Substituted-Quinoxaline-Type Piperidine Compounds and the Uses Thereof

• US 20100216726A1
• Filed: 02/24/2010
• Published: 08/26/2010
• Est. Priority Date: 08/31/2007
• Status: Active Grant

• Current Assignee: Purdue Pharma L.P.
• Original Assignee: Purdue Pharma L.P., Shionogi & Co., Ltd.
• Inventors: Goehring, R. Richard, FUCHINO, Kouki, Whitehead, John William Frank, Matsumura, Akira, Shao, Bin, Tsuno, Naoki, Taoda, Yoshiyuki, Yao, Jiangchao
• Granted Patent: US 8,846,929 B2
• Time in Patent Office: Days
• US Class Current: 514/1.100
• CPC Class Codes: A61K 31/498 Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
• CPC Class Codes: A61P 1/10 Laxatives
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 11/14 Antitussive agents
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/06 Anti-spasmodics
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 25/36 Opioid-abuse
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 451/04 : with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
• CPC Class Codes: C07D 451/14 : containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof
• CPC Class Codes: C07D 471/08 : Bridged systems
• CPC Class Codes: C07D 471/14 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 498/08 : Bridged systems
• CPC Class Codes: C07D 519/00 : Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The invention relates to Substituted-Quinoxaline-Type Piperidine Compounds, compositions comprising an effective amount of a Substituted-Quinoxaline-Type Piperidine Compound and methods to treat or prevent a condition, such as pain, comprising administering to an animal in need thereof an effective amount of a Substituted-Quinoxaline-Type Piperidine Compound.

Claims

1. A compound of Formula (I) or (II):

or a pharmaceutically acceptable derivative thereof wherein;

Y₁ is O or S;

Q is fused benzo or fused (5- or 6-membered)heteroaryl;

each R₂ is independently;

(a) -halo, —

CN, —

NO₂, —

OT₃, —

C(═

O)T₃, —

C(═

O)OT₃, —

C(═

O)N(T₁)(T₂), —

S(═

O)₂OH, —

S(═

O)T₃, —

S(═

O)₂T₃, —

S(═

O)₂N(T₁)(T₂), —

N(T₁)(T₂), —

N(T₃)C(═

O)T₃, —

N(T₃)C(═

O)N(T₁)(T₂), —

N(T₃)S(═

O)₂T₃, or —

N(T₃)S(═

O)₂N(T₁)(T₂);

or

(b) —

(C₁-C₆)alkyl, —

(C₂-C₆)alkenyl, —

(C₂-C₆)alkynyl, —

(C₁-C₆)alkoxy, —

(C₃-C₇)cycloalkyl, —

(C₆-C₁₄)bicycloalkyl, —

(C₈-C₂₀)tricycloalkyl, —

(C₅-C₁₀)cycloalkenyl, —

(C₇-C₁₄)bicycloalkenyl, —

(C₈-C₂₀)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 R₈ groups;

or

(c) -phenyl, -naphthalenyl, —

(C_1-4)aryl, or -(5- or 6-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R₇ groups;

a is an integer selected from 0, 1, and 2;

the dashed line in the 6-membered, nitrogen-containing ring that is fused to the Q group denotes the presence or absence of a bond, and when that dashed line denotes the presence of a bond then R₃ and one R₄ are absent;

R₃ is;

(a) —

H;

or

(b) —

(C₁-C₄)alkyl which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from —

OH, —

(C₁-C₄)alkoxy, —

N(R₆)₂, —

C(═

O)OR₉, and —

C(═

O)N(R₆)₂;

or

(c) —

(C₃-C₇)cycloalkyl which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from —

OH, —

(C₁-C₄)alkyl, —

(C₁-C₄)alkoxy, —

N(R₆)₂, —

C(═

O)OR₉, and —

C(═

O)N(R₆)₂;

each R₄ is independently;

(a) —

H;

or

(b) -halo, —

CN, or —

NO₂;

or

(c) —

X, —

(C₁-C₆)alkyl-X, -(5- or 6-membered)heterocycle-X, or -(5- or 6-membered)heterocycle-(C₁-C₆)alkyl-X;

or

(d) —

C(═

Y)CN, —

C(═

Y)X, —

C(═

Y)T₃, —

C(═

Y)YX, —

C(═

Y)YT₃, —

C(═

Y)N(T₁)(T₂), —

C(═

Y)N(R₉)CN, —

C(═

Y)N(R₉)X, —

C(═

Y)N(R₉)YH, —

C(═

Y)N(R₉)YX, —

C(═

Y)N(R₉)YCH₂X, —

C(═

Y)N(R₉)YCH₂CH₂X, or —

C(═

Y)N(R₉)S(═

O)₂T₃;

or

(e) —

N(R₉)X, —

N(R₉)—

CH₂X, —

N(R₉)—

CH₂CH₂X, —

N(R₉)CH₂N(R₉)C(═

N(R₁₂))N(R₁₂)₂, —

N(R₉)—

CH₂CH₂N(R₉)C(═

N(R₁₂))N(R₁₂)₂, —

N(T₁)(T₂), —

N(T₃)C(═

Y)T₃, —

N(T₃)C(═

Y)YT₃, —

N(T₃)C(═

Y)N(T₁)(T₂), —

N(T₃)S(═

O)₂T₃, or —

N(T₃)S(═

O)₂N(T₁)(T₂);

or

(f) —

YH, —

CH₂YH, —

CH₂CH₂YH, —

YX, or —

YT₃;

or

(g) —

S(═

O)T₃, —

S(═

O)₂T₃, —

S(═

O)N(T₁)(T₂), —

S(═

O)₂N(T₁)(T₂), —

S(═

O)X, or —

S(═

O)₂X;

X is;

(a) —

H, —

(C₁-C₆)alkyl, —

(C₂-C₆)alkenyl, —

(C₂-C₆)alkynyl, —

(C₁-C₆)alkoxy, —

(C₃-C₇)cycloalkyl, —

(C₆-C₁₄)bicycloalkyl, —

(C₈-C₂₀)tricycloalkyl, —

(C₅-C₁₀)cycloalkenyl, —

(C₇-C₁₄)bicycloalkenyl, —

(C₈-C₂₀)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 R₈ groups;

or

(b) -phenyl, -naphthalenyl, —

(C_1-4)aryl, or -(5- or 6-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R₇ groups;

each Y is independently O or S;

A and B are independently;

(a) —

H, —

CN, —

C(═

O)OT₃, or —

C(═

O)N(T)₁(T₂);

or

(b) —

(C₃-C₁₂)cycloalkyl, —

(C₃-C₁₂)cycloalkoxy, —

(C₁-C₆)alkyl, —

(C₂-C₆)alkenyl, —

(C₂-C₆)alkynyl, or —

(C₁-C₆)alkoxy, each of which is unsubstituted or substituted with 1 or 2 substituents independently selected from —

OH, —

S(═

O)₂NH₂, —

N(R₆)₂, ═

NR₆, —

C(═

O)OT₃, —

C(═

O)N(R₆)₂, —

N(R₆)C(═

O)R₉, and -(5- or 6-membered)heterocycle, or 1, 2 or 3 independently selected -halo;

or

(c) A-B can together form a (C₂-C₆)bridge, which is unsubstituted or substituted with 1, 2, 3, 4, 5, 6, 7 or 8 substituents independently selected from —

OH, —

(C₁-C₄)alkyl, -halo, and —

C(halo)₃, and which bridge optionally contains —

HC═

CH—

or —

O—

within the (C₂-C₆)bridge;

wherein the 6-membered, nitrogen-containing ring that is fused to the Q group can be in the endo- or exo-configuration with respect to the A-B bridge;

or

(d) A-B can together form a —

CH₂—

N(R_a)—

CH₂—

bridge, a

 

bridge, or a

 

bridge;

wherein the 6-membered, nitrogen-containing ring that is fused to the Q group can be in the endo- or exo-configuration with respect to the A-B bridge;

R_a is —

H, —

(C₃-C₇)cycloalkyl, —

CH₂—

C(═

O)—

R_c, —

(CH₂)—

C(═

O)—

OR_c, —

(CH₂)—

C(═

O)—

N(R_c)₂, —

(CH₂)₂—

O—

R_c, —

(CH₂)₂—

S(═

O)₂—

N(R_c)₂, R_c, or —

(CH₂)₂—

N(R_c)S(═

O)₂—

R_c;

R_b is;

(a) —

H, —

(C₁-C₆)alkyl, —

(C₃-C₇)cycloalkyl, -(3- to 7-membered)heterocycle, —

N(R_c)₂, —

N(R_c)—

(C₃-C₇)cycloalkyl, or —

N(R_c)-(3- to 7-membered)heterocycle;

or

(b) -phenyl, -naphthalenyl, or -(5- or 6-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R₇ groups;

or

(c) —

N(R_c)-phenyl, —

N(R_c)-naphthalenyl, —

NR_c)—

(C₁₄)aryl, or —

N(R_c)-(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R₇ groups;

each R_c is independently —

H or —

(C₁-C₄)alkyl;

Z is —

[(C₁-C₁₀)alkyl optionally substituted by R₁]_h—

, wherein h is 0 or 1;

or —

(C₁-C₁₀)alkyl-NR₆C(═

Y)—

;

each R₁ is independently;

(a) -halo, —

CN, —

OH, —

CH₂OH, —

CH₂CH₂OH, —

NO₂, —

N(R₆)₂, —

S(═

O)NH₂, —

S(═

O)₂NH₂, —

C(═

O)OV₁, or —

C(═

O)CN;

or

(b) —

(C₁-C₁₀)alkyl, —

(C₂-C₁₀)alkenyl, —

(C₂-C₁₀)alkynyl, —

O(C₁-C₆)alkyl, —

(C₃-C₇)cycloalkoxy, —

(C₆-C₁₄)bicycloalkyl, —

(C₈-C₂₀)tricycloalkyl, —

(C₅-C₁₀)cycloalkenyl, —

(C₇-C₁₄)bicycloalkenyl, —

(C₈-C₂₀)tricycloalkenyl, or -(3- to 7-membered)heterocycle, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R₈ groups;

or

(c)

 

or

(d) -phenyl, -naphthalenyl, or —

(C₁₄)aryl, each of which is unsubstituted or substituted with an R₇ group;

or

—

Z—

R₁ is 3,3-diphenylpropyl- optionally substituted at the 3 carbon of the propyl with —

CN, —

C(═

O)N(R₆)₂, —

C(═

O)OV₁, or -tetrazolyl;

or

—

Z—

R₁ is —

(C₁-C₄)alkyl substituted with tetrazolyl;

each R₅ is independently —

(C₁-C₄)alkyl, —

(C₂-C₆)alkenyl, —

(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl, —

(C₁-C₆)alkyl-C(═

O)OR₉, —

OR₉, —

SR₉, —

C(halo)₃, —

CH(halo)₂, —

CH₂(halo), —

CN, ═

O, ═

S, -halo, —

N₃, —

NO₂, —

CH═

N(R₉), —

N(R₉)(C₁-C₆)alkyl-C(═

O)OR₉, —

N(R₉)₂, —

N(R₉)OH, —

N(R₉)S(═

O)R₁₂, —

N(R₉)S(═

O)₂R₁₂, —

N(R₉)C(═

O)R₁₂, —

N(R₉)C(═

O)OR₁₂, —

C(═

O)R₉, —

C(═

O)OR₉, —

OC(═

O)R₉, —

OC(═

O)OR₉, —

S(═

O)R₉, or —

S(═

O)₂R₉;

each R₆ is independently —

H, —

(C₁-C₆)alkyl, or —

(C₃-C₇)cycloalkyl, or two R₆ groups attached to the same nitrogen atom can together form a 5- to 8-membered ring, wherein the number of atoms in the ring includes the nitrogen atom, and in which one of the 5- to 8-membered ring carbon atoms is optionally replaced by O, S, or N(T₃);

each R₇ is independently —

(C₁-C₄)alkyl, —

(C₂-C₆)alkenyl, —

(C₂-C₆)alkynyl, —

OR₉, —

SR₉, —

C(halo)₃, —

CH(halo)₂, —

CH₂(halo), —

CN, -halo, —

N₃, —

NO₂, —

CH═

N(R₉), —

N(R₉)₂, —

N(R₉)OH, —

N(R₉)S(═

O)R₁₂, —

N(R₉)S(═

O)₂R₁₂, —

N(R₉)C(═

O)R₁₂, —

N(R₉)C(═

O)N(T₁)(T₂), —

N(R₉)C(═

O)OR₁₂, —

C(═

O)R₉, —

C(═

O)N(T₁)(T₂), —

C(═

O)OR₉, —

OC(═

O)R₉, —

OC(═

O)N(T₁)(T₂), —

OC(═

O)OR₉, —

S(═

O)R₉, or —

S(═

O)₂R₉;

each R₈ is independently —

(C₁-C₄)alkyl, —

(C₂-C₆)alkenyl, —

(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl, —

(C₁-C₆)alkyl-C(═

O)OR₉, —

OR₉, —

SR₉, —

C(halo)₃, —

CH(halo)₂, —

CH₂(halo), —

CN, ═

O, ═

S, -halo, —

N₃, —

NO₂, —

CH═

N(R₉), —

N(R₉)(C₁-C₆)alkyl-C(═

O)OR₉, —

N(R₉)₂, —

N(R₉)OH, —

N(R₉)S(═

O)R₁₂, —

N(R₉)S(═

O)₂R₁₂, —

N(R₉)C(═

O)R₁₂, —

N(R₉)C(═

O)N(T₁)(T₂), —

N(R₉)C(═

O)OR₁₂, —

C(═

O)R₉, —

C(═

O)N(T₁)(T₂), —

C(═

O)OR₉, —

OC(═

O)R₉, —

OC(═

O)N(T₁)(T₂), —

OC(═

O)OR₉, —

S(═

O)R₉, or —

S(═

O)₂R₉;

each R₉ is independently —

H, —

(C₁-C₆)alkyl, —

(C₂-C₆)alkenyl, —

(C₂-C₆)alkynyl, —

(C₃-C₈)cycloalkyl, —

(C₅-C₈)cycloalkenyl, -phenyl, -benzyl, -(3- to 6-membered)heterocycle, —

C(halo)₃, —

CH(halo)₂, or —

CH₂(halo);

if h is 0, then R₁₁ can be —

H, —

CN, —

C(═

O)OR₉, and —

C(═

O)N(R₆)₂ or R₁₁ can be —

(C₁-C₄)alkyl which is unsubstituted or substituted with —

OH, —

(C₁-C₄)alkoxy, —

N(R₆)₂, —

C(═

O)OR₉, or —

C(═

O)N(R₆)₂;

if h is 1, then R₁₁ can be —

H, —

CN, —

OH, -halo, —

C(═

O)OR₉, or —

C(═

O)N(R₆)₂ or R_H can be —

(C₁-C₄)alkyl which is unsubstituted or substituted with —

OH, —

(C₁-C₄)alkoxy, —

N(R₆)₂, —

C(═

O)OR₉, or —

C(═

O)N(R₆)₂;

otherwise, wherein Z is —

(C₁-C₁₀)alkyl-NR₆C(═

Y)—

, then R₁₁ can be —

H, —

CN, —

C(═

O)OR₉, or —

C(═

O)N(R₆)₂ or R₁₁ can be —

(C₁-C₄)alkyl which is unsubstituted or substituted with —

OH, —

(C₁-C₄)alkoxy, —

N(R₆)₂, —

C(═

O)OR₉, or —

C(═

O)N(R₆)₂;

each R₁₂ is independently —

H or —

(C₁-C₄)alkyl;

m is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11;

e and f are each an integer independently selected from 0, 1, 2, 3, 4, and 5 provided that 2≦

