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CA-3005656-C - OXOISOINDOLINYL COMPOUNDS AS MODULATORS OF CHEMOKINE RECEPTORS

CA3005656CCA 3005656 CCA3005656 CCA 3005656CCA-3005656-C

Abstract

Compounds are provided as chemokine inhibitors having the structure: Formula (A).

Inventors

  • Xi Chen
  • Hiroko Tanaka
  • Ju Yang
  • Chao Yu
  • Penglie Zhang
  • Dean R. DRAGOLI
  • Junfa FAN
  • Jaroslaw Kalisiak
  • Antoni Krasinski
  • Manmohan Reddy Leleti
  • Venkat MALI
  • Jeffrey MCMAHON
  • Rajinder Singh

Assignees

  • CHEMOCENTRYX, INC.

Dates

Publication Date
20260505
Application Date
20161117
Priority Date
20151119

Claims (20)

  1. 140 CLAIMS: 1. A compound having the Formula (A): (A) wherein is independently selected from the group consisting of ; B is furanyl or oxazolyl, each of which is optionally substituted with R1a and R1b which are independently selected from the group consisting of halogen, CN, C1-4 alkyl, C1-4 alkoxy and C1-4 haloalkyl; R3 is selected from the group consisting of H and D; R4 is selected from the group consisting of H, C1-8 alkyl, OH, - NRaRb, -C1-4 alkoxy, and Y; wherein the C1-8 alkyl is optionally substituted with halogen, -CN, -CO2Ra, -CONRaRb, - C(O)Ra, OC(O)NRaRb, -NRaC(O)Rb, -NRaC(O)2Rc, -NRaC(O)NRaRb, -NRaRb, -ORa, - S(O)2NRaRb, -NRaS(O)2Rb and Y, wherein Y is a 4 to 8 membered cycloheteroalkyl group or a 3 to 8 membered cycloalkyl group, a phenyl, or a 5- or 6-membered heteroaryl, wherein the cycloheteroalkyl, cycloalkyl, phenyl or heteroaryl is optionally substituted with from 1 to four substituents selected from halogen, oxo, -CN, -C1-6 alkyl, - 141 C1-6 alkoxy, -C1-6 hydroxyalkyl, -C1-6 haloalkyl, O- C1-6 haloalkyl, -C1-4alkyl-O-C1-4 alkyl, -C1-6 alkyl-NRaRb , -C1-6 alkyl-CO2H, -C1-6 alkyl-CO2Ra, -C1-6 alkyl-CONRaRb, - C1-6 alkyl-C(O)Ra, -C1-6 alkyl-OC(O)NRaRb, -C1-6 alkyl-NRaC(O)Rb, -C1-6 alkyl- NRaC(O)2Rc, -C1-6 alkyl-NRaC(O)NRaRb, -C1-6 alkyl-ORa, -C1-6 alkyl-S(O)2NRaRb, -C1-6 alkyl-NRaS(O)2Rb , -CO2Ra, -CONRaRb, -C(O)Ra, -OC(O)NRaRb, -NRaC(O)Rb, - NRaC(O)2Rc, -NRaC(O)NRaRb, -NRaRb, -ORa, -S(O)2NRaRb, -NRaS(O)2Rb, and - CH2CO2Ra; each Ra and Rb is independently selected from hydrogen, C1-4 alkyl, C1-4 hydroxyalkyl and C1-4 haloalkyl, and Rc is selected from C1-4 alkyl, C1-4 hydroxyalkyl and C1-4 haloalkyl; and wherein the 4 to 8 membered cycloheteroalkyl group and the 3 to 8 membered cycloalkyl group may additionally be optionally substituted with oxo; R5a and R5b are each independently selected from the group consisting of H, halogen, C1-4 alkyl, C1-4 haloalkyl, O-C1-4 haloalkyl, C1-4 alkoxy, CO2H and CN; and R7 is selected from the group consisting of methyl, ethyl and C1-2 haloalkyl; wherein each 5- or 6-membered heteroaryl has from one to four heteroatoms as ring vertices selected from N, O, and S, and each 4 to 8 membered cycloheteroalkyl group has from one to five heteroatoms as ring vertices selected from N, O, and S; or a pharmaceutically acceptable salt or tautomer thereof.
  2. 2. The compound of claim 1, or a pharmaceutically acceptable salt or tautomer thereof, wherein R4 is H, C1-3 alkyl or Y, wherein the C1-3 alkyl is substituted with tetrazolyl or tetrazolonyl, wherein the tetrazolyl or tetrazolonyl is optionally substituted with C1-6 alkyl, C1-6 hydroxyalkyl, or C1-4alkyl-O-C1-4alkyl wherein Y is selected from the group consisting of pyridinyl, pyrazolyl, and phenyl wherein the pyridinyl, pyrazolyl, and phenyl have from one to three substituents each of which is independently selected from -C1-4 alkyl, -C1-4 alkoxy and -CO2H.
  3. 3. The compound of claim 1, or a pharmaceutically acceptable salt or tautomer thereof, wherein R4 is selected from the group consisting of: 142
  4. 4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt or tautomer thereof, wherein R7 is selected from the group consisting of methyl, ethyl and CF3.
