Substituted heterocycle fused gamma-carbolines
First Claim
1. A method for treating a human suffering from sleep disorders associated with 5HT2A receptor modulation, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I):
2 Assignments
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Accused Products
Abstract
The present invention is directed to methods of treating addictive behavior and sleep disorders by administering compounds represented by structural Formula (I)
or pharmaceutically acceptable salt forms thereof, wherein R1, R5, R6a, R6b, R7, R8, R9, X, b, k, m, and n, and the dashed lines are described herein. The compounds used in the method of treatment of this invention are serotonin agonists and antagonists and are useful in the control or prevention of central nervous system disorders including addictive behavior and sleep disorders.
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Citations
15 Claims
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1. A method for treating a human suffering from sleep disorders associated with 5HT2A receptor modulation, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I):
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15)
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2. The method as defined in claim 1 where in the compound administered:
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X is —
NR10A—
;R1 is selected from H, C(═
O)R2,C(═
O)OR2,C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-7 cycloalkyl, C1-6 alkyl substituted with 0–
2 R2,C2-6 alkenyl substituted with 0–
2 R2,C2-6 alkynyl substituted with 0–
2 R2,aryl substituted with 0–
2 R2, and5–
6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O, and S, said heterocyclic ring system substituted with 0–
2 R2;R2, at each occurrence, is independently selected from F, Cl, CH2F, CHF2, CF3, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, phenyl substituted with 0–
5 R42;C3-10 carbocyclic group substituted with 0–
3 R41, and5–
10 membered heterocyclic ring system containing from 1–
4 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R41;R5 is H, methyl, ethyl, propyl, or butyl; R6a is selected from H, —
OH, —
NR46R47, —
CF3,C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, and aryl substituted with 0–
3 R44;R6b is H; R7 and R9, at each occurrence, are independently selected from H, halo, —
CF3, —
OCF3, —
OH, —
CN, —
NO2, —
NR46R47,C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-4 haloalkyl, C1-8 alkoxy, (C1-4 haloalkyl)oxy, C3-10 cycloalkyl substituted with 0–
2 R33,C1-4 alkyl substituted with 0–
2 R11,C3-10 carbocyclic group substituted with 0–
3 R33,aryl substituted with 0–
5 R33,5–
10 membered heterocyclic ring system containing from 1–
4 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R31;OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, OC(O)OR12, CH(═
NR14)NR12R13, NHC(═
NR14)NR12R13, S(O)R12, S(O)2R12, S(O)NR12R13, S(O)2NR12R13, NR14S(O)R12, NR14S(O)2R12, NR12C(O)R15, NR12C(O)OR15, NR12S(O)2R15, and NR12C(O)NHR15;R8 is selected from H, halo, —
CF3, —
OCF3, —
OH, —
CN, —
NO2,C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-4 haloalkyl, C1-8 alkoxy, (C1-4 haloalkyl)oxy, C3-10 cycloalkyl substituted with 0–
2 R33,C1-4 alkyl substituted with 0–
2 R11,C2-4 alkenyl substituted with 0–
2 R11,C2-4 alkynyl substituted with 0–
1 R11,C3-10 carbocyclic group substituted with 0–
3 R33,aryl substituted with 0–
5 R33,5–
10 membered heterocyclic ring system containing from 1–
4 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R31;OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, OC(O)OR12, CH(═
NR14)NR12R13, NHC(═
NR14)NR12R13, S(O)R12, S(O)2R12, S(O)NR12R13, S(O)2NR12R13, NR14S(O)R12, NR14S(O)2R12, NR12C(O)R15, NR12C(O)OR15, NR12S(O)2R15, and NR12C(O)NHR15;R10A is selected from H, C1-6 alkyl substituted with 0–
1 R10B,C2-6 alkenyl substituted with 0–
1 R10B,C2-6 alkynyl substituted with 0–
1 R10B, andC1-6 alkoxy; R10B is selected from C1-4 alkoxy, C3-6 cycloalkyl, C3-10 carbocyclic group substituted with 0–
3 R33,phenyl substituted with 0–
3 R33, and5–
6 membered heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
2 R44;R11 is selected from H, halo, —
CF3, —
CN, —
NO2,C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-4 haloalkyl, C1-8 alkoxy, C3-10 cycloalkyl, C3-10 carbocyclic group substituted with 0–
3 R33,aryl substituted with 0–
5 R33,5–
10 membered heterocyclic ring system containing from 1–
4 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R31;OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, OC(O)OR12, CH(═
NR14)NR12R13, NHC(═
NR14)NR12R13, S(O)R12, S(O)2R12, S(O)NR12R13, S(O)2NR12R13, NR14S(O)R12, NR14S(O)2R12, NR12C(O)R15, NR12C(O)OR15, NR12S(O)2R15, and NR12C(O)NHR15;R12, at each occurrence, is independently selected from C1-4 alkyl substituted with 0–
1 R12a,C2-4 alkenyl substituted with 0–
1 R12a,C2-4 alkynyl substituted with 0–
1 R12a,C3-6 cycloalkyl substituted with 0–
3 R33,phenyl substituted with 0–
5 R33;C3-10 carbocyclic group substituted with 0–
3 R33, and5–
10 membered heterocyclic ring system containing from 1–
4 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R31;R12a, at each occurrence, is independently selected from phenyl substituted with 0–
5 R33;C3-10 carbocyclic group substituted with 0–
3 R33, and5–
10 membered heterocyclic ring system containing from 1–
4 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R31;R13, at each occurrence, is independently selected from H, C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl; alternatively, R12 and R13 join to form a 5- or 6-membered ring optionally substituted with —
O—
or —
N(R14)—
;alternatively, R12 and R13 when attached to N may be combined to form a 9- or 10-membered bicyclic heterocyclic ring system containing from 1–
3 heteroatoms selected from the group consisting of N, O, and S, wherein said bicyclic heterocyclic ring system is unsaturated or partially saturated, wherein said bicyclic heterocyclic ring system is substituted with 0–
3 R16;R14, at each occurrence, is independently selected from H and C1-4 alkyl; R15, at each occurrence, is independently selected from H, C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl; R16, at each occurrence, is independently selected from H, OH, halo, CN, NO2, CF3, SO2R45, NR46R47, —
C(═
O)H,C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-3 haloalkyl-oxy-, and C1-3 alkyloxy-; R31, at each occurrence, is independently selected from H, OH, halo, CF3, SO2R45, NR46R47, and C1-4 alkyl; R33, at each occurrence, is independently selected from H, OH, halo, CN, NO2, CF3, SO2R45, NR46R47, —
C(═
O)H,C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-4 haloalkyl, C1-4 haloalkyl-oxy-, C1-4 alkyloxy-, C1-4 alkylthio-, C1-4 alkyl-C(═
O)—
, C1-4 alkyl-C(═
O)NH—
, C1-4 alkyl-OC(═
O)—
,C1-4 alkyl-C(═
O)O—
, C3-6 cycloalkyl-oxy-, C3-6 cycloalkylmethyl-oxy-;C1-6 alkyl substituted with OH, methoxy, ethoxy, propoxy, or butoxy; and C2-6 alkenyl substituted with OH, methoxy, ethoxy, propoxy, or butoxy; R41, at each occurrence, is independently selected from H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN; C2-8 alkenyl, C2-8 alkynyl, C1-4 alkoxy, C1-4 haloalkyl C1-4 alkyl substituted with 0–
1 R43,aryl substituted with 0–
3 R42, and5–
10 membered heterocyclic ring system containing from 1–
4 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R44;R42, at each occurrence, is independently selected from H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN, CH(═
NH)NH2, NHC(═
NH)NH2,C2-6 alkenyl, C2-6 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, C3-6 cycloalkyl, C1-4 alkyl substituted with 0–
1 R43,aryl substituted with 0–
3 R44, and5–
10 membered heterocyclic ring system containing from 1–
4 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R44;R43 is C3-6 cycloalkyl or aryl substituted with 0–
3 R44;R44, at each occurrence, is independently selected from H, halo, —
OH, NR46R47, CO2H, SO2R45, —
CF3, —
OCF3, —
CN, —
NO2, C1-4 alkyl, and C1-4 alkoxy;R45 is C1-4 alkyl; R46, at each occurrence, is independently selected from H and C1-4 alkyl; R47, at each occurrence, is independently selected from H and C1-4 alkyl; k is 1 or 2; m is 0, 1, or 2; and n is 1, 2, or 3.
