# US 10,246,480 B2 · Compounds for the treatment of cancer

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- Number: US 10,246,480 B2
- Document ID: US10246480B2
- Status: Granted
- Kind: B2
- Application number: 15/898,533
- Filed: 2018-02-17
- Published: 2018-08-23
- Granted: 2019-04-02
- Earliest claimed: 2017-02-17
- Assignees: Eisai R&D Management Co., Ltd.
- Applicants: Eisai R&D Management Co., Ltd.
- Inventors: Dae-Shik Kim; Frank Fang; Atsushi Endo; Hyeong-Wook Choi; Ming-Hong Hao; Xingfeng Bao; Kuan-Chun Huang
- Web page: https://patentgrep.com/patent/US10246480B2

## CPC

- C07H 21/02: with ribosyl as saccharide radical
- A61K 31/7084: Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
- A61P 31/04: Antibacterial agents
- A61P 35/02: specific for leukemia
- A61P 37/04: Immunostimulants
- C07F 9/6587: having two phosphorus atoms as ring hetero atoms in the same ring
- C07H 21/00: Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

Provided herein are compounds useful for the treatment of cancer.

## Claims

### Claim 1

A compound of Formula (III):
or a pharmaceutically acceptable salt thereof, wherein
R1a is selected from the group consisting of —H, —OH, and —F;
R1b is selected from the group consisting of —H, —OH, and —F, wherein at least one of R1a and R1b is —H;
R4a is selected from the group consisting of —H, —OH, and —F;
R4b is selected from the group consisting of —H, —OH, and —F, wherein at least one of R4a and R4b is —H;
P1 and P2 each independently has an S or R stereochemical configuration;
Z is —O— or —NH—;
X1a and X2a are the same or different and are independently selected from ═O or ═S;
X1b and X2b are the same or different and are independently selected from —OR5 and —SR5;
wherein R5 is selected from the group consisting of —H, —C1-6alkyl, —C(O)C1-6alkyl, and —CH2OC(O)OC1-6alkyl;
L1 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 L1 indicates a triple bond; or (ii) 0, 1, or 2 occurrences of in L1 indicates a double bond, wherein geometry about each double bond is cis or trans; and (iii) wherein when 1 occurrence of in L1 indicates a triple bond, 0 occurrences of in L1 indicates a double bond; and (iv) wherein, when 2 occurrences of in L1 indicate a double bond, those double bonds are either adjacent bonds or alternating bonds;
wherein X10, X11, X12, X13, X14, and X15 are independently selected from a bond, —CH2—, or —CH—, wherein the —CH2— or —CH— is unsubstituted or substituted by (i) —OH, (ii) —F, (iii) —Cl, (iv) —NH2, or (v) -D, and when X10 or X15 is a bond, that bond is not a double bond or triple bond;
and wherein any two adjacent members of the group including X10, X11, X12, X13, X14, and X15 may optionally form, with additional atoms, a C3 cycloalkyl or a C3 heterocycloalkyl, said C3 heterocycloalkyl including an N or O atom;
wherein B1 and B2 are independently selected from:
where the bonds at points q and r on B1 and B2 are attached at points q and r on Formula (III).

### Claim 2 (depends on 1)

A compound or pharmaceutically acceptable salt of claim 1, wherein:
R1a is selected from the group consisting of —H and —F;
R1b is selected from the group consisting of —H and —F, wherein R1a and R1b may not both be —F;
R4a is selected from the group consisting of —H and —F;
R4b is selected from the group consisting of —H and —F, wherein R4a and R4b may not both be —F;
P1 and P2 each independently has an S or R stereochemical configuration;
X1a and X2a are the same or different and are independently selected from ═O or ═S;
X1b and X2b are the same or different and are independently selected from —OR5 and —SR5;
wherein R5 is selected from the group consisting of —H, C1-6alkyl, and —C(O)C1-6alkyl;
L1 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 L1 indicates a double bond, wherein geometry about the double bond is cis or trans;
wherein X10 and X14 are independently selected from a bond, —CH—, or —CH2—, and wherein, when X10 or X14 is a bond, that bond is not a double bond;
wherein B1 and B2 are independently selected from:
where the bonds at points q and r on B1 and B2 are attached at points q and r on Formula (III).

### Claim 3 (depends on 1)

A compound or pharmaceutically acceptable salt of claim 1, wherein
(i) stereochemical configuration of P1 and P2 are both R, stereochemical configuration of P1 is R and P2 is S, or stereochemical configuration of P1 is S and P2 is R;
(ii) one occurrence of in L1 indicates a double bond, wherein geometry about the double bond is trans; and
(iii) Z is —O—.

