KYNURENINE-3-MONOOXYGENASE INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND METHODS OF USE THEREOF

Abstract

Certain compounds, or pharmaceutically acceptable salts or prodrugs thereof, are provided herein. Also provided are pharmaceutical compositions comprising at least one compound, or pharmaceutically acceptable salt or prodrug thereof, described herein 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 compound, or pharmaceutically acceptable salt or prodrug thereof, described herein 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 compound, or pharmaceutically acceptable salt or prodrug thereof, described herein as a single active agent or administering at least one compound, or pharmaceutically acceptable salt or prodrug thereof, described herein in combination with one or more other therapeutic agents. Also provided are methods for screening compounds capable of inhibiting KMO activity.

Claims

1.-21. (canceled)

22. A method of treating a condition or disorder mediated by Kynurenine 3 mono-oxygenase activity in a subject in need of such a treatment, wherein the method comprises administering to the subject a therapeutically effective amount of at least one compound of formula: ##STR00153## or a pharmaceutically acceptable salt or prodrug thereof, wherein R.sub.1 is 1,3-benzothiazol-2-yl, 2-methyl-1,3-benzothiazol-6-yl, 8-chloroquinoxalin-6-yl, 8-chloroquinolin-6-yl, 7-chloro-2-methyl-1-benzofuran-5-yl, 7-chloro-1-benzofuran-5-yl, 8-chloroisoquinolin-6-yl, 5-chloroquinazolin-7-yl, 8-chloroquinazolin-6-yl, 8-chlorocinnolin-6-yl, 4-chlorobenzo[d]oxazol-6-yl, 4-chloro-2-methylbenzo[d]oxazol-6-yl, 4-chloro-1H-benzo[d]imidazol-6-yl, 7-chlorobenzo[d]oxazol-5-yl, 7-chloro-2-methylbenzo[d]oxazol-5-yl, 7-chlorobenzo[d]thiazol-5-yl, 7-chloro-2-methylbenzo[d]thiazol-5-yl, 7-chloro-1H-indol-5-yl, 7-chloro-1H-indazol-5-yl, 7-chloro-1-methyl-1H-indazol-5-yl, 7-chlorobenzo[d]isoxazol-5-yl, 7-chloro-1-methyl-1H-indol-5-yl, or 7-chlorobenzofuran-5-yl; X is CR.sub.2R.sub.3; R.sub.2 and R.sub.3 are independently chosen from hydrogen, optionally substituted amino, hydroxyl, lower alkoxy, and optionally substituted lower alkyl; L is C(O)O; R.sub.5 is hydrogen; and R.sub.6 and R.sub.7 are independently chosen from hydrogen, halo, optionally substituted amino, hydroxyl, lower alkoxy, and optionally substituted lower alkyl.

23. The method of claim 22, wherein said condition or disorder is a neurodegenerative disease.

24. The method of claim 22, wherein said condition or disorder is Huntington's Disease.

25. The method of claim 22, wherein said condition or disorder is a polyglutamine disorder, a spinocerebellar ataxias neurodegenerative disease, a psychiatric of neurological disease or disorder, Alzheimer's disease, Parkinson's disease, amyotropic lateral sclerosis, Creutzfeld-Jacob disease, trauma-induced neurodegeneration, high-pressure neurological syndrome, dystonia, olivopontocerebellar atrophy, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, consequences of stroke, cerebral ischemia, an ischemic disorder, stroke, hypoxia, multi-infarct dementia, consequences of cerebral trauma or damage, damage to the spinal cord, dementia, AIDS-dementia complex, AIDS-induced encephalopathy, other infection related encephalopathy, viral or bacterial meningitis, an infectious disease caused by viral, bacterial and other parasites, cancer, cancer with cerebral localization, hepatic encephalopathy, systemic lupus, an analgesia and opiate withdrawal symptom, feeding behavior, a psychiatric disorder, a disorder of the developing or aged brain, diabetes, Tourette's syndrome, Fragile X syndrome, an autism spectrum disorder, a psychological disorder characterized by abnormalities of emotional state, a cyclothymic disorder, a dysthymic disorder, a mood disorder due to general medical condition, a mood disorder not otherwise specified and substance-induced mood disorders, acute necrotizing pancreatitis, AIDS (disease), analgesia, aseptic meningitis, brain disease, Gilles de la Tourette syndrome, Asperger syndrome, Rett syndrome, a pervasive developmental disorder, aging-related Brain disease, developmental brain disease, burnout syndrome, carbon monoxide poisoning, cardiac arrest or insufficiency and hemorrhagic shock (global brain ischemia), cataract formation and aging of the eye, central nervous system disease, cerebrovascular disease, chronic fatigue syndrome, chronic stress, a cognitive disorder, a convulsive disorder, diabetes mellitus, disease of the nervous system, drug dependence, drug withdrawal, feeding disorders, Guillain Barr Syndrome and other neurophaties, hepatic encephalopathy, immune disease, an immunitary disorder and therapeutic treatment aimed at modifying a biological response, systemic inflammatory response syndrome, an inflammatory disorder of the central or peripheral nervous system, a mental and behavioral disorder, metabolic disease, inflammatory pain, neurophathic pain, migraine, allodynia, hyperalgesis pain, phantom pain, neurophatic pain related to diabetic neuropathy, multiple organ failure, near drowning, necrosis, neoplasms of the brain, a neoplastic disorder, lymphoma, a malignant blood disorder, nervous system disease, nicotine addiction, an addictive disorder, change in appetite, a sleep disorder, changes in sleep pattern, lack of energy, fatigue, low self-esteem, self-reproach inappropriate guilt, frequent thoughts of death or suicide, plans or attempts to commit suicide, feelings of hopelessness and worthlessness, psychomotor agitation or retardation, diminished capacity for thinking, diminished capacity for concentration, diminished capacity for decisiveness, post-traumatic stress disorder, sepsis, spinal cord disease, spinocerebellar ataxias, lupus erythematosis, traumatic damage to the brain and spinal cord, a tremor syndrome, a movement disorder (diskynesia), poor balance, brakykinesia, rigidity, tremor, change in speech, loss of facial expression, micrographia, difficulty swallowing, drooling, dementia, confusion, fear, sexual disfunction, language impairment, impairment in decision making, violent outbursts, aggression, hallucination, apathy, impairment in abstract thinking, cardiovascular diseases, transplant rejection, graft vs host disease, chronic kidney disease, systemic inflammatory disorders, or a brain inflammatory disorder.

26. The method of claim 22, wherein R.sub.2 is hydrogen, hydroxyl, lower alkoxy, amino optionally substituted with one or more alkyl groups, or lower alkyl optionally substituted with one or more groups independently chosen from halo, hydroxyl, lower alkoxy, and amino optionally substituted with one or more alkyl groups.

27. The method of claim 22, wherein R.sub.2 is hydrogen, amino, methylamino, dimethylamino, hydroxyl, methyl, methoxy, difluoromethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, aminomethyl, (methylamino)methyl, or (dimethylamino)methyl.

28. The method of claim 22, wherein R.sub.3 is hydrogen or lower alkyl.

29. The method of claim 22, wherein R.sub.3 is hydrogen or methyl.

30. The method of claim 22, wherein R.sub.2 and R.sub.3 are hydrogen.

31. The method of claim 22, wherein R.sub.2 is methyl and R.sub.3 is hydrogen.

32. The method of claim 22, wherein R.sub.2 and R.sub.3 are methyl.

33. The method of claim 22, wherein R.sub.1 is 7-chlorobenzofuran-5-yl, 7-chloro-2-methylbenzo[d]oxazol-5-yl, or 4-chlorobenzo[d]oxazol-6-yl.

34. The method of claim 22, wherein R.sub.7 is hydrogen, amino, methylamino, dimethylamino, aminomethyl, (methylamino)methyl, (dimethylamino)methyl, methoxymethyl, methyl, 1-aminoethyl, 1-methoxy-ethyl, methoxy, or halo.

35. The method of claim 22, wherein R.sub.7 is methyl.

36. The method of claim 22, wherein R.sub.7 is hydrogen.

37. The method of claim 22, wherein R.sub.6 is hydrogen, amino, methylamino, dimethylamino, aminomethyl, methylaminomethyl, (dimethylamino)methyl, or methyl.

