# US 12,760,034 B2 · Rifamycin analogs

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- Number: US 12,760,034 B2
- Document ID: US12760034B2
- Status: Granted
- Kind: B2
- Application number: 18/261,932
- Filed: 2022-01-19
- Published: 2025-06-12
- Granted: 2026-10-13
- Earliest claimed: 2021-01-19
- Assignees: The Regents of the University of Michigan; The Board of Trustees of the University of Illinois; The Penn State Research Foundation
- Applicants: The Regents of the University of Michigan; The Board of Trustees of the University of Illinois; The Penn State Research Foundation
- Inventors: George Garcia; Hollis Showalter; Walajapet Rajeswaran; Pil Lee; Scott Franzblau; Katsuhiko Murakami
- Web page: https://patentgrep.com/patent/US12760034B2

## CPC

- C07D 498/18: Bridged systems
- A61K 31/5386: spiro-condensed or forming part of bridged ring systems
- A61K 31/541: Non-condensed thiazines containing further heterocyclic rings
- A61P 31/06: for tuberculosis
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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

## Abstract

Provided herein are compounds that are potent inhibitors of the Mycobacterium tuberculosis (MTB) RNA polymerase (RNAP), which exhibit significantly reduced activation of the human pregnane X receptor (hPXR), resulting in dramatically reduced C induction of hepatic cytochromes P450 2C9 and 3A4 (CYP2C9, CYP3A4), as well as a number of Phase II metabolism enzymes. Also provided herein are pharmaceutical compositions comprising the compounds, and methods of treating tuberculosis using the compounds.

## Claims

### Claim 1

A compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, —C(O)Ra, —N(Rb)2, —ORc, —SR4, —CH═N—Z, and heterocyclyl, wherein the heterocyclyl is unsubstituted or substituted with one substituent selected from C1-C6 alkyl, C1-C6 alkenyl, —C(O)Ra1, —C(O)ORb1, —C(O)NHRc1, —(CH2)n1—X1a, —SO2—X1b, aryl, heteroaryl, cycloalkyl, and heterocyclyl, wherein when the substituent is aryl, heteroaryl, cycloalkyl, or heterocyclyl, the substituent is optionally further substituted with C1-C6 alkyl or —O—X1c;
X is selected from O, S, SO2, NHSO2, NRX, and a bond;
RX is selected from hydrogen and C1-C3 alkyl;
R2 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C3-C6 cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH2)m1-aryl, —(CH2)m2-heterocyclyl, and —CH2-Ph-CH2-heterocyclyl, wherein each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or two substituents independently selected from C1-C6 alkyl, hydroxy, amino, —C(O)Ra2, —C(O)ORb2, —C(O)NHRc2, —(CH2)n2—X2a, —SO2—X2b, aryl, heteroaryl, cycloalkyl, and heterocyclyl;
each Ra, Rb, Rc, and Rd is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and aryl;
Ra1 and Ra2 are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and —(CH2)p—Y, wherein each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently unsubstituted or substituted with one substituent selected from aryl, heteroaryl, C1-C6 alkyl, halo, and nitro, and when the substituent is aryl or heteroaryl, it is unsubstituted or substituted with one substituent selected from halo, hydroxy, and —CONH2;
Rb1 and Rb2 are each independently selected from hydrogen, C1-C6 alkyl, and heterocyclyl, wherein the heterocyclyl is optionally further substituted with one substituent selected from C1-C6 alkyl, hydroxy, halo, and nitro;
Rc1 and Rc2 are each independently selected from hydrogen, C1-C6 alkyl, and aryl, wherein the aryl is unsubstituted or substituted with one substituent selected from C1-C6 alkyl, halo, and nitro;
X1a, X1b, X1c, X2a, and X2b are each independently selected from aryl, heteroaryl, cycloalkyl, heterocyclyl, —O-heterocyclyl, —COOH, and —N(CH3)2, wherein each aryl, heteroaryl, cycloalkyl, or heterocyclyl is independently unsubstituted or substituted with one substituent selected from C1-C6 alkyl, hydroxy, halo, and nitro;
Y is selected from aryl, heteroaryl, cycloalkyl, and heterocyclyl, each of which is independently unsubstituted or substituted with one substituent selected from C1-C6 alkyl, halo, and nitro;
Z is selected from aryl and heteroaryl, each of which is optionally substituted with one substituent selected from heterocyclyl; and
m1, m2, n1, n2, and p are each independently 1, 2, 3, 4, 5, or 6;
wherein when R1 is hydrogen, —X—R2 is not:
—CH3,
and when R1 is
—X—R2 is not: —CH3, —SH, or
and when R1 is
—X—R2 is not —CH3;
and when R1 is CH3, —X—R2 is not hydrogen;
and when X is O, R2 is not hydrogen.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from hydrogen and methyl.

