Compounds for the treatment of cancer

Patent metadata

Field	Value
Publication number	US-10246480-B2
Application number	US-201815898533-A
Country	US
Kind code	B2
Filing date	Feb 17, 2018
Priority date	Feb 17, 2017
Publication date	Apr 2, 2019
Grant date	Apr 2, 2019

Abstract

Provided herein are compounds useful for the treatment of cancer.

First claim

We claim:

1. A compound of Formula (III):

or a pharmaceutically acceptable salt thereof, wherein
R 1a is selected from the group consisting of —H, —OH, and —F;
R 1b is selected from the group consisting of —H, —OH, and —F, wherein at least one of R 1a and R 1b is —H;
R 4a is selected from the group consisting of —H, —OH, and —F;
R 4b is selected from the group consisting of —H, —OH, and —F, wherein at least one of R 4a and R 4b is —H;
P 1 and P 2 each independently has an S or R stereochemical configuration;
Z is —O— or —NH—;
X 1a and X 2a are the same or different and are independently selected from ═O or ═S;
X 1b and X 2b are the same or different and are independently selected from —OR 5 and —SR 5 ;
wherein R 5 is selected from the group consisting of —H, —C 1-6 alkyl, —C(O)C 1-6 alkyl, and —CH 2 OC(O)OC 1-6 alkyl;

L 1 in formula (III) is four, five, or six carbons in length, and is

wherein indicates a singe bond, a double bond, or a triple bond and wherein (i) either 0 or 1 occurrence of in L 1 indicates a triple bond; or (ii) 0, 1, or 2 occurrences of in L 1 indicates a double bond, wherein geometry about each double bond is cis or trans; and (iii) wherein when 1 occurrence of in L 1 indicates a triple bond, 0 occurrences of in L 1 indicates a double bond; and (iv) wherein, when 2 occurrences of in L 1 indicate a double bond, those double bonds are either adjacent bonds or alternating bonds;
wherein X 10 , X 11 , X 12 , X 13 , X 14 , and X 15 are independently selected from a bond, —CH 2 —, or —CH—, wherein the —CH 2 — or —CH— is unsubstituted or substituted by (i) —OH, (ii) —F, (iii) —Cl, (iv) —NH 2 , or (v) -D, and when X 10 or X 15 is a bond, that bond is not a double bond or triple bond;
and wherein any two adjacent members of the group including X 10 , X 11 , X 12 , X 13 , X 14 , and X 15 may optionally form, with additional atoms, a C 3 cycloalkyl or a C 3 heterocycloalkyl, said C 3 heterocycloalkyl including an N or O atom;

wherein B 1 and B 2 are independently selected from:

where the bonds at points q and r on B 1 and B 2 are attached at points q and r on Formula (III).

2. A compound or pharmaceutically acceptable salt of claim 1 , wherein:
R 1a is selected from the group consisting of —H and —F;
R 1b is selected from the group consisting of —H and —F, wherein R 1a and R 1b may not both be —F;
R 4a is selected from the group consisting of —H and —F;
R 4b is selected from the group consisting of —H and —F, wherein R 4a and R 4b may not both be —F;
P 1 and P 2 each independently has an S or R stereochemical configuration;
X 1a and X 2a are the same or different and are independently selected from ═O or ═S;
X 1b and X 2b are the same or different and are independently selected from —OR 5 and —SR 5 ;
wherein R 5 is selected from the group consisting of —H, C 1-6 alkyl, and —C(O)C 1-6 alkyl;

L 1 in formula (III) is four or five carbons in length, and is

wherein indicates a single bond or a double bond, and wherein either 0 or 1 occurrence of in L 1 indicates a double bond, wherein geometry about the double bond is cis or trans;
wherein X 10 and X 14 are independently selected from a bond, —CH—, or —CH 2 —, and wherein, when X 10 or X 14 is a bond, that bond is not a double bond;
wherein B 1 and B 2 are independently selected from:

where the bonds at points q and r on B 1 and B 2 are attached at points q and r on Formula (III).

3. A compound or pharmaceutically acceptable salt of claim 1 , wherein
(i) stereochemical configuration of P 1 and P 2 are both R, stereochemical configuration of P 1 is R and P 2 is S, or stereochemical configuration of P 1 is S and P 2 is R;
(ii) one occurrence of in L 1 indicates a double bond, wherein geometry about the double bond is trans; and
(iii) Z is —O—.

4. A compound or pharmaceutically acceptable salt of claim 1 , wherein R 1a and R 4a are each —F.

5. A compound or pharmaceutically acceptable salt of claim 1 , wherein B 1 and B 2 are each

6. A compound or pharmaceutically acceptable salt of claim 1 , wherein X 1a and X 2a are both ═O, and wherein X 1b and X 2b are both —SH.

7. A compound or pharmaceutically acceptable salt of claim 1 , wherein L 1 is

8. A compound or pharmaceutically acceptable salt of claim 1 , wherein L 1 is four carbons in length.

9. A compound or pharmaceutically acceptable salt thereof, selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

10. A compound or pharmaceutically acceptable salt thereof of claim 9 , selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

11. A compound or pharmaceutically acceptable salt of claim 1 , wherein the compound or pharmaceutically acceptable salt has (i) an EC 50 value below 100 micromolar in reporter cells expressing human STING HAQ variant; (ii) an EC 50 value below 100 micromolar in reporter cells expressing human STING AQ variant; (iii) an EC 50 value below 100 micromolar in reporter cells expressing human STING WT variant; or (iv) an EC 50 value below 100 micromolar in reporter cells expressing human STING REF variant.

12. A compound or pharmaceutically acceptable salt wherein the compound is:

or a pharmaceutically acceptable salt thereof.

13. A pharmaceutically acceptable salt of claim 1 , wherein the salt is a diammonium salt.

14. A pharmaceutical composition comprising a compound of claim 12 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

15. A method of treating cancer, comprising adminis

Assignees

• Eisai R&D Man Co Ltd

Inventors

• Kim Dae-Shik
• Fang Frank
• Endo Atsushi
• Choi Hyeong-Wook
• Hao Ming-Hong
• Bao Xingfeng
• Huang Kuan-Chun

Classifications

• A61P37/04

  Immunostimulants · CPC title

• C07H21/00 Primary

  Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• C07H21/02 Primary

  with ribosyl as saccharide radical · CPC title

• A61P35/02

  specific for leukemia · CPC title