# US 7,411,064 B2 · 1-Heterocyclylalkyl-3-sulfonylazaindole or -azaindazole derivatives as 5-hydroxytryptamine-6 ligands

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- Number: US 7,411,064 B2
- Document ID: US7411064B2
- Status: Granted
- Kind: B2
- Application number: 11/354,459
- Filed: 2006-02-15
- Published: 2006-06-29
- Granted: 2008-08-12
- Earliest claimed: 2002-07-18
- Assignees: Wyeth
- Inventors: Ronald Charles Bernotas; Steven Edward Lenicek; Hassan Mahmoud Elokdah; David Zenan Li
- Web page: https://patentgrep.com/patent/US7411064B2

## CPC

- C07D 487/08: Bridged systems
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/4745: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48)
- A61K 31/498: Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
- A61K 31/503: spiro-condensed
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/22: Anxiolytics
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 25/30: for treating abuse or dependence
- A61P 25/32: Alcohol-abuse
- A61P 25/34: Tobacco-abuse
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides a compound of formula I and the use thereof for the treatment of a central nervous system disorder related to or affected by the 5-HT6 receptor

## Claims

### Claim 1

A compound of formula I
wherein
W is N;
X is N or CR9;
Y is N or CR10;
Z is N or CR11;
Q is N or CR12 with the proviso that at least one and not more than two of X, Y, Z and Q must be N;
R1 is an optionally substituted C1-C6alkyl, C3-C7cycloalkyl, aryl, or heteroaryl group or an optionally substituted 8- to 13-membered bicyclic or tricyclic ring system having a N atom at the bridgehead and optionally containing 1, 2 or 3 additional heteroatoms selected from N, O or S;
R2 is H, halogen, or a C1-C6alkyl, C1-C6alkoxy, C3-C7cycloalkyl, aryl or heteroaryl group each optionally substituted;
R3 and R4 are each independently H or an optionally substituted C1-C6alkyl group;
R5 is H or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R6 is a C1-C6alkyl, C3-C7cycloalkyl, C2-C6alkenyl or C2-C6alkynyl group each optionally substituted; R7 and R8 are each independently H or a C1-C6alkyl, C3-C7cycloalkyl, C2-C6alkenyl or C2-C6alkynyl group each optionally substituted;
m and n are each independently 0 or an integer of 1, 2 or 3;
p is 0 or an integer of 1 or 2;
R9, R10, R11 and R12 are each independently H, halogen, CN, OCO2R13, CO2R14, CONR15R16, SOxR17, NR18R19, OR20, COR21 or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, aryl or heteroaryl group each optionally substituted;
R13, R14, R17 and R21 are each independently H or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R15, R16, R18 and R19 are each independently H or an optionally substituted C1-C4alkyl group or R15 and R16 or R18 and R19 may be taken together with the atom to which they are attached to form a 5- to 7-membered ring optionally containing another heteroatom selected from O, NR22 or SOq;
R20 is a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
x and q are each independently 0 or an integer of 1 or 2; and
R22 is H or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, cycloheteroalky, aryl or heteraryl group each optionally substituted; or
the stereoisomers thereof or the pharmaceutically acceptable salts thereof.

### Claim 2 (depends on 1)

The compound according to claim 1 wherein n is 0 or 1.

### Claim 3 (depends on 1)

The compound according to claim 1 wherein R5 is H or methyl.

### Claim 4 (depends on 1)

The compound according to claim 1 wherein R1 is an optionally substituted phenyl, thienyl or imidazothiazolyl group.

### Claim 5 (depends on 2)

The compound according to claim 2 wherein p is 0 or 1.

### Claim 6 (depends on 2)

The compound according to claim 2 wherein m is 0.

### Claim 7 (depends on 5)

The compound according to claim 5 wherein the piperidinyl group is attached in the 3-position of the piperidine ring or the pyrrolidinyl group is attached in the 2-position of the pyrrolidine ring.

### Claim 8 (depends on 7)

The compound according to claim 7 wherein R5 is H or methyl and R1 is an optionally substituted phenyl, thienyl or imidazothiazolyl group.