38. The method of claim 22, wherein R.sub.6 is hydrogen.

39. A method of treating a condition or disorder mediated by Kynurenine 3-mono-oxygenase activity in a subject in need of such a treatment, wherein the method comprises administering to the subject a therapeutically effective amount of at least one compound selected from: (1S,2S)-2-(2-methyl-1,3-benzothiazole-6-carbonyl)cyclopropane-1-carboxylic acid, (1S,2S)-2-(7-chloro-1-benzofuran-5-carbonyl)cyclopropane-1-carboxylic acid, (1S,2S)-2-(7-chloro-2-methyl-1-benzofuran-5-carbonyl)cyclopropane-1-carboxylic acid, (1S,2S)-2-(8-chloroquinoline-6-carbonyl)cyclopropane-1-carboxylic acid, (1S,2S)-2-(8-chloroquinoxaline-6-carbonyl)cyclopropane-1-carboxylic acid, (1S,2S)-2-[(1,3-Benzothiazol-2-yl)carbonyl]cyclopropane-1-carboxylic acid, (1S,2S)-2-(8-chloroisoquinoline-6-carbonyl)cyclopropanecarboxylic acid, (1S,2S)-2-(5-chloroquinazoline-7-carbonyl)cyclopropanecarboxylic acid, (1S,2S)-2-(8-chloroquinazoline-6-carbonyl)cyclopropanecarboxylic acid, (1S,2S)-2-(8-chlorocinnoline-6-carbonyl)cyclopropanecarboxylic acid, (1S,2S)-2-(4-chlorobenzo[d]oxazole-6-carbonyl)cyclopropanecarboxylic acid, (1S,2S)-2-(4-chloro-2-methylbenzo[d]oxazole-6-carbonyl)cyclopropanecarboxylic acid, (1S,2S)-2-(4-chloro-1H-benzo[d]imidazole-6-carbonyl)cyclopropanecarboxylic acid, (1S,2S)-2-(7-chlorobenzo[d]oxazole-5-carbonyl)cyclopropanecarboxylic acid, (1S,2S)-2-(7-chloro-2-methylbenzo[d]oxazole-5-carbonyl)cyclopropanecarboxylic acid, (1S,2S)-2-(7-chlorobenzo[d]thiazole-5-carbonyl)cyclopropanecarboxylic acid, (1S,2S)-2-(7-chloro-2-methylbenzo[d]thiazole-5-carbonyl)cyclopropanecarboxylic acid, (1S,2S)-2-(7-chloro-1H-indole-5-carbonyl)cyclopropanecarboxylic acid, (1S,2S)-2-(7-chloro-1H-indazole-5-carbonyl)cyclopropanecarboxylic acid, (1S,2S)-2-(7-chloro-1-methyl-1H-indazole-5-carbonyl)cyclopropanecarboxylic acid, (1S,2S)-2-(7-chlorobenzo[d]isoxazole-5-carbonyl)cyclopropanecarboxylic acid, (1S,2S)-2-(7-chloro-1-methyl-1H-indole-5-carbonyl)cyclopropanecarboxylic acid, (1R,2S)-1-amino-2-(7-chlorobenzofuran-5-carbonyl)cyclopropanecarboxylic acid, (1R,2S)-2-(7-chlorobenzofuran-5-carbonyl)-1-(methylamino)cyclopropanecarboxylic acid, (1R,2S)-2-(7-chlorobenzofuran-5-carbonyl)-1-(dimethylamino)cyclopropanecarboxylic acid, (1S,2S)-1-(aminomethyl)-2-(7-chlorobenzofuran-5-carbonyl)cyclopropanecarboxylic acid, (1S,2S)-2-(7-chlorobenzofuran-5-carbonyl)-1-((methylamino)methyl)cyclopropanecarboxylic acid, (1S,2S)-2-(7-chlorobenzofuran-5-carbonyl)-1-((dimethylamino)methyl)cyclopropanecarboxylic acid, (1S,2S)-2-(7-chlorobenzofuran-5-carbonyl)-1-methylcyclopropanecarboxylic acid, (1R,2R)-2-(7-chlorobenzofuran-5-carbonyl)-1-fluorocyclopropanecarboxylic acid, (1R,2S)-2-(7-chlorobenzofuran-5-carbonyl)-1-methoxycyclopropanecarboxylic acid, (1S,2S)-2-(7-chlorobenzofuran-5-carbonyl)-1-(methoxymethyl)cyclopropanecarboxylic acid, (1R,3R)-2-amino-3-(7-chlorobenzofuran-5-carbonyl)cyclopropanecarboxylic acid, (1R,2R)-2-(7-chlorobenzofuran-5-carbonyl)-3-(methylamino)cyclopropanecarboxylic acid, (1R,2R)-2-(7-chlorobenzofuran-5-carbonyl)-3-(dimethylamino)cyclopropanecarboxylic acid, (1S,2S)-2-(7-chlorobenzofuran-5-carbonyl)-3-methylcyclopropanecarboxylic acid, (1R,3R)-3-(7-chlorobenzofuran-5-carbonyl)-2,2-dimethylcyclopropanecarboxylic acid, (1R,3R)-3-(7-chlorobenzofuran-5-carbonyl)-2-hydroxy-2-methylcyclopropanecarboxylic acid, (1R,3R)-3-(7-chlorobenzofuran-5-carbonyl)-2-(hydroxymethyl)-2-methylcyclopropanecarboxylic acid, (1R,3R)-3-(7-chlorobenzofuran-5-carbonyl)-2-(methoxymethyl)-2-methylcyclopropanecarboxylic acid, (1R,3R)-2-(aminomethyl)-3-(7-chlorobenzofuran-5-carbonyl)-2-methylcyclopropanecarboxylic acid, (1R,3R)-3-(7-chlorobenzofuran-5-carbonyl)-2-methyl-2-((methylamino)methyl)cyclopropanecarboxylic acid, (1R,3R)-2-amino-3-(7-chlorobenzofuran-5-carbonyl)-2-methylcyclopropanecarboxylic acid, (1R,3R)-3-(7-chlorobenzofuran-5-carbonyl)-2-methyl-2-(methylamino)cyclopropanecarboxylic acid, (1S,3 S)-2-(aminomethyl)-3-(7-chlorobenzofuran-5-carbonyl)cyclopropanecarboxylic acid, (1S,2S)-2-(7-chlorobenzofuran-5-carbonyl)-3-((methylamino)methyl)cyclopropanecarboxylic acid, (1S,2S)-2-(7-chlorobenzofuran-5-carbonyl)-3-((dimethylamino)methyl)cyclopropanecarboxylic acid, (1S,2R)-2-amino-2-(7-chlorobenzofuran-5-carbonyl)cyclopropanecarboxylic acid, (1S,2R)-2-(7-chlorobenzofuran-5-carbonyl)-2-(methylamino)cyclopropanecarboxylic acid, (1S,2R)-2-(7-chlorobenzofuran-5-carbonyl)-2-(dimethylamino)cyclopropanecarboxylic acid, (1S,2S)-2-(aminomethyl)-2-(7-chlorobenzofuran-5-carbonyl)cyclopropanecarboxylic acid, (1S,2S)-2-(7-chlorobenzofuran-5-carbonyl)-2-((methylamino)methyl)cyclopropanecarboxylic acid, (1S,2S)-2-(7-chlorobenzofuran-5-carbonyl)-2-((dimethylamino)methyl)cyclopropanecarboxylic acid, and (1S,2S)-2-(7-chlorobenzofuran-5-carbonyl)-2-methylcyclopropanecarboxylic acid, or a pharmaceutically acceptable salt or prodrug thereof.

40. The method of claim 39, wherein said condition or disorder involves a neurodegenerative disease.

41. The method of claim 39, wherein said condition or disorder is Huntington's Disease.

42. The method of claim 39, wherein said condition or disorder is a polyglutamine disorder, a spinocerebellar ataxias neurodegenerative disease, a psychiatric of neurological disease or disorder, Alzheimer's disease, Parkinson's disease, amyotropic lateral sclerosis, Creutzfeld-Jacob disease, trauma-induced neurodegeneration, high-pressure neurological syndrome, dystonia, olivopontocerebellar atrophy, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, consequences of stroke, cerebral ischemia, an ischemic disorder, stroke, hypoxia, multi-infarct dementia, consequences of cerebral trauma or damage, damage to the spinal cord, dementia, AIDS-dementia complex, AIDS-induced encephalopathy, other infection related encephalopathy, viral or bacterial meningitis, an infectious disease caused by viral, bacterial and other parasites, cancer, cancer with cerebral localization, hepatic encephalopathy, systemic lupus, an analgesia and opiate withdrawal symptom, feeding behavior, a psychiatric disorder, a disorder of the developing or aged brain, diabetes, Tourette's syndrome, Fragile X syndrome, an autism spectrum disorder, a psychological disorder characterized by abnormalities of emotional state, a cyclothymic disorder, a dysthymic disorder, a mood disorder due to general medical condition, a mood disorder not otherwise specified and substance-induced mood disorders, acute necrotizing pancreatitis, AIDS (disease), analgesia, aseptic meningitis, brain disease, Gilles de la Tourette syndrome, Asperger syndrome, Rett syndrome, a pervasive developmental disorder, aging-related Brain disease, developmental brain disease, burnout syndrome, carbon monoxide poisoning, cardiac arrest or insufficiency and hemorrhagic shock (global brain ischemia), cataract formation and aging of the eye, central nervous system disease, cerebrovascular disease, chronic fatigue syndrome, chronic stress, a cognitive disorder, a convulsive disorder, diabetes mellitus, disease of the nervous system, drug dependence, drug withdrawal, feeding disorders, Guillain Barr Syndrome and other neurophaties, hepatic encephalopathy, immune disease, an immunitary disorder and therapeutic treatment aimed at modifying a biological response, systemic inflammatory response syndrome, an inflammatory disorder of the central or peripheral nervous system, a mental and behavioral disorder, metabolic disease, inflammatory pain, neurophathic pain, migraine, allodynia, hyperalgesis pain, phantom pain, neurophatic pain related to diabetic neuropathy, multiple organ failure, near drowning, necrosis, neoplasms of the brain, a neoplastic disorder, lymphoma, a malignant blood disorder, nervous system disease, nicotine addiction, an addictive disorder, change in appetite, a sleep disorder, changes in sleep pattern, lack of energy, fatigue, low self-esteem, self-reproach inappropriate guilt, frequent thoughts of death or suicide, plans or attempts to commit suicide, feelings of hopelessness and worthlessness, psychomotor agitation or retardation, diminished capacity for thinking, diminished capacity for concentration, diminished capacity for decisiveness, post-traumatic stress disorder, sepsis, spinal cord disease, spinocerebellar ataxias, lupus erythematosis, traumatic damage to the brain and spinal cord, a tremor syndrome, a movement disorder (diskynesia), poor balance, brakykinesia, rigidity, tremor, change in speech, loss of facial expression, micrographia, difficulty swallowing, drooling, dementia, confusion, fear, sexual disfunction, language impairment, impairment in decision making, violent outbursts, aggression, hallucination, apathy, impairment in abstract thinking, cardiovascular diseases, transplant rejection, graft vs host disease, chronic kidney disease, systemic inflammatory disorders, or a brain inflammatory disorder.

Description

EXAMPLES

[0173] The compounds, pharmaceutically acceptable salts and prodrugs thereof, described herein, compositions, and methods described herein are further illustrated by the following non-limiting examples.

[0174] As used herein, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning.

[0175] CDI=carbonyldiimidazole

[0176] DCM=dichloromethane

[0177] DME=dimethyl ether

[0178] DMEM=Dulbecco's modified Eagle's medium

[0179] DMF=N,N-dimethylformamide

[0180] DMSO=dimethylsulfoxide

[0181] EDC.HCl=1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0182] EtOH=ethanol

[0183] Et.sub.2O=diethylether

[0184] EtOAc=ethyl acetate

[0185] g=gram

[0186] hr=hour

[0187] hrs=hours

[0188] HOBt=1-Hydroxybenzotriazol

[0189] LiHMDS=lithium hexamethyl-disilazide

[0190] LC/MS=liquid chromatography/mass spectrometry

[0191] mg=milligram

[0192] min=minutes

[0193] mL=milliliter

[0194] mmol=millimoles

[0195] mM=millimolar

[0196] ng=nanogram

[0197] nm=nanometer

[0198] nM=nanomolar

[0199] PBS=phosphate buffered saline

[0200] rt=room temperature

[0201] TBME=t-butyl methyl ether

[0202] THF=tetrahydrofuran

[0203] TMOF=trimethylorthoformate

[0204] L=microliter

[0205] M=micromolar

[0206] 1 g/1 ml=1 vol

Experimental

[0207] Commercially available reagents and solvents (HPLC grade) were used without further purification.

[0208] Thin-layer chromatography (TLC) analysis was performed with Kieselgel 60 F.sub.254 (Merck) plates and visualized using UV light. Microwave reactions were carried out using CEM focussed microwaves.

[0209] .sup.1H NMR spectra were recorded on a Bruker DRX 500 MHz spectrometer or Bruker DPX 250 MHz spectrometer in deuterated solvents.

[0210] Analytical HPLC-MS was performed on Agilent HP1100 and Shimadzu 2010, systems using reverse phase Atlantis dC18 columns (5 m, 2.150 mm), gradient 5-100% B (A=water/0.1% formic acid, B=acetonitrile/0.1% formic acid) over 2 or 3.5 minutes, injection volume 3 l, flow=1.0 ml/min. UV spectra were recorded at 215 nm using a Waters 2487 dual wavelength UV detector or the Shimadzu 2010 system. Mass spectra were obtained over the range m/z 150 to 850 at a sampling rate of 2 scans per second using Waters ZMD and over m/z 100 to 1000 at a sampling rate of 2 Hz using Electrospray ionisation, by a Shimadzu 2010 LC-MS system, or analytical HPLC-MS was performed on Agilent HP1100 and Shimadzu 2010, systems using reverse phase Water Atlantis dC18 columns (3 m, 2.1100 mm), gradient 5-100% B (A=water/0.1% formic acid, B=acetonitrile/0.1% formic acid) over 7 min, injection volume 3 l, flow=0.6 ml/min. UV spectra were recorded at 215 nm using a Waters 2996 photo diode array or on the Shimadzu 2010 system. Mass spectra were obtained over the range m/z 150 to 850 at a sampling rate of 2 scans per second using Waters ZQ and over m/z 100 to 1000 at a sampling rate of 2 Hz using Electrospray ionisation, by a Shimadzu 2010 LC-MS system. Data were integrated and reported using OpenLynx and OpenLynx Browser software or via Shimadzu PsiPort software.

Method 1

Scheme for Method 1: (+)-(1S,2S)-cyclopropane-1,2-dicarboxylic acid Monomethyl Ester was Prepared as Described in EP1475385, 2004

[0211] ##STR00003##

Step 1, Method 1: Methyl (1S,2S)-2-[methoxy(methyl)carbamoyl]cyclopropane-1-carboxylate

[0212] Oxalyl chloride (0.4 mL, 4.6 mmol) was added dropwise over 5 minutes to a round bottomed flask containing (+)-(1S,2S)-cyclopropane-1,2-dicarboxylic acid monomethyl ester (0.1 g, 0.69 mmol) at room temperature under a nitrogen atmosphere and the resulting mixture was stirred for 2 hours. After this time, the reaction mixture was concentrated and the resulting residue was re-dissolved in DCM (1 mL). N,O-Dimethylhydroxylamine (0.08 g, 0.76 mmol) and pyridine (0.12 mL, 1.5 mmol) were then added sequentially to the mixture and the resulting mixture was stirred at room temperature for 18 hours. The mixture was then diluted with DCM (10 mL) and washed sequentially with water (10 mL), saturated sodium bicarbonate (10 mL) and brine (10 mL) before being dried (MgSO.sub.4), filtered and concentrated to give the title compound (0.12 g, 92% yield) as a colourless oil which was used directly without further purification.

Step 2, Method 1: Methyl (1S,2S)-2-[(5-chlorothiophen-2-yl)carbonyl]cyclopropane-1-carboxylate

[0213] 5-Chloro-2-thienyl magnesium bromide (0.5M solution in THF, 1.28 mL, 0.64 mmol) was added dropwise to a cooled (0 C.) solution of methyl (1S,2S)-2-[methoxy(methyl)carbamoyl]cyclopropane-1-carboxylate (0.08 g, 0.43 mmol) in THF (1 mL) under a nitrogen atmosphere. Upon complete addition, the mixture was warmed to room temperature and stirred for 2 hours. After this time the reaction mixture was quenched by the addition of 2M HCl solution (2 mL) and the resulting mixture diluted with water (5 mL) before being extracted with DCM (310 mL). The combined organic extracts were washed with brine (10 mL) before being dried (MgSO.sub.4), filtered and concentrated. The resulting residue was purified by flash column chromatography (elution: 10% ethyl acetate, 90% heptane) to give the title compound (0.04 g, 40% yield) as a green oil. Tr=2.04 min (3.5 minute method) m/z (ES.sup.+) (M+H.sup.+) 245.

Intermediate 2, Step 2, Method 1: Methyl (1S,2S)-2-[(Thiophen-3-yl)carbonyl]cyclopropane-1-carboxylate

[0214] Tr=1.71 min (3.5 minute method) m/z (ES.sup.+) (M+H.sup.+) 211.

Intermediate 3, Step 2, Method 1: Methyl (1S,2S)-2-[(thiophen-2-yl)carbonyl]cyclopropane-1-carboxylate

[0215] Tr=1.74 min (3.5 minute method) m/z (ES.sup.+) (M+H.sup.+) 211.

Step 3, Method 1: (1S,2S)-2-[(5-Chlorothiophen-2-yl)carbonyl]cyclopropane-1-carboxylic acid

[0216] NaOH (1M solution, 1.0 mL, 1.0 mmol) was added in one portion to a stirred solution of methyl (1S,2S)-2-[(5-chlorothiophen-2-yl)carbonyl]cyclopropane-1-carboxylate (0.04 g, 0.16 mmol) in Methanol (1 mL) and the mixture was stirred at room temperature for 1 hour. After this time, the reaction mixture was partitioned between water (5 mL) and DCM (5 mL). The aqueous layer was removed, acidified to pH 1 with 2M HCl and extracted with DCM (35 mL). The combined organic extracts were combined, dried (MgSO.sub.4), filtered and concentrated to give the title compound (0.02 g, 51% yield) as a yellow solid.

Example 1, Method 1: (1S,2S)-2-[(5-Chlorothiophen-2-yl)carbonyl]cyclopropane-1-carboxylic acid

[0217] .sub.H (500 MHz, DMSO) 8.18 (d, J=4.17 Hz, 1H), 7.34 (d, J=4.14 Hz, 1H), 3.17 (ddd, J=3.83, 5.53, 8.94 Hz, 1H), 2.08 (ddd, J=3.79, 5.99, 8.73 Hz, 1H), 1.45 (dddd, J=3.45, 5.76, 8.88, 14.01 Hz, 2H). Tr=3.71 min m/z (ES.sup.+) (M+H.sup.+) 231.

[0218] The following compounds were prepared substantially as described above.

Example 2, Method 1: (1S,2S)-2-[(Thiophen-3-yl)carbonyl]cyclopropane-1-carboxylic acid

[0219] .sub.H (500 MHz, DMSO) 8.79 (dd, J=1.24, 2.75 Hz, 1H), 7.67 (dd, J=2.79, 5.06 Hz, 1H), 7.53 (dd, J=1.23, 5.07 Hz, 1H), 3.14 (ddd, J=3.82, 5.58, 9.09 Hz, 1H), 2.06 (ddd, J=3.79, 5.88, 8.71 Hz, 1H), 1.43 (dddd, J=3.32, 5.74, 8.80, 14.07 Hz, 2H). Tr=3.12 min m/z (ES.sup.+) (M+H.sup.+) 197.

Example 3, Method 1: (1S,2S)-2-[(Thiophen-2-yl)carbonyl]cyclopropane-1-carboxylic acid

[0220] .sub.H (500 MHz, DMSO) 8.22 (dd, J=0.97, 3.82 Hz, 1H), 8.07 (dd, J=0.97, 4.93 Hz, 1H), 7.28 (dd, J=3.89, 4.88 Hz, 1H), 3.17 (ddd, J=3.81, 5.71, 8.56 Hz, 1H), 2.08 (ddd, J=3.77, 6.03, 8.53 Hz, 1H), 1.51-1.38 (m, 2H). Tr=3.13 min m/z (ES.sup.+) (M+H.sup.+) 197.

TABLE-US-00004 Molecular % Inhibition Structure IUPAC Name Weight LCMS Data at 30 M [00004] (1S,2S)-2-[(5- Chlorothiophen-2- yl)carbonyl]cyclopropane- 1-carboxylic acid 230 Tr = 3.71 min m/z (ES.sup.+) (M + H.sup.+) 231 100.7 [00005] (1S,2S)-2-[(Thiophen-3- yl)carbonyl]cyclopropane- 1-carboxylic acid 196 Tr = 3.12 min m/z (ES.sup.+) (M + H.sup.+) 197 83.2 [00006] (1S,2S)-2-[(Thiophen-2- yl)carbonyl]cyclopropane- 1-carboxylic acid 196 Tr = 3.13 min m/z (ES.sup.+) (M + H.sup.+) 197 80.3

Method 2

Scheme for Method 2: (+)-(1S,2S)-cyclopropane-1,2-dicarboxylic acid Monomethyl Ester was Prepared as Described in EP1475385, 2004

[0221] ##STR00007##

Step 1, Method 2: (1S,2S)-2-[(1,3-Thiazol-2-yl)carbonyl]cyclopropane-1-carboxylic acid

[0222] n-Butyl lithium (1.6M solution in THF, 0.87 mL, 1.4 mmol) was added dropwise over 5 minutes to a cold (70 C.), stirred solution of 2-bromothiazole (0.23 g, 1.4 mmol) in THF (1 mL) under a nitrogen atmosphere and the mixture was stirred for 30 minutes. After this time, (+)-(1S,2S)-cyclopropane-1,2-dicarboxylic acid monomethyl ester (0.1 g, 0.69 mmol) in THF (1 mL) was added dropwise over 10 minutes and stirring was continued for 1 hour. After this time the reaction mixture was quenched by the addition of 2M HCl solution (2 mL) and the resulting mixture diluted with water (5 mL) before being extracted with DCM (310 mL). The combined organic extracts were dried (MgSO.sub.4), filtered and concentrated. The resulting residue was purified by prep HPLC to give the title compound (0.01 g, 4% yield) as a colourless oil.

Example 1, Method 2: (1S,2S)-2-[(1,3-Thiazol-2-yl)carbonyl]cyclopropane-1-carboxylic acid

[0223] .sub.H (500 MHz, DMSO) 8.28 (d, J=3.01 Hz, 1H), 8.21 (d, J=3.01 Hz, 1H), 3.48 (td, J=3.76, 7.46 Hz, 1H), 2.16-2.03 (m, 1H), 1.58-1.46 (m, 2H). Tr=2.92 min m/z (ES.sup.+) (M+H.sup.+) 198.

[0224] The following compounds were prepared substantially as described above.

Example 2, Method 2: (1S,2S)-2-[(1,3-Benzothiazol-2-yl)carbonyl]cyclopropane-1-carboxylic acid

[0225] .sub.H (400 MHz, DMSO) 8.29 (ddd, J=1.72, 6.90, 17.74 Hz, 2H), 7.67 (pd, J=1.43, 7.16 Hz, 2H), 3.72-3.59 (m, 1H), 2.26 (td, J=3.82, 7.29 Hz, 1H), 1.73-1.55 (m, 2H). Tr=3.73 min m/z (ES.sup.+) (M+H.sup.+) 248.

Example 3, Method 2: (1S,2S)-2-[(Pyridin-2-yl)carbonyl]cyclopropane-1-carboxylic acid

[0226] .sub.H (400 MHz, CDCl.sub.3) 8.76 (d, J=4.10 Hz, 1H), 8.05 (d, J=7.82 Hz, 1H), 7.88 (td, J=1.67, 7.71 Hz, 1H), 7.54 (ddd, J=1.24, 4.81, 7.52 Hz, 1H), 4.12-3.94 (m, 1H), 2.36 (s, OH), 1.86-1.57 (m, 2H). Tr=2.82 min m/z (ES.sup.+) (M+H.sup.+) 192.

TABLE-US-00005 Molecular % Inhibition Structure IUPAC Name Weight LCMS Data at 30 M [00008] (1S,2S)-2-[(1,3-Thiazol-2 yl)carbonyl]cyclopropane- 1-carboxylic acid 197 Tr = 2.92 min m/z (ES.sup.+) (M + H.sup.+) 198 28.7 (at 10 uM) [00009] (1S,2S)-2-[(1,3- Benzothiazol-2- yl)carbonyl]cyclopropane- 1-carboxylic acid 247 Tr = 3.73 min m/z (ES.sup.+) (M + H.sup.+) 248 91.8 [00010] (1S,2S)-2-[(Pyridin-2- yl)carbonyl]cyclopropane- 1-carboxylic acid 191 Tr = 2.82 min m/z (ES.sup.+) (M + H.sup.+) 192 45.6

Method 3

Scheme for Method 3: (1S,2S)-2-(2-Methyl-1,3-benzothiazole-6-carbonyl)cyclopropane-1-carboxylic acid

[0227] ##STR00011##

Step 1, Method 3: 2-Methyl-6-(trimethylstannyl)-1,3-benzothiazole

[0228] 6-Bromo-2-methyl-1,3-benzothiazole (820 mg, 3.60 mmol) and lithium chloride (170 mg, 3.95 mmol) were dissolved in anhydrous dioxane (10 ml) and degassed with nitrogen for 5 min. Hexamethyldistannane (0.82 ml, 3.95 mmol) and Pd(PPh.sub.3).sub.4 (210 mg, 1.18 mmol) were added and the reaction was stirred at 100 C. for 1 h. The dark reaction mixture was cooled to room temperature and concentrated to give a black residue. Column chromatography (eluent: 0-15% EtOAc-heptane) afforded the title compound as an orange oil (906 mg, 76%). .sub.H (500 MHz, CDCl.sub.3) 8.00-7.85 (m, 2H), 7.61-7.48 (m, 1H), 2.84 (s, 3H), 0.43-0.25 (m, 9H). Tr=2.47 min m/z (ES.sup.+) (M+H.sup.+) 314, 316.

Intermediate 2, Step 1, Method 3: 5-Chloro-7-(trimethylstannyl)quinoxaline

[0229] .sub.H (500 MHz, DMSO-d6) 8.94 (d, J=1.64 Hz, 1H), 8.90 (d, J=1.56 Hz, 1H), 8.27-8.11 (m, 1H), 8.10-7.85 (m, 1H), 0.60-0.24 (m, 9H). Tr=2.20 min m/z (ES.sup.+) (M+H.sup.+) 325, 327, 329, 331, 333.

Intermediate 3, Step 1, Method 3: 8-Chloro-6-(trimethylstannyl)quinoline

[0230] Tr=2.40 min m/z (ES.sup.+) (M+H.sup.+) 326, 328, 330.

Step 2, Method 3: Methyl (1S,2S)-2-(2-methyl-1,3-benzothiazole-6-carbonyl)cyclopropane-1-carboxylate

[0231] 2-Methyl-6-(trimethylstannyl)-1,3-benzothiazole (94% purity, 902 mg, 2.89 mmol) and methyl (1S,2S)-2-(carbonochloridoyl)cyclopropane-1-carboxylate (470 mg, 2.89 mmol) were dissolved in anhydrous toluene (20 ml) and de-oxygenated with stream of nitrogen for 5 min. PdCl.sub.2(PPh.sub.3).sub.2 (101 mg, 0.145 mmol) was added and the reaction was stirred at 110 C. under nitrogen for 2 h. The reaction mixture was cooled to room temperature and concentrated to afford a black residue. Column chromatography (eluent 0-80% EtOAc-heptane) afforded the title compound as an orange oil (486 mg, 55%). .sub.H (500 MHz, DMSO-d6) 8.93 (d, J=1.6 Hz, 1H), 8.10 (dd, J=8.6, 1.8 Hz, 1H), 8.02 (d, J=8.5 Hz, 1H), 3.68 (s, 3H), 3.46-3.36 (m, 1H), 2.86 (s, 3H), 2.26 (ddd, J=8.6, 5.9, 3.9 Hz, 1H), 1.56 (dtd, J=11.0, 5.8, 2.9 Hz, 2H). Tr=1.88 min m/z (ES.sup.+) (M+H.sup.+) 276.

Intermediate 2, Step 2, Method 3: Methyl (1S,2S)-2-(8-chloroquinoxaline-6-carbonyl)cyclopropane-1-carboxylate

[0232] .sub.H (500 MHz, DMSO-d6) 9.06 (d, J=1.72 Hz, 1H), 9.02 (d, J=1.68 Hz, 1H), 8.75 (d, J=1.78 Hz, 1H), 8.45 (d, J=1.81 Hz, 1H), 3.77 (s, 3H), 3.34 (ddd, J=3.84, 5.94, 8.27 Hz, 1H), 2.49 (ddd, J=3.81, 6.29, 8.62 Hz, 1H), 1.73 (ddd, J=3.19, 6.17, 11.35 Hz, 2H). Tr=1.98 min m/z (ES.sup.+) (M+H.sup.+) 291, 293.

Intermediate 3, Step 2, Method 3: Methyl (1S,2S)-2-(8-chloroquinoline-6-carbonyl)cyclopropane-1-carboxylate

[0233] .sub.H (500 MHz, DMSO-d6) 9.16 (dd, J=4.26, 1.73 Hz, 1H) 9.01 (d, J=1.73 Hz, 1H) 8.72 (dd, J=8.28, 1.65 Hz, 1H) 8.34 (d, J=1.89 Hz, 1H) 7.80 (dd, J=8.28, 4.18 Hz, 1H) 3.61-3.79 (m, 3H) 3.50 (ddd, J=8.91, 5.44, 3.94 Hz, 1H) 2.29-2.38 (m, 1H) 1.50-1.69 (m, 2H). Tr=1.78 min m/z (ES.sup.+) (M+H.sup.+) 290, 292.

Step 3, Method 3: (1S,2S)-2-(2-Methyl-1,3-benzothiazole-6-carbonyl)cyclopropane-1-carboxylic acid

[0234] Methyl (1S,2S)-2-(2-methyl-1,3-benzothiazole-6-carbonyl)cyclopropane-1-carboxylate (50 mg, 0.182 mmol) was dissolved in dioxane (3 ml) and treated with 2M NaOH (82 l, 0.163 mmol). The reaction mixture was stirred at rt for 72 h. The reaction mixture was evaporated to dryness and the resulting residue dissolved in water (2 ml). The aqueous layer was washed with TBME (21 ml) and DCM (21 ml). The aqueous layer was acidified to pH 1 using 2M HCl, and then extracted with EtOAc (23 ml). The combined organic layers were washed with water (2 ml), dried using MgSO.sub.4, filtered and evaporated to give a brown solid. The solid was triturated in 1 ml MeCN/water to afford the title compound as a brown solid. (7 mg, 15%).

Example 1, Method 3: (1S,2S)-2-(2-Methyl-1,3-benzothiazole-6-carbonyl)cyclopropane-1-carboxylic acid

[0235] .sub.H (500 MHz, DMSO-d6) 12.66 (s, 1H), 8.95-8.90 (m, 1H), 8.09 (d, J=8.5 Hz, 1H), 8.02 (d, J=8.5 Hz, 1H), 3.30 (obscured. m, 1H), 2.86 (s, 3H), 2.17-2.10 (m, 1H), 1.50 (dt, J=8.7, 4.3 Hz, 2H). Tr=2.19 min; m/z (M+H.sup.+) 262.

[0236] The following examples were prepared using the method described above:

Example 2, Method 3: (1S,2S)-2-(8-Chloroquinoxaline-6-carbonyl)cyclopropane-1-carboxylic acid

[0237] .sub.H (500 MHz, DMSO-d6) 9.17 (s, 2H), 8.65 (d, J=1.61 Hz, 1H), 8.34 (d, J=1.52 Hz, 1H), 3.10 (dq, J=3.82, 6.66 Hz, 1H), 1.84 (td, J=3.76, 7.75 Hz, 1H), 1.42-1.29 (m, 2H). Tr=2.18 min m/z (M+H.sup.+) 277, 279.

Example 3, Method 3: (1S,2S)-2-(8-Chloroquinoline-6-carbonyl)cyclopropane-1-carboxylic acid

[0238] .sub.H (500 MHz, D.sub.2O) 8.68 (dd, J=4.41, 1.58 Hz, 1H) 8.14 (dd, J=8.35, 1.42 Hz, 1H) 8.07 (d, J=1.73 Hz, 1H) 7.74 (d, J=1.73 Hz, 1H) 7.46 (dd, J=8.28, 4.33 Hz, 1H) 2.97-3.07 (m, 1H) 2.08-2.20 (m, 1H) 1.47-1.60 (m, 2H). Tr=2.26 min m/z (M+H.sup.+) 276, 278.

TABLE-US-00006 Molecular % Inhibition Structure IUPAC Name Weight LCMS Data at 30 M [00012] (1S,2S)-2-(2-methyl-1,3- benzothiazole-6- carbonyl)cyclopropane- 1-carboxylic acid 261 Tr = 2.19 min m/z (ES+) (M + H+) 262 74.5 [00013] (1S,2S)-2-(8- chloroquinoxaline-6- carbonyl)cyclopropane- 1-carboxylic acid 276 Tr = 2.18 min m/z (ES+) (M + H+) 277/279 100.6 [00014] (1S,2S)-2-(8- chloroquinoline-6- carbonyl)cyclopropane- 1-carboxylic acid 275 Tr = 2.26 min m/z (ES+) (M + H+) 276/278 100.5

Method 4

Scheme for Method 4: (1S,2S)-2-(7-Chloro-1-benzofuran-5-carbonyl)cyclopropane-1-carboxylic acid

[0239] ##STR00015##

Step 1, Method 4: Methyl-(1S,2S)-2-(7-chloro-1-benzofuran-5-carbonyl)cyclopropane-1-carboxylate

[0240] Methyl (1S,2S)-2-(7-chloro-2,3-dihydro-1-benzofuran-5-carbonyl)cyclopropane-1-carboxylate (0.42 g, 1.49 mmol), and DDQ (0.35 g, 1.56 mmol) were suspended in anhydrous toluene (20 mL) and stirred at reflux under a nitrogen atmosphere for 24 hours. After this time the reaction was cooled to room temperature and another 0.5 eq of DDQ (0.17 g, 0.74 mmol) was added and the reaction was heated to reflux for a further 24 hours. The reaction mixture was cooled to room temperature and the reaction mixture was concentrated. The resulting residue was dry loaded onto silica and loaded onto a 50 g isolute cartridge and purified by Biotage, eluting the product in 0-30% ethyl acetate in heptanes over 12 CV. The resulting purified fractions were combined, concentrated and re-dissolved in 1.5 mL of DMSO:MeCN (2:1) before being purified by Prep HPLC (Low pH: MeCN +0.1% Formic Acid) to give the title compound (0.05 g, 11% yield) as a pale brown gum. .sub.H (500 MHz, CDCl.sub.3) 8.23 (d, J=1.5 Hz, 1H), 8.01 (d, J=1.4 Hz, 1H), 7.78 (d, J=2.1 Hz, 1H), 6.93 (d, J=2.2 Hz, 1H), 3.75 (s, 3H), 3.21 (ddd, J=9.4, 5.7, 3.9 Hz, 1H), 2.43 (ddd, J=8.9, 5.9, 3.8 Hz, 1H), 1.65 (dddd, J=17.9, 9.3, 5.8, 3.5 Hz, 2H). Tr=2.18 min m/z (ES+) (M+H.sup.+) 279.

Step 2, Method 4: (1S,2S)-2-(7-Chloro-1-benzofuran-5-carbonyl)cyclopropane-1-carboxylic acid

[0241] 2M NaOH solution (0.14 mL) was added in one portion to a stirred solution of methyl (1S,2S)-2-(7-chloro-1-benzofuran-5-carbonyl)cyclopropane-1-carboxylate (0.039 g, 0.14 mmol) in 1,4-Dioxane (1 mL) and the resulting reaction mixture was stirred for 5 hours at room temperature. After this time the reaction mixture was acidified using 1 ml of 2M HCl, adjusting the pH to 1, the reaction mixture was then taken up into ethyl acetate (15 mL), washed with water (25 mL) and the aqueous extracted again with ethyl acetate (15 mL). The organic layer was dried (MgSO.sub.4), filtered and concentrated to give the title compound (0.03 g, 89% yield) as a white solid.

Example 1, Method 4: (1S,2S)-2-(7-Chloro-1-benzofuran-5-carbonyl)cyclopropane-1-carboxylic acid

[0242] .sub.H (500 MHz, CDCl.sub.3) 0.23 (d, J=1.2 Hz, 1H), 8.01 (s, 1H), 7.78 (d, J=2.0 Hz, 1H), 6.94 (d, J=2.2 Hz, 1H), 3.27 (ddd, J=9.3, 5.8, 3.9 Hz, 1H), 2.44 (ddd, J=9.1, 5.7, 3.9 Hz, 1H), 1.71 (dddd, J=22.5, 9.1, 5.7, 3.6 Hz, 2H). Tr=2.87 min (7 minute method, low pH) m/z (ES+) (M+H.sup.+) 264.

TABLE-US-00007 Molecular % Inhibition Structure Weight IUPAC Name LCMS Data at 30 M [00016] 264.661 (1S,2S)-2-(7-chloro-1- benzofuran-5- carbonyl)cyclopropane- 1-carboxylic acid Tr = 2.87 min m/z (ES+) (M + H+) 264 100.4

Method 5 (Modified Stannane Formation)

Scheme for Method 5

[0243] ##STR00017##

Step 1, Method 5: 2,3-Dihydro-1,4-benzodioxin-6-yltrimethylstannane

[0244] n-Butyllithium (3.1 ml of a 1.6M solution in hexane, 4.98 mmol) was added dropwise under nitrogen to a stirred solution of 6-bromo-2,3-dihydro-1,4-benzodioxine (1.00 g, 4.65 mmol) in dry THF (20 ml) at 78 C. After 45 min, trimethyltin chloride (5.0 ml of a 1.0M solution in THF, 5 mmol) was added dropwise over 5 min. After 20 min the reaction mixture was allowed to warm to room temperature and left overnight. The reaction mixture was poured into brine (100 ml), extracted with ethyl acetate (380 ml) and the combined, dried (Na.sub.2SO.sub.4) organic extracts were evaporated in vacuo to give the title compound (1.363 g, 98%). as a colourless oil. .sub.H (500 MHz, CDCl.sub.3) 6.78 (d, J=1.1 Hz, 1H), 6.74 (dd, J=7.7, 1.1 Hz, 1H), 6.67 (d, J=7.7 Hz, 1H), 4.06 (s, 4H), 0.06 (s, 9H). Tr=2.42 min; no ionisation.

Intermediate 2, Step 1, Method 5: 2-Methyl-6-(trimethylstannyl)-1,3-benzothiazole

[0245] .sub.H NMR (500 MHz, Chloroform-d) 8.00-7.85 (m, 2H), 7.61-7.48 (m, 1H), 2.84 (s, 3H), 0.43-0.25 (m, 9H). Tr=2.47 min m/z (ES.sup.+) (M+H.sup.+) 314/316.

Intermediate 3, Step 1, Method 5: 3,4-Dihydro-2H-1-benzopyran-6-yltrimethylstannane

[0246] .sub.H NMR (500 MHz, Chloroform-d) 7.21 (d, J=7.9 Hz, 1H), 7.15 (s, 1H), 6.81 (d, J=7.9 Hz, 1H), 4.21-4.17 (m, 2H), 2.80 (t, J=6.6 Hz, 2H), 2.05-2.00 (m, 2H), 0.26 (s, 9H). Tr=2.59 min, 62% pure, compound doesn't ionise).

Step 2, Method 5: Methyl (1S,2S)-2-(2,3-dihydro-1,4-benzodioxine-6-carbonyl)cyclopropane-1-carboxylate

[0247] A mixture of 2,3-dihydro-1,4-benzodioxin-6-yltrimethylstannane (700 mg, 2.34 mmol), (1S,2S)-2-(methoxycarbonyl)cyclopropane-1-carboxylic acid (571 mg, 3.51 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (82 mg, 0.12 mmol), and toluene (8 mL) was de-gassed by bubbling a stream of nitrogen through the mixture for 15 min, and then stirred at 110 C. for 2 h. The reaction was cooled, and then absorbed onto silica gel (Merck 9385, 8 mL). The resultant silica was purified on a Biotage machine (100 g cartridge of silica gel) eluting with ethyl acetate-heptane (5% EtOAc, 1 CV; 5% to 40% EtOAc 10 CV; 40% EtOAc, 2 CV), to give the desired product (373 mg, 58%) as pale yellow oil. .sub.H (500 MHz, CDCl.sub.3) 7.61-7.57 (m, 2H), 7.00-6.86 (m, 1H), 4.33 (ddd, J=20.0, 5.8, 2.6 Hz, 4H), 3.13 (ddd, J=9.4, 5.8, 3.9 Hz, 1H), 2.36 (ddd, J=9.5, 5.8, 3.9 Hz, 1H), 1.59 (dddd, J=25.1, 9.1, 5.8, 3.4 Hz, 2H).). Tr=1.86 min; 100% m/z (ES+) 263 (M+H.sup.+).

Intermediate 2, Step 2, Method 5: Methyl (1S,2S)-2-(2-methyl-1,3-benzothiazole-6-carbonyl)cyclopropane-1-carboxylate

[0248] .sub.H NMR (500 MHz, DMSO-d6) 8.93 (d, J=1.6 Hz, 1H), 8.10 (dd, J=8.6, 1.8 Hz, 1H), 8.02 (d, J=8.5 Hz, 1H), 3.68 (s, 3H), 3.46-3.36 (m, 1H), 2.86 (s, 3H), 2.26 (ddd, J=8.6, 5.9, 3.9 Hz, 1H), 1.56 (dtd, J=11.0, 5.8, 2.9 Hz, 2H). Tr=1.88 min m/z (ES.sup.+) 276 (M+H).sup.+.

Intermediate 3, Step 2, Method 5: 3,4-Dihydro-2H-1-benzopyran-6-yltrimethylstannane

[0249] .sub.H NMR (500 MHz, Chloroform-d) 7.80 (dd, J=8.5, 2.2 Hz, 1H), 7.77 (d, J=2.0 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 4.29-4.23 (m, 2H), 3.74 (s, 3H), 3.14 (ddd, J=8.8, 5.8, 3.9 Hz, 1H), 2.85 (t, J=6.4 Hz, 2H), 2.36 (ddd, J=8.7, 5.8, 3.8 Hz, 1H), 2.09-2.01 (m, 2H), 1.58 (dddd, J=27.0, 9.0, 5.8, 3.4 Hz, 2H). Tr=1.90 min m/z (ES+) 261 (M+H).sup.+.

Step 3, Method 5: (1S,2S)-2-(2,3-Dihydro-1,4-benzodioxine-6-carbonyl)cyclopropane-1-carboxylic acid

[0250] A solution of methyl (1S,2S)-2-(2,3-dihydro-1,4-benzodioxine-6-carbonyl)cyclopropane-1-carboxylate (347 mg, 1.32 mmol) in 1,4-dioxane (8 ml) was treated with aqueous 2M sodium hydroxide (595 l, 1.19 mmol) at room temperature, and stirred for 22 h under nitrogen. The reaction mixture was evaporated in vacuo, treated with water (25 ml), extracted with ether (330 ml), and the ethereal extracts were discarded. The aqueous phase was filtered through a PTFE frit (0.45 M). The aqueous solution was freeze-dried to give a foam (300 mg). A solution of the foam in DMSO (3 ml) was treated with aqueous 2M hydrochloric acid (0.6 ml) and purified by low pH HPLC. The resultant gum was further dried in vacuo at 40 C. to give the title compound (104 mg, 31%) as a colourless gum.

Example 2, Method 5: (1S,2S)-2-(2-Methyl-1,3-benzothiazole-6-carbonyl)cyclopropane-1-carboxylic acid

[0251] .sub.H NMR (500 MHz, DMSO-d6) 12.66 (s, 1H), 8.95-8.90 (m, 1H), 8.09 (d, J=8.5 Hz, 1H), 8.02 (d, J=8.5 Hz, 1H), 3.30 (obscured. m, 1H), 2.86 (s, 3H), 2.17-2.10 (m, 1H), 1.50 (dt, J=8.7, 4.3 Hz, 2H). Tr=2.19 min; m/z (ES+) 262 (M+H).sup.+.

TABLE-US-00008 Molecular % Inhibition Structure IUPAC Name Weight LCMS Data at 30 M [00018] 261.3 (1S,2S)-2-(2-methyl- 1,3-benzothiazole-6- carbonyl)cyclopropane- 1-carboxylic acid Tr = 2.19 min m/z (ES+) (M + H+) 262 98.3

Method 6

Scheme for Method 6

[0252] ##STR00019##

Step 1, Method 6: 5-Bromo-7-chloro-2-(iodomethyl)-2,3-dihydro-1-benzofuran

[0253] N-Iodosuccinimide (5.85 g, 26.0 mmol) was added to a solution of 4-bromo-2-chloro-6-(prop-2-en-1-yl)phenol (86%, 4.99 g, 17.34 mmol) in DCM (50 mL). The reaction mixture was stirred at room temperature for 17.5 hours, washed with a saturated aqueous solution of sodium thiosulfate (220 mL), dried (MgSO.sub.4), filtered and concentrated under reduced pressure to leave a thick orange oil (7.25 g). Purification by column chromatography (Biotage, 1-10% EtOAc in heptane Rf=0.29 in 5% EtOAc in heptane) afforded the title compound as a pale yellow oil (3.07 g, 38% yield), which was used in the next step without further purification. .sub.H NMR (500 MHz, Chloroform-d) 7.29-7.27 (m, 1H), 7.18-7.15 (m, 1H), 4.97 (dddd, J=9.0, 8.1, 6.7, 4.1 Hz, 1H), 3.52-3.42 (m, 2H), 3.36 (dd, J=10.2, 8.1 Hz, 1H), 3.13 (dd, J=16.3, 6.6 Hz, 1H). Tr=2.34 min, no mass ion.

Step 2, Method 6: 5-Bromo-7-chloro-2-methyl-1-benzofuran

[0254] DBU (1.0 mL, 7.9 mmol) was added to a solution of 5-bromo-7-chloro-2-(iodomethyl)-2,3-dihydro-1-benzofuran (80%, 3.07 g, 6.6 mmol) in anhydrous DMF (30 mL). The reaction mixture was stirred at 50 C. under nitrogen for 16 hours, allowed to cool to room temperature and partitioned between water (50 mL) and EtOAc (50 mL). The aqueous layer was separated and extracted further with EtOAc (250 mL). The combined organic extracts were washed with water (250 mL), brine (50 mL), dried (MgSO.sub.4), filtered and concentrated under reduced pressure to leave a sticky orange solid (2.01 g). Purification by column chromatography (Biotage, heptane, Rf=0.43 in heptane) afforded the title compound as a white solid (1.38 g, 100% purity, 85% yield). .sub.H NMR (500 MHz, Chloroform-d) 7.49 (d, J=1.7 Hz, 1H), 7.34 (d, J=1.8 Hz, 1H), 6.38-6.35 (m, 1H), 2.49 (d, J=0.8 Hz, 3H). Tr=2.37 min, no mass ion.

Step 3, Method 6: (7-Chloro-2-methyl-1-benzofuran-5-yl)trimethylstannane

[0255] n-Butyllithium (3.9 mL of a 1.6M solution in hexanes, 6.2 mmol) was added dropwise over 15 minutes to a cold (78 C.) solution of 5-bromo-7-chloro-2-methyl-1-benzofuran (1.38 g, 5.62 mmol) in anhydrous THF (20 mL) under a nitrogen atmosphere. The reaction mixture was stirred for 45 minutes and chloro(trimethyl)stannane (1M solution in THF, 6.2 mL, 6.2 mmol) was added dropwise over 15 minutes. After 20 minutes, the reaction mixture was allowed to warm to room temperature, stirred for 22 hours and poured in brine (50 mL). The aqueous layer was separated and extracted further with EtOAc (250 mL). The combined organic extracts were washed with brine (50 mL), dried (MgSO.sub.4), filtered and concentrated under reduced pressure to leave a yellow oil (1.72 g). Purification by column chromatography (Biotage, heptane, Rf=0.28 in heptane) afforded the title compound as a colourless oil (1.12 g, 50% yield), which was used in the next step without further purification. .sub.H NMR (500 MHz, Chloroform-d) 7.45 (s, 1H), 7.26 (s, 1H), 6.38 (d, J=1.0 Hz, 1H), 2.49 (d, J=0.8 Hz, 3H), 0.32 (s, 9H). Tr=2.72 min, no mass ion.

Step 4, Method 6: Methyl (1S,2S)-2-(7-chloro-2-methyl-1-benzofuran-5-carbonyl)cyclopropane-1-carboxylate

[0256] A solution of (7-chloro-2-methyl-1-benzofuran-5-yl)trimethylstannane (82%, 1.12 g, 2.79 mmol) and (1S,2S)-2-(carbonochloridoyl)cyclopropane-1-carboxylate (718 mg, 4.42 mmol) in anhydrous toluene (10 mL) was degassed for 20 minutes by bubbling nitrogen. PdCl.sub.2(PPh.sub.3).sub.2 (98 mg, 0.14 mmol) was added. The reaction mixture was stirred at 110 C. under an atmosphere of nitrogen for 3 hours, allowed to cool to room temperature and concentrated under reduced pressure to leave a brown oil (618 mg). Purification by column chromatography (Biotage, 5-40% EtOAc in heptane, Rf=0.29 in 20% EtOAc in heptane) afforded the title compound as a pale yellow oil (618 mg, 65% yield), which was used in the next step without further purification. Tr=2.15 min m/z (ES.sup.+) (M+H.sup.+) 293, 295.

Step 5, Method 6: (1S,2S)-2-(7-chloro-2-methyl-1-benzofuran-5-carbonyl)cyclopropane-1-carboxylic acid

[0257] 2M Sodium hydroxide (1.8 mL, 3.6 mmol) was added to a solution of methyl (1S,2S)-2-(7-chloro-2-methyl-1-benzofuran-5-carbonyl)cyclopropane-1-carboxylate (86%, 618 mg, 1.82 mmol) in dioxane (5 mL) and the reaction mixture was stirred at room temperature for 3 hours. 2N HCl (1.8 mL, 3.6 mmol) was added and the reaction mixture was concentrated under reduced pressure to leave a pale yellow solid. Trituration with MeCN (3 mL) afforded a white solid (383 mg), which was filtered-off and discarded. The filtrate was concentrated under reduced pressure to leave an-off white solid (383 mg), which was purified by acidic preparative HPLC to afford the title compound as a white solid (214 mg, 42% yield).

Example 1, Method 6: (1S,2S)-2-(7-chloro-2-methyl-1-benzofuran-5-carbonyl)cyclopropane-1-carboxylic acid

[0258] .sub.H NMR (500 MHz, Chloroform-d) 8.08 (d, J=1.5 Hz, 1H), 7.92 (d, J=1.5 Hz, 1H), 6.52 (d, J=1.0 Hz, 1H), 3.25 (ddd, J=9.5, 5.9, 3.8 Hz, 1H), 2.54 (d, J=0.8 Hz, 3H), 2.46-2.39 (m, 1H), 1.69 (dddd, J=23.4, 9.2, 5.8, 3.6 Hz, 2H). Tr=3.14 min m/z (ES.sup.+) (M+H.sup.+) 279, 281.

TABLE-US-00009 Molecular % Inhibition Structure IUPAC Name Weight LCMS Data at 30 M [00020] 278.69 (1S,2S)-2-(7-chloro-2- methyl-1-benzofuran- 5- carbonyl)cyclopropane- 1-carboxylic acid Tr = 3.14 min m/z (ES+) (M + H+) 279/281 102.4

Method 7

[0259] The following routes (A, B, C, D, E & F) describe methods for the synthesis of compounds described in the table below. Ar refers to R.sub.1.

Route A:

[0260] ##STR00021## ##STR00022## ##STR00023##

Method 8

[0261] The following route (G) describes a generic method for the synthesis of compounds described in the table below. Ar refers to R.sub.1.

Route G:

[0262] ##STR00024##

Method 9:

[0263] The following route (H) describes a generic method for the synthesis of compounds described in the table below. Ar refers to R.sub.1.

Route H:

[0264] ##STR00025##

Prophetic Examples

[0265] The following examples may be prepared using the methods described above, and are expected to have activity against KMO and in the treatment of KMO-mediated diseases such as those disclosed herein.

TABLE-US-00010 Structure IUPAC Name [00026] (1S,2S)-2-(8-chloroisoquinoline-6- carbonyl)cyclopropanecarboxylic acid [00027] (1S,2S)-2-(5-chloroquinazoline-7- carbonyl)cyclopropanecarboxylic acid [00028] (1S,2S)-2-(8-chloroquinazoline-6- carbonyl)cyclopropanecarboxylic acid [00029] (1S,2S)-2-(8-chlorocinnoline-6- carbonyl)cyclopropanecarboxylic acid [00030] (1S,2S)-2-(8-chloroquinoxaline-6- carbonyl)cyclopropanecarboxylic acid [00031] (1S,2S)-2-(4-chlorobenzo[d]oxazole-6- carbonyl)cyclopropanecarboxylic acid [00032] (1S,2S)-2-(4-chloro-2-methylbenzo[d]oxazole-6- carbonyl)cyclopropanecarboxylic acid [00033] (1S,2S)-2-(4-chloro-1H-benzo[d]imidazole-6- carbonyl)cyclopropanecarboxylic acid [00034] (1S,2S)-2-(7-chlorobenzo[d]oxazole-5- carbonyl)cyclopropanecarboxylic acid [00035] (1S,2S)-2-(7-chloro-2-methylbenzo[d]oxazole-5- carbonyl)cyclopropanecarboxylic acid [00036] (1S,2S)-2-(7-chlorobenzo[d]thiazole-5- carbonyl)cyclopropanecarboxylic acid [00037] (1S,2S)-2-(7-chloro-2-methylbenzo[d]thiazole-5- carbonyl)cyclopropanecarboxylic acid [00038] (1S,2S)-2-(7-chloro-1H-indole-5- carbonyl)cyclopropanecarboxylic acid [00039] (1S,2S)-2-(7-chloro-1H-indazole-5- carbonyl)cyclopropanecarboxylic acid [00040] (1S,2S)-2-(7-chloro-1-methyl-1H-indazole-5- carbonyl)cyclopropanecarboxylic acid [00041] (1S,2S)-2-(7-chlorobenzo[d]isoxazole-5- carbonyl)cyclopropanecarboxylic acid [00042] (1S,2S)-2-(7-chloro-1-methyl-1H-indole-5- carbonyl)cyclopropanecarboxylic acid [00043] (1R,2S)-1-amino-2-(7-chlorobenzofuran-5- carbonyl)cyclopropanecarboxylic acid [00044] (1R,2S)-2-(7-chlorobenzofuran-5-carbonyl)-1- (methylamino)cyclopropanecarboxylic acid [00045] (1R,2S)-2-(7-chlorobenzofuran-5-carbonyl)-1- (dimethylamino)cyclopropanecarboxylic acid [00046] (1S,2S)-1-(aminomethyl)-2-(7-chlorobenzofuran-5- carbonyl)cyclopropanecarboxylic acid [00047] (1S,2S)-2-(7-chlorobenzofuran-5-carbonyl)-1- ((methylamino)methyl)cyclopropanecarboxylic acid [00048] (1S,2S)-2-(7-chlorobenzofuran-5-carbonyl)-1- ((dimethylamino)methyl)cyclopropanecarboxylic acid [00049] (1S,2S)-2-(7-chlorobenzofuran-5-carbonyl)-1- methylcyclopropanecarboxylic acid [00050] (1R,2R)-2-(7-chlorobenzofuran-5-carbonyl)-1- fluorocyclopropanecarboxylic acid [00051] (1R,2S)-2-(7-chlorobenzofuran-5-carbonyl)-1- methoxycyclopropanecarboxylic acid [00052] (1S,2S)-2-(7-chlorobenzofuran-5-carbonyl)-1- (methoxymethyl)cyclopropanecarboxylic acid [00053] (1R,3R)-2-amino-3-(7-chlorobenzofuran-5- carbonyl)cyclopropanecarboxylic acid [00054] (1R,2R)-2-(7-chlorobenzofuran-5-carbonyl)-3- (methylamino)cyclopropanecarboxylic acid [00055] (1R,2R)-2-(7-chlorobenzofuran-5-carbonyl)-3- (dimethylamino)cyclopropanecarboxylic acid [00056] (1S,2S)-2-(7-chlorobenzofuran-5-carbonyl)-3- methylcyclopropanecarboxylic acid [00057] (1R,3R)-3-(7-chlorobenzofuran-5-carbonyl)-2,2- dimethylcyclopropanecarboxylic acid [00058] (1R,3R)-3-(7-chlorobenzofuran-5-carbonyl)-2-hydroxy-2- methylcyclopropanecarboxylic acid [00059] (1R,3R)-3-(7-chlorobenzofuran-5-carbonyl)-2- (hydroxymethyl)-2-methylcyclopropanecarboxylic acid [00060] (1R,3R)-3-(7-chlorobenzofuran-5-carbonyl)-2- (methoxymethyl)-2-methylcyclopropanecarboxylic acid [00061] (1R,3R)-2-(aminomethyl)-3-(7-chlorobenzofuran-5- carbonyl)-2-methylcyclopropanecarboxylic acid [00062] (1R,3R)-3-(7-chlorobenzofuran-5-carbonyl)-2-methyl-2- ((methylamino)methyl)cyclopropanecarboxylic acid [00063] (1R,3R)-2-amino-3-(7-chlorobenzofuran-5-carbonyl)-2- methylcyclopropanecarboxylic acid [00064] (1R,3R)-3-(7-chlorobenzofuran-5-carbonyl)-2-methyl-2- (methylamino)cyclopropanecarboxylic acid [00065] (1S,3S)-2-(aminomethyl)-3-(7-chlorobenzofuran-5- carbonyl)cyclopropanecarboxylic acid [00066] (1S,2S)-2-(7-chlorobenzofuran-5-carbonyl)-3- ((methylamino)methyl)cyclopropanecarboxylic acid [00067] (1S,2S)-2-(7-chlorobenzofuran-5-carbonyl)-3- ((dimethylamino)methyl)cyclopropanecarboxylic acid [00068] (1S,2R)-2-amino-2-(7-chlorobenzofuran-5- carbonyl)cyclopropanecarboxylic acid [00069] (1S,2R)-2-(7-chlorobenzofuran-5-carbonyl)-2- (methylamino)cyclopropanecarboxylic acid [00070] (1S,2R)-2-(7-chlorobenzofuran-5-carbonyl)-2- (dimethylamino)cyclopropanecarboxylic acid [00071] (1S,2S)-2-(aminomethyl)-2-(7-chlorobenzofuran-5- carbonyl)cyclopropanecarboxylic acid [00072] (1S,2S)-2-(7-chlorobenzofuran-5-carbonyl)-2- ((methylamino)methyl)cyclopropanecarboxylic acid [00073] (1S,2S)-2-(7-chlorobenzofuran-5-carbonyl)-2- ((dimethylamino)methyl)cyclopropanecarboxylic acid [00074] (1S,2S)-2-(7-chlorobenzofuran-5-carbonyl)-2- methylcyclopropanecarboxylic acid

[0266] The following are examples of compounds of Formula I which may be considered prodrugs, which may be prepared using the methods described above and known in the art and are expected to have activity against KMO and in the treatment of KMO-mediated diseases such as those disclosed herein.

TABLE-US-00011 Mol. Structure Weight IUPAC Name [00075] 278.688 methyl (1S,2S)-2-(7-chloro-1-benzofuran-5- carbonyl)cyclopropane-1-carboxylate [00076] 426.802 [(3R,4S,5R,6S)-3,4,5,6-tetrahydroxyoxan-2- yl]methyl (1S,2S)-2-(7-chloro-1-benzofuran-5- carbonyl)cyclopropane-1-carboxylate [00077] 426.802 [(3S,4S,5R)-3,4,5,6-tetrahydroxyoxan-2- yl]methyl (1S,2S)-2-(7-chloro-1-benzofuran-5- carbonyl)cyclopropane-1-carboxylate [00078] 308.714 2-hydroxyethyl (1S,2S)-2-(7-chloro-1- benzofuran-5-carbonyl)cyclopropane-1- carboxylate [00079] 279.676 (1S,2S)-2-(7-chloro-1-benzofuran-5-carbonyl)- N-hydroxycyclopropane-1-carboxamide [00080] 306.741 propan-2-yl (1S,2S)-2-(7-chloro-1-benzofuran- 5-carbonyl)cyclopropane-1-carboxylate [00081] 363.835 2-(diethylamino)ethyl (1S,2S)-2-(7-chloro-1- benzofuran-5-carbonyl)cyclopropane-1- carboxylate [00082] 392.833 (2S)-2-amino-6-{[(1S,2S)-2-(7-chloro-1- benzofuran-5- carbonyl)cyclopropyl]formamido}hexanoic acid [00083] 378.804 [(1S,2S)-2-(7-chloro-1-benzofuran-5- carbonyl)cyclopropanecarbonyloxy]methyl 2,2- dimethylpropanoate [00084] 350.75 1-[(1S,2S)-2-(7-chloro-1-benzofuran-5- carbonyl)cyclopropanecarbonyloxy]ethyl acetate [00085] 408.853 {3-carboxy-2-[(1S,2S)-2-(7-chloro-1- benzofuran-5- carbonyl)cyclopropanecarbonyloxy]propyl} trimethylazanium [00086] 394.803 1-{[(propan-2-yloxy)carbonyl]oxy}ethyl (1S,2S)-2-(7-chloro-1-benzofuran-5- carbonyl)cyclopropane-1-carboxylate [00087] 380.776 1-[(ethoxycarbonyl)oxy]ethyl (1S,2S)-2-(7- chloro-1-benzofuran-5-carbonyl)cyclopropane- 1-carboxylate [00088] 396.863 4-tert-butylphenyl (1S,2S)-2-(7-chloro-1- benzofuran-5-carbonyl)cyclopropane-1- carboxylate [00089] 320.767 2-methylpropyl (1S,2S)-2-(7-chloro-1- benzofuran-5-carbonyl)cyclopropane-1- carboxylate [00090] 320.767 butyl (1S,2S)-2-(7-chloro-1-benzofuran-5- carbonyl)cyclopropane-1-carboxylate [00091] 351.738 (2S)-2-{[(1S,2S)-2-(7-chloro-1-benzofuran-5- carbonyl)cyclopropyl]formamido}-3- hydroxypropanoic acid [00092] 292.714 methyl (1S,2S)-2-(7-chloro-2-methyl-1- benzofuran-5-carbonyl)cyclopropane-1- carboxylate [00093] 440.828 [(3R,4S,5R,6S)-3,45,6-tetrahydroxyoxan-2- yl]methyl (1S,2S)-2-(7-chloro-2-methyl-1- benzofuran-5-carbonyl)cyclopropane-1- carboxylate [00094] 440.828 [(3S,4S,5R)-3,4,5,6-tetrahydroxyoxan-2- yl]methyl (1S,2S)-2-(7-chloro-2-methyl-1- benzofuran-5-carbonyl)cyclopropane-1- carboxylate [00095] 322.74 2-hydroxyethyl (1S,2S)-2-(7-chloro-2-methyl-1- benzofuran-5-carbonyl)cyclopropane-1- carboxylate [00096] 293.702 (1S,2S)-2-(7-chloro-2-methyl-1-benzofuran-5- carbonyl)-N-hydroxycyclopropane-1- carboxamide [00097] 320.767 propan-2-yl (1S,2S)-2-(7-chloro-2-methyl-1- benzofuran-5-carbonyl)cyclopropane-1- carboxylate [00098] 377.862 2-(diethylamino)ethyl (1S,2S)-2-(7-chloro-2- methyl-1-benzofuran-5-carbonyl)cyclopropane- 1-carboxylate [00099] 406.86 (2S)-2-amino-6-{[(1S,2S)-2-(7-chloro-2-methyl- 1-benzofuran-5- carbonyl)cyclopropyl]formamido}hexanoic acid [00100] 392.83 [(1S,2S)-2-(7-chloro-2-methyl-1-benzofuran-5- carbonyl)cyclopropanecarbonyloxy]methyl 2,2- dimethylpropanoate [00101] 364.777 1-[(1S,2S)-2-(7-chloro-2-methyl-1-benzofuran- 5-carbonyl)cyclopropanecarbonyloxy]ethyl acetate [00102] 422.879 {3-carboxy-2-[(1S,2S)-2-(7-chloro-2-methyl-1- benzofuran-5- carbonyl)cyclopropanecarbonyloxy]propyl} trimethylazanium [00103] 408.83 1-{[(propan-2-yloxy)carbonyl]oxy}ethyl (1S,2S)-2-(7-chloro-2-methyl-1-benzofuran-5- carbonyl)cyclopropane-1-carboxylate [00104] 394.803 1-[(ethoxycarbonyl)oxy]ethyl (1S,2S)-2-(7- chloro-2-methyl-1-benzofuran-5- carbonyl)cyclopropane-1-carboxylate [00105] 410.89 4-tert-butylphenyl (1S,2S)-2-(7-chloro-2- methyl-1-benzofuran-5-carbonyl)cyclopropane- 1-carboxylate [00106] 334.794 2-methylpropyl (1S,2S)-2-(7-chloro-2-methyl-1- benzofuran-5-carbonyl)cyclopropane-1- carboxylate [00107] 334.794 butyl (1S,2S)-2-(7-chloro-2-methyl-1- benzofuran-5-carbonyl)cyclopropane-1- carboxylate [00108] 365.765 (2S)-2-{[(1S,2S)-2-(7-chloro-2-methyl-1- benzofuran-5- carbonyl)cyclopropyl]formamido}-3- hydroxypropanoic acid [00109] 293.702 methyl (1S,2S)-2-(4-chloro-2-methyl-1,3- benzoxazole-6-carbonyl)cyclopropane-1- carboxylate [00110] 441.816 [(3R,4S,5R,6S)-3,4,5,6-tetrahydroxyoxan-2- yl]methyl (1S,2S)-2-(4-chloro-2-methyl-1,3- benzoxazole-6-carbonyl)cyclopropane-1- carboxylate [00111] 441.816 [(3S,4S,5R)-3,4,5,6-tetrahydroxyoxan-2- yl]methyl (1S,2S)-2-(4-chloro-2-methyl-1,3- benzoxazole-6-carbonyl)cyclopropane-1- carboxylate [00112] 323.728 2-hydroxyethyl (1S,2S)-2-(4-chloro-2-methyl- 1,3-benzoxazole-6-carbonyl)cyclopropane-1- carboxylate [00113] 294.69 (1S,2S)-2-(4-chloro-2-methyl-1,3-benzoxazole- 6-carbonyl)-N-hydroxycyclopropane-1- carboxamide [00114] 321.756 propan-2-yl (1S,2S)-2-(4-chloro-2-methyl-1,3- benzoxazole-6-carbonyl)cyclopropane-1- carboxylate [00115] 378.85 2-(diethylamino)ethyl (1S,2S)-2-(4-chloro-2- methyl-1,3-benzoxazole-6- carbonyl)cyclopropane-1-carboxylate [00116] 407.848 (2S)-2-amino-6-{[(1S,2S)-2-(4-chloro-2-methyl- 1,3-benzoxazole-6- carbonyl)cyclopropyl]formamido}hexanoic acid [00117] 393.818 [(1S,2S)-2-(4-chloro-2-methyl-1,3-benzoxazole- 6-carbonyl)cyclopropanecarbonyloxy]methyl 2,2-dimethylpropanoate [00118] 365.765 1-[(1S,2S)-2-(4-chloro-2-methyl-1,3- benzoxazole-6- carbonyl)cyclopropanecarbonyloxy]ethyl acetate [00119] 423.867 {3-carboxy-2-[(1S,2S)-2-(4-chloro-2-methyl- 1,3-benzoxazole-6- carbonyl)cyclopropanecarbonyloxy]propyl} trimethylazanium [00120] 409.818 1-{[(propan-2-yloxy)carbonyl]oxy}ethyl (1S,2S)-2-(4-chloro-2-methyl-1,3-benzoxazole- 6-carbonyl)cyclopropane-1-carboxylate [00121] 395.791 1-[(ethoxycarbonyl)oxy]ethyl (1S,2S)-2-(4- chloro-2-methyl-1,3-benzoxazole-6- carbonyl)cyclopropane-1-carboxylate [00122] 411.878 4-tert-butylphenyl (1S,2S)-2-(4-chloro-2- methyl-1,3-benzoxazole-6- carbonyl)cyclopropane-1-carboxylate [00123] 335.782 2-methylpropyl (1S,2S)-2-(4-chloro-2-methyl- 1,3-benzoxazole-6-carbonyl)cyclopropane-1- carboxylate [00124] 335.782 butyl (1S,2S)-2-(4-chloro-2-methyl-1,3- benzoxazole-6-carbonyl)cyclopropane-1- carboxylate [00125] 366.753 (2S)-2-{[(1S,2S)-2-(4-chloro-2-methyl-1,3- benzoxazole-6- carbonyl)cyclopropyl]formamido}-3- hydroxypropanoic acid [00126] 293.702 methyl (1S,2S)-2-(7-chloro-2-methyl-1,3- benzoxazole-5-carbonyl)cyclopropane-1- carboxylate [00127] 441.816 [(3R,4S,5R,6S)-3,4,5,6-tetrahydroxyoxan-2- yl]methyl (1S,2S)-2-(7-chloro-2-methyl-1,3- benzoxazole-5-carbonyl)cyclopropane-1- carboxylate [00128] 441.816 [(3S,4S,5R)-3,4,5,6-tetrahydroxyoxan-2- yl]methyl (1S,2S)-2-(7-chloro-2-methyl-1,3- benzoxazole-5-carbonyl)cyclopropane-1- carboxylate [00129] 323.728 2-hydroxyethyl (1S,2S)-2-(7-chloro-2-methyl- 1,3-benzoxazole-5-carbonyl)cyclopropane-1- carboxylate [00130] 294.69 (1S,2S)-2-(7-chloro-2-methyl-1,3-benzoxazole- 5-carbonyl)-N-hydroxycyclopropane-1- carboxamide [00131] 321.756 propan-2-yl (1S,2S)-2-(7-chloro-2-methyl-1,3- benzoxazole-5-carbonyl)cyclopropane-1- carboxylate [00132] 378.85 2-(diethylamino)ethyl (1S,2S)-2-(7-chloro-2- methyl-1,3-benzoxazole-5- carbonyl)cyclopropane-1-carboxylate [00133] 407.848 (2S)-2-amino-6-{[(1S,2S)-2-(7-chloro-2-methyl- 1,3-benzoxazole-5- carbonyl)cyclopropyl]formamido}hexanoic acid [00134] 393.818 [(1S,2S)-2-(7-chloro-2-methyl-1,3-benzoxazole- 5-carbonyl)cyclopropanecarbonyloxy]methyl 2,2-dimethylpropanoate [00135] 365.765 1-[(1S,2S)-2-(7-chloro-2-methyl-1,3- benzoxazole-5- carbonyl)cyclopropanecarbonyloxy]ethyl acetate [00136] 423.867 {3-carboxy-2-[(1S,2S)-2-(7-chloro-2-methyl- 1,3-benzoxazole-5- carbonyl)cyclopropanecarbonyloxy]propyl} trimethylazanium [00137] 409.818 1-{[(propan-2-yloxy)carbonyl]oxy}ethyl (1S,2S)-2-(7-chloro-2-methyl-1,3-benzoxazole- 5-carbonyl)cyclopropane-1-carboxylate [00138] 395.791 1-[(ethoxycarbonyl)oxy]ethyl (1S,2S)-2-(7- chloro-2-methyl-1,3-benzoxazole-5- carbonyl)cyclopropane-1-carboxylate [00139] 411.878 4-tert-butylphenyl (1S,2S)-2-(7-chloro-2- methyl-1,3-benzoxazole-5- carbonyl)cyclopropane-1-carboxylate [00140] 335.782 2-methylpropyl (1S,2S)-2-(7-chloro-2-methyl- 1,3-benzoxazole-5-carbonyl)cyclopropane-1- carboxylate [00141] 335.782 butyl (1S,2S)-2-(7-chloro-2-methyl-1,3- benzoxazole-5-carbonyl)cyclopropane-1- carboxylate [00142] 366.753 (2S)-2-{[(1S,2S)-2-(7-chloro-2-methyl-1,3- benzoxazole-5- carbonyl)cyclopropyl]formamido}-3- hydroxypropanoic acid

Biology Example 1

[0267] A generalized procedure for monitoring L-Kynurenine (KYN) hydroxylation to form product 3-Hydroxy-Kynurenine (30H-KYN) by LC/MS is described below. Product is quantified by multiple reaction monitoring using MS.

Key Reagents:

[0268] Compound: Stock concentrations: 10 mM in 100% DMSO [0269] Cell line: CHO GST HIS KMO cell line, 1E4 cells/well/100 l in 96 well cell plate [0270] Substrate: L-Kynurenine (Sigma: Cat# K3750, stock concentration: 10 mM in 100 mM potassium phosphate buffer, pH 7.4)

Assay Conditions:

[0271] Medium: OptiMem (Reduced Serum Medium 1, +L-Glutamine+HEPES-Phenol Red; GIBCO: Cat#11058) [0272] Assay Volume: 200 l [0273] Plate Format: 96 well plate, transparent (Corning) [0274] Read-Out: product (30H-KYN) quantification using product specific MRM [0275] Reader: LC/MS/MS

Assay Protocol:

[0276] prepare serial dilution (factor 3) of compound in 100% DMSO (top concentration=6.67 mM, 100% DMSO) [0277] [8 points: 6.67 mM; 2.22 mM; 0.74 mM; 0.247 mM; 0.082 mM; 0.027 mM; 0.009 mM; 0.003 mM] [0278] prepare 300-fold concentrated solution of each compound concentration (top concentration 22.22 M, 0.3% DMSO) in OptiMem medium [0279] [22.2 M; 7.41 M; 2.47 M; 0.82 M; 0.27 M; 0.09 M; 0.03 M; 0.01 M] [0280] prepare substrate (10 mM) at concentration of 1.1 mM in medium [0281] medium of cell plate is drawed off [0282] cells are washed with OptiMem (100 l/well) and drawed off again [0283] assay mix: 90 l OptiMem/well+90 l compound/well of each concentration [0284] [final compound top concentration: 10 M; 0.15% DMSO] [0285] [final compound bottom concentration: 0.004 M; 0.15% DMSO] [0286] pre-incubation: 30 min at 37 C. [0287] add 20 l/well of the 1.1 mM substrate solution (final assay concentration: 100 M) [0288] positive control: 200 l OptiMem [0289] negative control: 180 l OptiMem+20 l 1.1 mM substrate [0290] incubate24 h at 37 C. [0291] transfer 100 l of each well in a transparent 96 well plate (Corning) [0292] add 100 l/well 10% trichloro acetic acid (TCA) in water [0293] centrifugate plate for 3 min at 4000 rpm [0294] detect product by LC/MS (injection of 50 l/well; 2.5 fold overfill of the 20 l sample loop)

Data Analysis:

[0295] IC.sub.50's are calculated using automated fitting algorithm (A+ Analysis).

Biology Example 2

[0296] A method of monitoring L-Kynurenine (KYN) hydroxylation to form product 3-Hydroxy-Kynurenine (30H-KYN) by LC/MS is described below. Product is quantified by multiple reaction monitoring.

Key Reagents:

[0297] Compound: Stock concentrations: 10 mM in 100% DMSO [0298] Enzyme: KMO enzyme prepared at Evotec via mitochondria isolation from CHO-GST HIS KMO cells [0299] Substrate: L-Kynurenine (Sigma: Cat# K3750) [0300] [stock concentration: 10 mM in 100 mM potassium phosphate buffer, pH 7.4]

Assay Conditions:

[0301] Buffer: 100 mM potassium phosphate, pH 7.4, 20004 NADPH, 0.4 U/ml G6P-DH (Glucose 6-phosphate dehydrogenase), 3 mM G6P (D-Glucose 6-phosphate) [0302] Assay Volume: 40 l [0303] Plate Format: 384 well plate, transparent (Matrix) [0304] Read-Out: product (30H-KYN) quantification using product specific MRM [0305] Reader: LC/MS/MS

Assay Protocol:

[0306] prepare serial dilution (factor 3) of compound in 100% DMSO (top concentration=10 mM, 100% DMSO) [0307] [8 points: 10 mM; 3.33 mM; 1.11 mM; 0.37 mM; 0.12 mM; 0.04 mM; 0.0137 mM; 0.0045 mM, 0.0015 mM] [0308] prepare 3.33-fold concentrated solution of each compound concentration (top concentration 300 M, 3% DMSO) in assay buffer [0309] [concentrations: 300 M; 100 M; 33.3 M; 11.1 M; 3.70 M; 1.23 M; 0.41 M; 0.137 M] [0310] prepare substrate (10 mM) at concentration of 1 mM in assay buffer [0311] assay mix: 4 l compound/well of each concentration+24 l assay buffer/well+8 l KMO human enzyme+4 l 1 mM substrate (final concentration=100 M) [0312] [final compound top concentration: 30 M; 0.3% DMSO] [0313] [final compound bottom concentration: 0.0137 M; 0.3% DMSO] [0314] positive control: 4 l 150 M FCE28833 in assay buffer[0.5% DMSO] (final assay concentration=50 M)+24 l assay buffer/well+8 l KMO human enzyme+4 l 1 mM substrate (final concentration=100 M) [0315] negative control: 28 l assay buffer/well+8 l KMO human enzyme+4 l 1 mM substrate (final concentration=100 M) [0316] incubate 400 min at RT [0317] add 40 l/well 10% trichloro acetic acid in water to stop the assay and precipitate protein [0318] centrifuge plate for 3 min at 4000 rpm [0319] product detection by LC/MS (injection of 50 l/well; 2.5 fold overfill of the 20 l sample loop)

Data Analysis:

[0320] IC.sub.50's are calculated using automated fitting algorithm (A+ Analysis).

Biology Example 3

[0321] A method of monitoring L-Kynurenine (KYN) hydroxylation to form 3-Hydroxy-Kynurenine (30H-KYN) by LC/MS is described. Product is quantified by multiple reaction monitoring (MRM method).

Key Reagents:

[0322] Compound: Stock concentrations: 10 mM in 100% DMSO [0323] Enzyme: KMO enzyme prepared at Evotec from mouse liver (4-6 weeks old) via mitochondria isolation as described in the literature [0324] Substrate: L-Kynurenine (Sigma: Cat# K3750, stock concentration: 10 mM in 100 mM potassium phosphate buffer, pH 7.4)

Assay Conditions:

[0325] Buffer: 100 mM potassium phosphate, pH 7.4, 200 M NADPH, 0.4 U/ml G6P-DH (Glucose 6-phosphate Dehydrogenase), 3 mM G6P (D-Glucose 6-phosphate) [0326] Assay Volume: 40 l [0327] Plate Format: 384 well plate, transparent (Matrix) [0328] Read-Out: product (30H-KYN) quantification using product specific MRM [0329] Reader: LC/MS/MS

Assay Protocol:

[0330] prepare serial dilution (factor 3) of compound in 100% DMSO (top concentration=10 mM, 100% DMSO) [0331] [8 points: 10 mM; 3.33 mM; 1.11 mM; 0.37 mM; 0.12 mM; 0.04 mM; 0.0137 mM; 0.0045 mM, 0.0015 mM] [0332] prepare 3.33-fold concentrated solution of each compound concentration (top concentration 300 M, 3% DMSO) in assay buffer [0333] [concentrations: 300 M; 100 M; 33.3 M; 11.1 M; 3.70 M; 1.23 M; 0.41 M; 0.137 M] [0334] prepare substrate (10 mM) at concentration of 1 mM in assay buffer [0335] assay mix: 4 l compound/well of each concentration+24 l assaybuffer/well+8 l KMO mouse enzyme+4 l 1 mM substrate (final concentration=100 M) [0336] [final compound top concentration: 30 M; 0.3% DMSO] [0337] [final compound bottom concentration: 0.0137 M; 0.3% DMSO] [0338] positive control: 4 l 50 M FCE28833 in assay buffer, 0.5% DMSO [final assay concentration=50 M]+24 l assaybuffer/well+8 l KMO mouse enzyme+4 l 1 mM substrate[final concentration=100 M] [0339] negative control: 28 l assay buffer/well+8 l KMO mouse enzyme+4 l 1 mM substrate [final concentration=100 M] [0340] incubate 40 min at RT [0341] add 40 l/well 10% trichloro acetic acid in water to stop the assay and precipitate protein [0342] centrifuge plate for 3 min at 4000 rpm [0343] product detection by LC/MS (injection of 20 l/well, 2 fold overfill of the 10 l sample loop)

Data Analysis:

[0344] IC.sub.50's are calculated using automated fitting algorithm (A+ Analysis).

Biology Example 4

[0345] Using the assay protocols substantially similar to those of Biology Example 3, the following compounds were tested.

TABLE-US-00012 Table of compounds with inhibition information Percent Inhibition Structure IUPAC Name at 30 M [00143] (1S,2S)-2-[(5-Chlorothiophen-2- yl)carbonyl]cyclopropane-1-carboxylic acid 100.7 [00144] (1S,2S)-2-[(Thiophen-3- yl)carbonyl]cyclopropane-1-carboxylic acid 83.2 [00145] (1S,2S)-2-[(Thiophen-2- yl)carbonyl]cyclopropane-1-carboxylic acid 80.3 [00146] (1S,2S)-2-[(1,3-Thiazol-2- yl)carbonyl]cyclopropane-1-carboxylic acid 28.7 (at 10 uM) [00147] (1S,2S)-2-[(1,3-Benzothiazol-2- yl)carbonyl]cyclopropane-1-carboxylic acid 91.8 [00148] (1S,2S)-2-[(Pyridin-2- yl)carbonyl]cyclopropane-1-carboxylic acid 45.6 [00149] (1S,2S)-2-(2-methyl-1,3-benzothiazole-6- carbonyl)cyclopropane-1-carboxylic acid 74.5 [00150] (1S,2S)-2-(8-chloroquinoxaline-6- carbonyl)cyclopropane-1-carboxylic acid 100.6 [00151] (1S,2S)-2-(8-chloroquinoline-6- carbonyl)cyclopropane-1-carboxylic acid 100.5 [00152] (1S,2S)-2-(7-chloro-1-benzofuran-5- carbonyl)cyclopropane-1-carboxylic acid 100.4

[0346] While some embodiments have been shown and described, various modifications and substitutions may be made thereto without departing from the spirit and scope of the invention. For example, for claim construction purposes, it is not intended that the claims set forth hereinafter be construed in any way narrower than the literal language thereof, and it is thus not intended that exemplary embodiments from the specification be read into the claims. Accordingly, it is to be understood that the present invention has been described by way of illustration and not limitations on the scope of the claims.