SUBSTITUTED PIPERIDIN-4-AMINO-TYPE COMPOUNDS AND USES THEREOF

1. FIELD

The disclosure relates to Substituted Piperidin-4-amino-Type Compounds, compositions comprising an effective amount of a Substituted Piperidin-4-amino-Type 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 Piperidin-4-amino-Type Compound.

2. BACKGROUND

Chronic pain is a major contributor to disability and is the cause of much suffering. The successful treatment of severe and chronic pain is a primary goal of the physician, with opioid analgesics being preferred drugs for doing so.

Three major classes of opioid receptors in the central nervous system (CNS) have long been known, with each class having subtype receptors. These receptor classes are known as μ, κ and δ. As opiates have a high affinity for these receptors while not being endogenous to the body, research followed in order to identify and isolate the endogenous ligands to these receptors. These ligands were identified as endorphins, dynorphins and enkephalins, respectively.

Experimentation eventually led to the identification of an opioid receptor-like (ORL-1) receptor with a high degree of homology to the known receptor classes. The ORL-1 receptor was classified as an opioid receptor based only on structural grounds, as the receptor did not exhibit pharmacological homology. It was initially demonstrated that non-selective ligands having a high affinity for μ, κ and δ receptors had low affinity for the ORL-1 receptor. This characteristic, along with the fact that an endogenous ligand had not yet been discovered, led to the term “orphan receptor.” See, e.g., Henderson et al., “The orphan opioid receptor and its endogenous ligand-nociceptin/orphanin FQ,” Trends Pharmacol. Sci. 18(8):293-300 (1997).

Subsequent research led to the isolation and structure of the endogenous ligand of the ORL-1 receptor (i.e., nociceptin; also known as orphanin FQ (OFQ)). This ligand is a seventeen amino acid peptide structurally similar to members of the opioid peptide family.

The discovery of the ORL-1 receptor presents an opportunity in drug discovery for novel compounds that can be administered for pain management or other syndromes modulated by this receptor.

International PCT Publication No. WO 2008/089201 describes heterocyclic-substituted piperidine compounds for use in treating a condition, such as pain.

International PCT Publication No. WO 2010/010458 describes substituted-quinoxaline-type bridged-piperidine compounds for use in treating a condition, such as pain.

International PCT Publication No. WO 2012/085648 describes phosphorus-substituted quinoxaline-type piperidine compounds for use in treating a condition, such as pain.

Citation of any reference in Section 2 of this application is not to be construed as an admission that such reference is prior art to the present application.

3. SUMMARY

In one aspect of the disclosure, new compounds that exhibit affinity for the ORL-1 receptor are described.

In some embodiments, such new compounds exhibit agonist activity or partial agonist activity at the ORL-1 receptor. In other embodiments, such new compounds exhibit agonist activity at the ORL-1 receptor. In other embodiments, such new compounds exhibit partial agonist activity at the ORL-1 receptor. In yet other embodiments, such new compounds exhibit antagonist activity at the ORL-1 receptor.

In another embodiment of the disclosure, such new compounds exhibit affinity for the ORL-1 receptor, and also for one or more of the μ, κ or δ receptors. In some embodiments, a new compound of the disclosure exhibits affinity for both the ORL-1 receptor and the receptor. In other embodiments, a new compound of the disclosure acts as an ORL-1 receptor agonist or partial agonist and as a receptor agonist or partial agonist. In other embodiments, a new compound of the disclosure acts as an ORL-1 receptor agonist and as a receptor agonist or partial agonist. In other embodiments, a new compound of the disclosure acts as an ORL-1 receptor partial agonist and as a g receptor agonist or partial agonist. In other embodiments, a new compound of the disclosure acts as an ORL-1 receptor agonist or partial agonist and as a p receptor agonist. In other embodiments, a new compound of the disclosure acts as an ORL-1 receptor agonist or partial agonist and as a p receptor partial agonist. In other embodiments, a new compound of the disclosure acts as an ORL-1 receptor agonist and as a p receptor agonist. In other embodiments, a new compound of the disclosure acts as an ORL-1 receptor agonist and as a g receptor partial agonist. In other embodiments, a new compound of the disclosure acts as an ORL-1 receptor partial agonist and as a μ receptor agonist. In other embodiments, a new compound of the disclosure acts as an ORL-1 receptor partial agonist and as a p receptor partial agonist. In other embodiments, a new compound of the disclosure acts as an ORL-1 receptor agonist or partial agonist and as a p receptor antagonist. In other embodiments, a new compound of the disclosure acts as an ORL-1 receptor agonist and as a p receptor antagonist. In other embodiments, a new compound of the disclosure acts as an ORL-1 receptor partial agonist and as a p receptor antagonist. In other embodiments, a new compound of the disclosure acts as an ORL-1 receptor antagonist and as a p receptor agonist or partial agonist. In other embodiments, a new compound of the disclosure acts as an ORL-1 receptor antagonist and as a g receptor agonist. In other embodiments, a new compound of the disclosure acts as an ORL-1 receptor antagonist and as a p receptor partial agonist.

Certain new compounds of the disclosure can be used to treat an animal suffering from chronic or acute pain.

In another embodiment of the disclosure, methods for treating chronic or acute pain in an animal by administering one or more Substituted Piperidin-4-amino-Type Compounds to an animal in need of such treatment are described. In certain embodiments, such new Substituted Piperidin-4-amino-Type Compounds effectively treat chronic or acute pain in the animal, while producing fewer or reduced side effects compared to previously available compounds.

Compounds of the disclosure include those of Formula (I):

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and the pharmaceutically acceptable salts and solvates thereof, wherein:

Q¹is phenyl, naphthalenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl;

Q²is (C₃-C₁₀)cycloalkyl, (3- to 9-membered)heterocycle, or a direct bond;

E¹and E²are, independently, C(═O), C(═S), S(═O)_q, CH₂, or a direct bond;

W is S, O, N(R*), or a direct bond;

D is H, OR*, SR*, NO₂, or N(R*)₂;

R* is, independently for each occurrence, H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl each of which is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from -halo, —CN, —NO₂, —N₃, —OH, —O(C₁-C₆)alkyl, —SH, —S(C₁-C₆)alkyl, —NH₂, —N(H)((C₁-C₆)alkyl), —N((C₁-C₆)alkyl)₂, ═O, and ═S;

each R²and R³is, independently for each occurrence:

(a) —H; or

(b) -halo, —CN, or —NO₂; 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(R²))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, independently for each occurrence:

(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)tri cycloalkenyl, -(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 R⁸groups; or

(b) -phenyl, -benzyl, -naphthalenyl, —(C₁₄)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 R⁷groups;

each Y is independently O or S;

A and B 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;

Z is —[(C₁-C₁₀)alkyl optionally substituted by R¹³]_h—, wherein h is 0 or 1; or —[(C₂-C₁₀)alkenyl optionally substituted by R¹³]—, or —[(C₁-C₁₀)alkyl-NR⁶C(═Y)]—;

R¹is selected from:

- (a) —H, -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂, —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and
- (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₃-C₁₄)cycloalkyl, —(C₆-C₁₄)bicycloalkyl, —(C₈-C₂₀)tricycloalkyl, —(C₈-C₁₄)cycloalkenyl, —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, and -(3- to 7-membered)heterocycle, each of which is unsubstituted or substituted with 1, 2, 3, or 4 independently selected R⁸groups; and
- (c)

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and

- (d) -phenyl, -naphthalenyl, —(C₁₄)aryl, and -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2, 3, or 4 independently selected R⁷groups;

each R⁵is independently —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, -(5- to 9-membered)heteroaryl, (6-membered)aryl unsubstituted or substituted with OR⁹, —(C₁-C₆)alkyl-C(═O)OR⁹, —OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, ═NH, ═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)R², —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 R⁶is independently —H, —(C₁-C₆)alkyl, or —(C₃-C₇)cycloalkyl, or two R⁶groups 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 R⁷is 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 R⁸is independently —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, -(5- to 9-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹, —N(R⁹)(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)₂, —N(R⁹)OH, —N(R⁹)S(═O)R², —N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹², —N(R⁹)C(═O)N(T¹)(T²), —N(R⁹)C(═O)OR¹², N(R⁹)C(═NH)N(R⁹)₂, —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 R⁹is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₈-C₈)cycloalkenyl, -phenyl, -benzyl, -(3- to 7-membered)heterocycle, —C(halo)₃, —CH(halo)₂, or —CH₂(halo);

if h is 0, then R¹¹can be —H, —CN, —C(═O)OR⁹, —C(═O)N(R⁶)₂or R¹¹can 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 R¹¹can be —H, —CN, —OH, -halo, —C(═O)OR⁹, or —C(═O)N(R⁶)₂or R¹¹can 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, when Z is —[(C₂-C₁₀)alkenyl optionally substituted by R¹³]— or —[(C₁-C₁₀)alkyl-N(R⁶)C(═Y)]—, then R¹¹can be —H, —CN, —C(═O)OR⁹, or —C(═O)N(R⁶)₂or R¹¹can 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 R¹²is independently —H or —(C₁-C₄)alkyl;

R¹³is selected from:

- (a) -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂, —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and
- (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₅-C₁₀)cycloalkenyl, and -(3- to 7-membered)heterocycle, each of which is unsubstituted or substituted with 1, 2, 3, or 4 independently selected R⁸groups; and
- (c)

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and

- (d) -phenyl and -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2, or 3 independently selected R⁷groups;

R¹⁴is —H, —CN, —OH, -halo, —C(═O)OR⁹, or —C(═O)N(R⁶)₂or R¹⁴can 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;

a is an integer selected from 0, 1, 2, 3, and 4;

b is an integer selected from 0, 1, 2, 3, and 4;

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

x is an integer selected from 0, 1, 2, 3, 4, 5, and 6;

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

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

e and fare each an integer independently selected from 0, 1, 2, 3, 4, and 5 provided that 2≦(e+f)≦5;

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

each q is, independently, an integer selected from 1 and 2;

each T¹and T²is independently —H or —(C₁-C₁₀)alkyl which is unsubstituted or substituted with 1, 2, or 3 independently selected R⁵groups and, optionally, in which any —(C₁-C₁₀)alkyl carbon atom except the carbon atom bonded directly to the atom to which T¹or T²is attached is independently replaced by O, S, or N(R⁶), or T¹and T²can together form a 5- to 8-membered ring wherein the number of atoms in the ring includes the nitrogen atom to which T¹and T²are bonded, said 5- to 8-membered ring is unsubstituted or substituted with 1, 2, or 3 independently selected R⁵groups and, optionally, any carbon atom in said 5- to 8-membered ring is independently replaced by O, S, or N(R⁶);

each T³is independently —H or —(C₁-C₁₀)alkyl which is unsubstituted or substituted with 1, 2, or 3 independently selected R⁵groups and, optionally, in which any —(C₁-C₁₀)alkyl carbon atom except the carbon atom bonded directly to the atom to which T³is attached is independently replaced by O, S, or N(R¹²);

each V¹is independently —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -phenyl, or -benzyl;

each halo is independently —F, —Cl, —Br, or —I;

with the proviso that when x is 0, E²is a direct bond, n is 0, W is a direct bond, Q²is a direct bond, b is 1, and R³is H, R²is not NH₂or NO₂.

A compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof (referred to hereinafter as a “Substituted Piperidin-4-amino-Type Compound”) is useful, e.g., as an analgesic, anti-inflammatory, diuretic, anesthetic agent, neuroprotective agent, anti-hypertensive, an anxiolytic agent, an agent for appetite control, hearing regulator, anti-tussive, anti-asthmatic, modulator of locomotor activity, modulator of learning and memory, regulator of neurotransmitter release, regulator of hormone release, kidney function modulator, anti-depressant, agent to treat memory loss due to Alzheimer's disease and/or other dementias, anti-epileptic, anti-convulsant, agent to treat withdrawal from alcohol, agent to treat withdrawal from drug(s) of addiction, agent to control water balance, agent to control sodium excretion, and/or agent to control arterial blood pressure disorder(s).

A Substituted Piperidin-4-amino-Type Compound is useful for treating and/or preventing pain (see, e.g., Courteix, et al. (2004). Evidence for an exclusive antinociceptive effect of nociceptin/orphanin FQ, an endogenous ligand for the ORL1 receptor, in two animal models of neuropathic pain. Pain, 110: 236-245; Reinscheid, et al. (1995). Orphanin FQ: a neuropeptide that activates an opioid-like G protein-coupled receptor. Science, 270: 792-794; Bignan et al. (2005). Recent advances towards the discovery of ORL-1 receptor agonists and antagonists. Expert Opinion on Therapeutic Patents, 15(4): 357-388; Meunier, et al. (1995). Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor. Nature, 377: 532-535; Briscini, et al (2002). Up-regulation of ORL-1 receptors in spinal tissue of allodynic rats after sciatic nerve injury. Eur. J. Pharmacol., 447: 59-65; Li, et al. (2004). Role of nociceptin in the modulation of nociception in the arcuate nucleus of rats. Brain Res., 1025: 67-74), anxiety (see, e.g., Jenck, et al. (1997). Orphanin FQ acts as an anxiolytic to attenuate behavioral responses to stress. Proc. Natl. Acad. Sci., U.S.A., 94: 14854-14858; Koster, et al. (1999). Targeted disruption of the orphanin FQ/nociceptin gene increases stress susceptibility and impairs stress adaptation in mice. Proc. Natl. Acad. Sci. U.S.A., 96: 10444-10449; Griebel, et al. (1999). Orphanin FQ, a novel neuropeptide with anti-stress-like activity. Brain Res., 836: 221-224; Jenck, et al. (2000). A synthetic agonist at the orphanin FQ/nociceptin receptor ORL1: Anxiolytic profile in the rat. Proc. Natl. Acad. Sci., 97: 4938-4943), cough (see, e.g., Fischer, et al. (1998). Nociceptin-induced inhibition of tachykinergic neurotransmission in guinea pig bronchus. J. Pharmacol. Ther., 285: 902-907; Rizzi, et al. (1999). Nociceptin receptor activation inhibits tachykinergic non adrenergic non cholinergic contraction of guinea pig isolated bronchus. Life Sci., 64: L157-L163; Shah, et al. (1998). Nociceptin inhibits non-cholinergic contraction in guinea-pig airway. Br. J. Pharmacol., 125: 510-516; Patel, et al., (1997). Naloxone-insensitive inhibition of acetylcholine release from parasympathetic nerves innervating guinea-pig trachea by the novel opioid, nociceptin. Br. J. Pharmacol., 120: 735-736; Helyes, et al. (1997). Inhibition by nociceptin ofneurogenic inflammation and the release of SP and CGRP from sensory nerve terminals. Br. J. Pharmacol., 121: 613-615; Nemeth, et al., (1998). Inhibition of nociceptin on sensory neuropeptide release and mast cell-mediated plasma extravasation in rats. Eur. J. Pharmacol., 347: 101-104; McLeod, et al. (2001). Nociceptin inhibits cough in the guinea-pig by activation of ORL1 receptors. Br. J. Pharmacol., 132: 1175-1178; Corboz, et al. (2000). Nociceptin inhibits capsaicin-induced bronchoconstriction in isolated guinea pig lung. Eir. J. Pharmacol., 402: 171-179), gut motility disorders (such as diarrhea and constipation) (see, e.g., Wang, et al. (1994). cDNA cloning of an orphan opiate receptor gene family member and its splice variant. FEBS Lett., 348: 75-79; Calo', et al. (1996). The mouse deferens: a pharmacological preparation sensitive to nociceptin. Eur. J. Pharmacol., 311: R3-R5; Zhang, et al. (1997). Orphanin FQ has an inuhibitory effect on the guinea pig ileum and the mouse vas deferens. Brain Res., 772: 102-106; Osinski, et al. (1999). Cloning, expression and functional role of a nociceptin/orphanin FQ receptor in the porcine gastrointestinal tract. Eur. J. Pharmacol., 365: 281-289; Yasdani, et al. (1999). Functional significance of a newly discovered neuropeptide, orphanin FQ, in rat gastrointestinal motility. Gastroenterology, 116: 108-117; Corbett, et al. (1998). The pharmacological actions of nociceptin in the isolated colon of rat, mouse, and man. Naunyn Schmiedebergs Arch. Pharmacol., 358(Suppl 1): P40.47; Osinski, et al. (1999). Peripheral and central actions of orphanin FQ (nociceptin) on murine colon. Am. J. Physiol., 276: G125-G131; Rizzi, et al. (1999). [Nphe¹]nociceptin(1-13)NH₂antagonizes nociceptin effects in the mouse colon. Eur. J. Pharmacol., 285: R3-R5; Taniguchi, et al. (1998). The effect of nociceptin an endogenous ligand for the ORL1 receptor, on rat colonic contraction and transit. Eur. J. Pharmacol., 353: 265-271; Pheng, et al. (2000). [Nphe¹]nociceptin(1-13)NH₂selectively antagonizes