HK1162352B

HK1162352B - Certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof

Info

Publication number: HK1162352B
Application number: HK12103228.4A
Authority: HK
Inventors: John Wityak; Leticia M. Toledo-Sherman; Celia Dominguez; Stephen Martin Courtney; Christopher John Yarnold; Paula Cristina De Aguiar Pena; Andreas Scheel; Dirk Winkler
Original assignee: Chdi基金会股份有限公司
Priority date: 2008-08-04
Filing date: 2009-08-04
Publication date: 2015-01-30

Description

Certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use

This application claims priority to U.S. provisional application 61/086,090 filed on 4.8.2008, which is incorporated herein by reference.

The present application provides certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions thereof, and methods of their use.

Kynurenine-3-monooxygenase (KMO) is an enzyme that catalyzes the conversion of kynurenine to 3-hydroxykynurenine (3-HK) in the tryptophan degradation pathway, which is a precursor of the neurotoxin quinolinic acid (QUIN). Therefore, compounds acting as KMO inhibitors are of great interest as they can block the metabolism to QUIN while increasing the production of the neuroprotective metabolite kynurenic acid (KYNA).

KMO inhibitors have been suggested as therapeutic agents for the treatment of neurodegenerative diseases such as huntington's disease, alzheimer's disease, dementia caused by Acquired Immune Deficiency Syndrome (AIDS), infarct dementia, cerebral ischemia, cerebral hypoxia, parkinson's disease, epilepsy, head and spinal cord trauma, amyotrophic lateral sclerosis, glaucomatous retinopathy, brain infection or brain inflammation. There remains a need for compounds that are effective inhibitors of KMO and that are useful in the treatment of neurodegenerative disorders.

The present application provides at least one chemical entity selected from compounds of formula I and pharmaceutically acceptable salts and prodrugs thereof,

formula I

Wherein:

x and Y are independently selected from CH and N, provided that at least one of X and Y is N;

R₁selected from aryl and heteroaryl, each substituted with 1, 2 or 3 groups selected from: halogen, optionally substituted lower alkyl, lower alkoxy, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and hydroxy;

l is selected from the group consisting of-C (O) O-, -C (O) N (R)₃)-、-N(R₃)C(O)-、-N(R₃)S(O)₂-, and-S (O)₂N(R₃)-；

R₂Selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, with the proviso that when L is-N (R)₃)S(O)₂Is-time R₂Is not hydrogen;

R₃selected from hydrogen and lower alkyl; or

R₂And R₃Together with any intervening atoms, form an optionally substituted heterocycloalkyl ring;

R₄selected from hydrogen and optionally substituted lower alkyl; and

R₅selected from the group consisting of hydrogen and fluorine,

with the proviso that the compound of the formula I is not

N- (1-hydroxy-3- (1H-indol-3-yl) propan-2-yl) -6- (4-methoxyphenyl) pyrimidine-4-carboxamide;

3-chloro-2-methyl-N- (6-phenylpyrimidin-4-yl) benzenesulfonamide;

4-methoxy-N- (6-phenylpyrimidin-4-yl) benzamide;

n- (6-phenylpyrimidin-4-yl) benzamide;

6-phenylpyrimidine-4-carboxylic acid;

6-phenylpyrimidine-4-carboxylic acid methyl ester;

6-phenylpyrimidine-4-carboxylic acid ethyl ester;

6-phenylpyrimidine-4-carboxamide;

n-methyl-6-phenylpyrimidine-4-carboxamide; or

N, N-dimethyl-6-phenylpyrimidine-4-carboxamide.

The present application also provides pharmaceutical compositions comprising at least one chemical entity described herein and at least one pharmaceutically acceptable excipient.

The present application also provides a packaged pharmaceutical composition comprising at least one pharmaceutical composition described herein and instructions for using the composition to treat a subject having a condition or disorder mediated by kynurenine-3-monooxygenase activity.

The present application also provides a method of treating a condition or disorder mediated by kynurenine-3-monooxygenase activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one chemical entity as described herein.

The following words, phrases and symbols used in this specification are generally intended to have the meanings as set forth below, unless the context in which they are used indicates otherwise. The following abbreviations and terms have the meanings indicated below throughout:

a dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH₂Are attached via a carbon atom.

"optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optionally substituted alkyl" encompasses "alkyl" and "substituted alkyl" as defined below. It will be understood by those skilled in the art that, for any group containing one or more substituents, such groups are meant to not introduce any sterically impractical, synthetically non-feasible and/or inherently unstable substitution or substitution patterns.

"alkyl" encompasses straight and branched chains having the indicated number of carbon atoms (typically 1 to 20 carbon atoms, for example 1 to 8 carbon atoms, such as 1 to 6 carbon atoms). E.g. C₁-C₆The alkyl group includes straight chain and branched chain alkyl groups of 1-6 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-methylpentyl, and the like. Alkylene is another subgroup of alkyl groups which,refers to having the same residue as alkyl, but with two points of attachment. The alkylene group typically has 2 to 20 carbon atoms, for example 2 to 8 carbon atoms, such as 2 to 6 carbon atoms. E.g. C₀Alkylene means a covalent bond, C₁Alkylene is methylene. When an alkyl residue having a particular carbon atom is named, all geometric isomers having the number of carbon atoms are intended to be encompassed; thus, for example, "butyl" is intended to include n-butyl, sec-butyl, isobutyl, and tert-butyl; "propyl" includes n-propyl and isopropyl. "lower alkyl" refers to an alkyl group having 1 to 4 carbons.

"cycloalkyl" refers to a cyclic saturated hydrocarbon group having a specific carbon atom, typically 3 to 7 ring carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bridged and caged saturated rings such as norbornane.

"alkoxy" refers to an alkyl group having the indicated number of carbon atoms attached through an oxygen bridge, e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-methylpentyloxy, and the like. The alkoxy group typically has 1 to 6 carbon atoms connected by an oxygen bridge. "lower alkoxy" refers to alkoxy having 1 to 4 carbons.

"aryl" encompasses:

5-and 6-membered carbocyclic aromatic rings, for example, benzene;

bicyclic ring systems in which at least one ring is an aromatic carbocyclic ring, for example, naphthalene, indane and tetralin; and

tricyclic ring systems in which at least one ring is an aromatic carbocyclic ring, e.g., fluorene.

For example, aryl includes 5-and 6-membered carbocyclic aromatic rings fused to a 5-to 7-membered heterocycloalkyl ring containing 1 or more heteroatoms selected from N, O and S, provided that the point of attachment of the aryl is on the carbocyclic aromatic ring. Divalent radicals formed from substituted benzene derivatives and having a free valence on the ring atoms are designated as substituted phenylene radicals. Divalent radicals derived from monovalent polycyclic hydrocarbon radicals having the name "base" ending by the removal of one hydrogen atom from a carbon atom having a free valence are named below, with the addition of a "subunit" to the corresponding monovalent radical name, e.g., a naphthyl radical having two points of attachment is referred to as naphthylene. However, aryl does not in any way encompass or overlap with heteroaryl, which is defined separately below. Thus, if one or more carbocyclic aromatic rings are fused to a heterocycloalkyl aromatic ring, the resulting ring system is heteroaryl rather than aryl as defined herein.

The term "halo" includes fluoro, chloro, bromo and iodo, while the term "halogen" includes fluoro, chloro, bromo and iodo.

"heteroaryl" encompasses:

a 5-to 7-membered aromatic monocyclic ring containing one or more (e.g., 1-4, or in some embodiments 1-3) heteroatoms selected from N, O and S, with the remaining ring atoms being carbon; and

a bicyclic heterocycloalkyl ring containing one or more (e.g., 1 to 4, or in some embodiments 1 to 3) heteroatoms selected from N, O and S with the remaining ring atoms being carbon and wherein at least one heteroatom is present in the aromatic ring.

For example, heteroaryl includes a 5-to 7-membered heterocycloalkyl, an aromatic ring fused to a 5-to 7-membered cycloalkyl ring. For example, heteroaryl also includes 5 or 6 membered heterocycloalkyl, an aromatic ring fused to a 5 to 7 membered aryl ring. For the fused bicyclic heteroaryl ring systems described above, wherein only one ring contains one or more heteroatoms, the point of attachment may be on the heteroaryl or cycloalkyl ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group is no more than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle does not exceed 1. Examples of heteroaryl groups include, but are not limited to (numbering starting from the attachment position assigned as priority 1): 2-pyridyl, 3-pyridyl, 4-pyridyl, 2, 3-pyrazinyl, 3, 4-pyrazinyl, 2, 4-pyrimidinyl, 3, 5-pyrimidinyl, 2, 3-pyrazolinyl, 2, 4-imidazolinyl, isoxazolinyl, oxazolinyl, thiazolinyl, thiadiazolinyl, tetrazolyl, thienyl, benzothienyl, furyl, benzofuryl, benzimidazolinyl, indolinyl, pyridizinyl, triazolyl, quinolinyl, pyrazolyl, and 5, 6, 7, 8-tetrahydroisoquinolinyl. Divalent radicals derived from monovalent heteroaryl radicals ending in the name of "-yl" by removing one hydrogen atom from a carbon atom having a free valence are named below, with the addition of an "-ylidene" to the corresponding monovalent radical name, e.g., a pyridyl group having two points of attachment is a pyridylene group. Heteroaryl does not encompass aryl or overlap with aryl, which is as defined above.

Substituted heteroaryl also includes ring systems substituted with one or more oxides (-O)^-) Substituents, such as pyridyl nitroxides.

"Heterocycloalkyl" refers to an aliphatic monocyclic ring of generally 3 to 7 ring atoms containing at least 2 carbon atoms in addition to 1 to 3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, and combinations comprising at least one of the foregoing heteroatoms. "heterocycloalkyl" also refers to 5-and 6-membered carbocyclic aromatic rings fused to a 5-to 7-membered heterocycloalkyl ring containing 1 or more heteroatoms selected from N, O and S, provided that the point of attachment is on the heterocycloalkyl ring. Suitable heterocycloalkyl groups include, for example (numbering starting from the attachment position assigned as priority 1), 2-pyrrolidinyl, 2, 4-imidazolidinyl, 2, 3-pyrazolidinyl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl and 2, 5-piperazinyl. Heterocycloalkyl also encompasses morpholinyl, including 2-morpholinyl and 3-morpholinyl (wherein oxygen assignments are numbered first 1). Substituted heterocycloalkyl also includes ring systems substituted with one or more oxo moieties, such as piperidinyl-nitroxide, morpholinyl-nitroxide, 1-oxo-1-thiomorpholinyl, and 1, 1-dioxo-1-thiomorpholinyl.

The term "substituted" as used herein means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded. When the substituent is oxo (i.e., ═ O), then 2 hydrogens on the atom are replaced. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. By stable compound or stable structure is meant that the compound is sufficiently robust to withstand isolation from the reaction mixture and subsequent formulation into at least a practical reagent. Unless otherwise indicated, substituents are named into the parent structure. For example, it is understood that when a (cycloalkyl) alkyl group is listed as a possible substituent, the point of attachment of that substituent to the parent nuclear structure is located on the alkyl moiety.

Unless otherwise specifically defined, the terms "substituted" alkyl (including but not limited to lower alkyl), cycloalkyl, aryl (including but not limited to phenyl), heterocycloalkyl (including but not limited to morpholin-4-yl, 3, 4-dihydroquinolin-1 (2H) -yl, indolin-1-yl, 3-oxopiperazin-1-yl, piperidin-1-yl, piperazin-1-yl, pyrrolidin-1-yl, azetidin-1-yl, and isoindol-2-yl), and heteroaryl (including but not limited to pyridyl) refer to alkyl, respectively, one or more (e.g., up to 5, such as up to 3) hydrogen atoms in the cycloalkyl, aryl, heterocycloalkyl, and heteroaryl groups are substituted with substituents each independently selected from the group consisting of: -R^a，-OR^b，-O(C₁-C₂Alkyl) O- (e.g. methylenedioxy-), -SR^bGuanidine, guanidine wherein one or more guanidine hydrogens are substituted with the following substituents: lower alkyl, -NR^bR^cHalogen, cyano, oxo (as a substituent of heterocycloalkyl), nitro, -COR^b、-CO₂R^b、-CONR^bR^c、-OCOR^b、-OCO₂R^a、-OCONR^bR^c、-NR^cCOR^b、-NR^cCO₂R^a、-NR^cCONR^bR^c、-SOR^a、-SO₂R^a、-SO₂NR^bR^cand-NR^cSO₂R^a，

Wherein R is^aSelected from optionally substituted C₁-C₆Alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, and optionally substituted heteroaryl;

R^bselected from H, optionally substituted C₁-C₆Alkyl, optionally substituted aryl and optionally substituted heteroaryl; and

R^cselected from hydrogen and optionally substituted C₁-C₄An alkyl group; or

R^bAnd R^cAnd together with the nitrogen to which they are attached form an optionally substituted heterocycloalkyl; and

wherein each optionally substituted group is unsubstituted or independently substituted with one or more, for example 1, 2 or 3, substituents independently selected from the group consisting of: c₁-C₄Alkyl radical, C₃-C₆Cycloalkyl, aryl, heteroaryl, aryl-C₁-C₄Alkyl-, heteroaryl-C₁-C₄Alkyl-, C₁-C₄Haloalkyl-, -OC₁-C₄Alkyl, -OC₁-C₄Alkylphenyl, -C₁-C₄alkyl-OH, -C₁-C₄alkyl-O-C₁-C₄Alkyl, -OC₁-C₄Haloalkyl, halogen, -OH, -NH₂、-C₁-C₄alkyl-NH₂、-N(C₁-C₄Alkyl) (C₁-C₄Alkyl), -NH (C)₁-C₄Alkyl), -N (C)₁-C₄Alkyl) (C₁-C₄Alkylphenyl), -NH (C)₁-C₄Alkylphenyl), cyano, nitro, oxo (as a substituent for heteroaryl), -CO₂H、-C(O)OC₁-C₄Alkyl, -CON (C)₁-C₄Alkyl) (C₁-C₄Alkyl), -CONH (C)₁-C₄Alkyl), -CONH₂、-NHC(O)(C₁-C₄Alkyl), -NHC (O) (phenyl), -N (C)₁-C₄Alkyl radical C (O) (C)₁-C₄Alkyl), -N (C)₁-C₄Alkyl group C (O) (phenyl), -C (O) C₁-C₄Alkyl, -C (O) C₁-C₄Phenyl, -C (O) C₁-C₄Haloalkyl, -OC (O) C₁-C₄Alkyl, -SO₂(C₁-C₄Alkyl), -SO₂(phenyl), -SO₂(C₁-C₄Haloalkyl), -SO₂NH₂、-SO₂NH(C₁-C₄Alkyl), -SO₂NH (phenyl), -NHSO₂(C₁-C₄Alkyl), -NHSO₂(phenyl) and-NHSO₂(C₁-C₄Haloalkyl).

The term "substituted alkoxy" refers to an alkoxy group in which the alkyl moiety is substituted (i.e., -O- (substituted alkyl)), wherein "substituted alkyl" is as described herein. "substituted alkoxy" also includes derivatives of glycosides (i.e., glycosyl groups) and ascorbic acid.

