US 8,013,156 B2Granted

Tie-2 modulators and methods of use

AssigneeExelixis, Inc.

InventorsLynne Canne Bannen, S. David Brown, Wei Cheng, Vasu Jammalamadaka, John M. Nuss, Morrison B. Mac, Jason Jevious Parks, Matthew A. Williams, Wei Xu, Atwood Kim Cheung, Lisa Esther Dalrymple, Sergey Epshteyn, Mohamed Abdulkader Ibrahim, James William Leahy, Gary Lee Lewis, Robin Tammie Noguchi, Larry Wayne Mann, Brian Hugh Ridgway, Joan C. Sangalang, Kevin Luke Schnepp, Xian Shi, Richard George Khoury

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Abstract

The present invention provides compounds for modulating protein kinase enzymatic activity for modulating cellular activities such as proliferation, differentiation, programmed cell death, migration and chemoinvasion. Compounds of the invention inhibit, regulate and/or modulate kinases, particularly Tie-2. Methods of using the compounds and pharmaceutical compositions thereof to treat kinase-dependent diseases and conditions are also an aspect of the invention.

Claims26

Dependent claims

A compound of Formula I,

or a pharmaceutically acceptable salt thereof, wherein,
Ar is selected from the following formulae
wherein Ar is substituted with —X and —Y-L-Z, in an ortho relationship to each other, and said Ar is optionally substituted with up to four R1;
each R1 is independently selected from —H, halogen, —CN, —NO2, —OR3, —N(R3)R3, —S(O)0-2R3, —SO2N(R3)R3, —CO2R3, —C(O)N(R3)R3, —N(R3)SO2R3, —N(R3)C(O)R3, —N(R3)CO2R3, —C(O)R3, —OC(O)R3, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl;
X is selected from the following formulae
wherein R4a is —C(O)N(R3)R3;
n=1 or 2;
p=0 or 1;
q is 1 to 3;
M is −OR3 or —N(R3)R4;
each R2 is independently selected from —H, haloalkyl, —C1-6alkyl-N(R3)R3, —C1-6alkyl-OR3, —C1-6alkyl-CO2R3, and —C1-6alkyl-C(O)N(R3)R3;
each R3 is independently selected from —H, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl;
or
two of R3, when taken together with a common nitrogen to which they are attached, form an optionally substituted five- to seven-membered heterocyclyl ring, said optionally substituted five- to seven-membered heterocyclyl ring optionally containing at least one additional heteroatom selected from N, O, S, and P;
each R4 is independently selected from R3, —SO2R3, —SO2N(R3)R3, —CO2R3, —C(O)N(R3)R3, and —C(O)R3;
Y-L-Z is selected from the following formulae,
wherein g is zero to two;
T is selected from absent, —N(R3)—, —S— and —O—;
and each methylene between Y and T is optionally substituted;
provided that when both Y and T are heteroatoms then g must be two;
Y is —O— or optionally substituted —CH2—;
R5 is selected from —H, halogen, —CN, —NO2, —OR3, —N(R3)R4, —S(O)0-2R3, —SO2N(R3)R3, —CO2R3, —C(O)N(R3)R3, —N(R3)SO2R3, —N(R3)C(O)R3, —N(R3)CO2R3, —C(O)R3, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl;
and
optionally two of R5, together with the atoms to which they are attached, form a second ring system fused with said five- to seven-membered ring system, said second ring system substituted with zero to four of R5.

