IP Library › Granted Patent US 9,573,911
Granted Patent B2
US 9,573,911 · App. 14/131,024 · Granted Feb 21, 2017

Diphosphate mimetics and uses thereof

Inventors: Suzanne Walker Kahne (Brookline, MA); Jiaoyang Jiang (Boston, MA); Michael Block Lazarus (West Newton, MA)
Assignee: President and Fellows of Harvard College
C07D263/58A61K45/06
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Quick Facts
Patent No.
US 9,573,911
App. No.
14/131,024
Granted
Feb 21, 2017
Kind
B2
Abstract

The present invention provides compounds of Formulae (I)-(V), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. In one aspect, compounds of the present invention are useful as glycosyltransferase inhibitors, in particular, O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) inhibitors. In another aspect, compounds of the present invention are useful as kinase inhibitors, in particular, PLK1 inhibitors, GSK3P inhibitors, or MAPKAPK2 inhibitors. The present invention further provides methods of using the inventive compounds, e.g., as biological probes to study the inhibition of OGT and/or kinase activity and as therapeutics, e.g., for the treatment of OGT-associated and/or kinase-associated conditions.

Claims (54)

1. A compound of Formula (I-i):

or a pharmaceutically acceptable salt thereof;

wherein:

X is O or S;

Y is O or S;

R 1 and R 2 are taken together to form a 5-membered oxazolidin-2-one ring or a 6-membered 1,3-oxazinan-2-one ring, wherein the ring is optionally substituted or fused to an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl ring;

each instance of R B is independently selected from the group consisting of halogen, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR B1 , —N(R B2 ) 2 , —SR B1 , —C(═O)R B1 , —C(═O)OR B1 , —C(═O)SR B1 , —C(═O)N(R B2 ) 2 , —OC(═O)R B1 , —OC(═O)OR B1 , —OC(═O)SR B1 , —OC(═O)N(R B2 ) 2 , —NR B2 C(═O)R B2 , —NR B2 C(═O)OR B1 , —NR B2 C(═O)SR B1 , —NR B2 C(═O)N(R B2 ) 2 , —SC(═O)R B1 , —SC(═O)OR B1 , —SC(═O)SR B1 , —SC(═O)N(R B2 ) 2 , —C(═NR B2 )R B1 , —C(═NR B2 )OR B1 , —C(═NR B2 )SR B1 , —C(═NR B2 )N(R B2 ) 2 , —OC(═NR B2 )R B1 , —OC(═NR B2 )OR B1 , —OC(═NR B2 )SR B1 , —OC(═NR B2 )N(R B2 ) 2 , —NR B2 C(═NR B2 )R B2 , —NR B2 C(═NR B2 )OR B1 , —NR B2 C(═NR B2 )SR B1 , —NR B2 C(═NR B2 )N(R B2 ) 2 , —SC(═NR B2 )R B1 , —SC(═NR B2 )OR B1 , —SC(═NR B2 )SR B1 , —SC(═NR B2 )N(R B2 ) 2 , —C(═S)R B1 , —C(═S)OR B1 , —C(═S)SR B1 , —C(═S)N(R B2 ) 2 , —OC(═S)R B1 , —OC(═S)OR B1 , —OC(═S)SR B1 , —OC(═S)N(R B2 ) 2 , —NR B2 C(═S)R B2 , —NR B2 C(═S)OR B1 , —NR B2 C(═S)SR B1 , —NR B2 C(═S)N(R B2 ) 2 , —SC(═S)R B1 , —SC(═S)OR B1 , —SC(═S)SR B1 , —SC(═S)N(R B2 ) 2 , —S(═O)R B1 , —SO 2 R B1 , —NR B2 SO 2 R B1 , —SO 2 N(R B2 ) 2 , —CN, —SCN, and —NO 2 ;

each occurrence of R B1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and each occurrence of R B2 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an amino protecting group, or two R B2 groups are joined to form a heterocyclic ring; and

n is 0, 1, 2, 3, 4, or 5; and

provided that the compound is not:

