# US 11,078,228 B2 · Ectonucleotidase inhibitors and methods of use thereof

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- Number: US 11,078,228 B2
- Document ID: US11078228B2
- Status: Granted
- Kind: B2
- Application number: 16/447,159
- Filed: 2019-06-20
- Published: 2019-12-26
- Granted: 2021-08-03
- Earliest claimed: 2018-06-21
- Assignees: Calithera Biosciences, Inc.
- Applicants: Calithera Biosciences, Inc.
- Inventors: Lijing Chen; Roland Joseph Billedeau; Jim Li
- Web page: https://patentgrep.com/patent/US11078228B2

## CPC

- C07H 19/167: with ribosyl as the saccharide radical
- A61P 33/00: Antiparasitic agents
- C07H 19/048: Pyridine radicals
- C07H 19/052: Imidazole radicals
- C07H 19/06: Pyrimidine radicals
- C07H 19/067: with ribosyl as the saccharide radical
- C07H 19/23: Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22
- 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

The invention relates to novel heterocyclic compounds and pharmaceutical preparations thereof. The invention further relates to methods of treating or preventing cancer using the novel heterocyclic compounds of the invention.

## Claims

### Claim 1

A compound of formula (I):
or a pharmaceutically acceptable salt and/or prodrug thereof, wherein
Y is
Het is an optionally substituted purinyl ring or an optionally substituted 5-methyl-pyrimidin-2,4-dione ring;
R1a is selected from H, halo, hydroxy, cyano, azido, amino, C1-6alkyl, hydroxyC1-6alkyl, amino-C1-6alkyl, —O—C(O)—O—C1-6alkyl, C1-6acyloxy, C1-6alkoxy, C2-6alkenyl, and C2-6alkynyl;
R1b is selected from H, halo, C1-6alkyl, hydroxy-C1-6alkyl, amino-C1-6alkyl, C2-6alkenyl, and C2-6alkynyl;
R2a is selected from halo, hydroxy, cyano, azido, amino, C1-6alkyl, hydroxy-C1-6alkyl, amino-C1-6alkyl, C1-6acyloxy, —O—C(O)—O—C1-6alkyl, C1-6alkoxy, C2-6alkenyl, and C2-6alkynyl;
R2b is C2-6alkynyl;
R3 is selected from H and alkyl;
R4 is selected from H, alkyl, CN, aryl, heteroaryl, —C(O)OR9, —C(O)NR11R12, —S(O)2R10, —P(O)(OR11)(OR12), and —P(O)(OR11)(NR13R14);
R5 is aralkyl or heteroaralkyl wherein the aralkyl is substituted with one or more substituents selected from halo, haloalkyl, alkyl, alkoxy, carbonyl, aryl amino, amino, cycloalkyl, heterocyclyl, and heteroaryl;
R6 is selected from —C(O)OR9, —C(O)NR16R17, and —P(O)(OR11)(OR12);
R9 is independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;
R10 is independently selected from alkyl, alkenyl, alkynyl, amino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; and
each R11 and R12 is independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; or
R11 and R12, together with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocyclyl;
R13 is, independently for each occurrence, H or alkyl;
R14 is, independently for each occurrence, alkyl or aralkyl;
each R15 is independently selected from hydroxy, alkoxy acyloxy and NR13R14;
each R16 and R17 is independently selected from H, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl; or
R16 and R17, together with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocyclyl.

### Claim 2 (depends on 1)

The compound of claim 1, wherein:
a) if R4 and R6 are each —C(O)OH and R5 is benzyl substituted on the phenyl ring with a heterocyclyl or heteroaryl substituent, then the heterocyclyl or heteroaryl substituent is selected from unsubstituted or substituted pyrrolidinyl, piperazinonyl, piperidonyl, tetrahydropyrimidonyl, pyridonyl, and pyridyl; and
b) if R4 is —C(O)OH or tetrazolyl, R6 is —C(O)OH, and R5 is benzyl substituted on the phenyl ring with a second phenyl ring, then either the benzyl phenyl ring or the second phenyl ring is substituted with —C(O)OR9 where R9 is H or alkyl.

### Claim 3 (depends on 1)

The compound of claim 1, wherein
R5 is aralkyl or heteroaralkyl with a para substituent on the aryl or heteroaryl ring selected from heterocyclyl, heteroaryl, and aryl; and
R2b is substituted or unsubstituted C2alkynyl.

### Claim 4 (depends on 1)

The compound of claim 1, wherein Y is R

### Claim 5 (depends on 1)

The compound of claim 1, wherein R5 is benzyl substituted on the phenyl ring with a heterocyclyl or heteroaryl substituent.

### Claim 6 (depends on 1)

The compound of claim 1, wherein R5 is benzyl substituted on the phenyl ring at the 4-position with

### Claim 7 (depends on 1)

The compound of claim 1, wherein
represents

### Claim 8 (depends on 1)

The compound of claim 1, wherein Y is

### Claim 9 (depends on 8)

The compound of claim 8, wherein each R15 is hydroxy.

### Claim 10 (depends on 1)

The compound of claim 1, wherein Het is

### Claim 11 (depends on 1)

The compound of claim 1, wherein Het is
wherein
Z is N;
Ra is selected from H, halo, hydroxy, alkyl, thiophenyl, —NR7R8, aralkyl, aryl, and heteroaryl;
Rb is selected from halo, alkyl, haloalkyl, hydroxy alkyl, alkylthio, amido, carbonyl, amido, and heteroaryl; and
R7 is selected from H, hydroxy, alkyl, aralkyl, heteroaralkyl, cycloalkyl, and heterocyclyl and
R8 is H or alkyl; or
R7 and R8, together with the nitrogen atom to which they are attached, form a 4- to 7-membered heterocyclyl ring.

