Use of LRRK2 inhibitors for neurodegenerative diseases

The present invention relates to a novel use of a class of kinase inhibitors, including pharmaceutically acceptable salts, prodrugs and metabolites thereof, which are useful for modulating protein kinase activity. More specifically the invention provides compounds which inhibit, regulate and/or modulate kinase activity, in particular LRRK2 activity for use in a method of treating or preventing diseases and disorders associated with LRRK2 such as

Parkinson's Disease and Alzheimer's Disease. The invention further relates to processes for preparing said compounds.

Parkinson's disease (PD) is a heterogeneous movement disorder characterized by the degeneration of dopaminergic neurons within the substancia nigra of the basal ganglia. It affects 2% of the population over 60 years.

Current therapeutic strategies for PD focus primarily on reducing the severity of its symptoms using dopaminergic medications. Levodopa (L-dopa or L-3,4-dihydroxyphenylalanine), an immediate precursor of dopamine, is the most commonly prescribed drug for the treatment of this disease. Although providing benefit to patients, these medications display adverse side effects and may become ineffective after prolonged treatment (wearing off effect). None of these treatments addresses the underlying problem, the progressive loss of dopaminergic neurons.

Broadly, there are two clinicopathological components of PD. First, there is clinically defined parkinsonism, a syndromic term which comprises the cardinal features of the Parkinsonian movement disorder. These are a resting tremor, bradykinesia (slowness of movement), rigidity and postural instability, all problems in initiating or stopping movements. Their pathological correlate is the loss of dopaminergic neurons in the substancia nigra. Second,

Parkinson's disease is marked postmortem by the presence of Lewy bodies and Lewy neurites in surviving neurons. These are intracellular aggregations of lipids and proteins including ubiquitin and alpha-synuclein. Pathological definitions of PD require the presence of alpha-

synuclein-positive Lewy pathology in surviving nigral neurons, combined with nigral cell loss and intact striatal neurons (Cookson, 2005. Annual Reviews in Biochemistry 74, 29-52).

Genetic evidence has recently been presented that mutations of the Leucine-rich repeat kinase 2 (LRRK2, synonym Dardarin) cause autosomal dominant PD previously linked to the

PARK8 locus. LRRK2 mutations are estimated to account for 5 to 6% of PD cases with a positive family history, and were also identified in sporadic cases. LRRK2 encodes a large multi-domain protein that consists of N-terminal leucine-rich repeats, a GTPase ROC/COR domain, a mitogen-activated protein kinase kinase kinase (MAPKKK) and C-terminal WD40 repeats (Paisan-Ruiz et al, 2004. Neuron 44, 595-600; Zimprich et al, 2004. Neuron 44, 601-

607).

LRRK2 encodes a protein kinase and is capable of autophosphorylation (West et al., 2005. PNAS 102, 16842-16847, Gloeckner, et al., 2005. Hum. MoI. Genet. 15, 223-232). Significantly, three PD-associated LRRK2 mutations, two in the kinase domain (G2019S and I2020T) and one in the ROC/COR GTPase domain (R1441 C) increase LRRK2 autophosphorylation, suggesting a dominant gain-of- function mechanism. Indeed, overexpression of R1441C, Y1699C or G2019S mutants of LRRK2 is sufficient to induce neuronal degeneration in mouse primary cortical neurons (Smith et al., 2005. PNAS 102, 18676-18681).

Moreover, manipulating the kinase activity of LRRK2 by replacing the kinase domain with a "kinase-dead" mutated version blocks the formation of inclusion bodies and delays cell death, two cellular phenotypes of PD (Greggio et al., 2006. Neurobiol. Dis. 23(2), 329-341). This observation suggets that kinase inhibitors will be useful therapeutic agents for patients with LRRK2 mutations and presuambly also sporadic PD.

The recent discovery that LRRK2 mutations lead to late-onset PD with pleomorphic pathology, including alpha-synuclein, tau and ubiquitin pathology places LRRK2 upstream in a common neurodegenerative pathway for parkinsonism. Thus, LRRK2 has become an attractive therapeutic target for intervention and neuroprotection in Parkinson's disease (Taylor et al., 2006. Trends in Molecular Medicine 12, 76-82).

In view of the above, there is a need for providing LRRK2 inhibitors.

Thus, an object of the present invention is to provide compounds as kinase inhibitors, especially LRRK2 inhibitors which may be effective in the treatment or prophylaxes of neurodegenerative diseases or other diseases or disorders associated with LRRK2.

Accordingly, the present invention provides compounds of formula (I)

or a pharmaceutically acceptable salt, prodrug, metabolite, or pharmaceutical composition thereof, wherein

R ¹ , R ² , R ³ are independently selected from the group consisting of H; halogen; CN; C(O)OR ¹⁰ ; OR ¹⁰ ; C(O)R ¹⁰ ; C(O)N(R ¹⁰ R ^10a ); S (O) ₂ N(R ¹⁰ R ^{1 Oa} ); S (O)N(R ¹⁰ R ^{1 Oa} ); S(O) ₂ R ¹⁰ ; S(O)R ¹⁰ ; SR ¹⁰ ; N(R ¹⁰ R ^10a ); NO ₂ ; OC(O)R ¹⁰ ; N(R ¹⁰ )C(O)R ^10a ; N(R ¹⁰ )S(O) ₂ R ^10a ; N(R ¹⁰ )S(O)R ^10a ; N(R ¹⁰ )C(O)N(R ^10a R ^10b ); N(R ¹⁰ )C(O)OR ^10a ; OC(O)N(R ¹⁰ R ^10a ); Ci _-6 alkyl; C ₂ - 6 alkenyl; C ₂ _6 alkynyl; and T, wherein Ci_6 alkyl; C ₂ _6 alkenyl; and C ₂ _6 alkynyl are optionally substituted with one or more R ¹¹ , which are the same or different;

Optionally, one of the pairs RVR ² and R ² /R ³ is joined together with the phenyl ring to which it is attached to form a bicyclic ring T ¹ ;

R ¹⁰ , R ^1Oa , R ^10b are independently selected from the group consisting of H; T; Ci_6 alkyl; C ₂ _6 alkenyl; and C ₂ _6 alkynyl, wherein Ci_6 alkyl; C ₂ _6 alkenyl; and C ₂ _6 alkynyl are optionally

I ₂ substituted with one or more R , which are the same or different;

R , 1 1 , T Rj _{1 2} are independently selected from the group consisting of T; halogen; CN; C(O)OR 13 ;. OR ¹³ ; C(O)R ¹³ ; C(O)N(R ¹³ R ^13a ); S(O) ₂ N(R ¹³ R ^13a ); S(O)N(R ¹³ R ^13a ); S(O) ₂ R ¹³ ; S(O)R ¹³ ; SR ¹³ ;

N(R ¹³ R ^13a ) N O ₂ OC(O)R , 1 ¹ 3. N(R ¹³ )C(O)R ^13a ; N(R ¹³ )S(O) ₂ R ^13a ; N(R ¹³ )S(O)R ^13a ; N(R ¹³ )C(O)N(R ^13a R ^13b ); N(R ¹³ )C(O)OR ^13a ; OC(O)N(R ¹³ R ^13a ); Ci _-6 alkyl; C ₂ - ₆ alkenyl; and C ₂ _6 alkynyl, wherein Ci_6 alkyl; C ₂ _6 alkenyl; and C ₂ _6 alkynyl are optionally substituted with one or more halogen, which are the same or different;

R ¹³ , R ^13a , R ^13b are independently selected from the group consisting of H; Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;

T is phenyl; C3_7 cycloalkyl; or 4 to 7 membered heterocyclyl, wherein T is optionally substituted with one or more R ¹⁴ , which are the same or different;

T ¹ is naphthyl; indenyl; indanyl; or 9 to 11 membered benzo-fused heterobicyclyl, wherein T ¹ is optionally substituted with one or more R ¹⁵ , which are the same or different;

