# US 12,735,445 B2 · 3′3′ cyclic dinucleotides containing isonucleotidic units

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- Number: US 12,735,445 B2
- Document ID: US12735445B2
- Status: Granted
- Kind: B2
- Application number: 18/280,527
- Filed: 2022-03-01
- Published: 2024-05-23
- Granted: 2026-09-15
- Earliest claimed: 2021-03-11
- Assignees: Institute of Organic Chemistry and Biochemistry AS Cr, V. V. I.
- Applicants: Institute of Organic Chemistry and Biochemistry AS Cr, V. V. I.
- Inventors: Gabriel Birkus; Milan Dejmek; Radim Nencka; Michal Sala
- Web page: https://patentgrep.com/patent/US12735445B2

## CPC

- C07H 19/213: containing cyclic phosphate
- 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
- A61K 39/39: characterised by the immunostimulating additives, e.g. chemical adjuvants
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 37/04: Immunostimulants
- C07H 19/11: containing cyclic phosphate
- A61K 2039/55561: {CpG containing adjuvants; Oligonucleotide containing adjuvants}
- 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

The present disclosure relates to 3′3′ cyclic dinucleotides containing isonucleotidic units, their pharmaceutically acceptable salts, their pharmaceutical composition and combinations of substances and other medicaments or pharmaceuticals. The disclosure also relates to the compounds for the treatment or prevention of diseases or conditions modifiable by STING protein modulation, such as cancer or viral, allergic and inflammatory diseases. In addition, these substances can be used as adjuvants in vaccines.

## Claims

### Claim 1

A compound of formula (J):
or an enantiomer, hydrate, solvate, or pharmaceutically acceptable salt or addition salt thereof,
wherein
Y1 and Y2 are each independently —O— or —CH2—;
X1 and X3 are each independently OH, SH, OR15, or SR15,
X2 and X4 are each independently O or S;
RB1 is selected from Base′ and H,
RB2 is selected from Base′ and H,
wherein one of RB1 and RB2 is Base′;
R1 is H or CN or F or Cl;
R4 is H or OH or F;
R6 is selected from H, CN, N3, F, Cl, COOR15, CON(R15)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, OR15, SR15, and N(R15)2;
each R15 is independently H, —C(═Z)R16, —C(═Z)OR16, —C(═Z)SR16, —C(═Z)N(R16)2, —CH2—Z—C(═Z)R16, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C2-C10 heterocycloalkyl, C6-C10 aryl, or C2-C10 heteroaryl;
each R16 is independently H, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C7 cycloalkyl, C2-C10 heterocycloalkyl, C6-C10 aryl, or C2-C10 heteroaryl; preferably each R16 is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C2-C10 heterocycloalkyl, C6-C10 aryl, or C2-C10 heteroaryl;
each Z is independently O or S;
Base′ and Base are each independently:
wherein
A1, A2, A3 and A4 are each independently H, OH, SH, F, Cl, Br, I, NH2, OR15, SR15, NHR15, N(R15)2, or R16, and
wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C2-C10 heterocycloalkyl, C6-C10 aryl, or C2-C10 heteroaryl independently in each instance is optionally substituted with 1, 2, or 3 substituents independently selected from —OH; —SH; —NH2; —O; ═NH; —S; halogen; —N3; C6-C10 aryl optionally substituted with 1, 2, or 3 substituents independently selected from —OH, —CN, —O(C═O)ORB, —O(C═O)RB, and —COORB; unsubstituted C1-C6 alkyl; unsubstituted C1-C6 alkoxy; unsubstituted C1-C6 alkylthio; unsubstituted C1-C6 alkylamino; unsubstituted C1-C6 dialkylamino; —CN; —O(C═O)ORB; —O(C═O)RB; and —COORB; wherein RB is H or unsubstituted C1-C6 alkyl.

### Claim 2 (depends on 1)

The compound according to claim 1, having the structure Ja

### Claim 3 (depends on 1)

The compound according to claim 1, having the structure I

### Claim 4 (depends on 1)

The compound according to claim 1, having the structure II

### Claim 5 (depends on 1)

The compound according to claim 1, having the structure III

### Claim 6 (depends on 1)

The compound according to claim 1, wherein R4 is H or F.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein Base and Base′ are each independently selected from:
wherein
A, A1, A2, A3 and A4 are each independently H, OH, SH, F, Cl, Br, I, NH2, OR15, SR15, NHR15 N(R15)2, or R16.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein Base and Base′ are each independently selected from:

### Claim 9 (depends on 1)

The compound according to claim 1, wherein Base and Base′ are each independently selected from:

### Claim 10

The compound according to, wherein
Base′ is and Base is
or Base′ is and Base is
or Base′ is and Base is

### Claim 11 (depends on 1)

The compound of claim 1, wherein the compound is selected from:
wherein X1, X2, X3, X4 are as defined in claim 1.

### Claim 12 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1, or an enantiomer, solvate, hydrate, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, and/or diluent.

### Claim 13 (depends on 1)

A method of administering a medicament comprising the step of administering the compound according to claim 1 for treatment to a subject in need thereof.

### Claim 14 (depends on 1)

A method of treatment comprising the step of administering the compound according to claim 1 for in vivo modulating the activity of STING adaptor protein to induce production of a type I interferon, cytokine and/or chemokine dependent on the STING adaptor protein.

### Claim 15 (depends on 1)

A method of treatment comprising the step of administering the compound according to claim 1 in treating a viral infection, hepatitis B virus infection, HIV infection, a coronavirus infection (including SARS-CoV-2 infection), a flavivirus infection, allergic diseases, inflammatory diseases, hyperproliferative disease or cancer in a human or animal.

### Claim 16 (depends on 1)

A method of treatment comprising the step of administering the compound according to claim 1 for in vitro modulating the activity of STING adaptor protein to induce production of a type I interferon, cytokine and/or chemokine dependent on the STING adaptor protein.

### Claim 17 (depends on 1)

A method of treatment comprising the step of administering the compound according to claim 1 as a vaccine adjuvant.