2. The compound of claim 1 , wherein R 1 , R 2 , or the ring formed therefrom, is substituted with at least one substituent selected from the group consisting of —C(═O)R B1 , —C(═O)OR B1 , —C(═O)SR B1 , —C(═O)N(R B2 ) 2 , —OC(═O)R B1 , —OC(═O)OR B1 , —OC(═O)SR B1 , —OC(═O)N(R B2 ) 2 , —NR B2 C(═O)R B2 , —NR B2 C(═O)OR B1 , —NR B2 C(═O)SR B1 , —NR B2 C(═O)N(R B2 ) 2 , —SC(═O)R B1 , —SC(═O)OR B1 , —SC(═O)SR B1 , —SC(═O)N(R B2 ) 2 , —C(═NR B2 )R B1 , —C(═NR B2 )OR B1 , —C(═NR B2 )SR B1 , —C(═NR B2 )N(R B2 ) 2 , —OC(═NR B2 )R B1 , —OC(═NR B2 )OR B1 , —OC(═NR B2 )SR B1 , —OC(═NR B2 )N(R B2 ) 2 , —NR B2 C(═NR B2 )R B2 , —NR B2 C(═NR B2 )OR B1 , —NR B2 C(═NR B2 )SR B1 , —NR B2 C(═NR B2 )N(R B2 ) 2 , —SC(═NR B2 )R B1 , —SC(═NR B2 )OR B1 , —SC(═NR B2 )SR B1 , —SC(═NR B2 )N(R B2 ) 2 , —C(═S)R B1 , —C(═S)OR B1 , —C(═S)SR B1 , —C(═S)N(R B2 ) 2 , —OC(═S)R B1 , —OC(═S)OR B1 , —OC(═S)SR B1 , —OC(═S)N(R B2 ) 2 , —NR B2 C(═S)R B2 , —NR B2 C(═S)OR B1 , —NR B2 C(═S)SR B1 , —NR B2 C(═S)N(R B2 ) 2 , —SC(═S)R B1 , —SC(═S)OR B1 , —SC(═S)SR B1 , —SC(═S)N(R B2 ) 2 , —S(═O)R B1 , —SO 2 R B1 , —NR B2 SO 2 R B1 , —SO 2 N(R B2 ) 2 , —CN, —SCN, and —NO 2 , wherein each occurrence of R A1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and each occurrence of R A2 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an amino protecting group, or two R A2 groups are joined to form an optionally substituted heterocyclic ring.

3. The compound of claim 1 , wherein R 1 and R 2 are taken together to form a 5-membered oxazolidin-2-one ring, wherein the ring is optionally substituted or fused to an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl ring.

4. The compound of claim 1 , wherein the compound is of Formula (II-B), (III-B), (IV-B), or (V-B):

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein the compound is of Formula (II-C), (III-C), (IV-C), or (V-C):

or a pharmaceutically acceptable salt thereof,

wherein:

each instance of R A is independently selected from the group consisting of halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR A1 , —N(R A2 ) 2 , —SR A1 , —C(═O)R A1 , —C(═O)OR A1 , —C(═O)SR A1 , —C(═O)N(R A2 ) 2 , —OC(═O)R A1 , —OC(═O)OR A1 , —OC(═O)SR A1 , —OC(═O)N(R A2 ) 2 , —NR A2 C(═O)R A2 , —NR A2 C(═O)OR A1 , —NR A2 C(═O)SR A1 , —NR A2 C(═O)N(R A2 ) 2 , —SC(═O)R A1 , —SC(═O)OR A1 , —SC(═O)SR A1 , —SC(═O)N(R A2 ) 2 , —C(═NR A2 )R A1 , —C(═NR A2 )OR A1 , —C(═NR A2 )SR A1 , —C(═NR A2 )N(R A2 ) 2 , —OC(═NR A2 )R A1 , —OC(═NR A2 )OR A1 , —OC(═NR A2 )SR A1 , —OC(═NR)N(R A2 ) 2 , —NR A2 C(═NR A2 )R A2 , —NR A2 C(═NR A2 )OR A1 , —NR A2 C(═NR A2 )SR A1 , —NR A2 C(═NR A2 )N(R A2 ) 2 , —SC(═NR A2 )R A1 , —SC(═NR A2 )OR A1 , —SC(═NR A2 )SR A1 , —SC(═NR A2 )N(R A2 ) 2 , —C(═S)R A1 , —C(═S)OR A1 , —C(═S)SR A1 , —C(═S)N(R A2 ) 2 , —OC(═S)R A1 , —OC(═S)OR A1 , —OC(═S)SR A1 , —OC(═S)N(R A2 ) 2 , —NR A2 C(═S)R A2 , —NR A2 C(═S)OR A1 , —NR A2 C(═S)SR A1 , —NR A2 C(═S)N(R A2 ) 2 , —SC(═S)R A1 , —SC(═S)OR A1 , —SC(═S)SR A1 , —SC(═S)N(R A2 ) 2 , —S(═O)R A1 , —SO 2 R A1 , —NR A2 SO 2 R A1 , —SO 2 N(R A2 ) 2 , —CN, —SCN, and —NO 2 ;