R ¹⁴ , R ¹⁵ are independently selected from the group consisting of halogen; CN; C(O)OR ¹⁶ ;

OR ¹⁶ ; oxo (=0), where the ring is at least partially saturated; C(O)R ¹⁶ ; C(O)N(R ¹⁶ R ^16a );

S(O) ₂ N(R ¹⁶ R ^16a ); S(O)N(R ¹⁶ R ^16a ); S(O) ₂ R ¹⁶ ; S(O)R ¹⁶ ; SR ¹⁶ ; N(R ¹⁶ R ^16a ); NO ₂ ; OC(O)R ¹⁶ ;

N(R ¹⁶ )C(O)R ^16a ; N(R ¹⁶ )S(O) ₂ R ^16a ; N(R ¹⁶ )S(O)R ^16a ; N(R ¹⁶ )C(O)N(R ^16a R ^16b ); N(R ¹⁶ )C(O)OR ^16a ; OC(O)N(R ¹⁶ R ^16a ); Ci _-6 alkyl; C ₂ - ₆ alkenyl; and C ₂ - ₆ alkynyl, wherein Ci _-6 alkyl; C ₂ -6 alkenyl; and C ₂ -6 alkynyl are optionally substituted with one or more halogen, which are the same or different;

R ¹⁶ , R ^16a , R ^16b are independently selected from the group consisting of H; Ci_6 alkyl; C ₂ -6 alkenyl; and C ₂ -6 alkynyl, wherein Ci_6 alkyl; C ₂ -6 alkenyl; and C ₂ -6 alkynyl are optionally substituted with one or more halogen, which are the same or different;

One of R ⁴ R ^4a is X ¹ and the other is H;

R ⁵ , R ⁶ , R ⁷ are independently selected from the group consisting of H; halogen; CN;

C(O)OR ¹⁷ ; OR ¹⁷ ; C(O)R ¹⁷ ; C(O)N(R ¹⁷ R ^17a ); S (O) ₂ N(R ¹⁷ R ^17a ); S (O)N(R ¹⁷ R ^17a ); S(O) ₂ R ¹⁷ ;

S(O)R ¹⁷ ; SR ¹⁷ ; N(R ¹⁷ R ^17a ); NO ₂ ; OC(O)R ¹⁷ ; N(R ¹⁷ )C(O)R ^17a ; N(R ¹⁷ )S(O) ₂ R ^17a ;

N(R ¹⁷ )S(O)R ^17a ; N(R ¹⁷ )C(O)N(R ^17a R ^17b ); N(R ¹⁷ )C(O)OR ^17a ; OC(O)N(R ¹⁷ R ^17a ); Ci _-6 alkyl; C ₂ -

₆ alkenyl; C ₂ -6 alkynyl; and T ² , wherein Ci_6 alkyl; C ₂ -6 alkenyl; and C ₂ -6 alkynyl are optionally substituted with one or more R ¹⁸ , which are the same or different;

Optionally, one of the pairs R ⁵ /R ⁶ , R ⁶ /R ⁷ is joined together with the phenyl ring to which it is attached to form a bicyclic ring T ;

R ¹⁷ , R ^17a , R ^17b are independently selected from the group consisting of H; T ² ; Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more R ¹⁹ , which are the same or different;

R ¹⁸ , R ¹⁹ are independently selected from the group consisting of T ² ; halogen; CN; C(O)OR ²⁰ ; OR ²⁰ ; C(O)R ²⁰ ; C(O)N(R ²⁰ R ^20a ); S(O) ₂ N(R ²⁰ R ^20a ); S(O)N(R ²⁰ R ^20a ); S(O) ₂ R ²⁰ ; S(O)R ²⁰ ; SR ²⁰ ; N(R ²⁰ R ^20a ) ; N O ₂ ; OC(O)R ²⁰ ; N(R ²⁰ )C(O)R ^20a ; N(R ²⁰ )S(O) ₂ R ^20a ; N(R ²⁰ )S(O)R ^20a ; N(R ²⁰ )C(O)N(R ^20a R ^20b ); N(R ²⁰ )C(O)OR ^20a ; OC(O)N(R ²⁰ R ^20a ); Ci _-6 alkyl; C ₂ - ₆ alkenyl; and C ₂ -6 alkynyl, wherein Ci_6 alkyl; C ₂ -6 alkenyl; and C ₂ -6 alkynyl are optionally substituted with one or more halogen, which are the same or different;

R ²⁰ , R ^20a , R ^20b are independently selected from the group consisting of H; Ci_6 alkyl; C ₂ -6 alkenyl; and C ₂ -6 alkynyl, wherein Ci_6 alkyl; C ₂ -6 alkenyl; and C ₂ -6 alkynyl are optionally substituted with one or more halogen, which are the same or different;

T ² is phenyl; C ₃ _ ₇ cycloalkyl; or 4 to 7 membered heterocyclyl, wherein T ² is optionally substituted with one or more R ²¹ , which are the same or different;

T ³ is naphthyl; indenyl; indanyl; or 9 to 11 membered benzo-fused heterobicyclyl, wherein T ³ is optionally substituted with one or more R ²² , which are the same or different;

R ²¹ , R ²² are independently selected from the group consisting of halogen; CN; C(O)OR ²³ ; OR ²³ ; oxo (=0), where the ring is at least partially saturated; C(O)R ²³ ; C(O)N(R ²³ R ^23a ); S(O) ₂ N(R ²³ R ^23a ); S(O)N(R ²³ R ^23a ); S(O) ₂ R ²³ ; S(O)R ²³ ; SR ²³ ; N(R ²³ R ^23a ); NO ₂ ; OC(O)R ²³ ; N(R ²³ )C(O)R ^23a ; N(R ²³ )S(O) ₂ R ^23a ; N(R ²³ )S(O)R ^23a ; N(R ²³ )C(O)N(R ^23a R ^23b );

N(R ²³ )C(O)OR ^23a ; OC(O)N(R ²³ R ^23a ); Ci _-6 alkyl; C ₂ - ₆ alkenyl; and C ₂ - ₆ alkynyl, wherein Ci _-6 alkyl; C ₂ -6 alkenyl; and C ₂ -6 alkynyl are optionally substituted with one or more halogen, which are the same or different;

R ²³ , R ^23a , R ^23b are independently selected from the group consisting of H; Ci_6 alkyl; C ₂ -6 alkenyl; and C ₂ -6 alkynyl, wherein Ci_6 alkyl; C ₂ -6 alkenyl; and C ₂ -6 alkynyl are optionally substituted with one or more halogen, which are the same or different;

X ¹ is N(R ^24a )S(O) ₂ R ²⁴ ; S(O) ₂ N(R ²⁴ R ^24a ); C(O)N(R ²⁴ R ^24a ); N(R ^24a )C(O)R ²⁴ ; or N(R ^24a )C(O)N(R ^24b R ²⁴ ).