21 more elements

A compound of Formula IV,

or a pharmaceutically acceptable salt thereof, wherein,
Ar is selected from the following formulae:
each R1 is independently selected from —H, halogen, —CN, —NO2, —OR3, —N(R3)R3, —S(O)0-2R3, —SO2N(R3)R3, —CO2R3, —C(O)N(R3)R3, —N(R3)SO2R3, —N(R3)C(O)R3, —N(R3)CO2R3, —C(O)R3, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl;
optionally two of R1, together with the atoms to which they are attached, form a first ring system fused with Ar, said first ring system substituted with zero to three additional of R1;
each R2 is independently selected from —H, halogen, oxo, —CN, —NH2, —NO2, —OR3, —N(R3)R3, —N(R3)R5, —S(O)0-2R3, —SO2N(R3)R3, —CO2R3, —C(O)N(R3)R3, —N(R3)SO2R3, —N(R3)C(O)R3, —N(R3)CO2R3, —N(R3)C(O)N(R3)R3, —C(O)R3, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl;
two of R2, together with the atoms to which they are attached, can form an optionally substituted three- to seven-membered ring system;
each R3 is independently selected from —H, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl;
or
two of R3, when taken together with a common nitrogen to which they are attached, form an optionally substituted five- to seven-membered heterocyclyl ring, said optionally substituted five- to seven-membered heterocyclyl ring optionally containing at least one additional heteroatom selected from N, O, S, and P;
each R4 is independently selected from R3, —SO2R3, —SO2N(R3)R3, —CO2R3, —C(O)N(R3)R3, and —C(O)R3;
Y is selected from optionally substituted —CH2—, —O—, —S—, and —N(R3)—;
L is selected from optionally substituted —CH2—, —O—, —S—, —N(R3)— and absent;
provided that Y and L are not both heteroatoms;
B is ═N— or ═C(H)—;
at each instance, R5 and R6 are independently selected from —H, halogen, —CN, —NO2, —OR3, —N(R3)R4, —S(O)0-2R3, —SO2N(R3)R3, —CO2R3, —C(O)N(R3)R, —N(R3)SO2R3, —N(R3)C(O)R3, —N(R3)CO2R3, —C(O)R3, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl;
and
optionally two of R5, together with the atoms to which they are attached, form a ring system fused with the ring containing B according to formula IV, said ring system substituted with zero to two additional of R5.

14 more elements

A compound selected from Table 4.

TABLE 4
97
N-[3,5-bis(trifluoromethyl)phenyl]-4- {3-[(pyridin-4-ylmethyl)oxy]pyridin-2- yl}piperazine-1-carboxamide
103
N-(4-chlorophenyl)-4-{3-[(pyridin-4- ylmethyl)oxy]yridin-2-yl}piperazine- 1-carboxamide
105
N-(3-chlorophenyl)-4-{3-[(pyridin-4- ylmethyl)oxy]pyridin-2-yl}piperazine- 1-carboxamide
142
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-[3,5- bis(trifluoromethyl)phenyl]piperazine-1- carboxamide
144
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(3- ethylphenyl)piperazine-1-carboxamide
161
methyl {4-({[2-(4-{[(3- methylphenyl)amino]carbonyl}piperazin- 1-yl)pyridin-3-yl]oxy}methyl)pyridin-2- yl]carbamate
164
methyl [4-({[2-(4-{[(3- bromophenyl)amino]carbonyl}piperazin- 1-yl)pyridin-3-yl]oxy}methyl)pyridin- 2-yl]carbamate
165
methyl {4-[({2-[4-({[3- (methyloxy)phenyl]amino}carbonyl)pipe- razin-1-yl]pyridin-3- yl}oxy)methyl]pyridin-2-yl}carbamate
166
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-[3- (methyloxy)phenyl]piperazine-1- carboxamide
167
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-[3-(1- methylethyl)phenyl]piperazine-1- carboxamide
168
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-{3- [(trifluoromethyl)oxy]phenyl}piperazine- 1-carboxamide
169
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-[2- fluoro-5-(trifluoromethyl)phenyl]piperazine-1- carboxamide
170
N-(3-ethylphenyl)-4-[3-({[2-({[(3- ethylphenyl)amino]carbonyl}amino)pyri- din-4-yl]methyl}oxy)pyridin-2- yl]piperazine-1-carboxamide
171
N-(3-ethylphenyl)-4-(3-{[(2-{[(4- methylpiperazin-1- yl)acetyl]amino}pyridin-4- yl)methyl]oxy}pyridin-2-yl)piperazine- 1-carboxamide
173
N-[3,5-bis(trifluoromethyl)phenyl]-4-(3- {[(2-{[(4-methylpiperazin-1- yl)acetyl]amino}pyridin-4- yl)methyl]oxy}pyridin-2-yl)piperazine- 1-carboxamide
174
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-[3- (trifluoromethyl)phenyl]piperazine-1- carboxamide
175
4-[3-({[2-(acetylamino)pyridin-4- yl]methyl}oxy)pyridin-2-yl]-N-(3- ethylphenyl)piperazine-1-carboxamide
176
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(3-ethyl- 4-fluorophenyl)piperazine-1- carboxamide
177
2-[4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)piperazin-1- yl]-N-[3,5- bis(trifluoromethyl)phenyl]acetamide
178
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N- phenylpiperazine-1-carboxamide
179
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(3- chloro-5-ethylphenyl)piperazine-1- carboxamide
180
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(5-ethyl- 2-fluorophenyl)piperazine-1- carboxamide
181
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(3- bromo-5-ethylphenyl)piperazine-1- carboxamide
182
2-(4-methylpiperazin-1-yl)ethyl [4-({[2- (4-{[(3- ethylphenyl)amino]carbonyl}piperazin- 1-yl)pyridin-3-yl]oxy}methyl)pyridin-2- yl]carbamate
183
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(3- chlorophenyl)piperazine-1-carboxamide
184
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(3- bromophenyl)piperazine-1-carboxamide
185
N-[4-({[2-(4-acetylpiperazin-1- yl)pyridin-3-yl]oxy}methyl)pyridin-2- yl]-2-(4-methylpiperazin-1-yl)acetamide
186
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(3- fluorophenyl)piperazine-1-carboxamide
187
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(4- fluorophenyl)piperazine-1-carboxamide
188
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(2- fluorophenyl)piperazine-1-carboxamide
189
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(3,5- diethylphenyl)piperazine-1-carboxamide
190
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}-5-bromopyridin-2-yl)- N-(3-ethylphenyl)piperazine-1- carboxamide
191
N-methyl-4-(3-{[(2-{[(4- methylpiperazin-1- yl)acetyl]amino}pyridin-4- yl)methyl]oxy}pyridin-2-yl)piperazine- 1-carboxamide
192
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-[2- chloro-5- (trifluoromethyl)phenyl]piperazine-1- carboxamide
193
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(5- chloro-2-fluorophenyl)piperazine-1- carboxamide
194
4-(3-{[(2-amino-5-bromopyrimidin-4- yl)methyl]oxy}-5-bromopyridin-2-yl)- N-(3-ethylphenyl)piperazine-1- carboxamide
195
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-[2- fluoro-3- (trifluoromethyl)phenyl]piperazine-1- carboxamide
196
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-[3- fluoro-5- (trifluoromethyl)phenyl]piperazine-1- carboxamide
197