nociceptin effects in the rabbit isolated ileum. Eur. J. Pharmacol., 397: 383-388), high blood pressure (see, e.g., Champion & Kadowitz (1997). Nociceptin, an endogenous ligand for the ORL1 receptor, has novel hypotensive activity in the rat. Life Sci., 60: PL 241-245; Giuliani, et al. (1997). Effect of nociceptin on heart rate and blood pressure in anaesthetized rats. Eur. J. Pharmacol., 333: 177-179; Kapusta, et al. (1997). Diuretic and antinatriuretic responses produced by the endogenous opioid-like peptide, noceptin (orphanin FQ). Life Sci., 60: PL15-PL21; Kapusta, et al. (1999). Central administration of [Phe1psi(CH₂—NH)Gly2]nociceptin(1-13)-NH₂and orphanin FQ/nociceptin (OFQ/N) produce similar cardiovascular and renal responses in conscious rats. J. Pharmacol. Exp. Ther., 289: 173-180; Madeddu, et al. (1999). Cardiovascular effects of nociceptin in unanesthetized mice. Hypertension, 33: 914-919; Bigoni, et al. (1999). Characterization of nociceptin receptors in the periphery: in vitro and in vivo studies. Naunyn Schmiedebergs Arch. Pharmacol., 359: 160-167; Chu, et al. (1999). Inhibition of cardiovascular activity following microinjection of novel opioid-like neuropeptide nociceptin (orphanin FQ) into the rat rostral ventrolateral medulla. Brain Res., 829: 134-142; Chu, et al. (1999). The nociceptin receptor-mediated inhibition of the rat rostral ventrolateral medulla neurons in vitro. Eur. J. Pharmacol., 364: 49-53; Arndt, et al. (1999). Nociceptin/orphanin FQ increases blood pressure and heart rate via sympathetic activation in sheep. Peptides, 20: 465-470; Gumusel, et al. (1997). Nociceptin: an endogenous agonist for central opioid-likel (ORL1) receptors possesses systemic vasorelaxant properties. Life Sci., 69: PL 141-PL 145; Champion et al. (1998). Nociceptin, a novel endogenous ligand for the ORL1 receptor, dilates isolated resistance arteries from the rat. Regul. Peptides, 78: 69-74; Czapla, et al. (1997). Decreases in systemic arterial and hindquarters perfusion pressure in response to nociceptin are not inhibited by naloxone in the rat. Peptides, 18: 1197-1200; Armstead (1999), Nociceptin/orphanin FQ dilates pial arteries by K(ATP) and k(ca) channel activation. Brain Res., 835: 315-323; Bucher (1998), ORL1 receptor-mediated inhibition by nociceptin of noradrenaline release from perivascular sympathetic nerve endings of the rat tail artery. Naunyn Schmiedebergs Arch. Pharmacol., 358: 682-685; Champion et al. (1997). Nociceptin, a novel endogenous ligand for the ORL1 receptor, has potent erectile activity in the cat. Am. J. Physiol., 73: E214-E219), epilepsy (see, e.g., Nicol, et al. (1996), Nociceptin induced inhibition of K+ evoked glutamate release from rat cerebrocortical slices. Br. J. Pharmacol., 119: 1081-1083; Nicol, et al. (1998). Nociceptin inhibits glutamate release from rat cerebellar slices. Br. J. Pharmacol., 123: 217P; Allen, et al. (1999). Orphanin-FQ/nociceptin (OFQ/N) modulates the activity of suprachiasmatic nucleus neurons. J. Neurosci., 19: 2152-2160; Faber, et al. (1996). Depression of glutamatergic transmission by nociceptin in the neonatal rat hemisected spinal cord preparation in vitro. Br. J. Pharmacol., 119: 189-190; Vaughn, et al. (1997). Actions of the ORL1 receptor ligand nociceptin on membrane properties of rat periaqueductal gray neurons in vitro. J. Neurosci., 17: 996-1003; Wang, et al. (1996). Nociceptin (orphanin FQ), and endogenous ligand for the ORL1 (opioid receptor-like1) receptor, modulates responses of trigeminal neurons evoked by excitatory amino acids and somatosensory stimuli. J. Neurophysiol., 76: 3568-3572; Yu & Xie (1998). Orphanin FQ/nociceptin inhibits synaptic transmission and long-term potentiation in rat dentate gyrus through postsynaptic mechanisms. J. Neurophysiol., 80: 1277-1284; Bregola, et al. (1999). Limbic seizures increase pronociceptin mRNA levels in the thalamic reticular nucleus. Neuroreport, 19: 541-546; Sieklucka-Dziuba, et al. (2002). Nociceptin, OP4 receptor Iigand in different models of experimental epilepsy. Peptides, 23: 497-505; Gutierrez, et al, (2001). Orphanin FQ/nociceptin inhibits kindling epileptogenesis and enhances hippocampal feed-forward inhibition. Neuroscience, 105: 325-333; Tallent, et al. (2001). Nociceptin reduces epileptiform events in CA3 hippocampus via presynaptic and postsynaptic mechanisms. J. Neurosci., 21: 6940-6948), eating-related disorders (such as anorexia/cachexia and obesity) (see, e.g., Pomonis, et al. (1996). Orphanin FQ, agonist of orphan opioid receptor ORL1, stimulates feeding in rats. Neuroreport, 8: 369-371; Stratford et al. (1997). Injections of nociceptin into nucleus accumbens shell of ventromedial hypothalamic nucleus increase food intake. Neuroreport, 8: 423-426; Lee, et al. (1997). Nociceptin hyperpolarises neurones in the rt ventromedial hypothalamus. Neurosci. Lett., 239: 37-40; Polidori, et al. (1999). Sensitivity of brain sites to the orexigenic effect of nociceptin or of its analog [Phe]psi(CH₂—NH)Gly2]NC(1-13)NH₂. Regul. Peptides, 80:126; Polidori, et al. (2000). Pharmacological characterization of the nociceptin receptor mediating hyperphagia: indentification of a selective antagonist. Psychopharmacology, 148: 430-437; Rowland, et al. (1996). The physiology