# US 8,541,438 B2 · Substituted imidazoquinolines, imidazopyridines, and imidazonaphthyridines

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- Number: US 8,541,438 B2
- Document ID: US8541438B2
- Status: Granted
- Kind: B2
- Application number: 12/974,459
- Filed: 2010-12-21
- Published: 2011-04-21
- Granted: 2013-09-24
- Earliest claimed: 2004-06-18
- Assignees: 3M Innovative Properties Company
- Applicants: Doris Stoermer; Joseph F. Dellaria, Jr.; David T. Amos; Bernhard M. Zimmermann; Luke T. Dressel; Jason D. Bonk; Matthew R. Radmer
- Inventors: Doris Stoermer; Joseph F. Dellaria, Jr.; David T. Amos; Bernhard M. Zimmermann; Luke T. Dressel; Jason D. Bonk; Matthew R. Radmer
- Web page: https://patentgrep.com/patent/US8541438B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61K 31/341: not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
- A61K 31/351: not condensed with another ring
- A61K 31/435: having six-membered rings with one nitrogen as the only ring hetero atom
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/445: Non condensed piperidines, e.g. piperocaine
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- C07D 471/14: Ortho-condensed systems
- 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

Imidazo-quinoline, -pyridine, and -naphthyridine ring systems (particularly quinolines, tetrahydroquinolines, pyridines, [1,5]naphthyridines, [1,5]tetrahydronaphthyridines) substituted at the 1-position with a cyclic substituent, pharmaceutical compositions containing the compounds, methods of making these compounds, and methods of use of these compounds as immunomodulators, for inducing cytokine biosynthesis in animals and in the treatment of diseases including viral and neoplastic diseases are disclosed.

## Claims

### Claim 1

A compound of the Formula (I):
wherein:
m is an integer from 1 to 5;
R′ is selected from the group consisting of:
hydroxy,
thiol,
—S(O)0-2-alkyl,
—S(O)2—NH—R9,
alkoxy,
—O—C1-3 alkylene-S(O)2-alkyl,
—N(R9)2, and
—NH-Q-R4;
Z is selected from the group consisting of:
a bond,
C1-5 alkylene,
A′ is selected from the group consisting of:
—O—,
—C(O)—,
—N(R8)—,
—N(Q-R4)—,
—N(C1-5 alkylene-NH-Q-R4)—,
—N(C1-5 alkylene-W—NH—R8)—, and
—S(O)0-2—;
R2 is selected from the group consisting of: hydrogen, alkyl, alkoxyalkylenyl, haloalkyl, and hydroxyalkyl;
when taken together, RA and RB form a fused 6-membered heteroaryl ring containing one N wherein the heteroaryl ring is unsubstituted or substituted by one R group;
or when taken together, RA and RB form a fused 6-membered saturated ring, containing one N, and unsubstituted or substituted by one R groups;
R is selected from the group consisting of:
halogen,
hydroxy,
alkyl,
alkenyl,
haloalkyl,
alkoxy,
alkylthio, and
—N(R9)2;
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, acetylamino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;
R6 is selected from the group consisting of ═O and ═S;
R8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl;
R9 is selected from the group consisting of hydrogen and alkyl;
R11 is selected from the group consisting of hydrogen, alkyl, halogen, and trifluoromethyl;
R12 is selected from the group consisting of hydrogen, alkyl, phenyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl;
Q is selected from the group consisting of a bond, —C(R6)—, —C(R6)—C(R6), —S(O)2—, —C(R6)—N(R8)—W—, —S(O)2—N(R8)—, —C(R6)—O—, and —C(R6)—N(OR9)—; and
W is selected from the group consisting of a bond, —C(O)—, and —S(O)2—;
with the proviso that when Z is a bond or C1-5 alkylene then R′ is other than —O—C1-3 alkylene-S(O)2-alkyl;
or a pharmaceutically acceptable salt thereof.