(e+f)≦

5;

j and k are each an integer independently selected from 0, 1, 2, 3, and 4 provided that 1≦

(j+k)≦

4;

each p is an integer independently selected from 0 and 1;

each T₁ and T₂ is independently —

H or —

(C₁-C₁₀)alkyl which is unsubstituted or substituted with 1, 2 or 3 independently selected R₅ groups and, optionally, in which any —

(C₁-C₁₀)alkyl carbon atom except the carbon atom bonded directly to the atom to which T₁ or T₂ is attached is independently replaced by O, S, or N(R₆), or T₁ and T₂ can together form a 5- to 8-membered ring wherein the number of atoms in the ring includes the nitrogen atom to which T₁ and T₂ are bonded, said 5- to 8-membered ring is unsubstituted or substituted with 1, 2 or 3 independently selected R₅ groups and, optionally, any carbon atom in said 5- to 8-membered ring is independently replaced by O, S, or N(R₆);

each T₃ is independently —

H or —

(C₁-C₁₀)alkyl which is unsubstituted or substituted with 1, 2 or 3 independently selected R₅ groups and, optionally, in which any —

(C₁-C₁₀)alkyl carbon atom except the carbon atom bonded directly to the atom to which T₃ is attached is independently replaced by O, S, or N(R₁₂);

each V₁ is independently —

H, —

(C₁-C₆)alkyl, —

(C₃-C₇)cycloalkyl, -phenyl, or -benzyl; and

each halo is independently —

F, —

Cl, —

Br, or —

I.

2. The compound of claim 1, wherein the compound is a compound of Formula (II):

or a pharmaceutically acceptable derivative thereof.

3. The compound of claim 2, wherein Y₁ is O.

4. The compound of claim 3, wherein the dashed line is present as a bond in a double bond and only one R₄ is present.

5. The compound of claim 4, wherein Q is fused benzo, fused pyridino, fused pyrimidino, fused pyrazino, or fused pyridazino.

6. The compound of claim 5, wherein Q is fused benzo or fused pyridino.

7. The compound of claim 5, wherein Q is fused benzo.

8. The compound of claim 6, wherein a is 0.

9. The compound of claim 6, wherein A and B are each —

H.

10. The compound of claim 6, wherein A and B together form a bridge such that the bridged-piperidine is:

wherein each R_d is independently —

H, —

(C₁-C₄)alkyl, -halo, or —

C(halo)₃.

11. The compound of claim 10, wherein A and B together form a bridge such that the bridged-piperidine is:

12. The compound of claim 10, wherein the 6-membered, nitrogen-containing ring that is fused to the Q group is in the endo configuration with respect to the A-B bridge of the bridged-piperidine.

13. The compound of claim 10, wherein h is 0 and R₁ is:

wherein each R_z is independently —

H, —

(C₁-C₄)alkyl, —

OH, or —

CN.

14. The compound of claim 13, wherein each R_z is independently —

H or —

CH₃.

15. The compound of claim 11, wherein h is 0 and R₁ is:

wherein each R_z, is independently —

H, —

(C₁-C₄)alkyl, —

OH, or —

CN.

16. The compound of claim 15, wherein each R_z is independently —

H or —

CH₁.

17. The compound of claim 11, wherein h is 0 and R₁ is:

wherein each R_z is —

H.

18. The compound of claim 10, wherein the R₁ group is in the exo-configuration with respect to the A-B bridge of the bridged piperidine.

19. The compound of claim 1, wherein the pharmaceutically acceptable derivative is a pharmaceutically acceptable salt.

20. The compound of claim 19, wherein the pharmaceutically acceptable derivative is a HCl-salt, a sodium-salt, or a potassium-salt.

21. A composition comprising an effective amount of the compound or a pharmaceutically acceptable derivative of the compound of claim 1 and a pharmaceutically acceptable carrier or excipient.

22. A method for modulating ORL-1 receptor function in a cell, comprising contacting a cell capable of expressing the ORL-1 receptor with an effective amount of the compound or a pharmaceutically acceptable derivative of the compound of claim 1.

23. The method of claim 22, wherein the compound or the pharmaceutically acceptable derivative of the compound acts as an agonist or a partial agonist at the ORL-1 receptor.

24. The method of claim 22, wherein the compound or the pharmaceutically acceptable derivative of the compound acts as an antagonist at the ORL-1 receptor.

25. A method for treating pain in an animal, comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable derivative of the compound of claim 1.

26. A method for treating a memory disorder, obesity, constipation, depression, dementia, Parkinsonism, anxiety, cough, diarrhea, high blood pressure, epilepsy, anorexia/cachexia, urinary incontinence, or drug abuse in an animal, comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable derivative of the compound of claim 1.

27. A compound of Formula (I) or (II):

or a pharmaceutically acceptable derivative thereof wherein;

Y₁ is O or S;

Q is fused benzo or fused (5- or 6-membered)heteroaryl;

each R₂ is independently;

(a) -halo, —

CN, —

NO₂, —

OT₃, —

C(═

O)T₃, —

C(═

O)OT₃, —

C(═

O)N(T₁)(T₂), —

S(═

O)₂OH, —

S(═

O)T₃, —

S(═

O)₂T₃, —

S(═

O)₂N(T₁)(T₂), —

N(T₁)(T₂), —

N(T₃)C(═

O)T₃, —

N(T₃)C(═

O)N(T₁)(T₂), —

N(T₃)S(═

O)₂T₃, or —

N(T₃)S(═

O)₂N(T₁)(T₂);

or

(b) —

(C₁-C₆)alkyl, —

(C₂-C₆)alkenyl, —

(C₂-C₆)alkynyl, —

(C₁-C₆)alkoxy, —

(C₃-C₇)cycloalkyl, —

(C₆-C₁₄)bicycloalkyl, —

(C₈-C₂₀)tricycloalkyl, —

(C₅-C₁₀)cycloalkenyl, —

(C₇-C₁₄)bicycloalkenyl, —

(C₈-C₂₀)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 R₈ groups;

or

(c) -phenyl, -naphthalenyl, —

(C_1-4)aryl, or -(5- or 6-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R₇ groups;

a is an integer selected from 0, 1, and 2;

the dashed line in the 6-membered, nitrogen-containing ring that is fused to the Q group denotes the presence or absence of a bond, and when that dashed line denotes the presence of a bond then R₃ and one R₄ are absent;

