# US 10,117,871 B2 · 3-hydroxypyrimidine-2,4-dione-5-carboxamides as potent inhibitors of HIV

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- Number: US 10,117,871 B2
- Document ID: US10117871B2
- Status: Granted
- Kind: B2
- Application number: 15/553,508
- Filed: 2016-03-03
- Published: 2018-02-01
- Granted: 2018-11-06
- Earliest claimed: 2015-03-03
- Assignees: Regents of the University of Minnesota
- Applicants: Regents of the University of Minnesota
- Inventors: Zhengqiang Wang
- Web page: https://patentgrep.com/patent/US10117871B2

## CPC

- A61K 31/513: having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
- A61P 31/18: for HIV
- C07D 239/557: with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. orotic acid
- A61K 31/03: aromatic
- C12N 2740/16063: by chemical treatment
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

Various embodiments described herein are directed to compounds of formula (I), (II), (III) or (IV) for use as potent inhibitors of HIV integrase and for treatment of patients afflicted with AIDS. A major challenge of human immunodeficiency virus (HIV) chemotherapy continues to be the inevitable selection of resistance by the virus towards known drug regimens. Treating resistant HIV strains calls for novel antivirals with unique structural cores. Some embodiments are directed to compounds featuring a 3-hydroxypyrimidine-2,4-dione-5-carboxamide core that consistently confers low nanomolar potencies against HIV-1 in cell culture. Biochemical testing and molecular modeling results corroborate an antiviral mechanism of action of inhibiting integrase strand transfer (INST). Preliminary testing against raltegravir-resistant HIVs showed marginal cross resistance, suggesting that the chemotypes of the various embodiments described herein could fit an inhibitory profile of second generation INSTIs.

## Claims

### Claim 1

A compound of formula (I)
wherein R1 is H, (C1-C6)alkyl, (C3-C6) cycloalkyl, or (C6-C12)aryl; R2 is benzyl, which can be unsubstituted or can be substituted with one to three occurrences of a substituent independently selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkylC(═O)NH, (C1-C6)alkylNHC(═O), ((C1-C6)alkyl)2NC(═O), (C1-C6)alkylSO2, (C1-C6)alkylNHSO2, and ((C1-C6)alkyl)2NSO2; R3 is H, (C1-C6)alkyl, (C3-C6) cycloalkyl, or (C6-C12)aryl; or a pharmaceutically acceptable salt thereof; or
a compound of formula (II)
wherein R1 is H, (C1-C6)alkyl, (C3-C6) cycloalkyl, or (C6-C12)aryl; R2 is hydrogen, benzyl, which can be unsubstituted or can be substituted with one to three occurrences of a substituent independently selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkylC(═O)NH, (C1-C6)alkylNHC(═O), ((C1-C6)alkyl)2NC(═O), (C1-C6)alkylSO2, (C1-C6)alkylNHSO2, and ((C1-C6)alkyl)2NSO2; R3 is H, (C1-C6)alkyl, (C3-C6) cycloalkyl, or (C6-C12)aryl or R1 and R3 can form a five- or six-membered heterocyclic ring; and R4 is a hydrogen or (C1-C6)alkyl; or a pharmaceutically acceptable salt thereof, In some embodiments, R1 and R3 can form a five- or six-membered heterocyclic ring; or
a compound of formula (III)
wherein R1 is H, (C1-C6)alkyl, (C3-C6) cycloalkyl, or (C6-C12)aryl; R2 is (C3-C6) cycloalkyl, or (C6-C12)aryl; and R3 is H, (C1-C6)alkyl, (C3-C6) cycloalkyl, or (C6-C12)aryl or R1 and R3 can form a five- or six-membered heterocyclic ring; or a pharmaceutically acceptable salt thereof, In some embodiments, R1 and R3 can form a five- or six-membered heterocyclic ring; or
a compound of formula (IV)
wherein R1 is H, (C1-C6)alkyl, (C3-C6) cycloalkyl, or (C6-C12)aryl; R2 is (C3-C6) cycloalkyl, or (C6-C12)aryl; R3 is H, (C1-C6)alkyl, (C3-C6) cycloalkyl, or (C6-C12)aryl or R1 and R3 can form a five- or six-membered heterocyclic ring; and R4 is a hydrogen or (C1-C6)alkyl; or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the compound is of formula (IA)
wherein R1 is H, (C1-C6)alkyl or (C3-C6) cycloalkyl, and R′ is zero to three occurrences of a substituent independently selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkylC(═O)NH, (C1-C6)alkylNHC(═O), ((C1-C6)alkyl)2NC(═O), (C1-C6)alkylSO2, (C1-C6)alkylNHSO2, and ((C1-C6)alkyl)2NSO2; R3 is H, (C1-C6)alkyl, (C3-C6) cycloalkyl, or (C6-C12)aryl; or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 2)

The compound of claim 2, wherein R1 is hydrogen, methyl or ethyl; or wherein R3 is hydrogen; or both.

### Claim 4 (depends on 3)

The compound of claim 3, wherein R′ is a one or two occurrences of fluoro, or one occurrence of fluoro and one occurrence of chloro.

### Claim 5 (depends on 1)

The compound of claim 1, wherein the compound is any one of:
or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

The compound of claim 1, wherein the compound has a half maximal HIV-1 integrase strand transfer inhibitory concentration (IC50) of from about 1 nM to about 250 μM.

### Claim 7 (depends on 1)

The compound of claim 1, wherein the compound has a half maximal effective concentration (EC50) of from about 1 nM to about 250 nM.

### Claim 8 (depends on 1)

The compound of claim 1, wherein the compound has a half maximal cytotoxic concentration (CC50) of from about 10 μM to about 100 μM and a therapeutic index of from about 70 to about 2000.

### Claim 9 (depends on 1)

A method of inhibiting the human immunodeficiency virus (HIV) integrase, comprising contacting the HIV integrase with an effective amount or concentration of a compound of claim 1.

### Claim 10 (depends on 9)

The method of claim 9, wherein the contacting is in an intact virus in vivo in a human host.

### Claim 11 (depends on 1)

A method of treating a patient afflicted with Acquired Immunodeficiency Syndrome (AIDS), comprising administering to the patient an effective dose of a compound of claim 1.

### Claim 12 (depends on 11)

The method of claim 11, further comprising administering to the patient an effective dose of a second antiviral compound.

### Claim 13 (depends on 12)

The method of claim 12, wherein the second antiviral compound is a protease inhibitor or a reverse transcriptase inhibitor.

### Claim 14 (depends on 1)

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