# US 2020/0399276 A1 · Compounds and methods for the treatment of malaria

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- Number: US 2020/0399276 A1
- Document ID: US20200399276A1
- Status: Published application
- Kind: A1
- Application number: 16/915,660
- Filed: 2020-06-29
- Published: 2020-12-24
- Earliest claimed: 2013-11-11
- Assignees: The Broad Institute, Inc.
- Applicants: The Broad Institute, Inc.
- Inventors: EAMON COMER; NOBUTAKA KATO; CHRISTINA SCHERER; JESSICA BASTIEN; JEREMY DUVALL; TIMOTHY LEWIS; MORGANE SAYES; MATTHEW LEIGHTY; JUN PU; JENNIFER BEAUDOIN; BERTRAND BRAIBANT; BENITO MUNOZ
- Web page: https://patentgrep.com/patent/US20200399276A1

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 33/06: Antimalarials
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Provided herein are compounds of the formula (I): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of malaria.

## Claims

### Claim 1

A compound according to formula (I):
wherein the dotted line represents an optional double bond;
m is 0 or 1;
n is 0, 1, or 2;
A is CH or N;
X is absent or —C≡C—;
R1 is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C6-C10 aryl, or C2-C9 heteroaryl;
Y is C1-C6 alkylene;
R2 is C1-C6 perfluoroalkyl, C6-C10 aryl, C6-C10 aryl C1-C6 alkyl, C3-C10 carbocyclyl, or C2-C9 heteroaryl, wherein R2 is not 2-methoxyphenyl;
Z is absent, C1-C6 alkylene, or C1-C6 heteroalkylene;
R3 is hydrogen, hydroxyl, —NR5R6, —C(O)R7, or C2-C9 heterocyclyl;
R4 is hydrogen or C1-C6 alkyl;
R5 and R6 are independently hydrogen, C1-C6 alkyl, or C1-C6 acyl; and
R7 is hydroxyl, C1-C6 heteroalkyl, or C2-C9 heterocyclyl;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein said compound has the structure:

### Claim 3 (depends on 1)

The compound of claim 1, wherein said compound has the structure:

### Claim 4 (depends on 1)

The compound of claim 1, wherein X is —C≡C—.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R1 is C6-C10 aryl.

### Claim 6

(canceled)

### Claim 7 (depends on 1)

The compound of claim 1, wherein R2 is C6-C10.

### Claim at position 8

8-9. (canceled)

### Claim 10 (depends on 1)

The compound of claim 1, wherein Z is methylene.

### Claim 11 (depends on 1)

The compound of claim 1, wherein R3 is hydroxyl, 4-methylpiperazyl, 4-hydroxy-4-methyl-piperidyl, 3-hydroxyl-3-methyl-azetidinyl, —OCH2C(O)OH, —NH2, morpholinyl, —NHC(O)CH3, —NHCH3, —N(CH3)2, or —N(CH3)C(O)CH3.

### Claim at position 11

12-15. (canceled)

### Claim 16 (depends on 1)

The compound claim 1, wherein Y is methylene.

### Claim 17 (depends on 1)

The compound of claim 1, wherein R2 is substituted phenyl.

### Claim at position 14

18-38. (canceled)

### Claim 39

A pharmaceutical composition comprising a therapeutically effective amount of a compound having the structure:
wherein the dotted line represents an optional double bond;
m is 0 or 1;
n is 0, 1, or 2;
A is CH or N;
X is absent or —C≡C—;
R1 is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C6-C10 aryl, or C2-C9 heteroaryl;
Y is C1-C6 alkylene;
R2 is C1-C6 perfluoroalkyl, C6-C10 aryl, C6-C10 aryl C1-C6 alkyl, C3-C10 carbocyclyl, or C2-C9 heteroaryl, wherein R2 is not 2-methoxyphenyl;
Z is absent, C1-C6 alkylene, or C1-C6 heteroalkylene;
R3 is hydrogen, hydroxyl, —NR5R6, —C(O)R7, or C2-C9 heterocyclyl;
R4 is hydrogen or C1-C6 alkyl;
R5 and R6 are independently hydrogen, C1-C6 alkyl, or C1-C6 acyl; and
R7 is hydroxyl, C1-C6 heteroalkyl, or C2-C9 heterocyclyl;
or a pharmaceutically acceptable salt thereof; and
a pharmaceutically acceptable excipient.

### Claim at position 16

40-41. (canceled)

### Claim 42

A method of preventing or treating malaria in a subject, comprising the step of administering to the subject an effective amount of a compound having the structure:
wherein the dotted line represents an optional double bond;
m is 0 or 1;
n is 0, 1, or 2;
A is CH or N;
X is absent or —C≡C—;
R1 is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C6-C10 aryl, or C2-C9 heteroaryl;
Y is C1-C6 alkylene;
R2 is C1-C6 perfluoroalkyl, C6-C10 aryl, C6-C10 aryl C1-C6 alkyl, C3-C10 carbocyclyl, or C2-C9 heteroaryl, wherein R2 is not 2-methoxyphenyl;
Z is absent, C1-C6 alkylene, or C1-C6 heteroalkylene;
R3 is hydrogen, hydroxyl, —NR5R6, —C(O)R7, or C2-C9 heterocyclyl;
R4 is hydrogen or C1-C6 alkyl;
R5 and R6 are independently hydrogen, C1-C6 alkyl, or C1-C6 acyl; and
R7 is hydroxyl, C1-C6 heteroalkyl, or C2-C9 heterocyclyl;
or a pharmaceutically acceptable salt thereof.

### Claim 43

(canceled)

### Claim 44 (depends on 42)

The method of claim 42, wherein said malaria is drug resistant malaria.

### Claim 45 (depends on 44)

The method of claim 44, wherein drug resistant malaria is resistant to chloroquine, quinine, prymethamine, sulfadoxine, mefloquine, artemether, lumefantrine, artesunate, amodiaquine, dihydroartemisinin, piperaquine, proguanil, doxycycline, clindamycin, artemisinin, atovaquone, or any combination thereof.

### Claim 46 (depends on 42)

The method of claim 42, wherein said malaria is liver stage malaria, blood stage malaria, or transmission stage malaria.

### Claim 47 (depends on 42)

The method of claim 42, wherein the liver of said subject is infected with a malaria-causing parasite and said treatment prevents spread of said infection from their liver.

### Claim at position 23

48-49. (canceled)

### Claim 50 (depends on 1)

The compound according to claim 1, wherein R2 is phenyl substituted with —CH3, —OCH3 or halogen.

### Claim 51 (depends on 1)

The compound according to claim 1, wherein R2 is phenyl substituted with halogen.

### Claim 52 (depends on 1)

The compound according to claim 1, wherein R2 is not 3-methoxyphenyl or 4-methoxyphenyl.

### Claim 53 (depends on 1)

The compound according to claim 1, wherein R1 is substituted phenyl.