, a packaging product, a medical device, and a food product. In one further embodiment, the present invention relates to a compound as defined herein above for use in therapy. In one further embodiment, the present invention relates to a compound as defined herein above for use in the treatment of pain. In one further embodiment, the present invention relates to the use of a compound as defined herein for the modulation of the taste of a food product. In one further embodiment, the present invention relates to an in vitro, in vivo or ex vivo use of a compound as defined herein above as soothing agent. In one further embodiment, the present invention relates to a cosmetic use of a compound as defined herein above as soothing agent, i.e. its use as soothing agent in a cosmetic product, a wound dressing or a hygiene product. In one further embodiment, the present invention relates to an in vitro method of inhibiting TRPA1, wherein TRPA1 is contacted with a compound as defined herein above.

(440) In the context of the present invention, the phrase effective amount, when used in connection with a compound of the invention, means an amount effective for: (a) treating or preventing a condition; or (b) detectably blocks binding of another agent (such as an endogenous ligand) to TRPA1 in a cell or detectably blocks the functional modulation of TRPA1 by another agent (such as an endogenous ligand) in a cell (e.g. as evaluated in a functional cell based assay under standard conditions as described herein or as evaluated in a cell-based (label-free) impedance assay under standard conditions as described herein).

(441) The terms modulate, modulating, and the like as used herein with respect to TRPM8 or TRPA1 mean the mediation of a pharmacodynamic response in a cell from (i) inhibiting or activating the respective channel, or (ii) directly or indirectly affecting the normal regulation of the channel activity (e.g., as evaluated in a functional cell based assay under standard conditions as described herein). Compounds that modulate the channel activity include agonists, partial agonists, antagonists, mixed agonists/antagonists, mixed partial agonists/antagonists and compounds which directly or indirectly affect regulation of the channel activity (as evaluated in a functional cell based assay under standard conditions as described herein).

(442) The terms selective modulation, selectively modulate, and the like as used herein with respect to TRPM8 or TRPA1 mean the mediation of a pharmacodynamic response in a cell from (i) inhibiting or activating the respective channel (in particular, TRPA1) without substantially triggering another channel (in particular, TRPM8), or (ii) directly or indirectly affecting the normal regulation of the activity of the respective channel (in particular, TRPA1) without substantially affecting the normal regulation of the activity of another channel (in particular, TRPM8) (e.g., as evaluated in a functional cell based assay under standard conditions as described herein).

(443) As used herein, a compound disclosed herein that binds to a channel and mimics the regulatory effect(s) of an endogenous ligand is defined as an agonist (e.g., as evaluated in a functional cell based assay under standard conditions as described herein). As used herein, a compound that binds to a channel and is only partly effective as an agonist is defined as a partial agonist (e.g., as evaluated in a functional cell based assay under standard conditions as described herein). As used herein, a compound that binds to a channel but produces no regulatory effect, but rather blocks binding of another agent to the channel or blocks the functional modulation of the channel by another agent is defined as an antagonist or silent agonist (i.e. a compound with no efficacy but binding capacity). For an overview of drug binding mechanisms see: Ross and Kenakin, Pharmacodynamics: Mechanisms of Drug Action and the Relationship Between Drug Concentration and Effect, Chapter 2 in Goodman & Gilman's The Pharmacological Basis of Therapeutics 31-32 (J. G. Hardman, L. E. Limbird and A. Goodman-Gilman eds., 10.sup.th ed 2001).

(444) In the context of the present invention, the phrase antagonist, when used in connection with a compound of the invention, means a compound according to the invention that binds to a channel (in particular, TRPA1) and produces no regulatory effect, but rather blocks binding of another agent to the channel or blocks the functional modulation of the channel by another agent such as an endogenous ligand, e.g., as evaluated in a functional cell based assay under standard conditions as described herein.

(445) In the context of the present invention, the phrase selective antagonist, and the like, when used in connection with a compound of the invention, means a compound according to the invention that binds to a channel (in particular, TRPA1) and produces no regulatory effect, but rather blocks binding of another agent to the channel or blocks the functional modulation of the channel by another agent such as an endogenous ligand, however without substantially affecting the normal regulation of the activity of another channel (in particular, TRPM8) (e.g., as evaluated in a functional cell based assay under standard conditions as described herein). However, it can be desirable to provide a compound that binds to a channel (in particular, TRPA1) and produces no regulatory effect, but rather blocks binding of another agent to the channel or blocks the functional modulation of the channel by another agent such as an endogenous ligand, but which compound antagonizes another channel (in particular, TRPM8), e.g., as evaluated in a functional cell based assay under standard conditions as described herein.

(446) The term exhibit antagonist activity on TRPA1 and the like as used herein with respect to TRPA1 mean the inhibitory activity (if the compound acts as antagonist) at TRPA1, as can be evaluated in a functional cell based assay under standard conditions as described herein. In particular, the term exhibit antagonist activity and the like as used herein with respect to e.g. TRPA1 mean the mediation of a pharmacodynamic response in a cell from (i) inhibiting the respective channel (in particular, TRPA1), or (ii) blocking binding of another agent to the channel (in particular, TRPA1) or blocking the functional modulation of the channel (in particular, TRPA1) by another agent such as an endogenous ligand.

(447) As used herein, a functional cell based assay under standard conditions means evaluating the cellular activity of compounds with regard to the modulation of the intracellular calcium level using cells recombinantly expressing human TRPM8 or human TRPA1. In particular, in this context the term standard conditions means an activity test using HEK293 cells recombinantly expressing either human TRPM8 or human TRPA1, which cells have been contacted with a calcium-sensitive dye (such as Fluo-4AM, i.e. Fluo-4-acetoxymethylester), wherein the cells are incubated with the compound to be tested, and receptor modulation is quantitatively detected by calcium-dependent changes is fluorescence intensity. Such a test system is disclosed, inter alia, in Behrendt H J et al., Br. J. Pharmacol. 2004, 141:737-745, which is enclosed herein by reference.

(448) As used herein, a cell-based (label-free) impedance assay under standard conditions means evaluating the antagonistic activity of compounds by measuring changes in the complex impedance of the confluent cell monolayer. In particular, in this context the term standard conditions means an activity test using HaCaT cells (immortalized human epithelial keratinocytes) (Boukamp, 1988), wherein the measurement is performed when the cells established a confluent monolayer (roughly 24 h after seeding) and cellular changes (like alterations in cell adherence, shape, volume, and interaction) due to channel activation are monitored using a label-free, non-invasive assay platform based on cellular dielectric spectroscopy (such as, e.g., CellKey system, Molecular Devices). Performing such a cell-based (label-free) impedance assay is routine to a person skilled in the art.

(449) According to an optional embodiment, the personal-care product is selected from the group consisting of a cosmetic product, a wound dressing or a hygiene product. According to an optional embodiment, the cosmetic product is selected from the group consisting of an insect repellent composition, an oral hygiene composition, a skin care composition, and a hair care composition. Personal hygiene applications such as skin care compositions and hair care compositions include lotions, shaving cream, post shaving preparations, shampoos, conditioners, facial cleansers, soaps, bath oils and foams, antiperspirants, deodorants. Oral hygiene applications include toothpastes, mouthwashes, dental floss, chewing gum and breath fresheners.

(450) In one embodiment the food product is selected from beverages and edibles. According to an optional embodiment the beverages are selected from wine, coffee, fruit juices or tea. According to another optional embodiment the beverages are selected from wine, coffee or fruit juices. According to an optional embodiment the edibles are selected from bakery and dairy products, products based on fruit or vegetables, convenience meals, sweets or snack food. According to another optional embodiment, the food product is selected from the group consisting of ice cream, mousse, creme, beverages and confectionery.

(451) In a further embodiment of the invention the food product comprises one or more ingredient(s) which impart(s) a strong and potentially unpleasant, e.g. astringent and/or pungent taste to the food product. Such a strong and potentially unpleasant taste may be caused by compounds present in fruits, vegetables, wines, spices or nuts. Optionally, these ingredients may include, without limitation, vitamins, minerals, cinnamaldehyde, carvacrol, menthol and/or organosulfur compounds such as allylisothiocyanat, allicin and diallyl sulphides.

(452) In a further embodiment, the present invention relates to a food product, which product comprises one or more ingredient(s) imparting a strong and potentially unpleasant taste as described above and a compound selected from the group consisting of Compounds I.3, II.3, III.3, IV.3, and V.3, wherein said compounds have the chemical structures as defined herein above.