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3. The method as defined in claim 2 where in the compound administered:
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X is —
NR10A—
;R1 is selected from H, C(═
O)R2,C(═
O)OR2,C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-4 alkyl substituted with 0–
2 R2,C2-4 alkenyl substituted with 0–
2 R2, andC2-4 alkynyl substituted with 0–
2 R2;R2, at each occurrence, is independently selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, phenyl substituted with 0–
5 R42;C3-10 carbocyclic group substituted with 0–
3 R41, and5–
10 membered heterocyclic ring system containing from 1–
4 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R41;R5 is H, methyl, ethyl, propyl, or butyl; R6a is selected independently from H, —
OH, —
NR46R47, —
CF3, C1-3 alkyl, and C1-3 alkoxy;R6b is H; R7 and R9, at each occurrence, are independently selected from H, halo, —
CF3, —
OCF3, —
OH, —
CN, —
NO2, —
NR46R47,C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, (C1-4 haloalkyl)oxy, C3-10 cycloalkyl substituted with 0–
2 R33,C1-4 alkyl substituted with 0–
2 R11,C3-10 carbocyclic group substituted with 0–
3 R33,aryl substituted with 0–
5 R33,5–
10 membered heterocyclic ring system containing from 1–
4 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R31;OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, OC(O)OR12, CH(═
NR14)NR12R13, NHC(═
NR14)NR12R13, S(O)R12, S(O)2R12, S(O)NR12R13, S(O)2NR12R13, NR14S(O)R12, and NR14S(O)2R12;R8 is selected from H, halo, —
CF3, —
OCF3, —
OH, —
CN, —
NO2,C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, (C1-4 haloalkyl)oxy, C3-10 cycloalkyl substituted with 0–
2 R33,C1-4 alkyl substituted with 0–
2 R11,C2-4 alkenyl substituted with 0–
2 R11,C2-4 alkynyl substituted with 0–
1 R11,C3-10 carbocyclic group substituted with 0–
3 R33,aryl substituted with 0–
5 R33,5–
10 membered heterocyclic ring system containing from 1–
4 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R31;OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, OC(O)OR12, CH(═
NR14)NR12R13, NHC(═
NR14)NR12R13, S(O)R12, S(O)2R12, S(O)NR12R13, S(O)2NR12R13, NR14S(O)R12, NR14S(O)2R12, NR12C(O)R15, NR12C(O)OR15, NR12S(O)2R15, and NR12C(O)NHR15;R10A is selected from H, C1-4 alkyl substituted with 0–
1 R10B,C2-4 alkenyl substituted with 0–
1 R10B,C2-4 alkynyl substituted with 0–
1 R10B, andC1-6 alkoxy; R10B is selected from C1-4 alkoxy, C3-6 cycloalkyl, phenyl substituted with 0–
3 R33, and5–
6 membered heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
2 R44;R111 is selected from H, halo, —
CF3, —
CN, —
NO2, C1-6 alkyl,C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C3-10 cycloalkyl, C3-10 carbocyclic group substituted with 0–
3 R33,aryl substituted with 0–
5 R33,5–
10 membered heterocyclic ring system containing from 1–
4 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R31;OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, OC(O)OR12, CH(═
NR14)NR12R13, NHC(═
NR14)NR12R13, S(O)R12, S(O)2R12, S(O)NR12R13, S(O)2NR12R13, NR14S(O)R12, and NR14S(O)2R12;R12, at each occurrence, is independently selected from C1-4 alkyl substituted with 0–
1 R12a,C2-4 alkenyl substituted with 0–
1 R12a,C2-4 alkynyl substituted with 0–
1 R12a,C3-6 cycloalkyl substituted with 0–
3 R33,phenyl substituted with 0–
5 R33;C3-10 carbocyclic group substituted with 0–
3 R33, and5–
10 membered heterocyclic ring system containing from 1–
4 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R31;R12a, at each occurrence, is independently selected from phenyl substituted with 0–
5 R33;C3-10 carbocyclic group substituted with 0–
3 R33, and5–
10 membered heterocyclic ring system containing from 14 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R31;R13, at each occurrence, is independently selected from H, C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl; alternatively, R12 and R13 join to form a 5- or 6-membered ring optionally substituted with —
O—
or —
N(R14)—
;alternatively, R12 and R13 when attached to N may be combined to form a 9- or 10-membered bicyclic heterocyclic ring system containing from 1–
3 heteroatoms selected from the group consisting of N, O, and S, wherein said bicyclic heterocyclic ring system is unsaturated or partially saturated, wherein said bicyclic heterocyclic ring system is substituted with 0–
3 R16;R14, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl; R15, at each occurrence, is independently selected from H, C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl; R16, at each occurrence, is independently selected from H, OH, F, Cl, CN, NO2, CF3, SO2R45, NR46R47, —
C(═
O)H,methyl, ethyl, methoxy, ethoxy, trifluoromethyl, and trifluoromethoxy; R31, at each occurrence, is independently selected from H, OH, halo, CF3, SO2R45, NR46R47, and C1-4 alkyl; R33, at each occurrence, is independently selected from H, OH, halo, CN, NO2, CF3, SO2R45, NR46R47, —
C(═
O)H,C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-4 haloalkyl, C1-4 haloalkyl-oxy-, C1-4 alkyloxy-, C1-4 alkylthio-, C1-4 alkyl-C(═
O)—
, C1-4 alkyl-C(═
O)NH—
, C1-4 alkyl-OC(═
O)—
,C1-4 alkyl-C(═
O)O—
, C3-6 cycloalkyl-oxy-, C3-6 cycloalkylmethyl-oxy-;C1-6 alkyl substituted with OH, methoxy, ethoxy, propoxy, or butoxy; and C2-6 alkenyl substituted with OH, methoxy, ethoxy, propoxy, or butoxy; R41, at each occurrence, is independently selected from H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN, C2-8 alkenyl, C2-8 alkynyl, C1-14 alkoxy, C1-4 haloalkyl C1-4 alkyl substituted with 0–
1 R43,aryl substituted with 0–
3 R42, and5–
10 membered heterocyclic ring system containing from 1–
4 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R44;R42, at each occurrence, is independently selected from H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN, CH(═
NH)NH2, NHC(═
NH)NH2,C2-6 alkenyl, C2-6 alkynyl, C1-14 alkoxy, C1-4 haloalkyl, C3-6 cycloalkyl, C1-4 alkyl substituted with 0–
1 R43,aryl substituted with 0–
3 R44, and5–
10 membered heterocyclic ring system containing from 1–
4 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R44;R43 is C3-6 cycloalkyl or aryl substituted with 0–
3 R44;R44, at each occurrence, is independently selected from H, halo, —
OH, NR46R47, CO2H, SO2R45, —
CF3, —
OCF3, —
CN, —
NO2, C1-4 alkyl, and C1-4 alkoxy;R45 is C1-4 alkyl; R46, at each occurrence, is independently selected from H and C1-4 alkyl; R47, at each occurrence, is independently selected from H and C1-4 alkyl; k is 1 or 2; m is 0 or 1; and n is 1 or 2.