and brain mechanisms of feeding. Nutrition, 12: 626-639), urinary incontinence (see, e.g., Giuliani, et al. (1998). The inhibitory effect of nociceptin on the micturition reflex in anaesthetized. Br. J. Pharmacol., 24: 1566-1572; Giuliani, et al. (1999). Nociceptin protects capsaicin-sensitive afferent fibers in the rat urinary bladder from desensitization. Nanyn Schmiedeberg's Arch. Pharmacol., 360: 202-208; Lecci, et al. (2000). Multiple sites of action in the inhibitory effect of nociceptin on the micturition reflex. J. Urology, 163: 638-645), renal function (see, e.g., Kapusta, et al. (1997). Diuretic and antinatriuretic responses produced by the endogenous opioid-like peptide, noceptin (orphanin FQ). Life Sci., 60: PL15-PL21; Kapusta, et al. (1999). Central administration of [Phel psi(CH2-NH)Gly2]nociceptin(1-13)-NH2 and orphanin FQ/nociceptin (OFQ/N) produce similar cardiovascular and renal responses in conscious rats. J. Pharmacol. Exp. Ther., 289: 173-180; drug abuse (see, e.g., Devine et al. (1996). The novel neuropeptide orphanin FQ fails to produce conditioned place preference or aversion. Brain Res., 727: 225-229; Ciccocioppo, et al. (1999). Effect of nociceptin on alcohol intake in alcohol-preferring rats. Psychopharmacology, 141: 220-224; Angeletti, et al., (1999). Effect of nociceptin on morphine-induced conditioned place preference in rats. Regulatory Peptides, 80: 222; Murphy et a). (1999). Orphanin FQ/nociceptin blocks acquisition of morphine place preference. Brain Res., 832: 168-170; Pieretti & Di Giannuario (1999). Orphanin FQ effects on morphine-induced dopamine release in the accumbens of rats. Regulatory Peptides, 80: 126; Walker et al. (1998). Nociceptin fails to affect heroin self-administration in the rat. Neuroreport, 9: 2243-2247; Narayanan & Maidment (1999). Orphanin FQ and behavioral sensitization to cocaine. Pharmacol. Biochem. Behav., 63: 271-277), memory disorders (see, e.g., Sandin, et al. (1997). Nociceptin/orphanin FQ microinjected into hippocampus impairs spatial learning in rats. Eur. J. Neurosci., 9: 194-197; Yu, et al. (1997). Orphanin FQ inhibits synaptic transmission and long-term potentiation in rat hippocampus. Hippocampus, 7: 88-94; Yu & Xie (1998). Orphanin FQ/nociceptin inhibits synaptic transmission and long-term potentiation in rat dentate gyrus through postsynaptic mechanisms. J. Neurophysiol., 80: 1277-1284; Manabe, et al. (1998). Facilitation of long-term potentiation and memory in mice lacking nociceptin receptors. Nature, 394: 577-581; Hiramatsu & Inoue (1999). Effects of nocistatin on nociceptin-induced impairment of learning and memory in mice. Eur. J. Pharmacol., 367: 151-155; Mamiya, et al. (1999). Nociceptin system plays a role in the memory retention: involvement of naloxone benzoylhydrazone binding sites. Neuroreport, 10: 1171-1175; Hiramatsu & Inoue (2000). Improvement by low doses of nociceptin on scopolamine-induced impairment of learning and/or memory. Eur. J. Pharmacol., 395: 149-156), depression (see, e.g., Rizzi, et al. (2011). Nociceptin/orphanin FQ receptor knockout rats: in vitro and in vivo studies. Neuropharmacology, 60: 572-579; Goeldner, et al. (2010). Endogenous nociceptin/orphanin-FQ in the dorsal hippocampus fcilitates despair-related behavior. Hippocampus, 20: 911-916; Vitale, et al. (2009). Chronic treatment with the selective NOP receptor antagonist [Nphe 1, Arg 14, Lys 15]N/OFQ-NH2 (UFP-101) reverses the behavioural and biochemical effects of unpredictable chronic mild stress in rats. Psychopharmacology, 207: 173-189; Zambello, et al. (2008). Acute stress differentially affects corticotropin-releasing hormone mRNA expression in the central amygdala of the “epressed” flinders sensitive line and the control flinders resistant line rats. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 32: 651-661; Gavioli & Calo' (2006). Antidepressant—an anxiolytic-like effects of nociceptin/orphanin FQ receptor ligands. Naunyn-Schmiedebergs Arch. Pharmacol., 372: 319-330; Gavioli, et al. (2003). Blockade of nociceptin/orphanin FQ-NOP receptor signalling produces antidepressant-like effects: pharmacological and genetic evidences from the mouse forced swimming test. Eur. J. Neurosci., 17: 1987-1990), dementia, or locomotor disorders (such as Parkinsonism) (see, e.g., Reinscheid, et al. (1995). Orphanin FQ: a neuropeptide that activates an opioidlike G protein-coupled receptor. Science, 270: 792-794; Calo' et al. (1999). Characterization of nociceptin receptors modulating locomotor activity in mice. Fund. Clin. Pharmnacol., 13-S1: S27.6; Devine, et al, (1996). Rats rapidly develop tolerance to the locomotor-inhibiting effects of the novel neuropeptide orphanin FQ. Neurochem. Res., 21: 1387-1396; Noble & Roques (1997). Association of aminopeptidase N and endopeptidase 14.15 inhibitors potentiate behavorial effects mediated by nociceptin/orphanin FQ in mice. FEBS Lett., 401: 227-229; Florin, et al. (1996). Nociceptin stimulates locomotion and exploratory behaviour in mice. Eur. J. Pharmacol., 317: 9-13) (each being a “Condition”) in an animal. For a general discussion of ORL1 receptors see Calo' et al. (2000). Pharmacology of nociceptin and its receptor: a novel therapeutic target. Br. J. Pharmacol. 129: 1261-1283.

