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CA-3086370-C - TRICYCLIC INHIBITORS OF THE BCL6 BTB DOMAIN PROTEIN-PROTEIN INTERACTION AND USES THEREOF

CA3086370CCA 3086370 CCA3086370 CCA 3086370CCA-3086370-C

Abstract

The present application relates to compounds of Formula (I) or pharmaceutically acceptable salts, solvates and/or prodrugs thereof, to compositions comprising these compounds or pharmaceutically acceptable salts, solvates and/or prodrugs thereof, and various uses in the treatment of diseases, disorders or conditions that are treatable by inhibiting interactions with BCL6 BTB, such as cancer.

Inventors

  • Anh My Chau
  • Methvin Isaac
  • Rima Al-Awar
  • Gennady Poda
  • David Uehling
  • Brian Wilson
  • Pandiaraju Subramanian
  • Ahmed Mamai
  • Iain Watson

Assignees

  • ONTARIO INSTITUTE FOR CANCER RESEARCH (OICR)

Dates

Publication Date
20260505
Application Date
20181221
Priority Date
20171221

Claims (20)

  1. Claims: 1. A compound of formula I, or a pharmaceutically acceptable salt, and/or solvate thereof: (I) wherein X is selected from CR4R5, O, S, S(O), SO2 and NR4; X1, X2 and X3 are independently selected from CR6 and N, or X2 and X3 are linked to form, together with the carbon atoms to which they are attached, a 3-8-membered heterocycloalkyl or heteroaromatic ring, both of which optionally contain one to two additional heteroatoms selected from O, S, S(O), SO2 and NR7; Cy1 is selected from phenyl and C5-6heteroaryl, both of which are unsubstituted or substituted with one to three substituents selected from halo, C1-6alkyl and OC1-6alkyl; R1 is selected from C(O)NR8R9, C(O)OR8, CN and ; R2 and R3 are independently selected from H, C1-10alkyl and C1-6alkylene-O-C1-6alkyl, or R2 and R3 are linked to form, together with the nitrogen atom to which they are attached, a 3-10-membered heterocycloalkyl or heteroaromatic ring, both of which optionally contain one to two additional heteroatoms selected from O, S, S(O), SO2, NH and NR10, and both of which are unsubstituted or substituted with one to four substituents selected from R11; R4 and R5 are independently selected from H and C1-6alkyl; R6 is selected from H, OH, OC1-6alkyl, C1-6alkyl and halo; R7 is selected from H and C1-6alkyl; R8 and R9 are independently selected from H and C1-6alkyl; R10 is selected from C1-10alkyl, ZC3-10cycloalkyl, ZC3-10heterocycloalkyl, ZC6-10aryl and ZC5-10heteroaryl, each of which is unsubstituted or substituted with one to three substituents selected from C1-6alkyl, OC1-6alkyl, OH and halo; R11 is selected from C1-10alkyl, OC1-6alkyl, OH, C1-6alkylene-O-C1-6alkyl, C1-10alkylene-OH C1-10alkylene(OH)2 and halo; Z is selected from a direct bond and C1-6alkylene; n and m are independently selected from 0, 1, 2 and 3; and all alkyl and alkylene groups are optionally fluoro-substituted.
  2. 2. The compound of claim 1, wherein X is selected from CR4R5, O and NR4, and R4 and R5 are independently selected from H and C1-4alkyl.
  3. 3. The compound of claim 2, wherein X is selected from CR4R5, O and NR4, and R4 and R5 are independently selected from H and CH3.
  4. 4. The compound of claim 3, wherein X is selected from CH2, CHCH3, C(CH3)2 and O.
