US 201701.44997 A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0144997 A1 CHEN et al. (43) Pub. Date: May 25, 2017 (54) MODULATORS OF CHEMOKINE A6II 45/06 (2006.01) RECEPTORS C07D 405/2 (2006.01) A6II 3/4725 (2006.01) (71) Applicant: CHEMOCENTRYX, INC., Mountain A63L/455 (2006.01) View, CA (US) A6II 3/4439 (2006.01) C07D 209/246 (2006.01) (72) Inventors: Xi CHEN, E. Palo Alto, CA (US); A63L/506 (2006.01) Dean R. DRAGOLI, Los Altos, CA A63L/454 (2006.01) (US); Junfa FAN, Palo Alto, CA (US); C07D 307/52 (2006.01) Jaroslaw KALISAK, Mountain View, A63L/4035 (2006.01) CA (US); Antoni KRASINSKI, (52) U.S. C. Sunnyvale, CA (US); Manmohan CPC ......... C07D405/14 (2013.01); C07D 307/52 Reddy Leleti, San Jose, CA (US); (2013.01); A61 K3I/341 (2013.01); A61 K Venkat MALI, Cupertino, CA (US); 45/06 (2013.01); C07D405/12 (2013.01); Jeffrey McMAHON, San Francisco, A61K 31/4035 (2013.01); A61K 31/4155 CA (US); Rajinder SINGH, Belmont, (2013.01); A61 K3I/4439 (2013.01); C07D CA (US); Hiroko TANAKA, Mountain 209/46 (2013.01); A61 K3I/506 (2013.01); View, CA (US); Ju YANG, Palo Alto, A6 IK3I/454 (2013.01); A61K 31/4725 CA (US); Chao YU, Sunnyvale, CA (2013.01) (US); Penglie ZHANG, Foster City, CA (US) (57) ABSTRACT Compounds are provided as chemokine inhibitors having (21) Appl. No.: 15/353,889 the structure: (22) Filed: Nov. 17, 2016 Related U.S. Application Data R5a R55 O O R7 (60) Provisional application No. 62/257,389, filed on Nov. Xal \ 19, 2015, provisional application No. 62/277,711, R3. S. N N '' filed on Jan. 12, 2016. Rgb H H B pi Publication Classification R6a N O (51) Int. Cl. R4 CO7D 405/4 (2006.01) A6 IK3I/34 (2006.01) Patent Application Publication May 25, 2017. Sheet 1 of 38 US 2017/O144997 A1 FIGURE 1A CCR6 Cso CXCR2 Co O. O. N-2 N C- \ . --- OOO no o -- re re f\,-CO2H Nad O O C-Cya's N NSN 1.001 'n ŠO O5 X- es resea r t ; N-CO2H O-N O O C s y N. N. 1.002 N-so O2 ----- ------ --/f\,-CO2H O O Cl-, ---M Y s N Y OO3 SO o ------ ---- Patent Application Publication May 25, 2017. Sheet 2 of 38 US 2017/O144997 A1 FIGURE B CCR6 Cso CXCR2 Cso 1004 O2 ---- ----- \ face 1,005 d --- --- 006 --- 1.007 '. W 0.2 --- --- 1,008 |- --- --- d -- Patent Application Publication May 25, 2017. Sheet 4 of 38 US 2017/O144997 A1 FIGURE 1) CCR6 Co CXCR2 Cso O. O. s 1. Ni C/sC N ---- NN 014 (NSO d ----- ----- f; N-CO2h 's- Meo-Saj O O C/sy ---- l Aé-N N 1.05 N-so d ------ --- N--F N CO2H Ci?sy o, O Yi in Ns' \-i 1.016 N-so o re ter Meo-i(-)NF 101.7 is co-h --- --- Med-R- MeO O. O. 1.018 Y Oé ----- ----- Patent Application Publication May 25, 2017. Sheet 6 of 38 US 2017/O144997 A1 FIGURE F CCR6 Co CXCR2 Cso ci.sy Š-(? - i.- Aé's: N N & i-y N-so or --- --- 1.024 iš-CO2H o r -i.F f O O f Cl- is . 1,025 N SO o i N-CO2H N O C \-& N C/S Y A 2 1,026 ^ ------ Nrso! d (NCO2H N 1.027 ----- is-CO2Hf as N c A N N 'N 1.028 - - - -- N\COHso or Patent Application Publication May 25, 2017. Sheet 7 of 38 US 2017/O144997 A1 FIGURE 1G CCR6 IC50 CXCR2 Cso S 2-n" n O29 N SO d --- r \-ed O to C-?is2-N Nr. - 1.030 N-so? d)s ----- --- ) al -Co-H O O C. ^s ---- -- Aé-N N'S f N CO2H Fr. C. ^s O. o Yf Ala-N Nr y 1,032 N-so o --- ---- Chrf\,-CO2H c/s, O ... y y- N NS y n-s O% 1033 N-so --- --- f\,-CO2H Nal O Patent Application Publication May 25, 2017. Sheet 8 of 38 US 2017/O144997 A1 FIGURE 1H CCR6 Co CXCR2Cso C/s, A 2-N TN 1.034 - ----- --- f N-CO2H MeOS - O O \,-4% N Cls\ ---- +- 1.035 A?Niso N. N.OY ----- --- fN-CO2H - al o, O -\ \ Yi y --N No" - 1.036 , Niso, o s: es - O to Cl-k \ . - 1037 N- SO o H.