# Patent

## Title
Hydroxy alkyl substituted 1,3,8-triazaspiro[4.5]decan-4-one derivatives useful for the treatment of ORL-1 receptor mediated disorders

## Abstract

The present invention is directed to novel hydroxy alkyl substituted 1,3,8-triazaspiro[4.5]decan-4-one derivatives of the general formula




wherein all variables are as defined herein, 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, 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 disorder (ADHD), Alzheimer's disease, for improved cognition or memory and for mood stabilization.

## Background
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a continuation of U.S. application Ser. No. 10/656,934 filed on Sep. 5, 2003 now U.S. Pat. No. 7,081,463, which claims benefit of nonprovisional of U.S. Application No. 60/409,134 filed on Sep. 9, 2002, the complete disclosures of aforesaid applications being incorporated herein by reference.


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)




wherein

R0 is selected from the group consisting of




each RA and RB is independently selected from the group consisting of hydrogen and C1-4alkyl;
each RC and RD is independently selected from the group consisting of hydrogen, hydroxy, carboxy, C1-4alkyl, C1-4alkoxy, nitro, cyano, N(RE)2, aryl, arC1-4alkyl, heteroaryl or heterocycloalkyl; wherein the aryl, arC1-4alkyl, heteroaryl or heterocycloalkyl substituent is optionally substituted with one or more substituents independently selected from hydroxy, carboxy, C1-4alkyl, C1-4alkoxy, nitro, cyano or N(RE)2;
each RE is independently selected from the group consisting of hydrogen and C1-4alkyl;
X is selected from the group consisting of —NR1R2, —C(O)—NR1R2, —NR1—C(O)—R2, —OR1, —SR1, —SOR1, —SO2R1, —S—(C2-4alkyl)-NR1R2, —S—(C2-4alkyl)-NR1—C(O)O—C(CH3)3, —SO—(C1-4alkyl)-NR1R2 and —SO2—(C1-4alkyl)-NR1R2; wherein the alkyl portion of the —S—(C2-4alkyl)-NR1R2, —SO—(C1-4alkyl)-NR1R2 or —SO2—(C1-4alkyl)-NR1R2 group is optionally substituted with one or more substituents independently selected from carboxy, hydroxy, hydroxyC1-4alkyl, C1-4alkyl, C1-4alkoxycarbonyl or —CONR1R2;
each R1 and R2 is independently selected from the group consisting of hydrogen, C1-8alkyl, C1-8alkoxy, C1-8alkoxycarbonyl, cycloalkyl, cycloalkyl-C1-4alkyl, partially unsaturated carbocyclyl, partially unsaturated carbocyclyl-C1-4alkyl, aryl, arC1-4alkyl, arC1-4alkoxy, heteroaryl, heteroaryl-C1-4alkyl, heterocycloalkyl, heterocycloalkyl-C1-4alkyl, —C(O)—C1-6alkyl, —C(O)-aryl, —C(O)-arC1-4alkyl, —C(O)-heteroaryl, —C(O)-heterocycloalkyl, —C(O)O-cycloalkyl and —C(O)O-aryl, —C(O)O-arC1-4alkyl, —C(O)O-(partially unsaturated carbocyclyl), C(O)-heteroaryl, —C(O)O-heterocycloalkyl; wherein the C1-8alkyl, cycloalkyl, partially unsaturated carbocyclyl, aryl, arC1-4alkyl, 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, C1-4alkyl, C1-4alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, C(O)—C1-4alkyl, C1-4alkoxycarbonyl, N(RE)2, N(RE)2—C1-4alkyl, N(RE)—C(O)C(CH3)3, —C1-4alkyl-N(RE)C(O)O—C1-4alkyl and —N(RE)C(O)O—C1-4alkyl, aryl, aryloxy, cycloalkyl, heteroaryl, aryl substituted heteroarylaminosulfonyl or C1-6alkylthio;
alternatively when R1 and R2 are both bound to the same nitrogen atom, R1 and R2 are 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, C1-4alkyl, hydroxy substituted C1-4alkyl, C1-4alkoxy, C1-4alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, nitro, cyano, N(RE)2, aryl, arC1-4alkyl, heteroaryl, heterocycloalkyl, di(C1-6)alkylamino-carbonyl, C1-4alkoxycarbonyl-N(RE)— or arylamino-C1-4alkyl; wherein the aryl, arC1-4alkyl, heteroaryl or heterocycloalkyl substituent is optionally further substituted with one or more substituents independently selected from halogen, hydroxy, carboxy, C1-4alkyl, C1-4alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, N(RE)2, phenyl or substituted phenyl; wherein the substituents on the phenyl are one or more independently selected from halogen, hydroxy, carboxy, C1-4alkyl, C1-4alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano or N(RE)2;
R3 is selected from the group consisting of aryl, arC1-6alkyl and heteroaryl; wherein the aryl, arC1-6alkyl or heteroaryl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, carboxy, C1-4alkyl, C1-4alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano or N(RE)2;
n is an integer from 0 to 2;
R4 is selected from the group consisting of hydroxy, C1-4alkyl and hydroxy substituted C1-4alkyl;
m is an integer from 0 to 1;
L1 is selected from the group consisting of C1-6alkyl and C3-6alkenyl; wherein the double bond of the C3-6alkenyl group is at least one carbon atom removed from the attachment point to the N atom; and wherein the C1-6alkyl or C3-6alkenyl group is optionally substituted with one to two substituents independently selected from hydroxy, fluoro, C1-6alkyl, fluorinated C1-6alkyl or C1-6alkoxy;




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

p is an integer from 0 to 5;
R5 is selected from the group consisting of hydroxy, carboxy, halogen, C1-6alkyl, hydroxy substituted C1-6alkyl, C1-6alkoxy, nitro, cyano, NR1R2, trifluoromethyl, trifluoromethoxy, C1-4alkoxycarbonyl, —SO—NR1R2, —S2—NR1R2 and —C(O)—NR1R2;
q is an integer from 0 to 1;
R6 is selected from the group consisting of -(L2)0-1-R7;
L2 is selected from the group consisting of —C1-6alkyl-, —C2-4alkenyl-, —C2-6alkynyl-, —O—, —S—, —NH—, —N(C1-4alkyl)-, —C1-6alkyl-O—, —C1-6alkyl-S—, —O—C1-6alkyl-, —S—C1-6alkyl-, —O—C2-6alkyl-O—, —S—C2-6alkyl-S—, —SO2—, —SO2NH—, —SO2N(C1-4alkyl)-, —NH—SO2—, —N(C1-4alkyl)-SO2—, —C(O)—O— and —O—C(O)—;
R7 is 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, C1-6alkyl, C1-6alkoxy, nitro, cyano, N(RE)2, trifluoromethyl, trifluoromethoxy, C1-4alkoxycarbonyl, —SO2—N(RE)2 and —C(O)—N(RE)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)




wherein

R3 is selected from the group consisting of aryl, arC1-6alkyl and heteroaryl; wherein the aryl, arC1-6alkyl or heteroaryl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, carboxy, C1-4alkyl, C1-4alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano or N(RE)2;
wherein each RE is independently selected from hydrogen or C1-4alkyl;
n is an integer from 0 to 2;
R4 is selected from the group consisting of hydroxy, C1-4alkyl and hydroxy substituted C1-4alkyl;
Y is selected from the group consisting of hydrogen, C1-4alkyl, t-butoxycarbonyl and




m is an integer from 0 to 1;

L1 is selected from the group consisting of C1-6alkyl and C3-6alkenyl; wherein the double bond of the C3-6alkenyl group is at least one carbon atom removed from the attachment point to the N atom; and wherein the C1-6alkyl or C3-6alkenyl group is optionally substituted with one to two substituents independently selected from hydroxy, fluoro, C1-6alkyl, fluorinated C1-6alkyl or C1-6alkoxy;




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

p is an integer from 0 to 5;
R5 is selected from the group consisting of hydroxy, carboxy, halogen, C1-6alkyl, hydroxy substituted C1-6alkyl, C1-6alkoxy, nitro, cyano, NR1R2, trifluoromethyl, trifluoromethoxy, C1-4alkoxycarbonyl, —SO—NR1R2, —SO2—NR1R2 and —C(O)—NR1R2;
q is an integer from 0 to 1;
R6 is selected from the group consisting of -(L2)0-1-R7;
L2 is selected from the group consisting of —C1-6alkyl-, —C2-4alkenyl-, —C2-6alkynyl-, —O—, —S—, —NH—, —N(C1-4alkyl)-, —C1-6alkyl-O—, —C1-6alkyl-S—, —O—C1-6alkyl-, —S—C1-6alkyl-, —O—C2-6alkyl-O—, —S—C2-6alkyl-S—, —SO2—, —SO2NH—, —SO2N(C1-4alkyl)-, —NH—SO2—, —N(C1-4alkyl)-SO2—, —C(O)—O— and —O—C(O)—;
R7 is 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, C1-6alkyl, C1-6alkoxy, nitro, cyano, N(RE)2, trifluoromethyl, trifluoromethoxy, C1-4alkoxycarbonyl, —SO2—N(RE)2 and —C(O)—N(RE)2;
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)




wherein R0, R3, n, R4, m, L1,





p, R5, q and R6 are 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 R0 is selected from the group consisting of




each RA and RB is independently selected from the group consisting of hydrogen and C1-4alkyl;

