# US 11,440,887 B2 · Substituted 1,2,3,4-tetrahydroquinolines as inhibitors of repair enzyme 8-oxoguanine deoxyribonucleic acid glycosylase activity

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- Number: US 11,440,887 B2
- Document ID: US11440887B2
- Status: Granted
- Kind: B2
- Application number: 16/637,594
- Filed: 2018-08-07
- Published: 2020-06-18
- Granted: 2022-09-13
- Earliest claimed: 2017-08-07
- Assignees: The Board of Trustees of the Leland Stanford Junior University
- Applicants: The Board of Trustees of the Leland Stanford Junior University
- Inventors: Eric T. Kool; Yuki Tahara
- Web page: https://patentgrep.com/patent/US11440887B2

## CPC

- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- C07D 215/38: Nitrogen atoms (nitro radicals C07D215/18)
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- C07D 209/08: with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
- C07D 223/16: Benzazepines; Hydrogenated benzazepines
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- 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)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Noncovalent small-molecule inhibitors of the enzyme OGG1, methods of their manufacture, and applications for their administration are provided. Small molecule inhibitors were shown to be selective for inhibiting OGG1 over multiple repair enzymes, including other base excision repair enzymes, and it displayed no toxicity in two human cell lines. The inhibitors provide a tool for the study of the role of OGG1 in multiple disease-related pathways, and a therapeutic target for the treatment thereof. Various embodiments include substituted 1,2,3,4-tetrahydroquinolines, such as compounds of the of the formula ABCDE:

## Claims

### Claim 1

A compound of formula ABCDE:
wherein:
A is R1;
B is 1,2,3,4-tetrahydroquinolin-1,7-diyl;
C is —NHS(O)2—;
D is —R4—;
E is R5;
R1 is C(O)R10;
R4 is phenylene;
wherein the phenylene is optionally substituted with 1 or more substituents independently selected from the group consisting of D, halogen, B(OR)2, CN, alkyl, haloalkyl, C(O)R, C(O)N(R)2, C(O)OR, NC, NCO, NCS, N3, NO2, N(R)2, NRC(O)R, NRC(O)N(R)2, NRC(O)OR, NRS(O)2R, NRS(O)2N(R)2, OCN, OC(O)R, OC(O)N(R)2, ONO2, OP(O)(OR)2, OR, SCN, SR, S(O)R, S(O)2R, S(O)2N(R)2, S(O)2OR, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
R5 is phenyl;
wherein the phenyl is optionally substituted with 1 or more substituents independently selected from the group consisting of D, halogen, B(OR)2, CN, alkyl, alkenyl, alkynyl, C(O)R, C(O)N(R)2, C(O)OR, NC, NCO, NCS, N3, NO2, N(R)2, NRC(O)R, NRC(O)N(R)2, NRC(O)OR, NRS(O)2R, NRS(O)2N(R)2, OCN, OC(O)R, OC(O)N(R)2, ONO2, OP(O)(OR)2, OR, SCN, SR, S(O)R, S(O)2R, S(O)2N(R)2, S(O)2OR, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
R10 is C1-4 alkyl, C1-4 alkylene-aryl, cyclopropyl, or cyclobutyl;
wherein the C1-4 alkyl of R10 is optionally substituted with 1 or more substituents independently selected from the group consisting of D, halogen, B(OR)2, CN, NCS, N3, NO2, N(R)2, ONO2, OP(O)(OR)2, OR, SCN, SR, S(O)2R, and S(O)2OR;
wherein the aryl of the C1-4 alkylene-aryl is optionally substituted with 1 or more substituents independently selected from the group consisting of D, halogen, B(OR)2, CN, alkyl, NCS, N3, NO2, N(R)2, ONO2, OP(O)(OR)2, OR, SCN, SR, S(O)2R, and S(O)2OR;
wherein the cyclopropyl of R10 is optionally substituted with 1 CH3 substituent and/or optionally further substituted with 1 or more additional substituents independently selected from the group consisting of D, halogen, B(OR)2, CN, NCS, N3, NO2, N(R)2, ONO2, OP(O)(OR)2, OR, SCN, SR, S(O)2R, and S(O)2OR;
wherein the CH3 substituent of the cyclopropyl of R10 is optionally substituted with 1 or more substituents independently selected from the group consisting of D and halogen; and
wherein the cyclobutyl of R10 is optionally substituted with 1 or more substituents independently selected from the group consisting of D, halogen, B(OR)2, CN, NCS, N3, NO2, N(R)2, ONO2, OP(O)(OR)2, OR, SCN, SR, S(O)2R, and S(O)2OR; and
each R is independently H, D, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, cyclopropyl, or cyclobutyl, wherein each C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, cyclopropyl, and cyclobutyl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of D, halogen, B(OH)2, B(OC1-4 alkyl)2, CN, NCS, N3, NO2, NH2, NHC1-4alkyl, N(C1-4alkyl)2, ONO2, OP(O)(OH)2, OP(O)(OC1-4 alkyl)2, OH, OC1-4 alkyl, SCN, SH, SC1-4 alkyl, S(O)2H, S(O)2C1-4 alkyl, S(O)2OH, S(O)2OC1-4 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; or
each R, taken together with the atom(s) to which they are attached, optionally and independently forms a ring.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R4 is phenylene, wherein the phenylene is optionally substituted with 1 or more substituents independently selected from the group consisting of halogen, B(OR)2, CN, alkyl, haloalkyl, C(O)R, C(O)N(R)2, C(O)OR, NC, NCO, NCS, N3, NO2, N(R)2, NRC(O)R, NRC(O)N(R)2, NRC(O)OR, NRS(O)2R, NRS(O)2N(R)2, OCN, OC(O)R, OC(O)N(R)2, ONO2, OP(O)(OR)2, OR, SCN, SR, S(O)R, S(O)2R, S(O)2N(R)2, S(O)2OR, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

