Hydroxy alkyl substituted 1,3,8-Triazaspiro[4.5]decan-4-one derivatives useful for the treatment of orl-1receptor mediated disorders

FIELD OF THE INVENTION

The present invention is directed to novel hydroxy alkyl substituted 1,3,8-triazaspiro[4.5]decan-4-one derivatives useful in the treatment of disorders and conditions mediated by the ORL-1 G-protein coupled receptor. More particularly, the compounds of the present invention are useful in the treatment of disorders and conditions such as anxiety, depression, panic, mania, dementia, bipolar disorder, substance abuse, neuropathic pain, acute pain, chronic pain, migraine, asthma, cough, psychosis, schizophrenia, epilepsy, hypertension, obesity, eating disorders, cravings, diabetes, cardiac arrhythmia, irritable bowel syndrome, Crohn's disease, urinary incontinence, adrenal disorders, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), Alzheimer's disease, for improved cognition or memory and for mood stabilization.

BACKGROUND OF THE INVENTION

The ORL-1 (orphan opioid receptor) G-protein coupled receptor, also known as the nociceptin receptor, was first reported in 1994, and was discovered based on its homology with the classic delta-(OP-1), mu-(OP-3), and kappa-(OP-2) opioid receptors. The ORL-1 G-protein coupled receptor does not bind opioid ligands with high affinity. The amino acid sequence of ORL-1 is 47% identical to the opioid receptors overall, and 64% identical in the transmembrane domains. (Nature, 1995, 377, 532.)

The endogenous ligand of ORL-1, known as nociceptin, a highly basic 17 amino acid peptide, was isolated from tissue extracts in 1995. It was named both nociceptin, because it increased sensitivity to pain when injected into mouse brain, and orphanin FQ (OFQ) because of the terminal phenylalanine (F) and glutamine (Q) residues that flank the peptide on the N- and C-termini respectively. (WO97/07212)

Nociceptin binding to ORL-1 receptors causes inhibition of cAMP synthesis, inhibition of voltage-gated calcium channels, and activation of potassium conductance. In vivo, nociceptin produces a variety of pharmacological effects that at times oppose those of the opioids, including hyperalgesia and inhibition of morphine-induced analgesia. Mutant mice lacking nociceptin receptors show better performance in learning and memory tasks. These mutant mice also have normal responses to painful stimuli.

The ORL-1 receptor is widely distributed/expressed throughout the human body, including in the brain and spinal cord. In the spinal cord, the ORL-1 receptor exists in both the dorsal and ventral horns, and precursor mRNA has been found in the superficial lamina of the dorsal horn, where primary afferent fibers of nociceptors terminate. Therefore, the ORL-1 has an important role in nociception transmission in the spinal cord. This was confirmed in recent studies wherein nociceptin, when given to mice by i.c.v. injection, induced hyperalgesia and decreased locomotor activity. (Brit. J. Pharmacol. 2000, 129, 1261.)

Ito, et al., in EP 0997464 disclose 1,3,8-triazaspiro[4.5]decan-4-one compounds as ORL-1 receptor agonists, useful as analgesics or the like in mammalian subjects.

Hohlweg et al., in PCT publication WO 01/36418 disclose triazaspirodecanones with high affinity for opioid receptor subtypes useful in the treatment of migraine, non-insulin dependent diabetes mellitus, sepsis, inflammation, incontinence and/or vasomotor disturbances.

Tulshian et al. in PCT publication WO00/06545 disclose high affinity ligands for the nociceptin receptor ORL-1 and the use of said compounds as nociceptin receptor inhibitors useful in the treatment of pain, anxiety, cough, asthma, depression and alcohol abuse.

Higgins, et. al., in European Forum of Neuroscience 2000, Brighton, U.K., Jun. 24–28, 2000, Poster 077.22 disclosed, 8-[(1R,3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one useful as cognition enhancers.

We now describe novel small molecule modulators of the ORL-1 receptor, useful for the treatment of disorders and conditions mediated by the ORL-1 receptor, such as anxiety, depression, panic, dementia, mania, bipolar disorder, substance abuse, neuropathic pain, acute pain, chronic pain, migraine, asthma, cough, psychosis, schizophrenia, epilepsy, hypertension, obesity, eating disorders, cravings, diabetes, cardiac arrhythmia, irritable bowel syndrome, Crohn's disease, urinary incontinence, adrenal disorders, attention deficit disorder (ADD), attention deficit hyperactivity disorders (ADHD), Alzheimer's disease, for improved cognition or memory and for mood stabilization.

SUMMARY OF THE INVENTION

The present invention is directed to compounds of the general formula (I)

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wherein

R⁰is selected from the group consisting of

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each R^Aand R^Bis independently selected from the group consisting of hydrogen and C_1-4alkyl;

each R^Cand R^Dis independently selected from the group consisting of hydrogen, hydroxy, carboxy, C_1-4alkyl, C_1-4alkoxy, nitro, cyano, N(R^E)₂, aryl, arC_1-4alkyl, heteroaryl or heterocycloalkyl; wherein the aryl, arC_1-4alkyl, heteroaryl or heterocycloalkyl substituent is optionally substituted with one or more substituents independently selected from hydroxy, carboxy, C_1-4alkyl, C_1-4alkoxy, nitro, cyano or N(R^E)₂;

each R^Eis independently selected from the group consisting of hydrogen and C_1-4alkyl;

X is selected from the group consisting of —NR¹R², —C(O)—NR¹R², —NR¹—C(O)—R², —OR¹, —SR¹, —SOR¹, —SO₂R¹, —S—(C_2-4alkyl)-NR¹R², —S—(C_2-4alkyl)—NR¹—C(O)O—C(CH₃)₃, —SO—(C_1-4alkyl)-NR¹R²and —SO₂—(C_1-4alkyl)-NR¹R²; wherein the alkyl portion of the —S—(C_2-4alkyl)-NR¹R², —SO—(C_1-4alkyl)-NR¹R²or —SO₂—(C_1-4alkyl)-NR¹R²group is optionally substituted with one or more substituents independently selected from carboxy, hydroxy, hydroxyC_1-4alkyl, C_1-4alkyl, C_1-4alkoxycarbonyl or —CONR¹R²;

each R¹and R²is independently selected from the group consisting of hydrogen, C_1-8alkyl, C_1-8alkoxy, C_1-8alkoxycarbonyl, cycloalkyl, cycloalkyl-C_1-4alkyl, partially unsaturated carbocyclyl, partially unsaturated carbocyclyl-C_1-4alkyl, aryl, arC_1-4alkyl, arC_1-4alkoxy, heteroaryl, heteroaryl-C_1-4alkyl, heterocycloalkyl, heterocycloalkyl-C_1-4alkyl, —C(O)—C_1-6alkyl, —C(O)-aryl, —C(O)-arC_1-4alkyl, —C(O)-heteroaryl, —C(O)-heterocycloalkyl, —C(O)O-cycloalkyl and —C(O)O-aryl, —C(O)O-arC_1-4akyl, —C(O)O-(partially unsaturated carbocyclyl), C(O)-heteroaryl, —C(O)O-heterocycloalkyl; wherein the C_1-8alkyl, cycloalkyl, partially unsaturated carbocyclyl, aryl, arC_1-4alkyl, heteroaryl or heterocycloalkyl group, whether alone or part of a substituent group, is optionally substituted with one or more substituents independently selected from halogen, hydroxy, carboxy, C_1-4alkyl, C_1-4alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, C(O)—C_1-4alkyl, C_1-4alkoxycarbonyl, N(R^E)₂, N(R^E)₂—C_1-4alkyl, N(R^E)—C(O)C(CH₃)₃, —C_1-4alkyl-N(R^E)—C(O)O—C_1-4alkyl and —N(R^E)—C(O)O—C_1-4alkyl, aryl, aryloxy, cycloalkyl, heteroaryl, aryl substituted heteroarylaminosulfonyl or C_1-6alkylthio;

alternatively when R¹and R²are both bound to the same nitrogen atom, R¹and R²are taken together with the nitrogen atom to which they are bound to form a heteroaryl or heterocycloalkyl group; wherein the heteroaryl or heterocycloalkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, carboxy, C_1-4alkyl, hydroxy substituted C_1-4alkyl, C_1-4alkoxy, C_1-4alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, nitro, cyano, N(R^E)₂, aryl, arC_1-4alkyl, heteroaryl, heterocycloalkyl, di(C_1-6)alkylamino-carbonyl, C_1-4alkoxycarbonyl-N(R^E)— or arylamino-C_1-4alkyl; wherein the aryl, arC_1-4alkyl, heteroaryl or heterocycloalkyl substituent is optionally further substituted with one or more substituents independently selected from halogen, hydroxy, carboxy, C_1-4alkyl, C_1-4alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, N(R^E)₂, phenyl or substituted phenyl; wherein the substituents on the phenyl are one or more independently selected from halogen, hydroxy, carboxy, C_1-4alkyl, C_1-4alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano or N(R^E)₂;

R³is selected from the group consisting of aryl, arC_1-6alkyl and heteroaryl; wherein the aryl, arC_1-6alkyl or heteroaryl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, carboxy, C_1-4alkyl, C_1-4alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano or N(R^E)₂;

n is an integer from 0 to 2;

R⁴is selected from the group consisting of hydroxy, C_1-4alkyl and hydroxy substituted C_1-4alkyl;

m is an integer from 0 to 1;

L¹is selected from the group consisting of C_1-6alkyl and C_3-6alkenyl; wherein the double bond of the C_3-6alkenyl group is at least one carbon atom removed from the attachment point to the N atom; and wherein the C_1-6alkyl or C_3-6alkenyl group is optionally substituted with one to two substituents independently selected from hydroxy, fluoro, C_1-6alkyl, fluorinated C_1-6alkyl or C_1-6alkoxy;

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selected from the group consisting of cycloalkyl, partially unsaturated carbocyclyl, aryl, heteroaryl and heterocycloalkyl;

p is an integer from 0 to 5;

R⁵is selected from the group consisting of hydroxy, carboxy, halogen, C_1-6alkyl, hydroxy substituted C_1-6alkyl, C_1-6alkoxy, nitro, cyano, NR¹R², trifluoromethyl, trifluoromethoxy, C_1-4alkoxycarbonyl, —SO—NR¹R², —SO₂—NR¹R²and —C(O)—NR¹R²;

q is an integer from 0 to 1;

R⁶is selected from the group consisting of -(L²)_0-1-R⁷;

L²is selected from the group consisting of —C_1-6alkyl-, —C_2-4alkenyl-, —C_2-6alkynyl-, —O—, —S—, —NH—, —N(C_1-4alkyl)-, —C_1-6alkyl-O—, —C_1-6alkyl-S—, —O—C_1-6alkyl-, —S—C_1-6alkyl-, —O—C_2-6alkyl-O—, —S—C_2-6alkyl-S—, —SO₂—, —SO₂NH—, —SO₂N(C_1-4alkyl)-, —NH—SO₂—, —N(C_1-4alkyl)-SO₂—, —C(O)—O— and —O—C(O)—;

R⁷is selected from the group consisting of aryl, partially unsaturated carbocyclyl, cycloalkyl, heteroaryl and heterocycloalkyl; wherein the aryl, partially unsaturated carbocyclyl, cycloalkyl, heteroaryl or heterocycloalkyl group is optionally substituted with one or more substituents independently selected from hydroxy, carboxy, halogen, C_1-6alkyl, C_1-6alkoxy, nitro, cyano, N(R^E)₂, trifluoromethyl, trifluoromethoxy, C_1-4alkoxycarbonyl, —SO₂—N(R^E)₂and —C(O)—N(R^E)₂;

or a pharmaceutically acceptable salt thereof.

Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compounds described above. An illustration of the invention is a pharmaceutical composition made by mixing any of the compounds described above and a pharmaceutically acceptable carrier. Illustrating the invention is a process for making a pharmaceutical composition comprising mixing any of the compounds described above and a pharmaceutically acceptable carrier.

Exemplifying the invention are methods of treating disorders and conditions mediated by the ORL-1 receptor in a subject in need thereof comprising administering to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.

An example of the invention is a method of treating a condition selected from the group consisting of anxiety, depression, panic, mania, dementia, bipolar disorder, substance abuse, neuropathic pain, acute pain, chronic pain migraine, asthma, cough, psychosis, schizophrenia, epilepsy, hypertension, obesity, eating disorders, cravings, diabetes, cardiac arrhythmia, irritable bowel syndrome, Crohn's disease, urinary incontinence, adrenal disorders, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), Alzheimer's disease, for improved cognition or memory and for mood stabilization, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.

Another example of the invention is the use of any of the compounds described herein in the preparation of a medicament for treating: (a) anxiety, (b) depression, (c) panic, (d) mania, (e) dementia, (f) bipolar disorder, (g) substance abuse (h) neuropathic pain, (i) acute pain, (j) chronic pain, (k) migraine, (l) asthma, (m) cough, (n) psychosis, (o) schizophrenia, (p) epilepsy, (q) hypertension, (r) obesity, (s) eating disorders, (t) cravings, (u) diabetes), (v) cardiac arrhythmia, (w) irritable bowel syndrome, (x) Crohn's disease, (uy) urinary incontinence, (z) adrenal disorders, (aa) attention deficit disorder (ADD), (bb) attention deficit hyperactivity disorder (ADHD), (cc) Alzheimer's disease, for (dd) improved cognition, (ee) improved memory and (ff) mood stabilization, in a subject in need thereof.

The present invention is further directed to a compound of formula (E)

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wherein

wherein each R^Eis independently selected from hydrogen or C_1-4alkyl;

n is an integer from 0 to 2;

R⁴is selected from the group consisting of hydroxy, C_1-4alkyl and hydroxy substituted C_1-4alkyl;

Y is selected from the group consisting of hydrogen, C_1-4alkyl, t-butoxycarbonyl and

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m is an integer from 0 to 1;

L¹is selected from the group consisting of C_1-6alkyl and C_3-6alkenyl;

wherein the double bond of the C_3-6alkenyl group is at least one carbon atom removed from the attachment point to the N atom; and wherein the C_1-6alkyl or C_3-6alkenyl group is optionally substituted with one to two substituents independently selected from hydroxy, fluoro, C_1-6alkyl, fluorinated C_1-6alkyl or C_1-6alkoxy;

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is selected from the group consisting of cycloalkyl, partially unsaturated carbocyclyl, aryl, heteroaryl and heterocycloalkyl;

p is an integer from 0 to 5;

q is an integer from 0 to 1;

R⁶is selected from the group consisting of -(L²)_0-1-R⁷;

or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides hydroxy alkyl substituted 1,3,8-triazaspiro[4.5]decan-4-one derivatives useful for the treatment of disorders and conditions mediated by the ORL-1 receptor. More particularly, the compounds of the present invention are of the general formula (I)

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wherein R⁰, R³, n, R⁴, m, L¹,

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p, R⁵, q and R⁶are as herein defined, or a pharmaceutically acceptable salt thereof. The compounds of formula (I) are useful in the treatment of disorders mediated by the ORL-1 receptor. The compound of formula (I) are further useful for the treatment of disorders associated with the adrenal gland.

More particularly, the compound of formula (I) are useful in the treatment of anxiety, depression, panic, mania, dementia, bipolar disorder, substance abuse, neuropathic pain, acute pain, chronic pain migraine, asthma, cough, psychosis, schizophrenia, epilepsy, hypertension, obesity, eating disorders, cravings, diabetes, cardiac arrhythmia, irritable bowel syndrome, Crohn's disease, urinary incontinence, adrenal disorders, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), Alzheimer's disease, for improved cognition or memory and for mood stabilization. Preferably, the compounds of formula (I) are useful in the treatment of anxiety, depression, substance abuse, neuropathic pain, acute pain, chronic pain, migraine, cough, hypertension, cardiac arrhythmia, irritable bowel syndrome and Crohn's disease.

In an embodiment of the present invention are compounds of formula (I) wherein R⁰is selected from the group consisting of

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each R^Aand R^Bis independently selected from the group consisting of hydrogen and C_1-4alkyl;

each R^Eis independently selected from the group consisting of hydrogen and C_1-4alkyl;

X is selected from the group consisting of —NR¹R², —C(O)—NR¹R², —NR¹—C(O)—R², —OR¹, —SR¹, —SOR¹, —SO₂R¹, —S—(C_2-4alkyl)-NR¹R², —S—(C_2-4alkyl)-NR¹—C(O)O—C(CH₃)₃, —SO—(C_1-4alkyl)-NR¹R²and —SO₂—(C_1-4alkyl)-NR¹R²; wherein the alkyl portion of the —S—(C_2-4alkyl)-NR¹R², —SO—(C_1-4alkyl)-NR¹R²or —SO₂—(C_1-4alkyl)-NR¹R²group is optionally substituted with one or more substituents independently selected from carboxy, hydroxy, hydroxyC_1-4alkyl, C_1-4alkyl, C_1-4alkoxycarbonyl or —CONR¹R²;

each R¹and R²is independently selected from the group consisting of hydrogen, C_1-8alkyl, C_1-8alkoxy, cycloalkyl, cycloalkyl-C_1-4alkyl, partially unsaturated carbocyclyl, aryl, arC_1-4alkyl, arC_1-4alkoxy, heteroaryl, heteroaryl-C_1-4alkyl, heterocycloalkyl, heterocycloalkyl-C_1-4alkyl, —C(O)—C_1-6alkyl, —C(O)-aryl, —C(O)-arC_1-4alkyl, —C(O)-heteroaryl and —C(O)-heterocycloalkyl; wherein the C_1-8alkyl, cycloalkyl, partially unsaturated carbocyclyl, aryl, arC_1-4alkyl, heteroaryl or heterocycloalkyl group, whether alone or part of a substituent group, is optionally substituted with one or more substituents independently selected from halogen, hydroxy, carboxy, C_1-4alkyl, C_1-4alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, C(O)—C_1-4alkyl, C_1-4alkoxycarbonyl, N(R^E)₂, N(R^E)₂—C_1-4alkyl, N(R^E)—C(O)C(CH₃)₃, aryl, aryloxy, cycloalkyl, heteroaryl, aryl substituted heteroarylaminosulfonyl or C_1-6alkylthio;

alternatively when R¹and R²are both bound to the same nitrogen atom, R¹and R²are taken together with the nitrogen atom to which they are bound to form a heteroaryl or heterocycloalkyl group; wherein the heteroaryl or heterocycloalkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, carboxy, C_1-4alkyl, C_1-4alkoxy, C_1-4alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, nitro, cyano, N(R^E)₂, aryl, arC_1-4alkyl, heteroaryl, heterocycloalkyl, di(C_1-6)alkylamino-carbonyl, t-butoxycarbonyl or arylamino-C_1-4alkyl; wherein the aryl, arC_1-4alkyl, heteroaryl or heterocycloalkyl substituent is optionally further substituted with one or more substituents independently selected from halogen, hydroxy, carboxy, C_1-4alkyl, C_1-4alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, N(R^E)₂or substituted phenyl; wherein the substituents on the phenyl are one or more independently selected from halogen, hydroxy, carboxy, C_1-4alkyl, C_1-4alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano or N(R^E)₂;

n is an integer from 0 to 2;

R⁴is selected from the group consisting of hydroxy, C_1-4alkyl and hydroxy substituted C_1-4alkyl;

m is an integer from 0 to 1;

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is selected from the group consisting of cycloalkyl, partially unsaturated carbocyclyl, aryl, heteroaryl and heterocycloalkyl;

p is an integer from 0 to 5;

R⁵is selected from the group consisting of hydroxy, carboxy, halogen, C_1-6alkyl, C_1-6alkoxy, nitro, cyano, NR¹R², trifluoromethyl, trifluoromethoxy, C_1-4alkoxycarbonyl, —SO—NR¹R², —SO₂—NR¹R²and —C(O)—NR¹R²;

q is an integer from 0 to 1;

R⁶is selected from the group consisting of -(L²)_0-1-R⁷;

L²is selected from the group consisting of —C_1-6alkyl-, —C_2-4alkenyl-, —C_2-6alkynyl-, —O—, —S—, —NH—, —N(C_1-4alkyl)-, —C_1-6-alkyl-O—, —C_1-6alkyl-S—, —O—C_1-6alkyl-, —S—C_1-6alkyl-, —O—C_2-6alkyl-O—, —S—C_2-6alkyl-S—, —SO₂—, —SO₂NH—, —SO₂N(C_1-4alkyl)-, —NH—SO₂—, —N(C_1-4alkyl)-SO₂—, —C(O)—O— and —O—C(O)—;

and pharmaceutically acceptable salts thereof.

In an embodiment of the present invention are compounds of the formula (E)

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wherein R³, n, R⁴, and Y are as herein defined, or a pharmaceutically acceptable salt thereof. The compounds of formula (E) are useful as intermediates in the preparation of compounds of formula (I).

In an embodiment of the present invention are compounds of formula (E) wherein R³is selected from the group consisting of aryl, arC_1-6alkyl and heteroaryl; wherein the aryl, arC_1-6alkyl or heteroaryl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, carboxy, C_1-4alkyl, C_1-4alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano or N(R^E)₂; wherein each R^Eis independently selected from hydrogen or C_1-4alkyl;

n is an integer from 0 to 2;

R⁴is selected from the group consisting of hydroxy, C_1-4alkyl and hydroxy substituted C_1-4alkyl;

Y is selected from the group consisting of hydrogen, C_1-4alkyl, t-butoxycarbonyl and

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m is an integer from 0 to 1;

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is selected from the group consisting of cycloalkyl, partially unsaturated carbocyclyl, aryl, heteroaryl and heterocycloalkyl;

p is an integer from 0 to 5;

q is an integer from 0 to 1;

R⁶is selected from the group consisting of -(L²)_0-1-R⁷;

and pharmaceutically acceptable salts thereof.

In an embodiment of the present invention are compounds of the formula (Ia)

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wherein X, R³, n, R⁴, m, L¹,

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R⁵, q and R⁶are as herein defined, or a pharmaceutically acceptable salt thereof. The compounds of formula (I) are useful in the treatment of disorders mediated by the ORL-1 receptor.

In an embodiment of the present invention is a compound of formula (I) wherein the binding of the compound to the ORL-1 receptor is 10 fold greater than the binding of the compound to the μ opioid (OP-3) receptor. In another embodiment of the present invention is a compound of formula (I) wherein the binding of the compound to the ORL-1 receptor is 100 fold greater, preferably 500 fold greater, more preferably 1000 fold greater, than the binding of the compound to the μ opioid (OP-3) receptor.

In an embodiment of the present invention is a compound of formula (I) wherein the compound's measured IC₅₀to the ORL-1 receptor is less than or equal to about 100 nM, preferably less than or equal to about 50 nM. In another embodiment of the present invention is a compound of formula (I) wherein the compound's measured Ki to the ORL-1 receptor is less than or equal to about 100 nM, preferably less than or equal to about 50 nM.

In an embodiment of the present invention R⁰is

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In another embodiment of the present invention, R⁰is

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In yet another embodiment of the present invention, R⁰is

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Preferably, R⁰is selected from the group consisting of

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More preferably, R⁰is

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In yet another embodiment of the present invention, R⁰is

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Preferably, R⁰is

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In an embodiment of the present invention, the hydroxy group on the

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group is present in the R stereo-configuration. In another embodiment of the present invention, the hydroxy group on the

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group is present in the S stereo-configuration.

In an embodiment of the present invention R^Aand R^Bare each independently selected from hydrogen, methyl and ethyl, preferably R^Aand R^Bare each hydrogen. In another embodiment of the present invention R^Cand R^Dare each independently selected from hydrogen and C_1-4alkyl, preferably R^Cand R^Dare each hydrogen. In yet another embodiment of the present invention R^Eis selected from the group consisting of hydrogen, methyl and ethyl, preferably R^Eis hydrogen.

In an embodiment of the present invention X is selected from the group consisting of —NR¹R², —C(O)—NR¹R², —NR¹—C(O)—R²—OR¹, —SR¹, —SO—R¹, —SO²—R¹, —S—(C_2-4alkyl)-NR¹R², —SO—(C_1-4alkyl)-NR¹R², —SO₂—(C_1-4alkyl)-NR¹R²wherein the alkyl portion of the —S—(C_2-4alkyl)-NR¹R², —S—(C_1-4alkyl)-NR¹—C(O)O—C(CH₃)₃, —SO—(C_1-4alkyl)-NR¹R²or —SO₂—(C_1-4alkyl)-NR¹R²group is optionally substituted with one to two substituents independently selected from C_1-4alkyl, hydroxyC_1-4alkyl, C_1-4alkoxycarbonyl or carboxy. Preferably, X is selected from the group consisting of —NR¹R², —OR¹, —SR¹, —S—(C_2-4alkyl)-NR¹—C(O)O—C(CH₃)₃, —S—(C_2-4alkyl)-NR¹R²wherein the alkyl portion of the —S—(C_2-4alkyl)-NR¹R²or —S—(C_2-4alkyl)-NR¹—C(O)O—C(CH₃)₃group is optionally substituted with a carboxy or C_1-4alkoxycarbonyl group. More preferably, X is selected from the group consisting of —NR¹R², —OR¹, —SR¹, —S—CH₂CH(CO₂H)—NH—C(O)—CH₃and —S—CH₂CH(CO₂H)—NH—C(O)O—C(CH₃)₃. More preferably still, X is selected from the group consisting of —NR¹R², —SR¹and —S—CH₂CH(CO₂H)—NH—C(O)—CH₃.

In an embodiment of the present invention R¹is selected from the group consisting of hydrogen, C_1-4alkyl, C_1-4alkoxy, C_1-4alkoxycarbonyl, aryl, arC_1-4alkyl, arC_1-4alkyloxy, heteroaryl, heteroaryl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, cycloalkyl-alkyl, C(O)—C_1-4alkyl and —C(O)-heteroaryl; wherein the C_1-4alkyl, aryl, arC_1-4alkyl, heteroaryl, heterocycloalkyl or cycloalkyl group, whether alone or part of a substituent group, is optionally substituted with one to three substituents independently selected from halogen, hydroxy, carboxy, C_1-4alkyl, C_1-4alkoxy, C_1-4alkoxycarbonyl, N(R^E)₂, N(R^E)₂—C_1-4alkyl, N(R^E)—C(O)OC(CH₃)₃, nitro, trifluoromethyl, trifluoromethoxy, phenyl, phenoxy, heteroaryl, cycloalkyl, 1-phenyl-pyrazol-2-yl-aminosulfonyl or C_1-4alkylthio. Preferably, In an embodiment of the present invention R¹is selected from the group consisting of hydrogen, C_1-4alkyl, C_1-4alkoxy, aryl, arC_1-4alkyl, arC_1-4alkyloxy, heteroaryl, heteroaryl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, cycloalkyl-alkyl, C(O)—C_1-4alkyl and —C(O)-heteroaryl; wherein the C_1-4alkyl, aryl, arC_1-4alkyl, heteroaryl, heterocycloalkyl or cycloalkyl group, whether alone or part of a substituent group, is optionally substituted with one to three substituents independently selected from halogen, hydroxy, carboxy, C_1-4alkyl, C_1-4alkoxy, C_1-4alkoxycarbonyl, N(R^E)₂, N(R^E)₂—C_1-4alkyl, N(R^E)—C(O)OC(CH₃)₃, nitro, trifluoromethyl, trifluoromethoxy, phenyl, phenoxy, heteroaryl, cycloalkyl, 1-phenyl-pyrazol-2-yl-aminosulfonyl or C_1-4alkylthio.

In another embodiment of the present invention, R¹is selected from the group consisting of hydrogen, C_1-4alkyl, arC_1-4alkyl, C_1-4alkoxycarbonyl and C(O)—C_1-4alkyl; wherein the C_1-4alkyl, arC_1-4alkyl or aryl group, whether alone or part of a substituent group, is optionally substituted with one to two substituents independently selected from carboxy, C_1-4alkyl, C_1-4alkoxy, C_1-4alkoxycarbonyl, N(R^E)₂, N(R^E)₂—C_1-4alkyl or N(R^E)—C(O)OC(CH₃)₃. Preferably, R¹is selected from the group consisting of hydrogen, C_1-4alkyl, arC_1-4alkyl and C(O)—C_1-4alkyl; wherein the C_1-4alkyl, arC_1-4alkyl or aryl group, whether alone or part of a substituent group, is optionally substituted with one to two substituents independently selected from carboxy, C_1-4alkyl, C_1-4alkoxy, C_1-4alkoxycarbonyl, N(R^E)₂, N(R^E)₂—C_1-4alkyl or N(R^E)—C(O)OC(CH₃)₃.

In another embodiment of the present invention, R¹is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, t-butyl, amino-n-propyl, dimethylaminoethyl, benzyl, phenylethyl, 4-methyl-benzyl,

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2-(3,4-dimethoxy-phenyl)ethyl, 3-methylphenyl, 2-amino-2-methoxycarbonyl-ethyl, ethoxy-carbonyl-methyl, t-butoxycarbonyl, and

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Preferably, R¹is selected from the group consisting of hydrogen, methyl, n-propyl, n-butyl, t-butyl, dimethylaminoethyl, benzyl, 4-methyl-benzyl,

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2-(3,4-dimethoxy-phenyl)ethyl, 3-methylphenyl, 2-amino-2-methoxycarbonyl-ethyl and

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In another embodiment of the present invention, R¹is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, t-butyl, dimethylaminoethyl, benzyl, phenylethyl,

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3-methyl-phenyl, 2-(3,4-dimethoxyphenyl)-ethyl, ethoxy-carbonyl-methyl, dimethylamino-ethyl and 2-amino-2-methoxycarbonyl-ethyl. Preferably, R¹is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, t-butyl, dimethylaminoethyl, benzyl,

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3-methyl-phenyl and 2-amino-2-methoxycarbonyl-ethyl.

In yet another embodiment of the present invention, R¹is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, t-butyl, dimethylaminoethyl, benzyl, phenylethyl, 2-(3,4-dimethoxyphenyl)-ethyl, dimethylamino-ethyl, ethoxy-carbonyl-methyl,

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Preferably, R¹is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, t-butyl, dimethylaminoethyl, benzyl,

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In another embodiment of the present invention R¹is selected from the group consisting of hydrogen, t-butoxycarbonyl, 2-(3,4-dimethoxyphenyl)-ethyl, 1-(3,4-dimethoxyphenyl)-n-ethyl and amino-n-propyl. In yet another embodiment of the present invention R¹is selected from the group consisting of hydrogen, t-butoxycarbonyl and amino-n-propyl.

In an embodiment of the present invention R²is selected from the group consisting of hydrogen, C_1-4alkyl, C_1-4alkoxy, cycloalkyl, cycloalkyl-C_1-4alkyl, aryl, arC_1-4alkyl, arC_1-4alkyloxy, partially unsaturated carbocyclyl, partically unsaturated carbocyclyl-C_1-4alkyl, heteroaryl, heteroaryl-C_1-4alkyl, heterocycloalkyl, heterocycloalkyl-C_1-4alkyl, —C(O)—C_1-4alkyl, —C(O)-aryl, —C(O)-arC_1-4alkyl, —C(O)-heteroaryl, —C(O)-heterocycloalkyl, —C(O)O-cycloalkyl and —C(O)—C_1-4alkyl; wherein the C_1-4alkyl, aryl, arC_1-4alkyl, partially unsaturated carbocyclyl, heteroaryl, heterocycloalkyl or cycloalkyl group, whether alone or part of a substituent group, is optionally substituted with one to three substituents independently selected from halogen, hydroxy, carboxy, C_1-4alkyl, C_1-4alkoxy, C_1-4alkoxycarbonyl, N(R^E)₂, N(R^E)₂—C_1-4alkyl, (CH₃)₃COC(O)—N(R^E)—C_1-4-alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, phenyl, phenoxy, heteroaryl, cycloalkyl, 1-phenyl substituted heteroaryl-aminosulfonyl, —C(O)—C_1-4alkyl or C_1-4alkylthio. Preferably, R²is selected from the group consisting of hydrogen, C_1-4alkyl, C_1-4alkoxy, cycloalkyl-C_1-4alkyl, aryl, arC_1-4alkyl, arC_1-4alkyloxy, partially unsaturated carbocyclyl, heteroaryl, heteroaryl-C_1-4alkyl, heterocycloalkyl, heterocycloalkyl-C_1-4alkyl, —C(O)—C_1-4alkyl, —C(O)-aryl, —C(O)-arC_1-4alkyl, —C(O)-heteroaryl and —C(O)-heterocycloalkyl; wherein the C_1-4alkyl, aryl, arC_1-4alkyl, partially unsaturated carbocyclyl, heteroaryl, heterocycloalkyl or cycloalkyl group, whether alone or part of a substituent group, is optionally substituted with one to three substituents independently selected from halogen, hydroxy, carboxy, C_1-4alkyl, C_1-4alkoxy, C_1-4alkoxycarbonyl, N(R^E)₂, N(R^E)₂—C_1-4alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, phenyl, phenoxy, heteroaryl, cycloalkyl, 1-phenyl substituted heteroaryl-aminosulfonyl, —C(O)—C_1-4alkyl or C_1-4alkylthio.

In an embodiment of the present invention, R²is selected from the group consisting of hydrogen, C_1-4alkyl, C_1-4alkoxy, cycloalkyl, aryl, arC_1-4alkyl, arC_1-4alkyloxy, partially unsaturated carbocyclyl, partially unsaturated carbocyclyl-C_1-4alkyl, heteroaryl, heteroaryl-C_1-4alkyl, heterocycloalkyl, heterocycloalkyl-C_1-4alkyl, cycloalkyl-C_1-4alkyl, —C(O)arC_1-4alkyl, —C(O)-heteroaryl, —C(OO)-cycloalkyl and —C(O)O—C_1-4alkyl; wherein the C_1-4alkyl, aryl, arC_1-4alkyl, partially unsaturated carbocyclyl, heteroaryl, heterocycloalkyl or cycloalkyl group, whether alone or part of a substituent group, is optionally substituted with one to three substituents independently selected from halogen, hydroxy, carboxy, C_1-4alkyl, C_1-4alkoxy, C_1-4alkoxycarbonyl, N(R^E)₂, N(R^E)₂—C_1-4alkyl, (CH₃)₃CO—C(O)—N(R^E)—C_1-4alkyl, nitro, trifluoromethyl, trifluoromethoxy, phenyl, phenoxy, heteroaryl, cycloalkyl, 1-phenyl-pyrazol-2-yl-aminosulfonyl or C_1-4alkylthio. Preferably, R²is selected from the group consisting of hydrogen, C_1-4alkyl, C_1-4alkoxy, aryl, arC_1-4alkyl, arC_1-4alkyloxy, partially unsaturated carbocyclyl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, cycloalkyl-alkyl and —C(O)-heteroaryl; wherein the C_1-4alkyl, aryl, arC_1-4alkyl, partially unsaturated carbocyclyl, heteroaryl, heterocycloalkyl or cycloalkyl group, whether alone or part of a substituent group, is optionally substituted with one to three substituents independently selected from halogen, hydroxy, carboxy, C_1-4alkyl, C_1-4alkoxy, C_1-4alkoxycarbonyl, N(R^E)₂, N(R^E)₂—C_1-4alkyl, nitro, trifluoromethyl, trifluoromethoxy, phenyl, phenoxy, heteroaryl, cycloalkyl, 1-phenyl-pyrazol-2-yl-aminosulfonyl or C_1-4alkylthio.

