Tie-2 modulators and methods of use

1. 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 R 1 ;

each R 1 is independently selected from —H, halogen, —CN, —NO 2 , —OR 3 , —N(R 3 )R 3 , —S(O) 0-2 R 3 , —SO 2 N(R 3 )R 3 , —CO 2 R 3 , —C(O)N(R 3 )R 3 , —N(R 3 )SO 2 R 3 , —N(R 3 )C(O)R 3 , —N(R 3 )CO 2 R 3 , —C(O)R 3 , —OC(O)R 3 , 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 R 4a is —C(O)N(R 3 )R 3 ;

n=1 or 2;

p=0 or 1;

q is 1 to 3;

M is −OR 3 or —N(R 3 )R 4 ;

each R 2 is independently selected from —H, haloalkyl, —C 1-6 alkyl-N(R 3 )R 3 , —C 1-6 alkyl-OR 3 , —C 1-6 alkyl-CO 2 R 3 , and —C 1-6 alkyl-C(O)N(R 3 )R 3 ;

each R 3 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 R 3 , 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 R 4 is independently selected from R 3 , —SO 2 R 3 , —SO 2 N(R 3 )R 3 , —CO 2 R 3 , —C(O)N(R 3 )R 3 , and —C(O)R 3 ;

Y-L-Z is selected from the following formulae,

wherein g is zero to two; T is selected from absent, —N(R 3 )—, —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 —CH 2 —;

R 5 is selected from —H, halogen, —CN, —NO 2 , —OR 3 , —N(R 3 )R 4 , —S(O) 0-2 R 3 , —SO 2 N(R 3 )R 3 , —CO 2 R 3 , —C(O)N(R 3 )R 3 , —N(R 3 )SO 2 R 3 , —N(R 3 )C(O)R 3 , —N(R 3 )CO 2 R 3 , —C(O)R 3 , optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl; and

optionally two of R 5 , 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 R 5 .

2. The compound according to claim 1 , wherein g is one or two.

3. The compound according to claim 2 , wherein each R 5 is independently selected from —H, halogen, —CN, —NH 2 , —NO 2 , —OR 3 , —N(R 3 )R 4 , —S(O) 0-2 R 3 , —SO 2 N(R 3 )R 3 , —CO 2 R 3 , —C(O)N(R 3 )R 3 , —N(R 3 )SO 2 R 3 , —N(R 3 )C(O)R 3 , —N(R 3 )CO 2 R 3 , —C(O)R 3 , and optionally substituted lower alkyl.

4. The compound according to claim 3 , wherein —Y-L-Z is selected from the following formulae

wherein R 4b is selected from R 3 , H, CO 2 R 3 , C(O)N(R 3 )R 3 , and C(O)R 3 .

5. The compound according to claim 4 , having formula III,

wherein J is N, and B is ═N— or ═C(R 5 )—. R 3a is selected from optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl;

R 3b is H, and

R 4b is R 3 , —H, —CO 2 R 3 , —C(O)N(R 3 )R 4 , or —C(O)R 3 .

6. The compound according to claim 5 , wherein R 3a is selected from optionally substituted aryl and optionally substituted heteroaryl.

7. The compound according to claim 6 , wherein R 3a is optionally substituted phenyl.

8. The compound according to claim 7 , wherein said optionally substituted phenyl is substituted with at least one of halogen, —CN, —CF 3 , —NH 2 , —NO 2 , —OR 3 , —N(R 3 )R 3 , —S(O) 0-2 R 3 , —SO 2 N(R 3 )R 3 , —CO 2 R 3 , —C(O)N(R 3 )R 3 , —N(R 3 )SO 2 R 3 , —N(R 3 )C(O)R 3 , —N(R 3 )CO 2 R 3 , —C(O)R 3 , optionally substituted lower alkyl, and optionally substituted aryl.

9. The compound according to claim 8 , wherein said optionally substituted phenyl group is substituted with at least one trifluoromethyl group.

