# US 11,299,467 B2 · Chemical compounds

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- Number: US 11,299,467 B2
- Document ID: US11299467B2
- Status: Granted
- Kind: B2
- Application number: 16/631,218
- Filed: 2018-07-20
- Published: 2020-10-29
- Granted: 2022-04-12
- Earliest claimed: 2017-07-21
- Assignees: Antabio SAS
- Applicants: Antabio SAS
- Inventors: David Thomas Davies; Simon Leiris; Nicolas Sprynski; Martin Everett; Magdalena Zalacain
- Web page: https://patentgrep.com/patent/US11299467B2

## CPC

- C07D 277/587: with aliphatic hydrocarbon radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms, said aliphatic radicals being substituted in the alpha-position to the ring by a hetero atom, e.g. [IMAGE cpc-sch-C07D-1029.gif] with m >= 0, Z being a singly or a doubly bound hetero atom
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- A61K 31/426: 1,3-Thiazoles
- A61K 31/427: not condensed and containing further heterocyclic rings
- A61K 31/439: the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46)
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 31/04: Antibacterial agents
- C07D 277/30: Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- A61K 31/407: condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- 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)
- 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
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The invention relates to a compound which is a thiazole derivative of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, Formula (A), Z, L, X, m, n and p are as defined herein. The compounds are useful in the treatment and prevention of bacterial infection. The invention also relates to combinations of the compound of Formula (I) with further active agents.

## Claims

### Claim 1

A compound of Formula (I), or a pharmaceutically acceptable salt thereof,
wherein
R1 is selected from H, R1a and —CH2OC(O)R1a, wherein R1a is selected from an unsubstituted C1 to C4 alkyl group and phenyl;
{circle around (A)} is a cyclic group selected from C6 to C10 aryl and 5- to 10-membered heteroaryl;
each R2 is independently selected from:
(i) halo or R8;
(ii) C1-3 alkyl, O(C1-3 alkyl), S(C1-3 alkyl), SO(C1-3 alkyl) or SO2(C1-3 alkyl), any of which may optionally be substituted with 1, 2 or 3 halo substituents and/or one R′substituent; and
(iii) NRaC(O)Rc, and NRaC(O)NRbRc, wherein each Ra and Rb is independently selected from hydrogen and unsubstituted C1-2 alkyl and each Rc is unsubstituted C1-2 alkyl;
and
each R8 is independently selected from CN, OH, —C(O)NRfRg, —NRfRg, —NR10C(NR11)R12, —C(NR10)NR11R12, and —NR10C(NR11)NR12R13; wherein each of Rf and Rg is independently H or unsubstituted C1-2 alkyl;
m is 0, 1, 2 or 3
R3 is selected from hydrogen and a C1 to C3 alkyl group which is unsubstituted or is substituted with 1, 2 or 3 substituents selected from halogen, —OR10, and —NR10R11;
n is 0 or 1
Z is a bond or is selected from —NR10C(O)—, —C(O)NR10—, —NR10C(O)NR11—, —NR10C(O)O—, —OC(O)NR10, —NR10C(O)S—, —SC(O)NR10, —NR10C(NR11)—, —C(NR10)NR11—, —NR10C(NR11)NR12—, —NR10C(N+R11R12)—, —C(N+R10R11)NR12—, —NR10C(N+R11R12)NR13—, —NR10C(NR11)O—, —OC(NR10)NR11, —NR10C(N+R11R12)O—, —OC(N+R10R11)NR12—, —NR10C(NR11)S—, —SC(NR10)NR11, —NR10C(N+R11R12)S—, —SC(N+R10R11)NR12—, —C(O)NR15—, —NR10C(O)NR15—, —OC(O)NR15, —SC(O)NR15, —C(NR10)NR15—, —NR10C(NR11)NR15—, —C(N+R10R11)NR15—, —NR10C(N+R11R12)NR15—, —OC(NR10)NR15, —OC(N+R10R11)NR15—, —SC(NR10)NR15, and —SC(N+R10R11)NR15—;
L is a bond or is selected from C1-4 alkylene, C2-4 alkenylene, C2-4 alkynylene, C1-3 alkylene-(C3-6cycloalkylene)-C1-3 alkylene, C1-4 alkylene-(C3-6cycloalkylene) and (C3-6cycloalkylene)-C1-4 alkylene, wherein L is unsubstituted or is substituted with 1 or 2 substituents selected from halogen, —OR10, and —NR10R11; or L is —C(R10)═N—;
X is a bond or, when L is other than a bond or —C(R10)═N—, X is a bond or is selected from —NR10—, —O—, —NR10C(NR11)—, and —C(NR10)—;
p is 0 or 1;
R4 is selected from H, —CN and C1 to C3 alkyl which is unsubstituted or is substituted with 1, 2 or 3 substituents selected from halogen, —OR10, —NR10R11, and —CN;
R5 is selected from H, —CN and C1 to C3 alkyl which is unsubstituted or is substituted with 1, 2 or 3 substituents selected from halogen, —OR10, —NR10R11, and —CN;
R6 is selected from H, —CN and C1 to C3 alkyl which is unsubstituted or is substituted with 1, 2 or 3 substituents selected from halogen, —OR10, —NR10R11, and —CN;
R7 if present is selected from H, —CN and C1 to C3 alkyl which is unsubstituted or is substituted with 1, 2 or 3 substituents selected from halogen, —OR10, —NR10R11, and —CN;
each R10, R11, R12, and R13 is independently H or methyl;
each R15 is independently substituted C1 to C4 alkyl or unsubstituted C2 to C4 alkyl, wherein when R15 is a substituted C1 to C4 alkyl group, the alkyl group is substituted with 1, 2 or 3 substituents independently selected from halogen, CN, OR10 and —NR10R11.

