IP Library Granted Patent US 8,975,265
Granted Patent B2
US 8,975,265 · App. 13/808,430 · Granted Mar 10, 2015

Substituted imidazo[1,2-a]pyrimidines and —pyridines

Inventors: Stuart Ince (Berlin, DE); Andrea Hägebarth (Berlin, DE); Oliver Politz (Panketal OT Zepernick, DE); Roland Neuhaus (Berlin, DE); Ulf Bömer (Glienicke, DE); William Scott (Guilford, CT)
Assignee: Bayer Intellectual Property GmbH
A61K31/437C07D471/04C07D487/04A61K31/519A61K45/06C07F5/04
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 8,975,265
App. No.
13/808,430
Granted
Mar 10, 2015
Kind
B2
Abstract

Compounds of formula (I) which are effective inhibitors of the Pi3K/Akt pathway, processes for their production and their use as pharmaceuticals.

Claims (320)

1. A compound of formula (I)

in which

R1 is hydrogen, hydroxy, halogen, cyano, CO-(1-6C-alkyl), C(O)OR10, CO(NR8R9), NR8R9, NH—C(O)NR8R9, NH—C(O)R11, 2-6C-alkinyl, or

a group selected from 1-6C-alkyl, 2-6C-alkenyl, 1-6C-alkoxy, 3-7C-cycloalkyl, aryl, heteroaryl, -(1-6C-alkylen)-aryl, -(1-6C-alkylen)-heteroaryl, —O-(3-7C-cycloalkyl), —O-aryl, —O-(3-7C-heterocyclyl), —O-heteroaryl, —O-(1-6C-alkylen)-(3-7C-cycloalkyl), —O-(1-6C-alkylen)-aryl, —O-(1-6C-alkylen)-(3-7C-heterocyclyl), —O-(1-6C-alkylen)-heteroaryl,

wherein said group is optionally substituted independently with one or more substituents selected from:

hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, —NR8R9, cyano, (═O), —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O) 2 R11, heteroaryl,

wherein said substituent can be optionally substituted with 1-6C-alkoxy,

R2 is hydrogen, hydroxy, halogen, cyano, CO-(1-6C-alkyl),C(O)OR10, CO(NR8R9), NR8R9, —NH—C(O)R11, —NH—C(O)NR8R9, —NHS(O) 2 R11 or

a group selected from 1-6C-alkyl, 2-6C-alkenyl, 1-6C-alkoxy, 3-7C-cycloalkyl, aryl, heteroaryl,

wherein said group is optionally substituted independently with one or more substituents selected from:

hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O) 2 R11, NH-(1-6C-alkyl)-O-(1-6C-alkyl),

R3 is hydrogen, 1-6C-alkyl,

R4 is phenyl optionally substituted by 1-6C-alkyl, halogen, cyano,

R5 is hydrogen, halogen,

R6 is hydrogen, 1-6C-alkyl,

A is N, C(R7),

R7 is hydrogen, hydroxy, halogen, cyano, C(O)OR10, CO(NR8R9), 3-7C-cycloalkyl, or

a group selected from 1-6C-alkyl, 2-6C-alkenyl, 1-6C-alkoxy, aryl, heteroaryl,

wherein said group is optionally substituted independently with one or more substituents selected from:

hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O) 2 R11,

X is —CH 2 —,

Y is —CH 2 —, —CH(OH)—,

R8, R9 which can be the same or different, is hydrogen, hydroxy, 3-7C-cycloalkyl or

a group selected from 1-4C-alkyl, 1-6C-alkoxy, wherein said group is optionally substituted, independently with one or more substituents selected from:

halogen, hydroxy, mono- or di-(1-4C-alkylamino), 1-4C-alkoxy, or 3-7C-cycloalkyl or,

R8 and R9 together with the nitrogen to which they are attached may also form a saturated or unsaturated 3-6C-heterocyclic ring,

which is optionally substituted by (═O)