  5. 5. The compound of any one of claims 1 to 4, wherein X1, X2 and X3 are independently selected from CR6 and N, and R6 is selected from H, OH, C1-4alkyl, OC1-4alkyl, F and Cl.
  6. 6. The compound of claim 5, wherein X1, X2 and X3 are independently selected from CH, CF, CCl, CCH3, COCH3 and N.
  7. 7. The compound of claim 6, wherein X1 is CH and X2 and X3 are independently selected from CH, CF, CCl and COCH3.
  8. 8. The compound of any one of claims 1 to 4, wherein X2 and X3 are linked to form, together with the carbon atoms to which they are attached, a 4-6-membered heterocycloalkyl ring which optionally contains one or two additional heteroatoms selected from O, S, S(O), SO2 and NR7, and R7 is selected from H and C1-4alkyl.
  9. 9. The compound of claim 8, wherein X2 and X3 are linked to form, together with the carbon atoms to which they are attached, a 5-6-membered heterocycloalkyl ring which CA 3086370 optionally contain one or two additional heteroatom selected from O and NR7, and R7 is selected from H and CH3.
  10. 10. The compound of claim 9, wherein X2 and X3 are linked to form, together with the carbon atoms to which they are attached, a 5-membered heterocycloalkyl ring which optionally contains one additional heteroatom selected from O and NR7, and R7 is selected from H and CH3.
  11. 11. The compound of any one of claims 1 to 10, wherein Cy1 is selected from phenyl and C6heteroaryl, both of which are unsubstituted or substituted with one to three substituents selected from Cl, F, C1-4alkyl and OC1-4alkyl.
  12. 12. The compound of claim 11, wherein Cy1 is selected from phenyl and pyridyl, both of which are unsubstituted or substituted with one to two substituents selected from Cl, F, CH3 and OCH3.
  13. 13. The compound of any one of claims 1 to 12, wherein R1 is selected from C(O)NR8R9 and CN, and R8 and R9 are independently selected from H and C1-4alkyl.
  14. 14. The compound of any one of claims 1 to 12, wherein R1 is C(O)NH2.
  15. 15. The compound of any one of claims 1 to 14, wherein R2 and R3 are independently selected from H, C1-6alkyl and C1-4alkylene-O-C1-4alkyl.
  16. 16. The compound of claim 15, wherein R2 and R3 are independently selected from C1-6alkyl and C1-4alkylene-O-C1-4alkyl.
  17. 17. The compound of claim 16, wherein R2 and R3 are independently selected from C1-6alkyl.
  18. 18. The compound of any one of claims 1 to 14, wherein R2 and R3 are linked to form, together with the nitrogen atom to which they are attached, a 4-10-membered heterocycloalkyl ring, which optionally contains one to two additional heteroatoms selected from O, S, S(O), SO2, NH and NR10, and is unsubstituted or substituted with one to four substituents selected from R11. CA 3086370
  19. 19. The compound of claim 18, wherein R2 and R3 are linked to form, together with the nitrogen atom to which they are attached, a 5-10-membered heterocycloalkyl ring, which optionally contains one additional heteroatom selected from O, NH and NR10, and is unsubstituted or substituted with one to four substituents selected from R11.
  20. 20. The compound of claim 19, wherein R2 and R3 are linked to form, together with the nitrogen atom to which they are attached a heterocycloalkyl ring selected from: , each of which is unsubstituted or substituted with one or two substituents selected from R11.

Description

TITLE: TRICYCLIC INHIBITORS OF THE BCL6 BTB DOMAIN PROTEINPROTEIN INTERACTION AND USES THEREOF [0001] Intentionally Left Blank FIELD [0002] The present application relates to novel tricyclic compounds, to processes for their preparation, to compositions comprising them, and to their use in therapy. More particularly, it relates to tricyclic compounds useful in the treatment of diseases, disorders or conditions treatable by inhibiting or blocking the interaction of BCL6 BTB domain with its binding partners. BACKGROUND [0003] BCL6 (B Cell Lymphoma 6) is a member of the BTB/POZ (bric-abrac, tramtrack, broad complex/pox virus zinc finger) family of transcription factors. The BCL6 gene was initially cloned by several groups in 1993 from a translocation occurring on chromosome 3q27 in diffuse large B-cell lymphoma (DLBCL) [Histol Histopathol 2004, 19:637-650]. Targeted disruption of the BCL6 gene revealed that BCL6 during normal B-cell development is a master regulator of antibody affinity maturation in germinal centers (GCs) [Nat Rev lmmunol 2008, 8:22-33]. BCL6 is almost universally expressed in GC-derived B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL) and follicular lymphomas (FLs), regardless of translocations. [0004] In normal lymphoid biology, BCL6 is required for na"ive B cells to form GCs which are cellular compartments dedicated to the affinity maturation of antibodies. The GC is the site of two key molecular processes unique to Bcells: somatic hypermutation (SHM) and class switching recombination (CSR) [Trends Biochem Sci 2003, 28: 305-312]. Upon antigen-induced B-cell activation, B-cells proliferate and differentiate into either centroblasts or plasma cells [Annu Rev lmmunol 1994 12: 117-139]. The centroblasts go through the dark zone of the GC where they rapidly proliferate, differentiate and revise their Date Rer;ue/Date Received 2024-03-27 antigen receptors via SHM and CSR [Ce// 1991 67: 1121-9; Nature 1991 354: 389-92; Ce// 1981 27: 573-581]. SHM modulates the affinity of the antibodies to a specific antigen and, while not wishing to be limited by theory, it is believed that the mistargeting of SHM can result in the translocation of oncogenes. [0005] BCL6 is a transcriptional repressor that reduces mRNA expression of its target genes by regulating survival and differentiation via distinct corepressor complexes [Proc Natl Acad Sci US A, 2007. 104(9): 3207- 12; Blood 2007. 110(6): 2067-74.; Biochem Biophys Res Commun, 2003. 300(2): 391-6]. BCL6 has six zinc fingers at its carboxyl terminus mediating sequence-specific DNA binding to regulatory sequences [Nat lmmunol, 2007. 8(7): p. 705-14]. BCL6 binds to DNA as a homo-dimer and recruits, through its N-terminal domain, class I and II histone deacetylase complexes (HDACs) either directly or through corepressor molecules such as SMRT, NCOR1 and BCOR. [0006] Different subsets of target genes appear to be repressed depending on which corepressors are engaged by BCL6 through the BTB domain [Blood 2007. 110(6): 2067-74]. The corepressors that bind to the BTB appear to be involved in the regulation of transcription associated with early stages of the GC process. Genome-wide studies indicate that BCL6 may, for example, target as many as 500 genes [Blood 2007. 110(6): 2067-74] mainly involved in cell cycle, gene transcription, DNA damage sensing, protein ubiquitylation and chromatin structure modification. [0007] Direct BCL6 repressed target genes include ataxia telangectasia and Rad3 related (ATR), CHK1 checkpoint homolog (S. pombe) (CHEK1), tumor protein p53 (TP53) and cyclin dependent kinase inhibitor 1A or p21 (CDKN1A) [Nat lmmunol, 2007. 8(7): 705-14]. These genes belong to survival pathways involved in DNA damage sensing and checkpoint activation. They are primarily regulated through the SMRT and NCOR corepressors. Both of these corepressors contain a highly conserved 17-residue BCL6 binding domain (BBD) that interacts with the homodimeric BTB domain [Mo/ Ce//, 2003. 12(6): 11561- 64] forming a promoter-localized protein complex. This complex represses the transcription of target genes such as ATR, TP53 and CDKN1A which in turn attenuates the DNA damage response and promote cell survival. [0008] In addition to its role in survival, BCL6 also regulates differentiation through a specific BCL6 corepressor complex that represses B-lymphocyteinduced maturation protein1 or PRDM1 (BLIMP1 ), a transcription factor that promotes plasmacytic differentiation [Ce//, 2004. 119(1 ): 75-86]. Maturation of GC B cells toward memory B-cells and plasma cells usually requires the downregulation of BCL6. Such down-regulation of BCL6 function can occur via antigeninduced B cell receptor (BCR) mediated activation that subsequently leads to rapid BCL6 proteasomal degradation [Genes Dev, 1998. 12(13): 1953-61]. Alternatively, T-cell-mediated stimulation through the CD40 pathway leads to NF-KB driven induction of interferon regulatory factor 4 (IRF4), a regulato