# US 2018/0022696 A1 · Novel n-acyl-arylsulfonamide derivatives as aminoacyl-trna synthetase inhibitors

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- Number: US 2018/0022696 A1
- Document ID: US20180022696A1
- Status: Published application
- Kind: A1
- Application number: 15/550,839
- Filed: 2016-02-11
- Published: 2018-01-25
- Earliest claimed: 2015-02-13
- Assignees: Latvian Institute of Organic Synthesis
- Applicants: Latvian Institute of Organic Synthesis
- Inventors: Aigars JIRGENSONS; Einars LOZA; Michael CHARLTON; Paul William FINN; Lluis RIBAS DE POUPLANA; Adelaide SAINT-LÉGER
- Web page: https://patentgrep.com/patent/US20180022696A1

## CPC

- C07C 311/51: Y being a hydrogen or a carbon atom
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/00: Drugs for disorders of the urinary system
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 27/02: Ophthalmic agents
- A61P 27/16: Otologicals
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 31/10: Antimycotics
- A61P 33/00: Antiparasitic agents
- C07D 213/71: to which a second hetero atom is attached
- C07D 215/06: having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
- C07D 215/36: Sulfur atoms (C07D215/24 takes precedence)
- C07D 217/04: with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
- C07D 217/22: with hetero atoms or with 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 carbon atoms of the nitrogen-containing ring
- C07D 217/26: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D 239/42: One nitrogen atom (nitro radicals C07D239/30)
- C07D 239/47: One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
- C07D 239/48: Two nitrogen atoms
- C07D 251/22: to two ring carbon atoms
- C07D 311/04: Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D 311/20: hydrogenated in the hetero ring
- C07D 487/04: Ortho-condensed systems
- C07C 2601/02: with a three-membered ring
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention relates to novel N-acyl-diarysulfonamides acting as inhibitors of bacterial aminoacyl-tRNA synthetase. These can be used as medicines or as constituent of medicines for the treatment of bacterial infections.

## Claims

### Claim 1

At least one chemical entity selected from a compound of Formula I:
enantiomers, diastereomers, tautomers or pharmaceutically acceptable salts thereof, wherein:
R1 represents C1-4alkyl;
R2 represents C1-4alkyl or H;
R3 represents C1-4alkyl or H;
R1, R2 or R1, R3 together with the atoms to which they are attached may form one of 3-membered to 6-membered rings;
provided that R2 and R3 are not both hydrogen;
provided that R1, R2 and R3 do not form a cycle together with L1 or L5
L1 is independently C—R4 or N;
L2 is independently C—R5 or N;
L3 is independently C—R6 or N;
L4 is independently C—R7 or N;
L5 is independently C—R8 or N;
R4 is independently H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C5-9heteroaryl, C6-10carboaryl, C3-6cycloalkyl, C1-5heterocyclyl, CN, C(═O)Ra, C(═O)ORa, C(═O)N(Ra)Rb, ORa, OC(═O)Ra, OC(═O)N(Ra)Rb, N(Ra)Rb, N(Ra)S(O)0-2Rb, N(Ra)C(═O)Rb, N(Ra)C(═O)ORb, S(O)0-2Ra, S(O)0-2N(Ra)Rb, wherein said alkyl, alkenyl, alkynyl, carboaryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted by 1 to 5 substituents independently selected from ORa, N(Ra)Rb, oxo, halo, S(O)0-2Ra and S(O)0-2N(Ra)Rb;
R5 is independently H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C5-9heteroaryl, C6-10carboaryl, C3-6cycloalkyl, C1-5heterocyclyl, CN, C(═O)Ra, C(═O)ORa, C(═O)N(Ra)Rb, ORa, OC(═O)Ra, OC(═O)N(Ra)Rb, S(O)0-2Ra, S(O)0-2N(Ra)Rb, wherein said alkyl, alkenyl, alkynyl, carboaryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted by 1 to 5 substituents independently selected from ORa, N(Ra)Rb, oxo, halo, S(O)0-2Ra and S(O)0-2N(Ra)Rb; or
R4 and R5 taken together with the atoms to which they are attached form a C4-6heterocyclic ring, C4-6 carbocyclic ring, C6 aromatic ring or C5-6heteroaromatic ring optionally substituted by halogen, C(═O)N(Ra)Rb, oxo, ORa, N(Ra)Rb or C1-3alkyl;
R6 is independently H, halo, C2-6alkyl, C2-6alkenyl, C2-6alkynyl, C5-9heteroaryl, C6-10carboaryl, C3-6cycloalkyl, C1-5heterocyclyl, CN, C(═O)Ra, C(═O)ORa, C(═O)N(Ra)Rb, ORa, OC(═O)Ra, OC(═O)N(Ra)Rb, S(O)0-2Ra, S(O)0-2N(Ra)Rb, wherein said alkyl, alkenyl, alkynyl, carboaryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted by 1 to 5 substituents independently selected from ORa, N(Ra)Rb, oxo, halo, S(O)0-2Ra and S(O)0-2N(Ra)Rb; or
R5 and R6 taken together with the atoms to which they are attached form a C4-6heterocyclic ring, C4-6 carbocyclic ring, C6 aromatic ring or C5-6heteroaromatic ring optionally substituted by halogen, C(═O)N(Ra)Rb, oxo, ORa, N(Ra)Rb or C1-3alkyl;
R7 is independently H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C5-9heteroaryl, C6-10carboaryl, C3-6cycloalkyl, C1-5heterocyclyl, CN, C(═O)Ra, C(═O)ORa, C(═O)N(Ra)Rb, ORa, OC(═O)Ra, OC(═O)N(Ra)Rb, S(O)0-2Re, S(O)0-2N(Ra)Rb, wherein said alkyl, alkenyl, alkynyl, carboaryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted by 1 to 5 substituents independently selected from ORa, N(Ra)Rb, oxo, halo, S(O)0-2Ra and S(O)0-2N(Ra)Rb
R8 is independently H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C5-9heteroaryl, C6-10carboaryl, C3-6cycloalkyl, C1-5heterocyclyl, CN, C(═O)Ra, C(═O)ORa, C(═O)N(Ra)Rb, ORa, OC(═O)Ra, OC(═O)N(Ra)Rb, N(Ra)Rb, N(Ra)S(O)0-2Rb, N(Ra)C(═O)Rb, N(Ra)C(═O)ORb, S(O)0-2Ra, S(O)0-2N(Ra)Rb, wherein said alkyl, alkenyl, alkynyl, carboaryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted by 1 to 5 substituents independently selected from ORa, N(Ra)Rb, oxo, halo, S(O)0-2Ra and S(O)0-2N(Ra)Rb;
Ra and Rb are independently H, C1-6alkyl, C5-6heteroaryl or C6carboaryl, wherein each alkyl, heteroaryl or aryl are optionally substituted by 1 to 3 substituents selected from oxo, halo, NH2, OH.

### Claim 2 (depends on 1)

A compound according to claim 1, wherein R1 is methyl, R2 is methyl and R3 is H.

### Claim 3 (depends on 1)

A compound according to claim 1 wherein R1 is Methyl, R2 is H and R3 is methyl.

### Claim 4 (depends on 1, 2, 3)

A compound according to any of claims 1 to 3, wherein, the radical
is pyridyl, quinolyl, isoquinolyl, naphthyl, benzopyranyl, tetrahydroisoquinolyl, optionally substituted with 1 to 4 substituents selected from halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C5-9heteroaryl, C6-10carboaryl, C3-6cycloalkyl, C1-5heterocyclyl, CN, C(═O)Rc, C(═O)ORc, C(═O)N(Rc)Rd, ORc, OC(═O)Rc, OC(═O)N(Rc)Rc, S(O)0-2Rc, S(O)0-2N(Rc)Rd, wherein said alkyl, alkenyl, alkynyl, carboaryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted by 1 to 5 substituents independently selected from ORc, N(Rc)Rd, oxo, halo, S(O)0-2Rc and S(O)0-2N(Rc)Rd;
Rc and Rd are independently H, C1-8alkyl, C3-8cycloalkyl, C5-6heteroaryl or C6-10carboaryl, wherein each alkyl, cycloalkyl, heteroaryl or carboaryl are optionally substituted by 1 to 3 substituents selected from oxo, halo, NH2, OH.

### Claim 5 (depends on 4)

A compound according to claim 4, wherein, the radical
is pyridyl, quinolyl, isoquinolyl, naphthyl, benzopyranyl, tetrahydroisoquinolyl, optionally substituted with 1 to 2 substituents selected from halo, C(═O)N(Re)Rf, ORe; NRe, Rf;
Re and Rf are independently H, C1-8alkyl optionally substituted by 1 to 3 substituents selected from oxo, halo, NH2, OH.

### Claim 6 (depends on 1, 2, 3)

A compound according to any of claims 1 to 3, wherein, the radical:
R9 is independently H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C5-9heteroaryl, C6-10carboaryl, C3-6cycloalkyl, C1-5heterocyclyl, CN, C(═O)Re, C(═O)ORe, C(═O)N(Re)Rf, ORe, OC(═O)Re, OC(═O)N(Re)Rf, N(Re)Rf, N(Re)S(O)0-2Rf, N(Re)C(═O)Rf, N(Re)C(═O)ORf, S(O)0-2Re, S(O)0-2N(Re)Rf, wherein said alkyl, alkenyl, alkynyl, carboaryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted by 1 to 5 substituents independently selected from ORe, N(Re)Rf, oxo, halo, S(O)0-2Re and S(O)0-2N(Re)Rf;
R10 is independently H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C5-9heteroaryl, C6-10carboaryl, C3-6cycloalkyl, C1-5heterocyclyl, CN, C(═O)Re, C(═O)ORe, C(═O)N(Re)Rf, ORe, OC(═O)Re, OC(═O)N(Re)Rf, S(O)0-2Re, S(O)0-2N(Re)Rf, wherein said alkyl, alkenyl, alkynyl, carboaryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted by 1 to 5 substituents independently selected from ORe, N(Re)Rf, oxo, halo, S(O)0-2Re and S(O)0-2N(Re)Rf;
R11 is independently H, halo, C2-6alkyl, C2-6alkenyl, C2-6alkynyl, C5-9heteroaryl, C6-10carboaryl, C3-6cycloalkyl, C1-5heterocyclyl, CN, C(═O)Re, C(═O)ORf, C(═O)N(Re)Rf, ORe, OC(═O)Re, OC(═O)N(Re)Rf, S(O)0-2Re, S(O)0-2N(Re)Rf, wherein said alkyl, alkenyl, alkynyl, carboaryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted by 1 to 5 substituents independently selected from ORe, N(Re)Rf, oxo, halo, S(O)0-2Ra and S(O)0-2N(Ra)Rb;
R12 is independently H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C5-9heteroaryl, C6-10carboaryl, C3-6cycloalkyl, C1-5heterocyclyl, CN, C(═O)Re, C(═O)ORe, C(═O)N(Re)Rf, ORe, OC(═O)Re, OC(═O)N(Re)Rf, S(O)0-2Re, S(O)0-2N(Re)Rf, wherein said alkyl, alkenyl, alkynyl, carboaryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted by 1 to 5 substituents independently selected from ORe, N(Re)Rf, oxo, halo, S(O)0-2Re and S(O)0-2N(Re)Rf;
R13 is independently H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C5-9heteroaryl, C6-10carboaryl, C3-6cycloalkyl, C1-5heterocyclyl, CN, C(═O)Re, C(═O)ORe, C(═O)N(Re)Rf, ORe, OC(═O)Re, OC(═O)N(Re)Rf, N(Re)Rf, N(Re)S(O)0-2Rf, N(Re)C(═O)Rf, N(Re)C(═O)ORf, S(O)0-2Re, S(O)0-2N(Re)Rf, wherein said alkyl, alkenyl, alkynyl, carboaryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted by 1 to 5 substituents independently selected from ORe, N(Re)Rf, oxo, halo, S(O)0-2Re and S(O)0-2N(Re)Rf;
or R9 and R10 taken together with the atoms to which they are attached form a C4-6 heterocyclic ring, C4-6 carbocyclic ring, C6 aromatic ring or C5-6 heteroaromatic ring optionally substituted by halogen, C(═O)N(Re)Rf, oxo, ORe, N(Re)Rf or C1-3alkyl;
or R10 and R11 taken together with the atoms to which they are attached form a C4-6 heterocyclic ring, C4-6 carbocyclic ring, C6 aromatic ring or C5-6 heteroaromatic ring optionally substituted by halogen, C(═O)N(Re)Rf, oxo, ORe, N(Re)Rf or C1-3alkyl;
Re and Rf are independently H, C1-8alkyl, C5-6heteroaryl or C6carboaryl, wherein each alkyl, heteroaryl or carboaryl are optionally substituted by 1 to 3 substituents selected from oxo, halo, NH2, OH.

### Claim 7 (depends on 6)

A compound according to claim 6 wherein R9 is independently H, halo, C1-6alkyl, C6 aryl.

### Claim 8 (depends on 7)

A compound according to claim 7 wherein R9 is independently H, F, Cl, isopropyl or phenyl.

### Claim 9 (depends on 6)

A compound according to claim 6 wherein, R10 is independently H, halo, C5-9heteroaryl, C6-10carboaryl, wherein said heteroaryl and carboaryl are optionally substituted by 1 to 3 substituents independently selected from NH2, NMe2, SMe, methyl, ethyl, halo, OH, OC1-4alkyl, or phenyl.

### Claim 10 (depends on 9)

A compound according to claim 9 wherein, R10 is independently H, halo, pyridyl, pyrimidyl, triazinyl, phenyl or purinyl wherein said heteroaryl and carboaryl are optionally substituted by 1 to 3 substituents independently selected from NH2, NMe2, SMe, methyl, ethyl, halo, OH, OC1-4alkyl, or phenyl.

### Claim 11 (depends on 6)

A compound according to claim 6 wherein R11 is independently H, C1-6alkyl, aryl, O-aryl.

### Claim 12 (depends on 11)

A compound according to claim 11 wherein R11 is independently H, butyl, isopropyl, phenyl, phenoxy.

### Claim 13 (depends on 6)

A compound according to claim 6 wherein, R12 is independently H, halo, C5-9heteroaryl, C6-10carboaryl, wherein said heteroaryl and carboaryl are optionally substituted by 1 to 3 substituents independently selected from NH2, NMe2, SMe, methyl, ethyl, halo, OH, OC1-4alkyl, or phenyl.

### Claim 14 (depends on 13)

A compound according to claim 13 wherein, R12 is independently H, halo, pyridyl, pyrimidyl, triazinyl, phenyl or purinyl wherein said heteroaryl and carboaryl are optionally substituted by 1 to 3 substituents independently selected from NH2, NMe2, SMe, methyl, ethyl, halo, OH, OC1-4alkyl, or phenyl.

### Claim 15 (depends on 6)

A compound according to claim 6 wherein R13 is independently H, C1-6alkyl, aryl, O-aryl.

### Claim 16 (depends on 15)

A compound according to claim 15 wherein R13 is independently H, butyl, isopropyl, phenyl, phenoxy.

### Claim 17 (depends on 6)

A compound according to claim 6 wherein, R9 is independently H, halo, C1-6alkyl, C6-aryl;
R10 is independently H, halo, C5-9heteroaryl, C6-10carboaryl, wherein said heteroaryl and carboaryl are optionally substituted by 1 to 3 substituents independently selected from NH2, NMe2, SMe, methyl, ethyl, halo, OH, OC1-4alkyl, or phenyl;
R11 is independently H, C1-6alkyl, aryl, O-aryl;
R12 is independently H, halo, C5-9heteroaryl, C6-10carboaryl, wherein said heteroaryl and carboaryl are optionally substituted by 1 to 3 substituents independently selected from NH2, NMe2, SMe, methyl, ethyl, halo, OH, OC1-4alkyl, or phenyl;
R13 is independently H, halo, C1-6alkyl, C6-10aryl.

### Claim 18 (depends on 17)

A compound according to claim 17 wherein,
R9 is independently H, F, Cl, isopropyl or phenyl;
R10 is independently H, halo, pyridyl, pyrimidyl, triazinyl, phenyl or purinyl wherein each heteroaryl and carboaryl are optionally substituted by 1 to 3 substituents independently selected from NH2, NMe2, methyl, ethyl, halo, OH, OC1-4alkyl, or phenyl;
R11 is independently H, butyl, isopropyl, phenyl, phenoxy;
R12 is independently H, halo, pyridyl, pyrimidyl, triazinyl, phenyl or purinyl wherein each aryl are optionally substituted by 1 to 3 substituents independently selected from NH2, NMe2, methyl, ethyl, halo, OH, OC1-4alkyl, or phenyl;
R13 is independently H, F, Cl, isopropyl or phenyl.

### Claim 19 (depends on 1)

A compound selected from a list below according to claim 1:
ID
Structure
IK-698
IK-713
IK-718
LL-20
LL-19
EO-99
LL-23
MZ-377
IK-681
DL-23-340
IK-707
IK-719
IK-666
IK-665
DG-500
MZ-335
MZ-343
MZ-368
MZ-370
KS-1189
MZ-375
C-2724
C-2775
IK-603
C-2727
AC-486
DG-459
DG-457
DG-460
IK-656
DG-466
DG-470
IK-685
DG-469
IK-580
IK-617
IK-587
K-615
IK-621
BM-13
IK-625
IK-636
IK-634
IK-635
IK-627
DG-435
DG-437
DG-440
DG-444
DG-445
DG-455
DG-453

### Claim 20 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)

At least one chemical entity according to any of claims 1 to 19 for use in the treatment of infections by bacteria, fungi or parasites.

### Claim 21 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)

At least one chemical entity according to any of claims 1 to 19 for use in the treatment of infectious diseases for example central nervous system infections, external ear infections, infections of the middle ear, such as acute otitis media, infections of the cranial sinuses, eye infections, infections of the oral cavity, such as infections of the teeth, gums and mucosa, upper respiratory tract infections, lower respiratory tract infections, genitourinary infections, gastrointestinal infections, gynecological infections, septicemia, bone and joint infections, skin and skin structure infections, bacterial endocarditis, burns, antibacterial prophylaxis of surgery, and antibacterial prophylaxis in immunosuppressed patients, such as patients receiving cancer chemotherapy, or organ transplant patients.

### Claim 22 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)

At least one chemical entity according to any of claims 1 to 19 for use in the treatment of disorders caused by a variety of bacterial organisms which include but not limited to Gram positive and Gram negative aerobic and anaerobic bacteria.

### Claim 23 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)

At least one chemical entity according to any claims 1 to 19 for use in the treatment of disorder or condition susceptible to mediation by a tRNA synthetase which include but not limited to the treatment of central nervous system infections, external ear infections, infections of the middle ear, such as acute otitis media, infections of the cranial sinuses, eye infections, infections of the oral cavity, such as infections of the teeth, gums and mucosa, upper respiratory tract infections, lower respiratory tract infections, genitourinary infections, gastrointestinal infections, gynecological infections, septicemia, bone and joint infections, skin and skin structure infections, bacterial endocarditis, burns, antibacterial prophylaxis of surgery, and antibacterial prophylaxis in immunosuppressed patients, such as patients receiving cancer chemotherapy, or organ transplant patients.

### Claim 24 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)

At least one chemical entity according to any claims 1 to 19 for the use in the treatment of a human or animal subject suffering from a condition susceptible to mediation by a tRNA synthetase inhibitor.

### Claim 25 (depends on 24)

At least one chemical entity according to claim 24 comprising administering to said human or animal subject an effective amount which range from about 0.1 mg/kg/day to about 5000 mg/kg/day in single or in divided doses.

### Claim 26 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)

At least one chemical entity according to any claims 1 to 19 for use in a method for the treating bacteria, fungi, parasites characterized in that at least one chemical entity is administrated in an effective amount which range from about 0.1 mg/kg/day to about 5000 mg/kg/day in single or in divided doses.

### Claim 27 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)

A pharmaceutical composition comprising at least one chemical entity according to any one of claims 1 to 19 in admixture with one or more pharmaceutically acceptable carrier and/or excipient.