In an embodiment of the present invention, R²is selected from the group consisting of hydrogen, methyl, methoxy, ethyl, carboxy-methyl, ethoxycarbonylmethyl, 2,2,2,-triluoroethyl, ethoxy, dimethylaminoethyl, t-butoxycarbonylamino-ethyl, n-butyl, t-butyl, n-propyl, 3-hydroxy-n-propyl, 3-methoxy-n-propyl, methylamino-n-propyl, dimethylamino-n-propyl, di(n-butyl)amino-n-propyl, t-butoxycarbonylamino-n-propyl, 3-phenyl-n-propyl, 3-(2-pyridyl)-n-propyl, t-butoxycarbonyl, cyclopropyl, phenyl, 4-fluorophenyl, 4-methylphenyl, 3,4-dimethoxyphenyl, 2-aminophenyl, 4-biphenyl, 2-ethoxyphenyl, 4-((1-phenyl-pyrazol-2-yl)-aminosulfonyl)-phenyl, 4-cyclohexylphenyl, 4-(aminoethyl)phenyl, 4-(t-butoxycarbonylamino-ethyl)-phenyl, —CH(CH₃)-phenyl, benzyl, benzyloxy, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-ethoxybenzyl, 3-ethoxybenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-chlorobenzyl, 4-chlorobenzyl), 3-iodobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 4-trifluoromethoxybenzyl, 4-methoxycarbonylbenzyl, 2,3-dimethoxybenzyl, 2,4-dichlorobenzyl, 3,4-dichlorobenzyl, 2,4-difluorobenzyl, 2,5-difluorobenzyl, 3,4-difluorobenzyl, 3,4,5-trimethoxybenzyl, 2,4,6-trimethoxybenzyl, 4-carboxybenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, 3,4-difluorobenzyl, 3,5-di(trifluoromethyl)benzyl, 4-(dimethylamino)benzyl, 2-phenylethyl, 2-(4-bromophenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(4-methoxyphenyl)ethyl, 2-(3,4-dimethoxyphenyl)ethyl, 2-(2-nitro-4,5-dimethoxy-phenyl)ethyl, 3-(4-morpholinyl)-n-propyl, 2-(4-morpholinyl)ethyl, 2-(4-imidazolyl)ethyl, 1-adamantanyl, 1-adamantanyl-methyl, (2,5-dimethoxy-2,5-dihydro-fur-2-yl)methyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridyl-methyl, 3-pyridyl-methyl, 4-pyridyl-methyl, 2-(3,4-dimethyl-pyridyl), 2-(5-bromopyridyl), 2-(4,6-dimethyl-pyridyl), 2-(5-methyl-pyridyl), 3-(6-methoxy-pyridyl), 6-methylthio-2-pyridyl-carbonyl, thienyl-methyl, 2-thienylethyl, 4-pyridinyl, 1-naphthyl, 1-naphthyl-methyl, 1-(3,4-methylenedioxyphenyl)methyl, 2-(3,4-methylenedioxyphenyl)ethyl, 1-phenyl-2-(t-butoxycarbonyl)ethyl, —C(O)—C(OCH₃)(CF₃)-phenyl, —C(O)O-(2-isopropyl-5-methyl-cyclohexyl), 1-(4-ethoxycarbonyl-piperidinyl), 2-(3H-imidazol4-yl)ethyl, 2-(1,2,3,4-tetrahydro-isoquinolinyl), 2-furyl-methyl,

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2S-hydroxy-S-cyclopentyl-methyl, 2S-hydroxy-S-cyclohexyl-methyl, 2S-hydroxy-S-cycloheptyl-methyl, 2-phenoxy-ethyl, 2-(2-pyridyl)-ethyl, 2-(6-fluoro-2-indolyl)ethyl and 2-phenyl-cyclopropyl. Preferably, R²is selected from the group consisting of hydrogen, methyl, methoxy, ethyl, carboxy-methyl, ethoxycarbonylmethyl, 2,2,2,-triluoroethyl, ethoxy, dimethylaminoethyl, n-butyl, t-butyl, n-propyl, di(n-butyl)amino-n-propyl, 3-phenyl-n-propyl, 3-(2-pyridyl)-n-propyl, phenyl, 4-biphenyl, 2-ethoxyphenyl, 4-((1-phenyl-pyrazol-2-yl)-aminosulfonyl)-phenyl, 4-cyclohexylphenyl, 4-(aminoethyl)phenyl, benzyl, benzyloxy, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-ethoxybenzyl, 3-ethoxybenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-chlorobenzyl, 4-chlorobenzyl), 3-iodobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 4-trifluoromethoxybenzyl, 4-methoxycarbonylbenzyl, 2,3-dimethoxybenzyl, 2,4-dichlorobenzyl, 3,4-dichlorobenzyl, 2,4-difluorobenzyl, 2,5-difluorobenzyl, 3,4-difluorobenzyl, 3,4,5-trimethoxybenzyl, 2,4,6-trimethoxybenzyl, 4-carboxybenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, 3,4-difluorobenzyl, 3,5-di(trifluoromethyl)benzyl, 4-(dimethylamino)benzyl, 2-phenylethyl, 2-(4-bromophenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(4-methoxyphenyl)ethyl, 2-(3,4-dimethoxyphenyl)ethyl, 2-(2-nitro-4,5-dimethoxy-phenyl)ethyl, 3-(4-morpholinyl)-n-propyl, 2-(4-morpholinyl)ethyl, 2-(4-imidazolyl)ethyl, 1-adamantanyl, 1-adamantanyl-methyl, (2,5-dimethoxy-2,5-dihydro-fur-2-yl)methyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridyl-methyl, 3-pyridyl-methyl, 4-pyridyl-methyl, 2-(3,4-dimethyl-pyridyl), 2-(5-bromopyridyl), 2-(4,6-dimethyl-pyridyl), 2-(5-methyl-pyridyl), 3-(6-methoxy-pyridyl), 6-methylthio-2-pyridyl-carbonyl, 2-thienylethyl, 1-naphthyl, 1-naphthyl-methyl, 1-(3,4-methylenedioxyphenyl)methyl, 2-(3,4-methylenedioxyphenyl)ethyl, 1-phenyl-2-(t-butoxycarbonyl)ethyl, 2-(1,2,3,4-tetrahydro-isoquinolinyl), 2-furyl-methyl,

In an embodiment of the present invention, R²is selected from the group consisting of hydrogen, methyl, methoxy, ethyl, ethoxycarbonyl-methyl, 2,2,2-triluoroethyl, ethoxy, dimethylaminoethyl, n-butyl, t-butyl, n-propyl, di(n-butyl)amino-n-propyl, 3-phenyl-n-propyl, 3-(2-pyridyl)-n-propyl, cyclopropyl, phenyl, 4-fluorophenyl, 4-methylphenyl, 2-aminophenyl, 4-(t-butoxycarbonylamino-ethyl)-phenyl, 3,4-dimethoxyphenyl, 4-biphenyl, 2-ethoxyphenyl, 4-((1-phenyl-pyrazol-2-yl)-aminosulfonyl)-phenyl, 4-(aminoethyl)-phenyl, benzyl, benzyloxy, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-ethoxybenzyl, 3-ethoxybenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 3-iodobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 4-trifluoromethoxybenzyl, 4-methoxycarbonyl-benzyl, 2,3-dimethoxybenzyl, 2,4-dichlorobenzyl, 3,4-dichlorobenzyl, 2,4-difluorobenzyl, 2,5-difluorobenzyl, 3,4-difluorobenzyl, 3,4,5-trimethoxybenzyl, 2,4,6-trimethoxybenzyl, 4-carboxybenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, 3,4-difluorobenzyl, 3,5-di(trifluoromethyl)-benzyl, 2-phenylethyl, 2-(4-bromophenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(4-methoxyphenyl)ethyl, 2-(3,4-dimethoxyphenyl)ethyl, 2-(2-nitro-4,5-dimethoxy-phenyl)ethyl, 3-(4-morpholinyl)-n-propyl, 2-(4-morpholinyl)ethyl, 2-(4-imidazolyl)ethyl, adamantanyl, 1-adamantanyl-methyl, 2-(2,5-dimethoxy-2,5-dihydro-furyl)methyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridyl-methyl, 3-pyridyl-methyl, 4-pyridyl-methyl, 2-(3,4-dimethyl-pyridyl), 2-(5-bromopyridyl), 2-(4,6-dimethyl-pyridyl), 2-(5-methyl-pyridyl), 3-(6-methoxy-pyridyl), thienylmethyl, 2-thienylethyl, 1-naphthyl, 1-naphthyl-methyl, 1-(3,4-methylenedioxyphenyl)methyl, 2-(3,4-methylenedioxyphenyl)ethyl, 2-furyl-methyl,

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2S-hydroxy-S-cyclopentyl-methyl, 2S-hydroxy-S-cyclohexyl-methyl, 2S-hydroxy-S-cycloheptyl-methyl, 2-phenoxy-ethyl and 2-(6-fluoro-2-indolyl)-ethyl. Preferably still, R²is selected from the group consisting of hydrogen, methyl, methoxy, ethyl, ethoxycarbonyl-methyl, 2,2,2-triluoroethyl, ethoxy, dimethylaminoethyl, n-butyl, t-butyl, n-propyl, di(n-butyl)amino-n-propyl, 3-phenyl-n-propyl, 3-(2-pyridyl)-n-propyl, phenyl, 4-biphenyl, 2-ethoxyphenyl, 4-((1-phenyl-pyrazol-2-yl)-aminosulfonyl)-phenyl, 4-(aminoethyl)-phenyl, benzyl, benzyloxy, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-ethoxybenzyl, 3-ethoxybenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 3-iodobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 4-trifluoromethoxybenzyl, 4-methoxycarbonyl-benzyl, 2,3-dimethoxybenzyl, 2,4-dichlorobenzyl, 3,4-dichlorobenzyl, 2,4-difluorobenzyl, 2,5-difluorobenzyl, 3,4-difluorobenzyl, 3,4,5-trimethoxybenzyl, 2,4,6-trimethoxybenzyl, 4-carboxybenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, 3,4-difluorobenzyl, 3,5-di(trifluoromethyl)-benzyl, 2-phenylethyl, 2-(4-bromophenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(4-methoxyphenyl)ethyl, 2-(3,4-dimethoxyphenyl)ethyl, 2-(2-nitro-4,5-dimethoxy-phenyl)ethyl, 3-(4-morpholinyl)-n-propyl, 2-(4-morpholinyl)ethyl, 2-(4-imidazolyl)ethyl, adamantanyl, 1-adamantanyl-methyl, 2-(2,5-dimethoxy-2,5-dihydro-furyl)methyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridyl-methyl, 3-pyridyl-methyl, 4-pyridyl-methyl, 2-(3,4-dimethyl-pyridyl), 2-(5-bromopyridyl), 2-(4,6-dimethyl-pyridyl), 2-(5-methyl-pyridyl), 3-(6-methoxy-pyridyl), 2-thienylethyl, 1-naphthyl, 1-naphthyl-methyl, 1-(3,4-methylenedioxyphenyl)methyl, 2-(3,4-methylenedioxyphenyl)ethyl, 2-furyl-methyl,

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2S-hydroxy-S-cyclopentyl-methyl, 2S-hydroxy-S-cyclohexyl-methyl, 2S-hydroxy-S-cycloheptyl-methyl, 2-phenoxy-ethyl and 2-(6-fluoro-2-indolyl)-ethyl.

In an embodiment of the present invention, R²is selected from the group consisting of hydrogen, methyl, methoxy, ethyl, ethoxycarbonyl-methyl, ethoxy, dimethylaminoethyl, n-butyl, n-propyl, di(n-butyl)amino-n-propyl, 3-phenyl-n-propyl, 3-(2-pyridyl)-n-propyl, cyclopropyl, phenyl, 4-fluorophenyl, 4-methylphenyl, 2-aminophenyl, 3,4-dimethoxyphenyl, 4-(t-butoxycarbonylamino-ethyl)-phenyl, 4-biphenyl, 2-ethoxyphenyl, 4-((1-phenyl-pyrazol-2-yl)-aminosulfonyl)-phenyl, 4-(aminoethyl)-phenyl, benzyl, benzyloxy, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-ethoxybenzyl, 3-ethoxybenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 3-iodobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 4-trifluoromethoxybenzyl, 4-methoxycarbonyl-benzyl, 2,3-dimethoxybenzyl, 2,4-dichlorobenzyl, 3,4-dichlorobenzyl, 2,4-difluorobenzyl, 2,5-difluorobenzyl, 3,4,5-trimethoxybenzyl, 2,4,6-trimethoxybenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, 3,4-difluorobenzyl, 3,5-di(trifluoromethyl)-benzyl, 2-phenylethyl, 2-(4-bromophenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(4-methoxyphenyl)ethyl, 2-(3,4-dimethoxyphenyl)ethyl, 2-(2-nitro-4,5-dimethoxy-phenyl)ethyl, 3-(4-morpholinyl)-n-propyl, 2-(4-morpholinyl)ethyl, 2-(4-imidazolyl)ethyl, 1-adamantanyl, 1-adamantanyl-methyl, 2-(2,5-dimethoxy-2,5-dihydro-furyl)methyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridyl-methyl, 3-pyridyl-methyl, 4-pyridyl-methyl, 2-(3,4-dimethyl-pyridyl), 2-(5-bromopyridyl), 2-(4,6-dimethyl-pyridyl), 2-(5-methyl-pyridyl), 3-(6-methoxy-pyridyl), thienylmethyl, 2-thienylethyl, 1-naphthyl, 1-naphthyl-methyl, 1-(3,4-methylenedioxyphenyl)methyl, 2-(3,4-methylenedioxyphenyl)ethyl, 2-furyl-methyl,

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2S-hydroxy-S-cyclopentyl-methyl, 2S-hydroxy-S-cyclohexyl-methyl, 2S-hydroxy-S-cycloheptyl-methyl and 2-phenoxy-ethyl. Preferably, R²is selected from the group consisting of hydrogen, methyl, methoxy, ethyl, ethoxycarbonyl-methyl, ethoxy, dimethylaminoethyl, n-butyl, n-propyl, di(n-butyl)amino-n-propyl, 3-phenyl-n-propyl, 3-(2-pyridyl)-n-propyl, 4-biphenyl, 2-ethoxyphenyl, 4-((1-phenyl-pyrazol-2-yl)-aminosulfonyl)-phenyl, 4-(aminoethyl)-phenyl, benzyl, benzyloxy, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-ethoxybenzyl, 3-ethoxybenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 3-iodobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 4-trifluoromethoxybenzyl, 4-methoxycarbonyl-benzyl, 2,3-dimethoxybenzyl, 2,4-dichlorobenzyl, 3,4-dichlorobenzyl, 2,4-difluorobenzyl, 2,5-difluorobenzyl, 3,4,5-trimethoxybenzyl, 2,4,6-trimethoxybenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, 3,4-difluorobenzyl, 3,5-di(trifluoromethyl)-benzyl, 2-phenylethyl, 2-(4-bromophenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(4-methoxyphenyl)ethyl, 2-(3,4-dimethoxyphenyl)ethyl, 2-(2-nitro-4,5-dimethoxy-phenyl)ethyl, 3-(4-morpholinyl)-n-propyl, 2-(4-morpholinyl)ethyl, 2-(4-imidazolyl)ethyl, 1-adamantanyl, 1-adamantanyl-methyl, 2-(2,5-dimethoxy-2,5-dihydro-furyl)methyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridyl-methyl, 3-pyridyl-methyl, 4-pyridyl-methyl, 2-(3,4-dimethyl-pyridyl), 2-(5-bromopyridyl), 2-(4,6-dimethyl-pyridyl), 2-(5-methyl-pyridyl), 3-(6-methoxy-pyridyl), 2-thienylethyl, 1-naphthyl, 1-naphthyl-methyl, 1-(3,4-methylenedioxyphenyl)methyl, 2-(3,4-methylenedioxyphenyl)ethyl, 2-furyl-methyl,

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2S-hydroxy-S-cyclopentyl-methyl, 2S-hydroxy-S-cyclohexyl-methyl, 2S-hydroxy-S-cycloheptyl-methyl and 2-phenoxy-ethyl.

In an embodiment of the present invention R²is selected from the group consisting of hydrogen, methyl, n-butyl, 3-hydroxy-n-propyl, 3-methoxy-n-propyl, methylamino-n-propyl, dimethylamino-n-propyl, t-butoxycarbonylamino-n-propyl, N-methyl-N-t-butoxycarbonyl-amino-n-ethyl, 3-nitrobenzyl, 4-methoxycarbonyl-benzyl, —CH(CH₃)-phenyl, 4-pyridinyl, 1-(4-ethoxycarbonyl-piperidinyl) and 2-(3H-imidazol-4-yl)-ethyl.

Preferably, R²is selected from the group consisting of hydrogen, methyl, n-butyl, 3-hydroxy-n-propyl, 3-methoxy-n-propyl, methylamino-n-propyl, dimethylamino-n-propyl, N-methyl-N-t-butoxycarbonyl-amino-n-ethyl, 3-nitrobenzyl, 4-methoxycarbonyl-benzyl, —CH(CH₃)-phenyl, 4-pyridinyl and 2-(3H-imidazol-4-yl)-ethyl.

In an embodiment of the present invention, when R¹and R²are both bound to the same nitrogen atom, R¹and R²are taken together with the nitrogen atom to which they are bound to form a heteroaryl or heterocycloalkyl group; wherein the heteroaryl or heterocycloalkyl is optionally substituted with one to three substituents independently selected from halogen, hydroxy, carboxy, C_1-4alkyl, hydroxy substituted C_1-4alkyl, C_1-4alkoxy, C_1-4alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, nitro, cyano, N(R^E)₂, phenyl, arC_1-4alkyl, heterocycloalkyl, di(C_1-4alkyl)amino-carbonyl, C_1-4alkoxycarbonylamino or phenylamino-C_1-4alkyl; wherein the phenyl or arC_1-4alkyl substituent on the heteroaryl or heterocycloalkyl group is optionally substituted with one or two substituents independently selected from halogen, hydroxy, carboxy, C_1-4alkyl, C_1-4alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, N(R^E)₂or substituted phenyl; wherein the substituents on the phenyl are one to three independently selected from halogen. Preferably, when R¹and R²are both bound to the same nitrogen atom, R¹and R²are taken together with the nitrogen atom to which they are bound to form a heteroaryl or heterocycloalkyl group; wherein the heteroaryl or heterocycloalkyl is optionally substituted with one to three substituents independently selected from halogen, hydroxy, carboxy, C_1-4alkyl, C_1-4alkoxy, C_1-4alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, nitro, cyano, N(R^E)₂, phenyl, arC_1-4alkyl, heterocycloalkyl, di(C_1-4alkyl)amino-carbonyl, or phenylamino-C_1-4alkyl; wherein the phenyl or arC_1-4alkyl substituent on the heteroaryl or heterocycloalkyl group is optionally substituted with one or two substituents independently selected from halogen, hydroxy, carboxy, C_1-4alkyl, C_1-4alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, N(R^E)₂or substituted phenyl; wherein the substituents on the phenyl are one to three independently selected from halogen.

In an embodiment of the present invention, when R¹and R²are both bound to the same nitrogen atom, R¹and R²are taken together with the nitrogen atom to which they are bound to form a group selected from heterocycloalkyl and heteroaryl; wherein the heteroaryl or heterocycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, carboxy, C_1-4alkyl, hydroxy substituted C_1-4alkyl, C_1-4alkoxy, phenyl, arC_1-4alkyl, heterocycloalkyl, C_1-4alkoxycarbonyl, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, di(C_1-4alkyl)amino-carbonyl, t-butoxycarbonyl, t-butoxycarbonylamino or phenylamino-C_1-4alkyl; wherein the phenyl or arC_1-4alkyl substituent is optionally substituted with one or two substituents independently selected from chloro, trifluoromethyl or chlorophenyl. Preferably, when R¹and R²are both bound to the same nitrogen atom, R¹and R²are taken together with the nitrogen atom to which they are bound to form a group selected from heterocycloalkyl and heteroaryl; wherein the heteroaryl or heterocycloalkyl is optionally substituted with one or more substituents independently selected from C_1-4alkyl, C_1-4alkoxy, phenyl, arC_1-4alkyl, heterocycloalkyl, C_1-4alkoxycarbonyl, di(C_1-4alkyl)amino-carbonyl or phenylamino-C_1-4alkyl; wherein the phenyl or arC_1-4alkyl substituent is optionally substituted with one or two substituents independently selected from trifluoromethyl or chlorophenyl.

In an embodiment of the present invention, when R¹and R²are both bound to the same nitrogen atom, R¹and R²are taken together with the nitrogen atom to which they are bound to form a group selected from 1-morpholinyl, 1-(4-(3-trifluoromethyl-phenyl)-piperazinyl), 1-(4-piperidinyl—piperidinyl), 1-(4-pyrrolidinyl-piperidinyl), 1-(4-phenyl-piperidinyl), 1-(3-hydroxy-piperidinyl), 1-(4-hydroxy-piperidinyl), 1-(3-hydroxymethyl-piperidinyl), 1-(3,5-dimethyl-piperidinyl), 1-(4-dimethylamino-piperidinyl), 1-(4-(3,4-methylenedioxyphenylmethyl)-piperazinyl), 1-(3-(diethylaminocarbonyl)-piperidinyl), 1-(4-t-butoxycarbonylamino-piperidinyl), 1-(2,3-dihydro-1H-pyrrolyl), 1-(4-[(4-chlorophenyl)-phenyl-methyl]-piperazinyl), 2-(1,2,3,4-tetrahydro-isoquinolinyl), 1-(4-t-butoxycarbonyl-piperazinyl), 2-(1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinolinyl), 4-(2,6-dimethyl-morpholinyl), 1-(4-benzyl-piperazinyl), 1-pyrrolidinyl, 1-(2,3,-dihydro-pyrrolidinyl), 1-(3-hydroxy-pyrrolidinyl), 1-(3-(S)-hydroxy-pyrrolidinyl), 1-piperidinyl, 1-(3-ethoxycarbonyl-piperidinyl), 1-(4-ethoxycarbonyl-piperidinyl), 1-imidazolyl, 1-(2-(phenylamino-methyl)-N-pyrrolidinyl), 1-(3-(R)-dimethylamino-pyrrolidinyl), 1-(3-(R)-hydroxy-pyrrolidinyl), 1-(3,4-dihydroxy-2,5-bis-hydrooxymethyl-pyrrolidinyl), 1-(3-(R)-t-butoxycarbonylamino-pyrrolidinyl), 1-(3-(S)-ethylamino-pyrrolidinyl), 1-(3-(R)-amino-pyrrolidinyl), 1-(3-(S)-amino-pyrrolidinyl), 1-(3-(R)-methylamino-pyrrolidinyl), 1-(3-(S)-methylamino-pyrrolidinyl), 1-(3-(N-methyl-N-t-butoxycarbonyl-amino)-pyrrolidinyl) or 1-(2-(3,5-dichlorophenyl)-3-methyl-5-carboxy-1,2,4-triazolyl). Preferably, when R¹and R²are both bound to the same nitrogen atom, R¹and R²are taken together with the nitrogen atom to which they are bound to form a group selected from 1-(4-(3-trifluoromethyl-phenyl)-piperazinyl), 1-(4-piperidinyl-piperidinyl), 1-(4-(3,4-methylenedioxyphenylmethyl)-piperazinyl), 1-(3-(diethylaminocarbonyl)-piperidinyl), 1-(2,3-dihydro-1H-pyrrolyl), 1-(4-[(4-chlorophenyl)-phenyl-methyl]-piperazinyl), 2-(1,2,3,4-tetrahydro-isoquinolinyl), 1-(4-t-butoxycarbonyl-piperazinyl), 2-(1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinolinyl), 4-(2,6-dimethyl-morpholinyl), 1-(4-benzyl-piperazinyl), 1-pyrrolidinyl, 1-piperidinyl, 1-(4-ethoxycarbonyl-piperidinyl), 1-imidazolyl and 1-(2-(phenylamino-methyl)-N-pyrrolidinyl).

In an embodiment of the present invention, when R¹and R²are both bound to the same nitrogen atom, R¹and R²are taken together with the nitrogen atom to which they are bound to form a group selected from 2-(1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinolinyl), 1-(4-[(4-chlorophenyl)-phenyl-methyl]-piperazinyl), 1-pyrrolidinyl, 1-(3-hydroxy-pyrrolidinyl), 1-(3-(R)-hydroxy-pyrrolidinyl), 1-(4-hydroxy-piperidinyl), 1-(3-(R)-dimethylamino-pyrrolidinyl), 1-(4-t-butoxycarbonylamino-pyrrolidinyl), 1-(3-(R)-t-butoxycarbonylamino-pyrrolidinyl), 1-(3-(R)-amino-pyrrolidinyl), 1-(3-(S)-amino-pyrrolidinyl), 1-(3-(R)-methylamino-pyrrolidinyl), 1-(3-(S)-ethylamino-pyrrolidinyl), 1-(4-dimethylamino-pyrrolidinyl), 1-(3-(N-methyl-N-t-butoxycarbonyl-amino-pyrrolidinyl) or 1-(2-(3,5-dichlorophenyl)-3-methyl-5-carboxy-1,2,4-triazolyl).

Preferably, when R¹and R²are both bound to the same nitrogen atom, R¹and R²are taken together with the nitrogen atom to which they are bound to form a group selected from 2-(1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinolinyl), 1-(4-[(4-chlorophenyl)-phenyl-methyl]-piperazinyl), 1-pyrrolidinyl, 1-(3-hydroxy-pyrrolidinyl), 1-(3-(R)-hydroxy-pyrrolidinyl), 1-(4-hydroxy-piperidinyl), 1-(3-(R)-dimethylamino-pyrrolidinyl), 1-(4-t-butoxycarbonylamino-pyrrolidinyl), 1-(3-(R)-t-butoxycarbonylamino-pyrrolidinyl), 1-(3-(R)-amino-pyrrolidinyl), 1-(3-(S)-amino-pyrrolidinyl), 1-(3-(S)-methylamino-pyrrolidinyl), 1-(3-(R)-methylamino-pyrrolidinyl), 1-(3-(S)-ethylamino-pyrrolidinyl), 1-(4-dimethylamino-pyrrolidinyl), 1-(3-(N-methyl-N-t-butoxycarbonyl-amino-pyrrolidinyl) or 1-(2-(3,5-dichlorophenyl)-3-methyl-5-carboxy-1,2,4-triazolyl).

In an embodiment of the present invention, n is an integer from 0 to 1, preferably n is 0. In an embodiment of the present invention m is 0. In another embodiment of the present invention m is 1.

In an embodiment of the present invention p is an integer from 0 to 2, preferably p is an integer from 0 to 1. In an embodiment of the present invention q is 0. In another embodiment of the present invention, q is 1.

In an embodiment of the present invention, R³is selected from the group consisting of aryl and arC_1-4alkyl; wherein the aryl or arC_1-4alkyl group is optionally substituted with one to three substituents independently selected from halogen, hydroxy, carboxy, C_1-4alkyl, C_1-4alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano or N(R^E)₂. Preferably, R³is aryl; wherein the aryl group is optionally substituted with one or more substituents independently selected from halogen. More preferably, R³is selected from the group consisting of phenyl and 4-fluorophenyl.

In an embodiment of the present invention, L¹is C_1-4alkyl; wherein the C_1-4alkyl group is optionally substituted with one to two substituents independently selected from hydroxy, fluoro, C_1-4alkyl, fluorinated C_1-4alkyl or C_1-4alkoxy. Preferably, L¹is unsubstituted C_1-4alkyl. More preferably, L¹is selected from the group consisting of —CH₂—, —CH(CH₃)— and —CH₂CH₂—. More preferably still, L¹is —CH₂— or —CH₂CH₂—;

In an embodiment of the present invention,

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is selected from the group consisting of partially unsaturated carbocyclyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl.

In another embodiment of the present invention,

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is selected from the group consisting of cyclooctyl, 1-acenaphthenyl, R-1-acenaphthenyl, S-1-acenaphthenyl, cyclohexyl, phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydro-naphthyl, 2-thienyl, benzothienyl, 4,5,6,7-tetrahydro-benzothienyl, bicyclo[3.1.1]hepten-2-yl, bicyclo[3.1.1]heptyl and (3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl. Preferably,

In another embodiment of the present invention,

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is selected from the group consisting of cyclooctyl, 1-acenaphthenyl, R-1-acenaphthenyl, S-1-acenaphthenyl, cyclohexyl, phenyl, 1-naphthyl and (3a-S)-2,3,3a,4,5,6-hexahydro-1H-phenalen-2-yl.

In another embodiment of the present invention,

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is selected from the group consisting of cyclooctyl, 1-naphthyl, 1-acenaphthenyl, R-1-acenaphthenyl, S-1-acenaphthenyl, bicyclo[3.1.1]hepten-2-yl and (3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl.

In an embodiment of the present invention, R⁵is selected from the group consisting of hydroxy, carboxy, halogen, C_1-4alkyl, C_1-4alkoxy, nitro, cyano, N(R^E)₂, trifluoromethyl, trifluoromethoxy, C_1-4alkoxycarbonyl, —SO—N(R^E)₂, —SO₂—N(R^E)₂and —C(O)—N(R^E)₂.

In another embodiment of the present invention, R⁵is selected from the group consisting of halogen, C_1-4alkyl and trifluoromethyl. Preferably, R⁵is selected from the group consisting of chloro, methyl, n-propyl and trifluoromethyl.

In another embodiment of the present invention, R⁵is selected from the group consisting of methyl, n-propyl, chloro and trifluoromethyl. Preferably, R⁵is selected from the group consisting of methyl, n-propyl and trifluoromethyl. More preferably, R⁵is selected from the group consisting of methyl and n-propyl. In yet another embodiment of the present invention, R⁵is methyl.

In an embodiment of the present invention R⁶is -(L²)₀-R⁷. In another embodiment of the present invention, R⁶is -(L²)—R⁷and L is selected from the group consisting of —C_1-4alkyl-, —O—, —S—, —N(R^E)—, —C(O)O— and —O—C(O)—.

In an embodiment of the present invention, R⁷is selected from the group consisting of cycloalkyl, aryl, heteroaryl and heterocycloalkyl; wherein the aryl, heteroaryl or heterocycloalkyl group is optionally substituted with one to two substituents independently selected from hydroxy, carboxy, halogen, C_1-4alkyl, C_1-4alkoxy, nitro, cyano, N(R^E)₂, trifluoromethyl, trifluoromethoxy or C_1-4alkoxycarbonyl. Preferably, R⁷is selected from the group consisting of aryl and heteroaryl. More preferably, R⁷is selected from the group consisting of phenyl and 2-thienyl. More preferably still, R⁷is 2-thienyl.

In an embodiment of the present invention is a compound of formula (I) selected from the group consisting of

8-(R)acenaphthen-1-yl-3-(3-amino-2-(S)-hydroxy-propyl)-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one;
8-(R)acenaphthen-1-yl-3-(3-amino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one;
8-(R)-Acenaphthen-1-yl-3-(3-dimethylamino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one;
3-(3-Amino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one;
3-(3-Dimethylamino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one;
8-(R)-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-[2-(R)-hydroxy-3-(3-hydroxymethyl-piperidin-1-yl)-propyl]-1,3,8-triaza-spiro[4.5]decan-4-one;
3-(3-Amino-2-(R)-hydroxy-propyl)-8-cyclooctyl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one;
3-(3-Amino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-1-(S)-(3aS)-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1,3,8-triaza-spiro[4.5]decan-4-one;
1-(4-Fluoro-phenyl)-3-[2-(R)-hydroxy-3-(3-hydroxy-propylamino)-propyl]-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one;
1-(4-Fluoro-phenyl)-3-[2-(R)-hydroxy-3-(3-methylamino-propylamino)-propyl]-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one;
3-[3-(3-Dimethylamino-propylamino)-2-(R)-hydroxy-propyl]-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one

and pharmaceutically acceptable salts thereof.

With regard to compounds of formula (E), in an embodiment of the present invention Y is selected from the group consisting of hydrogen, C_1-4alkyl and t-butoxycarbonyl, preferably, C_1-4alkyl or t-butoxycarbonyl, more preferably ethyl. In another embodiment of the present invention Y is

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Additional embodiments of the present invention, include those wherein the substituents selected for one or more of the variables defined herein (i.e. R⁰, R³, n, R⁴, m, L¹,

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p, R⁵, q, R⁶and Y) are independently selected to be any individual substituent or any subset of substituents selected from the complete list as defined herein.

As used herein, unless otherwise noted, “halogen” shall mean chlorine, bromine, fluorine and iodine.

As used herein, the term “alkyl”, whether used alone or as part of a substituent group, include straight and branched alkyl chain, preferably comprising one to eight carbon atoms. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and the like. As used herein, the term “lower alkyl” shall mean a straight or branched alkyl chain comprising one to four carbon atoms. Suitable examples of a lower alkyl group include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and the like.

As used herein, unless otherwise noted, the term “hydroxy substituted alkyl” shall mean any straight or branched alkyl chain which is substituted with one or more hydroxy groups, for example hydroxymethyl, 1-hydroxy-eth-2-yl, and the like. Preferably, the alkyl chain is substituted with one to three hydroxy groups, more prefereably one hydroxy group.

As used herein, unless otherwise noted, “alkoxy” shall denote an oxygen ether radical of the above described straight or branched chain alkyl groups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like.

As used herein, unless otherwise noted, “aryl” shall refer to unsubstituted carbocylic aromatic groups such as phenyl, naphthyl, and the like.

As used herein, unless otherwise noted, “arC_1-4alkyl” shall mean any lower alkyl group (i.e. C_1-4alkyl group) substituted with an aryl group such as phenyl, naphthyl and the like. Suitable examples of an arC_1-4alkyl group include, benzyl, 2-phenylethyl (i.e. Phenyl-CH₂—CH₂—), 3-phenyl-n-propyl (i.e. Phenyl-CH₂—CH₂—CH₂—), naphthyl-methyl, and the like.

As used herein, unless otherwise noted, the term “acyl” shall mean a radical formed from an organic acid by removal of the hydroxy group. Suitable example include acetyl, benzoyl, and the like.

As used herein, unless otherwise noted, the term “cycloalkyl” shall mean any stable three to fourteen membered monocyclic, bicyclic, tricyclic or bridged carbon based, saturated ring system, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantanyl, bicyclo[3.1.1]heptyl, and the like.

As used herein, unless otherwise noted, the term “carbocyclyl” shall mean four to fourteen membered, preferably five to thirteen membered, more preferably five to ten membered monocyclic, bicyclic or tricyclic, carbon based ring structure. Similarly, unless otherwise noted, the term “partially unsaturated carbocyclyl” shall mean any five to fourteen, preferably five to thirteen, more preferably five to ten, membered monocyclic, bicyclic or tricyclic, carbon based ring structure containing at least one unsaturated (double or triple) bond. Suitable examples of partially unsaturated carbocyclyl groups include 1,2,3,4-tetrahydronaphthyl, cyclohexen-1-yl, 1-acenaphthenyl,

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and the like.

As used herein, unless otherwise noted, “heteroaryl” shall denote any five to seven, preferably five to six, membered monocyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S; or a nine to ten membered bicyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to four additional heteroatoms independently selected from the group consisting of O, N and S. The heteroaryl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure.

Examples of suitable heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, isoindolinyl, indazolyl, benzofuryl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, and the like. Preferred heteroaryl groups include thienyl, pyridyl, furyl, imidazolyl, pyrazolyl, pyrrolyl, indolyl and quinolinyl.

One skilled in the art will recognize that wherein the heteroaryl group contains one or more nitrogen atoms, said heteroaryl group may optionally be present as or within a substituent group in a quaternary form, for example as in 1-(2-(3,5-dichlorophenyl)-3-methyl-5-carboxy-1,2,4-triazolyl), a substituent of the formula

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As used herein, the term “heterocycloalkyl” shall denote any five to seven, preferably five to six, membered monocyclic, saturated or partially unsaturated ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S; or a nine to ten membered saturated, partially unsaturated or partially aromatic bicyclic ring system containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to four additional heteroatoms independently selected from the group consisting of O, N and S. The heterocycloalkyl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure.

Examples of suitable heterocycloalkyl groups include, but are not limited to, pyrrolinyl, pyrrolidinyl, dioxalanyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, indolinyl, chromenyl, 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuryl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 4,5,6,7-tetrahydro-benzo[b]thienyl and the like. Preferred heterocycloalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydro-benzo[b]thienyl, 3,4-methylenedioxyphenyl and 3,4-dihydro-2H-benzo[b][1,4]dioxepine.

As used herein, the name “1-acenaphthenyl” shall mean a substituent group of the formula

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As used herein, the name “2-(3,4-methylenedioxyphenyl)ethyl” shall mean a substituent group of the formula

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As used herein, the name “2-(1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinolinyl)” shall mean a substituent group of the formula

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As used herein, the name “2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl shall mean a substituent group of the formula

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As used herein, the name “oxarinyl-methyl” shall mean a substituent group of the formu

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As used herein, the name “6,6-dimethyl-bicyclo[3.1.1]heptyl” shall mean a substituent group of the formula

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As used herein, the name “6,6-dimethyl-bicyclo[3.1.1]hept-2-enyl” shall mean a substituent group of the formula

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As used herein, the notation “*” shall denote the presence of a stereogenic center.

When a particular group is “substituted” (e.g., alkyl, aryl, carbocyclyl, heterocycloalkyl, heteroaryl), that group may have one or more substituents, preferably from one to five substituents, more preferably from one to three substituents, most preferably from one to two substituents, independently selected from the list of substituents.

With reference to substituents, the term “independently” means that when more than one of such substituents is possible, such substituents may be the same or different from each other.

Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. Thus, for example, a “phenylC₁–C₆alkylaminocarbonylC₁–C₆alkyl” substituent refers to a group of the formula

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Abbreviations used in the specification, particularly the Schemes and Examples, are as follows:

AcCN
Acetonitrile

BINAP
2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl

Boc
t-Butoxycarbonyl

CBz
benzyloxycarbonyl (C₆H₅—CH₂—O—C(O)—)

DAMGO
Tyr-D-Ala-Gly-N-methyl-Phe-Gly-ol

DCC
N,N-dicyclohexylcarbodiimide

DCE
Dichloroethane

DCM
Dichloromethane

DIPEA or DIEA
Diisopropylethylamine

DMF
N,N-Dimethylformamide

DME
1,2-dimethoxyethane

DMSO
Dimethylsulfoxide

DPDPE
Tyr-D-Pen-Gly-p-Chloro-Phe-D-Pen[Disulfide

Bridge: 2–5]

EDCI
1-(3-dimethylaminopropyl)-3-

ethylcarbodiimide hydrochloride

EDTA
Ethylenediaminetetraacetic acid

EGTA
Ethylene glycol-O,O′-bis(2-aminoethyl)-

N,N,N′,N′-tetracacetic acid

EtOAc
Ethyl acetate

Fmoc
9-Fluorenylmethoxycarbonyl

HBTU
O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-

tetramethyluronium hexafluorophosphate

hex
Hexane

HPLC
High Pressure Liquid Chromatography

KO-t-Bu
Potassium t-butoxide

LiHMDS
Lithium bis(trimethylsilyl)amide

mCPBA
meta-chloroperoxybenzoic acid

MeCN
Acetonitrile

Ms
mesyl or methanesulfonyl group

μW
Microwave

NaHMDS
Sodium bis(trimethylsilyl)amide

NatBuO or tBuONa
Sodium t-butoxide

NMP
N-methyl-2-pyrrolidinone

Pd₂(dba)₃
Tris(dibenzylideneacetone) dipalladium (0)

Pd(OAc)₂
Palladium (II) acetate

Pd(PPh₃)₄
tetrakis(triphenylphosphine)palladium(0)

PdCl₂(PPh₃)₂or
di(chloro)di(triphenylphosphine)palladium(0)

Pd(PPh₃)₂Cl₂

P(tBu)₃
Tri-t-butyl phosphine

PEI
Polyethylimine

TEA or Et₃N
Triethylamine

TFA
Trifluoroacetic acid

THF
Tetrahydrofuran

TLC
Thin Layer Chromatography

TNE Buffer
50 mM Tris-HCl, pH 7.4 + 5 mM EDTA +

150 mM NaCl

Tris HCl
Tris[hydroxymethyl]aminomethyl

hydrochloride

Ts
Tosyl or p-toluenesulfonyl group

U69593
(+)-(5α,7α,8β)-N-methyl-N-7-(1-pyrrolidinyl)-

1-oxaspiro[4.5]dec-8-yl] benzene acetamide

As used herein, unless otherwise noted, the term “eating disorders” shall mean any disorder associated with eating. Suitable examples include, but are not limited to anorexia nervosa, bulimia, binge eating, food cravings, and the like.

As used herein, unless otherwise noted, the term “adrenal disorders” shall mean disorders mediated by the adrenal gland. Suitable examples include, but are not limited to Cushing's syndrome, Addison's disease, and the like.

The term “subject” as used herein, refers to an animal, preferably a mammal, most preferably a human, who is or has been the object of treatment, observation or experiment.

The term “therapeutically effective amount” as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.

As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

For use in medicine, the salts of the compounds of this invention refer to non-toxic “pharmaceutically acceptable salts.” Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include the following:

acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, tosylate, triethiodide and valerate.

The compounds of formula (I) of the present invention may be prepared according to the processes described in more detail herein. More particularly, the compounds of formula (I) may be prepared through intermediates of formula (M1) or (M2), as outlined in Scheme 1.

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More particularly, a suitably substituted compound of formula (II), a known compound or compound prepared by known methods, is reacted to yield the compound of formula (M1), which is then further reacted to yield the corresponding compound of formula (I).

Alternatively, the compound of formula (II) is reacted to yield the corresponding compound of formula (M2), which is further reacted to yield the corresponding compound of formula (I).

One skilled in the art will recognize that in the processes outlined above, more particularly in the reaction of a compound of formula (II) to form the compound of formula (M1), the N atom at the 8 position of the 1,3,8-triazaspiro[4.5]decan-4-one core is preferably protected, by known methods, with a known protecting group such as BOC, Fmoc, CBz, benzoyl, benzhydryl, and the like. One skilled in the art will further recognize that when a protecting group is utilized in the preparation of the compound of formula (M1), the protecting group is removed, by known methods, prior to reacting the compound of formula (M1) to yield the compound of formula (I).

One skilled in the art will recognize that the processes hereinafter outlined in Schemes 2 to 7 incorporate the R⁰or “top” substituent portion of the molecule onto the core structure, whereas Schemes 8 to 14 incorporate the

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or “bottom” substituent portion of the molecule onto the core structure. One skilled in the art will further recognize that the top and bottom substituent portions may be incorporated into the compound of formula (I) in any order which yields the desired product.

Compounds of formula (M1) wherein R⁰is —CR^AR^B—CH(OH)—CR^CR^D—X and X is NR¹R²may be prepared from a suitably substituted compound of formula (II) according to the process outlined in Scheme 2.

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Accordingly, a suitably substituted compound of formula (II), is protected by known methods, with a suitably protecting group PG¹, such as t-butoxycarbonyl (BOC), CBz, Fmoc, benzhydryl, triphenylmethyl, 4-methoxybenzyl, benzoyl, and the like, to yield the corresponding compound of formula (III).

The compound of formula (III) is reacted with a suitable substituted compound of formula (IV) wherein Q is a suitable leaving group such as Cl, Br, I, tosylate, mesylate, and the like, a known compound or compound prepared by known methods, in the presence of a base such as NaH, KO-t-Bu, K₂CO₃, NaHMDS, LiHMDS, and the like, in an organic solvent such as NMP, DMF, THF, and the like, to yield the corresponding compound of formula (V).

The compound of formula (V) is reacted with a suitably substituted amine of formula (VI), a known compound or compound prepared by known methods, in an organic solvent such as ethanol, acetonitrile, methanol, isopropanol, and the like, to yield the corresponding compound of formula (VII).