R₃ is;

(a) —

H;

or

(b) —

(C₁-C₄)alkyl which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from —

OH, —

(C₁-C₄)alkoxy, —

N(R₆)₂, —

C(═

O)OR₉, and —

C(═

O)N(R₆)₂;

or

(c) —

(C₃-C₇)cycloalkyl which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from —

OH, —

(C₁-C₄)alkyl, —

(C₁-C₄)alkoxy, —

N(R₆)₂, —

C(═

O)OR₉, and —

C(═

O)N(R₆)₂;

each R₄ is independently;

(a) —

H;

or

(b) -halo, —

CN, or —

NO₂;

or

(c) —

X, —

(C₁-C₆)alkyl-X, -(5- or 6-membered)heterocycle-X, or -(5- or 6-membered)heterocycle-(C₁-C₆)alkyl-X;

or

(d) —

C(═

Y)CN, —

C(═

Y)X, —

C(═

Y)T₃, —

C(═

Y)YX, —

C(═

Y)YT₃, —

C(═

Y)N(T₁)(T₂), —

C(═

Y)N(R₉)CN, —

C(═

Y)N(R₉)X, —

C(═

Y)N(R₉)CH₂CH₂N(T₁)(T₂), —

C(═

Y)N(R₉)YH, —

C(═

Y)N(R₉)YX, —

C(═

Y)N(R₉)YCH₂X, —

C(═

Y)N(R₉)YCH₂CH₂X, or —

C(═

Y)N(R₉)S(═

O)₂T₃;

or

(e) —

N(R₉)X, —

N(R₉)—

CH₂X, —

N(R₉)—

CH₂CH₂X, —

N(R₉)—

CH₂CH₂N(R₉)X, —

N(R₉)CH₂CH₂N(T₁)(T₂), —

N(R₉)CH₂C(═

Y)X, —

N((C₁-C₆)alkyl-C(═

O)OR₉)₂, —

N(R₉)CH₂N(R₉)C(═

N(R₁₂))N(R₁₂)₂, —

N(R₉)—

CH₂CH₂N(R₉)C(═

N(R₁₂))N(R₁₂)₂, —

N(R₁)(T₂), —

N(T₃)C(═

Y)T₃, —

N(T₃)C(═

Y)YT₃, —

N(T₃)C(═

Y)N(T₁)(T₂), —

N(T₃)S(═

O)₂T₃, or —

N(T₃)S(═

O)₂N(T₁)(T₂);

or

(f) —

YH, —

CH₂YH, —

CH₂CH₂YH, —

YX, or —

YT₃;

or

(g) —

S(═

O)T₃, —

S(═

O)₂T₃, —

S(═

O)N(T₁)(T₂), —

S(═

O)₂N(T₁)(T₂), —

S(═

O)X, or —

S(═

O)₂X;

X is;

(a) —

H, —

(C₁-C₆)alkyl, —

(C₂-C₆)alkenyl, —

(C₂-C₆)alkynyl, —

(C₁-C₆)alkoxy, —

(C₃-C₇)cycloalkyl, —

(C₆-C₁₄)bicycloalkyl, —

(C₈-C₂₀)tricycloalkyl, —

(C₅-C₁₀)cycloalkenyl, —

(C₇-C₁₄)bicycloalkenyl, —

(C₈-C₂₀)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 R₈ groups;

or

(b) -phenyl, -benzyl, -naphthalenyl, —

(C_1-4)aryl, —

(C₁-C₆)alkyl-(5- or 6-membered)heteroaryl or -(5- or 6-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R₇ groups;

each Y is independently O or S;

A and B are independently;

(a) —

H, —

CN, —

C(═

O)OT₃, or —

C(═

O)N(T)₁(T₂);

or

(b) —

(C₃-C₁₂)cycloalkyl, —

(C₃-C₁₂)cycloalkoxy, —

(C₁-C₆)alkyl, —

(C₂-C₆)alkenyl, —

(C₂-C₆)alkynyl, or —

(C₁-C₆)alkoxy, each of which is unsubstituted or substituted with 1 or 2 substituents independently selected from —

OH, —

S(═

O)₂NH₂, —

N(R₆)₂, ═

NR₆, —

C(═

O)OT₃, —

C(═

O)N(R₆)₂, —

N(R₆)C(═

O)R₉, and -(5- or 6-membered)heterocycle, or 1, 2 or 3 independently selected -halo;

or

(c) A-B can together form a (C₂-C₆)bridge, which is unsubstituted or substituted with 1, 2, 3, 4, 5, 6, 7, or 8 substituents independently selected from —

OH, —

(C₁-C₄)alkyl, -halo, and —

C(halo)₃, and which bridge optionally contains —

HC═

CH—

or —

O—

within the (C₂-C₆)bridge;

wherein the 6-membered, nitrogen-containing ring that is fused to the Q group can be in the endo- or exo-configuration with respect to the A-B bridge;

or

(d) A-B can together form a —

CH₂—

N(R_a)—

CH₂—

bridge, a

 

bridge, or a

 

bridge;

wherein the 6-membered, nitrogen-containing ring that is fused to the Q group can be in the endo- or exo-configuration with respect to the A-B bridge;

R_a is —

H, —

(C₁-C₆)alkyl, —

(C₃-C₇)cycloalkyl, —

CH₂—

C(═

O)—

R_c, —

(CH₂)—

C(═

O)—

R_c, —

(CH₂)—

C(═

O)—

N(R_c)₂, —

(CH₂)₂—

O—

R_c, —

(CH₂)₂—

S(═

O)₂—

N(R_c)₂, R_c, or —

(CH₂)₂—

N(R_c)S(═

O)₂—

R_c;

R_b is;

(a) —

H, —

(C₁-C₆)alkyl, —

(C₃-C₇)cycloalkyl, -(3- to 7-membered)heterocycle, —

N(R_c)₂, —

N(R_c)—

(C₃-C₇)cycloalkyl, or —

N(R_a)-(3- to 7-membered)heterocycle;

or

(b) -phenyl, -naphthalenyl, or -(5- or 6-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R₇ groups;

or

(c) —

N(R_c)-phenyl, —

N(R_a)-naphthalenyl, —

N(R_c)—

(C₁₄)aryl, or —

N(R_c)-(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R₇ groups;

each R_c is independently —

H or —

(C₁-C₄)alkyl;

Z is —

[(C₁-C₁₀)alkyl optionally substituted by R₁]_h—

, wherein h is 0 or 1;

—

[(C₂-C₁₀)alkenyl optionally substituted by R₁]—

;

or —

(C₁-C₁₀)alkyl-NR₆C(═

Y)—

;

each R₁ is independently;

(a) -halo, —

CN, —

OH, —

CH₂OH, —

CH₂CH₂OH, —

NO₂, —

N(R₆)₂, —

S(═

O)NH₂, —

S(═

O)₂NH₂, —

C(═

O)OV₁, or —

C(═

O)CN;

or

(b) —

(C₁-C₁₀)alkyl, —

(C₂-C₁₀)alkenyl, —

(C₂-C₁₀)alkynyl, —

O(C₁-C₆)alkyl, —

(C₃-C₇)cycloalkoxy, —

(C₆-C₁₄)bicycloalkyl, —

(C₈-C₂₀)tricycloalkyl, —

(C₅-C₁₀)cycloalkenyl, —

(C₇-C₁₄)bicycloalkenyl, —

(C₈-C₂₀)tricycloalkenyl, or -(3- to 7-membered)heterocycle, each of which is unsubstituted or substituted with 1, 2, or 3 independently selected R₈ groups;

or

(c)

