IP Library › Granted Patent US 11,649,251

Granted Patent B2

US 11,649,251 · App. 16/647,855 · Granted May 16, 2023

Substituted inhibitors of menin-MLL and methods of use

Inventors: Tao Wu (Carlsbad, CA); Liansheng Li (San Diego, CA); Pingda Ren (San Diego, CA)

Assignee: KURA ONCOLOGY, INC.

C07D519/00 A61P35/00 C07D471/10 C07D487/04 C07D487/10 A61K9/0019 A61K9/0053

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Quick Facts

Patent No.: US 11,649,251
App. No.: 16/647,855
Granted: May 16, 2023
Kind: B2

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Abstract

The present disclosure provides methods of inhibiting the interaction of menin with MLL1, MLL2 and MLL-fusion oncoproteins. The methods 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. Compositions for use in these methods are also provided.

Claims (64)

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is hydrogen or R 50 ;

R 2 is NHCH 3 ;

R 3 is hydrogen or R 50 ;

A is

each of Z 1 , Z 2 , Z 3 , and Z 4 is independently selected from —C(R A1 )(R A2 )—, —C(R A1 )(R A2 )—C(R A1 )(R A2 )—, —C(O)—, and —C(R A1 )(R A2 )—C(O)—, wherein no more than one of Z 1 , Z 2 , Z 3 , and Z 4 is —C(O)— or —C(R A1 )(R A2 )—C(O)—, and wherein two of Z 1 , Z 2 , Z 3 , and Z 4 is —C(R A1 )(R A2 )—C(R A1 )(R A2 ); or

A is

Z 5 and Z 6 are each independently selected from —C(H)— and —N—;

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

L 1 is a bond;

L 2 is alkylene optionally substituted with one or more R 50 ;

R 50 is, at each occurrence, independently 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)NR 53 R 54 , —P(O)(OR 52 ) 2 , —P(O)(R 52 ) 2 , —P(O)(OR 52 )(R 52 ), —P(O)(NR 52 )(R 52 ), —NR 52 P(O)(R 52 ), —P(O)(NR 52 )(OR 52 ), and —P(O)(NR 52 ) 2 , or two R 50 groups attached to the same carbon are taken together to form ═O, ═S, or ═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 , —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 , —P(O)(OR 52 )(R 52 ), —P(O)(NR 52 )(R 52 ), —NR 52 P(O)(R 52 ), —P(O)(NR 52 )(OR 52 ), —P(O)(NR 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 , —P(O)(OR 52 )(R 52 ), —P(O)(NR 52 )(R 52 ), —NR 52 P(O)(R 52 ), —P(O)(NR 52 )(OR 52 ), —P(O)(NR 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, 1- to 6-membered 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;

R A1 is, at each occurrence, independently selected from hydrogen and R 50 ;

R A2 is, at each occurrence, independently selected from hydrogen and R 50 ;

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

each of p is an integer from 0 to 2.

2. The compound of claim 1 , wherein R 50 is methyl.

3. The compound of claim 1 , wherein A is selected from:

4. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is hydrogen or R 50 ;

R 2 is —NHCH 3 ;

R 3 is hydrogen or R 50 ;

A is selected from

Z 5 and Z 6 are each independently selected from —C(H)— and —N—;

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

L 1 is a bond;

L 2 is alkylene optionally substituted with one or more R 50 ;

R 50 is, at each occurrence, independently selected from:

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 2 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 , —P(O)(OR 52 )(R 52 ), —P(O)(NR 52 )(R 52 ), —NR 52 P(O)(R 52 ), —P(O)(NR 52 )(OR 52 ), —P(O)(NR 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 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle;

R A1 is, at each occurrence, independently selected from hydrogen and R 50 ;

R A2 is, at each occurrence, independently selected from hydrogen and R 50 ;

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

each of p is an integer from 0 to 2.

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

6. A method of treating hematological cancer in a subject exhibiting a mutation in the nucleophosmin (NPM1) gene, DNA (cytosine-5)-methyltransferase 3A (DNMT3A) gene, FMS-like tyrosine kinase-3 (FLT3) gene, isocitrate dehydrogenase 1 (IDH1) gene, isocitrate dehydrogenase 2 (TDH2) gene, or combination thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

7. The compound of claim 4 , wherein A is selected from

8. The compound of claim 4 , wherein A is selected from:

9. The compound of claim 1 , wherein A is:

10. The compound of claim 1 , wherein L 2 is —CH 2 —.

11. The compound of claim 1 , wherein B is C 3-12 carbocycle.

12. The compound of claim 1 , wherein B is C 3-6 carbocycle.

13. The compound of claim 1 , wherein R B is, at each occurrence, independently selected from —CN, —OR 52 , —N(R 52 ) 2 , —S(═O)R 52 , —S(═O) 2 R 52 , —S(═O) 2 N(R 52 ) 2 , —NR 52 S(═O) 2 R 52 , —NR 52 S(═O) 2 N(R 52 ) 2 , —NR 52 C(O)R 52 , and C 1-10 alkyl optionally substituted at each occurrence with one or more substituents selected from halogen, —OR 52 , —N(R 52 ) 2 , —NR 52 S(═O) 2 R 52 , and —NR 52 C(O)R 52 , or two R B groups attached to the same carbon are taken together to form ═O or ═S.

14. The compound of claim 1 , wherein R B is, at each occurrence, independently selected from —CN, —NR 52 S(═O) 2 R 52 , —NR 52 S(═O) 2 N(R 52 ) 2 , —NR 52 C(O)R 52 , and C 1-10 alkyl optionally substituted at each occurrence with one or more substituents selected from halogen, —OR 52 , —N(R 52 ) 2 , —NR 52 S(═O) 2 R 52 , and —NR 52 C(O)R 52 , or two R B groups attached to the same carbon are taken together to form ═O or ═S.

15. A compound that is:

or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a compound of claim 4 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

17. A method of treating a hematological cancer in a subject exhibiting a mutation in the nucleophosmin (NPM1) gene, DNA (cytosine-5)-methyltransferase 3A (DNMT3A) gene, FMS-like tyrosine kinase-3 (FLT3) gene, isocitrate dehydrogenase 1 (IDH1) gene, isocitrate dehydrogenase 2 (IDH2) gene, or combination thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 4 , or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a compound of claim 15 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

19. A method of treating a hematological cancer in a subject exhibiting a mutation in the nucleophosmin (NPM1) gene, DNA (cytosine-5)-methyltransferase 3A (DNMT3A) gene, FMS-like tyrosine kinase-3 (FLT3) gene, isocitrate dehydrogenase 1 (IDH1) gene, isocitrate dehydrogenase 2 (IDH2) gene, or combination thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 15 , or a pharmaceutically acceptable salt thereof.

Assignments (5)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 7, 2024

From: LI, LIANSHENG

To: WELLSPRING BIOSCIENCES LLC

Reel/Frame 069324/0755 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 7, 2024

From: REN, PINGDA

To: WELLSPRING BIOSCIENCES LLC

Reel/Frame 069324/0800 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 7, 2024

From: WU, TAO

To: WELLSPRING BIOSCIENCES LLC