IP Library › Granted Patent US 10,874,686

Granted Patent B2

US 10,874,686 · App. 15/765,004 · Granted Dec 29, 2020

Anthranilyl-adenosinemonosulfamate analogs and uses thereof

Inventors: Derek Shieh Tan (New York, NY); Cheng Ji (Buffalo Grove, IL); Indrajeet Sharma (Norman, OK); Debarshi Pratihar (Kolkata, IN); James P. Coleman (Farmville, NC); Everett C. Pesci (Greenville, NC); Laurence G. Rahme (Brookline, MA)

Assignees: Memorial Sloan-Kettering Cancer Center; The General Hospital Corporation; East Carolina University

A61K31/7076 A61P31/04 C07D473/34 A61K45/06 A61K2300/00

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Quick Facts

Patent No.: US 10,874,686
App. No.: 15/765,004
Granted: Dec 29, 2020
Kind: B2

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Abstract

Provided herein are compounds of Formula (I) and pharmaceuticals acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, and prodrugs thereof. Also provided are pharmaceutical compositions, kits, and methods involving the inventive compounds for the treatment and/or of an infectious disease (e.g., bacterial infection (e.g., P. aeruginosa infection).

Claims (197)

1. A compound of Formula (I):

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:

G 2 is —S(═O) 2 —, —P(═O)(R e )—, —P(═O)(OR e )—, —P(═O)(N(R e ) 2 )—, —P(═S)(R e )—, —P(═S)(OR e )—, —P(═S)(N(R e ) 2 )—, —Si(OR e ) 2 —, —C(═O)—, —C(═S)—, —C(═NR f )—, —(CH 2 ) h —,

or optionally substituted monocyclic 5- or 6-membered heteroarylene, wherein 1, 2, 3, or 4 atoms in the heteroarylene ring system are independently oxygen, nitrogen, or sulfur;

G is of formula:

each of W, Y, and Z is independently optionally substituted heteroaryl or of the formula:

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

each of R Z1 and R Z2 is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group, or R Z1 and R Z2 are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring;

each occurrence of R Z3 is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —NO 2 , —CN, —OR e , or —N(R e ) 2 , or two R Z3 are joined to form an optionally substituted aryl or optionally substituted heteroaryl ring;

X 1 is a bond, —O—, —C(R d ) 2 —, —(CH 2 ) q , —NH—, or —NR f —;

X 2 is a bond, —O—, —C(R d ) 2 —, —(CH 2 ) t —, —NH—, or —NR f —;

each instance of R f is optionally substituted C 1-6 alkyl, optionally substituted acyl, or a nitrogen protecting group;

X 3 is a bond, —O—, —C(R d ) 2 —, or —(CH 2 ) t —;

A-B is —(R A ) 2 C—C(R B ) 2 — or —R A C═CR B —, wherein each occurrence of R A is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted acyl, —OR S1 , or —N(R e ) 2 , and each occurrence of R B is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted acyl, —OR S2 , or —N(R e ) 2 ,

X 5 is —O—, —S—, —C(R d ) 2 —, or —NR c —;

each of R 7a and R 7b is independently hydrogen, halogen, optionally substituted C 1-6 alkyl, —OR e , or —N(R e ) 2 ,

each of R 8a and R 8b is independently hydrogen, halogen, optionally substituted C 1-6 alkyl, —OR e , or —N(R e ) 2 ;

each of R 9a and R 9b is independently hydrogen, halogen, optionally substituted C 1-6 alkyl, —OR e , or —N(R e ) 2 ;

each of R S1 and R S2 is independently hydrogen, optionally substituted C 1-6 alkyl, optionally substituted acyl, or an oxygen protecting group, or R S1 and R S2 are joined to form an optionally substituted heterocyclic ring;

L S is a bond, —O—, —NR c —, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted acylene, or optionally substituted arylene;

each of V 1 , V 2 , V 3 , V 7 , V 8 , and V 9 is independently N or CR V , wherein each R V is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —NO 2 , —CN, —OR e , or —N(R e ) 2 ;

V N is N, NR N , or CR N ;

R N is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —NO 2 , —CN, —OR e , or —N(R Na ) 2 ,

each occurrence of R Na independently hydrogen, optionally substituted C 1-6 alkyl, optionally substituted acyl, or a nitrogen protecting group, or both R Na are joined to form and optionally substituted heterocyclic or optionally substituted heteroaryl ring;

each occurrence of R d is independently hydrogen, halogen, optionally substituted C 1-6 alkyl, —OR e , or —N(R e ) 2 ;

each occurrence of R e is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R e are joined to form and optionally substituted heterocyclic or optionally substituted heteroaryl ring;

each occurrence of R c is independently hydrogen, optionally substituted C 1-6 alkyl, optionally substituted acyl, or a nitrogen protecting group;

each of h, q, and t is independently 1, 2, or 3; and

indicates that each bond of the ring is a single or double bond;

provided that the compound is not any of the following:

2. The compound of claim 1 , wherein the compound is of Formula (II):

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

3. The compound of claim 1 , wherein the compound is of one of the following formulae:

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

4. The compound of claim 1 , wherein the compound is of formula:

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

5. The compound of claim 1 , wherein the compound is of one of the following formulae:

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

6. A compound of Formula (IV):

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; wherein:

Y is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted alkoxy, optionally substituted amino, —OR e , —N(R e ) 2 , optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or of formula:

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

each occurrence of R Z3 is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —NO 2 , —CN, —OR e , or —N(R e ) 2 , or two R Z3 are joined to form an optionally substituted aryl or optionally substituted heteroaryl ring;

X 1 is a bond, —O—, —C(R d ) 2 —, —(CH 2 ) q —, —NH— or —NR f —;

q is 1, 2, or 3;

R f is optionally substituted C 1-6 alkyl, optionally substituted acyl, or a nitrogen protecting group;

R A is hydrogen, halogen, optionally substituted alkyl, optionally substituted acyl, —OR S1 , or —N(R e ) 2 ;

R B is hydrogen, halogen, optionally substituted alkyl, optionally substituted acyl, —OR S2 , or —N(R e ) 2 ;

each R V is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —NO 2 , —CN, —OR e , or —N(R e ) 2 ;

each occurrence of R d is independently hydrogen, halogen, optionally substituted C 1-6 alkyl, —OR e , or —N(R e ) 2 ; and

each occurrence of R c is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R e are joined to form and optionally substituted heterocyclic or optionally substituted heteroaryl ring;

provided that the compound is not the following:

7. The compound of claim 6 , wherein the compound is of one of the following formulae:

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

8. The compound of claim 6 , wherein the compound is of formula:

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

9. A compound of Formula (V):

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; wherein:

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

X 1 is a bond, —O—, —C(R d ) 2 —, —(CH 2 ) q —, —NH— or —NR f —;

q is 1, 2, or 3;

R f is optionally substituted C 1-6 alkyl, optionally substituted acyl, or a nitrogen protecting group;

R A is hydrogen, halogen, optionally substituted alkyl, optionally substituted acyl, —OR S1 , or —N(R e ) 2 ;

R B is hydrogen, halogen, optionally substituted alkyl, optionally substituted acyl, —OR S2 , or —N(R e ) 2 ;

each occurrence of R d is independently hydrogen, halogen, optionally substituted C 1-6 alkyl, —OR e , or —N(R e ) 2 ; and

10. The compound of claim 9 , wherein the compound is of one of the following formulae:

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

11. The compound of claim 9 , wherein the compound is of formula:

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

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

and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.

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

and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.

14. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable excipient.

15. A method of treating a Pseudomonas infection in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:

G 2 is —S(═O) 2 —, —P(═O)(R e )—, —P(═O)(OR e )—, —P(═O)(N(R e ) 2 )—, —P(═S)(R e )—, P(═S)(OR e )—, —P(═S)(N(R e ) 2 )—, —Si(OR e ) 2 —, —C(═O)—, —C(═S)—, —C(═NR f )—,

or optionally substituted monocyclic 5- or 6-membered heteroarylene, wherein 1, 2, 3, or 4 atoms in the heteroarylene ring system are independently oxygen, nitrogen, or sulfur;

G is of formula:

each of W, Y, and Z is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted alkoxy, optionally substituted amino, —OR e , —N(R e ) 2 , optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or of formula:

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

X 1 is a bond, —O—, —C(R d ) 2 —, —(CH 2 ) q —, —NH—, or —NR f —;

X 2 is a bond, —O—, —C(R d ) 2 —, —(CH 2 ) t —, —NH—, or —NR f —;

X 3 is a bond, —O—, —C(R d ) 2 —, or —(CH 2 ) t —;

R f is optionally substituted C 1-6 alkyl, optionally substituted acyl, or a nitrogen protecting group;

X 5 is —O—, —S—, —C(R d ) 2 —, or —NR c —;

each of R 7a and R 7b is independently hydrogen, halogen, optionally substituted C 1-6 alkyl, —OR e , or —N(R e ) 2 ;

each of R 8a and R 8b is independently hydrogen, halogen, optionally substituted C 1-6 alkyl, —OR e , or —N(R e ) 2 ;

each of R 9a and R 9b is independently hydrogen, halogen, optionally substituted C 1-6 alkyl, —OR e , or —N(R e ) 2 ;

V N is N, NR N , or CR N ;

each occurrence of R d is independently hydrogen, halogen, optionally substituted C 1-6 alkyl, —OR e , or —N(R e ) 2 ;

each occurrence of R c is independently hydrogen, optionally substituted C 1-6 alkyl, optionally substituted acyl, or a nitrogen protecting group;

each of h, q, and t is independently 1, 2, or 3; and

indicates that each bond of the ring is a single or double bond.

16. A method of inhibiting PQS biosynthesis in an infection in a subject or in a microorganism, the method comprising administering to the subject or contacting the microorganism with a compound of Formula (I):

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:

G 2 is —S(═O) 2 —, —P(═O)(R e )—, —P(═O)(OR e )—, —P(═O)(N(R e ) 2 )—, —P(═S)(R e )—,

P(═S)(OR e )—, —P(═S)(N(R e ) 2 )—, —Si(OR e ) 2 —, —C(═O)—, —C(═S)—, —C(═NR f )—,

or optionally substituted monocyclic 5- or 6-membered heteroarylene, wherein 1, 2, 3, or 4 atoms in the heteroarylene ring system are independently oxygen, nitrogen, or sulfur;

G is of formula:

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

X 1 is a bond, —O—, —C(R d ) 2 —, —(CH 2 ) q —, —NH—, or —NR f —;

X 2 is a bond, —O—, —C(R d ) 2 —, —(CH 2 ) t —, —NH—, or —NR f —;

X 3 is a bond, —O—, —C(R d ) 2 —, or —(CH 2 ) t —;

R f is optionally substituted C 1-6 alkyl, optionally substituted acyl, or a nitrogen protecting group;

X 5 is —O—, —S—, —C(R d ) 2 —, or —NR c —;

each of R 7a and R 7b is independently hydrogen, halogen, optionally substituted C 1-6 alkyl, —OR e , or —N(R e ) 2 ;

each of R 8a and R 8b is independently hydrogen, halogen, optionally substituted C 1-6 alkyl, —OR e , or —N(R e ) 2 ;

each of R 9a and R 9b is independently hydrogen, halogen, optionally substituted C 1-6 alkyl, —OR e , or —N(R e ) 2 ;

V N is N, NR N , or CR N ;

each occurrence of R Na independently hydrogen, optionally substituted C 1-6 alkyl, optionally substituted acyl, or a nitrogen protecting group, or both R d are joined to form and optionally substituted heterocyclic or optionally substituted heteroaryl ring;

each occurrence of R d is independently hydrogen, halogen, optionally substituted C 1-6 alkyl, —OR e , or —N(R e ) 2 ;

each occurrence of R e is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R c are joined to form and optionally substituted heterocyclic or optionally substituted heteroaryl ring;

each occurrence of R c is independently hydrogen, optionally substituted C 1-6 alkyl, optionally substituted acyl, or a nitrogen protecting group;

each of h, q, and t is independently 1, 2, or 3; and

indicates that each bond of the ring is a single or double bond.

17. A method of inhibiting HHQ biosynthesis in an infection in a subject or in a microorganism, the method comprising administering to the subject or contacting the microorganism with a compound of Formula (I):

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:

or optionally substituted monocyclic 5- or 6-membered heteroarylene, wherein 1, 2, 3, or 4 atoms in the heteroarylene ring system are independently oxygen, nitrogen, or sulfur;

G is of formula:

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

each occurrence of R Z3 is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —NO 2 , —CN, —OR e , or —N(R e ) 2 , or two R are joined to form an optionally substituted aryl or optionally substituted heteroaryl ring;

X 1 is a bond, —O—, —C(R d ) 2 —, —(CH 2 ) q —, —NH—, or —NR f —;

X 2 is a bond, —O—, —C(R d ) 2 —, —(CH 2 ) t —, —NH—, or —NR f —;

X 3 is a bond, —O—, —C(R d ) 2 —, or —(CH 2 ) t —;

R f is optionally substituted C 1-6 alkyl, optionally substituted acyl, or a nitrogen protecting group;

X 5 is —O—, —S—, —C(R d ) 2 —, or —NR c —;

each of R 7a and R 7b is independently hydrogen, halogen, optionally substituted C 1-6 alkyl, —OR e , or —N(R e ) 2 ;

each of R 8a and R 8b is independently hydrogen, halogen, optionally substituted C 1-6 alkyl, —OR e , or —N(R e ) 2 ;

each of R 9a and R 9b is independently hydrogen, halogen, optionally substituted C 1-6 alkyl, —OR e , or —N(R e ) 2 ;

V N is N, NR N , or CR N ;

each occurrence of R d is independently hydrogen, halogen, optionally substituted C 1-6 alkyl, —OR e , or —N(R e ) 2 ;

each occurrence of R e is independently hydrogen, optionally substituted C 1-6 alkyl, optionally substituted acyl, or a nitrogen protecting group;

each of h, q, and t is independently 1, 2, or 3; and

indicates that each bond of the ring is a single or double bond.

18. A method of inhibiting biosynthesis of a virulence factor in an infection in a subject or in a microorganism, the method comprising administering to the subject or contacting the microorganism with a compound of claim 1 , or a pharmaceutically acceptable salt stereoisomer, or tautomer thereof.

19. A method of inhibiting biofilm formation in a subject or on a surface, the method comprising administering to the subject or contacting the surface with a compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

20. A method of eradicating a biofilm, the method comprising contacting the biofilm with a compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

21. A method of treating an infectious disease in a subject comprising administering to the subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

22. The compound of claim 6 , wherein the compound is selected from the group consisting of:

and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.

23. A pharmaceutical composition comprising a compound of claim 6 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable excipient.

24. A method of treating an infectious disease in a subject in need thereof comprising administering to the subject an effective amount of a compound of claim 6 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

25. A method of inhibiting biosynthesis of a virulence factor in an infection in a subject or in a microorganism, the method comprising administering to the subject or contacting the microorganism with a compound of claim 6 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

26. A method of inhibiting biofilm formation or eradicating a biofilm in a subject or on a surface, the method comprising administering to the subject or contacting the surface with a compound of claim 6 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

27. The compound of claim 9 , wherein the compound is selected from the group consisting of:

and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.

28. A pharmaceutical composition comprising a compound of claim 9 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable excipient.

29. A method of treating an infectious disease in a subject in need thereof comprising administering to the subject an effective amount of a compound of claim 9 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

30. A method of inhibiting biosynthesis of a virulence factor in an infection in a subject or in a microorganism, the method comprising administering to the subject or contacting the microorganism with a compound of claim 9 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

31. A method of inhibiting biofilm formation or eradicating a biofilm in a subject or on a surface, the method comprising administering to the subject or contacting the surface with a compound of claim 9 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

32. The method of claim 15 , wherein the compound is of Formula (II):

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

33. The method of claim 15 , wherein the compound is of one of the following formulae:

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

34. The method of claim 15 , wherein the compound is of one of the following formulae:

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

35. The method of claim 15 , wherein the compound is selected from the group consisting of:

and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.

36. The method of claim 15 , wherein the Pseudomonas infection is a P. aeruginosa infection.

Assignments (4)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 23, 2018

From: COLEMAN, JAMES P.; PESCI, EVERETT C.

To: EAST CAROLINA UNIVERSITY

Reel/Frame 046673/0877 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 23, 2018

From: RAHME, LAURENCE G.

To: THE GENERAL HOSPITAL CORPORATION

Reel/Frame 046673/0972 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 23, 2018

From: TAN, DEREK SHIEH; JI, CHENG; SHARMA, INDRAJEET; PRATIHAR, DEBARSHI

To: MEMORIAL SLOAN-KETTERING CANCER CENTER

Reel/Frame 046674/0032 →

CONFIRMATORY LICENSE Recorded Apr 11, 2018

From: SLOAN-KETTERING INST CAN RESEARCH

To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT

Reel/Frame 045909/0174 →

Continuity (2)

Provisional Application 62236031 · Oct 1, 2015

Related Publication 20190038656A1 · Feb 7, 2019

Cited By (1)

US 12,435,088