R10 is hydrogen, 1-6C-alkyl,

R11 is 1-4C-alkyl (optionally substituted independently with one or more halogen or hydroxyl groups) or 3-7C-cycloalkyl,

or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

2. The compound of formula (I) according to claim 1 ,

wherein

R1 is hydrogen, hydroxy, halogen, cyano, —CO-(1-6C-alkyl), C(O)OR10, CO(NR8R9), NR8R9, NH—C(O)NR8R9, NH—C(O)R11, 2-6C-alkinyl, or

a group selected from 1-6C-alkyl, 2-6C-alkenyl, 1-6C-alkoxy, 3-7C-cycloalkyl, aryl, heteroaryl, -(1-6C-alkylen)-aryl, -(1-6C-alkylen)-heteroaryl, —O-(3-7C-cycloalkyl), —O-aryl, —O-(3-7C-heterocyclyl), —O-heteroaryl, —O-(1-6C-alkylen)-heteroaryl, —O-(1-6C-alkylen)-(3-7C-heterocyclyl), —O-(1-6C-alkylen)-aryl, —O-(1-6C-alkylen)-(3-7C-cycloalkyl)

wherein said group is optionally substituted with one or more substituents selected from:

hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O) 2 R11, heteroaryl,

wherein said substituent can be optionally substituted with 1-6C-alkoxy,

R2 is hydrogen, hydroxy, halogen, cyano, C(O)OR10, CO(NR8R9), NR8R9, —NH—C(O)R11, —NH—C(O)NR8R9, —NHS(O) 2 R11 or

a group selected from 1-6C-alkyl, 2-6C-alkenyl, 1-6C-alkoxy, 3-7C-cycloalkyl, aryl, heteroaryl,

wherein said group is optionally substituted independently with one or more substituents selected from:

hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O) 2 R11, NH-(1-6-alkyl)-O-(1-6-alkyl),

R3 is hydrogen,

R4 is phenyl optionally substituted by 1-6C-alkyl, halogen, cyano,

R5 is hydrogen, halogen,

R6 is hydrogen,

A is N, C(R7),

R7 is hydrogen, hydroxy, halogen, cyano, C(O)OR10, CO(NR8R9), 3-7C-cycloalkyl, or

a group selected from 1-6C-alkyl, 2-6C-alkenyl, 1-6C-alkoxy, aryl, heteroaryl,

wherein said group is optionally substituted independently with one or more substituents selected from:

hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O) 2 R11,

X is —CH 2 —,

Y is —CH 2 —, —CH(OH)—,

R8, R9 which can be the same or different, is hydrogen, hydroxy, or

a group selected from 1-4C-alkyl, 1-6C-alkoxy, wherein said group is optionally substituted, independently with one or more substituents selected from:

halogen, hydroxy, mono- or di-(1-4C-alkylamino), 1-4C-alkoxy, or 3-7C-cycloalkyl, or,

R8 and R9 together with the nitrogen to which they are attached may also form a saturated or unsaturated 3-6C-heterocyclic ring,

which is optionally substituted by (═O)

R10 is hydrogen, 1-6C-alkyl,

R11 is 1-4C-alkyl (optionally substituted independently with one or more halogen or hydroxyl groups) or 3-7C-cycloalkyl,

or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

3. The compound of formula (I) according to claim 1 ,

wherein

R1 is hydrogen, hydroxy, halogen, cyano, —CO-(1-6C-alkyl), C(O)OR10, CO(NR8R9), NR8R9, NH—C(O)NR8R9, NH—C(O)R11, 2-6C-alkinyl, or

a group selected from 1-6C-alkyl, 2-6C-alkenyl, 1-6C-alkoxy, 3-7C-cycloalkyl, aryl, heteroaryl, -(1-6C-alkylen)-aryl, -(1-6C-alkylen)-heteroaryl, —O -(3-7C-cycloalkyl), —O-aryl, —O-(3-7C-heterocyclyl), —O-heteroaryl, —O-(1-6C-alkylen)-heteroaryl, —O-(1-6C-alkylen)-(3-7C-heterocyclyl), —O-(1-6C-alkylen)-aryl, —O-(1-6C-alkylen)-(3-7C-cycloalkyl)

wherein said group is optionally substituted independently with one or more substituents selected from:

hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O)2R11, heteroaryl,

wherein said substituent can be optionally substituted with 1-6C-alkoxy,

R2 is hydrogen, hydroxy, halogen, cyano, C(O)OR10, CO(NR8R9), NR8R9, —NH—C(O)R11, —NH—C(O)NR8R9, —NHS(O)2R11 or

a group selected from 1-6C-alkyl, 2-6C-alkenyl, 1-6C-alkoxy, 3-7C-cycloalkyl, aryl, heteroaryl,

wherein said group is optionally substituted independently with one or more substituents selected from:

hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O)2R11, NH-(1-6C-alkyl)-O-(1-6C-alkyl),