 

or

(d) -phenyl, -naphthalenyl, or —

(C_1-4)aryl, each of which is unsubstituted or substituted with an R₇ group;

or

—

Z—

R₁ is 3,3-diphenylpropyl- optionally substituted at the 3 carbon of the propyl with —

CN, —

C(═

O)N(R₆)₂, —

C(═

O)OV₁, or -tetrazolyl;

or

—

Z—

R₁ is —

(C₁-C₄)alkyl substituted with tetrazolyl;

each R₅ is independently —

(C₁-C₄)alkyl, —

(C₂-C₆)alkenyl, —

(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl, -phenyl, —

(C₁-C₆)alkyl-C(═

O)OR₉, —

OR₉, —

SR₉, —

C(halo)₃, —

CH(halo)₂, —

CH₂(halo), —

CN, ═

O, ═

S, -halo, —

N₃, —

NO₂, —

CH═

N(R₉), —

N(R₉)(C₁-C₆)alkyl-C(═

O)OR₉, —

N(R₉)₂, —

N(R₉)OH, —

N(R₉)S(═

O)R₁₂, —

N(R₉)S(═

O)₂R₁₂, —

N(R₉)S(═

O)R₁₂, —

N(R₉)C(═

O)OR₁₂, —

C(═

O)R₉, —

C(═

O)—

C(═

O)OR₉, —

C(═

O)OR₉, —

OC(═

O)R₉, —

OC(═

O)OR₉, —

S(═

O)R₉, or —

S(═

O)₂R₉;

each R₆ is independently —

H, —

(C₁-C₆)alkyl, or —

(C₃-C₇)cycloalkyl, or two R₆ groups attached to the same nitrogen atom can together form a 5- to 8-membered ring, wherein the number of atoms in the ring includes the nitrogen atom, and in which one of the 5- to 8-membered ring carbon atoms is optionally replaced by O, S, or N(T₃);

each R₇ is independently —

(C₁-C₄)alkyl, —

(C₂-C₆)alkenyl, —

(C₂-C₆)alkynyl, —

OR₉, —

SR₉, —

C(halo)₃, —

CH(halo)₂, —

CH₂(halo), —

CN, -halo, —

N₃, —

NO₂, —

CH═

N(R₉), —

N(R₉)₂, —

N(R₉)OH, —

N(R₉)S(═

O)R₁₂, —

N(R₉)S(═

O)₂R₁₂, —

N(R₉)C(═

O)R₁₂, —

N(R₉)C(═

O)N(T₁)(T₂), —

N(R₉)C(═

O)OR₁₂, —

C(═

O)R₉, —

C(═

O)N(T₁)(T₂), —

C(═

O)OR₉, —

OC(═

O)R₉, —

OC(═

O)N(T₁)(T₂), —

OC(═

O)OR₉, —

S(═

O)R₉, or —

S(═

O)₂R₉;

each R₈ is independently —

(C₁-C₄)alkyl, —

(C₂-C₆)alkenyl, —

(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl, -phenyl, —

(C₁-C₆)alkyl-C(═

O)OR₉, —

OR₉, —

SR₉, —

C(halo)₃, —

CH(halo)₂, —

CH₂(halo), —

CN, ═

O, ═

S, -halo, —

N₃, —

NO₂, —

CH═

N(R₉), —

N(R₉)(C₁-C₆)alkyl-C(═

O)OR₉, —

N(R₉)₂, —

N(R₉)OH, —

N(R₉)S(═

O)R₁₂, —

N(R₉)S(═

O)₂R₁₂, —

N(R₉)C(═

O)R₁₂, —

N(R₉)C(═

O)N(T₁)(T₂), —

N(R₉)C(═

O)OR₁₂, —

C(═

O)R₉, —

C(═

O)—

C(═

O)OR₉, —

C(═

O)N(T₁)(T₂), —

C(═

O)OR₉, —

OC(═

O)R₉, —

OC(═

O)N(T₁)(T₂), —

OC(═

O)OR₉, —

S(═

O)R₉, or —

S(═

O)₂R₉;

each R₉ is independently —

H, —

(C₁-C₆)alkyl, —

(C₂-C₆)alkenyl, —

(C₂-C₆)alkynyl, —

(C₃-C₈)cycloalkyl, —

(C₅-C₈)cycloalkenyl, -phenyl, -benzyl, -(3- to 6-membered)heterocycle, —

C(halo)₃, —

CH(halo)₂, or —

CH₂(halo);

if h is 0, then R₁₁ can be —

H, —

CN, —

C(═

O)OR₉, or —

C(═

O)N(R₆)₂ or R₁₁ can be —

(C₁-C₄)alkyl which is unsubstituted or substituted with —

OH, —

(C₁-C₄)alkoxy, —

N(R₆)₂, —

C(═

O)OR₉, or —

C(═

O)N(R₆)₂;

if h is 1, then R₁₁ can be —

H, —

CN, —

OH, -halo, —

C(═

O)OR₉, or —

C(═

O)N(R₆)₂ or R₁₁ can be —

(C₁-C₄)alkyl which is unsubstituted or substituted with —

OH, —

(C₁-C₄)alkoxy, —

N(R₆)₂, —

C(═

O)OR₉, or —

C(═

O)N(R₆)₂;

otherwise, wherein Z is —

(C₁-C₁₀)alkyl-NR₆C(═

Y)—

, then R₁₁ can be —

H, —

CN, —

C(═

O)OR₉, or —

C(═

O)N(R₆)₂ or R₁₁ can be —

(C₁-C₄)alkyl which is unsubstituted or substituted with —

OH, —

(C₁-C₄)alkoxy, —

N(R₆)₂, —

C(═

O)OR₉, or —

C(═

O)N(R₆)₂;

each R₁₂ is independently —

H or —

(C₁-C₄)alkyl;

m is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11;

e and f are each an integer independently selected from 0, 1, 2, 3, 4, and 5 provided that 2≦

(e+f)≦

5;

j and k are each an integer independently selected from 0, 1, 2, 3, and 4 provided that 1≦

(j+k)≦

4;

each p is an integer independently selected from 0, 1, 2, 3, and 4;

each T₁ and T₂ is independently —

H or —

(C₁-C₁₀)alkyl which is unsubstituted or substituted with 1, 2 or 3 independently selected R₅ groups and, optionally, in which any —

(C₁-C₁₀)alkyl carbon atom except the carbon atom bonded directly to the atom to which T₁ or T₂ is attached is independently replaced by O, S, or N(R₆), or T₁ and T₂ can together form a 5- to 8-membered ring wherein the number of atoms in the ring includes the nitrogen atom to which T₁ and T₂ are bonded, said 5- to 8-membered ring is unsubstituted or substituted with 1, 2 or 3 independently selected R₅ groups and, optionally, any carbon atom in said 5- to 8-membered ring is independently replaced by O, S, or N(R₆);

each T₃ is independently —

H or —

(C₁-C₁₀)alkyl which is unsubstituted or substituted with 1, 2 or 3 independently selected R₅ groups and, optionally, in which any —

(C₁-C₁₀)alkyl carbon atom except the carbon atom bonded directly to the atom to which T₃ is attached is independently replaced by O, S, or N(R₁₂);

each V₁ is independently —

H, —

(C₁-C₆)alkyl, —

(C₃-C₇)cycloalkyl, -phenyl, or -benzyl; and

each halo is independently —

F, —

Cl, —

Br, or —

I, provided that if Z is —

[(C₁-C₁₀)alkyl optionally substituted by R₁]_h— and

h is 0 then R₄ is not COOH.

