HK1227387B - 2-phenylaminopyrimidine derivatives as kinase lrrk2 modulators for the treatment of parkinson's disease - Google Patents

Description

2-Phenylaminopyrimidine derivatives as LRRK2 kinase modulators for the treatment of Parkinson's disease

This application is a divisional application of an application with a PCT international application date of November 28, 2012, PCT international application number PCT/EP2012/073762, Chinese national application number 201280058444.X, and invention name “2-Phenylaminopyrimidine derivatives as kinase LRRK2 regulators for the treatment of Parkinson's disease”.

Technical Field

The present invention relates to compounds that modulate the function of LRRK2 and are useful in treating LRRK2-mediated diseases and disorders, such as Parkinson's disease.

Background Art

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 disorder that affects approximately one in every 1,000 people, with hereditary Parkinson's disease accounting for 5-10% of all patients. Parkinson's disease is caused by the progressive loss of midbrain dopamine neurons, resulting in patients with impaired ability to direct and control their actions. Primary Parkinson's disease symptoms are tremors, stiffness, slow movements and impaired balance. Many Parkinson's patients also experience other symptoms such as mood changes, memory loss, speech problems and sleep disorders.

The gene encoding leucine-rich repeat kinase 2 (LRRK2) has been identified as being associated with hereditary Parkinson's disease (Paisan-Ruiz et al., Neuron, Vol. 44(4), 2004, pp. 595-600; Zimprich et al., Neuron, Vol. 44(4), 2004, pp. 601-607). In vitro studies have shown that Parkinson's disease-associated mutations result in increased LRRK2 kinase activity and decreased GTP hydrolysis rate compared to wild-type (Guo et al., Experimental Cell Research, Vol. 313(16), 2007, pp. 3658-3670). Anti-LRRK2 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 Lewy body formation and the pathogenesis associated with these diseases (Zhou et al., Molecular Degeneration, 2006, 1:17 doi: 10.1186/1750-1326-1-17). 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 has also been implicated in the transition from mild cognitive impairment to Alzheimer's disease (WO2007/149789); L-dopa-induced dyskinesias (Hurley et al., Eur. J. Neurosci., Vol. 26, 2007, pp. 171-177); CNS disorders associated with differentiation of neuronal precursors (Milosevic et al., Neurodegen., Vol. 4, 2009, p. 25); cancers such as renal, breast, prostate, blood and lung cancers, and acute myeloid leukemia (WO2011/038572); papillary renal and thyroid cancers (Looyenga et al., www.pnas.org/cgi/doi/10.1073/pnas.1012500108 ); multiple myeloma (Chapman et al., Nature Vol.471, 2011, pp.467-472); amyotrophic lateral sclerosis (Shtilbans et al., Amyotrophic Lateral Sclerosis" Early Online 2011, pp.1-7); rheumatoid arthritis (Nakamura et al., DNA Res. Vol.13(4), 2006, pp.169-183); and ankylosing spondylytis (Danoy et al., PLoS Genetics, Vol.6(12), 2010, e1001195, pp.1-5).

Thus, compounds and compositions that effectively modulate LRRK2 activity may provide treatments for neurodegenerative diseases such as Parkinson's disease and Lewy body dementia, CNS disorders such as Alzheimer's disease and L-dopa-induced dyskinesia, cancers such as renal, breast, prostate, blood, mastoid, and lung cancers, acute myeloid leukemia, and multiple myeloma, and inflammatory diseases such as leprosy, Crohn's disease, amyotrophic lateral sclerosis, rheumatoid arthritis, and spondylosis. In particular, there is a need for compounds that have affinity for LRRK2, are selective for LRRK2 relative to other kinases such as JAK2, and that may provide effective drugs for treating neurodegenerative diseases such as Parkinson's disease.

Summary of the Invention

The present invention provides a compound of formula I:

or a pharmaceutically acceptable salt thereof,

in:

m is 0 to 3;

X is: -NR ^a -; -O-; or -S(O) _r -, wherein r is 0 to 2 and ^Ra is hydrogen or C _1-6 alkyl;

R ¹ is: C _1-6 alkyl; C _2-6 alkenyl; C _2-6 alkynyl; halo-C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; hydroxy-C _1-6 alkyl; amino-C _1-6 alkyl; C _1-6 alkylsulfonyl-C _1-6 alkyl; C _{3-6 cycloalkyl optionally substituted by C 1-6 alkyl} or halo; C _3-6 cycloalkyl-C _1-6 alkyl, wherein the C _3-6 cycloalkyl portion is optionally substituted by C _1-6 alkyl; tetrahydropyranyl; tetrahydrofuranyl; tetrahydrofuranyl-C _1-6 alkyl; oxetanyl; or oxetanyl-C _1-6 alkyl;

or R ¹ and R ^a together with the atoms to which they are attached may form a three to six membered ring, said three to six membered ring may optionally include additional heteroatoms selected from O, N and S, and which is substituted with oxo, halo or C _1-6 alkyl;

R ² is: halo; C _1-6 alkoxy; cyano; C _2-6 alkynyl; C _2-6 alkenyl; halo-C _1-6 alkyl; halo-C _1-6 alkoxy; C _3-6 cycloalkyl, wherein the C _3-6 cycloalkyl portion is optionally substituted with C _1-6 alkyl; C _3-6 cycloalkyl-C _1-6 alkyl, wherein the C _3-6 cycloalkyl portion is optionally substituted with C _1-6 alkyl; tetrahydrofuranyl; tetrahydrofuranyl-C _1-6 alkyl; acetyl; oxetanyl; or oxetanyl-C _1-6 alkyl;

R ³ is: -OR ⁴ ; halo; cyano; C _1-6 alkyl; halo-C _1-6 alkyl; C _3-6 cycloalkyl optionally substituted by C _1-6 alkyl; C _3-6 cycloalkyl-C _1-6 alkyl, wherein the C _3-6 cycloalkyl portion is optionally substituted by C _1-6 alkyl; tetrahydrofuranyl; tetrahydrofuranyl-C _1-6 alkyl; oxetanyl; or oxetanyl-C _1-6 alkyl;

R ⁴ is: hydrogen; C _1-6 alkyl; halo-C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; C _3-6 cycloalkyl optionally substituted by C _1-6 alkyl or halo; C _3-6 cycloalkyl-C _1-6 alkyl, wherein the C _3-6 cycloalkyl portion is optionally substituted by C _1-6 alkyl or halo; tetrahydrofuranyl; tetrahydrofuranyl-C _1-6 alkyl; oxetanyl; or oxetanyl-C _1-6 alkyl;

^R5 is: hydrogen; or _C1-6 alkyl;

R ⁶ is: hydrogen; C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; hydroxy-C _1-6 alkyl; amino-C _1-6 alkyl; C _3-6 cycloalkyl; C _3-6 cycloalkyl-C _1-6 alkyl; heterocyclyl; or heterocyclyl-C _1-6 alkyl; wherein the C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-6 alkyl, heterocyclyl and heterocyclyl-C _1-6 alkyl each may be optionally substituted with one, two, three or four groups independently selected from: C _1-6 alkyl; halo-C _1-6 alkyl; C _1-6 alkoxy; halo-C _1-6 alkoxy; hydroxy; hydroxy-C _1-6 alkyl; halo; nitrile; C _1-6 alkyl-carbonyl; C _1-6 alkyl-sulfonyl; C _3-6 cycloalkyl; C _3-6 cycloalkyl-C _1-6 alkyl; C _3-6 cycloalkyl-carbonyl; amino; or heterocyclyl; or two of said groups together with the atoms to which they are attached may form a five- or six-membered ring;

or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a three to seven membered ring, said three to seven membered ring optionally including additional heteroatoms selected from O, N and S(O) _n , and which is optionally substituted by one, two, three or four groups independently selected from: C _1-6 alkyl; halo-C _1-6 alkyl; C _1-6 alkoxy; halo-C _1-6 alkoxy; hydroxy; C _1-6 alkoxy-C _1-6 alkyl; hydroxy-C _1-6 alkyl; halo, nitrile; C _1-6 alkyl-carbonyl; C _1-6 alkyl-sulfonyl; C _3-6 cycloalkyl; C _3-6 cycloalkyl-C _1-6 alkyl; C _3-6 cycloalkyl-carbonyl; amino; or heterocyclyl; or two of said groups together with the atom to which they are attached may form a five or six membered ring; and

R ⁷ is: halo; C _1-6 alkyl; C _1-6 alkoxy; halo-C _1-6 alkyl; or halo-C _1-6 alkoxy;

wherein the compound is selected from:

[5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-[4-(2-methoxy-ethyl)-piperazin-1-yl]-methanone;

[5-Chloro-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[5-Methoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[2-Fluoro-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-methanone;

[2-Fluoro-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(1S,5R)-8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl-methanone;

[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-(1S,5R)-8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl-methanone;

2-Fluoro-5-methoxy-N-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-benzamide;

[2-Fluoro-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(4-morpholin-4-yl-piperidin-1-yl)-methanone;

[4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-3-hydroxy-phenyl]-morpholin-4-yl-methanone;

[5-Chloro-2-hydroxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[2-Fluoro-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-methanone;

[2,3-Difluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[4-(5-Chloro-4-methylamino-pyrimidin-2-ylamino)-2,3-difluoro-phenyl]-morpholin-4-yl-methanone;

[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-methanone;

[5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-methanone;

