Spiro bicyclic inhibitors of menin-MLL interaction

Patent metadata

Field	Value
Publication number	US-11220517-B2
Application number	US-201716331606-A
Country	US
Kind code	B2
Filing date	Sep 13, 2017
Priority date	Sep 14, 2016
Publication date	Jan 11, 2022
Grant date	Jan 11, 2022

Abstract

The present invention relates to compounds of formula (I):wherein the variables have the meaning defined in the Specification. The compounds according to the present invention are useful for therapy and/or prophylaxis in a mammal, and in particular to spiro bicyclic compounds, pharmaceutical composition comprising such compounds, and their use as menin/MLL protein/protein interaction inhibitors, useful for treating diseases such as cancer, myelodysplastic syndrome (MDS) and diabetes.

First claim

The invention claimed is:

1. A compound of Formula (I)

or a tautomer or a stereoisomeric form thereof, wherein
R 1 is selected from the group consisting of CH 3 , CH 2 F, CHF 2 , and CF 3 ;
R 2 is selected from the group consisting of hydrogen and CH 3 ;
L 1 is N-linked to the thienopyrimidinyl heterocycle and selected from

wherein a represents the position of linkage to the thienopyrimidinyl heterocycle; and
-L 2 -R 3 is selected from (b) or (f), wherein
(b) L 2 is selected from the group consisting of >CR 4c R 4d and —CHR 4c CHR 5a —, wherein R 4c , R 4d , and R 5a are each independently selected from the group consisting of hydrogen and C 1-4 alkyl; and
R 3 is selected from the group consisting of

 wherein R 12a , R 12b , and R 12c are each independently selected from the group consisting of C 1-6 alkyl optionally substituted with a OH or a NH 2 substituent; and —OC 1-6 alkyl; or

(f) -L 2 -R 3 is

 wherein
R 18 is selected from the group consisting of hydrogen; C 1-4 alkyl optionally substituted with a fluoro or a —CN substituent; and C 2-4 alkyl substituted with a substituent selected from the group consisting of —OR 19 and —NR 20a R 20b ; wherein
R 19 , R 20a and R 20b are each independently selected from the group consisting of hydrogen;
C 1-4 alkyl optionally substituted with a substituent selected from the group consisting of fluoro, —CN, and —C(═O)NR 21a R 21b ; C 2-4 alkyl substituted with a substituent selected from the group consisting of —OR 22 and —NR 21a R 21b ; and C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; wherein
R 21a , R 21b and R 22 are each independently selected from the group consisting of hydrogen and C 1-4 alkyl; and
R 18a is selected from the group consisting of hydrogen, fluoro and C 1-4 alkyl;
R 18b is selected from the group consisting of fluoro, —OC 1-4 alkyl, and C 1-4 alkyl optionally substituted with 1, 2 or 3 fluoro substituents; or
R 18a and R 18b are bound to the same carbon atom and together form a C 3-5 cycloalkyl or a C-linked 4- to 6-membered heterocyclyl containing an oxygen atom;
or a pharmaceutically acceptable salt or a solvate thereof.

2. The compound according to claim 1 , wherein
(b) L 2 is selected from the group consisting of >CR 4c R 4d and —CHR 4c CHR 5a —, wherein R 4c , R 4d , and R 5a are each independently selected from the group consisting of hydrogen and C 1-4 alkyl; and
R 3 is selected from the group consisting of

 wherein R 12a , R 12b , and R 12c are each independently selected from the group consisting of C 1-6 alkyl optionally substituted with a —OH or a —NH 2 substituent; or
(f) -L 2 -R 3 is selected from the group consisting of

 wherein
R 18 is hydrogen.

3. The compound according to claim 1 , wherein
(b) L 2 is >CR 4c R 4d , wherein R 4c and R 4d are each independently selected from the group consisting of hydrogen and C 1-4 alkyl; and
R 3 is selected from the group consisting of

 wherein R 12a , R 12b , and R 12c are each independently selected from the group consisting of C 1-6 alkyl optionally substituted with a —NH 2 substituent.

4. The compound according to claim 1 , wherein
R 1 is CF 3 ; and
L 1 is selected from the group consisting of (a), (b), (c), (e), (f) and (g)

wherein a represents the position of linkage to the thienopyrimidinyl heterocycle.

5. The compound according to claim 1 , wherein
R 1 is CF 3 ;
R 2 is hydrogen; and
L 1 is selected from the group consisting of (a), (b), (c), (e), (f) and (g)

wherein a represents the position of linkage to the thienopyrimidinyl heterocycle.

6. A pharmaceutical composition comprising a compound as claimed in claim 1 and a pharmaceutically acceptable carrier or diluent.

7. A process for preparing a pharmaceutical composition comprising mixing a pharmaceutically acceptable carrier or diluent with a therapeutically effective amount of a compound according to claim 1 .

8. A method of inhibiting menin/MLL protein in a subject in need thereof comprising administering to the subject an effective amount of a compound as claimed in claim 1 , wherein the subject is suffering from a disorder selected from cancer, myelodysplastic syndrome (MDS) and diabetes.

9. The method according to claim 8 wherein the disorder is cancer.

10. The method according to claim 9 wherein the cancer is selected from leukemias, myeloma, prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma and glioblastoma.

11. The method according to claim 9 wherein the cancer is selected from acute leukemias, chronic leukemias, myeloid leukemias, myelogeneous leukemias, lymphoblastic leukemias, lymphocytic leukemias, Acute myelogeneous leukemias (AML), Chronic myelogenous leukemias (CIVIL), Acute lymphoblastic leukemias (ALL), Chronic lymphocytic leukemias (CLL), T cell prolymphocytic leukemias (T-PLL), Large granular lymphocytic leukemia, Hairy cell leukemia (HCL), MLL-rearranged leukemias, MLL-PTD leukemias, MLL amplified leukemias, MLL-positive leukemias, and leukemias exhibiting HOX/MEIS1 gene expression signatures.

12. A method of inhibiting menin/MLL protein in a subject comprising administering to the subject an effective amount of a compound as claimed in claim 1 .

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Angibaud Patrick Rene
• Pande Vineet
• Herkert Barbara
• Krosky Daniel Jason
• Querolle Olivier Alexis Georges
• Patrick Aaron Nathaniel
• Pilatte Isabelle Noelle Constance

Classifications

• A61P35/02

  specific for leukemia · CPC title

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/519

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