R ⁹ , R ^24a , R ^24b are independently selected from the group consisting of H; Ci_ ₄ alkyl; C3-5 cycloalkyl; and C3-5 cycloalkylmethyl, wherein Ci_ ₄ alkyl; C3-5 cycloalkyl and C3-5 cycloalkylmethyl are optionally substituted with one or more halogen, which are the same or different;

R ²⁴ is H; T ⁴ ; Ci_6 alkyl; C ₂ -6 alkenyl; or C ₂ -6 alkynyl, wherein Ci_6 alkyl; C ₂ -6 alkenyl; and C ₂ -6 alkynyl are optionally substituted with one or more R ²⁵ , which are the same or different;

R ²⁵ is T ⁴ ; halogen; CN; C(O)OR ²⁶ ; OR ²⁶ ; C(O)R ²⁶ ; C(O)N(R ²⁶ R ^26a ); S(O) ₂ N(R ²⁶ R ^26a ); S(O)N(R ²⁶ R ^26a ); S(O) ₂ R ²⁶ ; S(O)R ²⁶ ; SR ²⁶ ; N(R ²⁶ R ^26a ); NO ₂ ; OC(O)R ²⁶ ; N(R ²⁶ )C(O)R ^26a ; N(R ²⁶ )S(O) ₂ R ^26a ; N(R ²⁶ )S(O)R ^26a ; N(R ²⁶ )C(O)N(R ^26a R ^26b ); N(R ²⁶ )C(O)OR ^26a ; OC(O)N(R ²⁶ R ^26a ); Ci_ ₆ alkyl; C ₂ - ₆ alkenyl; or C ₂ - ₆ alkynyl, wherein Ci_ ₆ alkyl; C ₂ - ₆ alkenyl; and C ₂ -6 alkynyl are optionally substituted with one or more halogen, which are the same or different;

R ²⁶ , R ^26a , R ^26b are independently selected from the group consisting of H; Ci_6 alkyl; C ₂ -6 alkenyl; and C ₂ -6 alkynyl, wherein Ci_6 alkyl; C ₂ -6 alkenyl; and C ₂ -6 alkynyl are optionally substituted with one or more halogen, which are the same or different;

T ⁴ is phenyl; C ₃ _ ₇ cycloalkyl; or 4 to 7 membered heterocyclyl, wherein T ⁴ is optionally substituted with one or more R ²⁷ , which are the same or different;

R ²⁷ is halogen; CN; C(O)OR ²⁸ ; OR ²⁸ ; oxo (=0), where the ring is at least partially saturated;

C(O)R ²⁸ ; C(O)N(R ²⁸ R ^28a ); S(O) ₂ N(R ²⁸ R ^28a ); S(O)N(R ²⁸ R ^28a ); S(O) ₂ R ²⁸ ; S(O)R ²⁸ ; SR ²⁸ ;

N(R ²⁸ R ^28a ); NO ₂ ; OC(O)R ²⁸ ; N(R ²⁸ )C(O)R ^28a ; N(R ²⁸ )S(O) ₂ R ^28a ; N(R ²⁸ )S(O)R ^28a ;

N(R ²⁸ )C(O)N(R ^28a R ^28b ); N(R ²⁸ )C(O)OR ^28a ; OC(O)N(R ²⁸ R ^28a ); Ci _-6 alkyl; C ₂ - ₆ alkenyl; or C ₂ - ₆ alkynyl, wherein Ci_6 alkyl; C ₂ -6 alkenyl; and C ₂ -6 alkynyl are optionally substituted with one or more halogen, which are the same or different;

R , R , R are independently selected from the group consisting of H; Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;

R ⁸ is H; F; Cl; Br; CN; Ci _-4 alkyl; CH ₂ F; CHF ₂ ; CF ₃ ; OH; OCH ₃ ; NO ₂ ; NH ₂ ; NHCH ₃ ; N(CH ₃ ) ₂ ; or NO ₂

for use in a method of treating or preventing diseases and disorders associated with LRRK2.

In case a variable or substituent can be selected from a group of different variants and such variable or substituent occurs more than once the respective variants can be the same or different.

Within the meaning of the present invention the terms are used as follows:

"Alkyl" means a straight-chain or branched saturated hydrocarbon chain. Each hydrogen of an alkyl carbon may be replaced by a substituent.

"Alkenyl" means a straight-chain or branched hydrocarbon chain, that contains at least one carbon-carbon double bond. Each hydrogen of an alkenyl carbon may be replaced by a substituent.

"Alkynyl" means a straight-chain or branched hydrocarbon chain, that contains at least one carbon-carbon triple bond. Each hydrogen of an alkynyl carbon may be replaced by a substituent.

"Ci_ ₄ alkyl" means an alkyl chain having 1 - 4 carbon atoms, e.g. if present at the end of a molecule: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl tert-butyl, or e.g. -CH ₂ -, -CH ₂ -CH ₂ -, -CH(CH ₃ )-, -CH ₂ -CH ₂ -CH ₂ -, -CH(C ₂ H ₅ )-, -C(CH ₃ ) ₂ -, when two moieties of a molecule are linked by the alkyl group. Each hydrogen of a Ci_4 alkyl carbon may be replaced by a substituent.

"Ci_6 alkyl" means an alkyl chain having 1 - 6 carbon atoms, e.g. if present at the end of a molecule: Ci_ ₄ alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,

n-pentyl, n-hexyl, or e.g. -CH ₂ -, -CH ₂ -CH ₂ -, -CH(CH ₃ )-, -CH ₂ -CH ₂ -CH ₂ -, -CH(C ₂ H ₅ )-, -C(CH ₃ ) ₂ -, when two moieties of a molecule are linked by the alkyl group. Each hydrogen of a Ci_6 alkyl carbon may be replaced by a substituent.

"C ₂ _6 alkenyl" means an alkenyl chain having 2 to 6 carbon atoms, e.g. if present at the end of a molecule: -CH=CH ₂ , -CH=CH-CH ₃ , -CH ₂ -CH=CH ₂ , -CH=CH-CH ₂ -CH ₃ , -CH=CH- CH=CH ₂ , or e.g. -CH=CH-, when two moieties of a molecule are linked by the alkenyl group. Each hydrogen of a C ₂ _ ₆ alkenyl carbon may be replaced by a substituent.

"C ₂ _6 alkynyl" means an alkynyl chain having 2 to 6 carbon atoms, e.g. if present at the end of a molecule: -C≡CH, -CH ₂ -C≡CH, CH ₂ -CH ₂ -C≡CH, CH ₂ -C≡C-CH ₃ , or e.g. -C≡C- when two moieties of a molecule are linked by the alkynyl group. Each hydrogen of a C ₂ _6 alkynyl carbon may be replaced by a substituent.

"C ₃ _ ₇ cycloalkyl" or "C ₃ _ ₇ cycloalkyl ring" means a cyclic alkyl chain having 3 - 7 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl. Each hydrogen of a cycloalkyl carbon may be replaced by a substituent. Accordingly, "C ₃ _ ₅ cycloalkyl" means a cycloalkyl having 3 to 5 carbon atoms.

"Halogen" means fluoro, chloro, bromo or iodo. It is generally preferred that halogen is fluoro or chloro.

"4 to 7 membered heterocyclyl" or "4 to 7 membered heterocycle" means a ring with 4, 5, 6 or 7 ring atoms that may contain up to the maximum number of double bonds (aromatic or non- aromatic ring which is fully, partially or un-saturated) wherein at least one ring atom up to 4 ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O) ₂ -), oxygen and nitrogen (including =N(O)-) and wherein the ring is linked to the rest of the molecule via a carbon or nitrogen atom. Examples for a 4 to 7 membered heterocycles are azetidine, oxetane, thietane, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazoline, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyran, dihydropyran, tetrahydropyran,

imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazole, triazole, triazolidine, tetrazolidine, diazepane, azepine or homopiperazine.

"9 to 11 membered heterobicyclyl" or "9 to 11 membered heterobicycle" means a heterocyclic system of two rings with 9 to 11 ring atoms, where at least one ring atom is shared by both rings and that may contain up to the maximum number of double bonds (aromatic or non-aromatic ring which is fully, partially or un-saturated) wherein at least one ring atom up to 6 ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O) ₂ -), oxygen and nitrogen (including =N(O)-) and wherein the ring is linked to the rest of the molecule via a carbon or nitrogen atom. Examples for a 9 to 11 membered heterobicycle are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydro quinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine or pteridine. The term 9 to 1 1 membered heterobicycle also includes spiro structures of two rings like l,4-dioxa-8-azaspiro[4.5]decane or bridged heterocycles like 8-aza-bicyclo[3.2.1]octane.

"benzo fused" heterobicyclyl or "benzofused" heterobicycle means that one of the two rings of the bicycle is a benzene ring.

"5 to 6 membered aromatic heterocyclyl" or "5 to 6 membered aromatic heterocycle" means a heterocycle derived from cyclopentadienyl or benzene, where at least one carbon atom is replaced by a heteoatom selected from the group consisting of sulfur (including -S(O)-, - S(O) ₂ -), oxygen and nitrogen (including =N(O)-). Examples for such heterocycles are furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, pyranium, pyridine, pyridazine, pyrimidine, triazole, tetrazole.