### Claim 9 (depends on 1)

The compound according to claim 1 selected from the group consisting of:
4-chloro-3-(phenylsulfonyl)-1-(piperidin-4-ylmethyl)-1H-pyrazolo[4,3-b]pyridine;
3-(phenylsulfonyl)-1-(piperidin-4-ylmethyl)-1H-pyrazolo[4,3-b]pyridine;
3-(phenylsulfonyl)-1-(piperidin-3-ylmethyl)-1H-pyrazolo[4,3-c]pyridine;
3-(phenylsulfonyl)-1-(piperidin-2-ylmethyl)-1H-pyrazolo[4,3-b]pyridine;
3-(phenylsulfonyl)-1-(pyrrolidin-3-ylmethyl)-1H-pyrazolo[3,4-c]pyridine;
3-(phenylsulfonyl)-1-(pyrrolidin-2-ylmethyl)-1H-pyrazolo[3,4-b]pyridine;
1-(piperidin-3-ylmethyl)-3-(2-thienylsulfonyl)-1H-pyrazolo[4,3-b]pyridine;
1-(piperidin-2-ylmethyl)-3-(2-thienylsulfonyl)-1H-pyrazolo[4,3-b]pyridine;
3-(phenylsulfonyl)-1-piperidin-3-yl-1H-pyrazolo[4,3-b]pyridine;
3-[(2-fluorophenyl)sulfonyl]-1-pyrrolidin-3-yl-1H-pyrazolo[4,3-b]pyridine;
1-(1-methylpiperidin-4-yl)-3-(phenylsulfonyl)-1H-pyrazolo[4,3-b]pyridine;
the stereoisomers thereof; and
the pharmaceutically acceptable salts thereof.

### Claim 10

A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a compound of formula I
wherein
W is N;
X is N or CR9;
Y is N or CR10;
Z is N or CR11;
Q is N or CR12 with the proviso that at least one and not more than two of X, Y, Z and Q must be N;
R1 is an optionally substituted C1-C6alkyl, C3-C7cycloalkyl, aryl, or heteroaryl group or an optionally substituted 8- to 1 3-membered bicyclic or tricyclic ring system having a N atom at the bridgehead and optionally containing 1, 2 or 3 additional heteroatoms selected from N, O or S;
R2 is H, halogen, or a C1-C6alkyl, C1-C6alkoxy, C3-C7cycloalkyl, aryl or heteroaryl group each optionally substituted;
R3 and R4 are each independently H or an optionally substituted C1-C6alkyl group;
R5 is H or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R6 is a C1-C6alkyl, C3-C7cycloalkyl, C2-C6alkenyl or C2-C6alkynyl group each optionally substituted;
R7 and R8 are each independently H or a C1-C6alkyl, C3-C7cycloalkyl, C2-C6alkenyl or C2-C6alkynyl group each optionally substituted;
m and n are each independently 0 or an integer of 1, 2 or 3;
p is 0 or an integer of 1 or 2;
R9, R10, R11 and R12 are each independently H, halogen, CN, OCO2R13, CO2R14, CONR15R16, SOxR17, NR18R19, OR20, COR21 or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, aryl or heteroaryl group each optionally substituted;
R13, R14, R17 and R21 are each independently H or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R15, R16, R18 and R19 are each independently H or an optionally substituted C1-C4alkyl group or R15 and R16 or R18 and R19 may be taken together with the atom to which they are attached to form a 5- to 7-membered ring optionally containing another heteroatom selected from O, NR22 or SOq;
R20 is a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
x and q are each independently 0 or an integer of 1 or 2; and
R22 is H or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, cycloheteroalkyl, aryl or heteraryl group each optionally substituted; or
the stereoisomers thereof or the pharmaceutically acceptable salts thereof.

### Claim 11 (depends on 10)

The composition according to claim 10 having a formula I compound wherein n is 0 or 1.

### Claim 12 (depends on 11)

The composition according to claim 11 having a formula I compound wherein R1 is an optionally substituted phenyl, thienyl or imidazothiazolyl group and R5 is H or methyl.

### Claim 13 (depends on 12)

The composition according to claim 12 having a formula I compound wherein p is 0 or 1 and the piperidinyl group is attached in the 3-position of the piperidine ring or the pyrrolidinyl group is attached in the 2-position of the pyrrolidine ring.