  5. 5. The compound of claim 1 having the Formula (I): (I) wherein is independently selected from the group consisting of ; 143 B is furanyl or oxazolyl, each of which is optionally substituted with R1a and R1b which are independently selected from the group consisting of halogen, CN, C1-4 alkyl, C1-4 alkoxy and C1-4 haloalkyl; R3 is selected from the group consisting of H and D; R4 is selected from the group consisting of H, C1-8 alkyl, and Y; wherein the C1-8 alkyl is optionally substituted with halogen, -CN, -CO2Ra, -CONRaRb, -C(O)Ra, OC(O)NRaRb, - NRaC(O)Rb, -NRaC(O)2Rc, -NRaC(O)NRaRb, -NRaRb, -ORa, -S(O)2NRaRb, -NRaS(O)2Rb and Y, wherein Y is a phenyl or a 5- or 6-membered heteroaryl, wherein the phenyl or heteroaryl is substituted with from one to four substituents selected from halogen, -CN, - C1-4 alkyl, -C1-4 alkoxy, -C1-4 hydroxyalkyl, -C1-4 haloalkyl, OCF3, -CO2Ra, -CONRaRb, - C(O)Ra, -OC(O)NRaRb, -NRaC(O)Rb, and -CH2CO2Ra; and each Ra and Rb is independently selected from hydrogen, C1-4 alkyl, C1-4 hydroxyalkyl and C1-4 haloalkyl, and Rc is selected from C1-4 alkyl, C1-4 hydroxyalkyl and C1-4 haloalkyl; R5a and R5b are each independently selected from the group consisting of H, halogen, C1-4 alkyl, C1-4 alkoxy, CO2H and CN; or a pharmaceutically acceptable salt or tautomer thereof.
  6. 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt or tautomer thereof, wherein B is selected from the group consisting of: .
  7. 7. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt or tautomer thereof, wherein B is furanyl substituted with R1a which is CH3 or Cl and optionally substituted with R1b which is CH3. 144
  8. 8. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt or tautomer thereof, wherein: B is selected from the group consisting of:
  9. 9. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt or tautomer thereof, wherein R3 is H.
  10. 10. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt or tautomer thereof, wherein each of R5a and R5b is independently selected from the group consisting of H, CH3, Cl and F.
  11. 11. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt or tautomer thereof, wherein is selected from the group consisting of: 145 .
  12. 12. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt or tautomer thereof, wherein is selected from the group consisting of:
  13. 13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt or tautomer thereof, wherein 146 is independently selected from the group consisting of
  14. 14. The compound of claim 1, having the formula (A1): (A1) wherein R1a is selected from CH3 and Cl; R1b is H or is CH3; R3 is H or D; R4 is H or Y; R5a and R5b are each independently selected from H, F, Cl, Br and CH3; R6a and R6b are each independently selected from H and CH3; and R7 is methyl or ethyl; or a pharmaceutically acceptable salt or tautomer thereof.
  15. 15. The compound of claim 14, wherein R1a is CH3; R1b is H or is CH3; R3 is H or D; R4 is H; R5a is H, F, Me or Cl or Br; R5b is H or F; R6a and R6b are each H; and R7 is methyl or ethyl; or a pharmaceutically acceptable salt or tautomer thereof.
  16. 16. The compound of claim 14, wherein R4 is Y; or a pharmaceutically acceptable salt or tautomer thereof.
  17. 17. The compound of claim 1, having the formula (A2): 147 (A2) wherein R1a is selected from CH3 and Cl; R1b is H or CH3; R3 is H or D; R4a and R4b are independently selected from halogen, -CN, -C1-4 alkyl, -C1-4 alkoxy, -C1-4 hydroxyalkyl, -C1-4 haloalkyl, OCF3, -CO2Ra, -CONRaRb, -C(O)Ra, -OC(O)NRaRb, -NRaC(O)Rb, and -CH2CO2Ra, and Ra and Rb are independently selected from hydrogen, C1-4 alkyl, C1-4 hydroxyalkyl and C1-4 haloalkyl; R5a and R5b are each independently selected from H, F, Cl, Br and CH3; R6a and R6b are each independently selected from H and CH3; and R7 is selected from the group consisting of methyl, ethyl and C1-2 haloalkyl; or a pharmaceutically acceptable salt or tautomer thereof.
  18. 18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt or tautomer thereof, which compound is substantially free of other isomers at the carbon atom bearing R3.
  19. 19. The compound of claim 1 selected from the group consisting of: 148 149 150 151 152 153 154 O O F N O N N O O N F N O N O O and , or a pharmaceutically acceptable salt or tautomer thereof.
  20. 20. The compound of claim 1 selected from the group consisting of: 155 and , or a pharmaceutically acceptable salt or tautomer thereof.

