# US 2019/0375779 A1 · Phosphoramidate nucleoside derivatives as anticancer agents

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- Number: US 2019/0375779 A1
- Document ID: US20190375779A1
- Status: Published application
- Kind: A1
- Application number: 16/305,153
- Filed: 2017-05-31
- Published: 2019-12-12
- Earliest claimed: 2016-06-01
- Assignees: NuCana plc
- Applicants: NuCana plc
- Inventors: Hugh Griffith
- Web page: https://patentgrep.com/patent/US20190375779A1

## CPC

- C07H 19/207: the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- C07H 19/173: with 2-deoxyribosyl as the saccharide radical
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

One aspect of the invention relates to derivatives of cladribine of Formula (I). The compounds are phosphoramidate derivatives in which the phosphoramidate moiety is situated on the 3′-hydroxyl group of cladribine. The invention also relates to pharmaceutical formulations of the cladribine derivatives, and their use in methods of treatment. The compounds are useful in the treatment of cancer.

## Claims

### Claim 1

A compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
R1 is aryl;
R2 is selected from the group consisting of C1-C24-alkyl, C3-C24-alkenyl, C3-C24-alkynyl, C0-C4-alkylene-C3-C7-cycloalkyl and C0-C4-alkylene-aryl;
R3 and R4 are each independently selected from the group consisting of H, C1-C6-alkyl and C1-C3-alkylene-R9; or R3 and R4 together with the atom to which they are attached form a 3- to 6-membered cycloalkyl or heterocycloalkyl group;
R5 and R7 are each independently selected from the group consisting of H and C1-C4-alkyl;
R6 is independently selected from the group consisting of H and C(O)R10;
R8 is independently selected from the group consisting of H, C(O)OR10 and C(O)R10;
R9 is independently selected from the group consisting of aryl, imidazole, indole, SRa, ORa, CO2Ra, CO2NRaRa, NRaRb and NH(═NH)NH2;
R10 is independently at each occurrence selected from the group consisting of C1-C24-alkyl, C3-C24-alkenyl, C3-C24-alkynyl, C0-C4-alkylene-C3-C7-cycloalkyl and C0-C4-alkylene-aryl;
wherein any aryl group is selected from the group consisting of phenyl, naphthyl and tetrahydronaphthyl; and wherein any phenyl, alkyl, alkyne, alkene, alkylene, cycloalkyl, naphthyl or tetrahydronaphthyl group is optionally substituted with from 1 to 4 substituents selected from the group consisting of halo, nitro, cyano, NRaRa, NRaS(O)2Ra, NRaC(O)Ra, NRaCONRaRa, NRaCO2Ra, ORa, SRa, SORa, SO3Ra, SO2Ra, SO2NRaRa, CO2Ra C(O)Ra, CONRaRa, CRaRaNRaRa, C1-C4alkyl, C2-C4-alkenyl, C2-C4-alkynyl and C1-C4-haloalkyl; and
wherein Ra is independently at each occurrence selected from the group consisting of H and C1-C4-alkyl; and Rb is independently at each occurrence selected from the group consisting of H, C1-C4-alkyl, C(O)—C1-C4-alkyl, and S(O)2—C1-C4-alkyl.

### 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 R1 is phenyl.

### Claim 4 (depends on 3)

The compound of claim 3, wherein R1 is unsubstituted phenyl.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R1 is 1-naphthyl.

### Claim 6

(canceled)

### Claim 7 (depends on 1)

The compound of claim 1, wherein R2 is C4-C8-alkyl.

### Claim 8 (depends on 7)

The compound of claim 7, wherein R2 is selected from the group consisting of iso-butyl, tert-butyl, n-butyl, n-pentyl, CH2C(Me)3 and n-hexyl.

### Claim 9 (depends on 1)

The compound of claim 1, wherein R2 is C5-C7-cycloalkyl.

### Claim 10 (depends on 9)

The compound of claim 9, wherein R2 is unsubstituted cyclohexyl.

### Claim 11 (depends on 1)

The compound of claim 1, wherein R2 is CHR11-phenyl; wherein R11 is selected from the group consisting of H and C1-C4-alkyl.

### Claim 12 (depends on 11)

The compound of claim 11, wherein R2 is unsubstituted benzyl.

### Claim 13 (depends on 1)

The compound of claim 1, wherein one of R3 and R4 is H and the other is selected from the group consisting of H, Me, isopropyl, isobutyl and benzyl.

### Claim 14 (depends on 13)

The compound of claim 13, wherein R4 is H; and R3 is selected from the group consisting of H, Me, isopropyl, isobutyl and benzyl.

### Claim 15 (depends on 14)

The compound of claim 14, wherein R4 is H; and R3 is Me.

### Claim 16 (depends on 1)

The compound of claim 1, wherein the compound is selected from the group consisting of:
2-Chloro-2′-deoxyadenosine-3′-[phenyl-(ethoxy-L-alaninyl)]-phosphate,
2-Chloro-2′-deoxyadenosine-3′-[phenyl-(tert-butoxy-L-alaninyl)]-phosphate,
2-Chloro-2′-deoxyadenosine-3′-[phenyl-(benzoxy-D-alaninyl)]-phosphate,
2-Chloro-2′-deoxyadenosine-3′-[phenyl-(benzoxy-glycinyl)]-phosphate,
2-Chloro-2′-deoxyadenosine-3′-[phenyl-(benzoxy-L-leucinyl)]-phosphate,
2-Chloro-2′-deoxyadenosine-3′-[1-naphthyl-(2,2-dimethylpropoxy-L-alaninyl)] phosphate,
2-Chloro-2′-deoxyadenosine-3′-[1-naphthyl-(pentoxy-L-leucinyl)]-phosphate,
2-Chloro-2′-deoxyadenosine-3′-[1-naphthyl-(cyclohexoxy-L-alaninyl)]-phosphate,
2-Chloro-2′-deoxyadenosine-3′-[phenyl-(cyclohexoxy-L-alaninyl)]-phosphate,
2-Chloro-2′-deoxyadenosine-3′-[phenyl-(2,2-dimethylpropoxy-L-alaninyl)]-phosphate,
2-Chloro-2′-deoxyadenosine-3′-[phenyl-(ethoxy-2,2-dimethylglycinyl)]-phosphate,
2-Chloro-2′-deoxyadenosine-3′-[phenyl-(benzoxy-L-phenylalaninyl)] phosphate,
2-Chloro-2′-deoxyadenosine-3′-[1-naphthyl-(benzoxy-L-phenylaninyl)] phosphate,
2-Chloro-2′-deoxyadenosine-3′-[phenyl-(benzoxy-L-valinyl)] phosphate,
2-Chloro-2′-deoxyadenosine-3′-[phenyl(iso-propoxy-L-alaninyl)] phosphate,
2-Chloro-2′-deoxyadenosine-3′-[phenyl-(2-butoxy-L-alaninyl)] phosphate,
2-Chloro-2′-deoxyadenosine-3′-[phenyl-((S)-1-phenylethoxy-L-alaninyl)-phosphate,
2-Chloro-2′-deoxyadenosine-3′-[1-naphthyl-(benzoxy-L-alaninyl) phosphate and
2-Chloro-2′-deoxyadenosine-3′-[phenyl-(benzoxy-L-alaninyl)-phosphate.

### Claim at position 17

17-21. (canceled)

### Claim 22 (depends on 1)

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

### Claim 23 (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 24 (depends on 23)

The method of claim 23, 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 25 (depends on 23)

The method of claim 23, wherein the subject has mycoplasma infected cells.

### Claim 26 (depends on 23)

The method of claim 23, wherein the method targets cancer stem cells.