The compound of formula (VII) is de-protected by known methods, to yield the corresponding compound of formula (M1a).

One skilled in the art will recognize that in the preparation of compounds of formula (I) and (M1a) as in Scheme 2 above (i.e. in reactions where the oxarinyl group is opened with a suitably substituted compound of formula (VI)), the stereo-configuration of the hydroxy group will be determined by the stereo-configuration of the compound of formula (IV), with the naming (R or S) of the stereo-center based on chemical nomenclature rules. Thus, for example, wherein the process outlined in Scheme 2 above R¹, R², R^A, R^B, R^Cand R^Dare each hydrogen, the compound of formula (IV) is 2-(R)-chloromethyl-oxirane, then the compound of formula (M1a) will have the hydroxy group in the (R) position.

Compounds of formula (M1a) wherein R⁰is

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may be similarly prepared according to the process outlined in Scheme 2 above, with substitution of a suitably substituted compound of formula (VII)

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wherein Q is a suitable leaving group as previously defined, a known compound or compound prepared by known methods, for the compound (IV).

Compounds of formula (M1) wherein X is —O—R¹may be prepared from a suitably substituted compound of formula (V) according to the process outlined in Scheme 3.

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Accordingly, a suitably substituted compound of formula (V), is reacted with suitably substituted compound of formula (IX), a known compound or compound prepared by known methods, in the presence of a base such as NaH, KH, sodium trimethylsilylamide, TEA, DIPEA, and the like, wherein the base is present in amount equal to or greater than about one molar equivalent, in an organic solvent such as THF, NMP, DMF, and the like, to yield the corresponding compound of formula (X).

The compound of formula (X) is de-protected, by known methods, to yield the corresponding compound of formula (M1b).

Compounds of formula (M1) wherein X is selected from the group consisting of —S—R¹, —SO—R¹or —SO₂—R¹may be prepared from a suitably substituted compound of formula (V) according to the process outlined in Scheme 4.

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Accordingly, a suitably substituted compound of formula (V) is reacted with a suitably substituted compound of formula (XI), a known compound or compound prepared by known methods, in the presence of a base such as TEA, DIPEA, and the like, in a protic solvent such as ethanol, methanol, NMP, and the like, or a mixture thereof, preferably at an elevated temperature in the range of about room temperature to about 100° C., preferably at a temperature of about 50 to about 100° C., to yield the corresponding compound of formula (XII).

The compound of formula (XII) is de-protected by known methods, to yield the corresponding compound of formula (M1c), wherein X is —S—R¹.

Alternatively, the compound of formula (XII) is oxidized with an oxidizing agent such as hydrogen peroxide, mCPBA, and the like, according to known methods, to yield the corresponding compound of formula (XIII).

The compound of formula (XIII) is de-protected by known methods, to yield the corresponding compound of formula (M1d), wherein X is —SO—R¹or —SO₂—R¹.

One skilled in the art will recognize that in the processes described in Scheme 4 above, the PG¹protecting group on the N atom at the 8-position of the 1,3,8-triazaspiro[4.5]decan-4-one is not mandatory (but may be preferred), as the reactions will yield the desired compounds even in the absence of protection of the N atom.

One skilled in the art will recognize that compounds of formula (M1) wherein X is selected from —S-(alkyl)-NR¹R², —SO-(alkyl)-NR¹R²or —SO₂— (alkyl)-NR¹R²may be similarly prepared according to the process outlined in Scheme 4 above, with substitution of a suitably substituted compound of formula (XIV)

HS-(alkyl)-NR¹R² (XIV)

a known compound or compound prepared by known methods, for the compound of formula (XI).

Compounds of formula (M1) wherein X is —NR¹—C(O)—R²may be prepared according to the process outlined in Scheme 5.

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Accordingly, a suitably substituted compound of formula (VII), wherein R¹is hydrogen, is reacted with a suitably substituted compound of formula (XV), wherein Z is Cl, Br or OH, a known compound or compound prepared by known methods, in the presence of a base such as TEA, DIPEA, pyridine, and the like, wherein the base is present in an amount equal to or greater than about one molar equivalent, in an organic solvent such as THF, DMF, NMP, DCM, and the like, preferably at room temperature, to yield the corresponding compound of formula (XVI). Wherein the compound of formula (XV) Z is OH, the compound of formula (VII) is reacted with the compound of formula (XV) in the presence of a coupling agent such as HBTU, DCC, and the like.

The compound of formula (XVI) is de-protected by known methods, to yield the corresponding compound of formula (M1e).

Compounds of formula (M1) wherein X is —C(O)—NR¹NR²may be prepared according to the process outlined in Scheme 6.

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Accordingly, a suitably substituted compound of formula (V) is reacted with potassium cyanide, in a co-solvent such as methanol-water, and the like, preferably at room temperature, to yield the corresponding compound of formula (XVII).

The compound of formula (XVII) is reacted with a base such as KOH, NaOH, and the like or with an acid such as H₂SO₄, HCl, and the like, or NaBH₄in the presence of AlCl₃, to yield the corresponding compound of formula (XVIII).

The compound of formula (XVIII) is reacted with a suitably substituted compound of formula (VI), a known compound or compound prepared by known methods, in the presence of a coupling agent such as DCC, EDCI, and the like, in an organic solvent such as CH₂Cl₂, THF, DMF, and the like, to yield the corresponding compound of formula (XIX).

The compound of formula (XIX) is de-protected by known methods, to yield the corresponding compound of formula (M1f).

Alternatively, the compound of formula (XVII) is reacted with a suitably substituted alcohol, a compound of the formula R¹—OH, a known compound or compound prepared by known methods, in the presence of an acid such as acetic acid, H₂SO₄, HCl, and the like, to yield the corresponding compound of formula (M1) wherein X is C(O)NHR¹. One skilled in the art will recognize that compounds of formula (M1) wherein X is C(O)N(R¹)₂may be similarly prepared by reacting the compound of formula (XVII) with a suitably substituted alcohol of the formula R¹—OH, in the presence of an acid such as H₂SO₄, HCl, and the like, wherein the alcohol of formula R¹—OH is present in an excess amount.

Compounds of formula (M1a) wherein R⁰is

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may alternatively be prepared according to the process outlined in Scheme 7.

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Accordingly, a suitably substituted compound of formula (III), is reacted with a suitably substituted compound of formula (XX), wherein Q is a suitable leaving group such as Cl, Br, I, tosylate, mesylate, and the like, and wherein PG²is a suitably protecting group such as benzyl, acyl, and the like, a known compound or compound prepared by known methods, in the presence of a base such as NaH, KO-t-Bu, K₂CO₃, NaHMDS, LiHMDS, and the like, in an organic solvent such as NMP, DMF, THF, and the like, to yield the corresponding compound of formula (XXI).

The compound of formula (XXI) is de-protected by known methods, to yield the corresponding compound of formula (M1a). One skilled in the art will recognize that the protecting groups PG¹and PG²on the compound of formula (XXI) may be removed simultaneously or sequentially, in any order, by known methods.

One skilled in the art will recognize, that compounds of formula (M1) wherein R⁰is selected from the group consisting of

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may be similarly prepared according to the process outlined in Scheme 7 above, with selection and substitution of a suitably substituted compound of formula (XXII)

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or the compound of formula (XXIII),

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respectively, for the compound of formula (XX).

One skilled in the art will recognize that the processes outlined in Schemes 2 to 7 above may be similarly applied to the preparation of compounds of formula (I) with substitution of a suitably substituted compound of formula (M2) for the compound of formula (II).

Compounds of formula (M2), wherein m is an integer from 0 to 1, provided that when

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is aryl or heteroaryl, then m is 1, may be prepared according to the process outlined in Scheme 8.

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Accordingly, a suitably substituted compound of formula (II), a known compound or compound prepared by known methods, is reacted with a suitably substituted compound of formula (XXIV), a known compound or compound prepared by known methods, in the presence of a base such as TEA, DIPEA, pyridine, Na₂CO₃, K₂CO₃, and the like, wherein the base is present in an amount equal to or greater than about one molar equivalent, in an organic solvent such as DMF, DMSO, NMP, and the like, to yield the corresponding compound of formula (M2).

Compounds of formula (M2) wherein m is 0 and

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is aryl or heteroaryl may be prepared according to the process outlined in Scheme 9.

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Accordingly, a suitably substituted compound of formula (II), a known compound or compound prepared by known methods, is reacted with a suitably substituted compound of formula (XXV), wherein Q is a suitable leaving group such as Cl, Br, I, triflate, and the like, a known compound or compound prepared by known methods, in the presence of a catalyst such as Pd(OAc)₂, Pd₂(dba)₃, and the like, in the presence of a phosphine ligand such as BINAP, P(tBu)₃, and the like, in the presence of a base such as Na₂CO₃, tBuONa, and the like, in an organic solvent such as toluene, dioxane, and the like, preferably at an elevated temperature in the range of about 30 to about 120° C., to yield the corresponding compound of formula (M2a).

Compounds of formula (M2) may alternatively be prepared according to the process outlined in Scheme 10.

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Accordingly, a suitably substituted compound of formula (II), a known compound or compound prepared by known methods, is reacted with a suitably substituted compound of formula (XXVI), a known compound or compound prepared by known methods, in the presence of a base such as TEA, DIPEA, pyridine, Na₂CO₃, K₂CO₃, and the like, wherein the base is present in an amount equal to or greater than about one molar equivalent, in an organic solvent such as DMF, DMSO, NMP, and the like, to yield the corresponding compound of formula (XXVII).

The compound of formula (XXVII) is reacted with a suitably substituted boronic acid, a compound of formula (XXVIII), a known compound or compound prepared by known methods, in the presence of a catalyst such as Pd(PPh₃)₄, Pd(PPh₃)₂Cl₂, and the like, in the presence of a base such as Na₂CO₃, K₃PO₄, and the like, in a non-protic organic solvent or mixture thereof, such as toluene, DME, DMF, and the like, or a mixture thereof such as toluene/ethanol, and the like, to yield the corresponding compound of formula (M2).

One skilled in the art will recognize that for compounds of formula (XXVI), the Br may alternatively be replaced with an I or triflate.

Compounds of formula (M2) wherein m is 1, L¹is C_1-6alkyl or C_3-6alkenyl, R⁶is (L²)₀-R⁷and R⁷is an aryl or heteroaryl group may be prepared according to the process outlined in Scheme 11.

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Accordingly, a suitably substituted compound of formula (II), a known compound or compound prepared by known methods, is reacted with a suitably substituted aldehyde, a compound of formula (XXIX), wherein D is C_1-5alkyl or C_2-5alkenyl, a known compound or compound prepared by known methods, in the presence of a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride, and the like, in the presence of an acid such as acetic acid, and the like, in an organic solvent such as DCE, THF, acetonitrile, and the like, to yield the corresponding compound of formula (M2a).

Compounds of formula (XXIX) may be prepared according to the processes outlined in Scheme 12.

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Accordingly, a suitably substituted compound of formula (XXX), wherein D is C_1-5alkyl or C_2-5alkenyl, a known compound or compound prepared by known methods, is reacted with a suitably substituted boronic acid, a compound of formula (XXXI), a known compound or compound prepared by known methods, in the presence of a catalyst such as Pd(PPh₃)₄, Pd(PPh₃)₂Cl₂, and the like, in the presence of a base such as Na₂CO₃, NaHCO₃, K₃PO₄, and the like, in a non-protic organic solvent or mixture thereof such as toluene, toluene/ethanol, DME, DMF, benzene, and the like, to yield the corresponding compound of formula (XXIX).

Alternatively, a suitably substituted compound of formula (XXXII), wherein D is C_1-5alkyl or C_2-5alkenyl, a known compound or compound prepared by known methods, is reacted with a suitably substituted compound of formula (XXXIII), a known compound or compound prepared by known methods, in the presence of a catalyst such as Pd(PPh₃)₄, PdCl₂(PPh₃)₂, and the like, in the presence of a base such as aqueous NaHCO₃, Na₂CO₃, K₃PO₄, and the like, in an organic solvent such as DME, DMF, toluene, benzene, and the like, to yield the corresponding compound of formula (XXIX).

One skilled in the art will recognize that for compounds of formula (XXXI) and/or compounds of formula (XXXIII), the Br may alternatively be replaced with an I or triflate.

Compounds of formula (M2) wherein q is 1, R⁶is (L²)₁-R⁷and L²is —O— may be prepared according to the process outlined in Scheme 13.

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Accordingly, a suitably substituted compound of formula (XXXIV), wherein D is C_1-5alkyl or C_2-5alkenyl, a known compound or compound prepared by known methods, is reacted with a suitably substituted alcohol, a compound of formula (XXXV), a known compound or compound prepared by known methods, in the presence of an activating agent such as tributylphosphine, triphenylphosphine, diphenyl-2-pyridylphosphine, and the like, in an anhydrous organic solvent such as benzene, THF, DCM, and the like, (via a Mitsunobu reaction) in the presence of a dehydrating agent such as 1,1′-(azodicarbonyl)dipiperidine, diethylazodicarboxylate, diisopropylazodicarboxylate, and the like, to yield the corresponding compound of formula (XXXVII).

Alternatively, the compound of formula (XXXVII) may be prepared by reacting a compound of formula (XXXIV) with a compound of formula (XXXV), wherein the hydroxy (OH) group on the compound of formula (XXXV) is replaced with a fluoro, bromo or triflate, in the presence of a base such as K₂CO₃, sodium carbonate, sodium bicarbonate, and the like, in a dipolar aprotic solvent such as (CH₃)₂NCOCH₃, DMF, DMSO, and the like.

Alternatively, the compound of formula (XXXIV) is reacted with a suitably substituted boronic acid, a compound of formula (XXXVI), a known compound or compound prepared by known methods, in the presence of a catalyst such as copper (II) acetate, and the like, in the presence of an base such as TEA, pyridine, and the like, in the presence of molecular sieves, preferably 4 Angstrom molecular sieves, in an organic solvent such as DCM, DCE, and the like, preferably at ambient temperature, to yield the corresponding compound of formula (XXXVII).

The compound of formula (XXXVII) is reacted with a suitably substituted compound of formula (II), a known compound or compound prepared by known methods, in the presence of a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride, and the like, in an organic solvent such as DCE, THF, acetonitrile, and the like, to yield the corresponding compound of formula (M2b).

One skilled in the art will recognize that compounds of formula (M2) wherein L²is —S— may similarly be prepared according to the process outlined above with appropriate selection and substitution of suitably substituted starting materials (e.g. substitution of the OH group on the compound of formula (XXXIV) with Cl or Br and substitution of a suitably substituted compound of the formula R⁷—SH for the compound of formula (XXXV), preferably in the presence of a copper catalyst, according to known methods. The sulfur group may then be further oxidized with a suitable oxidizing agent such as hydrogen peroxide, mCPBA, and the like, according to known methods, to yield the corresponding compound wherein L²is selected from —SO— or —SO₂—.

Compounds of formula (M2) wherein R⁶is -L²-R⁷and L²is C_2-4akenyl may be prepared according to the process outlined in Scheme 14.

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Accordingly, a suitably substituted compound of formula (XXXVIII), a known compound or compound prepared by known methods, is reacted with a suitably substituted boronic acid, a compound of formula (XXVIII), a known compound or compound prepared by known methods, in the presence of a catalyst such as Pd(PPh₃)₄, Pd(PPh₃)₂Cl₂, and the like, in the presence of a base such as NaHCO₃, K₂CO₃, Na₂CO₃, and the like, to yield the corresponding compound of formula (XXXIX).

The compound of formula (XXXIX) is reacted with methanesulfonyl chloride, a known compound, in the presence of an organic base such as TEA, DIPEA, N-methylmorpholine, and the like, in an aprotic solvent such as DCM, THF, acetonitrile, CHCl₃, and the like, to yield the corresponding compound of formula (XXXX), wherein Ms is a mesyl group.

The compound of formula (XXXX) is reacted with a suitably substituted compound of formula (II), a known compound or compound prepared by known methods, in the presence of a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride, and the like, in an organic solvent such as DCM, DCE, THF, methanol, acetonitrile, and the like, to yield the corresponding compound of formula (M2c).

One skilled in the art will recognize that the processes outlined in Schemes 8 to 14 above may be similarly applied to the preparation of compounds of formula (I) with substitution of a suitably substituted compound of formula (M1) for the compound of formula (II).

Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.

Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (−)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.

During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

Following the procedures described herein, representative compounds of the present invention were prepared as listed in Tables 1–8. In the Tables below, the column headed with a * shall define the stereochemical configuration of the bond denoted with the “*” symbol in the general structure at the head of the table. In addition to “R” and “S” designations, racemic mixtures will be denoted with the term “Rac”. For the

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substituent, the stereoconfiguration is racemic, unless otherwise noted with an “R” or “S”. In the columns headed (L¹)_m, a listing of “absent” shall mean that m is 0.

TABLE 1

ID #
*
R²
R³
(L¹)_m

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1
S
2-(4-morpholinyl) ethyl
4-fluorophenyl
CH₂
cyclooctyl

2
R
3,4-dimethoxy benzyl
4-fluorophenyl
CH₂
cyclooctyl

3
R
3,5-di(trifluoromethyl)benzyl
4-fluorophenyl
CH₂
cyclooctyl

4
R
2-(4-imidazolyl)ethyl
4-fluorophenyl
CH₂
cyclooctyl

5
R
4-bromobenzyl
4-fluorophenyl
CH₂
cyclooctyl

6
R
3,4-dimethoxy benzyl
4-fluorophenyl
CH₂
cyclooctyl

7
S
2,4-difluorobenzyl
4-fluorophenyl
CH₂
cyclooctyl

8
S
2,4-dimethoxy benzyl
4-fluorophenyl
CH₂
cyclooctyl

9
S
4-biphenyl
4-fluorophenyl
CH₂
cyclooctyl

10
S
2-ethoxybenzyl
4-fluorophenyl
CH₂
cyclooctyl

11
S
2-phenylethyl
4-fluorophenyl
CH₂
cyclooctyl

12
S
2,5-difluorobenzyl
4-fluorophenyl
CH₂
cyclooctyl

13
S
2-(5-bromopyridyl)
4-fluorophenyl
CH₂
cyclooctyl

14
S
2-methoxybenzyl
4-fluorophenyl
CH₂
cyclooctyl

15
S
4-bromobenzyl
4-fluorophenyl
CH₂
cyclooctyl

16
S
3,5-di(trifluoromethyl)benzyl
4-fluorophenyl
CH₂
cyclooctyl

17
S
1-adamantanyl-methyl
4-fluorophenyl
CH₂
cyclooctyl

18
S
3-methylbenzyl
4-fluorophenyl
CH₂
cyclooctyl

19
S
2-(2,5-dimethoxy-2,5-di-
4-fluorophenyl
CH₂
cyclooctyl

hydro-furyl)-methyl

20
S
3-bromobenzyl
4-fluorophenyl
CH₂
cyclooctyl

21
S
3-chlorobenzyl
4-fluorophenyl
CH₂
cyclooctyl

22
S
3,4-dimethoxy benzyl
4-fluorophenyl
CH₂
cyclooctyl

23
S
4-nitrobenzyl
4-fluorophenyl
CH₂
cyclooctyl

24
S
4-pyridyl
4-fluorophenyl
CH₂
cyclooctyl

25
S
3,5-dimethoxy-benzyl
4-fluorophenyl
CH₂
cyclooctyl

26
S
2-(2-thienyl)ethyl
4-fluorophenyl
CH₂
cyclooctyl

27
S
2-methylbenzyl
4-fluorophenyl
CH₂
cyclooctyl

28
S
2-(4-imidazolyl)-ethyl
4-fluorophenyl
CH₂
cyclooctyl

29
S
4-trifluoromethyl benzyl
4-fluorophenyl
CH₂
cyclooctyl

30
S
2-(4-bromophenyl) ethyl
4-fluorophenyl
CH₂
cyclooctyl

31
S
2,4-dichlorobenzyl
4-fluorophenyl
CH₂
cyclooctyl

32
S
3-pyridylmethyl
4-fluorophenyl
CH₂
cyclooctyl

33
S
3-trifluoromethyl benzyl
4-fluorophenyl
CH₂
cyclooctyl

34
S
2-(4-methoxy-phenyl)ethyl
4-fluorophenyl
CH₂
cyclooctyl

35
S
3-methoxybenzyl
4-fluorophenyl
CH₂
cyclooctyl

36
S
4-pyridyl
4-fluorophenyl
CH₂
cyclooctyl

38
S
2-(3,4-dimethoxy phenyl)ethyl
4-fluorophenyl
CH₂
cyclooctyl

39
S
2-pyridylmethyl
4-fluorophenyl
CH₂
cyclooctyl

40
S
1-naphthyl
4-fluorophenyl
CH₂
cyclooctyl

41
S
4-methylbenzyl
4-fluorophenyl
CH₂
cyclooctyl

42
S
2-(3,5-dimethyl-pyridyl)
4-fluorophenyl
CH₂
cyclooctyl

43
S
3,4,5-trimethoxy-benzyl
4-fluorophenyl
CH₂
cyclooctyl

44
S
2-bromobenzyl
4-fluorophenyl
CH₂
cyclooctyl

45
S
2,3-dimethoxy benzyl
4-fluorophenyl
CH₂
cyclooctyl

46
S
3,4-dichlorobenzyl
4-fluorophenyl
CH₂
cyclooctyl

47
R
2-(4-morpholinyl) ethyl
4-fluorophenyl
absent
1-acenaphthenyl

48
S
2-(3,4-dimethoxy-
4-fluorophenyl
absent
1-acenaphthenyl

phenyl)ethyl

49
S
2-(3,4-dimethoxy-phenyl)ethyl
4-fluorophenyl
absent
4-n-propyl-cyclohexyl

50
S
2-(4-morpholinyl) ethyl
4-fluorophenyl
CH₂CH₂
phenyl

51
S
2-(3,4-dimethoxy-phenyl)ethyl
4-fluorophenyl
CH₂CH₂
phenyl

52
Rac
2-(3,4-dimethoxy-phenyl)ethyl
phenyl
absent
1-acenaphthenyl

53
R
2-(4-morpholinyl) ethyl
phenyl
absent
1-acenaphthenyl

251
S
2-(4-morpholinyl) ethyl
4-fluorophenyl
CH₂
1-naphthyl

253
S
2-(3,4-dimethoxy-phenyl)ethyl
4-fluorophenyl
CH₂
1-naphthyl

254
S
2-(3,4-methylene
4-fluorophenyl
CH₂
1-naphthyl

dioxyphenyl)ethyl

255
S
2-(2-nitro-4,5-di-
4-fluorophenyl
CH₂
1-naphthyl

methoxy-phenyl) ethyl

259
S
2-(4-morpholinyl) ethyl
4-fluorophenyl
CH₂
2-naphthyl

261
S
2-(3,4-dimethoxy-phenyl)ethyl
4-fluorophenyl
CH₂
2-naphthyl

262
S
2-(3,4-methylene
4-fluorophenyl
CH₂
2-naphthyl

dioxyphenyl)ethyl

265
S
2-(4-morpholinyl) ethyl
4-fluorophenyl
CH₂
4-chlorophenyl

267
R
2-(3,4-dimethoxy-phenyl)ethyl
4-fluorophenyl
CH₂
4-chlorophenyl

268
R
2-(3,4-methylene
4-fluorophenyl
CH₂
4-chlorophenyl

dioxyphenyl)ethyl

269
R
2-(2-nitro-4,5-di-
4-fluorophenyl
CH₂
4-chlorophenyl

methoxy-phenyl) ethyl

271
R
2-(3,4-methylene
4-fluorophenyl
absent
1-acenaphthenyl

dioxyphenyl)ethyl

276
S
2-(2-nitro-4,5-di-
4-fluorophenyl
absent
1-acenaphthenyl

methoxy-phenyl) ethyl

279
S
1-(t-butoxy-carbonyl)-2-phenyl-
4-fluorophenyl
CH₂
cyclooctyl

ethyl

281
S
2-ethoxy-phenyl
4-fluorophenyl
CH₂
cyclooctyl

282
S
4-((1-phenyl-pyrazol-2-yl)-amino-
4-fluorophenyl
CH₂
cyclooctyl

sulfonyl)phenyl

285
S
4-cyclohexyl-phenyl
4-fluorophenyl
CH₂
cyclooctyl

292
S
2-(3,4-dimethoxy-phenyl)ethyl
4-fluorophenyl
CH₂
5-phenyl-2-thienyl

293
S
2-(4-morpholinyl) ethyl
4-fluorophenyl
CH₂
5-phenyl-2-thienyl

298
R
2-(4-morpholinyl) ethyl
4-fluorophenyl
absent
1-acenaphthenyl

300
R
2-(3,4-dimethoxy-phenyl)ethyl
4-fluorophenyl
absent
1-acenaphthenyl

307
S
3,4-dimethoxy-benzyl
4-fluorophenyl
absent
1-acenaphthenyl

308
S
4-nitrobenzyl
4-fluorophenyl
absent
1-acenaphthenyl

309
S
2-(1,2,3,4-tetrahydro-isoquinolinyl)
4-fluorophenyl
absent
1-acenaphthenyl

310
S
4-biphenyl
4-fluorophenyl
absent
1-acenaphthenyl

311
S
2-furylmethyl
4-fluorophenyl
absent
1-acenaphthenyl

312
S
3-iodobenzyl
4-fluorophenyl
absent
1-acenaphthenyl

314
S
3,4-difluorobenzyl
4-fluorophenyl
absent
1-acenaphthenyl

315
S
3-bromobenzyl
4-fluorophenyl
absent
1-acenaphthenyl

316
S
4-chlorobenzyl
4-fluorophenyl
absent
1-acenaphthenyl

317
S
4-methoxybenzyl
4-fluorophenyl
absent
1-acenaphthenyl

318
S
2-methoxybenzyl
4-fluorophenyl
absent
1-acenaphthenyl

319
S
3,5-di(trifluoromethyl) benzyl
4-fluorophenyl
absent
1-acenaphthenyl

320
S
3,4,5-tri-methoxybenzyl
4-fluorophenyl
absent
1-acenaphthenyl

321
S
3-fluorobenzyl
4-fluorophenyl
absent
1-acenaphthenyl

322
S
3-methoxybenzyl
4-fluorophenyl
absent
1-acenaphthenyl

323
S
2-(4-methoxy-phenyl)ethyl
4-fluorophenyl
absent
1-acenaphthenyl

324
S
3,5-dimethoxybenzyl
4-fluorophenyl
absent
1-acenaphthenyl

325
S
4-methyl-benzyl
4-fluorophenyl
absent
1-acenaphthenyl

326
S
3-(phenyl)-n-propyl
4-fluorophenyl
absent
1-acenaphthenyl

327
S
4-pyridyl
4-fluorophenyl
absent
1-acenaphthenyl

328
S
4-trifluoromethoxy benzyl
4-fluorophenyl
absent
1-acenaphthenyl

329
S
2-(phenoxy)ethyl
4-fluorophenyl
absent
1-acenaphthenyl

330
S
2-methyl-benzyl
4-fluorophenyl
absent
1-acenaphthenyl

331
S
2,3-dimethoxybenzyl
4-fluorophenyl
absent
1-acenaphthenyl

338
S
3-di(n-butyl)amino-n-propyl
4-fluorophenyl
absent
1-acenaphthenyl

341
S
2-phenylethyl
4-fluorophenyl
absent
1-acenaphthenyl

342
S
2,5-difluoro-benzyl
4-fluorophenyl
absent
1-acenaphthenyl

343
S
3,4-dichloro-benzyl
4-fluorophenyl
absent
1-acenaphthenyl

344
S
3-trifluoromethyl benzyl
4-fluorophenyl
absent
1-acenaphthenyl

345
S
benzyl
4-fluorophenyl
absent
1-acenaphthenyl

346
S
2-fluoro-benzyl
4-fluorophenyl
absent
1-acenaphthenyl

347
S
4-trifluoromethyl benzyl
4-fluorophenyl
absent
1-acenaphthenyl

348
S
4-methoxycarbonyl-benzyl
4-fluorophenyl
absent
1-acenaphthenyl

349
S
2,4-dimethoxybenzyl
4-fluorophenyl
absent
1-acenaphthenyl

350
S
3-chlorobenzyl
4-fluorophenyl
absent
1-acenaphthenyl

351
S
3-ethoxybenzyl
4-fluorophenyl
absent
1-acenaphthenyl

352
S
4-bromobenzyl
4-fluorophenyl
absent
1-acenaphthenyl

353
S
3-methylbenzyl
4-fluorophenyl
absent
1-acenaphthenyl

354
S
4-fluorobenzyl
4-fluorophenyl
absent
1-acenaphthenyl

355
S
2-bromobenzyl
4-fluorophenyl
absent
1-acenaphthenyl

356
S
2-(3,4-methylene
4-fluorophenyl
absent
1-acenaphthenyl

dioxyphenyl)ethyl

358
S
2,4-difluorobenzyl
4-fluorophenyl
absent
1-acenaphthenyl

365
S
2-(4-bromophenyl)ethyl
4-fluorophenyl
absent
1-acenaphthenyl

366
S
3-pyridyl-methyl
4-fluorophenyl
absent
1-acenaphthenyl

367
S
2,4,6-trimethoxybenzyl
4-fluorophenyl
absent
1-acenaphthenyl

368
S
2,4-dichlorobenzyl
4-fluorophenyl
absent
1-acenaphthenyl

370
S
3-nitrobenzyl
4-fluorophenyl
absent
1-acenaphthenyl

371
S
1-naphthyl-methyl
4-fluorophenyl
absent
1-acenaphthenyl

372
S
2-(2-thienyl)ethyl
4-fluorophenyl
absent
1-acenaphthenyl

373
S
2-trifluoromethyl benzyl
4-fluorophenyl
absent
1-acenaphthenyl

385
R
2-(3,4-dimethoxy-phenyl)ethyl
4-fluorophenyl
CH₂
1-(8-methyl-naphtyl)

386
S
2-(3,4-dimethoxy-phenyl)ethyl
4-fluorophenyl
CH₂
1-(8-methyl-naphtyl)

387
R
2-(4-morpholinyl) ethyl
4-fluorophenyl
CH₂
1-(8-methyl-naphtyl)

374
S

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4-fluorophenyl
absent
1-acenaphthenyl

375
S
2-(4,6-dimethyl)-pyridyl
4-fluorophenyl
absent
1-acenaphthenyl

376
S
4-pyridyl-methyl
4-fluorophenyl
absent
1-acenaphthenyl

378
R
2-pyridyl-methyl
4-fluorophenyl
absent
1-acenaphthenyl

379
R
4-pyridyl
4-fluorophenyl
absent
1-acenaphthenyl

380
R
3-(6-methoxy-pyridyl)
4-fluorophenyl
absent
1-acenaphthenyl

381
R
3-pyridyl
4-fluorophenyl
absent
1-acenaphthenyl

383
R
2-(5-methyl-pyridyl)
4-fluorophenyl
absent
1-acenaphthenyl

390
R
2-(3,4-methylene
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

dioxyphenyl)ethyl

392
R
4-methoxybenzyl
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

393
R
4-pyridyl
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

396
S
2-(4-morpholinyl) ethyl
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

398
S
4-methoxybenzyl
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

418
S
2-(3,4-methylene
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

dioxyphenyl)ethyl

419
S
2-pyridyl
4-fluorophenyl
absent
1-acenaphthenyl

420
R
H
4-fluorophenyl
absent
R-1-acenaphthenyl

421
R
2-pyridyl
4-fluorophenyl
absent
R-1-acenaphthenyl

422
S
H
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

424
S
H
4-fluorophenyl
absent
R-1-acenaphthenyl

425
R
methyl
4-fluorophenyl
absent
R-1-acenaphthenyl

426
R
H
4-fluorophenyl
absent
S-1-acenaphthenyl

427
R
methyl
4-fluorophenyl
absent
S-1-acenaphthenyl

430
S
H
4-fluorophenyl
absent
S-1-acenaphthenyl

431
S
methyl
4-fluorophenyl
absent
S-1-acenaphthenyl

437
S
methyl
4-fluorophenyl
absent
R-1-acenaphthenyl

438
R
H
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

443
S
methoxy
4-fluorophenyl
absent
R-1-acenaphthenyl

444
S
ethoxy
4-fluorophenyl
absent
R-1-acenaphthenyl

446
R
2-(3,4-methylene
4-fluorophenyl
absent
1-acenaphthenyl

dioxyphenyl)ethyl

448
S
2-phenoxyethyl
4-fluorophenyl
absent
1-acenaphthenyl

451
S
4-(1-phenyl-2-pyrazolyl-
4-fluorophenyl
CH₂
cyclooctyl

amino-sulfonyl)phenyl

452
S
4-carboxy-benzyl
4-fluorophenyl
CH₂
cyclooctyl

453
S
H
4-fluorophenyl
CH₂
cyclooctyl

454
S
n-butyl
4-fluorophenyl
CH₂
cyclooctyl

458
S
phenyl
4-fluorophenyl
CH₂
2-trifluoromethyl-6-chloro-

phenyl

461
R
2-(2-nitro-4,5-di-
4-fluorophenyl
absent
1-acenaphthenyl

methoxy-phenyl)ethyl

463
S
benzyloxy
4-fluorophenyl
absent
R-1-acenaphthenyl

464
R
4-(aminoethyl)-phenyl
4-fluorophenyl
absent
S-1-acenaphthenyl

600
S
phenyl
4-fluorophenyl
absent
R-1-acenaphthenyl

601
R
4-(t-butoxycarbonyl-
4-fluorophenyl
absent
S-1-acenaphthenyl

amino-ethyl)-phenyl

602
S
4-fluorophenyl
4-fluorophenyl
absent
R-1-acenaphthenyl

603
S
3,4-d(dimethoxy)-phenyl
4-fluorophenyl
absent
R-1-acenaphthenyl

604
S
4-(methyl)-phenyl
4-fluorophenyl
absent
R-1-acenaphthenyl

605
R
2-(aminoethyl)-phenyl
4-fluorophenyl
absent
S-1-acenaphthenyl

606
S
1-cyclopropyl
4-fluorophenyl
absent
R-1-acenaphthenyl

607
S
1-Adamantanyl
4-fluorophenyl
CH₂
3,5-bis-tri-

fluoromethyl-phenyl

608
S
4-pyridyl
4-fluorophenyl
CH₂
3,5-bis-tri-

fluoromethyl-phenyl

609
S
1-(3-pyridyl)-methyl
4-fluorophenyl
CH₂
3,5-bis-tri-

fluoromethyl-phenyl

610
S
3-di(n-butyl)amino-n-propyl
4-fluorophenyl
CH₂
3,5-bis-tri-

fluoromethyl-phenyl

611
R
1-(3-pyridyl)-methyl
4-fluorophenyl
absent
R-1-acenaphthenyl

612
S
1-(4-pyridyl)-methyl
4-fluorophenyl
absent
R-1-acenaphthenyl

613
S
1-(3-pyridyl)-methyl
4-fluorophenyl
absent
R-1-acenaphthenyl

614
S
1-(2-thienyl)-methyl
4-fluorophenyl
absent
R-1-acenaphthenyl

615
R

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4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

616
S
H
4-fluorophenyl
absent
cyclooctyl

617
S
4-pyridinyl
4-fluorophenyl
absent
cyclooctyl

618
S
4-pyridinyl
4-fluorophenyl
CH₂

embedded image

619
S
H
4-fluorophenyl
CH₂

embedded image

620
R
H
4-fluorophenyl
CH₂
cyclooctyl

621
R
4-pyridinyl
4-fluorophenyl
CH₂
cyclooctyl

622
S

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4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

623
R
H
4-fluorophenyl
absent
cyclooctyl

624
R
n-butyl
4-fluorophenyl
absent
cyclooctyl

625
R
3-nitrobenzyl
4-fluorophenyl
absent
cyclooctyl

626
R

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4-fluorophenyl
absent
cyclooctyl

627
R
4-pyridinyl
4-fluorophenyl
absent
cyclooctyl

628
R
4-methoxycarbonyl-
4-fluorophenyl
absent
cyclooctyl

benzyl

629
R
1-[2-(3H-imidazol-4-yl)-ethyl]
4-fluorophenyl
absent
cyclooctyl

630
—

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4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

631
R
C(O)O-t-butyl
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

632
R
H
4-fluorophenyl
CH(CH₃)

embedded image

633
S
dimethylamino-n-propyl
4-fluorophenyl
CH₂
cyclooctyl

634
S
3-hydroxy-n-propyl
4-fluorophenyl
CH₂
cyclooctyl

635
R
3-hydroxy-n-propyl
4-fluorophenyl
CH₂
cyclooctyl

636
R
dimethylamino-n-propyl
4-fluorophenyl
CH₂
cyclooctyl

637
S
3-hydroxy-n-propyl
4-fluorophenyl
absent
S-1-acenaphthenyl

638
S
dimethylamino-n-propyl
4-fluorophenyl
absent
S-1-acenaphthenyl

639
R
3-hydroxy-n-propyl
4-fluorophenyl
absent
S-1-acenaphthenyl

640
R
H
phenyl
absent
1S-(3a-S)-2,3,3a,4,5,6-hexa-

hydro-1H-phenalen-1-yl

641
S
3-methoxy-n-propyl
4-fluorophenyl
absent
R-1-acenaphthenyl

642
S
3-hydroxy-n-propyl
4-fluorophenyl
absent
R-1-acenaphthenyl

643
R
3-hydroxy-n-propyl
4-fluorophenyl
absent
R-1-acenaphthenyl

644
R
3-methoxy-n-propyl
4-fluorophenyl
absent
R-1-acenaphthenyl

645
R

embedded image

4-fluorophenyl
absent
R-1-acenaphthenyl

646
S

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4-fluorophenyl
absent
R-1-acenaphthenyl

647
R
dimethylamino-n-propyl
4-fluorophenyl
absent
R-1-acenaphthenyl

648
S
methyl
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

649
S
3-hydroxy-n-propyl
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

650
S
3-methoxy-n-propyl
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

651
R
3-hydroxy-n-propyl
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

652
R
3-methoxy-n-propyl
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

653
S
dimethylamino-n-propyl
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

654
S
methylamino-n-propyl
4-fluorophenyl
absent
S-1-acenaphthenyl

655
S
methylamino-n-propyl
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

656
R
methylamino-n-propyl
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

657
R
methylamino-n-propyl
4-fluorophenyl
CH₂
cyclooctyl

658
S
methylamino-n-propyl
phenyl
absent
1S-(3a-S)-2,3,3a,4,5,6-hexa-

hydro-1H-phenalen-1-yl

659
S
H
phenyl
absent
1S-(3a-S)-2,3,3a,4,5,6-hexa-

hydro-1H-phenalen-1-yl

660
R
methyl
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

661
R
methylamino-ethyl
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

662
R
1-(4-ethoxycarbonyl-
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

piperidinyl)