### Claim 3 (depends on 1)

The compound of claim 1, wherein R4 is phenylene, wherein the phenylene is optionally substituted with 1 substituent selected from the group consisting of halogen, cyclohexyl, phenyl, pyrazolyl, and pyridyl.

### Claim 4 (depends on 1)

The compound of claim 1, wherein R10 is CH3, CH2CH3, cyclopropyl, or cyclobutyl;
wherein the CH3 or CH2CH3 is optionally substituted with 1 or more substituents independently selected from the group consisting of D, halogen, B(OR)2, CN, NCS, N3, NO2, N(R)2, ONO2, OP(O)(OR)2, OR, SCN, SR, S(O)2R, and S(O)2OR;
wherein the cyclopropyl is optionally substituted with 1 CH3 substituent and/or optionally further substituted with 1 or more additional substituents independently selected from the group consisting of D, halogen, B(OR)2, CN, NCS, N3, NO2, N(R)2, ONO2, OP(O)(OR)2, OR, SCN, SR, S(O)2R, and S(O)2OR; and
wherein the CH3 substituent of the cyclopropyl is optionally substituted with 1 or more substituents independently selected from the group consisting of D and halogen.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R5 is phenyl, wherein the phenyl is optionally substituted with 1 substituent selected from the group consisting of C(O)NH2, N(CH3)2, NHC(O)CH3, OCH3, cyclohexyl, phenyl, pyrazolyl, and pyridyl.

### Claim 6 (depends on 1)

The compound of claim 1, wherein:
D is optionally substituted with 1 or more substituents independently selected from the group consisting of D, halogen, B(OR)2, CN, alkyl, haloalkyl, C(O)R, C(O)N(R)2, C(O)OR, NC, NCO, NCS, N3, NO2, N(R)2, NRC(O)R, NRC(O)N(R)2, NRC(O)OR, NRS(O)2R, NRS(O)2N(R)2, OCN, OC(O)R, OC(O)N(R)2, ONO2, OP(O)(OR)2, OR, SCN, SR, S(O)R, S(O)2R, S(O)2N(R)2, S(O)2OR, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
E is optionally substituted with 1 substituent selected from the group consisting of D, halogen, B(OR)2, CN, alkyl, alkenyl, alkynyl, C(O)R, C(O)N(R)2, C(O)OR, NC, NCO, NCS, N3, NO2, N(R)2, NRC(O)R, NRC(O)N(R)2, NRC(O)OR, NRS(O)2R, NRS(O)2N(R)2, OCN, OC(O)R, OC(O)N(R)2, ONO2, OP(O)(OR)2, OR, SCN, SR, S(O)R, S(O)2R, S(O)2N(R)2, S(O)2OR, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and
R10 is C1-4 alkyl or cyclopropyl.

### Claim 7 (depends on 1)

A pharmaceutical formulation comprising a pharmaceutically acceptable excipient and a compound of claim 1.

### Claim 8 (depends on 7)

The pharmaceutical formulation of claim 7, wherein the pharmaceutically acceptable excipient is selected from the group consisting of a binder, a buffer, a disintegrant, a filler, a glidant, and a lubricant.

### Claim 9 (depends on 1)

A method for inhibiting repair enzyme 8-oxoguanine deoxyribonucleic acid glycosylase activity in an individual, wherein the method comprises administering to the individual in need thereof a therapeutically effective amount of the compound of claim 1.

### Claim 10 (depends on 9)

The method of claim 9, wherein the administering step is performed by intraperitoneal injection.

### Claim 11 (depends on 7)

A method for inhibiting repair enzyme 8-oxoguanine deoxyribonucleic acid glycosylase activity in an individual, wherein the method comprises administering to the individual in need thereof a therapeutically effective amount of the pharmaceutical formulation of claim 7.

### Claim 12 (depends on 11)

The method of claim 11, wherein the pharmaceutically acceptable excipient is selected from the group consisting of a binder, a buffer, a disintegrant, a filler, a glidant, and a lubricant.