llIIlIlllIlIlIllIlIllIllIllIIIIIIIIIIIIIIIIIIIIllIllllIIlIllllllIIIlllIlIllIIIIIIIIIIIIIII US 20140275135A1 (») United States (12) Patent Application Publication (io) Pub. No.: US 2014/0275135 A1 GENOV et al. (43) Pub. Date: Sep. 18, 2014 (54) SAI.TS AND SOI.ID IJORVIS Olr (22) liiled: Msr. 13, 2014 ISOQUI Ij OLINONES AND COMPOSITION Ol'SIN('HE Related U.S. Application Data COMPRISIN(1 A'vD VIETIIODS SAME (60) Provisional application No. 61/789,740, lilcd on Mar. 15. 2013. (71) Applicant: Infinity Pharmaceuticals, Inc., Publication ('lsssilicstisn ('anibridge, MA (US) (51) Int. CL (72) Inventors Daniel G. GENOV, Boston. MA (US). Ct)7D 401//4 (2006.01) Louis GRENIER, Newton. )vLA (US). G/11N 31/16 (2006 01) Andrew u. IIA(IUI'., ( helmsford. MA (52) U.S. «L (J.JS); Alcsandcr Redvers 1(BERI.IN, CPC ............ Cd 7D 401//4 GP/Ãdh'168 ('anibridge (2013.01)1 ((iu); I.udouc Sylvsin (2013.01) Merc RENOU. Cambridge ((iB); 514/275: 544/324; 436/42 Susana DEL RIO GANCEDO, IJSV('......... Ctunbridgc (GB) (5 7) ABSTRACT Sohd fonus of chemical compounds that modulate kinase activity, including PI3 kinase activity, and compounds, phar- (73) Assigncc. Infinity Pharmaceuticslt, Inc., maceutical compositions, mid methods of treatment of dis- Ctunbridgc, MA ((JS) eases md conditions associated with kinase activity. includ- uig PL3 kinasc acuvity. arc descnbed hcrmn. Also providtxl hcrmn arc proccsscs for prcpanng compounds, solid fonna (21) Appl. No . 14/209,842 thereof, turd phannaccutwsl compositions thereof Patent Application Publication Sep. 18, 2014 Sheet 1 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 2 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 3 of 54 US 2014/0275135 A1 95 90 85 80 75 /0 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340'C FIG. 2A 1TA, 9.1880m9 Step -2.7575!, 100 -" '5'4m 95 =- 90= 85-. 25.9657K 2.385/mg 80~ 75 70 "I "I ' 9 . 9 7: 7 40 Ki 80 100 120 140 160 180 2i30 220~240 260 280 300 320 340'C FIG. 2B 04 12Ã00mo 40 60 80 100 120 140 160 180 200 220 240 260 280 'C FIG. 2C Patent Application Publication Sep. 18, 2014 Sheet 4 of 54 US 2014/027i135 A1 Wg -1 40 60 80 100 120 140 160 180 200 220 240 260 280 800 „20 340 C FIG. 3A Wq -1 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340'C FIG. 3B letegrel - 24.41mJ - novelized -12,67Jg I 0neet 21 8.42 'C Wg -1 0.0 40 60 80 100 120 140 160 180 200 220 240 260 280 *C FIG. 3C Patent Application Publication Sep. 18, 2014 Sheet 5 of 54 US 2014/0275135 A1 0. /0 0,60 E Ã 0. 50 ~ 0.40 4 0.30 Patent Application Publication Sep. 18, 2014 Sheet 6 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 7 of 54 US 2014/027i135 A1 C C R E CD CCt CG 1 ! ! 1 T ! ! l ! ! lm CD CO (2& ~ ~ M CO CD ~ ~ C3 CG eX& LC) CFl CB CA CC CC CF& QO CO CQ CQ CO j 0$ Patent Application Publication Sep. 18, 2014 Sheet 8 of 54 US 2014/027i135 A1 Form 1 .'=orrn 1A After 24 hours standing Li ~ Form 1A After filtration 'l0 20 2 —Theta — Scale Patent Application Publication Sep. 18, 2014 Sheet 9 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 10 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 11 of 54 US 2014/027i135 A1 C CN j i/3 p ~ C:i 93 t3 c& E lo o cudQ K V Patent Application Publication Sep. 18, 2014 Sheet 12 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 13 of 54 US 2014/027i135 A1 300 5 10 l5 20 25 30 35 40 8 -28Ideg) Patent Application Publication Sep. 18, 2014 Sheet 14 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 15 of 54 US 2014/0275135 A1 Patent Application Publication Sep. 18, 2014 Sheet 16 of 54 US 2014/027i135 A1 o ! ~ 8 8 8 8 g 8 8 8 8 ssmmwsIIIQN8IQQ88$8$88~ (""ivf103)v!) (SlLao0)93 Patent Application Publication Sep. 18, 2014 Sheet 17 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 18 of 54 US 2014/0278135 A1 ";0)iep -0.89? 