### Claim 14 (depends on 10)

The composition according to claim 10 having a formula I compound selected from the group consisting of:
4-chloro-3-(phenylsulfonyl)-1-(piperidin-4-ylmethyl)-1H-pyrazolo[4,3-b]pyridine;
3-(phenylsulfonyl)-1-(piperidin-4-ylmethyl)-1H-pyrazolo[4,3-b]pyridine;
3-(phenylsulfonyl)-1-(piperidin-3-ylmethyl)-1H-pyrazolo[4,3-c]pyridine;
3-(phenylsulfonyl)-1-(piperidin-2-ylmethyl)-1H-pyrazolo[4,3-b]pyridine;
3-(phenylsulfonyl)-1-(pyrrolidin-3-ylmethyl)-1H-pyrazolo[3,4-c]pyridine;
3-(phenylsulfonyl)-1-(pyrrolidin-2-ylmethyl)-1H-pyrazolo[3,4-b]pyridine;
1-(piperidin-3-ylmethyl)-3-(2-thienylsulfonyl)-1H-pyrazolo[4,3-b]pyridine;
1-(piperidin-2-ylmethyl)-3-(2-thienylsulfonyl)-1H-pyrazolo[4,3-b]pyridine;
3-(phenylsulfonyl)-1-piperidin-3-yl-1H-pyrazolo[4,3-b]pyridine;
3-[(2-fluorophenyl)sulfonyl]-1-pyrrolidin-3-yl-1H-pyrazolo[4,3-b]pyridine;
1-(1-methylpiperidin-4-yl)-3-(phenylsulfonyl)-1H-pyrazolo[4,3-b]pyridine;
the stereoisomers thereof; and
the pharmaceutically acceptable salts thereof.

### Claim 15

A process for the preparation of a compound of formula I
wherein
W is N;
X is N or CR9;
Y is N or CR10;
Z is N or CR11;
Q is N or CR12 with the proviso that at least one and not more than two of X, Y, Z and Q must be N;
R1 is an optionally substituted C1-C6alkyl, C3-C7cycloalkyl, aryl, or heteroaryl group or an optionally substituted 8- to 13-membered bicyclic or tricyclic ring system having a N atom at the bridgehead and optionally containing 1, 2 or 3 additional heteroatoms selected from N, O or S;
R2 is H, halogen, or a C1-C6alkyl, C1-C6alkoxy, C3-C7cycloalkyl, aryl or heteroaryl group each optionally substituted;
R3 and R4 are each independently H or an optionally substituted C1-C6alkyl group;
R5 is H or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, cycloheteroalkyl; aryl or heteroaryl group each optionally substituted;
R6 is a C1-C6alkyl, C3-C7cycloalkyl, C2-C6alkenyl or C2-C6alkynyl group each optionally substituted;
R7 and R8 are each independently H or a C1-C6alkyl, C3-C7cycloalkyl, C2-C6alkenyl or C2-C6alkynyl group each optionally substituted;
m and n are each independently 0 or an integer of 1, 2 or 3;
p is 0 or an integer of 1 or 2;
R9, R10, R11 and R12 are each independently H, halogen, CN, OCO2R13, CO2R14, CONR15R16, SOxR17, NR18R19, OR20, COR21 or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, aryl or heteroaryl group each optionally substituted;
R13, R14, R17 and R21 are each independently H or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R15, R16, R18 and R19 are each independently H or an optionally substituted C1-C4alkyl group or R15 and R16 or R18 and R19 may be taken together with the atom to which they are attached to form a 5- to 7-membered ring optionally containing another heteroatom selected from O, NR22 or SOq;
R20 is a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
x and q are each independently 0 or an integer of 1 or 2; and
R22 is H or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, cycloheteroalkyl, aryl or heteraryl group each optionally substituted
which process comprises reacting a compound of formula II
wherein W, X, Y, Z and Q are described hereinabove with a protected azacyclic compound of formula III
wherein L represents a leaving group; P represents a protecting group and R3, R4, R6, R7, R8, N m and p are as described hereinabove in the presence of a first base to give the protected amine of formula I; and deprotecting said amine to give the compound of formula I wherein R5 is H optionally alkylating said formula I compound with a compound, R5-L′, wherein L′ is a leaving group in the presence of a second base.