# US 11,304,948 B2 · Quinazoline compounds

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- Number: US 11,304,948 B2
- Document ID: US11304948B2
- Status: Granted
- Kind: B2
- Application number: 16/718,311
- Filed: 2019-12-18
- Published: 2020-11-19
- Granted: 2022-04-19
- Earliest claimed: 2014-12-24
- Assignees: Gilead Sciences, Inc.; Institute of Organic Chemistry and Biochemistry of the AS CR, V.V.I.
- Applicants: Gilead Sciences, Inc.; Institute of Organic Chemistry and Biochemistry of the AS CR, V.V.I.
- Inventors: Ondrej Baszczynski; Milan Dejmek; Yunfeng Eric Hu; Petr Jansa; Eric Lansdon; Richard L. Mackman; Petr Simon
- Web page: https://patentgrep.com/patent/US11304948B2

## CPC

- A61K 31/517: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
- 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 31/18: for HIV
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 239/84: Nitrogen atoms
- C07D 239/94: Nitrogen atoms
- C07D 239/95: with hetero atoms directly attached in positions 2 and 4
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- 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)

## Abstract

Described herein are compounds of Formula (I) and tautomers and pharmaceutical salts thereof, compositions and formulations containing such compounds, and methods of using and making such compounds.

## Claims

### Claim 1

A pharmaceutical composition comprising a compound of formula (I):
wherein
Q is
X1, X2, and X3 are each independently N or C(R11), provided that, at most 2 of X1, X2, and X3 are N;
R1 is —H, —CN, —OR, —C(O)ORa, halogen, C1-6alkyl, C3-10cycloalkyl, or C1-6heteroalkyl, wherein each C1-6alkyl, C3-10cycloalkyl, and C1-6heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
R2 is —CN;
R3 is —H, —ORa, —SRa, —NRaRb, —NHC(O)NRaRb, C1-6alkyl, C3-10cycloalkyl, or C1-6 heteroalkyl, wherein each C1-6alkyl, C3-10cycloalkyl, and C1-6heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
R4 is —H or —ORa;
R5 is —H, —ORa, halogen, —NO2, —CN, —NRaRb, —NHC(O)NRaRb, —OC(O)NaRb, —CH2C(O)NRaRb, C1-6alkyl, C3-10cycloalkyl, or C1-6 heteroalkyl, wherein each C1-6alkyl, C3-10cycloalkyl, and C1-6 heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
R6 is —H;
R7 is C1-6alkyl, halogen, or —ORa;
R8 is C1-6alkyl, halogen, or —ORa;
R9 is —H, C1-6alkyl, orc C3-10cycloalkyl, wherein each C1-6alkyl and C3-10cycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
R11 is —H, C1-6alkyl, or C3-10cycloalkyl, wherein each C1-6alkyl and C3-10cycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
each R11 is independently —H, —CN, —ORa, —C(O)ORa, halogen, C1-6alkyl, C3-10cycloalkyl, or C1-6heteroalkyl, which may be same or different, wherein each C1-6alkyl, C3-10cycloalkyl, and C1-6heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
each R12 is independently C1-6alkyl, C3-10cycloalkyl, C1-6heteroalkyl, 5-10 membered heterocyclyl, C6-10aryl, 5-10 membered heteroaryl, halogen, —ORa, —C(O)Ra, —C(O)ORa, —C(O)NRaRb, —OC(O)NRaRb, —NRaC(O)ORb, —SR, —S(O)1-2Ra, —S(O)2F, —S(O)2NRaRb, —NRaS(O)2Rb, —N3, —CN, or —NO2; wherein each C1-6alkyl, C3-10cycloalkyl, C1-6heteroalkyl, and 5-10 membered heterocyclyl is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from halogen, —ORa, —C(O)Ra, —C(O)ORa, —C(O)NRaRb, —OC(O)NRaRb, —NRaC(O)ORb, —SRa, —S(O)1-2Ra, —S(O)2F, —S(O)2NRaRb, —NRaS(O)2Rb, —N3, —CN, and —NO2, groups, which may be same or different;
each Ra and Rb is independently —H, —NH2, C1-6alkyl, C3-10cycloalkyl, C1-6heteroalkyl, 5-10 membered heterocyclyl, C6-10aryl, or 5-10 membered heteroaryl, wherein each C1-6alkyl, C3-10cycloalkyl, C1-6heteroalkyl, 5-10 membered heterocyclyl, C6-10aryl, and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 R13 groups, which may be same or different; or Ra and Rb together with the atoms to which they are attached form a 5-10 membered heterocycle; and
each R13 is independently —CN, halogen, C1-6alkyl, C3-10cycloalkyl, C1-6heteroalkyl, or 5-10 membered heterocyclyl,
or a tautomer or a pharmaceutically acceptable salt thereof; and
one, two, three, or four additional therapeutic agents independently selected from raltegravir, Truvada® (tenofovir disoproxil fumarate+emtricitabine, TDF+FTC), maraviroc, enfuvirtide, Epzicom® (Livexa®, abacavir sulfate+lamivudine, ABC+3TC), Trizivir® (abacavir sulfate+zidovudine+lamivudine, ABC+AZT+3TC), adefovir, adefovir dipivoxil, Stribild® (elvitegravir+cobicistat+tenofovir disoproxil fumarate+emtricitabine), rilpivirine, rilpivirine hydrochloride, Complera® (Eviplera®, rilpivirine+tenofovir disoproxil fumarate+emtricitabine), Cobicistat, Atripla® (efavirenz+tenofovir disoproxil fumarate+emtricitabine), atazanavir, atazanavir sulfate, dolutegravir, elvitegravir, Aluvia® (Kaletra®, lopinavir+ritonavir), ritonavir, emtricitabine, atazanavir sulfate+ritonavir, darunavir, lamivudine, Prolastin, fosamprenavir, fosamprenavir calcium, efavirenz, Combivir® (zidovudine+lamivudine, AZT+3TC), etravirine, nelfinavir, nelfinavir mesylate, interferon, didanosine, stavudine, indinavir, indinavir sulfate, tenofovir+lamivudine, zidovudine, nevirapine, saquinavir, saquinavir mesylate, aldesleukin, zalcitabine, tipranavir, amprenavir, delavirdine, delavirdine mesylate, Radha-108 (Receptol), Hlviral, lamivudine+tenofovir disoproxil fumarate, efavirenz+lamivudine+tenofovir disoproxil fumarate, phosphazid, lamivudine+nevirapine+zidovudine, abacavir, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide fumarate, and tenofovir alafenamide hemifumarate.