(453) According to an optional embodiment, the textile product is selected from the group consisting of shirts, trousers, socks, towels, headgear, underwear and shoes.

(454) According to an optional embodiment, the pharmaceutical composition is selected from the group consisting of medicaments for the treatment of pain. The present invention further relates to a compound as defined herein above for use in the treatment of (e.g. inflammatory) pain.

(455) A soothing effect can also be desirable in packaging products, wherein such soothing effect is particularly desired upon contact with the content of such packaging products (which can comprise different materials such as paper or plastics). Compounds according to the present invention may be associated with the packaging product material in various ways, e.g., by spin coating, printing, micro capsules, direct incorporation into the material (e.g. extrusion), covalent binding to molecules of the packaging material etc. Suitable methods are known to the person skilled in the art.

(456) A soothing effect can also be desirable in textile products, wherein such soothing effect is particularly desired by wearing such products. Compounds according to the present invention may be associated with the textile product material in various ways, e.g., by spin coating, printing, micro capsules, direct incorporation into the material (e.g. extrusion), covalent binding to molecules of the packaging material etc. Suitable methods are known to the person skilled in the art.

(457) A further embodiment of the present invention relates to the use of the compounds as defined herein, and in particular as defined in Table 1 herein above, and methods of using said compounds. A further embodiment of the present invention also relates to the use of variants of the compounds and methods of using said compounds. In a preferred embodiment of the present invention, said compounds or the corresponding (e.g. cosmetic) compositions are to be applied to the skin of a human subject. In a further preferred embodiment, said application has a skin irritation-reducing (soothing) effect on the part of the body to which the compound or cosmetic composition is applied to.

(458) The specific nature of the products and compositions of the present invention (e. g. the nature of the additional components, the relative proportions of the components and the physical nature of the composition) will depend on the particular application and are known to the skilled person. While the above invention has been described with respect to some of its preferred embodiments, this is in no way to limit the scope of the invention. The person skilled in the art is clearly aware of further embodiments and alterations to the previously described embodiments that are still within the scope of the present invention.

EXAMPLES

(459) Experimental Procedures and Methods:

(460) Calcium influx into cells (under defined buffer conditions) was measured by a calcium-sensitive fluorescence assay (cf. example 3) to quantify activation of the non-selective TRPA1 cation channel. The assay system was used to screen a library of commercially available substances (of synthetic or natural origin) with respect to their antagonistic activity. Afterwards, the activity of hit compounds was tested against different TRPA1 agonists that are relevant in the technical field referred to. A cell-based impedance assay system was used to confirm the antagonistic activity of the screened compounds in a more physiological context (cf. example 4).

Example 1: Cloning of Human TRPA1

(461) The human TRPA1 ion channel was cloned from cDNA derived from a human fetal lung fibroblast cell line (type: IMR-90). First-strand cDNA was generated from total RNA by standard techniques. The TRPA1 coding sequence (according to the NCBI database entry NM_007332) was cloned using standard PCR methods. The isolated gene was confirmed (with a known SNP (single nucleotide polymorphism) in exon I leading to an arginine at position 3) by DNA sequencing and subcloned to generate a suitable expression vector equipped with a tetracycline-regulated promoter for controlled expression of the ion channel. The generation of such expression systems are routine to the person skilled in the art. Alternatively, the expression system could have been generated by chemical DNA synthesis of the TRPA1 gene.

Example 2: Establishment of a Cell-Based Screening System

(462) To identify substances with antagonistic activity a high-throughput cell-based in vitro assay system was established. For this purpose, a stable TRPA1 expressing human embryonic kidney cell line (type: HEK293) was generated using a suitable expression vector (cf. example 1). For the present invention, stable cell lines were generated by transfection of vector DNA using Lipofectamine 2000 reagent, purchased from Invitrogen, according to the instructions in the suppliers' manual. Techniques for the generation of stable cell lines are known to persons skilled in the art.

