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CN-108697684-B - Modulators of chemokine receptors

CN108697684BCN 108697684 BCN108697684 BCN 108697684BCN-108697684-B

Abstract

Providing a compound having formula (a) as a chemokine inhibitor:

Inventors

  • CHEN XI
  • TANAKA YUKO
  • YANG JU
  • YU CHAO
  • ZHANG PENGLIE
  • D - R - dragolj
  • FAN JUNFA
  • J Kailixi.
  • A krasinski
  • M R Le Le
  • MALI VIKAS
  • J. MCMAHON
  • R. SINGER

Assignees

  • 凯莫森特里克斯股份有限公司

Dates

Publication Date
20260508
Application Date
20161117
Priority Date
20151119

Claims (20)

  1. 1. A compound having formula (A), or a pharmaceutically acceptable salt, tautomer, or rotamer thereof, (A) Wherein, the Selected from the group consisting of: ; b is selected from the group consisting of: ; r 3 is a member selected from H and D; R 4 is selected from H, C 1-3 alkyl or Y, wherein C 1-3 alkyl is substituted with tetrazolyl or tetrazolonyl (tetrazolonyl), wherein tetrazolyl or tetrazolonyl is substituted with 0 or 1 group selected from C 1-6 alkyl, C 1-6 hydroxyalkyl or C 1-4 alkyl-O-C 1-4 alkyl, wherein Y is selected from the group consisting of pyridinyl, pyrazolyl and phenyl, wherein pyridinyl, pyrazolyl and phenyl have 1-3 substituents independently selected from halogen, -C 1-4 alkyl, -C 1-4 alkoxy and-CO 2 H; R 5a and R 5b are members each independently selected from H, halogen, C 1-4 alkyl, -C 1-4 haloalkyl, O-C 1-4 haloalkyl, C 1-4 alkoxy, CO 2 H, and CN; R 7 is a member selected from methyl, ethyl, and C 1-2 haloalkyl.
  2. 2. The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, or rotamer thereof, wherein B is selected from the group consisting of: 。
  3. 3. the compound of claim 1, or a pharmaceutically acceptable salt, tautomer, or rotamer thereof, wherein R 3 is H.
  4. 4. The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, or rotamer thereof, wherein each R 5a and R 5b is independently selected from the group consisting of H, CH 3 , cl, and F.
  5. 5. The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, or rotamer thereof, wherein Selected from the group consisting of: 。
  6. 6. The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, or rotamer thereof, wherein Selected from the group consisting of: 。
  7. 7. The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, or rotamer thereof, wherein R 6a and R 6b are each independently selected from H and C 1-2 alkyl.
  8. 8. The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, or rotamer thereof, wherein R 4 is selected from the group consisting of: 。
  9. 9. The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, or rotamer thereof, wherein R 7 is selected from the group consisting of methyl, ethyl, and CF 3 .
  10. 10. The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, or rotamer thereof, which is substantially free of other isomers at the carbon atom bearing R 3 .
  11. 11. The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, or rotamer thereof, wherein R 4 is Y.
  12. 12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: And 。
  13. 13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: 。
  14. 14. the compound of claim 1, or a pharmaceutically acceptable salt thereof, having the formula: 。
  15. 15. the compound of claim 1, or a pharmaceutically acceptable salt thereof, having the formula: 。
  16. 16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the formula: 。
  17. 17. the compound of claim 1, or a pharmaceutically acceptable salt thereof, having the formula: 。
  18. 18. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: 。
  19. 19. a pharmaceutical composition comprising a compound according to any one of claims 1 to 18.
  20. 20. Use of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19, for the manufacture of a medicament for the treatment of a CXCR2 and/or CCR6 mediated disease or condition, wherein the CXCR2 and/or CCR6 mediated disease or condition is psoriasis.

