# US 7,745,646 B2 · Bicyclic heteroaryl inhibitors of PDE4

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- Number: US 7,745,646 B2
- Document ID: US7745646B2
- Status: Granted
- Kind: B2
- Application number: 11/774,058
- Filed: 2007-07-06
- Published: 2008-01-31
- Granted: 2010-06-29
- Earliest claimed: 2006-07-07
- Assignees: Kalypsys, Inc.
- Inventors: Steven Govek; Andrew K. Shiau; Stewart A. Noble; David J. Thomas
- Web page: https://patentgrep.com/patent/US7745646B2

## CPC

- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/4704: 2-Quinolinones, e.g. carbostyril
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 27/02: Ophthalmic agents
- A61P 27/04: Artificial tears; Irrigation solutions
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 27/14: Decongestants or antiallergics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention relates to compounds and methods which may be useful as inhibitors of phosphodiesterase 4 (PDE4) for the treatment or prevention of inflammatory diseases and other diseases involving elevated levels of cytokines and proinflammatory mediators.

## Claims

### Claim 1

A compound of structural Formula IV
or a salt thereof, wherein:
R1 and R2 are independently selected from the group consisting of —(CH2)sG1G2G3, acyl, acylalkyl, carboxyalkyl, cyanoalkyl, alkoxy, alkoxyalkyl, amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl, alkenyl, alkynyl, carboxyl, carboxyalkyl, ether, heteroalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aralkyl, aryl, guanidine, heteroaryl, heteroaralkyl, and hydroxyalkyl, any of which may be optionally substituted;
s is 0-8;
G1 is selected from the group consisting of alkoxy, amino, amido, carbonyl, hydroxy, ether, an amino acid, and null;
G2 is selected from the group consisting of alkyl, alkoxy, amino, aryl, halo, haloalkyl, heterocycloalkyl, heteroaryl, carboxylalkylamino, guanidine, an amino acid, and null, any of which may be optionally substituted;
G3 is selected from the group consisting of alkyl, alkoxy, amino, hydroxy, ether, carboxyl, hydroxamic acid, an amino acid, phosphonate, phosphoamide, and null, any of which may be optionally substituted;
when s is 0, G1, G2, and G3 may not all together be null;
R3 and R4 are independently selected from the group consisting of alkoxy, lower alkyl, halogen and hydrogen;
R5 is selected from the group consisting of (CH2)p, C(O)NH, N(R7) and S(O)q;
p is 1,2,3 or 4;
q is 0, 1 or 2;
R6 is selected from the group consisting of aryl heteroaryl, either of which may be optionally substituted;
R7 selected from the group consisting of hydrogen and optionally substituted lower alkyl; R17 is selected from the group consisting of hydrogen, halogen, hydroxyl, lower alkyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, amino, aminoalkyl and aminoalkoxy.

### Claim 2 (depends on 1)

The compound as recited in claim 1, wherein
R17 is selected from the group consisting of hydrogen, halogen, lower alkyl, haloalkyl, alkoxy, haloalkoxy, amino, aminoalkyl and aminoalkoxy.

### Claim 3 (depends on 2)

The compound as recited in claim 2, wherein R17 is hydrogen.

### Claim 4 (depends on 3)

The compound as recited in claim 3, wherein R6 is selected from the group consisting of phenyl, pyridine, pyrimidine, pyridazine, and pyrazine, any of which may be optionally substituted.

### Claim 5 (depends on 4)

The compound as recited in claim 4, wherein R3 and R4 are both hydrogen.

### Claim 6 (depends on 5)

The compound as recited in claim 5, wherein:
R5 N(R7); and
R7 hydrogen.

### Claim 7 (depends on 6)

The compound as recited in claim 6, wherein R2 is lower alkyl.

### Claim 8 (depends on 7)

The compound as recited in claim 7, wherein:
R1 is selected from the group consisting of —(CH2)sG1G2G3, lower alkyl, cycloalkyl, cycloalkylalkyl, and heterocycloalkyl, any of which may be optionally substituted;
s is 1-6;
G1 is selected from the group consisting of amino, amido, and null;
G2 is selected from the group consisting of alkoxy, aryl, halo, heterocycloalkyl, and null, any of which may be optionally substituted; and
G3 is selected from the group consisting of alkyl, carboxyl, and null, any of which may be optionally substituted.

### Claim 9 (depends on 8)

The compound as recited in claim 8, wherein R2 is methyl.

### Claim 10 (depends on 9)

The compound as recited in claim 9, wherein R6 has a formula selected from the group consisting of:
R19, R20, R 21, R22, and R23 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, amino, and carboxyl.

