HK1195300B

HK1195300B - 2-(phenyl or pyrid-3-yl) aminopyrimidine derivatives as kinase lrrk2 modulators for the treatment of parkinson's disease

Info

Publication number: HK1195300B
Application number: HK14108599.2A
Authority: HK
Inventors: 查尔斯．贝克-格伦; 马克．钱伯斯; 布赖恩．K．尚; 安东尼．埃斯特拉德; 扎卡里．凯文．斯威尼
Original assignee: 健泰科生物技术公司
Priority date: 2011-11-29
Filing date: 2012-11-28
Publication date: 2017-09-15

Description

2- (phenyl or pyridin-3-yl) aminopyrimidine derivatives as kinase LRRK2 modulators for the treatment of Parkinson's disease

Technical Field

The present invention relates to compounds that modulate the function of LRRK2 and are useful for the treatment of LRRK2 mediated diseases and disorders, such as parkinson's disease.

Background

Neurodegenerative diseases such as Parkinson's disease, Lewy body dementia and Huntington's disease affect millions of individuals. Parkinson's disease is a chronic, progressive motor system disorder, with about one suffering per 1000 persons, with hereditary parkinson's disease accounting for 5-10% of all patients. Parkinson's disease is caused by progressive loss of mesencephalic dopamine neurons, giving patients impaired ability to direct and control their actions. The primary parkinson's disease symptoms are trembling, stiffness, bradykinesia, and impaired balance. Many parkinson's disease patients also experience other symptoms such as mood changes, memory loss, speech problems and sleep disturbances.

Genes encoding leucine-rich repeat kinase 2 protein (LRRK2) have been identified as being associated with hereditary Parkinson's disease (Paisan-Ruiz et al, Neuron, Vol.44(4), 2004, pp 595-600; Zimphrich et al, Neuron, Vol.44(4), 2004, 601-607). In vitro studies have shown that parkinson-disease-associated mutations lead to increased LRRK2 kinase activity and a reduced rate of GTP hydrolysis compared to wild-type (Guo et al, Experimental Cell Research, vol.313(16), 2007, pp.3658-3670). anti-LRRK 2 antibodies have been used to label brainstem Lewy bodies associated with Parkinson's disease and cortical antibodies associated with Lewis body dementia, suggesting that LRRK2 may play an important role in Lewis body formation and pathogenesis associated with these diseases (Zhou et al, molecular characterization, 2006, 1: 17 doi: 10.1186/1750-. LRRK2 has also been identified as a gene potentially associated with increased susceptibility to crohn's disease and leprosy (Zhang et al, New England j.med.vol.361(2009) pp.2609-2618).

LRRK2 is also related to: the shift from mild cognitive impairment to alzheimer's disease (WO 2007/149789); l-dopa-induced dyskinesia (Hurley et al, Eur. J. Neurosci., Vol.26, 2007, pp.171-177; CNS disorders associated with neuronal precursor differentiation (Milosevic et al, Neurodeen., Vol.4, 2009, p.25); cancers such as renal, breast, prostate, blood and lung cancer and acute myeloid leukemia (WO 2011/038572); papillary renal and thyroid cancers (Looyenga et al,www.pnas.org/cgi/doi/10.1073/pnas.1012500108) (ii) a Multiple myeloma (Chapman et al, Nature Vol.471, 2011, pp.467-472); amyotrophic Lateral Sclerosis (Shtilbans et al, Amyotropic Laterial Sclerosis "Early Online2011, pp.1-7); rheumatoid arthritis (Nakamura et al, DNARS. Vol.13(4), 2006, pp.169-183); and spinal rigidity (alkylosingspindylitis) (Danoy et al, PLoS Genetics, Vol.6(12), 2010, e1001195, pp.1-5).

Thus, compounds and compositions effective to modulate LRRK2 activity may provide treatment for the following diseases: neurodegenerative diseases such as parkinson's disease and lewis body dementia, CNS disorders such as alzheimer's disease and L-dopa induced dyskinesia, cancer such as renal, breast, prostate, blood, papillary and lung cancers, acute myeloid leukemia and multiple myeloma, and inflammatory diseases such as leprosy, crohn's disease, amyotrophic lateral sclerosis, rheumatoid arthritis and spinal stiffness. In particular, there is a need for compounds with LRRK2 affinity that are selective for LRRK2 over other kinases such as JAK2, and which can provide effective drugs for the treatment of neurodegenerative diseases such as parkinson's disease.

Disclosure of Invention

The present invention provides compounds of formula I:

or a pharmaceutically acceptable salt thereof,

wherein:

m is 0 to 3;

x is: -NRa-; -O-; or-S (O) r-, wherein r is 0 to 2 and Ra is hydrogen or C1-6 alkyl;

y is C or N;

r1 is: c1-6 alkyl; c1-6 alkenyl; c1-6 alkynyl; halo-C1-6 alkyl; c1-6 alkoxy-C1-6 alkyl; hydroxy-C1-6 alkyl; amino-C1-6 alkyl; c1-6 alkylsulfonyl-C1-6 alkyl; c3-6 cycloalkyl optionally substituted with C1-6 alkyl; c3-6 cycloalkyl-C1-6 alkyl wherein the C3-6 cycloalkyl moiety is optionally substituted with C1-6 alkyl; a tetrahydrofuranyl group; tetrahydrofuryl-C1-6 alkyl; an oxetanyl group; or oxetane-C1-6 alkyl;

or R1 and Ra together with the atoms to which they are attached may form a three to six membered ring, which may optionally include a further heteroatom selected from O, N and S, and which is substituted by oxo, halo or C1-6 alkyl;

r2 is: halogenating; c1-6 alkoxy; a cyano group; c1-6 alkynyl; c1-6 alkenyl; halo-C1-6 alkyl; halo-C1-6 alkoxy; c3-6 cycloalkyl wherein the C3-6 cycloalkyl moiety is optionally substituted with C1-6 alkyl; c3-6 cycloalkyl-C1-6 alkyl wherein the C3-6 cycloalkyl moiety is optionally substituted with C1-6 alkyl; a tetrahydrofuranyl group; tetrahydrofuryl-C1-6 alkyl; acetyl; an oxetanyl group; or oxetane-C1-6 alkyl;

r3 and R4 are each independently: halogenating; c1-6 alkyl; c1-6 alkoxy; c3-6 cycloalkyloxy; halo-C1-6 alkyl; or halo-C1-6 alkoxy; and is

R5 is 5 membered heteroaryl optionally substituted one or more times by R6; and is

R6 is: c1-6 alkyl; c3-6 cycloalkyl; c3-6 cycloalkyl-C1-6 alkyl; halogenating; halo-C1-6 alkyl; c1-6 alkoxy; a heterocyclic group; oxo; or-C (O) -NRbRc, wherein Rb and Rc are each independently hydrogen or-C1-6 alkyl.

The invention also provides pharmaceutical compositions comprising the compounds, methods of using the compounds, and methods of making the compounds.

Detailed Description

Definition of

Unless otherwise indicated, the following terms used in the present application, including the specification and claims, have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

"alkyl" means a monovalent straight or branched chain saturated hydrocarbon moiety consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms. "lower alkyl" refers to alkyl of one to six carbon atoms, i.e., C1-6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl and the like.

"alkenyl" means a straight chain monovalent hydrocarbon group of two to six carbon atoms or a branched monovalent hydrocarbon group of three to six carbon atoms containing at least one double bond, such as ethenyl, propenyl, and the like.

"alkynyl" means a straight-chain monovalent hydrocarbon group of two to six carbon atoms or a branched-chain monovalent hydrocarbon group of three to six carbon atoms containing at least one triple bond, such as ethynyl, propynyl, and the like.

"alkylene" means a straight chain saturated divalent hydrocarbon group of one to six carbon atoms or a branched saturated divalent hydrocarbon group of three to six carbon atoms, such as methylene, ethylene, 2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene, and the like.

"alkoxy" and "alkyloxy" are used interchangeably to refer to a moiety of the formula-OR, wherein R is an alkyl moiety as defined herein. Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.

"alkoxyalkyl" refers to a moiety of the formula Ra-O-Rb-, wherein Ra and Rb are, respectively, alkyl and alkylene as defined herein. Exemplary alkoxyalkyl groups include, for example, 2-methoxyethyl, 3-methoxypropyl, 1-methyl-2-methoxyethyl, 1- (2-methoxyethyl) -3-methoxypropyl, and 1- (2-methoxyethyl) -3-methoxypropyl.

"Alkoxyalkyloxy" refers to a group of the formula-O-R-R ', where R and R' are, respectively, alkylene and alkoxy as defined herein.

"alkylcarbonyl" refers to a moiety of the formula-c (o) -R, wherein R is alkyl as defined herein.

"alkoxycarbonyl" refers to a group of formula-C (O) -R, wherein R is alkoxy as defined herein.

"Alkylcarbonylalkyl" refers to a group of the formula-R-C (O) -R, wherein R and R' are, respectively, alkylene and alkyl as defined herein.

"Alkoxycarbonylalkyl" refers to a group of the formula-R-C (O) -R, where R and R' are, respectively, alkylene and alkoxy as defined herein.

"Alkoxycarbonylalkoxy" refers to a group of the formula-O-R-C (O) -R ', wherein R and R' are, respectively, alkylene and alkoxy as defined herein.

"Hydroxycarbonylalkoxy" refers to a group of the formula-O-R-C (O) -OH, wherein R is alkylene as defined herein.

"Alkylaminocarbonylalkoxy" refers to a group of the formula-O-R-C (O) -NHR ', wherein R and R' are, respectively, alkylene and alkyl as defined herein.

"Dialkylaminocarbonylalkoxy" refers to a group of the formula-O-R-C (O) -NR 'R ", wherein R is alkylene as defined herein and R' and R" are alkyl as defined herein.

"alkylaminoalkoxy" refers to a group of the formula-O-R-NHR ', wherein R and R' are, respectively, alkylene and alkyl as defined herein.

"Dialkylaminoalkoxy" refers to a group of the formula-O-R-NR ' R ', wherein R is an alkylene group as defined herein and R ' and R "are alkyl groups as defined herein.

"alkylsulfonyl" refers to a moiety of the formula-SO 2-R, wherein R is alkyl as defined herein.

"Alkylsulfonylalkyl" refers to a moiety of the formula-R '-SO 2-R', wherein R 'and R' are, respectively, alkylene and alkyl as defined herein.

"Alkylsulfonylalkoxy" refers to a group of the formula-O-R-SO 2-R ', wherein R and R' are, respectively, alkylene and alkyl as defined herein.

"amino" refers to a moiety of the formula-NRR ', where R and R' are each independently hydrogen or alkyl as defined herein. "amino" thus includes "alkylamino (where one of R and R 'is alkyl and the other is hydrogen) and" dialkylamino (where R and R' are both alkyl).

"aminocarbonyl" refers to a group of formula-C (O) -R, wherein R is amino as defined herein.

"Alkoxyamino" refers to a moiety of the formula-NR-OR 'where R is hydrogen OR alkyl and R' is alkyl, where alkyl is as defined herein.

"alkylthio" refers to a moiety of formula-SR, wherein R is alkyl as defined herein.

"aminoalkyl" refers to the group-R-R ', wherein R' and R are, respectively, amino and alkylene as defined herein. "aminoalkyl" includes aminomethyl, aminoethyl, 1-aminopropyl, 2-aminopropyl and the like. The amino moiety of "aminoalkyl" may be substituted once or twice with alkyl to provide "alkylaminoalkyl" and "dialkylaminoalkyl", respectively. "alkylaminoalkyl" includes methylaminomethyl, methylaminoethyl, methylaminopropyl, ethylaminoethyl, and the like. "dialkylaminoalkyl" includes dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, N-methyl-N-ethylaminoethyl, and the like.

"Aminoalkoxy" refers to the group-OR-R ', where R' and R are, respectively, amino and alkylene as defined herein.

"Alkylsulfonamide" refers to a moiety of the formula-NR 'SO 2-R, wherein R is alkyl and R' is hydrogen or alkyl.

"Aminocarbonyloxyalkyl" or "carbamoylalkyl" refers to a group of the formula-R-O-C (O) -NR 'R ", wherein R is alkylene and R', R" are each independently hydrogen or alkyl as defined herein.

"Alkynylalkoxy" refers to a group of the formula-O-R-R ', wherein R and R' are alkylene and alkynyl groups, respectively, as defined herein.

"aryl" refers to a monovalent cyclic aromatic hydrocarbon moiety composed of a monocyclic, bicyclic, or tricyclic aromatic ring. Aryl groups may be optionally substituted as defined herein. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfide, diphenylsulfonyl, diphenylisopropylidene,benzodi (benzo-b)Alkyl, benzofuranyl, benzodioxolyl, benzopyranyl, benzoAzinyl radical, benzoOxazinonyl (benzoxazinonyl), benzopiperidinyl (benzopiperadinyl), benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, and the like, which may be optionally substituted as defined herein.

"arylalkyl" and "aralkyl" are used interchangeably to refer to the group-RaRb, where Ra and Rb are alkylene and aryl, respectively, as defined herein; for example, phenylalkyl such as benzyl, phenethyl, 3- (3-chlorophenyl) -2-methylpentyl and the like are examples of arylalkyl groups.

"arylsulfonyl" refers to a group of the formula-SO 2-R, wherein R is aryl as defined herein.

"aryloxy" refers to a group of the formula-O-R, wherein R is aryl as defined herein.

"aralkyloxy" refers to a group of the formula-O-R-R ", wherein R and R' are, respectively, alkylene and aryl as defined herein.

"carboxy" or "hydroxycarbonyl" are used interchangeably and refer to a group of the formula-C (O) -OH.

