# US 10,765,681 B2 · Purine compounds possessing anticancer activity

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- Number: US 10,765,681 B2
- Document ID: US10765681B2
- Status: Granted
- Kind: B2
- Application number: 16/075,202
- Filed: 2017-02-03
- Published: 2018-12-27
- Granted: 2020-09-08
- Earliest claimed: 2016-02-05
- Assignees: Academia Sinica; National Taiwan University
- Applicants: Academia Sinica; National Taiwan University
- Inventors: Chi-Huey Wong; Pan-Chyr Yang; Jim-Min Fang; Szu-Hua Pan; Ting-Jen R. Cheng; Ling-Wei Li
- Web page: https://patentgrep.com/patent/US10765681B2

## CPC

- A61K 31/522: having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
- A61K 31/167: having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
- A61K 31/337: having four-membered rings, e.g. taxol
- A61K 31/4025: not condensed and containing further heterocyclic rings, e.g. cromakalim
- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/502: ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/517: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
- A61K 31/52: Purines, e.g. adenine
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/69: Boron compounds
- A61K 35/00: Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K 38/05: Dipeptides
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- C07D 473/00: Heterocyclic compounds containing purine ring systems
- A61K 2300/00: Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
- 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

The present disclosure provides compounds of Formulas (I′) and (I), and pharmaceutically acceptable salts thereof. The compounds described herein may be useful in treating and/or preventing proliferative diseases (e.g., cancer). Also provided in the present disclosure are pharmaceutical compositions, kits, and uses thereof for treating proliferative diseases.

## Claims

### Claim 1

A compound of Formula (I′):
or a pharmaceutically acceptable salt thereof,
wherein:
Z1 is independently Cl, N, O, or S, as valency permits;
h1 is 0, 1, or 2;
R1 is
in which G1 is independently halogen, —CN, —NO2, —N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —ORA, —SRA, —NHRB, —N(RB)2, —C(═O)RA, —C(═O)ORA, —OC(═O)RA, —C(═O)NHRB, —C(═O)N(RB)2, —NRBC(═O)RA, —OC(═O)N(RB)2, —NRBC(═O)ORA, —NRBC(═O)N(RB)2, —S(═O)RA, —OS(═O)2RA, —SO2RA, —NRBSO2RA, or —SO2N(RB)2; and m is 1, 2, 3, 4 or 5;
wherein when Z1 is S, G1 is hydrogen;
R2 is
in which each instance of G2 is independently halogen, —CN, —NO2, —N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —ORA, —SRA, —NHRB, —N(RB)2, —C(═O)RA, —C(═O)ORA, —OC(═O)RA, —C(═O)NHRB, —C(═O)N(RB)2, —NRBC(═O)RA, —OC(═O)N(RB)2, NRBC(═O)ORA, NRBC(═O)N(RB)2, —S(═O)RA, —OS(═O)2RA, —SO2RA, —NRBSO2RA, or —SO2N(RB)2;
R3 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —ORA, —SRA, —NHRB, —N(RB)2, —C(═O)RA, —C(═O)ORA, —C(═O)NHRB, —C(═O)N(RB)2, —SO2RA, or two instances of R3 are taken together with Z1 to form optionally substituted heterocyclyl;
R4a is —C(═NH)NH(ORA), —C(═N(ORA)NH2, —C(═NH)NHN(RB)2, —C(═NHN(RB)2)NH2, or —C(═NH)N(RB)2;
wherein
RA is hydrogen or optionally substituted C1-6 alkyl; and
each instance of RB is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted aryl.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the compound is the formula:
wherein:
Z1, R1, R2, R3 and R4a are defined therein.

### Claim 3 (depends on 2)

The compound of claim 2, wherein the compound is of Formula (IA′-2):
wherein:
R1, R2, R3 and R4a are defined therein.

### Claim 4 (depends on 1)

The compound of claim 1, wherein the compound is of the formula:
wherein R1, R2, R3, and R4a are defined therein.

### Claim 5 (depends on 1)

The compound of claim 1, wherein the compound is of the formula:
wherein:
R3, R4a, G1, G2, m, and n are defined therein.

### Claim 6 (depends on 1)

The compound of claim 1, wherein R1 is:

### Claim 7 (depends on 5)

The compound of claim 5, wherein RB is of the formula: —(CH2)qG, wherein:
q is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;
G is hydrogen, optionally substituted alkyl, —N3, or —N(Ra1)2; and
Ra1 is hydrogen or optionally substituted alkyl.

### Claim 8 (depends on 1)

The compound of claim 1, wherein R2 is:

### Claim 9 (depends on 1)

The compound of claim 1, wherein R2 is:

### Claim 10 (depends on 8)

The compound of claim 8, wherein R2 is:
in which RA is hydrogen or optionally substituted C1-6 alkyl.

### Claim 11 (depends on 1)

The compound of claim 1, wherein at least one instance of R3 is of the formula: —(CH2)pC(═O)ORA, in which:
p is 0, 1, or 2; and
RA is hydrogen or optionally substituted C1-6 alkyl.

### Claim 12 (depends on 1)

The compound of claim 1, wherein the two instances of R3, taken together with Z1, form optionally substituted heterocyclyl, in which Z1 is N.

### Claim 13 (depends on 1)

The compound of claim 1, wherein the compound is of the formula:
wherein Z1, R3, R4a, G1, G2, m, and n are defined therein.

### Claim 14 (depends on 1)

The compound of claim 1, wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.

### Claim 15 (depends on 1)

A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

### Claim 16 (depends on 1)

A method for treating a proliferative disease, comprising administering to a subject in need thereof an effective amount of the compound of claim 1.

### Claim 17

A compound, wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.

### Claim 18 (depends on 17)

A pharmaceutical composition, comprising a compound of claim 17 and a pharmaceutically acceptable carrier.

### Claim 19 (depends on 17)

A method for treating a proliferative disease, comprising administering to a subject in need thereof an effective amount of the compound of claim 17.