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(12) Patent Application Publication (10) Pub. No.: US 2016/0058872 A1 Crew Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2016/0058872 A1 Crew Et Al US 2016.0058872A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0058872 A1 Crew et al. (43) Pub. Date: Mar. 3, 2016 (54) IMIDE-BASED MODULATORS OF A613 L/426 (2006.01) PROTEOLYSIS AND ASSOCATED METHODS A 6LX3 L/505 (2006.01) OF USE A613 L/454 (2006.01) A613 L/55 (2006.01) (71) Applicant: Arvinas, Inc., New Haven, CT (US) C07D40 L/4 (2006.01) A6II 45/06 (2006.01) (72) Inventors: Andrew P. Crew, Guilford, CT (US); (52) U.S. Cl. Craig Crews, New Haven, CT (US), CPC ............ A61K 47/481 (2013.01); C07D401/14 Hanging Dong, Madison, CT (US); Jing (2013.01); C07D 495/14 (2013.01); C07D Wang, Milford, CT (US); Yimin Qian, 417/14 (2013.01); A61K 45/06 (2013.01); Plainsboro, NJ (US); Kam Siu Milford, A6 IK3I/505 (2013.01); A61 K3I/454 CT (US); Meizhong Jin, East Northport, (2013.01); A61 K3I/551 (2013.01); A61 K NY (US) 3 1/426 (2013.01) (21) Appl. No.: 14/792,414 (57) ABSTRACT (22) Filed: Jul. 6, 2015 The description relates to imide-based compounds, including Related U.S. Application Data bifunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially (63) Continuation-in-part of application No. 14/686.640, inhibitors of a variety of polypeptides and other proteins filed on Apr. 14, 2015. which are degraded and/or otherwise inhibited by bifunc (60) Provisional application No. 61/979,351, filed on Apr. tional compounds according to the present invention. In par 14, 2014, provisional application No. 62/171,090, ticular, the description provides compounds, which contain filed on Jun. 4, 2015. on one end a ligand which binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds a target Publication Classification protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of (51) Int. Cl. that protein. Compounds can be synthesized that exhibit a A6 IK 47/48 (2006.01) broad range of pharmacological activities consistent with the CO7D 495/4 (2006.01) degradation/inhibition of targeted polypeptides of nearly any CO7D 417/4 (2006.01) type. Patent Application Publication Mar. 3, 2016 Sheet 1 of 21 US 2016/0058872 A1 5 wer- c. * is 533 . 3. - 3 4, 33 a. X. -------. Patent Application Publication Mar. 3, 2016 Sheet 2 of 21 US 2016/0058872 A1 Patent Application Publication Mar. 3, 2016 Sheet 3 of 21 US 2016/0058872 A1 Figure 3A NAMALWA Cells OTX-15 - BRD4 |wu0001?Wu0001 - Actin Figure 3B Ramos Cells |wu000£WU000€ OTX. 15 OSI/NOI #{{{{}{}{}WU009 |U I CD Cr C) <+ - Actin Patent Application Publication Mar. 3, 2016 Sheet 4 of 21 US 2016/0058872 A1 Figure 3C Figure 3D CA-46 DAUD - BRD4. Patent Application Publication Mar. 3, 2016 Sheet 5 of 21 US 2016/0058872 A1 ** * * * DOI** * * *? * * * * * * * * * SIXIO 8f77Z/#7ZIG’0:SunOH Tor :SunOH Patent Application Publication Mar. 3, 2016 Sheet 6 of 21 US 2016/0058872 A1 Figure 3G NAMALWA Cells c Patent Application Publication Mar. 3, 2016 Sheet 7 of 21 US 2016/0058872 A1 Figure 3H NAMALWA Cells Figure 3 Ramos Cells t h X C OH O 2 92 g ?h3 C s &3 ?g O: SF is Patent Application Publication Mar. 3, 2016 Sheet 8 of 21 US 2016/0058872 A1 Figure 4A Figure 4B NAMALWA CA-46 A8 A825 a a s e S. s is BRD4- BRD4 Actin - Š8 Actin -8 & Patent Application Publication Mar. 3, 2016 Sheet 9 of 21 US 2016/0058872 A1 †7Z/#7ZIG’00:SunOH &&&&&&&&&&&&&&&& Patent Application Publication Mar. 3, 2016 Sheet 10 of 21 US 2016/0058872 A1 Figure 4E Figure 4F NAMALWA RamOS Pomalidomide Pomalidomide J 8 O .9 t 8 O Ch. BRD4.- ::::::: BRD4 Actin - is::88&:s Actin - six WY: 8x Patent Application Publication Mar. 3, 2016 Sheet 12 of 21 US 2016/0058872 A1 Figure 5A Figure 5B MAMALWA Cells Ramos Cells A825 JO1 OTX15 A825 JO1 OTX15 w s & s a s c. 3 s x as a s is is s is c s s & - e.5 s is & & 5 s& S S 3 & 5 S S 3 S is 5 S 3 3 & & . : . & . : . x . & . (; ; ; ; E; S ; S , Sf w x SR: x S ; : S. S.. & . S.. a. BRD4.- : BRD4.- : c-Myc - Actin Patent Application Publication Mar. 3, 2016 Sheet 13 of 21 US 2016/0058872 A1 Figure 5C NAMALWA Cells irre- 2 4.hr 6hr 24hr lf f f 3 f t 2 : 9 : 2 f 2 &< S- O 2 &C. 3S. O 2 &a 3 o 2? &C. S.3 Oa & aS -S Oa BRD4- &::38& ::::::::s & Actin - W Patent Application Publication Mar. 3, 2016 Sheet 14 of 21 US 2016/0058872 A1 -- -- uOSSejdx e/\ee a | -- Patent Application Publication Mar. 3, 2016 Sheet 15 of 21 US 2016/0058872 A1 r 2-8 e 3 2. ? -2. - c. s ? S QO 3 %/ 3. O .