# US 2019/0375778 A1 · Adenosine derivatives for use in the treatment of cancer

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- Number: US 2019/0375778 A1
- Document ID: US20190375778A1
- Status: Published application
- Kind: A1
- Application number: 16/305,159
- Filed: 2017-05-31
- Published: 2019-12-12
- Earliest claimed: 2016-06-01
- Assignees: NuCana plc
- Applicants: NuCana plc
- Inventors: Hugh Griffith; Michaela Serpi; Magadalena Slusarczyk; Christopher McGuigan
- Web page: https://patentgrep.com/patent/US20190375778A1

## CPC

- C07H 19/20: with the saccharide radical esterified by phosphoric or polyphosphoric acids
- A61K 31/7076: containing purines, e.g. adenosine, adenylic acid
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- C07H 19/207: the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- 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

## Abstract

The present invention relates to chemical compounds of formula (I), their preparation, and their use in the treatment of cancer.

## Claims

### Claim 1

A compound of formula I:
wherein:
each of R1 and R2 is independently selected from the group consisting of H, C1-8alkyl, benzyl, C2-8alkenyl, C1-4alkoxyC1-4alkyl, C2-8alkynyl, C3-8cycloalkyl, and 4-8heterocycloalkyl, any of which is optionally substituted;
R3 is selected from the group consisting of H, C1-8alkyl, benzyl, C2-8alkenyl, C1-4alkoxyC1-4alkyl, C2-8alkynyl, C3-8cycloalkyl, 4-8heterocycloalkyl, phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl and 9- or 10 membered bicyclic heteroaryl, any of which is optionally substituted;
R4 is selected from the group consisting of H, C1-8alkyl, benzyl, C2-8alkenyl, C1-4alkoxyC1-4alkyl, C2-8alkynyl, C3-8cycloalkyl, and 4-8heterocycloalkyl, any of which is optionally substituted;
R5 is independently selected from OAr and
and
Ar is selected from the group consisting of phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl and 9- or 10 membered bicyclic heteroaryl, each of which is optionally substituted;
or a pharmaceutically acceptable salt, ester, salt of an ester, solvate, prodrug or salt of a prodrug thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the compound is represented by formula (II)

### Claim 3 (depends on 1)

The compound of claim 1, wherein Ar is phenyl.

### Claim 4 (depends on 3)

The compound of claim 3, wherein Ar is naphthyl.

### Claim 5

(canceled)

### Claim 6 (depends on 1)

The compound of claim 1, wherein the compound is represented by formula (III)

### Claim 7 (depends on 1)

The compound of claim 1, wherein R1 and R2 are each independently at each occurrence selected from the group consisting of H, C1-4-alkyl and —CH2-phenyl.

### Claim 8 (depends on 7)

The compound of claim 7, wherein R1 is H; and R2 is Me.

### Claim 9 (depends on 1)

The compound of claim 1, wherein R3 is independently at each occurrence selected from the group consisting of benzyl, C3-7cycloalkyl and C1-6alkyl.

### Claim 10 (depends on 9)

The compound of claim 9, wherein R3 is benzyl.

### Claim 11 (depends on 1)

The compound of claim 1, wherein R4 is H.

### Claim 12 (depends on 1)

The compound of claim 1, wherein Ar, R1, R2, R3 and R4 are unsubstituted.

