# US 12,110,308 B2 · Phosphor(n)amidatacetal and phosph(on)atalcetal compounds

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- Number: US 12,110,308 B2
- Document ID: US12110308B2
- Status: Granted
- Kind: B2
- Application number: 16/960,819
- Filed: 2019-01-08
- Published: 2021-06-24
- Granted: 2024-10-08
- Earliest claimed: 2018-01-10
- Assignees: Nucorion Pharmaceuticals, Inc.
- Applicants: Nucorion Pharmaceuticals, Inc.
- Inventors: Lin Zhi
- Web page: https://patentgrep.com/patent/US12110308B2

## CPC

- C07F 9/65616: {containing the ring system [IMAGE cpc-sch-C07F-1006.gif] having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs}
- A61K 31/4178: not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
- A61K 31/439: the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46)
- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61K 31/47: Quinolines; Isoquinolines
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/513: having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61K 31/7056: containing five-membered rings with nitrogen as a ring hetero atom
- A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K 31/7072: having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
- A61K 38/212: {IFN-alpha}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- C07F 9/65586: {at least one of the hetero rings does not contain nitrogen as ring hetero atom}
- C07H 19/10: with the saccharide radical esterified by phosphoric or polyphosphoric acids
- A61K 31/4162: condensed with heterocyclic ring systems
- A61K 31/7052: having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K 31/7076: containing purines, e.g. adenosine, adenylic acid
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- 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
- 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)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Provided herein are phosphor (n) amidatacetal and phosph (on) atacetal compounds, their preparation and their uses, such as treating liver diseases or nonliver diseases via intervening in the molecular pathways in the liver. These compounds may be effective in the treatment of hepatitis or other viral infections either alone or in combination with one or more additional therapeutic agents.

## Claims

### Claim 1

A compound of Formula IVa:
or a stereoisomer or a pharmaceutically acceptable salt thereof
wherein:
R1 and R2 are independently selected from the group consisting of an optionally substituted C1-C6 alkyl, an optionally substituted C6-C10 aryl, and an optionally substituted 5- to 10-membered heteroaryl; or alternatively, R1 and R2 together with the atoms to which they are attached form a four to ten membered heterocycle optionally substituted with a C1-C6 alkyl;
each R3 is independently selected from the group consisting of hydrogen, an optionally substituted C1-C6 alkyl, an optionally substituted C7-C16 arylalkyl, and an optionally substituted 5- to 10-membered heteroaryl(C1-C6)alkyl;
each R6 is independently selected from halogen, an optionally substituted C1-C6 alkyl, and an optionally substituted C1-C6 alkyloxy;
m is 0, 1, 2, or 3;
n is 1 or 2; and
X is O (oxygen) or NH.

### Claim 2 (depends on 1)

The compound of claim 1, wherein each R3 is independently an optionally substituted C1-C6 alkyl.

### Claim 3 (depends on 1)

The compound of claim 1, wherein m is 0, 1, or 2.

### Claim 4 (depends on 1)

The compound of claim 1, wherein n is 1.

### Claim 5 (depends on 1)

The compound of claim 1, wherein X is NH.

### Claim 6 (depends on 1)

The compound of claim 1, wherein R3 is hydrogen or C1-C6 alkyl.

### Claim 7 (depends on 1)

The compound of claim 1, wherein R6 is C1-C6 alkyl; and m is 1, 2, or 3.

### Claim 8 (depends on 1)

The compound of claim 1, wherein the compound is selected from the group consisting of:

### Claim 9 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.

### Claim 10 (depends on 9)

The pharmaceutical composition of claim 9, further comprising one or more of cobicistat, emtricitabine and elvitegravir.

### Claim 11 (depends on 9)

The pharmaceutical composition of claim 9, further comprising one or more of ribavirin, peginterferon-alfa, simeprevir, ledipasvir, or daclatasvir.

### Claim 12 (depends on 1)

A method of treating hepatitis or viral infection, comprising administering an effective amount of the compound of claim 1 to a subject in need thereof.

### Claim 13 (depends on 12)

The method of claim 12, further comprising administering an effective amount of at least one additional therapeutic agent to the subject in need thereof.

### Claim 14 (depends on 12)

The method of claim 12, wherein the subject is a mammal.

### Claim 15 (depends on 12)

The method of claim 12, wherein the subject is human.

### Claim 16 (depends on 1)

A method of inhibiting viral replication in a cell comprising contacting the cell with the compound of claim 1.

### Claim 17 (depends on 1)

A composition comprising a compound of claim 1 for use in treating a viral infection in a subject.

### Claim 18 (depends on 17)

The composition of claim 17, in combination with one or more additional therapeutic agents.

### Claim 19 (depends on 18)

The composition of claim 18, wherein the additional therapeutic agents are selected from the group consisting of thymosin alpha-1, interferon-λ, an inhibitor of HCV protease, an inhibitor of HCV NS5A replication complex, an inhibitor of HCV NS5B polymerase, an inhibitor of HCV helicase, a cyclophilin inhibitor, an inhibitor of inosine monophosphate dehydrogenase, ribavirin, interferon-α, and pegylated interferon-α.

### Claim 20 (depends on 18)

The composition of claim 18, wherein the additional therapeutic agents comprise a direct-acting antiviral agent.

### Claim 21 (depends on 20)

The composition of claim 20, wherein the direct-acting antiviral agent is selected from the group consisting of an inhibitor of HCV protease, an inhibitor of HCV NS5A replication complex, a nucleoside-based inhibitor of HCV NS5B polymerase, a non-nucleoside inhibitor of HCV NS5B polymerase, and an inhibitor of HCV helicase.

### Claim 22 (depends on 18)

The composition of claim 18, wherein the additional therapeutic agents are selected for HBV treatment from the group consisting of: a HBV entry inhibitor, a HBV cccDNA inhibitor, a HBV capsid inhibitor, an interferon, and a HBV assembly inhibitor.

### Claim 23 (depends on 18)

The composition of claim 18, wherein the additional therapeutic agents are selected from the group consisting of: sorafenib, regorafenib, and a PD-1 or PD-L1 checkpoint inhibitor.

### Claim 24 (depends on 18)

The composition of claim 18, wherein the additional therapeutic agents are selected for HIV treatment from the group of non-nucleoside reverse transcriptase inhibitors, other nucleoside analog reverse transcriptase inhibitors, and protease inhibitors.