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

Patent metadata

Field	Value
Publication number	US-10174041-B2
Application number	US-201816014996-A
Country	US
Kind code	B2
Filing date	Jun 21, 2018
Priority date	Jun 4, 2015
Publication date	Jan 8, 2019
Grant date	Jan 8, 2019

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 method of treating a menin-mediated disease or condition in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula II-A:

or a pharmaceutically acceptable salt thereof, wherein:
X 2 is CR 2 or N;
X 5 is S;
X 6 is CR 3 or N;
L 3 is a carbonyl, O, S, —NR 5 —, —NR 6 CH 2 —, —NR 6 C(═O)—, —NR 6 SO 2 —, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl, or heteroalkylenecarbonyl;
L 2 is a bond, carbonyl, O, S, —NR 5 —, —NR 6 CH 2 —, —NR 6 C(═O)—, —NR 6 SO 2 —, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl, or heteroalkylenecarbonyl;
m is an integer from 0 to 12;
B is selected from B-I, B-II, B-III, and B-IV;
wherein B is connected at any ring atom to L 2 ;
B-I is

B-II is

B-III is

B-IV is

each of Z 1 , Z 2 , Z 3 , and Z 4 is independently CR 7 , N, or NR 9 ;
Z 5 is C or N;
each of Z 6 , Z 7 , and Z 8 is independently CR 8 , N, NR 9 , O, or S;
each of Z 9 , Z 10 , and Z 11 is independently CR 10 , CR 11 R 12 , NR 13 , O, or S;
n is an integer from 0 to 6;
each of R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is, at each occurrence, independently selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclyl alkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino;
each of R A and R B is, at each occurrence, independently selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, 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,
wherein two R A groups or two R B groups attached to the same atom or different atoms can together optionally form a bridge or ring; and
R 14 is halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, 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, or heteroarylalkylamino,
wherein the disease or condition comprises a leukemia, a lymphoma, a hematologic malignancy, a solid tumor cancer, prostate cancer, pancreatic cancer, lung cancer, skin cancer, breast cancer, liver cancer, a brain tumor, or diabetes.

2. The method of claim 1 , wherein R 14 is halo, hydroxyl, alkoxy, alkylamino, amino, cyano, amido, alkyl, heteroalkyl, or haloalkyl.

3. The method of claim 2 , wherein R 14 is hydroxyl, alkylamino, or amino.

4. The method of claim 1 , wherein X 6 is CR 3 and R 3 in X 6 is selected from H, halo, amino, carboxyl, and alkyl.

5. The method of claim 1 , wherein L 3 is carbonyl, O, S, or —NR 5 —.

6. The method of claim 1 , wherein L 2 is C 1 -C 4 alkylene.

7. The method of claim 1 , wherein X 2 is N.

8. The method of claim 1 , wherein R 1 is haloalkyl.

9. The method of claim 1 , wherein m is 0 and n is 1 or 2.

10. The method of claim 1 , wherein R 5 is H or alkyl.

11. The method of claim 1 , wherein B is B-II.

12. The method of claim 11 , wherein B-II is

13. The method of claim 1 , comprising B-II, wherein:
Z 1 and Z 2 are CR 7 ;
Z 5 is C;
Z 6 is NR B ; and
Z 7 and Z 8 are CR 8 .

14. The method of claim 1 , comprising B-II, wherein:
Z 1 is CCH 3 ;
Z 2 and Z 8 are CH;
Z 5 is C;
Z 6 is NR B ; and
Z 7 is CCN.

15. The method of claim 1 , comprising an R B selected from:

wherein:
G is selected from a bond, alkylene, heteroalkylene, C 3-12 carbocycle, 3- to 12-membered heterocycle, and combinations thereof, 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 , —SR 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 selected from halogen, —OR 20 , —SR 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 , —CN, C 3-10 carbocycle, and 3- to 10-membered heterocycle; and
C 3-10 carbocycle and 3- to 10-membered heterocycle;
wherein two R 32 on the same carbon atom can come together to form a C 3-10 carbocycle or 3- to 10-membered heterocycle;
wherein each C 3-10 carbocycle and 3- to 10-membered heterocycle of R 32 is independently optionally substituted with one or more substituents selected from halogen, —OR 20 , —SR 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 , —CN, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

R 20 is, at each occurrence, independently selected from:
hydrogen;
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 selected from halogen, —OR 30 , —SR 30 , —N(R 30 ) 2 , —N(R 30 )C(O)R 30 , —C(O)R 30 , —C(O)OR 30 , —C(O)N(R 30 ) 2 , —OC(O)R 30 , —S(O) 2 R 30 , —S(O)

Assignees

• Kura Oncology Inc
• Univ Michigan Regents

Inventors

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

Classifications

• A61P35/02

  specific for leukemia · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · 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

• C07D495/04

  Ortho-condensed systems · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title