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CA-3088025-C - INHIBITORS OF THE BCL6 BTB DOMAIN PROTEIN-PROTEIN INTERACTION AND USES THEREOF

CA3088025CCA 3088025 CCA3088025 CCA 3088025CCA-3088025-C

Abstract

The present application relates to compounds of Formula I (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
  • Michael Prakesch
  • Iain Watson
  • Justin-Alexander Morin
  • Methvin Isaac
  • Rima Al-Awar
  • Gennady Poda
  • David Uehling
  • Brian Wilson
  • Babu Joseph
  • Pandiaraju Subramanian
  • Ahmed Mamai

Assignees

  • ONTARIO INSTITUTE FOR CANCER RESEARCH (OICR)

Dates

Publication Date
20260505
Application Date
20190206
Priority Date
20180206

Claims (20)

  1. Claims: 1. A compound of formula I, or a pharmaceutically acceptable salt and/or solvate thereof: (I) wherein X1 and X3 are independently selected from CR6 and N, X2 is CH; X4 is selected from CR7 and N; X5 is selected from CR8 and N; R1 is selected from H, C1-6alkyl, C1-6alkyleneOC1-6alkyl, C1-6alkyleneC3-6cycloalkyl, C1- 6alkyleneC3-6heterocycloalkyl, C1-6alkyleneC5-6heteroaryl, C1-6alkylenephenyl, C1- 6alkyleneC(O)C3-6cycloalkyl, C1-6alkyleneC(O)C3-6heterocycloalkyl, C1-6alkyleneC(O)C5- 6heteroaryl, C1-6alkyleneC(O)phenyl, C2-6alkynyleneOC1-6alkyl, C2-6alkynyleneC3- 6cycloalkyl, C2-6alkynyleneC3-6heterocycloalkyl, C2-6alkynyleneC5-6heteroaryl, C2- 6alkynylenephenyl, C2-6alkenyleneOC1-6alkyl, C2-6alkenyleneC3-6cycloalkyl, C2- 6alkenyleneC3-6heterocycloalkyl, C2-6alkenyleneC5-6heteroaryl and C2-6alkenylenephenyl, and each cycloalkyl, heterocycloalkyl, heteroaryl and phenyl is optionally substituted with one to three substituents independently selected from halo and C1-4alkyl; R2 is selected from H, C1-6alkyl, OH, SH, NH2, NHC1-6alkyl, N(C1-6alkyl)(C1-6alkyl), OC1- 6alkyl, halo, Z1C3-6cycloalkyl, Z1C3-6heterocycloalkyl, Z1C5-6heteroaryl, Z1phenyl, Z1C1- 6alkyleneOC1-6alkyl, Z1C1-6alkyleneC3-6cycloalkyl, Z1C1-6alkyleneC3-6heterocycloalkyl, Z1C1-6alkyleneC5-6heteroaryl, Z1C1-6alkylenephenyl, Z1C2-6alkynyleneOC1-6alkyl, Z1C2- 6alkynyleneC3-6cycloalkyl, Z1C2-6alkynyleneC3-6heterocycloalkyl, Z1C2-6alkynyleneC5- 6heteroaryl, Z1C2-6alkynylenephenyl, Z1C2-6alkenyleneOC1-6alkyl, Z1C2-6alkenyleneC3-6cycloalkyl, Z1C2-6alkenyleneC3-6heterocycloalkyl, Z1C2-6alkenyleneC5-6heteroaryl and Z1C2-6alkenylenephenyl, and each cycloalkyl, heterocycloalkyl, heteroaryl and phenyl, is optionally substituted with one to three substituents independently selected from halo, OH, SH, NH2, NHC1-6alkyl and N(C1-6alkyl)(C1-6alkyl); Z1 is selected from a direct bond, O, NH, NC1-6alkyl, S(O) and SO2; R3 is selected from C6-10aryl, C6-10heteroaryl, C6-10cycloalkyl and C6-10heterocycloalkyl, each of which is optionally substituted with one to four substituents independently selected from halo, =O, C1-6alkyl, CN, NO2, C2-6alkenyl, C2-6alkynyl and OC1-6alkyl and optionally substituted with one substituent selected from Z2R9; Z2 is selected from a direct bond, C1-6alkylene, C(O), O, S, S(O) and SO2; R4 is selected from H and C1-6alkyl; R5 is OH; R6 is selected from H and halo; R7 and R8 are independently selected from H, halo, C1-6alkyl, OC1-6alkyl, and SO2NH2, or R7 and R8 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 contain one to two additional heteroatoms selected from O, S, S(O), SO2, NH and NC1-6alkyl; R9 is selected from C1-6alkyl, NR10R11, C3-10cycloalkyl, C3-10heterocycloalkyl, C5-10heteroaryl and C6-10aryl, the latter 4 groups being