PU.1 inhibitors

Patent metadata

Field	Value
Publication number	US-10774049-B2
Application number	US-201816227739-A
Country	US
Kind code	B2
Filing date	Dec 20, 2018
Priority date	Jun 23, 2016
Publication date	Sep 15, 2020
Grant date	Sep 15, 2020

Abstract

Disclosed herein are inhibitors of PU.1. The inhibitors are useful for treating disorders associated with abnormal PU.1 levels and function.

First claim

What is claimed is:

1. A compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein:
x and x′ are each 3;
R is in each case independently selected from the group consisting of R a , OR a, , N(R a ) 2 , SR a , SO 2 R a , SO 2 N(R a ) 2 , COOR a , C(O)N(R a ) 2 , OC(O)N(R a ) 2 , N(R a )C(O)N(R a ) 2 , F, Cl, Br, I, cyano, and nitro, wherein R a is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, C 2-8 heterocyclyl, C 6-12 aryl, and C 3-12 heteroaryl, wherein any two or more of R and R a may together form a ring;
G and G′ are independently selected from C 3-8 cycloalkyl, C 2-8 heterocyclyl, C 6-12 aryl, and C 3-12 heteroaryl, wherein each C 6-12 aryl is optionally and independently substituted with R 8 or R 9 ;
A and A′ are independently selected from the group consisting of NR 1 , O, S, and Se, wherein R 1 , when present, is in each case independently selected from the group consisting of R b , SO 2 R b , SO 2 N(R b ) 2 , COOR b , and C(O)N(R b ) 2 , wherein R b is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, C 2-8 heterocyclyl, C 6-12 aryl, and C 3-12 heteroaryl, wherein any two or more of R and R 1 may together form a ring;
B and B′ are independently selected from the group consisting of N and CR;
α has the formula:

wherein Q a is O or NR 1a , wherein R 1a , R 2a , and R 3a are independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, and C 2-8 heterocyclyl; wherein any two or more of R 1a , R 2a , R 3a , R and R 1 can together form a ring;
β has the formula:

wherein Q b is O or NR 1b , wherein R 1b , R 2b , and R 3b are independently selected from hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, and C 2-8 heterocyclyl; wherein any two or more of R 1b , R 2b , and R 3b , R and R 1 can together form a ring;
wherein Q a and Q b are not both O;
Z is
(a) a linking group having the formula:
—X—(C(R 2 ) 2 ) m —C z —(C(R 2 ) 2 ) n —Y—;

wherein X and Y are independently selected from the group consisting of O, S, Se, and NR 4 ; wherein R 4 , when present, is in each case independently selected from the group consisting of R c , SO 2 R c , SO 2 N(R c ) 2 , COOR c , and C(O)N(R c ) 2 , wherein R c is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, C 2-8 heterocyclyl, C 6-12 aryl, and C 3-12 heteroaryl;
R 2 is in each case independently H or F;
m and n are each an integer independently selected from 0-4;
C z is selected from O, S, Se, NR 4 , C 3-8 cycloalkyl, C 2-8 heterocyclyl, C 6-12 aryl, and C 3-12 heteroaryl;
or
(b) X—(C(R 5 ) 2 ) m —C z —(C(R 5 ) 2 ) n —Y—, wherein X and Y are independently selected from the group consisting of O, S, Se, and NR 4 , wherein R 4 , m and n are as defined in (a), wherein C z is a chemical bond, wherein R 5 is in each case independently H or F and at least one R 5 is F, and wherein the sum of m and n is greater than 2;
R 8 ═H or R 9 ;
R 9 ═O(CH 2 )n a N(R 10 ) 2 or O(CH 2 )n a NH (C═NH)NH 2 ;
R 10 ═C 1 -C 6 alkyl or cyclo-alkyl; and
n a =2-8.

2. The compound according to claim 1 , wherein C z in (a) of Z is a group of the formula:

wherein A″ is O, S, Se, or NR 6 ; wherein R 6 is hydrogen, C 1-8 alkyl; C 3-8 cycloalkyl, and C 2-8 heterocyclyl.

3. The compound according to claim 1 , wherein Z is as defined in (a), and X and Y are both O.

4. The compound according to claim 1 , wherein B and B′ are both N.

5. The compound according to claim 1 , wherein A and A′ are both NR 4 .

6. The compound according to claim 1 , having the formula:

7. The compound according to claim 1 , wherein α is in the 7 position.

8. The compound according to claim 1 , wherein α is in the 4, 5 or 6 position.

9. The compound according to claim 1 , wherein β is in the 7 position.

10. The compound according to claim 1 , wherein β is in the 4, 5 or 6 position.

11. The compound according to claim 1 , wherein C z in (a) of Z is:

wherein R is selected from the group consisting of hydrogen, F, Cl, Br, I, cyano and nitro, wherein A″ is selected from the group consisting of O, S, Se, and NR 6 ; wherein R 6 is selected from the group consisting of hydrogen, C 1-8 alkyl; C 3-8 cycloalkyl, and C 2-8 heterocyclyl; and wherein R 7 is selected from the group consisting of R, hydrogen, F, Cl, Br, I, cvano and nitro.

12. The compound according to claim 1 , wherein C z is O or NR 4 .

13. The compound according to claim 1 , wherein C z is NR 4 , wherein R 4 is C 1-4 alkyl.

14. The compound according to claim 1 , wherein C z is a chemical bond.

15. The compound according to claim 1 , wherein Z is selected from the group consisting of O—CH 2 —CF 2 —CF 2 —CF 2 —CH 2 —O—, O—CH 2 —CF 2 —CF 2 —O—, —O—CF 2 —CF 2 —CF 2 —O—, and —O—CH 2 —CF 2 —CH 2 —O—.

16. The compound according to claim 1 , wherein α has the formula:

17. The compound according to claim 1 , wherein β has the formula:

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

or
a pharmaceutically acceptable salt thereof.

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

20. A method of inhibiting PU.1, comprising contacting one or more cells with a compound according to claim 1 .

21. A method of ameliorating a symptom of a disease associated with abnormal PU.1 function in a patient, comprising administering to the patient in need thereof the compound of claim 1 in an amount effective to inhibit PU.1.

22. The method according to claim 21 , wherein the disease is selected from the group consisting of hematologic cancer, bone cancer, inflammatory disease, autoimmune disorders, endotoxemia neurodegenerative disease, leukemia, acute myeloid leukemia, rheumatoid arthritis, contact dermatitis, asthma, inflammatory bowel disease, chronic inflammatory disease, pediatric atropy, giant cell arteritis, Alzheimer's disease, amyotrophic lateral sclerosis and systemic lupus.

23. The method according to claim 21 , wherein

Assignees

• Albert Einstein College Medicine
• Univ Georgia State Res Found

Inventors

• Wilson W David
• Boykin David W
• Poon Gregory
• Steidl Ulrich
• Anthony-Debré Iléana

Classifications

• C07D409/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61P35/02

  specific for leukemia · CPC title

• C07D235/20 Primary

  Two benzimidazolyl-2 radicals linked together directly or via a hydrocarbon or substituted hydrocarbon radical · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D421/14

  containing three or more hetero rings · CPC title