# US 2021/0329919 A9 · Synthesis and anti-cancer activity of communesin alkaloids

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- Number: US 2021/0329919 A9
- Document ID: US20210329919A9
- Status: Published application
- Kind: A9
- Application number: 16/863,015
- Filed: 2020-04-30
- Published: 2021-10-28
- Earliest claimed: 2019-07-01
- Applicants: Massachusetts Institute of Technology
- Inventors: Mohammad Movassaghi; Matthew M. Pompeo; Jaime Cheah
- Web page: https://patentgrep.com/patent/US20210329919A9

## CPC

- A01N 43/90: having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
- C07D 471/22: in which the condensed systems contains four or more hetero rings
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- A01N: PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF (preservation of food or foodstuff A23); BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES (preparations for medical, dental or toiletry purposes which kill or prevent the growth or proliferation of unwanted organisms A61K); PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Described herein are compounds of Formula (I): and salts, tautomers, and stereoisomers thereof. Methods of making the compounds, salts, tautomers, and stereoisomers are also described. Further described herein are composition, kits, methods, and uses involving the compounds, salts, tautomers, and stereoisomers. The methods include methods of treating and preventing diseases (e.g., cancers) in subjects (e.g., humans).

## Claims

### Claim 1

A compound of Formula (I):
or a salt, tautomer, or stereoisomer thereof, wherein:
R1 and R4 are each independently selected from H, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, —C(═O)R9, —C(═O)NR9R10, —S(═O)bR12, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl;
each instance of R2 and R5 is independently selected from F, Cl, Br, I, —OH, —OR9, —OC(═O)R9, —S(═O)bR12, —NR9R10, substituted or unsubstituted C2-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl;
each instance of R3 is independently selected from substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl;
R6 is H, —OH, —OR9, —OC(═O)R9, —S(═O)bR12, —NR9R10, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C1-C12 heteroalkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl;
each instance of R7 and R8 is independently selected from H, halogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, —C(═O)R9, —C(═O)NR9R10, —S(═O)bR12, —OH, —OR9, —OC(═O)R9, —NR9R10, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl, or wherein two R7 or two R8 groups taken together with the carbon atoms to which they are attached form a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclic, or substituted or unsubstituted heterocyclic ring;
each instance of R9 and R10 is independently selected from H, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl, or wherein R9 and R10 taken together with the carbon atoms to which they are attached form a substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclic ring;
each instance of R12 is independently substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, —(CH2)cSiMe3, or —(CH2)cR9;
m and t are each independently an integer from 0 to 3, inclusive;
n, r, and s are each independently an integer from 0 to 4, inclusive;
each instance of c is independently an integer from 0 to 6, inclusive;
each instance of b is independently 0, 1, or 2;
u is 0, 1, or 2;
p is an integer selected from 1 or 2; and
q is an integer from 1 to 6, inclusive.

### Claim 2

(canceled)

### Claim 3 (depends on 1)

The compound of claim 1, or a salt, tautomer, or stereoisomer thereof, wherein R6 is
and wherein
X is O, NR9, or —S(═O)2, or S;
v is an integer from 0 to 4, inclusive; and
each instance of R15 and R16 is independently selected from H, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl, or wherein R15 and R16 taken together with the carbon atoms to which they are attached form a substituted or unsubstituted carbocyclic, or substituted or unsubstituted heterocyclic ring.

### Claim 4

(canceled)

### Claim 5 (depends on 1)

The compound of claim 1, or a salt, tautomer, or stereoisomer thereof, wherein R4 is H, —C(═O)R9, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

### Claim at position 6

6-9. (canceled)

### Claim 10 (depends on 1)

The compound of claim 1, or a salt, tautomer, or stereoisomer thereof, wherein p is 2.

### Claim at position 8

11-12. (canceled)

### Claim 13 (depends on 1)

The compound of claim 1, or a salt, tautomer, or stereoisomer thereof, wherein R1 is —C(═O)R9.

### Claim at position 10

14-15. (canceled)

### Claim 16 (depends on 1)

The compound of claim 1, or a salt, tautomer, or stereoisomer thereof, wherein u is 1.

### Claim 17 (depends on 1)

The compound of claim 1, or a salt, tautomer, or stereoisomer thereof, wherein t is 1.

### Claim at position 13

18-21. (canceled)

### Claim 22 (depends on 1)

The compound of claim 1, wherein the compound is of the formula:

### Claim 23 (depends on 1)

A composition comprising a compound of claim 1, or a salt, tautomer, or stereoisomer thereof, and an excipient.

### Claim 24

(canceled)

### Claim 25 (depends on 1)

A method of treating a disease, comprising administering an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, to a subject in need thereof.

### Claim 26 (depends on 1)

A method of preventing a disease, comprising administering an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, to a subject in need thereof.

### Claim at position 19

27-39. (canceled)

### Claim 40 (depends on 1)

A method of treating an insect infestation comprising contacting the insect with an effective amount of a compound of claim 1, or a salt, tautomer, or stereoisomer thereof.