optionally substituted with one to six substituents independently selected from halo, CN, C1-6alkyl and OC1-6alkyl, and optionally substituted with one substituent selected from C1-6alkyleneOC1-6alkyl, C1-6alkyleneOH, C1-6alkylene(diOH), SO2C1-4alkyl, Z3C3-10cycloalkyl, Z3C3-10heterocycloalkyl, Z3C5-10heteroaryl and Z3C6-10aryl the latter four groups being optionally substituted with one to four substituents independently selected from halo and C1-6alkyl; R10 and R11 are independently selected from H, C1-6alkyl, C1-6alkyleneOH, C1-6alkylene(diOH), C1-6alkyleneOC1-6alkyl, SO2C1-6alkyl, Z4C3-10cycloalkyl, Z4C3-10heterocycloalkyl, Z4C5-10heteroaryl and Z4C6-10aryl, the latter four groups being optionally substituted with one to six substituents independently selected from halo and C1-6alkyl, Z3 and Z4 are independently selected from a direct bond and C1-6alkylene; CA 3088025 and all alkyl and alkylene groups are optionally fluoro-substituted and all available hydrogens are optionally replaced with deuterium.
  2. 2. The compound of claim 1, wherein X1 is N.
  3. 3. The compound of claim 1 or claim 2, wherein X3 is selected from N, CH and CF.
  4. 4. The compound of claim 3, wherein X3 is selected from CH and CF.
  5. 5. The compound of claim 4, wherein X3 is CH.
  6. 6. The compound of any one of claims 1 to 5, wherein X4 is CR7.
  7. 7. The compound according to any one of claims 1 to 6, wherein X5 is CR8.
  8. 8. The compound of claim 6 or 7, wherein R7 and R8 are independently selected from H, F, Cl, CH3, CH2CH3, CF3, OCH3, OCF3 and SO2NH2.
  9. 9. The compound of claim 8, wherein R7 and R8 are both H.
  10. 10. The compound of claim 6 or 7, wherein R7 and R8 are linked to form, together with the carbon atoms to which they are attached, a 3-6-membered heterocycloalkyl or heteroaromatic ring, both of which contain one to two additional heteroatoms selected from O, S, NH and NCH3.
  11. 11. The compound of claim 10, wherein R7 and R8 are linked to form, together with the carbon atoms to which they are attached, a 5-6-membered heterocycloalkyl ring, which contains one to two additional O.
  12. 12. The compound of any one of claims 1 to 11, wherein R1 is selected from H, C1-4alkyl, C1-4alkyleneOC1-4alkyl, C1-4alkyleneC3-6cycloalkyl, C1-4alkyleneC3-6heterocycloalkyl, C1-4alkyleneC5-6heteroaryl, C1-4alkylenephenyl, C1-4alkyleneC(O)C3-6cycloalkyl, C1-4alkyleneC(O)C3-6heterocycloalkyl, C1-4alkyleneC(O)C5-6heteroaryl, C1-4alkyleneC(O)phenyl, C2-4alkynyleneOC1-4alkyl, C2-4alkynyleneC3-6cycloalkyl, C2-4alkynyleneC3-6heterocycloalkyl, C2-4alkynyleneC5-6heteroaryl, C2-4alkynylenephenyl, C2- 4 alkenyleneOC1-4alkyl, C2-4alkenyleneC3-6cycloalkyl, C2-4alkenyleneC3-6heterocycloalkyl, C2-4alkenyleneC5-6heteroaryl and C2-4alkenylenephenyl, and each cycloalkyl, heterocycloalkyl, heteroaryl and phenyl is optionally substituted with one to two substituents independently selected from F, Cl, CH3 and CF3.
  13. 13. The compound of claim 12, wherein R1 is selected from H, CH3, CF3, CH2OCH3, CH2OCF3, CH2C3-6cycloalkyl, CH2C3-6heterocycloalkyl, CH2C5-6heteroaryl, CH2phenyl, CH2CH2C(O)C3-6cycloalkyl, CH2CH2C(O)C3-6heterocycloalkyl, CH2CH2C(O)C5-6heteroaryl, CH2CH2C(O)phenyl, CH2C≡CC3-6cycloalkyl, CH2C≡CC3-6heterocycloalkyl, CH2C≡CC5-6heteroaryl and CH2C≡Cphenyl, and each cycloalkyl, heterocycloalkyl, heteroaryl and phenyl is optionally substituted with one to two substituents independently selected from F, Cl, CH3 and CF3.
