Compounds for the treatment of cancer

Patent metadata

Field	Value
Publication number	US-10618930-B2
Application number	US-201916277522-A
Country	US
Kind code	B2
Filing date	Feb 15, 2019
Priority date	Feb 17, 2017
Publication date	Apr 14, 2020
Grant date	Apr 14, 2020

Abstract

Provided herein are compounds useful for the treatment of cancer.

First claim

We claim:

1. A compound of Formula (IV):

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;
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 (IV) is four, five, or six carbons in length, and is

wherein indicates a single 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 (IV).

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, 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 (IV) 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 (IV).

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 1a 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 L 1 is

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

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

or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

10. A compound of Formula (V):

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, and 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;
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 (V) is four, five, or six carbons in length, and is

wherein indicates a single 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 f

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

• A61P31/04

  Antibacterial agents · 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

• A61P35/02

  specific for leukemia · CPC title

• C07F9/6587

  having two phosphorus atoms as ring hetero atoms in the same ring · CPC title

• A61P37/04

  Immunostimulants · CPC title