# US 10,766,896 B2 · Imidazo[4,5-c] ring compounds containing guanidine substituted benzamide groups

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- Number: US 10,766,896 B2
- Document ID: US10766896B2
- Status: Granted
- Kind: B2
- Application number: 16/471,632
- Filed: 2018-02-27
- Published: 2020-03-19
- Granted: 2020-09-08
- Earliest claimed: 2017-03-01
- Assignees: 3M Innovative Properties Company
- Applicants: 3M Innovative Properties Company
- Inventors: Bryon A. Merrill; George W. Griesgraber; Chad A. Haraldson; Kevin J. Bechtold
- Web page: https://patentgrep.com/patent/US10766896B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61P 37/02: Immunomodulators
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Imidazo[4,5-c] ring compounds of formula I, (particularly imidazo4,5-c]quinolines, 6,7,8,9-tetrahydroimidazo[4,5-c]quinolines, imidazo[4,5-c]naphthyridines, and 6,7,8,9-tetrahydroimidazo[4,5-c]naphthyridine compounds) having a guanidine substituted benzamide that is attached at the N−1 position by a linking group, pharmaceutical compositions containing the compounds, and methods of making the compounds are disclosed. Methods of use of the compounds as immune response modifiers, for inducing cytokine biosynthesis in animals and in the treatment of diseases including viral and neoplastic diseases are also disclosed.

## Claims

### Claim 1

A compound of the Formula (I):
wherein:
R3 and R4 are taken together to form a fused benzene ring, a fused pyridine ring, a fused cyclohexene ring, or a fused tetrahydropyridine ring; wherein the fused benzene ring, fused pyridine ring, fused cyclohexene ring, or fused tetrahydropyridine ring is either unsubstituted or substituted by one or more R groups;
R is selected from the group consisting of halogen, hydroxyl, alkyl, alkoxy, haloalkyl, —C(O)—O-alkyl, —C(O)—O—CH2Ph, —C(O)—O-aryl, amino, alkylamino, and dialkylamino aryl, arylalkylenyl, aryloxyalkylenyl, arylalkyleneoxy, aryloxy, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkyenyl, heteroarylalkyleneoxy, and heteroaryloxy, wherein the alkyl, aryl, arylalkylenyl, aryloxyalkylenyl, arylalkyleneoxy, aryloxy, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkyenyl, heteroaryalkyleneoxy, and heteroaryloxy groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxyl, hydroxyalkylenyl, alkoxyalkylenyl, arylalkyleneoxy, and nitrile;
W is selected from the group consisting of a covalent bond, —O—, and NH—;
X is selected from the group consisting of alkylene, alkenylene, and alkynylene, wherein any of the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated by arylene or heteroarylene and optionally interrupted by one or more —O— groups;
R9 is -Q-N(R7)—C(═N—R5)—N(H)R6;
Q is selected from the group consisting of a covalent bond and alkylene;
R2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, —O-alkyl, hydroxyalkylenyl, alkoxyalkylenyl, alkylaminoalkylenyl, hydroxyl, —CH2—NH—O-alkyl, and —CH2NHC(O)-alkyl;
R8 is selected from the group consisting of hydrogen, alkyl, arylalkylenyl, alkoxyalkylenyl, aryloxyalkylenyl, benzyloxyalkylenyl, aryl-(CH2)2-6—O-alkylenyl, and cycloalkylalkylenyl; wherein any of the alkyl, arylalkylenyl, alkoxyalkylenyl, aryloxyalkylenyl, benzyloxyalkylenyl, aryl-(CH2)2-6—O-alkylenyl, and cycloalkylalkylenyl groups can be either unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, alkyl, alkoxy, haloalkyl, and nitrile;
R7 is selected from the group consisting of hydrogen, alkyl, arylalkylenyl, alkoxyalkylenyl, aryloxyalkylenyl, benzyloxyalkylenyl, aryl-(CH2)2-6—O-alkylenyl, and cycloalkylalkylenyl; wherein any of the alkyl, arylalkylenyl, alkoxyalkylenyl, aryloxyalkylenyl, benzyloxyalkylenyl, aryl-(CH2)2-6—O-alkylenyl, and cycloalkylalkylenyl groups can be either unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, alkyl, alkoxy, haloalkyl, and nitrile;
R5 and R6 are independently selected from the group consisting of hydrogen, —C(O)—O— alkyl, alkyl, cycloalkyl, aryl, arylalkylenyl, aryloxyalkylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, cycloalkylalkylenyl, aryl-(CH2)2-6—O-alkylenyl, and benzyloxyalkylenyl; wherein any of the alkyl, cycloalkyl, aryl, arylalkylenyl, aryloxyalkylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, cycloalkylalkylenyl, aryl-(CH2)2-6—O-alkylenyl, and benzyloxyalkylenyl groups can be either unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, alkoxy, alkyl, haloalkyl, cycloalkyl, nitrile, aryl, heteroaryl, and dialkylamino; or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound or salt of claim 1, wherein R3 and R4 are taken together to form a fused benzene ring, a fused pyridine ring, or a fused cyclohexene ring, and the fused benzene ring, fused pyridine ring, or fused cyclohexene ring is either unsubstituted or substituted by one and only one R group.

### Claim 3 (depends on 1)

The compound or salt of claim 1, wherein R7 is hydrogen and R8 is hydrogen.

### Claim 4 (depends on 1)

The compound or salt of claim 1, wherein W is a covalent bond or —O—.

### Claim 5 (depends on 1)

The compound or salt of claim 1, wherein X is alkylene optionally interrupted by one or more —O— groups.

### Claim 6 (depends on 1)

The compound or salt of claim 1, wherein X is selected from the group consisting of —CH2CH2—, —CH2CH2CH2—, —CH2CH2CH2CH2—, —CH2CH2CH2CH2CH2—, —CH2CH2CH2CH2CH2CH2—, —CH2CH2CH2CH2CH2CH2CH2—, —CH2CH2CH2CH2CH2CH2CH2CH2—, —CH2C(CH3)2—, —CH2C(CH3)2CH2—, —CH2CH2—O—CH2CH2—, —CH2CH2—O—CH2CH2CH2—, —CH2CH2—O—CH2CH2—O—CH2CH2—, —(CH2)2-4—O—(CH2)2-4—, —(CH2)2-4—(OCH2CH2-)1-5, and —(CH2)2-6—(OCH2CH2-)1-4.

### Claim 7 (depends on 1)

The compound or salt of claim 1, wherein X is —C1-5alkylene-arylene-C1-5alkylene- or —C1-5alkylene-heteroarylene-C1-5alkylene-.

### Claim 8 (depends on 1)

The compound or salt of claim 1, wherein X is —CH2-phenylene-CH2—.

### Claim 9 (depends on 1)

The compound or salt of claim 1, wherein R2 is selected from the group consisting hydrogen, alkyl, alkoxyalkylenyl.

### Claim 10 (depends on 1)

The compound or salt of claim 1, wherein R2 is selected from the group consisting of hydrogen, —CH3, —CH2CH3, —CH2CH2CH3, —CH2CH2CH2CH3, —CH2OCH3, —CH2OCH2CH3, —CH2CH2OCH3.

### Claim 11 (depends on 1)

The compound or salt of claim 1, wherein R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, phenyl, and phenylalkylenyl.

### Claim 12 (depends on 1)

The compound or salt of claim 1, wherein R5 is hydrogen and R6 is hydrogen.