The present invention further provides compositions comprising an effective amount of a Substituted Piperidin-4-amino-Type Compound and a pharmaceutically acceptable carrier or excipient. The compositions are useful for treating or preventing a Condition in an animal.

The present disclosure further provides methods for treating or preventing a Condition, comprising administering to an animal in need thereof an effective amount of a Substituted Piperidin-4-amino-Type Compound.

The present disclosure further provides Substituted Piperidin-4-amino-Type Compounds for use in the manufacture of a medicament useful for treating a Condition or for preventing a Condition.

The present disclosure further provides methods for inhibiting ORL-1 receptor function in a cell, comprising contacting a cell capable of expressing the ORL-1 receptor with an ORL-1 receptor function-inhibiting amount of a Substituted Piperidin-4-amino-Type Compound. The present invention further provides methods for activating ORL-1 receptor function in a cell, comprising contacting a cell capable of expressing the ORL-1 receptor with an ORL-1 receptor function-activating amount of a Substituted Piperidin-4-amino-Type Compound.

The present invention further provides methods for preparing a composition, comprising the step of admixing a Substituted Piperidin-4-amino-Type Compound and a pharmaceutically acceptable carrier or excipient.

The present disclosure further provides a kit comprising a sterile container containing an effective amount of a Substituted Piperidin-4-amino-Type Compound.

The present disclosure further provides novel intermediates for use in making a Substituted Piperidin-4-amino-Type Compound.

The disclosure can be understood more fully by reference to the following detailed description and illustrative examples, which are intended to exemplify non-limiting embodiments of the disclosure.

4. DETAILED DESCRIPTION

In certain embodiments, the Substituted Piperidin-4-amino-Type Compounds of Formula (I) include the following:

(1) Compounds of Formula (I):

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and the pharmaceutically acceptable salts and solvates thereof, wherein:

Q¹is phenyl, naphthalenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl;

Q²is (C₃-C₁₀)cycloalkyl, (3- to 9-membered)heterocycle, or a direct bond;

E¹and E²are, independently, C(═O), C(═S), S(═O)_q, CH₂, or a direct bond;

W is S, O, N(R*), or a direct bond;

D is H, OR*, SR*, NO₂, or N(R*)₂;

each R²and R³is, independently for each occurrence:

(a) —H; or

(b) -halo, —CN, or —NO₂; 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(R²))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(T)(T²), —S(═O)X, or —S(═O)₂X;

X is, independently for each occurrence:

(a) —H, —(C₁-C₈)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 R⁸groups; or

each Y is independently O or S;

Z is —[(C₁-C₁₀)alkyl optionally substituted by R¹³]_h—, wherein h is 0 or 1; or —[(C₂-C₁₀)alkenyl optionally substituted by R¹³]—, or —[(C₁-C₁₀)alkyl-NR⁶C(═Y)]—;

R¹is selected from:

- (a) —H, -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂, —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and
- (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₃-C₁₄)cycloalkyl, —(C₆-C₁₄)bicycloalkyl, —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₄)cycloalkenyl, —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, and -(3- to 7-membered)heterocycle, each of which is unsubstituted or substituted with 1, 2, 3, or 4 independently selected R⁸groups; and
- (c)

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and

- (d) -phenyl, -naphthalenyl, —(C₁₄)aryl, and -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2, 3, or 4 independently selected R⁷groups;

each R⁵is independently —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, -(5- to 9-membered)heteroaryl, (6-membered)aryl unsubstituted or substituted with OR⁹, —(C₁-C₆)alkyl-C(═O)OR⁹, —OR⁹, —SR⁹, —C(halo)₃, —CH₂(halo)₂, —CH₂(halo), —CN, ═NH, ═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)R², —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 R⁶is independently —H, —(C₁-C₆)alkyl, or —(C₃-C₇)cycloalkyl, or two R⁶groups 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 R⁸is independently —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, -(5- to 9-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹, —N(R⁹)(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)₂, —N(R⁹)OH, —N(R⁹)S(═O)R¹², —N(R⁹)S(═O)₂R², —N(R⁹)C(═O)R¹², —N(R⁹)C(═O)N(T¹)(T²), —N(R⁹)C(═O)OR¹², N(R⁹)C(═NH)N(R⁹)₂, —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 R⁹is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -benzyl, -(3- to 7-membered)heterocycle, —C(halo)₃, —CH(halo)₂, or —CH₂(halo);

R¹³is selected from:

- (a) -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂, —S(═O)NH₂, —S(═O)NH₂, —C(═O)OV¹, and —C(═O)CN; and
- (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₅-C₁₀)cycloalkenyl, and -(3- to 7-membered)heterocycle, each of which is unsubstituted or substituted with 1, 2, 3, or 4 independently selected R⁸groups; and
- (c)

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and

- (d) -phenyl and -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2, or 3 independently selected R⁷groups;

a is an integer selected from 0, 1, 2, 3, and 4;

b is an integer selected from 0, 1, 2, 3, and 4;

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

x is an integer selected from 0, 1, 2, 3, 4, 5, and 6;

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

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

e and fare each an integer independently selected from 0, 1, 2, 3, 4, and 5 provided that 2≦(e+f)≦5;

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

each q is, independently, an integer selected from 1 and 2;

each V¹is independently —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -phenyl, or -benzyl;

each halo is independently —F, —Cl, —Br, or —I;

with the proviso that when x is 0, E²is a direct bond, n is 0, W is a direct bond, Q²is a direct bond, b is 1, and R³is H, R²is not NH₂or NO₂.

(i.e., “Substituted Piperidin-4-amino-Type Compounds”).

