Inhibitors of human tumor-expressed CCXCKR2
AssigneeChemoCentryx, Inc.
InventorsAnita Melikian, Jennifer Burns, Brian E. McMaster, Thomas Schall, J.J. Wright
Life of this patent
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Abstract
Pharmaceutical compositions containing organic compounds or salts thereof that serve as modulators for the SDF-1 or I-TAC chemokines are disclosed. The compounds and compositions are useful in the treatment of cancer, especially in the inhibition of cancer proliferation, growth, and metastasis. Methods of interfering with SDF-1 and/or I-TAC binding to the CCXCKR2 receptor and treating cancer using the compounds and pharmaceutical compositions of the present invention are also disclosed.
Claims38
A modulator of the structure (I), or a salt thereof:
- 215
- where m is an integer from 1 to 5;
- each Y is independently selected from the group consisting of hydrogen, halogen, —CN, —NO2, —OH, —OR′, —C(O)R′, —CO2R′, —O(CO)R′, —C(O)NR′R″, —OC(O)NR′R″, —SR′, —SOR′, —SO2R′, —SO2NR′R″, —NR′R″, —NR′C(O)R″, —NR′C(O)2R″, —NR′SO2R″, —NR′(CO)NR″R′″, unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted C3-8 cycloalkyl, unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5- to 10-membered heteroaryl, and unsubstituted or substituted 3- to 10-membered heterocyclyl;
- where each R′, R″ and R′″ are independently hydrogen, halogen, unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5- to 10-membered heteroaryl, and unsubstituted or substituted 3- to 10-membered heterocyclyl;
- n is 0, 1, 2 or 3;
- Z is —CHR1R2—, —OR1, or —NR1R2;
- R1 and R2 are each independently substituted or unsubstituted alkyl or hydrogen, or Z in combination with R1 and R2 form a substituted or unsubstituted 5- to 8-membered ring comprising at least one nitrogen and 0 to 3 additional heteroatoms;
- R6 is alkyl, hydrogen, or halogen;
- and
- R3, R4, and R5 are each independently selected from the group consisting of hydrogen, halogen, —CN, —NO2, —OH, —OR′, —C(O)R′, —CO2R′, —O(CO)R′, —C(O)NR′R″, —OC(O)NR′R″, —SR′, —SOR′, —SO2R′, —SO2NR′R″, —NR′R″, —NR′C(O)R″, —NR′C(O)2R″, —NR′SO2R″, —NR′(CO)NR″R′″, unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted C3-8 cycloalkyl, unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5- to 10-membered heteroaryl, and unsubstituted or substituted 3- to 10-membered heterocyclyl, or where any two of R3, R4 or R5 together with the atoms which they substituted form a substituted or unsubstituted 3- to 10-membered heterocycyl.
A modulator having the structure (II):
- 222
- where n=0-4
- where each Y is independently hydrogen or halogen;
- R3, R4, and R5 are each independently R3, R4, and R5 are each independently selected from the group consisting of hydrogen, halogen, and —OR′;
- or any two of R3, R4, and R5, together with the atoms which they substituted, form unsubstituted or substituted 3- to 10-membered heterocyclyl;
- and
- R7 is selected from the group consisting of hydrogen, —C(O)R′, —CO2R′, —C(O)NR′R″, —SO2R′, unsubstituted or substituted C1-8 alkyl (optionally C1-8 alkoxyalkyloxy, CH2CH2OCH2CH2OMe)alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted C3-8 cycloalkyl, unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5- to 10-membered heteroaryl, and unsubstituted or substituted 3- to 10-membered heterocyclyl.
A modulator comprising one of the following formulae:
- 3 1 223 2 224 3 225 4 226 5 227 6 228 7 229 8 230 9 231 10 232 11 233 12 234 13 235 14 236 15 237 16 238 17 239 18 240 19 241 20 242 21 243 22 244 23 245 24 246 25 247 26 248 27 249 28 250 29 251 30 252 31 253 32 254 33 255 34 256 35 257 36 258 37 259 38 260 39 261 40 262 41 263 42 264 43 265 44 266 45 267 46 268 47 269 48 270 49 271 50 272 51 273 52 274 53 275 54 276 55 277 56 278 57 279 58 280 59 281 60 282 61 283 62 284 63 285 64 286 65 287 66 288 67 289 68 290 69 291 70 292 71 293 72 294 73 295 74 296 75 297 76 298 77 299 78 300 79 301 80 302 81 303 82 304 83 305 84 306 85 307 86 308 87 309 88 310 89 311 90 312 91 313 92 314 93 315 94 316 95 317 96 318 97 319 98 320 99 321 100 322 101 323 102 324 103 325 104 326 105 327 106 328
A pharmaceutical composition comprising the modulator of claim and a pharmaceutically acceptable carrier.
A pharmaceutical composition comprising a compound of the formulae:
- 329 330 331
- and a pharmaceutically acceptable carrier.
A method of inhibiting the binding of chemokines I-TAC and/or SDF-1 to a CCXCKR2 receptor, comprising contacting the composition of claim 3234 with a cell that expresses the CCXCKR2 receptor for a time sufficient to inhibit the binding of the chemokines to the CCXCKR2 receptor.
A method of treating cancer, comprising administering a therapeutically effective amount of the composition of claim 3234 to a cancer patient for a time sufficient to treat the cancer.
Dependencies are inferred from the claim text.