### Claim 2 (depends on 1)

The compound according to claim 1 wherein R1 is H.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein {circle around (A)} is a cyclic group selected from phenyl and 5- to 6-membered heteroaryl.

### Claim 4 (depends on 1)

The compound according to claim 1 wherein {circle around (A)} is selected from phenyl, pyridazine, pyridine and thiazole.

### Claim 5 (depends on 1)

The compound according to claim 1 wherein each R2 is independently selected from:
(i) halo, CN, OH, —C(O)NRfRg, or —NRfRg; wherein each of Rf and Rg is independently H or methyl; and
(ii) C1-2 alkyl, O(C1-2 alkyl), S(C1-2 alkyl), or SO(C1-2 alkyl); any of which may optionally be substituted with 1, 2 or 3 halo substituents and/or one substituent selected from CN and OH.

### Claim 6 (depends on 1)

The compound according to claim 1 wherein R3 is H.

### Claim 7 (depends on 1)

The compound according to claim 1 wherein n is 0.

### Claim 8 (depends on 1)

The compound according to claim 1 wherein Z is a bond or is selected from —NR10C(O)—, —C(O)NR10—, —NR10C(O)NR11—, —NR10C(O)O—, —OC(O)NR10, —NR10C(O)S—, —SC(O)NR10, —NR10C(NR11)—, —C(NR10)NR11—, and —NR10C(NR11)NR12—.

### Claim 9 (depends on 1)

The compound according to claim 1 wherein Z is selected from —NR10C(O)—, —C(O)NR10—, and —NR10C(O)NR11—.

### Claim 10 (depends on 1)

The compound according to claim 1 wherein L is a bond or is selected from C1-4 alkylene, C2-4 alkenylene, and C2-4 alkynylene;
or L is —C(R10)═N—.

### Claim 11 (depends on 1)

The compound according to claim 1 wherein L is selected from C1-3 alkylene and C2-3 alkenylene.

### Claim 12 (depends on 1)

The compound according to claim 1 wherein X is a bond.

### Claim 13 (depends on 1)

The compound according to claim 1 wherein p is 1 and R7 is H or methyl.

### Claim 14 (depends on 1)

The compound according to claim 1 wherein R4 is H.

### Claim 15 (depends on 1)

The compound according to claim 1 wherein R5 is selected from H, —CN and C1 to C2 alkyl which is unsubstituted or is substituted with 1, 2 or 3 halo substituents and/or one —NR10R11 substituent and R6 is H or methyl.

