Bridged bicyclic inhibitors of menin-MLL and methods of use

Patent metadata

Field	Value
Publication number	US-10752639-B2
Application number	US-201716082645-A
Country	US
Kind code	B2
Filing date	Mar 15, 2017
Priority date	Mar 16, 2016
Publication date	Aug 25, 2020
Grant date	Aug 25, 2020

Abstract

The present disclosure provides compounds of Formula (I-E) for inhibiting the interaction of menin with MLL1, MLL2 and MLL-fusion oncoproteins. The compounds are useful for the treatment of leukemia, solid cancers, diabetes and other diseases dependent on activity of MLL1, MLL2, MLL fusion proteins, and/or menin.

First claim

What is claimed is:

1. A compound of Formula (I-E):

or a pharmaceutically acceptable salt or isotopic form thereof, wherein:
R C is R 50 ;
R 2 is selected from hydrogen and R 50 ;
R 50 is independently selected at each occurrence from:
halogen, —NO 2 , —CN, —OR 52 , —SR 52 , —N(R 52 ) 2 , —NR 53 R 54 , —S(═O)R 52 , —S(═O) 2 R 52 , —S(═O) 2 N(R 52 ) 2 , —S(═O) 2 NR 53 R 54 , —NR 52 S(=O) 2 R 52 , —NR 52 S(═O) 2 N(R 52 ) 2 , —NR 52 S(═O) 2 NR 53 R 54 , —C(O)R 52 , —C(O)OR 52 , —OC(O)R 52 , —OC(O)OR 52 , —OC(O)N(R 52 ) 2 , —OC(O)NR 53 R 54 , —NR 52 C(O)R 52 , —NR 52 C(O)OR 52 , —NR 52 C(O)N(R 52 ) 2 , —NR 52 C(O)NR 53 R 54 , —C(O)N(R 52 ) 2 , —C(O)NR 53 R 54 , —P(O)(OR 52 ) 2 , and —P(O)(R 52 ) 2 ;

C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO 2 , —CN, —OR 52 , —SR 52 , —N(R 52 ) 2 , —NR 53 R 54 , —S(═O)R 52 , —S(═O) 2 R 52 , —S(═O) 2 N(R 52 ) 2 , —S(═O) 2 NR 53 R 54 , —NR 52 S(═O) 2 R 52 , —NR 52 S(═O) 2 N(R 52 ) 2 , —NR 52 S(═O) 2 NR 53 R 54 , —C(O)R 52 , —C(O)OR 52 , —OC(O)R 52 , —OC(O)OR 52 , —OC(O)N(R 52 ) 2 , —OC(O)NR 53 R 54 , —NR 52 C(O)R 52 , —NR 52 C(O)OR 52 , —NR 52 C(O)N(R 52 ) 2 , —NR 52 C(O)NR 53 R 54 , —C(O)N(R 52 ) 2 , —C(O)NR 53 R 54 , —P(O)(OR 52 ) 2 , —P(O)(R 52 ) 2 , ═O, ═S, ═N(R 52 ), C 3-12 carbocycle, and 3- to 12-membered heterocycle; and
C 3-12 carbocycle and 3- to 12-membered heterocycle,
wherein each C 3-12 carbocycle and 3- to 12-membered heterocycle in R 50 is independently optionally substituted with one or more substituents selected from halogen, —NO 2 , —CN, —OR 52 , —SR 52 , —N(R 52 ) 2 , —NR 53 R 54 , —S(═O)R 52 , —S(═O) 2 R 52 , —S(═O) 2 N(R 52 ) 2 , —S(═O) 2 NR 53 R 54 , —NR 52 S(═O) 2 R 52 , —NR 52 S(═O) 2 N(R 52 ) 2 , —NR 52 S(═O) 2 NR 53 R 54 , —C(O)R 52 , —C(O)OR 52 , —OC(O)R 52 , —OC(O)OR 52 , —OC(O)N(R 52 ) 2 , —OC(O)NR 53 R 54 , —NR 52 C(O)R 52 , —NR 52 C(O)OR 52 , —NR 52 C(O)N(R 52 ) 2 , —NR 52 C(O)NR 53 R 54 , —C(O)N(R 52 ) 2 , —C(O)NR 53 R 54 , —P(O)(OR 52 ) 2 , —P(O)(R 52 ) 2 , ═O, ═S, ═N(R 52 ), C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl;
R 52 is independently selected at each occurrence from hydrogen; and C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 2-6 heteroalkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, —CN, —NO 2 , —NH 2 , —NHCH 3 , —NHCH 2 CH 3 , ═O, —OH, —OCH 3 , —OCH 2 CH 3 , C 3-12 carbocycle, or 3- to 6-membered heterocycle; and
R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle.

