Spiroazacyclic compounds as monoamine receptor modulators
First Claim
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1. A compound of formula I, salts and stereoisomers thereof wherein X is selected from the group consisting of CH2, CH2CH2, CH2O, OCH2, O, CH2S, SCH2, S, CH2N(RN), N(Rk)CH2 and N(RN);
- wherein RN is selected from hydrogen and C1-6 alkyl;
Y is selected from the group consisting of O and S;
Z is absent or selected from the group consisting of CH and N;
R1 is selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, optionally substituted C3-6 cycloalkyl, aryl, and heteroaryl;
m is selected from the group consisting of 0 and 1, wherein if m is 1 and X is CH2 or N(RN), then Z is absent, and if m is 1 and X is O, then Z is CH or N, and if m is 0 and X is 0, then Z is N or absent;
R4, R5, and R6 are independently selected from the group consisting of hydrogen, C1-6 alkyl, aryl(C1-6 alkyl), heteroaryl(C1-6 alkyl), heterocyclyl(C1-6 alkyl), hydroxy(C1-6 alkyl), amino(C1-6 alkyl), halo(C1-6 alkyl), optionally substituted C3-6 cylcoalkyl, aryl, and heteroaryl, wherein at least two of R4, R5, and R6 are independently selected from the group consisting of aryl(C1-6 alkyl), heteroaryl(C1-6 alkyl), and heterocyclyl(C1-6 alkyl);
R2 and R3 are independently selected from the group consisting of hydrogen, halogen, hydroxy, and optionally substituted C1-6 alkyl or selected such that R2 and R3 together form a ring system such that is selected from the group consisting of wherein R7 and R8 are independently selected from the group consisting of hydrogen, halogen, hydroxy, and C1-6 alkyl.
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Abstract
The present invention relates to spiroazacyclic compounds as monoamine receptor modulators; compositions comprising the same; methods of inhibiting an activity of a monoamine receptor with said compounds; methods of treating a disease condition associated with a monoamine receptor using said compounds; and methods for identifying a subject suitable for treatment using said compounds.
101 Citations
19 Claims
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1. A compound of formula I, salts and stereoisomers thereof
wherein X is selected from the group consisting of CH2, CH2CH2, CH2O, OCH2, O, CH2S, SCH2, S, CH2N(RN), N(Rk)CH2 and N(RN);- wherein RN is selected from hydrogen and C1-6 alkyl;
Y is selected from the group consisting of O and S;
Z is absent or selected from the group consisting of CH and N;
R1 is selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, optionally substituted C3-6 cycloalkyl, aryl, and heteroaryl;
m is selected from the group consisting of 0 and 1, wherein if m is 1 and X is CH2 or N(RN), then Z is absent, and if m is 1 and X is O, then Z is CH or N, and if m is 0 and X is 0, then Z is N or absent;
R4, R5, and R6 are independently selected from the group consisting of hydrogen, C1-6 alkyl, aryl(C1-6 alkyl), heteroaryl(C1-6 alkyl), heterocyclyl(C1-6 alkyl), hydroxy(C1-6 alkyl), amino(C1-6 alkyl), halo(C1-6 alkyl), optionally substituted C3-6 cylcoalkyl, aryl, and heteroaryl, wherein at least two of R4, R5, and R6 are independently selected from the group consisting of aryl(C1-6 alkyl), heteroaryl(C1-6 alkyl), and heterocyclyl(C1-6 alkyl);
R2 and R3 are independently selected from the group consisting of hydrogen, halogen, hydroxy, and optionally substituted C1-6 alkyl or selected such that R2 and R3 together form a ring system such that is selected from the group consisting of wherein R7 and R8 are independently selected from the group consisting of hydrogen, halogen, hydroxy, and C1-6 alkyl. - View Dependent Claims (2, 3, 4, 5, 6, 7, 9, 10, 11, 13, 15, 17, 18, 19)
- wherein RN is selected from hydrogen and C1-6 alkyl;
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8. The compound of claim 8, wherein two of R4, R5, and R6 are independently selected from the group consisting of aryl(C1-6 alkyl) and heteroaryl(C1-6 alkyl) and the remaining one of R4, R5., and R6, if present, is hydrogen.
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12. The compound of claim 12, wherein the halogen is fluorine and the optionally substituted O—
- C 1-6-alkyl is an unsubstituted or fluorinated O—
C i6-alkyl.
