# US 2020/0399295 A1 · Cancer treatment with (2,2-bishydroxymethyl) methylenecyclopropane nucleotides

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- Number: US 2020/0399295 A1
- Document ID: US20200399295A1
- Status: Published application
- Kind: A1
- Application number: 16/979,152
- Filed: 2019-03-08
- Published: 2020-12-24
- Earliest claimed: 2018-03-09
- Assignees: Medivir AB
- Applicants: Medivir AB
- Inventors: Björn KLASSON; Fredrik ÖBERG
- Web page: https://patentgrep.com/patent/US20200399295A1

## CPC

- A61K 31/513: having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
- C07F 9/062: {Organo-phosphoranes without P-C bonds}
- A61K 31/522: having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61P 35/02: specific for leukemia
- C07D 239/47: One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
- C07D 473/16: two nitrogen atoms
- C07D 473/18: one oxygen and one nitrogen atom, e.g. guanine
- C07F 9/6512: having the nitrogen atoms in positions 1 and 3
- C07F 9/65616: {containing the ring system [IMAGE cpc-sch-C07F-1006.gif] having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs}
- 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)
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The invention provides a compound of formula (I) wherein B is a nucleobase; U is O or S; Rx is —OC(═O)Ry, —OC(═O)CH(Ry)NH2, —OCH2OC(═O)Ry; Ry is optionally substituted alkyl or alkenyl or the side chain of a natural or unnatural amino acid R1 is H, or optionally substituted phenyl, benzyl, naphthyl, pyridyl or indolyl, or Rx and R1 together define a bond thus forming a cyclic phosphate; R2 and R2′ together define the side chain of a natural or unnatural amino acid; R3 is optionally substituted alkyl, cycloalkyl, phenyl or benzyl; and pharmaceutically acceptable salts and compositions thereof which are useful in the treatment of cancer, especially leukemias.

## Claims

### Claim 1

A compound represented by formula I:
wherein:
B is a nucleobase selected from the groups (a) to (d):
U is O or S;
Rx is —OC(═O)Ry, —OC(═O)CH(Ry)NH2, —OCH2OC(═O)Ry; or
Rx and R1 together define a bond thus forming a cyclic phosphate;
Ry is C1-C20alkyl or C2-C20alkenyl any of which is optionally substituted with one, two or three substituents each independently selected from fluoro, hydroxy and amino; or
Ry is the side chain of a natural amino acid, which may be in the D or L configuration;
R1 is H, or a cyclic group selected from phenyl, benzyl, naphthyl, pyridyl or indolyl, each of which cyclic groups is optionally substituted with one, two or three R22; or
R1 and Rx together define a bond thus forming a cyclic phosphate;
each R22 is independently selected from halo, hydroxy, C1-C6alkyl, C3-C6cycloalkyl, haloC1-C6alkyl, hydroxyC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, C1-C6alkylcarbonyl, C3-C6cycloalkylcarbonyl, azido, cyano, amino, or any two R22 groups attached to adjacent ring carbon atoms can combine to form —O—(CH2)1-2—O—, wherein C3-C6cycloalkyl is optionally substituted with C1-C3alkyl;
R2 and R2′ are each independently selected from H, C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkylC1-C3alkyl, phenyl, benzyl and indolyl; or
R2 and R2′ together with the carbon atom to which they are attached form a C3-C7cycloalkylene group;
wherein each C1-C6alkyl is optionally substituted with halo or OR12, and each C3-C7cycloalkyl, C3-C7cycloalkylene, phenyl and benzyl is optionally substituted with one or two groups independently selected from C1-C3alkyl, halo and OR12; or
one of R2 and R2′ is H, and the other is the side chain of a natural amino acid, wherein the carboxy terminus of an Asp or Glu is optionally esterified with C1-C6 alkyl;
R3 is C1-C10alkyl, C3-C7cycloalkyl, C1-C3alkylC3-C7cycloalkyl, phenyl or benzyl; any of which is optionally substituted with 1, 2 or 3 substituents each independently selected from halo, hydroxy, C1-C6alkoxy, C1-C6haloalkoxy and N(R12)2; R4, R5, R7 and R8 are each independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, halo, —OR12 or —N(R12)2;
R6, R9, R1 and R11 are each independently H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, halo, OR12, —N(R12)2, —NHC(O)OR12, cyano, —C(O)OR12, —C(O)N(R12)2 or —NHC(O)R13, wherein C2-C6alkenyl and C2-C6alkynyl is optionally substituted with halo or C3-C7cycloalkyl;
each R12 is independently H, C1-C6alkyl, haloC1-C6alkyl, C3-C7cycloalkyl or C1-C6alkyC3-C7cycloalkyl;
R13 is R12 or CH2CH(NH2)C(═O)OH;
or a pharmaceutically acceptable salt thereof, with the proviso that the compound is not