"cyanoalkyl" refers to a moiety of the formula-R '-R', wherein R 'is alkylene as defined herein and R' is cyano or nitrile.

"cycloalkyl" refers to a monovalent saturated carbocyclic moiety consisting of a single ring or a double ring. Particular cycloalkyl groups are unsubstituted or substituted with alkyl groups. Cycloalkyl groups may be optionally substituted as defined herein. Unless otherwise defined, cycloalkyl groups may be optionally substituted with one or more substituents, wherein each substituent is independently hydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, or dialkylamino. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, including partially unsaturated (cycloalkenyl) derivatives thereof.

"cycloalkylalkyl" refers to a moiety of the formula-R '-R', where R 'and R' are alkylene and cycloalkyl, respectively, as defined herein.

"cycloalkylalkoxy" refers to a group of the formula-O-R-R ', wherein R and R' are, respectively, alkylene and cycloalkyl as defined herein.

"heteroaryl" means a monocyclic or bicyclic group of 5 to 12 ring atoms having at least one aromatic ring containing one, two or three ring heteroatoms selected from N, O or S, the remaining ring atoms being C, wherein it is understood that the point of attachment of the heteroaryl group is on the aromatic ring. The heteroaryl ring may be optionally substituted as defined herein. Examples of heteroaryl moieties include, but are not limited to, optionally substituted imidazolyl,azolyl radical, isoAn azole group, a thiazole group, an isothiazole group,oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thienyl, furyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, benzothiopyranyl, benzimidazolyl, benzofuranyl, benzothiophenyl, thienyl, and the likeAzolyl radical, benzoOxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, aza-azanylRadical, diazaA group, acridinyl, and the like, each of which may be optionally substituted as defined herein.

"heteroarylalkyl" or "heteroaralkyl" refers to a group of the formula-R-R ', wherein R and R' are alkylene and heteroaryl, respectively, as defined herein.

"Heteroarylsulfonyl" refers to a group of the formula-SO 2-R, wherein R is heteroaryl as defined herein.

"heteroaryloxy" refers to a group of the formula-O-R, wherein R is heteroaryl as defined herein.

"Heteroaralkyloxy" refers to a group of the formula-O-R-R ", wherein R and R' are alkylene and heteroaryl, respectively, as defined herein.

The terms "halo", "halogen" and "halide" are used interchangeably to refer to the substituents fluorine, chlorine, bromine or iodine.

"haloalkyl" refers to an alkyl group, as defined herein, wherein one or more hydrogens have been replaced with the same or different halogen. Exemplary haloalkyl groups include-CH 2C1, -CH2CF3, -CH2CCl3, perfluoroalkyl groups (e.g., -CF3), and the like.

"haloalkoxy" refers to a moiety of the formula-OR, wherein R is a haloalkyl moiety as defined herein. An exemplary haloalkoxy group is difluoromethoxy.

"heterocyclic amino" refers to a saturated ring wherein at least one ring atom is N, NH or N-alkyl and the remaining ring atoms form an alkylene group.

"Heterocyclyl" refers to a monovalent saturated moiety consisting of one to three rings, incorporating one, two or three or four heteroatoms (selected from nitrogen, oxygen or sulfur). The heterocyclyl ring may be optionally substituted as defined herein. Examples of heterocyclyl moieties include, but are not limited to, optionally substituted piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azaA pyrrolidinyl group, an azetidinyl group, a tetrahydropyranyl group, a tetrahydrofuranyl group, an oxetanyl group, etc. The heterocyclyl group may be optionally substituted as defined herein.

"Heterocyclylalkyl" refers to a moiety of the formula-R-R ', where R and R' are alkylene and heterocyclyl, respectively, as defined herein.

"Heterocyclyloxy" refers to a moiety of formula-OR, wherein R is heterocyclyl as defined herein.

"Heterocyclylalkoxy" refers to a moiety of the formula-OR-R ', where R and R' are alkylene and heterocyclyl, respectively, as defined herein.

"Heterocyclylsulfonyl" means a group of the formula-SO 2-R, wherein R is heterocyclyl as defined herein.

"Hydroxyalkoxy" refers to a moiety of the formula-OR, where R is hydroxyalkyl as defined herein.

"Hydroxyalkylamino" refers to a moiety of the formula-NR-R ', wherein R is hydrogen or alkyl and R' is hydroxyalkyl as defined herein.

"Hydroxyalkylaminoalkyl" refers to a moiety of the formula-R-NR '-R ", wherein R is alkylene, R' is hydrogen or alkyl, and R" is hydroxyalkyl as defined herein.

"Hydroxycarbonylalkyl" or "carboxyalkyl" refers to a group of the formula-R- (CO) -OH, wherein R is alkylene as defined herein.

"Hydroxyalkyloxycarbonylalkyl" or "hydroxyalkoxycarbonylalkyl" refers to a group of the formula-R-C (O) -O-R-OH, wherein each R is alkylene and may be the same or different.

"hydroxyalkyl" refers to an alkyl moiety as defined herein, which is substituted with one or more, e.g., one, two, or three, hydroxyl groups, provided that the same carbon atom does not carry more than one hydroxyl group. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2, 3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2, 3-dihydroxybutyl, 3, 4-dihydroxybutyl and 2- (hydroxymethyl) -3-hydroxypropyl.

"Hydroxycycloalkyl" refers to a cycloalkyl moiety as defined herein wherein one, two or three hydrogen atoms in the cycloalkyl group have been replaced with a hydroxyl substituent. Representative examples include, but are not limited to, 2-, 3-, or 4-hydroxycyclohexyl and the like.

"Alkoxyhydroxyalkyl" and "hydroxyalkoxyalkyl" are used interchangeably and refer to an alkyl group, as defined herein, substituted at least once with a hydroxy group and at least once with an alkoxy group. Thus "alkoxyhydroxyalkyl" and "hydroxyalkoxyalkyl" encompass, for example, 2-hydroxy-3-methoxy-propan-1-yl and the like.

"Urea" or "ureido" refers to a group of the formula-NR '-C (O) -NR "R'", wherein R ', R "and R'" are each independently hydrogen or alkyl.

"carbamate" refers to a group of the formula-O-C (O) -NR 'R "wherein R' and R" are each independently hydrogen or alkyl.

"carboxy" refers to a group of the formula-O-C (O) -OH.

"Sulfonamido" (sulfonamide) "refers to a group of the formula-SO 2-NR ' R", wherein R ', R "and R '" are each independently hydrogen or alkyl.

"optionally substituted," when used with an "aryl," "phenyl," "heteroaryl," "cycloalkyl," or "heterocyclyl" moiety, means that the moiety may be unsubstituted (i.e., all open valences are occupied by a hydrogen atom), or substituted with a specific group as referred to herein.

"leaving group" means a group having the meaning conventionally associated therewith in synthetic organic chemistry, i.e., an atom or group displaceable under substitution reaction conditions. Examples of leaving groups include, but are not limited to, halogen, alkyl-or arylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, toluenesulfonyloxy, and thienyloxy, dihalophosphonooxy, optionally substituted benzyloxy, isopropyloxy, acyloxy, and the like.

"modulator" refers to a molecule that interacts with a target. Such interactions include, but are not limited to, agonism, antagonism, and the like, as defined herein.

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

"disease" and "disease state" refer to any disease, condition, symptom, disorder, or sign.

By "inert organic solvent" or "inert solvent" is meant that the solvent is inert under the conditions of the reaction described in connection therewith and includes, for example, benzene, toluene, acetonitrile, tetrahydrofuran, N-dimethylformamide, chloroform, methylene chloride or dichloromethane, dichloroethane, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, di-N-butanol, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, N-dimethylformamide, NAlkanes, pyridines, and the like. Unless specified to the contrary, the solvent used in the reaction of the present invention is an inert solvent.

By "pharmaceutically acceptable" it is meant that it can be used to prepare pharmaceutical compositions that are generally safe, non-toxic, and not biologically or otherwise undesirable, and include that they are acceptable for veterinary as well as human pharmaceutical use.

By "pharmaceutically acceptable salt" of a compound is meant a pharmaceutically acceptable salt as defined herein and which possesses the desired pharmacological activity of the parent compound.

It is to be understood that all references to pharmaceutically acceptable salts include the solvent addition forms (solvates) or crystalline forms (polymorphs) of the same acid addition salt as defined herein.

"protecting group" or "protecting group" refers to a group that selectively blocks one reactive site in a polyfunctional compound so that a chemical reaction can be selectively carried out at another unprotected reactive site, in the sense conventionally associated therewith in synthetic chemistry. Certain processes of the present invention rely on protecting groups to block reactive nitrogen and/or oxygen atoms present in the reactants. For example, the terms "amino-protecting group" and "nitrogen-protecting group" are used interchangeably herein and refer to those organic groups intended to protect a nitrogen atom from unwanted reactions during synthetic procedures. Exemplary nitrogen protecting groups include, but are not limited to, trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl (carbonylbenzyloxy, CBZ), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-Butoxycarbonyl (BOC), and the like. The person skilled in the art knows how to select groups that are easy to remove and that have the ability to withstand subsequent reactions.

"solvate" refers to a solvent addition form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thereby forming solvates. If the solvent is water, the solvate formed is a hydrate, and when the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more water molecules with one of the substances in which water maintains its molecular state as H2O, such combination being capable of forming one or more hydrates.

"Parkinson's disease" refers to a degenerative disorder of the central nervous system that impairs motor skills, speech and/or cognitive function. Symptoms of parkinson's disease may include, for example, muscle stiffness, tremor, slowing of body movement (bradykinesia), and loss of body movement (akinesia).

"Lewy body disease," also known as "Lewy body dementia," diffuse Lewy body disease, "cortical Lewy body disease," refers to a disorder of neurogenesis that is anatomically characterized by the presence of Lewy bodies in the brain.

By "subject" is meant both mammals and non-mammals. Mammal refers to any member of the mammalian class, including but not limited to humans; non-human primates such as chimpanzees and other apes and monkey species; livestock such as cattle, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; the experimental animals include rodents such as rats, mice, guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds and the like. The term "subject" does not denote a particular age or gender.

By "therapeutically effective amount" is meant an amount of a compound that, when administered to a subject to treat a disease state, is sufficient to effect such treatment of the disease state. The "therapeutically effective amount" will vary depending on the compound, the disease state being treated, the severity or disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors.

When referring to a variable, the terms "those defined above" and "those defined herein" are incorporated by reference to the broad definition of the variable as well as the specific definitions, if any.

"treating" or "treatment" of a disease state includes, inter alia, inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms, and/or alleviating the disease state, i.e., temporary or permanent diminution of the disease state or its clinical symptoms.

The terms "treating", "contacting …", and "reacting …" when referring to a chemical reaction refer to adding or mixing two or more reagents under appropriate conditions to produce the specified and/or desired product. It will be appreciated that the reaction that produces the specified and/or desired product may not necessarily result directly from the combination of the two reagents initially added, i.e., there may be one or more intermediates produced in the mixture that ultimately result in the formation of the specified and/or desired product.

"C" in combination with any other term herein_1-6"means a range of one to six carbons, i.e., 1, 2, 3, 4, 5, or 6 carbons," C_2-6"means a range of two carbons to six carbons, i.e., 2, 3, 4, 5, or 6 carbons," C_3-6"refers to the range of one carbon to six carbons, i.e., 3, 4, 5, or 6 carbons.

Naming and Structure

In general, nomenclature and chemical names used in this application are based on Cambridge Soft^TMIs chembioooffice^TM. Unless otherwise indicated, any open valency appearing on a carbon, oxygen, sulfur or nitrogen atom in the structures herein indicates the presence of a hydrogen atom. Where a nitrogen-containing heteroaryl ring is shown having an open valency on a nitrogen atom, and variables such as Ra, Rb, or Rc are shown on the heteroaryl ring, such variables may be bound or joined to the open valency nitrogen. In the case where a chiral center is present in a structure but no specific stereochemistry is shown for the chiral center, both enantiomers associated with the chiral center are encompassed by the structure. Where a structure shown herein can exist in multiple tautomeric forms, all such tautomers are encompassed by the structure. The atoms represented in the structures herein are intended to encompass all natural isotopes of such atoms. Thus, for example, hydrogen atoms represented herein are meant to include deuterium and tritium,and carbon atoms are meant to include C13 and C14 isotopes.

Compounds of the invention

The present invention provides compounds of formula I:

or a pharmaceutically acceptable salt thereof,

wherein:

m is 0 to 3;

y is C or N;

r2 is: halogenating; c1-6 alkoxy; a cyano group; c1-6 alkynyl; c1-6 alkenyl; halo-C1-6 alkyl; halo-C1-6 alkoxy; c3-6 cycloalkyl, wherein the C3-6 cycloalkyl moiety is optionally substituted with C1-6 alkyl; c3-6 cycloalkyl-C1-6 alkyl wherein the C3-6 cycloalkyl moiety is optionally substituted with C1-6 alkyl; a tetrahydrofuranyl group; tetrahydrofuryl-C1-6 alkyl; acetyl; an oxetanyl group; or oxetane-C1-6 alkyl;

R5 is 5 membered heteroaryl optionally substituted one or more times with R6; and is

In a particular embodiment of the formula I,

m is 0 to 1;

x is: NH;

y is C or N;

r1 is: c1-6 alkyl

R2 is: halo or halo-C1-6 alkyl;

r3 and R4 are each independently: halogenating; c1-6 alkyl or C1-6 alkoxy;

R6 is: c1-6 alkyl; c1-6 alkoxy; heterocyclyl or-C (O) -NRbRc, wherein Rb and Rc are each independently hydrogen or-C1-6 alkyl.