each RC and RD is independently selected from the group consisting of hydrogen, hydroxy, carboxy, C1-4alkyl, C1-4alkoxy, nitro, cyano, N(RE)2, aryl, arC1-4alkyl, heteroaryl or heterocycloalkyl; wherein the aryl, arC1-4alkyl, heteroaryl or heterocycloalkyl substituent is optionally substituted with one or more substituents independently selected from hydroxy, carboxy, C1-4alkyl, C1-4alkoxy, nitro, cyano or N(RE)2;
each RE is independently selected from the group consisting of hydrogen and C1-4alkyl;
X is selected from the group consisting of —NR1R2, —C(O)—NR1R2, —NR1—C(O)—R2, —OR1, —SR1, —SOR1, —SO2R1, —S—(C2-4alkyl)-NR1R2, —S—(C2-4alkyl)-NR1—C(O)O—C(CH3)3, —SO—(C1-4alkyl)-NR1R2 and —SO2—(C1-4alkyl)-NR1R2; wherein the alkyl portion of the —S—(C2-4alkyl)-NR1R2, —SO—(C1-4alkyl)-NR1R2 or —SO2—(C1-4alkyl)-NR1R2 group is optionally substituted with one or more substituents independently selected from carboxy, hydroxy, hydroxyC1-4alkyl, C1-4alkyl, C1-4alkoxycarbonyl or —CONR1R2;
each R1 and R2 is independently selected from the group consisting of hydrogen, C1-8alkyl, C1-8alkoxy, cycloalkyl, cycloalkyl-C1-4alkyl, partially unsaturated carbocyclyl, aryl, arC1-4alkyl, arC1-4alkoxy, heteroaryl, heteroaryl-C1-4alkyl, heterocycloalkyl, heterocycloalkyl-C1-4alkyl, —C(O)—C1-6alkyl, —C(O)-aryl, —C(O)-arC1-4alkyl, —C(O)-heteroaryl and —C(O)-heterocycloalkyl; wherein the C1-8alkyl, cycloalkyl, partially unsaturated carbocyclyl, aryl, arC1-4alkyl, 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, C1-4alkyl, C1-4alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, C(O)—C1-4alkyl, C1-4alkoxycarbonyl, N(RE)2, N(RE)2—C1-4alkyl, N(RE)—C(O)C(CH3)3, aryl, aryloxy, cycloalkyl, heteroaryl, aryl substituted heteroarylaminosulfonyl or C1-6alkylthio;
alternatively when R1 and R2 are both bound to the same nitrogen atom, R1 and R2 are 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, C1-4alkyl, C1-4alkoxy, C1-4alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, nitro, cyano, N(RE)2, aryl, arC1-4alkyl, heteroaryl, heterocycloalkyl, di(C1-6)alkylamino-carbonyl, t-butoxycarbonyl or arylamino-C1-4alkyl; wherein the aryl, arC1-4alkyl, heteroaryl or heterocycloalkyl substituent is optionally further substituted with one or more substituents independently selected from halogen, hydroxy, carboxy, C1-4alkyl, C1-4alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, N(RE)2 or substituted phenyl; wherein the substituents on the phenyl are one or more independently selected from halogen, hydroxy, carboxy, C1-4alkyl, C1-4alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano or N(RE)2;
R3 is selected from the group consisting of aryl, arC1-6alkyl and heteroaryl; wherein the aryl, arC1-6alkyl or heteroaryl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, carboxy, C1-4alkyl, C1-4alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano or N(RE)2;
n is an integer from 0 to 2;
R4 is selected from the group consisting of hydroxy, C1-4alkyl and hydroxy substituted C1-4alkyl;
m is an integer from 0 to 1;
L1 is selected from the group consisting of C1-6alkyl and C3-6alkenyl; wherein the double bond of the C3-6alkenyl group is at least one carbon atom removed from the attachment point to the N atom; and wherein the C1-6alkyl or C3-6alkenyl group is optionally substituted with one to two substituents independently selected from hydroxy, fluoro, C1-6alkyl, fluorinated C1-6alkyl or C1-6alkoxy;




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

p is an integer from 0 to 5;
R5 is selected from the group consisting of hydroxy, carboxy, halogen, C1-6alkyl, C1-6alkoxy, nitro, cyano, NR1R2, trifluoromethyl, trifluoromethoxy, C1-4alkoxycarbonyl, —SO—NR1R2, —SO2—NR1R2 and —C(O)—NR1R2;
q is an integer from 0 to 1;
R6 is selected from the group consisting of -(L2)0-1-R7;
L2 is selected from the group consisting of —C1-6alkyl-, —C2-4alkenyl-, -C2-6alkynyl-, —O—, —S—, —NH—, —N(C1-4alkyl)-, —C1-6alkyl-O—, —C1-6alkyl-S—, —O—C1-6alkyl-, —S—C1-6alkyl-, —O—C2-6alkyl-O—, —S—C2-6alkyl-S—, —SO2—, —SO2NH—, —SO2N(C1-4alkyl)-, —NH—SO2—, —N(C1-4alkyl)-SO2—, —C(O)—O— and —O—C(O)—;
R7 is 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, C1-6alkyl, C1-6alkoxy, nitro, cyano, N(RE)2, trifluoromethyl, trifluoromethoxy, C1-4alkoxycarbonyl, —SO2—N(RE)2 and —C(O)—N(RE)2;
and pharmaceutically acceptable salts thereof.
In an embodiment of the present invention are compounds of the formula (E)




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 R3 is selected from the group consisting of aryl, arC1-6alkyl and heteroaryl; wherein the aryl, arC1-6alkyl or heteroaryl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, carboxy, C1-4alkyl, C1-4alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano or N(RE)2; wherein each RE is independently selected from hydrogen or C1-4alkyl;
n is an integer from 0 to 2;
R4 is selected from the group consisting of hydroxy, C1-4alkyl and hydroxy substituted C1-4alkyl;
Y is selected from the group consisting of hydrogen, C1-4alkyl, t-butoxycarbonyl and




m is an integer from 0 to 1;

L1 is selected from the group consisting of C1-6alkyl and C3-6alkenyl; wherein the double bond of the C3-6alkenyl group is at least one carbon atom removed from the attachment point to the N atom; and wherein the C1-6alkyl or C3-6alkenyl group is optionally substituted with one to two substituents independently selected from hydroxy, fluoro, C1-6alkyl, fluorinated C1-6alkyl or C1-6alkoxy;




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

p is an integer from 0 to 5;
R5 is selected from the group consisting of hydroxy, carboxy, halogen, C1-6alkyl, C1-6alkoxy, nitro, cyano, NR1R2, trifluoromethyl, trifluoromethoxy, C1-4alkoxycarbonyl, —SO—NR1R2, —SO2—NR1R2 and —C(O)—NR1R2;
q is an integer from 0 to 1;
R6 is selected from the group consisting of -(L2)0-1-R7;
L2 is selected from the group consisting of —C1-6alkyl-, —C2-4alkenyl-, —C2-6alkynyl-, —O—, —S—, —NH—, —N(C1-4alkyl)-, —C1-6alkyl-O—, —C1-6alkyl-S—, —O—C1-6alkyl-, —S—C1-6alkyl-, —O—C2-6alkyl-O—, —S—C2-6alkyl-S—, —SO2—, —SO2NH—, —SO2N(C1-4alkyl)-, —NH—SO2—, —N(C1-4alkyl)-SO2—, —C(O)—O— and —O—C(O)—;
R7 is 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, C1-6alkyl, C1-6alkoxy, nitro, cyano, N(RE)2, trifluoromethyl, trifluoromethoxy, C1-4alkoxycarbonyl, —SO2—N(RE)2 and —C(O)—N(RE)2;
and pharmaceutically acceptable salts thereof.
In an embodiment of the present invention are compounds of the formula (Ia)




wherein X, R3, n, R4, m, L1,





p, R5, q and R6 are 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 IC50 to 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 R0 is




In another embodiment of the present invention, R0 is





In yet another embodiment of the present invention, R0 is





Preferably, R0 is selected from the group consisting of





and





More preferably, R0 is





In yet another embodiment of the present invention, R0 is





Preferably, R0 is





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




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





group is present in the S stereo-configuration.

In an embodiment of the present invention RA and RB are each independently selected from hydrogen, methyl and ethyl, preferably RA and RB are each hydrogen. In another embodiment of the present invention RC and RD are each independently selected from hydrogen and C1-4alkyl, preferably RC and RD are each hydrogen. In yet another embodiment of the present invention RE is selected from the group consisting of hydrogen, methyl and ethyl, preferably RE is 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—(C2-4alkyl)-NR1R2, —SO—(C1-4alkyl)-NR1R2, —SO2—(C1-4alkyl)-NR1R2 wherein the alkyl portion of the —S—(C2-4alkyl)-NR1R2, —S—(C1-4alkyl)-NR1—C(O)O—C(CH3)3, —SO—(C1-4alkyl)-NR1R2 or —SO2—(C1-4alkyl)-NR1R2 group is optionally substituted with one to two substituents independently selected from C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxycarbonyl or carboxy. Preferably, X is selected from the group consisting of —NR1R2, —OR1, —SR1, —S—(C2-4alkyl)—NR1—C(O)O—C(CH3)3, —S—(C2-4alkyl)-NR1R2 wherein the alkyl portion of the —S—(C2-4alkyl)-NR1R2 or —S—(C2-4alkyl)-NR1—C(O)O—C(CH3)3 group is optionally substituted with a carboxy or C1-4alkoxycarbonyl group. More preferably, X is selected from the group consisting of —NR1R2, —OR1, —SR1, —S—CH2CH(CO2H)—NH—C(O)—CH3 and —S—CH2CH(CO2H)—NH—C(O)O—C(CH3)3. More preferably still, X is selected from the group consisting of —NR1R2, —SR1 and —S—CH2CH(CO2H)—NH—C(O)—CH3.
In an embodiment of the present invention R1 is selected from the group consisting of hydrogen, C1-4alkyl, C1-4alkoxy, C1-4alkoxycarbonyl, aryl, arC1-4alkyl, arC1-4alkyloxy, heteroaryl, heteroaryl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, cycloalkyl-alkyl, C(O)—C1-4alkyl and —C(O)-heteroaryl; wherein the C1-4alkyl, aryl, arC1-4alkyl, 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, C1-4alkyl, C1-4alkoxy, C1-4alkoxycarbonyl, N(RE)2, N(RE)2—C1-4alkyl, N(RE)—C(O)OC(CH3)3, nitro, trifluoromethyl, trifluoromethoxy, phenyl, phenoxy, heteroaryl, cycloalkyl, 1-phenyl-pyrazol-2-yl-aminosulfonyl or C1-4alkylthio. Preferably, In an embodiment of the present invention R1 is selected from the group consisting of hydrogen, C1-4alkyl, C1-4alkoxy, aryl, arC1-4alkyl, arC1-4alkyloxy, heteroaryl, heteroaryl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, cycloalkyl-alkyl, C(O)—C1-4alkyl and —C(O)-heteroaryl; wherein the C1-4alkyl, aryl, arC1-4alkyl, 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, C1-4alkyl, C1-4alkoxy, C1-4alkoxycarbonyl, N(RE)2, N(RE)2—C1-4alkyl, N(RE)—C(O)OC(CH3)3, nitro, trifluoromethyl, trifluoromethoxy, phenyl, phenoxy, heteroaryl, cycloalkyl, 1-phenyl-pyrazol-2-yl-aminosulfonyl or C1-4alkylthio.
In another embodiment of the present invention, R1 is selected from the group consisting of hydrogen, C1-4alkyl, arC1-4alkyl, C1-4alkoxycarbonyl and C(O)—C1-4alkyl; wherein the C1-4alkyl, arC1-4alkyl or aryl group, whether alone or part of a substituent group, is optionally substituted with one to two substituents independently selected from carboxy, C1-4alkyl, C1-4alkoxy, C1-4alkoxycarbonyl, N(RE)2, N(RE)2—C1-4alkyl or N(RE)—C(O)OC(CH3)3. Preferably, R1 is selected from the group consisting of hydrogen, C1-4alkyl, arC1-4alkyl and C(O)—C1-4alkyl; wherein the C1-4alkyl, arC1-4alkyl or aryl group, whether alone or part of a substituent group, is optionally substituted with one to two substituents independently selected from carboxy, C1-4alkyl, C1-4alkoxy, C1-4alkoxycarbonyl, N(RE)2, N(RE)2—C1-4alkyl or N(RE)—C(O)OC(CH3)3.
In another embodiment of the present invention, R1 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, t-butyl, amino-n-propyl, dimethylaminoethyl, benzyl, phenylethyl, 4-methyl-benzyl,