663
R

embedded image

4-fluorophenyl
absent
S-1-acenaphthenyl

664
R
methylamino-n-propyl
4-fluorophenyl
CH₂

embedded image

665
R
t-butoxycarbonyl-
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

amino-n-propyl

666
R
dimethylamino-n-propyl
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

667
R
N-methyl-N-t-butoxy-
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

carbonyl-amino-ethyl

TABLE 2

ID #
*
R¹
R²
R³
(L¹)_m

embedded image

54
S
n-butyl
benzyl
phenyl
absent
(3a-S)-2,3,3a,4,5,6-hexa-

hydro-1H-phenalen-2-yl

55
S
ethyl
4-methyl benzyl
4-fluorophenyl
absent
1-acenaphthenyl

56
S
t-butyl
benzyl
4-fluorophenyl
absent
1-acenaphthenyl

57
S
ethyl
4-methyl benzyl
4-fluorophenyl
absent
4-n-propyl-cyclohexyl

58
S
ethyl
4-methyl benzyl
4-fluorophenyl
CH₂CH₂
phenyl

59
S
t-butyl
benzyl
4-fluorophenyl
absent
4-n-propyl-cyclohexyl

60
S
t-butyl
benzyl
4-fluorophenyl
CH₂CH₂
phenyl

61
Rac
ethyl
4-methyl benzyl
phenyl
absent
1-acenaphthenyl

62
Rac
t-butyl
benzyl
phenyl
absent
1-acenaphthenyl

63
S
2-(dimethyl
benzyl
4-fluorophenyl
CH₂
cyclooctyl

amino)ethyl

64
S
n-butyl
benzyl
4-fluorophenyl
CH₂
cyclooctyl

65
S
benzyl
2-phenyl-ethyl
4-fluorophenyl
CH₂
cyclooctyl

78
S

embedded image

4-methyl benzyl
4-fluorophenyl
CH₂
cyclooctyl

79
S

embedded image

4-methyl benzyl
4-fluorophenyl
CH₂
cyclooctyl

250
S
t-butyl
benzyl
4-fluoro
CH₂
1-naphthyl

phenyl

252
S
ethyl
4-methyl
4-fluorophenyl
CH₂
1-naphthyl

benzyl

256
S
methyl
2-(3,4-dimeth-
4-fluorophenyl
CH₂
1-naphthyl

oxy-phenyl)ethyl

258
S
ethyl
4-methyl benzyl
4-fluorophenyl
CH₂
2-naphthyl

260
S
t-butyl
benzyl
4-fluorophenyl
CH₂
2-naphthyl

263
S
methyl
2-(3,4-di-
4-fluorophenyl
CH₂
2-naphthyl

methoxy-phenyl)ethyl

264
S
ethyl
4-methyl benzyl
4-fluorophenyl
CH₂
4-chlorophenyl

266
S
t-butyl
benzyl
4-fluorophenyl
CH₂
4-chlorophenyl

270
S
methyl
2-(3,4-di-
4-fluorophenyl
CH₂
4-chlorophenyl

methoxy-phenyl)ethyl

275
S
methyl
2-(3,4-di-
4-fluorophenyl
absent
1-acenaphthenyl

methoxy-phenyl)ethyl

280
S
n-butyl
benzyl
4-fluorophenyl
CH₂
2,3,4,5,6-penta-

methyl-phenyl

283
S
methyl
3-(2-pyridyl)-n-propyl
4-fluorophenyl
CH₂
cyclooctyl

289
S
benzyl
(1S,2S)-1-hy-
4-fluorophenyl
CH₂
cyclooctyl

droxy-cyclo-

pent-2-yl-methyl

290
S
benzyl
(1S,2S)-1-hy-
4-fluorophenyl
CH₂
cyclooctyl

droxy-cyclo-

hex-2-yl-methyl

291
S
benzyl
(1S,2S)-1-hy-
4-fluorophenyl
CH₂
cyclooctyl

droxy-cyclo-

hept-2-yl-methyl

294
S
ethyl
4-methyl benzyl
4-fluorophenyl
CH₂
5-phenyl-2-thienyl

295
Rac
methyl
2-(3,4-di-
phenyl
absent
1-acenaphthenyl

methoxy-phenyl)ethyl

299
R
t-butyl
benzyl
4-fluorophenyl
absent
1-acenaphthenyl

305
R
methyl
2-(3,4-di-
4-fluorophenyl
absent
1-acenaphthenyl

methoxy-phenyl)ethyl

313
S
benzyl
2-phenylethyl
4-fluorophenyl
absent
1-acenaphthenyl

339
R
methyl
2-(3,4-di-
4-fluorophenyl
absent
R-1-acenaphthenyl

methoxy-phenyl)ethyl

340
R
methyl
2-(3,4-di-
4-fluorophenyl
absent
S-1-acenaphthenyl

methoxy-phenyl)ethyl

362
S
benzyl
benzyl
4-fluorophenyl
absent
1-acenaphthenyl

364
S
methyl
2-(2-pyridyl)
4-fluorophenyl
absent
1-acenaphthenyl

ethyl

389
R
t-butyl
benzyl
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

391
R
methyl
2-(3,4-di-
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

methoxy-phenyl)ethyl

394
S
ethyl
4-methyl benzyl
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

395
S
t-butyl
benzyl
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

399
S
methyl
2-(3,4-di-
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

methoxy-phenyl)ethyl

423
R
methyl
methyl
4-fluorophenyl
absent
R-1-acenaphthenyl

428
R
methyl
methyl
4-fluorophenyl
absent
S-1-acenaphthenyl

429
R
methyl
ethyl
4-fluorophenyl
absent
S-1-acenaphthenyl

432
S
methyl
methyl
4-fluorophenyl
absent
S-1-acenaphthenyl

433
S
methyl
ethyl
4-fluorophenyl
absent
S-1-acenaphthenyl

434
R
methyl
ethyl
4-fluorophenyl
absent
R-1-acenaphthenyl

435
S
methyl
methyl
4-fluorophenyl
absent
R-1-acenaphthenyl

436
S
methyl
ethyl
4-fluorophenyl
absent
R-1-acenaphthenyl

439
S
methyl
methyl
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

440
S
methyl
ethyl
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

441
R
methyl
methyl
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

442
R
methyl
ethyl
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

455
S
4-methyl-benzyl
6-methylthio-2-py-
4-fluorophenyl
CH₂
cyclooctyl

ridyl-carbonyl

456
S
n-butyl
benzyl
4-fluorophenyl
CH₂
2-trifluoromethyl-6-chloro-phenyl

457
S
methyl
2-(3,4-di-
4-fluorophenyl
CH₂
2-trifluoromethyl-6-chloro-phenyl

methoxy-phenyl)ethyl

459
S
benzyl
2-(dimethyl-
4-fluorophenyl
CH₂
2-trifluoromethyl-6-chloro-phenyl

amino)ethyl

462
R
ethyl
4-methyl-benzyl
4-fluorophenyl
absent
1-acenaphthenyl

668
S
ethyl
phenyl
4-fluorophenyl
absent
R-1-acenaphthenyl

669
S
methyl
phenyl
4-fluorophenyl
absent
R-1-acenaphthenyl

670
S
ethoxy-carbonyl-methyl
benzyl
4-fluorophenyl
CH₂
3,5-bis-tri-

fluoromethyl-phenyl

671
S
n-butyl
benzyl
4-fluorophenyl
CH₂
3,5-bis-tri-

fluoromethyl-phenyl

672
S
1-phenyl-ethyl
benzyl
4-fluorophenyl
CH₂
3,5-bis-tri-

fluoromethyl-phenyl

673
S
2-(3,4-dimeth-
methyl
4-fluorophenyl
CH₂
3,5-bis-tri-

oxy-phenyl)-ethyl

fluoromethyl-phenyl

674
S
(dimethyl-amino)-ethyl
benzyl
4-fluorophenyl
CH₂
3,5-bis-tri-

fluoromethyl-phenyl

675
S
2-(3,4-di-
methyl
4-fluorophenyl
absent
cyclooctyl

methoxy-phenyl)-ethyl

676
S
benzyl
n-butyl
4-fluorophenyl
absent
cyclooctyl

677
S
benzyl
n-butyl
4-fluorophenyl
CH₂

embedded image

678
R
2-(3,4-di-
methyl
4-fluorophenyl
CH₂
cyclooctyl

methoxy-phenyl)-ethyl

679
S
t-butoxy-carbonyl
methyl
4-fluorophenyl
absent
R-1-acenaphthenyl

680
S
t-butoxy-carbonyl
methyl
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

681
R
amino-n-propyl
methyl
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

TABLE 3

ID #
*
T¹(NR¹R²taken together)

embedded image

66
S
1-(4-(3-trifluoromethyl-phenyl)-piperazinyl)
cyclooctyl-methyl

67
S
1-(4-piperidinyl-piperidinyl)
cyclooctyl-methyl

68
S
1-(4-(3,4-methylenedioxyphenyl-methyl)-
cyclooctyl-methyl

piperazinyl)

69
S
1-(3-(diethylaminocarbonyl)-piperidinyl)
cyclooctyl-methyl

70
S
1-(2,3-dihydro-1H-pyrrolyl)
cyclooctyl-methyl

71
S
1-(4-[(4-chlorophenyl)-phenylmethyl]-
cyclooctyl-methyl

piperazinyl)

72
S
2-(1,2,3,4-tetrahydro-isoquinolinyl)
cyclooctyl-methyl

73
S
1-(4-t-butoxycarbonyl-piperazinyl)
cyclooctyl-methyl

74
S
2-(1,2,3,4-tetrahydro-6,7-dimethoxy-
cyclooctyl-methyl

isoquinolinyl)

75
S
4-(2,6-dimethyl-morpholinyl)
cyclooctyl-methyl

76
S
1-(4-benzyl-piperazinyl)
cyclooctyl-methyl

115
S
2-(1,2,3,4-tetrahydro-isoquinolinyl)
2-(2-(2-thienyl)-phenyl)ethyl

160
R
1-(4-t-butoxycarbonyl-piperazinyl)
2-(2-(2-thienyl)-phenyl)ethyl

165
S
1-(4-t-butoxycarbonyl-piperazinyl)
2-(2-(2-thienyl)-phenyl)ethyl

166
S
2-(1,2,3,4-tetrahydro-6,7-dimethoxy-
2-(2-(2-thienyl)-phenyl)ethyl

isoquinolinyl)

181
R
2-(1,2,3,4-tetrahydro-6,7-dimethoxy-
2-(2-(2-thienyl)-phenyl)ethyl

isoquinolinyl)

183
R
1-pyrrolidinyl
2-(2-(2-thienyl)-phenyl)ethyl

188
R
1-(4-ethoxycarbonyl-piperidinyl)
2-(2-(2-thienyl)-phenyl)ethyl

257
S
2-(1,2,3,4-tetrahydro-6,7-dimethoxy-
2-(2-(2-thienyl)-phenyl)ethyl

isoquinolinyl)

284
S
1-(2S-(phenylamino-methyl)-
cyclooctyl-methyl

pyrrolidinyl)

682
S
2-(1,2,3,4-tetrahydro-isoquinolinyl)
3,5-bis-trifluoromethyl-benzyl

683
S
1-[4-(3-trifluoromethyl-phenyl)-
3,5-bis-trifluoromethyl-benzyl

piperazinyl]

684
S
1-(4-ethoxycarbonyl-piperidinyl)
3,5-bis-trifluoromethyl-benzyl

685
S
1-(2,3-dihydro-pyrrolidinyl)
3,5-bis-trifluoromethyl-benzyl

686
S
3-(diethylaminocarbonyl)-piperidinyl
3,5-bis-trifluoromethyl-benzyl

687
S

embedded image

cyclooctyl

688
R
1-(3,4-dihydroxy-2,5-bis-hy-
cyclooctyl

droxymethyl-pyrrolidinyl)

689
R
2-(1,2,3,4-tetrahydro-6,7-dimethoxy-
cyclooctyl

isoquinolinyl)

690
R

embedded image

cyclooctyl

TABLE 4

ID #
*
T²(NR¹R²taken together)

embedded image

296
R
2-(1,2,3,4-tetrahydro-6,7-dimethoxy-
1-acenaphthenyl

isoquinolinyl)

332
S
1-(4-benzyl-piperazinyl)
1-acenaphthenyl

333
S
1-(4-(3-trifluoromethyl-phenyl)-
1-acenaphthenyl

piperazinyl)

334
S
1-(4-(1-piperidinyl)-piperidinyl)
1-acenaphthenyl

335
S
1-(4-(3,4-methylenedioxyphenyl-
1-acenaphthenyl

methyl)-piperazinyl)

336
S
1-(3-(diethylaminocarbonyl)-
1-acenaphthenyl

piperidinyl)

337
S
1-(4-[(4-chlorophenyl)-phenyl-
1-acenaphthenyl

methyl]-piperazinyl)

360
S
1-(4-ethoxycarbonyl-piperidinyl)
1-acenaphthenyl

377
S
2-(1,2,3,4-tetrahydro-6,7-dimethoxy-
1-acenaphthenyl

isoquinolinyl)

382
R
1-imidazolyl
1-acenaphthenyl

388
S
2-(1,2,3,4-tetrahydro-6,7-di-
1-(8-methyl-naphthyl)

methoxy-isoquinolinyl)

445
R
2-(1,2,3,4-tetrahydro-6,7-dimethoxy-
1-acenaphthenyl

isoqinolinyl)

465
S
1-piperidinyl
R-1-acenaphthenyl

691
S
1-morpholinyl
R-1-acenaphthenyl

692
S
1-pyrrolidinyl
R-1-acenaphthenyl

693
R
1-(4-ethoxycarbonyl-piperidinyl)
R-1-acenaphthenyl

694
R
1-(4-phenyl-piperidinyl)
R-1-acenaphthenyl

695
R
1-(3-hydroxymethyl-piperidinyl)
R-1-acenaphthenyl

696
R
1-(3-ethoxycarbonyl-piperidinyl)
R-1-acenaphthenyl

697
R
1-piperidinyl
R-1-acenaphthenyl

698
R
1-pyrrolidinyl
R-1-acenaphthenyl

699
S
1-(3,5-dimethyl-piperidinyl)
R-1-acenaphthenyl

700
S
1-(4-phenyl-piperidinyl)
R-1-acenaphthenyl

701
S
1-(4-ethoxycarbonyl-piperidinyl)
R-1-acenaphthenyl

702
S
1-(3-hydroxymethyl-piperidinyl)
R-1-acenaphthenyl

703
R
1-(3,5-dimethyl-piperidinyl)
R-1-acenaphthenyl

704
S
1-pyrrolidinyl
1-(8-methyl-naphthyl)

705
R
1-pyrrolidinyl
1-(8-methyl-naphthyl)

706
R
1-(3-(R)-hydroxy-pyrrolidinyl)
1-(8-methyl-naphthyl)

707
R
1-(3-hydroxy-piperidinyl)
1-(8-methyl-naphthyl)

708
R
1-(3-(R)-dimethylamino-pyrrolidinyl)
1-(8-methyl-naphthyl)

709
R
1-(4-hydroxy-piperidinyl)
1-(8-methyl-naphthyl)

710
R
1-(3-(R)-t-butoxycarbonylamino-
1-(8-methyl-naphthyl)

pyrrolidinyl)

711
R
1-(4-t-butoxycarbonylamino-
1-(8-methyl-naphthyl)

piperidinyl)

712
R
1-(3-hydroxy-pyrrolidinyl)
1-(8-methyl-naphthyl)

713
R
1-(4-pyrrolidinyl-piperidinyl)
1-(8-methyl-naphthyl)

714
R
1-(3-(S)-hydroxy-pyrrolidinyl)
1-(8-methyl-naphthyl)

715
R
1-((3-(S)-ethylamino)pyrrolidinyl)
1-(8-methyl-naphthyl)

716
R
1-(3-(R)-amino-pyrrolidinyl)
1-(8-methyl-naphthyl)

717
R
1-(3-(S)-amino-pyrrolidinyl)
1-(8-methyl-naphthyl)

718
R
1-(4-dimethylamino-piperidinyl)
1-(8-methyl-naphthyl)

719
R
1-(3-(R)-methylamino-pyrrolidinyl)
1-(8-methyl-naphthyl)

720
R
1-(3-(S)-methylamino-pyrrolidinyl)
1-(8-methyl-naphthyl)

721
R
1-(3-(N-methyl-N-t-butoxycarbonyl-
1-(8-methyl-naphthyl)

amino)-pyrrolidinyl)

TABLE 5

ID #
*
R³
(L¹)_m

embedded image

100
R
4-fluorophenyl
CH₂
cyclooctyl

101
S
4-fluorophenyl
absent
1-acenaphthenyl

102
R
4-fluorophenyl
CH₂CH₂
phenyl

103
R
4-fluorophenyl
absent
4-n-propyl-cyclohexyl

104
Rac
phenyl
absent
1-acenaphthenyl

179
R
phenyl
CH₂CH₂
2-(2-thienyl)-phenyl

447
R
4-fluorophenyl
CH₂
cyclooctyl

TABLE 6

ID #
*
X
R³
(L¹)_m

embedded image

105
R
2-(3,4-dimethyoxyphenyl)-ethyloxy
4-fluorophenyl
CH₂
cyclooctyl

106
R
2-(3,4-dimethoxyphenyl)-ethyloxy
phenyl
CH₂CH₂
2-(2-thienyl)-phenyl

107
R
3-methylphenylthio
phenyl
CH₂CH₂
2-(2-thienyl)-phenyl

108
R
3-methylphenylthio
4-fluorophenyl
CH₂
cyclooctyl

178
S

embedded image

phenyl
CH₂CH₂
2-(2-thienyl)-phenyl

460
R

embedded image

4-fluorophenyl
CH₂
cyclooctyl

TABLE 7

ID

No.
*
R¹
R²

110
Rac
H
3-(4-morpholinyl)-n-propyl

111
S
H
3-(4-morpholinyl)-n-propyl

112
R
H
3-(4-morpholinyl)-n-propyl

113
S
H
3-chlorobenzyl

114
S
H
2-ethoxybenzyl

116
S
H
(2,5-dimethoxy-2,5-dihydro-fur-2-yl)-

methyl

117
S
n-butyl
benzyl

118
S
H
2,5-difluorobenzyl

119
S
H
2-phenyl-ethyl

120
S
H
2-(5-bromo-pyridyl)

121
S
H
3-iodobenzyl

122
S
H
2,2,2-trifluoroethyl

123
S
H
3-nitrobenzyl

124
S
H
3,4-difluorobenzyl

125
S
H
3-bromobenzyl

126
S
H
4-chlorobenzyl

127
S
H
4-methoxybenzyl

128
S
H
3,4,5-trimethoxybenzyl

129
S
H
2-(2-thienyl)ethyl

130
S
H
3-methylbenzyl

131
S
H
2-methoxybenzyl

132
S
H
benzyl

133
S
H
4-bromobenzyl

134
S
H
3,5-di(trifluoromethyl)benzyl

135
S
H
2-(3-methoxyphenyl)ethyl

136
S
benzyl
2-phenylethyl

137
R
H
2-bromobenzyl

138
R
H
2-(4-bromophenyl)ethyl

139
R
H
4-(N,N-dimethylamino)benzyl

140
R
H
4-methylbenzyl

141
R
H
2-methylbenzyl

142
R
H
2-(6-fluoro-2-indolyl)ethyl

143
R
H
3-fluorobenzyl

144
R
H
3-methoxybenzyl

145
R
H
2-(4-methoxyphenyl)ethyl

146
R
H
2-trifluoromethylbenzyl

147
R
H
2-(4-imidazolyl)ethyl

148
R
H
3,5-dimethoxybenzyl

149
R
H
t-butyl

150
R
H
2-pyridyl-methyl

151
R
H
2-(3,4-dimethoxyphenyl)ethyl

152
R
H
2-fluorobenzyl

153
R
H
3-trifluoromethylbenzyl

154
R
H
4-pyridyl

155
R
H
4-trifluoromethoxybenzyl

156
R
H
2-phenyloxy-ethyl

157
R
H
1-naphthyl-methyl

158
R
H
4-fluorobenzyl

159
R
H
4-trifluoromethylbenzyl

161
R
H
4-pyridyl-methyl

162
R
H
2,4-dichlorobenzyl

163
S
H

embedded image

164
S
benzyl
benzyl

167
S
H
1-(3,4-methylene

dioxyphenyl)methyl

168
S
benzyl
ethoxycarbonylmethyl

169
S
H
2-phenyl-cyclopropyl

170
S
H
4-methoxycarbonylbenzyl

171
S
benzyl
2-(N,N-dimethylamino)ethyl

173
S
methyl
benzyl

174
S
ethyl
benzyl

175
R
benzyl
carboxymethyl

176
R
benzyl
2-(N,N-dimethylamino)ethyl

177
R
n-butyl
benzyl

180
R
H
2-phenyl-cyclopropyl

182
R
H
4-methoxycarbonylbenzyl

187
R
H
2-(2,5-dimethoxy-2,5-dihydro-fur-2-

yl)-methyl

189
R
H
2,4-dimethoxybenzyl

190
R
H
4-biphenyl

191
R
benzyl
ethoxycarbonylmethyl

192
R
H
4-methoxybenzyl

193
S
H
2-methylbenzyl

194
S
H
3,5-dimethoxybenzyl

197
S
H
4-pyridyl

198
S
H
2,4-dichlorobenzyl

203
S
H
3,4-dimethoxybenzyl

204
R
H
4-bromobenzyl

205
R
H
3-methylbenzyl

206
R
H
2-(2-thienyl)-ethyl

208
S
H
3-nitrobenzyl

209
S
H
2-bromobenzyl

210
S
H
2-(4-imidazolyl)-ethyl

211
S
H
2-(phenoxy)-ethyl

215
S
H
2,3-dimethoxybenzyl

216
S
H

embedded image

217
S
H
adamantanyl

218
S
H
n-propyl

219
S
n-propyl
n-propyl

220
S
benzyl
benzyl

224
S
H
3-methoxybenzyl

225
S
H
3-pyridyl-methyl

227
S
H
2,4-difluorobenzyl

228
R
H
2-methoxybenzyl

229
S
H
3-(phenyl)-n-propyl

230
S
benzyl
2-phenylethyl

TABLE 8

ID #
*
R²
R³
(L¹)m

embedded image

722
S
H
4-fluorophenyl
absent
R-1-acenaphthenyl

Representative intermediates in the preparation of the compounds of the present invention are as listed in Tables 9 and 10. Wherein Table 9, A is listed as oxarinyl-methyl with no indication of the stereo-configuration, the oxarinyl-methyl group was present as racemate.

TABLE 9

ID #
A
R³
(L¹)m

embedded image

500
H
4-fluorophenyl
absent
1-acenaphthenyl

501
H
4-fluorophenyl
CH₂—CH(CH₃)—CH₂
phenyl

502
H
4-fluorophenyl
CH₂CH₃

503
H
4-fluorophenyl
CH₂CH₂
phenyl

504
H
4-fluorophenyl
absent
4-n-propyl-cyclohexyl

505
H
4-fluorophenyl
C(O)O-t-butyl

506
H
4-fluorophenyl
CH₂
2-naphthyl

507
H
4-fluorophenyl
CH₂
1-naphthyl

508
H
4-fluorophenyl
CH₂
4-chlorophenyl

521
H
4-fluorophenyl
CH₂
4-quinolinyl

522
H
4-fluorophenyl
CH₂
8-quinolinyl

544
H
4-fluorophenyl
absent
1,3,4-trihydro-2-naphthyl

546
H
4-fluorophenyl
CH₂
5-phenyl-2-thienyl

547
H
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

548
H
4-fluorophenyl
CH₂
1-(4-methyl-naphthyl)

549
H
4-fluorophenyl
absent
2-hydroxy-cycloheptyl

551
H
4-fluorophenyl
CH₂
1-(2-methyl-naphthyl)

555
H
4-fluorophenyl
absent
R-1-acenaphthenyl

556
H
4-fluorophenyl
absent
S-1-acenaphthenyl

509
oxiranylmethyl
phenyl
absent
1-acenaphthenyl

510
R-oxiranylmethyl
4-fluorophenyl
absent
4-n-propyl-cyclohexyl

511
R-oxiranylmethyl
4-fluorophenyl
CH₂CH₂
phenyl

512
oxiranylmethyl
4-fluorophenyl
absent
1-acenaphthenyl

513
R-oxiranylmethyl
4-fluorophenyl
CH₂
4-chlorophenyl

514
R-oxiranylmethyl
4-fluorophenyl
CH₂
1-naphthyl

516
R-oxiranylmethyl
4-fluorophenyl
C(O)O-t-butyl
absent

517
S-oxiranylmethyl
4-fluorophenyl
O(O)O-t-butyl
absent

518
oxiranylmethyl
phenyl
CH₂CH₂
2-(2-thienyl) phenyl

519
S-oxiranylmethyl
phenyl
CH₂CH₂
2-(2-thienyl) phenyl

520
R-oxiranylmethyl
phenyl
CH₂CH₂
2-(2-thienyl) phenyl

540
R-oxiranylmethyl
4-fluorophenyl
CH₂
cyclooctyl

541
R-oxiranylmethyl
4-fluorophenyl
CH₂
5-phenyl-2-thienyl

542
S-oxiranylmethyl
4-fluorophenyl
CH₂
2-naphthyl

543
S-oxiranylmethyl
4-fluorophenyl
CH₂CH₃
absent

550
S-oxiranylmethyl
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

552
methoxy-
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

carbonyl methyl

553
R-oxiranylmethyl
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

554
R-2,3-dihydroxy-
4-fluorophenyl
CH₂
1-(8-methyl-naphthyl)

n-propyl

564
S-oxiranylmethyl
4-fluorophenyl
absent
R-1-acenaphthenyl

565
R-oxiranylmethyl
4-fluorophenyl
absent
R-1-acenaphthenyl

566
S-oxiranylmethyl
4-fluorophenyl
absent
S-1-acenaphthenyl

567
R-oxiranylmethyl
4-fluorophenyl
absent
S-1-acenaphthenyl

568
2R-hydroxy-3-
4-fluorophenyl
absent
1-acenaphthenyl

ethoxy-n-propyl

569
2R-hydroxy-3-
4-fluorophenyl
absent
S-1-acenaphthenyl

ethoxy-n-propyl

570
2S-hydroxy-3-
4-fluorophenyl
absent
R-1-acenaphthenyl

ethoxy-n-propyl

571
2R-hydroxy-3-
4-fluorophenyl
absent
R-1-acenaphthenyl

ethoxy-n-propyl

572
H
4-fluorophenyl
CH₂

embedded image

573
H
4-fluorophenyl
CH₂
3-(2H)-chromenyl

576
oxiranylmethyl
phenyl
absent
1-acenaphthenyl

578
R-oxiranylmethyl
4-fluorophenyl
CH₂
2-trifluoromethyl-6-

chloro-phenyl

579
3-chloro-2S-
4-fluorophenyl
absent
R-1-acenaphthenyl

hydroxy-n-propyl

580
S-oxiranylmethyl
4-fluorophenyl
CH₂
cyclooctyl

581
H
phenyl
CH₂CH₂
2-(2-thienyl)-phenyl

582
H
4-fluorophenyl
CH₂
cyclooctyl

583
H
4-fluorophenyl
CH₂
2,3,4,5,6-

pentamethyl-phenyl

584
R-oxiranylmethyl
4-fluorophenyl
CH₂
2,3,4,5,6-

pentamethyl-phenyl

723
R-oxiranylethyl
4-fluorophenyl
absent
R-1-acenaphthenyl

725
R-oxiranylmethyl
4-fluorophenyl
CH₂
2,3,4,5,6-

pentamethylphenyl

726
H
4-fluorophenyl
CH₂

embedded image

727
R-oxiranylmethyl
4-fluorophenyl
CH₂

embedded image

728
H
4-fluorophenyl
CH₂
1-(8-methyl-1,2,3,4-

tetrahydro-naphthyl)

729
H
4-fluorophenyl
CH(CH₃)

embedded image

730
H
4-fluorophenyl
absent

embedded image

731
S-oxiranylmethyl
4-fluorophenyl
absent
cyclooctyl

732
H
4-fluorophenyl
CH₂

embedded image

733
H
4-fluorophenyl
CH₂
1-[8-methoxy)-naphthyl]

734
H
4-fluorophenyl
CH₂
1-[8-hydroxymethyl)-naphthyl]

735
H
4-fluorophenyl
absent
cyclooctyl

TABLE 10

ID #
*
R¹
R²
W

523
R
ethyl
4-methylbenzyl
H

524
R
H
2-(4-morpholinyl)-ethyl
H

525
R
t-butyl
benzyl
H

526
R
H
2-(3,4-dimethoxy-phenyl)-ethyl
H

527
R
H
2-(3,4-methylenedioxy phenyl)-ethyl
H

528
R
H
2-(2-nitro-4,5-dimethoxy-phenyl)-ethyl
H

529
S
ethyl
4-methylbenzyl
H

530
S
H
2-(4-morpholinyl)-ethyl
H

531
S
t-butyl
benzyl
H

532
S
H
2-(3,4-dimethoxy-phenyl)-ethyl
H

533
S
H
2-(3,4-methylenedioxy phenyl)-ethyl
H

534
S
H
2-(2-nitro-4,5-dimethoxy-phenyl)-ethyl
H

535
S
ethyl
4-methylbenzyl
t-butoxy-

carbonyl

536
R
ethyl
4-methylbenzyl
ethyl

537
R
H
2-(4-morpholinyl)-ethyl
ethyl

538
R
t-butyl
benzyl
ethyl

539
R
H
2-(3,4-dimethoxy-phenyl)-ethyl
ethyl

Molecular weights for representative compounds of the present invention exemplified in Tables 1–10 above were measured using a Micromass Platform LC-Electrospray Mass Spectrometer, Chemical Ionization Spectrometer HP5989A or Agilent LC/MSD Electrospray Mass Spectrometer with results listed in Table 11.

TABLE 11

ID #
Theor. MW
M/e[MH+]

1
559.77
560.8

2
596.78
597.7

3
672.73
673.6

4
540.72
541.7

5
615.63
617.9

6
610.81
611.8

7
572.71
573.3

8
596.78
597.5

9
598.8
599.5

10
580.78
581.5

11
550.76
551.5

12
572.71
573.5

13
602.60
604.3

14
566.76
567.5

15
615.60
617.4

16
672.73
673.5

17
594.85
595.5

18
550.76
551.5

19
588.76
589.5

20
615.63
617.4

21
571.18
571.5

22
596.78
597.5

23
581.73
582.5

24
537.72
538.4

25
596.78
597.2

26
556.79
557.4

27
550.76
552.4

28
540.72
541.5

29
604.73
605.5

30
629.65
630.5

31
605.62
607.3

32
537.72
538.4

33
604.73
605.4

34
566.76
567.5

35
566.76
567.7

36
523.69
523.9

38
610.81
611.5

39
537.72
538.5

40
586.79
587.4

41
550.76
551.4

42
551.75
551.5

43
626.81
627.4

44
615.63
616.4

45
596.78
597.3

46
605.62
607.4

47
587.70
588.3

48
638.70
639.3

49
610.81
611.4

50
539.63
540.3

51
590.74
591.3

52
621.00
622.0

53
569.00
570.0

54
620.88
621.5

55
606.70
607.3

56
620.80
621.3

57
578.81
579.5

58
558.74
559.3

59
592.84
593.4

60
572.77
573.3

61
588.00
589.0

62
602.00
603.0

63
607.28
608.3

64
592.84
593.5

65
640.88
641.5

66
659.81
660.1

67
597.86
598.2

68
649.85
650.1

69
613.86
614.3

70
498.68
499.5

71
716.38
717.4

72
562.77
563.5

73
615.83
616.4

74
622.82
623.2

75
544.75
545.4

76
605.84
606.2

78
649.89
650.2

79
750.01
751.5

100
592.77
593.8

101
620.70
621.3

102
572.70
573.3

103
592.77
593.3

104
602.70
603.0

105
611.79
612.4

106
655.86
656.4

107
597.84
598.4

108
553.78
554.6

110
617.85
618.3

111
617.85
618.3

112
617.85
618.3

113
615.24
615.3

114
624.85
625.3

115
606.83
607.3

116
632.82
633.3

117
636.90
637.4

118
616.78
617.3

119
594.80
595.3

120
646.65
648.2

121
706.68
707.2

122
572.69
573.3

123
625.79
626.3

124
616.77
617.3

125
659.68
661.2

126
615.30
615.3

127
610.82
611.3

128
670.87
671.3

129
600.85
601.2

130
594.82
595.3

131
610.82
611.3

132
580.79
581.2

133
659.69
661.2

134
716.79
717.2

135
624.85
625.3

136
684.94
685.3

137
659.69
661.2

138
673.72
675.3

139
623.86
624.4

140
594.82
595.4

141
594.82
595.4

142
651.85
652.3

143
598.78
599.3

144
610.82
611.3

145
624.85
625.3

146
648.80
649.3

147
584.76
585.3

148
640.85
641.3

149
546.77
547.3

150
581.78
582.3

151
654.87
655.5

152
598.78
599.3

153
648.79
649.3

154
567.75
568.3

155
664.79
665.3

156
610.82
611.3

157
630.85
631.3

158
598.78
599.3

159
648.80
649.3

160
659.89
660.4

161
581.78
582.3

162
649.68
651.1

163
759.11
759.1

164
670.82
671.4

165
659.89
660.5

166
666.88
667.4

167
624.80
625.4

168
666.88
667.4

169
606.83
607.5

170
638.83
639.4

171
651.92
653.0

173
594.80
595.8

174
608.85
609.9

175
638.83
639.6

176
651.92
652.9

177
636.90
637.6

178
694.91
695.8

179
636.90
637.6

180
606.83
607.9

181
666.88
667.8

182
638.83
639.8

183
544.76
545.7

187
632.82
633.9

188
630.85
631.9

189
640.85
641.9

190
642.86
643.8

191
666.88
667.8

192
610.82
611.9

193
594.82
595.8

194
640.85
641.9

197
567.75
568.8

198
649.68
651.6

203
640.85
641.7

204
659.69
662.0

205
594.82
595.9

206
600.85
601.7

208
625.79
626.8

209
659.69
661.2

210
584.79
585.8

211
610.82
611.8

215
640.85
641.7

216
759.11
759.7

217
638.92
639.8

218
532.75
533.6

219
574.83
575.9

220
670.92
671.7

224
610.82
611.8

225
581.78
582.7

227
616.78
617.7

228
610.82
611.8

229
608.85
609.7

230
684.94
685.7

250
608.79
609.3

251
575.72
576.3

252
594.76
595.3

253
626.76
627.3

254
610.72
611.2

255
671.76
672.3

256
640.79
641.4

257
638.77
639.3

258
594.76
595.3

259
575.72
576.3

260
608.79
609.3

261
626.76
627.3

262
610.72
611.2

263
640.78
641.4

264
579.15
579.3

265
560.10
560.2

266
593.17
593.3

267
611.15
691.2

268
595.10
595.2

269
656.14
656.2

270
625.17
625.3

271
622.72
623.2

275
652.80
653.4

276
683.79
684.3

279
650.88
651.3

280
628.88
629.2

281
566.77
567.5

282
743.95
744.1

283
565.75
566.4

284
605.85
605.9

285
604.86
605.3

289
634.89
635.3

290
648.91
649.2

291
662.94
663.3

292
658.84
659.2

293
607.80
608.3

294
626.84
627.3

295
634.82
635.4

296
650.80
651.3

298
587.74
588.3

299
620.82
621.4

300
638.79
639.3

305
652.82
653.3

307
624.76
625.3

308
609.71
610.3

309
619.79
620.3

310
626.78
627.3

311
554.67
555.4

312
690.61
691.2

313
668.86
669.3

314
600.69
601.3

315
643.61
643.6

316
599.15
599.2

317
594.74
595.3

318
594.74
595.3

319
700.71
701.2

320
654.79
655.3

321
582.70
583.3

322
594.74
595.3

323
608.76
609.3

324
624.76
625.3

325
578.74
579.3

326
592.76
593.4

327
551.67
552.3

328
648.71
649.3

329
594.74
595.3

330
578.74
579.0

331
624.76
625.3

332
633.82
634.3

333
687.79
688.3

334
625.84
626.4

335
677.83
678.3

336
641.84
642.5

337
744.36
744.3

338
643.90
644.4

339
652.82
653.4

340
652.82
653.4

341
578.74
579.3

342
600.69
601.3

343
633.60
633.2

344
632.71
634.0

345
564.71
565.3

346
582.70
583.3

347
632.71
634.0

348
622.75
623.2

349
624.76
625.3

350
599.15
599.2

351
608.76
609.3

352
643.10
643.2

353
578.74
579.3

354
584.72
583.3

355
643.61
645.2

356
608.72
609.0

358
600.69
601.0

360
614.77
615.0

362
654.84
655.3

364
593.75
594.2

365
657.63
659.2

366
565.70
566.2

367
654.79
655.3

368
633.60
635.2

370
609.71
610.3

371
614.77
615.3

372
584.76
595.3

373
632.71
633.3

374
743.03
743.6

375
579.72
580.3

376
565.70
566.2

377
650.80
651.3

378
551.67
552.2

379
551.67
552.2

380
581.70
582.2

381
551.67
552.3

382
525.63
526.2

383
565.70
566.2

385
640.81
641.4

386
640.81
641.4

387
589.76
590.4

388
652.82
653.4

389
622.83
623.4

390
624.76
625.3

391
654.83
655.3

392
596.75
597.3

393
553.69
554.2

394
608.81
609.4

395
622.83
623.4

396
589.76
590.4

398
596.75
597.3

399
654.83
655.3

418
624.76
625.3

419
551.67
552.3

420
474.58
475.2

421
551.67
552.3

422
476.6
477.3

423
502.64
503.3

424
474.58
475.2

425
488.61
489.3

426
474.58
475.2

427
488.61
489.3

428
502.64
503.3

429
516.66
517.3

430
474.58
475.2

431
488.61
489.3

432
502.64
503.3

433
516.66
517.3

434
516.66
517.3

435
502.64
503.3

436
516.66
517.3

437
488.61
489.3

438
476.6
477.3

439
504.65
505.4

440
518.68
519.3

441
504.65
505.4

442
518.68
519.3

443
504.61
505.2

444
518.64
519.3

445
650.80
651.3

446
622.75
623.2

447
592.78
593.4

448
594.74
595.3

451
743.95
744.1

452
580.75
581.5

453
446.61
447.9

454
502.72
503.2

455
701.95
702.0

456
661.19
662.5

457
693.19
694.0

458
591.05
592.0

459
676.20
677.4

460
564.77
565.2

461
683.79
684.3

462
606.79
607.3

463
580.71
581.3

464
593.75
594.3

465
542.70
543.3

500
401.49
402.2

501
367.47
368.2

502
277.34
278.2

503
353.44
354.2

504
373.52
374.2

505
349.41
372.0

506
389.48
390.1

507
389.48
390.1

508
373.86
374.1

509
439.56
440.2

510
409.51
410.2

511
429.58
430.3

512
457.55
458.3

513
429.93
430.2

514
445.54
446.3

516
405.47
428.3

517
405.47
428.3

518
473.65
474.1

519
473.65
474.1

520
473.65
474.1

521
390.45
391.2

522
390.45
391.0

523
454.58
455.0

524
435.54
436.0

525
468.61
469.0

526
486.58
487.0

527
470.54
471.0

528
531.58
532.0

529
454.48
544.0

530
435.54
436.0

531
468.61
469.0

532
486.58
488.0

533
470.54
471.0

534
531.58
532.0

535
554.70
555.3

536
482.65
483.3

537
463.60
464.3

538
496.67
497.4

539
514.65
515.2

540
429.58
430.5

541
477.61
478.2

542
445.54
446.3

543
333.41
334.2

544
379.48
380.2

546
421.54
422.1

547
403.50
404.2

548
403.50
404.2

549
361.46
362.3

550
459.57
460.2

551
403.50
404.2

552
475.57
476.2

553
459.57
460.2

554
477.58
478.2

555
401.49
402.1

556
401.49
402.1

564
457.55
458.3

565
457.55
458.3

566
457.55
458.3

567
457.55
548.3

568
503.62
504.3

569
503.62
504.3

570
503.62
504.3

571
503.62
504.3

572
411.48
412.2

573
393.47
394.2

576
439.56
458.3

578
497.92
498.9

579
494.01
494.2

581
417.58
418.1

582
373.52
374.1

583
409.55
410.5

584
465.62
466.1

600
550.68
551.7

601
693.87
694.9

602
568.67
569.7

603
610.74
611.7

604
564.71
565.7

605
593.75
594.8

606
514.65
515.7

607
696.76
697.8

608
625.59
626.6

609
639.62
640.6

610
717.82
718.8

611
565.7
566.7

612
565.7
566.7

613
565.7
566.7

614
570.73
571.7

615
692.76
693.8

616
432.59
433.6

617
509.67
510.7

618
533.7
534.7

619
456.61
457.6

620
446.61
447.6

621
523.7
524.7

622
692.76
693.8

623
432.59
433.6

624
488.69
489.7

625
567.71
568.7

626
701.03
702.0

627
509.67
510.7

628
580.75
581.8

629
526.7
527.7

630
658.86
659.9

631
576.72
577.7

632
496.65
497.7

633
531.76
532.8

634
504.69
505.7

635
504.69
505.7

636
531.76
532.8

637
532.66
533.7

638
559.73
560.7

639
532.73
533.7

640
474.65
475.7

641
546.69
547.7

642
532.66
533.7

643
532.66
533.7

644
546.69
547.7

645
690.74
691.7

646
690.74
691.7

647
559.73
560.7

648
490.63
491.6

649
534.68
535.7

650
548.71
549.7

651
534.68
535.7

652
235.13
236.1

653
430.5
431.5

654
545.71
546.7

655
547.72
548.7

656
547.72
548.7

657
517.74
518.7

658
545.77
546.8

659
474.65
475.7

660
490.63
491.6

661
533.7
534.7

662
631.8
632.8

663
578.74
579.7

664
529.75
530.8

665
633.81
634.8

666
561.75
562.8

667
633.80
634.2

668
578.74
579.7

669
564.71
565.7

670
724.73
725.7

671
694.74
695.7

672
742.79
743.8

673
726.74
727.7

674
709.76
710.8

675
610.82
611.8

676
578.82
579.8

677
602.84
603.8

678
564.74
565.7

679
645.82
646.8

680
647.84
648.8

681
547.72
548.7

682
664.67
665.7

683
761.71
762.7

684
688.69
689.7

685
600.58
601.6

686
715.76
716.8

687
688.66
689.7

688
578.73
579.7

689
608.8
609.8

690
702.36
703.4

691
544.68
545.7

692
528.68
529.7

693
614.77
615.8

694
618.8
619.8

695
572.73
573.7

696
614.77
615.8

697
542.7
543.7

698
528.68
529.7

699
570.76
571.8

700
618.8
619.8

701
614.77
615.8

702
572.73
573.7

703
570.76
571.8

704
530.69
531.7

705
530.69
531.7

706
546.69
547.7

707
560.72
561.7

708
573.76
574.8

709
560.72
561.7

710
645.82
646.8

711
659.85
660.9

712
546.69
547.7

713
613.83
614.8

714
546.60
647.7

715
573.76
574.8

716
545.71
546.7

717
545.71
546.7

718
587.79
588.8

719
559.73
560.7

720
559.73
560.7

721
659.85
660.9

722
488.61
489.6

723
471.58
472.6

725
465.62
466.6

726
383.51
384.5

727
439.58
440.6

728
407.54
408.5

729
423.56
424.6

730
385.51
386.5

731
415.56
416.6

732
385.53
386.4

733
433.53
434.5

734
419.5
420.5

735
359.49
360.5

The present invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the composition may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 5 to about 1000 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions, include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.