In particular embodiments of formula I, R1 and Ra, together with the atoms to which they are attached, may form a three-to six-membered ring that may optionally contain an additional heteroatom selected from O, N and S, and which may be optionally substituted by oxo, halo or C1-6 alkyl.

In particular embodiments of formula I, R1 and Ra together with the atoms to which they are attached form a five or six membered ring.

In particular embodiments of formula I, R1 and Ra together with the atom to which they are attached form pyrrolidinyl, piperidinyl, orAn oxazolidone group.

In certain embodiments of formula I, R2 is acetyl.

In particular embodiments of formula I, when R1 is cyclopropyl, cyclobutyl, cyclopropyl-C1-6 alkyl or cyclobutyl-C1-6 alkyl, then X is-O-.

In certain embodiments of formula I, m is 0 to 2.

In particular embodiments of formula I, m is 0 or 1.

In particular embodiments of formula I, m is 0.

In a particular embodiment of formula I, m is 1.

In certain embodiments of formula I, r is 0.

In a particular embodiment of formula I, r is 2.

In certain embodiments of formula I, X is-NRa-or-O-.

In certain embodiments of formula I, X is-NRa.

In certain embodiments of formula I, X is-O-.

In certain embodiments of formula I, X is-S (O) n-.

In certain embodiments of formula I, X is-NH-or-O-.

In certain embodiments of formula I, Y is C.

In certain embodiments of formula I, Y is N.

In certain embodiments of formula I, Ra is hydrogen.

In certain embodiments of formula I, Ra is C1-6 alkyl.

In particular embodiments of formula I, R1 is: c1-6 alkyl; halo-C1-6 alkyl; c1-6 alkoxy-C1-6 alkyl; amino-C1-6 alkyl; c1-6 alkylsulfonyl-C1-6 alkyl; c3-6 cycloalkyl; or C3-6 cycloalkyl-C1-6 alkyl.

In particular embodiments of formula I, R1 is: c1-6 alkyl; c3-6 cycloalkyl optionally substituted with C1-6 alkyl; or C3-6 cycloalkyl-C1-6 alkyl, wherein the C3-6 cycloalkyl moiety is optionally substituted with C1-6 alkyl.

In particular embodiments of formula I, R1 is: c1-6 alkyl; halo-C1-6 alkyl; c1-6 alkoxy-C1-6 alkyl; amino-C1-6 alkyl; c1-6 alkylsulfonyl-C1-6 alkyl; a tetrahydrofuranyl group; tetrahydrofuryl-C1-6 alkyl; an oxetanyl group; or oxetane-C1-6 alkyl.

In particular embodiments of formula I, R1 is: c1-6 alkyl; halo-C1-6 alkyl; c1-6 alkoxy-C1-6 alkyl; amino-C1-6 alkyl; or C1-6 alkylsulfonyl-C1-6 alkyl.

In certain embodiments of formula I, R1 is C1-6 alkyl.

In certain embodiments of formula I, R1 is halo-C1-6 alkyl.

In particular embodiments of formula I, R1 is C1-6 alkoxy-C1-6 alkyl.

In a particular embodiment of formula I, R1 is amino-C1-6 alkyl.

In a particular embodiment of formula I, R1 is C1-6 alkylsulfonyl-C1-6 alkyl optionally substituted with C1-6 alkyl.

In particular embodiments of formula I, R1 is C3-6 cycloalkyl optionally substituted with C1-6 alkyl.

In particular embodiments of formula I, R1 is C3-6 cycloalkyl-C1-6 alkyl, wherein the C3-6 cycloalkyl moiety is optionally substituted with C1-6 alkyl.

In certain embodiments of formula I, R1 is tetrahydrofuranyl.

In particular embodiments of formula I, R1 is tetrahydrofuranyl-C1-6 alkyl; an oxetanyl group.

In a particular embodiment of formula I, R1 is oxetane-C1-6 alkyl.

In particular embodiments of formula I, R1 is: a methyl group; an ethyl group; n-propyl; isopropyl group; an isobutyl group; 3, 3-dimethylpropyl; a cyclopropyl group; a cyclobutyl group; a cyclopentyl group; a cyclohexyl group; a cyclopropyl methyl group; a cyclobutylmethyl group; a cyclopentyl methyl group; a cyclopropyl ethyl group; a methoxyethyl group; an oxetanyl group; or tetrahydrofurylmethyl.

In particular embodiments of formula I, R1 is: a methyl group; an ethyl group; n-propyl; isopropyl group; an isobutyl group; 3, 3-dimethylpropyl; a cyclopentyl group; a cyclohexyl group; a cyclopropyl methyl group; a cyclobutylmethyl group; a cyclopentyl methyl group; a cyclopropyl ethyl group; a methoxyethyl group; an oxetanyl group; or tetrahydrofurylmethyl.

In particular embodiments of formula I, R1 is: a methyl group; an ethyl group; n-propyl; isopropyl group; an isobutyl group; 3, 3-dimethylpropyl; a cyclopentyl group; a cyclohexyl group; a cyclopentyl methyl group; a methoxyethyl group; an oxetanyl group; or tetrahydrofurylmethyl.

In particular embodiments of formula I, R1 is: a methyl group; an ethyl group; n-propyl; isopropyl group; or an isobutyl group.

In particular embodiments of formula I, R1 is methyl or ethyl.

In certain embodiments of formula I, R1 is methyl.

In a particular embodiment of formula I, R1 is ethyl.

In particular embodiments of formula I, R1 is: a cyclopropyl group; a cyclobutyl group; a cyclopentyl group; a cyclohexyl group; a cyclopropyl methyl group; a cyclobutylmethyl group; a cyclopentyl methyl group; or a cyclopropylethyl group.

In particular embodiments of formula I, R1 is: a cyclopentyl group; a cyclohexyl group; or a cyclopentylmethyl group.

In particular embodiments of formula I, R2 is: halogenating; c1-6 alkoxy; halo-C1-6 alkyl; halo-C1-6 alkoxy; c3-6 cycloalkyl wherein the C3-6 cycloalkyl moiety is optionally substituted with C1-6 alkyl; c3-6 cycloalkyl-C1-6 alkyl wherein the C3-6 cycloalkyl moiety is optionally substituted with C1-6 alkyl; a tetrahydrofuranyl group; tetrahydrofuryl-C1-6 alkyl; an oxetanyl group; or oxetane-C1-6 alkyl.

In particular embodiments of formula I, R2 is: halogenating; c1-6 alkoxy; halo-C1-6 alkyl; a cyano group; c1-6 alkynyl; c1-6 alkenyl; c3-6 cycloalkyl; or C3-6 cycloalkyl-C1-6 alkyl.

In particular embodiments of formula I, R2 is: halogenating; c1-6 alkoxy; halo-C1-6 alkyl; a cyano group; c3-6 cycloalkyl; or C3-6 cycloalkyl-C1-6 alkyl.

In particular embodiments of formula I, R2 is: halogenating; c1-6 alkoxy; halo-C1-6 alkyl; c3-6 cycloalkyl; or C3-6 cycloalkyl-C1-6 alkyl.

In particular embodiments of formula I, R2 is: halogenating; halo-C1-6 alkyl; or a cyano group.

In particular embodiments of formula I, R2 is: halogenating; or halo-C1-6 alkyl.

In certain embodiments of formula I, R2 is halo.

In a particular embodiment of formula I, R2 is C1-6 alkoxy.

In a particular embodiment of formula I, R2 is halo-C1-6 alkoxy.

In certain embodiments of formula I, R2 is halo-C1-6 alkyl.

In certain embodiments of formula I, R2 is C3-6 cycloalkyl.

In particular embodiments of formula I, R2 is C3-6 cycloalkyl-C1-6 alkyl.

In certain embodiments of formula I, R2 is tetrahydrofuranyl.

In a particular embodiment of formula I, R2 is tetrahydrofuranyl-C1-6 alkyl.

In certain embodiments of formula I, R2 is oxetanyl.

In a particular embodiment of formula I, R2 is oxetane-C1-6 alkyl.

In particular embodiments of formula I, R2 is halo, trifluoromethyl or cyano.

In particular embodiments of formula I, R2 is chloro, trifluoromethyl or cyano.

In particular embodiments of formula I, R2 is chloro or trifluoromethyl.

In particular embodiments of formula I, R2 is fluoro, chloro, or bromo.

In certain embodiments of formula I, R2 is chloro.

In certain embodiments of formula I, R2 is fluoro.

In certain embodiments of formula I, R2 is bromo.

In certain embodiments of formula I, R2 is trifluoromethyl.

In certain embodiments of formula I, R2 is methoxy.

In certain embodiments of formula I, R2 is cyano.

In certain embodiments of formula I, R2 is C1-6 alkynyl.

In particular embodiments of formula I, R2 is C1-6 alkenyl.

In particular embodiments of formula I, R3 is: c1-6 alkyl.

In certain embodiments of formula I, R3 is halo.

In certain embodiments of formula I, R3 is C1-6 alkyl.

In a particular embodiment of formula I, R3 is C1-6 alkoxy.

In particular embodiments of formula I, R3 is halo or C1-6 alkoxy.

In certain embodiments of formula I, R3 is C3-6 cycloalkyloxy.

In certain embodiments of formula I, R3 is halo-C1-6 alkyl.

In a particular embodiment of formula I, R3 is halo-C1-6 alkoxy.

In certain embodiments of formula I, R3 is halo or methoxy.

In particular embodiments of formula I, R3 is fluoro, chloro or methoxy.

In particular embodiments of formula I, R3 is fluoro or chloro.

In certain embodiments of formula I, R3 is methoxy.

In a particular embodiment of formula I, R3 is methyl

In certain embodiments of formula I, R3 is chloro.

In certain embodiments of formula I, R3 is fluoro.

In particular embodiments of formula I, R4 is: c1-6 alkyl;

in certain embodiments of formula I, R4 is halo.

In certain embodiments of formula I, R4 is C1-6 alkyl.

In a particular embodiment of formula I, R4 is C1-6 alkoxy.

In certain embodiments of formula I, R4 is halo-C1-6 alkyl.

In a particular embodiment of formula I, R4 is halo-C1-6 alkoxy.

In certain embodiments of formula I, R4 is halo or methoxy.

In particular embodiments of formula I, R4 is fluoro, chloro, methyl or methoxy.

In particular embodiments of formula I, R4 is fluoro, chloro or methoxy.

In particular embodiments of formula I, R4 is fluoro or chloro.

In certain embodiments of formula I, R4 is methoxy.

In a particular embodiment of formula I, R4 is methyl

In certain embodiments of formula I, R4 is chloro.

In certain embodiments of formula I, R4 is fluoro.

In certain embodiments of formula I, R4 is C3-6 cycloalkyloxy.

In particular embodiments of formula I, R5 is: (5- (methoxymethyl) -3-methyl-1H-pyrazol-1-yl, 1- (oxetan-3-yl) -1H-pyrazol-4-yl, 1, 3, 5-trimethyl-1H-pyrazol-4-yl) phenyl, 1, 3-dimethyl-1H-pyrazol-4-yl, 1, 5-dimethyl-1H-pyrazol-4-yl, 1H-1, 2, 4-triazol-1-yl, 1H-tetrazol-1-yl, 1-methyl-1H-1, 2, 3-triazol-5-yl, 1-methyl-1H-imidazol-2-yl, 1-methyl-1H-imidazol-5-yl, 1-methyl-1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-5-yl, 1-methyl-1H-tetrazol-5-yl, 1-trimethyl-1H-pyrazol-5-yl, 2H-tetrazol-5-yl, 2-methyl-2H-tetrazol-5-yl, 3, 5-dimethylisoOxazol-4-yl, 3-methyl-1, 2, 4-Oxadiazol-5-yl, 4-methyl-4H-1, 2, 4-triazol-3-yl, 5- (methoxymethyl) -1H-tetrazol-1-yl, 5- (methoxymethyl) -3-methyl-1H-pyrazol-1-yl, 5-methyl-1, 3, 4-Oxadiazol-2-yl, 5-methyl-1H-tetrazol-1-yl, isoAn azole-4-yl group, which is,oxazol-2-yl, (thiazol-4-yl) pyridin-3-yl or (thiazol-5-yl) pyridin-3-yl.

In particular embodiments of formula I, R5 is:an azole group; a thiazolyl group; a pyrazolyl group; an imidazolyl group; different from each otherAn azole group; an isothiazolyl group;a diazolyl group; a thiadiazolyl group; a triazolyl group; or a tetrazolyl group; each optionally substituted one or more times with R6.

In particular embodiments of formula I, R5 is: a pyrazolyl group; an imidazolyl group;a diazolyl group; a thiadiazolyl group; a triazolyl group; or a tetrazolyl group; each of which is optionally substituted one or more times with R6.

In particular embodiments of formula I, R5 is: a pyrazolyl group;a diazolyl group; a triazolyl group; or a tetrazolyl group; each of which is optionally substituted one or more times with R6.

In particular embodiments of formula I, R5 is:a diazolyl group; a triazolyl group; or a tetrazolyl group; each of which is optionally substituted one or more times with R6.

In certain embodiments of formula I, R5 is optionally substituted one or more times with R6An azole group.

In particular embodiments of formula I, R5 is thiazolyl optionally substituted one or more times with R6.

In certain embodiments of formula I, R5 is pyrazolyl optionally substituted one or more times with R6.

In certain embodiments of formula I, R5 is imidazolyl optionally substituted one or more times with R6.

In particular embodiments of formula I, R5 is iso optionally substituted one or more times with R6An azole group.

In particular embodiments of formula I, R5 is isothiazolyl optionally substituted one or more times with R6.

