# US 10,865,211 B2 · Functionalized heterocycles as antiviral agents

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- Number: US 10,865,211 B2
- Document ID: US10865211B2
- Status: Granted
- Kind: B2
- Application number: 16/577,283
- Filed: 2019-09-20
- Published: 2020-03-26
- Granted: 2020-12-15
- Earliest claimed: 2018-09-21
- Assignees: Enanta Pharmaceuticals, Inc.
- Applicants: Enanta Pharmaceuticals, Inc
- Inventors: Joseph Panarese; Samuel Bartlett; Dexter Davis; Katherine Chong; Yat Sun Or
- Web page: https://patentgrep.com/patent/US10865211B2

## CPC

- C07D 491/048: the oxygen-containing ring being five-membered
- C07D 491/147: the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- 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)

## Abstract

The present invention discloses compounds of Formula (I), or pharmaceutically acceptable salts, thereof: which inhibit the protein(s) encoded by hepatitis B virus (HBV) or interfere with the function of the HBV life cycle of the hepatitis B virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HBV infection. The invention also relates to methods of treating an HBV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.

## Claims

### Claim 1

A compound represented by Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
Z1 is O, NR1, or S;
Z2 is N or CR2;
Z3 is N or CR3;
Z4 is N or CR4;
Z5 is N or CR5;
R1 is hydrogen, optionally substituted —C1-C8 alkyl, optionally substituted —C2-C8 alkenyl, optionally substituted —C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R2, R3, R4, and R5 are each independently selected from:
1) hydrogen;
2) halogen;
3) —NO2;
4) Cyano;
5) Optionally substituted —C1-C8 alkyl;
6) Optionally substituted —C2-C8 alkenyl;
7) Optionally substituted —C2-C8 alkynyl;
8) Optionally substituted —C3-C8 cycloalkyl;
9) Optionally substituted 3- to 8-membered heterocycloalkyl;
10) Optionally substituted aryl;
11) Optionally substituted arylalkyl;
12) Optionally substituted heteroaryl;
13) Optionally substituted heteroarylalkyl;
14) —SR11;
15) —S(O)2R11;
16) —S(O)2N(R11)(R12);
17) —C(O)R11;
18) —C(O)OR11;
19) —C(O)N(R11)(R12);
20) —C(O)N(R11)S(O)2(R12);
21) —N(R11)(R12);
22) —N(R13)C(O) N(R11)(R12);
23) —N(R11)C(O)(R12);
24) —N(R11)C(O)2(R12);
25) —N(R13) S(O)2N(R11)(R12);
26) —N(R11)S(O)2(R12);
27) —OR11;
28) —OC(O)R11;
29) —OC(O)OR11; and
30) —OC(O)N(R11)(R12);
wherein R11, R12, and R13 are each independently selected from hydrogen, optionally substituted —C1-C8 alkyl, optionally substituted —C2-C8 alkenyl, optionally substituted —C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; alternatively, R11 and R12 are taken together with the nitrogen atom to which they attached to form an optionally substituted 3-8 membered heterocyclic containing 0, 1, 2, or 3 double bonds;
alternatively, Z2 is CR2, Z3 is CR3, and R2 and R3 are taken together with the carbon atoms to which they are attached to form an optionally substituted 3-8 membered heterocyclic or carbocyclic ring containing 0, 1, 2, or 3 double bonds;
alternatively, Z3 is CR3, Z4 is CR4, and R3 and R4 are taken together with the carbon atoms to which they are attached to form an optionally substituted 3-8 membered heterocyclic or carbocyclic ring containing 0, 1, 2, or 3 double bonds;
alternatively, Z4 is CR4, Z5 is CR5, and R4 and R5 are taken together with the carbon atoms to which they are attached to form an optionally substituted 3-8 membered heterocyclic or carbocyclic ring containing 0, 1, 2, or 3 double bonds;
Q1, Q2, and Q3 are each independently selected from hydrogen, halo, NR11, optionally substituted —C1-C6 alkyl, optionally substituted —C1-C6 alkoxy, optionally substituted —C3-C8 cycloalkyl; optionally substituted 3- to 8-membered heterocycloalkyl; optionally substituted aryl; and optionally substituted heteroaryl;
Q4 is selected from halo, NR11, optionally substituted —C1-C6 alkyl, optionally substituted —C1-C6 alkoxy, optionally substituted —C3-C8 cycloalkyl; optionally substituted 3- to 8-membered heterocycloalkyl optionally substituted aryl; and optionally substituted heteroaryl;
alternatively, Q1 is taken together with Q2 or Q3 and the carbon atoms to which they are attached to form an optionally substituted 3-8 membered heterocyclic or carbocyclic ring containing 0, 1, 2, or 3 double bonds;
alternatively, Q2 is taken together with Q4 and the carbon atoms to which they are attached to form an optionally substituted 3-8 membered heterocyclic or carbocyclic ring containing 0, 1, 2, or 3 double bonds;
alternatively, Q3 and Q4 are taken together with the carbon atoms to which they are attached to form an optionally substituted 3-8 membered heterocyclic or carbocyclic ring containing 0, 1, 2, or 3 double bonds;
Y1 is hydrogen, halo, or optionally substituted C1-C6 alkyl;
Y2 is O, NR11, N(OR11), or N(NR11);
Y3 is —COOR11, —C(O)NHSO2R11, —C(O)NHSO2NR11R12, 5-tetrazolyl, or 1,2,4-oxadiazol-3-yl-5(4H)-one; and
Y4 is hydrogen or optionally substituted methyl;
alternatively, Y2 and Y3 are taken together with the carbon atoms to which they are attached to form an optionally substituted 5-12 membered heterocyclic ring containing 1, 2, or 3 double bonds.

### Claim 2 (depends on 1)

The compound of claim 1, wherein at least one of Z2, Z3, Z4 and Z5 is not nitrogen and at least one of R2, R3, R4, and R5 is selected from one of the following by removal of a hydrogen atom:
wherein each of these groups is optionally substituted with one to four groups selected from halo, CN, —OR11, —NR11R12, optionally substituted C1-C6 alkyl, and optionally substituted 3- to 8-membered heterocyclic, wherein R11 and R12 are as defined in claim 1.

### Claim 3 (depends on 1)

The compound of claim 1, wherein at least one of Z2, Z3, Z4 and Z5 is not nitrogen and at least one of R2, R3, R4, and R5 is selected from hydrogen, halogen, —CN, —CH3, —CF3, —CHF2, —C(O)CH3, —OCH3, —OCF3, —OCHF2, —OH, —OR11, —NH2, and —NHR12, wherein R11 and R12 are each independently selected from one of the following by removal of a hydrogen atom:
wherein each of these groups is optionally substituted with one to four groups selected from halo, CN, —OR11, —NR11R12, optionally substituted C1-C6 alkyl, and optionally substituted 3- to 8-membered heterocyclic.

### Claim 4 (depends on 1)

The compound of claim 1, wherein at least one of Z2, Z3, Z4 and Z5 is not nitrogen and at least one of R2, R3, R4, and R5 is selected from
wherein each R21 is independently selected from —CH3, —CHF2, —CF3, -isopropyl, and -t-butyl; or at least one of R2, R3, R4, and R5 is selected from one of the following groups by removal of a hydrogen atom:
wherein each of these groups is optionally substituted with one to four groups selected from halo, CN, —OR11, —NR11R12, optionally substituted C1-C6 alkyl, and optionally substituted 3- to 8-membered heterocyclic, wherein R11 and R12 are as defined in claim 1.

### Claim 5 (depends on 1)

The compound of claim 1, represented by Formula (II), or a pharmaceutically acceptable salt thereof:
wherein Y1, Y3, Y4, Z1, Z2, Z3, Z4, Z5, Q1, Q2, Q3, and Q4 are as defined in claim 1.

### Claim 6 (depends on 1)

The compound of claim 1, represented by Formula (IV-1) or Formula (IV-2), or a pharmaceutically acceptable salt thereof:
wherein Y1, Y3, Y4, Z1, Z2, Z3, Z4, and Z5 are as defined in claim 1.

### Claim 7 (depends on 1)

The compound of claim 1, represented by Formula (VI), or a pharmaceutically acceptable salt thereof:
wherein one V is —O—, —C(O)—, —S—, —S(O)2—, —NR22— or —C(R22)2—, and the other Vs are independently —O—, —NR22— or —C(R22)2—; each R22 is independently hydrogen, optionally substituted —C1-C6 alkyl, optionally substituted —C2-C6 alkenyl, optionally substituted-C2-C6 alkynyl, optionally substituted C1-C6 alkoxy; optionally substituted —C3-C7 cycloalkyl, optionally substituted 3- to 7-membered heterocyclic, optionally substituted aryl or optionally substituted heteroaryl; n is 0, 1, 2 or 3; and Y1, Y3, Y4, Z1, Z2, Z3, Z4, and Z5 are as defined in claim 1.

### Claim 8 (depends on 1)

The compound of claim 1, represented by one of Formulae (VIII-1)˜(VIII-6) and Formulae (IX-1)˜(IX-6), or a pharmaceutically acceptable salt thereof:
wherein one V is —O—, —C(O)—, —S—, —S(O)2—, —NR22— or —C(R22)2—, and the other Vs are independently —O—, —NR22— or —C(R22)2—; each R22 is independently hydrogen, optionally substituted —C1-C6 alkyl, optionally substituted —C2-C6 alkenyl, optionally substituted —C2-C6 alkynyl, optionally substituted C1-C6 alkoxy; optionally substituted —C3-C7 cycloalkyl, optionally substituted 3- to 7-membered heterocyclic, optionally substituted aryl or optionally substituted heteroaryl; and Y1, Y3, Y4, R1, R2, R3, Z2, Z3, Z4, and Z5 are as defined in claim 1.

### Claim 9 (depends on 1)

The compound of claim 1, represented by one of Formulae (XIII-1) or (XIII-2), or a pharmaceutically acceptable salt thereof:
wherein R2, R3, and Q4 are as are as defined in claim 1.

### Claim 10

A compound selected from the compounds set forth below or a pharmaceutically acceptable salt thereof:
Compound
Structure
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84

### Claim 11

A pharmaceutical composition, comprising a compound represented by Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
Z1 is O, NR1, or S;
Z2 is N or CR2;
Z3 is N or CR3;
Z4 is N or CR4;
Z5 is N or CR5;
R1 is hydrogen, optionally substituted —C1-C8 alkyl, optionally substituted —C2-C8 alkenyl, optionally substituted —C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R2, R3, R4, and R5 are each independently selected from:
1) hydrogen;
2) halogen;
3) —NO2;
4) Cyano;
5) Optionally substituted —C1-C8 alkyl;
6) Optionally substituted —C2-C8 alkenyl;
7) Optionally substituted —C2-C8 alkynyl;
8) Optionally substituted —C3-C8 cycloalkyl;
9) Optionally substituted 3- to 8-membered heterocycloalkyl;
10) Optionally substituted aryl;
11) Optionally substituted arylalkyl;
12) Optionally substituted heteroaryl;
13) Optionally substituted heteroarylalkyl;
14) —SR11;
15) —S(O)2R11;
16) —S(O)2N(R11)(R12);
17) —C(O)R11;
18) —C(O)OR11;
19) —C(O)N(R11)(R12);
20) —C(O)N(R11)S(O)2(R12);
21) —N(R11)(R12);
22) —N(R13)C(O) N(R11)(R12);
23) —N(R11)C(O)(R12);
24) —N(R11)C(O)2(R12);
25) —N(R13) S(O)2N(R11)(R12);
26) —N(R11)S(O)2(R12);
27) —OR11;
28) —OC(O)R11;
29) —OC(O)OR11; and
30) —OC(O)N(R11)(R12);
wherein R11, R12, and R13 are each independently selected from hydrogen, optionally substituted —C1-C8 alkyl, optionally substituted —C2-C8 alkenyl, optionally substituted —C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl: alternatively, R11 and R12 are taken together with the nitrogen atom to which they attached to form an optionally substituted 3-8 membered heterocyclic containing 0, 1, 2, or 3 double bonds;
alternatively, Z2 is CR2, Z3 is CR3, and R2 and R3 are taken together with the carbon atoms to which they are attached to form an optionally substituted 3-8 membered heterocyclic or carbocyclic ring containing 0, 1, 2, or 3 double bonds;
alternatively, Z3 is CR3, Z4 is CR4, and R3 and R4 are taken together with the carbon atoms to which they are attached to form an optionally substituted 3-8 membered heterocyclic or carbocyclic ring containing 0, 1, 2, or 3 double bonds;
alternatively, Z4 is CR4, Z5 is CR5, and R4 and R5 are taken together with the carbon atoms to which they are attached to form an optionally substituted 3-8 membered heterocyclic or carbocyclic ring containing 0, 1, 2, or 3 double bonds;
Q1, Q2, Q3 and Q4 are each independently selected from hydrogen, halo, NR11, optionally substituted —C1-C6 alkyl, optionally substituted —C1-C6 alkoxy, optionally substituted —C3-C8 cycloalkyl; optionally substituted 3- to 8-membered heterocycloalkyl: optionally substituted aryl; and optionally substituted heteroaryl;
alternatively, Q1 is taken together with Q2 or Q3 and the carbon atoms to which they are attached to form an optionally substituted 3-8 membered heterocyclic or carbocyclic ring containing 0, 1, 2, or 3 double bonds;
alternatively, Q2 is taken together with Q4 and the carbon atoms to which they are attached to form an optionally substituted 3-8 membered heterocyclic or carbocyclic ring containing 0, 1, 2, or 3 double bonds;
alternatively, Q3 and Q4 are taken together with the carbon atoms to which they are attached to form an optionally substituted 3-8 membered heterocyclic or carbocyclic ring containing 0, 1, 2, or 3 double bonds;
Y1 is hydrogen, halo, or optionally substituted C1-C6 alkyl;
Y2 is O, NR11, N(OR11), or N(NR11);
Y3 is —COOR11, —C(O)NHSO2R11, —C(O)NHSO2NR11R12, 5-tetrazolyl, or 1,2,4-oxadiazol-3-yl-5(4H)-one; and
Y4 is hydrogen or optionally substituted methyl;
alternatively, Y2 and Y3 are taken together with the carbon atoms to which they are attached to form an optionally substituted 5-12 membered heterocyclic ring containing 1, 2, or 3 double bonds;
and a pharmaceutically acceptable carrier or excipient.

### Claim 12 (depends on 11)

A method of treating or preventing an HBV infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to claim 11.

### Claim 13 (depends on 12)

The method of claim 12, further comprising administering to the subject an additional therapeutic agent selected from the group consisting of a HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, literature-described capsid assembly modulator, reverse transcriptase inhibitor, TLR-agonist, inducer of cellular viral RNA sensor, therapeutic vaccine, and agents of distinct or unknown mechanism, and a combination thereof.

### Claim 14 (depends on 13)

The method of claim 13, wherein the pharmaceutical composition comprises the additional therapeutic agent.

### Claim 15 (depends on 13)

The method of claim 13, wherein the compound and the additional therapeutic agent are co-administered.

### Claim 16 (depends on 13)

The method of claim 13, wherein the additional therapeutic agent is administered at a lower dose or frequency compared to the dose or frequency of the additional therapeutic agent that is required to treat an HBV infection when administered alone.

### Claim 17 (depends on 13)

The method of claim 13, wherein the subject is refractory to at least one compound selected from the group consisting of a HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, distinct capsid assembly modulator, inducer of cellular viral RNA sensor, therapeutic vaccine, antiviral compounds of distinct or unknown mechanism, and combination thereof.