10. The compound according to claim 9 , wherein said optionally substituted phenyl group is substituted with at least two trifluoromethyl groups.

11. The compound according to claim 8 , wherein said optionally substituted phenyl group is substituted with at least one lower alkyl group.

12. The compound according to claim 8 , wherein R 3b is —H.

13. The compound according to claim 12 , wherein R 4b is selected from R 3 , —H, —CO 2 R 3 , —C(O)N(R 3 )R 4 , and —C(O)R 3 .

14. The compound according to claim 13 , wherein Ar is according to the formula below

15. The compound according to claim 13 , wherein Ar is according to the formula below

16. A compound of Formula IV,

or a pharmaceutically acceptable salt thereof, wherein,

Ar is selected from the following formulae:

each R 1 is independently selected from —H, halogen, —CN, —NO 2 , —OR 3 , —N(R 3 )R 3 , —S(O) 0-2 R 3 , —SO 2 N(R 3 )R 3 , —CO 2 R 3 , —C(O)N(R 3 )R 3 , —N(R 3 )SO 2 R 3 , —N(R 3 )C(O)R 3 , —N(R 3 )CO 2 R 3 , —C(O)R 3 , optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl;

optionally two of R 1 , 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 R 1 ;

each R 2 is independently selected from —H, halogen, oxo, —CN, —NH 2 , —NO 2 , —OR 3 , —N(R 3 )R 3 , —N(R 3 )R 5 , —S(O) 0-2 R 3 , —SO 2 N(R 3 )R 3 , —CO 2 R 3 , —C(O)N(R 3 )R 3 , —N(R 3 )SO 2 R 3 , —N(R 3 )C(O)R 3 , —N(R 3 )CO 2 R 3 , —N(R 3 )C(O)N(R 3 )R 3 , —C(O)R 3 , optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl;

two of R 2 , together with the atoms to which they are attached, can form an optionally substituted three- to seven-membered ring system;

each R 3 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 R 3 , 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 R 4 is independently selected from R 3 , —SO 2 R 3 , —SO 2 N(R 3 )R 3 , —CO 2 R 3 , —C(O)N(R 3 )R 3 , and —C(O)R 3 ;

Y is selected from optionally substituted —CH 2 —, —O—, —S—, and —N(R 3 )—;

L is selected from optionally substituted —CH 2 —, —O—, —S—, —N(R 3 )— and absent;

provided that Y and L are not both heteroatoms;

B is ═N— or ═C(H)—;

at each instance, R 5 and R 6 are independently selected from —H, halogen, —CN, —NO 2 , —OR 3 , —N(R 3 )R 4 , —S(O) 0-2 R 3 , —SO 2 N(R 3 )R 3 , —CO 2 R 3 , —C(O)N(R 3 )R, —N(R 3 )SO 2 R 3 , —N(R 3 )C(O)R 3 , —N(R 3 )CO 2 R 3 , —C(O)R 3 , optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl; and

optionally two of R 5 , 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 R 5 .

17. The compound according to claim 16 , wherein Y is —O— and L is optionally substituted —CH 2 —.

18. The compound according to claim 17 , wherein at least one of R 6 is optionally substituted lower alkyl.

19. The compound according to claim 18 , wherein said at least one optionally substituted lower alkyl is meta- to the piperazine urea function as depicted in formula IV.

20. The compound according to claim 19 , wherein R 4a is selected from R 3 , —H, —CO 2 R 3 , —C(O)N(R 3 )R 4 , and —C(O)R 3 .

21. The compound according to claim 20 , wherein R 4a is selected from —H, —CO 2 R 3 , —C(O)N(R 3 )R 4 , and —C(O)R 3 .

22. The compound according to claim 21 , wherein —Y-L- is —OCH 2 —.

23. The compound according to claim 22 , wherein Ar is according to the formula below

24. The compound according to claim 22 , wherein Ar is according to the formula below

25. 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

26. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier.