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EP-4736854-A2 - HETEROCYCLIC COMPOUNDS AS MODULATORS OF BCL6 AS LIGAND DIRECTED DEGRADERS

EP4736854A2EP 4736854 A2EP4736854 A2EP 4736854A2EP-4736854-A2

Abstract

Provided herein are compounds and compositions thereof for modulating BCL6. In some embodiments, the compounds and compositions are provided for treatment of cancer or an autoimmune disease.

Inventors

  • HUANG, DEHUA
  • GRIFFIN, JENNIFER
  • ALEXANDER, MATTHEW DAVID
  • WHITEFIELD, BRANDON WADE
  • SHUNATONA, Hunter Paul
  • DODD, DHARMPAL S.
  • Mortensen, Deborah S.
  • MISEO, Giulianna
  • HOLMBERG-DOUGLAS, Natalie
  • RHODES, Jayce

Assignees

  • Bristol-Myers Squibb Company

Dates

Publication Date
20260506
Application Date
20230427

Claims (15)

  1. A compound of Formula (IA): or a pharmaceutically acceptable salt thereof, wherein: X 1 and X 2 are each independently N or CH, provided that at least one of X 1 and X 2 is N; R 1a and R 1b are each independently H, halo, or C 1 -C 6 alkyl; R 2a and R 2b are each independently H, C 1 -C 6 alkyl, -O(C 1 -C 6 alkyl), -OH, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl-OH, or R 2a and R 2b are taken together with the carbon atom to which they are attached to form a spiro C 3 -C 5 cycloalkyl, or R 2a and R 2b are taken together to form oxo; or R 1a and R 2a are taken together to form a bridging C 2 -C 3 alkylene; R 3a and R 3b are each independently H, halo, or C 1 -C 6 alkyl; R 4a and R 4b are each independently H, halo, or C 1 -C 6 alkyl, or R 4a and R 4b are taken together with the carbon atom to which they are attached to form a spiro C 3 -C 5 cycloalkyl; R 5a and R 5b are each independently H, halo, or C 1 -C 6 alkyl; w is 0 or 1; R 6 is H or C 1 -C 6 alkyl; R 7 is H or C 1 -C 6 alkyl; x and y are each independently 0 or 1, provided that x and y are not both 1; R 8 is Cl or -CN; R 9 is F; X 3 is N or CH; z is 0 or 1; R 10a and R 10b are each independently H or halo; R 11 is H, C 1 -C 6 alkyl, -(C 1 -C 6 alkylene)-(5- to 6-membered heterocyclyl), -(C 1 -C 6 alkylene)-O(C 1 -C 6 alkyl), C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-OH, or -(C 1 -C 6 alkylene)-NH(C 1 -C 6 alkyl), wherein the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S; R 12 is H, halo, or C 1 -C 6 alkyl; R 13 is H or halo; R 14 is H or C 1 -C 6 alkyl; X 4 is N or CR 15 ; R 15 is H or C 1 -C 6 alkyl; X 5 and X 6 are each independently N or CH; and - - - is a single or double bond; wherein one or more hydrogen atoms in the compound are optionally replaced by deuterium.
  2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I): wherein: X 1 and X 2 are each independently N or CH, provided that at least one of X 1 and X 2 is N; R 1a and R 1b are each independently H, halo, or C 1 -C 6 alkyl; R 2a and R 2b are each independently H, C 1 -C 6 alkyl, -OH, halo, or C 1 -C 6 alkyl-OH, or R 2a and R 2b are taken together with the carbon atom to which they are attached to form a spiro C 3 -C 5 cycloalkyl, or R 2a and R 2b are taken together to form oxo; or R 1a and R 2a are taken together to form a bridging C 2 -C 3 alkylene; R 3a and R 3b are each independently H, halo, or C 1 -C 6 alkyl; R 4a and R 4b are each independently H, halo, or C 1 -C 6 alkyl, or R 4a and R 4b are taken together with the carbon atom to which they are attached to form a spiro C 3 -C 5 cycloalkyl; R 5a and R 5b are each independently H, halo, or C 1 -C 6 alkyl; w is 0 or 1; R 6 is H or C 1 -C 6 alkyl; R 7 is H or C 1 -C 6 alkyl; x and y are each independently 0 or 1, provided that x and y are not both 1; R 8 is Cl or -CN; R 9 is F; X 3 is N or CH; z is 0 or 1; R 10a and R 10b are each independently H or halo; R 11 is H, C 1 -C 6 alkyl, -(C 1 -C 6 alkylene)-(5- to 6-membered heterocyclyl), -(C 1 -C 6 alkylene)-O(C 1 -C 6 alkyl), C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-OH, or -(C 1 -C 6 alkylene)-NH(C 1 -C 6 alkyl), wherein the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S; R 12 is H, halo, or C 1 -C 6 alkyl; R 13 is H or halo; R 14 is H or C 1 -C 6 alkyl; X 4 is N or CR 15 ; R 15 is H or C 1 -C 6 alkyl; X 5 and X 6 are each independently N or CH; and - - - is a single or double bond; wherein one or more hydrogen atoms in the compound are optionally replaced by deuterium.
