# US 8,148,532 B2 · Spiro substituted compounds as angiogenesis inhibitors

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- Number: US 8,148,532 B2
- Document ID: US8148532B2
- Status: Granted
- Kind: B2
- Application number: 12/036,244
- Filed: 2008-02-23
- Published: 2008-09-18
- Granted: 2012-04-03
- Earliest claimed: 2007-03-14
- Inventors: Guoqing Paul Chen
- Web page: https://patentgrep.com/patent/US8148532B2

## CPC

- C07D 401/12: linked by a chain containing hetero atoms as chain links
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 239/74: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
- C07D 239/88: Oxygen atoms
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to compound of Formula I, processes for their preparation, pharmaceutical compositions containing them as active ingredient, methods for the treatment of disease states associated with angiogenesis, such as cancers associated with protein tyrosine kinases, to their use as medicaments for use in the production of inhibition of tyrosine kinases reducing effects in warm-blooded animals such as humans.

## Claims

### Claim 1

A compound of Formula II
Wherein
W and Z are each independently selected from O, or N—R;
G is selected from C—R, or N;
R, R1, R2 and R3 are each independently selected from H, halogen, halogeno-lower alkyl, lower alkyl, hydroxy, lower alkoxy;
R4 and R5 are each independently selected from H, halogen, halogeno-lower alkyl, lower alkyl, cycloalkyl, hydroxy, lower alkoxy, lower alkoxyalkoxy, lower alkenyl, lower alkynyl, lower alkyl-OC(═O)—, ary-OC(═O)—, ary lower alkylenyl-OC(═O)—, lower alkyl-C(═O)—, ary-C(═O)—, ary lower alkylenyl-C(═O)—;
R6 is H or F;
b is selected from 1, 2 or 3;
ring Q is selected from following groups:
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

A compound of according to claim 1, represented by Formula III
Wherein
G is selected from C—R, or N;
R, R1, R2 and R3 are each independently selected from H, halogen, halogeno-lower alkyl, lower alkyl, hydroxy, lower alkoxy;
R4 and R5 are each independently selected from H, halogen, halogeno-lower alkyl, lower alkyl, cycloalkyl, hydroxy, lower alkoxy, lower alkoxyalkoxy, lower alkenyl, lower alkynyl, lower alkyl-OC(═O)—, ary-OC(═O)—, ary lower alkylenyl-OC(═O)—, lower alkyl-C(═O)—, ary-C(═O)—, ary lower alkylenyl-C(═O)—;
b is selected from 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

A compound of according to claim 1, represented by Formula IV
Wherein
R1 is H or 4-F;
R4 is H or CH3;
R5 is selected from H, CH3, CH3CO—, BzlOCO— or t-BuOCO—;
b is selected from 1, 2 or 3;
G is CH or N;
R is H or 2-CH3;
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

A compound of according to claim 1 that is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

A compound of according to claim 1 that is selected from the group consisting of:
Benzyl 1-((4-(1H-indol-5-ylamino)-6-methoxyquinolin-7-yloxy)methyl)cyclopropylcarbamate
7-((1-Aminocyclopropyl)methoxy)-N-(1H-indol-5-yl)-6-methoxyquinolin-4-amine
7-((1-(Dimethylamino)cyclopropyl)methoxy)-N-(1H-indol-5-yl)-6-methoxyquinolin-4-amine
N-(1-((4-(1H-indol-5-ylamino)-6-methoxyquinolin-7-yloxy)methyl)cyclopropyl)acetamide
Benzyl 1-((6-methoxy-4-(2-methyl-1H-indol-5-ylamino)quinolin-7-yloxy)methyl)cyclopropylcarbamate
7-((1-Aminocyclopropyl)methoxy)-6-methoxy-N-(2-methyl-1H-indol-5-yl)quinolin-4-amine
7-((1-(Dimethylamino)cyclopropyl)methoxy)-6-methoxy-N-(2-methyl-1H-indol-5-yl)quinolin-4-amine
N-(1-((6-methoxy-4-(2-methyl-1H-indol-5-ylamino)quinolin-7-yloxy)methyl)cyclopropyl)acetamide
Methyl 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanecarboxylate
1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclo-propane-carboxylic acid
1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)-N,N-dimethyl-cyclopropanecarboxamide
1-(1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropyl)-N,N-dimethylmethanamine
(1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropyl) (pyrrolidin-1-yl)methanone
4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)quinoline
(1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropyl)(4-methylpiperazin-1-yl)methanone
4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((1-((4-methylpiperazin-1-yl)methyl)-cyclopropyl)methoxy)quinoline
(1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropyl) (morpholino)methanone
4-((1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropyl)methyl)morpholine
Benzyl 1-((4-(1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropylcarbamate
1-((4-(1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine
1-((4-(1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)-N,N-dimethylcyclopropanamine
N-(1-((4-(1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropyl)acetamide
Benzyl 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropyl carbamate
1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine
1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)-N,N-dimethylcyclopropanamine
N-(1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropyl)acetamide
N-(cyclopropylmethyl)-1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)-methyl)cyclo-propanamine
N-(cyclopropylmethyl)-1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)-N-methylcyclopropanamine
Benzyl 1-((6-methoxy-4-(2-methyl-1H-indol-5-yloxy)quinolin-7-yloxy)methyl)cyclopropylcarbamate
1-((6-Methoxy-4-(2-methyl-1H-indol-5-yloxy)quinolin-7-yloxy)methyl)cyclopropanamine
1-((6-Methoxy-4-(2-methyl-1H-indol-5-yloxy)quinolin-7-yloxy)methyl)-N,N-dimethylcyclopropanamine
N-(1-((6-methoxy-4-(2-methyl-1H-indol-5-yloxy)-quinolin-7-yloxy)methyl)cyclopropyl)acetamide
N-cyclopropyl-1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)-cyclopropanecarboxamide
N-((1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropyl)-methyl)cyclopropanamine
N-((1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropyl)-methyl)-N-methylcyclopropanamine
or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1, 2, 3, 4, 5)

A pharmaceutical composition that comprises as an active ingredient a compound as defined in any one of claims 1 to 5 or a pharmaceutically acceptable salt of the compound and a pharmaceutically acceptable carrier.