Example 3: Cell-Based Calcium Assay for the Identification of TRPA1 Modulators

(463) The HEK293 cell line expressing recombinant human TRPA1 under the control of a tetracycline-regulated promoter was used in this assay (cf. example 2). Functional modulation of TRPA1 by the tested compounds was measured and quantified using the calcium sensitive fluorescent probe Fluo-4 M on a fluorescence microplate reader. Activation of TRPA1 by an agonist led to an increase in the intracellular calcium concentration and thus an increase in fluorescence intensity. Inhibition of the TRPA1 related bioactivity by an antagonist reduced an agonist-evoked increase in fluorescence intensity significantly or preferably blocked the agonist-evoked signal completely.

(464) Procedure: Cells were cultured in DMEM (high glucose) supplemented with tetracycline-free FCS (10% v/v), L-glutamine (4 mM), blasticidin (15 g/ml) and hygromycin (100 g/mL) in a water-saturated atmosphere at 37 C. and 5% CO.sub.2. Cells were seeded onto 96-well clear-bottom black-walled assay plates at a density of 70,000 cells per well in 100 l of cell culture medium. Expression of the ion channel was induced or not induced by addition of tetracycline (1 g/ml final concentration) to the cell culture medium (while seeding the cells). Calcium influx into the living cells due to channel activation was monitored 24 h later using the calcium sensitive fluorescent probe Fluo-4 M on a fluorescence microplate reader (FlexStation system, Molecular Devices). Therefore 100 l Krebs-HEPES (KH) buffer (118 mM NaCl; 4.7 mM KCl; 1.3 mM CaCl.sub.2; 1.2 mM MgSO.sub.4; 1.2 mM KH.sub.2PO.sub.4; 4.2 mM NaHCO.sub.3; 10 mM Hepes, pH 7.4) supplemented with sulfinpyrazone (250 M) and Fluo-4 M (4 M) were added and the cells were incubated for an additional hour in a water-saturated atmosphere at 37 C. and 5% CO.sub.2.

(465) Measurement of agonistic activity: Medium was replaced with 200 l KH buffer supplemented with sulfinpyrazone (250 M). Subsequently, 50 l KH buffer supplemented with the agonists or control substances were added. Changes in fluorescence were recorded at 20-26 C.

(466) Measurement of antagonistic activity (screening): Medium was replaced with 150 l KH buffer supplemented with sulfinpyrazone (250 M). Subsequently, 50 l KH buffer supplemented with the screening compounds (50 M; leading to a final concentration of 10 M under measurement conditions) or control substances were added and the cells were incubated for 10 min. under assay conditions in the microplate reader. Changes in fluorescence were recorded at 20-26 C. after addition of 50 l KH buffer supplemented with the TRPA1 agonist menthol (175 M; leading to a final concentration of 35 M under measurement conditions). The published TRPA1 antagonist AP-18 (Petrus, 2007) was used as a control for TRPA1-specific agonistic activity. Subsequently, the inventive compounds were tested for their capacity to reduce signals triggered by addition of propylparaben (EC.sub.80=80 M), retinol (EC.sub.80=150 M), and allyl isothiocyanate (EC.sub.80=5 M) (cf. Table 2).

(467) Analysis: Calcium mobilization was quantified as the change of peak fluorescence (F) over the baseline level (F). The data was analyzed with the software of the microplate reader. Potential TRPA1 antagonists were tested in an effective range of 0.1-50 M for their capacity to reduce the menthol-evoked signal.

Example 4: Cell-Based (Label-Free) Impedance Assay

(468) HaCaT cells (immortalized human epithelial keratinocytes) were used in this assay (Boukamp, 1988). Antagonistic activity of the tested compounds was quantified by measuring changes in the complex impedance of the confluent cell monolayer.

(469) Procedure: Cells were cultured in DMEM (low glucose) supplemented with FCS (10% v/v) and L-glutamine (4 mM) in a water-saturated atmosphere at 37 C. and 5% CO.sub.2. Cells were seeded onto CellKey standard 96W microplates at a density of 80000 cells per well in 100 l of cell culture medium. The measurement was performed when the cells established a confluent monolayer (roughly 24 h after seeding). Cellular changes (like alterations in cell adherence, shape, volume, and interaction) due to channel activation were monitored using a label-free, non-invasive assay platform based on cellular dielectric spectroscopy (CellKey system, Molecular Devices).