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4. The method as defined in claim 2 where in the compound administered:
-
X is —
NH—
;R1 is selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-4 cycloalkyl, C1-3 alkyl substituted with 0–
1 R2,C2-3 alkenyl substituted with 0–
1 R2, andC2-3 alkynyl substituted with 0–
1 R2;R2, at each occurrence, is independently selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, phenyl substituted with 0–
5 R42;C3-6 carbocyclic group substituted with 0–
3 R41, and5–
6 membered heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R41;R5 is H, methyl, ethyl, propyl, or butyl; R6a is H, methyl, ethyl, methoxy, —
OH, or —
CF3;R6b is H; R7 and R9, at each occurrence, are independently selected from H, halo, —
CF3, —
OCF3, —
OH, —
CN, —
NO2, —
NR46R47,C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 alkoxy, (C1-4 haloalkyl)oxy, C3-10 cycloalkyl substituted with 0–
2 R33,C1-4 alkyl substituted with 0–
2 R11,C3-10 carbocyclic group substituted with 0–
3 R33,aryl substituted with 0–
5 R33, and5–
6 membered heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R31;R8 is selected from H, halo, —
CF3, —
OCF3, —
OH, —
CN, —
NO2,C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 alkoxy, (C1-4 haloalkyl)oxy, C3-10 cycloalkyl substituted with 0–
2 R33,C1-4 alkyl substituted with 0–
2 R11,C2-4 alkenyl substituted with 0–
2 R11,C2-4 alkynyl substituted with 0–
1 R11,C3-10 carbocyclic group substituted with 0–
3 R33,aryl substituted with 0–
5 R33,5–
6 membered heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R31;OR12, SR12, NR12R13, NR12C(O)R15, NR12C(O)OR15, NR12S(O)2R15, and NR12C(O)NHR15; R11 is selected from H, halo, —
CF3, —
CN, —
NO2,C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 alkoxy, (C1-4 haloalkyl)oxy, C3-10 cycloalkyl substituted with 0–
2 R33,C3-10 carbocyclic group substituted with 0–
3 R33,aryl substituted with 0–
5 R33, and5–
6 membered heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R31;R12, at each occurrence, is independently selected from C1-4 alkyl substituted with 0–
1 R12a,C2-4 alkenyl substituted with 0–
1 R12a,C2-4 alkynyl substituted with 0–
1 R12a,C3-6 cycloalkyl substituted with 0–
3 R33,phenyl substituted with 0–
5 R33;C3-10 carbocyclic group substituted with 0–
3 R33, and5–
10 membered heterocyclic ring system containing from 1–
4 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R31;R12a, at each occurrence, is independently selected from phenyl substituted with 0–
5 R33;C3-0 carbocyclic group substituted with 0–
3 R33, and5–
10 membered heterocyclic ring system containing from 1–
4 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R31;R13, at each occurrence, is independently selected from H, C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl; alternatively, R12 and R13 join to form a 5- or 6-membered ring optionally substituted with —
O—
or —
N(R14)—
;alternatively, R12 and R13 when attached to N may be combined to form a 9- or 10-membered bicyclic heterocyclic ring system containing from 1–
3 heteroatoms selected from the group consisting of one N, two N, three N, one N one O, and one N one S;
wherein said bicyclic heterocyclic ring system is unsaturated or partially saturated, wherein said bicyclic heterocyclic ring system is substituted with 0–
2 R16;R14, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl; R15, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl; R16, at each occurrence, is independently selected from H, OH, F, Cl, CN, NO2, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, and trifluoromethoxy; R31, at each occurrence, is independently selected from H, OH, halo, CF3, methyl, ethyl, and propyl; R33, at each occurrence, is independently selected from H, OH, halo, CN, NO2, CF3, SO2R45, NR46R47, —
C(═
O)H,C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-4 haloalkyl, C1-4 haloalkyl-oxy-, C1-4 alkyloxy-, C1-4 alkylthio-, C1-4 alkyl-C(═
O)—
, C1-4 alkyl-C(═
O)NH—
, C1-4 alkyl-OC(═
O)—
,C1-4 alkyl-C(═
O)O—
, C3-6 cycloalkyl-oxy-, C3-6 cycloalkylmethyl-oxy-;C1-6 alkyl substituted with OH, methoxy, ethoxy, propoxy, or butoxy; and C2-6 alkenyl substituted with OH, methoxy, ethoxy, propoxy, or butoxy; R41, at each occurrence, is independently selected from H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN, C2-4 alkenyl, C2-4 alkynyl, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 alkyl; R42, at each occurrence, is independently selected from H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN, CH(═
NH)NH2, NHC(═
NH)NH2,C2-4 alkenyl, C2-4 alkynyl, C1-3 alkoxy, C1-3 haloalkyl, C3-6 cycloalkyl, and C1-3 alkyl; R43 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or pyridyl, each substituted with 0–
3 R44;R44, at each occurrence, is independently selected from H, halo, —
OH, NR46R47, CO2H, SO2R45, —
CF3, —
OCF3, —
CN, —
NO2, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, and butoxy;R45 is methyl, ethyl, propyl, or butyl; R46, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl; R47, at each occurrence, is independently selected from from H, methyl, ethyl, propyl, and butyl; k is 1; m is 1; and n is 1 or 2.