(2) Substituted Piperidin-4-amino-Type Compounds, wherein:

Q¹is phenyl;

Q²is (C₃-C₁₀)cycloalkyl, (3- to 9-membered)non-aromatic heterocycle, or a direct bond;

E¹and E²are, independently, C(═O), S(═O)₂, CH₂, or a direct bond;

W is N(R*) or a direct bond;

D is H, NO₂, or N(R*)₂;

R* is, independently for each occurrence, H or (C₁-C₆)alkyl unsubstituted or substituted with 1 or 2 substituents independently selected from —OH, —O(C₁-C₆)alkyl, and ═O;

each R²and R³is, independently for each occurrence, —H, -halo, —NO₂, —X, —C(═Y)YX, —N(T¹)(T²), —YH, or —YX;

X is, independently for each occurrence, —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, or -(5- or 6-membered)heterocycle, each of which is unsubstituted or substituted with 1 or 2 independently selected R⁸groups;

each Y is O;

each R⁵is independently OR⁹or =0;

each R⁸is independently —OR⁹, ═O, or —C(═O)OR⁹;

each R⁹is independently —H or —(C₁-C₆)alkyl;

a is an integer selected from 0 and 1;

b is an integer selected from 0 and 1;

n is an integer selected from 0 and 1;

x is an integer selected from 0 and 1; and

each T¹and T²is independently —H or —(C₁-C₁₀)alkyl which is unsubstituted or substituted with 1, 2, or 3 independently selected R⁵groups.

(3) Substituted Piperidin-4-amino-Type Compounds of the above (1) or (2), wherein R¹is selected from:

- (a) -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂, —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and
- (b) —(C₁-C₁₀)alkyl, —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₃-C₁₄)cycloalkyl, —(C₆-C₁₄)bicycloalkyl, —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₄)cycloalkenyl, —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, and -(3- to 7-membered)heterocycle, each of which is unsubstituted or substituted with 1, 2, 3, or 4 independently selected R⁸groups; and
- (c) -phenyl, -naphthalenyl, —(C₁₄)aryl, and -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2, or 3 independently selected R⁷groups.

(4) Substituted Piperidin-4-amino-Type Compounds of the above (1) or (2), wherein

Z is —[(C₁-C₁₀)alkyl]_h—, wherein h is 0 or 1; and

R¹is selected from:

- (a) —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂, —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and
- (b) —(C₁-C₁₀)alkyl, —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₃-C₁₄)cycloalkyl, —(C₆-C₁₄)bicycloalkyl, —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₄)cycloalkenyl, —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, and -(3- to 7-membered)heterocycle, each of which is unsubstituted or substituted with 1, 2, 3, or 4 independently selected R⁸groups; and
- (c)

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and

- (d) -phenyl and -(5- to 0-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2, or 3 independently selected R⁷groups.

(5) Substituted Piperidin-4-amino-Type Compounds of any one of the above (1)-(4), wherein h is 1.

(6) Substituted Piperidin-4-amino-Type Compounds of any one of the above (1)-(3), or (5), wherein Z is —(C₁-C₃)alkyl- optionally substituted by R¹³.

(7) Substituted Piperidin-4-amino-Type Compounds of any one of the above (1)-(6), wherein R¹³is absent.

(8) Substituted Piperidin-4-amino-Type Compounds of any one of the above (1)-(7), wherein R¹¹is absent and Z is —CH₂—CH—.

(9) Substituted Piperidin-4-amino-Type Compounds of any one of the above (1)-(8), wherein —Z—R¹is:

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wherein each R^zis independently —H, —(C₁-C₄)alkyl, —OH, or —CN and preferably each R^zis independently —H, —CH₃, or —CH₂CH₃.

(10) Substituted Piperidin-4-amino-Type Compounds of any one of the above (1)-(4), wherein h is 0.

(11) Substituted Piperidin-4-amino-Type Compounds of any one of the above (1)-(10), wherein A and B together form a bridge such that the bridged-piperidine is:

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wherein each R^dis independently —H, —(C₁-C₄)alkyl, -halo, or —C(halo)₃.

(12) Substituted Piperidin-4-amino-Type Compounds of any one of the above (1)-(11), wherein A and B together form a bridge such that the bridged-piperidine is:

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(13) Substituted Piperidin-4-amino-Type Compounds of any one of the above (1)-(12), wherein A and B together form a bridge such that the bridged-piperidine is:

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(14) Substituted Piperidin-4-amino-Type Compounds of any one of the above (1)-(4) or (10)-(13), wherein:

- (a) h is 0;
- (b) R¹is —(C₁-C₁₀)alkyl, —(C₃-C₁₄)cycloalkyl, —(C₅-C₁₄)cycloalkenyl, —(C₆-C₁₄)bicycloalkyl, —(C₇-C₁₄)bicycloalkenyl, or —(C₈-C₂₀)tricycloalkyl, each of which is unsubstituted or substituted with 1, 2, 3, or 4 independently selected R⁸groups and preferably R¹is —(C₃-C₁₄)cycloalkyl, —(C₈-C₁₄)cycloalkenyl, —(C₆-C₁₄)bicycloalkyl, —(C₇-C₁₄)bicycloalkenyl, or —(C₈-C₂₀)tricycloalkyl, each of which is unsubstituted or substituted with 1, 2, 3, or 4 independently selected R⁸groups; and
- (c) each R⁸is independently —(C₁-C₄)alkyl, —(C₁-C₆)alkyl-C(═O)OR⁹, —N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —OR⁹, —C(halo)₃, —CH(halo)₂, —CH₂(halo), -halo, —N(R⁹)₂, —C(═O)N(T¹)(T²), or —C(═O)OR⁹.

(15) Substituted Piperidin-4-amino-Type Compounds of any one of the above (1)-(4) or (10)-(14), wherein —Z—R¹is:

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wherein each R^zis independently —H, —(C₁-C₄)alkyl, —OH, or —CN and preferably each R^zis independently —H, —CH₃, or —CH₂CH₃.