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





Preferably, R1 is selected from the group consisting of hydrogen, methyl, n-propyl, n-butyl, t-butyl, dimethylaminoethyl, benzyl, 4-methyl-benzyl,









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





In another embodiment of the present invention, R1 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, t-butyl, dimethylaminoethyl, benzyl, phenylethyl,








3-methyl-phenyl, 2-(3,4-dimethoxyphenyl)-ethyl, ethoxy-carbonyl-methyl, dimethylamino-ethyl and 2-amino-2-methoxycarbonyl-ethyl. Preferably, R1 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, t-butyl, dimethylaminoethyl, benzyl,





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

In yet another embodiment of the present invention, R1 is 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,




Preferably, R1 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, t-butyl, dimethylaminoethyl, benzyl,





In another embodiment of the present invention R1 is 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 R1 is selected from the group consisting of hydrogen, t-butoxycarbonyl and amino-n-propyl.
In an embodiment of the present invention R2 is selected from the group consisting of hydrogen, C1-4alkyl, C1-4alkoxy, cycloalkyl, cycloalkyl-C1-4alkyl, aryl, arC1-4alkyl, arC1-4alkyloxy, partially unsaturated carbocyclyl, particularly unsaturated carbocyclyl-C1-4alkyl, heteroaryl, heteroaryl-C1-4alkyl, heterocycloalkyl, heterocycloalkyl-C1-4alkyl, —C(O)—C1-4alkyl, —C(O)-aryl, —C(O)-arC1-4alkyl, —C(O)-heteroaryl, —C(O)-heterocycloalkyl, —C(O)O-cycloalkyl and —C(OO)—C1-4alkyl; wherein the C1-4alkyl, aryl, arC1-4alkyl, 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, C1-4alkyl, C1-4alkoxy, C1-4alkoxycarbonyl, N(RE)2, N(RE)2—C1-4alkyl, (CH3)3COC(O)—N(RE)—C1-4-alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, phenyl, phenoxy, heteroaryl, cycloalkyl, 1-phenyl substituted heteroaryl-aminosulfonyl, —C(O)—C1-4alkyl or C1-4alkylthio. Preferably, R2 is selected from the group consisting of hydrogen, C1-4alkyl, C1-4alkoxy, cycloalkyl-C1-4alkyl, aryl, arC1-4alkyl, arC1-4alkyloxy, partially unsaturated carbocyclyl, heteroaryl, heteroaryl-C1-4alkyl, heterocycloalkyl, heterocycloalkyl-C1-4alkyl, —C(O)—C1-4alkyl, —C(O)-aryl, —C(O)-arC1-4alkyl, —C(O)-heteroaryl and —C(O)-heterocycloalkyl; wherein the C1-4alkyl, aryl, arC1-4alkyl, 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, C1-4alkyl, C1-4alkoxy, C1-4alkoxycarbonyl, N(RE)2, N(RE)2—C1-4alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, phenyl, phenoxy, heteroaryl, cycloalkyl, 1-phenyl substituted heteroaryl-aminosulfonyl, —C(O)—C1-4alkyl or C1-4alkylthio.
In an embodiment of the present invention, R2 is selected from the group consisting of hydrogen, C1-4alkyl, C1-4alkoxy, cycloalkyl, aryl, arC1-4alkyl, arC1-4alkyloxy, partially unsaturated carbocyclyl, partially unsaturated carbocyclyl-C1-4alkyl, heteroaryl, heteroaryl-C1-4alkyl, heterocycloalkyl, heterocycloalkyl-C1-4alkyl, cycloalkyl-C1-4alkyl, —C(O)arC1-4alkyl, —C(O)-heteroaryl, —C(OO)-cycloalkyl and —C(O)O—C1-4alkyl; wherein the C1-4alkyl, aryl, arC1-4alkyl, 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, C1-4alkyl, C1-4alkoxy, C1-4alkoxycarbonyl, N(RE)2, N(RE)2—C1-4alkyl, alkyl, nitro, trifluoromethyl, trifluoromethoxy, phenyl, phenoxy, heteroaryl, cycloalkyl, 1-phenyl-pyrazol-2-yl-aminosulfonyl or C1-4alkylthio. Preferably, R2 is selected from the group consisting of hydrogen, C1-4alkyl, C1-4alkoxy, aryl, arC1-4alkyl, arC1-4alkyloxy, partially unsaturated carbocyclyl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, cycloalkyl-alkyl and —C(O)-heteroaryl; wherein the C1-4alkyl, aryl, arC1-4alkyl, 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, C1-4alkyl, C1-4alkoxy, C1-4alkoxycarbonyl, N(RE)2, N(RE)2—C1-4alkyl, nitro, trifluoromethyl, trifluoromethoxy, phenyl, phenoxy, heteroaryl, cycloalkyl, 1-phenyl-pyrazol-2-yl-aminosulfonyl or C1-4alkylthio.
In an embodiment of the present invention, R2 is selected from the group consisting of hydrogen, methyl, methoxy, ethyl, carboxy-methyl, methoxycarbonylmethyl, 2,2,2-trifluoroethyl, 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-dimethoxyphenyl)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-imidazol-4-yl)ethyl, 2-(1,2,3,4-tetrahydro-isoquinolinyl), 2-furyl-methyl,




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, R2 is selected from the group consisting of hydrogen, methyl, methoxy, ethyl, carboxy-methyl, ethoxycarbonylmethyl, 2,2,2,-trifluoroethyl, 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-dimethoxyphenyl)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,





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.

In an embodiment of the present invention, R2 is selected from the group consisting of hydrogen, methyl, methoxy, ethyl, ethoxycarbonyl-methyl, 2,2,2-trifluoroethyl, 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,




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, R2 is selected from the group consisting of hydrogen, methyl, methoxy, ethyl, ethoxycarbonyl-methyl, 2,2,2-trifluoroethyl, 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,





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, R2 is 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,




2S-hydroxy-S-cyclopentyl-methyl, 2S-hydroxy-S-cyclohexyl-methyl, 2S-hydroxy-S-cycloheptyl-methyl and 2-phenoxy-ethyl. Preferably, R2 is 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,