The term "substituted amino" refers to the group-NHR^dor-NR^dR^dWherein R is^dEach independently selected from: hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted acyl, aminocarbonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkoxycarbonyl, sulfinyl, and sulfonyl, each as described herein, with the proviso that only one R is present^dMay be a hydroxyl group. The term "substituted amino" also refers to-NHR^dand-NR^dR^dNitroxide of the radical, -NHR^dand-NR^dR^dEach as described above. The nitroxides can be prepared by treating the corresponding amino groups with, for example, hydrogen peroxide or m-chloroperbenzoic acid. Those skilled in the art are familiar with the reaction conditions under which the nitrogen oxidation is carried out.

"aminocarbonyl" embraces radicals of the formula- (C ═ O) (optionally substituted amino) wherein the substituted amino is as described herein.

"acyl" refers to the group: (alkyl) -c (o) -; (cycloalkyl) -c (o) -; (aryl group)-c (o) -; (heteroaryl) -c (o) -; and (heterocycloalkyl) -c (o) -, wherein the groups are attached to the parent structure via a carbonyl functionality, and wherein alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are as described herein. Acyl groups have the indicated number of carbon atoms, with the carbon of the keto group being included within the counted number of carbon atoms. E.g. C₂Acyl is of the formula CH₃(C ═ O) -, acyl group.

"alkoxycarbonyl" refers to an ester group of the formula (alkoxy) (C ═ O) -, attached through a carbonyl carbon, where the alkoxy group has the indicated number of carbon atoms. Thus, C₁-C₆The alkoxycarbonyl group is an alkoxy group having 1 to 6 carbon atoms bonded to a carbonyl linking group via its oxygen.

"amino" refers to the group-NH₂。

The term "sulfinyl" includes the groups: -S (O) - (optionally substituted (C)₁-C₆) Alkyl), -s (o) -optionally substituted aryl), -s (o) -optionally substituted heteroaryl), -s (o) - (optionally substituted heterocycloalkyl); and-s (o) - (optionally substituted amino).

The term "sulfonyl" includes the following groups: -S (O)₂) - (optionally substituted (C)₁-C₆) Alkyl), -S (O)₂) -optionally substituted aryl), -S (O)₂) -optionally substituted heteroaryl), -S (O)₂) - (optionally substituted heterocycloalkyl), -S (O)₂) - (optionally substituted alkoxy), -S (O)₂) -optionally substituted aryloxy), -S (O)₂) -optionally substituted heteroaryloxy), -S (O)₂) - (optionally substituted heterocyclyloxy); and-S (O)₂) - (optionally substituted amino).

The term "substituted acyl" refers to the group: (substituted alkyl) -c (o) -; (substituted cycloalkyl) -c (o) -; (substituted aryl) -c (o) -; (substituted heteroaryl) -c (o) -; and (substituted heterocycloalkyl) -c (o) -, wherein the groups are attached to the parent structure via a carbonyl functional group, and wherein substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are as described herein.

The term "substituted alkoxy" refers to an alkoxy in which the alkyl moiety is substituted (i.e., -O- (substituted alkyl)), wherein "substituted alkyl" is as described herein.

The term "substituted alkoxycarbonyl" refers to a (substituted alkyl) -O-c (O) -group, wherein the group is attached to the parent structure via a carbonyl functionality, and wherein substituted alkyl is as described herein.

"glycoside" refers to any of a wide variety of sugar derivatives that contain a non-sugar group attached to the oxygen or nitrogen atom of the sugar and which, when hydrolyzed, produce a sugar. An example of a glycosyl group is glucosyl.

"ascorbic acid derivative" or "ascorbic acid derivative" refers to any of a wide variety of derivatives that contain a non-sugar group attached to the oxygen or nitrogen atom of ascorbic acid and that upon hydrolysis yield ascorbic acid (i.e., (R) -5- ((S) -1, 2-dihydroxyethyl) -3, 4-dihydroxyfuran-2 (5H) -one).

The compounds described herein include, but are not limited to, their optical isomers, racemates, and other mixtures thereof. In these cases, single enantiomers or diastereomers (i.e., optically active forms) can be obtained by asymmetric synthesis or resolution of racemates. Resolution of the racemates can be accomplished, for example, by conventional methods (e.g., crystallization in the presence of a resolving agent, or chromatography, e.g., using a chiral High Performance Liquid Chromatography (HPLC) column). Furthermore, the compounds having a carbon-carbon double bond include Z-and E-forms (or cis-and trans-forms) of the compound. When a compound described herein exists in various tautomeric forms, the term "compound" is intended to include all tautomeric forms of the compound. The compounds also include crystalline forms of the compounds (including polymorphic forms and clathrate forms). Similarly, the term "salt" is intended to include all tautomeric and crystalline forms of the compound.

Chemical substances include, but are not limited to, the compounds described herein and all pharmaceutically acceptable forms thereof. The pharmaceutically acceptable forms of the compounds described herein include pharmaceutically acceptable salts, prodrugs and mixtures thereof. In some embodiments, the compounds described herein are in the form of a pharmaceutically acceptable salt or prodrug. Thus, the term "chemical" also encompasses pharmaceutically acceptable salts, prodrugs, and mixtures thereof.

"pharmaceutically acceptable salts" include, but are not limited to, salts with inorganic acids such as hydrochlorides, phosphates, diphosphates, hydrobromides, sulfates, sulfites, nitrates, and the like; and salts with organic acids, for example malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, benzoate, salicylate, stearate, and alkanoates such as acetate, HOOC- (CH) and stearate₂)_n-COOH (n is 0 to 4). Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.

Furthermore, if the compounds described herein are obtained as addition salts with acids, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, the addition salts (especially pharmaceutically acceptable addition salts) may be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid in accordance with conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize a variety of synthetic methods that may be used to prepare non-toxic pharmaceutically acceptable addition salts.

As noted above, prodrugs also fall within the scope of the chemistry described herein. In some embodiments, a "prodrug" as described herein includes any compound that becomes a compound of formula I when administered to a patient (e.g., upon metabolic processing of the prodrug). Examples of prodrugs include derivatives of functional groups, such as carboxylic acid groups, in compounds of formula I. Exemplary prodrugs of carboxylic acid groups include, but are not limited to, carboxylic acid esters such as alkyl esters, hydroxyalkyl esters, arylalkyl esters, and aryloxyalkyl esters. Other exemplary prodrugs include lower alkyl esters such as ethyl esters, acyloxyalkyl esters such as Pivaloyloxymethyl (POM), glycosides, and ascorbic acid derivatives.

Other exemplary prodrugs include amides of carboxylic acids. Exemplary amide prodrugs include metabolically labile amides of amines with carboxylic acids. Exemplary amines include NH₂Primary and secondary amines such as NHR^xAnd NR^xR^yWherein R is^xIs hydrogen, (C)₁-C₁₈) Alkyl radicals, (C)₃-C₇) -cycloalkyl, (C)₃-C₇) -cycloalkyl- (C)₁-C₄) -alkyl-, (C)₆-C₁₄) Aryl, which is unsubstituted or substituted with a residue (C)₁-C₂) Alkyl radicals, (C)₁-C₂) -alkoxy, fluoro or chloro; heteroaryl-, (C)₆-C₁₄) -aryl- (C)₁-C₄) -alkyl-, wherein aryl is unsubstituted or substituted with a residue (C)₁-C₂) Alkyl radicals, (C)₁-C₂) -alkoxy, fluoro or chloro; or heteroaryl- (C)₁-C₄) -alkyl-and wherein R^yHaving a function of R^xOf the indicated significance (other than hydrogen), or in which R^xAnd R^yTogether with the nitrogen to which they are attached form an optionally substituted 4-to 7-membered heterocycloalkyl ring, said 4-to 7-membered heterocycloalkyl ring optionally including 1 or 2 additional heteroatoms selected from nitrogen, oxygen and sulfur. See T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S.Sympossium Series, in Edward B.Roche, ed., Bioreversible Carriers in drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and in drug Design of drugs, ed.H.Bundgaard, Elsevier, 1985.

A "solvate" is formed by the interaction of a solvent with a compound. The term "compound" is intended to include solvates of the compounds. Similarly, "salt" includes solvates of the salt. Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including mono-and hemihydrate.

"chelate" is formed by the coordination of a compound with a metal ion at two or more sites. The term "compound" is intended to include chelates of compounds. Similarly, "salt" includes chelates of salts.

A "non-covalent complex" is formed by a compound interacting with another molecule, wherein no covalent bond is formed between the compound and the molecule. For example, complexation can occur via van der waals forces, hydrogen bonding, and electrostatic interactions (also referred to as ionic bonding). Such non-covalent complexes are also included in the term "compound".

The term "hydrogen bond" refers to the form of bonding between an electronegative atom (also known as a hydrogen bond acceptor) and a hydrogen atom that is attached to another, relatively electronegative atom (also known as a hydrogen bond donor). Suitable Hydrogen Bond donors and acceptors are well known in pharmaceutical chemistry (G.C. Pimentel and A.L. McClellan, the Hydrogen Bond, Freeman, San Francisco, 1960; R.Taylor and O.Kennard, "Hydrogen Bond Geometry in Organic Crystals", Accounts of Chemical Research, 17, pp.320-326 (1984)).

"Hydrogen bond acceptor" refers to a group containing oxygen or nitrogen, e.g., oxygen or sp²Heterocyclic nitrogen, ether oxygen, or sulfoxide or nitroxide oxygen.

The term "hydrogen bond donor" refers to oxygen, nitrogen, or a heteroaromatic carbon containing a ring nitrogen atom with hydrogen, or a heteroaryl group containing a ring nitrogen atom.

As used herein, the terms "group", or "fragment" are synonymous and are intended to describe a functional group or fragment of a molecule that can be attached to a bond or other fragment of the molecule.

The term "active agent" is used to describe a chemical substance that has biological activity. In some embodiments, an "active agent" is a compound having pharmaceutical efficacy. For example, the active agent may be an anti-neurodegenerative therapeutic agent.

The term "therapeutically effective amount" with respect to a chemical substance described herein refers to an amount effective to provide a therapeutic effect, e.g., ameliorating symptoms, delaying disease progression, or preventing disease, when administered to a human or non-human patient, e.g., a therapeutically effective amount can be an amount sufficient to reduce the symptoms of a disease responsive to inhibition of KMO activity. In some embodiments, a therapeutically effective amount is an amount sufficient to treat a neurodegenerative pathway or a symptom of a disease (e.g., Huntington's disease, Alzheimer's disease, Parkinson's disease, olivopontocerebellar atrophy, non-Alzheimer's dementia, multi-infarct dementia, cerebral amyotrophic lateral sclerosis, cerebral ischemia, cerebral hypoxia, spinal or head injury, or epilepsy). In some embodiments, a therapeutically effective amount is an amount sufficient to reduce signs or side effects of a neurodegenerative disease. In some embodiments, a therapeutically effective amount of a chemical is an amount sufficient to avoid significantly increasing or to significantly reduce the level of neuronal cell death. In some embodiments, a therapeutically effective amount is an amount sufficient to reduce signs or side effects of a neurodegenerative disease. In some embodiments, a therapeutically effective amount of a chemical is an amount sufficient to avoid significantly increasing or to significantly reduce QUIN levels associated with neuronal cell death. In some embodiments, the therapeutically effective amount of the chemical is an amount sufficient to cause an increase in KYNA levels associated with neuronal cell health. In some embodiments, a therapeutically effective amount of a chemical is an amount sufficient to increase the anticonvulsant and neuroprotective properties associated with decreased QUIN levels and increased KYNA levels.

In the methods of treating neurodegenerative disorders described herein, a therapeutically effective amount can also be an amount sufficient to detectably delay the progression of the neurodegenerative disease or prevent the symptoms of the neurodegenerative disease from being exhibited by a patient receiving the chemical when administered to the patient. In some of the methods of treating neurodegenerative diseases described herein, the therapeutically effective amount can also be an amount sufficient to detectably reduce the level of neuronal cell death. For example, in some embodiments, a therapeutically effective amount is an amount of a chemical substance described herein that is sufficient to significantly reduce the level of neuronal death by causing a detectable reduction in the amount of QUIN and an increase in the amount of KYNA.

The term "inhibit" refers to a significant decrease in the baseline activity of a biological activity or process. By "inhibiting KMO activity" is meant a decrease in KMO activity relative to KMO activity in the absence of at least one chemical species, as a direct or indirect response to the presence of at least one chemical species described herein. The reduction in activity may be due to direct interaction of the compound with KMO, or due to interaction of one or more chemicals described herein with one or more other factors which in turn affect KMO activity. For example, the presence of one or more chemical substances may decrease KMO activity by binding directly to KMO, or by causing (directly or indirectly) another factor to decrease KMO activity, or by decreasing (directly or indirectly) the amount of KMO present in a cell or organism.

"inhibiting KMO activity" refers to a decrease in KMO activity relative to KMO activity in the absence of at least one chemical substance, as a direct or indirect response to the presence of at least one chemical substance described herein. The reduction in activity may be due to direct interaction of the compound with KMO, or due to interaction of one or more chemicals described herein with one or more other factors which in turn affect KMO activity.

Inhibition of KMO activity also refers to the observable inhibition of the production of 3-HK and QUIN in standard assays, such as those described below. Inhibition of KMO activity also refers to an observable increase in KYNA production. In some embodiments, the IC of a chemical species described herein₅₀The value is less than or equal to 1 micromole/liter. In some embodiments, the IC of the chemical species₅₀The value is less than or equal to 100 micromoles per liter. In some embodiments, the IC of the chemical species₅₀The value is less than or equal to 10 nanomoles per liter.

"KMO activity" also includes activation, redistribution, recombination or capping of one or more distinct KMO membrane receptors, or receptor sites that can undergo redistribution and capping that can lead to signal transduction. KMO activity also includes the synthesis or production of QUIN and 3-HK.

A "disease responsive to inhibition of KMO activity" is one in which inhibition of KMO provides a therapeutic effect, e.g., ameliorating symptoms, slowing disease progression, preventing or delaying the onset of disease, or inhibiting abnormal activity and/or death of certain cell types (neuronal cells).

"treatment" refers to any treatment of a disease in a patient, including:

a) prevention of disease, i.e., the clinical symptoms of the disease do not develop;

b) inhibiting the disease;

c) slowing or arresting the development of clinical symptoms; and/or

d) Abrogate the disease, i.e., cause regression of clinical symptoms.

A "subject" or "patient" refers to an animal, such as a mammal, that has been or is to be the subject of treatment, observation or experiment. The methods described herein can be used for human therapy as well as in veterinary applications. In some embodiments, the subject is a mammal; in some embodiments, the subject is a human.

The present application provides that at least one chemical entity is selected from compounds of formula I, and pharmaceutically acceptable salts and prodrugs thereof,

formula I

Wherein:

R₁selected from aryl and heteroarylSaid aryl and heteroaryl groups being each substituted with 1, 2 or 3 groups selected from: halogen, optionally substituted lower alkyl, lower alkoxy, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and hydroxy;

l is selected from the group consisting of-C (O) O-, -C (O) N (R)₃)-、-N(R₃)C(O)-、-N(R₃)S(O)₂-and-S (O)₂N(R₃)-；

R₃selected from hydrogen and lower alkyl; or

R₄selected from hydrogen and optionally substituted lower alkyl;

R₅selected from the group consisting of hydrogen and fluorine,

with the proviso that the compound of the formula I is not

N- (1-hydroxy-3- (1H-indol-3-yl) propan-2-yl) -6- (4-methoxyphenyl) pyrimidine-4-carboxamide,

3-chloro-2-methyl-N- (6-phenylpyrimidin-4-yl) benzenesulfonamide;

4-methoxy-N- (6-phenylpyrimidin-4-yl) benzamide;

n- (6-phenylpyrimidin-4-yl) benzamide;

6-phenylpyrimidine-4-carboxylic acid;

6-phenylpyrimidine-4-carboxylic acid methyl ester;

6-phenylpyrimidine-4-carboxylic acid ethyl ester;

6-phenylpyrimidine-4-carboxamide;

n-methyl-6-phenylpyrimidine-4-carboxamide; or

N, N-dimethyl-6-phenylpyrimidine-4-carboxamide.

In some embodiments, the compound of formula I is selected from compounds of formula II

Formula II

Wherein:

R₁selected from aryl and heteroaryl, each substituted with 1, 2 or 3 groups selected from: halogen, lower alkyl, lower alkoxy, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and hydroxy;

R₃selected from hydrogen and lower alkyl; and

R₄selected from hydrogen and optionally substituted lower alkyl;

with the proviso that the compound of the formula II is not

3-chloro-2-methyl-N- (6-phenylpyrimidin-4-yl) benzenesulfonamide;

4-methoxy-N- (6-phenylpyrimidin-4-yl) benzamide;

n- (6-phenylpyrimidin-4-yl) benzamide;

6-phenylpyrimidine-4-carboxylic acid;

6-phenylpyrimidine-4-carboxylic acid methyl ester;

6-phenylpyrimidine-4-carboxylic acid ethyl ester;

6-phenylpyrimidine-4-carboxamide;

n-methyl-6-phenylpyrimidine-4-carboxamide; or

N, N-dimethyl-6-phenylpyrimidine-4-carboxamide.

In some embodiments, R₁Is phenyl, optionally substituted with 1, 2 or 3 groups selected from: halogen, lower alkyl, lower alkoxy, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and hydroxy. In some embodiments, R₁Is phenyl, optionally substituted with 1, 2 or 3 groups selected from: halogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, and hydroxy. In some embodiments, R₁Is phenyl, optionally substituted with 1, 2 or 3 groups selected from: halogen, lower alkyl, trifluoromethyl, lower alkoxy, and hydroxy. In some embodiments, R₁Is phenyl, optionally substituted with 1, 2 or 3 groups selected from: halogen, lower alkyl, and trifluoromethyl. In some embodiments, R₁Selected from the group consisting of phenyl, 2, 4-difluorophenyl, 3-chloro-2-fluorophenyl, 3-chloro-4-trifluoromethylphenyl, 2-fluoro-5-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-fluoro-3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 3, 4-dichlorophenyl, 3-chlorophenyl, 4-chlorophenyl and 3, 5-dichlorophenyl. In some embodiments, R₁Selected from the group consisting of 2-trifluoromethylphenyl, 3, 4-dichlorophenyl, 3-chlorophenyl, 4-chlorophenyl and 3, 5-dichlorophenyl.

In some embodimentsIn, R₁Is pyridin-3-yl optionally substituted with 1, 2 or 3 groups selected from: halogen, lower alkyl, lower alkoxy, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and hydroxy. In some embodiments, R₁Is pyridin-3-yl optionally substituted with 1, 2 or 3 groups selected from: halogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, and hydroxy. In some embodiments, R₁Is pyridin-3-yl optionally substituted with 1, 2 or 3 groups selected from: halogen, lower alkyl, trifluoromethyl, lower alkoxy, and hydroxy. In some embodiments, R₁Is pyridin-3-yl optionally substituted with 1, 2 or 3 groups selected from: halogen, lower alkyl and trifluoromethyl. In some embodiments, R₁Selected from pyridin-3-yl, 5-fluoropyridin-3-yl and 5-chloropyridin-3-yl.

In some embodiments, L is selected from the group consisting of-C (O) O-, -C (O) N (R)₃) -and-N (R)₃)S(O)₂-. In some embodiments, L is-C (O) N (R)₃) -. In some embodiments, L is-N (R)₃)S(O)₂-. In some embodiments, L is-C (O) O-.

In some embodiments, R₃Is hydrogen. In some embodiments, R₃Is a lower alkyl group. In some embodiments, R₃Is methyl.

In some embodiments, R₄Selected from hydrogen and lower alkyl. In some embodiments, R₄Is hydrogen. In some embodiments, R₄Is a lower alkyl group. In some embodiments, R₄Is methyl.

In some embodiments, R₂Selected from the group consisting of hydrogen, lower alkyl, optionally substituted heteroaryl and optionally substituted phenyl. In some embodiments, R₂Selected from the group consisting of hydrogen, lower alkyl, optionally substituted pyridyl and optionally substituted phenyl. In some embodiments, R₂Selected from hydrogen, lower alkyl, pyridineAnd phenyl, wherein said pyridyl and phenyl are each optionally substituted with 1 or 2 groups selected from: halogen, hydroxy, lower alkyl and lower alkoxy. In some embodiments, R₂Selected from the group consisting of hydrogen, lower alkyl, pyridyl and phenyl, wherein said phenyl is optionally substituted with 1 or 2 groups selected from: halogen, hydroxy, lower alkyl and lower alkoxy.

In some embodiments, R₂And R₃Together with any intervening atoms, form an optionally substituted heterocycloalkyl ring. In some embodiments, R₂And R₃Together with any intervening atoms, form an optionally substituted heterocycloalkyl ring selected from morpholin-4-yl, 3, 4-dihydroquinolin-1 (2H) -yl, indolin-1-yl, 3-oxopiperazin-1-yl, piperidin-1-yl, piperazin-1-yl, pyrrolidin-1-yl, azetidin-1-yl, and isoindolin-2-yl, each of which is optionally substituted. In some embodiments, R₂And R₃Together with any intervening atoms, form an optionally substituted heterocycloalkyl ring selected from morpholin-4-yl, 3, 4-dihydroquinolin-1 (2H) -yl, indolin-1-yl, 3-oxopiperazin-1-yl, piperidin-1-yl, piperazin-1-yl, pyrrolidin-1-yl, azetidin-1-yl, and isoindol-2-yl, each of which is optionally substituted with 1 or 2 groups selected from: halogen, hydroxy, lower alkyl, lower alkoxy, -C (O) (lower alkyl), -C (O) NH₂C (O) N (H) (lower alkyl), and C (O) (lower alkyl).

In some embodiments, R₅Is hydrogen. In some embodiments, R₅Is fluorine.

In some embodiments, X is N; y is CH.

In some embodiments, X is CH; y is N.

In some embodiments, X is N; y is N.

The present application also provides at least one chemical selected from the group consisting of:

6- (2-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid;

n- [6- (2-trifluoromethyl-phenyl) -pyrimidin-4-yl ] -methanesulfonamide;

3, 4-dimethoxy-N- [6- (2-trifluoromethyl-phenyl) -pyrimidin-4-yl ] -benzenesulfonamide;

n- [6- (3, 4-dichloro-phenyl) -pyrimidin-4-yl ] -methanesulfonamide;

6- (3, 4-dichloro-phenyl) -pyrimidine-4-carboxylic acid methyl ester;

n- [6- (3, 4-dichloro-phenyl) -pyrimidin-4-yl ] -3, 4-dimethoxy-benzenesulfonamide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid methyl ester;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid;

6- (3, 4-dichloro-phenyl) -pyrimidine-4-carboxylic acid pyridin-3-ylamide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid pyridin-3-ylamide;

6- (3, 4-dichloro-phenyl) -pyrimidine-4-carboxylic acid;

6- (3, 5-dichloro-phenyl) -pyrimidine-4-carboxylic acid;

6- (3, 5-dichloro-phenyl) -pyrimidine-4-carboxylic acid methyl ester;

n- [6- (3-chloro-phenyl) -pyrimidin-4-yl ] -nicotinamide;

6- (3, 4-dichloro-phenyl) -2-methyl-pyrimidine-4-carboxylic acid methyl ester;

6- (3, 4-dichloro-phenyl) -2-methyl-pyrimidine-4-carboxylic acid;

6- (3, 4-dichloro-phenyl) -2-methyl-pyrimidine-4-carboxylic acid pyridin-3-ylamide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid (2, 6-dimethyl-pyridin-3-yl) -amide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid pyrimidin-5-ylamide;

6- (4-morpholin-4-yl-phenyl) -pyrimidine-4-carboxylic acid methyl ester;

6- (4-fluoro-3-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid methyl ester;

6- (3-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid methyl ester;

6- (4-fluoro-3-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid;

6- (3-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid pyridin-2-ylamide;

6- (4-fluoro-3-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid pyridin-3-ylamide;

6- (3, 5-dichloro-phenyl) -pyrimidine-4-carboxylic acid pyridin-3-ylamide;

6- (3-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid pyridin-3-ylamide;

6- (3-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid acetamide;

6- (5-fluoro-pyridin-3-yl) -pyrimidine-4-carboxylic acid;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid amide;

6- (3-fluoro-5-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid methyl ester;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid methylamide;

6- (5-fluoro-pyridin-3-yl) -pyrimidine-4-carboxylic acid methyl ester;

6- (3-fluoro-5-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid;

6- (5-chloro-pyridin-3-yl) -pyrimidine-4-carboxylic acid methyl ester;

6- (5-chloro-pyridin-3-yl) -pyrimidine-4-carboxylic acid;

6- (2-fluoro-5-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid methyl ester;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid isopropylamide;

[6- (3-chloro-phenyl) -pyrimidin-4-yl ] -morpholin-4-yl-methanone;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid propionamide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid phenylamide;

6-phenyl-pyrimidine-4-carboxylic acid;

6- (2-fluoro-5-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid o-tolylamide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid p-tolylamide;

[6- (3-chloro-phenyl) -pyrimidin-4-yl ] - (3, 4-dihydro-2H-quinolin-1-yl) -methanone;

6-phenyl-pyrimidine-4-carboxylic acid methyl ester;

6- (2, 4-difluoro-phenyl) -pyrimidine-4-carboxylic acid methyl ester;

6- (2, 4-difluoro-phenyl) -pyrimidine-4-carboxylic acid;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid (6-methoxy-pyridin-3-yl) -amide;

[6- (3-chloro-phenyl) -pyrimidin-4-yl ] - (2, 3-dihydro-indol-1-yl) -methanone;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid m-tolylamide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid methyl-pyridin-3-yl-amide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid (5-methoxy-pyridin-3-yl) -amide;

6- (3-chloro-2-fluoro-phenyl) -pyrimidine-4-carboxylic acid methyl ester;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid dimethylamide;

6- (3-chloro-phenyl) -2-methyl-pyrimidine-4-carboxylic acid methyl ester;

4- [6- (3-chloro-phenyl) -pyrimidine-4-carbonyl ] -piperazin-2-one;

6-phenyl-pyrimidine-4-carboxylic acid pyridin-3-ylamide;

6- (3-chloro-2-fluoro-phenyl) -pyrimidine-4-carboxylic acid;

6- (3, 4-dichloro-phenylamino) -pyrimidine-4-carboxylic acid methyl ester;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid (4-methoxy-pyridin-3-yl) -amide;

6- (3-chloro-phenyl) -2-methyl-pyrimidine-4-carboxylic acid;

6- (3-chloro-phenyl) -2-methyl-pyrimidine-4-carboxylic acid pyridin-3-ylamide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid (2-hydroxy-ethyl) -amide;

[6- (3-chloro-phenyl) -pyrimidin-4-yl ] - (4-hydroxy-piperidin-1-yl) -methanone;

6- (3-methoxy-phenyl) -pyrimidine-4-carboxylic acid;

6- (3-methoxy-phenyl) -pyrimidine-4-carboxylic acid methyl ester;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid benzylamide;

[6- (3-chloro-phenyl) -pyrimidin-4-yl ] - (4-methyl-piperazin-1-yl) -methanone;

[6- (3-chloro-phenyl) -pyrimidin-4-yl ] -pyrrolidin-1-yl-methanone;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid ((S) -2-hydroxy-propyl) -amide;

6-m-tolyl-pyrimidine-4-carboxylic acid methyl ester;

1- {4- [6- (3-chloro-phenyl) -pyrimidine-4-carbonyl ] -piperazin-1-yl } -ethanone;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid ((R) -2-hydroxy-propyl) -amide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid (2-methoxy-phenyl) -amide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid (4-methoxy-phenyl) -amide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid (3-methoxy-phenyl) -amide;

6- (3-chloro-phenyl) -pyrimidine-4-sulfonic acid sodium salt;

6-m-tolyl-pyrimidine-4-carboxylic acid;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid methyl-phenyl-amide;

[6- (3, 4-dichloro-phenyl) -pyrimidin-4-yl ] - (2, 3-dihydro-indol-1-yl) -methanone;

n- [6- (3-chloro-phenyl) -pyrimidine-4-carbonyl ] -methanesulfonamide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid pyridin-2-ylamide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid pyridin-4-ylamide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid (pyridin-4-ylmethyl) -amide;

[6- (3-chloro-phenyl) -pyrimidin-4-yl ] - (4-methyl-piperidin-1-yl) -methanone;

[6- (3-chloro-phenyl) -pyrimidin-4-yl ] - ((R) -3-hydroxy-pyrrolidin-1-yl) -methanone;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid [1, 3, 4] thiadiazol-2-ylamide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid isoxazol-3-ylamide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid ((R) -1-phenyl-ethyl) -amide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid ((S) -1-phenyl-ethyl) -amide;

[6- (3-chloro-phenyl) -pyrimidin-4-yl ] - ((S) -3-hydroxy-pyrrolidin-1-yl) -methanone;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid [4- (4-methyl-piperazin-1-yl) -phenyl ] -amide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid (6-trifluoromethyl-pyridin-3-yl) -amide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid (pyridin-3-ylmethyl) -amide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid pyridazin-3-ylamide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid pyrazin-2-ylamide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid (4-morpholin-4-yl-phenyl) -amide;

(S) -1- [6- (3-chloro-phenyl) -pyrimidine-4-carbonyl ] -pyrrolidine-2-carboxylic acid amide;

(R) -1- [6- (3-chloro-phenyl) -pyrimidine-4-carbonyl ] -pyrrolidine-2-carboxylic acid amide;

azetidin-1-yl- [6- (3-chloro-phenyl) -pyrimidin-4-yl ] -methanone;

6- (4-methoxy-phenyl) -pyrimidine-4-carboxylic acid;

[6- (3-chloro-phenyl) -pyrimidin-4-yl ] - (1, 3-dihydro-isoindol-2-yl) -methanone;

[6- (3, 4-dichloro-phenyl) -pyrimidin-4-yl ] - (3, 4-dihydro-2H-quinolin-1-yl) -methanone;

6- (3, 4-dichloro-phenyl) -pyrimidine-4-carboxylic acid phenylamide;

6- (3, 4-dichloro-phenyl) -pyrimidine-4-carboxylic acid p-tolylamide;

6- (3, 4-dichloro-phenyl) -pyrimidine-4-carboxylic acid (5-methoxy-pyridin-3-yl) -amide;

6- (3, 4-dichloro-phenyl) -pyrimidine-4-carboxylic acid pyrimidin-5-ylamide;

6- (3, 4-dichloro-phenyl) -pyrimidine-4-carboxylic acid (6-methyl-pyridin-3-yl) -amide;

6- (3, 4-dichloro-phenyl) -pyrimidine-4-carboxylic acid (2-methyl-pyridin-3-yl) -amide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid pyrimidin-2-ylamide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid methyl-p-tolyl-amide;

6- (3-fluoro-phenyl) -pyrimidine-4-carboxylic acid methyl ester;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid (6-methyl-pyridin-3-yl) -amide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid (2-methyl-pyridin-3-yl) -amide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid (4-fluoro-phenyl) -amide;

6- (3-fluoro-phenyl) -pyrimidine-4-carboxylic acid;

6- (3, 5-dichloro-phenyl) -pyrimidine-4-carboxylic acid phenylamide;

[6- (3, 5-dichloro-phenyl) -pyrimidin-4-yl ] - (2, 3-dihydro-indol-1-yl) -methanone;

6- (3, 5-dichloro-phenyl) -pyrimidine-4-carboxylic acid p-tolylamide;

6- (3, 5-dichloro-phenyl) -pyrimidine-4-carboxylic acid (5-methoxy-pyridin-3-yl) -amide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid (1-methyl-1H-pyrazol-3-yl) -amide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid (1-methyl-1H-pyrazol-4-yl) -amide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid (4-methoxy-phenyl) -methyl-amide;

[6- (3-chloro-phenyl) -pyrimidin-4-yl ] - (2-methyl-2, 3-dihydro-indol-1-yl) -methanone;

6- (3-fluoro-phenyl) -pyrimidine-4-carboxylic acid pyridin-3-ylamide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid (2, 2-difluoro-benzo [1, 3] dioxol-5-yl) -amide;

[6- (3-chloro-phenyl) -pyrimidin-4-yl ] - (5-fluoro-2, 3-dihydro-indol-1-yl) -methanone;

(5-chloro-2, 3-dihydro-indol-1-yl) - [6- (3-chloro-phenyl) -pyrimidin-4-yl ] -methanone;

6- (3, 5-dichloro-phenyl) -pyrimidine-4-carboxylic acid pyrimidin-5-ylamide;

6- (3-chloro-4-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid methyl ester;

6- (3-chloro-4-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid;

6- (3-chloro-4-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid pyridin-3-ylamide;

[6- (3-chloro-phenyl) -pyrimidin-4-yl ] - (2, 3-dihydro-pyrrolo [3, 2-c ] pyridin-1-yl) -methanone;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid (2, 2-difluoro-benzo [1, 3] dioxol-5-yl) -methyl-amide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid thiazol-2-ylamide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid (3-methyl-isoxazol-5-yl) -amide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid (5-methyl- [1, 3, 4] oxadiazol-2-yl) -amide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid oxazol-2-ylamide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid (3-methyl- [1, 2, 4] thiadiazol-5-yl) -amide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid (4H- [1, 2, 4] triazol-3-yl) -amide;

6- (3, 4-difluoro-phenyl) -pyrimidine-4-carboxylic acid methyl ester;

6- (5-chloro-2-fluoro-phenyl) -pyrimidine-4-carboxylic acid methyl ester;

6- (3, 4-difluoro-phenyl) -pyrimidine-4-carboxylic acid;

6- (3, 4-difluoro-phenyl) -pyrimidine-4-carboxylic acid pyrimidin-5-ylamide;

6- (5-chloro-2-fluoro-phenyl) -pyrimidine-4-carboxylic acid;

[6- (3, 4-dichloro-phenyl) -pyrimidin-4-yl ] - (1 ', 2' -dihydro-spiro [ cyclopropane-1, 3 '- [3H ] indol ] -1') -methanone;

6- (3, 4-dichloro-phenyl) -pyrimidine-4-carboxylic acid (2, 6-dimethyl-pyridin-3-yl) -amide;

6- (3, 4-dichloro-phenyl) -pyrimidine-4-carboxylic acid (3-methyl-isoxazol-5-yl) -amide;

6- (3-chloro-4-fluoro-phenyl) -pyrimidine-4-carboxylic acid methyl ester;

6- (3, 4-dichloro-phenyl) -pyrimidine-4-carboxylic acid (5-methyl- [1, 3, 4] oxadiazol-2-yl) -amide;

6- (3-chloro-4-methoxy-phenyl) -pyrimidine-4-carboxylic acid methyl ester;

6- (3-chloro-4-methoxy-phenyl) -pyrimidine-4-carboxylic acid;

6- (3, 4-dichloro-phenyl) -pyrimidine-4-carboxylic acid (pyridin-4-ylmethyl) -amide;

6- (3-chloro-4-fluoro-phenyl) -pyrimidine-4-carboxylic acid;

6- (3, 4-dichloro-phenyl) -pyrimidine-4-carboxylic acid [1, 3, 4] thiadiazol-2-ylamide;

6- (3, 4-dichloro-phenyl) -pyrimidine-4-carboxylic acid (2-amino-ethyl) -amide;

(5-chloro-2, 3-dihydro-indol-1-yl) - [6- (3, 4-dichloro-phenyl) -pyrimidin-4-yl ] -methanone;

[6- (3, 4-dichloro-phenyl) -pyrimidin-4-yl ] - (5-fluoro-2, 3-dihydro-indol-1-yl) -methanone;

[6- (3, 4-dichloro-phenyl) -pyrimidin-4-yl ] - (5-morpholin-4-yl-2, 3-dihydro-indol-1-yl) -methanone;

6- (3, 4-dichloro-phenyl) -5-fluoro-pyrimidine-4-carboxylic acid;

6- (3, 4-dichloro-phenyl) -pyrimidine-4-carboxylic acid pyridin-4-ylamide;

6- (3, 4-dichloro-phenyl) -pyrimidine-4-carboxylic acid pyridin-2-ylamide;

6- (3, 4-dichloro-phenyl) -pyrimidine-4-carboxylic acid (1-methyl-1H-pyrazol-4-yl) -amide;

6- (3, 4-dichloro-phenyl) -pyrimidine-4-carboxylic acid isoxazol-3-ylamide;

6- (3, 4-dichloro-phenyl) -pyrimidine-4-carboxylic acid thiazol-2-ylamide;

[6- (3, 4-dichloro-phenyl) -pyrimidin-4-yl ] - (1, 3-dihydro-isoindol-2-yl) -methanone;

6- (3, 4-dichloro-phenyl) -pyrimidine-4-carboxylic acid (4H- [1, 2, 4] triazol-3-yl) -amide;

4- (3, 4-dichloro-phenyl) -6- (5-fluoro-pyridin-2-yl) -pyrimidine;

6- (3, 4-difluoro-phenyl) -pyrimidine-4-carboxylic acid pyridin-3-ylamide;

6- (3-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid pyrimidin-5-ylamide;

6- (3, 4-dichloro-phenyl) -pyrimidine-4-carboxylic acid (2-methyl-pyrimidin-5-yl) -amide;

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-fluoro-phenyl) -pyrimidine-4-carboxylic acid pyridin-3-ylamide;

6- (3-chloro-4-fluoro-phenyl) -pyrimidine-4-carboxylic acid (2, 6-dimethyl-pyridin-3-yl) -amide;

6- (3, 4-dichloro-phenyl) -pyrimidine-4-carboxylic acid (2-acetylamino-ethyl) -amide;

[6- (3, 4-dichloro-phenyl) -pyrimidin-4-yl ] - (3, 3-dimethyl-2, 3-dihydro-indol-1-yl) -methanone;

[6- (3, 4-dichloro-phenyl) -pyrimidin-4-yl ] - (4-hydroxy-piperidin-1-yl) -methanone;

[6- (3, 4-dichloro-phenyl) -pyrimidin-4-yl ] -morpholin-4-yl-methanone;

6- (3-chloro-4-fluoro-phenyl) -pyrimidine-4-carboxylic acid pyrimidin-5-ylamide;

6- (3, 4-dichloro-phenyl) -5-fluoro-pyrimidine-4-carboxylic acid methyl ester;

6- (3, 4-dichloro-phenyl) -5-fluoro-pyrimidine-4-carboxylic acid;

6- (3, 4-dichloro-phenyl) -5-fluoro-pyrimidine-4-carboxylic acid pyridin-3-ylamide;

6- (3, 4-dichloro-phenyl) -5-fluoro-pyrimidine-4-carboxylic acid (2, 6-dimethyl-pyridin-3-yl) -amide;

6- (3, 4-dichloro-phenyl) -5-fluoro-pyrimidine-4-carboxylic acid pyrimidin-5-ylamide;

2- (3-chloro-phenyl) -isonicotinic acid methyl ester;

4- (3-chloro-phenyl) -pyridine-2-carboxylic acid;

4- (3-chloro-phenyl) -pyridine-2-carboxylic acid methyl ester;

4- (3-chloro-phenyl) -pyridine-2-carboxylic acid pyridin-3-ylamide;

4- (3-chloro-phenyl) -pyridine-2-carboxylic acid phenylamide;

[4- (3-chloro-phenyl) -pyridin-2-yl ] - (2, 3-dihydro-indol-1-yl) -methanone;

4- (3-chloro-phenyl) -pyridine-2-carboxylic acid p-tolylamide;

4- (3-chloro-phenyl) -pyridine-2-carboxylic acid (5-methoxy-pyridin-3-yl) -amide;

4- (3, 5-dichloro-phenyl) -pyridine-2-carboxylic acid phenylamide;

4- (3, 5-dichloro-phenyl) -pyridine-2-carboxylic acid p-tolylamide;

4- (3, 5-dichloro-phenyl) -pyridine-2-carboxylic acid pyridin-3-ylamide;

4- (3, 5-dichloro-phenyl) -pyridine-2-carboxylic acid (5-methoxy-pyridin-3-yl) -amide;

[4- (3, 5-dichloro-phenyl) -pyridin-2-yl ] - (2, 3-dihydro-indol-1-yl) -methanone;

4- (3-chloro-phenyl) -pyridine-2-carboxylic acid pyrimidin-5-ylamide;

4- (3, 4-dichloro-phenyl) -pyridine-2-carboxylic acid phenylamide;

4- (3, 4-dichloro-phenyl) -pyridine-2-carboxylic acid p-tolylamide;

4- (3, 4-dichloro-phenyl) -pyridine-2-carboxylic acid pyridin-3-ylamide;

[4- (3, 4-dichloro-phenyl) -pyridin-2-yl ] - (2, 3-dihydro-indol-1-yl) -methanone;

4- (3, 4-dichloro-phenyl) -pyridine-2-carboxylic acid (5-methoxy-pyridin-3-yl) -amide;

4- (3, 4-dichloro-phenyl) -pyridine-2-carboxylic acid pyrimidin-5-ylamide;

4- (3, 5-dichloro-phenyl) -pyridine-2-carboxylic acid pyrimidin-5-ylamide; and

5-morpholin-4-yl-pyridine-2-carboxylic acid tert-butyl ester,

and pharmaceutically acceptable salts and prodrugs thereof.

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid sodium salt;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid cyclohexylammonium salt;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid pyridin-3-ylamide hydrochloride;

6- (3, 4-dichloro-phenyl) -pyrimidine-4-carboxylic acid sodium salt;

6-pyridin-3-yl-pyrimidine-4-carboxylic acid methyl ester trifluoroacetate salt;

6-morpholin-4-yl-pyrimidine-4-carboxylic acid hydrochloride;

6- (3, 4-dichloro-phenyl) -pyrimidine-4-carboxylic acid (6-methyl-pyridin-3-yl) -amide hydrochloride;

6- (3, 4-dichloro-phenyl) -pyrimidine-4-carboxylic acid (2, 6-dimethyl-pyridin-3-yl) -amide hydrochloride;

6- (3, 4-dichloro-phenyl) -pyrimidine-4-sulfonic acid sodium salt;

2- (3-chloro-phenyl) -isonicotinic acid hydrochloride;

4- (3, 5-dichloro-phenyl) -pyridine-2-carboxylic acid hydrochloride; and

4- (3, 4-dichloro-phenyl) -pyridine-2-carboxylic acid hydrochloride.

6- (2-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid methyl ester;

6- (3, 4-dichloro-phenyl) -pyrimidine-4-carboxylic acid methyl ester;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid methyl ester;

6- (3, 5-dichloro-phenyl) -pyrimidine-4-carboxylic acid methyl ester;

6- (3, 4-dichloro-phenyl) -2-methyl-pyrimidine-4-carboxylic acid methyl ester;

6- (2-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid;

6- (3, 4-dichloro-phenyl) -pyrimidine-4-carboxylic acid;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid;

6- (3, 5-dichloro-phenyl) -pyrimidine-4-carboxylic acid;

6- (3, 4-dichloro-phenyl) -2-methyl-pyrimidine-4-carboxylic acid;

6- (3, 4-dichloro-phenyl) -pyrimidine-4-carboxylic acid pyridin-3-ylamide;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid pyridin-3-ylamide;

n- [6- (3-chloro-phenyl) -pyrimidin-4-yl ] -nicotinamide;

n- [6- (3, 4-dichloro-phenyl) -pyrimidin-4-yl ] -methanesulfonamide; and

n- [6- (2-trifluoromethyl-phenyl) -pyrimidin-4-yl ] -methanesulfonamide;

and pharmaceutically acceptable salts and prodrugs thereof.

Suitable procedures are described, for example, in the following reaction schemes and examples, and in references cited herein, and methods of obtaining the chemicals described herein will be apparent to those skilled in the art.

Reaction scheme 1

Referring to scheme 1, step 1, a compound of formula 101, formula R, is placed in a pressure tube₁B(OH)₂Compound and Pd (PPh)₃)₄Suspended in a suitable solvent such as dioxane. Adding a base such as aqueous potassium carbonate solution e.g. 2M K₂CO₃Solution, the reaction mixture is heated at about 90 ℃ under an inert atmosphere. The reaction mixture is cooled to room temperature and the product compound of formula 103 is isolated and optionally purified.

Referring to reaction scheme 1, step 2, a compound of formula 103, PdCl, is placed in a vessel equipped with a magnetic stirrer₂(dppf.) DCM and triethylamine are suspended in a suitable solvent such as degassed MeOH. The vessel was pressurized to about 5 bar CO and heated at about 50 ℃ for about 5 hours with stirring. The reaction vessel is allowed to cool and the product compound of formula 105 is isolated and optionally purified.

Referring to reaction scheme 1, step 3, a compound of formula 105 is suspended in a suitable solvent, such as methanol. An aqueous base solution, e.g., aqueous sodium hydroxide solution such as 1M NaOH solution, is added and the reaction mixture is stirred at room temperature for about 4 hours. The product, a compound of formula 107, is isolated and optionally purified.

Referring to reaction scheme 1, step 4, to a solution of the compound of formula 107 in a suitable solvent such as DMF is added edc.hcl and HOBt. The reaction mixture is stirred at ambient temperature for about 30 minutes, after which the formula R is added₂NH₂The amine of (1). The product compound of formula 109 is isolated and optionally purified.

Reaction scheme 2

Referring to reaction scheme 2, step 1, the compound of formula 201 is suspended in ammonium hydroxide and then microwave-irradiated at about 100 ℃ for about 1 hour with stirring. The product compound of formula 203 is isolated and optionally purified.

Reference reaction scheme 2 StepsStep 2, the compound of formula 203 is suspended in a suitable solvent, such as dioxane. An excess of sodium hydride (e.g., about 3-10 equivalents) is added and the suspension is stirred at room temperature for about 30 minutes. An excess (e.g., about 1.1 equivalents) of formula R is added₂S(O)₂Cl compound, the reaction mixture was stirred at room temperature. The product compound of formula 205 is isolated and optionally purified.

Referring to reaction scheme 2, step 3, the compound of formula 203 is suspended in an inert solvent, such as dioxane. A base such as sodium hydride is added and the suspension is stirred at room temperature for about 30 minutes. An excess (e.g., about 1.1 equivalents) of the corresponding compound of formula Cl-C (O) -R is added₃The acid chloride, and the reaction mixture was stirred at room temperature for about 3 days. Optionally with the addition of a base. The product compound of formula 207 is isolated and optionally purified.

The present application provides methods of inhibiting KMO catalytic activity comprising contacting the KMO with an effective amount of at least one chemical described herein.

The present application also provides a method of treating a condition or disorder mediated by KMO activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of at least one chemical substance as described herein.

The present application also provides a method of treating a KMO activity mediated neurodegenerative pathology in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of at least one chemical substance as described herein. The present application also provides methods of treating disorders mediated by (or at least in part by) the presence of KYNA and/or QUIN. Such diseases include, for example, huntington's disease and other polyglutamine disorders such as spinocerebellar ataxia, alzheimer's disease, parkinson's disease, hypertensive syndromes, dystonia, olivopontocerebellar atrophy, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, stroke consequences, cerebral ischemia, hypoxia, multi-infarct dementia, cerebral trauma or damage consequences, spinal cord injury, AIDS-dementia complex, viral or bacterial encephalo [ ridgetis ], systemic Central Nervous System (CNS) infections such as viral, bacterial or parasitic infections, e.g., polio, lyme disease (borrelia infection) and malaria, brain (centrally) localized cancer, Tourette's syndrome, hepatic encephalopathy, systemic lupus erythematosus, analgesia and opiate withdrawal symptoms, feeding behavior, schizophrenia, chronic anxiety disorders, depression, disorders of the developing or aging brain, diabetes, and complications thereof, the method of treatment comprising administering to the subject an effective amount of at least one chemical substance described herein.

The present application also provides methods of treatment wherein at least one chemical entity described herein is the only active agent administered to the subject; the present application also includes methods of treatment wherein at least one chemical entity described herein is administered to the subject in combination with one or more additional active agents.

Generally, the chemical agents described herein will be administered in a therapeutically effective amount by any of the dosage regimens acceptable for agents of similar utility. The actual amount of the compound of the invention, i.e., the active ingredient, will depend on a variety of factors, such as the severity of the disease to be treated, the age and relative health of the subject, the efficacy of the compound used, the route and form of administration, and other factors well known to those skilled in the art. The medicament may be administered at least once daily, for example 1 or 2 times daily.

In some embodiments, the chemical agents described herein are administered in a pharmaceutical composition. Accordingly, the present application provides pharmaceutical compositions comprising at least one chemical entity described herein and at least one pharmaceutically acceptable vehicle selected from carriers, adjuvants, and excipients.

The pharmaceutically acceptable vehicles must be of sufficiently high purity and of sufficiently low toxicity to render them suitable for administration to the animal being treated. The vehicle may be inert or it may have pharmaceutical benefits. The amount of vehicle used in conjunction with the chemical substance is sufficient to provide a practical amount of the substance for administration as a unit dose of the chemical substance.

Exemplary pharmaceutically acceptable carriers or components thereof are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; tragacanth powder; malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; synthetic oil; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; a phosphate buffer solution; emulsifiers such as tween; wetting agents such as sodium lauryl sulfate; a colorant; a flavoring agent; preparing tablets; a stabilizer; an antioxidant; a preservative; pyrogen-free water; isotonic saline water; and phosphate buffer solutions.

Optional active agents are also included in the pharmaceutical composition that do not significantly interfere with the activity of the chemicals described herein.

An effective concentration of at least one chemical substance described herein is mixed with a suitable pharmaceutically acceptable vehicle. When the chemical substance shows insufficient solubility, a method of solubilizing the compound may be used. Such methods are known to those skilled in the art and include, but are not limited to, the use of co-solvents such as dimethyl sulfoxide (DMSO), the use of surfactants such as TWEEN, or dissolution in aqueous sodium bicarbonate.

When chemicals described herein are mixed or added, the resulting mixture may be a solution, suspension, emulsion, or the like. The form of the resulting mixture depends on a number of factors, including the intended dosing regimen and the solubility of the chemical substance in the chosen vehicle. Effective concentrations sufficient to ameliorate the symptoms of the disease being treated can be determined empirically.

The chemical substances described herein may be administered orally, topically, parenterally, intravenously, intramuscularly, by inhalation or spray, sublingually, transdermally, buccally, rectally, as an ophthalmic solution, or by other means in dosage unit formulations.

The pharmaceutical compositions may be formulated for oral administration, for example as tablets, troches, lozenges, aqueous or oily suspensions, divisible or granules, emulsions, hard or soft capsules, or syrups or elixirs. Pharmaceutical compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents, for example sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide pharmaceutically effective and palatable preparations. In some embodiments, an oral pharmaceutical composition comprises 0.1-99% of at least one chemical species described herein. In some embodiments, an oral pharmaceutical composition comprises at least 5% (wt%) of at least one chemical species described herein. Some embodiments comprise 25% to 50% or 5% to 75% of at least one chemical species described herein.

Pharmaceutical compositions for oral administration also include liquid solutions, emulsions, suspensions, powders, granules, elixirs, tinctures, syrups and the like. Pharmaceutically acceptable carriers suitable for preparing the compositions are well known in the art. Oral pharmaceutical compositions may contain preservatives, flavouring agents, sweetening agents such as sucrose or saccharin, taste-masking agents and colouring agents.

Typical carrier ingredients for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. The pharmaceutical composition may further comprise a slip agent.

The chemicals described herein may be formulated as oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs. In addition, pharmaceutical compositions containing these chemicals may be presented as a dry product for use in combination with water or other suitable vehicle. The liquid preparations may contain conventional additives such as suspending agents (e.g. sorbitol syrup, methyl cellulose, glucose/sucrose, syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gum and hydrogenated edible fats), emulsifying agents (e.g. lecithin, sorbitan monooleate or acacia), non-aqueous vehicles (including edible oils (e.g. almond oil, fractionated coconut oil, silyl esters, propylene glycol and ethanol)), and preservatives (e.g. methyl or propyl p-hydroxybenzoates and sorbic acid).

For suspension, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, AvicelRC-591, gum tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methylparaben and sodium benzoate.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; a dispersing or wetting agent; it may be a naturally occurring phosphatide such as lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol (heptadecaethyleneoxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol substitutes, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitol substitutes. The aqueous suspension may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These pharmaceutical compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

The pharmaceutical composition may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin, or mixtures thereof. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol or hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are listed above.

Tablets typically contain conventional pharmaceutically acceptable adjuvants, for example inert diluents such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmellose; lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve the flowability of the powder mixture. Colorants such as FD & C dyes may be added for aesthetic purposes. Sweeteners and flavoring agents such as aspartame, saccharin, menthol, peppermint, and fruit flavors may be used as adjuvants for chewable tablets. Capsules (including timed release and sustained release formulations) typically contain one or more solid diluents as disclosed above. The choice of carrier ingredients often depends on secondary considerations such as mouthfeel, cost and storage stability.

The pharmaceutical compositions may also be coated by conventional means, typically using a pH or time dependent coating, so that the chemical substance is released in the gastrointestinal tract either near the desired topical application or at different times to prolong the desired effect. Such dosage forms typically include, but are not limited to, one or more of the following: cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, eudragit coatings, waxes and shellac.

Pharmaceutical compositions for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

The pharmaceutical compositions may be in the form of sterile aqueous or oily suspensions for injection. This suspension may be formulated according to the known art using those suitable dispersing or wetting and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable vehicle, for example as a solution in 1, 3-butane diol. Suitable vehicles are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile non-volatile oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The chemicals described herein may be administered parenterally in a sterile medium. Parenteral administration includes subcutaneous injection, intravenous injection, intramuscular injection, intrathecal injection or infusion techniques. Depending on the vehicle and concentration used, the chemicals described herein may be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle. In many pharmaceutical compositions for parenteral administration, the carrier comprises at least 90% by weight of the total composition. In some embodiments, the carrier for parenteral administration is selected from the group consisting of propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil.

The chemical substances described herein may also be administered in the form of suppositories for rectal administration of the drug. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.

The chemicals described herein may also be formulated for topical or local administration, e.g., for topical administration to the skin and mucous membranes, e.g., in the form of gels, creams or lotions for intraocular administration as well as for administration to the eye. The topically administered pharmaceutical composition can be in any form, including, for example, solutions, creams, ointments, gels, lotions, emulsions, cleansers, moisturizers, sprays, skin patches, and the like.

The solution can be prepared into 0.01-10% isotonic solution with pH of 5-7 by using proper salt. The chemicals described herein may also be formulated as transdermal patches for transdermal administration.

A typical pharmaceutical composition comprising at least one chemical species described herein may be mixed with various carrier materials well known in the art, such as water, alcohol, aloe vera, allantoin, glycerin, vitamin a and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, and the like.

Other materials suitable for use as carriers for topical administration include, for example, emollients, solvents, humectants, thickeners and powders. Each of these types of substances may be used alone or as a mixture of one or more substances, examples of which are as follows:

representative lubricating agents include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-1, 2-diol, butane-1, 3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecyl-2-ol, isocetyl alcohol, cetyl palmitate, dimethylpolysiloxane, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, peanut oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, Myristyl lactate, decyl oleate and myristyl myristate; propellants such as propane, butane, isobutane, dimethyl ether, carbon dioxide and nitrous oxide; solvents such as ethanol, dichloromethane, isopropanol, castor oil, monoethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran; humectants such as glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, and gelatin; and powders such as chalk, talc, china clay, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetraalkyl ammonium montmorillonite, trialkyl aryl ammonium montmorillonite, chemically modified magnesium aluminum silicate, organically modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, and ethylene glycol monostearate.

The chemicals described herein can also be administered regionally in the form of a liposomal delivery system (e.g., small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles). Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearamide, or lecithin phosphate.

Other pharmaceutical compositions that may be used to achieve systemic delivery of chemical substances include sublingual, buccal, intranasal dosage forms. The pharmaceutical compositions typically comprise one or more soluble filler materials such as sucrose, sorbitol and mannitol, and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants, and flavoring agents disclosed above may also be included.

Pharmaceutical compositions for inhalation may be conveniently presented in the form of solutions, suspensions or emulsions, which may be administered as a dry powder or aerosol using conventional propellants, such as dichlorodifluoromethane or trichlorofluoromethane.

The pharmaceutical composition may also optionally comprise an activity enhancer. The activity enhancer may be selected from a wide variety of molecules that function in various ways to enhance or be independent of the therapeutic effect of the chemical substances described herein. Specific types of activity enhancers include skin penetration enhancers and absorption enhancers.

The pharmaceutical composition may also comprise additional active agents, which may be selected from a wide variety of molecules, that may act in various ways to enhance the therapeutic effect of at least one of the chemicals described herein. These optional additional active agents, if present, are typically used in the pharmaceutical composition in an amount of 0.01% to 15%. In some embodiments from 0.1% to 10% by weight of the composition. In other embodiments from 0.5% to 5% by weight of the composition.

Packaged pharmaceutical compositions are also provided. The packaged composition comprises: pharmaceutical compositions comprising at least one chemical entity described herein and instructions for using the compositions to treat a subject, typically a human patient. In some embodiments, the instructions are for using the pharmaceutical composition to treat a subject having a condition or disorder mediated by kynurenine-3-monooxygenase activity. The packaged pharmaceutical composition may include providing prescription information: for example to a patient or health care provider, or as a label within a packaged pharmaceutical composition. The prescription information may include, for example, potency, dosage and dosing regimen, contraindications and side-reaction information relating to the pharmaceutical composition.

All of the foregoing chemicals may be administered alone, as a mixture or in combination with other active agents.

The methods described herein include methods of treating huntington's disease (including treating memory and/or cognitive impairment associated with huntington's disease) comprising administering to a subject, simultaneously or sequentially, at least one chemical substance described herein and one or more additional agents useful in treating huntington's disease, such as, but not limited to, amitriptyline, imipramine, Despiramine, nortriptyline, paroxetine, fluoxetine, Setraline, Terabenazine, haloperidol, chlorpromazine, thioridazine, Sulpride, quetiapine, clozapine, and risperidone. In methods employing simultaneous administration, the agents may be present in a combined composition or may be administered separately. Accordingly, the present application also provides pharmaceutical compositions comprising at least one chemical entity described herein and one or more additional drugs for the treatment of huntington's disease, such as, but not limited to, amitriptyline, imipramine, Despiramine, nortriptyline, paroxetine, fluoxetine, Setraline, Terabenazine, haloperidol, chlorpromazine, thioridazine, Sulpride, quetiapine, clozapine, and risperidone. Similarly, the present application also provides packaged pharmaceutical compositions comprising a pharmaceutical composition comprising at least one chemical substance described herein and another composition comprising one or more additional drugs for the treatment of huntington's disease, such as, but not limited to, amitriptyline, imipramine, Despiramine, nortriptyline, paroxetine, fluoxetine, Setraline, Terabenazine, haloperidol, chlorpromazine, thioridazine, Sulpride, quetiapine, clozapine, and risperidone.

The present application also provides methods of treating parkinson's disease (including treating memory and/or cognitive impairment associated with parkinson's disease), the methods comprising administering to a subject, simultaneously or sequentially, at least one chemical described herein and one or more additional agents useful for treating parkinson's disease, such as, but not limited to, levodopa, Parlodel, pergolide, pramipexole, tolcapone, Contan, kamadrine, trihexyphenidyl, and benztropine. In methods employing simultaneous administration, the agents may be present in a combined composition or may be administered separately. The present application also provides pharmaceutical compositions comprising at least one chemical described herein and one or more additional drugs for treating parkinson's disease, such as, but not limited to, levodopa, Parlodel, pergolide, pramipexole, tolcapone, continan, kamadrine, trihexyphenidyl, and benztropine. Also provided are packaged pharmaceutical compositions comprising a pharmaceutical composition comprising at least one chemical entity described herein and another composition comprising one or more additional drugs for use in the treatment of parkinson's disease, such as, but not limited to, levodopa, Parlodel, pergolide, pramipexole, tolcapone, Contan, Kamadrin, trihexyphenidyl, and benztropine.

The present application also provides methods of treating memory and/or cognitive impairment associated with alzheimer's disease comprising administering to a subject, either simultaneously or sequentially, at least one chemical substance described herein and one or more additional agents useful in treating alzheimer's disease, such as, but not limited to, Reminyl, tacrine, aricept, exendin, memantine, diammonidine, selegiline, estrogen, and clioquinol. In methods employing simultaneous administration, the agents may be present in a combined composition or may be administered separately. The present application also provides pharmaceutical compositions comprising at least one chemical entity described herein and one or more additional drugs useful in the treatment of alzheimer's disease, such as, but not limited to, Reminyl, tacrine, aricept, exendin, memantine, diammonibutoxypyridine, selegiline, estrogen, and iodochlorohydroxyquinoline. Similarly, the present application also provides packaged pharmaceutical compositions comprising a pharmaceutical composition comprising at least one chemical substance described herein and another composition comprising one or more additional drugs for the treatment of alzheimer's disease, such as, but not limited to, Reminyl, tacrine, aricept, exendin, memantine, diammonidine, selegiline, estrogen, and clioquinol.

The present application also provides methods of treating memory and/or cognitive impairment associated with dementia comprising administering to a subject, either simultaneously or sequentially, at least one chemical as described herein and one or more additional agents useful in the treatment of dementia, such as, but not limited to, thioridazine, haloperidol, risperidone, tacrine, aricept, and exendin. In methods employing simultaneous administration, the agents may be present in a combined composition or may be administered separately. The present application also provides pharmaceutical compositions comprising at least one chemical entity described herein and one or more additional drugs for the treatment of dementia, such as, but not limited to, thioridazine, haloperidol, risperidone, tacrine, aricept, and exenatide. The present application also provides packaged pharmaceutical compositions comprising a pharmaceutical composition comprising at least one chemical entity described herein and another composition comprising one or more additional drugs for the treatment of dementia, such as, but not limited to, thioridazine, haloperidol, risperidone, tacrine, aricept, and exendin.

The present application also provides methods of treating memory and/or cognitive impairment associated with epilepsy, the methods comprising administering to a subject, either simultaneously or sequentially, at least one chemical entity described herein and one or more additional agents useful in the treatment of epilepsy, such as, but not limited to, phenytoin, luminol, carbamazepine, divalproex sodium, dipropylacetate sodium, ethosuximide, gabapentin, barbital, phenobarbital, and felbamate formulations. In methods employing simultaneous administration, the agents may be present in a combined composition or may be administered separately. The present application also provides pharmaceutical compositions comprising at least one chemical entity described herein and one or more additional pharmaceutical agents useful for treating epilepsy, such as, but not limited to, phenytoin, luminol, carbamazepine, divalproex sodium, sodium dipropylacetate, ethosuximide, gabapentin, barbital, phenobarbital, and felbamate formulations. Also provided are packaged pharmaceutical compositions comprising a pharmaceutical composition comprising at least one chemical entity described herein and another composition comprising one or more additional pharmaceutical agents useful for the treatment of epilepsy, such as, but not limited to, phenytoin, luminol, carbamazepine, divalproex sodium, dipropylacet sodium, ethosuximide, gabapentin, barbital, phenobarbital, and felbamate formulations.

The present application also provides methods of treating memory and/or cognitive impairment associated with multiple sclerosis comprising administering to a subject, either simultaneously or sequentially, at least one chemical as described herein and one or more additional agents useful in the treatment of multiple sclerosis, such as, but not limited to, Detrol, oxybutynin chloride formulation, oxycodone, recombinant interferon beta-1 b, interferon beta-1 a powder injection, azathiopurine, methotrexate, and Copaxone. In methods employing simultaneous administration, the agents may be present in a combined composition or may be administered separately. The present application also provides pharmaceutical compositions comprising at least one chemical entity described herein and one or more additional drugs for the treatment of multiple sclerosis, such as, but not limited to, Detrol, oxybutynin chloride, oxycodone, recombinant interferon beta-1 b, interferon beta-1 a powder injection, azathiopurine, methotrexate, and Copaxone. Also provided are packaged pharmaceutical compositions, including a pharmaceutical composition containing at least one chemical entity described herein and another composition containing one or more additional drugs for the treatment of multiple sclerosis, such as, but not limited to, Detrol, oxybutynin chloride, oxycodone, recombinant interferon beta-1 b, interferon beta-1 a powder injection, azathiopurine, methotrexate, and Copaxone.

When used in combination with one or more additional drugs, the chemical substances described herein may be administered prior to, concurrently with, or subsequent to the administration of the drug.

The dosage of the compounds described herein will depend on a variety of factors including the particular syndrome being treated, the severity of the symptoms, the route of administration, the frequency of dosing intervals, the particular compound used, the potency, toxicological and pharmacokinetic properties of the compound, and any adverse side effects present, and the like.

The chemicals described herein are generally administered at dosage levels and in a manner customary for KMO inhibitors. For example, the chemical may be administered in single or multiple doses, typically at a dosage level of from 0.001 to 100 mg/kg/day, for example from 0.01 to 100 mg/kg/day, such as from 0.1 to 70 mg/kg/day, for example from 0.5 to 10 mg/kg/day, for oral administration. The unit dosage form may typically contain 0.01 to 1000mg of at least one chemical substance described herein, for example, 0.1 to 50mg of at least one chemical substance described herein. For intravenous administration, the compounds may be administered in single or multiple doses, e.g., at a dosage level of 0.001-50 mg/kg/day, such as 0.001-10 mg/kg/day, such as 0.01-1 mg/kg/day. The unit dosage form may contain, for example, 0.1-10mg of at least one chemical entity described herein.

Labeled forms of the chemicals described herein can be used as diagnostics for identifying and/or obtaining compounds that function to modulate KMO activity as described herein. The chemistry described herein can also be used to validate, optimize, and standardize bioassays.

As used herein, "label" refers to labeling a compound, directly or indirectly, with a label that provides a detectable signal, e.g., a radioisotope, a fluorescent label, an enzyme, an antibody, a particle such as a magnetic particle, a chemiluminescent label, or a specific binding molecule, among others. Specific binding molecules include pairs of molecules such as biotin and streptavidin, digoxin and anti-digoxin, and the like. For specific binding members, the complementary member is typically labeled with a molecule that provides for detection according to known methods as outlined above. The label may provide a detectable signal, either directly or indirectly.

In practicing the methods described herein, it is to be understood that reference to particular buffers, media, reagents, cells, culture conditions, and the like, is not intended to be limiting, but is to be understood to include all relevant material that one of ordinary skill in the art would recognize as being relevant or valuable in the particular context in which the discussion is provided. For example, it is often possible to replace one buffer system or medium with another while still achieving similar (if not identical) results. Those skilled in the art will have sufficient knowledge of such systems and methodologies to make such substitutions, without undue experimentation, that will best perform their function in using the methods and steps disclosed herein.

Examples

The chemicals, compositions, and methods described herein are further illustrated by the following non-limiting examples.

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

CDI ═ carbonyldiimidazole

DCM ═ dichloromethane

DME ═ dimethyl ether

DMEM Dulbecco's modified Eagle Medium

DMF ═ N, N-dimethylformamide

DMSO ═ dimethyl sulfoxide

EDC HCl-1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride

EtOH ═ ethanol

Et₂Ethyl ether (O ═ ethyl ether)

EtOAc ═ ethyl acetate

g is g ═ g

hr as hour

hrs is hour

HOBt ═ tert-butanol

LiHMDS (lithium hexamethyldisilazide)

LC/MS liquid chromatography/mass spectrometry

mg ═ mg

min is minutes

mL to mL

mmol ═ mmol

mM ═ mmol/l

ng-nanogram

nm-nm

nM nmol/l

PBS-phosphate buffered saline

rt-room temperature

TBME ═ tert-butyl methyl ether

THF ═ tetrahydrofuran

TMOF trimethyl orthoformate

μ L ═ microliter

μ M-millimol/l

Experiment of

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

Kieselgel 60F for Thin Layer Chromatography (TLC) analysis₂₅₄(Merck) plates and visualisation using UV light. The microwave reaction was performed using CEM focused microwaves.

Analytical HPLC-MS was performed on Agilent HP1100 and Shimadzu2010 systems using a reverse phase Atlantis dC18 column (5 μm, 2.1X50mm), gradient 5-100% B (a ═ water/0.1% formic acid, B ═ acetonitrile/0.1% formic acid) over 3min, injection volume 3 μ l, flow rate 1.0 ml/min. The UV spectrum was recorded at 215nm using a Waters 2487 dual wavelength UV detector or Shimadzu2010 system. Collecting mass spectrum in the range of m/z 150-850, sampling at the rate of 2 scans/second, and using Waters ZMD; collecting in the range of m/z 100-1000, sampling at the rate of 2Hz, and carrying out electrospray ionization by using a Shimadzu2010 LC-MS system; alternatively, analytical HPLC-MS was performed on Agilent HP1100 and Shimadzu2010 systems using reverse phase Water Atlantis dC18 column (3 μm, 2.1X100mm), gradient 5-100% B (a ═ Water/0.1% formic acid, B ═ acetonitrile/0.1% formic acid) over 7min, injection volume 3 μ l, flow rate 0.6 ml/min. UV spectra were recorded at 215nm, using a Waters 2996 photodiode array or on a Shimadzu2010 system. Collecting mass spectrum in the range of m/z 150-850, sampling at the rate of 2 scans/second, and using Waters ZQ; collecting in the range of m/z 100-1000, sampling at the rate of 2Hz, and carrying out electrospray ionization by using a Shimadzu2010 LC-MS system. Data were integrated, reported using OpenLynx and OpenLynx Browser software or via Shimadzu PsiPort software.

1g/1ml＝1vol

General procedure

Method a. amide coupling to a solution of carboxylic acid (1eq) in DMF was added edc.hcl (1eq) and HOBt (1 eq). The reaction mixture was stirred at ambient temperature for 30 minutes, then the appropriate amine was added. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was poured into water and the solution precipitated, filtered, washed with water then heptane and dried under vacuum to give the title compound, or if no precipitate was formed, the reaction mixture was extracted with EtOAc (3X) and the combined organic layers were washed with water then saturated aqueous NaCl and dried (Na)₂SO₄Or MgSO (MgSO)₄) The solvent was removed in vacuo to give the crude product. Purification is performed by flash column chromatography, preparative HPLC or a combination thereof.

Method b. amide coupling to a solution of carboxylic acid (1eq) in DCM (20vol) under nitrogen was added oxalyl chloride (3eq) and 1 drop DMF (catalyst amount). The reaction mixture was stirred at ambient temperature for 30 minutes, then the solvent was removed in vacuo. DCM (20vol) or THF (20vol) was added followed by the desired amine (1-3 eq) and triethylamine (2eq) and the reaction mixture was stirred at ambient temperature. The reaction was monitored by LCMS until completion, at which time water was added. The reaction mixture was then extracted with dichloromethane, the organic layer was washed with water and then saturated aqueous NaCl, and Na₂SO₄Or MgSO (MgSO)₄Drying and removal of the solvent in vacuo gave the crude product. Purification is carried out by flash column chromatography, preparative HPLC, a combination of both or trituration in a suitable solvent.

Example 1

Preparation of pyrimidine analogs

Scheme 1

Stage 1

To a stirred suspension of dichloropyrimidine (1eq) in 1, 4-dioxane (15vol) was added boric acid (0.7eq) and Pd (PPh)₃)₄(0.025 eq). To the resulting mixture was added 2M K₂CO₃The solution (7.5vol) was heated at 90 ℃ overnight under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in EtOAc: water (1: 1) (100vol) and the resulting solution was filtered through celite. The organic layer was separated and the aqueous layer was further extracted with EtOAc (50 vol). The combined organic layers were washed with saturated aqueous NaCl (20vol) and Na₂SO₄Drying, filtering and removing the solvent in vacuum. The residue obtained is subjected to flash column chromatography (eluent: 0: 1 to 1: 19)]EtOAc: heptane) to afford the desired target compound.

Stage 2

4-chloro-6-substituted-phenyl-pyrimidines (1eq), PdCl in a bomb reactor equipped with magnetic stirrer₂(dppf), DCM (0.05eq) and triethylamine (2eq) were suspended in degassed MeOH (50 vol). The air in the reaction vessel was replaced with nitrogen by successively evacuating and charging nitrogen (this operation was repeated 3 times). The bomb reactor was then flushed with CO by successively charging with CO and evacuating. The vessel was pressurized to 5 bar CO and heated at 50 ℃ for 5 hours with stirring. The reaction vessel was cooled to room temperature, then CO was vented and N was used₂And (5) flushing. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in EtOAc (30vol) and water (30 vol). The solution was filtered through raw cotton, the organic layer was separated, washed with saturated aqueous NaCl (15vol), and washed with Na₂SO₄Drying, filtering and concentrating under reduced pressure. Purifying by flash column chromatography (eluent: 0: 1-1: 9)]EtOAc: heptane) The target compound is obtained.

Stage 3

6-substituted-phenyl-pyrimidine-4-carboxylic acid methyl ester (1eq) was suspended in MeOH (20vol) and 1M NaOH solution (20vol) and stirred at room temperature for 4 hours. The reaction mixture was acidified with 2M HCl. The soluble product was extracted with DCM (2X20vol) and the combined organic layers were MgSO₄Drying, filtering and concentrating under reduced pressure to obtain the target compound. The insoluble product was filtered off, washed with water (3x10vol) followed by heptane (3x10vol) and then dried in vacuo to give the title compound.

Stage 4

The claimed amide analogues were prepared following the procedure described in method a or B.

Example 2

Step 1

4-chloro-6-substituted-phenyl-pyrimidine (1eq) was suspended in ammonium hydroxide (60vol) and then microwave irradiated at 100 ℃ for 1 hour with stirring. The reaction mixture was extracted with DCM (5 × 20 vol). The solvent was removed in vacuo to afford the title compound.

Step 2

The 6-substituted-phenyl-pyrimidin-4-ylamine (1eq) was suspended in dioxane (30 vol). Sodium hydride (3 to 10eq) was added and the suspension was stirred at room temperature for 30 minutes. The corresponding sulfonyl chloride (1.1eq) was added and the reaction mixture was stirred at room temperature for 1-5 days. The reaction was quenched by the addition of water (40vol) and EtOAc (40vol) was added and the mixture was allowed to separate. The aqueous layer was washed with EtOAc (3 × 20vol) and the organic layer was discarded. The aqueous layer was then acidified to pH about 1 with concentrated hydrochloric acid and extracted with EtOAc (4 × 40 vol). The combined organic layers were washed with saturated aqueous NaCl (40vol) and Na₂SO₄Drying, filtering and vacuum concentrating to obtain the target compound.

Step 3

The 6-substituted-phenyl-pyrimidin-4-ylamine (1eq) was suspended in dioxane (20 vol). Sodium hydride (4eq) was added and the suspension was stirred at room temperature for 30 min. The corresponding acid chloride (1.1eq) was added and the reaction mixture was stirred at room temperature for 3 days. Additional sodium hydride (4eq) was added and the reaction mixture was stirred at room temperature for 24 hours. The reaction was quenched by the addition of water (75vol) and then acidified to pH 1 with HCl. The acidic solution was extracted with DCM (2 × 50 vol). The combined organic layers were washed with saturated aqueous NaCl (50vol) and Na₂SO₄Drying, filtering and vacuum concentrating. The residue was recrystallized from hot MeOH to give the title compound.

Example 3

To a solution of 6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid amide (1eq) in DMF (25vol) was added sodium hydride (1.1eq) with stirring. The reaction mixture was stirred at ambient temperature for 30 minutes and methyl iodide (2eq) was added. The reaction mixture is stirred at ambient temperature for 3-4 hours. Water was added and the resulting mixture was extracted with ethyl acetate or DCM. The organic layer was washed with water and brine, then MgSO₄Drying, filtration and removal of the solvent in vacuo afforded the crude amide which was further purified by flash column chromatography or preparative HPLC.

Example 4

To a solution of 6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid (1eq) or 6- (3, 4-dichloro-phenyl) -pyrimidine-4-carboxylic acid methyl ester in THF (20vol) was added dropwise a 1M NaOH solution with stirring. The mixture was stirred at ambient temperature and the resulting precipitate was filtered and washed with water/THF or water followed by heptane to give the salt.

Example 5

To a solution of 6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid (1eq) in a minimal amount of THF was added cyclohexylamine with stirring. The mixture was stirred at ambient temperature for 1 hour, the resulting precipitate was filtered and washed with THF to give the salt.

Example 6

To a suspension of 6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid pyridin-3-ylamide (1eq) in methanol at ambient temperature with stirring was added 6N HCl. After complete dissolution was observed, the solvent was removed in vacuo and the resulting salt was purified by trituration in acetone followed by tert-butyl methyl ether. Recrystallization from ethanol gives the desired compound.

Example 7

Stage 1

To a solution of 6- (substituted-phenyl) -pyrimidine-4-carboxylic acid (1eq) in DCM (20vol) under nitrogen atmosphere was added oxalyl chloride (3eq) and 1 drop DMF (catalyst amount) with stirring. The reaction mixture was stirred at ambient temperature for 30 minutes, then the solvent was removed in vacuo. The residue obtained was used in the next stage without further purification.

Stage 2

The resulting residue was dissolved in THF (10 vol). To the reaction mixture was added triethylamine (1eq) and the appropriate sulfonamide (1.5eq) and stirred at ambient temperature for 4-16 hours. The solvent was removed in vacuo and the resulting residue was purified by trituration with water and diethyl ether. The solid was filtered off and washed with water and dichloromethane. When no precipitation occurred, the solvent was removed in vacuo and DCM was added. The organic phase was washed with saturated aqueous sodium bicarbonate and 2M citric acid solution, over Na₂SO₄Drying, filtration and removal of the solvent in vacuo afforded the crude compound which was purified by flash column chromatography (eluent: [ 1: 10 ]]To [ 1: 0]]EtOAc: heptane) to afford the desired target compound.

Example 8

Stage 1

To a solution of formamidine acetate (1eq) in ethanol (50vol) was added a solution of sodium ethoxide in ethanol (2% w/w) (3eq) with stirring at 0 ℃, and the reaction mixture was stirred at this temperature for 30 minutes. The resulting mixture was added to a solution of diethyl fluoromalonate (1eq) in ethanol (5vol) and the reaction mixture was stirred at ambient temperature for 72 hours. The reaction mixture was cooled to 0 ℃ and concentrated HCl (3vol) was added to adjust the pH of the reaction mixture to 6. The resulting precipitate was filtered off and washed with isopropanol, diethyl ether and hexane, to give the desired intermediate, which was used in the next stage without further purification.

Stage 2

To a solution of N, N-dimethylaniline (1eq) in phosphorus oxychloride (4vol) was added 5-fluoro-pyrimidine-4, 6-diol (1eq) with stirring, and the reaction mixture was heated under reflux for 16 hours. After cooling to room temperature, the solvent was removed in vacuo and the resulting residue was poured into ice. The desired product was then extracted with EtOAcAn intermediate. The organic layer was MgSO₄Drying, filtration and removal of the solvent in vacuo afforded the desired intermediate, which was used in the next stage without further purification.

Stage 3

4, 6-dichloro-5-fluoro-pyrimidine (1eq), 3, 4-dichlorophenylboronic acid (0.7eq) and Pd (PPh)₃)₄(0.05eq) was suspended in 1, 4-dioxane (20 vol). 2M K was added₂CO₃Solution (6.75vol), the reaction mixture was heated at 90 ℃ for 2 hours under nitrogen atmosphere with stirring. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in EtOAc and water. The mixture was partitioned, the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with saturated aqueous sodium chloride and Na₂SO₄Drying, filtering and removing the solvent in vacuum. The residue obtained is purified by flash column chromatography (eluent: [ 1: 15 ]]EtOAc: heptane) to afford the desired target compound.

Stage 4

4-chloro-6- (3, 4-dichloro-phenyl) -5-fluoro-pyrimidine (1eq), PdCl in a bomb reactor equipped with a magnetic stirrer₂(dppf), DCM (0.05eq) and triethylamine (2eq) were suspended in degassed MeOH (50 vol). The air in the reaction vessel was replaced with nitrogen by successively evacuating and charging nitrogen (this operation was repeated 3 times). The bomb reactor was then flushed with CO by successively charging with CO and evacuating. The vessel was pressurized to 5 bar CO and heated at 50 ℃ for 5 hours with stirring. The reaction vessel was cooled to room temperature, then CO was vented and N was used₂And (5) flushing. The reaction mixture was concentrated in vacuo. The residue was purified by flash column chromatography (eluent: [ 1: 15 ]]EtOAc: heptane) to afford the title compound.

Stage 5

6- (3, 4-dichloro-phenyl) -5-fluoro-pyrimidine-4-carboxylic acid methyl ester (1eq) was suspended in THF (30vol) and 2M NaOH solution (5eq) and stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in EtOAc and water. The aqueous layer was separated and filtered to remove the precipitate. The aqueous layer was acidified with concentrated HCl, the resulting precipitate was filtered and washed with water to give the desired target compound.

Stage 6

The claimed amide analogues were prepared following the procedure described in method B, and purified by trituration in acetonitrile/water (1/1).

Example 9

Stage 1

2-chloro-isonicotinic acid (1eq), 3-chlorophenylboronic acid (1.5eq) and Pd (PPh)₃)₄(0.03eq) was suspended in 1, 4-dioxane (20 vol). 2M K was added to the reaction mixture₂CO₃The solution (7.5vol) was heated and stirred at 90 ℃ for 16 hours under a nitrogen atmosphere. To the reaction mixture was added 3-chlorophenylboronic acid (0.5eq), Pd (PPh)₃)₄(0.03eq) and 2M K₂CO₃The solution (7.5vol) was then heated at 90 ℃ for an additional 1 hour. The reaction mixture was cooled to room temperature and washed with EtOAc followed by dichloromethane. The aqueous layer was acidified with concentrated HCl and the resulting precipitate was isolated by filtration and used in the next stage without further purification.

Stage 2

To a suspension of the intermediate obtained in stage 1 in methanol (50vol) was added concentrated HCl (4 drops) with stirring and the reaction mixture was stirred at 65 ℃ for 16 hours. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in DCM and water. The organic phases were collected, the solvent was removed in vacuo and purified by flash column chromatography (eluent: [ 1: 20] EtOAc: heptane) followed by preparative HPLC to give the title compound.

Stage 3

To a solution of 2- (3-chloro-phenyl) -isonicotinic acid methyl ester (1eq) in THF (30vol) was added 2M NaOH solution (8vol) with stirring and the reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in 2M HCl solution and the resulting precipitate was filtered off and washed with water followed by heptane to give the desired target compound.

Example 10

Stage 1

To a suspension of 4-bromo-pyridine-2-carboxylic acid methyl ester (1eq) in 1, 4-dioxane (20vol) was added, with stirring, the appropriate substituted phenylboronic acid (1.1eq) and Pd (PPh)₃)₄(0.05 eq). 2M K was added₂CO₃Solution (7.5vol), the reaction mixture was heated and stirred at 90 ℃ for 16 hours under nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature and the resulting precipitate was isolated by filtration to give the acid intermediate, which was the potassium salt and used without further purification in this stage. In the case of the 3-chlorophenyl analogue, no precipitate precipitated on cooling, so the solvent was removed in vacuo and the resulting residue was dissolved in EtOAc and water. The two phases were separated. EtOAc was removed in vacuo and the resulting residue was purified by flash column chromatography (eluent: [ 5: 95 ]]DCM) to give the desired methyl 4- (3-chloro-phenyl) -pyridine-2-carboxylate. The aqueous phase was acidified and the resulting precipitate was isolated by filtration and used directly in stage 2. Further purification by preparative HPLC gave the desired 4- (3-chloro-phenyl) -pyridine-2-carboxylic acid.

Stage 2

The claimed amide analogues were prepared from 4- (3-chloro-phenyl) -pyridine-2-carboxylate acid salt following the procedure described in method a, purified by trituration in acetonitrile/water (1/1) or water followed by heptane.

Stage 3

The potassium salt separated off in stage 1 was suspended in HCl (2M) and stirred at ambient temperature for 2 hours. The solid was filtered off and washed with water to give the desired target compound.

Stage 4

The claimed amide analogues were prepared from 4- (substituted-phenyl) -pyridine-2-carboxylic acid potassium salt following the procedure described in method a, purified by trituration in acetonitrile/water (1/1) or water followed by heptane.

Example 11

The following compounds were prepared essentially as described above.

IUPAC name	Mass spectrum results
		6- (2-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid methyl ester	[M+H]⁺＝283，94％rt＝3.90min
6- (2-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid	[M+H]⁺＝269，100％rt＝3.34min
		N- [6- (2-trifluoromethyl-phenyl) -pyrimidin-4-yl]-methanesulfonamide	[M+H]⁺＝311，98％rt＝4.00min
3, 4-dimethoxy-N- [6- (2-trifluoromethyl-phenyl) -pyrimidin-4-yl]-benzenesulfonamides	[M+H]⁺＝318，98％rt＝3.92min
		N- [6- (3, 4-dichloro-phenyl) -pyrimidin-4-yl]-methanesulfonamide	[M+H]⁺＝440，100％rt＝4.41min
6- (3, 4-dichloro-phenyl) -pyrimidine-4-carboxylic acid methyl ester	[M+H]⁺＝283，100％rt＝4.47min
		N- [6- (3, 4-dichloro-phenyl) -pyrimidin-4-yl]-3, 4-dimethoxy-benzenesulfonamide	[M+H]⁺＝440，100％rt＝3.88min
6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid methyl ester	[M+H]⁺＝249，97％rt＝3.98min
		6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid	[M+H]⁺＝235，100％rt＝3.66min
6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid sodium salt	[M+H]⁺＝235，89％rt＝3.93min
		6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid cyclohexylammonium salt	[M+H]⁺＝235，92％rt＝3.84min
6- (3, 4-dichloro-phenyl) -pyrimidine-4-carboxylic acid pyridin-3-ylamide	[M+H]⁺＝345，95％rt＝4.17min
		6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid pyrilePyridin-3-ylamides	[M+H]⁺＝311，100％rt＝3.74min
6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid pyridin-3-ylamide hydrochloride	[M+H]⁺＝311，100％rt 3.73min
		6- (3, 4-dichloro-phenyl) -pyrimidine-4-carboxylic acid	[M+H]⁺＝269，100％rt＝4.04min
6- (3, 4-dichloro-phenyl) -pyrimidine-4-carboxylic acid sodium salt	[M+H]⁺＝269/271，100％rt＝4.17min
		6- (3, 5-dichloro-phenyl) -pyrimidine-4-carboxylic acid	[M+H]⁺＝269，99％rt＝4.30min
6- (3, 5-dichloro-phenyl) -pyrimidine-4-carboxylic acid methyl ester	[M+H]⁺＝283，99％rt＝4.58min

IUPAC name	Mass spectrum results
		N- [6- (3-chloro-phenyl) -pyrimidin-4-yl]-nicotinoylAmines as pesticides	[M+H]⁺＝318，94％rt＝3.39min
6- (3, 4-dichloro-phenyl) -2-methyl-pyrimidine-4-carboxylic acid methyl ester	[M+H]⁺＝297，100％rt＝4.78min
		6- (3, 4-dichloro-phenyl) -2-methyl-pyrimidine-4-carboxylic acid	[M+H]⁺＝283，99％rt＝4.43min
6- (3, 4-dichloro-phenyl) -2-methyl-pyrimidine-4-carboxylic acid pyridin-3-ylamide	[M+H]⁺＝359，100％rt＝4.50min
		6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid (2, 6-dimethyl-pyridin-3-yl) -amide	[M+H]⁺＝339，100％rt＝3.17min
6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid pyrimidin-5-ylamide	[M+H]⁺＝312，98％rt＝4.00min
		6- (4-Morpholin-4-yl-phenyl) -pyrimidine-4-carboxylic acid methyl ester	[M+H]⁺＝300，96％rt＝3.61min
6- (4-fluoro-3-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid methyl ester	[M+H]⁺＝300，95％rt＝4.39min
		6- (3-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid methyl ester	[M+H]⁺＝282，97％rt＝4.16min
6- (4-fluoro-3-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid	[M+H]⁺＝286，100％rt＝4.07min
		6- (3-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid pyridin-2-ylamide	[M+H]⁺＝345，100％rt＝4.92min
6- (4-fluoro-3-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid pyridin-3-ylamide	[M+H]⁺＝363，99％rt＝4.06min
		6- (3, 5-dichloro-phenyl) -pyrimidine-4-carboxylic acid pyridin-3-ylamide	[M+H]⁺＝344，100％rt＝4.38min
6- (3-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid pyridin-3-ylamide	[M+H]⁺＝344，100％rt＝3.89min
		6- (3-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid	[M+H]⁺＝268，100％rt＝3.78min
6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid acetamide	[M+H]⁺＝262，99％rt＝4.34min
		6- (5-fluoro-pyridin-3-yl) -pyrimidine-4-carboxylic acid	[M+H]⁺＝219，99％rt＝2.66min
6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid amides	[M+H]⁺＝234，100％rt＝3.60min
		6- (3-fluoro-5-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid methyl ester	[M+H]⁺＝300，100％rt＝4.52min
6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid methylamides	[M+H]⁺＝248，100％rt＝3.85min
		6- (5-fluoro-pyridin-3-yl) -pyrimidine-4-carboxylic acid methyl ester	[M+H]⁺＝233，100％rt＝2.96min
6- (3-fluoro-5-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid	[M+H]⁺＝286，97％rt＝4.26min
		6- (5-chloro-pyridin-3-yl) -pyrimidine-4-carboxylic acid methyl ester	[M+H]⁺＝249，100％rt＝3.30min
6- (5-chloro-pyridin-3-yl) -pyrimidine-4-carboxylic acid	[M+H]⁺＝236，100％rt＝2.92min
		6- (2-fluoro-5-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid methyl ester	[M+23]⁺＝301，100％rt＝4.17min
6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid isopropylamide	[M+H]⁺＝275，99％rt＝4.68min
		[6- (3-chloro-phenyl) -pyrimidin-4-yl]-morpholin-4-yl-methanones	[M+H]⁺＝304，100％rt＝3.64min
6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid propionamide	[M+H]⁺＝276，100％rt＝4.39min
		6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid phenylamides	[M+H]⁺＝309，100％rt＝5.17min

