Prmt5 inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-2016137631-A1
Application number	US-201514882638-A
Country	US
Kind code	A1
Filing date	Oct 14, 2015
Priority date	Dec 21, 2012
Publication date	May 19, 2016
Grant date	—

Abstract

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention are useful for inhibiting PRMT5 activity. Methods of using the compounds for treating PRMT5-mediated disorders are also described.

First claim

1 - 214 . (canceled)

215 . A compound of formula (IV D ):

or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is hydrogen, R z , or —C(O)R z , wherein R z is optionally substituted C 1-6 alkyl;
R 4 is -L-Cy D ;
L 1 is a bond, —O—, —S—, —N(R)—, —C(O)—, —C(O)N(R)—, —N(R)C(O)N(R)—, —N(R)C(O)—, —N(R)C(O)O—, —OC(O)N(R)—, —SO 2 —, —SO 2 N(R)—, —N(R)SO 2 —, —OC(O)—, —C(O)O—, or an optionally substituted, straight or branched, C 1-6 aliphatic chain wherein one, two, or three methylene units of L 1 are optionally and independently replaced by —O—, —S—, —N(R)—, —C(O)—, —C(O)N(R)—, —N(R)C(O)N(R)—, —N(R)C(O)—, —N(R)C(O)O—, —OC(O)N(R)—, —SO 2 —, —SO 2 N(R)—, —N(R)SO 2 —, —OC(O)—, or —C(O)O—;
each R is independently hydrogen or optionally substituted C 1-6 aliphatic;
Cy D is an optionally substituted, monocyclic, bicyclic or tricyclic, saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R 5B , R 6B , R 7B , and R 8B are independently hydrogen, halo, or optionally substituted aliphatic;
each R x is independently selected from the group consisting of halo, —CN, optionally substituted aliphatic, and —OR′;
R′ is hydrogen or optionally substituted aliphatic;
n is 0 or 1; and
m is 0.

216 - 227 . (canceled)

228 . The compound of claim 215 , wherein the compound is of formula (IV D -a):

or a pharmaceutically acceptable salt thereof.

229 . The compound of claim 215 , wherein the compound is of formula (IV D -b):

or a pharmaceutically acceptable salt thereof.

230 . The compound of claim 215 , herein the compound is of formula (IV D -e):

or a pharmaceutically acceptable salt thereof.

231 - 234 . (canceled)

235 . The compound of claim 215 , wherein R 1 is hydrogen.

236 . The compound of claim 215 , wherein n is 0.

237 . The compound of claim 215 , wherein n is 1.

238 - 258 . (canceled)

259 . The compound of claim 215 , wherein the compound is of formula (VI D ):

or a pharmaceutically acceptable salt thereof, wherein L D is —O—.

260 - 261 . (canceled)

262 . The compound of claim 215 , wherein the compound is of formula (VI D -c):

or a pharmaceutically acceptable salt thereof.

263 - 278 . (canceled)

279 . The compound of claim 215 , wherein L 1 is a bond.

280 . The compound of claim 215 , wherein L 1 is an optionally substituted, straight or branched, C 1-3 aliphatic chain wherein one methylene unit of L 1 is re laced by —N(R)—.

281 . The compound of claim 215 , wherein Cy D is an optionally substituted 5- to 6-membered carbocyclic ring.

282 - 283 . (canceled)

284 . The compound of claim 215 , wherein Cy D is an optionally substituted 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

285 . The compound of claim 284 , wherein Cy D is optionally substituted indazole, optionally substituted quinoline, optionally substituted benzimidazole, optionally substituted benzothiazole, optionally substituted deazapurine, optionally substituted indole, optionally substituted purine, optionally substituted pyrazolopyridine, optionally substituted pyrrolopyridine, optionally substituted pyrrolopyrimidine, optionally substituted imidazopyridine, or optionally substituted imidazopyridine.

286 . The compound of claim 215 , wherein the compound is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

287 . A pharmaceutical composition comprising a compound of claim 215 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

288 . A kit or packaged pharmaceutical comprising a compound of claim 215 , or a pharmaceutically acceptable salt thereof, and instructions for use thereof.

289 . A method of inhibiting PRMT5 comprising contacting a cell with an effective amount of a compound of claim 215 or a pharmaceutically acceptable salt thereof.

290 . A method of altering gene expression comprising contacting a cell with an effective amount of a compound of claim 215 or a pharmaceutically acceptable salt thereof.

291 . A method of altering transcription comprising contacting a cell with an effective amount of a compound of claim 215 or a pharmaceutically acceptable salt thereof.

292 - 293 . (canceled)

294 . A method of treating a PRMT5-mediated disorder, comprising administering to a, subject in need thereof a therapeutically effective amount of a, compound of claim 215 , or a pharmaceutically acceptable salt thereof.

295 . (canceled)

296 . The method of claim 294 , wherein the disorder is cancer metabolic disorder, or a blood disorder.

297 . The method of claim 296 , wherein the disorder is cancer, and the cancer is a hematopoietic cancer, lung cancer, prostate cancer, melanoma, or pancreatic cancer.

298 . (canceled)

299 . The method of claim 296 , wherein the disorder is a metabolic disorder, and the metabolic disorder is diabetes or obesity.

300 - 301 . (canceled)

302 . The method of claim 296 , wherein the disorder is a blood disorder, and the blood disorder is a hemoglobinopathy.

303 . The method of claim 302 , wherein the hemoglobinopathy is sickle cell anemia or β-thalessemia.

304 . (canceled)

Assignees

• Epizyme Inc

Inventors

• Duncan Kenneth W
• Chesworth Richard
• Boriack-Sjodin Paula Ann
• Munchhof Michael John

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P7/06

  Antianaemics · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title