US 20190112268A1 ( 19) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2019 /0112268 A1 Nomura et al . ( 43 ) Pub . Date: Apr . 18 , 2019 ( 54 ) MTORC1 MODULATORS filed on Mar. 6 , 2018, provisional application No . (71 ) Applicant : THE REGENTS OF HE 62/ 572 ,234 , filed on Oct . 13 , 2017 . UNIVERSITY OF CALIFORNIA , Publication Classification Oakland , CA (US ) (51 ) Int. CI. ( 72 ) Inventors : Daniel K . Nomura , Berkeley , CA (US ) ; C07D 209 / 08 (2006 .01 ) Roberto Zoncu , San Francisco , CA A61P 35 / 00 ( 2006 . 01 ) (US ) ; Allison M . Rpberts , Kensington , A61P 25 / 16 ( 2006 . 01) CA (US ) ; Kelvin F . Cho , San A61P 25 / 28 ( 2006 . 01 ) Francisco , CA (US ) ; Yik Sham Clive A61P 3 / 10 (2006 .01 ) Chung , Berkeley, CA (US ) ; Hijai Shin , ( 52 ) U . S . CI. Albany, CA (US ) ; Benjamin Croze, CPC . .. .. C07D 209 /08 ( 2013 .01 ) ; A61P 35 /00 Lafayette , CA (US ) ( 2018 .01 ) ; A61K 47 /64 ( 2017 .08 ) ; A61P 25 / 28 ( 2018 .01 ) ; A61P 3 / 10 (2018 . 01 ) ; A61P 25/ 16 (21 ) Appl . No. : 16 / 159 , 380 (2018 .01 ) ( 22 ) Filed : Oct . 12 , 2018 (57 ) ABSTRACT Provided herein , inter alia , are methods and compounds for Related U . S . Application Data inhibiting mTORC1 and for treating diseases associated ( 60 ) Provisional application No . 62 / 645, 365 , filed on Mar . with mTORC1 activity. 20 , 2018 , provisional application No. 62 /639 ,431 , Specification includes a Sequence Listing . totit drug Patent Application Publication Apr. 18 , 2019 Sheet 1 of 20 US 2019 / 0112268 A1 FIG . IA A ON . WL FIG . 1B FLAG -GFP -RagB FLAG -GFP .Rage FLAG -GFP - RagB W / O FLAG - 3x peptide + 1x FLAG - 3x peptide + 10x FLAG - 3x peptide . .X X . Fluorescence(A.U) Fluorescence(A.U) Fluorescence(A.U) WWW 100 Distance Distance Distance mensPatent Application Publication Apr. 18 ,* 2019 Sheet 2 of 20 US 2019 / 0112268 A1 FIG . IC sonup ** * drugs SA pattidessert... * * ** * WWWME X < FIG . 2A menanamanamanatnamanandaiwanan GFPIRFPratio 295 111111111 wwwwwwwwwwwww www XXX FIG . 2B Patent Application Publication Apr. 18 , 2019 Sheet 3 of 20 US 2019 / 0112268 A1 FIG . 2C mTORCH Lysosomalmembrane FIG . 2D GFP GFP -RAGB + C Cmpd A25 Cmpd A26 YP1- 44 Lamtor DMSO DMSO GFP merge Patent Application Publication Apr. 18 , 2019 Sheet 4 of 20 US 2019 / 0112268 A1 FIG . 2E .• : : TIIIIIIII KO GFP/RFPRatio .177777777777777777TTTTTTTTTTTTTTT MW -1 . DMSOFlag -GFP YP1Compound -44Compound A6 Compound A25 A26 FIG . 2F boundfraction YP1 -44 (nM ) Patent Application Publication Apr . 18 , 2019 Sheet 5 of 20 US 2019 / 0112268 A1 FIG . 3A X siin ' .' . 1 Hun acidsaminoA6wioCompound MTORLamp2 acidsaminoA6Compound* .- mTORLamp2 .- .. Lamp2 RW: YP1-44Woaminoacids mTORLamp2 YP1-44*aminoacids : . DMSOwioaminoacids MTORLamp2 DMSO*aminoacids Lamp2MTOR Patent Application Publication Apr. 18 , 2019 Sheet 6 of 20 US 2019 / 0112268 A1 FIG . 3B FIG .3C 14. Lamp2 LLLLLLLLLL L CompoundA6wloaminoacids $PºEOWLUEOJAT6€¥punodwo zdweVões kikkkkk Ragc !. Lamp2 . 5 Lamp2 YP4-44woaminoacids Ragc Raga Lamp2 SPIOBOULUIBOJAOSWO zd???????14141417 Ragc Patent Application Publication Apr. 18 , 2019 Sheet 7 of 20 US 2019 / 0112268 A1 FIG . 