### Claim 16 (depends on 1)

The compound according to claim 1 wherein:
R1 is H; {circle around (A)} is a cyclic group selected from phenyl and 5- to 6-membered heteroaryl;
m is 0, 1 or 2;
each R2 is independently selected from:
halo or R8;
C1-2 alkyl, O(C1-2 alkyl), S(C1-2 alkyl), SO(C1-2 alkyl) or SO2(C1-2 alkyl), any of which may optionally be substituted with 1, 2 or 3 halo substituents and/or one R8 substituent; and
NRaC(O)Rc, and NRaC(O)NRbRc, wherein each Ra and Rb is independently selected from hydrogen and unsubstituted C1-2 alkyl and each Rc is unsubstituted C1-2 alkyl;
each R8 is independently selected from CN, OH, —C(O)NRfRg, and —NRfRg; wherein each of Rf and Rg is independently H or unsubstituted C1-2 alkyl;
n is 0; or n is 1 and R3 is H
Z is selected from —NR10C(O)—, —C(O)NR10—, —NR10C(O)NR11—, —NR10C(O)O—, —OC(O)NR10, —NR10C(O)S—, —SC(O)NR10, —NR10C(NR11)—, —C(NR10)NR11—, and —NR10C(NR11)NR12—;
L is a bond or is selected from C1-4 alkylene, C2-4 alkenylene and C2-4 alkynylene; or L is —C(R10)═N—;
X is a bond;
i) p is 0;
R4 is H and R5 is selected from H, —CN and C1 to C2 alkyl which is unsubstituted or is substituted with 1, 2 or 3 halo substituents and/or one —NR10R11 substituent; and
R6 is H or methyl;
or
ii) p is 1; and
R4 is H; R5 is selected from H, —CN and C1 to C2 alkyl which is unsubstituted or is substituted with 1, 2 or 3 halo substituents and/or one —NR10R11 substituent; R6 is H or methyl and R7 is H or methyl.

### Claim 17 (depends on 1)

The compound according to claim 1 wherein:
R1 is H; {circle around (A)} is selected from phenyl, pyridazine, pyridine and thiazole;
m is 1 or 2;
each R2 is independently selected from:
or
halo, CN, OH, —C(O)NRfRg, or —NRfRg; wherein each of Rf and R9 is independently H or methyl; and
C1-2 alkyl, O(C1-2 alkyl), S(C1-2 alkyl), or SO(C1-2 alkyl); any of which may optionally be substituted with 1, 2 or 3 substituents selected from halo, CN, OH;
n is 0;
Z is selected from —NR10C(O)—, —C(O)NR10—, and —NR10C(O)NR11—;
L is selected from C1-3 alkylene and C2-3 alkenylene;
X is a bond;
p is 0; or p is 1 and R7 is H;
R4 is H;
R5 is selected from H, —CN and C1 to C2 alkyl which is unsubstituted or is substituted with 1, 2 or 3 halo substituents and/or one —NR10R11 substituent; and
R6 is H.

### Claim 18 (depends on 1)

The compound according to claim 1 wherein R4, R5, R6 and R7 if present are each hydrogen.

### Claim 19 (depends on 1)

The compound according to claim 1, wherein:
R1 is selected from H, R1a and —CH2OC(O)R1a, wherein R1a is selected from an unsubstituted C1 to C4 alkyl group and phenyl;
{circle around (A)} is phenyl;
m is 2;
each R2 is independently a halo group;
n is 0;
Z is —NR10C(O)NR11—;
L is a bond;
X is a bond;
p is 1;
R7 is H;
R4 is H;
R5 is H;
R6 is H; and
R10 and R11 are each H.