### Claim 13 (depends on 1)

The compound of claim 1, wherein the compound is selected from the group consisting of:
Cyclohexyl 2-(((((2R,3S,4R,5R)-5-(6-amino-8-chloro-9H-purin-9-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)acetate;
Benzyl 2-(((((2R,3S,4R,5R)-5-(6-amino-8-chloro-9H-purin-9-yl)-3,4-dihydroxytetra-hydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)acetate;
(2S)-Benzyl 2-(((((2R,3S,4R,5R)-5-(6-amino-8-chloro-9H-purin-9-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate;
(2S)-Benzyl 2-(((((2R,3S,4R,5R)-5-(6-amino-8-chloro-9H-purin-9-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphoryl)amino)propanoate;
(2S)-Pentyl 2-(((((2R,3S,4R,5R)-5-(6-amino-8-chloro-9H-purin-9-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphoryl)amino)propanoate;
5′-([(Ethyloxy-L-alanin-N-yl)-naphth-1-yl]-phosphatyl) 8-chloroadenosine;
5′-([(Cyclohexyloxy-L-alanin-N-yl)-naphth-1-yl]-phosphatyl) 8-chloroadenosine;
5′-([(Benzyloxy-L-leucin-N-yl)-naphth-1-yl]-phosphatyl) 8-chloroadenosine;
5′-([(Pent-1-yloxy-L-leucin-N-yl)-naphth-1-yl]-phosphatyl) 8-chloroadenosine;
5′-([(Cyclohexyloxy-L-leucin-N-yl)-naphth-1-yl]-phosphatyl) 8-chloroadenosine;
5′-([(ethyloxy-L-leucin-N-yl)-naphth-1-yl]-phosphatyl) 8-chloroadenosine;
5′-([(benzyloxy-glycin-N-yl)-naphth-1-yl]-phosphatyl) 8-chloroadenosine;
5′-([(Cyclohexyloxy-glycin-N-yl)-naphth-1-yl]-phosphatyl) 8-chloroadenosine;
5′-([(ethyloxy-glycin-N-yl)-naphth-1-yl]-phosphatyl) 8-chloroadenosine;
5′-([(Pent-1-yloxy-glycin-N-yl)-naphth-1-yl]-phosphatyl) 8-chloroadenosine;
5′-([(Benzyloxy-L-phenylalanin-N-yl)-naphth-1-yl]-phosphatyl) 8-chloroadenosine;
5′-([(Pent-1-yloxy-L-phenylalanin-N-yl)-naphth-1-yl]-phosphatyl) 8-chloroadenosine;
5′-([(Cyclohexyloxy-L-phenylalanin-N-yl)-naphth-1-yl]-phosphatyl) 8-chloroadenosine;
5′-([(Ethyloxy-L-phenylalanin-N-yl)-naphth-1-yl]-phosphatyl) 8-chloroadenosine;
5′-([(Benzyloxy-D-alanin-N-yl)-phenyl]-phosphatyl) 8-chloroadenosine;
5′-([(Benzyloxy-L-phenylalanin-N-yl)-phenyl]-phosphatyl) 8-chloroadenosine;
5′-([(Benzyloxy-L-leucin-N-yl)-phenyl]-phosphatyl) 8-chloroadenosine;
5′-([(Isopropyloxy-L-alanin-N-yl)-phenyl]-phosphatyl) 8-chloroadenosine;
5′-([(Cyclohexyloxy-L-alanin-N-yl)-phenyl]-phosphatyl) 8-chloroadenosine;
5′-([(Neopentyloxy-2,2-dimethylglycin-N-yl)-phenyl]-phosphatyl) 8-chloroadenosine;
5′-([(Methyloxy-L-methionin-N-yl) phenyl]-phosphatyl) 8-chloroadenosine;
5′-([(Benzyloxy-L-valin-N-yl)-phenyl]-phosphatyl) 8-chloroadenosine;
8-Chloroadenosine 5′-O-bis(benzyloxy-L-alanin-N-yl) phosphate; and
8-Chloroadenosine 5′-O-bis(benzyloxy-glycin-N-yl) phosphate.

### Claim 14 (depends on 13)

The compound of claim 13, wherein the compound of formula (I) is
(2S)-Benzyl 2-(((((2R,3S,4R,5R)-5-(6-amino-8-chloro-9H-purin-9-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphoryl)amino)propanoate.

### Claim 15

The compound of 14, wherein the compound of formula (I) is
(2S)-Benzyl 2-(((((2R,3S,4R,5R)-5-(6-amino-8-chloro-9H-purin-9-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)-(Sp)-phosphoryl)amino)propanoate in substantially diastereoisomerically pure form.

### Claim 16

The compound of 14, wherein the compound of formula (I) is
(2S)-Benzyl 2-(((((2R,3S,4R,5R)-5-(6-amino-8-chloro-9H-purin-9-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)-(Rp)-phosphoryl)amino)propanoate in substantially diastereoisomerically pure form.

### Claim 17 (depends on 13)

The compound of claim 13, wherein the compound of formula (I) is benzyl 2-(((((2R,3S,4R,5R)-5-(6-amino-8-chloro-9H-purin-9-yl)-3,4-dihydroxytetra-hydrofuran-2-yl)methoxy)(phenoxy)phosphoryl) amino)acetate.

### Claim 18

The compound of 17, wherein the compound of formula (I) is benzyl 2-(((((2R,3S,4R,5R)-5-(6-amino-8-chloro-9H-purin-9-yl)-3,4-dihydroxytetra-hydrofuran-2-yl)methoxy)(phenoxy)-(Sp)-phosphoryl)amino)acetate in substantially diastereoisomerically pure form.

### Claim 19

The compound of 17, wherein the compound of formula (I) is benzyl 2-(((((2R,3S,4R,5R)-5-(6-amino-8-chloro-9H-purin-9-yl)-3,4-dihydroxytetra-hydrofuran-2-yl)methoxy)(phenoxy)-(Rp)-phosphoryl)amino)acetate in substantially diastereoisomerically pure form.

### Claim at position 20

20-24. (canceled)

### Claim 25 (depends on 1)

A pharmaceutical formulation comprising a compound of claim 1; and a pharmaceutically acceptable excipient.

### Claim 26

(canceled)

### Claim 27

(canceled)

### Claim 28 (depends on 1)

A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1.

### Claim 29 (depends on 28)

The method of claim 28, wherein the cancer is selected from the group consisting of leukemia, multiple myeloma, lung cancer, liver cancer, breast cancer, head and neck cancer, neuroblastoma, thyroid carcinoma, skin cancer, oral squamous cell carcinoma, urinary bladder cancer, Leydig cell tumor, colon cancer, colorectal cancer, and gynecological cancer.

### Claim 30 (depends on 28)

The method of claim 28, wherein the cancer is leukemia.

### Claim 31 (depends on 30)

The method of claim 30, wherein the leukemia is selected from the group consisting of acute lymphoblastic leukemia, acute myelogenous leukemia, acute premyelocytic leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, monoblastic leukemia, and hairy cell leukemia.