In a particular embodiment of formula I, R5 isA diazolyl group; a thiadiazolyl group; a triazolyl group; or a tetrazolyl group; which is optionally substituted one or more times by R6.

In particular embodiments of formula I, R5 is thiadiazolyl optionally substituted one or more times with R6.

In a particular embodiment of formula I, R5 is triazolyl optionally substituted one or more times with R6.

In certain embodiments of formula I, R5 is tetrazolyl optionally substituted one or more times with R6.

In a particular embodiment of formula I, R5 is thiazol-5-yl optionally substituted one or more times with R6.

In a particular embodiment of formula I, R5 is thiazol-4-yl optionally substituted one or more times with R6.

In a particular embodiment of formula I, R5 is thiazol-2-yl optionally substituted one or more times with R6.

In certain embodiments of formula I, R5 is optionally substituted one or more times with R6Oxazol-5-yl.

In certain embodiments of formula I, R5 is optionally substituted one or more times with R6Oxazol-4-yl.

In certain embodiments of formula I, R5 is optionally substituted one or more times with R6Oxazol-2-yl.

In a particular embodiment of formula I, R5 is isothiazol-2-yl optionally substituted one or more times with R6.

In a particular embodiment of formula I, R5 is isothiazol-3-yl optionally substituted one or more times with R6.

In a particular embodiment of formula I, R5 is isothiazol-4-yl optionally substituted one or more times with R6.

In particular embodiments of formula I, R5 is iso optionally substituted one or more times with R6Oxazol-2-yl.

In a particular embodiment of formula IWherein R5 is an iso-isomer optionally substituted one or more times with R6Oxazol-3-yl.

In particular embodiments of formula I, R5 is iso optionally substituted one or more times with R6Oxazol-4-yl.

In a particular embodiment of formula I, R5 is imidazol-2-yl optionally substituted one or more times with R6.

In a particular embodiment of formula I, R5 is imidazol-1-yl optionally substituted one or more times with R6.

In a particular embodiment of formula I, R5 is imidazol-4-yl optionally substituted one or more times with R6.

In a particular embodiment of formula I, R5 is imidazol-5-yl optionally substituted one or more times with R6.

In a particular embodiment of formula I, R5 is pyrazol-1-yl optionally substituted one or more times with R6.

In a particular embodiment of formula I, R5 is pyrazol-3-yl optionally substituted one or more times with R6.

In a particular embodiment of formula I, R5 is pyrazol-4-yl optionally substituted one or more times with R6.

In a particular embodiment of formula I, R5 is pyrazol-5-yl optionally substituted one or more times with R6.

In a particular embodiment of formula I, R5 is 1, 2, 3-triazol-1-yl optionally substituted one or more times with R6.

In a particular embodiment of formula I, R5 is 1, 2, 3-triazol-4-yl optionally substituted one or more times with R6.

In a particular embodiment of formula I, R5 is 1, 2, 3-triazol-5-yl optionally substituted one or more times with R6.

In particular embodiments of formula I, R5 is 1, 2, 4-triazol-1-yl optionally substituted one or more times with R6.

In a particular embodiment of formula I, R5 is 1, 2, 4-triazol-3-yl optionally substituted one or more times with R6.

In a particular embodiment of formula I, R5 is 1, 2, 4-triazol-5-yl optionally substituted one or more times with R6.

In particular embodiments of formula I, R5 is 1, 3, 4-substituted optionally with R6Oxadiazol-2-yl.

In particular embodiments of formula I, R5 is 1, 2, 4-substituted optionally with R6Oxadiazol-3-yl.

In particular embodiments of formula I, R5 is 1, 2, 4-substituted optionally with R6Oxadiazol-5-yl.

In certain embodiments of formula I, R5 is 1, 3, 4-thiadiazol-2-yl optionally substituted with R6.

In certain embodiments of formula I, R5 is 1, 2, 4-thiadiazol-3-yl optionally substituted with R6.

In particular embodiments of formula I, R5 is 1, 2, 4-thiadiazol-5-yl optionally substituted with R6.

In a particular embodiment of formula I, R5 is tetrazol-1-yl optionally substituted with R6.

In a particular embodiment of formula I, R5 is tetrazol-5-yl optionally substituted with R6.

In particular embodiments of formula I, R5 is: thiazol-5-yl; thiazol-4-yl;oxazol-2-yl; different from each otherOxazol-4-yl; 3, 5-dimethylisoOxazol-4-yl; 1-methyl-1H-imidazol-2-yl;

1-methyl-1H-imidazol-5-yl; 1, 3, 5-trimethyl-1H-pyrazol-4-yl; 1-methyl-1H-pyrazol-5-yl; 1-methyl-1H-pyrazol-4-yl; 1, 3-dimethyl-1H-pyrazol-4-yl; 1, 5-dimethyl-1H-pyrazol-4-yl; 5- (dimethylaminocarbonyl) -1-methyl-1H-pyrazoyl-4-yl; 1- (oxetan-3-yl) -1H-pyrazol-4-yl; 5- (methoxymethyl) -3-methyl-1H-pyrazol-1-yl; 1-methyl-1H-1, 2, 3-triazol-5-yl; 1H-1, 2, 4-triazol-1-yl; 4-methyl-4H-1, 2, 4-triazol-3-yl; 5-methyl-1, 3, 4-Oxadiazol-2-yl; 3-methyl-1, 2, 4-Oxadiazol-5-yl; 1-methyl-1H-tetrazol-5-yl; 2-methyl-2H-tetrazol-5-yl; 1H-tetrazol-1-yl; 2H-tetrazol-5-yl; 5-methyl-1H-tetrazol-1-yl; or 5- (methoxymethyl) -1H-tetrazol-1-yl.

In particular embodiments of formula I, R5 is: 1-methyl-1H-imidazol-2-yl; 1-methyl-1H-imidazol-5-yl; 1, 3, 5-trimethyl-1H-pyrazol-4-yl; 1-methyl-1H-pyrazol-5-yl; 1-methyl-1H-pyrazol-4-yl; 1, 3-dimethyl-1H-pyrazol-4-yl; 1, 5-dimethyl-1H-pyrazol-4-yl; 5- (dimethylaminocarbonyl) -1-methyl-1H-pyrazol-4-yl; 1- (oxetan-3-yl) -1H-pyrazol-4-yl; 5- (methoxymethyl) -3-methyl-1H-pyrazol-1-yl; 1-methyl-1H-1, 2, 3-triazol-5-yl; 1H-1, 2, 4-triazol-1-yl; 4-methyl-4H-1, 2, 4-triazol-3-yl; 5-methyl-1, 3, 4-Oxadiazol-2-yl; 3-methyl-1, 2, 4-Oxadiazol-5-yl; 1-methyl-1H-tetrazol-5-yl; 2-methyl-2H-tetrazol-5-yl; 1H-tetrazol-1-yl; 2H-tetrazol-5-yl; 5-methyl-1H-tetrazol-1-yl; or 5- (methoxymethyl) -1H-tetrazol-1-yl.

In particular embodiments of formula I, R5 is: 1-methyl-1H-1, 2, 3-triazol-5-yl; 1H-1, 2, 4-triazol-1-yl; 4-methyl-4H-1, 2, 4-triazol-3-yl; 5-methyl-1, 3, 4-Oxadiazol-2-yl; 3-methyl-1, 2, 4-Oxadiazol-5-yl; 1-methyl-1H-tetrazol-5-yl; 2-methyl-2H-tetrazol-5-yl; 1H-tetrazol-1-yl; 2H-tetrazol-5-yl; 5-methyl-1H-tetrazol-1-yl; or 5- (methoxymethyl) -1H-tetrazol-1-yl.

In particular embodiments of formula I, R5 is: 1-methyl-1H-imidazol-2-yl; or 1-methyl-1H-imidazol-5-yl.

In particular embodiments of formula I, R5 is: 1, 3, 5-trimethyl-1H-pyrazol-4-yl; 1-methyl-1H-pyrazol-5-yl; 1-methyl-1H-pyrazol-4-yl; 1, 3-dimethyl-1H-pyrazol-4-yl; 1, 5-dimethyl-1H-pyrazol-4-yl; 5- (dimethylaminocarbonyl) -1-methyl-1H-pyrazol-4-yl; 1- (oxetan-3-yl) -1H-pyrazol-4-yl; or 5- (methoxymethyl) -3-methyl-1H-pyrazol-1-yl.

In particular embodiments of formula I, R5 is: 1-methyl-1H-1, 2, 3-triazol-5-yl; 1H-1, 2, 4-triazol-1-yl; or 4-methyl-4H-1, 2, 4-triazol-3-yl.

In particular embodiments of formula I, R5 is: 5-methyl-1, 3, 4-Oxadiazol-2-yl; or 3-methyl-1, 2, 4-Oxadiazol-5-yl.

In particular embodiments of formula I, R5 is: 1-methyl-1H-tetrazol-5-yl; 2-methyl-2H-tetrazol-5-yl; 1H-tetrazol-1-yl; 2H-tetrazol-5-yl; 5-methyl-1H-tetrazol-1-yl; or 5- (methoxymethyl) -1H-tetrazol-1-yl.

In a particular embodiment of formula I, R5 is thiazol-5-yl. In a particular embodiment of formula I, R5 is thiazol-4-yl.

In a particular embodiment of formula I, R5 is thiazol-5-yl. In a particular embodiment of formula I, R5 is thiazol-5-yl.

In a particular embodiment of formula I, R5 is thiazol-5-yl. In certain embodiments of formula I, R5 is isoOxazol-4-yl.

In a particular embodiment of formula I, R5 is thiazol-5-yl.

In certain embodiments of formula I, R5 is isoOxazol-4-yl.

In a particular embodiment of formula I, R5 is thiazol-5-yl.

In certain embodiments of formula I, R5 is isoOxazol-4-yl.

In a particular embodiment of formula I, R5 is 3, 5-dimethylisoOxazol-4-yl.

In a particular embodiment of formula I, R5 is 1-methyl-1H-imidazol-2-yl.

In a particular embodiment of formula I, R5 is 1-methyl-1H-imidazol-5-yl.

In a particular embodiment of formula I, R5 is 1, 3, 5-trimethyl-1H-pyrazol-4-yl.

In a particular embodiment of formula I, R5 is 1-methyl-1H-pyrazol-5-yl.

In a particular embodiment of formula I, R5 is 1-methyl-1H-pyrazol-4-yl.

In a particular embodiment of formula I, R5 is 1, 3-dimethyl-1H-pyrazol-4-yl.

In a particular embodiment of formula I, R5 is 1, 5-dimethyl-1H-pyrazol-4-yl.

In a particular embodiment of formula I, R5 is 5- (dimethylaminocarbonyl) -1-methyl-1H-pyrazol-4-yl.

In a particular embodiment of formula I, R5 is 1- (oxetan-3-yl) -1H-oxazol-4-yl.

In a particular embodiment of formula I, R5 is 5- (methoxymethyl) -3-methyl-1H-pyrazol-1-yl.

In a particular embodiment of formula I, R5 is 1-methyl-1H-1, 2, 3-triazol-5-yl.

In a particular embodiment of formula I, R5 is 1H-1, 2, 4-triazol-1-yl.

In a particular embodiment of formula I, R5 is 4-methyl-4H-1, 2, 4-triazol-3-yl.

In a particular embodiment of formula I, R5 is 5-methyl-1, 3, 4-Oxadiazol-2-yl.

In a particular embodiment of formula I, R5 is 3-methyl-1, 2, 4-Oxadiazol-5-yl.

In a particular embodiment of formula I, R5 is 1-methyl-1H-tetrazol-5-yl.

In a particular embodiment of formula I, R5 is 2-methyl-2H-tetrazol-5-yl.

In a particular embodiment of formula I, R5 is 1H-tetrazol-1-yl.

In a particular embodiment of formula I, R5 is 2H-tetrazol-5-yl.

In a particular embodiment of formula I, R5 is 5-methyl-1H-tetrazol-1-yl.

In a particular embodiment of formula I, R5 is 5- (methoxymethyl) -1H-tetrazol-1-yl.

In certain embodiments of formula I, R6 is C1-6 alkyl.

In certain embodiments of formula I, R6 is C3-6 cycloalkyl.

In particular embodiments of formula I, R6 is C3-6 cycloalkyl-C1-6 alkyl.

In certain embodiments of formula I, R6 is halo.

In certain embodiments of formula I, R6 is halo-C1-6 alkyl.

In a particular embodiment of formula I, R6 is C1-6 alkoxy.

In certain embodiments of formula I, R6 is heterocyclyl.

In certain embodiments of formula I, R6 is oxo.

In certain embodiments of formula I, R6 is-C (O) -NRbRc, wherein Rb and Rc are each independently hydrogen or-C1-6 alkyl.

In a particular embodiment of the invention, the target compound is a compound of formula II

Wherein m, X, R1, R2, R3, R4 and R5 are the same as defined herein for formula I.

In a particular embodiment, the present invention relates to a compound of formula I selected from the group consisting of:

n2- (2-chloro-4- (2H-tetrazol-5-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine,

n2- (2-chloro-4- (1-methyl-1H-tetrazol-5-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine,

n2- (2-chloro-4- (2-methyl-2H-tetrazol-5-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine,

n2- (2-methoxy-4- (1H-1, 2, 4-triazol-1-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine,

n2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine,

n2- (5-fluoro-2-methoxy-4- (3-methyl-1, 2, 4-)Oxadiazol-5-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine,

n2- (2-chloro-5-methoxy-4- (5-methyl-1, 3, 4-)Oxadiazol-2-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine,

n2- (2-methoxy-4- (1-methyl-1H-imidazol-5-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine,

n2- (4-methoxy-6- (thiazol-5-yl) pyridin-3-yl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine,

5-chloro-N2- (2-methoxy-4- (1-methyl-1H-tetrazol-5-yl) phenyl) -N4-methylpyrimidine-2, 4-diamine,

n2- (2-chloro-5-methoxy-4- (1-methyl-1H-1, 2, 3-triazol-5-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine,

n2- (4-methoxy-6- (thiazol-4-yl) pyridin-3-yl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine,

n2- (4-methoxy-6-) (Oxazol-2-yl) pyridin-3-yl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine,

5-chloro-N2- (4- (iso)Oxazol-4-yl) -2-methoxyphenyl) -N4-methylpyrimidine-2, 4-diamine,

5-chloro-N2- (2-methoxy-4- (1-methyl-1H-imidazol-2-yl) phenyl) -N4-methylpyrimidine-2, 4-diamine,

5-chloro-N2- (2-methoxy-4- (1-methyl-1H-imidazol-5-yl) phenyl) -N4-methylpyrimidine-2, 4-diamine,

n2- (2-methoxy-4- (1-methyl-1H-1, 2, 3-triazol-5-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine,

n2- (2-methoxy-4- (2-methyl-2H-tetrazol-5-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine,

n2- (2-chloro-5-methoxy-4- (1-methyl-1H-imidazol-2-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine,

n2- (2-methoxy-4- (1-methyl-1H-tetrazol-5-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine,

n2- (2-chloro-5-methoxy-4- (1-methyl-1H-imidazol-5-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine,

n2- (5-fluoro-2-methoxy-4- (1-methyl-1H-tetrazol-5-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine,

5-chloro-N2- (2-methoxy-4- (1-methyl-1H-1, 2, 3-triazol-5-yl) phenyl) -N4-methylpyrimidine-2, 4-diamine,

n2- (2-chloro-5-methoxy-4- (1, 3, 5-trimethyl-1H-pyrazol-4-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine,

n2- (2-methoxy-4- (1-methyl-1H-pyrazol-5-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine,

n2- (4- (3, 5-dimethyliso)Oxazol-4-yl) -2-methoxyphenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine,

n2- (2-methoxy-4- (1H-tetrazol-1-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine,

n2- (2-chloro-5-methoxy-4- (1-methyl-1H-pyrazol-5-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine,

N4-Ethyl-N2- (5-fluoro-2-methoxy-4- (5-methyl-1, 3, 4-)Oxadiazol-2-yl) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine,

n2- (5-fluoro-2-methoxy-4- (5-methyl-1, 3, 4-)Oxadiazol-2-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine,

n2- (2-chloro-5-methoxy-4- (3-methyl-1, 2, 4-)Oxadiazol-5-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine,

n2- (2-chloro-5-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine,

5-chloro-N2- (2-chloro-4- (5-methyl-1, 3, 4-)Oxadiazol-2-yl) phenyl) -N4-methylpyrimidine-2, 4-diamine,

5-chloro-N2- (2-chloro-4- (3-methyl-1, 2, 4-)Oxadiazol-5-yl) phenyl) -N4-methylpyrimidine-2, 4-diamine,

5-chloro-N2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N4-methylpyrimidine-2, 4-diamine,

5-chloro-N2- (2-chloro-5-methoxy-4- (3-methyl-1, 2, 4-)Oxadiazol-5-yl) phenyl) -N4-methylpyrimidine-2, 4-diamine,

5-chloro-N2- (2-chloro-5-methoxy-4- (5-methyl-1, 3, 4-)Oxadiazol-2-yl) phenyl) -N4-methylpyrimidine-2, 4-diamine,

n2- (4- (1, 3-dimethyl-1H-pyrazol-4-yl) -2-methoxyphenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine,

n2- (4- (1, 5-dimethyl-1H-pyrazol-4-yl) -2-methoxyphenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine,

n2- (2-methoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine,

4- (2-fluoro-5-methoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) -N, N, 1-trimethyl-1H-pyrazole-5-carboxamide,

n2- (5-fluoro-2-methoxy-4- (5-methyl-1H-tetrazol-1-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine,

n2- (5-fluoro-2-methoxy-4- (1-methyl-1H-1, 2, 3-triazol-5-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine,

n2- (5-fluoro-2-methoxy-4- (1- (oxetan-3-yl) -1H-pyrazol-4-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine,

n2- (2-methoxy-5-methyl-4- (5-methyl-1H-tetrazol-1-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine,

n2- (2-methoxy-4- (5- (methoxymethyl) -1H-tetrazol-1-yl) -5-methylphenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine,

n2- (5-fluoro-2-methoxy-4- (5- (methoxymethyl) -3-methyl-1H-pyrazol-1-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine,

n2- (2-methoxy-4- (5- (methoxymethyl) -3-methyl-1H-pyrazol-1-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine and

n2- (5-fluoro-2-methoxy-4- (5- (methoxymethyl) -1H-tetrazol-1-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine.

The present invention also relates to a composition comprising: a pharmaceutically acceptable carrier; and a compound as described herein.

The present invention also relates to a method for the treatment of parkinson's disease, said method comprising administering to a subject in need thereof an effective amount of a compound as described herein.

The invention also relates to compounds of formula I as described herein for use in the prevention or treatment of parkinson's disease.

The present invention also relates to a pharmaceutical composition as described herein, wherein said pharmaceutical composition is useful for the prevention or treatment of parkinson's disease.

The invention also relates to a compound of formula I as described herein for use in the manufacture of a medicament for the prevention or treatment of parkinson's disease.

The present invention also provides a method for the treatment of a disease or condition mediated by or otherwise associated with the LRRK2 receptor, which method comprises administering to a subject in need thereof an effective amount of a compound of the present invention.

The disease may be a neurodegenerative disease such as parkinson's disease, huntington's disease or lewy body dementia.

The disease may be a CNS disorder such as alzheimer's disease and L-dopa induced dyskinesia.

The disease may be cancer or a proliferative disorder such as renal, breast, prostate, blood, papillary or lung cancer, acute myeloid leukemia or multiple myeloma.

The disease may be an inflammatory disease such as leprosy, crohn's disease, amyotrophic lateral sclerosis, rheumatoid arthritis, and ankylosing spondylitis.

The present invention also provides a method for enhancing cognitive memory, comprising administering to a subject in need thereof an effective amount of a compound of the present invention.

Representative compounds of the process according to the invention are shown in the following experimental examples.

Synthesis of

The compounds of the present invention may be prepared by various methods depicted in the exemplary synthetic reaction schemes shown and described below.

The starting materials and Reagents used in preparing these compounds are generally available from commercial suppliers such as aldrich chemical co, or prepared by methods known to those skilled in the art according to procedures set forth in the references, such as Fieser and Fieser's Reagents for Organic Synthesis; wiley & Sons: new York, 1991, volume 1-15; rodd's Chemistry of Carbon compounds, Elsevier Science Publishers, 1989, volumes 1-5 and desiccation; and Organic Reactions, Wiley & Sons: new York, 1991, volume 1-40. The following synthetic reaction schemes are merely illustrative of the methods by which the compounds of the present invention may be synthesized and various modifications may be made to these synthetic reaction schemes and will be suggested to one skilled in the art having referred to the disclosure contained in this application.

If desired, the starting materials and intermediates of the synthetic reaction schemes can be isolated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.

Unless otherwise specified, the reactions described herein may be carried out under an inert atmosphere at atmospheric pressure at a temperature in the range of from about-78 ℃ to about 150 ℃, for example from about 0 ℃ to about 125 ℃, or conveniently at about room (ambient) temperature, for example about 20 ℃.

Scheme a below illustrates one synthetic procedure that may be used to prepare particular compounds of formula I or formula II, wherein X, m, R1, R2, R3, R4, and R5 are as defined herein.

Scheme A

In step 1 of scheme a, dichloropyrimidine compound a is reacted with reagent b to provide pyrimidine compound c. The reaction of step 1 may occur under polar solvent conditions. In embodiments of the invention where X is-O- (i.e., reagent b is an alcohol), the reaction of step 1 may be carried out in the presence of a base.

In step 2, the pyrimidine compound c undergoes a reaction with the aniline compound d to provide a phenylaminopyridine compound of formula I according to the present invention. The reaction of step 2 may take place in a polar protic solvent and in the presence of an acid such as HCl. Many aniline compounds d are commercially available or can be readily prepared from nitrobenzene as shown in the examples below.

Many variations to the procedure of scheme a are possible and will suggest themselves to those skilled in the art. Specific details for the preparation of the compounds of the present invention are described in the following examples.

Administration and pharmaceutical compositions

The present invention includes pharmaceutical compositions comprising at least one compound of the present invention, or an individual isomer, or a racemic or non-racemic mixture of isomers, or a pharmaceutically acceptable salt or solvate thereof, together with at least one pharmaceutically acceptable carrier, and optionally other therapeutic and/or prophylactic ingredients.

Typically, the compounds of the invention are administered in a therapeutically effective amount by any of the accepted modes of administration for agents used for similar purposes. Suitable dosage ranges are generally from 1 to 500 mg/day, for example from 1 to 100 mg/day, and most preferably from 1 to 30 mg/day, depending on a number of factors such as the severity of the disease being treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication involved in the administration, and the preference and experience of the medical practitioner involved. One of ordinary skill in the art of treating such diseases, without undue experimentation and relying on personal knowledge and the disclosure of this application, will be able to determine a therapeutically effective amount of a compound of the present invention for a given disease.

The compounds of the invention may be administered as pharmaceutical formulations including those suitable for oral (including buccal and sublingual), rectal, nasal, topical, pulmonary, vaginal or parenteral (including intramuscular, intraarterial, intrathoracic, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. One particular mode of administration is usually oral, using a convenient daily dosage regimen which may be adjusted according to the degree of affliction.

A compound or compounds of the invention, together with one or more conventional adjuvants, carriers or diluents, may be placed in the form of pharmaceutical compositions and unit dosages. The pharmaceutical compositions and unit dosage forms can be comprised of conventional ingredients in conventional proportions (with or without additional active compounds or ingredients), and the unit dosage forms can contain any suitable effective amount of the active ingredient commensurate with the desired daily dosage range to be employed. The pharmaceutical compositions may be employed as solids such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use. Formulations containing about one (1) milligram of active ingredient per tablet, or more broadly from about 0.01 to about one hundred (100) milligrams, are accordingly suitable representative unit dosage forms.

The compounds of the present invention may be formulated into a wide variety of oral dosage forms. Pharmaceutical compositions and dosage forms may comprise a compound or compounds of the invention or a pharmaceutically acceptable salt thereof as the active ingredient. The pharmaceutically acceptable carrier may be a solid or a liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances that may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is usually a finely divided solid, which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is usually mixed with a carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Powders and tablets may contain from about one (1) to about seventy (70) percent of the active compound. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax, cocoa butter, and the like. The term "formulation" is intended to include the formulation of the active compound with encapsulating material as a carrier, providing a capsule in which the active ingredient (with or without a carrier) is surrounded by a carrier with which it is associated. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be as solid forms suitable for oral administration.

Other forms suitable for oral administration include liquid form preparations, including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted into liquid form preparations immediately prior to use. Emulsions may be prepared in solution, for example in aqueous propylene glycol, or may contain emulsifying agents, for example lecithin, sorbitan monooleate or acacia. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable colorants, fragrances, stabilizers and thickeners. Aqueous suspensions may be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents. Solid form preparations include solutions, suspensions, and emulsions, and may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

The compounds of the invention may be formulated for parenteral administration (e.g., by injection, e.g., bolus injection or continuous infusion) and may be presented in unit dosage form in ampoules, pre-filled syringes, small volume infusions or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example, solutions in aqueous polyethylene glycol solutions. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preservatives, wetting, emulsifying or suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by sterile isolation of a sterile solid, or by lyophilization from a solution thereof which is reconstituted with a suitable vehicle, e.g., sterile pyrogen-free water, prior to use.

The compounds of the invention may be formulated for topical administration to the epidermis as an ointment, cream or lotion, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include lozenges comprising the active agent in a flavoured base, usually sucrose and arabinose or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

The compounds of the present invention may be formulated for administration as suppositories. A low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active ingredient is dispersed homogeneously, for example by stirring. The molten homogeneous mixture is then poured into a conveniently sized mold, allowed to cool and solidify.

The compounds of the invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing such carriers in addition to the active ingredient are known in the art to be suitable.

The subject compounds may be formulated for nasal administration. The solution or suspension is applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or nebulizer. The formulations may be provided in single or multiple dose forms. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined amount of solution or suspension. In the case of a nebulizer, this can be achieved, for example, by means of a metered nebulization spray pump.

The compounds of the invention may be formulated for aerosol administration, particularly to the respiratory tract, and include intranasal administration. The compounds typically have a small particle size, for example on the order of five (5) microns or less. Such particle sizes may be obtained by means known in the art, for example by micronisation. The active ingredient is provided in pressurized packs with a suitable propellant such as a chlorofluorocarbon (CFC), e.g., dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dosage of the drug may be controlled by a metering valve. Alternatively, the active ingredient may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). The powder carrier forms a gel in the nasal cavity. Powder compositions may be presented in unit dosage form, for example in capsules or cartridges, for example in gelatin or film packs, from which the powder may be administered by the inhaler.

When desired, the formulations may be prepared with an enteric coating suitable for sustained or controlled release administration of the active ingredient. For example, the compounds of the present invention may be formulated in a transdermal or subcutaneous drug delivery device. These delivery systems are advantageous when sustained release of the compound is desired and patient compliance with a treatment regimen is critical. The compounds in transdermal delivery systems are often attached to a skin-adherent solid carrier. The compound of interest may also be combined with a penetration enhancer, such as azone (1-dodecylazacycloheptan-2-one). The sustained release delivery system is inserted subcutaneously into the subcutaneous layer by surgery or injection. The subcutaneous implants encapsulate the compound in a lipid-soluble membrane, such as silicone rubber, or a biodegradable polymer, such as polylactic acid.

The pharmaceutical preparation may be in unit dosage form. In such form, the preparation can be subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, a package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Moreover, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

Other suitable pharmaceutical carriers and their formulations are described in Remington: the Science and practice of Pharmacy1995, edited by E.W Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania. Representative pharmaceutical formulations containing the compounds of the present invention are described below.

Utility of

The compounds of the invention are useful for treating LRRK2 mediated diseases or conditions, including neurodegenerative diseases such as parkinson's disease, Lewy body dementia, and huntington's disease, and for enhancing cognitive memory in a subject in general need thereof.

Examples

The following preparations and examples are given to enable those skilled in the art to more clearly understand and practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being exemplary and representative thereof.

All temperatures, including melting points (i.e., MP) are in degrees celsius (° c), unless otherwise indicated. It will be appreciated that the reaction which produces the specified and/or desired product may not necessarily result directly from the combination of the two reagents initially added, i.e. there may be one or more intermediates produced in the mixture which ultimately results in the formation of the specified and/or desired product. The following abbreviations may be used in the preparations and examples.

List of abbreviations

AcOH acetic acid

AIBN 2, 2' -azobis (2-methylpropanenitrile)

Atm. atmospheric pressure

(BOC)₂Di-tert-butyl O carbonate

DavePhos 2-dicyclohexylphosphino-2' - (N, N-dimethylamino) biphenyl

DCM chloromethane/methylene chloride

DIAD diisopropyl azodicarboxylate

DIPEA isopropyl ethylamine

DMAP 4-dimethylaminopyridine

DME 1, 2-dimethoxyethane

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide

DPPF 1, 1' -bis (diphenylphosphino) ferrocene

Et₂O Ether

EtOH ethanol/Ethyl alcohol

EtOAc ethyl acetate

HATU 2- (1H-7-azabenzotriazol-1-yl) -1, 1, 3, 3-tetrakisMethyl ureaAmmonium methyl hexafluorophosphate

HBTU O-benzotriazole-1-yl-N, N, N ', N' -tetramethylureaHexafluorophosphates

HOBT 1-hydroxybenzotriazole

HPLC high pressure liquid chromatography

RPHPLC reversed-phase high-pressure liquid chromatography

i-PrOH Isopropanol/Isopropanol

LCMS liquid chromatography/Mass Spectrometry

MeOH methanol/methyl alcohol

MW microwave

NBS N-bromosuccinimide

NMP 1-methyl-2-pyrrolidone

PSI PSI

RT Room temperature

TBDMS tert-butyldimethylsilyl group

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

Preparation 1: 2-chloro-5-fluoro-N-methylpyrimidin-4-amine

To a 250mL round bottom flask equipped with a stir bar was added 9.0g of 5-fluoro-2, 4-dichloro-pyrimidine, 40mL of methanol and 15mL of 8M methylamine ethanol solution. The reaction was exothermic (mild exotherm) and stirred at room temperature for-30 minutes. Examination by TLC (1: 1 EtOAc: heptane) and LCMS showed the reaction was complete. The reaction was concentrated to give 9.77g of crude which was purified on a silica column running a gradient of 1% to 10% MeOH in DCM over 35 minutes to give 6.77g of pure 2-chloro-5-fluoro-N-methylpyrimidin-4-amine.

The same procedure was used to prepare the compounds shown in table 1 below using the appropriate commercially available substituted 2, 4-dichloro-pyrimidine and amine.

TABLE 1

Preparation 2: 2, 5-dichloro-4-methoxypyrimidine

To a 250mL round bottom flask equipped with a stir bar was added 1g 5-chloro-2, 4-dichloro-pyrimidine, and 15mL diethyl ether. The mixture was cooled to 0 ℃ in an ice bath, and then 1 equivalent of sodium methoxide methanol solution (prepared by reacting 120mg of sodium with 4mL of methanol at room temperature) was slowly added. The reaction was stirred at rt overnight and checked by LCMS. The white precipitate was filtered and the solid was washed with cold methanol. After drying, 0.98g of pure 2, 5-dichloro-4-methoxypyrimidine is obtained and this material is used without further purification.

The same procedure was used to prepare the compounds shown in table 2 below using the appropriate commercially available alcohol and the appropriately substituted 2, 4-dichloro-pyrimidine.

TABLE 2

Example 1: n2- (2-chloro-4- (2H-tetrazol-5-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine

Step 1: 3-chloro-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) benzonitrile

2-chloro-N-methyl-5- (trifluoromethyl) pyrimidin-4-amine (211mg, 1mmol), 4-amino-3-chlorobenzonitrile (305mg, 2mmol), cesium carbonate (0.65g, 2mmol), Xantphos (17mg, 0.03mmol) and Pd2(dba)3(5mg, 0.02mmol) in dioxaneThe mixture in alkane (3mL) was sonicated in an ultrasonic bath for 1 minute. The mixture was then degassed under a stream of nitrogen for 5 minutes. The tube was sealed and the reaction was heated at 100 ℃ for 18 h. The reaction mixture was cooled and diluted with ethyl acetate (15 mL). The organic layer was washed with water (2x20mL) and the combined aqueous extracts were further washed with ethyl acetate (2x15 mL). The combined organics were passed through a phase separation cartridge and the solvent was removed under reduced pressure. Purification of the residue by column chromatography on silica gel (0-100% ethyl acetate/isohexane) gave 3-chloro-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) benzonitrile as a white solid (140mg, 45%). 1H NMR (400MHz, CDCl 3): 8.85(d, J ═ 8.8, 1H); 8.23(d, J ═ 1.1, 1H); 7.80(s，1H)；7.68(d，J＝1.9，1H)；7.58-7.53(m，1H)；5.32(s br，1H)；3.11(d，J＝4.7，3H)。

Step 2: n2- (2-chloro-4- (2H-tetrazol-5-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine

To a solution of 3-chloro-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) benzonitrile (135mg, 6.41mmol) in DMF (2mL) was added sodium azide (80mg, 1.24mmol) and ammonium chloride (66mg, 1.24 mmol). The mixture was heated at 125 ℃ for 18 h. The mixture was cooled, filtered and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the crude residue was diluted with water (5mL) and diethyl ether (5 mL). A precipitate formed which was filtered and washed with additional portions of water and diethyl ether. The solid was co-evaporated with dichloromethane and methanol and then dried in a vacuum oven to give N2- (2-chloro-4- (2H-tetrazol-5-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine (130mg, 85%). LCMS (ESCI _ Formic _ MeCN): MH +]371, at 3.11 minutes.¹H NMR(400MHz，DMSO)：8.94(s，1H)；8.26-8.19(m，2H)；8.14(d，J＝2.0，1H)；8.03-7.96(m，1H)；7.30-7.22(m，1H)；2.89(t，J＝4.4，3H)。

Examples 2 and 3: n2- (2-chloro-4- (2-methyl-2H-tetrazol-5-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine and N2- (2-chloro-4- (1-methyl-1H-tetrazol-5-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine

N2- (2-chloro-4- (2H-tetrazol-5-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine (80mg, 0.22mmol), K2CO3(45mg, 0.32 mm)ol) and methyl iodide (15uL, 0.24mmol) in acetone (2mL) was heated at 40 ℃ for 1 h. The mixture was cooled and filtered. The filtrate was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography (0-100% ethyl acetate/isohexane) to give N2- (2-chloro-4- (2-methyl-2H-tetrazol-5-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine (58mg, 70%). LCMS (10cm _ ESCI _ Formic _ MeCN): [ MH +]385 at 4.31 minutes.¹H NMR(400MHz，CDCl3)：8.76(d，J＝8.7，1H)；8.23-8.19(m，2H)；8.05(dd，J＝8.7，2.0，1H)；7.72(s，1H)；5.29(s，1H)；4.40(s，3H)；3.12(d，J＝4.7，3H)。

The isomer N2- (2-chloro-4- (1-methyl-1H-tetrazol-5-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine was also isolated (10mg, 12%). LCMS (10cm _ ESCI _ Formic _ MeCN): [ MH +]385 at 3.8 minutes.¹H NMR(400MHz，CDCl3)：8.90(d，J＝8.7，1H)；8.24(s，1H)；7.86(d，J＝2.1，1H)；7.79(s，1H)；7.68(dd，J＝8.8，2.1，1H)；5.33(s，1H)；4.22(s，3H)；3.13(d，J＝4.7，3H)。

Example 4: n2- (2-methoxy-4- (1H-1, 2, 4-triazol-1-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine

Step 1: 2-methoxy-4- (1H-1, 2, 4-triazol-1-yl) aniline

A mixture of 4-bromo-2-methoxyaniline (208mg, 1.03mmol), 1, 2, 4-triazole (80mg, 1.13mmol), Cs2CO3(0.67g, 2.06mmol) and CuI (20mg, 0.103mmol) in DMF was heated at 110 ℃ for 20 h. An additional portion of 1, 2, 4-triazole (0.1g, 1.44mmol), Cs2CO3(0.67g, 2.06mmol) and CuI (0.1g, 0.52mmol) was added and the mixture was heated at 110 ℃ for an additional 72 h. The mixture was cooled, diluted with ethyl acetate (20mL) and washed with water (2 × 20 mL). To be combinedThe aqueous washes were re-extracted with ethyl acetate (20 mL). The combined organics were passed through a phase separation cartridge and the solvent was removed under reduced pressure. Purification of the residue by column chromatography on silica gel (0-100% ethyl acetate/isohexane) gave 2-methoxy-4- (1H-1, 2, 4-triazol-1-yl) aniline as a light red solid (92mg, 47%).¹H NMR(400MHz，CDCl3)：8.41(s，1H)；8.05(s，1H)；7.11(d，J＝2.3，1H)；6.99(dd，J＝8.3，2.3，1H)；6.74(d，J＝8.3，1H)；3.97(s，2H)；3.92(s，3H)。

Step 2: n2- (2-methoxy-4- (1H-1, 2, 4-triazol-1-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine

2-chloro-N-methyl-5- (trifluoromethyl) pyrimidin-4-amine (80mg, 0.38mmol), 2-methoxy-4- (1H-1, 2, 4-triazol-1-yl) aniline (72mg, 0.38mmol) and p-toluenesulfonic acid (72mg, 0.38mmol) were added to a solution of di (toluene-p-xylene-co-xylene-ethylene-co-ethylene) and p-toluenesulfonic acid (72mg, 0.38mmol)The mixture in alkane (2mL) was heated at 100 ℃ for 1 h. The mixture was cooled and filtered. The solid was partitioned between dichloromethane (10mL) and saturated aqueous NaHCO3 (10mL) and the product was extracted into dichloromethane (3 × 10 mL). The combined organics were passed through a phase separation cartridge and the solvent was removed under reduced pressure. Purification of the residue via silica gel column chromatography (0-100% ethyl acetate/isohexane) gave a residue, which was triturated with methanol/diethyl ether to give N2- (2-methoxy-4- (1H-1, 2, 4-triazol-1-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine as a white solid (34.5mg, 25%). LCMS (10cm _ ESCI _ Formic _ MeCN): [ MH +]366 at 3.13 minutes.¹H NMR(400MHz，DMSO)：9.29(s，1H)；8.33(d，J＝8.7，1H)；8.24-8.15(m，3H)；7.53(d，J＝2.4，1H)；7.45(dd，J＝8.7，2.4，1H)；7.23(d，J＝5.2，1H)；3.97(s，3H)；2.92(d，J＝4.4，3H)。

Example 5: n2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine

Step 1: n2- (4-bromo-2-methoxyphenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine

2-chloro-N-methyl-5- (trifluoromethyl) pyrimidin-4-amine (0.5g, 2.36mmol), 4-bromo-2-methoxyaniline (0.72g, 0.38mmol) and p-toluenesulfonic acid (0.49g, 2.6mmol) were added to a solution of di (toluene-p-xylene-co-xylene-ethylene-co-xylene-co-ethylene-co-xylene-ethylene-co-ethylene) and toluene-co-xylene-ethylene-coThe mixture in alkane (10mL) was heated at 100 ℃ for 2 h. Cooling the mixture, filtering and dissolving the solid in the solventAnd (5) washing with alkane. The solid was dried in a vacuum oven to give crude N2- (4-bromo-2-methoxyphenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine (1.31g), which was used in the next step without further purification.

Step 2: n2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine

N2- (4-bromo-2-methoxyphenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine (0.365g, 1mmol), Pd (PPh3)4(115mg, 0.1mmol), K2CO3(0.415g, 3mmol) and 1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.415g, 2mmol) in bisA mixture of alkane (10mL) and water (1.25mL) was degassed under a stream of nitrogen for 10 minutes. The reaction tube was sealed and the mixture was irradiated in a microwave for 20 minutes at 100 ℃. The mixture was cooled and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (20mL) and water (20mL) and the product was extracted into ethyl acetate (2 × 20 mL). The combined organics were passed through a phase separation cartridge and the solvent was removed under reduced pressure. Purification of the residue via silica gel column chromatography (0-100% ethyl acetate/isohexane) gave a residue, which was triturated with diethyl ether to give N2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine as an off-white solid (94mg, 25%). LCMS (10cm _ ESCI _ Formic _ MeCN): [ MH +]379, at 3.11 minutes.¹H NMR(400MHz，CDCl₃)：8.49(d，J＝8.4，1H)；8.17(s，1H)；7.76-7.68(m，2H)；7.58(s，1H)；7.10(dd，J＝8.4，1.9，1H)；6.98(d，J＝1.9，1H)；5.20(s，1H)；3.95(s，6H)；3.12(d，J＝4.7，3H)。

Example 6: n2- (5-fluoro-2-methoxy-4- (3-methyl-1, 2, 4-)Oxadiazol-5-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine

Step 1: 2-fluoro-5-methoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) benzoic acid

2-fluoro-5-methoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) benzoic acid was prepared by the procedure described in example 5, step 1 using 4-amino-2-fluoro-5-methoxybenzoic acid (1.35g, quantitative).

