# US 11,299,512 B2 · Cyclic di-nucleotide compounds and methods of use

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- Number: US 11,299,512 B2
- Document ID: US11299512B2
- Status: Granted
- Kind: B2
- Application number: 16/438,153
- Filed: 2019-06-11
- Published: 2020-01-09
- Granted: 2022-04-12
- Earliest claimed: 2016-03-18
- Assignees: ImmuneSensor Therapeutics, Inc.; Board of Regents, The University of Texas System
- Applicants: ImmuneSensor Therapeutics, Inc.; The Board of Regents of the University of Texas System
- Inventors: Boyu Zhong; Heping Shi; Yuanwei Dai; Qi Wei; Chuo Chen; Zhijian Chen; Lijun Sun
- Web page: https://patentgrep.com/patent/US11299512B2

## 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
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 35/00: Antineoplastic agents
- A61P 37/02: Immunomodulators
- A61P 37/04: Immunostimulants
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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 21/04: with deoxyribosyl as saccharide radical
- 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

## Abstract

Disclosed are cyclic-di-nucleotide cGAMP analogs, methods of synthesizing the compounds, pharmaceutical compositions comprising the compounds thereof, and use of compounds and compositions in medical therapy.

## Claims

### Claim 1

A compound, wherein the compound is of Formula Ic:
wherein
Z12 and Z15 are N;
Z13, Z14, Z16 and Z17 are independently CH or N;
R3 is C2alkyl functionalized with one or more halogen, thiol, hydroxyl, carboxyl, C1-6alkoxy, C1-6hydroxyalkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, or azido groups;
R4 is hydroxyl;
R9 and R10 are independently hydroxyl; thiol; C1-6alkyl; C1-6alkyl functionalized with one or more halogen, thiol, hydroxyl, carboxyl, C1-6alkoxy, C1-6hydroxyalkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, or azido groups; C1-6alkoxy; C1-6alkoxy functionalized with one or more halogen, thiol, hydroxyl, carboxyl, C1-6hydroxyalkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, or azido groups; C3-5alkenyl-O—; C3-5alkynyl-O—; oligo(ethylene glycol); poly(ethylene glycol); borano (—BH3−); or —NR7R8;
R7 and R8 are independently hydrogen; C1-6alkyl; C1-6alkyl functionalized with one or more halogen, thiol, hydroxyl, carboxyl, C1-6alkoxy, C1-6hydroxyalkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, or azido groups; cyclic —(C1-6alkyl)-; cyclic —(C1-6alkyl)- functionalized with one or more halogen, thiol, hydroxyl, carboxyl, C1-6alkoxy, C1-6hydroxyalkoxy, amino, C1-6alkylamino, or di(C1-6alkyl)amino groups; cyclic —(C1-6oxaalkyl)-; or cyclic —(C1-6oxaalkyl)-functionalized with one or more halogen, thiol, hydroxyl, carboxyl, C1-6hydroxyalkoxy, amino, C1-6alkylamino, or di(C1-6alkyl)amino groups;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein Z13 and Z16 are CH.

### Claim 3 (depends on 1)

The compound of claim 1, wherein Z14 and Z17 are N.

### Claim 4 (depends on 1)

The compound of claim 1, wherein Z13 and Z16 are CH, and Z14 and Z17 are N.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R9 and R10 are independently hydroxyl or thiol.

### Claim 6 (depends on 1)

The compound of claim 1, wherein R9 and R10 are hydroxyl.

### Claim 7 (depends on 1)

The compound of claim 1, wherein R9 and R10 are thiol.

### Claim 8 (depends on 1)

The compound of claim 1, wherein R3 is C2alkyl functionalized with one or more thiol, hydroxyl, carboxyl, C1-6hydroxyalkoxy, amino, or C1-6alkylamino groups.

### Claim 9 (depends on 1)

The compound of claim 1, wherein R3 is C2alkyl functionalized with one or more halogen, thiol, or hydroxyl.

### Claim 10

A compound, wherein the compound is of Formula Ic:
wherein
Z12 and Z15 are N;
Z13 and Z16 are CH;
Z14 and Z17 are independently CH or N;
R3 is C2alkyl functionalized with one or more halogen, thiol, hydroxyl, carboxyl, C1-6alkoxy, C1-6hydroxyalkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, or azido groups;
R4 is hydroxyl;
R9 and R10 are independently hydroxyl or thiol;
or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 10)

The compound of claim 10, wherein R3 is C2alkyl functionalized with one or more thiol, hydroxyl, carboxyl, C1-6hydroxyalkoxy, amino, or C1-6alkylamino groups.

### Claim 12 (depends on 10)

The compound of claim 10, wherein R3 is C2alkyl functionalized with hydroxyl.

### Claim 13 (depends on 10)

The compound of claim 10, wherein R3 is C2alkyl functionalized with thiol.

### Claim 14 (depends on 10)

The compound of claim 10, wherein R3 is C2alkyl functionalized with halogen.

### Claim 15

A compound, wherein the compound is of Formula Ic:
wherein
Z12 and Z15 are N;
Z13, Z14, Z16 and Z17 are independently CH or N;
R3 is C1-6alkyl functionalized with one or more halogen, thiol, or hydroxyl;
R4 is hydroxyl;
R9 and R10 are independently hydroxyl; thiol; C1-6alkyl; C1-6alkyl functionalized with one or more halogen, thiol, hydroxyl, carboxyl, C1-6alkoxy, C1-6hydroxyalkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, or azido groups; C1-6alkoxy; C1-6alkoxy functionalized with one or more halogen, thiol, hydroxyl, carboxyl, C1-6hydroxyalkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, or azido groups; C3-5alkenyl-O—; C3-5alkynyl-O—; oligo(ethylene glycol); poly(ethylene glycol); borano (—BH3−); or —NR7R8;
R7 and R8 are independently hydrogen; C1-6alkyl; C1-6alkyl functionalized with one or more halogen, thiol, hydroxyl, carboxyl, C1-6alkoxy, C1-6hydroxyalkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, or azido groups; cyclic —(C1-6alkyl)-; cyclic —(C1-6alkyl)- functionalized with one or more halogen, thiol, hydroxyl, carboxyl, C1-6alkoxy, C1-6hydroxyalkoxy, amino, C1-6alkylamino, or di(C1-6alkyl)amino groups; cyclic —(C1-6oxaalkyl)-; or cyclic —(C1-6oxaalkyl)-functionalized with one or more halogen, thiol, hydroxyl, carboxyl, C1-6hydroxyalkoxy, amino, C1-6alkylamino, or di(C1-6alkyl)amino groups;
or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 15)

The compound of claim 15 having the structure:
or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 15)

The compound of claim 15 having the structure:
or a pharmaceutically acceptable salt thereof.

### Claim 18 (depends on 15)

The compound of claim 15 having the structure:
or a pharmaceutically acceptable salt thereof.

### Claim 19 (depends on 15)

The compound of claim 15 having the structure:
or a pharmaceutically acceptable salt thereof.

### Claim 20

A compound, wherein the compound is of Formula Ic:
wherein
Z12 and Z15 are N;
Z13 and Z16 are CH;
Z14 and Z17 are independently CH or N;
R3 is C1-6alkyl functionalized with one or more halogen, thiol, or hydroxyl;
R4 is hydroxyl;
R9 and R10 are independently hydroxyl or thiol;
or a pharmaceutically acceptable salt thereof.

### Claim 21 (depends on 20)

The compound of claim 20, wherein R3 is C1-6alkyl functionalized with hydroxyl.

### Claim 22 (depends on 20)

The compound of claim 20, wherein R3 is C1-6alkyl functionalized with thiol.

### Claim 23 (depends on 20)

The compound of claim 20, wherein R3 is C1-6alkyl functionalized with halogen.

### Claim 24 (depends on 1)

A pharmaceutical composition that provides a therapeutically effective amount of a compound of claim 1 and one or more pharmaceutically acceptable excipients.

### Claim 25 (depends on 1)

A pharmaceutical composition that provides a therapeutically effective amount of a compound of claim 1 in combination with at least one further therapeutic agent and one or more pharmaceutically acceptable excipients.

### Claim 26 (depends on 1)

An immunogenic composition comprising an antigen or antigen composition and a compound of claim 1.

### Claim 27 (depends on 8)

A pharmaceutical composition that provides a therapeutically effective amount of a compound of claim 8 and one or more pharmaceutically acceptable excipients.

### Claim 28 (depends on 10)

A pharmaceutical composition that provides a therapeutically effective amount of a compound of claim 10 and one or more pharmaceutically acceptable excipients.

### Claim 29 (depends on 11)

A pharmaceutical composition that provides a therapeutically effective amount of a compound of claim 11 and one or more pharmaceutically acceptable excipients.

### Claim 30 (depends on 15)

A pharmaceutical composition that provides a therapeutically effective amount of a compound of claim 15 and one or more pharmaceutically acceptable excipients.

### Claim 31 (depends on 16)

A pharmaceutical composition that provides a therapeutically effective amount of a compound of claim 16 and one or more pharmaceutically acceptable excipients.

### Claim 32 (depends on 17)

A pharmaceutical composition that provides a therapeutically effective amount of a compound of claim 17 and one or more pharmaceutically acceptable excipients.

### Claim 33 (depends on 18)

A pharmaceutical composition that provides a therapeutically effective amount of a compound of claim 18 and one or more pharmaceutically acceptable excipients.

### Claim 34 (depends on 19)

A pharmaceutical composition that provides a therapeutically effective amount of a compound of claim 19 and one or more pharmaceutically acceptable excipients.