4Ã CA 3,!930ma -29. 3883e-03ma 1GG Siep -12.48! &Xp -0.4110mg Siep 6.449'i8) 0.2'24mg 80 ~- -r 40 60 80 100 120 140 160 180 200 220 240 260 280 300 220 340'0 FIG. 13A S)ep -1.0667'1) ! 63) 'ace CA 81 -65 88PPe- 8.8046/ 90~ .!a Sma 85~ 80 -„! 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 0 FIG. 138 Step -0.6189!. lCA 11,2966)mg — 69.997, e — 03!ai] ', 00 g)" ~ Step -14 6637/ -1.6481mg 90 -„ 85-1 40 60 80 100 120 140 160 180 200 220 240 260 280 '0 FIG. 13C Patent Application Publication Sep. 18, 2014 Sheet 19 of 54 US 2014/027i135 A1 Wg -1 2,0 0 0',0 -0" 40 60 80 100 120 140 160 180 200 22G 240 260 280 300 220 340'"C FIG. 34A 40 60 80 100 12G 140 160 180 20G 220 240 260 280 00 32G 340'C FIG. 34B Wg -1; 0 09C'6200rlg -1- 2~ 'C 0 i.-e: 1 9 l.99 ~er'9 196 66'",. 40 6G 80 100 120 140 160 180 00 220 240 260 280 'C FIG. 14C Patent Application Publication Sep. 18, 2014 Sheet 20 of 54 US 2014/027i135 A1 0.60 ~ 0.40 E 5 0X 0.25 ~ 0,20 0.15 0 !0 20 30 40 50 60 70 80 90 x-RH(x) FIG. 15 Patent Application Publication Sep. 18, 2014 Sheet 21 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 22 of 54 US 2014/027i135 A1 1 Patent Application Publication Sep. 18, 2014 Sheet 23 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 24 of 54 US 2014/027i135 A1 cD co c) I cD CD cD CD CD cD cD CD cD cD '') C' ) Patent Application Publication Sep. 18, 2014 Sheet 25 of 54 US 2014/0275135 A1 Step -7./6?5,"r,. -0.393." Ii9 Step -9.9'i 842 -0.5'-2') — — — — — — — r r r 1--r r r r-T r" r r r i r,, ] ] T 9 7 ] g I 1 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340"C FIG. 18A 40 60 80 100 120 140 160 180 200 ?20 '?40 260 280 300 320 340'&: FIG. 38B Patent Application Publication Sep. 18, 2014 Sheet 26 of 54 US 2014/027i135 A1 Wq -1 0.0 OSC ! 40„"Oreg btagra[ -43.34mJ — 0.4- ( aorraa[iz.d -3[296.:g -1 -06 ([, a 7 I .-"'aak [85.':.! 'C -1. 1 -1.2 -1A -r--"--r-- --v--r -T'--[-- r--f--&--T- T- 7--i-- --i--T - --T -r--[-- — T--t"- [--r--[--'- - i-- ["- T 40 60 80 100 120 140 160 180 20G 220 240 260 280 300 320 340 C FIG. 39A 1[/g --1 1,0 0.6 0.4 0.2 0.0 -0.2 40 60 80 100 12Q 140 160 180 200 220 240 260 280 300 320 340"C FIG. 19B Patent Application Publication Sep. 18, 2014 Sheet 27 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 28 of 54 US 2014/027i135 A1 (DCJEDCD&C)NCJN\DcD(-JCJED'.DER3 ]"T''T', 'T$ 'I (-JCIC)&D(- at ( I;t, T T T T i i 7 7TT, ar n&awaanac~nnac acianamnaconHC'BMOOf (SDIIJw"MM CVMCOI CGi'3M WC% C lMCM (0/UllOJ) Ul ] Patent Application Publication Sep. 18, 2014 Sheet 29 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 30 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 31 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 32 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 33 of 54 US 2014/027i135 A1 a a C! c «L «D F I«l canQ c c) CCl 4C ) ID «W «& V I ID «D I: I n- Patent Application Publication Sep. 18, 2014 Sheet 34 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 35 of 54 US 2014/0275135 A1 Patent Application Publication Sep. 18, 2014 Sheet 36 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 37 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 38 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 39 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 40 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 41 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 42 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 43 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 44 of 54 US 2014/027i135 A1 so'vent Posed in poiyrnonph ee(een IP.I I I THT 1-II!eTHI I80E iL 4eT 20 2 —Theta — Scoie FllG.