[2,5-Difluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[4-(5-Chloro-4-methylamino-pyrimidin-2-ylamino)-2,5-difluoro-phenyl]-morpholin-4-yl-methanone;

4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(2-hydroxy-2-methyl-propyl)-5-methoxy-benzamide;

4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(2-hydroxy-2-methyl-propyl)-5-methoxy-N-methyl-benzamide;

[5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(3-morpholin-4-yl-azetidin-1-yl)-methanone;

N-tert-Butyl-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methoxy-benzamide;

[3-Fluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(4-oxetan-3-yl-piperazin-1-yl)-methanone;

[5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(3,3-difluoro-pyrrolidin-1-yl)-methanone;

[4-(4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-morpholin-4-yl-methanone;

[4-(4-Azetidin-1-yl-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-morpholin-4-yl-methanone;

5-Fluoro-N-(2-hydroxy-2-methyl-propyl)-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide;

4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-N-(2-hydroxy-2-methyl-propyl)-2-methoxy-benzamide;

5-Fluoro-N-(2-hydroxy-2-methyl-propyl)-2-methoxy-N-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide;

4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-N-(2-hydroxy-2-methyl-propyl)-2-methoxy-N-methyl-benzamide;

[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,5-difluoro-phenyl]-morpholin-4-yl-methanone;

[2-Fluoro-4-(4-isopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-methoxy-phenyl]-morpholin-4-yl-methanone;

[3-Methoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-(1-oxa-6-aza-spiro[3.3]hept-6-yl)-methanone;

2-Fluoro-N-(2-hydroxy-2-methyl-propyl)-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide;

((3S,4S)-3,4-Difluoro-pyrrolidin-1-yl)-[2-fluoro-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-methanone;

4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-N-methyl-benzamide;

2-Fluoro-N-(2-hydroxy-2-methyl-propyl)-3-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide;

(3,3-Difluoro-pyrrolidin-1-yl)-[5-(2-fluoro-ethoxy)-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-methanone;

[5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(1-oxa-6-aza-spiro[3.3]hept-6-yl)-methanone;

[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-difluoro-phenyl]-morpholin-4-yl-methanone;

[4-(4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-methoxy-2-methyl-phenyl]-morpholin-4-yl-methanone;

[5-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-methoxy-phenyl]-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-methanone;

[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-methoxy-2-methyl-phenyl]-morpholin-4-yl-methanone;

4-(4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(2-hydroxy-2-methyl-propyl)-5-methoxy-benzamide;

N-tert-Butyl-4-(5-cyano-4-ethylamino-pyrimidin-2-ylamino)-3-methoxy-benzamide;

[3-Difluoromethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[2-Fluoro-5-(2-fluoro-ethoxy)-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-(2-fluoro-ethoxy)-phenyl]-morpholin-4-yl-methanone;

[2-Fluoro-5-methoxy-4-(4-methoxy-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[4-(4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-difluoro-phenyl]-morpholin-4-yl-methanone;

[4-(4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,5-difluoro-phenyl]-morpholin-4-yl-methanone;

[2-Chloro-5-fluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

4-Ethylamino-2-[4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-2-methoxy-phenylamino]-pyrimidine-5-carbonitrile;

5-Chloro-2-methoxy-N-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-N-(1-methyl-1H-pyrazol-4-yl)-benzamide;

(3,3-Difluoro-pyrrolidin-1-yl)-[4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,5-dimethoxy-phenyl]-methanone;

[4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-3-(2-fluoro-ethoxy)-phenyl]-morpholin-4-yl-methanone;

[2-Methoxy-5-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[2-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-phenyl]-morpholin-4-yl-methanone;

[3-Chloro-2-fluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

(3,3-Difluoro-pyrrolidin-1-yl)-[4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-(2-fluoro-ethoxy)-2-methoxy-phenyl]-methanone;

[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,6-difluoro-3-methoxy-phenyl]-morpholin-4-yl-methanone;

[2,6-Difluoro-3-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[4-(4-Ethoxy-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-morpholin-4-yl-methanone;

[2,5-Dimethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

(3,3-Difluoro-pyrrolidin-1-yl)-[4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoromethoxy-2-methoxy-phenyl]-methanone;

[5-Methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-trifluoromethyl-phenyl]-morpholin-4-yl-methanone;

[4-(5-Chloro-4-methylamino-pyrimidin-2-ylamino)-5-methoxy-2-trifluoromethyl-phenyl]-morpholin-4-yl-methanone;

[5-Chloro-2-fluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[4-(4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-(2-fluoro-ethoxy)-phenyl]-morpholin-4-yl-methanone;

[5-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-methyl-phenyl]-morpholin-4-yl-methanone;

[5-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoromethoxy-phenyl]-morpholin-4-yl-methanone;

[5-Fluoro-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[5-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-phenyl]-morpholin-4-yl-methanone;