3D . - DMSO option24 * * YP1. -44 500Mma * - - + + - - . ! ! . WO3 . 2 . * . olen amino acids - + - + + S757- : PULK1 ULK1 T3892 . -pS6K1 S6K1 S65 -p4E -BP1 4E - BP1 Patent Application Publication Apr. 18 , 2019 Sheet 8 of 20 US 2019 / 0112268 A1 FIG . 4A . mapping druggable hotspots targetedbycovalentligands . .. heavy:1light . control . , SYCWHIL notinhibited . heavyTEVtag . lightTEVtag . r. Cu-catalyzed . "clickchemistry . Cu-catalyzed . ligand "clickchemistry . lightheavy:3 . peptide1 control . IX . winni YWKDAC*SHR inhibited MS/LC- IsoTOP-ABPPplatformtomapdruggablehotspottargetedbycovalentligands reactivity-based probe reactivity.basedprobe * : ligand 2.avidinenrichment 3.trypticdigestion 4.TEVdigestion covalent WWW control covalentligand treated Patent Application Publication Apr. 18 , 2019 Sheet 9 of 20 US 2019 / 0112268 A1 FIG . 4B ISOTOPwww - ABPP analysis of YP 1 - 44 LAMTOR5 C23 with Ragulator complex QALC DGSAVMFSSK control(light)vs treated(heavy)ratio . LAMTOR5C148 LAMTOR5 C23 FIG . 5A Patent Application PublicationPublication Apr . 18 , 2019 Sheet 10 of 20 US 2019 /0112268 A1 FIG . 5B YP 1 - 44 H3CO H3CO CC 1 - 10 modelsCC 1 - 3 wereCC 1 - 1 OCH3 CC 1 - 14 ageCC 1 - 42 ängeCC 1 - 46 appeCC 1 - 39 mängeCC 1 -44 FIG . 5C (UM ) , DOO LAMTOR5E Patent Application Publication Apr. 18 , 2019 Sheet 11 of 20 US 2019 /0112268 A1 FIG . 5D FIG . 5E . Rapamycin(100nM ) Compounds VSO S AS Torint(250nM ) O wwwwwww * P .SOK w SOK 4EBP Patent Application Publication Apr . 18 , 2019 Sheet 12 of 20 US 2019 /0112268 A1 FIG . 5F 044 * * . *. .. * .. Compounds DMSO 159480 FIG . 6A DMSO YP . 1 - 44 001- 04 . 3 3 :: : : :: : : : : : . : : : . FIG . 6B DMSO [200M ) * AA morge . Patent Application Publication Apr . 18 , 2019 Sheet 13 of 20 US 2019 /0112268 A1 FIG . 6C Lamp2 S MTOR DMSO* AA NO Lamp2 Xx03 :. merge . .: cc - 1 - 44 :. MTOR :. [ 20uM : + AA | : merge FIG . 6D Bafilomycin A1 - - * p62 LC3b Bactin Patent Application Publication Apr . 18 , 2019 Sheet 14 of 20 US 2019 /0112268 A1 FIG . 7A HEART Control cc1- 44 Rapamycin w pS235 / 236 -S6 S6 PT37 /46 -4EBP 4EBP4EBP ????????? PS473 -Akt Akt BODDDDDDDDD Raga SOON . - - . Patent Application Publication Apr . 18 , 2019 Sheet 15 of 20 US 2019 /0112268 A1 FIG . 7B SKELE Control cc1- 44 Rapamycin ?????????? Patent Application Publication Apr . 18 , 2019 Sheet 16 of 20 US 2019 /0112268 A1 FIG . 7C KIDNEY Control 601 -44 Rapamycin AMMA MAAAAAAAAAAAAAAAAAAAAAAAAAAM PS235 / 236 - S6 S6 2 X * * * * * * PS473 - Akt p62 Raga See FIG . 8A . MW Patent Application Publication Apr . 18, 2019 Sheet 17 of 20 US 2019/ 0112268 A1 FIG . 8B 11/UMCC-2 MM 10101 * * * rhodamineazideclickingugCC2-11*complex.)+RagsRagulators(0/ fluorescencegel-In 1001 1001 40 kDa-72 Patent Application Publication Apr . 18 , 2019 Sheet 18 of 20 US 2019 /0112268 A1 FIG . 9A . .* 1 . " * . .. ' · * * * ' : : : t * * . = = = = = = = = = = = = = = = = = = = = = = = = = = = = { ? ? & #2311 # ## 1 Patent Application Publication Apr . 18 , 2019 Sheet 19 of 20 US 2019 /0112268 A1 FIG . 9B ber Y .. Attttt 2 ot * * MWENpereya 2 **** * w th desede of Patent Application Publication Apr . 18 , 2019 Sheet 20 of 20 US 2019 / 0112268 A1 FIG . 