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5. The method as defined in claim 2 where in the compound administered:
-
X is —
NH—
;R1 is selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-4 cycloalkyl, C1-3 alkyl substituted with 0–
1 R2,C2-3 alkenyl substituted with 0–
1 R2, andC2-3 alkynyl substituted with 0–
1 R2;R2, at each occurrence, is independently selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, phenyl substituted with 0–
5 R42;C3-6 carbocyclic group substituted with 0–
3 R41, and5–
6 membered heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R41;R5 is H, methyl, ethyl, propyl, or butyl; R6a is H, methyl, ethyl, methoxy, —
OH, or —
CF3;R6b is H; R7 and R9, at each occurrence, are independently selected from H, F, Cl, —
CH3, —
OCH3, —
CF3, —
OCF3, —
CN, and —
NO2,R8 is selected from H, F, Cl, Br, —
CF3, —
OCF3, —
OH, —
CN, —
NO2,C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 alkoxy, (C1-4 haloalkyl)oxy, C3-0 cycloalkyl substituted with 0–
2 R33,C1-4 alkyl substituted with 0–
2 R11,C2-4 alkenyl substituted with 0–
2 R11,C2-4 alkynyl substituted with 0–
1 R11,C3-10 carbocyclic group substituted with 0–
3 R33,aryl substituted with 0–
5 R33,5–
6 membered heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R31;OR12, SR12, NR12R13, NR12C(O)R15, NR12C(O)OR15, NR12S(O)2R15, and NR12C(O)NHR15; R111 is selected from H, halo, —
CF3, —
CN, —
NO2,C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 alkoxy, (C1-4 haloalkyl)oxy, C3-10 cycloalkyl substituted with 0–
2 R33,C3-10 carbocyclic group substituted with 0–
3 R33,aryl substituted with 0–
5 R33, and5–
6 membered heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R31;R12 at each occurrence, is independently selected from C1-4 alkyl substituted with 0–
1 R12a,C2-4 alkenyl substituted with 0–
1 R12a,C2-4 alkynyl substituted with 0–
1 R12a,C3-6 cycloalkyl substituted with 0–
3 R33,phenyl substituted with 0–
5 R33;C3-10 carbocyclic group substituted with 0–
3 R33, and5–
10 membered heterocyclic ring system containing from 1–
4 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R31;R12a, at each occurrence, is independently selected from phenyl substituted with 0–
5 R33;C3-10 carbocyclic group substituted with 0–
3 R33, and5–
10 membered heterocyclic ring system containing from 1–
4 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R31;R13, at each occurrence, is independently selected from H, C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl; alternatively, R12 and R13 join to form a 5- or 6-membered ring optionally substituted with —
O—
or —
N(R14)—
;alternatively, R12 and R13 when attached to N may be combined to form a 9- or 10-membered bicyclic heterocyclic ring system containing from 1–
3 heteroatoms selected from the group consisting of N, O, and S;
wherein said bicyclic heterocyclic ring system is selected from indolyl, indolinyl, indazolyl, benzimidazolyl, benzimidazolinyl, benztriazolyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, and dioxobenzthiazolyl;
wherein said bicyclic heterocyclic ring system is substituted with 0–
1 R16;R14, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl; R15, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl; R16, at each occurrence, is independently selected from H, OH, F, Cl, CN, NO2, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, and trifluoromethoxy; R31, at each occurrence, is independently selected from H, OH, halo, CF3, methyl, ethyl, and propyl; R33, at each occurrence, is independently selected from H, OH, halo, CN, NO2, CF3, SO2R45, NR46R47, —
C(═
O)H,C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-4 haloalkyl, C1-4 haloalkyl-oxy-, C1-4 alkyloxy-, C1-4 alkylthio-, C1-4 alkyl-C(═
O)—
, C1-4 alkyl-C(═
O)NH—
, C1-4 alkyl-OC(═
O)—
,C1-4 alkyl-C(═
O)O—
, C3-6 cycloalkyl-oxy-, C3-6 cycloalkylmethyl-oxy-;C1-6 alkyl substituted with OH, methoxy, ethoxy, propoxy, or butoxy; and C2-6 alkenyl substituted with OH, methoxy, ethoxy, propoxy, or butoxy; R41, at each occurrence, is independently selected from H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN, C2-4 alkenyl, C2-4 alkynyl, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 alkyl; R42, at each occurrence, is independently selected from H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN, CH(═
NH)NH2, NHC(═
NH)NH2,C2-4 alkenyl, C2-4 alkynyl, C1-3 alkoxy, C1-3 haloalkyl, C3-6 cycloalkyl, and C1-3 alkyl; R43 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or pyridyl, each substituted with 0–
3 R44;R44, at each occurrence, is independently selected from H, halo, —
OH, NR46R47, CO2H, SO2R45, —
CF3, —
OCF3, —
CN, —
NO2, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, and butoxy;R45 is methyl, ethyl, propyl, or butyl; R46, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl; R47, at each occurrence, is independently selected from from H, methyl, ethyl, propyl, and butyl; k is 1; m is 1; and n is 1 or 2.
-
-
6. The method as defined in claim 2 where in the compound administered:
-
X is —
NH—
;R1 is selected from H, C1-5 alkyl substituted with 0–
1 R2,C2-5 alkenyl substituted with 0–
1 R2, andC2-3 alkynyl substituted with 0–
1 R2;R2 is C3-6 cycloalkyl; R5 is H, methyl, ethyl, or propyl; R6a is H, methyl, or ethyl; R6b is H; R7 and R9, at each occurrence, are independently selected from H, F, Cl, —
CH3, —
OCH3, —
CF3, —
OCF3, —
CN, and —
NO2,R8 is selected from methyl substituted with R11; ethenyl substituted with R11; OR12, SR12, NR12R13, NR12C(O)R15, NR12C(O)OR15, NR12S(O)2R15, and NR12C(O)NHR15; R11 is selected from phenyl- substituted with 0–
5 fluoro;2-(H3CCH2C(═
O))-phenyl- substituted with R33;2-(H3CC(═
O))-phenyl- substituted with R33;2-(HC(═
O))-phenyl- substituted with R33;2-(H3CCH(OH))-phenyl- substituted with R33; 2-(H3CCH2CH(OH))-phenyl- substituted with R33; 2-(HOCH2)-phenyl- substituted with R33; 2-(HOCH2CH2)-phenyl- substituted with R33; 2-(H3COCH2)-phenyl- substituted with R33; 2-(H3COCH2CH2)-phenyl- substituted with R33; 2-(H3CCH(OMe))-phenyl- substituted with R33; 2-(H3COC(═
O))-phenyl- substituted with R33;2-(HOCH2CH═
CH)-phenyl- substituted with R33;2-((MeOC═
O)CH═