{2-Fluoro-4-[4-((1R,2S)-2-fluoro-cyclopropylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-5-methoxy-phenyl}-morpholin-4-yl-methanone;

(2,2-Dimethyl-morpholin-4-yl)-[2-fluoro-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-methanone;

[3-Cyclopropyloxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[5-Chloro-2-difluoromethoxy-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[5-Chloro-2-difluoromethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

4-Ethylamino-2-[5-fluoro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-2-methoxy-phenylamino]-pyrimidine-5-carbonitrile;

4-Ethylamino-2-[2-fluoro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-5-methoxy-phenylamino]-pyrimidine-5-carbonitrile;

[3-Chloro-2,6-dimethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

(2,2-Dimethyl-morpholin-4-yl)-[3-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-methanone;

[5-(2-Fluoro-ethoxy)-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[5-(2-Fluoro-ethoxy)-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-pyrrolidin-1-yl-methanone;

(5-chloro-4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-methoxyphenyl)(perdeuteromorpholino)methanone;

[4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-2,5-dimethoxy-phenyl]-morpholin-4-yl-methanone;

[5-Fluoromethoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

{4-[Ethyl-(4-methylamino-5-trifluoromethyl-pyrimidin-2-yl)-amino]-5-fluoromethoxy-2-methyl-phenyl}-morpholin-4-yl-methanone;

[5-Fluoromethoxy-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-pyrrolidin-1-yl-methanone;

[4-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-morpholin-4-yl-methanone;

[2-Fluoro-5-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-5-methoxy-2-methyl-phenyl]-morpholin-4-yl-methanone;

[4-(5-Chloro-4-ethoxy-pyrimidin-2-ylamino)-5-methoxy-2-methyl-phenyl]-morpholin-4-yl-methanone;

[2-Fluoro-5-fluoromethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-pyrrolidin-1-yl-methanone;

4-Cyclopropylamino-2-[4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-2-methoxy-phenylamino]-pyrimidine-5-carbonitrile;

4-Ethylamino-2-[4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-2-methoxy-5-methyl-phenylamino]-pyrimidine-5-carbonitrile;

4-Ethylamino-2-[2-fluoro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-phenylamino]-pyrimidine-5-carbonitrile;

[5-Isopropoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[5-Ethoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[5-Fluoromethoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-pyrrolidin-1-yl-methanone;

[5-Chloro-4-(4-cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoromethoxy-phenyl]-morpholin-4-yl-methanone;

[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-2-methyl-phenyl]-morpholin-4-yl-methanone;

(5-methoxy-2-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)(perdeuteromorpholino)methanone;

4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-N-(2-hydroxy-2-methyl-propyl)-5-methoxy-2-methyl-benzamide;

4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(2-hydroxy-1,1-dimethyl-ethyl)-5-methoxy-benzamide;

2-[2-Chloro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-5-methyl-phenylamino]-4-ethylamino-pyrimidine-5-carbonitrile;

2-[2-Chloro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-phenylamino]-4-ethylamino-pyrimidine-5-carbonitrile;

[5-Cyclopropylmethoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[5-Fluoromethoxy-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-piperidin-1-yl-methanone;

[5-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoromethoxy-phenyl]-pyrrolidin-1-yl-methanone;

[4-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-2-methoxy-phenyl]-morpholin-4-yl-methanone;

[5-Chloro-4-(4-cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-methoxy-phenyl]-morpholin-4-yl-methanone;

4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(1-hydroxymethyl-cyclopropyl)-5-methoxy-benzamide;

4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(1-hydroxy-cyclopropylmethyl)-5-methoxy-benzamide;

N-(2-Hydroxy-2-methyl-propyl)-5-methoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide;

2-[2-Chloro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-5-methoxy-phenylamino]-4-ethylamino-pyrimidine-5-carbonitrile;

[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methyl-phenyl]-morpholin-4-yl-methanone;

[4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-5-fluoromethoxy-2-methyl-phenyl]-pyrrolidin-1-yl-methanone;

5-Fluoromethoxy-2-methoxy-N,N-dimethyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide;

[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-2-fluoromethoxy-phenyl]-pyrrolidin-1-yl-methanone;

[3-Fluoro-2,6-dimethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

(4-(4-(2,3-tetradeuterio-cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxyphenyl)(morpholino)methanone;

[5-Methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-trifluoromethoxy-phenyl]-morpholin-4-yl-methanone;

[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,5-dimethoxy-phenyl]-morpholin-4-yl-methanone;

[2-Chloro-5-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

(4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxyphenyl)(perdeuteromorpholino)methanone;

(5-bromo-2-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)(morpholino)methanone;

[4-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-methoxy-2-methyl-phenyl]-morpholin-4-yl-methanone; and

[2,5-Dimethyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone.