Description

Modulators of chemokine receptors Cross Reference to Related Applications The present application is the priority application of U.S. provisional application No. 62/257,389 and U.S. provisional application No. 62/277,711 filed on 1-12 of 2016, each of which is hereby incorporated by reference in its entirety, as if set forth in 35u.s.c. ≡119 (e) claiming to be filed on 11-19 of 2015. Claim of rights to inventions under federally sponsored research and development Is not suitable for List attachment of computer program referring to 'sequence list', table or submitting in CD form Is not suitable for Background Chemokines are chemotactic cytokines that are released by various cells to attract macrophages, lymphocytes, eosinophils, basophils and neutrophils to sites of inflammation (reviewed in Schall, cytokines (Cytokine), 3:165-183 (1991), schall et al, curr opin. Immunol.6:865-873 (1994) and Murphy, rev. Immun.,12:593-633 (1994)). In addition to stimulating chemotaxis, chemokines can selectively induce other changes in responding cells, including changes in cell shape, transient increases in intracellular free calcium ion ([ Ca 2+ ]) concentration, granule exocytosis, integrin upregulation, formation of bioactive lipids (e.g., leukotrienes), and respiratory burst, which are associated with leukocyte activation. Thus, chemokines are early triggers of inflammatory responses, causing inflammatory mediator release, chemotaxis, and extravasation to the site of infection or inflammation. There are two main classes of chemokines, CXC (α) and CC (β), depending on whether the first two cysteines are separated by a single amino acid (C-X-C) or adjacent (C-C). Alpha-chemokines such as CXCL1 (GROα) and CXCL8 (interleukin-8, IL-8) are primarily chemotactic for neutrophils, while beta-chemokines such as CCL5 (RANTES) and CCL20 (LARC, MIP-3 α) are chemotactic for T cells, B cells, macrophages, eosinophils and basophils (Deng et al, nature 381:661-666 (1996)). Chemokines bind to specific cell surface receptors belonging to the family of G protein-coupled seven-transmembrane proteins (reviewed in Horuk, trends pharm.sci.,15:159-165 (1994)), which are termed "chemokine receptors". Upon binding their cognate ligands, chemokine receptors transduce intracellular signals through the associated trimeric G protein, resulting in a rapid increase in intracellular calcium concentration. At least 11 human chemokine receptors bind or respond to beta chemokines and at least 7 human chemokine receptors bind alpha chemokines. Furthermore, CX3CR1 (fractal chemokine) receptor can bind to fractal chemokines, which are distinguished by a series of three amino acids between the first two cysteines. Chemokine receptors are important mediators of inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune diseases, such as rheumatoid arthritis and atherosclerosis. Chemokine receptor CCR6 is known to be expressed by memory (rather than naive) CD4T cells, αβ T cells that secrete IL17, γδ T cells that secrete IL17, regulatory T cells, B cells, and dendritic cells. The only known ligand is CCL20 (MIP-3α, LARC), which shows strong binding to others. It is expressed on approximately 30-60% of adult peripheral blood effectors/memory cd4+ T cells. CCR6 is involved in leukocyte homing to inflammatory tissues, particularly skin, lung and intestine, and is co-expressed on a subset of T cells with a skin homing phenotype, i.e., T cells expressing the skin lymphocyte antigen (CLA) and CCR 4. CCR6 is therefore likely an important participant in the participation of leukocytes in skin lesions. CCR6 expression is associated with psoriasis. In humans, most skin homing CD4T cells expressing IL17 in peripheral blood express CCR6 (Homey et al, JI, 2000). In several inflammatory diseases, IL17 secreting cells are central mediators. T cells, such as γδ T cells and TH17T cells, produce IL17 after activation. Pathogenic effects of IL17 are associated with human diseases such as rheumatoid arthritis (Patel DD et al, ann Rheum Dis 2013), multiple sclerosis (Zepp J, wu L, and xli, trends Immunol 2011) and psoriasis (Martin DA et al, j. Invest Dermatol 2012). Evidence of a strong link between IL17 and psoriasis includes genome-wide association studies that indicate that psoriasis is closely related to either the upstream gene (IL-23) or the downstream gene (NFb) of the IL17 signaling pathway, as well as to the efficacy of targeting IL17 in a clinical setting (Martin DA et al, j. Invest dermat.2012; papp et al, NEJM, 2012). In addition to enhanced CCL 20-mediated chemotaxis, ccr6+ T cells isolated from psoriatic patients preferentially secrete IL-17A, IL and tnfα compared to healthy control groups (Kagami et al, j. Invest. Dermotol., 2010). Finally, CCL20mRNA up-regulates expression in focal psoriasis skin samples (Homey et al, JI,2000; dieu-Nosjean et al, JEM, 2000). In mice, CCR6 knockout mice are protected from I