CH)-phenyl- substituted with R33;2-(methyl)-phenyl- substituted with R33; 2-(ethyl)-phenyl- substituted with R33; 2-(i-propyl)-phenyl- substituted with R33; 2-(F3C)-phenyl- substituted with R33; 2-(NC)-phenyl- substituted with R33; 2-(H3CO)-phenyl- substituted with R33; 2-(fluoro)-phenyl- substituted with R33; 2-(chloro)-phenyl- substituted with R33; 3-(NC)-phenyl- substituted with R33; 3-(H3CO)-phenyl- substituted with R33; 3-(fluoro)-phenyl- substituted with R33; 3-(chloro)-phenyl- substituted with R33; 4-(NC)-phenyl- substituted with R33; 4-(fluoro)-phenyl- substituted with R33; 4-(chloro)-phenyl- substituted with R33; 4-(H3CS)-phenyl- substituted with R33; 4-(H3CO)-phenyl- substituted with R33; 4-(ethoxy)-phenyl- substituted with R33; 4-(i-propoxy)-phenyl- substituted with R33; 4-(i-butoxy)-phenyl- substituted with R33; 4-(H3CCH2CH2C(═
O))-phenyl- substituted with R33;4-((H3C)2CHC(═
O))-phenyl- substituted with R33;4-(H3CCH2C(═
O))-phenyl- substituted with R33;4-(H3CC(═
O))-phenyl- substituted with R33;4-(H3CCH2CH2CH(OH))-phenyl- substituted with R33; 4-((H3C)2CHCH(OH))-phenyl- substituted with R33; 4-(H3CCH2CH(OH))-phenyl- substituted with R33; 4-(H3CCH(OH))-phenyl- substituted with R33; 4-(cyclopropyloxy)-phenyl- substituted with R33; 4-(cyclobutyloxy)-phenyl- substituted with R33; and 4-(cyclopentyloxy)-phenyl- substituted with R33; R12 is selected from phenyl- substituted with 0–
5 fluoro;2-(H3CCH2C(═
O))-phenyl- substituted with R33;2-(H3CC(═
O))-phenyl- substituted with R33;2-(HC(═
O))-phenyl- substituted with R33;2-(H3CCH(OH))-phenyl- substituted with R33; 2-(H3CCH2CH(OH))-phenyl- substituted with R33; 2-(HOCH2)-phenyl- substituted with R33; 2-(HOCH2CH2)-phenyl- substituted with R33; 2-(H3COCH2)-phenyl- substituted with R33; 2-(H3COCH2CH2)-phenyl- substituted with R33; 2-(H3CCH(OMe))-phenyl- substituted with R33; 2-(H3COC(═
O))-phenyl- substituted with R33;2-(HOCH2CH═
CH)-phenyl- substituted with R33;2-((MeOC═
O)CH═
CH)-phenyl- substituted with R33;2-(methyl)-phenyl- substituted with R33; 2-(ethyl)-phenyl- substituted with R33; 2-(i-propyl)-phenyl- substituted with R33; 2-(F3C)-phenyl- substituted with R33; 2-(NC)-phenyl- substituted with R33; 2-(H3CO)-phenyl- substituted with R33; 2-(fluoro)-phenyl- substituted with R33; 2-(chloro)-phenyl- substituted with R33; 3-(NC)-phenyl- substituted with R33; 3-(H3CO)-phenyl- substituted with R33; 3-(fluoro)-phenyl- substituted with R33; 3-(chloro)-phenyl- substituted with R33; 4-(NC)-phenyl- substituted with R33; 4-(fluoro)-phenyl- substituted with R33; 4-(chloro)-phenyl- substituted with R33; 4-(H3CS)-phenyl- substituted with R33; 4-(H3CO)-phenyl- substituted with R33; 4-(ethoxy)-phenyl- substituted with R33; 4-(i-propoxy)-phenyl- substituted with R33; 4-(i-butoxy)-phenyl- substituted with R33; 4-(H3CCH2CH2C(═
O))-phenyl- substituted with R33;4-((H3C)2CHC(═
O))-phenyl- substituted with R33;4-(H3CCH2C(═
O))-phenyl- substituted with R33;4-(H3CC(═
O))-phenyl- substituted with R33;4-(H3CCH2CH2CH(OH))-phenyl- substituted with R33; 4-((H3C)2CHCH(OH))-phenyl- substituted with R33; 4-(H3CCH2CH(OH))-phenyl- substituted with R33; 4-(H3CCH(OH))-phenyl- substituted with R33; 4-(cyclopropyloxy)-phenyl- substituted with R33; 4-(cyclobutyloxy)-phenyl- substituted with R33; and 4-(cyclopentyloxy)-phenyl- substituted with R33; R13 is H, methyl, or ethyl; alternatively, R12 and R13 join to form a 5- or 6-membered ring selected from pyrrolyl, pyrrolidinyl, imidazolyl, piperidinyl, piperizinyl, methylpiperizinyl, and morpholinyl; alternatively, R12 and R13 when attached to N may be combined to form a 9- or 10-membered bicyclic heterocyclic ring system containing from 1–
3 heteroatoms selected from the group consisting of N, O, and S;
wherein said bicyclic heterocyclic ring system is selected from indolyl, indolinyl, indazolyl, benzimidazolyl, benzimidazolinyl, benztriazolyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, and dioxobenzthiazolyl;
wherein said bicyclic heterocyclic ring system is substituted with 0–
1 R16;R15 is H, methyl, ethyl, propyl, or butyl; R16, at each occurrence, is independently selected from H, OH, F, Cl, CN, NO2, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, and trifluoromethoxy; R33, at each occurrence, is independently selected from H, F, Cl, —
CH3, —
OCH3, —
CF3, —
OCF3, —
CN, and —
NO2;k is 1; m is 1; and n is 1 or 2.
-
-
7. The method as defined in claim 2 where the compound administered is a compound of Formula (I-a):
-
8. The method as defined in claim 7 where the compound administered is a compound of Formula (IV):
-
9. The method as defined in claim 1 where in the compound administered:
-
X is —
NR10A—
;R1 is selected from C1-6 alkyl substituted with Z, C2-6 alkenyl substituted with Z, C2-6 alkynyl substituted with Z, C3-6 cycloalkyl substituted with Z, aryl substituted with Z, 5–
6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O, and S, said heterocyclic ring system substituted with Z;C1-6 alkyl substituted with 0–
2 R2,C2-6 alkenyl substituted with 0–
2 R2,C2-6 alkynyl substituted with 0–
2 R2,aryl substituted with 0–
2 R2, and5–
6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O, and S, said heterocyclic ring system substituted with 0–
2 R2;Z is selected from H, —
CH(OH)R2,—
C(ethylenedioxy)R2,—
OR2,—
SR2,—
NR2R3,—
C(O)R2,—
C(O)NR2R3,—
NR3C(O)R2,—
C(O)OR2,—
OC(O)R2,—
CH(═
NR4)NR2R3,—
NHC(═
NR4)NR2R3,—
S(O)R2,—
S(O)2R2,—
S(O)2NR2R3, and —
NR3S(O)2R2;R2, at each occurrence, is independently selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, aryl substituted with 0–
5 R42;C3-10 carbocyclic group substituted with 0–
3 R41, and5–
10 membered heterocyclic ring system containing from 1–
4 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R41;R3, at each occurrence, is independently selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, and C1-4 alkoxy; alternatively, R2 and R3 join to form a 5- or 6-membered ring optionally substituted with —
O—
or —
N(R4)—
;R4, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl; R5 is H, methyl, ethyl, propyl, or butyl; R6a is selected from H, —
OH, —
NR46R47, —
CF3,C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, C3-6 cycloalkyl, and aryl substituted with 0–
3 R44;R6b is H; R7, R8, and R9, at each occurrence, are independently selected from H, halo, —
CF3, —
OCF3, —
OH, —
CN, —
NO2, —
NR46R47,C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-4 haloalkyl, C1-8 alkoxy, (C1-4 haloalkyl)oxy, C1-4 alkyl substituted with 0–
2 R11,C3-10 carbocyclic group substituted with 0–