Preferred compounds of formula (I) are those compounds in which one or more of the residues contained therein have the meanings given below, with all combinations of preferred substituent definitions being a subject of the present invention. With respect to all preferred compounds of the formula (I) the present invention also includes all tautomeric and stereoisomeric forms and mixtures thereof in all ratios, and their pharmaceutically acceptable salts.

In preferred embodiments of the present invention, the substituents mentioned below independently have the following meaning. Hence, one or more of these substituents can have the preferred or more preferred meanings given below.

Preferably, R ¹ , R ² , R ³ are independently selected from the group consisting of H; halogen; OR ¹⁰ ; T; and Ci_ ₄ alkyl, wherein Ci_ ₄ alkyl is optionally substituted with one or more halogen, which are the same or different.

Preferably, R ¹⁰ , R ^1Oa are independently selected from the group consisting of H; and Ci_4 alkyl, wherein Ci_ ₄ alkyl is optionally substituted with one or more halogen, which are the same or different.

Preferably, R ¹ , R ² , R ³ are independently selected from the group consisting of H; F; Cl; OH; OCH ₃ ; OCH ₂ CH ₃ ; OCH ₂ F; OCHF ₂ ; OCF ₃ ; OCH ₂ CH ₂ F; OCH ₂ CHF ₂ ; OCH ₂ CF ₃ ; OCHFCH ₂ F; OCHFCHF ₂ ; OCHFCF ₃ ; OCF ₂ CH ₂ F; OCF ₂ CHF ₂ ; OCF ₂ CF ₃ ; CH ₃ ; CH ₂ CH ₃ ; CH ₂ F; CHF ₂ ; CF ₃ ; CH ₂ CH ₂ F; CH ₂ CHF ₂ ; CH ₂ CF ₃ ; CHFCH ₂ F; CHFCHF ₂ ; CHFCF ₃ ; CF ₂ CH ₂ F; CF ₂ CHF ₂ ; and CF ₂ CF ₃ . More preferred are R ¹ , R ² , R ³ OCH ₃ , OCHF ₂ ; OCF _3; and OCF ₂ CHF ₂

Preferably, T is 4 to 7 membered heterocyclyl. More preferred is T a 5 membered heterocycle; even more preferred imidazolyl; pyrazolyl; triazolyl; morpholinyl; piperazinyl; pyrrolidinyl; or piperidinyl.

Preferably, each R ¹⁵ is independently selected from the group consisting of F; Cl; oxo (=0), where the ring is at least partially saturated; OH; OCH ₃ ; OCH ₂ CH ₃ ; OCH ₂ F; OCHF ₂ ; OCF ₃ ;

OCH ₂ CH ₂ F; OCH ₂ CHF ₂ ; OCH ₂ CF ₃ ; OCHFCH ₂ F; OCHFCHF ₂ ; OCHFCF ₃ ; OCF ₂ CH ₂ F;

OCF ₂ CHF ₂ ; OCF ₂ CF ₃ ; NO ₂ ; C(O)CH ₃ ; SH; SCH ₃ ; SCH ₂ F; SCHF ₂ ; SCF ₃ ; NH ₂ ; NHCH ₃ ;

N(CH ₃ ) ₂ ; CH ₃ ; CH ₂ CH ₃ ; CH ₂ F; CHF ₂ ; CF ₃ ; CH ₂ CH ₂ F; CH ₂ CHF ₂ ; CH ₂ CF ₃ ; CHFCH ₂ F;

CHFCHF ₂ ; CHFCF ₃ ; CF ₂ CH ₂ F; CF ₂ CHF ₂ ; and CF ₂ CF ₃ .

Preferably, one of R ⁴ , R ^4a is H and the other is S(O) ₂ NH ₂ ; CONH ₂ ; NHS(O) ₂ CH ₃ ; or

NHCOCH ₃ .

Preferably, R ⁵ , R ⁶ , R ⁷ , are selected from the group consisting of H; OH; OCH ₃ ; OCH ₂ CH ₃ ; and CH ₃ .

Preferably, R ⁹ ; and R ^24a are independently selected from the group consisting of H; and CH ₃ .

Preferably, R ²⁴ is Ci_ ₄ alkyl. More preferred is R ²⁴ CH ₃ .

Preferably, R ²⁴ is T ⁴ ; or Ci_4 alkyl, wherein Ci_4 alkyl is substituted with one or more R ²⁵ , which are the same or different.

Preferably, T ⁴ is phenyl; thiazolyl; imidazolyl; pyridyl; morpholinyl; piperazinyl, pyrrolidinyl; piperidinyl; or cyclopropyl.

Preferably, R ²⁵ is F; Cl; OH; OCH ₃ ; OCH ₂ CH ₃ ; OCH ₂ F; OCHF ₂ ; OCF ₃ ; OCH ₂ CH ₂ F; OCH ₂ CHF ₂ ; OCH ₂ CF ₃ ; OCHFCH ₂ F; OCHFCHF ₂ ; OCHFCF ₃ ; OCF ₂ CH ₂ F; OCF ₂ CHF ₂ ; OCF ₂ CF ₃ ; NO ₂ ; C(O)CH ₃ ; SH; SCH ₃ ; SCH ₂ F; SCHF ₂ ; SCF ₃ ; NH ₂ ; NHCH ₃ ; and N(CH ₃ ) ₂ .

Preferably, R ²⁴ is CH ₂ CF ₃ ; T ⁴ ; CH ₂ -T ⁴ ; CH ₂ CH ₂ -T ⁴ ; CH ₂ CH ₂ NHCH ₃ ; or CH ₂ CH ₂ N(CH ₃ ) ₂ .

Preferably, R ²⁷ is CH ₃ .

Preferably, R ⁸ is H; F; Cl; Br; CN; CH ₃ ; CH(CH ₃ ) ₂ ; CH ₂ F; CHF ₂ ; CF ₃ ; OH; OCH ₃ ; NO ₂ ; NH ₂ ; NHCH ₃ ; N(CH ₃ ) ₂ ; or NO ₂ . More preferred is R ⁸ H; CH ₃ ; Br; or F.

Compounds of formula (I) in which some or all of the above-mentioned groups have the preferred meanings are also an object of the present invention.

Further preferred compounds of the present invention are selected from the group consisting of

N-(2-(2-(3,5-difluorophenylamino)-5-fluoropyrimidin-4- ylamino)phenyl)methanesulfonamide;

N-(2-(2-(3-chloro-4-methoxyphenylamino)-5-fluoropyrimidin -4- ylamino)phenyl)methanesulfonamide;

N-(2-(2-(3-(3,5-dimethyl-lH-pyrazol-l-yl)phenylamino)-5-f luoropyrimidin-4- y lamino)pheny l)methanesulfonamide ;

N-(2-(2-(3-(difluoromethoxy)phenylamino)-5-fluoropyrimidi n-4- ylamino)phenyl)methanesulfonamide;

N-(2-(5-fluoro-2-(4-(trifluoromethoxy)phenylamino)pyrimid in-4- ylamino)phenyl)methanesulfonamide;

N-(2-(5-fluoro-2-(3-(trifluoromethoxy)phenylamino)pyrimid in-4- ylamino)phenyl)methanesulfonamide;

N-(2-(2-(4-chlorophenylamino)-5-fluoropyrimidin-4-ylamino )phenyl)methanesulfonamide;

N-(2-(5-fluoro-2-(3-(l,l,2,2-tetrafluoroethoxy)phenylamin o)pyrimidin-4- ylamino)phenyl)methanesulfonamide;

2-(5-fluoro-2-(3,4,5-trimethoxyphenylamino)pyrimidin-4-yl amino)benzamide;

N-(2-(2-(3-(lH-l,2,4-triazol-l-yl)phenylamino)-5-fluoropy rimidin-4- ylamino)phenyl)methanesulfonamide;

N-(2-(5-fluoro-2-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][ l,4]oxazin-7-ylamino)pyrimidin- 4-ylamino)phenyl)methanesulfonamide;

N-(2-(2-(4-(difluoromethoxy)phenylamino)-5-fluoropyrimidi n-4- y lamino)phenyl)methanesulfonamide ;

N-(2-(2-(2-ethoxy-4-morpholinophenylamino)-5-fluoropyrimi din-4- ylamino)phenyl)methanesulfonamide;

N-(2-(5-fluoro-2-(2-methoxy-4-morpholinophenylamino)pyrim idin-4- ylamino)phenyl)methanesulfonamide;

N-(2-(5-chloro-2-(2-methoxy-4-morpholinophenylamino)pyrim idin-4- ylamino)phenyl)methanesulfonamide; and

N-(2-(5-chloro-2-(2-ethoxy-4-morpholinophenylamino)pyrimi din-4- ylamino)phenyl)methanesulfonamide.