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

DETAILED DESCRIPTION

definition

Unless otherwise indicated, the following terms used in this application, including the specification and claims, have the definitions given below. It must be noted that, when 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" refers to a monovalent straight or branched chain saturated hydrocarbon moiety composed solely of carbon and hydrogen atoms, having from one to twelve carbon atoms. "Lower alkyl" refers to an alkyl group having from one to six carbon atoms, i.e., a C1 _{- C6} alkyl group. 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" refers to a linear 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, for example, ethenyl, propenyl, and the like.

"Alkynyl" refers to a straight-chain monovalent hydrocarbon radical of two to six carbon atoms or a branched-chain monovalent hydrocarbon radical of three to six carbon atoms containing at least one triple bond, for example, ethynyl, propynyl, and the like.

"Alkylene" refers to a straight-chain saturated divalent hydrocarbon group of one to six carbon atoms or a branched-chain saturated divalent hydrocarbon group of three to six carbon atoms, for example, methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene, etc.

"Alkoxy" and "alkyloxy" are used interchangeably and 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- ^ORb- , wherein ^Ra and ^Rb are alkyl and alkylene, respectively, 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.

"Alkoxyalkoxy" means a radical of the formula -O-R-R' wherein R and R' are alkylene and alkoxy respectively as defined herein.

"Alkylcarbonyl" means a moiety of the formula -C(O)-R, wherein R is alkyl as defined herein.

"Alkoxycarbonyl" means a group of the formula -C(O)-R where R is alkoxy as defined herein.

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

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

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

"Hydroxycarbonylalkoxy" means a group of the formula -O-R-C(O)-OH where R is alkylene as defined herein.

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

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

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

"Dialkylaminoalkoxy" refers to a radical of the formula -O-R-NR'R' where R is alkylene and R' and R" are alkyl as defined herein.

"Alkylsulfonyl" means a moiety of the formula _-SO2 -R, wherein R is alkyl as defined herein.

"Alkylsulfonylalkyl" means a moiety of the formula -R'-SO2- _R " wherein R' and R" are alkylene and alkyl, respectively, as defined herein.

"Alkylsulfonylalkoxy" refers to a radical of the formula -OR-SO2- _R ' wherein R and R' are alkylene and alkyl, respectively, as defined herein.

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

"Aminocarbonyl" means a group of the formula -C(O)-R wherein R is amino as defined herein.

"Alkoxyamino" means a moiety of the formula -NR-OR' wherein R is hydrogen or alkyl and R' is alkyl, wherein alkyl is as defined herein.

"Alkylthio" means a moiety of the formula -SR where R is alkyl as defined herein.

"Aminoalkyl" refers to the group -R-R', where R' and R are amino and alkylene, respectively, as defined herein. "Aminoalkyl" includes aminomethyl, aminoethyl, 1-aminopropyl, 2-aminopropyl, and the like. The amino portion 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', wherein R' and R' are amino and alkylene, respectively, as defined herein.

"Alkylsulfonamido" refers to a moiety of the formula -NR'SO2- _R , where R is alkyl and R' is hydrogen or alkyl.

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

"Alkynylalkoxy" means a radical of the formula -O-R-R' wherein R and R' are alkylene and alkynyl, respectively, as defined herein.

"Aryl" refers to a monovalent cyclic aromatic hydrocarbon moiety consisting of a monocyclic, bicyclic or tricyclic aromatic ring. Aryl can be optionally substituted as defined herein. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfide, diphenylsulfonyl, diphenylisopropylidene, benzodialkyl, benzofuranyl, benzodioxolyl (benzodioxylyl), benzopyranyl, benzoxazinyl, benzoxazinonyl (benzoxazinonyl), benzopiperidinyl (benzopiperadinyl), benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl etc., which can be optionally substituted as defined herein.

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

"Arylsulfonyl" means a group of the formula -SO2- _R where R is aryl as defined herein.

"Aryloxy" means a group of the formula -O-R wherein R is aryl as defined herein.

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

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

"Cyanoalkyl" means 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 monocyclic or bicyclic 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, each of which 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" means a moiety of the formula -R'-R", wherein R' and R" are alkylene and cycloalkyl, respectively, as defined herein.

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

"Heteroaryl" refers to 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, with 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,

oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thienyl, furanyl, pyranyl, pyridinyl, pyrrolyl, pyrazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, benzothiopyranyl, benzimidazolyl, benzoxazolyl, benzodiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, 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' where R and R' are alkylene and heteroaryl, respectively, as defined herein.

"Heteroarylsulfonyl" means a group of the formula _-SO2 -R where R is heteroaryl as defined herein.

"Heteroaryloxy" means a group of the formula -O-R where R is heteroaryl as defined herein.

"Heteroaralkyloxy" means a radical 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, in which one or more hydrogens have been replaced _{by the same or different halogens. Exemplary haloalkyl groups include -CH2Cl, -CH2CF3, -CH2CC13 , perfluoroalkyl (} eg, _-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, 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, azepine, pyrrolidinyl, azetidinyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, etc. The heterocyclyl may be optionally substituted as defined herein.

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

"Heterocyclyloxy" means a moiety of the formula -OR where R is heterocyclyl as defined herein.

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

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

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

"Hydroxyalkylaminoalkyl" means 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 where R is alkylene as defined herein.

"Hydroxycarbonylalkoxy" means a group of the formula -O-R-C(O)-OH where R is alkylene as defined herein.

"Hydroxyalkyloxycarbonylalkyl" or "hydroxyalkoxycarbonylalkyl" refers to a radical of the formula -R-C(O)-O-R-OH where each R is an alkylene radical and can be the same or different.

"Hydroxyalkyl" refers to an alkyl moiety as defined herein that is substituted with one or more, e.g., one, two, or three, hydroxy groups, provided that the same carbon atom does not carry more than one hydroxy 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 of the cycloalkyl group have been replaced by hydroxy substituents. 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 that is 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-prop-1-yl and the like.

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

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

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

"Sulfonamido" refers to a radical of the formula _-SO2- NR'R" wherein R', R" and R'" are each independently hydrogen or alkyl.

"Optionally substituted," when used in conjunction with an "aryl," "phenyl," "heteroaryl," "cycloalkyl," or "heterocyclyl" moiety, means that the moiety may be unsubstituted (i.e., all open valence states are occupied by hydrogen atoms) or substituted with a specific group as described 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 methylsulfonyloxy, ethylsulfonyloxy, thiomethyl, phenylsulfonyloxy, toluenesulfonyloxy, and thienyloxy, dihalophosphonyloxy, 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, etc., as defined herein.

"Optional" or "optionally" means that the subsequently described event or circumstance can 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 condition" refer to any disease, condition, symptom, disorder, or sign.

"Inert organic solvent" or "inert solvent" means that the solvent is inert under the conditions of the reaction described in conjunction with it, and includes, for example, benzene, toluene, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, chloroform, methylene chloride or dichloromethane, dichloroethane, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine, etc. Unless otherwise specified, the solvent used in the reaction of the present invention is an inert solvent.

"Pharmaceutically acceptable" means that it can be used to prepare a pharmaceutical composition that is generally safe, non-toxic, and not biologically or otherwise undesirable, and includes that it is acceptable for veterinary as well as human pharmaceutical use.

A "pharmaceutically acceptable salt" of a compound refers to a salt that is pharmaceutically acceptable, as defined herein, and that possesses the desired pharmacological activity of the parent compound.

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

"Protecting group" or "blocking group" refers to a group that, in the sense conventionally associated with it in synthetic chemistry, selectively blocks one reactive site in a multifunctional compound so that a chemical reaction can proceed selectively at another unprotected reactive site. 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 that are intended to protect the nitrogen atom from undesirable reactions during a synthetic procedure. 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. One skilled in the art will appreciate how to select a group that is easily removable and has the ability to withstand subsequent reactions.

"Solvate" refers to a solvent addition form containing either stoichiometric or non-stoichiometric amounts of a solvent. Some compounds have a tendency to capture a fixed molar ratio of solvent molecules in the crystalline solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate, while 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 a substance in which the water remains in its molecular form, _H₂O . Such a combination can form 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 can include, for example, muscle stiffness, tremors, slowed body movements (bradykinesia), and loss of body movement (akinesia).

Lewy body disease, also known as Lewy body dementia, diffuse Lewy body disease, or cortical Lewy body disease, is a neurogenic disorder characterized anatomically by the presence of Lewy bodies in the brain.

"Subject" refers to both mammals and non-mammals. Mammals refer to any member of the class mammalia, 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; and laboratory animals including rodents such as rats, mice, and guinea pigs. Examples of non-mammals include, but are not limited to, birds. The term "subject" does not denote a specific age or sex.

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

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

"Treatment" or "treatment" of a disease state specifically includes inhibiting the disease state, ie, arresting the development of the disease state or its clinical symptoms, and/or alleviating the disease state, ie, causing a temporary or permanent reduction in the disease state or its clinical symptoms.

When referring to a chemical reaction, the terms "treating," "contacting," and "reacting" refer to the addition or mixing of two or more reagents under appropriate conditions to produce a specified and/or desired product. It should be understood that the reaction to produce a 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 lead to the formation of the specified and/or desired product.

Naming and structure

Generally, the nomenclature and chemical names used in this application are based on ChembioOffice ^™ from CambridgeSoft ^™ . Unless otherwise indicated, any open valence present on a carbon, oxygen, sulfur, or nitrogen atom in the structure herein represents the presence of a hydrogen atom. Nitrogen-containing heteroaryl rings are shown to have open valence on the nitrogen atom, and variables such as ^Ra , ^Rb , or ^Rc are shown on the heteroaryl ring, such variables may be combined or bonded to the open valence nitrogen. Where a chiral center is present in the structure but no specific stereochemistry is shown for the chiral center, both enantiomers associated with the chiral center are encompassed by the structure. Where the structure shown in this article can exist in multiple tautomer forms, all such tautomers are encompassed by the structure. The atoms represented in the structure herein are intended to encompass all natural isotopes of such atoms. Therefore, for example, the hydrogen atoms represented herein are meant to include deuterium and tritium, and the carbon atom is meant to include ^C13 and ^C14 isotopes.

Compounds of the present invention

The present invention provides a compound of formula A:

or a pharmaceutically acceptable salt thereof,

in:

m is 0 to 3;

X is: -NR ^a -; -O-; or -S(O) _r -, wherein r is 0 to 2 and ^Ra is hydrogen or C _1-6 alkyl;

R ¹ is: C _1-6 alkyl; C _2-6 alkenyl; C _2-6 alkynyl; halo-C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; hydroxy-C _1-6 alkyl; amino-C _1-6 alkyl; C _1-6 alkylsulfonyl-C _1-6 alkyl; C _{3-6 cycloalkyl optionally substituted by C 1-6 alkyl} or halo; C _3-6 cycloalkyl-C _1-6 alkyl, wherein the C _3-6 cycloalkyl portion is optionally substituted by C _1-6 alkyl; tetrahydropyranyl; tetrahydrofuranyl; tetrahydrofuranyl-C _1-6 alkyl; oxetanyl; or oxetanyl-C _1-6 alkyl;

or R ¹ and R ^a together with the atoms to which they are attached may form a three to six membered ring, said three to six membered ring may optionally include additional heteroatoms selected from O, N and S, and which is substituted with oxo, halo or C _1-6 alkyl;

R ² is: halo; C _1-6 alkoxy; cyano; C _2-6 alkynyl; C _2-6 alkenyl; halo-C _1-6 alkyl; halo-C _1-6 alkoxy; C _3-6 cycloalkyl, wherein the C _3-6 cycloalkyl portion is optionally substituted with C _1-6 alkyl; C _3-6 cycloalkyl-C _1-6 alkyl, wherein the C _3-6 cycloalkyl portion is optionally substituted with C _1-6 alkyl; tetrahydrofuranyl; tetrahydrofuranyl-C _1-6 alkyl; acetyl; oxetanyl; or oxetanyl-C _1-6 alkyl;

R ^3a is: -OR ⁴ ; halo; cyano; C _1-6 alkyl; halo-C _1-6 alkyl; C _3-6 cycloalkyl optionally substituted by C _1-6 alkyl; C _3-6 cycloalkyl-C _1-6 alkyl, wherein the C _3-6 cycloalkyl portion is optionally substituted by C _1-6 alkyl; tetrahydrofuranyl; tetrahydrofuranyl-C _1-6 alkyl; oxetanyl; or oxetanyl-C _1-6 alkyl;

R ^3b is: hydrogen,

or R ^3a and R ^3b together with the atoms to which they are attached may form a five- or six-membered ring, said five- or six-membered ring optionally comprising one or two heteroatoms each independently selected from O, N and S, said ring optionally being substituted one or more times with R ⁸ ;

R ⁴ is: hydrogen; C _1-6 alkyl; halo-C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; C _3-6 cycloalkyl optionally substituted by C _1-6 alkyl or halo; C _3-6 cycloalkyl-C _1-6 alkyl, wherein the C _3-6 cycloalkyl portion is optionally substituted by C _1-6 alkyl or halo; tetrahydrofuranyl; tetrahydrofuranyl-C _1-6 alkyl; oxetanyl; or oxetanyl-C _1-6 alkyl;

^R5 is: hydrogen; or _C1-6 alkyl;

R ⁶ is: hydrogen; C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; hydroxy-C _1-6 alkyl; amino-C _1-6 alkyl; C _3-6 cycloalkyl; C _3-6 cycloalkyl-C _1-6 alkyl; heteroaryl, heterocyclyl; or heterocyclyl-C _1-6 alkyl; wherein the C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-6 alkyl, heteroaryl, heterocyclyl and heterocyclyl-C _1-6 alkyl each may be optionally substituted with one, two, three or four groups independently selected from: C _1-6 alkyl; halo-C _1-6 alkyl; C _1-6 alkoxy; halo-C _1-6 alkoxy; hydroxy; hydroxy-C _1-6 alkyl; halo; nitrile; C _1-6 alkyl-carbonyl; C _1-6 alkyl-sulfonyl; C _3-6 cycloalkyl; C _3-6 cycloalkyl-C _1-6 alkyl; C _3-6 cycloalkyl-carbonyl; amino; or heterocyclyl; or two of said groups together with the atoms to which they are attached may form a five- or six-membered ring;

