# US 11,078,189 B2 · Pharmaceutical compounds

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- Number: US 11,078,189 B2
- Document ID: US11078189B2
- Status: Granted
- Kind: B2
- Application number: 16/631,530
- Filed: 2018-07-20
- Published: 2020-06-04
- Granted: 2021-08-03
- Earliest claimed: 2017-07-20
- Assignees: Reviral Limited
- Applicants: Reviral Limited
- Inventors: Stuart George Cockerill; James Good
- Web page: https://patentgrep.com/patent/US11078189B2

## CPC

- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- A61P 11/06: Antiasthmatics
- C07D 401/14: containing three or more hetero rings
- C07D 403/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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

Benzimidazole derivatives of formula (I): wherein: R1 is —(CH2)m-R4 or R2 is halo, —(CH2)m—NH2 or —(CH2)n—C(═NH)—NH2; R3 is H or F; R4 is —NH—(CH2)2—(NH)r—R5, —NH—(CHR5R6) or a group of the following formula (A): (A) W is —(CH2)m—, —CH2—O—CH2—, —CH2—S—CH2—, —(CH2)r—S(O)2—CH2— or —(CH2)r—NR5—CH2—; m is an integer of 1 to 3; n is 1 or 2; p is 1 and V is CH; or p is O and V is N; q is 0 or 1; r is 0 or 1; R5 is H, —SO2Me, —SO2Et, —SO2CF3, —COMe, —CONMe2, —CONH2 or —CH2CH2SO2Me; R6 is H or C1-C6 alkyl; and R7 is —SO2Me, —SO2Et, —SO2CF3, —COMe, —CONMe2, —CONH2 or —CH2CH2SO2Me; and the pharmaceutically acceptable salts thereof are inhibitors of RSV and can therefore be used to treat or prevent an RSV infection.

## Claims

### Claim 1

A compound which is a benzimidazole derivative of formula (I):
wherein:
R1 is —(CH2)m—R4 or
R2 is halo, —(CH2)m—NH2 or —(CH2)n—C(═NH)—NH2;
R3 is H or F;
R4 is —NH—(CH2)2—(NH)r—R5, —NH—(CHR5R6) or a group of the following formula (A):
W is —(CH2)m, —CH2—O—CH2—, —CH2—S—CH2—, —(CH2)r—S(O)2—CH2— or —(CH2)r—NR5—CH2—;
m is an integer of 1 to 3;
n is 1 or 2;
p is 1 and V is CH; or p is 0 and V is N;
q is 0 or 1;
r is 0 or 1;
R5 is H, —SO2Me, —SO2Et, —SO2CF3, —COMe, —CONMe2, —CONH2 or —CH2CH2SO2Me;
R6 is H or C1-C6 alkyl; and
R7 is —SO2Me, —SO2Et, —SO2CF3, —COMe, —CONMe2, —CONH2 or —CH2CH2SO2Me;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

A compound according to claim 1 wherein R1 is —(CH2)m—R4 in which m is 2 or 3 and R4 is selected from:
(i) —NH—(CH2)2—(NH)r—R5 wherein r is 0 or 1 and R5 is selected from —SO2Me, —SO2Et and —SO2CF3;
(ii) —NH—(CHR5R6) wherein R5 is —CONH2 or —CONMe2 and R6 is C1-C6 alkyl;
(iii) —(CH2)m—R4 in which m is 2 or 3 and R4 is a group of formula (A) in which p is 1, q is 0, V is CH and W is —(CH2)r—S(O)2—CH2—or —(CH2)r—NR5—CH2-in which r is 0 and R5 is SO2Me or —SO2Et;
(iv) —(CH2)m—R4 in which m is 2 or 3 and R4 is a group of formula (A) in which p is 0, V is N, W is —(CH2)m—in which m is an integer of 1 to 3, q is 1 and R7 is —SO2Me, —SO2Et, —CONH2 or —CON Me2; and
(v) —(CH2)m—R4 in which m is 2 or 3 and R4 is a group of formula (A) in which p is 0, V is N, q is 0 and W is —CH2—O—CH2—, —CH2—S—CH2—, —(CH2)r—S(O)2—CH2— or —(CH2)r—NR5—CH2-in which r is 0 or 1 and R5 is —SO2Me, —SO2Et or —COMe.

### Claim 3 (depends on 1)

A compound according to claim 1 wherein:
R1 is in which R5 is H, —SO2Me, —SO2Et, —COMe, —CONMe2 or —CH2CH2SO2Me.

### Claim 4 (depends on 1)

A compound according to claim 1 wherein R2 is F, Cl or —CH2—NH2.

### Claim 5 (depends on 1)

A compound according to claim 1 wherein the group of formula (A) is selected from the following structures:

### Claim 6 (depends on 1)

A compound according to claim 1 which is selected from:
1′-({5-Chloro-1-[3-(4-methanesulfonylpiperazin-1-yl)propyl]-1H-1,3-benzodiazol-2-yl}methyl)-6′-fluoro-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2′-one;
1′-[(5-chloro-1-{2-[(2-methanesulfonylethyl)amino]ethyl}-1H-1,3-benzodiazol-2-yl)methyl]-6′-fluoro-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2′-one;
N-[2-({2-[5-chloro-2-({6′-fluoro-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-1′-yl}methyl)-1H-1,3-benzodiazol-1-yl]ethyl}amino)ethyl]1,1,1-trifluoromethanesulfonamide;
3-({2-[5-chloro-2-({6′-fluoro-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-1′-yl}methyl)-1H-1,3-benzodiazol-1- yl]ethyl}amino)-1λ6-thiolane-1,1-dione;
1′-[(5-chloro-1-{2-[(1-methanesulfonylpyrrolidin-3-yl)amino]ethyl}-1H-1,3-benzodiazol-2-yl)met hyl]-6′-fluoro-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2′-one;
1-{2-[5-chloro-2-({6′-fluoro-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-1′-yl}methyl)-1H-1,3-benzodiazol-1-yl]ethyl}pyrrolidine-2-carboxamide;
1′-({5-chloro-1-[2-(3-methanesulfonylpyrrolidin-1-yl)ethyl]-1H-1,3-benzodiazol-2-yl}methyl)6′-fluoro-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2′-one;
1-({5-chloro-1-[2-(4-methanesulfonylpiperidin-1-yl)ethyl]-1H-1,3-benzodiazol-2-yl}methyl)-6′-fluoro-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2′-one;
1-({5-chloro-1-[2-(4-methanesulfonylpiperazin-1-yl)ethyl]-1H-1,3-benzodiazol-2-yl}methyl)-6′fluoro-1′,2′-dihydrospiro[cyclopropan-1,3′-indole]-2′-one;
1′-[(5-Chloro-1-{3-[(2-methanesulfonylethy)amino]propyl}-1H-1,3-benzodiazol-2-yl)methyl]-6′-f luoro-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2′-one;
1′-{[5-Chloro-1-(3-{[2-(ethanesulfonyl)ethyl]amino}propyl)-1H-1,3-benzodiazol-2-yl]methyl}-6′fluoro-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2′-one;
(2S)-2-({3-[5-chloro-2-({6′-fluoro-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-1′-yl}methy l)-1H-1,3-benzodiazol-1-yl]propyl}amino)-3-methylbutanamide;
1-({5-Chloro-1-[3-(3-methanesulfonylazetidin-1-yl)propyl]-1H-1,3-benzodiazol-2-yl}methyl)-6′fluoro-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2′-one;
1-({5-Chloro-1-[3-(3-methanesulfonylpyrrolidin-1-yl)propyl]-1H-1,3-benzodiazol-2-yl}methyl)-6′-fluoro-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2′-one;
(2S)-1-{3-[5-chloro-2-({6′-fluoro-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-1′-yl}methyl)-1H-1,3-benzodiazol-1-yl]propyl}pyrrolidine-2-carboxamide;
3-({3-[5-Chloro-2-({6′-fluoro-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-1′-yl}methyl)-1H-1,3-benzodiazol-1-yl]propyl}amino)-1λ6-thiolane-1,1-dione;
1′-[(5-Chloro-1-{3-[(1-methanesulfonylpyrrolidin-3-yl)amino]propyl}-1H-1,3-benzodiazol-2-yl)m ethyl]-6′-fluoro-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2′-one;
1′-({5-Chloro-1-[3-(morpholin-4-yl)propyl]-1H-1,3-benzodiazol-2-yl}methyl)-6′-fluoro-1′,2′-dihyd rospiro[cyclopropane-1,3′-indole]-2′-one;
1′-({5-Chloro-1-[3-(thiomorpholin-4-yl)propyl]-1H-1,3-benzodiazol-2-yl}methyl)-6′-fluoro-1′,2′-di hydrospiro[cyclopropane-1,3′-indole]-2′-one;
4-{3-[5-Chloro-2-({6′-fluoro-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-1′-yl}methyl)-1H-1,3-benzodiazol-1-yl]propyl}-1λ6-thiomorpholine-1,1-dione;
1-({5-Chloro-1-[3-(4-methanesulfonylpiperidin-1-yl)propyl]-1H-1,3-benzodiazol-2-yl}methyl)-6′-fluoro-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2′-one;
1′-({1-[3-(4-Acetylpiperazin-1-yl)propyl]-5-chloro-1H-1,3-benzodiazol-2-yl}methyl)-6′-fluoro-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2′-one;
6′-Fluoro-1′-[(5-fluoro-1-{3-[(2-methanesulfonylethy)amino]propyl}-1H-1,3-benzodiazol-2-yl)methyl]-1′2′-dihydrospiro[cyclopropane-1,3′-indole]-2′-one;
(2S)-2-(({3-[5-Fluoro-2-({6′-fluoro-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-1′-yl}meth yl-1H-1,3-benzodiazol-1-yl]propyl}amino)-3-methylbutanamide;
(2S)-1-({3-[5-fluoro-2-({6′-fluoro-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-1′-yl}methyl)-1H-1,3-benzodiazol-1-yl]propyl}pyrrolidine-2-carboxamide;
6′-Fluoro-1′-({5-fluoro-1-[3-(morpholin-4-yl)propyl]-1H-1,3-benzodiazol-2-yl}methyl)-1′,2′-dihyd rospiro[cyclopropane-1,3′-indole]-2′-one;
1′-({1-[3-(4-Acetylpiperazin-1-yl)propyl]-5-fluoro-1H-1,3-benzodiazol-2-yl}methyl)-6′-fluoro-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2′-one;
6′-Fluoro-1′-({5-fluoro-1-[3-(4-methanesulfonylpiperazin-1-yl)propyl]-1H-1,3-benzodiazol-2-yl}m ethyl)-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2′-one;
1′-{[5-Chloro-1-(piperidin-4-yl)-1H-1,3-benzodiazol-2-yl]methyl}-6′-fluoro-1′,2′-dihydrospiro[cycl opropane-1,3′-indole]-2′-one;
1′-{[5-Chloro-1-(piperidin-4-yl)-1H-1,3-benzodiazol-2-yl]methyl}-6′-fluoro-1′,2′-dihydrospiro[cyclobutane-1,3′-indole]-2′-one;
1′-{[1-(1-Acetylpiperidin-4-yl)-5-chloro-1H-1,3-benzodiazol-2-yl]methyl}-6′-fluoro-1′,2′-dihydros piro[cyclopropane-1,3′-indole]-2′-one;
4-[5-Chloro-2-({6′-fluoro-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-1′-yl}methyl)-1H-1,3-benzodiazol-1-yl]-N,N-dimethylpiperidine-1-carboxamide;
1′-{[5-Chloro-1-(1-methanesulfonylpiperidin-4-yl)-1H-1,3-benzodiazol-2-yl]methyl}-6′-fluoro-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2′-one;
1′-{[5-Chloro-1-(1-methanesulfonylpiperidin-4-yl)-1H-1,3-benzodiazol-2-yl]methyl}-6′-fluoro-1′,2′-dihydrospiro[cyclobutane-1,3′-indole]-2′-one;
1′-({5-Chloro-1-[1-(ethanesulfonyl)piperidin-4-yl]-1H-1,3-benzodiazol-2-yl}methyl)-6′-fluoro-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2′-one;
1′-({5-Chloro-1-[1-(2-methanesulfonylethyl)piperidin-4-yl]-1H-1,3-benzodiazol-2-yl}methyl)-6′fluoro-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2′-one;
and the pharmaceutically acceptable salts thereof.

### Claim 7 (depends on 1)

A pharmaceutical composition which comprises a compound as defined in claim 1 and a pharmaceutically acceptable carrier or diluent.

### Claim 8 (depends on 1)

A method of treating a subject suffering from or susceptible to an RSV infection, which method comprises administering to said subject an effective amount of a compound as defined in claim 1.

### Claim 9 (depends on 1)

A pharmaceutical composition which comprises (a) a compound as defined in claim 1, and (b) one or more further therapeutic agents, together with a pharmaceutically acceptable carrier or diluent, wherein the further therapeutic agent is selected from the group consisting of:
(i) a RSV nucleocapsid(N)-protein inhibitor;
(ii) another protein inhibitor, such as one that inhibits the phosphoprotein (P) protein and/or large (L) protein;
(iii) an anti-RSV monoclonal antibody, such as an F-protein antibody;
(iv) an immunomodulating toll-like receptor compound;
(v) another respiratory virus anti-viral, such as an anti-influenza and/or anti-rhinovirus compound; and
(vi) an anti-inflammatory compound.

### Claim 10 (depends on 1)

A process for producing a pharmaceutically acceptable salt as defined in claim 1, which process comprises treating a pyrimidine of formula (I) as defined in claim 1 with a suitable acid in a suitable solvent.

### Claim 11 (depends on 10)

A process according to claim 10, wherein the acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulphonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, ethanesulfonic acid, aspartic acid and glutamic acid.

### Claim 12 (depends on 8)

A method according to claim 8, which method further comprises administering to the subject a further therapeutic agent selected from the group consisting of:
(i) a RSV nucleocapsid(N)-protein inhibitor;
(ii) another protein inhibitor, such as one that inhibits the phosphoprotein (P) protein and/or large (L) protein;
(iii) an anti-RSV monoclonal antibody, such as an F-protein antibody;
(iv) an immunomodulating toll-like receptor compound;
(v) another respiratory virus anti-viral, such as an anti-influenza and/or anti-rhinovirus compound; and
(vi) an anti-inflammatory compound.