Step 2: n2- (5-fluoro-2-methoxy-4- (3-methyl-1, 2, 4-)Oxadiazol-5-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine

A mixture of 2-fluoro-5-methoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) benzoic acid (0.1g, 0.28mmol), HATU (127mg, 0.33mmol), and DIPEA (60uL, 6.33mmol) in DMF (2mL) was stirred at room temperature for 5 minutes. N' -hydroxyethylamidine (25mg, 0.33mmol) was added and the mixture was stirred at room temperature for 30 minutes, then at 100 ℃ for 18 h. Additional HATU (127mg, 0.33mmol), DIPEA (60uL, 6.33mmol) and N' -hydroxyacetamidine (25mg, 0.33mmol) were added and the reaction heated at 100 ℃ for an additional 8 h. The mixture was cooled and diluted with ethyl acetate (10 mL). The organic layer was washed with saturated aqueous NaHCO3 (2x5mL) and the combined aqueous washes were extracted with additional ethyl acetate (2x10 mL). The combined organics were passed through a phase separation cartridge and the solvent was removed under reduced pressure. Purification of the residue by column chromatography on silica gel (0-100% ethyl acetate/isohexane) gave N2- (5-fluoro-2-methoxy-4- (3-methyl-1, 2, 4-Oxadiazol-5-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine as a white solid (16mg, 15%). LCMS (10em _ ESCI _ Formic _ MeCN): [ MH +]399 at 4.51 minutes.¹H NMR(400MHz，CDCl3)：8.67(d，J＝13。，1H)；8.23(s，1H)；8.01(s，1H)；7.48(d，J＝6.1，1H)；5.33(s，1H)；4.00(s，3H)；3.16(d，J＝4.7，3H)；2.51-2.44(m，3H)。

Example 7: n2- (2-chloro-5-methoxy-4- (5-methyl-1, 3, 4-)Oxadiazol-2-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine

Step 1: 5-chloro-2-methoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) benzoic acid

5-chloro-2-methoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) benzoic acid (1.01g, quantitative) was prepared by the procedure described in example 5, step 1 using 4-amino-5-chloro-2-methoxybenzoic acid.

Step 2: n' -acetyl-5-chloro-2-methoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) benzoylhydrazines

A suspension of 5-chloro-2-methoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) benzoic acid (144mg, 50% pure, 0.19mmol), HATU (85mg, 0.22mmol), acetohydrazide (16mg, 0.22mmol) and DIPEA (81uL, 0.46mmol) in dichloromethane (4mL) was stirred at room temperature for 18 h. The mixture was diluted with dichloromethane (10mL) and washed with saturated aqueous NaHCO3 solution (10 mL). The solids remain in the aqueous layer; it was filtered, washed with water and suspended in methanol. The solid was collected by filtration and dried in a vacuum oven to give N' -acetyl-5-chloro-2-methoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) benzoyl hydrazine as a white solid (68mg, 85%). It was passed through the next step without further purification.

And step 3: n2- (2-chloro-5-methoxy-4- (5-methyl-1, 3, 4-)Oxadiazol-2-yl) phenyl) -N4-methyl-5- (trifluoro-phenyl)Methyl) pyrimidine-2, 4-diamines

A mixture of N' -acetyl-5-chloro-2-methoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) benzoylhydrazine (68mg, 0.16mmol) and 1-methoxy-N-triethylammoniumsulfonyl-methanimine (Burgess reagent) (75mg, 0.32mmol) in THF (4mL) was irradiated in a microwave at 150 ℃ for 30 minutes. An additional portion of Burgess reagent (75mg, 0.32mmol) was added and the reaction was irradiated in the microwave for an additional 30 minutes at 150 ℃. The reaction mixture was concentrated and the crude residue was purified by silica gel column chromatography (0-100% ethyl acetate/isohexane) to give a residue, which was triturated with diethyl ether/methanol to give N2- (2-chloro-5-methoxy-4- (5-methyl-1, 3, 4-Oxadiazol-2-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine as a white solid (28mg, 43%). HPLC (15cm _ Formic _ Ascentis _ HPLC _ CH3 CN): at9.15 minutes. LCMS (10cm _ ESCI _ Formic _ MeCN): [ MH +]415 at 4.00 minutes.¹HNMR(400MHz，CDCl₃)：8.62(s，1H)；8.25(s，1H)；7.95(s，1H)；7.80(s，1H)；5.34(s，1H)；4.01(s，3H)；3.15(d，J＝4.7，3H)；2.61(s，3H)。

Example 8: n2- (2-methoxy-4- (1-methyl-1H-imidazol-5-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine

N2- (4-bromo-2-methoxyphenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine (0.151g, 0.4mmol), Pd (dppf) C12(33mg, 0.04mmol) and 1-methyl-5- (tributylstannyl) -1H-imidazole (2)97mg, 0.8mmol) in twoThe mixture in alkane (5mL) was degassed under a stream of nitrogen for 10 minutes. The reaction tube was sealed and heated at 100 ℃ over the course of 18 hours. The mixture was cooled and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (20mL) and water (20mL) and the product was extracted into ethyl acetate (2 × 20 mL). The combined organics were passed through a phase separation cartridge and the solvent was removed under reduced pressure. Purification of the residue via preparative HPLC gave N2- (2-methoxy-4- (1-methyl-1H-imidazol-5-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine as an off-white solid (64mg, 42%). LCMS (10cm _ ESCI _ BicaRb _ MeCN): MH +]379, at 3.59 minutes.¹H NMR(400MHz，DMSO)：8.33(d，J＝8.3，1H)；8.21(s，1H)；8.10(s，1H)；7.72(s，1H)；7.23(d，J＝5.2，1H)；7.16-7.07(m，3H)；3.95(s，3H)；3.74(s，3H)；2.96(d，J＝4.3，3H)。

Example 9: n2- (4-methoxy-6- (thiazol-5-yl) pyridin-3-yl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine

Step 1: 6-chloro-4-methoxypyridin-3-amine

A mixture of 2-chloro-4-methoxy-5-nitropyridine (208mg, 1.10mmol), ammonium chloride (295mg, 5.52mmol) and iron powder (246mg, 4.41mmol) in ethanol (5mL) and water (0.5mL) was heated at 80 ℃ for 18 h. The mixture was cooled and filtered through a celite cartridge and washed by washing with methanol. The combined filtrate and washings were evaporated and the residue was partitioned between DCM (10mL) and water (10mL), the organic phase was further washed with water (10mL) and the aqueous washes were combined and extracted with DCM (3 × 5 mL). The organic extracts were combined and filtered through a hydrophobic frit and the solvent was removed by evaporation to give the product as an off-white solid (155mg, 89%). 1HNMR (400MHz, CDCl 3): 7.73(s, lH); 6.71(s, 1H); 3.90(s, 3H); 3.71(s, 2H).

Step 2: n2- (6-chloro-4-methoxypyridin-3-yl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine

2-chloro-N-methyl-5- (trifluoromethyl) pyrimidin-4-amine (211mg, 1mmol), 6-chloro-4-methoxypyridin-3-amine (150mg, 0.95mmol) and p-toluenesulfonic acid (190mg, 1mmol) were added to 1, 4-bisThe mixture in alkane (2mL) was heated at 100 ℃ for 1 h. The mixture was cooled and filtered, and the solid was purified byThe alkane was washed and dried in vacuo to afford the product as an opalescent solid (436mg, > 100%).¹H NMR(400MHz，DMSO)：9.82(s，1H)；8.76(s，1H)；8.44(s，2H)；7.38(s，1H)；4.00(s，3H)；2.99-2.92(m，3H)。

And step 3: n2- (4-methoxy-6- (thiazol-5-yl) pyridin-3-yl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine

N2- (4-methoxy-6- (thiazol-5-yl) pyridin-3-yl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine was prepared by the procedure described in example 7 using N2- (6-chloro-4-methoxypyridin-3-yl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine and 5- (tributylstannyl) thiazole. LCMS (10cm _ ESCI _ Formic _ MeCN): [ MH +]383 at 2.60 minutes.¹H NMR(ppm)(CDCl3)：9.65(1H，s)，8.9(1H，d，J＝2.1)，8.2(1H，d，J＝1.1)，8.1(1H，d，J＝2.1)，7.75(1H，s)，7.55(1H，s)，5.27(1H，s)，4.1(3H，s)，3.2(3H，d，J＝4.7)。

Example 10: 5-chloro-N2- (2-methoxy-4- (1-methyl-1H-tetrazol-5-yl) phenyl) -N4-methylpyrimidine-2, 4-diamine

Step 1: 4-amino-3-methoxy-N-methylbenzamide

4-amino-3-methoxy-N-methylbenzamide was prepared by the procedure described in example 7 using 4-amino-3-methoxybenzoic acid and methylamine hydrochloride.

Step 2: 4- (5-chloro-4- (methylamino) pyrimidin-2-ylamino) -3-methoxy-N-methylbenzamide

4- (5-chloro-4- (methylamino) pyrimidin-2-ylamino) -3-methoxy-N-methylbenzamide was prepared by the procedure described in example 7 using 4-amino-3-methoxy-N-methylbenzamide and 2, 5-dichloro-N-methylpyrimidin-4-amine.¹H NMR(ppm)(CDCl3)：8.58(1H，d，J＝8.4)，7.95-7.92(1H，m)，7.70(1H，s)，7.45(1H，d，J＝1.9)，6.09(1H，s)，5.30(1H，s)，4.03-3.95(3H，m)，3.15-3.09(3H，m)，3.02(3H，t，J＝4.8)。

And step 3: 5-chloro-N2- (2-methoxy-4- (1-methyl-1H-tetrazol-5-yl) phenyl) -N4-methylpyrimidine-2, 4-diamine

A mixture of 4- (5-chloro-4- (methylamino) pyrimidin-2-ylamino) -3-methoxy-N-methylbenzamide (112mg, 0.35mmol) and 2-pyridyldiphenylphosphine (373mg, 1.42mmol) was washed with N2 for 10 minutes. After addition of anhydrous THF (2mL), diisopropyl azodicarboxylate (0.28mL, 1.42mmol) was added dropwise. Diphenylphosphoryl azide (0.31mL, 1.42mmol) was added dropwise over 5 minutes. The mixture was heated at 45 ℃ under N2 for 18 h. The mixture was diluted with ethyl acetate (20mL) and washed with saturated sodium bicarbonate solution (2 × 10 mL). The combined aqueous washes were back-extracted with ethyl acetate (10mL) and the combined organic extracts were filtered through a hydrophobic frit and evaporated. Purification of the residue via silica gel column chromatography (0-100% ethyl acetate/isohexane) followed by trituration with diethyl ether gave 5-chloro-N2- (2-methoxy-4- (1-methyl-1H-tetrazol-5-yl) phenyl) -N4-methylpyrimidine-2, 4-diamine as a white solid (45mg, 38%). LCMS (10cm _ ESCI _ BicaRb _ MeCN): [ MH +]347 at 2.67 minutes.¹H NMR(400MHz，CDCl3)：8.76(d，J＝8.5，1H)；7.96(s，1H)；7.75(s，1H)；7.40(d，J＝1.9，1H)；7.3(d，J＝2.0，1H)；5.35(s，1H)；4.21(s，3H)；4.00(s，3H)；3.13(d，J＝4.9，3H)。

Example 11: n2- (2-chloro-5-methoxy-4- (1-methyl-1H-1, 2, 3-triazol-5-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine

N2- (4-bromo-2-chloro-5-methoxyphenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine (50mg, 0.12mmol), 1-methyl-5- (tributylstannyl) -1H-1, 2, 3-triazole (68mg, 0.18mmol) and Pd (dppf)2C12(10mg, 0.012mmol) in dioxaneThe mixture in alkane (4mL) was degassed under a stream of nitrogen for 10 minutes. The reaction mixture was heated to 100 ℃ for 18h. Additional amounts of 1-methyl-5- (tributylstannyl) -1H-1, 2, 3-triazole (68mg, 0.18mmol) and Pd (dppf)2C12(10mg, 0.012mmol) were added and the mixture was held at 100 ℃ for an additional 24H, after which additional amounts of 1-methyl-5- (tributylstannyl) -1H-1, 2, 3-triazole (68mg, 0.18mmol) and Pd (dppf)2C12(10mg, 0.012mmol) were added. The mixture was kept at 100 ℃ for another 48 h. The mixture was cooled and concentrated to dryness in vacuo, and the residue was partitioned between DCM and water. The separated organic phase is concentrated to dryness in vacuo and the residue is purified by RP-HPLC; the product was isolated as a milky solid (22mg, 44%). LCMS (ESCI _ Formic _ MeCN): [ MH +]414 at 3.45 minutes.¹H NMR(DMSO-d6)：8.58(s，1H)；8.16(s，1H)；7.98(s，1H)；7.71(s，1H)；7.42(s，1H)；7.24(d，J＝5.1，1H)；3.82(s，3H)；3.76(s，3H)；2.87(d，J＝4.4，3H)。

The compounds in the above examples, together with further compounds prepared using the same procedure, are given below in table 3 together with LRRK2Ki values (micromolar).