9C ? . AAA 20000000 2 2 000 - 100 . ? . US 2019 /0112268 A1 Apr. 18, 2019 MTORC1 MODULATORS - continued (XI ) CROSS - REFERENCES TO RELATED a H APPLICATIONS ( R ? — L ') 21 Or [0001 ] This application claims the benefit of U . S . Provi sional Application No . 62 /572 ,234 , filed Oct. 13 , 2017 ; U . S . ( XXI) Provisional Application No. 62 /639 ,431 , filed Mar. 6 , 2018 ; and U . S . Provisional Application No . 62/ 645 ,365 , filed Mar. 20 , 2018 , which are incorporated herein by reference in their ( R ! — L ') entirety and for all purposes . STATEMENT AS TO RIGHTS TO INVENTIONS [ 0007 ] L is independently a bond , - S ( O ) 2 - , - NH — , MADE UNDER FEDERALLY SPONSORED 0 , S , C ( O ) , LC ( O ) NH , NHC( 0 ) , RESEARCH AND DEVELOPMENT — NHC ( O )NH — , - C ( O ) O - , - OC ( O ) - , substituted or 0002 ] This invention was made with government support unsubstituted alkylene, substituted or unsubstituted het under grants CA172668 and CA195761 awarded by the eroalkylene , substituted or unsubstituted cycloalkylene, sub National Institutes of Health . The government has certain stituted or unsubstituted heterocycloalkylene, substituted or rights in the invention . unsubstituted arylene , or substituted or unsubstituted het eroarylene . REFERENCE TO A “ SEQUENCE LISTING ,” A [ 0008 ] Rl is independently halogen , CX3, CHX ' z, TABLE , OR A COMPUTER PROGRAM LISTING CH , X ' , OCX " z , OCH , XP, OCHX ' , CN , APPENDIX SUBMITTED AS AN ASCII FILE _ SO, R15 , - SONRAR18 , NHC( O ) NRARP, - N ( O ) , NRARIB , C ( O ) RIC , C ( O ) ORIC , [0003 ] The Sequence Listing written in file 052103 C ( O )NRARIB , ORID , - NRASO ,RID , — NR14C ( O ) 511001US _ Sequence _ Listing_ ST25 . txt, created Oct . 12 , RIC, NR14C ( O )ORIC , NRAORIC , N3, substituted 2018 , 24 ,539 bytes , machine format IBM - PC , MS Windows or unsubstituted alkyl , substituted or unsubstituted het operating system , is hereby incorporated by reference . eroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubsti BACKGROUND tuted aryl, or substituted or unsubstituted heteroaryl; two [0004 ] Overwhelming evidence indicates that aberrant adjacent - L - R substituents may optionally be joined to activity of a multiprotein complex known as mechanistic form a substituted or unsubstituted cycloalkyl, substituted or Target of Rapamycin Complex 1 (mTORC1 ) underlies the unsubstituted heterocycloalkyl, substituted or unsubstituted growth advantage that many cancer types display over the aryl , or substituted or unsubstituted heteroaryl. surrounding healthy tissue . Current therapeutic investiga 10009 ) E is an electrophilic moiety . tions in cancer and other mTORC1 - related diseases suffer [0010 ] Each R14 , RIB , RC, and RID is independently from limitations and significant side effects , including high hydrogen , CX3, CHX2, CH X , CN , OH , toxicity and metabolic imbalance . Thus, renewed efforts COOH , CONH2, substituted or unsubstituted alkyl , must be directed toward identifying new ways to block substituted or unsubstituted heteroalkyl, substituted or mTORC1 selectively and safely . Disclosed herein , inter alia , unsubstituted cycloalkyl , substituted or unsubstituted