3 R33,aryl substituted with 0–
5 R33,5–
10 membered heterocyclic ring system containing from 1–
4 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R31;OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, OC(O)OR12, CH(═
NR14)NR12R13, NHC(═
NR14)NR12R13, S(O)R12, S(O)2R12, S(O)NR12R13, S(O)2NR12R13, NR14S(O)R12, NR14S(O)2R12, NR12C(O)R15, NR12C(O)OR15, NR12S(O)2R15, and NR12C(O)NHR15;R10A is selected from H, C1-6 alkyl substituted with 0–
1 R10B,C2-6 alkenyl substituted with 0–
1 R10B,C2-6 alkynyl substituted with 0–
1 R10B, andC1-6 alkoxy; R10B is selected from C1-4 alkoxy, C3-6 cycloalkyl, C3-10 carbocyclic group substituted with 0–
3 R33,phenyl substituted with 0–
3 R33, and5–
6 membered heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
2 R44;R11 is selected from H, halo, —
CF3, —
CN, —
NO2,C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-4 haloalkyl, C1-8 alkoxy, C3-10 cycloalkyl, C3-10 carbocyclic group substituted with 0–
3 R33,aryl substituted with 0–
5 R33,5–
10 membered heterocyclic ring system containing from 1–
4 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R31;OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, OC(O)OR12, CH(═
NR14)NR12R13, NHC(═
NR14)NR12R13, S(O)R12, S(O)2R12, S(O)NR12R13, S(O)2NR12R13, NR14S(O)R12, and NR14S(O)2R12;R12, at each occurrence, is independently selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, phenyl substituted with 0–
5 R33;C3-10 carbocyclic group substituted with 0–
3 R33, and5–
10 membered heterocyclic ring system containing from 1–
4 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R31;R13, at each occurrence, is independently selected from H, C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl; alternatively, R12 and R13 join to form a 5- or 6-membered ring optionally substituted with —
O—
or —
N(R14)—
;R14, at each occurrence, is independently selected from H and C1-4 alkyl; R31, at each occurrence, is independently selected from H, OH, halo, CF3, SO2R45, NR46R47, methyl, ethyl, and propyl; R33, at each occurrence, is independently selected from H, OH, halo, CN, NO2, CF3, SO2R45, NR46R47, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C3-5 cycloalkyl, C1-3 haloalkyl, C1-3 haloalkyl-oxy-, C1-3 alkyloxy-, C1-3 alkylthio-, C1-3 alkyl-C(═
O)—
, and C1-3 alkyl-C(═
O)NH—
;R41, at each occurrence, is independently selected from H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN, ═
O,C2-8 alkenyl, C2-8 alkynyl, C1-4 alkoxy, C1-4 haloalkyl C1-4 alkyl substituted with 0–
1 R43,aryl substituted with 0–
3 R42, and5–
10 membered heterocyclic ring system containing from 1–
4 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R44;R42, at each occurrence, is independently selected from H, CF3, halo, OH, CO2H, SO2R45, SR45, NR46R47, OR48, NO2, CN, CH(═
NH)NH2, NHC(═
NH)NH2,C2-6 alkenyl, C2-6 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, C3-6 cycloalkyl, C1-4 alkyl substituted with 0–
1 R43,aryl substituted with 0–
3 R44, and5–
10 membered heterocyclic ring system containing from 1–
4 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R44;R43 is C3-6 cycloalkyl or aryl substituted with 0–
3 R44;R44, at each occurrence, is independently selected from H, halo, —
OH, NR46R47, CO2H, SO2R45, —
CF3, —
OCF3, —
CN, —
NO2, C1-4 alkyl, and C1-4 alkoxy;R45 is C1-4 alkyl; R46, at each occurrence, is independently selected from H and C1-4 alkyl; R47, at each occurrence, is independently selected from H, C1-4 alkyl, —
C(═
O)NH(C1-4 alkyl), —
SO2(C1-4 alkyl),—
SO2(phenyl), —
C(═
O)O(C1-4 alkyl), —
C(═
O)(C1-4 alkyl), and —
C(═
O)H;R48, at each occurrence, is independently selected from H, C1-4 alkyl, —
C(═
O)NH(C1-4 alkyl), —
C(═
O)O(C1-4 alkyl),—
C(═
O)(C1-4 alkyl), and —
C(═
O)H;k is 1 or 2; m is 0, 1, or 2; and n is 1 or 2.
-
-
10. The method as defined in claim 9 where in the compound administered:
-
X is —
NR10A—
;R1 is selected from C2-5 alkyl substituted with Z, C2-5 alkenyl substituted with Z, C2-5 alkynyl substituted with Z, C3-6 cycloalkyl substituted with Z, aryl substituted with Z, 5–
6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O, and S, said heterocyclic ring system substituted with Z;C1-5 alkyl substituted with 0–
2 R2,C2-5 alkenyl substituted with 0–
2 R2, andC2-5 alkynyl substituted with 0–
2 R2;Z is selected from H, —
CH(OH)R2,—
C(ethylenedioxy)R2,—
OR2,—
SR2,—
NR2R3,—
C(O)R2,—
C(O)NR2R3,—
NR3C(O)R2,—
C(O)OR2,—
OC(O)R2,—
CH(═
NR4)NR2R3,—
NHC(═
NR4)NR2R3,—
S(O)R2,—
S(O)2R2,—
S(O)2NR2R3, and —
NR3S(O)2R2;R2, at each occurrence, is independently selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, aryl substituted with 0–
5 R42;C3-10 carbocyclic group substituted with 0–
3 R41, and5–
10 membered heterocyclic ring system containing from 1–
4 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R41;R3, at each occurrence, is independently selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, and C1-4 alkoxy; alternatively, R2 and R3 join to form a 5- or 6-membered ring optionally substituted with —
O—
or —
N(R4)—
;R4, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl; R5 is H, methyl, or ethyl; R6a is selected from H, —
OH, —
NR46R47, —
CF3,C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, and C3-6 cycloalkyl; R6b is H; R7, R8, and R9, at each occurrence, are independently selected from H, halo, —
CF3, —
OCF3, —
OH, —
OCH3, —
CN, —
NO2, —
NR46R47,C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, (C1-4 haloalkyl)oxy, C1-4 alkyl substituted with 0–
2 R11,C3-10 carbocyclic group substituted with 0–
3 R33,aryl substituted with 0–
5 R33,5–
10 membered heterocyclic ring system containing from 1–
4 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R31;OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, CH(═
NR14)NR12R13, NHC(═
NR14)NR12R13, S(O)R12, S(O)2R12, S(O)2NR12R13, NR14S(O)2R12, NR14S(O)R12, NR14S(O)2R12, NR12C(O)R15, NR12C(O)OR15, NR12S(O)2R15, and NR12C(O)NHR15;R10A is selected from H, C1-6 alkyl substituted with 0–
1 R10B,C2-6 alkenyl substituted with 0–
1 R10B,C2-6 alkynyl substituted with 0–
1 R10B, andC1-6 alkoxy; R10B is selected from C1-4 alkoxy, C3-6 cycloalkyl, C3-6 carbocyclic group substituted with 0–
3 R33,phenyl substituted with 0–
3 R33, and5–
6 membered heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
2 R44;R11 is selected from H, halo, —
CF3, —
OCF3, —
OH, —
OCH3, —
CN, —
NO2, —