  3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: (a) X 1 is CH and X 2 is N; or X 1 is N and X 2 is CH; or (b) X 1 and X 2 are each N.
  4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein: (a) R 1a and R 1b are each independently H, halo, or C 1 -C 3 alkyl; and/or (b) R 2a and R 2b are each independently H, C 1 -C 3 alkyl, -OH, halo, or C 1 -C 3 alkyl-OH, or R 2a and R 2b are taken together with the carbon atom to which they are attached to form a spiro C 3 -C 4 cycloalkyl, or R 2a and R 2b are taken together to form oxo; and/or (c) R 3a and R 3b are each independently H, halo, or C 1 -C 3 alkyl.
  5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein: R 4a and R 4b are each independently H, halo, or C 1 -C 3 alkyl, or R 4a and R 4b are taken together with the carbon atom to which they are attached to form a spiro C 3 -C 4 cycloalkyl, optionally wherein R 5a and R 5b are each independently H, halo, or C 1 -C 3 alkyl.
  6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein is:
  7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein: R 11 is H, C 1 -C 3 alkyl, -(C 1 -C 3 alkylene)-(6-membered heterocyclyl), -(C 1 -C 3 alkylene)-O(C 1 -C 3 alkyl), C 1 -C 5 haloalkyl, C 1 -C 5 alkyl-OH, or -(C 1 -C 3 alkylene)-NH(C 1 -C 3 alkyl), wherein the heterocyclyl contains 1-2 heteroatoms selected from N and O.
  8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein is:
  9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein is:
  10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein is:
  11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (II), (III), or (IV): optionally wherein the compound is of Formula (IIIb):
  12. A compound selected from: Compound No. Structure 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 and pharmaceutically acceptable salts thereof.
  13. A pharmaceutical composition comprising the compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  14. A compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 13, for use in a method of degrading B-cell lymphoma 6 protein (BCL6), wherein the method comprises contacting BCL6 with an effective amount of the compound, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition.
  15. A compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 13, for use in a method of treating a cancer or an autoimmune disease in a subject in need thereof, wherein the method comprises administering to the subject an effective amount of the compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority of US Provisional Application No. 63/336,104, filed on April 28, 2022, which is incorporated herein by reference herein in its entirety for any purpose. FIELD The present disclosure relates generally to compounds, compositions, and methods for their preparation and use of the compounds and compositions for treating cancer or an autoimmune disease. BACKGROUND BCL6 (B cell lymphoma 6) is a member of the BTB/POZ-zinc finger family that contains an N-terminal BTB/POZ domain and a zinc finger at the C-terminus. As a transcription factor for T follicular helper (Tfh) cells, BCL6 is required for germinal center (GC) formation of naive B cells and hence antibody affinity maturation. BCL6 was initially discovered as an oncogene in diffuse large B-cell lymphomas (DLBCLs) and its role has been implicated in many types of diseases including B-acute lymphoblastic leukemia, chronic myeloid leukemia, breast cancer, and non-small lung cancer (NSCLC) (Cardenas et al., Clin Cancer Res 2017, 23, 