### Claim 2 (depends on 1)

The pharmaceutical composition of claim 1, wherein Q is

### Claim 3 (depends on 1)

The pharmaceutical composition of claim 1, wherein X1, X2, and X3 are each CH.

### Claim 4 (depends on 1)

The pharmaceutical composition of claim 1, wherein X1, X2, and X3 are C(R11); each R11 is independently selected from —H, —CN, —ORa, halogen, and C1-6alkyl; and R1 is selected from —H, —CN, —ORa, halogen, and C1-6alkyl.

### Claim 5 (depends on 1)

The pharmaceutical composition of claim 1, wherein R3 is —H, —ORa, —CRaRb, —NHC(O)NRaRb, C1-6alkyl, or C1-6 heteroalkyl.

### Claim 6 (depends on 1)

The pharmaceutical composition of claim 1, wherein R3 is —NH2 or —OH.

### Claim 7 (depends on 1)

The pharmaceutical composition of claim 1, wherein R4 is —H, and R5 is —H, —ORa, halogen, —NO2, —CN, —NRaRb, —NHC(O)NRaRb, or C1-6alkyl.

### Claim 8 (depends on 1)

The pharmaceutical composition of claim 1, wherein R4, R5, and R6 are —H.

### Claim 9 (depends on 1)

The pharmaceutical composition of claim 1, wherein R7 is C1-6alkyl.

### Claim 10 (depends on 1)

The pharmaceutical composition of claim 1, wherein R8 is C1-6alkyl.

### Claim 11 (depends on 1)

The pharmaceutical composition of claim 1, wherein R7 and R8 are C1-6alkyl.

### Claim 12 (depends on 1)

The pharmaceutical composition of claim 1, wherein R7 and R8 are methyl.

### Claim 13 (depends on 1)

The pharmaceutical composition of claim 1, wherein R9 is —H or C1-6alkyl.

### Claim 14 (depends on 1)

The pharmaceutical composition of claim 1, wherein R10 is —H or C1-6alkyl.

### Claim 15 (depends on 1)

The pharmaceutical composition of claim 1, wherein Q is

### Claim 16 (depends on 1)

The pharmaceutical composition of claim 1, wherein the compound of formula (I), or a tautomer or a pharmaceutically acceptable salt thereof, is a compound of formula:
or a tautomer or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 1)

The pharmaceutical composition of claim 1, wherein one of the additional therapeutic agents is selected from tenofovir alafenamide, tenofovir alafenamide fumarate, and tenofovir alafenamide hemifumarate.