# US 10,479,801 B2 · Tetracyclic heterocycle compounds useful as HIV integrase inhibitors

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- Number: US 10,479,801 B2
- Document ID: US10479801B2
- Status: Granted
- Kind: B2
- Application number: 15/826,898
- Filed: 2017-11-30
- Published: 2018-06-07
- Granted: 2019-11-19
- Earliest claimed: 2016-12-02
- Assignees: Merck Sharp & Dohme Corp.
- Applicants: Merck Sharp & Dohme Corp.
- Inventors: Thomas H. Graham; Tao Yu; Yonglian Zhang; John A. McCauley
- Web page: https://patentgrep.com/patent/US10479801B2

## CPC

- C07D 498/22: in which the condensed system contains four or more hetero rings
- A61K 31/407: condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
- A61K 31/4188: condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
- A61K 31/4985: Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/5365: ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/553: having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
- A61P 31/18: for HIV
- C07D 471/22: in which the condensed systems contains four or more hetero rings
- C07D 487/16: Peri-condensed systems
- C07D 498/16: Peri-condensed systems
- A61K 2300/00: Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
- C12N 15/1132: {against retroviridae, e.g. HIV}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

The present invention relates to Tetracyclic Heterocycle Compounds of Formula (I): and pharmaceutically acceptable salts or prodrug thereof, wherein A, X, R1, R2, R3 and R7 are as defined herein. The present invention also relates to compositions comprising at least one Tetracyclic Heterocycle Compound, and methods of using the Tetracyclic Heterocycle Compounds for treating or preventing HIV infection in a subject.

## Claims

### Claim 1

A compound having the formula:
or a pharmaceutically acceptable salt thereof,
wherein:
----- represents an optional double bond;
ring A, inclusive of the carbon atom and nitrogen atom to which ring A is fused, is a 5- to 8-membered monocyclic or bicyclic heterocycloalkyl group, which can be optionally and independently substituted on ring A carbon atom with a group selected from C1-C6 alkyl, —O—(C1-C6 alkyl) and C3-C7 cycloalkyl, and which can be optionally and independently substituted on a ring nitrogen atom with a group selected from C1-C6 alkyl, —C(O)—(C1-C6 alkyl) and —S(O)2—(C1-C6 alkyl);
X is selected from 5 or 6-membered monocyclic heteroaryl and —N(R4)C(O)—;
R1 is a phenyl group which is optionally substituted with from 1 to 3 groups, each independently selected from C1-C6 alkyl, halo, —O—(C1-C6 alkyl), C1-C6 haloalkyl, —O—(C1-C6 haloalkyl), —CN, —NO2, —N(R4)2, —C(O)OR6, —C(O)N(R4)2 and —NHC(O)R6;
R2 is selected from H, C1-C6 alkyl, C3-C7 cycloalkyl, halo, C1-C6 haloalkyl, —OR5, —N(R4)2, —C(O)R5, —C(O)N(R4)2 and —NHC(O)R5, wherein said C1-C6 alkyl group is optionally substituted with one or more groups, each independently selected from halo, —OH, —O(C1-C6 alkyl) and —N(R4)2;
R3 is selected from H, C1-C6 alkyl and —O—(C1-C6 alkyl), —N(R4)2;
each occurrence of R4 is independently selected from H and C1-C6 alkyl;
each occurrence of R5 is independently selected from H, C1-C6 alkyl and C3-C7 cycloalkyl;
each occurrence of R6 is independently selected from H and C1-C6 alkyl; and
R7 is selected from H and C1-C6 alkyl.

### Claim 2 (depends on 1)

The compound of claim 1, wherein X is —NHC(O)— or thiadiazolyl, or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The compound of claim 1, wherein the optional double bond represented by
---- is not present, or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

The compound of claim 1, wherein R2 is H or —O—(C1-C6 alkyl), or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R3 is H, or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

The compound of claim 1, wherein ring A is selected from:
or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

The compound of claim 1, wherein the compound of formula (I) has the formula (Ia):
or a pharmaceutically acceptable salt thereof,
wherein
ring A, inclusive of the carbon atom and nitrogen atom to which ring A is fused, is selected from:
R1 is a phenyl group which is optionally substituted with from 1 to 3 groups, each independently selected from C1-C6 alkyl, halo and —O—(C1-C6 alkyl);
R2 is selected from H and O—(C1-C6 alkyl); and
R7 is selected from H and C1-C6 alkyl.

### Claim 8 (depends on 1)

The compound of claim 1, wherein R1 is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

The compound of claim 1, wherein R7 is H, or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 1)

A compound of claim 1 selected from
or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 1)

A pharmaceutical composition comprising an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 12 (depends on 11)

The pharmaceutical composition of claim 11, further comprising one or more additional therapeutic agents selected from: lamivudine, abacavir, ritonavir, darunavir, atazanavir, emtricitabine, tenofovir, rilpivirine and lopinavir.

### Claim 13

A compound having the structure:
or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 13)

The compound of claim 13 having the structure:

### Claim 15 (depends on 13)

A pharmaceutically acceptable salt of the compound of claim 13.

### Claim 16 (depends on 13)

A pharmaceutical composition comprising the compound of claim 13 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

### Claim 17

A compound having the structure:
or a pharmaceutically acceptable salt thereof.

### Claim 18 (depends on 17)

The compound of claim 17 having the structure:

### Claim 19 (depends on 17)

A pharmaceutically acceptable salt of the compound of claim 17.

### Claim 20 (depends on 17)

A pharmaceutical composition comprising the compound of claim 17 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

### Claim 21

A compound having the structure:
or a pharmaceutically acceptable salt thereof.

### Claim 22 (depends on 21)

The compound of claim 21 having the structure:

### Claim 23 (depends on 21)

A pharmaceutically acceptable salt of the compound of claim 21.

### Claim 24 (depends on 21)

A pharmaceutical composition comprising the compound of claim 21 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

### Claim 25

A compound having the structure:
or a pharmaceutically acceptable salt thereof.

### Claim 26 (depends on 25)

The compound of claim 25 having the structure:

### Claim 27 (depends on 25)

A pharmaceutically acceptable salt of the compound of claim 25.

### Claim 28 (depends on 25)

A pharmaceutical composition comprising the compound of claim 25 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

### Claim 29

A compound having the structure:
or a pharmaceutically acceptable salt thereof.

### Claim 30 (depends on 29)

The compound of claim 29 having the structure:

### Claim 31 (depends on 29)

A pharmaceutically acceptable salt of the compound of claim 29.

### Claim 32 (depends on 29)

A pharmaceutical composition comprising the compound of claim 29 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

### Claim 33

A compound having the structure:
or a pharmaceutically acceptable salt thereof.

### Claim 34 (depends on 33)

The compound of claim 33 having the structure:

### Claim 35 (depends on 33)

A pharmaceutically acceptable salt of the compound of claim 33.

### Claim 36 (depends on 33)

A pharmaceutical composition comprising the compound of claim 33 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

### Claim 37 (depends on 1)

A method for the inhibition of HIV integrase in a subject in need thereof which comprises administering to the subject an effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 38 (depends on 1)

A method for the treatment of infection by HIV or for the treatment or delay in the onset or progression of AIDS in a subject in need thereof, which comprises administering to the subject an effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 39 (depends on 1)

A method for the treatment of infection by HIV or for the treatment or delay in the onset or progression of AIDS in a subject in need thereof, which comprises administering to the subject an effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents selected from: abacavir, lamivudine, ritonavir and lopinavir, wherein the amounts administered of the compounds, are together effective to treat infection by HIV or to treat, prevent or delay the onset or progression of AIDS.