### Claim 13

A compound of the Formula XIV:
wherein:
WB is selected from the group consisting of a covalent bond, —O—, and —NH—;
XB is selected from the group consisting of alkylene, alkenylene, and alkynylene, wherein any of the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated by arylene or heteroarylene and optionally interrupted by one or more —O— groups;
R9B is -QB-N(R7B)—C(═N—R5B)—N(H)R6B;
QB is selected from the group consisting of a covalent bond and alkylene;
R2B is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, —O-alkyl, hydroxyalkylenyl, alkoxyalkylenyl, alkylaminoalkylenyl, hydroxyl, —CH2—NH—O-alkyl, and —CH2NHC(O)-alkyl;
R8B is selected from the group consisting of hydrogen, alkyl, arylalkylenyl, alkoxyalkylenyl, aryloxyalkylenyl, benzyloxyalkylenyl, aryl-(CH2)2-6—O-alkylenyl, and cycloalkylalkylenyl; wherein any of the alkyl, arylalkylenyl, alkoxyalkylenyl, aryloxyalkylenyl, benzyloxyalkylenyl, aryl-(CH2)2-6—O-alkylenyl, and cycloalkylalkylenyl groups can be either unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, alkyl, alkoxy, haloalkyl, and nitrile;
R7B is selected from the group consisting of hydrogen, alkyl, arylalkylenyl, alkoxyalkylenyl, aryloxyalkylenyl, benzyloxyalkylenyl, aryl-(CH2)2-6—O-alkylenyl, and cycloalkylalkylenyl; wherein any of the alkyl, arylalkylenyl, alkoxyalkylenyl, aryloxyalkylenyl, benzyloxyalkylenyl, aryl-(CH2)2-6—O-alkylenyl, and cycloalkylalkylenyl groups can be either unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, alkyl, alkoxy, haloalkyl, and nitrile;
R5B and R6B are independently selected from the group consisting of hydrogen, —C(O)—O-alkyl, alkyl, cycloalkyl, aryl, arylalkylenyl, aryloxyalkylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, cycloalkylalkylenyl, aryl-(CH2)2-6—O-alkylenyl, and benzyloxyalkylenyl;
wherein any of the, cycloalkyl, aryl, arylalkylenyl, aryloxyalkylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, cycloalkylalkylenyl, aryl-(CH2)2-6—O-alkylenyl, and benzyloxyalkylenyl groups can be either unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, alkoxy, alkyl, haloalkyl, cycloalkyl, nitrile, aryl, heteroaryl, and dialkylamino;
or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 13)

The compound or salt of claim 13, wherein R7B is hydrogen and R8B is hydrogen.

### Claim 15 (depends on 13)

The compound or salt of claim 13, wherein R2B is selected from the group consisting hydrogen, alkyl, alkoxyalkylenyl.

### Claim 16 (depends on 13)

The compound or salt of claim 13, wherein R2B is selected from the group consisting of hydrogen, —CH3, —CH2CH3, —CH2CH2CH3, —CH2CH2CH2CH3, —CH2OCH3, —CH2OCH2CH3, and —CH2CH2OCH3.

### Claim 17 (depends on 13)

The compound or salt of claim 13, wherein R5B and R6B are independently selected from the group consisting of hydrogen, alkyl, phenyl, phenylalkylenyl.

### Claim 18 (depends on 13)

The compound or salt of claim 13, wherein R5B is hydrogen and R6B is hydrogen.

### Claim 19 (depends on 13)

The compound or salt of claim 13, wherein XB is alkylene optionally interrupted by one or more —O— groups.

### Claim 20 (depends on 13)

The compound or salt of claim 13, wherein XB is selected from the group consisting of —CH2CH2—, —CH2CH2CH2—, —CH2CH2CH2CH2—, —CH2CH2CH2CH2CH2—, —CH2CH2CH2CH2CH2CH2—, —CH2CH2CH2CH2CH2CH2CH2—, —CH2CH2CH2CH2CH2CH2CH2CH2—, —CH2C(CH3)2—, —CH2C(CH3)2CH2—, —CH2CH2—O—CH2CH2—, —CH2CH2—O—CH2CH2CH2—, —CH2CH2—O—CH2CH2—O—CH2CH2—, —(CH2)2-4—O—(CH2)2-4—, —(CH2)2-4—(OCH2CH2-)1-5, and —(CH2)2-6—(OCH2CH2-)1-4.

### Claim 21 (depends on 13)

The compound or salt of claim 13, wherein XB is —C1-5alkylene-arylene-C1-5alkylene- or —C1-5alkylene-heteroarylene-C1-5alkylene-.

### Claim 22 (depends on 13)

The compound or salt of claim 13, wherein XB is —CH2-phenylene-CH2—.

### Claim 23 (depends on 1)

A method of inducing biosynthesis of IFN-alpha in an animal comprising administering an effective amount of a compound or salt of claim 1 to the animal.

### Claim 24 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 1 in combination with a pharmaceutically acceptable carrier.