# US 11,433,055 B2 · Chromane monobactam compounds for the treatment of bacterial infections

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- Number: US 11,433,055 B2
- Document ID: US11433055B2
- Status: Granted
- Kind: B2
- Application number: 16/651,456
- Filed: 2018-09-27
- Published: 2020-09-24
- Granted: 2022-09-06
- Earliest claimed: 2017-10-02
- Assignees: Merck Sharp & Dohme Corp.
- Applicants: Merck Sharp & Dohme Corp.
- Inventors: Tesfaye Biftu; Xianhai Huang; Weiguo Liu; Weidong Pan; Min Park; Alexander Pasternak; Wanying Sun; Haifeng Tang; Yi Zang
- Web page: https://patentgrep.com/patent/US11433055B2

## CPC

- A61K 31/427: not condensed and containing further heterocyclic rings
- A61K 31/424: condensed with heterocyclic ring systems, e.g. clavulanic acid
- A61K 31/43: Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula [IMAGE cpc-sch-A61K-0952.gif], e.g. penicillins, penems
- A61K 31/431: containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
- A61K 31/4425: Pyridinium derivatives, e.g. pralidoxime, pyridostigmine
- 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 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/551: having two nitrogen atoms, e.g. dilazep
- A61P 31/04: Antibacterial agents
- C07D 417/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- 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
- 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)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The present invention relates to monobactam compounds of Formula I: and pharmaceutically acceptable salts thereof. The present invention also relates to compositions which comprise a monobactam compound of the invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The invention further relates to methods for treating a bacterial infection comprising administering to the patient a therapeutically effective amount of a compound of the invention, either alone or in combination with a therapeutically effective amount of a second beta-lactam antibiotic.