NR46R47,C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, (C1-4 haloalkyl)oxy, C3-10 carbocyclic group substituted with 0–
3 R33,aryl substituted with 0–
5 R33,5–
10 membered heterocyclic ring system containing from 1–
4 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R31;OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, CH(═
NR14)NR12R13, NHC(═
NR14)NR12R13, S(O)R12, S(O)2R12, S(O)2NR12R13, and NR14S(O)2R12;R12, at each occurrence, is independently selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, phenyl substituted with 0–
5 R33;C3-10 carbocyclic group substituted with 0–
3 R33, and5–
10 membered heterocyclic ring system containing from 1–
4 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R31;R13, at each occurrence, is independently selected from H, C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl; alternatively, R12 and R13 join to form a 5- or 6-membered ring optionally substituted with —
O—
or —
N(R14)—
;R14, at each occurrence, is independently selected from H and C1-4 alkyl; R31, at each occurrence, is independently selected from H, OH, halo, CF3, methyl, and ethyl; R33, at each occurrence, is independently selected from H, OH, halo, CN, NO2, CF3, methyl, and ethyl; R41, at each occurrence, is independently selected from H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN, ═
O,C2-8 alkenyl, C2-8 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 alkyl substituted with 0–
1 R43,aryl substituted with 0–
3 R42, and5–
10 membered heterocyclic ring system containing from 1–
4 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R44;R42, at each occurrence, is independently selected from H, CF3, halo, OH, CO2H, SO2R45, SR45, NR46R47, OR48, NO2, CN, CH(═
NH)NH2, NHC(═
NH)NH2,C2-6 alkenyl, C2-6 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, C3-6 cycloalkyl, C1-4 alkyl substituted with 0–
1 R43,aryl substituted with 0–
3 R44, and5–
10 membered heterocyclic ring system containing from 1–
4 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R44;R43 is C3-6 cycloalkyl or aryl substituted with 0–
3 R44;R44, at each occurrence, is independently selected from H, halo, —
OH, NR46R47, CO2H, SO2R45, —
CF3, —
OCF3, —
CN, —
NO2, C1-4 alkyl, and C1-4 alkoxy;R45 is C1-4 alkyl; R46, at each occurrence, is independently selected from H and C1-3 alkyl; R47, at each occurrence, is independently selected from H, C1-4 alkyl, —
C(═
O)NH(C1-4 alkyl), —
SO2(C1-4 alkyl),—
SO2(phenyl), —
C(═
O)O(C1-4 alkyl), —
C(═
O)(C1-4 alkyl), and —
C(═
O)H;R48, at each occurrence, is independently selected from H, C1-4 alkyl, —
C(═
O)NH(C1-4 alkyl), —
C(═
O)O(C1-4 alkyl),—
C(═
O)(C1-4 alkyl), and —
C(═
O)H;k is 1 or 2; m is 0, 1, 2; and n is 1 or 2.
-
-
11. The method as defined in claim 9 where in the compound administered:
-
X is —
NR10A—
;R1 is selected from C2-4 alkyl substituted with Z, C2-4 alkenyl substituted with Z, C2-4 alkynyl substituted with Z, C3-6 cycloalkyl substituted with Z, aryl substituted with Z, 5–
6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O, and S, said heterocyclic ring system substituted with Z;C2-4 alkyl substituted with 0–
2 R2, andC2-4 alkenyl substituted with 0–
2 R2;Z is selected from H, —
CH(OH)R2,—
C(ethylenedioxy)R2,—
OR2,—
SR2,—
NR2R3,—
C(O)R2,—
C(O)NR2R3,—
NR3C(O)R2,—
C(O)OR2,—
S(O)R2,—
S(O)2R2,—
S(O)2NR2R3, and —
NR3S(O)2R2;R2, at each occurrence, is independently selected from phenyl substituted with 0–
5 R42;C3-10 carbocyclic group substituted with 0–
3 R41, and5–
10 membered heterocyclic ring system containing from 1–
4 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R41;R3, at each occurrence, is independently selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, and C1-4 alkoxy; alternatively, R2 and R3 join to form a 5- or 6-membered ring optionally substituted with —
O—
or —
N(R4)—
;R4, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl; R5 is H; R6a is selected from H, —
OH, —
CF3, methyl, ethyl, propyl, butyl, methoxy, and, ethoxy;R6b is H; R7, R8, and R9, at each occurrence, are independently selected from H, halo, —
CF3, —
OCF3, —
OH, —
OCH3, —
CN, —
NO2,C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, (C1-3 haloalkyl)oxy, and C1-4 alkyl substituted with 0–
2 R11;R10A is selected from H, C1-6 alkyl, C1-4 alkoxy, and C1-2 alkyl substituted with 0–
1 R10B;R10B is C3-6 cycloalkyl or phenyl substituted with 0–
3 R33;R11 is selected from H, halo, —
CF3, —
OCF3, —
OH, —
OCH3, —
CN, —
NO2,C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and (C1-3 haloalkyl)oxy; R33, at each occurrence, is independently selected from H, OH, halo, CF3, and methyl; R41, at each occurrence, is independently selected from H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN, ═
O,C2-8 alkenyl, C2-8 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 alkyl substituted with 0–
1 R43,aryl substituted with 0–
3 R42, and5–
10 membered heterocyclic ring system containing from 1–
4 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R44;R42, at each occurrence, is independently selected from H, CF3, halo, OH, CO2H, SO2R45, SR45, NR46R47, OR48, NO2, CN, CH(═
NH)NH2, NHC(═
NH)NH2,C2-6 alkenyl, C2-6 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, C3-6 cycloalkyl, C1-4 alkyl substituted with 0–
1 R43,aryl substituted with 0–
3 R44, and5–
10 membered heterocyclic ring system containing from 1–
4 heteroatoms selected from the group consisting of N, O, and S substituted with 0–
3 R44;R43 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or pyridyl, each substituted with 0–
3 R44;R44, at each occurrence, is independently selected from H, halo, —
OH, NR46R47, CO2H, SO2R45, —
CF3, —
OCF3, —
CN, —
NO2, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, and butoxy;R45 is methyl, ethyl, propyl, or butyl; R46, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl; R47, at each occurrence, is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, —
C(═
O)NH(methyl), —
C(═
O)NH(ethyl),—
SO2(methyl), —
SO2(ethyl), —
SO2(phenyl),—
C(═
O)O(methyl), —
C(═
O)O(ethyl), —
C(═
O)(methyl),—
C(═
O)(ethyl), and —
C(═
O)H;R48, at each occurrence, is independently selected from H, methyl, ethyl, n-propyl, i-propyl, —
C(═
O)NH(methyl), —
C(═
O)NH(ethyl), —
C(═
O)O(methyl), —
C(═
O)O(ethyl), —
C(═
O)(methyl), —
C(═
O)(ethyl), and —
C(═
O)H;k is 1; m is 0, 1, or 2; and n is 1 or 2.