R3 is hydrogen,

R4 is phenyl

R5 is hydrogen,

R6 is hydrogen,

A is N, C(R7),

R7 is hydrogen, hydroxy, halogen, cyano, C(O)OR10, CO(NR8R9), 3-7C-cycloalkyl, or

a group selected from 1-6C-alkyl, 2-6C-alkenyl, 1-6C-alkoxy, aryl, heteroaryl,

wherein said group is optionally substituted independently with one or more substituents selected from:

hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O)2R11,

X is —CH 2 —,

Y is —CH 2 —, —CH(OH)—,

R8, R9 which can be the same or different, is hydrogen, hydroxy, or

a group selected from 1-4C-alkyl, 1-6C-alkoxy, wherein said group is optionally substituted independently with one or more substituents selected from:

halogen, hydroxy, mono- or di-1-4C-alkylamino), 1-4C-alkoxy, or 3-7C-cycloalkyl, or,

R8 and R9 together with the nitrogen to which they are attached may also form a saturated or unsaturated 3-6C-heterocyclic ring,

which is optionally substituted by (═O)

R10 is hydrogen, 1-6C-alkyl,

R11 is 1-4C-alkyl (optionally independently with one or more halogen or hydroxyl groups) or 3-7C-cycloalkyl,

or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

4. The compound of formula (I) according to claim 1 ,

wherein,

R1 is hydrogen, 1-3C-alkyl, -(1-3C-alkylen)C(O)O(1-3C-alkyl), -(2-3Calkenylen)C(O)O(1-3C-alkyl), -(2-3Calkenylen)C(O)NH2, -(1-3C-alkylen)C(O)NH2, halogen, hydroxy, ONa, 1-3C-alkoxy, —O-cyclohexyl, —O-phenyl, —O-(1-3C-alkylen)-heteroaryl, —O-(1-3C-alkylen)-[(1-3C-alkoxy)heteroaryl], —O-(1-3C-alkylen)NH 2 , —O-(1-3C-alkylen)O-(1-3C-alkyl), —O-(1-3C-alkylen)-cyclopropane-C(O)NH2, —O-(1-3C-alkylen)-CN, —O-(1-3C-alkylen)-C(O)O(1-3C-alkyl), —O-(1-3C-alkylen)-C(O)N(1-3C-alkyl) 2 , —O-(1-3C-alkylen)-(heterocyclyl), -heteroaryl-(1-3Calkoxy), —O-(1-3C-alkylen)-(heteroaryl)-(1-3alkoxy), 3-7C-cycloalkyl, phenyl (which is optionally substituted with 1-3C-alkyl, halogen), cyano, —C(O)(1-3C-alkyl), —C(O)OH, —C(O)O(1-3C-alkyl), —CONH2, —C(O)NH(1-3C-alkyl), —C(O)NH-OH, —C(O)-heterocycyl, heteroaryl (which is optionally substituted with 1-3C-alkyl, (═O), 1-3Calkoxy,), NH—C(O)—NH-(1-3C-alkyl), amino, NH—C(O)-(1-3C-alkyl), NH—C(O)—NH2, N(1-3C-alkyl)-O-(1-3C-alkyl),