Prodrugs of the compounds of the present invention are also within the scope of the present invention.

"Prodrug" means a derivative that is converted into a compound according to the present invention by a reaction with an enzyme, gastric acid or the like under a physiological condition in the living body, e.g. by oxidation, reduction, hydrolysis or the like, each of which is carried out enzymatically. Examples of a prodrug are compounds, wherein the amino group in a compound of the present invention is acylated, alkylated or phosphorylated to form, e.g., eicosanoylamino, alanylamino, pivaloyloxymethylamino or wherein the hydroxyl group is acylated, alkylated, phosphorylated or converted into the borate, e.g. acetyloxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy or wherein the carboxyl group is esterified or amidated. These compounds can be produced from compounds of the present invention according to well-known methods.

Metabolites of compounds of formula (I) are also within the scope of the present invention.

The term "metabolites" refers to all molecules derived from any of the compounds according to the present invention in a cell or organism, preferably mammal.

Preferably the term relates to molecules which differ from any molecule which is present in any such cell or organism under physiological conditions

The structure of the metabolites of the compounds according to the present invention will be obvious to any person skilled in the art, using the various appropriate methods.

Where tautomerism, like e.g. keto-enol tautomerism, of compounds of general formula (I) may occur, the individual forms, like e.g. the keto and enol form, are comprised separately and together as mixtures in any ratio. The same applies for stereoisomers, like e.g. enantiomers, cis/trans isomers, conformers and the like.

If desired, isomers can be separated by methods well known in the art, e.g. by liquid chromatography. The same applies for enantiomers by using e.g. chiral stationary phases. Additionally, enantiomers may be isolated by converting them into diastereomers, i.e. coupling with an enantiomerically pure auxiliary compound, subsequent separation of the resulting diastereomers and cleavage of the auxiliary residue. Alternatively, any enantiomer of a compound of formula (I) may be obtained from stereoselective synthesis using optically pure starting materials.

In case the compounds according to formula (I) contain one or more acidic or basic groups, the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts. Thus, the compounds of the formula (I) which contain acidic groups can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids. Compounds of the formula (I) which contain one or more basic groups, i.e. groups which can be protonated, can be present and can be used according to the invention in the form of their addition salts with inorganic or organic acids. Examples for suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to the person skilled in the art. If the compounds of the formula (I) simultaneously contain acidic and basic groups in the molecule, the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). The respective salts according to the formula (I) can be obtained by customary methods which are known to the person skilled in the art like, for

example by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts. The present invention also includes all salts of the compounds of the formula (I) which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

The term "pharmaceutically acceptable" means approved by a regulatory agency such as the EMEA (Europe) and/or the FDA (US) and/or any other national regulatory agency for use in animals, preferably in humans.

The present invention furthermore includes all solvates of the compounds according to the invention.

The present invention provides novel uses for compounds of formula (I) as kinase inhibitors, especially as LRRK2 inhibitors. The compounds of formula (I) may inhibit the kinase, optionally in addition to other kinases without being limited by theory.

Accordingly, the compounds of the present invention are useful for the prevention or treatment of neurodegenerative diseases, especially Parkinson's disease (PD) and Alzheimer's disease (AD) (Wider and Wszolek, 2008. Neurodegenerative Diseases 5, 122-125).

Yet another object of the present invention is the use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prophylaxis of diseases and disorders associated with LRRK2.

According to the present invention, the expression "LRRK2" means Leucine-rich repeat kinase 2 (synonym Dardarin) (Paisan-Ruiz et al., 2004. Neuron 44, 595-600; Zimprich et al., 2004. Neuron 44, 601-607).

Moreover, according to the present invention, the expression "LRRK2" includes mutant forms of LRRK2, preferably such mutant forms which are observed in PD (in familial forms as well as sporadic cases). Mutations in the LRRK2 gene have been shown to cause familial autosomal dominant PD (West et al., 2005. PNAS 102, 16842-16847). More preferred, these mutant forms include single amino acid mutations.

The single amino acid substitution G2019S is one of the most frequently observed mutations (Taylor et al, 2006. Trends in Molecular Medicine 12, 76-82). This mutation is located in the kinase domain within a conserved region of the activation loop suggesting that modulation of the kinase activity may be involved in the pathogenic mechanism. Other mutations observed in PD include R1441C, Y1699C, and I2020T (see Table 2 of Taylor et al.).

Therefore, in a preferred embodiment, the expression "LRRK2" also includes an LRRK2 protein having a G2019S, R1441C, Y1699C, or I2020T mutation. More preferably, the expression "LRRK2" also includes an LRKK2 protein having one of the following single mutations: G2019S, R1441C, Y1699C, or I2020T.

Furthermore, 15 additional putatively pathogenic amino acid substitutions have been identified in LRRK2 (Taylor et al, 2006. Trends in Molecular Medicine 12, 76-82, see especially Fig. 2).

Yet another object of the present invention is a compound or a pharmaceutically acceptable salt thereof according to the present invention for use in a method of treating or preventing neurodegenerative diseases.

Yet another object of the present invention is the use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prophylaxis of neurodegenerative diseases (Wider and Wszolek, 2008. Neurodegenerative Diseases 5, 122-125).

More specifically, preferred disorders are Parkinson's disease (PD) and Alzheimer's disease (AD).

Parkinson's disease (PD) is a heterogeneous movement disorder characterized by the degeneration of dopaminergic neurons within the substancia nigra of the basal ganglia. It affects 2% of the population over 60 years.

Broadly, there are two clinicopathological components of PD. First, there is clinically defined parkinsonism, a syndromic term which comprises the cardinal features of the Parkinsonian movement disorder. These are a resting tremor, bradykinesia (slowness of movement), rigidity and postural instability, all problems in initiating or stopping movements. Their pathological correlate is the loss of dopaminergic neurons in the substancia nigra. Second, Parkinson's disease is marked postmortem by the presence of Lewy bodies and Lewy neurites

in surviving neurons. These are intracellular aggregations of lipids and proteins including ubiquitin and alpha-synuclein. Pathological definitions of PD require the presence of alpha- synuclein-positive Lewy pathology in surviving nigral neurons, combined with nigral cell loss and intact striatal neurons (Cookson, 2005. Annual Reviews in Biochemistry 74, 29-52).

Alzheimer's disease (AD) is the most common form of progressive dementia in the elderly. It is a neurodegenerative disorder characterized by the neuropatho logical findings of intracellular neurofibrillary tangles (NFT) and extracellular amyloid plaques that accumulate in vulnerable brainregions (Goedert et al., 2006. Science 314, 777-781).

Recently, it was reported that the genetic polymorphism LRRK2-T1602S is associated with the conversion from mild cognitive impairment (MCI) to AD, the patients with the TT genotype being at greater risk to progress to AD. The LRRK2-T2352 polymorphism also showed a trend for conversion to AD, with the CC genotype tending to progress to AD. The association between the two common LRRK2 polymorphisms and AD progression shows that LRRK2 may play a role in AD pathogenesis, especially disease progression (WO 2007/149798 A2).