TABLE 3

Example 12 in vitro LRRK2LabChip assay

The assay is used to determine Ki_app、IC₅₀Or percent inhibition value to determine the efficacy of the compound in inhibiting the activity of LRRK 2. In polypropylene plates, LRRK2, fluorescently labeled peptide substrate, ATP, and test compound were incubated together. Using LabChip3000(Caliper Life Sciences), after the reaction, the substrate was separated into two populations by capillary electrophoresis: phosphorylated and unphosphorylated. The relative amounts of each are quantified by fluorescence intensity. LRRK2Ki is determined according to the following equation:

Y＝V0*(1-((x+Ki*(1+S/Km)+Et)/(2*Et)-(((x+Ki*(1+S/Km)+Et)^2-(4*Et*x))^0.5)/(2*Et)))。

ki values in table 4 and elsewhere herein are shown in μ tM.

The assay conditions and materials used were as follows:

final assay conditions：

LRRK2G2019S at 5mM MgCl₂The method comprises the following steps: 5.2nM (Invitrogen lot #567054A)

LRRK2G2019S at 1mM MnCl₂The method comprises the following steps: 11nM (Invitrogen lot #567054A)

LRRK2 wild type at 5mM MgCl₂The method comprises the following steps: 15nM (Invitrogen lot #500607F)

LRRK212020T at 5mM MgCl₂The method comprises the following steps: 25nM (Invitrogen #43594)

ATp ^app Kms：

Material：

Solid carrier: black 50 μ L volume polypropylene 384 well plate (Matrical cat # MP101-1-PP)

Kinase enzymes: LRRK2G2019S (Invitrogen cat # PV 4882). LRRK2 wild type (Invitrogen cat # PV 4874).

Substrate: 5FAM-GAGRLGRDKYKTLRQIRQ-CONH₂

A non-bonded plate: a384 well clear V-bottom polypropylene plate (Greiner cat # 781280).

ATP：10mM ATP(Cell Signaling cat#9804)。

Triton X-100：Triton X-100。

Brij-35：Brij-35(Pierce cat#20150)。

Coating reagent # 3: coating reagent #3 (Caliper).

DMSO：DMSO(Sigma cat#34869-100ML)。

Complete reaction buffer: h₂O/25mM Tris，pH8.0/5mM MgCl₂/2mMDTT/0.01％Triton X-100。

Stopping liquid: h₂O/100mM HEPES, pH 7.2/0.015% Brij-35/0.2% coating reagent #3/20mM EDTA.

Separating buffer solution: h₂O/100mM HEPES, pH 7.2/0.015% Brij-35/0.1% coating reagent # 3/1: 200 coating reagent #8/10mM EDTA/5% DMSO.

Compound plate preparation:

for serial dilutions, 34.6. mu.l DMSO was added to columns 3-24. For assay controls, 37.5 μ l DMSO was added to columns 1 and 2 of rows A and P, and 50 μ l25 μ MG-028831(Staurosporine) was added to columns 1 and 2 of row B. For the samples: starting at 100. mu.M, 37.5. mu.l DMSO was added to columns 1 and 2, followed by 12.5. mu.l of 10mM compound; starting at 10. mu.M, 78. mu.l DMSO was added to columns 1 and 2, followed by 2. mu.l of 10mM compound; and starting at 1. mu.M, 25. mu.M compound (2. mu.l 10mM compound + 798. mu.l DMSO) was added to empty columns 1 and 2. Using precision instruments to perform 1: 3.16 Serial dilutions ("PLK _ BM _ serial _ halflog").

ATP preparation：

ATP was diluted to 282.1. mu.M (final concentration of 130. mu.M) in complete kinase buffer.

Bulk and blank preparation：

In complete reaction buffer, the substrate was diluted to 4 μ M. Equal volumes of complete reaction buffer and 4 μ M substrate were combined to obtain a blank. Equal volumes of complete reaction buffer and 4 μ M substrate were combined and 2X final LRRK2 concentration was added to the combined solution.

Measurement procedure：

To a 50. mu.l polypropylene plate, 5. mu.l/well buffer/substrate was added by hand to the blank well. The kinase reaction ("PLK SAR23 ATP") was initiated using Biomek FX. The following were added to the appropriate wells:

2 μ l compound +23 μ l ATP;

5 μ l/well compound/ATP in assay plate;

5 μ l/well kinase/substrate in assay plate;

the plates were incubated for 2 hours in the dark. The kinase reaction ("PLK Stop") was stopped using Biomek FX and 10. mu.l/well Stop solution was added to the assay plate. The results were read on a LabChip 3000.

Lab Chip3000 protocol：

The LabChip3000 was run using the work "LRRK 2IC 50" with the following work settings:

example 13 in vitro LRRK2Lanthascreen binding assay

The assay is used to determine Ki_app、IC₅₀Or percent inhibition value to determine the efficacy of the compound in inhibiting the activity of LRRK 2. LRRK2, Eu-anti-GST-antibody, Alexa in 384-well microwell plate F black (proteoplates Fblack) shallow well platesThe Kinase tracer 236 was incubated with the test compound.

Detection of Alexa by addition of Eu-labeled anti-GST antibodyBinding of a "tracer" to a kinase. Binding of the tracer and antibody to the kinase brings about a high degree of FRET, whereas displacement of the tracer by the kinase inhibitor results in loss of FRET.

The assay conditions and materials used were as follows:

final assay conditions：

Material：

384 well microwell plate F (propiplates F) Black light well plate Perkin Elmer cat #6008260

Reaction buffer solution: h₂O/50mM Tris，pH7.4/10mM MgCl₂/1mM EGTA/0.01％Brij35。

Compound plate preparation:

test compounds (10mM starting material) were serially diluted 1: 3.16(20ul +43.2ul) in 100% DMSO. 12pt curve. Each concentration was 1: 33.3(3ul +97ul) diluted in reaction buffer. 5ul was printed onto the assay plate. The final highest concentration tested was 100 uM.

Bulk and blank preparation：

In the reaction buffer, 5ul of DMSO (3%) was added to the bulk and blank wells and 5ul of Eu-labeled anti-GST antibody (6nM) was added to the blank wells.

Measurement procedure：

5ul of LRRK2(30 nM)/Eu-labeled anti-GST antibody (6nM) mix was added to the compounds and all wells. To all wells 5ul of kinase tracer (25.5nM) was added. The plates were incubated at room temperature for 1 hour on a plate shaker (gently shaking). Read according to the Perkin Ehner EnVision reader HTRF protocol.

Data processing:

calculating the proportion: (665/620)*10000. The average background value was subtracted from all data points. The% of control was calculated for each test value. The% of control is plotted against compound concentration. Ki values were calculated (xlfit curve fitting-Morrison equation).

The results are expressed as Ki in μ tM. The formula for Ki is: Y-V0 (1- ((x + Ki (1+ S/Km) + Et)/(2 Et) - ((x + Ki (1+ S/Km) + Et) ^2- (4 Et x)) > 0.5)/(2 Et)))

Wherein Et is 4nM

kd (tracer) ═ 8.5nM

Tracer concentration (S) 8.5 nM.

Example 14 animal models of Parkinson's disease

Parkinson's disease can replicate in mice and primates by administering 1-methyl-4-phenyltetrahydropyridine (MPTP), a selective nigrostriatal dopaminergic neurotoxin that produces a loss of striatal Dopamine (DA) nerve terminal markers. The efficacy of the compounds of the invention in the treatment of Parkinson's disease can be evaluated using MPTP-induced neurodegeneration, generally in accordance with the protocol described by Saponito et al, J.Pharmacology (1999) Vol.288, pp.421-427.

Briefly, MPTP was dissolved in PBS at a concentration of 2-4mg/ml and mice (male C57, 20-25g in weight) were injected subcutaneously with 20-40 mg/kg. The compounds of the invention were solubilized with polyethylene glycol hydroxystearate and dissolved in PBS. Mice were given a 10ml/kg solution of the compound by subcutaneous injection 4 to 6h prior to MPTP administration, and then daily for 7 days. On the day of the last injection, mice were sacrificed and the midbrain was blocked and postfixed (postfix) in paraformaldehyde. Striatum was cut, weighed and stored at-70 ℃.

The striatum thus collected was evaluated for its content of dopamine and its metabolites dihydroxyphenylacetic acid and homovanillic acid by HPLC with electrochemical detection as described by Sonsalla et al, J.Pharmacol.Exp.Ther. (1987) Vol.242, pp.850-857. The striatum may also be assayed using the tyrosine hydroxylase of Okunu et al, Anal Biochem (1987) Vol.129, pp.405-411, by measuring the tyrosine hydroxylase-mediated conversion of labeled tyrosine to L-dopa¹⁴CO₂The deposition was evaluated. Striatum may also be oxidized using monoamines as described by White et al, Life Sci, (1984), Vol.35, pp.827-833enzyme-B assay and evaluation by detecting dopamine uptake as described by Saponito et al, (1992) Vol.260, pp.1400-1409.

While the invention has been described with reference to specific embodiments thereof, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process step or steps, to the objective spirit and scope of the present invention. All such modifications are intended to be within the scope of the appended claims.

Claims

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof,

wherein:

m is 0 to 3;

x is: -NRa-, wherein Ra is hydrogen or C1-6 alkyl;

y is C or N;

r1 is: c1-6 alkyl; r2 is: halogenating; c1-6 alkoxy; a cyano group; halo-C1-6 alkyl; or halo-C1-6 alkoxy; r3 and R4 are each independently: halogenating; c1-6 alkyl; c1-6 alkoxy; halo-C1-6 alkyl; or halo-C1-6 alkoxy; and is

R6 is: c1-6 alkyl; halogenating; halo-C1-6 alkyl; c1-6 alkoxy; an azetidinyl group; or-C (O) -NRbRc, wherein Rb and Rc are each independently hydrogen or-C1-6 alkyl.

2. The compound of claim 1, wherein X is-NH-.

3. The compound of any one of claims 1-2, wherein R1 is methyl or ethyl.

4. The compound of any one of claims 1-2, wherein R2 is: halogenating; halo-C1-6 alkyl; or a cyano group.

5. The compound of any one of claims 1-2, wherein R2 is chloro or trifluoromethyl.

6. The compound of any one of claims 1-2, wherein R3 is halo or C1-6 alkoxy.

7. The compound of any one of claims 1-2, wherein R3 is methoxy.

8. The compound of any one of claims 1-2, wherein m is 0 or 1.

9. The compound of any one of claims 1-2, wherein R4 is halo or methoxy.

10. The compound of any one of claims 1-2, wherein R5 is: a pyrazolyl group; an imidazolyl group;a diazolyl group; a thiadiazolyl group; a triazolyl group; or a tetrazolyl group; each of which is optionally substituted one or more times with R6.

11. The compound of any one of claims 1-2, wherein R5 is: a pyrazolyl group;a diazolyl group; a triazolyl group; or a tetrazolyl group; each of which is optionally substituted one or more times with R6.

12. The compound of any one of claims 1-2, wherein R5 is:a diazolyl group; a triazolyl group; or a tetrazolyl group; each optionally substituted one or more times with R6.

13. The compound of any one of claims 1-2, wherein R5 is pyrazolyl optionally substituted one or more times with R6.

14. The compound of any one of claims 1-2, wherein R5 isA diazolyl group; a thiadiazolyl group; a triazolyl group; or a tetrazolyl group; which is optionally substituted one or more times by R6.

15. The compound of any one of claims 1-2, wherein R5 is triazolyl optionally substituted one or more times with R6.

16. The compound of any one of claims 1-2, wherein R5 is tetrazolyl optionally substituted one or more times with R6.

17. The compound of any one of claims 1-2, wherein R5 is: 1-methyl-1H-imidazol-2-yl; 1-methyl-1H-imidazol-5-yl; 1, 3, 5-trimethyl-1H-pyrazol-4-yl; 1-methyl-1H-pyrazol-5-yl; 1-methyl-1H-pyrazol-4-yl; 1, 3-dimethyl-1H-pyrazol-4-yl; 1, 5-dimethyl-1H-pyrazol-4-yl; 5- (dimethylaminocarbonyl) -1-methyl-1H-pyrazol-4-yl; 1- (oxetan-3-yl) -1H-pyrazol-4-yl; 1-methyl-1H-1, 2, 3-triazol-5-yl; 1H-1, 2, 4-triazol-1-yl; 4-methyl-4H-1, 2, 4-triazol-3-yl; 5-methyl-1, 3, 4-Oxadiazol-2-yl; 3-methyl-1, 2, 4-Oxadiazol-5-yl; 1-methyl-1H-tetrazol-5-yl; 2-methyl-2H-tetrazol-5-yl; 1H-tetrazol-1-yl; 2H-tetrazol-5-yl; or 5-methyl-1H-tetrazol-1-yl.

18. A compound selected from the group consisting of:

N2-(5-fluoro-2-methoxy-4- (5-methyl-1, 3, 4-)Oxadiazol-2-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine,

n2- (2-methoxy-4- (5- (methoxymethyl) -3-methyl-1H-pyrazol-1-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine, and

19. A pharmaceutical composition comprising:

(a) a pharmaceutically acceptable carrier; and

(b) the compound of claim 1.

20. The pharmaceutical composition according to claim 19, wherein the pharmaceutical composition is for the prevention or treatment of parkinson's disease.

21. The use of a compound of formula I according to any one of claims 1 to 17 for the preparation of a medicament for the prevention or treatment of parkinson's disease.