### Claim 20 (depends on 1)

The compound according to claim 1, which compound is selected from:
5-[[4-[(2-guanidinoacetyl)amino]-3-(trifluoromethoxy)phenyl]sulfonylamino] thiazole-4-carboxylic acid;
5-[[3-fluoro-4-[[(2-guanidinoacetyl)amino]methyl]phenyl]sulfonylamino]thiazole-4-carboxylic acid;
5-[[3-fluoro-4-(guanidinomethyl)phenyl]sulfonylamino]thiazole-4-carboxylic acid;
5-[[3-fluoro-4-(2-guanidinoethylsulfanylcarbonylamino)phenyl]sulfonylamino] thiazole-4-carboxylic acid;
5-[[4-[2-[(2-amino-2-imino-ethyl)amino]-2-oxo-ethyl]-3-fluoro-phenyl]sulfonylamino]thiazole-4-carboxylic acid;
5-[[3-carbamoyl-4-[(2-guanidinoacetyl)amino]phenyl]sulfonylamino]thiazole-4-carboxylic acid;
5-[[3-cyano-4-[(2-guanidinoacetyl)amino]phenyl]sulfonylamino]thiazole-4-carboxylic acid;
5-[[3-fluoro-4-(2-guanidinoethoxycarbonylamino)phenyl]sulfonylamino]thiazole-4-carboxylic acid;
5-[(4-guanidinophenyl)sulfonylamino]thiazole-4-carboxylic acid;
5-[[4-[2-(2-carbamimidoylhydrazino)-2-oxo-ethyl]-3-fluoro-phenyl]sulfonylamino]thiazole-4-carboxylic acid;
5-[[3-chloro-4-[(2-guanidinoacetyl)amino]phenyl]sulfonylamino]thiazole-4-carboxylic acid;
5-[[4-[(2-guanidinoacetyl)amino]-3-methoxy-phenyl]sulfonylamino]thiazole-4-carboxylic acid;
5-[[4-[[2-(2-carbamimidoylhydrazino)acetyl]amino]-3-fluoro-phenyl]sulfonylamino]thiazole-4-carboxylic acid;
5-[[4-[[(2E)-2-(carbamimidoylhydrazono)acetyl]amino]-3-fluoro-phenyl]sulfonylamino]thiazole-4-carboxylic acid;
5-[[4-[[2-(4,5-dihydro-1H-imidazol-2-ylamino)acetyl]amino]-3,5-difluoro-phenyl]sulfonylamino]thiazole-4-carboxylic acid;
5-[[6-[(2-guanidinoacetyl)amino]pyridazin-3-yl]sulfonylamino]thiazole-4-carboxylic acid;
5-[[4-[(2-amino-2-imino-ethyl)carbamoylamino]-3-fluoro-phenyl]sulfonylamino]thiazole-4-carboxylic acid;
5-[[4-[(3-amino-3-imino-propanoyl)amino]-3,5-difluoro-phenyl]sulfonylamino] thiazole-4-carboxylic acid;
5-[[4-[[3-(dimethylamino)-3-imino-propanoyl]amino]-3-fluoro-phenyl]sulfonylamino]thiazole-4-carboxylic acid;
5-[[3-fluoro-4-[(2-guanidinooxyacetyl)amino]phenyl]sulfonylamino]thiazole-4-carboxylic acid;
5-[[3-fluoro-4-[[3-imino-3-(methylamino)propanoyl]amino]phenyl]sulfonylamino]thiazole-4-carboxylic acid;
5-[[4-[3-(4,5-dihydro-1H-imidazol-2-yl)propanoylamino]-3-fluoro-phenyl]sulfonylamino]thiazole-4-carboxylic acid;
5-[[2-[(2-guanidinoacetyl)amino]thiazol-5-yl]sulfonylamino]thiazole-4-carboxylic acid;
5-[[4-[[2-[(N-cyanocarbamimidoyl)amino]acetyl]amino]-3-fluoro-phenyl]sulfonylamino]thiazole-4-carboxylic acid;
5-[[3-fluoro-4-(guanidinocarbamoylamino)phenyl]sulfonylamino]thiazole-4-carboxylic acid;
5-[[3-fluoro-4-[[2-(morpholine-4-carboximidoylamino)acetyl]amino]phenyl]sulfonylamino]thiazole-4-carboxylic acid;
5-[[4-[(3-amino-3-imino-2-methyl-propanoyl)amino]-3-fluoro-phenyl]sulfonylamino]thiazole-4-carboxylic acid;
5-[[4-[[2-(4,5-dihydro-1H-imidazol-2-yl)acetyl]amino]-3-fluoro-phenyl]sulfonylamino]thiazole-4-carboxylic acid;
5-[[4-(carbamimidoylcarbamoylamino)-3-fluoro-phenyl]sulfonylamino]thiazole-4-carboxylic acid;
5-[[4-[[(2R)-2-guanidinopropanoyl]amino]phenyl]sulfonylamino]thiazole-4-carboxylic acid;
5-[[3,5-difluoro-4-[(2-guanidinoacetyl)amino]phenyl]sulfonylamino]thiazole-4-carboxylic acid;
5-[[4-[(4-amino-4-imino-butanoyl)amino]-3-fluoro-phenyl]sulfonylamino]thiazole-4-carboxylic acid;
5-[[4-[[2-(4,5-dihydro-1H-imidazol-2-ylamino)acetyl]amino]-2,5-difluoro-phenyl]sulfonylamino]thiazole-4-carboxylic acid;
5-[[2,5-difluoro-4-[(2-guanidinoacetyl)amino]phenyl]sulfonylamino]thiazole-4-carboxylic acid;
5-[[3-fluoro-4-[[2-[(N-methylcarbamimidoyl)amino]acetyl]amino]phenyl]sulfonylamino]thiazole-4-carboxylic acid;
5-[[3-fluoro-4-[[2-(2-iminoimidazobdin-1-yl)acetyl]amino]phenyl]sulfonylamino]thiazole-4-carboxylic acid;
5-[[4-[[2-[carbamimidoyl(methyl)amino]acetyl]amino]-3-fluoro-phenyl]sulfonylamino]thiazole-4-carboxylic acid;
5-[[4-[[2-[[N-(2-aminoethyl)carbamimidoyl]amino]acetyl]amino]-3-fluoro-phenyl]sulfonylamino]thiazole-4-carboxylic acid;
5-[[5-fluoro-6-[(2-guanidinoacetyl)amino]-3-pyridyl]sulfonylamino]thiazole-4-carboxylic acid;
5-[[3-fluoro-4-(3-guanidinopropanoylamino)phenyl]sulfonylamino]thiazole-4-carboxylic acid;
5-[[4-[(3-amino-3-imino-propanoyl)amino]-3-fluoro-phenyl]sulfonylamino]thiazole-4-carboxylic acid;
5-[[3-fluoro-4-[(2-guanidinoacetyl)amino]phenyl]sulfonylamino]thiazole-4-carboxylic acid; and
5-[[4-[(2-guanidinoacetyl)amino]phenyl]sulfonylamino]thiazole-4-carboxylic acid;
and pharmaceutically acceptable salts thereof.