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 R2 is 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, R2 is 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 R1 and R2 are both bound to the same nitrogen atom, R1 and R2 are 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, C1-4alkyl, hydroxy substituted C1-4alkyl, C1-4alkoxy, C1-4alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, nitro, cyano, N(RE)2, phenyl, arC1-4alkyl, heterocycloalkyl, di(C1-4alkyl)amino-carbonyl, C1-4alkoxycarbonylamino or phenylamino-C1-4alkyl; wherein the phenyl or arC1-4alkyl substituent on the heteroaryl or heterocycloalkyl group is optionally substituted with one or two substituents independently selected from halogen, hydroxy, carboxy, C1-4alkyl, C1-4alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, N(RE)2 or substituted phenyl; wherein the substituents on the phenyl are one to three independently selected from halogen. Preferably, when R1 and R2 are both bound to the same nitrogen atom, R1 and R2 are 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, C1-4alkyl, C1-4alkoxy, C1-4alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, nitro, cyano, N(RE)2, phenyl, arC1-4alkyl, heterocycloalkyl, di(C1-4alkyl)amino-carbonyl, or phenylamino-C1-4alkyl; wherein the phenyl or arC1-4alkyl substituent on the heteroaryl or heterocycloalkyl group is optionally substituted with one or two substituents independently selected from halogen, hydroxy, carboxy, C1-4alkyl, C1-4alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, N(RE)2 or substituted phenyl; wherein the substituents on the phenyl are one to three independently selected from halogen.
In an embodiment of the present invention, when R1 and R2 are both bound to the same nitrogen atom, R1 and R2 are 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, C1-4alkyl, hydroxy substituted C1-4alkyl, C1-4alkoxy, phenyl, arC1-4alkyl, heterocycloalkyl, C1-4alkoxycarbonyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, di(C1-4alkyl)amino-carbonyl, t-butoxycarbonyl, t-butoxycarbonylamino or phenylamino-C1-4alkyl; wherein the phenyl or arC1-4alkyl substituent is optionally substituted with one or two substituents independently selected from chloro, trifluoromethyl or chlorophenyl. Preferably, when R1 and R2 are both bound to the same nitrogen atom, R1 and R2 are 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 C1-4alkyl, C1-4alkoxy, phenyl, arC1-4alkyl, heterocycloalkyl, C1-4alkoxycarbonyl, di(C1-4alkyl)amino-carbonyl or phenylamino-C1-4alkyl; wherein the phenyl or arC1-4alkyl substituent is optionally substituted with one or two substituents independently selected from trifluoromethyl or chlorophenyl.
In an embodiment of the present invention, when R1 and R2 are both bound to the same nitrogen atom, R1 and R2 are 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 R1 and R2 are both bound to the same nitrogen atom, R1 and R2 are 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 R1 and R2 are both bound to the same nitrogen atom, R1 and R2 are 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-phenyl-piperidinyl), 1-(4-piperidinyl-piperidinyl), 1-(4-(3,4-methylenedioxyphenyl-methyl)-piperazinyl), 1-(3-(diethylaminocarbonyl)-piperidinyl), 1-(4-[(4-chlorophenyl)-phenylmethyl]-piperiazinyl), 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-morpholinyl, 1-pyrrolidinyl, 1-(2,3-dihydro-pyrrolidinyl), 1-piperidinyl, 1-(3,5-dimethyl-piperidinyl), 1-(3-hydroxymethyl-piperidinyl), 1-(3-ethoxycarbonyl-piperidinyl), 1-(4-(ethoxycarbonyl)-piperidinyl), 1-imidazolyl and 1-(2-(phenylamino-methyl)-N-pyrrolidinyl). Preferably, when R1 and R2 are both bound to the same nitrogen atom, R1 and R2 are 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-methylenedioxyphenyl-methyl)-piperazinyl), 1-(3-(diethylaminocarbonyl)-piperidinyl), 1-(4-[(4-chlorophenyl)-phenylmethyl]-piperiazinyl), 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 R1 and R2 are both bound to the same nitrogen atom, R1 and R2 are 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-phenyl-piperidinyl), 1-(4-piperidinyl-piperidinyl), 1-(4-(3,4-methylenedioxyphenyl-methyl)-piperazinyl), 1-(3-(diethylaminocarbonyl)-piperidinyl), 1-(4-[(4-chlorophenyl)-phenylmethyl]-piperiazinyl), 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-(3,5-dimethyl-piperidinyl), 1-(3-hydroxymethyl-piperidinyl), 1-(3-ethoxycarbonyl-piperidinyl), 1-(4-(ethoxycarbonyl)-piperidinyl), 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, 1-imidazolyl, 1-(2,3-dihydro-pyrrolidinyl), and 1-(2-(phenylamino-methyl)-N-pyrrolidinyl). Preferably, when R1 and R2 are both bound to the same nitrogen atom, R1 and R2 are 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-methylenedioxyphenyl-methyl)-piperazinyl), 1-(3-(diethylaminocarbonyl)-piperidinyl), 1-(4-[(4-chlorophenyl)-phenylmethyl]-piperiazinyl), 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-(4-(ethoxycarbonyl)-piperidinyl), 1-piperidinyl, 1-imidazolyl and 1-(2-(phenylamino-methyl)-N-pyrrolidinyl).
In an embodiment of the present invention, when R1 and R2 are both bound to the same nitrogen atom, R1 and R2 are 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)-phenylmethyl]-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 R1 and R2 are both bound to the same nitrogen atom, R1 and R2 are 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, R3 is selected from the group consisting of aryl and arC1-4alkyl; wherein the aryl or arC1-4alkyl group is optionally substituted with one to three substituents independently selected from halogen, hydroxy, carboxy, C1-4alkyl, C1-4alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano or N(RE)2. Preferably, R3 is aryl; wherein the aryl group is optionally substituted with one or more substituents independently selected from halogen. More preferably, R3 is selected from the group consisting of phenyl and 4-fluorophenyl.
In an embodiment of the present invention, L1 is C1-4alkyl; wherein the C1-4alkyl group is optionally substituted with one to two substituents independently selected from hydroxy, fluoro, C1-4alkyl, fluorinated C1-4alkyl or C1-4alkoxy. Preferably, L1 is unsubstituted C1-4alkyl. More preferably, L1 is selected from the group consisting of —CH2—, —CH(CH3)— and —CH2CH2—. More preferably still, L1 is —CH2— or —CH2CH2—;
In an embodiment of the present invention,




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

In another embodiment of the present invention,




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,





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

In another embodiment of the present invention,




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,




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, R5 is selected from the group consisting of hydroxy, carboxy, halogen, C1-4alkyl, C1-4alkoxy, nitro, cyano, N(RE)2, trifluoromethyl, trifluoromethoxy, C1-4alkoxycarbonyl, —SO—N(RE)2, —SO2—N(RE)2 and —C(O)—N(RE)2.
In another embodiment of the present invention, R5 is selected from the group consisting of halogen, C1-4alkyl and trifluoromethyl. Preferably, R5 is selected from the group consisting of chloro, methyl, n-propyl and trifluoromethyl.
In another embodiment of the present invention, R5 is selected from the group consisting of methyl, n-propyl, chloro and trifluoromethyl. Preferably, R5 is selected from the group consisting of methyl, n-propyl and trifluoromethyl. More preferably, R5 is selected from the group consisting of methyl and n-propyl. In yet another embodiment of the present invention, R5 is methyl.
In an embodiment of the present invention R6 is -(L2)0-R7. In another embodiment of the present invention, R6 is -(L2)1-R7 and L2 is selected from the group consisting of —C1-4alkyl-, —O—, —S—, —N(RE)—, —C(O)O— and —O—C(O)—.
In an embodiment of the present invention, R7 is 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, C1-4alkyl, C1-4alkoxy, nitro, cyano, N(RE)2, trifluoromethyl, trifluoromethoxy or C1-4alkoxycarbonyl. Preferably, R7 is selected from the group consisting of aryl and heteroaryl. More preferably, R7 is selected from the group consisting of phenyl and 2-thienyl. More preferably still, R7 is 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, C1-4alkyl and t-butoxycarbonyl, preferably, C1-4alkyl or t-butoxycarbonyl, more preferably ethyl. In another embodiment of the present invention Y is




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,




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 preferably 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, “arC1-4alkyl” shall mean any lower alkyl group (i.e. C1-4alkyl group) substituted with an aryl group such as phenyl, naphthyl and the like. Suitable examples of an arC1-4alkyl 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,




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




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




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





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





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





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





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





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





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




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)2 or =
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, carnsylate, 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.




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 R0 or “top” substituent portion of the molecule onto the core structure, whereas Schemes 8 to 14 incorporate the




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 R0 is —CRARB—CH(OH)—CRCRD
—X and X is NR1R2 may be prepared from a suitably substituted compound of formula (II) according to the process outlined in Scheme 2.




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, RA, RB, RC and RD are 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 R0 is




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





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—R1 may be prepared from a suitably substituted compound of formula (V) according to the process outlined in Scheme 3.




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—R1 or —SO2—R1 may be prepared from a suitably substituted compound of formula (V) according to the process outlined in Scheme 4.




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—R1 or —SO2—R1.
One skilled in the art will recognize that in the processes described in Scheme 4 above, the PG1 protecting 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)-NR1R2 or —SO2-(alkyl)-NR1R2 may 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)—R2 may be prepared according to the process outlined in Scheme 5.




Accordingly, a suitably substituted compound of formula (VII), wherein R1 is 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)—NR1NR2 may be prepared according to the process outlined in Scheme 6.







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 NaBH4 in 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, EDCl, 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)2 may 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 R0 is




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





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 PG2 is 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 PG1 and PG2 on 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 R0 is selected from the group consisting of




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)





or the compound of formula (XXIII),





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




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





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




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





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.




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, L1 is C1-6alkyl or C3-6alkenyl, R6 is (L2)0-R7 and R7 is an aryl or heteroaryl group may be prepared according to the process outlined in Scheme 11.




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 C1-5alkyl or C2-5alkenyl, 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.




Accordingly, a suitably substituted compound of formula (XXX), wherein D is C1-5alkyl or C2-5alkenyl, 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 C1-5alkyl or C2-5alkenyl, 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, R6 is (L2)1-R7 and L2 is —O— may be prepared according to the process outlined in Scheme 13.




Accordingly, a suitably substituted compound of formula (XXXIV), wherein D is C1-5alkyl or C2-5alkenyl, 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 L2 is —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 L2 is selected from —SO— or —SO2—.
Compounds of formula (M2) wherein R6 is -L2-R7 and L2 is C2-4alkenyl may be prepared according to the process outlined in Scheme 14.




