# US 2019/0167683 A1 · Pyrimidine derivatives and their use in treating or preventing a respiratory syncytial virus infection

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- Number: US 2019/0167683 A1
- Document ID: US20190167683A1
- Status: Published application
- Kind: A1
- Application number: 16/322,264
- Filed: 2017-08-03
- Published: 2019-06-06
- Earliest claimed: 2016-08-04
- Assignees: Reviral Limited
- Applicants: Reviral Limited
- Inventors: Stuart Cockerill; Matthew Barrett
- Web page: https://patentgrep.com/patent/US20190167683A1

## CPC

- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/2009: {Inorganic compounds}
- A61K 9/2013: {Organic compounds, e.g. phospholipids, fats}
- A61K 9/2018: {Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates}
- A61K 9/2059: {Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin}
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/541: Non-condensed thiazines containing further heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 31/14: for RNA viruses
- C07D 401/14: containing three or more hetero rings
- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 403/14: containing three or more hetero rings
- C07D 405/14: containing three or more hetero rings
- 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

Pyrimidine derivatives of formula (I) wherein: Z is a direct bond or —(CH2)n— wherein n is 1 or 2; one of X and Y is N, CH or CF, and the other of X and Y is CH; one of R1 and R2 is selected from —NHR, —NR2, —OR, —SR, —S(O)R, —S(O)2R and a group of the following formula (A) and the other of R1 and R2 is selected from —NHR′, —OH, —OR′ and a group of the above formula (A); R is unsubstituted C1-C6 alkyl; R′ is a group selected from C1-C6 alkyl, 5- to 12-membered aryl and C3-C6 cycloalkyl, which group is unsubstituted or substituted; W is —(CH2)m—, —CH2—O—CH2—, —CH2—S—CH2— or —CH2—S(O)2—CH2—; p is 1, q is an integer of 1-6 and V is N; or p is 1, q is 0 and V is CH; or p is 0, q is 0 and V is N; r is 0 or 1; and R3 is —(CH2)s—NH2 or —(CH2)s—OH wherein s is 0 or an integer of 1 to 4; 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 pyrimidine derivative of formula (I):
wherein:
Z is a direct bond or —(CH2)n— wherein n is 1 or 2;
one of X and Y is N, CH or CF, and the other of X and Y is CH;
one of R1 and R2 is selected from —NHR, —NR2, —OR, —SR, —S(O)R, —S(O)2R and a group of the following formula (A):
and the other of R1 and R2 is selected from —NHR′, —OH, —OR′ and a group of the above formula (A);
R is unsubstituted C1-C6 alkyl;
R′ is a group selected from C1-C6 alkyl, 5- to 12-membered aryl and C3-C6 cycloalkyl, which group is unsubstituted or substituted;
W is —(CH2)m—, —CH2—O—CH2—, —CH2—S—CH2— or —CH2—S(O)2—CH2—;
m is an integer of 1 to 4;
p is 1, q is an integer of 1-6 and V is N; or p is 1, q is 0 and V is CH; or p is 0, q is 0 and V is N;
r is 0 or 1; and
R3 is —(CH2)s—NH2 or —(CH2)s—OH wherein s is 0 or an integer of 1 to 4;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

A compound according to claim 1 wherein R′ is a group selected from C1-C6 alkyl, 5- to 12-membered aryl and C3-C6 cycloalkyl, which group is unsubstituted or substituted by R, —OH, —OR, —CF3, —S(O)2R, —CN, —NH2, —NHR or NR2, wherein R is as defined in claim 1.

### Claim 3 (depends on 1)

A compound according to claim 1 wherein Z is a direct bond.

### Claim 4 (depends on 1)

A compound according to claim 1 wherein at least one of R1 and R2 is a group of formula (A).