28. The compound of claim 27, wherein the compound is a compound of Formula (II):

or a pharmaceutically acceptable derivative thereof.

29. The compound of claim 28, wherein Y₁ is O.

30. The compound of claim 29, wherein the dashed line is present as a bond in a double bond and only one R₄ is present.

31. The compound of claim 30, wherein Q is fused benzo, fused pyridino, fused pyrimidino, fused pyrazino, or fused pyridazino.

32. The compound of claim 31, wherein Q is fused benzo or fused pyridino.

33. The compound of claim 31, wherein Q is fused benzo.

34. The compound of claim 32, wherein a is 0.

35. The compound of claim 32, wherein R₄ is:

(a) —

C(═

Y)YX;

or

(b) —

N(R₉)X.

36. The compound of claim 35, wherein X of —

N(R₉)X is —

(C₁-C₆)alkyl substituted with one R₈ group, -(5- or 6-membered)heterocycle substituted with one R₈ group, -phenyl substituted with one R₇ group, or -(5- or 6-membered)heteroaryl substituted with one R₇ group.

37. The compound of claim 36, wherein each R₇ or R₈ is —

C(═

O)OR₉.

38. The compound of claim 37, wherein each R₉ of the R₇ or R₈ —

C(═

O)OR₉ is —

H.

39. The compound of claim 32, wherein R₄ is —

N(H)X and X is a -(5- or 6-membered)heterocycle substituted with one R₈ group.

40. The compound of claim 39, wherein the R₈ group is —

C(═

O)OR₉.

41. The compound of claim 40, wherein the R₈ group is —

COOH.

42. The compound of claim 32, wherein R₄ is —

N(H)X, X is —

(C₁-C₆)alkyl substituted with one R₈ group, and the R₈ group is —

C(═

O)OR₉.

43. The compound of claim 42, wherein the R₈ group is —

COOH.

44. The compound of claim 32, wherein R₄ is -(5- or 6-membered)heterocycle-X and X is phenyl or -(5- or 6-membered)heteroaryl, each of which is substituted with one R₇ group.

45. The compound of claim 44, wherein the R₇ group is —

C(═

O)OR₉.

46. The compound of claim 45, wherein R₉ of the R₇—

C(═

O)OR₉ group is —

H.

47. The compound of claim 32, wherein R₄ is -(5- or 6-membered)heterocycle-(C₁-C₆)alkyl-X and X is phenyl or -(5- or 6-membered)heteroaryl, each of which is substituted with one R₇ group.

48. The compound of claim 47, wherein the R₇ group is —

C(═

O)OR₉.

49. The compound of claim 48, wherein R₉ of the R₇—

C(═

O)OR₉ group is —

H.

50. The compound of claim 32, wherein R₄ is X and X is -(5- or 6-membered)heterocycle or -(5- or 6-membered)heteroaryl, each of which is optionally substituted with —

C(═

O)OR₉.

51. The compound of claim 50, wherein the R₉ of the —

C(═

O)OR₉ group is —

H.

52. The compound of claim 32, wherein R₄ is X and X is -tetrazolyl.

53. The compound of claim 32, wherein A and B are independently —

H or —

(C₁-C₆)alkyl.

54. The compound of claim 53, wherein A and B are each —

H.

55. The compound of claim 32, wherein A and B together form a bridge such that the bridged-piperidine is:

wherein each R_d is independently —

H, —

(C₁-C₄)alkyl, -halo, or —

C(halo)₃.

56. The compound of claim 55, wherein A and B together form a bridge such that the bridged-piperidine is:

57. The compound of claim 55, wherein the 6-membered, nitrogen-containing ring that is fused to the Q group is in the endo configuration with respect to the A-B bridge of the bridged-piperidine.

58. The compound of claim 32, wherein h is O and R₁ is —

(C₁-C₁₀)alkyl, —

(C₂-C₁₀)alkenyl, —

(C₂-C₁₀)alkynyl, —

(C₃-C₁₄)cycloalkyl, —

(C₃-C₁₄)cycloalkenyl, —

(C₆-C₁₄)bicycloalkyl, —

(C₇-C₁₄)bicycloalkenyl, or —

(C₈-C₂₀)tricycloalkyl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R₈ groups.

59. The compound of claim 58, wherein R₁ is —

(C₃-C₁₄)cycloalkyl, —

(C₃-C₁₄)cycloalkenyl, —

(C₆-C₁₄)bicycloalkyl, —

(C₇-C₁₄)bicycloalkenyl, or —

(C₈-C₂₀)tricycloalkyl, each of which is unsubstituted or substituted with 1, 2, or 3 independently selected R₈ groups.

60. The compound of claim 59, wherein R₁ is:

61. The compound of claim 55, wherein h is 0 and R₁ is:

wherein each R_z is independently —

H, —

(C₁-C₄)alkyl, —

OH, or —

CN.

62. The compound of claim 61, wherein each R_z is independently —

H or —

CH₃.

63. The compound of claim 56, wherein h is 0 and R₁ is:

wherein each R_z is independently —

H, —

(C₁-C₄)alkyl, —

OH, or —

CN.

64. The compound of claim 63, wherein each R_z is independently —

H or —

CH₃.

65. The compound of claim 56, wherein h is 0 and R₁ is:

wherein each R_z is —

H.

66. The compound of claim 32, wherein a is 1 and R₂ is -halo.

67. The compound of claim 66, wherein the R₂-halo is —

F.

68. The compound of claim 55, wherein the R₁ group is in the exo-configuration with respect to the A-B bridge of the bridged piperidine.

69. The compound of claim 32, wherein —

Z—

R₁ is;

(a) (C₆-C₁₂)cycloalkyl;

or

(b) (C₆-C₁₂)cycloalkenyl;

or

(c)

 

or

(d) (C₆-C₁₂)cycloalkyl optionally substituted by one —

(C₁-C₄)alkyl.

70. The compound of claim 69, wherein the —

Z—

R₁ (C₆-C₁₂)cycloalkyl is cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, or cyclododecyl.

71. The compound of claim 69, wherein the —

Z—

R₁ (C₆-C₁₂)cycloalkenyl is cyclohexenyl, cycloheptenyl, or cyclooctenyl.

72. The compound of claim 27, wherein the pharmaceutically acceptable derivative is a pharmaceutically acceptable salt.

73. The compound of claim 72, wherein the pharmaceutically acceptable derivative is a HCl-salt, a sodium-salt, or a potassium-salt.

74. A composition comprising an effective amount of the compound or a pharmaceutically acceptable derivative of the compound of claim 27 and a pharmaceutically acceptable carrier or excipient.

75. A method for modulating ORL-1 receptor function in a cell, comprising contacting a cell capable of expressing the ORL-1 receptor with an effective amount of the compound or a pharmaceutically acceptable derivative of the compound of claim 27.

76. The method of claim 75, wherein the compound or the pharmaceutically acceptable derivative of the compound acts as an agonist or a partial agonist at the ORL-1 receptor.

77. The method of claim 75, wherein the compound or the pharmaceutically acceptable derivative of the compound acts as an antagonist at the ORL-1 receptor.

78. A method for treating pain in an animal, comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable derivative of the compound of claim 27.

79. A method for treating a memory disorder, obesity, constipation, depression, dementia, Parkinsonism, anxiety, cough, diarrhea, high blood pressure, epilepsy, anorexia/cachexia, urinary incontinence, or drug abuse in an animal, comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable derivative of the compound of claim 27.

80. A compound of Formula (111 ), (IV), or (V):

or a pharmaceutically acceptable derivative thereof wherein;

the C₂- or C₃-bridge of the bridged piperidine ring of compounds of Formula (111 ) and (IV) may be unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from —

OH, —

(C₁-C₄)alkyl, -halo, and —

C(halo)₃,

A and B of Formula (V) are independently;

(a) —

H, —

CN, —

C(═

O)OT₃, or —

C(═

O)N(T)₁(T₂);

or

(b) —

(C₃-C₁₂)cycloalkyl, —

(C₃-C₁₂)cycloalkoxy, —

(C₁-C₆)alkyl, —

(C₂-C₆)alkenyl, —

(C₂-C₆)alkynyl, or —

(C₁-C₆)alkoxy, each of which is unsubstituted or substituted with 1 or 2 substituents independently selected from —

OH, —

S(═

O)₂NH₂, —

N(R₆)₂, ═

NR₆, —

C(═

O)OT₃, —

C(═

O)N(R₆)₂, —

N(R₆)C(═

O)R₉, and -(5- or 6-membered)heterocycle, or 1, 2 or 3 independently selected -halo;

Z is —

[(C₁-C₁₀)alkyl optionally substituted by R₁]_h—

, wherein h is 0;

R₁ is;

each R_z is independently —

H, —

(C₁-C₄)alkyl, —

OH, or —

CN;

each R₁₂ is independently —

H or —

(C₁-C₄)alkyl;

R₂₀ is NO₂ or NH₂;

each T₁ and T₂ is independently —

H or —

(C₁-C₁₀)alkyl which is unsubstituted or substituted with 1, 2 or 3 independently selected R₅ groups and, optionally, in which any —

(C₁-C₁₀)alkyl carbon atom except the carbon atom bonded directly to the atom to which T₁ or T₂ is attached is independently replaced by O, S, or N(R₆), or T₁ and T₂ can together form a 5- to 8-membered ring wherein the number of atoms in the ring includes the nitrogen atom to which T₁ and T₂ are bonded, said 5- to 8-membered ring is unsubstituted or substituted with 1, 2 or 3 independently selected R₅ groups and, optionally, any carbon atom in said 5- to 8-membered ring is independently replaced by O, S, or N(R₆);

each T₃ is independently —

H or —

(C₁-C₁₀)alkyl which is unsubstituted or substituted with 1, 2 or 3 independently selected R₅ groups and, optionally, in which any —

(C₁-C₁₀)alkyl carbon atom except the carbon atom bonded directly to the atom to which T₃ is attached is independently replaced by O, S, or N(R₁₂);

each R₅ is independently —

(C₁-C₄)alkyl, —

(C₂-C₆)alkenyl, —

(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl, -phenyl, —

(C₁-C₆)alkyl-C(═

O)OR₉, —

OR₉, —

SR₉, —

C(halo)₃, —

CH(halo)₂, —

CH₂(halo), —

CN, ═

O, ═

S, -halo, —

N₃, —

NO₂, —

CH═

N(R₉), —

N(R₉)(C₁-C₆)alkyl-C(═

O)OR₉, —

C(═

O)—

C(═

O)OR₉, —

N(R₉)₂, —

N(R₉)OH, —

N(R₉)S(═

O)R₁₂, —

N(R₉)S(═

O)₂R₁₂, —

N(R₉)C(═

O)R₁₂, —

N(R₉)C(═

O)OR₁₂, —

N((C₁-C₆)alkyl-C(═

O)OR₉)₂, —

C(═

O)R₉, —

C(═

O)—

C(═

O)OR₉, —

C(═

O)OR₉, —

OC(═

O)R₉, —

OC(═

O)OR₉, —

S(═

O)R₉, or —

S(═

O)₂R₉;

each R₆ is independently —

H, —

(C₁-C₆)alkyl, or —

(C₃-C₇)cycloalkyl, or two R₆ groups attached to the same nitrogen atom can together form a 5- to 8-membered ring, wherein the number of atoms in the ring includes the nitrogen atom, and in which one of the 5- to 8-membered ring carbon atoms is optionally replaced by O, S, or N(T₃);

each R₈ is independently —

(C₁-C₄)alkyl, —

(C₂-C₆)alkenyl, —

(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl, -phenyl, —

(C₁-C₆)alkyl-C(═

O)OR₉, —

OR₉, —

SR₉, —

C(halo)₃, —

CH(halo)₂, —

CH₂(halo), —

CN, ═

O, ═

S, -halo, —

N₃, —

NO₂, —

CH═

N(R₉), —

N(R₉)(C₁-C₆)alkyl-C(═

O)OR₉, —

C(═

O)—

C(═

O)OR₉, —

N(R₉)₂, —

N(R₉)OH, —

N(R₉)S(═

O)R₁₂, —

N(R₉)S(═

O)₂R₁₂, —

N(R₉)C(═

O)R₁₂, —

N(R₉)C(═

O)N(T₁)(T₂), —

N(R₉)C(═

O)OR₁₂, —

N((C₁-C₆)alkyl-C(═

O)OR₉)₂, —

C(═

O)R₉, —

C(═

O)—

C(═

O)OR₉, —

C(═

O)N(T₁)(T₂), —

C(═

O)OR₉, —

OC(═

O)R₉, —

OC(═

O)N(T₁)(T₂), —

OC(═

O)OR₉, —

S(═

O)R₉, or —

S(═

O)₂R₉;

each R₉ is independently —

H, —

(C₁-C₆)alkyl, —

(C₂-C₆)alkenyl, —

(C₂-C₆)alkynyl, —

(C₃-C₈)cycloalkyl, —

(C₅-C₈)cycloalkenyl, -phenyl, -benzyl, -(3- to 6-membered)heterocycle, —

C(halo)₃, —

CH(halo)₂, or —

CH₂(halo); and

each halo is independently —

F, —

Cl, —

Br, or —

I.

81. The compound of claim 80, wherein each R_z is independently —

H or —

CH₃.

82. The compound of claim 80, wherein A and B are each —

H.

83. The compound of claim 80, wherein R₁ is:

and each R_z is independently —

H, —

(C₁-C₄)alkyl, —

OH, or —

CN.

84. The compound of claim 83, wherein each R_z is independently —

H or —

CH₃.

85. The compound of claim 80, wherein R₁ is:

and each R_z is —

H.