## Claims

### Claim 1

A compound of Formula I
or a pharmaceutically acceptable salt thereof, wherein:
T, U and V are each CH;
W is O;
Q is CR3;
X is CH2;
Y is O or CH2,
Z is O or CHn,
A is
1) —C(═NH)—NH,
2) AryC, or
3) HetC,
wherein A is unsubstituted or substituted with one to four Ri;
AryC is a 5- to 6-membered monocyclic aromatic ring with 0, 1, 2, or 3 ring atoms independently selected from N, N as a quaternary salt, O and S, unsubstituted or substituted with one to four Ri, wherein AryC is optionally fused to a 4- to 7-membered heterocycloalkyl ring containing one to two heteroatoms selected from O, S and —NRg;
HetC is a 4- to 7-membered saturated or monounsaturated monocyclic ring with 1, 2, or 3 heteroatom ring atoms independently selected from N, N as a quaternary salt, O and S, unsubstituted or substituted with one to four Ri;
L is
1) absent,
2) R4,
3) —NHR4,
4) —N(R4)2,
5) —OR4,
6) —(CH2)nR4,
7) —C(O)R4,
8) —C(NH)R4, or
9) —S(O)mR4,
wherein L is unsubstituted or substituted with 1-4 substituents selected from Re;
M is
1) R5,
2) —NHR5,
3) —N(R5)2,
4) —OR5,
5) —(CH2)uR5,
6) —C(O)R5,
7) —C(NH)R5, or
8) —S(O)vR5,
wherein M is unsubstituted or substituted with 1-4 substituents selected from R6;
R1 and R2 are independently selected from:
1) hydrogen,
2) —C1-C8 alkyl, and
3) —C(O)ORe,
wherein —C1-C8 alkyl is unsubstituted or substituted with one to three Ra,
provided that if R1 is —C(O)ORe, then R2 is not —C(O)ORe,
R3 is hydrogen;
each occurrence of R4 is independently:
1) hydrogen,
2) —C1-C10 alkyl,
3) —C2-C8 alkenyl,
4) —(CH2)nORe,
5) —S(O)mRe,
6) —S(O)mNRcRd,
7) —(CH2)nNRcRd,
8) —OC(O)Re,
9) —C(O)ORe,
10) —CN,
11) —C(O)NRcRd,
12) —NRc(O)Re,
13) —NRcC(O)ORe,
14) —NRc(O)NRcRd,
15) —NRcS(O)mRe,
16) ═NR11,
17) —C3-C7 cycloalkyl,
18) —O—C3-C6cycloalkyl,
19) —C1-C10alkylene-C3-C6cycloalkyl,
20) —O—C1-C10alkylene-C3-C6cycloalkyl,
21) HetB,
22) —O-HetB,
23) —C1-C10alkylene-HetB,
24) —O—C1-C10alkylene-HetB,
25) AryB,
26) —O-AryB,
27) —C1-C10alkylene-AryB, or
28) —O—C1-C10alkylene-AryB,
wherein R4 is unsubstituted or substituted with one to four R6;
AryB is a 5- to 6-membered monocyclic aromatic ring with 0, 1, 2, or 3 ring atoms independently selected from N, O and S, unsubstituted or substituted with one to four W;
HetB is a 4- to 7-membered saturated or monounsaturated monocyclic ring with 1, 2, or 3 heteroatom ring atoms independently selected from N, N as a quaternary salt, O and S, unsubstituted or substituted with one to three Ra;
R5 is
1) hydrogen,
2) C1-C10 alkyl,
3) —C2-C8 alkenyl,
4) —(CH2)uORe,
5) —S(O)vRe,
6) —S(O)vNRcRd,
7) —(CH2)uNRcRd,
8) —OC(O)Re,
9) —C(O)ORe,
10) —CN,
11) —C(O)NReRd,
12) —NRcC(O)Re,
13) —NRcC(O)ORe,
14) —NRcC(O)NRcRd,
15) —NRcS(O)vRe,
16) ═NR11,
17) —C3-C7 cycloalkyl,
18) —O—C3-C6cycloalkyl,
19) —C1-C10alkylene-C3-C6cycloalkyl,
20) —O—C1-C10 alkylene-C3-C6cycloalkyl,
21) HetB,
22) —O-HetB,
23) —C1-C10alkylene-HetB,
24) —O—C1-C10 alkylene-HetB,
25) AryB,
26) —O-AryB,
27) —C1-C10alkylene-AryB, or
28) —O—C1-C10alkylene-AryB,
wherein R5 is unsubstituted or substituted with one to four R6;
each occurrence of R6 is independently:
1) halogen,
2) —C1-C6alkyl,
3) —ORe,
4) —S(O)vRe,
5) —S(O)vNRcRd,
6) —C(O)Re,
7) —OC(O)Re,
8) —C(O)ORe,
9) —CN,
10) —C(O)NRcRd,
11) —C(NH)NRcRd,
12) —(CH2)uNRcRd,
13) —(CH2)uNRcRd,
14) —N(Rc)(C(O)Re),
15) —N(Rc)(C(O)ORe),
16) —N(Rc)(C(O)NRcRd),
17) —N(Rc)(S(O)vRe), or
18) HetB;
R7 is
1) hydrogen,
2) C1-C3 alkyl, or
3) C3-C7 cycloalkyl,
wherein C1-C3 alkyl and C3-C7 cycloalkyl are unsubstituted or substituted with one to three Ra;
R8 is
1) hydrogen,
2) C1-C4 alkyl, or
3) C3-C7 cycloalkyl;
R9 is
1) hydrogen,
2) C1-C4 alkyl, or
3) C3-C7 cycloalkyl;
R10 is
1) hydrogen,
2) C1-C4 alkyl, or
3) C3-C7 cycloalkyl;
R11 is
1) hydrogen,
2) C1-C4 alkyl, or
3) C3-C7 cycloalkyl;
R12 and R13 are independently C1-C3 alkyl, wherein C1-C3 alkyl is unsubstituted or substituted with one to seven fluorines,
or alternatively R12 and R13 together with the carbon to which they are attached form a monocyclic C4-C6 cycloalkyl unsubstituted or substituted with one to three substituents independently selected from —F, —OH and —OC1-C3alkyl;
each occurrence of Ra is independently:
1) hydrogen,
2) halogen,
3) C1-C3alkyl,
4) —NRcRd, or
5) —ORe;
each occurrence of Rb is independently:
1) hydrogen,
2) —C1-C6 alkyl,
3) —OC1-C6 alkyl,
4) OH,
5) N(R9)2, or
6) halogen,
wherein —C1-C3 alkyl is unsubstituted or substituted with one to three Ra;
Rc and Rd are independently selected from:
1) hydrogen,
2) —C1-C10 alkyl, and
3) —C2-C10 alkenyl,
wherein each Rc and Rd is unsubstituted or substituted with one to three Rf;
each occurrence of Re is independently hydrogen, or —C1-C10alkyl, wherein each Re is unsubstituted or substituted with one to three Rh;
each occurrence of Rf is independently:
1) halogen,
2) —C1-C10 alkyl,
3) —OH,
4) —OC1-C4 alkyl,
5) —S(O)mC1-C4 alkyl,
6) —CN,
7) —CF3,
8) —OCHF2,
9) —OCF3, or
10) NH2,
wherein —C1-C10 alkyl is unsubstituted or substituted with one to three substituents independently
selected from —OH, halogen, cyano, and —S(O)2CH3;
each occurrence of Rg is independently:
1) hydrogen,
2) —C(O)Re, or
3) —C1-C10 alkyl,
wherein —C1-C10alkyl is unsubstituted or substituted with one to five fluorines;
each occurrence of Rh is independently:
1) halogen,
2) —C1-C10alkyl,
3) —OH,
4) —OC1-C4 alkyl,
5) —S(O)mC1-C4 alkyl,
6) —CN,
7) —CF3,
8) —OCHF2, or
9) —OCF3,
wherein —C1-C10 alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, halogen, cyano, or —S(O)2CH3;
each occurrence of Ri is independently:
1) —C1-C8 alkyl,
2) —C2-C8 alkenyl,
3) —C2-C8 alkynyl,
4) halogen,
5) —ORe,
6) —S(O)mRe,
7) —S(O)mNRcRd,
8) —C(O)Re,
9) —OC(O)Re,
10) —C(O)ORe,
11) —CN,
12) —C(O)NRcRd,
13) —NRcRd,
14) —(CH2)nNRcRd,
15) —NRcC(O)Re,
16) —NRcC(O)ORe,
17) —NRcC(O)NRcRd,
18) —NRcS(O)mRe,
19) ═NH,
20) —CF3,
21) —OCF3, or
22) —OCHF2;
each occurrence of Rj is independently:
1) hydrogen,
2) C1-C3 alkyl,
3) OR10,
4) ═NR10,
5) N(R10)2, or
6) halogen,
wherein C1-C3 alkyl unsubstituted or substituted with one to three Rb;
each n is independently 0, 1, 2, 3, 4, 5 or 6;
each m is independently 0, 1 or 2;
each p is independently 1 or 2;
each q is independently 0, 1, 2, 3, 4, 5 or 6;
each s is independently 0, 1, 2 or 3;
each t is independently 0, 1, 2 or 3;
each u is independently 0, 1, 2, 3, 4, 5 or 6; and
each v is independently 0, 1, or 2.

### Claim 2 (depends on 1)

The compound of claim 1 wherein
Y is CH2; and
Z is O;
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The compound of claim 1 wherein
R1 and R2 are independently selected from
1) —C1-C8 alkyl, and
2) —C(O)ORe,
provided if R1 is —C(O)ORe, then R2 is —C1-C8 alkyl, and if R2 is —C(O)ORe, then R1 is —C1-C8 alkyl;
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

The compound of claim 1 wherein A is
1) AryC, or
2) HetC,
wherein A is unsubstituted or substituted with one to four Ri;
or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

The compound of claim 1 wherein
A is —C(═NH)—NH, wherein A is unsubstituted or substituted with one to four Ri;
or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

The compound of claim 1 wherein
A is AryC, wherein A is unsubstituted or substituted with one to four Ri;
or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

The compound of claim 1 wherein
L is
1) absent, or
2) R4,
wherein L is unsubstituted or substituted with 1-4 substituents selected from Re; and
each occurrence of R4 is independently:
1) hydrogen,
2) —C1-C10 alkyl,
3) —(CH2)nORe,
4) —(CH2)nNRcRd, or
5) —C1-C10alkylene-HetB,
wherein R4 is unsubstituted or substituted with one to four R6;
or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 5)

The compound of claim 5 wherein
each occurrence of R4 is independently:
1) —C1-C10 alkyl,
2) —(CH2)nNRcRd, or
3) —C1-C10alkylene-HetB,
wherein R4 is unsubstituted or substituted with one to four R6;
or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

The compound of claim 1 wherein
M is
1) R5, or
2) —NHR5,
wherein M is unsubstituted or substituted with 1-4 substituents selected from R6; and
R5 is
1) hydrogen,
2) C1-C6 alkyl,
3) —C1-C4alkyl-(NRcRd)2,
4) —(CH2)uNRcRd, or
5) —C1-C10alkylene-HetB,
wherein R5 is unsubstituted or substituted with one to four R6;
or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 7)

The compound of claim 7 wherein
R5 is
1) —C1-C4alkyl-(NRcRd)2, or
2) —(CH2)uNRcRd,
wherein R5 is unsubstituted or substituted with one to four R6;
or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 1)

The compound of claim 1 wherein
T, U and V are CH;
W is O;
Q is CR3;
X is CH2;
Y is O or CH2;
Z is O or CH2;
R1 and R2 are independently selected from:
1) hydrogen,
2) —C1-C8 alkyl, and
3) —C(O)ORe,
wherein —C1-C8 alkyl is unsubstituted or substituted with one to three Ra, provided that if R1 is —C(O)ORe, then R2 is independently selected from hydrogen and —C1-C8 alkyl;
R3 is hydrogen;
R12 and R13 are independently C1-C3 alkyl, wherein C1-C3 alkyl is unsubstituted or substituted with one to seven fluorines,
or alternatively R12 and R13 together with the carbon to which they are attached form a monocyclic C4-C6 cycloalkyl unsubstituted or substituted with one to three substituents independently selected from —F, —OH and —OC1-C3alkyl;
A is
1) —C(═NH)—NH,
2) AryC, or
3) HetC,
wherein A is unsubstituted or substituted with one to four Ri;
L is
1) absent, or
2) R4,
wherein L is unsubstituted or substituted with 1-4 substituents selected from Re;
each occurrence of R4 is independently:
1) hydrogen,
2) —C1-C10 alkyl,
3) —(CH2)nORe,
4) —(CH2)nNRcRd, or
5) —C1-C10alkylene-HetB,
wherein R4 is unsubstituted or substituted with one to four R6;
M is
1) R5, or
2) —NHR5,
wherein M is unsubstituted or substituted with 1-4 substituents selected from R6; and
R5 is
1) hydrogen,
2) —C1-C6 alkyl,
3) —C1-C4alkyl-(NRcRd)2,
4) —(CH2)uNRcRd, or
5) —C1-C10alkylene-HetB,
wherein R5 is unsubstituted or substituted with one to four R6;
or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 1)

The compound of claim 1 wherein
T, U and V are CH;
W is O;
Q is CR3;
R3 is hydrogen;
X is CH2;
Y is CH2;
Z is O;
R1 and R2 are independently selected from
1) —C1-C6 alkyl, and
2) —C(O)ORe,
wherein —C1-C6 alkyl is unsubstituted or substituted with one to three Ra, provided that if R1 is —C(O)ORe, then R2 is —C1-C6 alkyl;
R12 and R13 are independently C1-C3 alkyl, wherein C1-C3 alkyl is unsubstituted or substituted with one to seven fluorines;
A is
1) AryC, or
2) HetC,
wherein A is unsubstituted or substituted with one to four Ri;
L is
1) absent, or
2) R4,
wherein L is unsubstituted or substituted with 1-4 substituents selected from Re;
each occurrence of R4 is independently:
1) —C1-C10 alkyl,
2) —(CH2)nNRcRd, or
3) —C1-C10alkylene-HetB,
wherein R4 is unsubstituted or substituted with one to four R6;
M is
1) R5, or
2) —NHR5,
wherein M is unsubstituted or substituted with 1-4 substituents selected from R6;
R5 is
1) —C1-C4alkyl-(NRcRd)2, or
2) —(CH2)uNRcRd,
wherein R5 is unsubstituted or substituted with one to four R6;
or a pharmaceutically acceptable salt thereof.

### Claim 13

A compound selected from:
or a pharmaceutically acceptable salt thereof.

### Claim 14

A compound which is:
or a pharmaceutically acceptable salt thereof.

### Claim 15

A compound which is:
or a pharmaceutically acceptable salt thereof.

### Claim 16

A compound which is:
or a pharmaceutically acceptable salt thereof.

### Claim 17

A compound which is:
or a pharmaceutically acceptable salt thereof.

### Claim 18

A compound which is:
or a pharmaceutically acceptable salt thereof.

### Claim 19 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 20 (depends on 19)

A pharmaceutical composition according to claim 19, which further comprises a therapeutically effective amount of a beta-lactamase inhibitor compound.

### Claim 21 (depends on 20)

A pharmaceutical composition according to claim 20, wherein the beta-lactamase inhibitor compound is selected from the group consisting of relebactam, tazobactam, clavulanic acid, sulbactam, and avibactam.