# US 11,440,905 B2 · Biheterocyclic compound

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- Number: US 11,440,905 B2
- Document ID: US11440905B2
- Status: Granted
- Kind: B2
- Application number: 17/079,761
- Filed: 2020-10-26
- Published: 2021-07-01
- Granted: 2022-09-13
- Earliest claimed: 2016-01-15
- Assignees: Sumitomo Pharma Co., Ltd.
- Applicants: Sumitomo Pharma Co., Ltd.
- Inventors: Hitoshi Watanabe; Yoshiaki Isobe; Hidenori Kimura; Yuji Fujiwara
- Web page: https://patentgrep.com/patent/US11440905B2

## CPC

- C07D 405/14: containing three or more hetero rings
- A61K 31/352: condensed with carbocyclic rings, e.g. methantheline {(cannabinoids A61K31/658)}
- A61K 31/4192: 1,2,3-Triazoles
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 27/04: Artificial tears; Irrigation solutions
- C07D 311/22: with oxygen or sulfur atoms directly attached in position 4
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 471/04: Ortho-condensed 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 provides a compound of formula (1) and a pharmaceutical composition comprising the compound useful as a nerve regeneration promoter wherein R1-L- is R1—OC(O)—, or the like, R1 is hydrogen atom, optionally-substituted C1-6 alkyl group, optionally-substituted 3- to 8-membered cycloalkyl group, or the like, R2 is hydrogen atom or the like, Ring A is formula (2) or formula (3) wherein R3 is hydrogen atom, optionally-substituted C1-6 alkyl group, or the like, the part of X, Y, and Z is X═Y—Z, X—Y═Z, or X—Y—Z, X is nitrogen atom, NR4 (R4 is hydrogen atom, optionally-substituted C1-6 alkyl group, or the like), or the like, Y is carbon atom or the like, and Z is carbon atom, nitrogen atom or the like.