(470) Medium was replaced with 135 l CellKey assay buffer (HBSS buffer, 20 mM Hepes; 0.1% BSA) in the microplate reader by the embedded fluid exchange protocol. Measurement was performed after an equilibration period of approximately 1 h under assay conditions according to the embedded antagonist adherent cell protocol: The compounds were applied in 15 l CellKey assay buffer 15 min. prior to the agonist. Cellular responses were recorded at 30 C. after addition of 15 l CellKey assay buffer supplemented with propylparaben (200 M final concentration) or retinol (300 M final concentration).

(471) Analysis: Cellular changes were quantified as changes in complex impedance (dZ) of the cell layer. The data was analyzed with the software of the microplate reader. Potential TRPA1 antagonists were tested in an effective range of 1-50 M.

Example 5: Exemplary Values for the Antagonistic Efficacy of the Compounds Disclosed Herein

(472) TABLE-US-00003 TABLE 2 Antagonistic efficacy (IC.sub.50 values) of compounds measured with the calcium assay Antagonistic activity (IC.sub.50 [M] values) Allyl Compounds Menthol Propylparaben Retinol isothiocyanate I.3 3.5 4.7 3.4 2.5 II.3 1.5 0.9 0.6 1.6 III.3 0.1 0.4 0.4 1.2 IV.3 0.3 4.3 3.3 3.5 V.3 4.5 26 14 26*.sup.) *.sup.)only partial antagonistic activity

(473) Surprisingly, analysis of the data revealed that TRPA1 antagonists according to the present invention could be described which antagonize activation of the TRPA1 ion channel by various agonists acting through different mechanisms.

(474) Exemplary dose-response curves are shown in FIGS. 1 and 2 (calcium assay) and FIGS. 3 and 4 (impedance assay), but should not be construed as being limiting.

Example 6: Test for Cross-Selectivity of the Compounds on TRPM8

(475) The test for cross-selectivity of the compounds on TRPM8 was performed in much the same way as the initial screening on TRPA1 (described in example 3). A HEK293 cell line expressing recombinant human TRPM8 under the control of a tetracycline-regulated promoter was used. Cells were cultured under the conditions mentioned in example 3. Functional modulation of TRPM8 was measured and quantified using the calcium sensitive fluorescent probe Fluo-4 AM on a fluorescence microplate reader. The assay was performed as described in example 3. Changes in fluorescence were recorded at 26-30 C. after addition of the compounds and/or the TRPM8 agonist menthol (EC.sub.80=12 M). Dose-response curves are shown in FIGS. 5 to 9 (calcium assay) against menthol, which is known to trigger both TRPA1 as well as TRPM8. In particular, the antagonistic activity of compound I.3, II.3, III.3, IV.3 and V.3 at TRPA1 (open circles, continuous line) as well as the antagonistic activity of said compounds at TRPM8 (filled squares, dotted line) was measured and compared. Activation of the two ion channels was triggered by addition of menthol (EC.sub.80[TRPA1]=35 M and EC.sub.80[TRPM8]=12 M). The receptor signals were normalized to the pure menthol signal in each case.

Example 7: Test for In Vivo Activity of the Compounds

(476) Antagonistic in vivo activity at TRPA1 was tested in a blinded study on the lid-cheek junction of 16 test persons. The ion channel was stimulated using a known TRPA1 agonist: flufenamic acid, a member of the group of NSAIDs (non-steroidal anti-inflammatory drugs) (Hu et al., 2010). The concentration of flufenamic acid was adjusted to a level that induced a pronounced stinging/burning sensation in the majority of the testers (0.75%).

(477) Procedure: One side of the face (the lid-cheek junction) was pre-incubated with the antagonist (compound I.3, 0.05%)the other side with placebo. Afterwards, flufenamic acid was applied to both sides simultaneously. Testers were asked several questions regarding their individual perception of irritation.

(478) Analysis: Testers were asked if they could feel the NSAID-triggered stinging/burning. The strength of the stimulus was not judged. Then they were asked if they could perceive a difference between the two areas. If the answer was yes, they were asked which side was perceived as more pleasant. The antagonistic effect was graded in three categories: no reduction, reduction and strong reduction of the irritation. 10 out of 14 testers perceived a soothing effect by the use of the antagonist (two individuals felt no stimulus at all).

(479) The results of this test are shown in FIG. 10.

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