The method of treating disorders mediated by the ORL-1 receptor described in the present invention may also be carried out using a pharmaceutical composition comprising any of the compounds as defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain between about 1 mg and 1000 mg, preferably about 10 to 500 mg, of the compound, and may be constituted into any form suitable for the mode of administration selected. Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings. Compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixers, emulsions, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.

Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

The liquid forms may include suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.

The compound of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phophatidylcholines.

The compound of the present invention can also be administered via transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyl-eneoxidepolylysine substituted with palmitoyl residue. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.

Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of disorders mediated by the ORL-1 receptor is required.

The daily dosage of the products may be varied over a wide range from 1 to 1,000 mg per adult human per day. For oral administration, the compositions are preferably provided in the form of tablets containing, 0.5, 1.0, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.01 mg/kg to about 30 mg/kg of body weight per day. Preferably, the range is from about 0.1 mg/kg to about 10 mg/kg of body weight per day, and especially from about 0.5 mg/kg to about 10 mg/kg of body weight per day. The compounds may be administered on a regimen of 1 to 4 times per day.

Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.

The following Examples are set forth to aid in the understanding of the invention, and are not intended and should not be construed to limit in any way the invention set forth in the claims which follow thereafter.

EXAMPLE 1
2-Thienylphenyl-2-ethanol

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3-Bromophenethyl alcohol (4 ml, 29.8 mmol) was dissolved in 1,2-dimethoxyethane (225 mL) and mixed with tetrakistriphenylphosphine palladium[0] (2.6 g, 2.25 mmol) at room temperature. The reaction mixture was then added to a solution of 2-thienyl-boronic acid (12.6 g, 99 mmol) and 1 N NaHCO₃(90 mL). The reaction mixture was heated to reflux under nitrogen atmosphere for 48 hours. The reaction mixture was partitioned with water and ethyl acetate. The organic layer was dried with MgSO₄, filtered through a plug of silica and the solvent was evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (30% EtOAc/hexane) to yield the title compounds as an oil.

MS (chemical ionization)=221 (M+NH₄)

¹H NMR (300 MHz, CDCl₃) δ 1.3 (t, 1H), 3.0 (t, 2H), 3.75 (q, 2H), 7.0–7.4 (m, 7H)

EXAMPLE 2
Methane sulfonic acid 2-(2-thien-2-yl-phenyl)-ethyl ester

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2-Thienylphenylethanol (13.6 mmol) and triethylamine (2.4 mL, 17.1 mmol) were dissolved in dichloromethane (50 mL). Methanesulfonylchloride 1.1 mL, 14 mmol) was then added slowly. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was carefully partitioned with water and dichloromethane. The organic layer was dried with Na₂SO₄, filtered and the solvent evaporated in vacuo to yield the title compounds, which was used without further purification.

MS (chemical ionization)=300 (M+NH₄), 283 (MH+), 187,

¹H NMR (300 MHz, CDCl₃) δ 2.8 (s, 3H), 3.2 (t, 2H), 4.3 (t, 2H), 7.0 (m, 1H), 7.1 (m, 1H), 7.2–7.5 (m, 5H)

EXAMPLE 3
1-Phenyl-8-[2-(2-thien-2-yl-phenyl)-ethyl]-1,3,8-triaza-spiro[4.5]decan-4-one Compound #581

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Methane sulfonic acid 2-(2-thien-2-yl-phenyl)-ethyl ester (23.14 mmol) was combined in NMP (100 mL) with 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one (5.08 g, 22 mmol) and DIPEA (5.11 mL, 27.8 mmol) in a reaction tube which was sealed and heated to 70° C. overnight. The reaction mixture was partitioned with water and ethyl acetate. The organic layer was dried with MgSO₄, filtered and the solvent was evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (5% methanol/CH₂Cl₂) to yield the title compound as a solid.

MS (electrospray)=418.1 (MH+), 313.0

¹H NMR (300 MHz, DMSO-d₆) δ 1.5 (d, 2H), 2.4 (m, 4H), 2.6 (m, 4H), 2.85 (m, 2H), 4.55 (s, 2H), 6.7–6.8 (m, 3H), 7.1–7.4 (m, 8H), 7.6 (s, 1H), 8.65 (s, 1H)

EXAMPLE 4
(R)-3-Oxiranylmethyl-1-phenyl-8-[2-(2-thien-2-yl-phenyl)-ethyl]-1,3,8-triaza-spiro[4.5]decan-4-one Compound #520

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1-Phenyl-8-[2-(2-thien-2-yl-phenyl)-ethyl]-1,3,8-triaza-spiro[4.5]decan-4-one (0.7 g, 1.68 mmol) was dissolved in NMP (50 mL). To the mixture was then added sodium hydride (60% in mineral oil, 0.1, 2.52 mmol) and the reaction mixture stirred for 1 hour. S-(+)-epichlorohydrin (0.15 mL, 1.9 mmol) was then added to the reaction mixture. The reaction mixture was stirred overnight at room temperature. The reaction mixture was partitioned with saturated sodium bicarbonate and ethyl acetate. The organic layer was then partitioned with water. The organic layer was dried with MgSO₄, filtered and the solvent was evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (80% EtOAc/hex) to yield the title compound as an oil.

MS (electrospray)=474.1 (MH+)

¹H NMR (300 MHz, CDCl₃) δ 1.6 (t, 2H), 2.5–3.0 (m, 12H), 3.1–3.2 (m, 2H), 4.05 (d, 1H), 4.7 (d, 1H), 4.8 (d, 1H), 6.8 (m, 2H), 7.0 (m, 1H), 7.2–7.4 (m, 9H).

EXAMPLE 5
3-[2-(S)-Hydroxy-3-(3-morpholin-4-yl-propylamino)-propyl]-1-phenyl-8-[2-(2-thien-2-yl-phenl)-ethyl]-1,3,8-triaza-spiro[4.5]decan-4-one Compound #111

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3-(R)-Oxiranylmethyl-1-phenyl-8-[2-(2-thien-2-yl-phenyl)-ethyl]-1,3,8-triaza-spiro[4.5]decan-4-one (0.1 g, 0.21 mmol) was dissolved in absolute ethanol (2 mL), mixed with 3-aminopropyl morpholino (90 μl, 0.63 mmol) and heated to 70° C. overnight. The solvent was evaporated and the resulting residue was purified by reverse phase chromatography (AcCN/water) to yield the title compounds as a trifluoroacetate salt, as a solid.

MS (electrospray)=618.3 (MH+)

¹H NMR (300 MHz, CD₃OD) δ 2.0 (d, 2H), 2.2 (m, 2H), 2.72–2.88 (m, 2H), 3.0–4.3 (m, 23H), 4.8–5.05 (m, 6H), 6.8–7.5 (m, 12H).

EXAMPLE 6
(S)-3-Oxiranylmethyl-1-phenyl-8-[2-(2-thienyl-phenyl)-ethyl]-1,3,8-triazaspiro[4,5]decan-4-one Compound #519

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1-Phenyl-8-[2-(2-thienyl-phenyl)-ethyl]-1,3,8-triazaspiro[4.5]decan-4-one (0.13 g, 0.3 mmol) was dissolved in NMP (10 mL). To the mixture was then added sodium hydride (60% in mineral oil, 31 mg, 0.8 mmol) and the reaction mixture stirred for 1 hour. R-(−)-epichlorohydrin 927 μL, 0.35 mmol) was then added to the reaction mixture, which was then stirred overnight at room temperature. The reaction mixture was partitioned with saturated sodium bicarbonate and ethyl acetate. The organic layer was then partitioned with water. The organic layer was dried with MgSO₄, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (80% EtOAc/hexanes) to yield the title compound as an oil.

MS (electrospray)=474.1 (MH+)

¹H NMR (300 MHz, CDCl₃) δ 1.65 (t, 2H), 2.0 (q, 1H), 2.4 (t, 1H), 2.5–3.0 (m, 11H), 3.2 (m, 1H), 3.3 (t, 1H), 4.0 (d, 1H), 4.7 (d, 1H), 4.8 (d, 1H), 6.9 (m, 2H), 7.0 (m, 1h), 7.15–7.4 (m, 9H).

EXAMPLE 7
3-[2-(R)-hydroxy-3-(3-morpholin-4-yl-propylamino)-propyl]-1-phenyl-8-[2-(2-thien-2-yl-phenyl)-ethyl]-1,3,8-triazaspiro[4.5]decan-4-one Compound #112

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3-(S)-Oxiranylmethyl-1-phenyl-8-[2-(2-thien-2-yl-phenyl)-ethyl]-1,3,8-triazaspiro[4.5]decan-4-one (0.13 g, 0.27 mmol) was dissolved in absolute ethanol (2 mL), mixed with 3-aminopropylmorpholino (100 μL, 0.68 mmol) and heated with stirring at 70° C. overnight. The solvent was evaporated and the resulting residue was purified by reverse phase chromatography (Acetonitrile/water) to yield the title compound as a trifluoroacetate salt as a solid.

MS (electrospray)=618.3 (MH+)

¹H NMR (300 MHz, CD₃OD) δ 2.0 (d, 2H), 2.2 (m, 2H), 2.75–2.9 (m, 2H), 3.0–4.3 (m, 23H), 4.8–5.05 (m, 6H), 6.8–7.5 (m, 12H).

EXAMPLE 8
1-bromo-acenaphthene

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Acenaphthen-1-ol (88 mol) was dissolved in diethyl ether (150 mL) and cooled down to 0° C. Phosphorous tribromide (3.2 mL, 35 mmol) was then added slowly under nitrogen atmosphere. The reaction mixture was stirred for 30 minutes at room temperature and cooled to 0° C. The reaction mixture was partitioned with water and diethyl ether. The organic layer was dried over Na₂SO₄, filtered and the solvent evaporated in vacuo to yield the title compound as a yellow solid.

EXAMPLE 9
8-Acenaphthen-1-yl-1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one Compound # 500

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1-Bromo-acenaphthene (20.5 g, 87.9 mmol) and 1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one (9.15 g, 36.6 mmol) were dissolved in N,N-dimethylformamide (190 mL). Potassium carbonate (15.15 g, 110 mmol) was then added and the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. The reaction mixture was partitioned with water and diethyl ether. The title compound precipitated from the organic layer as an off-white solid.

¹H NMR (300 MHz, CDCl₃) δ 7.68–7.66 91H, m), 7.60 (1H, d, J=8.2 Hz), 7.53–7.49 (2H, m), 7.43 (1H, t, J=8.1 Hz), 7.26 (1H, d, J=7.8 Hz), 7.04–6.94 (4H, m), 6.67 (1H, br, s), 4.95 (1H, br, s), 4.66–4.63 (2H, m), 3.51 (1H, d), 3.34 (1H, dd J=7.6 and 17.5 Hz), 3.13–2.94 (2H, m), 2.83 (1H, br, s), 2.43 (1H, br, a), 2.24 (1H, m), 1.80–1.66 (3H, m)

MS (ES⁺) m/z 402.1 (M+H)⁺

Chiral resolution: The racemate prepared as described above was resolved using a CHIRALCEL OD-H column with methanol as mobile phase and generated the two pure enantiomers R (RT=6.174 minutes, ee>99%) and S(RT=10.175 minutes, ee>99%).

EXAMPLE 10
1-(4-fluorophenyl)-8-(2-hydroxy-cycloheptyl)-1,3,8-triazaspiro[4.5]decan-4-one Compound #549

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1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one (0.15 g, 0.6 mmol) was dissolved in dichloromethane (1 mL) and 1,2-dichloromethane (0.25 mL) under a nitrogen atmosphere. The reaction mixture was then added slowly at 0° C. to 1.9M triethyl aluminum in toluene (0.315 mL, 0.6 mmol). After stirring for 30 minutes at room temperature, to the reaction mixture was added slowly a solution of 8-oxa-bicyclo[5.1.0]octane (68 mg, 0.6 mmol) in dichloromethane (16 mL). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 13 days and then partitioned with 1N NaOH and DCM. The organic layer was dried over Na₂SO₄, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (2% methanol/DCM) to yield the title compound as an oil.

¹H NMR (300 MHz, CDCl₃) δ 7.05–6.88 (4H, m), 4.69 (s, 2H), 3.44–3.31 (2H, m), 2.96–2.88 (1H, m), 2.73–2.69 (1H, m), 2.56–2.53 (1H, m), 2.42–2.17 (3H, m), 2.11–2.02 (1H, m), 1.94–1.87 (1H, m), 1.78 (1H, d), 1.72–1.19 (11H, m)

MS (ES⁺) m/z 362.3 (M+H)⁺.

EXAMPLE 11
(R)-8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-(R)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one Compound #556

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(R)-8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (1.5 g, 3.736 mmol) was dissolved in N,N-dimethylformamide (10.0 mL). To the reaction mixture was then added at 0° C. sodium hydride (60% in mineral oil, 0.195 g, 4.856 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 40 minutes and then warmed to room temperature. To the reaction mixture was then added (S)-epichlorhydrin (0.87 mL, 11.208 mmol). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 18 hours and partitioned with water and ethyl acetate. The organic layer was dried with Na₂SO₄, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (1.5% methanol/dichloromethane) to yield the title compound as a foam.

¹H NMR (300 MHz, CDCl₃) δ 7.70–7.65 (1H, m), 7.60 (1H, d, J=8.2 Hz), 7.54–7.49 (2H, m), 7.44 (1H, t), 7.26 (1H, d), 7.05–6.93 (4H, m), 4.95 (1H, dd, J=3.4 and 7.8 Hz), 4.77–4.74 (1H, m), 4.66–4.64 (1H, m), 4.0 (1H, d, J=12.5 Hz), 3.56–3.32 (2H, m), 3.21–3.03 (4H, m), 2.83–2.80 (2H, m), 2.59–2.55 (1H, m), 2.46–2.30 (2H, m), 2.27–2.21 (1H, m), 1.77–1.60 (2H, m)

MS (ES⁺) m/z 458.3 (M+H)⁺.

EXAMPLE 12
(R)-8-Acenaphthen-1-yl-3-(3-{[2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-amino}-(R)-2-hydroxy-propyl)-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one Compound #339

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8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-(S)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one (1.5 g, 3.28 mmol), [2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-amine hydrochloride (2.3 g, 9.92 mmol) and N,N-diisopropylethylamine (5 mL, 28.7 mmol) were dissolved in ethanol (40 mL). The reaction mixture was heated at 80° C. for 18 hours, then cooled to room temperature and the solvent evaporated in vacuo to yield an oil. The oil was partitioned with water and ethyl acetate. The organic layer was dried with Na₂SO₄, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (2% [methanol in ammonia 2.0M]/dichloromethane) to yield the title compound as a foam.

Chiral resolution: Diastereoisomers were separated using a CHIRALCEL OD-H column with methanol as mobile phase and generated the two pure diastereoisomers R, R and R, S.

¹H NMR (300 MHz, CDCl₃) δ 7.69–7.65 (1H, m), 7.60 (1H, d, J=8.2 Hz), 7.54–7.50 (2H, m), 7.44 (1H, t), 7.27–7.25 (1H, m), 7.04–6.92 (4H, m), 6.77–6.64 (3H, m), 4.97–4.94 (1H, m), 4.79–4.71 (2H, m), 3.82 (3H, s), 3.81 (3H, s), 3.58–3.51 (3H, m), 3.38–3.02 (5H, m), 2.84–2.80 (1H, m), 2.77–2.53 (4H, m), 2.49–2.26 (7H, m), 1.76–1.59 (2H, m)

MS (ES⁺) m/z 653.4 (M+H)⁺.

EXAMPLE 13
1-(4-Fluoro-phenyl)-8-naphthalen-1-ylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one Compound #507

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1-(4-Fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (1.0 g, 4.01 mmol) and naphthalene-1-carbaldehyde (0.75 g, 4.81 mmol) were dissolved in dry tetrahydrofuran (60 mL). To the reaction mixture was then added at 0° C. sodium triacetoxyborohydride (1.27 g, 6.01 mmol) under nitrogen atmosphere and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then partitioned with 1N NaOH and ethyl acetate. The organic layer was washed with brine, dried with Na₂SO₄, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (3% methanol/dichloromethane) to yield the title compound as a solid.

¹H NMR (300 MHz, CDCl₃) δ 8.39–8.36 (1H, m), 7.87–7.75 (2H, m), 7.56–7.37 (4H, m), 6.99–6.85 (4H, m), 4.67 (2H, s), 3.97 (2H, s), 2.91–2.83 (4H, m), 2.42–2.31 (2H, m), 1.75–1.71 (2H, m)

MS (ES⁺) m/z 390.1 (M+H)⁺.

EXAMPLE 14
1-(4-Fluoro-phenyl)-8-naphthalen-1-ylmethyl-(R)-3-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one Compound #514

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(R)-1-(4-Fluoro-phenyl)-8-naphthalen-1-ylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one (0.218 g, 0.559 mmol) was dissolved in N,N-dimethylformamide (2.2 mL). To the reaction mixture was then added at 0° C. sodium hydride (60% in mineral oil, 30 mg, 0.727 mmol) under nitrogen atmosphere and the reaction mixture was stirred at 0° C. for 40 minutes. To the reaction mixture was then added (S)-epichlorhydrin (0.13 mL, 1.679 mmol) at 0° C. The reaction mixture was stirred at room temperature under nitrogen atmosphere for 18 hours and partitioned with water and ethyl acetate. The organic layer was washed with brine, dried with Na₂SO₄, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (2% methanol/dichloromethane) to yield the title compound as a solid.

¹H NMR (300 MHz, CDCl₃) δ 8.38–8.35 (1H, m), 7.87–7.75 (2H, m), 7.56–7.37 (4H, m), 6.99–6.86 (4H, m), 4.78–4.65 (2H, m), 4.08–3.97 (3H, m), 3.21–3.12 (2H, m), 2.95–2.82 (5H, m), 2.61–2.59 (1H, m), 2.40–2.30 (2H, m), 1.72–1.59 (2H, m)

MS (ES⁺) m/z 446.3 (M+H)⁺.

EXAMPLE 15
1-(4-Fluoro-phenyl)-8-(5-phenyl-thien-2-ylmethyl)-1,3,8-triaza-spiro[4,5]decan-4-one Compound #546

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1-(4-Fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (0.15 g, 0.601 mmol) and 5-phenyl-thienyl-2-carbaldehyde (0.136 g, 0.722 mmol) were dissolved in dry tetrahydrofuran (12 mL). To the reaction mixture was then added at 0° C. sodium triacetoxyborohydride (0.192 g, 0.902 mmol) under nitrogen atmosphere and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned with 1 N NaOH and ethyl acetate. The organic layer was washed with brine, dried with Na₂SO₄, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (2% methanol/dichloromethane) to yield the title compound as a solid.

¹H NMR (300 MHz, CDCl₃) δ 7.59–7.56 (2H, m), 7.38–7.33 (2H, m), 7.27–7.22 (1H, m), 7.18–7.13 (1H, m), 7.05–6.92 (4H, m), 6.87 (1H, d, J=3.6 Hz), 6.26 (1H, br s), 4.67 (2H, s), 3.75 (2H, s), 2.87–2.78 (4H, m), 2.40–2.30 (2H, m), 1.76 (2H, d, J=14.1 Hz)

MS (ES⁺) m/z 422.1 (M+H)⁺.

EXAMPLE 16
(R)-1-(4-Fluoro-phenyl)-3-oxiranylmethyl-8-(5-phenyl-thien-2-yl-methyl)-1,3,8-triaza-spiro[4.5]decan-4-one Compound #541

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1-(4-Fluoro-phenyl)-8-(5-phenyl-thien-2-yl-methyl)-1,3,8-triaza spiro[4.5]decan-4-one (0.105 g, 0.249 mmol) was dissolved in N,N-dimethylformamide (2.5 mL). To the reaction mixture was then added at 0° C. sodium hydride (60% in mineral oil, 13 mg, 0.323 mmol) under nitrogen atmosphere and the reaction mixture was stirred at 0° C. for 40 minutes. To the reaction mixture was then added (S)-epichlorhydrin (0.058 mL, 0.747 mmol) at 0° C. The reaction mixture was stirred at room temperature under nitrogen atmosphere for 18 hours and partitioned with water and ethyl acetate. The organic layer was washed with brine, dried with Na₂SO₄, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (2% methanol/dichloromethane) to yield the title compound as a solid.

¹H NMR (300 MHz, CDCl₃) δ 7.59–7.55 (2H, m), 7.38–7.33 (2H, m), 7.27–7.22 (1H, m), 7.14 (1H, d, J=3.6 Hz), 7.05–6.92 (4H, m), 6.87 (1H, d, J=3.5 Hz), 4.77 (1H, d, J=4.8 Hz), 4.66 (1H, d, J=4.8 Hz), 4.06–3.99 (1H, m), 3.76 (2H, s), 3.20–3.13 (2H, m), 2.95–2.82 (3H, m), 2.60–2.58 (1H, m), 2.38–2.30 (2H, m), 1.75–1.67 (2H, m)

MS (ES⁺) m/z 478.2 (M+H)⁺.

EXAMPLE 17
1-(4-Fluoro-phenyl)-8-(4-propyl-cyclohexyl)-1,3,8-triaza-spiro[4.5]decan-4-one Compound #504

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1-(4-Fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (0.25 g, 1.00 mmol) was dissolved in dry toluene (10 mL). To the reaction mixture was then added 4-propyl-cyclohexanone (0.14 g, 1.00 mmol), powder molecular sieve 4A (0.5 g) and the reaction mixture was refluxing for 18 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered through Celite. The Celite cake was washed with dry dichloromethane and the combined filtrate evaporated in vacuo to dryness. The residue was dissolved in dry tetrahydrofuran (4 mL) and dry methanol (0.5 mL). To the solution was then added sodium cyanoborohydride (21 mg), the pH of the solution was adjusted to pH 4 with a few drops of glacial acetic acid and the reaction mixture was stirred for 48 hours at room temperature under nitrogen atmosphere. The reaction mixture was partitioned with 1N NaOH and ethyl acetate. The organic layer was dried with Na₂SO₄, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (gradient 2–4% methanol/dichloromethane) to yield the title compound.

¹H NMR (300 MHz, CDCl₃) δ 7.02–6.93 (4H, m), 6.54 (1H, br d, J=9.1 Hz), 4.67 (2H, s), 3.05–2.70 (4H, m), 2.38–2.15 (3H, m), 1.9–1.11 (15H, m), 0.94–0.84 (3H, m)

MS (ES⁺) m/z 374.0 (M+H)⁺.

EXAMPLE 18
1-Bromomethyl-8-methyl-naphthalene

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1,8-Dimethyl-naphthalene (1.30 g, 8.32 mmol) was dissolved in dry carbon tetrachloride (80 mL). To the reaction mixture was added N-bromosuccinimide (1.39 g, 7.82 mmol), dibenzoyl peroxide (6 mg, catalyst) and the reaction mixture was refluxing for 6 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature, a precipitate formed on cooling and the precipitate was separated by filtration. The filtrate was evaporated in vacuo to yield the title compound as a solid which was used in further steps without additional purification.

EXAMPLE 19
1-(4-Fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]-decan-4-one Compound #547

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1-Bromomethyl-8-methyl-naphthalene (1.72 g, 7.31 mmol) and 1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (1.29 g, 5.17 mmol) were dissolved in N,N-dimethylformamide (50 mL). Potassium carbonate (2.4 g, 15.52 mmol) and potassium iodide (0.02 g) were added and the reaction mixture was stirred at 30° C. under nitrogen atmosphere for 18 hours. The reaction mixture was partitioned with water and ethyl acetate. The organic layer was washed with brine, dried with Na₂SO₄, filtered and the solvent evaporated in vacuo to yield a crude solid. The crude solid was recrystallized from diethyl ether to yield the title compound as a solid.

¹H NMR (300 MHz, CDCl₃) δ 7.79–7.76 (1H, m), 7.72–7.69 (1H, m), 7.39–7.30 (4H, m), 6.98–6.92 (2H, m), 6.87–6.82 (2H, m), 6.24 (1H, br s), 4.66 (2H, s), 4.01 (2H, s), 3.12 (3H, s), 2.86–2.78 (4H, m), 2.33–2.23 (2H, m), 1.72 (2H, d, J=14.1 Hz)

MS (ES⁺) m/z 404.2 (M+H)⁺.

EXAMPLE 20
1-(4-Fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-3-(R)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one Compound #553

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1-(4-Fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]-decan-4-one (0.91 g, 2.25 mmol) was dissolved in N,N-dimethylformamide (10.5 mL). To the reaction mixture was then added at 0° C. sodium hydride (60% in mineral oil, 117 mg, 2.93 mmol) under nitrogen atmosphere and the reaction mixture was stirred at 0° C. for one hour, then warmed to room temperature. To the reaction mixture was then added (S)-epichlorhydrin (0.53 mL, 6.76 mmol). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 18 hours and partitioned with water and ethyl acetate. The organic layer was washed with brine, dried with Na₂SO₄, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (2.5% methanol/dichloromethane) to yield the title compound as a foam.

¹H NMR (300 MHz, CDCl₃) δ 7.78–7.75 (1H, m), 7.71–7.68 (1H, m), 7.39–7.30 (4H, m), 6.99–6.92 (2H, m), 6.88–6.83 (2H, m), 4.76 (1H, d, J=4.8 Hz), 4.64 (1H, d, J=4.8 Hz), 4.0 (2H, s), 3.21–3.11 (6H, m), 2.86–2.78 (5H, m), 2.60–2.58 (1H, m), 2.30–2.22 (2H, m), 1.70–1.62 (2H, m)

MS (ES⁺) m/z 460.2 (M+H)⁺.

EXAMPLE 21
3-{3-[8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-3-yl]-2-(R)-hydroxy-propylsulfanyl}-2-acetylamino-(R)-propionic acid Compound #100

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8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-(R)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one (0.022 g, 0.048 mmol) and N-acetyl-L-cysteine (0.03 g, 0.184 mmol) were dissolved in ethanol (1 mL). The reaction mixture was heated at 80° C. for 18 hours, then cooled to room temperature and the solvent evaporated in vacuo to yield an oil. The oil was partitioned with water and ethyl acetate. The organic layer was dried with Na₂SO₄, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via preparative TLC plate (10% methanol/dichloromethane) to yield the title compound as an oil.

EXAMPLE 22
8-Cyclooctylmethyl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4,5]decan-4-one Compounds #582

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Cyclooctanecarbaldehyde (0.676 g, 4.8 mmol) synthesized according to the procedure described in Kawamoto, H. et. al. Tetrahedron 2001, 57, 981–986 was reacted with 1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (1 g, 4 mmol) in tetrahydrofuran (anhydrous, 100 mL), with the addition of sodium triacetoxyborohydride (1.2 g, 6 mmol) at 0° C. The reaction was then stirred overnight at room temperature. The organic layer was partitioned with 1 N sodium hydroxide, water and brine. The organic layer was dried with sodium sulfate and filtered to yield a clear residue. Purification of the residue by flash chromatography yielded the title compound as a white powder.

MS (electrospray)=374.1 (MH+)

¹H NMR (300 MHz, CDCl₃) δ 1.1–1.9 (m, 15H), 2.1 (d, 2H), 2.2–2.4 (m, 2H), 2.7 (d, 4H), 3.3 (d, 2H), 4.7 (s, 2H), 6.4 (s, 1H), 6.8–7.0 (m, 4H).

EXAMPLE 23
8-Cyclooctylmethyl-1-(4-fluoro-phenyl)-(R)-3-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one Compound #540

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8-Cyclooctylmethyl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (4, 3 g, 8 mmol) was dissolved with NMP (150 mL) and stirred at 0° C. Sodium hydride (60% dispersion in oil, 0.75 g, 18.7 mmol) was added to the reaction mixture which was then stirred an additional 30 minutes at 0° C. S-(+)-epichlorohydrin (1.88 ml, 24 mmol) was added and the reaction was stirred overnight at room temperature. The reaction was then partitioned with water and ethyl acetate. The organic was dried with sodium sulfate and filtered. The solvent was evaporated to yield the title compound as an oil.

MS (electrospray)=430.5 (MH+)

¹H NMR (300 MHz, CDCl₃) δ 1.1–1.9 (m, 17H), 2.15 (d, 2H), 2.2–2.4 (m, 2H), 2.5–2.85 (m, 4H), 3.1 (m, 2H), 4.0 (m, 1H), 4.65 (d, 1H), 4.75 (d, 1H), 6.8–7.0 (m, 4H)

EXAMPLE 24
3-[3-(Benzyl-butyl-amino)-2-(S)-hydroxy-propyl]-8-cyclooctylmethyl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one Compound #64

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Cyclooctylmethyl-1-(4-fluoro-phenyl)-3-(R)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one (3.4 g, 8 mmol) was dissolved in absolute ethanol (75 mL), mixed with N-butylbenzylamine (3.1 mL, 17.6 mmol) and heated at reflux overnight. The solvent was evaporated and the resulting residue was purified by column chromatography (5% MeOH/CH₂Cl₂) to yield the free base as an oil. The oil (2.2 g, 3.7 mmol) was dissolved in diethyl ether (10 mL) and reacted with HCl (11 mL, [1 M in diethylether]) at 0° C. He resulting crystals were collected by filtration and recrystallized with eethanol to yield 1 g the title compound white powder.

MS (electrospray)=593.5 (MH+), 592.6

¹H NMR (300 MHz, CD₃OD) δ 1.1 (m, 3H), 1.3–1.9 (m, 15H), 2.1 (m, 2H), 2.4 (m, 2H), 2.9–3.6 (m, 14H), 3.65–3.8 (m, 2H), 4.2 (m, 1H), 4.3–4.3 (m, 3H), 4.8 (m, 2H), 7.0–7.2 (m, 4H), 7.4–7.7 (m, 5H)

EXAMPLE 25
8-Cyclooctylmethyl-3-{3-[2-(3,4-dimethoxy-phenyl)-ethoxy]-2-(R)-hydroxy-propyl}-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one Compound #105

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3,4-Dimethoxyphenethylalcohol was dissolved in NMP (2 mL) and stirred for 30 min. NaH (60% dipersion in oil) was added and the mixture was stirred for thirty minutes. 8-Cyclooctylmethyl-1-(4-fluoro-phenyl)-3-(S)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one (0.2 g, 0.46 mmol) was added and the reaction was stirred overnight at room temperature. The reaction was partitioned with saturated NaHCO₃solution and ethyl acetate. The organic layer was dried with MgSO₄, filtered and the solvent evaporated in vacuo to yield crude product. Purification by reverse phase chromatography (AcCN/water) yielded the title compound as a trifluoroacetate salt as a solid.

MS (electrospray)=612.1 (MH+), 522.0, 402.2

¹H NMR (300 MHz, CD₃OD) δ 1.3–1.8 (m, 14H), 2.0–2.1 (m, 4H), 2.2–2.4 (m, 2H), 2.8 (t, 2H), 3.0 (d, 2H), 3.35–3.8 (m, 13H), 3.9 (m, 4H), 4.7 (m, 2H), 6.8 (m, 3H), 7.1 (m, 4H)

EXAMPLE 26
2-Acetylamino-3-{3-[8-cyclooctylmethyl-1-(4-fluoro-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-3-yl]-2-(R)-hydroxy-propylsulfanyl}-propionic acid Compound #100

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1-(4fluorophenyl)-3R-oxarinyl-methyl-8-cyclooctylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one (0.06 g, 0.14 mmol) was dissolved in absolute ethanol (1 mL), mixed with N-acetylcysteine (68 mg, 0.42 mmol) and heated to 70° C. overnight. The solvent was evaporated and the resulting residue was purified by reverse phase chromatography (AcCN/water) to yield the title compounds as a trifluoroacetate salt as a solid.

MS (electrospray)=593.8 (MH+).

EXAMPLE 27
1-(4-Fluoro-phenyl)-8-pentamethylphenylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one Compound #583

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Pentamethylbenzaldehyde (4 g, 23 mmol, commercially available) was reacted with 1-(4-Fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (5.5 g, 20 mmol) in tetrahydrofuran (anhydrous, 250 mL), with addition of sodium triacetoxyborohydride (8.2 g, 42 mmol) at 0° C. The reaction was then stirred overnight at room temperature. The organic layer was partitioned with 1 N sodium hydroxide, water and brine. The organic layer was dried with sodium sulfate and filtered to yield the title compound as a white powder.

MS (electrospray)=410.5 (MH+), 250.0

¹H NMR (300 MHz, DMSO-d₆) δ 1.6 (d, 2H), 2.2–2.3 (m, 17H), 2.6–2.8 (m, 4H), 3.55 (s, 2H), 4.5 (s, 2H), 6.8 (m, 2H), 7.1 (t, 2H), 8.65 (s, 1H.

EXAMPLE 28
1-(4-Fluoro-phenyl)-3R-oxiranylmethyl-8-pentamethylphenylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one Compound #584

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1-(4-Fluoro-phenyl)-8-pentamethylphenylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one (0.6 g, 1.46 mmol) was dissolved with NMP (5 mL) and stirred at room temperature. Sodium hydride (60% dispersion in oil, 0.11 g, 1.6 mmol) was added and the mixture stirred an additional 30 minutes. S-(+)-epichlorohydrin (0.3 ml, 3.2 mmol) was added and the reaction was stirred overnight at room temperature. The reaction was then partitioned with water and ethyl acetate. The organic was dried with sodium sulfate and filtered. The solvent was evaporated to yield the title compounds as an oil.

MS (electrospray)=466.1 (MH+)

EXAMPLE 29
3-[3-(Benzyl-butyl-amino)-2-(S)-hydroxy-propyl]-1-(4-fluoro-phenyl)-8-pentamethylphenylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one Compound #280

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1-(4-Fluoro-phenyl)-3R-oxiranylmethyl-8-pentamethylphenylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one (0.1 g, 0.21 mmol) was dissolved in absolute ethanol (75 mL), mixed with N-butylbenzylamine (0.1 mL, 0.6 mmol) and heated at reflux overnight. The solvent was evaporated and the resulting residue was purified by reverse phase chromatography (AcCN/water) to yield the title compound as an oil.

MS (electrospray)=629.2 (MH+), 468.9, 315.3, 311.9, 161.1

¹H NMR (300 MHz, CD₃OD) δ 1.0 (m, 3H), 1.3 (m, 2H), 1.8 (m, 2H), 1.9 (m, 2H), 2.25 (d, 9H), 2.3 (s, 6H), 3.2 (m, 3H), 3.4 (m, 4H), 3.9 (m, 3H), 4.15 (m, 1H), 4.4 (m, 4H), 4.8 (m, 2H), 7.0 (m, 3H), 7.5 (m, 9H).

EXAMPLE 30
8-(2-Chloro-6-trifluoromethyl-benzyl)-1-(4-fluoro-phenyl)-3R-oxiranylmethyl-1,3,8-triaza-spiro[4,5]decan-4-one Compound #578

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8-(2-Chloro-6-trifluoromethyl-benzyl)-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (0.3 g, 0.68 mmol) was dissolved with NMP (20 mL) and stirred at room temperature. Sodium hydride (60% dispersion in oil, 0.066 g, 0.95 mmol) was added and the mixture was stirred an additional 30 minutes. S-(+)-epichlorohydrin (0.14 ml, 1.5 mmol) was added and the reaction was stirred overnight at room temperature. The reaction was then partitioned with water and ethyl acetate. The organic was dried with sodium sulfate and filtered. The solvent was evaporated to yield the title compound as an oil.

¹H NMR (300 MHz, CDCl₃) δ 1.6 (m, 2H), 2.3 (m, 2H), 2.7 (m, 2H), 2.9 (bt, 2H), 3.1 (m, 1H), 3.8 (s, 2H), 4.0 (d, 1H), 4.6 (d, 1H), 4.8 (d, 2H), 6.8 (m, 2H), 6.95 (m, 2H), 7.2 (t, 1H), 7.6 (t, 2H).