### Claim 41

(canceled)

### Claim 42

A compound of Formula (V):
or a salt, tautomer, or stereoisomer thereof, wherein
R4 is selected from H, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, —C(═O)R9, —C(═O)NR9R10, —S(═O)bR12, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl;
each instance of R2 and R5 are independently selected from F, Cl, Br, I, —OH, —OR9, —OC(═O)R9, —S(═O)bR12, —NR9R10, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted and heterocyclyl;
each instance of R3 is independently selected from substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl;
R6 is
X is O, NR9, or —S(═O)bR12;
each instance of R7 and R8 is independently selected from H, halogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, —C(═O)R9, —C(═O)NR9R10, —S(═O)bR12, —OH, —OR9, —OC(═O)R9, —NR9R10, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl, or wherein two R7 or two R8 groups taken together with the carbon atoms to which they are attached form a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclic, or substituted or unsubstituted heterocyclic ring;
each instance of R9 and R10 are independently selected from H, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl, or wherein R9 and R10 taken together with the carbon atoms to which they are attached form a substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclic ring;
each instance of R12 is independently substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, —(CH2)cSiMe3, or —(CH2)cR9;
R13 and R13′ are each independently hydrogen,
R14 is —CN, —OH, —OR9, —NR9R10, S(═O)bR12, or P(═O)(OR9)2
each instance of R15 and R16 is independently selected from H, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl, or wherein R15 and R16 taken together with the carbon atoms to which they are attached form a substituted or unsubstituted carbocyclic ring, or substituted or unsubstituted heterocyclic ring;
m and t are each independently an integer from 0 to 3, inclusive;
n, r, and s are each independently an integer from 0 to 4, inclusive;
v is an integer from 0 to 4, inclusive;
each instance of c is independently an integer from 0 to 6, inclusive;
each instance of b is independently 0, 1, or 2;
u is 0, 1, or 2; and
q is an integer from 1 to 6, inclusive.

### Claim 43 (depends on 1, 42)

A method of making a compound of claim 1, or a salt, tautomer, or stereoisomer thereof, comprising forming a bond between the nitrogen atom at the position N1 and the carbon atom at the position C8a′, and a bond between the nitrogen atom at the position N8′ and the carbon atom at the position C8a in a compound of claim 42, or a salt, tautomer, or stereoisomer thereof.

### Claim at position 24

44-49. (canceled)

### Claim 50

A compound of Formula (III′):
or a salt, tautomer, or stereoisomer thereof, wherein
R4 is selected from H, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, —C(═O)R9, —C(═O)NR9R10, —S(═O)bR12, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl;
each instance of R5 is independently selected from F, Cl, Br, I, —OH, —OR9, —OC(═O)R9, —S(═O)bR12, —NR9R10, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl;
R6 is
X is O, NR9, or —S(═O)bR12;
each instance of R8 is independently selected from H, halogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, —C(═O)R9, —C(═O)NR9R10, —S(═O)bR12, —OH, —OR9, —OC(═O)R9, —NR9R10, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl;
each instance of R9 and R10 is independently selected from H, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, aryl, heteroaryl, carbocyclyl, and heterocyclyl, or wherein R9 and R10taken together with the carbon atoms to which they are attached form a substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclic ring;
each instance of R12 is independently substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, —(CH2)cSiMe3, or —(CH2)cR9;
R13 is
each instance of R15 and R16 is independently selected from H, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl, or wherein R15 and R16 taken together with the carbon atoms to which they are attached form a substituted or unsubstituted carbocyclic, or substituted or unsubstituted heterocyclic ring;
m is an integer from 0 to 3, inclusive;
v is an integer from 0 to 4, inclusive;
r is an integer from 0 to 4, inclusive;
each instance of c is independently an integer from 0 to 6, inclusive;
each instance of b is independently 0, 1, or 2; and
u is 0, 1, or 2.

### Claim 51 (depends on 50)

A method of making a compound of claim 50, comprising desulfonylation of the sulfonamide at C3a in a compound of Formula (IX):
or a salt, tautomer, or stereoisomer thereof.

### Claim at position 27

52-59. (canceled)

### Claim 60

A compound of Formula (XIV):
or a salt, tautomer, or stereoisomer thereof, wherein
each instance of R3 is independently substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl; and
q is an integer from 1 to 6, inclusive.

### Claim at position 29

61-62. (canceled)

### Claim 63 (depends on 60)

A method of making a compound of claim 60, or a salt, tautomer, or stereoisomer thereof, comprising the steps of:
(1) reacting
with a chiral controller in the presence of a base, wherein the chiral controller comprises a hydroxy moiety; and
(2) reacting with an H2N− source.

### Claim at position 31

64-65. (canceled)

### Claim 66 (depends on 1)

A method of making a compound of Formula (I′):
or a salt, tautomer, or stereoisomer thereof, wherein
R1 and R4 are each independently selected from H, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, —C(═O)R9, —C(═O)NR9R10, —S(═O)bR12, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl;
each instance of R2 and R5 is independently selected from F, Cl, Br, I, —OH, —OR9, —OC(═O)R9, —S(═O)bR12, —NR9R10, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl;
R6 is H, —OH, —OR9, —OC(═O)R9, —S(═O)bR12, —NR9R10, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C1-C12 heteroalkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl;
each instance of R7 and R8 is independently selected from H, halogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, —C(═O)R9, —C(═O)NR9R10, —S(═O)bR12, —OH, —OR9, —OC(═O)R9, —NR9R10, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl, or wherein two R7 or two R8 groups taken together with the carbon atoms to which they are attached form a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclic, or substituted or unsubstituted heterocyclic ring;
each instance of R9 and R10 is independently selected from H, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl, or wherein R9 and R10 taken together with the carbon atoms to which they are attached form a substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclic ring;
each instance of R12 is independently substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, —(CH2)cSiMe3, or —(CH2)cR9;
m and t are each independently an integer from 0 to 3, inclusive;
n, r, and s are each independently an integer from 0 to 4, inclusive;
each instance of c is independently an integer from 0 to 6, inclusive;
each instance of b is independently 0, 1, or 2; and
u is 0, 1, or 2;
comprising desulfonylation of position N8′ in a compound of claim 1, or a salt, tautomer, or stereoisomer thereof.

### Claim at position 33

67-70. (canceled)

### Claim 71

A compound of formula:
or a salt, tautomer, or stereoisomer thereof.