### Claim 4 (depends on 1)

A compound or pharmaceutically acceptable salt of claim 1, wherein R1a and R4a are each —F.

### Claim 5 (depends on 1)

A compound or pharmaceutically acceptable salt of claim 1, wherein B1 and B2 are each

### Claim 6 (depends on 1)

A compound or pharmaceutically acceptable salt of claim 1, wherein X1a and X2a are both ═O, and wherein X1b and X2b are both —SH.

### Claim 7 (depends on 1)

A compound or pharmaceutically acceptable salt of claim 1, wherein L1 is

### Claim 8 (depends on 1)

A compound or pharmaceutically acceptable salt of claim 1, wherein L1 is four carbons in length.

### Claim 9

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

### Claim 10 (depends on 9)

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

### Claim 11 (depends on 1)

A compound or pharmaceutically acceptable salt of claim 1, wherein the compound or pharmaceutically acceptable salt has (i) an EC50 value below 100 micromolar in reporter cells expressing human STING HAQ variant; (ii) an EC50 value below 100 micromolar in reporter cells expressing human STING AQ variant; (iii) an EC50 value below 100 micromolar in reporter cells expressing human STING WT variant; or (iv) an EC50 value below 100 micromolar in reporter cells expressing human STING REF variant.

### Claim 12

A compound or pharmaceutically acceptable salt wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 1)

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

### Claim 14 (depends on 12)

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

### Claim 15 (depends on 12)

A method of treating cancer, comprising administering to a patient in need of treatment a compound or pharmaceutically acceptable salt of claim 12.

### Claim 16 (depends on 12)

A method of treating cancer comprising:
identifying an individual having a cancer treatable by a compound or a pharmaceutically acceptable salt of claim 12; and
administering to said individual a pharmaceutically effective amount of the compound or pharmaceutically acceptable salt by which the cancer has been identified as treatable.

### Claim 17 (depends on 12, 16)

The method of claim 16, wherein said individual is identified as having a cancer treatable by a compound or pharmaceutically acceptable salt of claim 12 by a presence of a REF STING variant allele in the patient.

### Claim 18 (depends on 15)

The method of claim 15, wherein the cancer is selected from the group consisting of lymphoma, melanoma, colorectal cancer, breast cancer, acute myeloid leukemia, colon cancer, liver cancer, prostate cancer, pancreatic cancer, renal cancer, and glioma.

### Claim 19 (depends on 12)

A method of treating cancer in a patient having a STING allele selected from the group consisting of a REF STING allele, a WT STING allele, a HAQ STING allele, and an AQ STING allele, comprising administering to said patient a compound or pharmaceutically acceptable salt of claim 12.

### Claim 20 (depends on 19)

The method of claim 19, wherein the cancer is selected from the group consisting of melanoma, colorectal cancer, breast cancer, acute myeloid leukemia, colon cancer, liver cancer, and glioma.

### Claim 21 (depends on 15)

The method of claim 15, wherein said cancer is metastatic.

### Claim 22 (depends on 1)

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

### Claim 23 (depends on 1)

A method of treating cancer, comprising administering to a patient in need of treatment a compound or pharmaceutically acceptable salt of claim 1.

### Claim 24 (depends on 23)

The method of claim 23, wherein said patient has a variant REF STING variant allele.

### Claim 25 (depends on 1)

A method of treating cancer comprising:
identifying an individual having a cancer treatable by a compound or a pharmaceutically acceptable salt of claim 1; and
administering to said individual a pharmaceutically effective amount of the compound or pharmaceutically acceptable salt by which the cancer has been identified as treatable.

### Claim 26 (depends on 1, 25)

The method of claim 25, wherein said individual is identified as having a cancer treatable by a compound or pharmaceutically acceptable salt of claim 1 by a presence of a REF STING variant allele in the patient.

### Claim 27 (depends on 26)

The method of claim 26, wherein the cancer is selected from the group consisting of lymphoma, melanoma, colorectal cancer, breast cancer, acute myeloid leukemia, colon cancer, liver cancer, prostate cancer, pancreatic cancer, renal cancer, and glioma.

### Claim 28 (depends on 1)

A method of treating cancer in a patient having a STING allele selected from the group consisting of a REF STING allele, a WT STING allele, a HAQ STING allele, and an AQ STING allele, comprising administering to said patient a compound or pharmaceutically acceptable salt of claim 1.

### Claim 29 (depends on 28)

The method of claim 28, wherein the cancer is selected from the group consisting of melanoma, colorectal cancer, breast cancer, acute myeloid leukemia, colon cancer, liver cancer, and glioma.

### Claim 30 (depends on 29)

The method of claim 29, wherein said cancer is metastatic.