### Claim 2

A compound of the Formula (V):
wherein:
m is an integer from 1 to 5;
p is an integer from 0 to 1;
R′ is selected from the group consisting of:
hydroxy,
thiol,
—S(O)0-2-alkyl,
—S(O)2—NH—R9,
alkoxy,
—O—C1-3 alkylene-S(O)2-alkyl,
—N(R9)2, and
—NH-Q-R4;
Z is selected from the group consisting of:
a bond,
C1-5 alkylene,
A′ is selected from the group consisting of:
—O—,
—C(O)—,
—N(R8)—,
—N(Q-R4)—,
—N(C1-5 alkylene-NH-Q-R4)—,
—N(C1-5 alkylene-W—NH—R8)—, and
—S(O)0-2—;
R2 is selected from the group consisting of: hydrogen, alkyl, alkoxyalkylenyl, haloalkyl, and hydroxyalkylenyl;
R is selected from the group consisting of:
halogen,
hydroxy,
alkyl,
alkenyl,
haloalkyl,
alkoxy,
alkylthio, and
—N(R9)2;
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, acetylamino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;
R6 is selected from the group consisting of ═O and ═S;
R8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl;
R9 is selected from the group consisting of hydrogen and alkyl;
R11 is selected from the group consisting of hydrogen, alkyl, halogen, and trifluoromethyl;
R12 is selected from the group consisting of hydrogen, alkyl, phenyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl;
Q is selected from the group consisting of a bond, —C(R6)—, —C(R6)—C(R6)5—S(O)2—, —C(R6)—N(R8)—W—, —S(O)2—N(R8)—, —C(R6)—O—, and —C(R6)—N(OR9)—; and
W is selected from the group consisting of a bond, —C(O)—, and —S(O)2—;
with the proviso that when Z is a bond or C1-5 alkylene then R′ is other than —O—C1-3 alkylene-S(O)2-alkyl;
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 2)

The compound or salt of claim 2 wherein p is 0.

### Claim 4 (depends on 2)

The compound or salt of claim 2 wherein m is 1.

### Claim 5 (depends on 2)

The compound or salt of claim 2 wherein Z is selected from the group consisting of a bond and C1-3 alkylene.

### Claim 6 (depends on 2)

The compound or salt of claim 2 wherein Z is —(CH2)0-1-A′-(CH2)0-1—.

### Claim 7 (depends on 6)

The compound or salt of claim 6 wherein A′ is —O—.

### Claim 8 (depends on 6)

The compound or salt of claim 6 wherein A′ is —N(R8)— or —N(Q-R4)—.

### Claim 9 (depends on 8)

The compound or salt of claim 8 wherein Q is —S(O)2— and R4 is C1-4 alkyl.

### Claim 10 (depends on 2)

The compound or salt of claim 2 wherein the compound is of the following formula:
wherein:
Z is a bond or C1-3 alkylene; and
R2 is selected from the group consisting of hydrogen, C1-4 alkyl, HO—C1-4 alkylenyl, and C1-4 alkyl-O—C1-4 alkylenyl;
or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 2)

The compound or salt of claim 2 wherein the compound is of the following Formula:
wherein R2 is selected from the group consisting of hydrogen, C1-4 alkyl, HO—C1-4 alkylenyl, and C1-4 alkyl-O—C1-4 alkylenyl; or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 2)

The compound or salt of claim 2 wherein R′ is hydroxy.

### Claim 13 (depends on 2)

The compound or salt of claim 2 wherein R2 is hydrogen, C1-4 alkyl, HO—C1-4 alkylenyl, or C1-4 alkyl-O—C1-4 alkylenyl.

### Claim 14 (depends on 2)

The compound or salt of claim 2, wherein R′ is selected from the group consisting of —NH2 and —NH-Q-R4, wherein:
Q is selected from the group consisting of —C(O)—, —C(O)—O—, —S(O)2—, and —C(R6)—N(R8)—, wherein R8 is selected from hydrogen and C1-4 alkyl; and
R4 is alkyl, aryl, arylalkylene, heteroaryl, and heterocyclyl, wherein the aryl group can be unsubstituted or substituted by acetylamino, alkyl, alkoxy, cyano, and halogen.

### Claim 15 (depends on 2)

The compound or salt of claim 2 wherein:
R2 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl.

### Claim 16 (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.

### Claim 17 (depends on 2)

A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 2 in combination with a pharmaceutically acceptable carrier.

### Claim 18 (depends on 1)

The compound or salt of claim 1 wherein Z is selected from the group consisting of a bond and C1-3 alkylene.

### Claim 19 (depends on 1)

The compound or salt of claim 1 wherein Z is —(CH2)0-1-A′-(CH2)0-1—.