US 201701 44996A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0144996 A1 CHEN et al. (43) Pub. Date: May 25, 2017 (54) INHIBITORS OF CXCR2 Publication Classification (51) Int. Cl. (71) Applicant: CHEMOCENTRYX, INC., Mountain C07D 405/2 (2006.01) View, CA (US) A6II 45/06 (2006.01) A6II 3/4439 (2006.01) C07D 413/12 (2006.01) (72) Inventors: Xi CHEN, E. Palo Alto, CA (US); A6II 3/422 (2006.01) Dean R. DRAGOLI, Los Altos, CA C07D 405/4 (2006.01) (US); Junfa FAN, Palo Alto, CA (US); A63L/4035 (2006.01) Jaroslaw KALISAK, Mountain View, C07B 59/00 (2006.01) CA (US); Manmohan Reddy LELETI, (52) U.S. Cl. San Jose, CA (US); Viengkham CPC ........ C07D405/12 (2013.01); A61K 31/4035 MALATHONG, Mountain View, CA (2013.01); A61K 45/06 (2013.01); C07B 59/002 (2013.01); C07D 413/12 (2013.01); (US); Jeffrey McMahon, San A61 K3I/422 (2013.01); C07D 405/14 Francisco, CA (US); Hiroko TANAKA, (2013.01); A61 K3I/4439 (2013.01); C07B Mountain View, CA (US); Ju YANG, 2200/05 (2013.01) Palo Alto, CA (US); Chao YU, (57) ABSTRACT Sunnyvale, CA (US); Penglie ZHANG, Compounds are provided as inhibitors of CXCR2, having Foster City, CA (US); Venkat Mali, the structure: Cupertino, CA (US) (21) Appl. No.: 15/353,949 (22) Filed: Nov. 17, 2016 Related U.S. Application Data (60) Provisional application No. 62/257.529, filed on Nov. 19, 2015. Patent Application Publication May 25, 2017. Sheet 1 of 10 US 2017/O144996 A1 FIGURE 1A CXCR2 IC5o (nM) ------ 1.OO1 ------ 1.OO2 -- 1.OO3 --- 1.OO4 -- 1.OO5 --- 1.OO6 Patent Application Publication May 25, 2017. Sheet 2 of 10 US 2017/O144996 A1 FIGURE 1B 1.OO7 1.OO8 1.OO9 1.010 1.011 1.012 Patent Application Publication May 25, 2017. Sheet 3 of 10 US 2017/O144996 A1 FIGURE 1C 1.O13 1.014 1. O15 1.016 1.017 1.018 Patent Application Publication May 25, 2017. Sheet 4 of 10 US 2017/O144996 A1 FIGURE 1D FOS ('Su N NSN ------ N1SO O / 1.019 1,021 1.022 1.O23 1.024 Patent Application Publication May 25, 2017. Sheet 5 of 10 US 2017/O144996 A1 FIGURE 1 E 1.O25 1.O26 1.O27 1.O28 1.O29 Patent Application Publication May 25, 2017. Sheet 6 of 10 US 2017/O144996 A1 FIGURE 1F N N ; ------ 1.031 1.032 1.033 1.O34 1.035 1.036 Patent Application Publication May 25, 2017. Sheet 7 of 10 US 2017/O144996 A1 FIGURE 1G 1.038 1.O39 1. O40 1.041 1.042 Patent Application Publication May 25, 2017. Sheet 8 of 10 US 2017/O144996 A1 FIGURE 1H 1.043 1.O44 1.O45 1.O46 1. O47 1.048 Patent Application Publication May 25, 2017. Sheet 9 of 10 US 2017/O144996 A1 FIGURE 1 Patent Application Publication May 25, 2017. Sheet 10 of 10 US 2017/0144996 A1 FIGURE 1. 1.052 1. O53 1.O54 1. O55 US 2017/O 144996 A1 May 25, 2017 INHIBITORS OF CXCR2 0006. A subset of CXC chemokines, those which contain the ELR motif (ELR-CXC), have been implicated in the CROSS-REFERENCES TO RELATED induction of tumor angiogenesis (new blood vessel growth). APPLICATIONS These include the CXCR2 ligand chemokines CXCL-1, 0001. This application is an application claiming benefit CXCL2, CXCL3, CXCL5 and (Strieter et al. JBC 270: under 35 U.S.C. S 119(e) of U.S. Provisional Application No. 27348-27357 (1995)) Some CXCR2 ligand ELR-CXC 62/257.529 filed Nov. 19, 2015, which is herein incorporated chemokines are exacerbating agents during ischemic stroke by reference in its entirety. (Connell et al., Neurosci. Lett., 15:301 11 (2015). All of these chemokines are believed to exert their actions by binding to STATEMENT AS TO RIGHTS TO INVENTIONS CXCR2. Thus, their angiogenic activity is due to their MADE UNDER FEDERALLY SPONSORED binding and activation of CXCR2 expressed on the surface RESEARCH AND DEVELOPMENT of vascular endothelial cells (ECs) in surrounding vessels. 0002 NOT APPLICABLE 0007. Many different types of tumors are known to produce ELR-CXC chemokines, and production of these REFERENCE TO A “SEQUENCE LISTING." A chemokines correlates with a more aggressive phenotype TABLE, OR A COMPUTER PROGRAM LISTING (Inoue et al. Clin Cancer Res 6:2104-2119 (2000)) and poor APPENDIX SUBMITTED ON A COMPACT prognosis (Yoneda et al. J Nat Cancer Inst 90:447-454 DISK (1998)). As ELR-CXC chemokines are potent chemotactic factors for EC chemotaxis, they probably induce chemotaxis 0003) NOT APPLICABLE of endothelial cells toward their site of production in the BACKGROUND OF THE INVENTION tumor. This may be a critical step in the induction of tumor angiogenesis. Inhibitors of CXCR2 will inhibit the angio 0004 Chemokines are chemotactic cytokines that are genic activity of the ELR-CXC chemokines and therefore released by a wide variety of cells, to attract cells such as block the tumor growth. This anti-tumor activity has been leukocytes (including macrophages, T-cells, eosinophils, demonstrated for antibodies to CXCL8 (Arenberg et al. J basophils, neutrophils and myeloid-derived suppressor Clin Invest 97:2792-2802 (1996)), ENA-78 (Arenberg et al. cells) and endothelial cells to sites of inflammation and J Clin Invest 102:465-72 (1998)), and CXCL1 (Haghnegah tumor growth. There are two main classes of chemokines, the CXC-chemokines and the CC-chemokines. The class dar et al. J. Leukoc Biology 67:53-62 (2000)). depends on whether the first two cysteines are adjacent 0008. Many tumor cells express CXCR2 and tumor cells (CC-chemokines), or are separated by a single amino acid may thereby stimulate their own growth by secreting ELR (CXC-chemokines). There are currently at least 17 known CXC chemokines. Thus, in addition to with decreasing CXC-chemokines, which include but are not limited to angiogenesis within tumors, CXCR2 inhibitors may directly CXCL1 (GROC), CXCL2 (GROB), CXCL3 (GROY), inhibit the growth of tumor cells. CXCL4 (PF4), CXCL5 (ENA-78), CXCL6 (GCP-2, CXCL7 (NAP-2), CXCL8 (IL-8, NAP-1), CXCL9 (MIG) 0009 CXCR2 is often expressed by myeloid-derived and CXCL10 (IP-10). There are currently at least 28 known suppressor cells (MDSC) within the microenvironment of CC chemokines, which include but are not limited to CCL2 tumors. MDSC are implicated in the suppression of tumor (MCP-1), CCL3 (MIP-1C), CCL4 (MIP-1 B), CCL5 immune responses, and migration of MDSC in response to (RANTES), CCL7 (MCP-3), CCL8 (MCP-2), CCL-11 (eo CXCR2 ligand chemokines is most likely responsible for taxin-1) and CCL20 (MIP-3 O.). Individual members of the attracting these cells into tumors. (see Marvel and chemokine families are known to be bound by at least one Gabrilovich, J. Clin. Invest. 13:1 (2015) and Mackall et al., chemokine receptor, with CXC-chemokines generally Sci. Trans. Med. 6:237 (2014). Thus, CXCR2 inhibitors may bound by members of the CXCR class of receptors, and reverse Suppressive processes and thereby allow immune CC-chemokines by members of the CCR class of receptors. cells to more effectively reject the tumor. In fact, blocking For example, CXCL8/IL-8 is bound by the receptors the activation of CXC-chemokine receptors has proven CXCR1 and CXCR2. useful as a combination therapy with checkpoint inhibitors 0005 Since CXC-chemokines often promote the accu in Suppressing tumor growth, Suggesting that CXCR2 block mulation and activation of neutrophils, these chemokines are ade may also enhance tumor rejection in combination with implicated in a wide range of acute and chronic inflamma other anti-tumor therapies, including but not limited to tory disorders such as psoriasis, rheumatoid arthritis, radia vaccines or traditional cytotoxic chemotherapies (see High tion-induced fibrotic lung disease, autoimmune bullous der fill et al., Science Translational Medicine, 6:237 (2014)). matoses (AIBD), chronic obstructive pulmonary disease (COPD) and ozone-induced airway inflammation (see, Bag 0010 Hence, the CXC-chemokine receptors represent giolini et al., FEBS Lett. 307:97 (1992); Miller et al., Crit. promising targets for the development of novel anti-inflam Rev. Immunol. 12:17 (1992); Oppenheim et al., Annu. Rev. matory and anti-tumor agents. Immunol. 9: 617 (1991); Seitz et al., J. Clin. Invest. 87: 463 0011. There remains a need for compounds that are (1991); Miller et al., Ann. Rev. Respir: Dis. 146:427 (1992); capable of modulating activity at CXC-chemokine recep and Donnely et al., Lancet 341: 643 (1993), Fox & Haston, tors. For example, conditions associated with an increase in Radiation Oncology, 85:215 (2013), Hirose et al., J. Genet. IL-8 production (which is responsible for chemotaxis of Syndr. Genet. Ther. S3:005 (2013), Miller et al., Eur: J. Drug neutrophil and T-cell subsets into the inflammatory site and Metab. Pharmacokinet. 39:173 (2014), Lazaar et al., Br. J. growth of tumors) would benefit by compounds that are Clin. Pharmacol., 72:282 (2011)). inhibitors of IL-8 receptor binding. US 2017/O 144996 A1 May 25, 2017 BRIEF SUMMARY OF THE INVENTION 0017. In some embodiments, an amount of a chemothera peutic agent or radiation is administered to the Subject prior 0012 Provided herein, in one aspect, are compounds to. Subsequent to or in combination with the compounds having formula (I), provided herein. In some embodiments, the amount is Sub therapeutic when the chemotherapeutic agent or radiation is administered alone. (I) R” O O BRIEF DESCRIPTION OF THE DRAWINGS R al R3a 0018 FIGS. 1A-1J provide structures and biological 2 \ ill R' activity for compounds described herein.