IP Library › Granted Patent US 12679843

Granted Patent B2

US 12679843 · App. 17/915,179 · Granted Jul 14, 2026

Pyrrolopyrimidine amines as complement inhibitors

Inventors: Pravin L. Kotian (Hoover, AL); Yarlagadda S. Babu (Birmingham, AL); Minwan Wu (Vestavia Hills, AL); Zhao Dang (Vestavia Hills, AL); Trung Xuan Nguyen (Hoover, AL); Krishnan Raman (Birmingham, AL)

Assignee: BioCryst Pharmaceuticals, Inc.

C07D487/04 C07D401/14 C07D471/04 C07D471/14

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Quick Facts

Patent No.: US 12679843
App. No.: 17/915,179
Granted: Jul 14, 2026
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

Abstract

Disclosed are compounds of formula (I), and pharmaceutically acceptable salts thereof, which are inhibitors of the complement system. Also provided are pharmaceutical compositions comprising such a compound, and methods of using the compounds and compositions in the treatment or prevention of a disease or condition characterized by aberrant complement system activity.

Claims (513)

1 . A compound represented by Formula (I), or a pharmaceutically acceptable salt thereof:

wherein, independently for each occurrence:

X is a bond or C(R X ) 2 ;

Y is a bond, C(R Y ) 2 , or —N(R b )—;

G is S or C(R 3 ) 2 ;

R a and R b are each independently H or (C 1 -C 6 )alkyl;

R 1 represents optionally substituted aryl or heteroaryl;

R 2 represents

R 3 is independently for each occurrence H, halogen, —CN, —NH 2 , —CH 2 NH 2 , (C 1 -C 6 )alkoxy or (C 1 -C 6 )alkyl; or two vicinal occurrences of R 3 taken together with the carbon atoms to which they are bonded form an optionally substituted fused (C 3 -C 7 )cycloalkyl or (C 6 )aryl; or two geminal occurrences of R 3 taken together with the carbon atom to which they are bonded form an optionally substituted spiro (C 3 -C 7 )cycloalkyl; or two hominal occurrences of R 3 taken together with the carbon atoms to which they are bonded form an optionally substituted bridged (C 3 -C 7 )cycloalkyl;

R X is independently for each occurrence H, (C 1 -C 6 )alkyl, or (C 3 -C 7 )cycloalkyl;

R Y is independently for each occurrence H, (C 1 -C 6 )alkyl, or (C 3 -C 7 )cycloalkyl;

optional substituents on R 1 each independently represent halogen, —CN, —NO 2 , —OR 13 , —NR 13 R 14 , —C(O)R 13 , —C(O)OR 13 , —C(O)NR 13 R 14 , —OC(O)R 13 , —NR 13 C(O)R 14 , —OC(O)NR 13 R 14 , —OC(O)OR 13 , —NR 13 C(O)OR 14 , —NR 13 C(O)NR 13 R 14 , —OS(O) p (R 13 ), —SR 13 , —NR 13 S(O) p (R 14 ), or optionally substituted alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkoxyalkyl, aryloxyalkyl, aralkyl, heteroaralkyl, heteroaryl, aryl, aryloxy, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, or (heterocycloalkyl)alkyl;

or wherein two substituents on R 1 , taken together with the intervening atoms, form a ring;

R 13 and R 14 , independently for each occurrence, represent H or optionally substituted alkyl, haloalkyl, alkenyl, alkynyl, aryl, or heteroaryl;

p is 0, 1, or 2;

Z 3 represents N;

Z 4 represents N or CR 4Z ;

Z 5 represents N or CR 5Z ;

Z 6 represents N or CR 6Z ;

Z 7 represents N or CR 7Z ;

Z 8 represents C;

Z 9 represents N or C;

k is an integer from 1-4;

m is an integer from 1-3; and

each occurrence of R 4Z , R 5Z , R 6Z , R 7Z , R 2A independently represents H, halogen, —CN, —NO 2 , —OR 13 , —NR 13 R 14 , —C(O)R 13 , —C(O)OR 13 , —C(O)NR 13 R 14 , —OC(O)R 13 , —NR 13 C(O)R 14 , —OC(O)NR 13 R 14 , —OC(O)OR 13 , —NR 13 C(O)OR 14 , —NR 13 C(O)NR 13 R 14 , —OS(O) p (R 13 ), —SR 13 , —NR 13 S(O) p (R 14 ), or optionally substituted alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkoxyalkyl, aryloxyalkyl, aralkyl, heteroaralkyl, heteroaryl, aryl, aryloxy, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, or (heterocycloalkyl)alkyl; or

wherein an occurrence of R 6Z and an occurrence of R 7Z taken together with the intervening atoms form a ring.

2 . The compound of claim 1 , wherein Y represents C(R Y ) 2 .

3 . The compound of claim 1 , wherein Y represents CH 2 .

4 . The compound of claim 1 , wherein X represents a bond.

5 . The compound of claim 1 , wherein X represents CH 2 .

6 . The compound of claim 1 , wherein R 1 represents optionally substituted heteroaryl.

7 . The compound of claim 1 , wherein R 1 represents optionally substituted phenyl (e.g., 3-halophenyl, or 2,3-dihalophenyl), pyridinyl (e.g., 6-halopyridin-2-yl), or pyrazinyl (e.g., 6-halopyrazin-2-yl).

8 . The compound of claim 1 , wherein R 1 represents

9 . The compound of claim 1 , wherein R 1 represents

10 . The compound of claim 1 , wherein R 2 represents

11 . The compound of claim 10 , wherein R 2 represents

12 . The compound of claim 10 , wherein k represents 2.

13 . The compound of claim 1 , wherein R 2 represents

14 . The compound of claim 1 , wherein R 7Z represents —NR 13 R 14 .

15 . The compound of claim 1 , wherein R 7Z represents —NH 2 .

16 . The compound of claim 1 , wherein R 6Z represents —C(O)R 13 , —C(O)OR 13 , —C(O)NR 13 R 14 , or hydroxyalkyl.

17 . The compound of claim 1 , wherein R 5Z represents alkyl, halo, or —NR 13 R 14 .

18 . The compound of claim 1 , wherein R 1Z represents —CN, halo, haloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, —C(O)R 13 , —SR 13 , —NR 13 R 14 , —OR 13 , —C(O)OR 13 , —C(O)NR 13 R 14 , or —NR 13 C(O)R 14 .

19 . The compound of claim 1 , wherein each occurrence of R 2A independently represents —CN, —NO 2 , halo, haloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted hydroxyalkyl, —C(O)R 13 , —C(O)OR 13 , —NR 13 C(O)OR 14 , —SR 13 , —NR 13 R 14 , —OR 13 , —C(O)NR 13 R 14 , or —NR 13 C(O)R 14 .

20 . The compound of claim 1 , wherein G is C(R 3 ) 2 .

21 . The compound of claim 1 , having the structure of formula (Ia):

22 . The compound of claim 1 , wherein two vicinal occurrences of R 3 taken together with the carbon atoms to which they are bonded form an optionally substituted fused C 3 -cycloalkyl.

23 . The compound of claim 1 , wherein at least one occurrence of R 3 is halo.

24 . The compound of claim 1 , wherein at least one occurrence of R 3 is methyl.

25 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from the following table:

Structure

20a

24a

19a

50f

32f

43a

35f

30f

47g

48d

21a

38e

27a

51g

25a

52f

26a

54g

44a

28a

29f

10b

22c and 22d

11f

33e

12a

49c

34e

58c

13b

59c

14a

17f

15a

18a

37a

31f

218a

60c

223a

61a

224b

46g

225e

62c

226c

63d

219a

53d

227c

55a

228a

56g

57g

229c

159a

230a

160a

231g

171b

246b

172a

247d

173a

248d

161a

232a

174g

234a

175a

267c

176a

268b

169f

269c

177d

274g

178d

276g

162g

277a

163g

278g

164a

279a

165a

280g

170c

281a

179d

282a

180e

283g

166a

292a

167a

297d

168g

299a

187c

301a

188g

303a

195e

304a

198a

308c

199a

310a

200a

317c

194a

319c

201e

321d

211e

334a

212e

313b

181a

312a

182a

324a

183a

325c

207b

327c

208d

329a

203a

331a

204a

337a

184g

316a

185a

344c

186a

346g

206c

338e

209b

348c

210d

350a

189g

332c

193a

365c

190a

352c

191a

354c

192g

340a

196d

342a

197c

357a

214b

359c

213d

361a

215g

368a

216g

362f

217a

364e

220a

381g

202a

385a

205c

386g

222a

383g

236f

389g

237a

376g

238g

379h

239a

374g

296a

391g

240g

370a

241g

371c

242a

373a

243a

307c

244d

305a

245a

309a

42a

311a

16e

318c

36e

320c

39f

322c

23f

335c

40a

314a

323a

45d

306a

41f

326c

221c

328f

250b

330f

270a

336c

271c

315a

249a

343a

252a

345c

253a

347a

254a

339g

263c

349c

272c

351a

255c

333c

256a

366c

273c

353a

257g

355a

258a

341c

259d

356c

260a

358c

261d

360c

262a

367g

264a

369g

265a

363a

266b

364d

275c

382a

284a

384g

285g

387a

286a

388a

287a

390a

288c

377a

289a

380a

290g

375a

291a

392a

295a

378c

298c

372a

300a

302a

26 . A pharmaceutical composition, comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

27 . A method of treating e a disease or condition characterized by aberrant complement system activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof;

wherein the disease or condition characterized by aberrant complement system activity is selected from the group consisting of paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, organ transplant rejection, myasthenia gravis, neuromyelitis optica, membranoproliferative glomerulonephritis, dense-deposit disease, cold agglutinin disease, catastrophic antiphospholipid syndrome, adult respiratory distress syndrome, myocardial infarct, lung inflammation, sepsis, cardiopulmonary bypass, burns, asthma, restenosis, multiple organ dysfunction, Guillain-Barré syndrome, hemorrhagic shock, glomerulonephritis, systemic lupus erythematosus, rheumatoid arthritis, infertility, Alzheimer's disease, multiple sclerosis, platelet storage, hemodialysis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), warm autoimmune hemolytic anemia, IgA nephropathy, C3 glomerulonephritis, focal segmental glomerulosclerosis, macular degeneration, age-related macular degeneration (AMD), wet AMD, geographic atrophy, macular edema, diabetic macular edema, choroidal neovascularization (CNV), uveitis, Behcet's uveitis, proliferative diabetic retinopathy, non-proliferative diabetic retinopathy, glaucoma, hypertensive retinopathy, a corneal neovascularization disease, post-corneal transplant rejection, a corneal dystrophic disease, an autoimmune dry eye disease, Stevens-Johnson syndrome, Sjogren's syndrome, an environmental dry eye disease, Fuchs' endothelial dystrophy, retinal vein occlusion, post-operative inflammation, obesity, insulin resistance, diabetes, dyslipidemia, nephropathy, neuropathy, angioedema, hereditary angioedema or acquired angioedema, thrombotic microangiopathy, generalized myasthenia gravis, Parkinson's disease, schizophrenia, periodontitis, Crohn's disease, chronic obstructive pulmonary disease, acute respiratory distress syndrome, atherosclerosis, C3 glomerulopathy, membranous nephropathy, lupus nephritis, osteoarthritis, bullous pemphigoid, psoriasis, hidradenitis suppurativa, ischemia/reperfusion injury, acute kidney injury, organ transplantation, kidney transplant, systemic inflammatory response syndrome, septic shock, trauma, cancer, antibody-mediated rejection, antiphospholipid syndrome, Berger's disease, delayed graft function, granulomatosis with polyangiitis, graft versus host disease, hematopoietic stem cell transplant-related thrombotic microangiopathy, immune complex-mediated membranoproliferative glomerulonephritis, immune-mediated necrotizing myopathy, idiopathic polypoidal choroidal vasculopathy, microscopic polyangiitis, pyoderma gangrenosum, and Stargardt Disease 1.

28 . A compound represented by Formula (I-b), or a pharmaceutically acceptable salt thereof:

wherein, independently for each occurrence:

X is a bond or C(R X ) 2 ;

Y is a bond, C(R Y ) 2 , or —N(R b )—;

G is S or C(R 3 ) 2 ;

R a and R b are each independently H or (C 1 -C 6 )alkyl;

R 1 represents optionally substituted aryl or heteroaryl;

R 2 represents

R X is independently for each occurrence H, (C 1 -C 6 )alkyl, or (C 3 -C 7 )cycloalkyl;

R Y is independently for each occurrence H, (C 1 -C 6 )alkyl, or (C 3 -C 7 )cycloalkyl;

or wherein two substituents on R 1 , taken together with the intervening atoms, form a ring;

R 13 and R 14 , independently for each occurrence, represent H or optionally substituted alkyl, haloalkyl, alkenyl, alkynyl, aryl, or heteroaryl;

p is 0, 1, or 2;

Z 1 represents N or CR 1Z ;

Z 2 represents N or CR 2Z ;

Z 3 represents N or C;

Z 4 represents N;

Z 5 represents N or CR 5Z ;

Z 6 represents N;

Z 7 represents N or CR 7Z ;

Z 8 represents C;

Z 9 represents N or C;