### Claim 2 (depends on 1)

The compound according to claim 1, wherein B is the group (d):
wherein
R11 is NH2 or NHCOC1-C6alkyl.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein B is the group (c):
wherein R9 is C1-C6alkoxy, C1-C6cycloalkoxy, C1-C6alkylamine or C3-C6cycloalkylamine, and R10 is NH2 or NHCOC1-C6alkyl.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein B is the group (a):
wherein: R4 is H,
R5 is F or H, and
R6 is NH2.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein R1 is H, or phenyl which is optionally substituted with one or two R22, and each R22 is independently selected from halo, C1-C3alkyl, C3-C4cycloalkyl, haloC1-C3alkyl, C1-C3alkoxy, haloC1-C3alkoxy, C1-C3alkylcarbonyl, C3-C4cycloalkylcarbonyl, wherein C3-C4cycloalkyl is optionally substituted with methyl;

### Claim 6 (depends on 5)

The compound according to claim 5, wherein phenyl is substituted in the 4-position with Br.

### Claim 7 (depends on 5)

The compound according to claim 5, wherein the phenyl is unsubstituted.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein R2′ is H and R2 is C1-C6alkyl or haloC1-C6alkyl.

### Claim 9 (depends on 8)

The compound according to claim 8, wherein the stereochemistry is as indicated in the partial formula:

### Claim 10 (depends on 8)

The compound according to claim 8, wherein R2 is methyl.

### Claim 11 (depends on 1)

The compound according to claim 1, wherein R3 is C1-C10alkyl, preferably methyl, isopropyl, 2-propylpentyl or 2-ethylbutyl.

### Claim 12 (depends on 1)

The compound according to claim 1, wherein R3 is benzyl or C3-C7cycloalkyl.

### Claim 13 (depends on 1)

The compound according to claim 1, wherein Rx is —OC(═O)C1-C6alkyl, preferably wherein the C1-C6alkyl moiety is methyl, isopropyl, isobutyl or t-butyl.

### Claim 14 (depends on 1)

The compound according to claim 1, wherein Rx is —OC(═O)C16-C20alkyl, preferably —OC(═O)C17alkyl.

### Claim 15 (depends on 1)

The compound according to claim 1, wherein Rx is —OC(═O)CH(Ry)NH2 and Ry is the side chain of a natural amino acid, preferably alanine, and the configuration at the chiral center to which Ry is attached is that of an L-amino acid.

### Claim 16 (depends on 1)

The compound of claim 1, wherein Rx is —OCH2OC(═O)CH3 or —OCH2OC(═O)C(CH3)3, preferably —OCH2OC(═O)C(CH3)3.

### Claim 17 (depends on 1)

The compound of claim 1, wherein U is O.

### Claim 18 (depends on 1)

The compound of claim 1, selected from
or a pharmaceutically acceptable salt thereof.

### Claim 19 (depends on 1)

A compound according to claim 1, selected from
or a pharmaceutically acceptable salt thereof.

### Claim 20

(canceled)

### Claim 21 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

### Claim 22 (depends on 1)

A method for the treatment of cancer comprising the administration to a subject in need thereof an effective amount of a compound according to claim 1.

### Claim 23

(canceled)

### Claim 24 (depends on 22)

The method according to claim 22, wherein the cancer is leukemia.