### Claim 21 (depends on 1)

A pharmaceutical composition comprising the compound according to claim 1 together with at least one pharmaceutically acceptable carrier or diluent.

### Claim 22 (depends on 21)

The pharmaceutical composition according to claim 21 further comprising an antibiotic agent.

### Claim 23 (depends on 22)

The pharmaceutical composition according to claim 22 wherein the antibiotic agent is a β-lactam antibiotic.

### Claim 24 (depends on 23)

The pharmaceutical composition according to claim 23 wherein the β-lactam antibiotic is selected from carbapenems, penicillins, cephalosporins and penems.

### Claim 25 (depends on 23)

The pharmaceutical composition according to claim 23 wherein the β-lactam antibiotic is meropenem.

### Claim 26 (depends on 21)

The pharmaceutical composition according to claim 21 further comprising a serine-β-lactamase inhibitor.

### Claim 27 (depends on 26)

The pharmaceutical composition according to claim 26 wherein the serine-β-lactamase inhibitor is a compound of Formula (II) or a pharmaceutically acceptable salt thereof,
wherein
G is selected from —CN and —C(O)NRjRk;
Rk is selected from —W and -Q-W; wherein W is selected from 5- to 6-membered heterocyclyl, Rj and —N(Rj)2; and Q is selected from —NRjC(O)—, —C(O)—NRj—, C1-3 alkylene, —O—C1-3 alkylene and —N(Rj)—C1-3 alkylene;
each Rj is selected from H and unsubstituted C1-3 alkyl.

### Claim 28 (depends on 26)

The pharmaceutical composition according to claim 26 wherein the serine-β-lactamase inhibitor is selected from WCK4234, avibactam, relebactam, zidebactam and nacubactam, or pharmaceutically acceptable salts thereof.