IP Library › Granted Patent US 10,781,218

Granted Patent B2

US 10,781,218 · App. 16/082,649 · Granted Sep 22, 2020

Substituted inhibitors of menin-MLL and methods of use

Inventors: Tao Wu (Carlsbad, CA); Liansheng Li (San Diego, CA); Yi Wang (San Diego, CA); Pingda Ren (San Diego, CA); Jolanta Grembecka (Ann Arbor, MI); Tomasz Cierpicki (Ann Arbor, MI); Szymon Klossowski (Ann Arbor, MI); Jonathan Pollock (Ann Arbor, MI); Dmitry Borkin (Ann Arbor, MI)

Assignees: KURA ONCOLOGY, INC.; THE REGENTS OF THE UNIVERSITY OF MICHIGAN

C07D495/04 A61P35/00

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Quick Facts

Patent No.: US 10,781,218
App. No.: 16/082,649
Granted: Sep 22, 2020
Kind: B2

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Abstract

The present disclosure provides compounds of Formula (II-A), which inhibit the interaction of menin with one or more of MLL1, MLL2 and MLL-fusion oncoproteins. Also disclosed are methods for the treatment of leukemia, solid cancers, diabetes and other diseases dependent on activity of MLL1, MLL2, MLL fusion proteins, and/or menin.

Claims (64)

1. A compound of Formula (II-A):

or a pharmaceutically acceptable salt thereof, wherein:

C is selected from C 3-12 carbocycle and 3- to 12-membered heterocycle;

L 2 is selected from bond, —O—, —S—, —N(R 51 )—, —N(R 51 )CH 2 —, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)N(R 51 )—, —C(O)N(R 51 )C(O)—, —C(O)N(R 51 )C(O)N(R 51 )—, —N(R 51 )C(O)—, —N(R 51 )C(O)N(R 51 )—, —N(R 51 )C(O)O—, —OC(O)N(R 51 )—, —C(NR 51 )—, —N(R 51 )C(NR 51 )—, —C(NR 51 )N(R 51 )—, —N(R 51 )C(NR 51 )N(R 51 )—, —S(O) 2- , —OS(O)—, —S(O)O—, —S(O)—, —OS(O) 2 —, —S(O) 2 O—, —N(R 51 )S(O) 2 —, —S(O) 2 N(R 51 )—, —N(R 51 )S(O)—, —S(O)N(R 51 )—, —N(R 51 )S(O) 2 N(R 51 )—, —N(R 51 )S(O)N(R 51 )—, alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is optionally substituted with one or more R 50 ;

L 3 is selected from alkylene, alkenylene, and alkynylene, each of which is substituted with one or more R 56 and optionally further substituted with one or more R 50 ;

R 1 and R 3 are each independently selected from hydrogen and R 50 ;

R 2 is R 50 ;

R A , R B , and R C are each independently selected at each occurrence from R 50 , or two R A groups, two R B groups, or two R C groups attached to the same atom or different atoms can together optionally form a bridge or ring;

m, n, and p are each independently an integer from 0 to 6;

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 , —P(O)(R 52 ) 2 , ═O, ═S, and ═N(R 52 );

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 51 is independently selected at each occurrence from:

hydrogen, —C(O)R 52 , —C(O)OR 52 , —C(O)N(R 52 ) 2 ,and —C(O)NR 53 R 54 ; and

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, —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 51 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 1—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;

R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 ;

R 56 is independently selected at each occurrence from:

—NO 2 , —SR 52 , —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 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle,

wherein each C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl in R 56 is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO 2 , —CN, —OR 59 , —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;

wherein each C 3-12 carbocycle and 3- to 12-membered heterocycle in R 56 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; and

further wherein R 56 optionally forms a bond to ring C; and

R 59 is independently selected at each occurrence from C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 1—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,

wherein for a compound or salt of Formula (II-A), when R 56 is —CH 3 , L 3 is not further substituted with —OH, —NH 2 , or —CN.

2. The compound of claim 1 , wherein R c is selected from —C(O)R 52 , —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 , =O, C 1-3 alkyl, and C 1-3 haloalkyl, or two R C groups attached to different atoms can together form a C 1-3 bridge.

3. The compound of claim 1 , wherein C is 5- to 12-membered saturated heterocycle, wherein the heterocycle comprises at least one nitrogen atom.

4. The compound of claim 1 , wherein C is selected from:

wherein R 57 is selected from —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 , and C 1-10 alkyl substituted with one or more substituents selected from —S(═O)R 52 , —S(═O) 2 R 52 , —S(═O) 2 N(R 52 ) 2 , —S(═O) 2 NR 53 R 54 , and —NR 52 S(=O) 2 R 52 .

5. The compound of claim 1 , wherein:

R 2 is selected from hydrogen, halogen, —OH, —OR 52 , —NH 2 , —N(R 52 ) 2 , —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; and

R 3 is selected from hydrogen, halogen, —OH, —N(R 52 ) 2 , —CN, —C(O)OR 52 , C 1-3 alkyl, and C 1-3 haloalkyl.

6. The compound of claim 1 , wherein R 1 is C 1-3 haloalkyl.

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

8. The compound of claim 1 , wherein n is an integer from 1 to 3.

9. The compound of claim 1 , wherein L 2 is C 1-4 alkylene, optionally substituted with one or more R 50 .

10. The compound of claim 1 , wherein L 3 is substituted with =O, C 1-6 alkyl, C 1-6 haloalkyl, C 1-3 alkyl(cyclopropyl), C 1-3 alkyl(NR 52 C(O)R 52 ) or —O(C 1-6 alkyl).

11. The compound of claim 1 , wherein L 3 is selected from

12. The compound of claim 11 , wherein R 56 is methyl.

13. The compound of claim 1 , wherein:

L 2 is selected from —O—, —S—, —NH—, and —CH 2 —;

L 3 is selected from C 1-6 alkylene, C 2-6 alkenylene, and C 2-6 alkynylene, each of which is substituted with one or more R 56 and optionally further substituted with one or more R 50 ;

m is an integer from 0 to 3;

n is an integer from 1 to 3;

p is an integer from 0 to 6;

R 56 is independently selected at each occurrence from:

—OR 59 , =O, C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl,

wherein each C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl in R 56 is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO 2 , —CN, —OR 59 , —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;

wherein each C 3-12 carbocycle and 3- to 12-membered heterocycle in R 56 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; and

further wherein R 56 optionally forms a bond to ring C; and

14. The compound of claim 13 , wherein p is 1 and R C is —S(═O) 2 R 52 , —S(═O) 2 N(R 52 ) 2 , or —S(═O) 2 NR 53 R 54 .

15. The compound of claim 13 , wherein the compound is a stereoisomer provided in at least 90% enantiomeric excess.

16. The compound of claim 1 , wherein the compound has the structure of Formula (II-C):

17. The compound of claim 1 , wherein the compound has the structure of Formula (II-F) or Formula (II-H):

18. The compound of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

19. The compound of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

Assignments (7)