R2 is hydrogen, 1-3C-alkyl, trifluoromethyl, -(1-3C-alkylen)C(O)O-(1-3C-alkyl), 2-3C-alkenyl, -(2-3C-alkenylen)C(O)O-(1-3C-alkyl), -(2-3C-alkenylen)C(O)NH 2 , -(1-3C-alkylen)-NH-(1-3C-alkylen)-O-(1-3C-alkyl), 1-3C-alkoxy, —O-(1-3C-alkylen)-CN, —O-(1-3C-alkylen)-C(O)O-(1-3C-alkyl), hydroxy, halogen, cyano, 3-7C-cycloalkyl, phenyl, —C(O)(1-3C-alkyl), C(O)O(1-3C-alkyl), —CONH 2 , —CONH-(1-3C-alkyl), C(O)—N(1-3C-alkyl), C(O)—NH-(1-3C-alkylen)F, C(O)—NH-(1-3C-alkylen)OH, C(O)—NH-(1-3C-alkylen)O-(1-3C-alkyl), C(O)NH-3-7C-cycloalkyl, C(O)NH-(1-3C-alkyl)-3-7C-cycloalkyl, C(O)NH—OH, -(1-3C-alkyl)O-(1-3C-alkyl), —CH(OH)-(1-3C-alkyl), -(1-3C-alkylen)OH, heteroaryl (which is optionally substituted with 1-3C-alkyl), amino, NH—C(O)-(1-3C-alkyl), NH—C(O)—NH 2 , NH—C(O)—NH-(1-3C-alkyl), NH—S(O) 2 -(1-3C-alkyl),

R3 is hydrogen, 1-3C-alkyl,

R4 is phenyl,

R5 is hydrogen,

R6 is hydrogen,

A is N, C(R7),

R7 is hydrogen, hydroxy, cyano, halogen, 1-3C-alkyl, 2-3C-alkenyl, 1-3C-alkoxy, -(1-3C-alkylen)OH, C(O)O-(1-3C-alkyl), —CONH 2, 3 -7C-cycloalkyl, phenyl (which is optionally substituted with halogen, 1-3C-alkox),

R8 is hydrogen, 1-3C-alkyl, hydroxy, 1-3C-alkoxy, 3-7C-cycloalkyl,

whereby 1-3C-alkyl is optionally substituted independently with one or more substituents

selected from

halogen, hydroxy, 1-3C-alkoxy, 3-7C-cycloalkyl,

R9 is hydrogen, 1-3C-alkyl,

or

R8 and R9 together with the nitrogen to which they are attached may also form a saturated or unsaturated 5- or 6-membered heterocyclic ring which optionally is substituted with (═O),

X is —CH 2 —,

Y is —CH 2 —, —CH(OH)—,

or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

5. The compound of formula (I) according to claim 1 , which is selected from the group consisting of:

1-[4-(3-phenyl-imidazo[1,2-a]pyrimidin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(7-methyl-3-phenyl-imidazo[1,2-a]pyrimidin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(7-cyclopropyl-3-phenyl-imidazo[1,2-a]pyrimidin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(3,7-diphenyl-imidazo[1,2-a]pyrimidin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(3-phenyl-7-O-tolyl-imidazo[1,2-a]pyrimidin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(6-chloro-3-phenyl-imidazo[1,2-a]pyrimidin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(6-methyl-3-phenyl-imidazo[1,2-a]pyrimidin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(6-methoxy-3-phenyl-imidazo[1,2-a]pyrimidin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(6-ethoxy-3-phenyl-imidazo[1,2-a]pyrimidin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(3,6-diphenyl-imidazo[1,2-a]pyrimidin-2-yl)-phenyl]-cyclobutylamine,

2-[4-(1-amino-cyclobutyI)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-6-carbonitrile,

1-[4-(7-methoxy-3-phenyl-imidazo[1,2-a]pyrimidin-2-yl)-phenyl]-cyclobutylamine,

2-[4-(1-amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyrimidin-7-ol,

1-[4-(3-phenyl-7-propoxy-imidazo[1,2-a]pyrimidin-2-yl)-phenyl]-cyclobutylamine,

2-[4-(1-amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-8-carbonitrile,

1-[4-(7-methyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl amine,

1-[4-(8-methyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl amine,

2-[4-(1-amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-7-carbonitrile,

1-[4-(6-methyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl amine,

1-[4-(7-methoxy-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

2-[4-(1-amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-6-carboxylic acid methylamide,

1-[4-(6-methoxymethyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(8-methoxy-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

1-{2-[4-(1-amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridin-6-yl}-ethanol,

{2-[4-(1-amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridin-7-yl}-methanol,

{2-[4-(1-amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridin-8-yl}-methanol,

1-[4-(6-bromo-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(6-methoxy-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

2-[4-(1-amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-6-carboxylic acid amide,

1-[4-(8-ethoxy-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(7-ethoxy-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(7-ethyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

1-{4-[3-phenyl-7-(1H-pyrazol-4-yl)-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutylamine,

{2-[4-(1-amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridin-6-yl}-methanol,

1-{4-[7-(6-methoxy-pyridin-3-ylmethoxy)-3-phenyl-imidazo[1,2-a]pyrimidin-2-yl]-phenyl}-cyclobutylamine,

1-{4-[7-(2-methoxy-ethoxy)-3-phenyl-imidazo[1,2-a]pyrimidin-2-yl]-phenyl}-cyclobutylamine,

1-{4-[7-(2-methoxy-pyridin-4-ylmethoxy)-3-phenyl-imidazo[1,2-a]pyrimidin-2-yl]-phenyl}-cyclobutylamine,

1-[4-(7-ethoxy-3-phenyl-imidazo[1,2-a]pyrimidin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(7-isopropoxy-3-phenyl-imidazo[1,2-a]pyrimidin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(7-cyclohexyloxy-3-phenyl-imidazo[1,2-a]pyrimidin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(7-phenoxy-3-phenyl-imidazo[1,2-a]pyrimidin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(6-ethyl-3-phenyl-imidazo[1,2-a]pyrimidin-2-yl)-phenyl]-cyclobutylamine,

1-{4-[7-(4-fluoro-phenyl)-3-phenyl-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutylamine,

1-[4-(7-cyclopropyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(6-ethyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(8-bromo-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(7-bromo-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

2-[4-(1-amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-7-carboxylic acid amide,

2-[4-(cis-1-amino-3-hydroxy-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyrimidin-7-ol,

1-{4-[7-(2-amino-ethoxy)-3-phenyl-imidazo[1,2-a]pyrimidin-2-yl]-phenyl}-cyclobutylamine,

2-[4-(1-amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridin-6-ol,

2-[4-(1-amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-8-carboxylic acid amide,

1-[4-(3-Phenyl-7-pyrazol-1-yl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

2-[4-(1-Amino-cyclobutyl)-phenyl]-8-methoxy-3-phenyl-imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester,

2-[4-(1-Amino-cyclobutyl)-phenyl]-8-methoxy-3-phenyl-imidazo[1,2-a]pyridine-6-carboxylic acid amide,

1-{2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridin-7-yl}-3-methyl-urea,

1-{2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridin-7-yl}-1H-pyridin-2-one,

1-{4-[3-Phenyl-6-(1H-pyrazol-1-yl)imidazo[1,2-a]pyridin-2-yl]phenyl}cyclobutanamine,

{2[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridin-7-yl}-pyrrolidin-1-yl-methanone,

2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-8-carboxylic acid ethyl ester,

1-[4-(8-Fluoro-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(8-Chloro-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(6-Fluoro-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(8-Cyclopropyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(3-Phenyl-6-vinyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(3-Phenyl-8-vinyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

1-{4-[3-Phenyl-8-(1H-pyrazol-4-yl)-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutylamine,

2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-6-carboxylic acid hydrochloride salt,

1-[4-(6-Bromo-8-methoxy-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-6-carboxylic acid isopropylamide,

2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-6-carboxylic acid (2-fluoro-ethyl)-amide,

2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-6-carboxylic acid (2-hydroxy-ethyl)-amide,

2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-6-carboxylic acid (2-methoxy-ethyl)-amide,

2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-6-carboxylic acid cyclopropylamide,

2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-6-carboxylic acid cyclopropyl methyl-amide,

2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-6-carboxylic acid hydroxyamide,

2-[4-(1-Amino-cyclobutyl)-phenyl]-8-chloro-3-phenyl-imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester,

2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-6-carboxylic acid dimethylamide,

2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-6-carboxylic acid ethylamide,

1-[4-(6-Cyclopropyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

1-(2-{2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyrimidin-7-yloxy}-ethyl)-pyrrolidin-2-one,