  14. 14. The compound of claim 13, wherein R1 is selected from H, CH3, CF3, CH2OCH3, CH2OCF3, CH2C5heteroaryl, CH2CH2C(O)C5heteroaryl and CH2C≡CC5heteroaryl, and each heteroaryl is optionally substituted with one to two substituents independently selected from F, Cl, CH3 and CF3.
  15. 15. The compound of claim 14, wherein the heteroaryl of R1 is a 5-membered heteroaryl containing one or 2 nitrogen atoms and is optionally substituted with one or two CH3.
  16. 16. The compound of any one of claims 1 to 15, wherein R2 is selected from H, C1-4alkyl, OH, NH2, NHC1-4alkyl, N(C1-4alkyl)(C1-4alkyl), OC1-4alkyl, Cl, F, Z1C3-6cycloalkyl, Z1C3-6heterocycloalkyl, Z1C5-6heteroaryl, Z1phenyl, Z1C1-4alkyleneOC1-4alkyl, Z1C1-4alkyleneC3-6cycloalkyl, Z1C1-4alkyleneC3-6heterocycloalkyl, Z1C1-4alkyleneC5-6heteroaryl, Z1C1-4alkylenephenyl, Z1C2-4alkynyleneOC1-6alkyl, Z1C2-4alkynyleneC3-6cycloalkyl, Z1C2-4alkynyleneC3-6heterocycloalkyl, Z1C2-4alkynyleneC5-6heteroaryl, Z1C2-4alkynylenephenyl, Z1C2-4alkenyleneOC1-4alkyl, Z1C2-4alkenyleneC3-6cycloalkyl, Z1C2-4alkenyleneC3-6heterocycloalkyl, Z1C2-4alkenyleneC5-6heteroaryl and Z1C2-4alkenylenephenyl, and each cycloalkyl, heterocycloalkyl, heteroaryl and phenyl, is optionally substituted with one to two substituents independently selected from Cl, F and N(C1-4alkyl)(C1-4alkyl). CA 3088025
  17. 17. The compound of claim 16, wherein R2 is selected from H, CH3, CF3, OH, NH2, N(CH3)2, N(CH3)(CH2CH3), OCH3, Cl, F, Z1C3-6cycloalkyl, Z1C3-6heterocycloalkyl, Z1C5- 6heteroaryl, Z1phenyl, Z1C1-4alkyleneOC1-4alkyl, Z1C1-4alkyleneC3-6cycloalkyl, Z1C1- 4alkyleneC3-6heterocycloalkyl, Z1C1-4alkyleneC5-6heteroaryl, Z1C1-4alkylenephenyl, Z1C2- 4alkenyleneOC1-4alkyl, Z1C2-4alkenyleneC3-6cycloalkyl, Z1C2-4alkenyleneC3- 6heterocycloalkyl, Z1C2-4alkenyleneC5-6heteroaryl and Z1C2-4alkenylenephenyl, and each cycloalkyl, heterocycloalkyl, heteroaryl and phenyl, is optionally substituted with one to two substituents independently selected from Cl, F and N(CH3)2.
  18. 18. The compound of claim 16, wherein R2 is selected from H, CH3, CF3, OH, NH2, NHCH3, N(CH3)2, N(CH3)(CH2CH3), OCH3, Cl, F, Z1C3-6cycloalkyl, Z1C3-6heterocycloalkyl, Z1C5-6heteroaryl, Z1phenyl, Z1C1-2alkyleneOCH3, Z1C1-2alkyleneC3-6cycloalkyl, Z1C1- 2alkyleneC3-6heterocycloalkyl, Z1C1-4alkyleneC5-6heteroaryl, Z1C1-4alkylenephenyl, Z1C2- 3alkenyleneOC1-4alkyl, Z1C2-3alkenyleneC3-6cycloalkyl, Z1C2-3alkenyleneC3- 6heterocycloalkyl, Z1C2-3alkenyleneC5-6heteroaryl and Z1C2-3alkenylenephenyl, and each cycloalkyl, heterocycloalkyl, heteroaryl and phenyl, is optionally substituted with one to two substituents independently selected from Cl, F and N(CH3)2.
  19. 19. The compound of any one of claims 1 to 15, wherein R2 is selected from H, CH3, CF3, OCH3, OCH2CH2OCH3, CH=CH-cyclopropyl, NH2, NHCH2cyclopropyl, NHCH2-pfluorophenyl, NHCH2CH2CF3, phenyl, Cl, N(CH3)2, NHCH3, N(CH3)(CH2CH3), OH, and .
  20. 20. The compound of claim 19, wherein R2 is H.

Description

TITLE: INHIBITORS OF THE BCL6 BTB DOMAIN PROTEIN-PROTEIN INTERACTION AND USES THEREOF [0001] Intentionally Left Blank FIELD [0002] The present application relates to compounds, to processes for their preparation, to compositions comprising them, and to their use in therapy. More particularly, it relates to 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 Rei;ue/Date Received 2024-06-07 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 regulator of plasma-cell development [Scien