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




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



















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




ethyl


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


3
R
3,5-di(trifluoro
4-fluorophenyl
CH2
cyclooctyl




methyl)benzyl


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(trifluoro
4-fluorophenyl
CH2
cyclooctyl




methyl)benzyl


17
S
1-adamantanyl-
4-fluorophenyl
CH2
cyclooctyl




methyl


18
S
3-methylbenzyl
4-fluorophenyl
CH2
cyclooctyl


19
S
2-(2,5-dimethoxy-2,5-




dihydro-furyl)-methyl
4-fluorophenyl
CH2
cyclooctyl


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
4-fluorophenyl
CH2
cyclooctyl




benzyl


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




ethyl


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


32
S
3-pyridylmethyl
4-fluorophenyl
CH2
cyclooctyl


33
S
3-trifluoromethyl
4-fluorophenyl
CH2
cyclooctyl




benzyl


34
S
2-(4-methoxy-
4-fluorophenyl
CH2
cyclooctyl




phenyl)ethyl


35
S
3-methoxybenzyl
4-fluorophenyl
CH2
cyclooctyl


36
S
4-pyridyl
4-fluorophenyl
CH2
cyclooctyl


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




phenyl)ethyl


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-
4-fluorophenyl
CH2
cyclooctyl




pyridyl)


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




benzyl


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)
4-fluorophenyl
absent
1-acenaphthenyl




ethyl


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




phenyl)ethyl


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




phenyl)ethyl


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




ethyl


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




phenyl)ethyl


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




phenyl)ethyl


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




ethyl


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




ethyl


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




phenyl)ethyl


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




dioxyphenyl)ethyl


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




dimethoxy-phenyl)




ethyl


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




ethyl


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




phenyl)ethyl


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




dioxyphenyl)ethyl


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




ethyl


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




phenyl)ethyl


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




dioxyphenyl)ethyl


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




dimethoxy-phenyl)




ethyl


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




dioxyphenyl)ethyl


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




dimethoxy-phenyl)




ethyl


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




2-phenylethyl


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


282
S
4-((1-phenyl-pyrazol-
4-fluorophenyl
CH2
cyclooctyl




2-yl)-aminosulfonyl)




phenyl


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


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




phenyl)ethyl


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




ethyl


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




ethyl


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




phenyl)ethyl


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-
4-fluorophenyl
absent
1-acenaphthenyl




isoquinolinyl)


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)
4-fluorophenyl
absent
1-acenaphthenyl




benzyl


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




trimethoxybenzyl


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


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


323
S
2-(4-methoxy-
4-fluorophenyl
absent
1-acenaphthenyl




phenyl)ethyl


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
4-fluorophenyl
absent
1-acenaphthenyl




benzyl


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-
4-fluorophenyl
absent
1-acenaphthenyl




propyl


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
4-fluorophenyl
absent
1-acenaphthenyl




benzyl


345
S
benzyl
4-fluorophenyl
absent
1-acenaphthenyl


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


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




benzyl


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




benzyl


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)
4-fluorophenyl
absent
1-acenaphthenyl




ethyl


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


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




trimethoxybenzyl


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
4-fluorophenyl
absent
1-acenaphthenyl




benzyl


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




phenyl)ethyl


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




phenyl)ethyl


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




ethyl


 


374
S




4-fluorophenyl
absent
1-acenaphthenyl


 


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




pyridyl


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




ethyl


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


418
S
2-(3,4-methylene




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


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-
4-fluorophenyl
CH2
cyclooctyl




pyrazolyl-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-
4-fluorophenyl
absent
1-acenaphthenyl




dimethoxy-




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-(dimethoxy)-
4-fluorophenyl
absent
R-1-acenaphthenyl




phenyl


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-







trifluoromethyl-phenyl


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







trifluoromethyl-phenyl


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







trifluoromethyl-phenyl


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




propyl


trifluoromethyl-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




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






 


619
S
H
4-fluorophenyl
CH2






 


620
R
H
4-fluorophenyl
CH2
cyclooctyl


621
R
4-pyridinyl
4-fluorophenyl
CH2
cyclooctyl


 


622
S




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




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-
4-fluorophenyl
absent
cyclooctyl




yl)-ethyl]


 


630
—




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)






 


633
S
dimethylamino-n-
4-fluorophenyl
CH2
cyclooctyl




propyl


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


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


636
R
dimethylamino-n-
4-fluorophenyl
CH2
cyclooctyl




propyl


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


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




propyl


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-







hexahydro-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




4-fluorophenyl
absent
R-1-acenaphthenyl


 


646
S




4-fluorophenyl
absent
R-1-acenaphthenyl


 


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




propyl


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




propyl


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-







hexahydro-1H-







phenalen-1-yl


659
S
H
phenyl
absent
1S-(3a-S)-







2,3,3a,4,5,6-







hexahydro-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




4-fluorophenyl
absent
S-1-acenaphthenyl


 


664
R
methylamino-n-propyl
4-fluorophenyl
CH2






 


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




amino-n-propyl


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




propyl


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




butoxycarbonyl-




amino-ethyl
















TABLE 2













 













ID#
*
R1
R2
R3
(L1)m




















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








hexahydro-1H-








phenalen-2-yl


55
S
ethyl
4-methyl
4-fluoro-
absent
1-acenaphthenyl





benzyl
phenyl


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






phenyl


57
S
ethyl
4-methyl
4-fluoro-
absent
4-n-propyl-cyclohexyl





benzyl
phenyl


58
S
ethyl
4-methyl
4-fluoro-
CH2CH2
phenyl





benzyl
phenyl


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






phenyl


60
S
t-butyl
benzyl
4-fluoro-
CH2CH2
phenyl






phenyl


61
Rac
ethyl
4-methyl
phenyl
absent
1-acenaphthenyl





benzyl


62
Rac
t-butyl
benzyl
phenyl
absent
1-acenaphthenyl


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




amino)ethyl

phenyl


64
S
n-butyl
benzyl
4-fluoro-
CH2
cyclooctyl






phenyl


65
S
benzyl
2-phenyl-
4-fluoro-
CH2
cyclooctyl





ethyl
phenyl


 


78
S




4-methyl benzyl
4-fluoro phenyl
CH2
cyclooctyl


 


79
S




4-methyl benzyl
4-fluoro phenyl
CH2
cyclooctyl


 


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






phenyl


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





benzyl
phenyl


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





dimethoxy-
phenyl





phenyl)ethyl


258
S
ethyl
4-methyl
4-fluoro-
CH2
2-naphthyl





benzyl
phenyl


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






phenyl


263
S
methyl
2-(3,4-
4-fluoro-
CH2
2-naphthyl





dimethoxy-
phenyl





phenyl)ethyl


264
S
ethyl
4-methyl
4-fluoro-
CH2
4-chlorophenyl





benzyl
phenyl


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






phenyl


270
S
methyl
2-(3,4-
4-fluoro-
CH2
4-chlorophenyl





dimethoxy-
phenyl





phenyl)ethyl


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





dimethoxy-
phenyl





phenyl)ethyl


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






phenyl

pentamethyl-phenyl


283
S
methyl
3-(2-pyridyl)-
4-fluoro-
CH2
cyclooctyl





n-propyl
phenyl


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





hydroxy-
phenyl





cyclopent-2-





yl-methyl


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





hydroxy-
phenyl





cyclohex-2-





yl-methyl


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





hydroxy-
phenyl





cyclohept-2-





yl-methyl


294
S
ethyl
4-methyl
4-fluoro-
CH2
5-phenyl-2-thienyl





benzyl
phenyl


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





dimethoxy-





phenyl)ethyl


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






phenyl


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





dimethoxy-
phenyl





phenyl)ethyl


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






phenyl


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





dimethoxy-
phenyl





phenyl)ethyl


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





dimethoxy-
phenyl





phenyl)ethyl


362
S
benzyl
benzyl
4-fluoro-
absent
1-acenaphthenyl






phenyl


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





ethyl
phenyl


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






phenyl


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





dimethoxy-
phenyl





phenyl)ethyl


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





benzyl
phenyl


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






phenyl


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





dimethoxy-
phenyl





phenyl)ethyl


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






phenyl


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






phenyl


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






phenyl


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






phenyl


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






phenyl


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






phenyl


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






phenyl


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






phenyl


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






phenyl


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






phenyl


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






phenyl


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






phenyl


455
S
4-methyl-
6-methylthio-
4-fluoro-
CH2
cyclooctyl




benzyl
2-pyridyl-
phenyl





carbonyl


456
S
n-butyl
benzyl
4-fluoro-
CH2
2-trifluoromethyl-6-






phenyl

chloro-phenyl


457
S
methyl
2-(3,4-
4-fluoro-
CH2
2-trifluoromethyl-6-





dimethoxy-
phenyl

chloro-phenyl





phenyl)ethyl


459
S
benzyl
2-(dimethyl-
4-fluoro-
CH2
2-trifluoromethyl-6-





amino)ethyl
phenyl

chloro-phenyl


462
R
ethyl
4-methyl-
4-fluoro-
absent
1-acenaphthenyl





benzyl
phenyl


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






phenyl


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






phenyl


670
S
ethoxy-
benzyl
4-fluoro-
CH2
3,5-bis-




carbonyl-

phenyl

trifluoromethyl-phenyl




methyl


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






phenyl

trifluoromethyl-phenyl


672
S
1-phenyl-
benzyl
4-fluoro-
CH2
3,5-bis-




ethyl

phenyl

trifluoromethyl-phenyl


673
S
2-(3,4-
methyl
4-fluoro-
CH2
3,5-bis-




dimethoxy-

phenyl

trifluoromethyl-phenyl




phenyl)-




ethyl


674
S
(dimethyl-
benzyl
4-fluoro-
CH2
3,5-bis-




amino)-

phenyl

trifluoromethyl-phenyl




ethyl


675
S
2-(3,4-
methyl
4-fluoro-
absent
cyclooctyl




dimethoxy-

phenyl




phenyl)-




ethyl


676
S
benzyl
n-butyl
4-fluoro-
absent
cyclooctyl






phenyl


 


677
S
benzyl
n-butyl
4-fluoro- phenyl
CH2






 


678
R
2-(3,4-
methyl
4-fluoro-
CH2
cyclooctyl




dimethoxy-

phenyl




phenyl)-




ethyl


679
S
t-butoxy-
methyl
4-fluoro-
absent
R-1-acenaphthenyl




carbonyl

phenyl


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




carbonyl

phenyl


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




propyl

phenyl
















TABLE 3













 










ID#
*
T1 (NR1R2 taken together)

















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




piperazinyl)


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


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




methyl)-piperazinyl)


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




piperidinyl)


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)-




isoquinolinyl)
phenyl)ethyl


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




isoquinolinyl)
phenyl)ethyl


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)-




isoquinolinyl)
phenyl)ethyl


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




pyrrolidinyl)


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





methyl-benzyl


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




piperazinyl]
methyl-benzyl


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





methyl-benzyl


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





methyl-benzyl


686
S
3-(diethylaminocarbonyl)-piperidinyl
3,5-bis-trifluoro-





methyl-benzyl


 


687
S




cyclooctyl


 


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




hydroxymethyl-pyrrolidinyl)


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




isoquinolinyl)


 


690
R




cyclooctyl
















TABLE 4













 










ID#
*
T2 (NR1R2 taken together)









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-dimethoxy-
1-(8-methyl-naphthyl)




isoquinolinyl)


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




isoquinolinyl)


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









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









105
R
2-(3,4-dimethoxy
4-fluoro
CH2
cyclooctyl




phenyl)-ethyloxy
phenyl


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




phenyl)-ethyloxy


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


108
R
3-methylphenylthio
4-fluoro
CH2
cyclooctyl





phenyl


 


178
S




phenyl
CH2CH2
2-(2-thienyl)-phenyl


 


460
R




4-fluoro phenyl
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
5
H
2,2,2-trifluoroethyl


123
5
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






 


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






 


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









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









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
oxiranyl-
phenyl
absent
1-acenaphthenyl



methyl


510
R-oxiranyl-
4-fluorophenyl
absent
4-n-propyl-



methyl


cyclohexyl


511
R-oxiranyl-
4-fluorophenyl
CH2CH2
phenyl



methyl


512
oxiranyl-
4-fluorophenyl
absent
1-acenaphthenyl



methyl


513
R-oxiranyl-
4-fluorophenyl
CH2
4-chlorophenyl



methyl


514
R-oxiranyl-
4-fluorophenyl
CH2
1-naphthyl



methyl


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



methyl


517
S-oxiranyl-
4-fluorophenyl
C(O)O-t-butyl
absent



methyl


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



methyl


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



methyl


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



methyl


540
R-oxiranyl-
4-fluorophenyl
CH2
cyclooctyl



methyl


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



methyl


542
S-oxiranyl-
4-fluorophenyl
CH2
2-naphthyl



methyl


543
S-oxiranyl-
4-fluorophenyl
CH2CH3
absent



methyl


550
S-oxiranyl-
4-fluorophenyl
CH2
1-(8-methyl-



methyl


naphthyl)


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



carbonyl-


naphthyl)



methyl


553
R-oxiranyl-
4-fluorophenyl
CH2
1-(8-methyl-



methyl


naphthyl)


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



dihydroxy-


naphthyl)



n-propyl


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



methyl


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



methyl


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



methyl


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



methyl


568
2R-
4-fluorophenyl
absent
1-acenaphthenyl



hydroxy-3-



ethoxy-n-



propyl


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



hydroxy-3-



ethoxy-n-



propyl


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



hydroxy-3-



ethoxy-n-



propyl


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



hydroxy-3-



ethoxy-n-



propyl


 


572
H
4-fluorophenyl
CH2






 


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


576
oxiranyl-
phenyl
absent
1-acenaphthenyl



methyl


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



methyl


chloro-phenyl


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



2S-



hydroxy-n-



propyl


580
S-oxiranyl-
4-fluorophenyl
CH2
cyclooctyl



methyl


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-oxiranyl-
4-fluorophenyl
CH2
2,3,4,5,6-



methyl


pentamethyl-phenyl


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



ethyl


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



methyl


pentamethylphenyl


 


726
H
4-fluorophenyl
CH2






 


727
R-oxiranyl- methyl
4-fluorophenyl
CH2






 


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






tetrahydro-naphthyl)


 


729
H
4-fluorophenyl
CH(CH3)






 


730
H
4-fluorophenyl
absent






 


731
S-oxiranyl-
4-fluorophenyl
absent
cyclooctyl



methyl


 


732
H
4-fluorophenyl
CH2






 


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)-
H





ethyl


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





ethyl


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)-
H





ethyl


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





ethyl


535
S
ethyl
4-methylbenzyl
t-






butoxycarbonyl


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 as 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




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 1N 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




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




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




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-phenyl)-ethyl]-1,3,8-triaza-spiro[4.5]decan-4-one Compound #111




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




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




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




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




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) δ7.68-7.66 (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




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) δ7.05-6.88 (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-triazaspiro[4.5]decan-4-one Compound #556




(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) δ7.70-7.65 (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




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) δ7.69-7.65 (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




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) δ8.39-8.36 (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




(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) δ8.38-8.35 (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




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 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 (2% methanol/dichloromethane) to yield the title compound as a solid.
1H NMR (300 MHz, CDCl3) δ7.59-7.56 (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




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) δ7.59-7.55 (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




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) δ7.02-6.93 (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




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




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) δ7.79-7.76 (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




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) δ7.78-7.75 (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




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




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 1N 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) δ1.1-1.9 (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




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) δ1.1-1.9 (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




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, [1M in diethylether]) at 0° C. He resulting crystals were collected by filtration and recrystallized with ethanol to yield 1 g the title compound white powder.
MS (electrospray)=593.5 (MH+), 592.6 1H NMR (300 MHz, CD3OD) δ1.1 (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




3,4-Dimethoxyphenethylalcohol was dissolved in NMP (2 mL) and stirred for 30 min. NaH (60% dispersion 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 NaHCO3 solution 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) δ1.3-1.8 (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




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




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 1N 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) δ1.6 (d, 2H), 2.2-2.3 (m, 17 H), 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




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




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) δ1.0 (m, 3H), 1.3 (m, 2 H), 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




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) δ1.6 (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)




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




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 NaHCO3 and 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




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) δ1.35 (m, 2H), 1.5-1.7 (m, 13 H), 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




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) δ7.77-7.75 (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




(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) δ7.68-7.65 (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




(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) δ7.68-7.64 (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




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




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) δ7.98-7.96 (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




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) δ8.25 (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




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) δ7.03-6.93 (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




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 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 (3.5% methanol/dichloromethane) to yield the title compound as a white foam.
1H NMR (300 MHz, CDCl3) δ7.30-7.15 (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




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) δ7.32-7.26 (4H, m), 7.04-6.91 (4H, m), 4.77 (H, d, J=4.9Hz), 4.66 (1H, d, J=4.9Hz), 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-4-1-ethylamino)-propyl]-8-(5-phenyl-thien-2-yl-methyl)-1,3,8-triaza-spiro[4.5]decan-4-one Compound #293




(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) δ7.59-7.56 (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 (1OH, m), 1.72 (2H, d, J=13.7 Hz) MS (ES+) m/z 608.3 (M+H)+.
EXAMPLE 44
1-(4-Fluoro-phenyl)-8-quinoline-8-ylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one Compound #522




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) δ8.93-8.91 (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




(R)-8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-(R)oxiranylmethyl-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) δ7.69-7.66 (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




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) δ7.77-7.75 (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




(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) δ7.68-7.65 (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




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) δ7.78-7.76 (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




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) δ7.78-7.75 (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




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, 0.07mmol) 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) δ7.78-7.75 (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




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) δ7.78-7.75 (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




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) δ7.78-7.75 (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




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) δ7.78-7.75 (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




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) δ7.78-7.75 (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




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




(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) δ7.69-7.49 (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




(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) δ7.68-7.59 (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




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




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




(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) δ7.70-7.65 (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




(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) δ7.70-7.65 (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




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




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, 16 H), 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




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




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 N2 was 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) δ7.85 (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 NaHCO3 it was dried over MgSO4 and 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 CH2Cl2 and the combined organics were dried over MgSO4 and 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 purified 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[4.5]-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 N2 in 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 Calculated: C: 69.26%, H: 7.06%, N: 11.34%, F: 3.91%, H2O: 1.85%.
Measured: C: 68.96%, H: 6.83%, N: 11.38%, F: 4.00%, H2O: 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 2×105 cells per well in 0.5 ml of normal growth medium (MEM+EBSS+NEAA+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% CO2 for 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 MgCl2 and 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 MgCl2 and 1 mM EGTA. 125I-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
      )
    
    +
    
      
        (
        
          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 as 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 μg/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 MgCl2 and 1 mM EGTA. Each test compound was diluted to a concentration in the range of from 100 μM to 10 μM (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% polyethyleneimine, 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 Ki's determined using Graphpad Prizm software (v3.0). The Kis were calculated using the following formula by Graphpad Prizm software, where

Ki=(IC50)/(1+[radioligand]/Kd)

For the ORL-1, the Kd is 0.5nM, 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 Kd.
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 IC50 measurements, 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 μM 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 μM 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.
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 Ki determined using Graphpad Prizm software (v3.0).
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
Total
Horizontal
Vertical


Dosage mg/kg, i.p.

Arm Time
Arm Entries
Entries
Activity
Movement


(# Animals)
Statistics
(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)
% Change
0.0%
0.0%
0.0%
0.0%
0.0%


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



% Change
3.2%
7.6%
0.95% 
1.5%
−0.4%



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



% Change
71.5%
92.7%
0.63% 
19.8%
11.4%



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



% Change
53.6%
42.9%
5.2%
10.9%
16.0%



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



% Change
57.0%
41.4%
0.0%
12.5%
7.6%



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



% Change
25.6%
34.2%
−4.2%  
7.4%
2.2%



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



% Change
32.3%
38.8%
−8.4%
−12.7%   
−6.2%



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





Dosage

Arm
Arm
Total
Horizontal
Vertical


mg/kg, p.o.

Time
Entries
Entries
Activity
Movement


(# Animals)
Statistics
(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


Methylcellulose)
% Change
0.0%
0.0%
0.0%
0.0%
0.0%


(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



% Change
−18.8%
−16.1%
13.4%
7.2%
5.7%



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



% Change
19.7%
17.3%
−1.0%
12.4%
17.2%



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



% Change
25.9%
19.1%
−3.2%
10.1%
5.9%



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



% Change
45.7%
44.9%
−2.3%
18.2%
9.9%



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



% Change
45.7%
34.7%
0.0%
17.4%
8.5%



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



% Change
76.9%
56.3%
−4.3%
4.0%
1.6%



P-value
P < 0.0001
P < 0.0001
NS
NS
NS


  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



% Change
10.3%
35.1%
−20.9%
−11.2%
−8.7%



P-value
NS
0.0197
P < 0.0001
NS
0.0091





(*)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





Dosage

Arm
Arm
Total
Horizontal
Vertical


mg/kg, p.o.