1-{2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyrimidin-7-yloxymethyl}-cyclopropanecarboxylic acid amide,

1-[4-(7-Chloro-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(7-Fluoro-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

1-{4-[8-(4-fluorophenyl)-3-phenyl-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutylarnine,

1-{4-[8-(3-Fluorophenyl)-3-phenyl-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutylamine,

1-{4-[8-(5-Methoxypyridin-3-yl)-3-phenyl-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutylcarbarnine,

1-{4-[3-Phenyl-8-(2H-pyrazol-3-yl)-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutylarnine,

1-{4-[8-(1H-indazol-6-yl)-3-phenyl-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutylarnine,

1-[4-(6,8-Dimethyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl]-phenyl]-cyclobutylamine,

1-[4-(8-Chloro-7-methyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl]-phenyl]-cyclobutylamine,

1-[4-(7,8-Difluoro-3-phenyl-imidazo[1,2-a]pyridin-2-yl]-phenyl]-cyclobutylamine,

1-[4-(6-Chloro-8-methyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl]-phenyl]-cyclobutylamine,

2-[4-(1-Arnino-cyclobutyl)-phenyl]-8-brorno-3-phenyl-imidazo[1,2-a]pyridine-6-carboxylic acid ethyl ester,

1-[4-(6,8-Dichloro-3-phenyl-imidazo[1,2-a]pyridin-2-yl]-phenyl]-cyclobutylamine,

2-[4-(1-Amino-cyclobutyl)-phenyl]-7-methoxy-3-phenyl-imidazo[1,2-a]pyridine -8-carbonitrile,

1-[4-(6,7-Dichloro-3-phenyl-imidazo[1,2-a]pyridin-2-yl]-phenyl]-cyclobutylamine,

1-[4-(8-Bromo-6-chloro-7-methyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl]-phenyl]-cyclobutylamine,

1-[4-(6-Bromo-8-methyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl]-phenyl]-cyclobutylamine,

1-[4-(8-Bromo-6-methyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl]-phenyl]-cyclobutylamine,

1-[4-(6-Bromo-7,8-dimethyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl]-phenyl]-cyclobutylamine,

1-[4-(8-Bromo-6-chloro-3-phenyl-imidazo[1,2-a]pyridin-2-yl]-phenyl]-cyclobutylamine,

1{-[4-(8-Bromo-3-phenyl-6-trifluoromethyl-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutylamine,

1-{4-[6-Chloro-8-(4-fluorophenyl)-7-methyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutylamine,

1-{4-[6-Chloro-7-methyl-3-phenyl-8-(2H-pyrazol-3-yl)-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutylamine,

1-{4-[7,8-Dimethyl-3-phenyl-6-(2H-pyrazol-3-yl)-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutylamine,

1-{4-[6-Methyl-3-phenyl-8-pyridin-3-yl-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutylamine,

1-{4-[8-(5-Methoxy-pyridin-3-yl)-6-methyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutylamine,

1-{4-[6-Methyl-3-phenyl-8-(2H-pyrazol-3-yl)-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutylamine,

1-{4-[6-Methyl-3-phenyl-8-(1H-pyrazol-4-yl)-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutylamine,

2-[4-(1-Amino-cyclobutyl)-phenyl]-6-bromo-3-phenyl-imidazo[1,2-a]pyridine-8-carboxylic acid amide,

2-[4-(1-Amino-cyclobutyl)-phenyl]-8-bromo-3-phenyl-imidazo[1,2-a]pyridine-6-carboxylic acid amide,

2-[4-(1-Amino-cyclobutyl)-phenyl]-6-methyl-3-phenyl-imidazo[1,2-a]pyridine-8-carboxylic acid amide,

2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-6-(1H-pyrazol-4-yl)-imidazo[1,2-a]pyridine-8-carboxylic acid amide,

2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-6-(2H-pyrazol-3-yl)-imidazo[1,2-a]pyridine-8-carboxylic acid amide,

2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-6-pyridin-3-yl)-imidazo[1,2-a]pyridine-8-carboxylic acid amide,

2-[4-(1-Amino-cyclobutyl)-phenyl]-7,8-dimethyl-3-phenyl-imidazo[1,2-a]pyridine-6-carboxylic acid amide,