- C 1-6-alkyl is an unsubstituted or fluorinated O—
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14. The compound of claim 14, wherein at least two of R4, R5, and R6 are optionally substituted benzyl.
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16. The compound of claim 16 selected from the group consisting of 1-(4- Fluorobenzyl)-2-(4-methoxybenzyl)-8-methyl-1,2,8-triaza-spiro[4.5]decan-3-one;
- 2-(4- Ethoxybenzyl)-1-(4-fluorobenzyl)-8-methyl-1,2,8-triaza-spiro[4.5]decan-3-one;
1-(4- Fluorobenzyl)-8-methyl-2-(4-propoxybenzyl) 1,2,8-triaza-spiro[4.5]decan-3-one;
1-(4- Fluorobenzyl)-2-(4-isopropoxybenzyl)-8-methyl-1,2,8-triaza-spiro[4.5]decan-3-one;
2-(4- Butoxybenzyll 1-(4-fluorobenzyl)-8-methyl-1,2,8-triaza-spiro[4.5]decan-3-one;
2-(4- Cyclopropylmethoxybenzyl)-1-(4-fluorobenzyl)-8-methyl-1,2,8-triaza-spiro[4.5]decan-3-one;
1-(4-Fluorobenzyl)-2-(4-isobutoxybenzyl 8-methyl-1,2,8-triaza-spiro[4.5]decan-3-one;
2-(4- Difluoromethoxybenzyl) 1-(4-fluorobenzyl)-8-methyl-1,2,8-triam-spiro[4.5]decan-3-one;
I- (4-Fluorobenzyl)-8-methyl-2-(4-trifluoromethoxybenzyl)-1,2,8-triaza-spiro[4.5]decan-3-one;
1-(4-Fluorobenzyl)-8-methyl-2-(4-pentoxybenzyl)-1,2,8-triaza-spiro[4.5]decan-3-one;
1-(4- Chlorobenzyl)-2-(4-ethoxybenzyl)-8-methyl-1,2,8-triaza-spiro[4.5]decan-3-one;
1-(4- Chlorobenzyl)-8-methyl-2-(4-propoxybenzyl)-1,2,8-triaza-spiro[4.5]decan-3-one;
1-(4- Chlorobenzyl)-2-(4-isobutoxybenzyl)-8-methyl-1,2,8-triaza-spiro[4.5]decan-3-one;
1-(4- Chlorobenzyl)-2-(4-cyclopropylmethoxybenzyl)-8-methyl-1,2,8-triaza-spiro[4.5]decan-3-one;
1-(4-Chlorobenzyl)-2-(4-difluoromethoxybenzyl)-8-methyl-1,2,8-triaza-spiro[4.5]decan-3- one;
1-(4-Ethylbenzyl)-2-(4-ethoxybenzyl)-8-methyl-1,2,8-triaza-spiro[4.5]decan-3-one;
1- (4-Ethylbenzyl)-2-(4-isopropoxybenzyl)-8-methyl-1,2,8-triaza-spiro[4.5]decan-3-one;
1-(4- Ethylbenzyl)-2-(4-isobutoxybenzyl)-8-methyl-1,2,8-triaza-spiro[4.5]decan-3-one;
1-(4- Ethylbenzyl)-2-(4-cyclopropylmethoxybenzyl)-8-methyl-1,2,8-triaza-spiro[4.5]decan-3-one;
1-(4-Ethylbenzyl)-8-methyl-2-(4-trifluoromethoxybenzyl)-1,2,8-triaza-spiro[4.5]decan-3-one;
2-(4-Difluoromethoxybenzyl)-1-(4-fluorobenzyl)-8-ethyl-1,2,8-triaza-spiro[4.5]decan-3-one;
2-(4-Difluoromethoxybenzyl)-1-(4-fluorobenzyl)-8-isopropyl-1,2,8-triaza-spiro[4.5]decan-3- one;
2-(4-Difluoromethoxybenzyl}- (4-fluorobenzyl)-8-cyclopropylmethyl-1,2,8-triaza- spiro[4.5]decan-3-one;
2-(4-Difluoromethoxybenzyl) 1-(4-fluorobenzyl)-8-(2-[1,3]dioxolan- 2-yl-ethyl)-1,2,8-triaza-spiro[4.5]decan-3-one;