-
-
12. The method as defined in claim 9 where in the compound administered:
-
X is —
NH—
;R1 is selected from ethyl substituted with Z, propyl substituted with Z, butyl substituted with Z, propenyl substituted with Z, butenyl substituted with Z, ethyl substituted with R2, propyl substituted with R2, butyl substituted with R2, propenyl substituted with R2, and butenyl substituted with R2; Z is selected from H, —
CH(OH)R2,—
OR2,—
SR2,—
NR2R3,—
C(O)R2,—
C(O)NR2R3,—
NR3C(O)R2,—
C(O)OR2,—
S(O)R2,—
S(O)2R2,—
S(O)2NR2R3, and —
NR3S(O)2R2;R2, at each occurrence, is independently selected from phenyl substituted with 0–
3 R42;naphthyl substituted with 0–
3 R42;cyclopropyl substituted with 0–
3 R41;cyclobutyl substituted with 0–
3 R41;cyclopentyl substituted with 0–
3 R41;cyclohexyl substituted with 0–
3 R41;pyridyl substituted with 0–
3 R41;indolyl substituted with 0–
3 R41;indolinyl substituted with 0–
3 R41;benziridazolyl substituted with 0–
3 R41;benzotriazolyl substituted with 0–
3 R41;benzothienyl substituted with 0–
3 R41;benzofuranyl substituted with 0–
3 R41;phthalimid-1-yl substituted with 0–
3 R41;inden-2-yl substituted with 0–
3 R41;2,3-dihydro-1H-inden-2-yl substituted with 0–
3 R41;indazolyl substituted with 0–
3 R41;tetrahydroquinolinyl substituted with 0–
3 R41; andtetrahydro-isoquinolinyl substituted with 0–
3 R41;R3, at each occurrence, is independently selected from H, methyl, and ethyl; R5 is H; R6a is selected from H, —
OH, methyl, and methoxy;R6b is H; R7, R8, and R9, at each occurrence, are independently selected from H, F, Cl, methyl, ethyl, methoxy, —
CF3,and —
OCF3;R41, at each occurrence, is independently selected from H, F, Cl, Br, OH, CF3, NO2, CN, ═
O, methyl, ethyl, propyl, butyl, methoxy, and ethoxy;R42, at each occurrence, is independently selected from H, F, Cl, Br, OH, CF3, SO2R45, SR45, NR46R47, OR48, NO2, CN, ═
O, methyl, ethyl, propyl, butyl, methoxy, and ethoxy;R45 is methyl, ethyl, propyl, or butyl; R46, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl; R47, at each occurrence, is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, —
C(═
O)NH(methyl), —
C(═
O)NH(ethyl),—
SO2(methyl), —
SO2(ethyl), —
SO2(phenyl),—
C(═
O)O(methyl), —
C(═
O)O(ethyl), —
C(═
O)(methyl),—
C(═
O)(ethyl), and —
C(═
O)H;R48, at each occurrence, is independently selected from H, methyl, ethyl, n-propyl, i-propyl, —
C(═
O)NH(methyl), —
C(═
O)NH(ethyl), —
C(═
O)O(methyl), —
C(═
O)O(ethyl), —
C(═
O)(methyl), —
C(═
O)(ethyl), and —
C(═
O)H;k is 1; m is 0, 1, or 2; and n is 1 or 2.
-
-
13. The method as defined in claim 9 where the compound administered is a compound of Formula (I-a):
-
14. The method as defined in claim 13 where the compound administered is a compound of Formula (IV-a):
-
15. The method as defined in claim 1 where the compound administered is selected from the group:
-
4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′
,4′
;
4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-pyridinyl)-1-butanone hydrochloride;(6bR,10aS)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′
,4′
;
4,5]pyrrolo[1,2,3-de]quinoxaline;4-((6bR,10aS)-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′
,4′
;
4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone;(6bR,10aS)-8-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′
,4′
;
4,5]pyrrolo[1,2,3-de]quinoxaline hydrochloride;(6bR,10aS)-8-[3-(1,2-benzisoxazol-3-yl)propyl]-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′
,4′
;
4,5]pyrrolo[1,2,3-de]quinoxaline hydrochloride;(6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′
,4′
;
4,5]pyrrolo[1,2,3-de]quinoxaline;(6bR,10aS)-3-ethyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′
,4′
;
4,5]pyrrolo[1,2,3-de]quinoxaline;(6bR,10aS)-3-propyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′
,4′
;
4,5]pyrrolo[1,2,3-de]quinoxaline;(6bR,10aS)-3-isopropyl-2,3,6b,7,8,9,10,10a-octahydro-4H-pyrido[3′
,4′
;
4,5]pyrrolo[1,2,3-de]quinoxaline;(6bR,10aS)-3-butyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′
,4′
;
4,5]pyrrolo[1,2,3-de]quinoxaline;(6bR,10aS)-3-benzyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′
,4′
;
4,5]pyrrolo[1,2,3-de]quinoxaline;4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′
,4′
;
4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone;4-((6bR,10aS)-3-ethyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′
,4′
;
4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone;4-((6bR,10aS)-3-isopropyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′
,4′
;
4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone;4-((6bR,10aS)-3-benzyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′
,4′
;
4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone;(6bR,10aS)-8-[3-(4-fluorophenoxy)propyl]-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′
,4′
;
4,5]pyrrolo[1,2,3-de]quinoxaline;(6bR,10aS)-5-(2,4-dichlorophenyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′
,4′
;
4,5]pyrrolo[1,2,3-de]quinoxaline;(6bR,10aS)-5-(2,4-dichlorophenyl)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′
,4′
;
4,5]pyrrolo[1,2,3-de]quinoxaline hydrochloride;4-((6bR,10aS)-5-bromo-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′
,4′
;
4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone;4-((6bR,10aR)-5-methoxy-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′
,4′
;
4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone;(8aS,12aR)-2-(2,4-dichlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydro[1,4]diazepino[3,2,1-hi]pyrido[4,3-b]indole hydrochloride; (8aS,12aR)-2-(4-methoxy-2-methylphenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydro[1,4]diazepino[3,2,1-hi]pyrido[4,3-b]indole hydrochloride; (6bS,11aS)-3-methyl-2,3,7,8,9,10,11,11a-octahydro-1H,6bH-azepino[4′
,5′
;
4,5]pyrrolo[1,2,3-de]quinoxaline;4-(3-methyl-2,3,6b,7,8,10,11,11a-octahydro-1H,9H-azepino[4′
,5′
;
4,5]pyrrolo[1,2,3-de]quinoxalin-9-yl)-1-(4-fluorophenyl)-1-butanone; and(+/−
)-1,1,3-Trimethyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′
,4′
;
4,5]pyrrolo[1,2,3-de]quinoxaline.
-
-
2. The method as defined in claim 1 where in the compound administered:
Specification
- Resources
-
Current AssigneeBristol-Myers Squibb Pharma Company (Bristol-Myers Squibb Company)
-
Original AssigneeBristol-Myers Squibb Pharma Company (Bristol-Myers Squibb Company)
-
InventorsMitchell, Ian S., Yang, Michael G., Deng, Wei, Lee, Taekyu, Robichaud, Albert J., Chen, Wenting, McClung, Christopher D., Zawrotny, David M., Calvello, Emilie J., Haydar, Simon
-
Primary Examiner(s)Kifle, Bruck
-
Application NumberUS10/787,941Publication NumberTime in Patent Office859 DaysField of Search514/219, 514/250US Class Current514/219CPC Class CodesA61P 25/00 Drugs for disorders of the ...C07D 221/18 Ring systems of four or mor...C07D 223/32 containing carbocyclic ring...C07D 471/06 Peri-condensed systemsC07D 471/16 Peri-condensed systemsC07D 487/06 Peri-condensed systemsC07D 491/06 Peri-condensed systemsC07D 495/06 Peri-condensed systemsC07D 513/06 Peri-condensed systemsC07D 513/16 Peri-condensed systemsC07D 519/00 Heterocyclic compounds cont...