## Claims

### Claim 1

A method of preparing a compound of Formula (1B):
wherein
R1-L- is R1—OC(O)— or R1—NHC(O)—; and
R1 is
(i) hydrogen atom,
(ii) optionally-substituted C1-6 alkyl group,
(iii) optionally-substituted C2-6 alkenyl group,
(iv) optionally-substituted C2-6 alkynyl group,
(v) optionally-substituted 3- to 8-membered cycloalkyl group,
(vi) optionally-substituted 4- to 8-membered cycloalkenyl group,
(vii) optionally-substituted 4- to 8-membered saturated aliphatic heterocyclyl group,
(viii) optionally-substituted 5- to 10-membered unsaturated aliphatic heterocyclyl group,
(ix) optionally-substituted 6- to 10-membered aryl group, or
(x) optionally-substituted 5- to 10-membered heteroaryl group,
wherein the substituent(s) of the (ii) optionally-substituted C1-6 alkyl group is one or more substituents selected independently from the group consisting of hydroxy group, methoxy group, ethoxy group, carboxyl group, carbamoyl group (which may be substituted with one or two the same or different C1-3 alkyl), NR5R6 (wherein R5 and R6 are independently hydrogen atom, C1-3 alkyl group, carboxylmethyl group, 2-hydroxyethyl group, or 2-aminoethyl group), optionally-substituted 3- to 6-membered cycloalkyl group (wherein the substituent(s) of said optionally-substituted 3- to 6-membered cycloalkyl group is one or more substituents selected independently from the group consisting of amino group which may be substituted with one or two the same or different C1-3 alkyl, C1-3 alkyl group, hydroxy group, and carboxyl group), optionally-substituted 4- to 6-membered saturated aliphatic heterocyclyl group (wherein the substituent(s) of said optionally-substituted 4- to 6-membered saturated aliphatic heterocyclyl group is one or more substituents selected independently from the group consisting of amino group which may be substituted with one or two the same or different C1-3 alkyl, C1-3 alkyl group, hydroxy group, and carboxyl group), and optionally-substituted 5- to 10-membered heteroaryl group (wherein the substituent(s) of said optionally-substituted 5- to 10-membered heteroaryl group is one or more substituents selected independently from the group consisting of amino group which may be substituted with one or two the same or different C1-3 alkyl, C1-3 alkyl group, hydroxy group, and carboxyl group), or
the (ii) optionally-substituted C1-6 alkyl group may be any one of the following groups of formulae (4)-(6):
formula (4):
wherein m is 1, 2, 3, 4, or 5, R7 is C1-3 alkoxy group, amino acid group (which binds to C(O) at its N terminus), and peptide consisting of 2-3 amino acid residues (which binds to C(O) at its N terminus),
formula (5):
R8-L2-(CH2CH2O)qCH2CH2 (5)
wherein q is 1, 2, 3, 4, or 5, L2 is single bond or C(O), R8 is hydroxy group, C1-3 alkoxy group, amino group which may be substituted with one or two the same or different C1-3 alkyl, amino acid group (which binds to L2 at its N terminus), or peptide consisting of 2-3 amino acid residues (which binds to L2 at its N terminus),
formula (6):
wherein L3 is CH2 or C(O), and R9 is hydroxy group, C1-3 alkoxy group, amino group which may be substituted with one or two the same or different C1-3 alkyl, amino acid group (which binds to L3 at its N terminus), or peptide consisting of 2-3 amino acid residues (which binds to L3 at its N terminus),
the substituent(s) of the (iii) optionally-substituted C2-6 alkenyl group, and the (iv) optionally-substituted C2-6 alkynyl group are independently one or more substituents selected independently from the group consisting of hydroxy group, methoxy group, ethoxy group, carboxyl group, carbamoyl group (which may be substituted with one or two the same or different C1-3 alkyl), NR5R6 (wherein R5 and R6 are independently hydrogen atom, C1-3 alkyl group, carboxylmethyl group, 2-hydroxyethyl group, or 2-aminoethyl group), optionally-substituted 3- to 6-membered cycloalkyl group (wherein the substituent(s) of said optionally-substituted 3- to 6-membered cycloalkyl group is one or more substituents selected independently from the group consisting of amino group which may be substituted with one or two the same or different C1-3 alkyl, hydroxy group, and carboxyl group), optionally-substituted 4- to 6-membered saturated aliphatic heterocyclyl group (wherein the substituent(s) of said optionally-substituted 4- to 6-membered saturated aliphatic heterocyclyl group is one or more substituents selected independently from the group consisting of amino group which may be substituted with one or two the same or different C1-3 alkyl, C1-3 alkyl group, hydroxy group, and carboxyl group), and 5- to 10-membered heteroaryl group,
the substituent(s) of the (v) optionally-substituted 3- to 8-membered cycloalkyl group, the (vi) optionally-substituted 4- to 8-membered cycloalkenyl group, the (vii) optionally-substituted 4- to 8-membered saturated aliphatic heterocyclyl group, the (viii) optionally-substituted 5- to 10-membered unsaturated aliphatic heterocyclyl group, the (ix) optionally-substituted 6- to 10-membered aryl group, and the (x) optionally-substituted 5- to 10-membered heteroaryl group are independently one or more substituents selected independently from the group consisting of hydroxy group, methoxy group, ethoxy group, amino group which may be substituted with one or two the same or different C1-3 alkyl, and carboxyl group;
R2 is hydrogen atom, hydroxy group, or carboxyl group;
R3 is
(i) hydrogen atom,
(ii) optionally-substituted C1-6 alkyl group,
(iii) optionally-substituted C2-6 alkenyl group,
(iv) optionally-substituted C2-6 alkynyl group,
(v) optionally-substituted 3- to 8-membered cycloalkyl group,
(vi) optionally-substituted 4- to 8-membered cycloalkenyl group,
(vii) optionally-substituted 4- to 8-membered saturated aliphatic heterocyclyl group,
(viii) optionally-substituted 5- to 10-membered unsaturated aliphatic heterocyclyl group,
(ix) optionally-substituted 6- to 10-membered aryl group, or
(x) optionally-substituted 5- to 10-membered heteroaryl group; and
X Y Z is X═Y—Z, X—Y═Z, or X—Y—Z,
X is nitrogen atom, or NR4,
R4 is
(i) hydrogen atom,
(ii) optionally-substituted C1-6 alkyl group,
(iii) optionally-substituted C2-6 alkenyl group,
(iv) optionally-substituted C2-6 alkynyl group,
(v) optionally-substituted 3- to 8-membered cycloalkyl group,
(vi) optionally-substituted 4- to 8-membered cycloalkenyl group,
(vii) optionally-substituted 4- to 8-membered saturated aliphatic heterocyclyl group,
(viii) optionally-substituted 5- to 10-membered unsaturated aliphatic heterocyclyl group,
(ix) optionally-substituted 6- to 10-membered aryl group, or
(x) optionally-substituted 5- to 10-membered heteroaryl group,
Y is carbon atom or CH, and
Z is carbon atom, CH, or nitrogen atom, provided that the combination of X, Y, and Z should be any one of chemically-possible selections
or a pharmaceutically acceptable salt thereof;
which comprises the following step:
(step A1) reacting the compound of Formula (1A):
wherein R2, R3, XyZ, X, Y and Z are as defined above, or a pharmaceutically acceptable salt thereof
in the presence of a halogenating agent, followed by reacting with R1NH2 or R1OH to give a compound of formula (1B).

### Claim 2 (depends on 1)

The method of claim 1, wherein the method further comprises the following steps B1 and B2 preparing for the compound of Formula (1A):
wherein R2, R3, XYZ, X, Y and Z are as defined in claim 1, or a pharmaceutically acceptable salt thereof; before the step A1:
(step B1) coupling the compound of Formula (1a):
wherein
R11 and R12 are independently a protecting group of hydroxy group;
R13 is a protecting group of carboxyl group; and
R14 is a functional group selected from the group consisting of tributyltin group, pinacolboryl group, and hydroxyboryl group, or a pharmaceutically acceptable salt thereof;
and a compound of Formula (1b):
wherein
R3, XYZ, X, Y and Z are as defined above;
R15 and R16 are independently a protecting group of hydroxy group;
R17 is hydrogen atom, a protected hydroxy group, or a protected carboxyl group; and
R18 is a halogen atom, or a pharmaceutically acceptable salt thereof
in the presence of a base, a phosphine ligand, a copper catalyst and a palladium catalyst to give a compound of Formula (1C):
wherein R3, R11, R12, R13, R15, R16, R17, XYZ, Y and Z are as defined above, or a pharmaceutically acceptable salt thereof; and
(step B2) removing the protecting groups from the compound of formula (1c) to obtain a compound of the formula (1A), or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The method of claim 1, wherein
R1 is (i) hydrogen atom, or (ii) optionally-substituted C1-3 alkyl group,
wherein the substituent(s) of the (ii) optionally-substituted C1-3 alkyl group is one or more substituents selected independently from the group consisting of hydroxy group, methoxy group, ethoxy group, carboxyl group, carbamoyl group (which may be substituted with one or two the same or different C1-3 alkyl), NR5R6 (wherein R5 and R6 are independently hydrogen atom, C1-3 alkyl group, carboxylmethyl group, 2-hydroxyethyl group, or 2-aminoethyl group), optionally-substituted 3- to 6-membered cycloalkyl group (wherein the substituent(s) of said optionally-substituted 3- to 6-membered cycloalkyl group is one or more substituents selected independently from the group consisting of amino group which may be substituted with one or two the same or different C1-3 alkyl, C1-3 alkyl group, hydroxy group, and carboxyl group), optionally-substituted 4- to 6-membered saturated aliphatic heterocyclyl group (wherein the substituent(s) of said optionally-substituted 4- to 6-membered saturated aliphatic heterocyclyl group is one or more substituents selected independently from the group consisting of amino group which may be substituted with one or two the same or different C1-3 alkyl, C1-3 alkyl group, hydroxy group, and carboxyl group), and optionally-substituted 5- to 10-membered heteroaryl group (wherein the substituent(s) of said optionally-substituted 5- to 10-membered heteroaryl group is one or more substituents selected independently from the group consisting of amino group which may be substituted with one or two the same or different C1-3 alkyl, C1-3 alkyl group, hydroxy group, and carboxyl group), or
the (ii) optionally-substituted C1-3 alkyl group may be any one of the groups of formulae (4)-(6),
in formula (4), m is 1, R7 is amino acid group (which binds to C(O) at its N terminus),
in formula (5), q is 1, 2, 3, 4, or 5, L2 is single bond or C(O), R8 is hydroxy group or amino acid group (which binds to L2 at its N terminus),
in formula (6), L3 is C(O), R9 is hydroxy group or amino acid group (which binds to L3 at its N terminus).

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

A method of preparing a compound of Formula (1Ba):
wherein R1, R2, R3, XYZ X, Y and Z are as defined in claim 1, or a pharmaceutically acceptable salt thereof;
which comprises the following steps C1 to C3:
(step C1) removing R13 which is among the protecting groups from the compound of formula (1c):
wherein
R11, R12, R13, R15, R16, R17 are as defined in claim 2; and
R3, XYZ, X, Y and Z are as defined above, or a pharmaceutically acceptable salt thereof;
to obtain a compound of the formula (1d):
wherein, R3, R11, R12, R15, R16, R17, XYZ, X, Y and Z are as defined above, or a pharmaceutically acceptable salt thereof;
(step C2) reacting the compound of Formula (1d) with R0-LG:
wherein
R0 is R1 or a protected R1;
R1 is as defined above; and
LG is a leaving group
in the presence of a base to give a compound of Formula (1e):
wherein
R0 is as defined above; and
R3, R11, R12, R15, R16, R17, XYZ, X, Y and Z are as defined in claim 1 or a pharmaceutically acceptable salt thereof; and
(step C3) removing R11, R12, R15, R16 and the protecting groups of R0 and R17 from the compound of formula (1e) to give a compound of Formula (1Ba) or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 4)

The method of claim 4, wherein
R1 is (i) hydrogen atom, or (ii) optionally-substituted C1-3 alkyl group,
wherein the substituent(s) of the (ii) optionally-substituted C1-3 alkyl group is one or more substituents selected independently from the group consisting of hydroxy group, methoxy group, ethoxy group, carboxyl group, carbamoyl group (which may be substituted with one or two the same or different C1-3 alkyl), NR5R6 (wherein R5 and R6 are independently hydrogen atom, C1-3 alkyl group, carboxylmethyl group, 2-hydroxyethyl group, or 2-aminoethyl group), optionally-substituted 3- to 6-membered cycloalkyl group (wherein the substituent(s) of said optionally-substituted 3- to 6-membered cycloalkyl group is one or more substituents selected independently from the group consisting of amino group which may be substituted with one or two the same or different C1-3 alkyl, C1-3 alkyl group, hydroxy group, and carboxyl group), optionally-substituted 4- to 6-membered saturated aliphatic heterocyclyl group (wherein the substituent(s) of said optionally-substituted 4- to 6-membered saturated aliphatic heterocyclyl group is one or more substituents selected independently from the group consisting of amino group which may be substituted with one or two the same or different C1-3 alkyl, C1-3 alkyl group, hydroxy group, and carboxyl group), and optionally-substituted 5- to 10-membered heteroaryl group (wherein the substituent(s) of said optionally-substituted 5- to 10-membered heteroaryl group is one or more substituents selected independently from the group consisting of amino group which may be substituted with one or two the same or different C1-3 alkyl, C1-3 alkyl group, hydroxy group, and carboxyl group), or
the (ii) optionally-substituted C1-3 alkyl group may be any one of the groups of formulae (4)-(6),
in formula (4), m is 1, R7 is amino acid group (which binds to C(O) at its N terminus),
in formula (5), q is 1, 2, 3, 4, or 5, L2 is single bond or C(O), R8 is hydroxy group or amino acid group (which binds to L2 at its N terminus),
in formula (6), L3 is C(O), R9 is hydroxy group or amino acid group (which binds to L3 at its N terminus).

### Claim 6 (depends on 1)

A method of preparing a compound of Formula (1Bd):
wherein R2, R3, L, R9, L3, XYZ, X, Y and Z are as defined in claim 1, or a pharmaceutically acceptable salt thereof;
which comprises the following step:
(step D1) reacting a compound of Formula (1Bc):
wherein R2, R3, XYZ, X, Y, Z and L are as defined above, or a pharmaceutically acceptable salt thereof;
with the compound of formula (1f):
wherein
R19 is a protected R9; and
R9 and L3 is as defined above
in the presence of a reducing agent, tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine, and a copper catalyst, followed by removing the protecting group to give the compound of formula (1Bd) or a pharmaceutically acceptable salt thereof,
wherein the step D1 may be replaced with the following step D2:
(step D2) reacting the compound of Formula (1Bc) with the compound of Formula (1j):
wherein R9 is as defined above, or a salt thereof, in the presence of a reducing agent, tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine, and a copper catalyst to give the compound of formula (1Bd) or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

A method of preparing the compound of Formula (1D):
wherein R1, R2, R3, L, XYZ, X, Y and Z are as defined in claim 1, or a pharmaceutically acceptable salt thereof;
which comprises the following step:
(step E1) reacting the compound of Formula (1C):
wherein R2, R3, XYZ, X, Y and Z are as defined above, or a pharmaceutically acceptable salt thereof,
with a halogenating agent, followed by reacting with an alcohol compound or an amine compound which corresponds to a desired R1 to give the compound of formula (1D).

### Claim 8 (depends on 1, 2, 7)

The method of claim 7, wherein the method further comprises the following steps F1 and F2 preparing the compound of Formula (1C):
wherein R2, R3, XYZ, X, Y and Z are as defined in claim 1, or a pharmaceutically acceptable salt thereof; before the step E1:
(step F1) coupling the compound of Formula (1a):
wherein R11, R12, R13 and R14 are as defined in claim 2, or a pharmaceutically acceptable salt thereof;
and a compound of Formula (1r):
wherein
R15, R16, R17 and R18 are as defined in claim 2; and
R3, XYZ, X, Y and Z are as defined above, or a pharmaceutically acceptable salt thereof
in the presence of a base, a phosphine ligand, a copper catalyst and a palladium catalyst to give a compound of Formula (1s):
wherein R3, R11, R12, R13, R15, R16, R17, XyZ, X, Y and Z are as defined above, or a pharmaceutically acceptable salt thereof; and
(step F2) removing the protecting groups from the compound of formula (Is) to obtain a compound of the formula (1C), or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 7)