885-893). The N-terminal BTB/POZ domain binds to and recruits of co-repressor molecules such as SMRT, NCOR1, and BCOR, to form class I and II histone deacetylase complexes, and the C-terminal zinc fingers bind to specific DNA recognition sequences (Yang et al., Cell Dev. Biol. 2019, 7, 272). Upon binding to its target genes and forming complexes, BCL6 reduces RNA expression of its targets, including several key tumor supressors. Over-expression of BCL6, common in malignanies such as Non-Hodgkin's lymphoma (NHL), leads to ectopic repression of cell cycle and DNA repair checkpoint proteins, causing unrestricted cell proliferation and tumorgenesis. GC reponses are known to result in increased production of pathogenic autoantibodies which are responsible for several diseases, suggesting that methods to suppress or degrade BCL6 hold potential therapeutic applicability. Structural characterization of the cocrystal structures of the BCL6 BTB/POZ domain and co-repressors has shown that binding occurs at the lateral grooves formed by the interface between BCL6 BTB/POZ homodimers (Melnick et al., Mol. Cell Biol. 2002, 22, 1804-1818; Ghetu et al., Mol. Cell. 2008, 29, 384-391). Since then, specific ligands that bind to this site have been investigated, purposed to exploit the binding affinity towards the lateral grooves to render BCL6 as a druggable target. Protein degradation is a highly regulated and essential process that maintains cellular homeostasis. Selective identification and removal of damaged, misfolded, or excess proteins is achieved through the ubiquitin-proteasome pathway (UPP). The UPP is central to the regulation of almost all cellular processes. Ubiquitination of the protein is accomplished by an E3 ubiquitin ligase that binds to a protein and adds ubiquitin molecules to the protein, thus marking the protein for proteasome degradation. Harnessing the UPP for therapeutic use has received significant interest (Zhou et al., Mol. Cell 2000, 6, 751-756). One promising therapy uses proteolysis targeting chimeras, commonly referred to as PROTACs, to effect removal of unwanted proteins by protein degradation (Scheepstra et al., Comp. Struct. Biotech. J. 2019, 17, 160-176). PROTACS are ligand directed degraders that bring together an E3 ligase and a target protein that is to be degraded. These bivalent molecules usually consist of an E3 ligase ligand connected through a linker moiety to small molecule that binds to the target protein. A PROTAC positions the E3 ligase at the appropriate distance and orientation to the target protein, allowing the latter to be ubiquitinated. The ubiquitinated target protein is subsequently recognized by the proteasome, where it is degraded. Accordingly, in one aspect, provided herein are compounds that target BCL6 for degradation. SUMMARY Described herein, in certain embodiments, are compounds and compositions thereof for modulating BCL6. In various embodiments, the compounds and compositions thereof may be used for treatment of cancer. The present embodiments can be understood more fully by reference to the detailed description and examples, which are intended to exemplify non-limiting embodiments. Embodiment 1. A compound of Formula (IA): or a pharmaceutically acceptable salt thereof, wherein: X1 and X2 are each independently N or CH, provided that at least one of X1 and X2 is N;R1a and R1b are each independently H, halo, or C1-C6 alkyl;R2a and R2b are each independently H, C1-C6 alkyl, -O(C1-C6 alkyl), -OH, halo, C1-C6 haloalkyl,or C1-C6 alkyl-OH,or R2a and R2b are taken together with the carbon atom to which they are attached to form a spiro C3-C5 cycloalkyl,or R2a and R2b are taken together to form oxo;or R1a and R2a are taken together to form a bridging C2-C3 alkylene;R3a and R3b are each independently H, halo, or C1-C6 alkyl;R4a and R4b are each independently H, halo, or C1-C6 alkyl,or R4a and R4b are taken toge