R 7Z represents —NR 13 R 14 ;

m is an integer selected from 1-3; and

each occurrence of R 1Z , R 2Z , R 5Z , and R 2A independently represents H, halogen, —CN, —NO 2 , —OR 13 , —NR 13 R 14 , —C(O)R 13 , —C(O)OR 13 , —C(O)NR 13 R 14 , —OC(O)R 13 , —NR 13 C(O)R 14 , —OC(O)NR 13 R 14 , —OC(O)OR 13 , —NR 13 C(O)OR 14 , —NR 13 C(O)NR 13 R 14 , —OS(O) p (R 13 ), —SR 13 , —NR 13 S(O) p (R 14 ), or optionally substituted alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkoxyalkyl, aryloxyalkyl, aralkyl, heteroaralkyl, heteroaryl, aryl, aryloxy, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, or (heterocycloalkyl)alkyl; or

wherein an occurrence of R Y and an occurrence of R 2Z taken together with the intervening atoms form a ring.

29 . The compound of claim 28 , or a pharmaceutically acceptable salt thereof, selected from the following table:

Structure

75d

76b

158e

77b

78a

79a

81a

80a

82a

86b

87f

84a

90d

101b

91a

92b

93a

104a

105b

96e

107b

108b

109e

110d

123g

112b

118a

119a

117d

120c

116b

121d

115e

122c

68a

114f

67c

113a

65a

66b

64a

124b

130e

132d

133b

138d

134b

139b

135a

125d

136a

126f

137b

142d

140a

143d

141a

148d

146a

149b

150d

152d

69a

153a

70a

71a

154e

72a

73a

74a

233h

293a and 293b

30 . The compound of claim 28 , wherein Y represents C(R Y ) 2 .

31 . The compound of claim 28 , wherein Y represents CH 2 .

32 . The compound of claim 28 , wherein X represents a bond.

33 . The compound of claim 28 , wherein X represents CH 2 .

34 . The compound of claim 28 , wherein R 1 represents optionally substituted heteroaryl.

35 . The compound of claim 28 , wherein R 1 represents optionally substituted phenyl (e.g., 3-halophenyl, or 2,3-dihalophenyl), pyridinyl (e.g., 6-halopyridin-2-yl), or pyrazinyl (e.g., 6-halopyrazin-2-yl).

36 . The compound of claim 28 , wherein R 1 represents

37 . The compound of claim 28 , wherein R 1 represents

38 . The compound of claim 28 , wherein R 2 represents

39 . The compound of claim 28 , wherein R 2 represents

40 . The compound of claim 28 , wherein R 2 represents

41 . The compound of claim 28 , wherein R 2 represents

42 . The compound of claim 28 , wherein R 2 represents

43 . The compound of claim 42 , wherein R 2 represents

44 . The compound of claim 28 , wherein R 7Z represents —NH 2 .

45 . The compound of claim 28 , wherein R 5Z represents alkyl, halo, or —NR 13 R 14 .

46 . The compound of claim 28 , wherein R 1Z represents —CN, halo, haloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, —SR 13 , —NR 13 R 14 , —OR 13 , or —NR 13 C(O)R 14 .

47 . The compound of claim 28 , wherein each occurrence of R 2A independently represents —CN, —NO 2 , halo, haloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted hydroxyalkyl, —C(O)R 13 , —C(O)OR 13 , —NR 13 C(O)OR 14 , —SR 13 , —NR 13 R 14 , —OR 13 , —C(O)NR 13 R 14 , or —NR 13 C(O)R 14 .

48 . The compound of claim 28 , wherein G is C(R 3 ) 2 .

49 . The compound of claim 28 , having the structure of formula (Ia):

50 . The compound of claim 28 , wherein two vicinal occurrences of R 3 taken together with the carbon atoms to which they are bonded form an optionally substituted fused C 3 -cycloalkyl.

51 . The compound of claim 28 , wherein at least one occurrence of R 3 is halo.

52 . The compound of claim 28 , wherein at least one occurrence of R 3 is methyl.

53 . A pharmaceutical composition, comprising the compound of claim 28 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

54 . A method of treating a disease or condition characterized by aberrant complement system activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 28 , or a pharmaceutically acceptable salt thereof;

55 . A compound or a pharmaceutically acceptable salt thereof, selected from the following table:

Structure

157a

129f

156e

144g

88f

85b

89b

100b

102b

94b

103b

106b

95c

111b

97b

131e

98b

147a

99b

145a

235a

151a

127d

128a

155f

294c

83d

251f

56 . A pharmaceutical composition, comprising the compound of claim 55 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

57 . A method of treating a disease or condition characterized by aberrant complement system activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 55 , or a pharmaceutically acceptable salt thereof;