IUPAC name	Mass spectrum results
		6-pyridin-3-Yl-pyrimidine-4-carboxylic acid methyl ester trifluoroacetate salt	[M+H]⁺＝216，100％rt＝2.27min
6-phenyl-pyrimidine-4-carboxylic acid	[M+H]⁺＝201，100％rt＝3.29min
		6- (2-fluoro-5-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid	[M+H]⁺＝286，100％rt＝4.03min
6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid o-tolylamide	[M+H]⁺＝324，100％rt＝5.08min
		6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid p-tolylamide	[M+H]⁺＝323，100％rt＝5.40min
[6- (3-chloro-phenyl) -pyrimidin-4-yl]- (3, 4-dihydro-2H-quinolin-1-yl) -methanones	[M+H]⁺＝350/352，100％rt＝4.57min
		6-phenyl-pyrimidine-4-carboxylic acid methyl ester	[M+H]⁺＝215，99％rt＝3.55min
6- (2, 4-difluoro-phenyl) -pyrimidine-4-carboxylic acid methyl ester	[M+H]⁺＝251，98％rt＝3.76min
		6- (2, 4-difluoro-phenyl) -pyrimidine-4-carboxylic acid	[M+H]⁺＝237，100％rt＝3.41min
6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid (6-methoxy-pyridin-3-yl) -amide	[M+H]⁺＝341，100％rt＝4.53min
		[6- (3-chloro-phenyl) -pyrimidin-4-yl]- (2, 3-dihydro-indol-1-yl) -methanones	[M+H]⁺＝336，100％rt＝4.57min
6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid m-tolylamide	[M+H]⁺＝324，100％rt＝5.25min
		6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid methyl-pyridin-3-yl-amide	[M+H]⁺＝325，100％rt＝3.71min
6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid (5-methoxy-pyridin-3-yl) -amide	[M+H]⁺＝341，100％rt＝4.15min
		6- (3-chloro-2-fluoro-phenyl) -pyrimidine-4-carboxylic acid methyl ester	[M+H]⁺＝267，100％rt＝3.99min
6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid dimethylamide	[M+H]⁺＝262，100％rt＝3.73min
		6- (3-chloro-phenyl) -2-methyl-pyrimidine-4-carboxylic acid methyl ester	[M+H]⁺＝262，99％rt＝4.48min
4- [6- (3-chloro-phenyl) -pyrimidine-4-carbonyl]-piperazin-2-one	[M+H]⁺＝317，100％rt＝3.30min
		6-phenyl-pyrimidine-4-carboxylic acid pyridin-3-ylamides	[M+H]⁺＝277，100％rt＝3.30min
6- (3-chloro-2-fluoro-phenyl) -pyrimidine-4-carboxylic acid	[M+H]⁺＝253，97％rt＝3.96min
		6- (3, 4-dichloro-phenylamino) -pyrimidine-4-carboxylic acid methyl ester	[M+H]⁺＝297，100％rt＝4.21min
6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid (4-methoxy-pyridin-3-yl) -amide	[M+H]⁺＝341，99％rt＝3.19min
		6- (3-chloro-phenyl) -2-methyl-pyrimidine-4-carboxylic acid	[M+H]⁺＝249，100％rt＝3.88mm
6- (3-chloro-phenyl) -2-methyl-pyrimidine-4-carboxylic acid pyridin-3-ylamide	[M+H]⁺＝325，100％rt＝4.14min
		6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid (2-hydroxy-ethyl) -amide	[M+H]⁺＝278，100％rt＝3.56min
[6- (3-chloro-phenyl) -pyrimidin-4-yl]- (4-hydroxy-piperidin-1-yl) -methanones	[M+H]⁺＝318，100％rt＝3.42min
		6- (3-methoxy-phenyl) -pyrimidinePyridine-4-carboxylic acids	[M+H]⁺＝231，100％rt＝3.20min
6- (3-methoxy-phenyl) -pyrimidine-4-carboxylic acid methyl ester	[M+H]⁺＝245，99％rt＝3.80min
		6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid benzylamide	[M+H]⁺＝324，100％rt＝4.97min

Example 12

The overall method for monitoring the hydroxylation of L-Kynurenine (KYN) by LC/MS to form the product 3-hydroxy-kynurenine (3OH-KYN) is described below. The product was quantified by multiple reaction monitoring using MS.

The main reagents are as follows:

a compound: stock concentration: 10mM in 100% DMSO

Cell line: CHO GST HIS KMO cell line, 1E4 cells/well/100. mu.l in 96-well cell plates

Substrate: l-kynurenine (Sigma Cat K3750, stock concentration: 10mM, in 100mM potassium phosphate buffer, pH 7.4)

The measurement conditions were as follows:

culture medium: OptiMem (serum-reduced Medium 1x, + L-Glutamine + HEPES-phenolsulfonphthalein; GIBCO catalog 11058)

And (3) measuring the volume: 200 μ l

Plate form: 96-well plate, transparent (Corning)

Reading: product (3OH-KYN) quantification Using product-specific MRM

A reader: LC/MS

Measurement protocol:

o prepare a diluted (3-fold) series of compounds in 100% DMSO (highest concentration 6.67mM, 100% DMSO)

[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)

Prepare a 300-fold diluted solution of each compound concentration in OptiMem medium (maximum concentration 22.22. mu.M, 0.3% DMSO),

[22.2μM；7.41μM；2.47μM；0.82μM；0.27μM；0.09μM；0.03μM；0.01μM]

substrate (10mM) was dissolved in the medium to prepare a substrate concentration of 1.1mM

Blotting of Medium from cell plates

O.Wash cells with OptiMem (100. mu.l/well) and aspirate the medium again

○The mixture was measured:90 μ l OptiMem/well +90 μ l of each concentration of compound/well

O [ final compound maximum concentration: 10 mu M; 0.15% DMSO ]

[ minimum final compound concentration: 0.004 μ M; 0.15% DMSO ]

Pre-culture: 30 minutes at 37 DEG C

Add 20. mu.l of 1.1mM substrate solution/well (final assay concentration: 100. mu.M)

Positive control: 200 μ l OptiMem

Negative control: mu.l OptiMem + 20. mu.l 1.1mM substrate

Breeding: about 24h, 37 deg.C

Transfer 100. mu.l of each well to a clear 96-well plate (Corning)

Add 100. mu.l of 10% trichloroacetic acid (TCA) aqueous solution/well

O plate centrifuge at 4000rpm for 3 minutes

Products were detected by LC/MS (injection 50. mu.l/well; 2.5-fold overfilled 20. mu.l sample loop)

And (3) data analysis: calculation of IC Using an auto-fitting Algorithm (A + analysis)₅₀。

Example 13

The overall method for monitoring the hydroxylation of L-Kynurenine (KYN) by LC/MS to form the product 3-hydroxy-kynurenine (3OH-KYN) is described below. Product was quantified by multiple reaction monitoring.

The main reagents are as follows:

a compound: stock concentration: 10mM in 100% DMSO

Enzyme: KMO enzyme, prepared from CHO-GST HIS KMO cells in Evotec by mitochondrial isolation

Substrate: l-kynurenine (Sigma catalog K3750), [ stock concentration: 10mM, dissolved in 100mM potassium phosphate buffer, pH 7.4]

The measurement conditions were as follows:

buffer solution: 100mM potassium phosphate, pH 7.4, 200. mu.M NADPH, 0.4U/ml G6P-DH (glucose 6-phosphate dehydrogenase), 3mM G6P (D-glucose-6-phosphate)

And (3) measuring the volume: 40 μ l

Plate form: 384 well plate, transparent (Matrix)

Reading: product (3OH-KYN) quantification Using product-specific MRM

A reader: LC/MS

Measurement protocol:

o prepare a diluted (3-fold) series of compounds in 100% DMSO (maximum concentration 10mM, 100% DMSO)

[8 points: 10 mM; 3.33 mM; 1.11 mM; 0.37 mM; 0.12 mM; 0.04 mM; 0.0137 mM; 0.0045mM, 0.0015mM ]

Prepare 3.33 times diluted solutions of each compound concentration in assay buffer (maximum concentration 300. mu.M, 3% DMSO)

[ concentration: 300 mu M; 100 mu M; 33.3 μ M; 11.1 μ M; 3.70 mu M; 1.23 μ M; 0.41 mu M; 0.137. mu.M)

Dissolve substrate (10mM) in assay buffer to prepare substrate at a concentration of 1mM

○The mixture was measured:4 μ l of each concentration of compoundSubstance/well +24 μ l assay buffer/well +8 μ l human KMO enzyme +4 μ l 1mM substrate (final concentration ═ 100 μ M)

[ final compound maximum concentration: 30 mu M; 0.3% DMSO ]

[ minimum final compound concentration: 0.0137 mu M; 0.3% DMSO ]

○Positive control:4 μ l of 50 μ M FCE28833 in assay buffer [ 0.5% DMSO](final assay concentration ═ 5 μ M) +24 μ l assay buffer/well +8 μ l KMO human enzyme +4 μ l 1mM substrate (final concentration ═ 100 μ M)

○Negative control:28 μ l assay buffer/well +8 μ l human KMO enzyme +4 μ l 1mM substrate (final concentration 100 μ M)

Culture: room temperature 400 minutes

Add 40. mu.l of 10% aqueous trichloroacetic acid solution/well to stop the assay and precipitate the protein

O plate centrifuge at 4000rpm for 3 minutes

Example 14

The overall method for monitoring the hydroxylation of L-Kynurenine (KYN) by LC/MS to form the product 3-hydroxy-kynurenine (3OH-KYN) is described below. The product was quantified by multiple reaction monitoring (MRM method).

The main reagents are as follows:

a compound: stock concentration: 10mM in 100% DMSO

Enzyme: KMO enzyme, prepared as described in the literature by mitochondrial isolation from mouse liver (4-6 weeks old) in Evotec

The measurement conditions were as follows:

And (3) measuring the volume: 40 μ l

Plate form: 384 well plate, transparent (Matrix)

Reading: product (3OH-KYN) quantification Using product-specific MRM

A reader: LC/MS

Measurement protocol:

○The mixture was measured:4 μ l of each concentration of compound/well +24 μ l assay buffer/well +8 μ l mouse KMO enzyme +4 μ l 1mM substrate (final concentration 100 μ M)

[ final compound maximum concentration: 30 mu M; 0.3% DMSO ]

[ minimum final compound concentration: 0.0137 mu M; 0.3% DMSO ]

○Positive control:4 μ l of 50 μ M FCE28833 in assay buffer solution 0.5% DMSO [ final assay concentration ═ 5 μ M]+ 24. mu.l assay bufferPerwell + 8. mu.l mouse KMO enzyme + 4. mu.l 1mM substrate [ final concentration 100. mu.M%]

○Negative control:28 μ l assay buffer/well +8 μ l mouse KMO enzyme +4 μ l 1mM substrate [ final concentration 100 μ M-]

Culture: room temperature 40 minutes

O plate centrifuge at 4000rpm for 3 minutes

Product detection by LC/MS (injection 20. mu.l/well, 2-fold overfill with 10. mu.l sample loop)

Example 15

The activity of the following compounds was determined using methods similar to those described herein.

Although a few embodiments have been shown and described herein, various changes and substitutions may be made thereto without departing from the spirit and scope of the invention. For example, with regard to interpretation of the claims, it is not intended that the claims set forth herein be interpreted in any way as being narrower than the literal language thereof, and thus it is not intended that exemplary embodiments of the specification be construed as the claims. It is, therefore, to be understood that the invention has been described by way of illustration and not as a limitation on the scope of the claims.

Claims

1. At least one chemical entity selected from compounds of formula I and pharmaceutically acceptable salts thereof,

wherein:

x and Y are N;

R₁is phenyl optionally substituted with 1, 2 or 3 groups selected from: halogen, optionally substituted having 1 to 4 carbonsAn alkyl group of atoms, an alkoxy group having 1 to 4 carbon atoms, and a hydroxyl group;

l is-C (O) O-;

R₂is hydrogen;

R₄is hydrogen; and

R₅selected from the group consisting of hydrogen and fluorine,

with the proviso that the compound of the formula I is not

6- (4-methoxyphenyl) -pyrimidine-4-carboxylic acid; or

6-phenylpyrimidine-4-carboxylic acid.

2. At least one chemical entity of claim 1 wherein R₁Is phenyl, optionally substituted with 1, 2 or 3 groups selected from: halogen, alkyl having 1 to 4 carbon atoms, trifluoromethyl, alkoxy having 1 to 4 carbon atoms and hydroxyl.

3. At least one chemical entity of claim 2 wherein R₁Is phenyl, optionally substituted with 1, 2 or 3 groups selected from: halogen, alkyl having 1 to 4 carbon atoms, and trifluoromethyl.

4. At least one chemical entity of claim 3 wherein R₁Selected from the group consisting of 2-trifluoromethylphenyl, 3, 4-dichlorophenyl, 3-chlorophenyl, 4-chlorophenyl and 3, 5-dichlorophenyl.

5. At least one chemical entity of any one of claims 1 to 4 wherein R₅Is hydrogen.

6. At least one chemical entity of any one of claims 1 to 4 wherein R₅Is fluorine.

7. At least one chemical substance selected from

6- (2-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid;

6- (3, 4-dichloro-phenyl) -pyrimidine-4-carboxylic acid;

6- (3, 5-dichloro-phenyl) -pyrimidine-4-carboxylic acid;

6- (4-fluoro-3-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid;

6- (3-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid;

6- (5-fluoro-pyridin-3-yl) -pyrimidine-4-carboxylic acid;

6- (3-fluoro-5-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid;

6- (5-chloro-pyridin-3-yl) -pyrimidine-4-carboxylic acid;

6- (2-fluoro-5-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid;

6- (2, 4-difluoro-phenyl) -pyrimidine-4-carboxylic acid;

6- (3-chloro-2-fluoro-phenyl) -pyrimidine-4-carboxylic acid;

6- (3-methoxy-phenyl) -pyrimidine-4-carboxylic acid;

6-m-tolyl-pyrimidine-4-carboxylic acid;

6- (4-methoxy-phenyl) -pyrimidine-4-carboxylic acid;

6- (3-fluoro-phenyl) -pyrimidine-4-carboxylic acid;

6- (3-chloro-4-trifluoromethyl-phenyl) -pyrimidine-4-carboxylic acid;

6- (3, 4-difluoro-phenyl) -pyrimidine-4-carboxylic acid;

6- (5-chloro-2-fluoro-phenyl) -pyrimidine-4-carboxylic acid;

6- (3-chloro-4-methoxy-phenyl) -pyrimidine-4-carboxylic acid;

6- (3-chloro-4-fluoro-phenyl) -pyrimidine-4-carboxylic acid;

6- (3, 4-dichloro-phenyl) -5-fluoro-pyrimidine-4-carboxylic acid;

6- (3-chloro-4-methyl-phenyl) -pyrimidine-4-carboxylic acid;

6- (3, 4-dichloro-phenyl) -5-fluoro-pyrimidine-4-carboxylic acid;

4- (3-chloro-phenyl) -pyridine-2-carboxylic acid;

and pharmaceutically acceptable salts thereof.

8. At least one chemical selected from the group consisting of:

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid sodium salt;

6- (3-chloro-phenyl) -pyrimidine-4-carboxylic acid cyclohexylammonium salt;

6- (3, 4-dichloro-phenyl) -pyrimidine-4-carboxylic acid sodium salt;

6-morpholin-4-yl-pyrimidine-4-carboxylic acid hydrochloride;

2- (3-chloro-phenyl) -isonicotinic acid hydrochloride;

4- (3, 5-dichloro-phenyl) -pyridine-2-carboxylic acid hydrochloride; and

4- (3, 4-dichloro-phenyl) -pyridine-2-carboxylic acid hydrochloride.

9. A pharmaceutical composition comprising at least one chemical entity of any one of claims 1 to 8 and at least one pharmaceutically acceptable excipient.

10. Use of at least one chemical entity of any one of claims 1 to 8 in the manufacture of a medicament for the treatment of a condition or disorder mediated by kynurenine-3-monooxygenase activity, wherein the condition or disorder comprises a neurodegenerative pathology.

11. Use according to claim 10, wherein the neurodegenerative pathology is selected from huntington's disease, alzheimer's disease, parkinson's disease, olivopontocerebellar atrophy, non-alzheimer's dementia, multi-infarct dementia, cerebral amyotrophic lateral sclerosis, cerebral ischemia, cerebral hypoxia, spinal or head trauma, and epilepsy.