EXAMPLE 31
3-[3-(Benzyl-butyl-amino)-2-(S)-hydroxy-propyl]-8-(2-chloro-6-trifluoromethyl-benzyl)-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one Compound #456)

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8-(2-Chloro-6-trifluoromethyl-benzyl)-1-(4-fluoro-phenyl)-3-(R)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one (0.05 g, 0.1 mmol) was dissolved in absolute ethanol (0.5 mL), mixed with N-butylbenzylamine (0.05 mL, 0.4 mmol) and heated at reflux overnight. The solvent was evaporated and the resulting residue was purified by reverse column chromatography (AcCN/water) to yield the title compound as an oil.

MS (electrospray)=661.0 (MH+), 571.1, 331.4

EXAMPLE 32
{1-[{3-[8-Cyclooctylmethyl-1-(4-fluoro-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-3-yl]-2-(S)-hydroxy-propyl}-(4-methyl-benzyl)-carbamoyl]-2-methyl-propyl}-carbamic acid tert-butyl ester Compound #79

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8-Cyclooctylmethyl-1-(4-fluoro-phenyl)-3-[2-hydroxy-3-(4-methyl-benzylamino)-propyl]-1,3,8-triaza-spiro[4.5]decan-4-one (0.05 g, 0.091 mmol) was dissolved in DMF (1 mL), mixed with BocD-Valine (0.02 g, 0.091 mmol), HBTU (0.035 g, 0.09 mmol) and diisopropylethylamine (0.1 mL) and stirred overnight at room temperature. The reaction mixture was partitioned with saturated NaHCO₃and ethyl acetate. The organic layer dried with, MgSO₄, filtered and the solvent evaporated in vacuo to yield the title compound as an oil.

MS (electrospray)=751.5 (MH+), 749.8, 373.6, 372.8, 203.1, 171.1

EXAMPLE 33
8-Cyclooctylmethyl-1-(4-fluoro-phenyl)-3-[2-(S)-hydroxy-3-(pyridin-4-ylamino)-propyl]-1,3,8-triaza-spiro[4.5]decan-4-one Compound #36

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Cyclooctylmethyl-1-(4-fluoro-phenyl)-3-(R)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one (0.5 g, 1.16 mmol) was dissolved in absolute ethanol (1 mL), mixed with 4-Aminopyridine (0.5 mL, 5.3 mmol) and heated at reflux overnight. The solvent was evaporated and the resulting residue was purified by reverse phase column chromatography (Acetonitrile/water) to yield the title compound as an oil.

¹H NMR (300 MHz, CD₃OD) δ 1.35 (m, 2H), 1.5–1.7 (m, 13H), 1.9 (s, 9H), 1.95 (m, 1H), 2.4 (m, 2H), 3.1 (d, 2H), 3.2 (m, 2H), 3.4 (m, 2H), 3.55 (d, 2H), 4.0 (m, 1H), 4.15 (m, 1H), 4.3 (m, 1H), 6.8 (d, 2H), 7.1 (m, 4H), 8.1 (d, 2H).

EXAMPLE 34
3-[3-Amino-2-(R)-hydroxy-propyl]-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one Compound#438

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1-(4-Fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-3-(S)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one (0.06 g, 0.13 mmol) was dissolved in ethyl alcohol (2 mL) and methyl alcohol (0.4 mL). To the solution was then added concentrated ammonium hydroxide (1 mL) and the reaction mixture was stirred at 40° C. for two hours in a pressure flask. The solvent was then evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (5.0% ammonia 2.0 M in methanol/dichloromethane) to yield the title compound as a foam.

¹H NMR (400 MHz, CDCl₃) δ 7.77–7.75 (1H, m), 7.71–7.68 (1H, m), 7.37–7.30 (4H, m), 6.97–6.91 (2H, m), 6.87–6.83 (2H, m), 4.74 (2H, s), 4.0 (2H, s), 3.79–3.74 (1H, m), 3.57–3.52 (1H, m), 3.41–3.36 (1H, m), 3.11 (3H, s), 2.91–2.74 (4H, m), 2.66–2.61 (1H, m), 2.30–2.23 (2H, m), 1.66 (2H, d, J=13.7 Hz)

MS (ES⁺) m/z 477.1 (M+H)⁺.

EXAMPLE 35
(R)-8-Acenaphthen-1-yl-3-(3-amino-2-hydroxy-(S)-propyl)-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one Compound #424

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(R)-8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-(R)oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one (0.514 g, 1.123 mmol) was dissolved in ethyl alcohol (16 mL). To the solution was then added concentrated ammonium hydroxide (8 mL) and the reaction mixture was stirred at 40° C. for two hours and a half in a pressure flask. The solvent was then evaporated in vacuo to yield the title compound as a foam.

¹H NMR (400 MHz, CDCl₃) δ 7.68–7.65 (1H, m), 7.60 (1H, d, J=8.2 Hz), 7.52–7.49 (2H, m), 7.43 (1H, t), 7.26 (1H, d), 7.03–6.94 (4H, m), 4.97–4.94 (1H, m), 4.76–4.72 (2H, m), 3.74 (1H, br s), 3.55–3.48 (2H, m), 3.38–3.32 (2H, m), 3.16–3.03 (2H, m), 2.88–2.82 (2H, m), 2.59 (1H, br s), 2.44–2.41 (2H, m), 2.31–2.24 (1H, m), 1.76–1.62 (2H, m)

MS (ES⁺) m/z 475.2 (M+H)⁺.

EXAMPLE 36
(R) 8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-(2-hydroxy-3-methylamino-(S)-propyl)-1,3,8-triaza-spiro[4.5]decan-4-one Compound #437

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(R)-8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-(R)oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one (0.045 g, 0.098 mmol) was dissolved in ethyl alcohol (2 mL). To the solution was then added a solution of 2.0M methylamine in THF (1 mL) and the reaction mixture was stirred at 40° C. for two hours and a half in a pressure flask. The solvent was then evaporated in vacuo to yield the title compound as a foam.

¹H NMR (400 MHz, CDCl₃) δ 7.68–7.64 (1H, m), 7.59 (1H, d, J=8.2 Hz), 7.53–7.49 (2H, m), 7.45 (1H, t), 7.26–7.24 (1H, m), 7.03–6.94 (4H, m), 4.96–4.93 (1H, m), 4.78–4.73 (2H, m), 3.86–3.83 (1H, m), 3.55–3.47 (2H, m), 3.37–3.30 (2H, m), 3.16–2.99 (2H, m), 2.87–2.79 (2H, m), 2.70–2.66 (1H, m), 2.52–2.23 (6H, m), 1.75–1.61 (2H, m)

MS (ES⁺) m/z 489.3 (M+H)⁺.

EXAMPLE 37
8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-[2-hydroxy-3-(pyridin-4-ylamino)-propyl]-1,3,8-triaza-spiro[4.5]decan-4-one Compound #327

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8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-(R)oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one (0.100 g, 0.21 mmol) was dissolved in absolute ethyl alcohol (0.5 mL), mixed with 4-aminopyridine (0.2 mL) and heated at reflux overnight. The solvent was evaporated and the resulting residue was purified by reverse phase chromatography (MeCN/water) to yield the title compound as an oil.

EXAMPLE 38
(R)-8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-[2-hydroxy-3-(pyridin-2-ylamino)-(R)-propyl]-1,3,8-triaza-spiro[4.5]decan-4-one Compound #421

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Sodium amide (0.0085 g, 0.21 mmol) and 2-aminopyridine (0.0165 g, 0.17 mmol) were suspended in toluene (0.25 mL) and benzene (0.15 mL). To the reaction mixture was then added (R)-8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-(S)oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one (0.100 g, 0.21 mmol). The mixture was refluxed overnight under nitrogen, cooled down to room temperature and partitioned with brine and dichloromethane. The organic layer was washed with brine, dried with Na₂SO₄, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (3.25% ammonia 2.0 M in methanol/dichloromethane) to yield the title compound as an oil.

¹H NMR (300 MHz, CDCl₃) δ 7.98–7.96 (1H, m), 7.69–7.65 (1H, m), 7.60 (1H, d, J=8.2 Hz), 7.53–7.51 (2H, m), 7.47–7.40 (1H, m), 7.28–7.26 (1H, m), 7.03–6.92 (4H, m), 6.66–6.47 (3H, m), 5.08–5.04 (1H, m), 4.98–4.94 (1H, m), 4.79–4.73 (2H, m), 4.0–3.94 (1H, m), 3.72–3.61 (2H, m), 3.57–3.49 (1H, m), 3.40–3.28 (2H, m), 3.14–3.02 (2H, m), 2.85–2.81 (1H, m), 2.44–2.26 (3H, m), 1.74–1.25 (2H, m)

MS (ES⁺) m/z 552.3 (M+H)⁺.

EXAMPLE 39
1-(4-Fluoro-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester Compound #535

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Di-tert-butyl dicarbonate (2.2 g, 10.0 mmol) and 1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (2.5 g, 10.0 mmol) were dissolved in dioxane (50 mL) and water (100 mL). Sodium hydrogeno carbonate (1.7 g, 20 mmol) was then added and the reaction mixture was stirred at room temperature under nitrogen atmosphere for 18 hours. The reaction mixture was concentrated in vacuo and partitioned with water and ethyl acetate. The organic layer was washed with brine, dried with Na₂SO₄, filtered and the solvent evaporated in vacuo to yield a solid. Recrystallization from hot ethyl acetate yielded the title compound as a white solid.

¹H NMR (300 MHz, CDCl₃) δ 8.25 (1H, br s), 7.0–6.95 (2H, m), 6.82–6.77 (2H, m), 4.71 (2H, s), 4.08–3.8 (2H, m), 3.65–3.40 (2H, m), 2.35–2.15 (2H, m), 1.8–1.65 (2H, m), 1.48 (9H, s)

MS (ES⁺) m/z 372.1 (MNa)⁺.

EXAMPLE 40
8-Ethyl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4,5]decan-4-one Compound #536

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2-iodoethane (0.47 g, 3.0 mmol) and 1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (0.6 g, 2.4 mmol) were dissolved in acetonitrile (15 mL). Potassium carbonate (0.66 g, 4.8 mmol) was then added and the reaction mixture was stirred at room temperature under nitrogen atmosphere for 18 hours. The reaction mixture was partitioned with water and diethyl ether. The organic layer was washed with brine, dried with Na₂SO₄, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (30–50% ethyl acetate/hexane) to yield the title compound as an oil.

¹H NMR (300 MHz, CDCl₃) δ 7.03–6.93 (4H, m), 6.46 (1H, br s), 4.67 (2H, s), 2.82–2.69 (4H, m), 2.48 (2H, q), 2.31–2.21 (2H, m), 1.81–1.76 (2H, m), 1.08 (3H, t)

MS (ES⁺) m/z 278.2 (M+H)⁺.

EXAMPLE 41
8-(4-Chloro-benzyl)-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one Compound #508

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1-(4-Fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (3.0 g, 12.03 mmol) and 4-chloro-benzaldehyde (2.03 g, 14.44 mmol) were dissolved in dry tetrahydrofuran (120 mL). To the reaction mixture was then added at 0° C. sodium triacetoxyborohydride (3.82 g, 18.05 mmol) under nitrogen atmosphere and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then partitioned with 1 N NaOH and ethyl acetate. The organic layer was washed with brine, dried with Na₂SO₄, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (3.5% methanol/dichloromethane) to yield the title compound as a white foam.

¹H NMR (300 MHz, CDCl₃) δ 7.30–7.15 (4H, m), 7.01–6.87 (4H, m), 4.63 (2H, s), 3.47 (2H, s), 2.78–2.65 (4H, m), 2.31–2.0 (2H, m), 1.73–1.68 (2H, m)

MS (ES⁺) m/z 374.1 (M+H)⁺.

EXAMPLE 42
8-(4-Chloro-benzyl)-1-(4-fluoro-phenyl)-3-(R)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one Compound #513

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8-(4-Chloro-benzyl)-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (0.220 g, 0.588 mmol) was dissolved in N,N-dimethylformamide (2.2 mL). To the reaction mixture was then added at 0° C. sodium hydride (60% in mineral oil, 31 mg, 0.765 mmol) under nitrogen atmosphere and the reaction mixture was stirred at 0° C. for 40 minutes. To the reaction mixture was then added (S)-epichlorhydrin (0.14 mL, 1.765 mmol) at 0° C. The reaction mixture was stirred at room temperature under nitrogen atmosphere for 18 hours and partitioned with water and ethyl acetate. The organic layer was washed with brine, dried with Na₂SO₄, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (2% methanol/dichloromethane) to yield the title compound as a foam.

¹H NMR (300 MHz, CDCl₃) δ 7.32–7.26 (4H, m), 7.04–6.91 (4H, m), 4.77 (1H, d, J=4.9 Hz), 4.66 (1H, d, J=4.9 Hz), 4.06–3.99 (1H, m), 3.52 (3H, s), 3.20–3.14 (2H, m), 2.85–2.68 (5H, m), 2.60–2.58 (1H, m), 2.33–2.23 (2H, m), 1.73–1.60 (2H, m)

MS (ES⁺) m/z 430.2 (M+H)⁺.

EXAMPLE 43
1-(4-Fluoro-phenyl)-3-(S)-[2-hydroxy-3-(2-morpholin-4-yl-ethylamino)-propyl]-8-(5-phenyl-thien-2-yl-methyl)-1,3,8-triaza-spiro[4.5]decan-4-one Compound #293

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(R)-1-(4-Fluoro-phenyl)-3-oxiranylmethyl-8-(5-phenyl-thien-2-yl-methyl)-1,3,8-triaza-spiro[4.5]decan-4-one (0.02 g, 0.041 mmol) was dissolved in absolute ethanol (1 mL), mixed with 2-morpholin-4-yl-ethylamine (16.3 mg, 0.125 mmol) and heated under stirring at 70° C. overnight. The solvent was evaporated and the resulting residue was purified via flash chromatography (9% methanol/dichloromethane) to yield the title compound as an oil.

¹H NMR (300 MHz, CDCl₃) δ 7.59–7.56 (2H, m), 7.38–7.33 (2H, m), 7.28–7.25 (2H, m), 7.14 (1H, d, J=3.6 Hz), 7.04–6.91 (3H, m), 6.87 (1H, d, J=3.5 Hz), 4.80–4.76 (2H, m), 3.86–3.69 (6H, m), 3.61–3.55 (1H, m), 3.36–3.29 (1H, m), 2.85–2.71 (7H, m), 2.58–2.32 (10H, m), 1.72 (2H, d, J=13.7 Hz)

MS (ES⁺) m/z 608.3 (M+H)⁺

EXAMPLE 44
1-(4-Fluoro-phenyl)-8-quinolin-8-ylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one Compound #522

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1-(4-Fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (0.15 g, 0.601 mmol) and quinoline-8-carbaldehyde (0.113 g, 0.722 mmol) were dissolved in dry tetrahydrofuran (12 mL). To the reaction mixture was then added at 0° C. sodium triacetoxyborohydride (0.192 g, 0.902 mmol) under nitrogen atmosphere and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then partitioned with 1N NaOH and ethyl acetate. The organic layer was washed with brine, dried with Na₂SO₄, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (5% methanol/dichloromethane) to yield the title compound as a white solid.

¹H NMR (300 MHz, CDCl₃) δ 8.93–8.91 (1H, m), 8.14 (1H, d, J=8.3 Hz), 7.89 (1H, br s), 7.71 (1H, m), 7.55 (1H, t, J=7.7 Hz), 7.41–7.38 (1H, m), 7.05–7.01 (4H, m), 6.79 (1H, br s), 4.69 (2H, s), 4.35 (2H, s), 3.01–2.90 (4H, m), 2.41 (2H, br s), 1.80 (2H, d, J=13.8 Hz)

MS (ES⁺) m/z 391.0 (M+H)⁺.

EXAMPLE 45
(R)-8-Acenaphthen-1-yl-3-(R)-(3-ethoxy-2-hydroxy-propyl)-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one Compound #571

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(R)-8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-(R)oxiranyl-methyl-1,3,8-triaza-spiro[4.5]decan-4-one (0.084 g, 0.183 mmol) was dissolved in ethanol (4 mL). The reaction mixture was heated at 80° C. for 18 hours, then cooled to room temperature and the solvent evaporated in vacuo to yield an oil. The oil was partitioned with water and ethyl acetate. The organic layer was dried with Na₂SO₄, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (4% [methanol in ammonia 2.0M]/dichloromethane) to yield the title compound as an oil.

¹H NMR (300 MHz, CDCl₃) δ 7.69–7.66 (1H, m), 7.61 (1H, d, J=8.2 Hz), 7.54–7.50 (2H, m), 7.44 (1H, t), 7.27–7.25 (1H, m), 7.05–6.90 (4H, m), 4.98–4.90 (1H, m), 4.77–4.71 (2H, m), 4.03–3.98 (1H, m), 3.57–3.31 (8H, m), 3.16–3.01 (3H, m), 2.88–2.85 (1H, m), 2.43 (2H, br s), 2.32–2.24 (1H, m), 1.77–1.62 (2H, m), 1.18 (3H, t);

MS (ES⁺) m/z 504.3 (M+H)⁺.

EXAMPLE 46
3-[3-(Ethyl-methyl-amino)-2-hydroxy-(S)-propyl]-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4,5]decan-4-one Compound #440

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1-(4-Fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-3-(R)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one (0.02 g, 0.043 mmol) was dissolved in ethyl alcohol (2 mL). To the solution was then added N-methylethylamine (0.2 mL) and the reaction mixture was stirred at 40° C. for 3 hrs in a pressure flask. The solvent was then evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (5.0% ammonia 2.0 M in methanol/dichloromethane) to yield the title compound as an oil.

¹H NMR (400 MHz, CDCl₃) δ 7.77–7.75 (1H, m), 7.71–7.68 (1H, m), 7.38–7.30 (4H, m), 6.96–6.91 (2H, m), 6.88–6.84 (2H, m), 4.82–4.75 (2H, m), 4.08–3.98 (3H, m), 3.61–3.57 (1H, m), 3.34–3.29 (1H, m), 3.11 (3H, s), 2.83–2.54 (8H, m), 2.44 (3H, s), 2.32–2.23 (2H, m), 1.68–1.63 (2H, m); 1.15 (3H, t, J=7.2 Hz)

MS (ES⁺) m/z 519.3 (M+H)⁺.

EXAMPLE 47
(R)-Acenaphthen-1-yl-3-(3-dimethylamino-2-hydroxy-(R)-propyl)-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one Compound #423

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(R)-8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-(S)oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one (0.057 g, 0.124 mmol) was dissolved in ethyl alcohol (2 mL). To the solution was then added a solution of 2.0M dimethylamine in THF (1 mL) and the reaction mixture was stirred at 40° C. for 2.5 hrs in a pressure flask. The solvent was then evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (6.0% ammonia 2.0 M in methanol/dichloromethane) to yield the title compound as a foam.

¹H NMR (400 MHz, CDCl₃) δ 7.68–7.65 (1H, m), 7.59 (1H, d, J=8.2 Hz), 7.52–7.49 (2H, m), 7.44 (1H, t), 7.26–7.25 (1H, m), 7.03–6.94 (4H, m), 4.97–4.94 (1H, m), 4.83–4.80 (2H, m), 4.77–4.75 (1H, m), 3.87–3.81 (1H, m), 3.60–3.03 (7H, m), 2.85–2.82 (1H, m), 2.49–2.42 (2H, m), 2.32–2.24 (8H, m), 1.75–1.62 (2H, m)

MS (ES⁺) m/z 503.3 (M+H)⁺.

EXAMPLE 48
1-(4-Fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-3-(S)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one Compound #550

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1-(4-Fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]-decan-4-one (2.0 g, 4.95 mmol) was dissolved in N,N-dimethylformamide (25.0 mL). To the reaction mixture was then added at 0° C. sodium hydride (60% in mineral oil, 238 mg, 5.94 mmol) under nitrogen atmosphere and the reaction mixture was stirred at 0° C. for one hour. To the reaction mixture was then added at 0° C. (2R)-(−)-glycidyl-3-nitrobenzenesulfonate (1.54 g, 5.94 mmol). The reaction mixture was stirred at 0° C. for one hour, then at room temperature under nitrogen atmosphere for 18 hours and partitioned with water and ethyl acetate. The organic layer was washed with brine, dried with Na₂SO₄, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (2.5% methanol/dichloromethane) to yield the title compound as a foam.

¹H NMR (300 MHz, CDCl₃) δ 7.78–7.76 (1H, m), 7.73–7.69 (1H, m), 7.38–7.31 (4H, m), 6.99–6.91 (2H, m), 6.89–6.84 (2H, m), 4.76 (1H, d, J=4.8 Hz), 4.65 (1H, d, J=4.8 Hz), 4.01 (2H, s), 3.20–3.11 (6H, m), 2.86–2.77 (5H, m), 2.61–2.59 (1H, m), 2.31–2.21 (2H, m), 1.69–1.63 (2H, m)

MS (ES⁺) m/z 460.2 (M+H)⁺.

EXAMPLE 49
3,3,3-Trifluoro-N-{3-[1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-3-yl]-2-(R)-hydroxy-propyl}-2-methoxy-2-phenyl-(R)-propionamide Compound #615

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3-(3-Amino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one (0.0118 g, 0.024 mmol) was dissolved in dichloromethane (1.0 mL) and pyridine (0.15 mL). To the reaction mixture was then added at 0° C. (S)-(+)-α-methoxy-α-(trifluoro methyl)phenyl acetyl chloride (8.7 mg, 0.034 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for one hour, then the solvent was evaporated in vacuo to yield a crude foam. The crude foam was dissolved in ethyl acetate and successively washed twice with aqueous 0.5N HCl, twice with aqueous NaHCO₃, brine, dried with Na₂SO₄, filtered and the solvent evaporated in vacuo to yield a white foam.

¹H NMR (300 MHz, CDCl₃) δ 7.78–7.75 (1H, m), 7.71–7.68 (1H, m), 7.64–7.61 (1H, m), 7.56–7.54 (2H, m), 7.42–7.40 (3H, m), 7.39–7.30 (3H, m), 6.97–6.93 (2H, m), 6.87–6.83 (2H, m), 4.70 (1H, d, J=4.9 Hz), 4.64 (1H, d, J=4.9 Hz), 3.99 (3H, s), 4.01 (1H, s), 3.60–3.54 (1H, m), 3.45–3.32 (5H, m), 3.1 (3H, s), 2.82–2.74 (4H, m), 2.24–2.20 (2H, m), 1.70–1.63 (4H, m)

MS (ES⁺) m/z 693.0 (M+H)⁺.

EXAMPLE 50
3-(3-Dimethylamino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one Compound #441

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1-(4-Fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-3-(S)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one (0.035 g, 0.07 mmol) was dissolved in ethyl alcohol (2 mL). To the solution was then added a 2.0M solution of dimethylamine in methanol (1.0 mL, 2.0 mmol) and the reaction mixture was stirred at 45° C. for 3 hrs in a pressure flask. The solvent was then evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (5.0% ammonia 2.0 M in methanol/dichloromethane) to yield the title compound as a foam.

¹H NMR (400 MHz, CDCl₃) δ 7.78–7.75 (1H, m), 7.71–7.68 (1H, m), 7.38–7.31 (4H, m), 6.96–6.91 (2H, m), 6.88–6.84 (2H, m), 4.80 (1H, d, J=5.1 Hz), 4.77 (1H, d, J=5.1 Hz), 4.01 (2H, m), 3.95–3.87 (1H, m), 3.62–3.58 (1H, m), 3.31–3.26 (1H, m), 3.11 (3H, s), 2.86–2.78 (6H, m), 2.36–2.22 (9H, m), 1.68–1.63 (2H, m)

MS (ES⁺) m/z 505.4 (M+H)⁺.

EXAMPLE 51
1-(4-Fluoro-phenyl)-3-(2-(R)-hydroxy-3-methylamino-propyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one Compound #660

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1-(4-Fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-3-(S)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one (0.05 g, 0.109 mmol) was dissolved in methanol (3 mL). To the solution was then added a 2.0M solution of methylamine in methanol (1.0 mL, 2.0 mmol) and the reaction mixture was stirred at 40° C. for 3 hrs in a pressure flask. The solvent was then evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (5.0% ammonia 2.0 M in methanol/dichloromethane) to yield the title compound as a foam.

¹H NMR (400 MHz, CDCl₃) δ 7.78–7.75 (1H, m), 7.71–7.68 (1H, m), 7.38–7.31 (4H, m), 6.96–6.91 (2H, m), 6.88–6.84 (2H, m), 4.80 (1H, d, J=5.1 Hz), 4.77 (1H, d, J=5.1 Hz), 4.00 (2H, m), 3.97–3.86 (1H, m), 3.58–3.53 (1H, m), 3.43–3.35 (1H, m), 3.12 (3H, s), 2.84–2.69 (7H, m), 2.56–2.49 (1H, m), 2.44 (3H, s), 2.31–2.24 (2H, m), 1.67–1.64 (2H, m)

MS (ES⁺) m/z 491.1 (M+H)⁺.

EXAMPLE 52
1-(4-Fluoro-phenyl)-3-[2-(R)-hydroxy-3-(3-methylamino-propylamino)-propyl]-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one Compound #656

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1-(4-Fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-3-(S)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one (0.035 g, 0.07 mmol) was dissolved in methanol (4 mL). To the solution was then added N-methyl-1-3-propanediamine (0.027 g, 0.35 mmol) and the reaction mixture was stirred at 45° C. for 12 hrs in a pressure flask. The solvent was then evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (5.0% ammonia 2.0 M in methanol/dichloromethane) to yield the title compound as a foam.

¹H NMR (400 MHz, CDCl₃) δ 7.78–7.75 (1H, m), 7.71–7.68 (1H, m), 7.38–7.30 (4H, m), 6.95–6.91 (2H, m), 6.87–6.84 (2H, m), 4.80 (1H, d, J=5.05 Hz), 4.77 (1H, d, J=5.05 Hz), 4.00 (2H, s), 3.96–3.89 (1H, m), 3.58–3.54 (1H, m), 3.32–3.30 (1H, m), 3.12 (3H, s), 2.85–2.77 (6H, m), 2.65–2.58 (1H, m), 2.49–2.12 (10H, m), 1.68–1.63 (4H, m)

MS (ES⁺) m/z 548.3 (M+H)⁺.

EXAMPLE 53
3-[3-(3-Dimethylamino-propylamino)-2-(R)-hydroxy-Propyl]-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one Compound #666

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1-(4-Fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-3-(S)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one (0.037 g, 0.07 mmol) was dissolved in ethanol (2 mL). To the solution was then added dimethylaminopropylamine (0.03 g, 0.3 mmol) and the reaction mixture was stirred at 45° C. for 12 hrs in a pressure flask. The solvent was then evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (5.0% ammonia 2.0 M in methanol/dichloromethane) to yield the title compound as a foam.

¹H NMR (300 MHz, CDCl₃) δ 7.78–7.75 (1H, m), 7.71–7.68 (1H, m), 7.38–7.30 (4H, m), 6.97–6.90 (2H, m), 6.87–6.82 (2H, m), 4.78–4.73 (2H, m), 4.00 (2H, s), 3.96–3.82 (1H, m), 3.59–3.53 (1H, m), 3.37–3.30 (1H, m), 3.12 (3H, s), 2.86–2.50 (9H, m), 2.35–2.11 (11H, m), 1.68–1.59 (4H, m)

MS (ES⁺) m/z 562.2 (M+H)⁺.

EXAMPLE 54
1-(4-Fluoro-phenyl)-3-[2-(R)-hydroxy-3-(3-hydroxy-propylamino)-propyl]-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one Compound #651

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1-(4-Fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-3-(S)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one (1.16 g, 2.5 mmol) was dissolved in methanol (20 mL). To the solution was then added 3-amino-1-propanol (0.375 g, 5.0 mmol,) and the reaction mixture was stirred at 40° C. for 12 hrs in a pressure flask. The solvent was then evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (5.0% ammonia 2.0 M in methanol/dichloromethane) to yield the title compound as a foam.

¹H NMR (300 MHz, CDCl₃) δ 7.78–7.75 (1H, m), 7.71–7.68 (1H, m), 7.38–7.30 (4H, m), 6.97–6.90 (2H, m), 6.87–6.82 (2H, m), 4.74–4.70 (2H, m), 3.99 (2H, s), 3.96–3.90 (1H, m), 3.81–3.77 (2H, m), 3.47–3.42 (3H, m), 3.11 (3H, s), 2.91–2.56 (10H, m), 2.30–2.20 (2H, m), 1.76–1.63 (4H, m)

MS (ES⁺) m/z 535.2 (M+H)⁺.

EXAMPLE 55
11-(4-Fluoro-phenyl)-8-(8-methyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4,5]decan-4-one Compound #728

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Step A:

8-Methyl-1,2,3,4-tetrahydro-naphthalene-1-carboxylic acid (J. Org. Chem. 1982, 47, 2590–2593) (0.066 g, 0.34 mmol) was dissolved in tetrahydrofuran (3 mL). To the solution was then added at 0° C. a 1.0M solution of borane-methyl sulfide complex in dichloromethane (0.7 mL, 0.69 mmol). The reaction mixture was stirred at room temperature for 15 minutes, refluxed for 2 hrs, then cooled down to 0° C. and quenched with methanol. The solvent was then evaporated in vacuo to yield a crude oil. The crude oil was partitioned with water and diethyl ether. The organic layer was dried with Na₂SO₄, filtered and the solvent evaporated in vacuo to yield crude (8-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-methanol as an oil which was used directly to the next step.

¹H NMR (400 MHz, CDCl₃) δ 7.05–6.92 (3H, m), 3.70–3.59 (2H, m), 3.15–3.10 (1H, m), 2.83–2.71 (2H, m), 2.34 (3H, s), 2.21–2.16 (1H, m), 1.95–1.83 (1H, m), 1.79.1.67 (2H, m), 1.52 (1H, br s)

Step B:

(8-Methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-methanol (0.03 g, 0.17 mmol) was dissolved in dichloromethane (0.5 mL). To the solution was then added 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H)-one, also known as Dess-Martin periodinane (0.087 g, 0.20 mmol). The reaction mixture was stirred for 2 hrs then partitioned with an aqueous saturated solution of thiosulfate and dichloromethane. The organic layer was washed with an aqueous saturated solution of thiosulfate, an aqueous saturated solution of sodium bicarbonate, brine, dried with Na₂SO₄, filtered and the solvent evaporated in vacuo to yield 8-methyl-1,2,3,4-tetrahydro-naphthalene-1-carbaldehyde as a solid.

¹H NMR (400 MHz, CDCl₃) δ 9.66 (1H, d, J=1.8 Hz), 7.13–6.99 (3H, m), 3.74–3.72 (1H, m), 2.81–2.77 (2H, m), 2.37–2.31 (1H, m), 2.2 (3H, s), 1.95–1.61 (3H, m).

Step C:

1-(4-Fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (0.035 g, 0.14 mmol) and 8-methyl-1,2,3,4-tetrahydro-naphthalene-1-carbaldehyde (0.03 g, 0.17 mmol) were dissolved in dry tetrahydrofuran (2 mL) and dry dichloromethane (0.5 mL). To the reaction mixture was then added at 0° C. sodium triacetoxyborohydride (0.045 g, 0.21 mmol) under nitrogen atmosphere and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then partitioned with 1N NaOH and ethyl acetate. The organic layer was washed with brine, dried with Na₂SO₄, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (5% methanol/dichloromethane) to yield the title compound as an oil.

¹H NMR (400 MHz, CDCl₃) δ 7.06–6.90 (7H, m), 6.56 (1H, br s), 4.68 (2H, s), 3.12–2.33 (12H, m), 1.91–1.53 (6H, m), 1.25–1.21 (2H, m)

MS (ES⁺) m/z 408.1 (M+H)⁺.

EXAMPLE 56
(R)-8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-[2-hydroxy-3-(3-hydroxymethyl-piperidin-1-yl)-(R)-propyl]-1,3,8-triaza-spiro[4.5]decan-4-one Compound #695

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(R)-8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-(S)oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one (0.02 g, 0.04 mmol) was dissolved in ethyl alcohol (1.5 mL). To the solution was then added 3-piperidinemethanol (0.01 g, 0.08 mmol) and the reaction mixture was stirred at 60° C. for 12 hrs in a pressure flask. The solvent was evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (6.0% ammonia 2.0 M in methanol/dichloromethane) to yield the title compound as a foam.

¹H NMR (400 MHz, CDCl₃) δ 7.69–7.49 (4H, m), 7.46–7.41 (1H, m), 7.26–7.25 (1H, m), 7.04–6.95 (4H, m), 4.97–4.94 (1H, m), 4.81–4.74 (2H, m), 3.97–3.90 (1H, m), 3.58–1.6 (27H, m)

MS (ES⁺) m/z 573.3 (M+H)⁺.

EXAMPLE 57
N-{3-[(R)-8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-3-yl]-2-hydroxy-(R)-propyl}-3,3,3-trifluoro-2-methoxy-2-phenyl-(R)-propionamide Compound #645

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(R)-8-Acenaphthen-1-yl-3-(3-amino-2-hydroxy-(R)-propyl)-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (0.02 g, 0.042 mmol) was dissolved in dichloromethane (3 mL) and pyridine (0.3 mL). To the reaction mixture was then added at 0° C. (S)-(+)-α-methoxy-α-(trifluoromethyl)phenyl acetyl chloride (13.8 mg, 0.055 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for one hour, then and the solvent evaporated in vacuo to yield a crude foam. The crude foam was dissolved in ethyl acetate and successively washed twice with aqueous 0.5N HCl, twice with aqueous NaHCO₃, brine, dried with Na₂SO₄, filtered and the solvent evaporated in vacuo to yield the title compounds as a white foam.

¹H NMR (400 MHz, CDCl₃) δ 7.68–7.59 (3H, m), 7.55–7.39 (8H, m), 7.03–6.99 (2H, m), 6.98–6.93 (2H, m), 4.95–4.92 (1H, m), 4.70 (1H, d, J=4.8 Hz), 4.65 (1H, d, J=4.9 Hz), 3.99–3.97 (1H, s), 3.76 (1H, s), 3.57–3.29 (5H, m), 3.08–3.00 (2H, m), 2.79–2.76 (1H, m), 2.46–2.37 (1H, m), 2.37–2.29 (1H, m), 2.24–2.16 (1H, m), 2.00 (3H, s), 1.74–1.60 (4H, m)

MS (ES⁺) m/z 691.3 (M+H)⁺.

EXAMPLE 58
1-(4-Fluoro-phenyl)-8-(8-hydroxymethyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one Compound #734

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Step A:

[8-(tert-Butyl-dimethyl-silanyloxymethyl)-naphthalen-1-yl]-methanol (Aust. J. Chem. 1996, 49, 793–800) (0.2 g, 0.66 mmol) was dissolved in dichloromethane (8 mL). To the solution was then added 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H)-one, also known as Dess-Martin periodinane (0.56 g, 1.32 mmol). The reaction mixture was stirred for 1 hr then partitioned with an aqueous saturated solution of thiosulfate and dichloromethane. The organic layer was washed with an aqueous saturated solution of thiosulfate, an aqueous saturated solution of sodium bicarbonate, brine, dried with Na₂SO₄, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (6.0% ammonia 2.0 M in methanol/dichloromethane) to yield 8-(tert-butyl-dimethyl-silanyloxymethyl)-naphthalene-1-carbaldehyde as a clear oil.

¹H NMR (400 MHz, CDCl₃) δ 10.73 (1H, s), 8.05–7.98 (2H, m), 7.86–7.84 (1H, m), 7.65–7.63 (1H, m), 7.55–7.48 (2H, m), 5.07 (2H, s), 0.83 (9H, s), 0.01 (6H, s)

Step B:

1-(4-Fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (0.056 g, 0.22 mmol) and 8-(tert-butyl-dimethyl-silanyloxymethyl)-naphthalene-1-carbaldehyde (0.067 g, 0.22 mmol) were dissolved in dry 1,2-dichloroethane (5 mL). To the reaction mixture was added crashed 4A Molecular Sieve (0.028 g), a catalytic amount of glacial acetic acid. The reaction mixture was stirred at room temperature for 1 hr and it was then added at room temperature sodium triacetoxyborohydride (0.071 g, 0.33 mmol) under nitrogen atmosphere and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then partitioned with water and dichloromethane. The organic layer was washed with brine, dried with Na₂SO₄, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via semi-preparative HPLC (aqueous 0.5% TFA/acetonitrile) to yield crude 8-[8-(tert-butyl-dimethyl-silanyloxymethyl)-naphthalen-1-ylmethyl]-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one which was directly used to the next step.

Step C:

To the crude intermediate prepared as in STEP B was added acetonitrile (5 mL) and aqueous 5% TFA (5 mL). The reaction mixture was stirred at room temperature for 6 hrs. The solvent was then evaporated in vacuo to yield the title compound as a solid.

¹H NMR (400 MHz, CDCl₃) δ 8.85 (1H, br s), 7.86–7.81 (2H, m), 7.53–7.51 (1H, m), 7.43–7.33 (3H, m), 6.98–6.92 (2H, m), 6.84–6.79 (2H, m), 6.55 (1H, s), 5.12 (2H, br s), 4.66 (2H, s), 4.33 (1H, br s), 3.03–2.93 (4H, m), 2.38–2.31 (2H, m), 1.79–1.75 (2H, m)

MS (ES⁺) m/z 420.1 (M+H)⁺.

EXAMPLE 59
1-(4-Fluoro-phenyl)-8-(8-methoxymethyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one Compound #733

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Step A:

(8-Methoxymethyl-naphthalen-1-yl)-methanol (Tetrahedron Lett. 1997; 38, 8161–8164) (0.36 g, 1.8 mmol) was dissolved in dichloromethane (10 mL). To the solution was then added 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H)-one, also known as Dess-Martin periodinane (1.5 g, 3.6 mmol). The reaction mixture was stirred for 1 hr, then partitioned with an aqueous saturated solution of thiosulfate and dichloromethane. The organic layer was washed with an aqueous saturated solution of thiosulfate, an aqueous saturated solution of sodium bicarbonate, brine, dried with Na₂SO₄, filtered and the solvent evaporated in vacuo to yield crude 8-methoxymethyl-naphthalene-1-carbaldehyde which was used directly into the next step.

Step B:

1-(4-Fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (0.45 g, 1.8 mmol) and crude 8-methoxymethyl-naphthalene-1-carbaldehyde (0.35 g, 1.8 mmol) were dissolved in dry dichloromethane (25 mL), dry 1,2-dichloroethane (5 mL) and glacial acetic acid (0.5 mL). The reaction mixture was stirred at room temperature for 1 hr. To the reaction mixture was then added, at room temperature, sodium triacetoxyborohydride (0.57 g, 2.7 mmol) under nitrogen atmosphere and the reaction mixture was stirred at room temperature for 4 days. The reaction mixture was partitioned with water and dichloromethane. The organic layer was washed with brine, dried with Na₂SO₄, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (40% ethyl acetate in hexanes) to yield the title compound as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.85–7.80 (2H, m), 7.60–7.58 (1H, m), 7.49–7.37 (3H, m), 6.94–6.83 (4H, m), 6.12 (1H, s), 5.23 (2H, s), 4.64 (2H, s), 4.10 (2H, s), 3.38 (3H, s), 2.91–2.81 (4H, m), 2.30–2.23 (2H, m), 1.73–1.70 (2H, m)

MS (ES⁺) m/z 434.2 (M+H)⁺.

EXAMPLE 60
(R)-8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-(2-(R)-oxiranyl-ethyl)-1,3,8-triaza-spiro[4.5]decan-4-one Compound #723

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(R)-8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (0.25 g, 0.62 mmol) was dissolved in N,N-dimethylformamide (2.0 mL). To the reaction mixture was then added at 0° C. sodium hydride (60% in mineral oil, 0.03 g, 0.80 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 30 minutes. To the reaction mixture was then added, at 0° C., 2-(R)-(2-bromo-ethyl)-oxirane (0.14 g, 0.93 mmol). The reaction mixture was stirred at 0° C. under nitrogen atmosphere for 1 hr, then room temperature for 18 hours and then partitioned with water and ethyl acetate. The organic layer was dried with Na₂SO₄, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (6% methanol/dichloromethane) to yield the title compound as a foam.

¹H NMR (400 MHz, CDCl₃) δ 7.70–7.65 (1H, m), 7.59 (1H, d, J=8.2 Hz), 7.54–7.50 (2H, m), 7.43 (1H, t), 7.26 (1H, d), 7.04–6.93 (4H, m), 4.95 (1H, dd, J=3.4 and 7.8 Hz), 4.64 (2H, dd, J=4.3 and 10.7 Hz), 3.64–3.50 (3H, m), 3.38–3.31 (1H, m), 3.19–3.03 (2H, m), 2.97–2.92 (1H, m), 2.83–2.80 (1H, m), 2.75–2.73 (1H, m), 2.48–2.39 (3H, m), 2.29–2.21 (1H, m), 2.03–1.95 (1H, m), 1.75–1.62 (3H, m)

MS (ES⁺) m/z 472.2 (M+H)⁺.

EXAMPLE 61
(R)-8-Acenaphthen-1-yl-3-(4-amino-3-(S)-hydroxy-butyl)-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one Compound #722

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(R)-8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-(2-(R)-(oxiranyl-ethyl)-1,3,8-triaza-spiro[4.5]decan-4-one (0.03 g, 0.06 mmol) was dissolved in ethyl alcohol (1.0 mL). To the solution was then added concentrated ammonium hydroxide (1.0 mL) and the reaction mixture was stirred at 40° C. for 7 hrs in a pressure flask. The solvent was then evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (6.0% ammonia 2.0 M in methanol/dichloromethane) to yield the title compound as a foam.

¹H NMR (400 MHz, CDCl₃) δ 7.70–7.65 (1H, m), 7.59 (1H, d, J=8.2 Hz), 7.54–7.50 (2H, m), 7.43 (1H, t), 7.26 (1H, d), 7.04–6.93 (4H, m), 4.96–4.94 (1H, m), 4.64 (2H, dd, J=4.3 and 10.7 Hz), 3.86–3.76 (1H, m), 3.57–3.45 (2H, m), 3.39–2.98 (4H, m), 2.85–2.76 (2H, m), 2.65–2.58 (1H, m), 2.52–2.40 (2H, m), 2.32–2.24 (1H, m), 2.10–1.90 (3H, m), 1.76–1.51 (4H, m)

MS (ES⁺) m/z 489.1 (M+H)⁺.

EXAMPLE 62
8-(S)-Acetonaphthen-1-yl-1-(4-fluoro-phenyl)-3-[2-(R)-hydroxy-3-(1-phenyl-ethylamino)-propyl]-1,3,8-triaza-spiro[4.5]decan-4-one Compound #663

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8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-(S)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one (0.45 g, 0.98 mmol) and R-(+)-α-methylbenzyl amine (0.178 g, 1.47 mmol) were dissolved in ethanol (3 mL). The reaction mixture was heated at 120° C. and microwaved for 600 sec. The solvent was evaporated in vacuo to yield an oil. The crude oil was purified via flash chromatography (80% ethyl acetate/heptane) to yield the title compound as a solid.

¹H NMR (300 MHz, CDCl₃) δ 7.65 (1H, t), 7.60 (1H, d, J=8.2 Hz), 7.50–7.54 (2H, d, J=5.1 Hz), 7.44 (1H, t), 7.07–7.28 (6H, m), 6.8–7.0 (4H, m), 4.9 (1H, m), 4.6 (2H, s), 3.8 (2H, m), 3.25–3.55 (5H, m), 2.95–3.1 (2H, m), 2.78–2.82 (1H, m), 2.6 (1H, m), 2.1–2.4 (5H, m), 1.5 (2H, m), 1.3 (3H, d)

MS (ES⁺) m/z 579.2 (MH+), 427.2

EXAMPLE 63
3-(3-Amino-2-(R)-hydroxy-propyl)-8-cyclooctylmethyl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one Compound #620

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Cyclooctylmethyl-1-(4-fluoro-phenyl)-3-(S)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one (0.71 g, 1.65 mmol) was dissolved in absolute ethanol (5 mL), then mixed with ammonium hydroxide (2 mL, 14.4 mmol) and heated to 120° C. and microwaved for 600 sec. The solvent was evaporated and the resulting residue was purified by column chromatography (80% ethyl acetate/heptane) to yield the title compound as an oil.

MS (electrospray)=447.4 (MH+)

¹H NMR (300 MHz, CDCl₃) δ 1.1–1.3 (m, 2H), 1.4–1.8 (m, 16H), 2.1 (d, 2H), 2.2–2.38 (m, 2H), 2.6–2.8 (m, 5H), 2.8–3.0 (m, 2H), 3.3–3.6 (m, 2H), 3.7–3.8 (m, 2H), 4.7 (s, 2H), 6.8–7.0 (m, 4H).

EXAMPLE 64
3-(3-Amino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1,3,8-triaza-spiro[4.5]decan-4-one dihydrochloride Compound #640

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1-(4-Fluoro-phenyl)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-3-(S)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one (60 mg, 0.131 mmol) was dissolved in absolute ethanol (1 mL), then mixed with ammonium hydroxide (0.3 mL) and heated to 120° C. and microwaved for 480 sec. The solvent was evaporated. The resulting residue was dissolved in ethyl acetate and then treated with HCl in diethyl ether (1M, 1 mL) to yield the title compound as a solid.

MS (electrospray)=475.2 (MH+), 305.1

1H NMR (300 MHz, CD₃OD) δ 0.9–1.0 (m, 1H), 1.1–1.5 (m, 5H) 1.7–1.8 (m, 1H), 2.0–2.25 (m, 6H), 2.3–2.7 (m, 4H), 2.7–3.2 (m, 7H), 3.32–3.7 (m, 2H), 3.85–4.2 (m, 2H), 4.9 (m, 2H), 6.9–7.4 (m, 8H)

EXAMPLE 65
1-(4-Fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]-decan-4-one Compound #547

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Step A: (8-Hydroxymethyl-naphthalen-1-yl)-methanol

A 12-L 4-neck flask equipped with a thermocouple, an overhead stirrer, a 2-L addition funnel, and a condenser under N₂was charged with 1,8-naphthalic anhydride (200 g, 1.0 mol) in toluene (2.5 L) at room temperature. The reaction mixture was agitated while adding DIBAL-H (1.5 M in toluene, 2.664 L, 4 mol) via the addition funnel over 1.5 h. The solution was then heated to 95° C. overnight, cooled to 15° C. and then slowly diluted with ethyl acetate (2.2 L) and H₂O (2 L) followed by addition of concentrated HCl (320 mL). The resulting suspension was stirred for 30 min at room temperature, filtered, and air dried on the filter for 2 h. The resultant material was in 95% ethanol (1.2 L), stirred at 70° C. for 2 h, and filtered to yield a wet solid which was air dried overnight on the filter and then dried at 70° C. in a vacuum oven to yield (8-hydroxymethyl-naphthalen-1-yl)-methanol as a solid;

¹H NMR (400 MHz, CD₃OD) δ 7.85 (2H, dd, J=1.3 and 8.2 Hz), 7.61 (2H, dd, J=1.0 and 7.0 Hz), 7.46–7.42 (2H, m), 5.22 (2H, s), 4.82 (4H, s).

Step B: 1H,3H-Benzo[de]isochromene

A 1-L 3-neck flask equipped with an overhead stirrer, a condenser, and a thermocouple was charged with (8-hydroxymethyl-naphthalen-1-yl)-methanol (33.0 g, 0.175 mol), concentrated phosphoric acid (225 mL), and water (5 mL). The reaction mixture was stirred at 140° C. for 3 h, cooled to room temperature, diluted with CH₂Cl₂(800 mL) and transferred to a 2-L separatory funnel. After washing the organic layer with water and saturated NaHCO₃it was dried over MgSO₄and evaporated to yield 1H,3H-Benzo[de]isochromene as a solid.

¹H NMR (400 MHz, DMSO-d₆): δ 6.96–6.92 (2H, m), 6.62–6.58 (2H, m), 6.39–6.37 (2H, m), 4.17 (3H, s).

Step C: (8-Methyl-naphthalen-1-yl)-methanol (See Tetrahedron, 2000, 56, 8375–8382)

A 3-L 4-neck flask equipped with an overhead stirrer, a thermocouple, a condenser, a nitrogen inlet, and a 1-L addition funnel was charged with potassium (30 g, 0.764 mol) and THF (1 L). The metal suspension was heated to 60° C. for 30 min and then stirred to room temperature. To the reaction mixture was then added naphthalene (2 g, 0.015 mol), the suspension was stirred at room temperature for 10 min and then cooled to −20° C. to afford a blue suspension. A solution of 1H,3H-Benzo[de]isochromene (26 g, 0.153 mol) in THF (500 ml) was slowly added via the addition funnel, with addition controlled so that the reaction temperature did not exceed −15° C. After stirring for 5 h at −20° C., the suspension was removed from the cooling bath, warmed with stirring to 0° C., and then allowed to stand without stirring (potassium metal settling). The solution was decanted and the residual potassium was cooled and carefully decomposed with isopropyl alcohol (IPA) under N₂. The decanted solution was carefully treated with water (20 mL) under nitrogen and stirring was continued for 20 min. Additional water and ether were added and the organic layer was separated. The aqueous layer was extracted with CH₂Cl₂and the combined organics were dried over MgSO₄and condensed in vacuo to yield a crude material. The crude material was purified by flash chromatography (7.5/2.5 hexane/EtOAc) to yield 8-methyl-1-napthalenemethanol as a solid.

¹H NMR (300 MHz, DMSO-d₆): δ 7.82–7.80 (1H, m), 7.73–7.69 (1H, m), 7.52–7.50 (1H, m), 7.41–7.32 (3H, m), 5.17 (2H, bs), 3.01 (3H, s).

Step D: 8-Methyl-naphthalene-1-carbaldehyde

A 1-L 4-neck equipped with an overhead stirrer, a condenser and a thermocouple was charged with 8-methyl-1-napthalenemethanol (18.5 g, 0.107 mol) in CH₂Cl₂(500 mL) and stirred at room temperature under N₂. Solid Mn_(IV)O₂(61 g, 0.7 mol) was carefully added and the reaction was stirred at room temperature for 3 h, then at 40° C. for 6 h and then at room temperature overnight. The reaction mixture was diluted with CH₂Cl₂(500 mL), filtered and the filtrate was washed with 1N HCl and then dried over MgSO₄. The resulting crude material was purifed using silica gel chromatography (8/2 hexane/ethyl acetate) to yield 8-methyl-naphthalene-1-carbaldehyde as a solid.

¹H NMR (400 MHz, CDCl₃) δ 10.92 (1H, s), 8.04 (1H, dd, J=1.3 and 8.1 Hz), 7.96 (1H, dd, J=1.4 and 7.1 Hz), 7.82–7.73 (1H, m), 7.55–7.51 (1H, m), 7.49–7.44 (2H, m), 2.82 (3H, s)

Step E: 1-(4-Fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.51-decan-4-one.

A 1-L 3-neck flask equipped with an overhead stirrer and a thermocouple was charged with 8-methyl-naphthalene-1-carbaldehyde (13.75 g, 0.08 mol) and 1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (21.5 g, 0.085 mol) under N₂in CH₂Cl₂(500 mL). After stirring for 20 min, HOAc (1 mL) was added followed by careful addition of solid NaBH(OAc)₃(33.4 g, 0.157 mol). The mixture was stirred for 16 h at room temperature (suspension becomes a solution). The reaction was then warmed at 50° C. for 2 h, cooled down to room temperature and then treated with 0.5 N NaOH (50 mL), stirred for 10 min and then diluted with CH₂Cl₂(100 mL). The organic layer was isolated and dried over MgSO₄. The solvent was evaporated to yield a residue, which was suspended in diethyl ether, stirred for 20 min, filtered and dried in a 60° C. vacuum oven to yield 1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]-decan-4-one as a white solid;

¹H NMR (400 MHz, CDCl₃) δ 7.79–7.76 (1H, m), 7.72–7.69 (1H, m), 7.39–7.30 (4H, m), 6.98–6.92 (2H, m), 6.87–6.82 (2H, m), 6.24 (1H, br s), 4.66 (2H, s), 4.01 (2H, s), 3.12 (3H, s), 2.86–2.78 (4H, m), 2.33–2.23 (2H, m), 1.72 (2H, d, J=14.1 Hz);

MS (ES⁺) m/z 404.2 (M+H)⁺.

Elemental Analysis

Cal-
C: 69.26%,
H: 7.06%,
N: 11.34%,
F: 3.91%,
H₂O:

culated:

1.85%

Mea-
C: 68.96%,
H: 6.83%,
N: 11.38%,
F: 4.00%,
H₂O:

sured:

0.58%

EXAMPLE 66
Production of Cells Expressing the ORL-1, Delta, Kappa or Mu Receptor

HEK293 cells were transfected with nociceptin receptor (ORL-1, human mRNA GenBank #AF348323) or any of the opioid receptor subtype delta (δ, human mRNA Genbank #U07882) kappa (κ, human mRNA Genbank #U17298) and mu (μ, human mRNA Genbank #L29301). The vector used was pCi-neo (G418 selection). The transfections were performed with LipofectAMINE 2000 (Life Technologies Cat. # 11668-019) using the following procedure.

The day before transfection, a 24 well plate was inoculated with 2×10⁵cells per well in 0.5 ml of normal growth medium (MEM+EBSS+NEM+10% BCS). Two wells were prepared for each specialty along with a no DNA control. For each well transfected, 0.8 μg of DNA was diluted into 50 μl (total volume) of OPTI-MEM I Reduced Serum Medium (Life Technologies Cat. # 51985-034). For each well transfected, 2 μl of LipofectAMINE 2000 (LF2000) was diluted into 50 μl (total volume) of OPTI-MEM I medium and incubated for 5 minutes at room temperature. The diluted DNA and LF2000 were combined and incubated at room temperature for 20 minutes. The growth medium was aspirated from each well and replaced with 1 ml of OPTI-MEM I. A total of 100 μl of the DNA-LF2000 complexes were added to each well and mixed with gentle swirling. The plate was incubated at 37° C., 5% CO₂for 5 hours. The OPTI-MEM I medium was aspirated from each transfected well and replaced with 1 ml growth medium. The plate was returned to the incubator for 24 hours. The wells were trypsinized and cells added to 100 mm tissue culture dishes (2 dishes per well). The dishes were incubated for 24 hours. The medium was aspirated from each dish and replaced with growth medium containing 400 μg/ml Geneticin (G418) selective antibiotic. The plates were refer every 3–4 days.

Distinct colonies appeared in approximately 3 weeks. One week later, 48 out of approximately 100 colonies per dish were subcultures to 1 well each of two 24 well plates containing 1 ml of selective medium per well.

Confluent wells were expanded to 6 well plates, then T25 flasks and T75 flasks. Cell lines showing poor growth patterns were eliminated. Membranes were prepared from each cell line and receptor activity determined by a receptor binding assay.

EXAMPLE 67
Method for Measuring Affinity for the ORL-1 Receptor

The nociceptin receptor binding assay measures the binding of ¹²⁵I-Tyr¹⁴-nociceptin (2200 Ci/mmol, New England Nuclear) to human nociceptin receptor (ORL-1) on HEK293 cell membranes.

HEK293 cell membrane (prepared as described in Pulito, V. L. et al., 2000, J. Pharmacol. Exp. Ther. 294, 224–229), with the exception that the buffer used was a mixture of 50 mM Tris-HCl pH7.8, 5 mM MgCl₂and 1 mM EGTA), was added to PEI treated WGA FlashPlates (New England Nuclear) at 1 μg/well in binding buffer of 50 mM Tris-HCl pH 7.8, 5 mM MgCl₂and 1 mM EGTA. ¹²⁵]-Tyr¹⁴-nociceptin was added at a final concentration of 0.5 nM and the volume adjusted to 50 μl with binding buffer. The plate was incubated for two hours at room temperature, the reactions were aspirated and the wells washed two times with 200 μl binding buffer and then filled with 200 μl binding buffer. The plates were then sealed and counted on a Packard Top Count to determine radioactivity bound to the membranes.

For each test compound, the total binding (% Inh) was measured at several concentrations and the IC₅₀(the concentration at which 50% of the binding is inhibited) was determined from the graphical display of X=logarithm of concentration versus Y=response, using the following calculation:

$Y = (Minimum) + \frac{(Maximum - Minimum)}{(1 + 10^{\log ({EC}_{50} - X)})}$

For some of the test compound, Ki was determined, using the following calculation:

Ki values were calculated using Graphpad Prizm software, where

Ki=(IC₅₀)/(+[radioligand]/Kd)

For the ORL-1 binding, the Kd was 0.5 nM. The [radioligand] used was the same as the Kd.

The ability of representative compounds of the present invention to bind to the ORL-1 receptor in a HEK cell line using a radio-labelled nociceptin as the displaceable ligand was determine according to the procedure described above with results listed in Table 12. (Note that for the compounds which were tested more than once, the value listed in Table 12 is the calculated mean.)

TABLE 12

ID #
ORL-1 IC₅₀(nM)
ORL-1 Ki (nM)

1
8.10

2
8.49

3
173.0

4
3.63

5
20.1

6
4.66

7
13.4

8
4.86

9
233.0

10
10.5

11
22.3

12
21.0

13
10.6

14
25.2

15
31.8

16
122.0

17
10.8

18
10.3

19
15.0

20
15.8

21
9.22

22
20.7

23
80.5

24
34.8

25
33.0

26
20.3

27
11.0

28
7.74

29
121.0

30
23.2

31
44.5

32
13.7

33
95.3

34
26.9

35
30.3

36
8.73

38
8.88

39
149.0

40
9.40

41
8.32

42
19.2

43
19.9

44
43.1

45
6.45

46
16.2

47
0.86

48
1.28

49
14.8

50
298.0

51
259.0

52
0.48

53
0.47

54
3.03

55
2.75

56
4.70

57
20.0

58
476.0

59
94.5

60
396.0

61
1.09

62
0.78

63
19.2

64
33.9

65
88.5

66
39.2

67
12.2

68
10.4

69
20.5

70
72.9

71
59.3

72
82.6

73
14.0

74
8.08

75
21.1

76
16.1

78
18.0

79
18.2

100
4.10

101
1.79

102
199.0

103
18.5

104
0.72

105
81.6

106
55.4

107
57.7

108
36.9

110
45.0

111
25.2

112
18.0

113
27.4

114
15.1

115
14.0

116
17.0

117
99.7

119
2.8

121
39.9

122
32.4

123
61.2

124
41.6

125
44.1

126
38.6

127
61.0

128
38.6

129
160.0

130
48.8

131
17.0

132
33.9

133
108.0

134
329.0

135
17.3

136
1330.0

137
101.0

138
31.9

139
139.0

140
108.0

141
26.0

142
49.9

143
39.7

144
40.0

145
12.8

146
85.6

147
34.3

148
81.1

149
40.9

150
28.5

151
10.9

152
37.6

153
60.4

154
6.96

155
98.9

156
21.8

157
43.5

158
41.9

159
298.0

160
53.5

161
90.7

162
46.0

163
539.0

164
252.0

165
54.5

166
52.2

167
45.5

168
151.0

169
219.0

170
>10,000

171
19.9

173
31.8

174
68.7

175
86.3

176
51.3

177
166.0

178
62.2

179
33.0

180
116.0

181
67.3

182
7.7

183
40.0

187
17.1

188
7.1

189
7.6

190
41.0

191
10.7

192
4.2

193
14.0

194
7.00

197
2.00

198
46.0

203
1.3

204
30.9

205
17.5

206
8.0

208
10.7

209
33.00

210
3.10

211
2.90

215
9.35

217
12.7

218
6.6

219
6.6

220
100.0

224
9.00

225
7.3

227
25.0

228
3.3

229
7.6

230
105.0

250
59.7

251
10.5

252
35.2

253
20.4

254
16.3

255
66.5

256
23.5

257
14.9

258
343.0

259
199.0

260
560.0

261
54.1

262
182.0

263
86.7

264
283.0

265
366.0

266
471.0

267
178.0

268
147.0

269
157.0

270
148.0

271
0.70

275
1.19

276
7.97

280
118.0

281
8.90

282
6.35

283
13.9

284
7.86

285
78.3

289
7.05

290
14.2

291
17.5

292
462.5

293
279.0

294
1360.0

295
0.52

296
1.78

298
0.87

299
3.06

300
0.89

305
0.996

307
2.22

308
1.99

309
0.36

310
10.7

311
0.83

312
1.16

313
6.03

314
1.37

315
0.78

316
1.01

317
1.06

318
0.87

319
3.44

320
1.70

321
0.65

322
0.51

323
0.82

324
2.51

325
1.64

326
0.74

327
0.23

328
4.55

329
2.02

330
0.91

331
0.90

332
0.41

333
1.68

334
0.53

335
0.40

336
0.50

337
1.40

338
0.82

339
0.75

340
0.12

341
0.30

342
135.0

343
1.05

344
1.92

345
0.24

346
0.72

347
2.72

348
0.66

349
0.90

350
0.58

351
0.81

352
1.55

353
0.42

354
0.92

355
2.13

356
0.57

358
0.10

360
0.25

362
2.37

364
1.67

365
1.30

366
1.59

367
4.05

368
5.54

370
2.10

371
2.96

372
1.13

373
3.48

374
20.9

375
3.93

376
0.85

377
0.82

378
0.56

379
0.17

380
1.03

381
0.28

382
0.80

383
0.32

385
135.0

386
111.0

387
37.8

388
30.5

389
106.0

390
69.7

391
51.5

392
121.0

393
6.68

394
198.0

395
130.0

396
23.1

398
77.5

399
65.8

418
79.5

419
1.17

420
0.33

421
0.26

422
13.6

423
0.34

424
0.23

425
1.01

426
2.19

427
3.23

428
2.48

429
2.53

430
2.64

431
2.07

432
3.41

433
1.95

434
1.02

435
0.78

436
0.99

437
1.24

438
49.6

439
34.2

440
22.7

441
70.5

442
27.4

443
1.19

444
1.18

445
1.78

446
1.98

447
17.9

448
2.02

451
6.35

452
29.0

453
39.4

454
4.71

455
183.0

456
462.0

457
377.0

458
35.9

459
128.0

460
42.7

461
1.32

462
1.54

463
1.44

464
0.81

465
0.16

500
0.74

501
567.0

502
3920.0

503
563.0

504
39.3

505
9770

506
493.6

507
23.9

508
383.0

509
0.36

510
165.0

511
35.7

512
1.02

513
254.0

514
20.8

516
>10,000

517
>10,000

518
19.0

519
24.4

520
84.0

521
>10,000

522
213.4

523
>10,000

524
>10,000

525
>10,000

526
>10,000

527
>10,000

528
>10,000

529
>10,000

530
>10,000

531
>10,000

532
>10,000

533
>10,000

534
>10,000

535
5720

536
4300

537
569.

538
>10,000

539
>10,000

541
897

542
283

543
2640

544
204.0

546
3530

547
42.6

548
132.0

549
1220

550
13.5

551
37.4

552
92.0

553
11.0

554
80.4

555
0.25

556
1.27

564
0.22

565
0.38

566
0.77

567
1.41

568
1.36

569
0.83

570
0.24

571
0.23

572
5600

573
896

576
0.46

578
164.0

579
0.83

581
9.00

582
40.00

600
1.11

601
7.59

602
1.11

603
1.98

604
2.06

605
0.81

606
1.03

607
3.05

608
10.00

609
10.00

610
10.00

611
0.37

612
1.85

613
0.83

614
1.69

616

17.95

617

5.83

618

6.23

619

30.21

620

6.16

621

5.05

623

19.77

624

5.83

625

5.50

626

158.30

627

4.66

628

20.21

629

19.58

633

18.87

634

6.49

635

4.80

636

6.08

637

2.26

638

4.30

639

0.11

640

0.61

641

0.28

642

0.43

643

0.47

644

0.42

647

0.44

648

320.4

649

35.44

650

21.43

651

5.87

652

17.34

653

177.1

654

1.10

655

26.55

656

8.17

657

2.18

658

0.32

659

0.75

660

19.2

661

25.74

662

29.86

663

1.60

664

117.90

665

44.36

666

8.02

667

0.04

668
3.25

669
1.40

670
10.00

671
10.00

672
10.00

673
10.00

674
10.00

675

25.49

677

56.99

678

6.73

679

0.53

680

115.7

681

7.54

682
10.00

683
10.00

684
10.00

685
10.00

686
10.00

687

18.68

688

76.33

689

25.05

690

23.51

691
0.35

692

0.48

693
0.37

694
0.46

695
0.19

696
0.29

697
0.34

698
0.26

699
0.55

700
0.94

701
0.52

702
0.84

703
0.72

704

20.11

705

11.78

706

15.04

707

13.72

708

9.42

709

17.45

710

23.32

711

17.87

712

27.59

713

4.87

714

27.61

715

5.16

716

5.76

717

5.25

718

4.41

719

4.34

720

5.21

721

17.62

722
0.57

723
0.88

726

10.58

727

75.12

728

104.9

729

476.6

733

3.77

734

72.8

EXAMPLE 68
Filtration Binding Assay: ORL-1, Mu, Kappa and Delta Opioid Receptors

The assay used to measure the binding of representative test compounds to the ORL-1, delta, kappa and mu opioid receptors was run similarly, with appropriate selection and substitution of cell membrane and radiolabeled ligand. The following cell membranes and ligands were used for the determination of binding to the respective opioid receptors.

ORL-1 (Nociceptin)
1 ug/well of 3C4 cell line membrane and

0.5 nM final concentration of ¹²⁵I nociceptin

Delta (δ) opioid:
1 μg/well of 2D4 cell line membrane and a

final concentration of 2.44 nM DPDPE-³H

ligand.

Mu (μ) opioid:
5 μg/well of 1D4 cell line membrane and a

final concentration 0.8993 nM DAMGO-³H

ligand.

Kappa (κ) opioid:
7 μg/well of 2C2 cell line membrane and a

final concentration of 2.76 nM U-69,593-³H

ligand.

Both membrane and ligand were diluted such that a 25 μl addition delivered the necessary amount per well, as noted above. Both membrane and ligand were diluted in 1×ORL-1 buffer. The ORL-1 buffer was composed of 50 mM Tris-HCl, pH=7.4, 5 mM MgCl₂and 1 mM EGTA. Each test compound was diluted to a concentration in the range of from 100 μM to 10 pM (half-log curve) with 100% DMSO. To each well of a 96 well plate was added 25 μL cell membrane (as listed above), 1 μL of the diluted test compound, and 25 μL labeled ligand (as listed above) for the mu, delta, kappa or ORL-1 opioid receptor, as desired.

The plate was incubated on a rotating shaker for 2 hours at room temperature. The plate was filtered over GF/C Filterplates, prewetted in 0.03% polyethleneimine, in Filtermate 196 apparatus (Packard). The plate was then washed 6 times with ORL-1 buffer in the filtration apparatus and dried in vacuum oven for 1 hour at a temperature of 50° C.

To each well was then added 25 μL Microscint 20 (Packard) (to solubilize bound radioactivity) and each well counted in a Packard TopCount for 1 minute/well using counting parameters optimized for the particular radioligand/opioid receptor being tested. Percent radioactive ligand bound in each reaction was calculated relative to a control using DMSO for maximum binding (no inhibition). Curves were fitted and K_i's determined using Graphpad Prizm software (v3.0). The K_is were calculated using the following formula by Graphpad Prizm software, where

Ki=(IC₅₀)/(1+[radioligand]/K_d)

For the ORL-1, the K_dis 0.5 nM, for Mu it is 0.8993 nM, for kappa it is 2.76 nM and for delta it is 2.44 nM. Note that the [radioligand] (concentration of radioligand) was equivalent to the K_d.

Representative compounds of the present invention were tested for binding to the mu, kappa and delta opioid receptors using the procedure, cell membranes and ligands as described above, with results as listed in Table 13. The values listed below correspond to IC₅₀measurements, unless followed with the notation “Ki” which denotes that for the listed value is a Ki measurement. (Note that for the compounds which were tested more than once, the value listed in Table 13 is the calculated mean.)

TABLE 13

ID #
Delta IC₅₀(μM)
Kappa IC₅₀(μM)
Mu IC₅₀(μM)

1
>10
0.13
0.62

2
>10
0.19
1.20

3
9.16
0.44
4.05

4
>10
0.11
0.16

5
>10
0.12
0.78

6
>10
0.23
0.42

7
7.11
0.13
1.38

8

0.05
0.83

9

1.40
0.94

10

0.08
0.85

11

0.29
0.82

12

0.20
0.52

13

0.12
0.62

14

0.40
1.20

15

0.33
0.85

16

0.55
1.12

17
>10
0.25
0.65

18
>10
0.28
0.45

19

0.09
0.59

20
>10
0.44
1.28

21
>10
0.32
0.80

22

0.30
0.60

23

0.49
9.20

24
>10
0.75
1.25

25

0.45
1.10

26

0.29
0.79

27

0.03
0.40

28
>10
0.18
0.41

29

0.41
5.41

30
>10
0.71
2.73

31

0.28
2.93

32
>10
0.27
0.45

33

1.16
>10

34

0.27
0.68

35
>10
0.66
0.82

36
1.76
0.23
1.76

38
>10
0.20
0.99

39
>10
3.25
8.83

40
>10
0.40
1.22

41
>10
0.25
2.10

42

0.26
0.54

43

0.32
0.54

44

0.16
1.13

45
1.18
0.10
0.51

46
9.87
0.19
1.32

47
>10
0.09
0.21

48
>10
0.17
0.54

49

0.08

50

1.04

51

0.18

52
4.41
0.05
0.29

53
4.74
0.03
0.07

54
>10
0.11
0.35

55
3.90
0.37
0.60

56
1.25
0.50
0.08

57

0.07

58

1.12

59

0.10

60

0.35

61
0.64
0.08
0.32

62
0.90
0.10
0.06

63
8.78
0.23
3.43

64
7.34
0.24
1.19

65

0.51
0.58

66
5.93
0.13
0.55

67
>10
0.04
0.71

68
>10
0.02
0.26

69
>10
0.04
0.51

70

0.63

71

0.57

72

0.79
1.84

73
>10
0.25
0.68

74
8.02
0.09
0.89

75
>10
0.30
0.98

76
>10
0.02
0.51

78

0.82

79

1.04
3.11

100
>10
0.28
0.23

101
3.93
0.78
0.076

102

0.18

103

0.02

104
0.52
0.08
0.02

105

2.26

106

0.016

107

0.003

108

0.54

115

0.012

116

0.022

117

0.036

124

0.023

127

0.029

129

0.029

130

0.061

131

0.051

132

0.043

133

0.087

137

0.100

138

0.066

139

0.103

140

0.074

142

0.104

143

0.048

144

0.049

145

0.104

146

0.038

147

0.044

148

0.037

149

0.057

152

0.044

153

0.057

155

0.050

156

0.016

158

0.066

159

0.068

160

0.021

161

0.049

164

0.082

165

0.011

166

0.022

167

0.053

168

0.010

169

0.057

171

0.037

173

0.038

174

0.022

175

0.030

176

0.055

177

0.047

178

0.018

179

0.020

180

0.045

181

0.034

183

0.047

192
2.51
0.01

203
3.08
0.02
0.04

228

0.070

229

0.060

230

0.152

250
>10
0.38
1.20

251
>10
0.45
1.58

252
>10
1.34
3.70

253
2.16
0.40
0.76

254
>10
0.80
2.83

255
>10
0.62
2.49

256
>10
1.18
5.45

257
>10
0.38
0.88

259

0.50

261
>10
0.27
1.56

262

0.85

263

0.59

267

0.77

268

0.95

269

2.49

270

0.41

271
>10
0.07
0.37

275
5.01
0.09
0.45

276
>10
0.70
0.86

280

1.08
2.52

281

0.96
0.58

282

0.77
0.324

283

1.15
3.24

284

0.42
3.20

285

2.69
4.78

289

0.19
1.39

290

0.93

291

0.57
4.56

298
6.06
0.05
0.38

299
>10
1.98
0.43

300
4.84
0.13
0.51

305
8.27
0.171
0.592

307

0.21
0.75

308

0.05
0.20

309

0.09
0.04

310

1.63
1.09

311
1.70
0.28
0.27

312

0.33
0.32

313

0.50
0.33

314

0.16
0.13

315

0.28
0.30

316

0.19
0.49

317

0.22
0.92

318

0.08
0.23

319

0.58
0.32

320

0.12
0.34

321

0.15
0.16

322

0.22
0.13

323

0.10
0.72

324

0.23
0.11

325

0.21
0.73

326

0.01
0.25

327
>10
0.11
0.13

328

0.30
1.03

330
>10
0.48
0.19

331

0.12
0.46

332

0.02
0.08

333

0.39
0.24

334

0.03
0.06

335

0.07
0.13

336

0.04
0.06

337

0.25
0.55

338

0.14
0.74

339
>10
0.18
0.21

340
7.34
0.495
1.29

341
>10
0.29
0.81

342
>10
0.29
0.35

343
2.70
0.42
0.55

344
4.81
0.23
0.55

345
9.27
0.668
0.37

346
1.10
0.14
0.17

347
9.13
0.62
5.4

348
>10
0.93
5.42

349
>10
0.38
1.4

350
3.16
0.078
0.25

351
8.00
0.081
0.38

352
>10
0.27
0.94

353
8.89
0.24
0.47

354
>10
0.15
0.30

355
4.15
0.16
0.18

356
>10
0.08
0.63

358
2.46
0.13
0.17

360
2.51
0.03
0.15

362

0.82
0.20

364

0.18
0.21

365

0.79
1.75

366

0.34
0.26

367

0.36
1.86

368

0.43
1.08

370

0.29
0.35

371

0.73
0.57

372

0.26
0.70

373

1.24
0.37

374

0.73
1.96

376

0.14
0.07

377
2.61
0.093
0.16

378

0.20
0.64

379

0.14
0.16

380

0.23
0.07

381

0.10
0.22

382

0.21
0.15

383

0.06
0.54

386

3.69
>10

388

0.23
>10

389

9.84
7.06

390

1.22
1.79

391

2.18
>10

392

1.39
>10

393

1.04
>10

395

>10
1.10

396

0.81
>10

398
>10
0.25
>10

399

0.75
>10

418
>10
>10
>10

419

0.16
0.13

420
>10
0.42
0.41

421

0.13
0.04

422

>10
>10

423
>1
0.59
0.31

424
0.28
0.60
0.28

425

0.82
0.29

426
>10
1.06
2.74

427

1.45
2.37

428

0.75
0.90

429

0.67
0.80

430
>10
0.89
2.47

431

0.58
1.74

432

0.37
1.00

433

0.42
1.26

434

0.88
0.24

435

0.60
0.22

436

0.83
0.25

437

1.40
0.36

438

>10
>10

439

>10
>10

440

>10
>10

441

>10
>10

442

>10
>10

443

1.75
0.17

444

1.71
0.25

445
>10
0.10
0.06

446
4.12
0.13
0.45

447
0.48

0.48

448

0.17
1.14

451

0.77
0.32

452

1.52
0.57

453

0.39
1.70

454

0.12
0.51

455

0.38
5.16

456

>10
>10

457

9.43
>10

458

1.45
>10

459

3.21
>10

460

0.83
0.90

461
>10
0.25
1.03

462
5.62
0.15
0.12

463

1.77
0.17

464

0.34
2.38

465

0.10
0.38

505
>10
>10
>10

506

0.67
0.529

507
>10
0.277
1.29

508

0.874
0.156

509
0.50
0.11
0.02

510
5.77
0.24
0.69

511
3.91
0.42
0.14

512
0.82
0.98
0.086

513

0.46
0.05

514

0.21
0.26

516

0.77
>10

517

0.45
>10

541
9.28
2.14
0.48

542
>10
0.53
0.16

543
>10
0.71
2.09

544
>10
0.379
0.582

546
>10
2.13
1.29

547
>10
>10
>10

548
>10
0.07
0.54

549
>10
4.37
>10

550
2.61
0.09
0.16

551

1.51

552
>10
1.22
0.066

553
>10
0.75
3.4

554
10.0
9.47
>10

555
0.1
0.56
0.10

556
>10
0.438
0.382

564

0.49
0.04

565

0.41
0.03

566

0.98
0.27

567

1.00
0.17

568

0.72
0.11

569

0.29
0.14

570

0.79
0.05

571
0.05
0.20
0.04

572
3.87
9.85

573
2.09
7.22

576
1.4
0.185
0.03

578

>10
2.86

579

2.75
0.17

600

0.49
0.04

601

1.77
0.77

602

0.88
0.07

603

1.32
0.08

604

0.79
0.08

605

0.33
2.38

606

0.58
0.09

607

10.0
10.0

608

10.0
10.0

609

10.0
10.0

610

9.02
10.0

611

0.18
0.05

612

0.44
0.28

613

0.51
0.27

614

1.58
0.56

616
>5
Ki
0.09
Ki
0.20 Ki

617
>5
Ki
0.02
Ki
0.09 Ki

618
>5
Ki
0.04
Ki
0.08 Ki

619
>5
Ki
0.17
Ki
0.14 Ki

620
>5
Ki
0.19
Ki
0.28 Ki

621
>5
Ki
0.02
Ki
0.04 Ki

623
>5
Ki
0.03
Ki
0.14 Ki

624
>5
Ki
0.006
Ki
0.07 Ki

625
0.35
Ki
0.003
Ki
0.01 Ki

626
1.45
Ki
0.05
Ki
0.05 Ki

627
>5
Ki
0.01
Ki
0.06 Ki

628
1.43
Ki
0.008
Ki
0.03 Ki

629
>5
Ki
0.01
Ki
0.07 Ki

633
>5
Ki
0.04
Ki
0.44 Ki

634
>5
Ki
0.03
Ki
0.12 Ki

635
>5
Ki
0.03
Ki
0.13 Ki

636
3.40
Ki
0.01
Ki
0.23 Ki

637
>5
Ki
0.08
Ki
0.10 Ki

638
>5
Ki
0.07
Ki
0.40 Ki

639
1.60
Ki
0.03
Ki
0.01 Ki

640
>5
Ki
0.21
Ki
0.12 Ki

641
1.58
Ki
0.02
Ki
0.01 Ki

642
3.06
Ki
0.08
Ki
0.02 Ki

643
4.42
Ki
0.04
Ki
0.01 Ki

644
2.28
Ki
0.03
Ki
0.03 Ki

647
>5
Ki
0.02
Ki
0.05 Ki

648
>5
Ki
2.87
Ki
5.00 Ki

649
>5
Ki
0.68
Ki
0.89 Ki

650
>5
Ki
0.46
Ki
0.74 Ki

651
>5
Ki
0.31
Ki
0.67 Ki

652
>5
Ki
0.75
Ki
1.06 Ki

653
>5
Ki
1.58
Ki
5.00 Ki

654
>5
Ki
0.06
Ki
0.13 Ki

655
>5
Ki
0.43
Ki
2.19 Ki

656
>5
Ki
0.42
Ki
1.52 Ki

657
>5
Ki
0.04
Ki
0.09 Ki

658
>5
Ki
0.13
Ki
0.17 Ki

659
>5
Ki
0.42
Ki
0.13 Ki

660

0.87 Ki

661

0.80 Ki

662

1.60 Ki

663
>5
Ki
0.018
Ki
0.071 Ki

664
>5
Ki
0.72
Ki
0.26 Ki

665
>5
Ki
0.29
Ki
2.71 Ki

666
>5
Ki
0.14
Ki
2.59 Ki

667
4.14
Ki
0.45
Ki
0.77 Ki

668

1.25
0.19

669

1.36
0.13

670

10.00
10.00

671

10.00
10.00

672

10.00
10.00

673

10.00
10.00

674

10.00
10.00

675
3.10
Ki
0.01
Ki
0.04 Ki

677
0.53
Ki
0.10
Ki
0.08 Ki

678
5.0
Ki
0.04
Ki
0.14 Ki

679
1.52
Ki
0.03
Ki
0.05 Ki

680
>5
Ki
0.66
Ki
3.02 Ki

681
>5
Ki
0.58
Ki
0.71 Ki

682

10.00
10.00

683

10.00
10.00

684

5.90
10.00

685

10.00
10.00

686

2.52
10.00

687
0.51
Ki
0.01
Ki
0.01 Ki

688
>5
Ki
0.16
Ki
0.11 Ki

689
1.46
Ki
0.005
Ki
0.01 Ki

690
1.07
Ki
0.004
Ki
0.03 Ki

691

0.25
0.03

692
3.36
Ki
0.06
Ki
0.02 Ki

693

0.03
0.17

694

0.01
0.85

695

0.16
0.18

696

0.05
0.04

697

0.16
0.20

698

0.19
0.17

699

0.07
0.19

700

0.03
0.92

701

0.05
0.20

702

0.41
0.30

703

0.45
0.11

704
>5
Ki
0.34
Ki
1.33 Ki

705
>5
Ki
0.71
Ki
1.50 Ki

706

0.48 Ki

707

0.55 Ki

708

0.49 Ki

709

0.89 Ki

710
>5
Ki
0.36
Ki
1.09 Ki

711

0.82 Ki

712

1.95 Ki

713

0.23 Ki

714
>5
Ki

0.59 Ki

715
>5
Ki
0.15
Ki
0.56 Ki

716
>5
Ki
0.47
Ki
1.31 Ki

717
>5
Ki
0.33
Ki
1.32 Ki

718
>5
Ki
0.03
Ki
0.48 Ki

719
>5
Ki
0.17
Ki
0.64 Ki

720
>5
Ki
0.16
Ki
0.57 Ki

721
>5
Ki
0.17
Ki
0.59 Ki

722

0.44
0.48

723

0.83
0.08

726
0.53
Ki
0.005
Ki
0.04 Ki

727
>5
Ki
0.21
Ki
0.12 Ki

728
>5
Ki
0.14
Ki
0.08 Ki

729
0.35
Ki
0.01
Ki
0.003 Ki

733
>5
Ki
0.07
Ki
0.08 Ki

734
>5
Ki
1.93
Ki
>5 Ki

EXAMPLE 69
In Vitro Assay—Filtration Binding Assay, Dopamine

The assay was used to measure the binding of representative compounds to D2 receptor, with appropriate selection and substitution of cell membrane and radiolabeled ligand. The following cell membranes and ligands were used for the determination of binding to the respective D2 receptor.

- Dopamine: 0.4 μg/well of membrane from cos-7 cell which has been transfected with cloned human Dopamine, Spiperone-I125 ligand at 150 pM final

Both membrane and ligand were diluted such that a 25 μl addition delivered the necessary amount per well, as noted above. Both membrane and ligand were diluted in TNE buffer. The TNE buffer was a mixture of 50 mM Tris-HCl pH=7.4, 5 mM EDTA and 50 mM NaCl. Each test compound was diluted to a concentration from 10 μM to 1 pM with 100% DMSO. To each well of a 96 well plate was added 140 μL of TNE buffer, 10 μL of the diluted test compound in DMSO, 25 μL of spiperone and 25 μL of membrane.

The plate was incubated on a rotating shaker for 1 hour at room temperature. The plate was filtered over GF/C Filterplates, prewetted in 0.03% polyethleneimine, in Filtermate 196 apparatus (Packard). The plate was then washed 6 times with ORL-1 buffer in the filtration apparatus and dried in vacuum oven for 1 hour at a temperature of 50° C.

Representative compounds of the present invention were tested according to the procedure outlined above with results as listed in Table 14.

TABLE 14

ID #
IC₅₀(nM)

422
2208

424
278.2

426
>10,000

430
>10,000

433
3520

439
2334

440
1517

442
3229

327
387.5

EXAMPLE 70
Elevated Plus Maze (EPM) and Spontaneous Locomotor Activity (SMA) (Pellow, S., Chopin, P., File. S. E. and Briley, M., J Neurosci Methods, (1985) 14, 149–167)

The procedure used in the EPM was based on the natural aversion of rodents to explore brightly illuminated open and high places, as well as their innate tendency for thigmotaxis. When rats are placed on the elevated-plus maze, they have a normal tendency to remain in the enclosed arms of the maze and avoid venturing into the open arms. Animals treated with typical or atypical anxiolytics show an increase in the percentage of time spent (% Time) and/or the percentage of entries made (% Entries) into the open arms.

The spontaneous locomotor activity test (SMA) was an automated procedure for measuring the effect of a test compound on spontaneous motor activity in an open-field. A drug-induced decrease in spontaneous horizontal or vertical motor activity is regarded as an indication of sedation.

Animals

Male Long-Evans Hooded rats weighing 180 to 200 grams were purchased from Charles River Inc (Portage Mich.). The rats were housed in groups of four at an ambient temperature of 21 to 23° C. in a room with an automated 12/12 hour light/dark cycle, and access to water and a commercial rodent food ad libitum.

EPM Test Apparatus

Each black plastic maze had two open arms and two arms with 40 cm high walls (enclosed arms) of equal 50 cm length extending from the center at right angles, such that arms of similar type are opposite each other. Each plus-maze was elevated approximately 60 cm above the floor. Infrared photo-beams that cross the entrance of each arm and the center of the maze detected the exploratory activity of an animal in the maze. Rats were divided into groups (N=8 to 12) and test compound or vehicle was administered either orally (p.o.) by gavage in a dose volume equivalent to 5 mL/kg or intraperitoneally (i.p.) in a dose volume of 1 mL/kg. One hour after dosing (for p.o. administration) or 30 minutes after dosing (for i.p. administration), rats were placed on an open arm of the plus-maze facing the center. The 10 minute test was initiated when the rat enters the center of the apparatus. Data collection was automated.

SMA Test Apparatus

The test apparatus consisted of a plastic cubicle (42.0 cm in length; 42.0 cm in width and 30.5 cm height) that was placed in the center of a main frame. Photocell sensors (16 beams from front to back and 16 beams from side to side) were built into the sides of the frame for monitoring horizontal movement. The photocells were located at right angles to each other, projecting horizontal infrared beams of light 2.5 cm apart and 3 cm above the floor to measure horizontal activity, and 2.5 cm apart and 14 cm above the floor to measure vertical activity. Rats were divided into groups (N=8 to 12). Test compound or vehicle was administered either orally (p.o.) by gavage in a dose volume equivalent to 5 mL/kg or intraperitoneally (i.p.) in a dose volume of 1 mL/kg. At 50 minutes after p.o. administration or at 20 minutes after i.p. administration, each rat was placed into a separate plastic cubicle, and spontaneous exploratory activity was recorded for 10 minutes. Horizontal activity and vertical movements of the rats were recorded by counting the number of times the beams of light were interrupted (horizontal and vertical counts). Collection of the data and preliminary data analysis was automated.

Combined SMA/EPM Test Procedure

All animals were tested in the SMA 50 minutes after drug administration, for a 10 minute test session. Upon completion of the SMA test, the same animals were immediately placed on the EPM for a 10 minute test session.

Test Compounds

The test compound was dissolved in polyethylene glycol, molecular weight 200 (PEG-200) for i.p. administration. Test compound was suspended in an aqueous vehicle (MC) comprised of 0.5% Methylcellulose for p.o. administration.

Derivation and Analysis of EPM Data

Anxiolytic activity of a test compound in the EPM was quantified using two parameters. The percent of total time spent by a rat in one of the two open arms of the apparatus (% open arm time) was calculated as 100× (time on open arms)/(total time of test session)

The number of times a rat entered the open arms relative to the total entries into all arms and the center area (% open arm entries) was calculated as 100× (entries into open arms)/(entries into open and closed arms, plus center)

A test compound was considered active in rats whose % open arm time or % open arm entries was significantly greater than in rats that received vehicle. Data was analyzed for statistical significance between drug and vehicle-treated groups via one tailed Mann-Whitney T-Test. If the probability was less than 5% (p<0.05) that an increase in the % open arm time and/or % open arm entries in the drug-treated group compared to the vehicle-treated group was due to chance, then the dose of the test compound was considered active.

The total number of entries into all arms and the center of the EPM was recorded as part of the automated data collection in this test. This information (total entries) served as a measure of spontaneous motor activity on the EPM. Compounds with sedative activity reduced the total number of entries in the EPM test. A test compound was considered to have sedative activity in rats whose total entries were significantly less than in rats that received vehicle. Data was analyzed for statistical significance between drug and vehicle-treated groups via one tailed Mann-Whitney T-Test. If the probability was less than 5% (p<0.05) that a decrease in the total entries in the drug-treated group compared to the vehicle-treated group was due to chance, then the dose of the test compound was considered to be a dose at which the compound produces sedation.

Derivation and Analysis of SMA Data

A test compound was considered sedative in rats whose horizontal activity (HA) or vertical movements (VM, rearing) counts were significantly less than that in vehicle-treated rats. HA data was analyzed for statistical significance between drug and vehicle-treated groups that were administered either the vehicle or each dose of the test compound by a one-way analysis of variance. Then Dunnett's multiple comparison method was used to test for a reduction (p<0.05, 1-tailed) in the average number of HA counts or VM counts in drug-treated groups, compared to a concurrently run vehicle-treated group. If the probability was less than 5% (p<0.05) that a decrease in HA and/or VM in the drug-treated group compared to a concurrently run vehicle-treated group was due to chance, then the dose of the test compound was considered to have sedative activity. Mann-Whitney T-Test was used in cases where the distribution of the data was non-gaussian.

Representative compounds of the present invention were tested according to the EPM and SMA procedures described above, with results as listed in Table 15–19, below. Statistical significance (P<0.05) was determined using a Mann-Whitney U Test (one-tailed); NS indicates results were not statistically significant.

TABLE 15

EPM and SMA Assay Results

Acute (30 min) Intraperitoneal Administration Compound #64 (*)

% Open
% Open

Hori-
Vertical

Dosage

Arm
Arm
Total
zontal
Move-

mg/kg, i.p.
Sta-
Time
Entries
Entries
Activity
ment

(# Animals)
tistics
(EPM)
(EPM)
(EPM)
(SMA)
(SMA)

Vehicle
Mean
8.92
5.50
94.8
3210
50.0

(PEG-200)
S.E.M.
±1.65
±0.86
±4.11
±158
±2.82

(40)
%
0.0%
0.0%
0.0%
0.0%
0.0%

Change

0.03 Mg/Kg
Mean
9.21
5.92
95.7
3259
49.8

(28)
S.E.M.
±2.14
±1.17
±2.73
±169
±2.37

%
3.2%
7.6%
0.95%
1.5%
−0.4%

Change

P-value
NS
NS
NS
NS
NS

0.1 Mg/Kg
Mean
15.3
10.6
95.4
3845
55.7

(32)
S.E.M.
±1.97
±1.17
±3.91
±200
±2.72

%
71.5%
92.7%
0.63%
19.8%
11.4%

Change

P-value
0.0053
0.0004
NS
0.0091
NS

0.3 Mg/Kg
Mean
13.7
7.86
99.7
3561
58.0

(32)
S.E.M.
±1.96
±0.87
±3.60
±181
±2.69

%
53.6%
42.9%
5.2%
10.9%
16.0%

Change

P-value
0.0159
0.0146
NS
NS
0.0270

1 Mg/Kg
Mean
14.0
7.78
94.8
3611
53.8

(32)
S.E.M.
±2.11
±0.89
±3.73
±184
±1.83

%
57.0%
41.4%
0.0%
12.5%
7.6%

Change

P-value
0.0155
0.0099
NS
NS
NS

3 Mg/Kg
Mean
11.2
7.38
90.8
3449
51.1

(28)
S.E.M.
±1.86
±1.00
±3.90
±172
±2.14

%
25.6%
34.2%
−4.2%
7.4%
2.2%

Change

P-value
NS
NS
NS
NS
NS

10 Mg/Kg
Mean
11.8
7.36
86.8
2803
46.9

(8)
S.E.M.
±4.03
±1.85
±6.91
±165
±3.72

%
32.3%
38.8%
−8.4%
−12.7%
−6.2%

Change

P-value
NS
NS
NS
NS
NS

(*) Compound #64 was also tested in the SMA and EPM assays, using oral administration, but found to be inactive.

TABLE 16

EPM and SMA Assay Results

Acute (1 hr) Oral Administration - Mixture 3 Parts

Compound #422 (*):1 Part Compound #438

% Open
% Open

Hori-
Vertical

Dosage

Arm
Arm
Total
zontal
Move-

mg/kg, p.o.
Sta-
Time
Entries
Entries
Activity
ment

(# Animals)
tistics
(EPM)
(EPM)
(EPM)
(SMA)
(SMA)

Vehicle
Mean
9.61
6.59
102.0
3085
50.7

(0.5%
S.E.M.
±1.04
±0.59
±3.02
±129
±1.27

Methyl-
%
0.0%
0.0%
0.0%
0.0%
0.0%

cellulose)
Change

(80)

0.03 Mg/Kg
Mean
7.80
5.53
88.3
3307
53.6

(16)
S.E.M.
±1.82
±1.00
±5.25
±240
±2.41

%
−18.8%
−16.1%
13.4%
7.2%
5.7%

Change

P-value
NS
NS
0.0235
NS
NS

0.1 Mg/Kg
Mean
11.5
7.73
101
3467
59.4

(32)
S.E.M.
±1.97
±1.04
±3.56
±165
±2.50

%
19.7%
17.3%
−1.0%
12.4%
17.2%

Change

P-value
NS
NS
NS
0.0077
0.0011

0.3 Mg/Kg
Mean
12.1
7.85
98.7
3397
53.7

(56)
S.E.M.
±1.38
±0.64
±2.26
±150
±1.68

%
25.9%
19.1%
−3.2%
10.1%
5.9%

Change

P-value
NS
0.0444
NS
0.0227
0.0408

1 Mg/Kg
Mean
14.0
9.55
99.7
3645
55.7

(48)
S.E.M.
±1.68
±0.75
±3.34
±164
±1.83

%
45.7%
44.9%
−2.3%
18.2%
9.9%

Change

P-value
0.0082
0.0009
NS
0.0015
0.0180

3 Mg/Kg
Mean
14.0
8.88
102.0
3621
55.0

(48)
S.E.M.
±1.44
±0.70
±2.23
±188
±1.81

%
45.7%
34.7%
0.0%
17.4%
8.5%

Change

P-value
0.0032
0.0043
NS
0.0051
0.0338

10 Mg/Kg
Mean
17.0
10.3
97.6
3207
51.5

(56)
S.E.M.
±1.51
±0.77
±3.06
±124
±1.51

%
76.9%
56.3%
−4.3%
4.0%
1.6%

Change

P-value
P <
P <
NS
NS
NS

0.0001
0.0001

30 Mg/Kg
Mean
10.6
8.90
80.7
2741
46.3

(24)
S.E.M.
±1.55
±1.16
±4.20
±171
±2.39

%
10.3%
35.1%
−20.9%
−11.2%
−8.7%

Change

P-value
NS
0.0197
P <
NS
0.0091

0.0001

(*) Compound #422 was also tested in the SMA and EPM assays, using oral administration, but was found to be inactive.

TABLE 17

EPM and SMA Assay Results

Acute (1 hr) Oral Administration Compound #424 (†)

% Open
% Open

Hori-
Vertical

Dosage

Arm
Arm
Total
zontal
Move-

mg/kg, p.o.
Sta-
Time
Entries
Entries
Activity
ment

(# Animals)
tistics
(EPM)
(EPM)
(EPM)
(SMA)
(SMA)

Vehicle
Mean
5.76
5.48
96.7
2881
49.1

(0.5%
S.E.M.
±1.50
±1.21
±4.65
±208
±3.28

Methyl-
%
0.0%
0.0%
0.0%
0.0%
0.0%

cellulose)
Change

(24)

0.3 Mg/Kg
Mean
9.80
7.33
90.0
3033
54.6

(24)
S.E.M.
±2.09
±1.09
±4.90
±232
±3.11

%
70.1%
33.8%
−6.9%
5.3%
11.2%

Change

P-value
0.0206
NS
NS
NS
NS

1 Mg/Kg
Mean
9.76
7.49
91.5
2752
50.3

(24)
S.E.M.
±1.83
±1.28
±3.11
±188
±3.65

%
69.4%
36.7%
−5.3%
−4.5%
2.4%

Change

P-value
NS
NS
NS
NS
NS

3 Mg/Kg
Mean
10.1
7.92
96.3
3300
56.8

(24)
S.E.M.
±1.83
±1.15
±3.43
±145
±2.35

%
75.3%
44.5%
−0.4%
14.5%
15.7%

Change

P-value
0.0426
0.0398
NS
0.0239
NS

10 Mg/Kg
Mean
7.54
7.49
102.6
2588
44.2

(24)
S.E.M.
±1.75
±1.32
±4.63
±215
±3.32

%
30.9%
36.7%
6.1%
−10.2%
−10.1%

Change

P-value
NS
NS
NS
NS
NS

(†) Compound #424 was also tested in the SMA and EPM assays, using intraperotineal administration, with the following results.

In the rat EPM, at doses of 0.1 mg/kg, 0.3 mg/kg and 3.0 mg/kg, Compound #424 produced significant increases in percent open arm time (P<0.04;) with peak activity occuring at doses 0.1 mg/kg and 3 mg/kg (97.5% increase as compared to vehicle). At doses of 0.1 mg/kg, 0.3 mg/kg, 3.0 mg/kg, and 10.0 mg/kg Compound #424 also produced significant increases in percent open arm entries (P<0.03) with peak activity occuring at 3.0 mg/kg and 10.0 mg/kg doses (205% and 237% increase as compared to from vehicle, respectively). Compound #424 significantly reduced the total number of entries into various zones of the maze at doses 1.0 mg/kg, 3.0 mg/kg and 10.0 mg/kg (18.6%, 60.3%, and 76.7% reductions, respectively).

In the rat SMA, at doses of 3.0 mg/kg and 10.0 mg/kg, Compound #424 produced significant reductions (55% and 83.7% reductions, respectively) in horizontal activity (P<0.001; Dunnett's multiple comparison test). At doses of 1.0 mg/kg, 3.0 mg/kg and 10.0 mg/kg (17.8%, 73.4%, 93.9% reductions, respectively) Compound #424 produced significant reductions (P<0.05; Dunnett's multiple comparison test) in the number of vertical movements (rearing behavior).

TABLE 18

EPM and SMA Assay Results

Acute (1 hr) Oral Administration of Compound #438

% Open
% Open

Hori-
Vertical

Dosage

Arm
Arm
Total
zontal
Move-

mg/kg, p.o.
Sta-
Time
Entries
Entries
Activity
ment

(# Animals)
tistics
(EPM)
(EPM)
(EPM)
(SMA)
(SMA)

Vehicle
Mean
8.21
5.78
101.0
3244
48.7

0.5%
S.E.M.
±1.18
±0.532
±3.81
±168
±1.85

Methyl-
%
0.0%
0.0%
0.0%
0.0%
0.0%

cellulose
Change

(40)

0.03 Mg/Kg
Mean
6.67
5.14
102.0
3565
54.8

(24)
S.E.M.
±1.59
±0.984
±3.67
±216
±2.75

%
−18.8%
−11.1%
1.0%
9.9%
12.5%

Change

P-value
NS
NS
NS
NS
NS

0.1 Mg/Kg
Mean
12.1
7.77
103
3435
53.1

(24)
S.E.M.
±1.92
±0.913
±3.81
±160
±2.25

%
47.4%
34.4%
2.0%
5.9%
9.0%

Change

P-value
0.0434
0.0352
NS
NS
NS

0.3 Mg/Kg
Mean
13.8
8.95
99.8
3450
51.7

(24)
S.E.M.
±1.56
±0.891
±3.64
±155
±2.36

%
68.1%
54.8%
−1.2%
6.4%
6.2%

Change

P-value
0.0038
0.0010
NS
NS
NS

1 Mg/Kg
Mean
14.8
9.95
103.0
3772
56.6

(24)
S.E.M.
±2.13
±1.23
±4.08
±170
±2.32

%
80.3%
72.1%
2.0%
16.3%
16.2%

Change

P-value
0.0053
0.0025
NS
NS
NS

3 Mg/Kg
Mean
12.4
8.34
101.0
3502
55.3

(24)
S.E.M.
±1.73
±1.02
±4.75
±223
±2.17

%
51.0%
44.3%
0.0%
8.0%
13.6%

Change

P-value
0.0170
0.0336
NS
NS
NS

10 Mg/Kg
Mean
8.14
6.42
94.5
3115
54.5

(24)
S.E.M.
±1.30
±0.856
±3.41
±168
±1.73

%
0.9%
11.1%
−6.4%
−4.0%
11.9%

Change

P-value
0.3644
NS
NS
NS
NS

30 Mg/Kg
Mean
3.21
6.65
86.3
2730
45.3

(7/8)
S.E.M.
±1.76
±2.28
±6.40
±185
±3.34

%
−60.9%
15.1%
−14.6%
−15.8%
−7.0%

Change

P-value
0.0486
NS
NS
NS
NS

TABLE 19

EPM and SMA Assay Results

Sub-Chroinc (8-day/once a day) Oral

Administration Compound #438

% Open
% Open

Hori-
Vertical

Dosage

Arm
Arm
Total
zontal
Move-

mg/kg, p.o.
Sta-
Time
Entries
Entries
Activity
ment

(# Animals)
tistics
(EPM)
(EPM)
(EPM)
(SMA)
(SMA)

Vehicle
Mean
7.96
6.53
101.0
3451
54.6

(0.5%
S.E.M.
±1.87
±1.05
±4.72
±196
±3.35

methyl-
%
0.0%
0.0%
0.0%
0.0%
0.0%

cellulose)
Change

(16)

0.1 Mg/Kg
Mean
17.2
9.17
102
3813
62.9

(16)
S.E.M.
±1.84
±0.931
±4.82
±170
±1.75

%
116.1%
40.4%
1.0%
10.5%
15.2%

Change

P-value
0.0012
0.0338
NS
NS
NS

0.3 Mg/Kg
Mean
21.8
11.8
99.1
4390
61.1

(16)
S.E.M.
±1.8
±0.891
±5.56
±253
±3.61

%
173.9%
80.7%
−1.9%
27.2%
11.9%

Change

P-value
P <
0.0007
NS
P < 0.05
NS

0.0001

1 Mg/Kg
Mean
15.1
9.57
99.6
3979
59.5

(16)
S.E.M.
±1.96
±1.12
±3.42
±151
±2.53

%
89.7%
46.6%
−1.4%
15.3%
9.0%

Change

P-value
0.0064
0.0007
NS
NS
NS

3 Mg/Kg
Mean
16.9
9.0
106.0
4253
59.9

(16)
S.E.M.
±2.9
±1.21
±4.42
±306
±3.47

%
112.3%
37.8%
5.0%
23.2%
9.7%

Change

P-value
0.0047
0.0367
NS
P < 0.05
NS

EXAMPLE 71
In Vivo Study—Vogel Rat Conflict Assay (Vogel, J. R., et al., Psychopharmacology, (1971), 21,1)

This behavioral assay assesses the anxiolytic activity of a test compound by determining the ability of rats to release (disinhibit) behavior that has been suppressed by punishment.

Method

Male adult rats were deprived of water for 48 hours and were deprived of food for 24 hours prior to testing. After the first 24 hours of water deprivation, the rats were placed in the conflict chamber for a training period; during which time the rats were allowed 200 unpunished licks from a bottle containing tap water. The experiment was run the following day. The rats were dosed with the test compound orally by gavage or intraperitoneally (i.p.). At the expected time of peak activity (30 minutes for i.p administration and 60 min for oral administration), the rats were placed in the conflict chamber and were allowed access to tap water. If they failed to drink, the experiment was terminated in 5 min, and the animals were evaluated for signs of CNS depression. The first lick initiated a 3 min test session. Subsequently, every 20^thlick was punished with an 0.2 sec, 0.6 milliampere (RMS) shock delivered via the stainless steel drinking tube. Vehicle treated control animals were generally willing to accept a median of 3 to 8 shocks per test session. Animals treated with an active anxiolytic drug tolerated significantly more shocks than control animals. The Wilcoxon rank-sum test (Mann-Whitney U-test) was used to test for an increase (p<0.05, 1 tailed) in the median number of shocks in the drug treated group compared with a concurrently run control treated group. The assay was considered to be valid if the effects of a known anxiolytic (a positive control) were detected within the same experiment. A test compound was considered active if there was a significant difference in the median number of shocks tolerated between the drug treated and the control group.

Compound #64 and a mixture of three parts Compound #422 to one part Compound 438 (denoted as “CMPD mix” in the table below) were tested according to the procedure described above, with results as listed in Table 20, below. No./Group indicates the number of animals tested for the listed dosage. % increase in mean no of shock is as compared with vehicle. Statistically significant results were those with a Mann-Whitney U Test (one tailed) p value of <0.05.

TABLE 20

% Increase

Dose
No/
Mean

(mg/kg, i.p.)
Group
No. of Shocks
P Value

PEG-200 (Vehicle)
0
25
0
—

Compound #64
0.3
8
−10%
0.3294

Compound #64
1
24
25%
0.3480

Compound #64
3
24
96%
0.0692

Compound #64
10
22
150%
0.0002

Compound #64
30
8
−26%
0.5000

% Increase

Dose
No/
Mean

(mg/kg, p.o.)
Group
No. of Shocks
P Value

0.5% Methylcellulose
0
17
0
—

(Vehicle)

CMPD mix
0.3
8
8%
0.3304

CMPD mix
1
8
39%
0.4418

CMPD mix
3
8
47%
0.0425

CMPD mix
10
18
54%
0.1634

CMPD mix
30
12
47%
0.0327

EXAMPLE 72
Stress Induced Hyperthermia in Vivo Assay

Procedure

Male Long-Evans Hooded rats weighing 180 to 200 grams at the time of purchase were obtained from Charles River Laboratories (Raleigh, N.C.). Upon arrival, the animals were group housed four per cage in quarantine for 5 days in wire-mesh cages at an ambient temperature of 21 to 23° C. with an automated 12/12 hour light/dark cycle and ad libitum access to water and a commercial rodent chow. The rats were then transferred to a general housing room for a one-week acclimation with housing and environmental conditions, and 12/12 hour light/dark cycle conditions. Animals were fasted overnight (18 hours) prior to experiment.

On the day of experiment, group-housed (4/group) Long-Evans Hooded rats were divided into various treatment groups (N=8 to 32) and test compound at 0.03–3.0 mg/kg or vehicle was administered orally (p.o.) by gavage in a dose volume equivalent to 5 mL/kg. One hour after dosing, baseline rectal temperatures were recorded for each rat. Rats were then immediately isolated in shoebox cages with ALPHA-DRY bedding. Rectal temperatures were then recorded at 15 min, 30 min, and 45 min after isolation (i.e, 1 hr 15 min, 1 hr 30 min, and 1 hr 45 minutes after test compound or vehicle administration). All experiments were conducted during the light cycle. After completion of the behavioral portion of the study, each animal was killed via decapitation using a guillotine and trunk blood was collected in 5 mL vacutainer tube containing EDTA and placed on ice. The samples were then centrifuged at 3800 RPM for 10 minutes and plasma was removed and placed on dry ice in an Eppendorff sample tube. Plasma samples were stored at −80° C. and later used for determining ACTH, corticosterone, and glucose levels. Plasma samples were outsourced to Anilytics, Inc. for determination of plasma levels of ACTH, coricosterone, and glucose. A Mann-Whitney U t-test (one-tailed) was used for statistical analysis of behavioral data and an unpaired t-test (one-tailed) was used for analysis of plasma ACTH, corticosterone, and glucose levels.

Results

Compound #438 was suspended in an aqueous vehicle comprised of 0.5% (w/v) methylcellulose (15 centipoises) solution.

Rats treated with Compound #438 showed an attenuation of rectal temperature in the SIH model as described above, at 0.03 mg/kg, 0.01 mg/kg, 0.3 mg/kg, 1.0 mg/kg and 3.0 mg/kg, with measured temperatures and p values as listed in Table 21. In the Table below, the abbreviation “S.E.M.” represents the standard error of the mean and the abbreviation “N.S.” indicates that the p value indicated that any measured difference in temperature was not statistically significant.

TABLE 21

Temp.
Temp.
Temp.
Temp.

Compound

° C.
° C.
° C.
° C.

(dose)

0 (Basal)
15 min
30 min
45 min

Vehicle
Mean
37.4
38.7
38.9
38.9

S.E.M.
±0.12
±0.062
±0.053
±0.049

P-value

Cmpd #438
Mean
37.5
38.7
38.6
38.4

(0.03 mg/kg)
S.E.M.
±0.166
±0.0707
±0.139
±0.128

P-value
NS
NS
0.0188
0.0018

Cmpd #438
Mean
37.2
38.4
38.5
38.5

(0.1 Mg/Kg)
S.E.M.
±0.119
±0.093
±0.101
±0.125

P-value
NS
0.0139
0.0011
0.0098

Cmpd #438
Mean
37.4
38.4
38.5
38.3

(0.3 Mg/Kg)
S.E.M.
±0.121
±0.0873
±0.0782
±0.0853

P-value
NS
0.0068
<0.0001
<0.0001

Cmpd #438
Mean
37.1
38.4
38.5
38.2

(1.0 Mg/Kg)
S.E.M.
±0.105
±0.108
±0.0856
±0.109

P-value
0.0280
0.0148
<0.0001
<0.0001

Cmpd #438
Mean
37.0
38.2
38.4
38.2

(3.0 Mg/Kg)
S.E.M.
±0.0949
±0.146
±0.124
±0.131

P-value
0.0121
0.0011
0.0002
<0.0001

Plasma stress hormone levels for rats treated with Compound #438 showed a 25% reduction in plasma ACTH levels at 0.3 mg/kg, the reduction calculated to be statistically significant (P=0.0170). Changes in the plasma levels of corticosterone were not statistically significant.

EXAMPLE 73
Tissue Distribution Assay

Procedure

Male Long-Evans Hooded rats weighing 180 to 200 grams at the time of purchase were obtained from Charles River Laboratories (Portage, Mich.). Upon arrival, the animals were group housed four per cage in quarantine for 5 days in wire-mesh cages at an ambient temperature of 21 to 23° C. with an automated 12/12 hour light/dark cycle and ad libitum access to water and a commercial rodent chow. The rats were then transferred to a general housing room for a one-week acclimation with housing and environmental conditions, and 12/12 hour light/dark cycle conditions. Animals were fasted overnight (18 hours) prior to experiment.

On the day of experiment, two Long-Evans Hooded rats were treated orally with a vehicle (0.5% methylcellulose) and eight rats were treated orally with 10.0 mg/kg of Compound #438. Five hours after drug administration, each treated animal was killed via decapitation using a guillotine, trunk blood was collected and the following tissues were harvested for analysis of compound distribution in the following tissues/systems: (1) brain regions including the cortex, cerebellum, hypothalamus and hippocampus, (2) heart, (3) lung, (4) kidney, (5) liver, (6) spleen, (7) adrenal glands, (8) small intestines, (9) large intestines, (10) muscle, as well as (11) whole blood and (12) plasma.

Whole blood and plasma samples were prepared for analysis as follows. 400 μL of acetonitrile containing 1 μM internal standard (propranolol) was added to 200 μL of plasma or whole blood to precipitate proteins. Samples were centrifuged at 5000 g for 5 minutes and supernatant removed for analysis by LC-MS. 400 μL of water was added to adjust sample solvent strength and prevent peak splitting. Calibration standards were prepared by adding appropriate volumes of stock solution directly into plasma and treated identically to collected plasma samples. LC-MS analysis was performed using MRM for detection of characteristic ions for each test compound and internal standard.

Tissue samples were prepared for analysis as follows. Individual tissue samples were extracted with 2 mLs of ethanol if the tissue weight was 1 gram or less. A volume of ethanol in milliliters equal to twice the weight in grams was added if the tissue weight was greater than 1 gram. The extracts were centrifuged to precipitate solids and the supernatant was transferred to clean Eppendorf tubes. 200 μL of this was transferred to autosampler vials and 20 μL of acetonitrile containing 1 μM internal standard (propranolol) was added for analysis by LC/MS. Calibration standards were prepared using an equivalent volume of tissue extract at 2 ml per gram from undosed or vehicle dosed animals. The extracts from brain tissue were concentrated in order to achieve lower detection limits (<1 nM). For these, 20 μL of 1 uM propranolol in acetonitrile was added to 700 μL of extract and blown to dryness under nitrogen. These were then reconstituted in 100 μL of 1:1:acetonitrile:water and analyzed by LC/MS. Calibration standards were prepared in blank extract and treated exactly as samples.

Measured values within the various samples were as listed in Table 22 and 23, for vehicle and Compound #438 treated rats, respectively. Results are reported in μmoles/kg or ng/g as appropriate converting the sample concentrations based on extraction solvent/tissue ratio. These units are on the same scale as μmoles/l or ng/ml as typically reported for plasma and can be used for comparison. Detection of analytes down to 0.005 μmoles/kg were typical for the LC-MS used.

TABLE 22

Vehicle (Control)

Animal 9 (Vehicle)

Animal 10 (Vehicle)

μM
μM/kg
μM
μM/kg

Cortex
0.000
0.000
0.000
0.000

Cerebellum
0.000
0.000
0.000
0.000

Hypothalamus
0.000
0.000
0.000
0.000

Hippocampus
0.000
0.000
0.000
0.000

Heart
0.000
0.000
0.000
0.000

Lung
0.000
0.000
0.000
0.000

Liver
0.000
0.000
0.000
0.000

Spleen
0.000
0.000
0.000
0.000

Kidney
0.000
0.000
0.000
0.000

Adrenal Glands
0.000
0.000
0.000
0.000

Lr intestine
0.000
0.000
0.000
0.000

Sm Intestine
0.011
0.027
0.000
0.000

Muscle
0.000
0.000
0.000
0.000

Plasma
0.000

0.000

Whole Blood
0.000

0.000

TABLE 23

Compund #438 Tissue Concentration

Animal 1
Animal 2
Animal 3

μM
μM/kg
μM
μM/kg
μM
μM/kg

Cortex
0.0062
0.030
0.0047
0.020
0.0047
0.030

Cerebellum
0.0402
0.161
0.014
0.090
0.0189
0.140

Hypothalamus
0.0124
0.413
0.0055
0.367
0.0064
0.427

Hippocampus
0.0195
0.650
0.0021
0.070
0.0009
0.030

Heart
2.036
4.072
2.485
5.144
2.346
4.692

Lung
5.821
15.119
4.737
12.632
5.153
13.741

Liver
6.664
13.257
6.409
12.785
4.632
9.294

Spleen
9.140
25.389
7.232
17.857
7.163
23.106

Kidney
3.747
7.546
4.031
8.062
4.123
8.027

Adrenal Glands
0.967
24.175
0.988
28.229
1.289
28.644

Lg intestine
4.518
9.036
12.478
29.019
30.593
59.694

Sm Intestine
21.836
53.916
27.120
84.750
17.359
48.219

Muscle
0.919
1.814
0.688
1.371
0.791
1.560

Plasma
0.419

0.426

0.360

Whole Blood
0.166

0.147

0.135

Animal 4
Animal 5
Animal 6

μM
μM/kg
μM
μM/kg
μM
μM/kg

Cortex
0.0026
0.0130
0.0038
0.017
0.0023
0.010

Cerebellum
0.0045
0.0350
0.0026
0.019
0.0101
0.067

Hypothalamus
0.0062
1.2400
0.0030
0.200
0.0036
0.360

Hippocampus
0.0140
0.2550
0.005
0.200
0.002
0.010

Heart
1.664
3.328
1.785
3.471
2.478
4.878

Lung
4.361
11.629
3.533
7.438
5.290
20.346

Liver
3.879
7.758
4.006
7.861
5.090
10.180

Spleen
5.207
13.703
6.730
19.229
7.742
26.697

Kidney
3.841
7.570
3.993
7.791
4.718
9.523

Adrenal Glands
1.088
31.086
1.075
26.875
1.487
59.480

Lr intestine
2.231
6.562
24.916
56.627
9.584
26.622

Sm Intestine
13.898
38.077
16.743
41.858
14.131
56.524

Muscle
0.651
1.280
0.917
1.754
0.977
1.954

Plasma
0.289

0.183

0.174

Whole Blood
0.088

0.469

0.266

Animal 7

Animal 8

μM
μM/kg
μM
μM/kg

Cortex
0.0055
0.025
0.0139
0.062

Cerebellum
0.0138
0.095
0.0102
0.068

Hypothalamus
0.0101
0.673
0.0027
0.180

Hippocampus
0.0065
0.217
0.0019
0.190

Heart
1.572
2.977
2.083
4.261

Lung
5.655
15.930
6.189
11.902

Liver
5.887
10.398
5.677
11.120

Spleen
8.062
29.859
9.205
28.766

Kidney
4.109
7.645
4.750
8.782

Adrenal Glands
1.267
42.233
1.946
64.867

Lr intestine
33.756
68.194
5.070
9.941

Sm Intestine
25.408
72.594
13.018
39.448

Muscle
0.882
1.707
1.509
3.006

Plasma
0.268

0.470

Whole Blood
0.061

0.093

EXAMPLE 74
Oral Formulation

As a specific embodiment of an oral composition, 100 mg of the compound #438 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gel capsule.

While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents.

Number	Name	Date	Kind
3238216	Janssen	Mar 1966	A
3839340	Scharpf	Oct 1974	A
4329353	Stokbroekx et al.	May 1982	A
5739336	Weinhardt et al.	Apr 1998	A
6043366	Adam et al.	Mar 2000	A
6060482	Heine et al.	May 2000	A
6071925	Adam et al.	Jun 2000	A
6113527	Adam et al.	Sep 2000	A
6262066	Tulshian et al.	Jul 2001	B1
6277991	Hohlweg et al.	Aug 2001	B1
6777421	Jordan et al.	Aug 2004	B1
20030109539	Jordan et al.	Jun 2003	A1

Number	Date	Country
921125	Jun 1999	EP
0997464	Mar 2000	EP
997464	May 2000	EP
2000-169476	Jun 2000	JP
WO 9312789	Jul 1993	WO
WO 9507294	Mar 1995	WO
9959997	Nov 1999	WO
WO 9959997	Nov 1999	WO
WO 0006545	Feb 2000	WO
WO 0107050	Feb 2001	WO
WO 0136418	May 2001	WO
WO 0139723	Jun 2001	WO
WO 01 46192	Jun 2001	WO
WO 0196337	Jun 2001	WO
WO 03010168	Jul 2001	WO
WO 0194346	Dec 2001	WO
WO 0283673	Oct 2002	WO
WO 02085355	Oct 2002	WO

Hydroxy alkyl substituted 1,3,8-Triazaspiro[4.5]decan-4-one derivatives useful for the treatment of orl-1receptor mediated disorders

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