8-Ethyl-1-(4-fluorobenzyl)-2-(4- isobutoxybenzyl)-1,2,8-triaza-spiro[4.5]decan-3-one;
1-(4-Fluorobenzyl)-2-(4- isobutoxybenzyl)-8-isopropyl-1,2,8-triaza-spiro[4.5]decan-3-one;
8-Cyclopropylmethyl-1-(4- fluorobenzyl)-2-(4-isobutoxybenzyl)-1,2,8-triaza-spiro[4.5]decan-3-one;
8-(2-[1,3]dioxolan- 2-yl-ethyl)-1-(4-fluorobenzy1)-2-(4-isobutoxybenzyl) 1,2,8-triaza-spiro[4.5]decan-3-one;
4- (4-Ethoxybenzyl)-5-(4-fluorobenzyl)-9-methyl-1-oxa-4,9-diaza-spiro[5.5]undecan-3-one;
5- (4-Fluorobenzyl)-9-methyl-4-(4-propoxybenzyl)-1-oxa-4,9-diaza-spiro[5.5]undecan-3-one;
5- (4-fluorobenzyl)-4-(4-isobutoxybenzyl)-9-methyl-1-oxa-4,9-diaza-spiro[5.5]undecan-3-one;
5-(4-fluorobenzyl)-9-methyl-4-(4-trifluoromethoxybenzyl) 1-oxa-4,9-diaza- spiro[5.5]undecan-3-one;
5-(4-Chlorobenzyl)-4-(4-isobutoxybenzyl)-9-methyl-1-oxa-4,9- diaza-spiro[5.5]undecan-3-one;
5-(4-Chlorobenzyl)-4-(4-cyclopropylmethoxybenzyl)-9- methyl-1-oxa-4,9-diaza-spiro[5.5]undecan-3-one;
9-Ethyl-5-(4-fluorobenzyl)-4-(4- propoxybenzyl) I -oxa-4,9-diaza-spiro[5.5]undecan-3-one;
1-(4-Fluorobenzyl)-2-(4- ethoxybenzyl)-9-methyl-1,2,9-triaza-spiro[5.5]undecan-3-one;
1-(4-Fluorobenzyl)-2-(4- cyclopropylmethoxybenzyl)-9-methyl-1,2,9-triaza-spiro[5.5]undecan-3-one;
1-(4- Fluorobenzyl)-2-(4-isobutoxybenzyl)-9-methyl-1,2,9-triaza-spiro[5.5]undecan-3-one;
1-(4- Fluorobenzyl)-2-(4-propoxybenzyl)-9-methyl-1,2,9-triaza-spiro[5.5]undecan-3-one;
1-(4- Ethylbenzyl)-2-(4-isobutoxybenzyl)-9-methyl-1,2,9-triaza-spiro[5.5]undecan-3-one;
1-(4- Fluorobenzyl)-2-(4-cyclopropylmethoxybenzyl)-9-ethyl-1,2,9-triaza-spiro[5.5]undecan-3- one;
2-(4-Ethoxybenzyl)-1-(4-fluorobenzyl)-8-methyl-1,2,4,8-tetraaza-spiro[4.5]decan-3-one;
1-(4-Fluorobenzyl)-2-(4-isobutoxybenzyl)-8-methyl-1,2,4,8-tetraaza-spiro[4.5]decan-3-one;
2-(4-Difluoromethoxybenzyl) 1-(4-fluorobenzyl)-8-methyl-2,8-diaza-spiro[4.5]decan-3-one;
1-(4-Fluorobenzyl)-2-(4-isobutoxybenzyl)-8-methyl-2,8-diaza-spiro[4.5]decan-3-one ;
2-(4- Cyclopropylmethoxybenzyl)-1-(4-fluorobenzyl)-8-methyl-2,8-diaza-spiro[4.5]decan-3-one;
8-Ethyl-i-(4-fluorobenzyl)-2-(4-isobutoxybenzyl)-2,.8-diaza-spiro[4.5]decan-3-one;
8-(2- [1,3]Dioxolan-2-yl-ethyl)-1-(4-fluorobenzyl)-2-(4-isobutoxybenzyl)-2,8-diaza- spiro[4.5]decan-3-one;
3-(4-Difluoromethoxybenzyl)-4-(4-fluorobenzyl)-8-methyl-1,3,8- triaza-spiro[4.5]decan-2-one;
4-(4-Fluorobenzyl)-3-(4-isobutoxybenzyl)-8-methyl-1,3,8- triaza-spiro[4.5]decan-2-one;