2-[4-(1-Amino-cyclobutyl)-phenyl]-8-methyl-3-phenyl-imidazo[1,2-a]pyridine-6-carboxylic acid amide,

1-{4-[8-Methyl-3-phenyl-6-(1H-pyrazol-4-yl)-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutylamine,

1-{4-[8-Methyl-3-phenyl-6-(2H-pyrazol-3-yl)-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutylamine,

1-{4-[8-Methyl-3-phenyl-6-pyridin-3-yl-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutylamine,

1-{4-[8-Methyl-3-phenyl-6-(5-methyl-2H-pyrazol-3-yl)-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutylamine,

1-[4-(3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(6-ethoxy-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(3-phenyl-7-vinyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(3-phenyl-7-pyridin-4-yl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(3-Phenyl-7-pyridin-3-yl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(3-Phenyl-7-pyridin-2-yl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

1-{4-[3-Phenyl-7-(1H-pyrazol-3-yl)-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutylamine,

1-{4-[3-Phenyl-7-(1H-pyrazol-4-yl)-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutylamine,

1-{4-[7-(1H-Imidazol-2-yl)-3-phenyl-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutylamine HCI salt,

1-{4-[7-(3H-Imidazol-4-yl)-3-phenyl-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutylamine HCI salt,

1-{4-[7-(3-Methyl-3H-imidazol-4-yl)-3-phenyl-imidazo[1,2-a]-pyridin-2-yl]-phenyl}-cyclobutylamine,

1-{4-[3-Phenyl-7-(2H-tetrazol-5-yl)-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutylamine HCI salt ,

2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]-pyridine-7-carboxylic acid methyl ester,

2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]-pyridine-7-carboxylic acid ethyl ester,

2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]-pyridine-7-carboxylic acid HCI salt,

2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]-pyridine-7-carboxylic acid amide,

2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]-pyridine-7-carboxylic acid methylamide,

(E)-3-{2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]-pyridin-7-yl}-acrylic acid methyl ester,

(E)-3-{2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]-pyridin-7-yl}-acrylamide,

3-{2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]-pyridin-7-yl}-propionic acid methyl ester,

2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]-pyridine-7-carboxylic acid ethylamide,

2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]-pyridine-7-carboxylic acid hydroxyamide,

1-{2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]-pyridin-7-yl}-ethanone,

1-{4-[6-(3H-Imidazol-4-yl)-3-phenyl-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutylamine HCI salt,

1-{4-[6-(1H-Imidazol-2-yl)-3-phenyl-imidazo[1,2a]pyridin-2-yl]-phenyl}-cyclobutylamine,

1-{4-[3-Phenyl-6-(1H-pyrazol-3-yl)-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutylamine,

1-{4-[3-Phenyl-6-(1H-pyrazol-4-yl)-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutylamine,

1-{4-[6-(3-Methyl-3H-imidazol-4-yl)-3-phenyl-imidazo[1,2-a]-pyridin-2-yl]-phenyl}-cyclobutylamine,

1-{4-[6-(1-Methyl-1H-pyrazol-4-yl)-3-phenyl-imidazo[1,2-a]-pyridin-2-yl]-phenyl}-cyclobutylamine,

1-{4-[3-Phenyl-6-(2H-tetrazol-5-yl)-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutylamine HCI salt,

1-[4-(3-Phenyl-6-pyridin-4-yl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(3-Phenyl-6-pyridin-3-yl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(3-Phenyl-6-pyridin-3-yl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(6-Bromo-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(6-Chloro-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

(E)-3-{2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridin-6-yl}-acrylic acid methyl ester,

(E)-3-{2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridin-6-yl}-acrylamide,

2-[4-(1-Amino-cyclobutyl)-3-phenyl-imidazo[1,2-a]pyridine-6-carboxylic acid ethyl ester ,

1-{2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridin-6-yl}-ethanone,

1-[4-(6-Chloro-8-methoxy-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(6,8-Dimethoxy-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

1-[4-(6-Ethyl-8-methoxy-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

1-{4-[6-(3H-Imidazol-4-yl)-8-methoxy-3-phenyl-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutylamine,

1-{4-[6-(1H-Imidazol-2-yl)-8-methoxy-3-phenyl-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutylamine,

1-{4-[7-(1-Methyl-1H-pyrazol-4-yl)-3-phenyl-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutylamine,

2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridin-7-ylamine,

N-{2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridin-7-yl}-acetamide,

{2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridin-7-yl}-urea,

2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-7-carboxylic acid methoxy-methyl-amide,

2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridin-6-ylamine,

N-{2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridin-6-yl}-acetamide,

{2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridin-6-yl}-urea ,

1-{2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridin-6-yl}-3-methyl-urea,

N-{2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridin-6-yl}-methanesulfonamide,

1-[4-(8-Methoxy-3-phenyl-6-yinyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine,

2-[4-(1-amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridin-8-ol,

2-[4-(1-amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-8-carboxylic acid amide,

1-[4-(7-ethynyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclo-butylamine,

3-{2-[4-(1-amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridin-7-yl}-propionamide,

{2-[4-(1-amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridin-7-yloxy}-acetic acid methyl ester,

2-[4-(1-amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridin-7-ol,

3-{2-[4-(1-amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridin-6-yl}-pyridin-2-ol,

1-{4-[6(5-methyl-2H-pyrazo1-3-yl)-3-phenyl-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutylamine,

1-{4-[8-methoxy-3-phenyl-6-(1H-pyrazol-4-yl)-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutylamine,

1-[4-(5-methyl-3-phenylimidazo[1,2-a]pyridin-2-yl)phenyl]cyclo-butanamine, and

2-[4-(1-aminocyclobutyl)phenyl]-8-chloro-3-phenylimidazo[1,2-a]pyridine-6-carbonitrile.

6. A pharmaceutical composition comprising at least one compound according to claim 1 , together with at least one pharmaceutically acceptable auxiliary.

7. A pharmaceutical composition comprising at least one compound according to claim 1 , and one or more second active ingredients selected from chemotherapeutic anti-cancer agents and target-specific anti-cancer agents.

8. Process for the manufacture of a compound of formula (I) according to claim 1 , wherein a compound of formula (III)

whereby R4, R5 and R6, X and Y are defined according to claim 1 and Rx is R6 or a protecting group; Ry is hydrogen or a protecting group, or Rx and Ry together, or Y and Rx together, may form a cyclic protecting group, Hal is halogen,

is reacted with a compound of formula (IV)

whereby R1, R2, and A are defined according to claim 1 ,

forming a compound of formula (IIa)

which is optionally subsequently deprotected to form a compound of general formula (I).

9. Process for the manufacture of a compound of formula (I) according to claim 1 , wherein a compound of formula (XIV)

wherein

R5 is hydrogen or halogen, and

R6 is hydrogen or 1-6C-alkyl,

X is —CH2— and

Y is —CH2—, —CH(OH)— and

Rx is R6 or a protecting group;

Ry is hydrogen or a protecting group, or Rx and Ry together, or

Y and Rx together, may form a cyclic protecting group,

is reacted with a compound of formula (XIII)

wherein R1, R2, R3, A and R4 are defined according to claim 1 , to obtain a compound of formula (II) which is optionally deprotected, to obtain a compound of formula (I)

10. A method for the treatment of a hyperproliferative disease or disorder responsive to the induction of apoptosis selected from breast cancer, prostate cancer, melanoma, non-small cell lung cancer (NSCLC), and brain cancer comprising administering to a human or animal in need thereof an effective amount of a compound according to claim 1 .

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 7, 2014
From: INCE, STUART, DR.; HAGEBARTH, ANDREA, DR.; POLITZ, OLIVER, DR.; NEUHAUS, ROLAND, DR.; BOMER, ULF, DR.; SCOTT, WILLIAM, DR.
To: BAYER INTELLECTUAL PROPERTY GMBH
Reel/Frame 032375/0602 →
Priority Claims (1)
EP 10169205 · Jul 12, 2010 · regional
Continuity (2)
Provisional Application 61392779 · Oct 13, 2010
Related Publication 20130190332A1 · Jul 25, 2013