- 3. CD E C. P. 8ts e 9 5 9.s Op de 3 bp () g LL- 8 s LL s yer s s Wolf enee& e c g r t e C CO U QO s o 8. CD (5 S1) St E k- S 3.x:3- a - 5 S < 9. O9 (U - % * , 9 O g : e s e L e s: s s LAO-5 eAlee Wolf eaea: Patent Application Publication Mar. 3, 2016 Sheet 16 of 21 US 2016/0058872 A1 Figure 6E NAA WA 24h treatment, then washout 4. 3. s&...ex8 &* Time after compounds removal Patent Application Publication Mar. 3, 2016 Sheet 17 of 21 US 2016/0058872 A1 Figure 6F NAMALWA CA-46 DAUDI 1. DMSO + A825-1OnM Pomalidomide-1.O.M * Pomalidomide-10.0M Figure 6G NAMALWA CA-46 DAUDI *** • ..) mae !| tì > cae)O + + A825-10OnM Pomalidomide-1.O.M * Pomalidomide-10.OuM Patent Application Publication Mar. 3, 2016 Sheet 18 of 21 US 2016/0058872 A1 Figure 6H S. S. S. S. x&x S $y- S.S.S.S. s. X 1.0- & &YYSs. SS S^$$. & ŠsSy. S. Š. & S&S ^sŠ aSas 0.5 - -8 -6 -4 log compound Patent Application Publication Mar. 3, 2016 Sheet 19 of 21 US 2016/0058872 A1 Figure 7A Caspase Activity (24h) 1uM JO-1 8 x 1 MOTX-15 Š 100nM A825 6 1 Oug/mL Puro 4. 2 Patent Application Publication Mar. 3, 2016 Sheet 20 of 21 US 2016/0058872 A1 Figure 7B A825 JO1 OTX15 C C > > 5 > >E >E is M C C C C C C C C C C D C S S > O C. O C O. O. O. O C C O O C CO O O C C O O O C sh or w y wh , Full length PARP RAMOS 8:8:8:: cleaved Full length PARP re-e cleaved CA-46 Patent Application Publication Mar. 3, 2016 Sheet 21 of 21 US 2016/0058872 A1 US 2016/0058872 A1 Mar. 3, 2016 MIDE-BASED MODULATORS OF tance. Cereblon forms an E3 ubiquitin ligase complex with PROTEOLYSIS AND ASSOCATED METHODS damaged DNA binding protein 1 (DDB1), Cullin-4A OF USE (CUL4A), and regulator of cullins 1 (ROC1). This complex ubiquitinates a number of other proteins. Through a mecha CROSS-REFERENCE TO RELATED nism which has not been completely elucidated, cereblon APPLICATIONS ubquitination of target proteins results in increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 0001. This application is a Continuation-In-Part of U.S. 10 (FGF10). FGF8 in turn regulates a number of developmen Nonprovisional application Ser. No. 14/686.640, filed Apr. tal processes, such as limb and auditory vesicle formation. 14, 2015, which claims the benefit of, and priority to, U.S. The net result is that this ubiquitin ligase complex is impor Provisional Application Ser. No. 61/979,351, filed Apr. 14, tant for limb outgrowth in embryos. In the absence of cere 2014, entitled “IMIDE-BASED MODULATORS OF PRO blon, DDB1 forms a complex with DDB2 that functions as a TEOLYSIS AND ASSOCIATED METHODS OF USE, and DNA damage-binding protein. also claims the benefit of, and priority to, U.S. Provisional Application Ser. No. 62/171,090, filed Jun. 4, 2015, titled 0006 Thalidomide, which has been approved for the treat IMIDE-BASED MODULATORS OF PROTEOLYSIS ment of a number of immunological indications, has also AND ASSOCIATED METHODS OF USE, all of which are been approved for the treatment of certain neoplastic dis incorporated by reference in their entireties. eases, including multiple myeloma. In addition to multiple myeloma, thalidomide and several of its analogs are also FIELD OF THE INVENTION currently under investigation for use in treating a variety of other types of cancer. While the precise mechanism of thali 0002 The description provides imide-based compounds, domides anti-tumor activity is still emerging, it is known to including bifunctional compounds comprising the same, and inhibit angiogenesis. Recent literature discussing the biology associated methods of use. The bifunctional compounds are of the imides includes Lu et al Science 343, 305 (2014) and useful as modulators of targeted ubiquitination, especially Krönke et al Science 343, 301 (2014). with respect to a variety of polypeptides and other proteins, 0007 Significantly, thalidomide and its analogs e.g. which are degraded and/or otherwise inhibited by bifunc pomolinamiode and lenalinomide, are known to bind cere tional compounds according to the present invention. blon. These agents bind to cereblon, altering the specificity of the complex to induce the ubiquitination and degradation of BACKGROUND Ikaros (IKZF1) and Aiolos (IKZF3), transcription factors 0003 Most small molecule drugs bind enzymes or recep essential for multiple myeloma growth.
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