3-(4-Cyclopropylmethoxybenzyl)-4-(4-fluorobenzyl)-8-methyl- 1,3,8-triaza-spiro[4.5]decan-2-one;
8-Ethyl-4-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1,3,8- triaza-spiro[4.5]decan-2-one;
8-(2-[1,3]Dioxolan-2-yl-ethyl)-4-(4-fluorobenzyl)-3-(4- isobutoxybenzyl)-l,3,8-triaza-spiro[4.5]decan-2-one;
1-(4-Fluorobenzyl)-2-(4-ethoxybenzyl} 9-methyl-2,4,9-triaza-spiro[5.5]undecan-3-one;
1-(4-Fluorobenzyl)-2-(4- cyclopropylmethoxybenzyl)-9-methyl-2,4,9-triaza-spiro[5.5]undecan-3-one;
1-(4- Fluorobenzyl)-2-(4-isobutoxybenzyl)-9-methyl-2,4,9-triaza-spiro[5.5]undecan-3-one;
1-(4- Fluorobenzyl)-2-(4-trifluoromethoxybenzyl)-9-methyl-2,4,9-triaza-spiro[5.5]undecan-3-one;
1-(4-Fluorobenzyl)-2-(4-isobutoxybenzyl)-9-ethyl-2,4,9-triaza-spiro[5.5]undecan-3-one;
4- (4-Ethoxybenzyl)-5-(4-fluorobenzyl)-9-methyl-1-oxa-3 ,9-diaza-spiro[5.5]undecan-2-one;
3- (4-Ethoxybenzyl)-5-(4-fluorobenzyl)-9-methyl-1-oxa-3 ,9-diaza-spiro[5.5]undecan-2-one;
3- (4-Ethoxybenzyl)-4-(4-fluorobenzyl)-9-methyl-1-oxa-3 ,9-diaza-spiro [5.5]undecan-2-one;
5- (4-Fluorobenzyl)-4-(4-propoxybenzyl)-9-methyl-1-oxa-3 ,9-diaza-spiro [5. 5]undecan-2-one;
5- (4-Fluorobenzyl)-3-(4-propxybenzyl)-9-methyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;
4- (4-Fluorobenzyl)-3-(4-propoxybenzyl)-9-methyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;
5- (4-Fluorobenzyl)-4-(4-isobutoxybenzyl)-9-methyl-1-oxa-3 ,9-diaza-spiro [5. 5]undecan-2-one;
4-(4-Fluorobenzyl)-3-(4-isobutoxybenzyl)-9-methyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2- one;
4-(4-Ethoxybenzyl)-5-(4-fluorobenzyl)-9-methyl-2-oxa-4,9-diaza-spiro[5.5]undecan-3- one;
5-(4-Fluorobenzyl)-4-(4-methoxybenzyl)-9-methyl-2-oxa-4,9-diaza-spiro[5.5]undecan- 3-one;
5-(4-Fluorobenzyl)-4-(4-propoxybenzyl)-9-methyl-2-oxa-4,9-diaza-spiro[5.5]undecan- 3-one;
5-(4-Fluorobenzyl)-4-(4-isobutoxybenzyl)-9-methyl-2-oxa-4,9-diaza- spiro[5.5]undecan-3-one;
4-(4-Ethoxybenzyl)-5-(4-fluorobenzyl)-9-methyl-2-oxa-4,9-diaza- spiro[5.5]undecan-3-one;
3-(4-Ethoxybenzyl)-4-(4-fluorobenzyl)-8-methyl-1-thia-3,8-diaza- spiro[4.5]decan-2-one;
4-(4-Fluorobenzyl)-3-(4-methoxybenzyl)-8-methyl-1-thia-3,8-diaza- spiro[4.5]decan-2-one;
4-(4-Fluorobenzyl)-3-(4-propoxybenzyl)-8-methyl-1-thia-3,8-diaza- spiro[4.5]decan-2-one; and
4-(4-Fluorobenzyl)-3-(4-isobutoxybenzyl)-8-methyl-1-thia-3,8- diaza-spiro[4.5]decan-2-one.
- 2-(4- Ethoxybenzyl)-1-(4-fluorobenzyl)-8-methyl-1,2,8-triaza-spiro[4.5]decan-3-one;
Specification