each occurrence of R A1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and each occurrence of R A2 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an amino protecting group, or two R A2 groups are joined to form an optionally substituted heterocyclic ring; and

m is 0, 1, 2, 3, or 4.

6. The compound of claim 5 , wherein at least one R A substituent is selected from the group consisting of —C(═O)R B1 , —C(═O)OR B1 , —C(═O)SR B1 , —C(═O)N(R B2 ) 2 , —OC(═O)R B1 , —OC(═O)OR B1 , —OC(═O)SR B1 , —OC(═O)N(R B2 ) 2 , —NR B2 C(═O)R B2 , —NR B2 C(═O)OR B1 , —NR B2 C(═O)SR B1 , —NR B2 C(═O)N(R B2 ) 2 , —SC(═O)R B1 , —SC(═O)OR B1 , —SC(═O)SR B1 , —SC(═O)N(R B2 ) 2 , —C(═NR B2 )R B1 , —C(═NR B2 )OR B1 , —C(═NR B2 )SR B1 , —C(═NR B2 )N(R B2 ) 2 , —OC(═NR B2 )R B1 , —OC(═NR B2 )OR B1 , —OC(═NR B2 )SR B1 , —OC(═NR B2 )N(R B2 ) 2 , —NR B2 C(═NR B2 )R B2 , —NR B2 C(═NR B2 )OR B1 , —NR B2 C(═NR B2 )SR B1 , —NR B2 C(═NR B2 )N(R B2 ) 2 , —SC(═NR B2 )R B1 , —SC(═NR B2 )OR B1 , —SC(═NR B2 )SR B1 , —SC(═NR B2 )N(R B2 ) 2 , —C(═S)R B1 , —C(═S)OR B1 , —C(═S)SR B1 , —C(═S)N(R B2 ) 2 , —OC(═S)R B1 , —OC(═S)OR B1 , —OC(═S)SR B1 , —OC(═S)N(R B2 ) 2 , —NR B2 C(═S)R B2 , —NR B2 C(═S)OR B1 , —NR B2 C(═S)SR B1 , —NR B2 C(═S)N(R B2 ) 2 , —SC(═S)R B1 , —SC(═S)OR B1 , —SC(═S)SR B1 , —SC(═S)N(R B2 ) 2 , —S(═O)R B1 , —SO 2 R B1 , —NR B2 SO 2 R B1 , —SO 2 N(R B2 ) 2 , —CN, —SCN, and —NO 2 .

7. The compound of claim 5 , wherein at least one R B substituent is selected from the group consisting of —OR B1 , —N(R B2 ) 2 , and —SR B1 , wherein each occurrence of R B1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and each occurrence of R B2 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an amino protecting group, or two R B2 groups are joined to form a heterocyclic ring.

8. The compound of claim 5 , wherein the compound is of Formula (II-C7), (III-C7), (IV-C7), or (V-C7):

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 5 , wherein the compound is of Formula (II-C2), (III-C2), (IV-C2), or (V-C2):

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 5 , wherein the compound is of Formula (II-C17), (III-C17), (IV-C17), or (V-C17):

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 5 , wherein the compound is of Formula (II-C22), (III-C22), (IV-C22), or (V-C22):

or a pharmaceutically acceptable salt thereof.

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

and pharmaceutically acceptable salts thereof.

13. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

14. The compound of claim 1 , wherein R 1 and R 2 are taken together to form a 5-membered oxazolidin-2-one ring.

15. The compound of claim 1 , wherein the compound is of Formula (II-B), (III-B), or (IV-B):

or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1 , wherein the compound is of Formula (II-C), (III-C), or (IV-C):

or a pharmaceutically acceptable salt thereof,

wherein:

each instance of R A is independently selected from the group consisting of halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR A1 , —N(R A2 ) 2 , —SR A1 , —C(═O)R A1 , —C(═O)OR A1 , —C(═O)SR A1 , —C(═O)N(R A2 ) 2 , —OC(═O)R A1 , —OC(═O)OR A1 , —OC(═O)SR A1 , —OC(═O)N(R A2 ) 2 , —NR A2 C(═O)R A2 , —NR A2 C(═O)OR A1 , —NR A2 C(═O)SR A1 , —NR A2 C(═O)N(R A2 ) 2 , —SC(═O)R A1 , —SC(═O)OR A1 , —SC(═O)SR A1 , —SC(═O)N(R A2 ) 2 , —C(═NR A2 )R A1 , —C(═NR)OR A1 , —C(═NR)SR A1 , —C(═NR A2 )N(R A2 ) 2 , —OC(═NR A2 )R A1 , —OC(═NR A2 )OR A1 , —OC(═NR)SR A1 , —OC(═NR)N(R A2 ) 2 , —NR A2 C(═NR A2 )R A2 , —NR A2 C(═NR A2 )OR A1 , —NR A2 C(═NR A2 )SR A1 , —NR A2 C(═NR A2 )N(R A2 ) 2 , —SC(═NR A2 )R A1 , —SC(═NR A2 )OR A1 , —SC(═NR A2 )SR A1 , —SC(═NR A2 )N(R A2 ) 2 , —C(═S)R A1 , —C(═S)OR A1 , —C(═S)SR A1 , —C(═S)N(R A2 ) 2 , —OC(═S)R A1 , —OC(═S)OR A1 , —OC(═S)SR A1 , —OC(═S)N(R A2 ) 2 , —NR A2 C(═S)R A2 , —NR A2 C(═S)OR A1 , —NR A2 C(═S)SR A1 , —NR A2 C(═S)N(R A2 ) 2 , —SC(═S)R A1 , —SC(═S)OR A1 , —SC(═S)SR A1 , —SC(═S)N(R A2 ) 2 , —S(═O)R A1 , —SO 2 R A1 , —NR A2 SO 2 R A1 , —SO 2 N(R A2 ) 2 , —CN, —SCN, and —NO 2 ;

each occurrence of R A1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and each occurrence of R A2 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an amino protecting group, or two R A2 groups are joined to form an optionally substituted heterocyclic ring; and

m is 0, 1, 2, 3, or 4.

17. The compound of claim 5 , wherein:

at least one instance of R A is: halogen, —OR A1 , —N(R A2 ) 2 , —C(═O)R A1 , or —NO 2 ;

at least one instance of R A1 is optionally substituted alkyl; and

at least one instance of R A2 is optionally substituted alkyl.

18. The compound of claim 16 , wherein:

at least one instance of R A is: halogen, —OR A1 , —N(R A2 ) 2 , —C(═O)R A1 , or —NO 2 ;

at least one instance of R A1 is optionally substituted alkyl; and

at least one instance of R A2 is optionally substituted alkyl.

19. The compound of claim 5 , wherein at least one instance of R B is —OR B1 .

20. The compound of claim 16 , wherein at least one instance of R B is —OR B1 .

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

and pharmaceutically acceptable salts thereof.

Assignments (2)
CONFIRMATORY LICENSE Recorded Mar 6, 2014
From: HARVARD UNIVERSITY
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 032398/0324 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 16, 2014
From: JIANG, JIAOYANG; LAZARUS, MICHAEL BLOCK; KAHNE, SUZANNE WALKER
To: PRESIDENT AND FELLOWS OF HARVARD COLLEGE
Reel/Frame 031983/0013 →
Continuity (3)
Provisional Application 61504958 · Jul 6, 2011
Provisional Application 61584443 · Jan 9, 2012
Related Publication 20140163079A1 · Jun 12, 2014