2. The compound of claim 1 , wherein R C is selected from —N(R 52 ) 2 , —NR 53 R 54 , —NR 52 S(═O) 2 R 52 , —C(O)R 52 , —C(O)OR 52 , —NR 52 C(O)R 52 , —NR 52 C(O)OR 52 , —NR 52 C(O)N(R 52 ) 2 , —NR 52 C(O)NR 53 R 54 , —C(O)N(R 52 ) 2 , and —C(O)NR 53 R 54 .

3. The compound of claim 2 , wherein R C is selected from —N(R 52 ) 2 , —NR 52 S(—O) 2 R 52 , —C(O)OR 52 , —NR 52 C(O)R 52 , —NR 52 C(O)N(R 52 ) 2 , and —C(O)N(R 52 ) 2 .

4. The compound of claim 3 , wherein R C is —NR 52 C(O)R 52 .

5. The compound of claim 1 , wherein R 52 is independently selected at each occurrence from hydrogen, C 1-20 alkyl, C 2-20 alkenyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, —NH 2 , —NHCH 3 , —NHCH 2 CH 3 , ═O, —OH, —OCH 3 , —OCH 2 CH 3 , C 3-12 carbocycle, or 3- to 6-membered heterocycle.

6. The compound of claim 1 , wherein:
R 2 is hydrogen.

7. The compound of claim 1 , wherein R 2 is selected from hydrogen, halogen, —OH, —OR 52 , —NH 2 , —N(R 52 ) 2 , —NR 53 R 54 , —CN, C 1-3 alkyl, C 1-3 alkyl-N(R 52 ) 2 , C 1-3 haloalkyl, C 2-3 alkenyl, and C 2-3 alkynyl.

8. The compound of claim 7 , wherein
R 2 is selected from hydrogen, —N(R 52 ) 2 and C 1-3 alkyl.

9. The compound of claim 8 , wherein R 2 is —N(R 52 ) 2 and R 52 is independently selected from hydrogen and C 1-20 alkyl.

10. The compound of claim 8 , wherein R 2 is C 1-3 alkyl.

11. The compound of claim 1 selected from:

or a pharmaceutically acceptable salt or isotopic form thereof.

12. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt or isotopic form thereof, and a pharmaceutically acceptable carrier.

13. A method of inhibiting an interaction of menin with one or more of MLL1, MLL2, an MLL fusion protein, and an MLL Partial Tandem Duplication, comprising contacting menin with an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or isotopic form thereof.

14. A method of treating a disease or condition in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition of a compound of claim 1 , or a pharmaceutically acceptable salt or isotopic form thereof, wherein the disease or condition comprises a leukemia, hematologic malignancy, solid tumor cancer, prostate cancer, breast cancer, liver cancer, brain tumor, or diabetes.

Assignees

• Kura Oncology Inc
• Univ Michigan Regents

Inventors

• Wu Tao
• Li Liansheng
• Wang Yi
• Ren Pingda
• Grembecka Jolanta
• Cierpicki Tomasz
• Klossowski Szymon
• Pollock Jonathan
• Borkin Dmitry

Classifications

• C07D495/04 Primary

  Ortho-condensed systems · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• A61K31/445 Primary

  Non condensed piperidines, e.g. piperocaine · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title