USOO8288373B2 (12) United States Patent (10) Patent No.: US 8,288,373 B2 Chen et al. (45) Date of Patent: Oct. 16, 2012 (54) MODULATORS OF CXCR7 FOREIGN PATENT DOCUMENTS AU 2006-230674 A1 11, 2006 (75) Inventors: Xi Chen, Palo Alto, CA (US); Pingchen WO WOO2,08221 A2 1, 2002 Fan, Fremont, CA (US); Mark M. WO WOO3,O764OO A1 9, 2003 Sleason, Redwood City, CA (US), Juan W. W333. A 3. C. Jaen, Burlingame, CA (US). Lianfa WO WO 2007/126935 A2 11/2007 Li, Palo Alto, CA (US); Jeffrey P. WO WO 2008/008518 A1 1/2008 McMahon, Mountain View, CA (US); WO 2008, 11215.6 A1 9, 2008 Jay Powers, Pacifica, CA (US); Yibin Zeng, Foster City, CA (US); Penglie OTHER PUBLICATIONS Zhang, Foster City, CA (US) Konishi et al. (Yakugaku Zasshi (1973), 93(5), 684-7). Abstract.* r Miao et al., “CXCR7 (RDC1) promotes breast and lung tumor growth (73) Assignee: Chemocentryx, Inc., Mountain View, in vivo and is expressed on tumor-associated vasculature.” 2007. CA (US) PNAS, vol. 104. No. 40, pp. 15735-15740. c Zabel et al., “Elucidation of CXCR-7-Mediated Signaling Events and (*) Notice: Subject to any disclaimer the term of this Inhibition of CXCR4-Mediated Tumor Cell Transendothelial Migra patent is extended or adjusted under 35 tion by CXCR7 Ligands.” The Journal of Immunology, 2009, vol. U.S.C. 154(b) by 171 days. 183, Issue 5, pp. 3204-3211. International Search Reportmailed on Jan. 27, 2010, for International (21) Appl. No.: 12/612,638 Application No. PCT/US09/63298 filed on Nov. 4, 2009, 1 page. Supplementary European Search Report, date May 31, 2012, EP (22) Filed: Nov. 4, 2009 Application No. 0982 5370, 4 pages. (65) Prior Publication Data * cited by examiner US 2010/O150831 A1 Jun. 17, 2010 Primary Examiner — Bruck Kifle Related U.S. Application Data (74) Attorney, Agent, or Firm — Kilpatrick Townsend & Stockton LLP (60) Provisional application No. 61/219,341, filed on Jun. 22, 2009, provisional application No. 61/111.251, filed on Nov. 4, 2008. (57) ABSTRACT Compounds having formula I, (51) Int. Cl. A 6LX3L/2197 (2006.01) CO7D 403/00 (2006.01) (I) (52) U.S. Cl. ........................................ 514/218: 540/575 (R'), (58) Field of Classification Search .................. 540/575: 3 |- 514/218 R2 R N-Cl See application file for complete search history. y - C3-C2 N-/ (56) References Cited U.S. PATENT DOCUMENTS or pharmaceutically acceptable salts, hydrates or N-oxides 3,920,636 A * 1 1/1975 Takahashi et al. ............ 540,575 thereof are provided and are useful for binding to CXCR7. 9:25: R ck 5.39 . SE t . 514,230.5 and treating diseases that are dependent, at least in part, on 2005/0074826- - A1 4/2005 BurnsCKa et al.Ca. CXCR7 activity. Accordingly, the present invention provides 2005/0214287 A1 9, 2005 Burns et al. in further aspects, compositions containing one or more of the 2006/0069102 A1 3f2006 Leban et al. above-noted compounds in admixture with a pharmaceuti 2006/0247253 A1 11/2006 Leban et al. cally acceptable excipient. 2007/0254886 A1 11/2007 Habashita et al. 2007/0275965 A1 11, 2007 Thomas et al. 2010, O150831 A1 6, 2010 Chen et al. 42 Claims, 41 Drawing Sheets U.S. Patent Oct. 16, 2012 Sheet 1 of 41 US 8,288,373 B2 FG. A CH CH, o-co "w A ( ) CUC NN J ------ re--- NS "v / H-H H "U) re ------ O o Ol N-1\1\N R ?1. ()-(?) & A "J s! re Hc ch C fe oac. () /s usury,(Y - - - ----- Hc C CH 3. ------ ------ --- -- as U.S. Patent Oct. 16, 2012 Sheet 3 of 41 US 8,288,373 B2 Ol. S - Cro - Cro Her - - Nu - ?n ch, "J NS re -N ?" ' 2 *N * "U is! -- - ------ (C-C, ( ) (IC 'a, w ------ ------ o ( )-(ICC C-C "N / ------ --- () (O. CH, ()--it) °, ch, rare - Ol O-ri,- N ------ ( - CYv CH, O- JO C S) r ch, , or ------ U.S. Patent Oct. 16, 2012 Sheet 4 of 41 US 8,288,373 B2 FG D chi N S. ; N . C-3- KX KDSJ)'s-e-d --- CH, Cd o aN hu ()-l-SuHe-o -a- --- a-- ------ ------ r --- U.S. Patent Oct. 16, 2012 Sheet 5 of 41 US 8,288,373 B2 --- ------ are - ------ U.S. Patent Oct. 16, 2012 Sheet 6 of 41 US 8,288,373 B2 FIG 1 F re- H ------ r U.S. Patent Oct. 16, 2012 Sheet 7 of 41 US 8,288,373 B2 F.G. 1G -- O se Oku- C C H - - ()--CUC DO s as - UC- C re C. C. () ---- - CC -- --- O-3 OP - He N 2- b 3 / ?n O "J) H --- U.S. Patent Oct. 16, 2012 Sheet 8 of 41 US 8,288,373 B2 FIG. 1H O,* CO - C O2 N 1N n-Qu. N / O N / ?n O HC-o "J r C-C-4) H Okuch s - C a C y O /1N "- --- C ', DO m "v/1N / -- r U.S. Patent Oct. 16, 2012 Sheet 9 of 41 US 8,288,373 B2 ------ He --- re re U.S. Patent Oct. 16, 2012 Sheet 10 of 41 US 8,288,373 B2 FIG. 2A Structure Avg Bind Structure Avg Bind IC50 (nM) IC50 (nM) O O),-D ornNN ) ------ / \ ------ GO- N--O O ()N N NH \-/'Y2J °C) O byN C iO, HN N ------ ------ / \ O N 5 e () A O N 1 OC) °C) V 2.D N -CiNYN ----- C. ) O Cle. ------ N O ..) os---OH cO-5'-r-S H e-O-O C -ON O -O ---- O ------ U.S. Patent Oct. 16, 2012 Sheet 11 of 41 US 8,288,373 B2 FIG. 2B Structure Avg Bind Structure Avg Bind IC50 (nM) IC50 (nM) O sN , , ------ c.O N1--O- ------ O ------ C N) ------ N F ------ ( o-(-FF ----- ----- ( N) ------ U.S. Patent Oct. 16, 2012 Sheet 12 of 41 US 8,288,373 B2 FIG. 2C Structure Avg Bind Structure Avg Bind IC50 (nM) IC50 (nM) ------ ---- \-/ o () ------ N N O ---- CON --- ------ U.S. Patent Oct. 16, 2012 Sheet 13 of 41 US 8,288,373 B2 FIG. 2D Structure Avg Bind Structure Avg Bind IC50 (nM) IC50 (nM) --- ( ------ N O --- N ()N + CO >es ------ ------ O ... -O- ------ U.S. Patent Oct. 16, 2012 Sheet 14 of 41 US 8,288,373 B2 FIG. 2E Structure Avg Bind Structure Avg Bind C IC50 (nM) IC50 (nM) (...) -NH. ------ O O (...) -- -C,"o Yo . *Oc) O (Or's ro ---- ------ (...) "O ---- (...) ------ U.S. Patent Oct. 16, 2012 Sheet 15 of 41 US 8,288,373 B2 FIG. 2F Structure Avg Bind Structure Avg Bind 'R, IC50 (nM) , , , IC50 (nM) exor. co-r. ---- ( ------ (...) ---- U.S. Patent Oct. 16, 2012 Sheet 16 of 41 US 8,288,373 B2 FIG. 2G Structure Avg Bind Structure Avg Bind to IC50 (nM) -O- IC50 (nM) H2N b ()N ---- °C)(...) --- °C). ---- C. O) ------ O (...) O-rr “OC) O -O- . - " * “OC) - O O . ) * ------ cer. " 're U.S. Patent Oct. 16, 2012 Sheet 17 of 41 US 8,288,373 B2 FIG. 2H Structure Avg Bind Structure Avg Bind IC50 (nM) IC50 (nM) O ... (-O. ------ (...) °C). ----- ---- () O Ol. + C) ------ ... C. ------ U.S. Patent Oct. 16, 2012 Sheet 18 of 41 US 8,288,373 B2 FIG. 2 Structure Avg Bind Structure Avg Bind IC50 (nM) IC50 (nM) () O NH2 --- A. N ) ------ ------ N ------ ) ----- N U.S. Patent Oct. 16, 2012 Sheet 19 of 41 US 8,288,373 B2 FIG. 2J Structure Avg Bind Structure Avg Bind IC50 (nM) IC50 (nM) N-N- 5'-C rt () 1s ----- “OC) c - ) . to ... -o- . U.S. Patent Oct. 16, 2012 Sheet 20 of 41 US 8,288,373 B2 FIG. 2K Structure IC50 (nM) ------ ------ ------ U.S. Patent Oct. 16, 2012 Sheet 21 of 41 US 8,288,373 B2 FIG. 2L Structure Avg Bind Structure Avg Bind IC50 (nM) IC50 (nM) ------ ------ ------ ----- ---- ---- U.S. Patent Oct. 16, 2012 Sheet 22 of 41 US 8,288,373 B2 FIG. 2M Structure Avg Bind Structure Avg Bind IC50 (nM) IC50 (nM) ------ ------ ------ ------ U.S. Patent Oct. 16, 2012 Sheet 23 of 41 US 8,288,373 B2 FIG. 2N Structure Avg Bind Structure Avg Bind IC50 (nM) IC50 (nM) ------ ------ ---- ------ ------ ---H -H- ------ U.S. Patent Oct. 16, 2012 Sheet 24 of 41 US 8,288,373 B2 FG, 2O Structure Avg Bind Structure Avg Bind IC50 (nM) IC50 (nM) C Ol RN O r ------ --- °C). als C O go - --- *Oc OC) C ------ re, -O) (...) a's ,O) 2 . O"(R, () . U.S. Patent Oct. 16, 2012 Sheet 25 of 41 US 8,288,373 B2 FIG. 2P Structure Avg Bind Structure Avg Bind IC50 (nM) IC50 (nM) (...) "O. ------ ------ O) ------ ------ ----- ------ U.S. Patent Oct. 16, 2012 Sheet 26 of 41 US 8,288,373 B2 FIG. 20 Structure Avg Bind Structure Avg Bind IC50 (nM) IC50 (nM) ( ) ------ (...) OH ------ ( N.) NH2 -H ON ------ N N ) O ------ N ------ O-R) Null- 00 (O-NP O (Q) \ ------ ...) 00 -H U.S. Patent Oct. 16, 2012 Sheet 27 of 41 US 8,288,373 B2 FIG. 2R Structure Avg Bind Structure Avg Bind IC50 (nM) IC50 (nM) -IO N ----- O O C N K -- C N- a ----- () & " " (). ---- N U.S. Patent Oct. 16, 2012 Sheet 28 of 41 US 8,288,373 B2 FG. 2S Avg Bind Structure Avg Bind IC50 (nM) IC50 (nM) ------ ----- ------ ------ ------ --H ------ U.S. Patent Oct. 16, 2012 Sheet 29 of 41 US 8,288,373 B2 FIG. 2T Structure Avg Bind Structure Avg Bind IC50 (nM) IC50 (nM) r O) CSIS os os. " " 5- or . U.S. Patent Oct. 16, 2012 Sheet 30 of 41 US 8,288,373 B2 FIG.