86. A compound of Formula (111 ), (IV), or (V):

or a pharmaceutically acceptable derivative thereof wherein;

the C₂- or C₃-bridge of the bridged piperidine ring of compounds of Formula (111 ) and (IV) may be unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from —

OH, —

(C₁-C₄)alkyl, -halo, and —

C(halo)₃;

A and B of Formula (V) are independently;

(a) —

H, —

CN, —

C(═

O)OT₃, or —

C(═

O)N(T)₁(T₂);

or

(b) —

(C₃-C₁₂)cycloalkyl, —

(C₃-C₁₂)cycloalkoxy, —

(C₁-C₆)alkyl, —

(C₂-C₆)alkenyl, —

(C₂-C₆)alkynyl, or —

(C₁-C₆)alkoxy, each of which is unsubstituted or substituted with 1 or 2 substituents independently selected from —

OH, —

S(═

O)₂NH₂, —

N(R₆)₂, ═

NR₆, —

C(═

O)OT₃, —

C(═

O)N(R₆)₂, —

N(R₆)C(═

O)R₉, and -(5- or 6-membered)heterocycle, or 1, 2 or 3 independently selected -halo;

Z is —

[(C₁-C₁₀)alkyl optionally substituted by R₁]_h—

, wherein h is 0;

R₁ is;

(a) —

(C₂-C₁₀)alkenyl, —

(C₂-C₁₀)alkynyl, —

O(C₁-C₆)alkyl, —

(C₃-C₇)cycloalkoxy, —

(C₆-C₁₄)bicycloalkyl, —

(C₈-C₂₀)tricycloalkyl, —

(C₅-C₁₀)cycloalkenyl, —

(C₇-C₁₄)bicycloalkenyl, —

(C₈-C₂₀)tricycloalkenyl, -(3- to 7-membered)heterocycle, -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R₈ groups;

or

(b)

R₁₁ can be —

H, —

CN, —

C(═

O)OR₉, or —

C(═

O)N(R₆)₂ or R₁₁ can be —

(C₁-C₄)alkyl which is unsubstituted or substituted with —

OH, —

(C₁-C₄)alkoxy, —

N(R₆)₂, —

C(═

O)OR₉, or —

C(═

O)N(R₆)₂;

each R₁₂ is independently —

H or —

(C₁-C₄)alkyl;

R₂₀ is NO₂ or NH₂;

each T₁ and T₂ is independently —

H or —

(C₁-C₁₀)alkyl which is unsubstituted or substituted with 1, 2 or 3 independently selected R₅ groups and, optionally, in which any —

(C₁-C₁₀)alkyl carbon atom except the carbon atom bonded directly to the atom to which T₁ or T₂ is attached is independently replaced by O, S, or N(R₆), or T₁ and T₂ can together form a 5- to 8-membered ring wherein the number of atoms in the ring includes the nitrogen atom to which T₁ and T₂ are bonded, said 5- to 8-membered ring is unsubstituted or substituted with 1, 2 or 3 independently selected R₅ groups and, optionally, any carbon atom in said 5- to 8-membered ring is independently replaced by O, S, or N(R₆);

each T₃ is independently —

H or —

(C₁-C₁₀)alkyl which is unsubstituted or substituted with 1, 2 or 3 independently selected R₅ groups and, optionally, in which any —

(C₁-C₁₀)alkyl carbon atom except the carbon atom bonded directly to the atom to which T₃ is attached is independently replaced by O, S, or N(R₁₂);

each R₅ is independently —

(C₁-C₄)alkyl, —

(C₂-C₆)alkenyl, —

(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl, -phenyl, —

(C₁-C₆)alkyl-C(═

O)OR₉, —

OR₉, —

SR₉, —

C(halo)₃, —

CH(halo)₂, —

CH₂(halo), —

CN, ═

O, ═

S, -halo, —

N₃, —

NO₂, —

CH═

N(R₉), —

N(R₉)(C₁-C₆)alkyl-C(═

O)OR₉, —

C(═

O)—

C(═

O)OR₉, —

N(R₉)₂, —

N(R₉)OH, —

N(R₉)S(═

O)R₁₂, —

N(R₉)S(═

O)₂R₁₂, —

N(R₉)C(═

O)R₁₂, —

N(R₉)C(═

O)OR₁₂, —

N((C₁-C₆)alkyl-C(═

O)OR₉)₂, —

C(═

O)R₉, —

C(═

O)—

C(═

O)OR₉, —

C(═

O)OR₉, —

OC(═

O)R₉, —

OC(═

O)OR₉, —

S(═

O)R₉, or —

S(═

O)₂R₉;

each R₆ is independently —

H, —

(C₁-C₆)alkyl, or —

(C₃-C₇)cycloalkyl, or two R₆ groups attached to the same nitrogen atom can together form a 5- to 8-membered ring, wherein the number of atoms in the ring includes the nitrogen atom, and in which one of the 5- to 8-membered ring carbon atoms is optionally replaced by O, S, or N(T₃);

each R₈ is independently —

(C₁-C₄)alkyl, —

(C₂-C₆)alkenyl, —

(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl, -phenyl, —

(C₁-C₆)alkyl-C(═

O)OR₉, —

OR₉, —

SR₉, —

C(halo)₃, —

CH(halo)₂, —

CH₂(halo), —

CN, ═

O, ═

S, -halo, —

N₃, —

NO₂, —

CH═

N(R₉), —

N(R₉)(C₁-C₆)alkyl-C(═

O)OR₉, —

C(═

O)—

C(═

O)OR₉, —

N(R₉)₂, —

N(R₉)OH, —

N(R₉)S(═

O)R₁₂, —

N(R₉)S(═

O)₂R₁₂, —

N(R₉)C(═

O)R₁₂, —

N(R₉)C(═

O)N(T₁)(T₂), —

N(R₉)C(═

O)OR₁₂, —

N((C₁-C₆)alkyl-C(═

O)OR₉)₂, —

C(═

O)R₉, —

C(═

O)—

C(═

O)OR₉, —

C(═

O)N(T₁)(T₂), —

C(═

O)OR₉, —

OC(═

O)R₉, —

OC(═

O)N(T₁)(T₂), —

OC(═

O)OR₉, —

S(═

O)R₉, or —

S(═

O)₂R₉;

each R₉ is independently —

H, —

(C₁-C₆)alkyl, —

(C₂-C₆)alkenyl, —

(C₂-C₆)alkynyl, —

(C₃-C₈)cycloalkyl, —

(C₅-C₈)cycloalkenyl, -phenyl, -benzyl, -(3- to 6-membered)heterocycle, —

C(halo)₃, —

CH(halo)₂, or —

CH₂(halo);

m is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11;

e and f are each an integer independently selected from 0, 1, 2, 3, 4, and 5 provided that 2≦

(e+f)≦

5;

j and k are each an integer independently selected from 0, 1, 2, 3, and 4 provided that 1≦

(j+k)≦

4;

each p is an integer independently selected from 0, 1, 2, 3, and 4; and

each halo is independently —

F, —

Cl, —

Br, or —

I.

87. The compound of claim 86, wherein A and B are each —

H.

88. The compound of claim 86, wherein R₁ is —

(C₂-C₁₀)alkenyl, —

(C₂-C₁₀)alkynyl, —

(C₃-C₁₄)cycloalkenyl, —

(C₆-C₁₄)bicycloalkyl, —

(C₇-C₁₄)bicycloalkenyl, or —

(C₈-C₂₀)tricycloalkyl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R₈ groups.

89. The compound of claim 88, wherein R₁ is —

(C₃-C₁₄)cycloalkenyl, —

(C₆-C₁₄)bicycloalkyl, —

(C₇-C₁₄)bicycloalkenyl, or —

(C₈-C₂₀)tricycloalkyl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R₈ groups.

90. The compound of claim 86, wherein —

Z—

R₁ is;

(a) (C₆-C₁₂)cycloalkenyl;

or

(b)

91. The compound of claim 90, wherein the —

Z—

R₁ (C₆-C₁₂)cycloalkenyl is cyclohexenyl, cycloheptenyl, or cyclooctenyl.