# US 12,600,710 B2 · Beta-catenin and b-cell lymphoma 9 (BCL9) inhibitors

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- Number: US 12,600,710 B2
- Document ID: US12600710B2
- Status: Granted
- Kind: B2
- Application number: 17/286,716
- Filed: 2019-10-18
- Published: 2021-12-09
- Granted: 2026-04-14
- Earliest claimed: 2018-10-18
- Assignees: Lee Moffitt Cancer Center and Research Institute, Inc.
- Applicants: H. Lee Moffitt Cancer Center and Research Institute, Inc.
- Inventors: Haitao Ji
- Web page: https://patentgrep.com/patent/US12600710B2

## CPC

- C07D 401/14: containing three or more hetero rings
- C07D 207/12: Oxygen or sulfur atoms
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 403/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Disclosed are inhibitors for the β-catenin/BCL9 interaction. The inhibitors are selective for β-catenin/BCL9 over β-catenin/cadherin interactions. Methods of using the disclosed compounds to treat cancer are also disclosed.

## Claims

### Claim 1

A compound having Formula I-B:
wherein A is selected from N or —CR8, where R8 is hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl;
wherein Z is selected from N or —CR2a, wherein R2a is hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl;
wherein L1 is optionally present, and when present, is O, S, NH, or CR12aR12b, wherein R12a and R12b are independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl;
wherein L2 is optionally present, and when present, is O, S, C1-C3 alkyl, or —(NR17a)—, wherein R17a is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl;
wherein each of R1a and R1b is independently hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl;
wherein each of R2b and R2c is independently hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl;
wherein R3 is Cy3 or Ar1; wherein Cy3 is a C3-C8 cycloalkyl or a C2-C7 heterocycloalkyl and Ar is selected from aryl and heteroaryl, wherein each of Cy3 and Ar1, when present, is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, R10NHCO—(R10 substituted carbamoyl group), wherein R10 is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl, or R11CONH—(R11 substituted amido group),
wherein R4 is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl;
wherein R4 is hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, or R15CONH—, wherein R15 is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl, or Ar2, wherein Ar2 is selected from aryl, heteroaryl, and wherein Ar2 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl;
wherein each occurrence of R5 is independently selected from hydrogen, C1-C8alkyl, C1-C8 monohaloalkyl, C1-C3 polyhaloalkyl, R14CONH—, wherein R14 is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl;
wherein R6 is C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, or Cy1; and wherein Cy1 is an amino C3-C8 cycloalkyl, a hydroxy C3-C8 cycloalkyl, or a C2-C7 heterocycloalkyl comprising at least one oxygen or nitrogen atom; and wherein Cy1 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl;
wherein R7 is Cy5, NR12aR12b-Cy5, NR12aR12b—C1-C6 unsubstituted alkyl-Cy5, C1-C6 unsubstituted alkyl-NH—(C═O)—; C1-C6 unsubstituted alkyl-(C═O)—NH—; or C1-C6 unsubstituted alkyl-NHCH2-Cy5—,
amino C1-C6 substituted or unsubstituted alkyl carbonyl, hydroxyl C1-C6 substituted or unsubstituted alkyl carbonyl, amino C1-C6 substituted or unsubstituted alkyl, hydroxyl C1-C6 substituted or unsubstituted alkyl,
wherein Cy5 is selected from a C2-C7 heterocycloalkyl or heteroaryl comprising at least one oxygen or nitrogen atom, amino C3-C8 cycloalkyl, a hydroxy C3-C8 cycloalkyl, a C3-C7 oxoheterocycloalkyl comprising at least one oxygen or nitrogen atom, an amino C3-C8 oxocycloalkyl, or a hydroxy C3-C8 oxocycloalkyl, and wherein Cy5 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, C1-C4 alkyl, C1-C4 monohaloalkyl, or C1-C4 polyhaloalkyl, and
m is 0, 1, 2, or 3,
or a pharmaceutically acceptable salt, ester, or prodrug thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein A and Z are both —CH.

### Claim 3 (depends on 1)

The compound of claim 1, wherein L1 is O.

### Claim 4 (depends on 1)

The compound of claim 1, wherein L2 is not present.

### Claim 5 (depends on 1)

The compound of claim 1, wherein L2 is present and selected from CH2, CH2CH2, CH2CH2CH2, or —(NR17a)—, wherein R17a is selected from hydrogen or C1-C3 alkyl.

### Claim 6 (depends on 1)

The compound of claim 1, wherein each of R1a, R1bb, R2a, R2b, and R2c is hydrogen.

### Claim 7 (depends on 1)

The compound of claim 1, wherein R3 is cyclohexyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and —CO2H.

### Claim 8 (depends on 1)

The compound of claim 1, wherein R4 is a halogen.

### Claim 9 (depends on 1)

The compound of claim 1, wherein R6 is a C2-C7 heterocycloalkyl comprising at least one nitrogen atom.

### Claim 10 (depends on 1)

The compound of claim 1, wherein R7 is selected from a piperazine, piperazine substituted with carbonyl, NR12aR12b—C1-C6 alkyl-triazole, amino-C1-C6 unsubstituted alkyl-(C═O)—, C1-C6 unsubstituted alkyl-NH—(C═O)— or C1-C6 unsubstituted alkyl-(C═O)—NH—.

### Claim 11 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, ester, or prodrug thereof, and a pharmaceutically acceptable carrier.

### Claim 12 (depends on 1)

The compound of claim 1, having a structure represented by a formula below or a pharmaceutically acceptable salt, ester, or prodrug thereof: