# US 2016/0251318 A1 · Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof

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- Number: US 2016/0251318 A1
- Document ID: US20160251318A1
- Status: Published application
- Kind: A1
- Application number: 14/241,374
- Filed: 2012-08-28
- Published: 2016-09-01
- Earliest claimed: 2011-08-30
- Assignees: CHDI Foundation, Inc.
- Inventors: Stephen Martin Courtney; Michael Prime; William Mitchell; Christopher John Brown; Paula C. De Aguiar Pena; Peter Johnson; Celia Dominguez; Leticia M. Toledo-Sherman; Ignacio Munoz
- Web page: https://patentgrep.com/patent/US20160251318A1

## CPC

- C07D 239/28: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- 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 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 239/42: One nitrogen atom (nitro radicals C07D239/30)
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/10: linked by a carbon chain containing aromatic rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/10: linked by a carbon chain containing aromatic rings
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 405/14: containing three or more hetero rings
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D 471/04: Ortho-condensed systems
- C07D 491/048: the oxygen-containing ring being five-membered
- C07D 491/052: the oxygen-containing ring being six-membered
- C07H 13/10: having the esterifying carboxyl radicals directly attached to heterocyclic rings
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Certain chemical entities are provided herein. Also provided are pharmaceutical compositions comprising at least one chemical entity and one or more pharmaceutically acceptable vehicle. Methods of treating patients suffering from certain diseases and disorders responsive to the inhibition of KMO activity are described, which comprise administering to such patients an amount of at least one chemical entity effective to reduce signs or symptoms of the disease or disorder are disclosed. These diseases include neurodegenerative disorders such as Huntington's disease. Also described are methods of treatment include administering at least one chemical entity as a single active agent or administering at least one chemical entity in combination with one or more other therapeutic agents. Also provided are methods for screening compounds capable of inhibiting KMO activity.

## Claims

### Claim 1

At least one chemical entity chosen from compounds of Formula I
and pharmaceutically acceptable salts and prodrugs thereof wherein:
X and Y are independently chosen from —N— and —CH—, provided that at least one of X and Y is —N—;
R1 is aryl or monocyclic heteroaryl, each of which is substituted with
a first group of the formula —Z—R6 wherein
Z is chosen from —O—, —S—, —S(O)—, —S(O)2—, —CR11R12—, —OCR11R12—, —NR13—, —NR13CR11R12—, —CR11R12NR13—, and —C(O)— where R11, R12, and R13 are independently chosen from hydrogen, lower alkyl, hydroxyl, and lower alkoxy,
R6 is chosen from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl, provided that if Z is —O—, then R6 is not optionally substituted benzyl or optionally substituted pyridylmethyl, or
R6 and R13, taken together with the nitrogen to which they are bound form an optionally substituted 5- to 7-membered heterocycloalkyl ring, and
a second group chosen from halo and lower alkyl optionally substituted with halo, or
R1 is chosen from: 2,3-dihydrobenzofuran-5-yl, chroman-6-yl, 1,3-benzodioxol-5-yl, 2,3-dihydro-1,4-benzodioxin-6-yl, 1,3-benzoxazol-5-yl, 1,3-benzoxazol-6-yl, 2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl, benzothiophen-5-yl, benzothiazol-5-yl, benzoimidazol-5-yl, benzofuran-5-yl, 1H-indol-5-yl, 1H-indazol-5-yl, isoindolin-5-yl, benzo[c][1,2,5]oxadiazol-5-yl, 1,2,3,4-tetrahydroquinolin-6-yl, imidazo[1,2-a]pyridin-6-yl, pyrazolo[1,5-a]pyridine-5-yl, quinolin-6-yl, quinazolin-6-yl, quinazolin-7-yl, and quinoxalin-6-yl, each of which is optionally substituted, or
R1 and R3, taken together with intervening atoms form a bicyclic ring of the formula
which is optionally substituted where m is 0 or 1 and n is 0 or 1, provided that at least one of m and n is 1 and W is —O—, or —N(R8)— where R8 is hydrogen or lower alkyl;
R2 is chosen from hydrogen and optionally substituted lower alkyl;
R3 is chosen from hydrogen, halo, optionally substituted lower alkyl, hydroxyl, optionally substituted lower alkoxy, and optionally substituted amino;
L is chosen from —C(O)—, —C(O)O—, —C(O)N(R4)—, —C(O)N(OR7)—, —N(R4)S(O)2—, —S(O)2N(R4)—, and —C(O)N(R4)—S(O)2—;
R4 is chosen from hydrogen and lower alkyl;
R5 is chosen from hydrogen, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; provided that when L is —N(R4)S(O)2—, then R5 is not hydrogen, or
R4 and R5 taken together with the nitrogen to which they are bound form an optionally substituted 4- to 7-membered heterocycloalkyl ring, which is optionally fused to an optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl ring; or
R3 and R5, taken together with the intervening atoms, form an optionally substituted 5- to 7-membered ring; and
R7 is chosen from hydrogen and lower alkyl;
provided that the compound of Formula I is not chosen from
6-(3-chloro-4-methyl-phenyl)-pyrimidine-4-carboxylic acid methyl ester;
6-(3-chloro-4-methyl-phenyl)-pyrimidine-4-carboxylic acid;
6-(3-chloro-4-methoxy-phenyl)-pyrimidine-4-carboxylic acid methyl ester; and
6-(3-chloro-4-methoxy-phenyl)-pyrimidine-4-carboxylic acid.

### Claim 2 (depends on 1)

At least one chemical entity of claim 1 wherein R1 is phenyl substituted with
a first group of the formula —Z—R6 wherein Z is chosen from —O—, —S—, —S(O)—, —S(O)2—, and —CR11R12—; and R6 is chosen from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, and
a second group chosen from halo and lower alkyl optionally substituted with halo.

### Claim 3 (depends on 1)

At least one chemical entity of claim 1 wherein Z is —O—.

### Claim 4 (depends on 1)

At least one chemical entity of claim 1 wherein Z is —S—.

### Claim 5 (depends on 1)

At least one chemical entity of claim 1 wherein Z is —S(O)2—.

### Claim 6 (depends on 1)

At least one chemical entity of claim 1 wherein Z is —CR11R12.

### Claim 7 (depends on 1)

At least one chemical entity of claim 1 wherein R6 is chosen from hydrogen, methyl, difluoromethyl, trifluoromethyl, ethyl, 2,2,2-trifluoro-1-methyl-ethyl, isopropyl, (S)-sec-butyl, (R)-sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, 2-morpholin-4-yl-ethyl, 2-piperidin-1-yl-ethyl, pyrrolidin-3-yl, and tetrahydro-furan-3-yl.

### Claim 8 (depends on 1)

At least one chemical entity of claim 1 wherein R1 is chosen from 3-chloro-4-cyclobutoxy-phenyl, 3-chloro-4-cyclopentyloxy-phenyl, 3-chloro-4-cyclopropoxy-phenyl, 3-chloro-4-isopropoxy-phenyl, 3-chloro-4-methoxy-phenyl, [4-chloro-3-(2-morpholin-4-yl-ethoxy)-phenyl, 3-chloro-4-(2-piperidin-1-yl-ethoxy)-phenyl, 3-chloro-4-(pyrrolidin-3-yloxy)-phenyl, 4-(S)-sec-butoxy-3-chloro-phenyl, 4-(R)-sec-butoxy-3-chloro-phenyl, 4-chloro-3-(tetrahydro-furan-3-yloxy)-phenyl, 3-chloro-4-trifluoromethoxy-phenyl, 3-chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy, 3-methoxy-phenyl, 4-methoxy-phenyl, 3,4-dimethoxyphenyl, 3-chloro-4-isopropylphenyl, 3-fluoro-4-methylphenyl, and 3-fluoro-4-isopropylphenyl, 3,4-bis(methylsulfanyl)phenyl, 3,4-bis(methylsulfonyl)phenyl, 3,4-bis(trifluoromethoxy)phenyl, 3-chloro-4-(difluoromethoxy)phenyl, 3-chloro-4-(methylsulfanyl)phenyl, 3-chloro-4-(methylsulfonyl)phenyl, 3-chloro-4-(trifluoromethoxy)phenyl, 3-chloro-4-(cyclopropoxymethyl)phenyl, 3-chloro-4-(cyclopropylmethyl)phenyl, 3-chloro-4-(cyclopropanesulfinyl)phenyl, 3-chloro-4-(cyclopropanesulfonyl)phenyl, 3-chloro-4-[cyclopropyl(hydroxy)methyl]phenyl, 3-chloro-4-(1-cyclopropoxyethyl)phenyl, 3-chloro-4-cyclopropanecarbonylphenyl, 3-chloro-4-cyclopropylphenyl, 4-(aziridin-1-ylmethyl)-3-chlorophenyl, 3-chloro-4-[(dimethylamino)methyl]phenyl, 3-chloro-4-(cyclopropylamino)phenyl, 3-chloro-4-[cyclopropyl(methyl)amino]phenyl, 3-chloro-4-[(cyclopropylamino)methyl]phenyl, 3-chloro-4-{[cyclopropyl(methyl)amino]methyl}phenyl, 3-chloro-4-(1-methoxycyclopropyl)phenyl, 4-chloro-3-[(1,1,1-trifluoropropan-2-yl)oxy]phenyl, 4-chloro-3-(trifluoromethoxy)phenyl, 4-chloro-3-(2-methylpropoxy)phenyl, 4-chloro-3-(propan-2-yloxy)phenyl, 4-chloro-3-(propan-2-yloxy)phenyl, 4-chloro-3-methoxyphenyl, 4-chloro-3-cyclopropoxyphenyl, and 3-chloro-4-{[1-(morpholin-4-yl)propan-2-yl]oxy}phenyl.

### Claim 9 (depends on 8)

At least one chemical entity of claim 8 wherein R1 is chosen from 3-chloro-4-methoxy-phenyl, 3-chloro-4-(trifluoromethoxy)phenyl, 3-chloro-4-cyclobutoxy-phenyl, 3-chloro-4-cyclopropoxy-phenyl, 3-chloro-4-isopropoxy-phenyl, 3-chloro-4-methoxy-phenyl, 3-chloro-4-(pyrrolidin-3-yloxy)-phenyl, 4-(S)-sec-butoxy-3-chloro-phenyl, 4-(R)-sec-butoxy-3-chloro-phenyl, 4-chloro-3-(tetrahydro-furan-3-yloxy)-phenyl, 3-chloro-4-trifluoromethoxy-phenyl, 3-chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy, 3-methoxy-phenyl, 4-methoxy-phenyl, 3,4-dimethoxyphenyl, 3-chloro-4-isopropylphenyl, 3-fluoro-4-methylphenyl, and 3-fluoro-4-isopropylphenyl, 3,4-bis(trifluoromethoxy)phenyl, 3-chloro-4-(difluoromethoxy)phenyl, 3-chloro-4-(trifluoromethoxy)phenyl, 3-chloro-4-(cyclopropoxymethyl)phenyl, 3-chloro-4-(cyclopropylmethyl)phenyl, 3-chloro-4-(cyclopropanesulfinyl)phenyl, 3-chloro-4-(cyclopropanesulfonyl)phenyl, 3-chloro-4-[cyclopropyl(hydroxy)methyl]phenyl, 3-chloro-4-(1-cyclopropoxyethyl)phenyl, 3-chloro-4-cyclopropanecarbonylphenyl, 3-chloro-4-cyclopropylphenyl, 4-(aziridin-1-ylmethyl)-3-chlorophenyl, 3-chloro-4-[(dimethylamino)methyl]phenyl, 3-chloro-4-(cyclopropylamino)phenyl, 3-chloro-4-[cyclopropyl(methyl)amino]phenyl, 3-chloro-4-[(cyclopropylamino)methyl]phenyl, 3-chloro-4-{[cyclopropyl(methyl)amino]methyl}phenyl, 3-chloro-4-(1-methoxycyclopropyl)phenyl, 4-chloro-3-[(1,1,1-trifluoropropan-2-yl)oxy]phenyl, 4-chloro-3-(trifluoromethoxy)phenyl, 4-chloro-3-(2-methylpropoxy)phenyl, 4-chloro-3-(propan-2-yloxy)phenyl, 4-chloro-3-(propan-2-yloxy)phenyl, 4-chloro-3-methoxyphenyl, and 4-chloro-3-cyclopropoxyphenyl.

### Claim 10 (depends on 1)

At least one chemical entity of claim 1 wherein R1 is chosen from 1,3-benzodioxol-5-yl, chroman-6-yl, 2,3-dihydrobenzofuran-5-yl, benzofuran-5-yl, 2,3-dihydro-1H-isoindol-5-yl, 1,3-benzoxazol-5-yl, 2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl, 1,3-benzoxazol-5-yl, imidazo[1,2-a]pyridin-6-yl, 1,3-benzoxazol-6-yl, quinolin-6-yl, and pyrazolo[1,5-a]pyridin-5-yl, each of which is optionally substituted with one or two groups chosen from halo, lower alkyl optionally substituted with halo, cycloalkyl, and lower alkoxy optionally substituted with halo.

### Claim 11 (depends on 10)

At least one chemical entity of claim 10 wherein R1 is chosen from 1,3-benzodioxol-5-yl, 2,2-difluoro-1,3-benzodioxol-5-yl, 8-chloro-chroman-6-yl, 7-chloro-benzofuran-5-yl, 7-chloro-2-cyclopropyl-2,3-dihydro-1H-isoindol-5-yl, 7-chloro-2-methyl-1,3-benzoxazol-5-yl, 7-chloro-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl, 7-chloro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl, 7-chloro-2-cyclopropyl-1,3-benzoxazol-5-yl, 8-chloroimidazo[1,2-a]pyridin-6-yl, 4-chloro-1,3-benzoxazol-6-yl, quinolin-6-yl, and pyrazolo[1,5-a]pyridin-5-yl.

### Claim 12 (depends on 11)

At least one chemical entity of claim 11 wherein R1 is chosen from 1,3-benzodioxol-5-yl, 2,2-difluoro-1,3-benzodioxol-5-yl, 8-chloro-chroman-6-yl, 7-chloro-benzofuran-5-yl, 7-chloro-2-methyl-1,3-benzoxazol-5-yl, 7-chloro-2-cyclopropyl-1,3-benzoxazol-5-yl, 8-chloroimidazo[1,2-a]pyridin-6-yl, 4-chloro-1,3-benzoxazol-6-yl, quinolin-6-yl, and pyrazolo[1,5-a]pyridin-5-yl.

### Claim 13 (depends on 1)

At least one chemical entity of claim 1 wherein R2 is hydrogen.

### Claim 14 (depends on 1)

At least one chemical entity of claim 1 wherein R2 is lower alkyl.

### Claim 15 (depends on 14)

At least one chemical entity of claim 14 wherein R2 is methyl or ethyl.

### Claim 16 (depends on 15)

At least one chemical entity of claim 15 wherein R2 is methyl.

### Claim 17 (depends on 1)

At least one chemical entity of claim 1 wherein R3 is hydrogen.

### Claim 18 (depends on 1)

At least one chemical entity of claim 1 wherein R3 is fluoro or chloro.

### Claim 19 (depends on 1)

At least one chemical entity of claim 1 wherein R3 is methyl.

### Claim 20 (depends on 1)

At least one chemical entity of claim 1 wherein R3 is —CH2OH.

### Claim 21 (depends on 1)

At least one chemical entity of claim 1 wherein X is —N—.

### Claim 22 (depends on 1)

At least one chemical entity of claim 1 wherein Y is —N—.

### Claim 23 (depends on 1)

At least one chemical entity of claim 1 wherein X and Y are —N—.

### Claim 24 (depends on 1)

At least one chemical entity of claim 1 wherein L is —C(O)O—.

### Claim 25 (depends on 1)

At least one chemical entity of claim 1 wherein L is —C(O)N(R4)—.

### Claim 26 (depends on 1)

At least one chemical entity of claim 1 wherein L is —N(R4)S(O)2—.

### Claim 27 (depends on 25)

At least one chemical entity of claim 25 wherein R4 is hydrogen.

### Claim 28 (depends on 1)

At least one chemical entity of claim 1 wherein R5 is lower alkyl.

### Claim 29 (depends on 1)

At least one chemical entity of claim 1 wherein R5 is hydrogen.

### Claim 30 (depends on 1)

At least one chemical entity of claim 1 wherein the compound of Formula I is chosen from compounds of Formula II
wherein n is chosen from 1 and 2.

### Claim 31 (depends on 30)

At least one chemical entity of claim 30 wherein n is 1.

### Claim 32 (depends on 30)

At least one chemical entity of claim 30 wherein n is 2.

### Claim 33 (depends on 1)

At least one chemical entity of claim 1, wherein the compound of Formula I is chosen from
6-(4-Chloro-3-methoxy-phenyl)-pyrimidine-4-carboxylic acid,
6-(3-Amino-4-chloro-phenyl)-pyrimidine-4-carboxylic acid,
6-[4-Chloro-3-(tetrahydro-furan-3-yloxy)-phenyl]-pyrimidine-4-carboxylic acid,
6-[4-Chloro-3-(tetrahydro-furan-3-yloxy)-phenyl]-pyrimidine-4-carboxylic acid pyridin-3-ylamide,
6-[4-Chloro-3-(2-morpholin-4-yl-ethoxy)-phenyl]-pyrimidine-4-carboxylic acid pyridin-3-yl-amide,
6-(3-Chloro-4-isopropyl-phenyl)-pyrimidine-4-carboxylic acid,
6-(3-Fluoro-4-methyl-phenyl)-pyrimidine-4-carboxylic acid,
6-(3-Chloro-4-isopropoxy-phenyl)-pyrimidine-4-carboxylic acid,
6-(3-Chloro-4-isopropoxy-phenyl)-2-methyl-pyrimidine-4-carboxylic acid,
6-(3-Fluoro-4-methyl-phenyl)-2-methyl-pyrimidine-4-carboxylic acid,
6-(3-Chloro-4-cyclopentyloxy-phenyl)-pyrimidine-4-carboxylic acid,
6-(3-Chloro-4-trifluoromethoxy-phenyl)-pyrimidine-4-carboxylic acid,
6-(3-Fluoro-4-isopropyl-phenyl)-pyrimidine-4-carboxylic acid,
6-(4-(R)-sec-Butoxy-3-chloro-phenyl)-pyrimidine-4-carboxylic acid,
6-(4-(S)-sec-Butoxy-3-chloro-phenyl)-pyrimidine-4-carboxylic acid,
6-(3-Chloro-4-cyclopropoxy-phenyl)-pyrimidine-4-carboxylic acid,
6-[3-Chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-pyrimidine-4-carboxylic acid,
4-(3-Chloro-4-cyclopropoxy-phenyl)-pyridine-2-carboxylic acid,
6-(4-(R)-sec-Butoxy-3-chloro-phenyl)-pyridine-4-carboxylic acid,
6-(4-(S)-sec-Butoxy-3-chloro-phenyl)-pyridine-4-carboxylic acid,
4-(3-Chloro-4-isopropoxy-phenyl)-pyridine-2-carboxylic acid,
4-(3-Chloro-4-trifluoromethoxy-phenyl)-pyridine-2-carboxylic acid,
6-(3-Chloro-4-cyclobutoxy-phenyl)-pyrimidine-4-carboxylic acid,
6-[3-Chloro-4-(2-piperidin-1-yl-ethoxy)-phenyl]-pyrimidine-4-carboxylic acid,
6-Quinolin-6-yl-pyrimidine-4-carboxylic acid,
6-(8-Chloro-chroman-6-yl)-pyrimidine-4-carboxylic acid,
6-(7-Chloro-benzofuran-5-yl)-pyrimidine-4-carboxylic acid,
6-[3-Chloro-4-(pyrrolidin-3-yloxy)-phenyl]-pyrimidine-4-carboxylic acid,
6-(8-chloro-1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)pyrimidine-4-carboxylic acid,
6-(8-chloroquinolin-6-yl)pyrimidine-4-carboxylate,
N-[6-(3-chloro-4-cyclopropoxyphenyl)pyrimidin-4-yl]benzenesulfonamide,
N-[6-(3-chloro-4-cyclopropoxyphenyl)pyrimidin-4-yl]-4-fluorobenzene-1-sulfonamide,
N-[6-(3-chloro-4-cyclopropoxyphenyl)pyrimidin-4-yl]-4-(trifluoromethoxy)benzene-1-sulfonamide,
N-[6-(3-chloro-4-cyclopropoxyphenyl)pyrimidin-4-yl]-3-(trifluoromethoxy)benzene-1-sulfonamide,
N-[6-(3-chloro-4-cyclopropoxyphenyl)pyrimidin-4-yl]-2-fluorobenzene-1-sulfonamide,
N-[6-(3-chloro-4-cyclopropoxyphenyl)pyrimidin-4-yl]cyclopropanesulfonamide,
6-(8-chloro-1,2,3,4-tetrahydroquinolin-6-yl)pyrimidine-4-carboxylate,
6-(3-chloro-4-cyclopropoxyphenyl)-5-methylpyrimidine-4-carboxylate,
6-{3-chloro-4-[2-(morpholin-4-yl)ethoxy]phenyl}pyrimidine-4-carboxylate,
6-[3-chloro-4-(cyclopropylmethoxy)phenyl]pyrimidine-4-carboxylate,
6-[3-chloro-4-(oxetan-3-yloxy)phenyl]pyrimidine-4-carboxylate,
4-(3-chloro-4-cyclopropoxyphenyl)-5H,7H-furo[3,4-d]pyrimidin-7-one,
6-(3-chloro-4-cyclopropoxyphenyl)-5-(hydroxymethyl)pyrimidine-4-carboxylic acid,
4-(3-chloro-4-cyclopropoxyphenyl)-5H,6H,8H-pyrano[3,4-d]pyrimidin-8-one,
[(2R,3S,4S,5R)-3,4,5,6-tetrahydroxyoxan-2-yl]methyl 6-(3-chloro-4-cyclopropoxyphenyl)pyrimidine-4-carboxylate,
6-(3-chloro-4-{[1-(morpholin-4-yl)propan-2-yl]oxy}phenyl)pyrimidine-4-carboxylic acid,
6-[3-chloro-4-(cyclopropoxymethyl)phenyl]pyrimidine-4-carboxylic acid,
6-[3-chloro-4-(cyclopropylmethyl)phenyl]pyrimidine-4-carboxylic acid,
6-[3-chloro-4-(cyclopropylsulfanyl)phenyl]pyrimidine-4-carboxylic acid,
6-[3-chloro-4-(cyclopropanesulfinyl)phenyl]pyrimidine-4-carboxylic acid,
6-[3-chloro-4-(cyclopropanesulfonyl)phenyl]pyrimidine-4-carboxylic acid,
6-{3-chloro-4-[cyclopropyl(hydroxy)methyl]phenyl}pyrimidine-4-carboxylic acid,
6-[3-chloro-4-(1-cyclopropoxyethyl)phenyl]pyrimidine-4-carboxylic acid,
6-(3-chloro-4-cyclopropanecarbonylphenyl)pyrimidine-4-carboxylic acid,
6-(3-chloro-4-cyclopropylphenyl)pyrimidine-4-carboxylic acid,
6-[4-(aziridin-1-ylmethyl)-3-chlorophenyl]pyrimidine-4-carboxylic acid,
6-{3-chloro-4-[(dimethylamino)methyl]phenyl}pyrimidine-4-carboxylic acid
6-[3-chloro-4-(cyclopropylamino)phenyl]pyrimidine-4-carboxylic acid,
6-{3-chloro-4-[cyclopropyl(methyl)amino]phenyl}pyrimidine-4-carboxylic acid,
6-{3-chloro-4-[(cyclopropylamino)methyl]phenyl}pyrimidine-4-carboxylic acid,
6-(3-chloro-4-{[cyclopropyl(methyl)amino]methyl}phenyl)pyrimidine-4-carboxylic acid,
6-(7-chloro-2-cyclopropyl-2,3-dihydro-1H-isoindol-5-yl)pyrimidine-4-carboxylic acid,
6-[3-chloro-4-(furan-2-yl)phenyl]pyrimidine-4-carboxylic acid,
6-[3-chloro-4-(1-methoxycyclopropyl)phenyl]pyrimidine-4-carboxylic acid,
6-(2,3-dihydro-1,4-benzodioxin-6-yl)pyrimidine-4-carboxylic acid,
6-(7-chloro-2-methyl-1,3-benzoxazol-5-yl)pyrimidine-4-carboxylic acid,
6-(7-chloro-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)pyrimidine-4-carboxylic acid,
6-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)pyrimidine-4-carboxylic acid,
6-(7-chloro-2-cyclopropyl-1,3-benzoxazol-5-yl)pyrimidine-4-carboxylic acid,
6-{8-chloroimidazo[1,2-a]pyridin-6-yl}pyrimidine-4-carboxylic acid,
6-(4-chloro-1,3-benzoxazol-6-yl)pyrimidine-4-carboxylic acid,
6-(quinolin-6-yl)pyrimidine-4-carboxylic acid,
6-{pyrazolo[1,5-a]pyridin-5-yl}pyrimidine-4-carboxylic acid,
6-(4-chloro-3-cyclopropoxyphenyl)pyrimidine-4-carboxylic acid,
6-(4-chloro-3-methoxyphenyl)pyrimidine-4-carboxylic acid,
6-[4-chloro-3-(propan-2-yloxy)phenyl]pyrimidine-4-carboxylic acid,
6-[4-chloro-3-(2-methylpropoxy)phenyl]pyrimidine-4-carboxylic acid,
6-[4-chloro-3-(trifluoromethoxy)phenyl]pyrimidine-4-carboxylic acid,
6-{4-chloro-3-[(1,1,1-trifluoropropan-2-yl)oxy]phenyl}pyrimidine-4-carboxylic acid,
6-(benzo[d][1,3]dioxol-5-yl)pyrimidine-4-carboxylic acid,
6-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrimidine-4-carboxylic acid,
6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrimidine-4-carboxylic acid,
6-(7-chlorobenzo[b]thiophen-5-yl)pyrimidine-4-carboxylic acid,
6-(7-chlorobenzo[d]thiazol-5-yl)pyrimidine-4-carboxylic acid,
6-(7-chlorobenzo[d]oxazol-5-yl)pyrimidine-4-carboxylic acid,
6-(7-chlorobenzo[c][1,2,5]oxadiazol-5-yl)pyrimidine-4-carboxylic acid,
6-(7-chloro-2,3,3a,7a-tetrahydrobenzofuran-5-yl)pyrimidine-4-carboxylic acid,
6-(7-chloro-3a,7a-dihydro-1H-indol-5-yl)pyrimidine-4-carboxylic acid,
6-(7-chloro-1-methyl-3a,7a-dihydro-1H-indazol-5-yl)pyrimidine-4-carboxylic acid,
6-(8-chloroquinazolin-6-yl)pyrimidine-4-carboxylic acid,
6-(5-chloroquinazolin-7-yl)pyrimidine-4-carboxylic acid,
6-(8-chloroquinoxalin-6-yl)pyrimidine-4-carboxylic acid,
6-(8-chloro-1,2,3,4-tetrahydroquinolin-6-yl)pyrimidine-4-carboxylic acid,
6-(7-chloro-1H-benzo[d]imidazol-5-yl)pyrimidine-4-carboxylic acid,
6-(3-chloro-4-(1-methylcyclopropyl)phenyl)pyrimidine-4-carboxylic acid,
6-(3-chloro-4-(1-(trifluoromethyl)cyclopropyl)phenyl)pyrimidine-4-carboxylic acid,
6-(3-chloro-4-(3-methyloxetan-3-yl)phenyl)pyrimidine-4-carboxylic acid,
6-(3-chloro-4-(pyrrolidin-1-yl)phenyl)pyrimidine-4-carboxylic acid,
6-(3-chloro-4-(pyrrolidin-3-yl)phenyl)pyrimidine-4-carboxylic acid,
6-(3-chloro-4-(pyrrolidin-2-yl)phenyl)pyrimidine-4-carboxylic acid,
6-(3-chloro-4-(1H-imidazol-2-yl)phenyl)pyrimidine-4-carboxylic acid,
6-(3-chloro-4-(1H-pyrrol-2-yl)phenyl)pyrimidine-4-carboxylic acid,
6-(4-tert-butyl-3-chlorophenyl)pyrimidine-4-carboxylic acid, and
7-chloro-8-cyclopropoxy-5H-chromeno[4,3-d]pyrimidine-4-carboxylic acid.

### Claim 34 (depends on 1)

At least one chemical entity of claim 1, wherein the compound of Formula I is chosen from
6-[3-chloro-4-(methylsulfanyl)phenyl]pyrimidine-4-carboxylic acid,
6-[3-chloro-4-(methylsulfinyl)phenyl]pyrimidine-4-carboxylic acid,
6-[3-chloro-4-(methylsulfonyl)phenyl]pyrimidine-4-carboxylic acid,
6-{3-chloro-4-[cyclopropyl(hydroxy)methyl]phenyl}pyrimidine-4-carboxylic acid,
6-(3-chloro-4-cyclopropanecarbonylphenyl)pyrimidine-4-carboxylic acid,
6-[3-chloro-4-(methoxymethyl)phenyl]pyrimidine-4-carboxylic acid,
6-[3-chloro-4-(1-methoxyethyl)phenyl]pyrimidine-4-carboxylic acid,
6-{3-chloro-4-[(dimethylamino)methyl]phenyl}pyrimidine-4-carboxylic acid,
6-[3-chloro-4-(cyclopropylamino)phenyl]pyrimidine-4-carboxylic acid,
6-{3-chloro-4-[cyclopropyl(methyl)amino]phenyl}pyrimidine-4-carboxylic acid,
6-(3-chloro-4-(pyrrolidin-1-yl)phenyl)pyrimidine-4-carboxylic acid,
6-(7-chloro-2-methyl-1,3-benzoxazol-5-yl)pyrimidine-4-carboxylic acid,
6-(8-chloroquinoxalin-6-yl)pyrimidine-4-carboxylic acid,
6-(7-chloro-2,3-dihydro-1-benzofuran-5-yl)pyrimidine-4-carboxylic acid,
6-(7-chloro-2-cyclopropyl-1,3-benzoxazol-5-yl)pyrimidine-4-carboxylic acid,
6-(4-chloro-2-methyl-1,3-benzoxazol-6-yl)pyrimidine-4-carboxylic acid,
6-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)pyrimidine-4-carboxylic acid,
6-(2H-1,3-benzodioxol-5-yl)pyrimidine-4-carboxylic acid,
4-(3,4-dichlorophenyl)-5-methylpyridine-2-carboxylic acid,
6-(3-chloro-4-{[1-(morpholin-4-yl)propan-2-yl]oxy}phenyl)pyrimidine-4-carboxylic acid,
6-[3-chloro-4-(cyclopropoxymethyl)phenyl]pyrimidine-4-carboxylic acid,
6-[3-chloro-4-(cyclopropylmethyl)phenyl]pyrimidine-4-carboxylic acid,
6-[3-chloro-4-(1-cyclopropoxyethyl)phenyl]pyrimidine-4-carboxylic acid,
6-(3-chloro-4-cyclopropylphenyl)pyrimidine-4-carboxylic acid,
6-[4-(aziridin-1-ylmethyl)-3-chlorophenyl]pyrimidine-4-carboxylic acid,
6-{3-chloro-4-[(cyclopropylamino)methyl]phenyl}pyrimidine-4-carboxylic acid,
6-(3-chloro-4-{[cyclopropyl(methyl)amino]methyl}phenyl)pyrimidine-4-carboxylic acid,
6-(7-chloro-2-cyclopropyl-2,3-dihydro-1H-isoindol-5-yl)pyrimidine-4-carboxylic acid,
6-[3-chloro-4-(furan-2-yl)phenyl]pyrimidine-4-carboxylic acid,
6-[3-chloro-4-(1-methoxycyclopropyl)phenyl]pyrimidine-4-carboxylic acid,
6-(2,3-dihydro-1,4-benzodioxin-6-yl)pyrimidine-4-carboxylic acid,
6-(7-chloro-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)pyrimidine-4-carboxylic acid,
6-{8-chloroimidazo[1,2-a]pyridin-6-yl}pyrimidine-4-carboxylic acid,
6-(4-chloro-1,3-benzoxazol-6-yl)pyrimidine-4-carboxylic acid,
6-(quinolin-6-yl)pyrimidine-4-carboxylic acid,
6-{pyrazolo[1,5-a]pyridin-5-yl}pyrimidine-4-carboxylic acid,
6-(4-chloro-3-cyclopropoxyphenyl)pyrimidine-4-carboxylic acid,
6-(4-chloro-3-methoxyphenyl)pyrimidine-4-carboxylic acid,
6-[4-chloro-3-(propan-2-yloxy)phenyl]pyrimidine-4-carboxylic acid,
6-[4-chloro-3-(2-methylpropoxy)phenyl]pyrimidine-4-carboxylic acid,
6-[4-chloro-3-(trifluoromethoxy)phenyl]pyrimidine-4-carboxylic acid,
6-{4-chloro-3-[(1,1,1-trifluoropropan-2-yl)oxy]phenyl}pyrimidine-4-carboxylic acid,
6-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrimidine-4-carboxylic acid,
6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrimidine-4-carboxylic acid,
6-(7-chlorobenzo[b]thiophen-5-yl)pyrimidine-4-carboxylic acid,
6-(7-chlorobenzo[d]thiazol-5-yl)pyrimidine-4-carboxylic acid,
6-(7-chlorobenzo[d]oxazol-5-yl)pyrimidine-4-carboxylic acid,
6-(7-chlorobenzo[c][1,2,5]oxadiazol-5-yl)pyrimidine-4-carboxylic acid,
6-(7-chloro-3a,7a-dihydro-1H-indol-5-yl)pyrimidine-4-carboxylic acid,
6-(7-chloro-1-methyl-3a,7a-dihydro-1H-indazol-5-yl)pyrimidine-4-carboxylic acid,
6-(8-chloroquinazolin-6-yl)pyrimidine-4-carboxylic acid,
6-(5-chloroquinazolin-7-yl)pyrimidine-4-carboxylic acid,
6-(7-chloro-1H-benzo[d]imidazol-5-yl)pyrimidine-4-carboxylic acid,
6-(3-chloro-4-(1-methylcyclopropyl)phenyl)pyrimidine-4-carboxylic acid,
6-(3-chloro-4-(1-(trifluoromethyl)cyclopropyl)phenyl)pyrimidine-4-carboxylic acid,
6-(3-chloro-4-(3-methyloxetan-3-yl)phenyl)pyrimidine-4-carboxylic acid,
6-(3-chloro-4-(pyrrolidin-2-yl)phenyl)pyrimidine-4-carboxylic acid,
6-(3-chloro-4-(1H-imidazol-2-yl)phenyl)pyrimidine-4-carboxylic acid,
6-(3-chloro-4-(1H-pyrrol-2-yl)phenyl)pyrimidine-4-carboxylic acid,
6-(4-tert-butyl-3-chlorophenyl)pyrimidine-4-carboxylic acid, and
7-chloro-8-cyclopropoxy-5H-chromeno[4,3-d]pyrimidine-4-carboxylic acid.

### Claim 35 (depends on 1)

A pharmaceutical composition comprising at least one chemical entity of claim 1 and at least one pharmaceutically acceptable excipient.

### Claim 36 (depends on 1)

A method of treating a condition or disorder mediated by Kynurenine 3-mono-oxygenase activity in a subject in need of such a treatment which method comprises administering to the subject a therapeutically effective amount of at least one chemical entity of claim 1.

### Claim 37 (depends on 36)

The method of claim 36 wherein said condition or disorder involves a neurodegenerative pathology.

### Claim 38 (depends on 35)

A packaged pharmaceutical composition comprising at least one pharmaceutical composition according claim 35 and instructions for using the composition to treat a subject suffering from a condition or disorder mediated by Kynurenine 3-mono-oxygenase activity.

### Claim 39 (depends on 38)

The packaged pharmaceutical composition according to claim 38, wherein the condition or disorder is Huntington's disease.