### 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′-((2-(3-Aminopyrrolidin-1-yl)-4-(isopentylamino)pyrimidin-5-yl)methyl)-6′-fluorospiro[cyclopropane-1,3′-indolin]-2′-one;
1′-((2-(3-Aminopyrrolidin-1-yl)-4-(((1r,4r)-4-hydroxycyclohexyl)amino)pyrimidin-5-yl)methyl)-6′-fluorospiro[cyclopropane-1,3′-indolin]-2′-one;
1′-((2-(3-Aminopyrrolidin-1-yl)-4-((2-morpholinoethyl)amino)pyrimidin-5-yl)methyl)-6′-fluorospiro[cyclopropane-1,3′-indolin]-2′-one;
1′-((2-(3-Aminopyrrolidin-1-yl)-4-((4-hydroxybutyl)amino)pyrimidin-5-yl)methyl)-6′-fluorospiro[cyclopropane-1,3′-indolin]-2′-one;
1′-((2-(3-Aminopyrrolidin-1-yl)-4-(isobutylamino)pyrimidin-5-yl)methyl)-6′-fluorospiro[cyclopropane-1,3′-indolin]-2′-one;
1′-((2-(4-Aminomethyl)piperidin-1-yl)-4-(isobutylamino)pyrimidin-5-yl)methyl)-6′-fluorospiro[cyclopropane-1,3′-indolin]-2′-one;
6′-Fluoro-1′-((4-(isopentylamino)-2-(pyrrolidin-1-yl)pyrimidin-5-yl)methyl)spiro[cyclopropane-1,3′-indolin]-2′-one;
6′-Fluoro-1′-((4-(isobutylamino)-2-morpholinopyrimidin-5-yl)methyl)spiro[cyclopropane-1,3′-indolin]-2′-one;
1′-((2-(3-Aminopyrrolidin-1-yl)-4-morpholinopyrimidin-5-yl)methyl)-6′-fluorospiro[cyclopropane-1,3′-indolin]-2′-one;
1′-((2-(3-Aminopyrrolidin-1-yl)-4-((3-methoxypropyl)amino)pyrimidin-5-yl)methyl)-6′-fluorospiro[cyclopropane-1,3′-indolin]-2′-one;
1′-((2-(3-Aminopyrrolidin-1-yl)-4-((3-methoxypropyl)amino)pyrimidin-5-yl)methyl)-6′-fluorospiro[cyclopropane-1,3′-indolin]-2′-one;
1′-((4-(3-Aminopyrrolidin-1-yl)-2-((4-hydroxybutyl)amino)pyrimidin-5-yl)methyl)-6′-fluorospiro[cyclopropane-1,3′-indolin]-2′-one;
1′-((2-(3-Aminopyrrolidin-1-yl)-4-(1,1-dioxidothiomorpholino)pyrimidin-5-yl)methyl)-6′-fluorospiro[cyclopropane-1,3′-indolin]-2′-one;
1′-{[2-(3-Aminopyrrolidin-1-yl)-4-(4-methanesulfonylpiperazin-1-yl)pyrimidin-5-yl]methyl}-6′-fluoro-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2′-one;
1-[2-(3-Aminopyrrolidin-1-yl)-5-({6′-fluoro-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-1′-yl}methyl)pyrimidin-4-yl]pyrrolidine-2-carboxamide;
1′-{[2-(3-Aminopyrrolidin-1-yl)-4-[(4-hydroxybutyl)sulfanyl]pyrimidin-5-yl]methyl}-6′-fluoro-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2′-one;
1′-{[4-(4-Acetylpiperazin-1-yl)-2-(3-aminopyrrolidin-1-yl)pyrimidin-5-yl]methyl}-6′-fluoro-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2′-one;
1′-{[2-(3-Aminopyrrolidin-1-yl)-4-[(2-methanesulfonylethyl)amino]pyrimidin-5-yl]methyl}-6′-fluoro-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2′-one;
1′-{[2-(3-Aminopyrrolidin-1-yl)-4-[(5-hydroxypentyl)amino]pyrimidin-5-yl]methyl}-6′-fluoro-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2′-one;
1′-{[2-(3-Aminopyrrolidin-1-yl)-4-[(4-hydroxycyclohexyl)amino]pyrimidin-5-yl]methyl}-6′-fluoro-1′,2′-dihydrospiro[cyclobutane-1,3′-indole]-2′-one;
1′-{[2-(3-Aminopyrrolidin-1l-yl)-4-(5-hydroxypent-1-yn-1-yl)pyrimidin-5-yl]methyl}-6′-fluoro-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2′-one;
1′-{[2-(3-Aminopyrrolidin-1-yl)-4-(3-fluoropropoxy)pyrimidin-5-yl]methyl}-6′-fluoro-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2′-one;
1′-{[2-(3-Aminopyrrolidin-1l-yl)-4-{[(oxan-4-yl)methyl]amino}pyrimidin-5-yl]methyl}-6′-fluoro-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2′-one;
1′-{[2-(4-Aminopiperidin-1-yl)-4-[(4-hydroxybutyl)amino]pyrimidin-5-yl]methyl}-6′-fluoro-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2′-one;
1′-({2-[(2-Aminoethyl)amino]-4-[(4-hydroxybutyl)amino]pyrimidin-5-yl}methyl)-6′-fluoro-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2′-one;
1′-{[2-(3-Aminopyrrolidin-1-yl)-4-[(2-hydroxyethyl)amino]pyrimidin-5-yl]methyl}-6′-fluoro-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2′-one;
1′-{[2-(3-Aminopyrrolidin-1-yl)-4-[(3-hydroxypropyl)amino]pyrimidin-5-yl]methyl}-6′-fluoro-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2′-one;
1′-{[2-(3-Aminopyrrolidin-1-yl)-4-(propylamino)pyrimidin-5-yl]methyl}-6′-fluoro-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2′-one; and
1′-{[2-(3-Aminopyrrolidin-1-yl)-4-(ethylamino)pyrimidin-5-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

(canceled)

### Claim 9

(canceled)

### Claim 10

(canceled)

### Claim 11 (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 12

(canceled)

### Claim 13

(canceled)

### Claim 14 (depends on 1, 13)

A pharmaceutical composition which comprises (a) a compound as defined in any one of claim 1, and (b) one or more further therapeutic agents, as defined in claim 13, 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 15 (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 16 (depends on 15)

A process according to claim 15, 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 17 (depends on 11)

A method according to claim 11, 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.