# US 10,501,481 B2 · Heterocyclic compounds and their use in preventing or treating bacterial infections

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- Number: US 10,501,481 B2
- Document ID: US10501481B2
- Status: Granted
- Kind: B2
- Application number: 15/563,889
- Filed: 2016-04-01
- Published: 2018-05-03
- Granted: 2019-12-10
- Earliest claimed: 2015-04-03
- Assignees: Mutabilis
- Applicants: Mutabilis
- Inventors: Julie Brias; Sophie Chasset; Francis Chevreuil; Nicolas Lecointe; Benôit Ledoussal; Frédéric Le Strat; Sophie Vomscheid; Sébastien Richard; Fabien Faivre; Julien Barbion; Audrey Caravano; Géraldine Le Fralliec; Christophe Simon
- Web page: https://patentgrep.com/patent/US10501481B2

## CPC

- C07D 513/18: Bridged systems
- A61K 31/439: the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46)
- A61K 31/546: containing further heterocyclic rings, e.g. cephalothin
- A61P 31/04: Antibacterial agents
- C07D 471/18: Bridged systems
- 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

The present invention relates to heterocyclic compounds, their process of preparation, pharmaceutical compositions comprising these compounds and use thereof, optionally in combination with other antibacterial agents and/or beta-lactam compounds, for the prevention or treatment of bacterial infections. The present invention also relates to the use of these compounds as β-lactamase inhibitors and/or as antibacterial agents.

## Claims

### Claim 1

A compound of formula (I)
wherein:
W, unsubstituted or substituted by one or more T, is a non-aromatic, unsaturated 5- or 6-member heterocycle comprising at least one N—R2 group and a (X)n group;
X, identical or different, is independently selected from the group consisting of represents C(O), O, N, N(R2), S, S(O), and S(O)2;
R1 is selected from the group consisting of a carbon-linked 4- or 5- or 6-member heterocycle comprising at least one nitrogen atom that is aromatic or saturated or totally unsaturated or partially unsaturated and optionally substituted by one or more T1, H, —CN, —C(O)NHQ1, —C(O)NHOQ1, —C(O)NH—NHQ1, —C(O)O—NHQ1, —C(O)OQ1, —(CH2)mOC(O)OQ1, —(CH2)mOQ1, —(CH2)mOC(O)Q1, —(CH2)mOC(O)NQ1Q2, —(CH2)m—NHC(O)Q1, —(CH2)mNHS(O)2Q1, —(CH2)mNHS(O)2NQ1Q2, —(CH2)mNHC(O)OQ1; —(CH2)mNHC(O)NQ1Q2, —(CH2)mNHQ3, —(CH2)mNH—C(NHQ3)═NQ4, —(CH2)mNH—CH═NQ3, and —C(NHQ3)═NQ4;
R2 is one of the following:
R2, identical or different, is independently selected from the group consisting of (CH2)qOQ5, —C(O)(CH2)vOQ5, —(C(O))w(CH2)v—CN, —(CH2)qOC(O)Q5, —C(O)—(CH2)vOC(O)Q5, —(C(O))w(CH2)v—C(O)OQ5, —(CH2)q—OC(O)OQ5, —C(O)(CH2)v—OC(O)OQ5, —(CH2)q—OC(O)NQ5Q6, —C(O)(CH2)v—OC(O)NQ5Q6, —(C(O))w(CH2)v—C(O)NQ5Q6, —(C(O))w(CH2)v—C(O)ONQ5, —(C(O))w(CH2)v—C(O)NHOQ5, —(C(O))w(CH2)v—C(O)NH—NHQ5, —(C(O))w(CH2)v—C(O)O—NHQ5, —(CH2)q—NHC(O)Q5, —C(O)(CH2)v—NHC(O)Q5, —(CH2)qNHS(O)2Q5, —C(O)(CH2)vNHS(O)2Q5, —(CH2)qNHS(O)2NQ5Q6, —C(O)(CH2)vNHS(O)2NQ5Q6, (CH2)q—NHC(O)OQ5, —C(O)(CH2)v—NHC(O)OQ5, —(CH2)q—NHC(O)NQ5Q6, —C(O)(CH2)v—NHC(O)NQ5Q6, —(CH2)qNQ5Q6, —C(O)(CH2)vNQ5Q6, —(CH2)q—NH—C(NHQ3)═NQ4, —C(O)(CH2)v—NH—C(NHQ3)═NQ4, (CH2)q—NH—CH═NQ3, —C(O)(CH2)v—NH—CH═NQ3, —(C(O))w(CH2)v—C(NHQ3)═NQ4, —C(O)NQ5Q6, and —C(NHQ3)═NQ4; or
R2, identical or different, is independently selected from the group consisting of (C(O))w—C1-C3-alkyl that is optionally substituted by one or more T2, (C(O))w—C1-C3-fluoroalkyl that is optionally substituted by one or more T2, (C(O))w(CH2)p—C3-C6-cycloalkyl that is optionally substituted by one or more T2, —(C(O))w—(CH2)p—C3-C6-cyclofluoroalkyl that is optionally substituted by one or more T2, and —(C(O))w—(CH2)p-(4- or 5- or 6-member aromatic or saturated or totally unsaturated or partially unsaturated heterocycle) that is optionally substituted by one or more T2;
R3 is selected from the group consisting of SO3H, CFHCO2H, and CF2CO2H;
Q1 and Q2 are one of the following:
Q1 and Q2, identical or different, are independently selected from the group consisting of H, —(CH2)qNHQ3, —(CH2)q—NH—C(NHQ3)═NQ4, (CH2)q—NH—CH═NQ3, (CH2)v—C(NHQ3)═NQ4, —(CH2)qOQ3, and —(CH2)vCONHQ3; or
Q1 and Q2, identical or different, are independently elected from the group consisting of a C1-C3 alkyl optionally substituted by one or more T2 and —(CH2)p-(4- or 5- or 6-member heterocycle) optionally substituted by one or more T2; or
Q1 and Q2 and the nitrogen atom to which they are bonded, form a saturated or partially unsaturated 4- or 5- or 6-member heterocycle comprising 1 or 2 or 3 or 4 heteroatoms;
Q3 and Q4, identical or different, are independently selected from the group consisting of H and a C1-C3 alkyl;
Q5 and Q6 are one of the following:
Q5 and Q6, identical or different, are independently selected from the group consisting of H, —(CH2)qNHQ3, —(CH2)q—NH—C(NHQ3)═NQ4, (CH2)q—NH—CH═NQ3, (CH2)v —C(NHQ3)═NQ4, —(CH2)qOQ3; and —(CH2)vCONHQ3; or
Q5 and Q6, identical or different, are independently selected from the group consisting of a C1-C4 alkyl optionally substituted by one or more T2 and —(CH2)p-(4- or 5- or 6-member heterocycle) optionally substituted by one or more T2; or
Q5 and Q6 and the nitrogen atom to which they are bonded form a saturated or partially unsaturated 4- or 5- or 6-member heterocycle comprising 1 or 2 or 3 or 4 heteroatoms;
T1 is one of the following:
T1, identical or different, is independently selected from the group consisting of F, —(CH2)pOQ1, —(CH2)p—CN, —(CH2)pOC(O)Q1, —(CH2)p—C(O)OQ1, —(CH2)p—OC(O)OQ1, (CH2)p—OC(O)NHQ1, —(CH2)p—C(O)NHQ1, —(CH2)p—C(O)NHOQ1, —CH2)p—C(O)NH—NHQ1, —(CH2)p—C(O)O—NHQ1, —(CH2)p—NHC(O)Q1, —(CH2)pNHS(O)2Q1, —(CH2)pNHS(O)2NQ1Q2, —(CH2)p—NHC(O)OQ1, —(CH2)p—NHC(O)NQ1Q2, —(CH2)pNHQ1, —(CH2)p—NH—C(NHQ3)═NQ4, —(CH2)pNH—CH═NQ3, and (CH2)p—C(NHQ3)═NQ4; or
T1, identical or different, is independently selected from the group consisting of C1-C3 alkyl optionally substituted by one or more T2, C1-C3 fluoroalkyl optionally substituted by one or more T2, O—C1-C3-fluoroalkyl optionally substituted by one or more T2, and —(CH2)p-(4- or 5- or 6-member heterocycle comprising at least one nitrogen atom that is aromatic or saturated or totally unsaturated or partially unsaturated) optionally substituted by one or more T2;
T2, identical or different, is independently selected from the group consisting of OH, NH2, and CONH2;
T, identical or different, is independently selected from the group consisting of F, C1-C3 alkyl, C1-C3 fluoroalkyl, O—C1-C3 fluoroalkyl, -(L)w-(CH2)p—C3-C6 cycloalkyl; -(L)w-(CH2)p—C3-C6 cyclofluoroalkyl, -(L)w-(CH2)p-heterocycle, -(L)w-(CH2)p—CN, -(L)w-(CH2)pOC(O)Q5, -(L)w-(CH2)p—C(O)OQ5, -(L)w-(CH2)pOC(O)OQ5, -(L)w-(CH2)p—OC(O)NQ5Q6, -(L)w-(CH2)p—C(O)NQ5Q6, -(L)w-(CH2)p—C(O)NQ5OQ6, -(L)w-(CH2)p—C(O)NQ5—NQ5Q6, -(L)w-(CH2)p—NQ5C(O)Q6, -(L)w-(CH2)pNQ5Q(O)2Q6, -(L)w-(CH2)p—NQ5C(O)OQ6, -(L)w-(CH2)p—NQ5C(O)NQ5Q6, -(L)w-(CH2)pNQ5Q6, -(L)w-(CH2)p—NH—C(NHQ3)═NQ4, -(L)w-(CH2)p—NH—CH═NQ3, and -(L)w(CH2)p—C(NHQ3)═NQ4;
L, identical or different, is independently selected from the group consisting of O, S, N(R2), S(O), and S(O)2;
m is 1 or 2;
n is 0, 1, or 2;
p, identical or different, is independently selected from the group consisting of 0, 1, 2, and 3;
q, identical or different, is independently selected from the group consisting of 2 and 3;
v, identical or different, is independently selected from the group consisting of 1, 2, and 3;
w, identical or different, is independently selected from the group consisting of 0 and 1;
wherein any carbon atom present within any of the foregoing alkyls, cycloalkyls, fluoroalkyls, cyclofluoroalkyls, and heterocycles can be oxidized to form a C═O group;
wherein any sulphur atom present within a heterocycle can be oxidized to form a S═O group or a S(O)2 group; and
wherein any nitrogen atom present within a heterocycle or a tertiary amino group can be further quaternized by a methyl group; or
a pharmaceutically acceptable salt, a zwitterion, a racemate, a diastereoisomer, an enantiomer, a geometric isomer, or a tautomer of formula (I).

### Claim 2 (depends on 1)

The compound according to claim 1 selected from the group consisting of compounds of formulae (A), (B), (I*), (A*), and (B*)

### Claim 3 (depends on 1)

The compound according to claim 1 selected from group consisting of compounds of formulae (A1) to (A68) and (B1) to (B8)

### Claim 4 (depends on 1)

The compound according to claim 1, wherein R1 is one of the following:
R1 is selected from the group consisting of a carbon-linked 4-, 5- or 6-membered heterocycle comprising at least one nitrogen atom that is aromatic or saturated or totally unsaturated or partially unsaturated and optionally substituted by one or more T1, H,—CN; —C(O)NHQ1; —C(O)NHOQ1; —C(O)NH—NHQ1; —(CH2)OQ1; and C(O)OQ1; or
R1 is selected from the group consisting of —(CH2)NHQ3 and —(CH2)NH—C(NHQ3)═NQ4.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein R1 is one of the following:
R1 is selected from the group consisting of —CN; C(O)NHQ1, —C(O)NHOQ1, and —C(O)NH—NHQ1; or
R1 is selected from the group consisting of —(CH2)m—OQ1, —(CH2)m—NHC(O)Q1, —(CH2)m—NHC(O)OQ1, and —(CH2)m—NHC(O)NQ1Q2; or
R1 is a carbon-linked 4- or 5- or 6-member heterocycle comprising at least one nitrogen atom that is saturated or partially unsaturated or totally unsaturated or aromatic and optionally substituted by one or more T1 and further comprises one or two or three additional heteroatoms wherein each additional heteroatom is selected from the group consisting of N, O, S, S(O), and S(O)2; or
R1 is H.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein:
R2 is selected from the group consisting of —(CH2)qNQ5Q6, —C(O)(CH2)vNQ5Q6, —(CH2)q—NH—C(NHQ3)═NQ4, C(O)NQ5Q6, —(C(O))w(CH2)v—C(NHQ3)═NQ4, —C(NHQ3)═NQ4, —(C(O))w(CH2)v—C(O)NQ5Q6, —(C(O))w—(CH2)p-(4- or 5- or 6-member heterocycle that is aromatic or saturated or totally unsaturated or partially unsaturated), —(CH2)qNHS(O)2NQ5Q6; —C(O)(CH2)vNHS(O)2NQ5Q6; —(CH2)qNHC(O)NQ5Q6; —C(O)(CH2)vNHC(O)NQ5Q6; —(C(O))w(CH2)v—C(O)OQ5; (C(O))w—C1-C3 alkyl; —(CH2)q—NHC(O)OQ5; —C(O)(CH2)v—NHC(O)OQ5; (CH2)qOQ5, and —C(O)(CH2)vOQ5; and
Q5 and Q6, identical or different, are independently selected from the group consisting of H, (CH2)q, NHQ3, and C1-C4-alkyl.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein:
R2 is selected from the group consisting of —(CH2)p-(4- or 5- or 6-member heterocycle that is aromatic or saturated or totally unsaturated or partially unsaturated), C1-C3 alkyl, —(CH2)v—C(O)OQ5; —(CH2)q—NHC(O)OQ5; —(CH2)qNQ5Q6, —(CH2)qOQ5, and —(CH2)vC(O)NH(CH2)qNHQ3;
Q5 and Q6, identical or different, are independently selected from the group consisting of H and C1-C4alkyl; and
Q3 is H.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein:
R1 is one of the following:
R1 is selected from the group consisting of H, a carbon-linked 4- or 5- or 6-member heterocycle comprising at least one nitrogen atom that is aromatic or saturated or totally unsaturated or partially unsaturated and optionally substituted by one or more T1, —CN, —C(O)NHQ1, —C(O)NHOQ1, —C(O)NH—NHQ1; —(CH2)OQ1, and —C(O)OQ1; or
R1 is selected from the group consisting of —(CH2)NHQ3 and —(CH2)NH—C(NHQ3)═NQ4; or
R1 is selected from the group consisting of H, a carbon-linked 4- or 5- or 6-member heterocycle comprising at least one nitrogen atom that is aromatic or saturated or totally unsaturated or partially unsaturated and optionally substituted by one or more T1, —CN; —C(O)NHQ1, —C(O)NHOQ1, —C(O)NH—NHQ1, —C(O)OQ1, —(CH2)OQ1, —(CH2)NHQ3, —(CH2)2NHQ3, —(CH2)NH—C(NHQ3)═NQ4, —(CH2)2NH—C(NHQ3)═NQ4, —(CH2)NH—CH═NQ3, —(CH2)2NH—CH═NQ3, and —C(NHQ3)═NQ4,
Q1 is H or methyl;
Q3 and Q4 are H;
R3 is SO3H;
W, unsubstituted or substituted by one or more T, is a non-aromatic, unsaturated 5-member heterocycle comprising at least one N—R2 group and a (X)n group;
R2 is selected from the group consisting of (C(O))w—C1-C3alkyl, (C(O))w—(CH2)v—C(O)OQ5, —(CH2)q—NH—C(NHQ3)═NQ4, —(C(O))w(CH2)v—C(O)NQ5Q6, (C(O))w—(CH2)qNQ5Q6, —C(O)(CH2)vNHC(O)NQ5Q6, (C(O))w—(CH2)qOQ5, (C(O))w—(CH2)q—NHC(O)OQ5, and —(C(O))w—(CH2)p-(4- or 5- or 6-member heterocycle that is aromatic or saturated or totally unsaturated or partially unsaturated);
Q5 and Q6, identical or different, are H or C1-C4alkyl;
w is 0; and
X is S.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein:
R1 is H;
R3 is SO3H;
W, unsubstituted or substituted by one or more T, is a non-aromatic, unsaturated 5-member heterocycle comprising at least one N—R2 group and a (X)n group;
R2 is selected from the group consisting of —(CH2)p-(4- or 5- or 6-member heterocycle that is aromatic or saturated or totally unsaturated or partially unsaturated), C1-C3 alkyl, —(CH2)v—C(O)OQ5, —(CH2)q—NHC(O)OQ5, —(CH2)qNQ5Q6, —(CH2)qOQ5, and —(CH2)qC(O)NQ5Q6;
Q5 and Q6, identical or different, are H or C1-C4alkyl; and
X is S.

### Claim 10 (depends on 1)

The compound according to claim 1 selected from the group consisting of
wherein PG, is a protective group.

### Claim 11 (depends on 1)

The compound according to claim 1 selected from the group consisting of
wherein PG is a protective group selected from the group consisting of allyl, benzyl, tertbutyldimethylsilyl (TBDMS), and tert-butoxycarbonyl (Boc).

### Claim 12 (depends on 1)

A pharmaceutical composition comprising at least one compound according to claim 1.

### Claim 13 (depends on 12)

The pharmaceutical composition according to claim 12 further comprising a an antibacterial compound selected from the group consisting of selected from aminoglycosides, β-lactams, glycylcyclines, tetracyclines, quinolones, fluoroquinolones, glycopeptides, lipopeptides, macrolides, ketolides, lincosamides, streptogramins, oxazolidinones, polymyxins and combinations thereof.

### Claim 14 (depends on 12)

The pharmaceutical composition according to claim 12, wherein the antibacterial compound is β-lactams selected from the group consisting penicillin, cephalosporins, penems, carbapenems, monobactam, and combinations thereof.

### Claim 15 (depends on 12)

The pharmaceutical composition according to claim 12 further comprising ceftazidime.

### Claim 16 (depends on 12)

The pharmaceutical composition according to claim 12 further comprising a pharmaceutically acceptable excipient.

### Claim 17 (depends on 11)

A kit comprising a pharmaceutical composition according to claim 11 and at least one second composition according to claim 11.

### Claim 18 (depends on 17)

The kit according to claim 17 further comprising ceftazidime.

### Claim 19 (depends on 1)

A method for the treatment of bacterial infections comprising the administration of a therapeutically effective amount of the compound of claim 1.

### Claim 20 (depends on 19)

The method according to claim 19, wherein the bacterial infection is caused by bacteria producing one or more beta-lactamases.

### Claim 21 (depends on 19)

A method according to claim 19, wherein the bacterial infection is caused by gram-negative bacteria.