Another object of the present invention is a method for treating, controlling, delaying or preventing in a mammalian patient in need of the treatment of one or more conditions selected from the group consisting of diseases and disorders associated with LRRK2, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound according to present invention or a pharmaceutically acceptable salt thereof.

Yet another object is a method for treating, controlling, delaying or preventing in a mammalian patient in need of the treatment of neurodegenerative diseases, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound according to the present invention or a pharmaceutically acceptable salt thereof.

More specifically the one or more conditions are preferably selected from the group consisting of Parkinson's disease and Alzheimer's disease.

As used herein, the term "treating" or "treatment" is intended to refer to all processes, wherein there may be a slowing, interrupting, arresting, or stopping of the progression of a disease, but does not necessarily indicate a total elimination of all symptoms.

The compounds of the present invention may be further characterized by determining whether they have an effect on LRRK2 activity, for example on its kinase activity (West et al, 2005. PNAS 102, 16842-16847; Jaleel et al., 2007. Biochemical Journal 405, 307-317).

The present invention provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as active ingredient together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.

"Pharmaceutical composition" means one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.

The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, including but not limited to peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered orally. Saline and aqueous dextrose are preferred carriers when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions are preferably employed as liquid carriers for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained- release formulations and the like. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical

carriers are described in "Remington's Pharmaceutical Sciences" by E. W. Martin. Such compositions will contain a therapeutically effective amount of the therapeutic, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration.

A pharmaceutical composition of the present invention may comprise one or more additional compounds as active ingredients like one or more compounds of formula (I) not being the first compound in the composition or LRRK2 inhibitors.

Other active ingredients for use in combination with other therapies for the treatment of

Parkinson's disease are dopaminergic medications, for example Levodopa (L-dopa or L-3,4- dihy droxypheny lalanine) .

The pharmaceutical compositions of the present invention include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.

In practical use, the compounds of formula (I) can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.

Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or non-aqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compounds can also be administered intranasally, for example, as liquid drops or spray.

The tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as fatty oil.

Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.

Compounds of formula (I) may also be administered parenterally . Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropyl-cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example,

water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. Preferably compounds of formula (I) are administered orally.

The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.

A general route for the preparation of compounds according to present invention is outlined in Schemes 1 and 2.

Scheme 1

Scheme 2

Compounds of formula (I) can be formed from compounds (II), (III) and (IV) by reacting (II) with (III) then reacting the resultant adduct with (IV) according to Scheme 1. Alternatively

(I) may be formed by the reaction of (II) with (IV) then reacting the resultant adduct with (III) according to Scheme 2. The person skilled in the art would understand that the order of events would depend on the conditions of the reaction and the nature of (I), (II) and (III). Compounds (II), (III) and (IV) are either commercially available or can be made by those skilled in the art. A wide range of solvents are optionally employed for these reactions, including protic solvents such as alcohols, or polar aprotic solvents such as dimethylsulfoxide, DMF, acetonitrile, dioxane, THF. The reactions can optionally be promoted by the addition of a base which include but are not limited to amine bases such as triethylamine and DIPEA; or metal carbonates. The reactions can be optionally promoted by acids including mineral acids such as hydrogen chloride; organic acids and Lewis acids such as zinc (II) chloride. These reactions are typically performed between -78°C and 160 ⁰ C depending on the nature of (I),

(II) and (III). A and B are suitable leaving groups such as halogens, O-Ci_6 alkyl, N-Ci_6 alkyl, N(Ci _-6 alkyl) ₂ , S-Ci _-6 alkyl and SO ₂ -CL ₆ alkyl.

In one embodiment, a compound of formula (II) is reacted with a compound of formula (III) in the presence of an amine base, such as DIPEA; in a protic solvent, such as IPA; at a temperature above 20 ⁰ C, such as 80 ⁰ C. The adduct is isolated by means known to those skilled in the art, then reacted with a compound of formula (IV) in the presence of a mineral acid, such as hydrogen chloride; in a protic solvent such as IPA; at a temperature above 20 ⁰ C, such as 80 ⁰ C to yield a compound of formula (I). In this embodiment it is conceivable that (I) is isolated in a salt form, such as a hydrochloride salt.

The functionality, X ¹ , may be introduced by reacting a compound of formula (I) wherein either R ^4a , or R ⁴ is NHR ^24a with a compound GS(O) ₂ R ²⁴ , GS(O) ₂ N(R ²⁴ R ^24a ), GC(O)R ²⁴ , or GC(O)N(R ^24b R ²⁴ ) , wherein G is a suitable leaving group. Commonly G is chlorine. Alternatively this transformation may be effected on compound (III) or at an intermediate step in the synthesis of (I). The skilled person would recognise that a wide range of solvents may be employed to effect this process and that the addition of a base may be beneficial. In one embodiment, DCM is used as a solvent and triethylamine is used as a base. In another embodiment, pyridine is used as base and solvent. Compounds of formula GS(O) ₂ R ²⁴ , GS(O) ₂ N(R ²⁴ R ^24a ), GC(O)R ²⁴ , or GC(O)N(R ^24b R ²⁴ ) are either commercially available or can be prepared by those skilled in the art.

Accordingly, another aspect of the present invention is a method for the preparation of a compound of the present invention, comprising the steps of

(a) reacting a compound of formula (II)

wherein R ⁸ has the meaning as indicated in claim 1 and A, B are suitable leaving groups with one of the compounds of formula (III) or (IV)

(III) (IV)

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ^4a have the meaning as indicated in claim 1 pprroovviiddeedd tthhaatt oonnie of R ⁴ , R ^4a is NHR ^24a ; or X ¹ , wherein X ¹ , R ^24a have the meaning as indicated above;

(b) further reacting the resulting product (Ha) from step (a) with the other compound of formula (III) or (IV); and

when one of R ⁴ , R ^4a is NHR ^24a ,

reacting the compound of formula (III) before step (a), product (Ha) after step (a) or the resulting product from step (b) with a compound of formula GS(O) ₂ R 24 GGSS((OO)) ₂₂ NN((RR ²²⁴⁴ RR ^2244aa )),, GGCC((OO))RR ²²⁴⁴ ,, oorr GGCC((OO)N(R ^24b R ²⁴ ), wherein G is a suitable leaving group to yield compounds of formula (I).

Examples

Analytical Methods

NMR spectra were obtained on a Bruker dpx400. LCMS was carried out on an Agilent 1100 using a ZORBAX ^® SB-C18, 4.6 x 150 mm, 5 microns or ZORBAX ^® SB-C18, 4.6 x 75 mm, 3.5 micron column. Column flow was lmL/min and solvents used were water and acetonitrile (0.1% formic acid) with an injection volume of 1 OuL. Wavelengths were 254 and 210 nm. Methods are described below.

Method A

Column: Gemini C 18, 3 x 30 mm, 3 microns Flow: 1.2 mL/min. Gradient: Table 1

Table 1

Time (min) Water Acetonitrile

0 95 5

3 5 95

4.5 5 95

4.6 95 5

5.00 STOP

Method B

Column: ZORBAX ^® SB-C 18, 4.6 x 150 mm, 5 microns. Flow: 1 mL/min. Gradient: Table 2

Table 2

Time (min) Water Acetonitrile

0 95 5

11 5 95

13 5 95

13.01 95 5

14.00 STOP

Abbreviations

Table 3

DCM dichloromethane

THF tetrahydrofuran

IPA ώo-propyl alcohol petrol petroleum ether, boiling point 40-60 ⁰ C

DMF λ/,λ/-dimethylformamide

TFA trifluoroacetic acid

DIPEA di-ώo-propylethylamine

Me methyl

Et ethyl

¹ Pr ώo-propyl

Ph phenyl

Bn benzyl

Boc te/t-butyloxycarbonyl h hour min minute

M molar sat. saturated

(aq) aqueous

NMR nuclear magnetic resonance

MeOD deuterated methanol (d ₄ -methanol)

S singlet d doublet dd doublet doublet

td triplet doublet br broad t triplet m multiplet

ES+ electrospray positive ionisation

RT retention time

Intermediate Ia

N-(2-(2-chloro-5-fluoropyrimidin-4-ylamino)phenyl)methane sulfonamide

Nl-(2-chloro-5-fluoropyrimidin-4-yl)benzene-l,2-diamine

A mixture of 2,4-dichloro-5-fluoropyrimidine (10.0 g, 0.06 mol), o-phenylene diamine (7.1 g, 0.066 mol) and DIPEA (20.8 ml, 0.12 mol) in n-butanol (80 mL) were stirred at 110 ⁰ C for 16 h then concentrated in vacuo then slurried with 0.1 M hydrochloric acid (20 mL). The solid was collected at the pump, washed with water (2 x 20 mL), n-butanol (30 mL and diethyl ether (2 x 30 mL), then dried under vacuum to afford Nl-(2-chloro-5-fluoropyrimidin- 4-yl)benzene-l,2-diamine as a colourless powder (10.8 g, 71 %). ¹ U NMR (d ₆ -DMSO) δ 9.31 (brs, IH), 8.18 (d, IH), 6.99-7.03 (m, 2H), 6.74-6.76 (m, IH), 6.54-6.58 (m, IH), 5.04 (brs, 2H); LCMS method A, (ES+) 239.9, RT = 1.90 min.

Step (if) N-(2-(2-chloro-5-fluoropyrimidin-4-ylamino)phenyl)methanesul fonamide

A solution of Nl-(2-chloro-5-fluoropyrimidin-4-yl)benzene-l ,2-diamine (1.5 g, 6.30 mmol) in pyridine (15 mL) was coolled to O ⁰ C before dropwise addition of methanesulfonyl chloride (0.54 mL, 6.93 mmol), the resultant solution was allowed to warn to room temperature and stirred for 18h. The mixture was diluted with H ₂ O (25 mL) and EtOAc (25 mL) the organic layer was collected and washed with 2M HCl (2 x 25 mL), brine (25 mL) dried (MgSO ₄ ) and concentrated i n v a c u o to provide N-(2-(2-chloro-5-fluoropyrimidin-4- ylamino)phenyl)methanesulfonamide as a beige solid (1.45 g, 72 %). ¹ H NMR (dβ-DMSQ) δ 9.41 (brs, IH), 9.25 (s, IH), 8.30 (d, IH), 7.47-7.52 (m, 2H), 7.32 (t, IH), 7.25 (t, IH), 2.99 (s, 3H) ; LCMS method A, (ES+) 316, RT = 2.26 min.

Intermediate Ib N-(2-(2-chloro-5-methylpyrimidin-4-ylamino)phenyl)methanesul fonamide

Ib was made according to the procedure of Ia using 2,4-dichloro-5-methylpyrimidine instead of 2,4-dichloro-5-fiuoropyrimidine in step (i). ¹ H NMR: (d ₆ -DMS0) δ 9.24 (s, IH), 8.49 (s, IH), 8.06 (s, IH), 7.60, (m, IH), 7.48 (m, IH), 7.29 (m, 2H), 3.07 (s, 3H), 2.17 (s, 3H); LCMS method A, (ES+) 278, RT 1.73 min

Intermediate Ic

6-(2-chloro-5-fluoropyrimidin-4-ylamino)-2H-benzo [b] [ 1 ,4] oxazin-3 (4H)-one

A mixture o f 2 , 4-dichloro-5-fluoropyrimidine (2.5 g, 0.015 mol), 6-(2-chloro-5- fluoropyrimidin-4-ylamino)-2H-benzo[b][l,4]oxazin-3(4H)-one (2.7 g, 0.16 mol) and DIPEA (5.0 mL, 0.03 mol) in n-butanol (80 mL) were stirred at 110 ⁰ C for 16 h then concentrated in vacuo then slurried with 0.1 M hydrochloric acid (20 mL). The solid was collected at the pump, washed with water (2 x 20 mL), n-butanol (30 mL) and diethyl ether (2 x 30 mL), then dr i e d un d e r v a c uum t o a ffo r d 6-(2-chloro-5-fluoropyrimidin-4-ylamino)-2H- benzo[b] [ 1,4] oxazin-3 (4H)-one as a pink powder (4.0 g, 89 %). ¹ U NMR (d ₆ -DMSO) δ 10.88 (brs, IH), 9.96 (d, IH), 8.29 (d, IH), 7.25 (d, IH), 7.21 - 7.19 (dd, IH), 6.96 (d, IH) 4.57 (s, 2H); LCMS method A, (ES+) 294.9, RT = 2.36 min.

Intermediate Id

N-(2-(2-chloro-5-methylpyrimidin-4-ylamino)phenyl)acetami de

Id was made according to the procedure of Ic using N-(2-aminophenyl)acetamide and 2,4- dichloro-5-methylpyrimidine. ¹ H NMR (d ₆ -DMS0) δ 10.24 (s, IH), 9.96 (s, IH), 7.88 (s, IH), 7.57 (d, IH), 7.53 (d, IH), 7.28 (t, IH), 7.16 (t, IH), 2.14 (s, 3H), 2.09 (s, 3H).

Example 1

N-(2-(2-(3,5-difluorophenylamino)-5-fluoropyrimidin-4-yla mino)phenyl) methanesulfonamide

A suspension of N-(2-(2-chloro-5-fluoropyrimidin-4-ylamino)phenyl) methanesulfonamide (100 mg, 0.32 mmol), 3,5-difluoroaniline (63.6 mg, 0.35 mmol), 4M HCl (in diaxane 0.1 mL) in n-butanol (2 mL) was heated in a microwave at 120 ⁰ C for 45 mins. The resultant ppt was collected by filtration and washed with n-butanol (2 x 10 mL) and Et ₂ O (2 x 10 mL) the resultant white solid was dried under air to afford. ¹ H NMR (d ₆ -DMSO) δ.9.83 (brs, IH),

9.28 (s, IH), 9.15 (brs, IH), 8.22 (d, IH), 7.67 (d, IH), 7.42 (d IH), 7.25-7.35 (m, 4H), 6.64 (t, IH), 2.93 (s, 3H); LCMS method A, (ES+) 410, RT = 2.14 min

Example 2

N-(2-(2-(3-chloro-4-methoxyphenylamino)-5-fluoropyrimidin -4-ylamino)phenyl) methanesulfonamide

Synthesized according to the procedure in Example 1 using intermediates Ia and 3-chloro-4- methoxyaniline. ¹ H NMR (d ₆ -DMSO) δ.10.08 (brs, IH), 9.62 (brs, IH), 9.31 (s, IH), 8.27 (d, IH), 7.62 (d, IH), 7.57 (d, IH), 7.46-7.51 (m, IH), 7.30-7.34 (m, 2H), 7.27 (d, IH), 6.98 (d, IH), 3.79 (s, 3H), 2.93 (s, 3H); LCMS method A, (ES+) 437, RT = 2.6 min

Example 3

N- (2- (5-fluoro-2- (4-methyl-3-nitrophenylamino)pyrimidin-4-ylamino)phenyl) methanesulfonamide

Synthesized according to the procedure in Example 1 using intermediates Ia and 4-methyl-3- nitroaniline. ¹ H NMR (d ₆ -DMSO) δ.10.11 (brs, IH), 9.51 (brs, IH), 9.30 (s, IH), 8.27 (d, IH), 8.13 (d, IH), 7.63 (m, 2H), 7.47 (d, 2H), 7.24-7.30 (m, 3H), 2.86 (s, 3H), 2.39 (s, 3H). LCMS method A, (ES+) 433, RT = 2.6 min.

Example 4

N-(2-(2-(3-(3,5-dimethyl-lH-pyrazol-l-yl)phenylamino)-5-f luoropyrimidin-4- ylamino)phenyl)methanesulfonaniide

Synthesized according to the procedure in Example 1 using intermediates Ia and 3-(3,5- dimethyl-lH-pyrazol-l-yl)aniline. ¹ H NMR (d ₆ -DMSO) δ.10.45 (brs, IH), 10.09 (brs, IH), 9.37 (s, IH), 8.35 (brs, IH), 7.60 (d, 2H), 7.55 (d, 2H), 7.48 (d, 2H), 7.34-7.37 (m, 2H), 7.24 (d, 2H), 6.06 (s, 2H), 2.92 (s, 3H), 2.22 (s, 3H), 2.17 (s, 3H); LCMS method A, (ES+) 468, RT = 2.4 min

Example 5

N- (2- (5-fluoro-2- (3-oxo-3, 4-dihydro-2H-benzo[b][l, 4]oxazin- 7-ylamino)pyrimidin-4- ylamino)phenyl)methanesulfonaniide

Synthesized according to the procedure in Example 1 using intermediates Ia and 7-amino- 2H-l,4-benzoxazin-3(4H)-one. ¹ H NMR (d ₆ -DMS0) δ.10.49 (brs, IH), 9.14 (brs, IH), 8.71 (brs, IH), 8.11 (d, IH), 7.90 (d, IH), 7.42 (d, IH), 7.32 (s, IH), 7.20-7.24 (m, 2H), 7.13 (d, IH), 6.66 (d, IH), 4.50 (s, 2H), 2.90 (s, 3H); LCMS method A, (ES+) 445, RT = 2.2 min.

Example 6 N-(2-(2-(3-(difluoromethoxy)phenylamino)-5-fluoropyrimidin-4 -ylamino)phenyl) methanesulfonamide

Synthesized according to the procedure in Example 1 using intermediates Ia and 3- (difluoromethoxy)aniline. ¹ H NMR (d ₆ -DMSO) δ.lθ.l l(brs, IH), 9.69 (s, IH), 9.32 (s, IH), 8.30 (d, IH), 7.65 (d, IH), 7.50 (d, IH), 7.30-7.35 (m, 4H), 7.18 (t, IH), 7.09 (t, J = 75Hz, IH), 6.75 (d, IH), 2.93 (s, 3H); LCMS method A, (ES+) 439 RT = 2.35 min

Example 7

N- (2- (5-fluoro-2- (4- (trifluoromethoxy)phenylamino)pyrimidin-4-ylamino)phenyl) methanesulfonamide

Synthesized according to the procedure in Example 1 using intermediates Ia and 4- trifluoromethoxyaniline. ¹ H NMR (d ₆ -DMSO) δ.10.16 (brs, IH), 9.78 (s, IH), 9.34 (s, IH), 8.29 (d, IH), 7.61 (d, IH), 7.51 (d, 3H), 7.29-7.37 (m, 2H), 7.13 (d, 2H), 2.93 (s, 3H); LCMS method A, (ES+) 458 RT = 2.35 min.

Example 8

N- (2- (5-fluoro-2- (3- (trifluoromethoxy)phenylamino)pyrimidin-4-ylamino)phenyl) methanesulfonamide

Synthesized according to the procedure in Example 1 using intermediates Ia and 3- trifluoromethoxyaniline. ¹ H NMR (d ₆ -DMSO) δ.10.10 (brs, IH), 9.56 (s, IH), 9.30 (s, IH), 8.29 (d, IH), 7.65 (d, IH), 7.58 (s, 3H), 7.58 (d, IH), 7.40 (d, IH). 7.25-7.32 (m, 3H), 6.68 (d, IH), 2.92 (s, 3H); LCMS method A, (ES+) 458, RT = 2.41 min

Example 9

N-(2-(2-(4-chlorophenylamino)-5-fluoropyrimidin-4-ylamino )phenyl )methanesulfonamide

Synthesized according to the procedure in Example 1 using intermediates Ia and 4- chloroaniline. ¹ H NMR (d ₆ -DMS0) δ.10.07 (brs, IH), 9.78 (s, IH), 9.31 (s, IH), 8.28 (d, IH), 7.62 (d, IH), 7.52 (d, IH), 7.45 (d, 2H), 7.33-7.37 (m, 2H), 7.17 (d, 2H), 2.93 (s, 3H); LCMS method A, (ES+) 408, RT = 2.3 min

Example 10

N- (2- (5-fluoro-2- (3- (1, 1, 2, 2-tetrafluoroethoxy)phenylamino)pyrimidin-4- ylamino)phenyl)methanesulfonamide

Synthesized according to the procedure in Example 1 using intermediates Ia and 3-(l, 1,2,2- tetrafluoroethoxy)aniline. ¹ H NMR (d ₆ -DMSO) δ.10.25 (brs, IH), 10.12 (s, IH), 9.35 (s, IH), 8.29 (d, IH), 7.70 (d, IH), 7.65 (s, 3H), 7.60 (d, IH), 7.45 (d, IH). 7.20-7.35 (m, 3H), 7.12 (d, IH), 2.94 (s, 3H); LCMS method A, (ES+) 490, RT = 2.40 min

Example 11

N-(2-(2-(2-ethoxy-4-morpholinophenylam,ino)-5-fluoropyrim idin-4-ylamino) phenyl) methanesulfonamide

Synthesized according to the procedure in Example 1 using intermediates Ia and 2-ethoxy-4- morpholinoaniline.1H NMR (CDCl ₃ ) δ.7.95 (d, IH), 7.84 (d, IH), 7.80 (d, IH), 7.45 (s, IH), 7.43 (d, IH), 7.31 (t, IH), 7.25 (s, IH), 6.45 (s, IH), 6.32 (d, IH), 4.03 (q, 2H), 3.84 (t, 2H), 3.05, (t, 2H), 2.90 (s, 3H), 1.40 (t, 3H); LCMS method A, (ES+) 503 RT = 2.41 min

Example 12 2- (5-fluoro-2- (3, 4, 5-trimethoxyphenylamino)pyrimidin-4-ylamino)benzamide

Synthesized according to the procedure in Example 1 using intermediates Id and 3,4,5- trimethoxyaniline. ¹ H NMR (CDCl ₃ ) δ.8.06 (d, IH), 7.18 (d, IH), 6.97 (d, IH), 6.67 (t, IH),

6.29 (t, IH), 6.15 (d, 2H), 2.60 (s, 6H), 2.94 (s, 3H); LCMS method A, (ES+) 414, RT = 2.14 mm

Example 13

N- (2- (5-methyl-2- (3, 4, 5-trimethoxyphenylamino)pyrimidin-4-ylamino)phenyl) methanesulfonamide

Synthesized according to the procedure in Example 1 using intermediates Ib and 3,4,5- trimethoxyaniline. ¹ H NMR (d ₆ -DMSO) δ 8.88 (s, IH), 8.17 (s, 2H), 8.01 (s, IH), 7.94 (s, IH), 7.37 (d, IH), 7.26 (t, IH), 7.16 (t, IH), 7.16 (t, IH), 7.00 (s, 2H), 3.56 (s, 3H), 3.53 (s, 6H), 2.92 (s, 3H), 2.11 (s, 3H); LCMS method A, (ES+) 460, RT = 2.28 min.

Example 14 Determination of the effect of the compounds according to the invention on LRRK2

The compounds of the present invention as described in the previous examples can be tested in the LRRK2 kinobeads assay as described in WO 2007/104763 Al. Briefly, test compounds (at various concentrations) and the affinity matrix with the immobilized capture ligand are added to cell lysate aliquots and allowed to bind to the proteins in the lysate sample. After the incubation time the beads with captured proteins are separated from the lysate. Bound proteins are then eluted and the presence LRRK2 is detected and quantified using a specific antibody in a dot blot procedure and the Odyssey infrared detection system. Conventionally, LRRK2 kinase activity can be measured as described in the literature (West et al, 2005. PNAS 102, 16842-16847; Jaleel et al, 2007. Biochemical Journal 405, 307-317).

In general, compounds of the invention are effective for the inhibition of LRRK2, with an IC ₅₀ of< 10μM.