(16) Substituted Piperidin-4-amino-Type Compounds of any one of the above (1)-(4) or (10)-(14), wherein —Z—R¹is:

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(17) Substituted Piperidin-4-amino-Type Compounds of any one of the above (1)-(4) or (10)-(15), wherein —Z—R¹is:

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wherein R¹is —H, —CH₃, or —CH₂CH₃.

(18) Substituted Piperidin-4-amino-Type Compounds of any one of the above (1)-(4), (10)-(17), wherein the R¹group is in the exo-configuration with respect to the A-B bridge of the bridged piperidine.

(19) Substituted Piperidin-4-amino-Type Compounds of any one of the above (1)-(18), wherein E¹is S(═O)₂, CH₂, or a direct bond.

(20) Substituted Piperidin-4-amino-Type Compounds of any one of the above (1)-(19), wherein Q¹is phenyl.

(21) Substituted Piperidin-4-amino-Type Compounds of any one of the above (1)-(20), wherein a is selected from 0 and 1.

(22) Substituted Piperidin-4-amino-Type Compounds of any one of the above (1)-(21), wherein b is 0 or 1.

(23) Substituted Piperidin-4-amino-Type Compounds of any one of the above (1)-(22), wherein x is 0 or 1.

(24) Substituted Piperidin-4-amino-Type Compounds of any one of the above (1)-(23), wherein E²is C(═O) or a direct bond.

(25) Substituted Piperidin-4-amino-Type Compounds of any one of the above (1)-(24), wherein n is 0 or 1.

(26) Substituted Piperidin-4-amino-Type Compounds of any one of the above (1)-(25), wherein:

- (a) D is H, NO₂or N(R*)₂; and
- (b) each R* is, independently for each occurrence in D, H or (C₁-C₆)alkyl unsubstituted or substituted with 1 or 2 substituents independently selected from —OH, —O(C₁-C₆alkyl), and ═O.

(27) Substituted Piperidin-4-amino-Type Compounds of any one of the above (1)-(26), wherein D is selected from

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(28) Substituted Piperidin-4-amino-Type Compounds of any one of the above (1)-(27), wherein W is NH or a direct bond.

(29) Substituted Piperidin-4-amino-Type Compounds of any one of the above (1)-(28), wherein Q²is (C₃-C₆)cycloalkyl, non-aromatic (3- to 6-membered)heterocycle, or a direct bond.

(30) Substituted Piperidin-4-amino-Type Compounds of any one of the above (1)-(29), wherein Q²-(R³)_bis selected from

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(31) Substituted Piperidin-4-amino-Type Compounds of any one of the above (1)-(30), wherein R²is, independently for each occurrence, -halo, —NO₂, —X, —C(═Y)YX, —N(T¹)(T²), —YH, or YX.

(32) Substituted Piperidin-4-amino-Type Compounds of any one of the above (1)-(31), wherein:

- (a) R²is, independently for each occurrence, -halo, —NO₂, —X, —C(═Y)YX, —N(T¹)(T²), —YH, or —YX;
- (b) Y is O;
- (b) each X is, independently for each occurrence in R², H, (C₁-C₆)alkyl, or (C₂-C₆)alkenyl unsubstituted or substituted with 1 or 2 substituents independently selected from —OH, —C(═O)OH, —C(═O)O(C₁-C₆)alkyl, —O(C₁-C₆alkyl), and ═O; and
- (c) T¹and T²are, independently for each occurrence in R², H or —(C₁-C₁₀)alkyl unsubstituted or substituted with 1, 2, or 3 substituents independently selected from —OH, —O(C₁-C₆)alkyl, and ═O.

(33) Substituted Piperidin-4-amino-Type Compounds of any one of the above (1)-(32), wherein R²is selected from

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(34) Substituted Piperidin-4-amino-Type Compounds of any one of the above (1)-(32), wherein R²is selected from

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(35) Substituted Piperidin-4-amino-Type Compounds of any one of the above (1)-(34), wherein R³is, independently for each occurrence, H, (C₁-C₆)alkyl, halo, —C(═O)OH, —C(═O)O(C₁-C₆alkyl), or tetrazolyl.

(36) Substituted Piperidin-4-amino-Type Compounds of any one of the above (1)-(35), wherein R³is selected from

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(37) Substituted Piperidin-4-amino-Type Compounds of any one of the above (1)-(35), wherein R³is selected from H and CH₃.

(38) Substituted Piperidin-4-amino-Type Compounds of any one of the above (1)-(33) and (35)-(36), wherein:

E¹is a direct bond or SO₂;

Q¹is phenyl;

a is selected from 0 and 1;

R²is selected from

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x is selected from 0 and;

E²is C(═O);

n is selected from 0 and 1;

D is selected from H and —N(CH₃)₂;

W is selected from —NH and a direct bond;

Q²is selected from pyrrolidinyl, cyclopropyl, cyclohexyl and a direct bond;

b is selected from 0 and 1; and

R³is selected from

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(39) Substituted Piperidin-4-amino-Type Compounds of the above (38), wherein:

E¹is a direct bond;

R²is

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D is H;

W is a direct bond;

Q²is selected from pyrrolidinyl and a direct bond;

b is 1; and

R³is selected from

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(40) Substituted Piperidin-4-amino-Type Compounds of any one of the above (1)-(32), (34)-(35), and (37), wherein:

E¹is selected from a C(═O), CH₂, and a direct bond;

Q¹is phenyl;

a is 1;

R²is selected from

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x is 0

E²is selected from C(═O) and a direct bond;

n is O;

W is a direct bond;

Q²is a direct bond;

b is 1; and

R³is selected from H and CH₃.

(41) Substituted Piperidin-4-amino-Type Compounds of the above (40), wherein

R²is selected from

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(42) A Substituted Piperidin-4-amino-Type Compound of any one of the above (1)-(33), (35)-(36), and (38), wherein the compound is:

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