The method of claim 7, wherein
R1 is (i) hydrogen atom, or (ii) optionally-substituted C1-3 alkyl group,
wherein the substituent(s) of the (ii) optionally-substituted C1-3 alkyl group is one or more substituents selected independently from the group consisting of hydroxy group, methoxy group, ethoxy group, carboxyl group, carbamoyl group (which may be substituted with one or two the same or different C1-3 alkyl), NR5R6 (wherein R5 and R6 are independently hydrogen atom, C1-3 alkyl group, carboxylmethyl group, 2-hydroxyethyl group, or 2-aminoethyl group), optionally-substituted 3- to 6-membered cycloalkyl group (wherein the substituent(s) of said optionally-substituted 3- to 6-membered cycloalkyl group is one or more substituents selected independently from the group consisting of amino group which may be substituted with one or two the same or different C1-3 alkyl, C1-3 alkyl group, hydroxy group, and carboxyl group), optionally-substituted 4- to 6-membered saturated aliphatic heterocyclyl group (wherein the substituent(s) of said optionally-substituted 4- to 6-membered saturated aliphatic heterocyclyl group is one or more substituents selected independently from the group consisting of amino group which may be substituted with one or two the same or different C1-3 alkyl, C1-3 alkyl group, hydroxy group, and carboxyl group), and optionally-substituted 5- to 10-membered heteroaryl group (wherein the substituent(s) of said optionally-substituted 5- to 10-membered heteroaryl group is one or more substituents selected independently from the group consisting of amino group which may be substituted with one or two the same or different C1-3 alkyl, C1-3 alkyl group, hydroxy group, and carboxyl group), or
the (ii) optionally-substituted C1-3 alkyl group may be any one of the groups of formulae (4)-(6),
in formula (4), m is 1, R7 is amino acid group (which binds to C(O) at its N terminus),
in formula (5), q is 1, 2, 3, 4, or 5, L2 is single bond or C(O), R8 is hydroxy group or amino acid group (which binds to L2 at its N terminus),
in formula (6), L3 is C(O), R9 is hydroxy group or amino acid group (which binds to L3 at its N terminus).

### Claim 10

A method for treating and/or preventing corneal disease, comprising administering a therapeutically effective amount of the compound which is selected from the group consisting of
3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylic acid,
N-({4-[({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic acid,
N2-({4-[({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-arginine,
N-{[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}-L-glutamic acid,
3-(6,7-dihydroxy-1,2-dimethyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylic acid,
N-({4-[({[3-(6,7-dihydroxy-1,2-dimethyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic acid,
3-(7,8-dihydroxy-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylic acid,
N-({4-[({[3-(7,8-dihydroxy-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic acid,
N-[({[3-(7,8-dihydroxy-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)acetyl]-L-glutamic acid, and
N-[({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)acetyl]-L-glutamic acid,
or a pharmaceutically acceptable salt thereof to a patient in need thereof.

### Claim 11

A method for treating and/or preventing corneal disease, comprising administering a therapeutically effective amount of the compound which is selected from the group consisting of
3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylic acid,
N-({4-[({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic acid,
N-({4-[({[3-(6,7-dihydroxy-1,2-dimethyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic acid,
N-({4-[({[3-(6,7-dihydroxy-1,4-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic acid, and
N-[({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)acetyl]-L-glutamic acid.

### Claim 12 (depends on 11)

The method of claim 11, wherein the compound is 3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylic acid, or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 11)

The method of claim 11, wherein the compound is N-({4-[({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic acid, or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 11)

The method of claim 11, wherein the compound is N-({4-[({[3-(6,7-dihydroxy-1,2-dimethyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic acid, or a pharmaceutically acceptable salt thereof.

### Claim 15 (depends on 11)

The method of claim 11, wherein the compound is N-({4-[({[3-(6,7-dihydroxy-1,4-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic acid, or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 11)

The method of claim 11, wherein the compound is N-[({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)acetyl]-L-glutamic acid, or a pharmaceutically acceptable salt thereof.

### Claim 17

3-(6,7-Dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylic acid or a pharmaceutically acceptable salt thereof.

### Claim 18

N-({4-[({[3-(6,7-Dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic acid or a pharmaceutically acceptable salt thereof.

### Claim 19

N-({4-[({[3-(6,7-Dihydroxy-1,2-dimethyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic acid or a pharmaceutically acceptable salt thereof.

### Claim 20

N-({4-[({[3-(6,7-Dihydroxy-1,4-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic acid or a pharmaceutically acceptable salt thereof.

### Claim 21

N-[({[3-(6,7-Dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)acetyl]-L-glutamic acid or a pharmaceutically acceptable salt thereof.