Time
Entries
Entries
Activity
Movement


(# Animals)
Statistics
(EPM)
EPM
(EPM)
(SMA)
(SMA)
















Vehicle
Mean
5.76
5.48
96.7
2881
49.1


(0.5% Methylcellulose)
S.E.M.
±1.50
±1.21
±4.65
±208
±3.28


(24)
% Change
0.0%
0.0%
0.0%
0.0%
0.0%


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



% Change
70.1%
33.8%
−6.9%
5.3%
11.2%



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



% Change
69.4%
36.7%
−5.3%
−4.5%
2.4%



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



% Change
75.3%
44.5%
−0.4%
14.5%
15.7%



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



% Change
30.9%
36.7%
6.1%
−10.2%
−10.1%



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 occurring 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 occurring 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





Dosage

Arm
Arm
Total
Horizontal
Vertical


mg/kg, p.o.

Time
Entries
Entries
Activity
Movement


(# Aminals)
Statistics
(EPM)
(EPM)
(EPM)
(SMA)
(SMA)
















Vehicle
Mean
8.21
5.78
101.0
3244
48.7


0.5% Methylcellulose
S.E.M.
±1.18
±0.532
±3.81
±168
±1.85


(40)
% Change
0.0%
0.0%
0.0%
0.0%
0.0%


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



% Change
−18.8%
−11.1%
1.0%
9.9%
12.5%



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



% Change
47.4%
34.4%
2.0%
5.9%
9.0%



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



% Change
68.1%
54.8%
−1.2%
6.4%
6.2%



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



% Change
80.3%
72.1%
2.0%
16.3%
16.2%



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



% Change
51.0%
44.3%
0.0%
8.0%
13.6%



P-value
0.0170
0.0336
NS
NS
NS


10 Mg/Kg
Mean
8.14
6.4
94.5
3115
54.5


(24)
S.E.M.
±1.30
±0.856
±3.41
±168
±1.73



% Change
0.9%
11.1%
−6.4%
−4.0%
11.9%



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



% Change
−60.9%
15.1%
−14.6%
−15.8%
−7.0%



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





Dosage

Arm
Arm
Total
Horizontal
Vertical


mg/kg, p.o.

Time
Entries
Entries
Activity
Movement


# Aminals
Statistics
(EPM)
(EPM)
(EPM)
(SMA)
(SMA)
















Vehicle
Mean
7.96
6.53
101.0
3451
54.6


(0.5% methylcellulose)
S.E.M.
±1.87
±1.05
±4.72
±196
±3.35


(16)
% Change
0.0%
0.0%
0.0%
0.0%
0.0%


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



% Change
116.1%
40.4%
1.0%
10.5%
15.2%



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



% Change
173.9%
80.7%
−1.9%
27.2%
11.9%



P-value
P < 0.0001
0.0007
NS
P < 0.05
NS


  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



% Change
89.7%
46.6%
−1.4%
15.3%
9.0%



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



% Change
112.3%
37.8%
5.0%
23.2%
9.7%



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 3min test session. Subsequently, every 20th lick 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




No/
Mean



Group
No. of Shocks
P Value





















Dose






(mg/kg, i.p.)


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



Dose



(mg/kg, p.o.)


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. ° C.
Temp. ° C.
Temp. ° C.
Temp. ° C.


Compound (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

Animal 10




(Vehicle)

(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







Compound #438 Tissue Concentration
















μM
μM/kg
μM
μM/kg
μM
μM/kg
μM
μM/kg















Animal 1
Animal 2
Animal 3
Animal 4















Cortex
0.0062
0.030
0.0047
0.020
0.0047
0.030
0.0026
0.0130


Cerebellum
0.0402
0.161
0.014
0.090
0.0189
0.140
0.0045
0.0350


Hypothalamus
0.0124
0.413
0.0055
0.367
0.0064
0.427
0.0062
1.2400


Hippocampus
0.0195
0.650
0.0021
0.070
0.0009
0.030
0.0140
0.2550


Heart
2.036
4.072
2.485
5.144
2.346
4.692
1.664
3.328


Lung
5.821
15.119
4.737
12.632
5.153
13.741
4.361
11.629


Liver
6.664
13.257
6.409
12.785
4.632
9.294
3.879
7.758


Spleen
9.140
25.389
7.232
17.857
7.163
23.106
5.207
13.703


Kidney
3.747
7.546
4.031
8.062
4.123
8.027
3.841
7.570


Adrenal Glands
0.967
24.175
0.988
28.229
1.289
28.644
1.088
31.086


Lg intestine
4.518
9.036
12.478
29.019
30.593
59.694
2.231
6.562


Sm Intestine
21.836
53.916
27.120
84.750
17.359
48.219
13.898
38.077


Muscle
0.919
1.814
0.688
1.371
0.791
1.560
0.651
1.280


Plasma
0.419

0.426

0.360
0.289


Whole Blood
0.166

0.147

0.135
0.088












Animal 5
Animal 6
Animal 7
Animal 8















Cortex
0.0038
0.017
0.0023
0.010
0.0055
0.025
0.0139
0.062


Cerebellum
0.0026
0.019
0.0101
0.067
0.0138
0.095
0.0102
0.068


Hypothalamus
0.0030
0.200
0.0036
0.360
0.0101
0.673
0.0027
0.180


Hippocampus
0.005
0.200
0.002
0.010
0.0065
0.217
0.0019
0.190


Heart
1.785
3.471
2.478
4.878
1.572
2.977
2.083
4.261


Lung
3.533
7.438
5.290
20.346
5.655
15.930
6.189
11.902


Liver
4.006
7.861
5.090
10.180
5.887
10.398
5.677
11.120


Spleen
6.730
19.229
7.742
26.697
8.062
29.859
9.205
28.766


Kidney
3.993
7.791
4.718
9.523
4.109
7.645
4.750
8.782


Adrenal Glands
1.075
26.875
1.487
59.480
1.267
42.233
1.946
64.867


Lr intestine
24.916
56.627
9.584
26.622
33.756
68.194
5.070
9.941


Sm Intestine
16.743
41.858
14.131
56.524
25.408
72.594
13.018
39.448


Muscle
0.917
1.754
0.977
1.954
0.882
1.707
1.509
3.006


Plasma
0.183

0.174

0.268

0.470


Whole Blood
0.469

0.266

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 O 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.

## Claims

1. A pharmaceutical dosage form selected from the group consisting of tablets, pills, capsules, powders, granules, sterile parenteral solutions, parenteral suspensions, metered aerosol or liquid spray, drops, ampoules and suppositories comprising a compound of the formula (I)



wherein
R0 is selected from the group consisting of




each RA and RB is independently selected from the group consisting of hydrogen and C1-4alkyl;
each RC and RD is independently selected from the group consisting of hydrogen and C1-4alkyl;
each RE is independently selected from the group consisting of hydrogen and C1-4alkyl;
X is —NR1R2;
each R1 and R2 is independently selected from the group consisting of hydrogen, C1-8alkyl, C1-8alkoxy, C1-8alkoxycarbonyl, cycloalkyl, cycloalkyl-C1-4alkyl, partially unsaturated carbocylyl, partially unsaturated carbocyclyl-C1-4alkyl, aryl, arC1-4alkyl, arC1-4alkoxy, —C(O)—C1-6alkyl, —C(O)-aryl, —C(O)-arC1-4alkyl, —C(O)O-cycloalkyl, —C(O)O-aryl, —C(O)O-arC1-4alkyl and —C(O)O-(partially unsaturated carbocyclyl); wherein the C1-8alkyl, cycloalkyl, partially unsaturated carbocyclyl, aryl or arC1-8alkyl group, whether alone or part of a substituent group, is optionally substituted with one or more substituents independently selected from halogen, hydroxy, carboxy, C1-4alkyl, C1-4alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, —C(O)—C1-4alkyl, C1-4alkoxycarbonyl, N(RE)2, N(RE)2—C1-4alkyl, N(RE)—C(O)C(CH3)3, —C1-4alkyl-N(RE)—C(O)O—C1-4alkyl and —N(RE)—C(O)O—C1-4alkyl, aryl, aryloxy, cycloalkyl, heteroaryl, aryl substituted heteroarylaminosulfonyl or C1-6alkylthio;
R3 is aryl; wherein the aryl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, carboxy, C1-4alkyl, C1-4alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano or N(RE)2;
n is an integer from 0 to 2;
R4 is selected from the group consisting of hydroxy, C1-4alkyl and hydroxy substituted C1-4alkyl;
m is an integer from 0 to 1;
L1 is selected from the group consisting of C1-6alkyl and C3-6alkenyl; wherein the double bond of the C3-6alkenyl group is at least one carbon atom removed from the attachment point to the N atom; and wherein the C1-6alkyl or C3-6alkenyl group is optionally substituted with one to two substituents independently selected from hydroxy, fluoro, C1-6alkyl, fluorinated C1-6alkyl or C1-6alkoxy;





is selected from the group consisting of phenyl, naphthyl and acenaphthyl;
p is an integer from 0 to 5;
R5 is selected from the group consisting of hydroxy, carboxy, halogen, C1-6alkyl, hydroxy substituted C1-6alkyl, C1-6alkoxy, nitro, cyano, NR1R2, trifluoromethyl, trifluoromethoxy, C1-4alkoxycarbonyl, —SO—NR1R2, —SO2—NR1R2 and —C(O)—NR1R2;
q is 0;
R6 selected from the group consisting of -(L2)0-1-R7;
L2 is selected from the group consisting of —C1-6alkyl-, -C2-4alkenyl-, -C2-6alkynyl-, —O—, —S—, —NH—, —N(C1-4alkyl)-, —C1-6alkyl-O—, —C1-6alkyl-S—, —O—C1-6alkyl-, —S—C1-6alkyl-, —O—C2-6alkyl—O—, —S—C2-6alkyl-S—, —SO2—, —SO2NH—, —SO2N(C1-4alkyl)-, —NH—SO2—, —N(C1-4alkyl)-SO2—, —C(O)—O— and —O—C(O)—;
R7 is 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, C1-6alkyl, C1-6alkoxy, nitro, cyano, N(RE)2, trifluoromethyl, trifluoromethoxy, C1-4alkoxycarbonyl, —SO2—N(RE)2 and —C(O)—N(RE)2;
or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

2. The pharmaceutical dosage form of claim 1 wherein in the compound of formula (I)
R0 is selected from the group consisting of




each RC and RD is independently selected from hydrogen and C1-4alkyl;
X is —NR1R2;
R1 is selected from the group consisting of hydrogen, C1-4alkyl, C1-4alkoxy, C1-4alkoxycarbonyl, aryl, arC1-4alkyl, arC1-4alkyloxy, cycloalkyl-alkyl and C(O)—C1-4alkyl;
wherein the C1-4alkyl, aryl, arC1-4alkyl 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, C1-4alkyl, C1-4alkoxy, C1-4alkoxycarbonyl, N(RE)2, N(RE)2—C1-4alkyl, N(RE)—C(O)OC(CH3)3, nitro, trifluoromethyl, trifluoromethoxy, phenyl, phenoxy, heteroaryl, cycloalkyl, 1-phenyl-pyrazol-2-yl-aminosulfonyl or C1-4alkylthio;
R2 is selected from the group consisting of hydrogen, C1-4alkyl, C1-4alkoxy, cycloalkyl, cycloalkyl-C1-4alkyl, aryl, arC1-4alkyl, arC1-4alkyloxy, partially unsaturated carbocyclyl, partically unsaturated carbocyclyl-C1-4alkyl, —C(O)—C1-4alkyl, —C(O)-aryl, —C(O)—arC1-4alkyl, —C(O)O-cycloalkyl and —C(OO)—C1-4alkyl;
wherein the C1-4alkyl, aryl, arC1-4alkyl, partially unsaturated carbocyclyl 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, C1-4alkyl, C1-4alkoxy, C1-4alkoxycarbonyl, N(RE)2, N(RE)2—C1-4alkyl, (CH3)3COC(O)—N(RE)—C1-4-alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, phenyl, phenoxy, heteroaryl, cycloalkyl, 1-phenyl substituted heteroaryl-aminosulfonyl, —C(O)—C1-4alkyl or C1-4alkylthio;
R3 is aryl; wherein the aryl is optionally substituted with one to three substituents independently selected from halogen, hydroxy, carboxy, C1-4alkyl, C1-4alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano or N(RE)2;
n is an integer from 0 to 1;
L1 is C1-4alkyl; wherein the C1-4alkyl group is optionally substituted with one to two substituents independently selected from hydroxy, fluoro, C1-4alkyl, fluorinated C1-4alkyl or C1-4alkoxy;
R5 is selected from the group consisting of hydroxy, carboxy, halogen, C1-4alkyl, C1-4alkoxy, nitro, cyano, N(RE)2, trifluoromethyl, trifluoromethoxy, C1-4alkoxycarbonyl, —SO—N(RE)2, —SO2— N(RE)2 and —C(O)— N(RE)2;
or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical dosage form of claim 1 wherein in the compound of formula (I)
R0 is selected from the group consisting of




each RA, RB, RC and RD is hydrogen;
X is —NR1R2;
R1 is selected from the group consisting of hydrogen, C1-4alkyl, C1-4alkoxycarbonyl, arC1-4alkyl and C(O)—C1-4alkyl;
wherein the C1-4alkyl or aryl group, whether alone or part of a substituent group, is optionally substituted with one to two substituents independently selected from carboxy, C1-4alkyl, C1-4alkoxy, C1-4alkoxycarbonyl, N(RE)2 or N(RE)—C(O)OC(CH3)3;
R2 is selected from the group consisting of hydrogen, C1-4alkyl, C1-4alkoxy, cycloalkyl, aryl, arC1-4alkyl, arC1-4alkyloxy, partially unsaturated carbocyclyl, partially unsaturated carbocyclyl-C1-4alkyl, cycloalkyl-C1-4alkyl, —C(O)arC1-4alkyl, —C(OO)-cycloalkyl and —C(O)O—C1-4alkyl;
wherein the C1-4alkyl, aryl, arC1-4alkyl, partially unsaturated carbocyclyl-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, C1-4alkyl, C1-4alkoxy, C1-4alkoxycarbonyl, N(RE)2, N(RE)2—C1-4alkyl, (CH3)3CO—C(O)—N(RE)—C1-4alkyl, nitro, trifluoromethyl, trifluoromethoxy, phenyl, phenoxy, heteroaryl, cycloalkyl, 1-phenyl-pyrazol-2-yl-aminosulfonyl or C1-4alkylthio;
R3 is aryl; wherein the aryl group is optionally substituted with one or more substituents independently selected from halogen;
n is 0;
L1 is C1-4alkyl;
R5 is selected from the group consisting of halogen, C1-4alkyl and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical dosage form of claim 1 wherein in the compound of formula (I)
R0 is selected from the group consisting of —CH2—CH(OH)—CH2—X and —CH2—CH2—CH(OH)—CH2—X;
X is —NR1R2;
R1 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, t-butyl, amino-n-propyl, dimethylaminoethyl, benzyl, phenylethyl, 4-methyl-benzyl,





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



R2 is 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, 1-adamantanyl, 1-adamantanyl-methyl, 1-naphthyl, 1-naphthyl-methyl, 1-phenyl-2-(t-butoxycarbonyl)ethyl, —C(O)—C(OCH3)(CF3)-phenyl, —C(O)O-(2-isopropyl-5-methyl-cyclohexyl),





2S-hydroxy-S-cyclopentyl-methyl, 2S-hydroxy-S-cyclohexyl-methyl, 2S-hydroxy-S-cycloheptyl-methyl, 2-phenoxy-ethyl and 2-phenyl-cyclopropyl;
R3 is selected from the group consisting of phenyl and 4-fluorophenyl;
L1 is selected from the group consisting of —CH2—, —CH(CH3)— and —CH2CH2—;





is selected from the group consisting of 1-acenaphthenyl, R-1-acenaphthenyl, S-1-acenaphthenyl, phenyl, 1-naphthyl, 2-naphthyl and 1,2,3,4-tetrahydro-naphthyl;
R5 is selected from the group consisting of chloro, methyl, n-propyl and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical dosage form of claim 4 wherein in the compound of formula (1)
X is —NR1R2;
R1 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, t-butyl, dimethylaminoethyl, benzyl, phenylethyl,





3-methyl-phenyl, 2-(3,4-dimethoxyphenyl)-ethyl, ethoxycarbonyl-methyl, dimethylamino-ethyl and 2-amino-2-methoxycarbonyl-ethyl;
R2 is 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, cyclopropyl, phenyl, 4-fluorophenyl, 4-methylphenyl, 2-aminophenyl, 4-(t-butoxycarbonylamino-ethyl)-phenyl, 3,4-dimethoxyphenyl, 4-biphenyl, 2-ethoxyphenyl, 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, adamantanyl, 1-adamantanyl-methyl, 1-naphthyl, 1-naphthyl-methyl,





2S-hydroxy-S-cyclopentyl-methyl, 2S-hydroxy-S-cyclohexyl-methyl, 2S-hydroxy-S-cycloheptyl-methyl and 2-phenoxy-ethyl;
L1 is selected from the group consisting of —CH2— and —CH2—CH2—;





is selected from the group consisting of 1-acenaphthenyl, R-1-acenaphthenyl, S-1-acenaphthenyl, phenyl-and 1-naphthyl;
p is an integer from 0 to 2;
or a pharmaceutically acceptable salt thereof.

6. The pharmaceutical dosage form of claim 5 wherein in the compound of formulate (I)
R1 is 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, ethoxycarbonyl-methyl,




R2 is 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-(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, 1-adamantanyl, 1-adamantanyl-methyl, 1-naphthyl, 1-naphthyl-methyl





2S-hydroxy-S-cyclopentyl-methyl, 2S-hydroxy-S-cyclohexyl-methyl, 2S-hydroxy-S-cycloheptyl-methyl and 2-phenoxy-ethyl;
p is an integer from 0 to 1;
R5 is selected from the group consisting of methyl, n-propyl and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical dosage form of claim 4 wherein in the compound of formula (I)
R0 —CH2—CH(OH)—CH2—X;
X is —NR1R2;
R1 is selected from the group consisting of hydrogen, 2-(3,4-dimethoxyphenyl)-ethyl, 1-(3,4-dimethoxyphenyl)-n-ethyl and amino-n-propyl;
R2 is 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 and —CH(CH3)-phenyl;
R3 is selected from the group consisting of phenyl and 4-fluorophenyl;
L1 selected from the group consisting of —CH2— and —CH2CH2—;





is selected from the group consisting 1-naphthyl, 1-acenaphthenyl, R-1-acenaphthenyl and S-1-acenaphthenyl;
p is an integer from 0 to 1;
R5 is methyl;
or a pharmaceutically acceptable salt thereof.

8. The pharmaceutical dosage form of claim 7 wherein in the compound of formula (I)
R1 is selected from the group consisting of hydrogen, 1-(3,4-dimethoxyphenyl)-n-ethyl and amino-n-propyl;
R2 is 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 and —CH(CH3)-phenyl;





is selected from the group consisting 1-naphthyl, 1-acenaphthenyl, R-1-acenaphthenyl and S-1-acenaphthenyl;
or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical dosage form of claim 7 wherein the compound is 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;
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.

10. The pharmaceutical dosage form of claim 1 wherein the compound is 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 and pharmaceutically acceptable salts thereof.

11. A pharmaceutical composition suitable for oral administration comprising 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 and pharmaceutically acceptable salts thereof and pharmaceutically acceptable carriers.

12. The pharmaceutical composition of claim 11 wherein the dosage form is a solid dosage form.

13. The pharmaceutical composition of claim 12 where in the solid dosage form is selected from the group consisting of pills, tablet, caplet, capsule granules and powders.

14. The pharmaceutical composition of claim 11 wherein the dosage form is a liquid dosage form selected from the group consisting of solution, syrups, elixirs, emulsions and suspensions.