-- --- f\,-CO2H- Y -s O. O.Y X- - N N Ni 1.038 N-so o ------ -- Patent Application Publication May 25, 2017. Sheet 9 of 38 US 2017/O144997 A1 FIGURE I CCR6 Cso CXCR2 Co O to O-SS - / SC N NS O39 N SO d S -CO2H -- O. O. % f -(f - 040 N SO d’s sess-r --- f\,-CO2H MeO-Self O to Yi /s - (y^-N : N ---- 1.041 N-Šs O OY ------ --- MeO-Redits co-h O. O. , sky - Y { /- N N \ - 1.042 N-so O% ------ --- Coo" 1,043 ------ --- Patent Application Publication May 25, 2017. Sheet 11 of 38 US 2017/0144997 A1 FIGURE 1 K CCR6 Cso CXCR2 Cso 1.049 N-so O --- --- A. Y OSO o d H- r O. O. F-y Š-1^N. A 2 N Nur 1.051 ANrso aY - ------ --- is-CO2H\-f O. O. F-A-,- -- A 's N T N \ 2-y. 1,052 so O- ----- --- frS-CO2H C N O O f F. \\ s r - y.a-. - N Nr.Ö 2 1053 N-so re --- &-COH Patent Application Publication May 25, 2017. Sheet 12 of 38 US 2017/O144997 A1 FIGURE L CCR6 Co CXCR2 Cso 1054 rare 1.055 re 1,056 ----- ---- 1.057 ------ 1.058 --- Patent Application Publication May 25, 2017. Sheet 13 of 38 US 2017/O144997 A1 FIGURE M. CCR6 Cso CXCR2 IC50 O. F^S FN Yi y - N N-- 059 K d2 ----- isNSo co-h s^ O \l- a 2-N N-- O60 NSO d ---- is co-h \-el O N^T N-- .06 N-S Oé ------ 1,062 Oé ----- vs. ----- Patent Application Publication May 25, 2017. Sheet 14 of 38 US 2017/O144997 A1 FIGURE 1N CCR6 Cso CXCR2 Co Cls, N-2. Yi A 2-N N- 2-y--- 1.064 N O o eas se f\, COOH C/s/s o :- o --- y 22-N - N Y. .065 N SO O ^ sess-r --- f N.-CO2H Nad O O ------ --- 1.066 1,067 ---- ------ 1,068 es ass Patent Application Publication May 25, 2017. Sheet 15 of 38 US 2017/0144997 A1 FIGURE O CCR6 Cso CXCR2 ICs O O Cl-, y - - y \r N N N. O69 N-so d as ev SNn O O ^s, N-Y f C/s NTt O70 N-so O4 -- SN Ns N N 1.07 ----- ----- 1.072 -- -- 1.073 ----- ----- Patent Application Publication May 25, 2017. Sheet 16 of 38 US 2017/0144997 A1 FIGURE 1P CCR6 Cso CXCR2 Co 1074 eas assa 1.075 N Yas Oé --- ear 1076 NSO o +--- --- 1.077 --- ear O O Cl-, f - 2 y -?-N / N' rev 1078 O N-so Oa --- Y-S N f Patent Application Publication May 25, 2017. Sheet 17 of 38 US 2017/O144997 A1 FIGURE i Q CCR6 Cso CXCR2 IC50 O O f Cls, ---- y A 2'-N N 1079 SO Oé’ --- sea HO-C-S- \ O. O. cus Š-6if Y 1,080 ----- --- -- HO-C-N O. O. Ci-s, Š-(?i. Y A 2'-N NS .08 po o ------ ------ CONH2 1,082 --- ----- o, to Cls. --- N-so O. A vs. ------ Patent Application Publication May 25, 2017. Sheet 18 of 38 US 2017/0144997 A1 FIGURE IR CCR6 Cso CXCR2 Cso O. O. , ^- N-- F ) is/ N irlfNN 1,084 N SO 2 - - --- -o N c/sy cP 9 Y| A 2-N N 1085 -- rer case { d 2 NSO O 2 N C-/s,A 2-N TN--- S- 1086 { N-so ds/ 2 ---- --- y N O. O N. & N } C/S -- 1087 N-S ".da ----- ------ f Y-Nd \ C/s ---- °l - 1.088 /C. - d) --- ----- Patent Application Publication May 25, 2017. Sheet 19 of 38 US 2017/0144997 A1 FIGURE IS CCR6 Cso CXCR2 Cso 1,089 sea- es O o Ni - C-x sy. ... N--f. 1.090 Nrso O. A re --- y H2NOC 109. -er ------ o o C -. ---- N Nut" y 1,092 -y O 22 ------ ------ CONH2o 1.093 --- Patent Application Publication May 25, 2017. Sheet 20 of 38 US 2017/O144997 A1 FIGURE T CCR6 Cso CXCR2Cso o o y C/s, n ... NNY. 1,094 N-so o --- Y co-h O. O. N. & N C. ^s Yi O95 re in .096 ------ --- Y.4% C-sA 2'-N i- Ne:Y 1097 N-so ".s ------ --- S HO2C O98 (se ----- Patent Application Publication May 25, 2017. Sheet 21 of 38 US 2017/0144997 A1 FIGURE 1U CCR6 Cso CXCR2 Cso O99 ev a 1100 - ----- 1.101 --- ----- O O C 102 --- re NSO N-W 103 N N e Patent Application Publication May 25, 2017. Sheet 22 of 38 US 2017/0144997 A1 FIGURE 1 V CCR6 IC50 CXCR2 ICs 1.104 sease -- a-- O. O cis N-% YN i AC 2-N N TNN ps-\ 105 N-so o -er r 1106 ----- --- 1107 ----- ----- 108 seats seats Patent Application Publication May 25, 2017. Sheet 23 of 38 US 2017/0144997 A1 FIGURE W CCR6 Co CXCR2 Cso 1.109 ----- -- a--- 1.10 e ------ 1.111 ----- ------ 1.112 ----- ------ O.