### Claim 3 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is a monocyclic 6-membered heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the heterocyclyl is unsubstituted or substituted with one substituent selected from C1-C6 alkyl, —C(O)Ra1, —C(O)ORb1, and —(CH2)n1—X1a.

### Claim 4 (depends on 3)

The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein the heterocyclyl is unsubstituted or substituted with one substituent selected from C1-C4 alkyl, —C(O)Ra1, and —C(O)ORb1; wherein:
Ra1 is selected from C1-C4 alkyl, aryl, and heteroaryl, wherein the aryl is unsubstituted or substituted with one heteroaryl substituent; and
Rb1 is selected from hydrogen and C1-C4 alkyl.

### Claim 5 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is:
wherein Ry is selected from C1-C4 alkyl, —C(O)Ra1, and —C(O)ORb1; wherein:
Ra1 is selected from C1-C4 alkyl, aryl, and heteroaryl, wherein the aryl is unsubstituted or substituted with one heteroaryl substituent; and
Rb1 is selected from hydrogen and C1-C4 alkyl.

### Claim 6 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from:

### Claim 7 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is:

### Claim 8 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is O or a bond.

### Claim 9 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from hydrogen, C1-C6 alkyl, heterocyclyl, and —CH2-Ph-CH2-heterocyclyl, wherein each heterocyclyl is independently unsubstituted or substituted with one substituent selected from C1-C6 alkyl, —C(O)Ra2, —C(O)ORb2, —C(O)NHRc2, —(CH2)n2—X2a, and heterocyclyl.

### Claim 10 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
X is O;
R2 is —CH2-Ph-CH2-heterocyclyl, wherein the heterocyclyl is a monocyclic 6-membered heterocyclyl having 1 or 2 heteroatoms independently selected from N and O, and is unsubstituted or substituted with one substituent selected from C1-C6 alkyl and —C(O)Ra2;
Ra2 is selected from C1-C6 alkyl and —(CH2)p—Y;
Y is selected from phenyl, monocyclic 5- or 6-membered heteroaryl, and monocyclic 5- or 6-membered heterocyclyl; and
p is 1 or 2.

### Claim 11 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein —X—R2 is selected from:
wherein:
each Q1 is independently selected from O, NRq1, S, and SO2,
each Q2 is independently selected from O, NRq2, S, SO, and SO2;
Rq1 and Rq2 are each independently selected from hydrogen, C1-C4 alkyl, and —C(O)Ra2;
Ra2 is selected from C1-C4 alkyl and —(CH2)p—Y;
Y is selected from aryl, heteroaryl, cycloalkyl, and heterocyclyl;
p is 1 or 2.

### Claim 12 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is C1-C6 alkyl.

### Claim 13 (depends on 12)

The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein R2 is methyl.

### Claim 14 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
R2 is a 6-membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N and O, wherein the heterocyclyl is unsubstituted or substituted with one substituent selected from C1-C4 alkyl, —C(O)Ra2, and —(CH2)n2—X2a;
Ra2 is selected from aryl and heteroaryl, each of which is independently unsubstituted or substituted with one substituent selected from heteroaryl;
X2a is selected from heteroaryl and —COOH; and
n2 is 1 or 2.

### Claim 15 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein —X—R2 is selected from:

### Claim 16 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein —X—R2 is:

### Claim 17 (depends on 1)

A method of manufacturing a compound of claim 1, or a pharmaceutically acceptable salt thereof, comprising:
(a) reacting rifamycin S with a compound of formula (A), followed by treatment with manganese dioxide, to provide a compound of formula (B):
(b) reacting the compound of formula (B) with a compound of formula R1—H, followed by treatment with manganese dioxide, to provide a compound of claim 1.

### Claim 18 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

### Claim 19 (depends on 1)

A method of treating tuberculosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 20 (depends on 1)

A method of killing Mycobacterium tuberculosis in a sample, comprising contacting the sample with an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 21 (depends on 16)

The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein R1 is:

### Claim 22 (depends on 19)

The method of claim 19, wherein R1 is:

### Claim 23 (depends on 19)

The method of claim 19, wherein -X-R2 is:

### Claim 24 (depends on 19)

The method of claim 19, wherein R1 is
and-X-R2 is

### Claim 25 (depends on 19)

The method of claim 19, wherein the subject is infected with human immunodeficiency virus.

### Claim 26 (depends on 19)

The method of claim 19, wherein the subject is infected with a drug-resistant strain of Mycobacterium tuberculosis.

### Claim 27 (depends on 19)

The method of claim 19, wherein the subject is infected with a rifampin-resistant strain of Mycobacterium tuberculosis.

### Claim 28 (depends on 19)

The method of claim 19, wherein the subject has a persistent tuberculosis infection.