### Claim 11

A compound of structural Formula VI
or a salt thereof, wherein:
R1 and R2 are independently selected from the group consisting of —(CH2)sG1G2G3, acyl, acylalkyl, carboxyalkyl, cyanoalkyl, alkoxy, alkoxyalkyl, amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl, alkenyl, alkynyl, carboxyl, carboxyalkyl, ether, heteroalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aralkyl, aryl, guanidine, heteroaryl, heteroaralkyl and hydroxyalkyl, any of which may be optionally substituted;
s is 1-8;
G1 is selected from the group consisting of alkoxy, acyl, amino, amido, carbonyl, ether, an amino acid, and null;
G2 is selected from the group consisting of alkyl, alkoxy, acyl, amino, aryl, halo, haloalkyl, heterocycloalkyl, heteroaryl, carboxylalkylamino, guanidine, an amino acid, and null, any of which may be optionally substituted;
G3 is selected from the group consisting of alkyl, alkoxy, amino, hydroxy, ether, carboxyl, hydroxamic acid, an amino acid, phosphonate, phosphoamide, and null, any of which may be optionally substituted;and
R19 and R23 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, amino, and carboxyl.

### Claim 12 (depends on 11)

The compound as recited in claim 11, wherein R19 and R23 are independently selected from the group consisting of hydrogen, halogen, and lower alkyl.

### Claim 13 (depends on 12)

The compound as recited in claim 12, wherein R2 is lower alkyl.

### Claim 14 (depends on 13)

The compound as recited in claim 13, wherein:
R1 is selected from the group consisting of —(CH2)sG1G2G3, lower alkyl, cycloalkyl, cycloalkylalkyl, and heterocycloalkyl, any of which may be optionally substituted;
s is 1-6;
G1 is selected from the group consisting of amino, amido, and null;
G2 is selected from the group consisting of alkoxy, aryl, halo, heterocycloalkyl, and null, any of which may be optionally substituted; and
G3 is selected from the group consisting of alkyl, carboxyl, and null, any of which may be optionally substituted.

### Claim 15 (depends on 14)

The compound as recited in claim 14, wherein R2 is methyl.

### Claim 16

A compound of structural Formula VII
or a salt thereof, wherein:
R1 and R2 are independently selected from the group consisting of —(CH2)sG1G2G3, acyl, acylalkyl, carboxyalkyl, cyanoalkyl, alkoxy, alkoxyalkyl, amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl, alkenyl, alkynyl, carboxyl, carboxyalkyl, ether, heteroalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aralkyl, aryl, guanidine, heteroaryl, heteroaralkyl and hydroxyalkyl, any of which may be optionally substituted;
s is 1-8; G1 is selected from the group consisting of alkoxy, acyl, amino, amido, carbonyl, ether, an amino acid, and null; G2 is selected from the group consisting of alkyl, alkoxy, acyl, amino, aryl, halo, haloalkyl, heterocycloalkyl, heteroaryl, carboxylalkylamino, guanidine, an amino acid, and null, any of which may be optionally substituted; G3 is selected from the group consisting of alkyl, alkoxy, amino, hydroxy, ether, carboxyl, hydroxamic acid, an amino acid, phosphonate, phosphoamide, and null, any of which may be optionally substituted; and
R19, R21, and R23 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, amino, and carboxyl.

### Claim 17 (depends on 16)

The compound as recited in claim 16, wherein R19, R21, and R23 are independently selected from the group consisting of hydrogen, halogen, and lower alkyl.

### Claim 18 (depends on 17)

The compound as recited in claim 17, wherein R2 is lower alkyl.

### Claim 19 (depends on 18)

The compound as recited in claim 18, wherein:
R1 is selected from the group consisting of —(CH2)sG1G2G3, ower alkyl, cycloalkyl, cycloalkylalkyl, and heterocycloalkyl, any of which may be optionally substituted;
s is 1-6;
G1 is selected from the group consisting of amino, amido, and null;
G2 is selected from the group consisting of alkoxy, aryl, halo, heterocycloalkyl, and null, any of which may be optionally substituted; and
G3 is selected from the group consisting of alkyl, carboxyl, and null, any of which may be optionally substituted.

### Claim 20 (depends on 19)

The compound as recited in claim 19, wherein R2 is methyl.

### Claim 21

A compound selected from the group consisting of Examples 1 to 105.

### Claim 22 (depends on 1)

A pharmaceutical composition comprising a compound as recited in claim 1 together with a pharmaceutically acceptable carrier.