Description

OXOISOINDOLINYL COMPOUNDS AS MODULATORS OF CHEMOKINE RECEPTORS [0001] STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLYSPONSOREDRESEARCHANDDEVELOPMENT [0002] NOT APPLICABLE REFERENCE TO A "SEQUENCE LISTING," A TABLE, OR A COMPUTER PROGRAM LISTING APPENDIX SUBMITTED ON A COMPACT DISK [0003] NOT APPLICABLE BACKGROUND OF THE INVENTION [0004] Chcmokincs arc chcmotactic cytokincs that arc released by a wide variety of cells to attract macrophages, lymphocytes, eosinophils, basophils and neutrophils to sites of inflammation (reviewed in Schall, C,ytokine, 3:165-183 (1991), Schall, et al., Curr Opin. lmmunol. 6:865-873 (1994) and Murphy, Rev. lmmun., 12:593-633 (1994)). In addition to 20 stimulating chemota.xis, other changes can be selectively induced by chemokines in responsive cells, including changes in cell shape, transient rises in the concentration of inlrncellular free calcium ions ([Ca2+]), granule cxocytosis, intcgrin uprcgulation, formation ofbioactivc lipids (e.g., leukotrienes) and respiratory burst, which is associated with leukocyte activation. Thus, the chemokines are early triggers of the inflammatory response, Date Rer;ue/Date Received 2023-11-08 WO 2017/087607 PCT/0S2016/062417 causing inflammatory mediator release, chemotaxis and extravasation to sites of infection or inflammation. [0005] There are two main classes of chemokines, CXC (alpha) and CC (beta), depending on whether the first two cysteines are separated by a single amino acid (C-X-C) or are 5 adjacent (C-C). The alpha-chemokines, such as CXCLl (GROa) and CXCL8 ( interleukin-8, IL-8) are chemotactic primarily for neutrophils, whereas beta-chemokines, such as CCL5 (RANTES) and CCL20 (LARC, MIP-3a), are chemotactic for T cells, B cells, macrophages, eosinophils and basophils (Deng, et al., Nature, 381:661-666 (1996)). The chemokines bind specific cell-surface receptors belonging to the family ofG-protein-coupled seven- 10 transmembrane-domain proteins (reviewed in Horuk, Trends Pharm. Sci., 15:159-165 (1994)) which are termed "chemokine receptors." [0006] On binding their cognate ligands, chemokine receptors transduce an intracellular signal through the associated trimeric G protein, resulting in a rapid increase in intracellular calcium concentration. There are at least eleven human chemokine receptors that bind or 15 respond to beta-chemokines and at least seven human chemokine receptors that bind to the alpha chemokines. Additionally CX3CR1 (fractalkine receptor) can bind to the fractalkine chemokine, which is distinguished by a series of three amino acids between the first two cysteines. Chemokine receptors, have been implicated as being important mediators of inflammatory and immunoregulatory disorders and diseases, including asthma and allergic 20 diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. [0007] The chemokine receptor CCR6 is known to be expressed by memory (but not naive) CD4 T cells, IL 17-secreting «P T cells, ILl 7-secreting y6 T cells, regulatory T cells, B cells and dendritic cells. Its only known ligand is CCL20 (MIP-3a, LARC), for which it shows strong binding. It is expressed on approximately 30-60% of adult peripheral blood 25 effector/memory CD4+ T cells. CCR6 is involved in leukocyte homing to inflamed tissue, particularly the skin, lungs and gut; and is co-expressed on a subset of T cells that have a skin homing phenotype (i.e., T cells that express the cutaneous lymphocyte antigen (CLA) and CCR4) . Thus CCR6 may be an important player in skin pathologies in which leukocytes participate. 30 [0008] CCR6 expression has been linked to psoriasis. In humans, a large majority ofIL17- expressing skin-homing CD4 T cells in the peripheral blood express CCR6 (Homey, et. al., JI, 2000). ILi 7 secreting cells are central agents in several inflammatory diseases. T cells, 2 WO 2017/087607 PCT/0S2016/062417 such as y6 T cells and TH 17 T cells produce IL 17 after activation. The pathogenic effects of IL17 have been associated with human diseases such as rheumatoid arthritis (Patel DD et. al., Ann Rheum Dis 2013), multiple sclerosis (Zepp J, Wu L, and X Li Trends lmmunol 2011), and psoriasis (Martin DA et. al., J lnvestDermatol 2012). Evidence strongly linking ILi 7 5 with psoriasis include gene wide association studies that show strong association between psoriasis and genes upstream (IL-23) or downstream (NFK:b) of IL 17 signaling pathways as well as efficacy in targeting ILi 7 in a clinical setting (Martin DA et. al., J. Invest Dermat. 2012; Papp et. al., NEJM, 2012; Papp et. al., NEJM, 2012). In addition to enhanced CCL20- mediated chemotaxis, CCR6+ T cells isolated from psoriatic patients preferentially secrete 10 IL-l 7A, IL22, and TNFa when compared to healthy controls (Kagami, et. al., J. lnvest. Dermatol., 2010). Lastly, ccl20 mRNA was up-regulated in lesional psoriatic skin samples (Homey, et. al., JI, 2000; Dieu-Nosjean, et. al., JEM, 2000). In mice, CCR6 knock-ou