### Claim 12 (depends on 11)

The compound of claim 11, wherein Ra is selected from H, Cl, —NR7R8, and phenyl.

### Claim 13 (depends on 11)

The compound of claim 11, wherein Rb is selected from Cl, —CF3, carbonyl, and —CONH2.

### Claim 14 (depends on 11)

The compound of claim 11, wherein R7 is selected from H, alkyl, aralkyl, heteroaralkyl, cycloalkyl, and heterocyclyl.

### Claim 15 (depends on 1)

The compound of claim 1, wherein R1a and R2a are each hydroxy.

### Claim 16 (depends on 1)

The compound of claim 1, wherein R1a is hydroxy and R1b is H.

### Claim 17 (depends on 1)

The compound of claim 1, wherein R2a is hydroxy or C1-6alkyl.

### Claim 18 (depends on 1)

The compound of claim 1, wherein R2b is substituted or unsubstituted C2alkynyl.

### Claim 19 (depends on 1)

The compound of claim 1, wherein R2a is Me and R2b is ethynyl.

### Claim 20 (depends on 1)

The compound of claim 1, wherein R2a is hydroxy and R2b is ethynyl.

### Claim 21 (depends on 1)

The compound of claim 1, wherein R2b is propynyl, butynyl,
or unsubstituted or substituted

### Claim 22 (depends on 1)

The compound of claim 1, wherein R4 is selected from —C(O)OR9, —C(O)NR11R12, —S(O)2R10, and —P(O)(OR11)(OR12).

### Claim 23 (depends on 22)

The compound of claim 22, wherein R4 is —C(O)OR9 and R9 is H or alkyl.

### Claim 24 (depends on 22)

The compound of claim 22, wherein R4 is —C(O)NR11R12.

### Claim 25 (depends on 24)

The compound of claim 24, wherein each R11 and R12 is independently selected from H and alkyl; or R11 and R12, together with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocyclyl.

### Claim 26 (depends on 1)

The compound of claim 1, wherein R6 is —C(O)OR9 and R9 is H or alkyl.

### Claim 27 (depends on 1)

The compound of claim 1, wherein R6 is —C(O)NR16R17.

### Claim 28 (depends on 1)

The compound of claim 1, wherein R4 and R6 are each —C(O)OH.

### Claim 29

A compound selected from:
Example #
Compound
2
3
4
5
6
7
8
9
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11
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15
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205
or a pharmaceutically acceptable salt thereof.

### Claim 30 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

### Claim 31 (depends on 1)

The compound of claim 1, wherein R2b is unsubstituted C2alkynyl.

### Claim 32 (depends on 5)

The compound of claim 5, wherein R5 is benzyl substituted on the phenyl ring at a para position.

### Claim 33 (depends on 5)

The compound of claim 5, wherein:
the phenyl ring substituent is selected from substituted piperidonyl, piperazinonyl, tetrahydropyrimidonyl, pyridonyl, and pyridyl, and, optionally,
the piperidonyl, tetrahydropyrimidonyl, pyridonyl, or pyridyl is substituted with one or more of alkyl, hydroxyalkyl or alkoxyalkyl.

### Claim 34 (depends on 28)

The compound of claim 28, wherein R5 is benzyl substituted on the phenyl ring.

### Claim 35

A compound of formula (I):
or a pharmaceutically acceptable salt and/or prodrug thereof wherein
Y is
Het is
wherein Z is N; Ra is selected from —NR7R8, aralkyl, aryl, and heteroaryl; Rb is selected from halo, alkyl, haloalkyl, hydroxyalkyl, alkylthio, amido, carbonyl, amido, and heteroaryl; R7 is selected from hydroxy, alkyl, aralkyl, heteroaralkyl, cycloalkyl, and heterocyclyl and R8 is H or alkyl; or R7 and R8, together with the nitrogen atom to which they are attached, form a 4- to 7-membered heterocyclyl ring;
R1a is selected from H, halo, hydroxy, cyano, azido, amino, C1-6alkyl, hydroxyC1-6alkyl, amino-C1-6alkyl, —O—C(O)—O—C1-6alkyl, C1-6acyloxy, C1-6alkoxy, C2-6alkenyl, and C2-6alkynyl;
R1b is selected from H, halo, C1-6alkyl, hydroxy-C1-6alkyl, amino-C1-6alkyl, C2-6alkenyl, and C2-6alkynyl;
R2a is selected from halo, hydroxy, cyano, azido, amino, C1-6alkyl, hydroxy-C1-6alkyl, amino-C1-6alkyl, C1-6acyloxy, —O—C(O)—O—C1-6alkyl, C1-6alkoxy, C2-6alkenyl, and C2-6alkynyl;
R2b is C2-6alkynyl;
R3 is selected from H and alkyl;
R4 is selected from H, alkyl, CN, aryl, heteroaryl, —C(O)OR9, —C(O)NR11R12, —S(O)2R10, —P(O)(OR11)(OR12), and —P(O)(OR11)(NR13R14);
R5 is aralkyl or heteroaralkyl;
R6 is selected from —C(O)OR9, —C(O)NR16R17, and —P(O)(OR11)(OR12);
R9 is independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;
R10 is independently selected from alkyl, alkenyl, alkynyl, amino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; and
each R11 and R12 is independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; or
R11 and R12, together with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocyclyl;
R13 is, independently for each occurrence, H or alkyl;
R14 is, independently for each occurrence, alkyl or aralkyl;
each R15 is independently selected from hydroxy, alkoxy acyloxy and NR13R14;
each R16 and R17 is independently selected from H, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl; or
R16 and R17, together with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocyclyl.