Methods and compositions for inhibiting the interaction of menin with MLL proteins

Patent metadata

Field	Value
Publication number	US-11542248-B2
Application number	US-201816619423-A
Country	US
Kind code	B2
Filing date	Jun 7, 2018
Priority date	Jun 8, 2017
Publication date	Jan 3, 2023
Grant date	Jan 3, 2023

Abstract

The present disclosure provides compositions and methods of use to inhibit the interaction of menin with MLL1, MLL2 and MLL-fusion oncoproteins. The compositions and methods of use 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 VIII:

or a pharmaceutically acceptable salt thereof, wherein:
H-VIII is an optionally substituted pyrimidinyl,
wherein ring carbons of H-VIII are, at each occurrence, independently optionally substituted with R 2 , R 14 , or R 16 ;
L 1 is a bond or —NR 5 —;
L 2 is —CH 2 —;
A is piperidinyl;
m is an integer from 0 to 9;
B is B-II,
wherein B is connected at any ring atom to L 2 ; and
B-II is

wherein Z 1 is CCH 3 ;
Z 2 and Z 8 are CH;
Z 5 is C;
Z 6 is NR 9 ; and
Z 7 is CCN;

n is an integer from 0 to 3;
each of R 2 , R 5 , R 9 , R 14 , and R 16 is, at each occurrence, independently selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino;
R A is, at each occurrence, independently selected from halo, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, and cycloalkylalkyl; and
R B is, at each occurrence, independently selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino.

2. The compound of claim 1 , wherein the compound is a compound of Formula VIII-A:

or a pharmaceutically acceptable salt thereof, wherein:
X 1 is CR 2 , X 2 is N, X 12 is C, X 14 is N, X 13 is CR 16 , and X 11 is CR 14 ; or
X 1 is N, X 2 is CR 2 , X 12 is C, and X 14 is CR 2 , X 13 is N, and X 11 is CR 14 ; or
X 1 is CR 2 , X 2 is N, X 12 is C, X 14 is CR 2 , X 13 is CR 16 , X 11 is N;
L 1 is a bond or —NR 5 —;
L 2 is —CH 2 —;
A is piperidinyl;
m is an integer from 0 to 9;
B is B-II,
wherein B is connected at any ring atom to L 2 ; and
B-II is

wherein Z 1 is CCH 3 ;
Z 2 and Z 8 are CH;
Z 5 is C;
Z 6 is NR 9 ; and
Z 7 is CCN;

n is an integer from 0 to 3;
each of R 2 , R 5 , R 9 , R 14 , and R 16 is, at each occurrence, independently selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino;
R A is, at each occurrence, independently selected from halo, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, and cycloalkylalkyl; and
R B is, at each occurrence, independently selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino.

3. The compound of claim 2 , wherein:
X 1 is CR 2 ;
X 2 is N;
X 11 is N;
X 12 is C;
X 13 is CR 16 ; and
X 14 is CR 2 .

4. The compound of claim 2 , wherein X 14 is CR 2 , wherein R 2 is aralkyl, aryloxy or arylamino, and wherein said aralkyl, aryloxy and arylamino are substituted with one or more substituents selected from halo, alkyl, —C(═O)R g and —C(═O)NR g R h , wherein R g and R h are independently hydrogen or alkyl.

5. The compound of claim 1 , wherein A has one of the following structures:

wherein the H of any CH or NH may be replaced with a bond to L 1 , L 2 or R A .

6. The compound of claim 2 , wherein the compound has the structure of Formula VIII-B:

or Formula VIII-C:

or Formula VIII-D:

or Formula VIII-E:

or Formula VIII-F:

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , wherein n is 0.

8. The compound of claim 1 , wherein R 2 , R 14 , and R 16 , when present, are each independently H or haloalkyl.

9. The compound of claim 1 , wherein R 9 is

wherein:
G is selected from a bond, alkylene, heteroalkylene, C 3-12 carbocycle, and 3- to 12-membered heterocycle, wherein G is optionally substituted with one or more R 32 groups;
V is absent or selected from a C 3-12 carbocycle, and 3- to 12-membered heterocycle; wherein V is optionally substituted with one or more R 32 groups;
each of R 21 and R 32 is, at each occurrence, independently selected from:
H, halogen, —OR 20 , —N(R 20 ) 2 , —N(R 20 )C(O)R 20 , —C(O)R 20 , —C(O)OR 20 , —C(O)N(R 20 ) 2 , —OC(O)R 20 , —S(O) 2 R 20 , —S(O) 2 N(R 20 ) 2 , —N(R 20 )S(O) 2 R 20 , —NO 2 , ═O, ═S, ═N(R 20 ), —P(O)(OR 20 ) 2 , —P(O)(R 20 ) 2 , —OP(O)(OR 20 ) 2 , and —CN;
C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents se

Assignees

• Kura Oncology Inc
• Univ Michigan Regents

Inventors

• Li Liansheng
• Wu Tao
• Feng Jun
• Ren Pingda
• Liu Yi
• Grembecka Jolanta
• Cierpicki Tomasz
• Borkin Dmitry
• Pollock Jonathan

Classifications

• C07D207/32

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• C07K14/4748

  Tumour specific antigens; Tumour rejection antigen precursors [TRAP], e.g. MAGE · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K9/0053

  Mouth and digestive tract, i.e. intraoral and peroral administration · CPC title