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(3,5- dichlorophenyl)piperazine-1- carboxamide
198
N-(3-chloro-5-ethylphenyl)-4-(3-{[(2- {[(4-methylpiperazin-1- yl)acetyl]amino}pyridin-4- yl)methyl]oxy}pyridin-2-yl)piperazine- 1-carboxamide
199
N-(5-ethyl-2-fluorophenyl)-4-(3-{[(2- {[(4-methylpiperazin-1- yl)acetyl]amino}pyridin-4- yl)methyl]oxy}pyridin-2-yl)piperazine- 1-carboxamide
200
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-[3-ethyl- 5-(trifluoromethyl)phenyl]piperazine-1- carboxamide
204
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N- methylpiperazine-1-carboxamide
205
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N- ethylpiperazine-1-carboxamide
206
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N- cyclohexylpiperazine-1-carboxamide
207
4-({[2-(4-acetylpiperazin-1-yl)pyridin- 3-yl]oxy}methyl)pyrimidin-2-amine
208
4-({[2-(4-propanoylpiperazin-1- yl)pyridin-3-yl]oxy}methyl)pyrimidin- 2-amine
209
N-(3-cyclopropylphenyl)-4-(3-{[(2- {[(4-methylpiperazin-1- yl)acetyl]amino}pyridin-4- yl)methyl]oxy}pyridin-2-yl)piperazine- 1-carboxamide
210
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(3- cyclopropylphenyl)piperazine-1- carboxamide
211
N-[2-fluoro-5-(trifluoromethyl)phenyl]- 4-(3-{[(2-{[(4-methylpiperazin-1- yl)acetyl]amino}pyridin-4- yl)methyl]oxy}pyridin-2-yl)piperazine- 1-carboxamide
212
N-[3-fluoro-5-(trifluoromethyl)phenyl]- 4-(3-{[(2-{[(4-methylpiperazin-1- yl)acetyl]amino}pyridin-4- yl)methyl]oxy}pyridin-2-yl)piperazine- 1-carboxamide
213
N-(3,5-dichlorophenyl)-4-(3-{[(2-{[(4- methylpiperazin-1- yl)acetyl]amino}pyridin-4- yl)methyl]oxy}pyridin-2-yl)piperazine- 1-carboxamide
214
4-(3-{[(2-{[(4-methylpiperazin-1- yl)acetyl]amino}pyridin-4- yl)methyl]oxy}pyridin-2-yl)-N-[3- (trifluoromethyl)phenyl]piperazine-1- carboxamide
216
4-(3-{[1-(2-aminopyrimidin-4- yl)ethyl]oxy}pyridin-2-yl)-N-[3,5- bis(trifluoromethyl)phenyl]piperazine-1- carboxamide
219
4-[({2-[4-(3,4-dihydroquinolin-1(2H)- ylcarbonyl)piperazin-1-yl]pyridin-3- yl}oxy)methyl]pyrimidin-2-amine
220
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(2- methylpropyl)piperazine-1-carboxamide
226
N-(3,5-diethylphenyl)-4-(3-{[(2-{[(4- methylpiperazin-1- yl)acetyl]amino}pyridin-4- yl)oxy]methyl}pyridin-2-yl)piperazine- 1-carboxamide
227
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}-6-methylpyridin-2-yl)- N-(3-ethylphenyl)piperazine-1- carboxamide
228
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}-6-methylpyridin-2-yl)- N-[3,5- bis(trifluoromethyl)phenyl]piperazine-1- carboxamide
233
N-[3-chloro-5-(trifluoromethyl)phenyl]- 4-(3-{[(2-{[(4-methylpiperazin-1- yl)acetyl]amino}pyridin-4- yl)methyl]oxy}pyridin-2-yl)piperazine- 1-carboxamide
235
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-[3- chloro-5- (trifluoromethyl)phenyl]piperazine-1- carboxamide
237
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}-6-chloropyridin-2-yl)- N-(3-ethylphenyl)piperazine-1- carboxamide
243
N-[3-chloro-2-fluoro-5- (trifluoromethyl)phenyl]-4-(3-{[(2-{[(4- methylpiperazin-1- yl)acetyl]amino}pyridin-4- yl)methyl]oxy}pyridin-2-yl)piperazine- 1-carboxamide
244
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}-6-chloropyridin-2-yl)- N-[3,5- bis(trifluoromethyl)phenyl]piperazine-1- carboxamide
245
4-(3-{[1-(2-aminopyrimidin-4- yl)ethyl]oxy}pyridin-2-yl)-N-(3- ethylphenyl)piperazine-1-carboxamide
246
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}-6-chloropyridin-2-yl)- N-(5-ethyl-2-fluorophenyl)piperazine-1- carboxamide
247
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(3-ethyl- 5-fluorophenyl)piperazine-1- carboxamide
249
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-[3- chloro-2-fluoro-5- (trifluoromethyl)phenyl]piperazine-1- carboxamide
250
4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-[3,5- bis(trifluoromethyl)phenyl]-N- methylpiperazine-1-carboxamide

136 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/549,300Filed 19 Mar 2004 · us provisional application
Priority: 19 Mar 2003
Published: US 2007/0275952 A129 Nov 2007
Granted: 6 Sep 2011
Term ends: Not estimatedThe source records don’t support an estimate.

Classification22 codes

A61K 31/496
Having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines: non-condensed piperazines…
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…
A61P 17/06
Drugs for dermatological disorders: antipsoriatics