or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a three to seven membered ring, said three to seven membered ring optionally including additional heteroatoms selected from O, N and S(O) _n , and which is optionally substituted by one, two, three or four groups independently selected from: C _1-6 alkyl; halo-C _1-6 alkyl; C _1-6 alkoxy; halo-C _1-6 alkoxy; hydroxy; C _1-6 alkoxy-C _1-6 alkyl; hydroxy-C _1-6 alkyl; halo, nitrile; C _1-6 alkyl-carbonyl; C _1-6 alkyl-sulfonyl; C _3-6 cycloalkyl; C _3-6 cycloalkyl-C _1-6 alkyl; C _3-6 cycloalkyl-carbonyl; amino; or heterocyclyl; or two of said groups together with the atom to which they are attached may form a five or six membered ring; and

R ⁷ is: halo; C _1-6 alkyl; C _1-6 alkoxy; halo-C _1-6 alkyl; or halo-C _1-6 alkoxy;

R ⁸ is: halo; C _1-6 alkyl; or oxo.

The present invention provides a compound of formula A, which is selected from the group consisting of formula I, II and III.

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , X, Y, Z, A and m are as defined herein.

The present invention provides a compound of formula A,

in:

m is 0 to 1;

X is: -NR ^a - or -O-, wherein R ^a is hydrogen;

R1 ^is : _C1-6 alkyl or _C3-6 cycloalkyl;

or R ¹ and R ^a together with the atoms to which they are attached can form a three- to six-membered ring;

^R2 is: halo; cyano or halo- _C1-6 alkyl;

R ^3a is: -OR ⁴ ; halogenated or C _1-6 alkyl;

R ^3b is: hydrogen,

or R ^3a and R ^3b together with the atoms to which they are attached may form a five- or six-membered ring, said five- or six-membered ring optionally comprising one or two heteroatoms each independently selected from O, N and S, said ring optionally being substituted one or more times with R ⁸ ;

R ⁴ is: hydrogen; C _1-6 alkyl; halo-C _1-6 alkyl; C _3-6 cycloalkyl optionally substituted by C _1-6 alkyl or halo; C _3-6 cycloalkyl-C _1-6 alkyl, wherein the C _3-6 cycloalkyl portion is optionally substituted by C _1-6 alkyl or halo;

^R5 is: hydrogen or _C1-6 alkyl;

R ⁶ is: C _1-6 alkyl; hydroxy-C _1-6 alkyl; C _3-6 cycloalkyl; C _3-6 cycloalkyl-C _1-6 alkyl or heterocyclyl; wherein the C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-6 alkyl and heterocyclyl can each be optionally substituted by one, two, three or four groups independently selected from: C _1-6 alkyl; hydroxy and hydroxy-C _1-6 alkyl;

or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a three to seven membered ring, said three to seven membered ring optionally including additional heteroatoms selected from O and N, and which is optionally substituted with one, two, three or four groups independently selected from: C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; halo; or heterocyclyl; or two of said groups together with the atom to which they are attached may form a five or six membered ring; and

R ⁷ is: halo; C _1-6 alkyl; C _1-6 alkoxy; halo-C _1-6 alkyl; or halo-C _1-6 alkoxy;

R ⁸ is: halo; C _1-6 alkyl; or oxo.

The present invention provides a compound of formula I:

or a pharmaceutically acceptable salt thereof,

in:

m is 0 to 3;

X is: -NR ^a -; -O-; or -S(O) _r -, wherein r is 0 to 2 and ^Ra is hydrogen or C _1-6 alkyl;

R ¹ is: C _1-6 alkyl; C _2-6 alkenyl; C _2-6 alkynyl; halo-C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; hydroxy-C _1-6 alkyl; amino-C _1-6 alkyl; C _1-6 alkylsulfonyl-C _1-6 alkyl; C _{3-6 cycloalkyl optionally substituted by C 1-6 alkyl} or halo; C _3-6 cycloalkyl-C _1-6 alkyl, wherein the C _3-6 cycloalkyl portion is optionally substituted by C _1-6 alkyl; tetrahydropyranyl; tetrahydrofuranyl; tetrahydrofuranyl-C _1-6 alkyl; oxetanyl; or oxetanyl-C _1-6 alkyl;

or R ¹ and R ^a together with the atoms to which they are attached may form a three to six membered ring, said three to six membered ring may optionally include additional heteroatoms selected from O, N and S, and which is substituted with oxo, halo or C _1-6 alkyl;

R ² is: halo; C _1-6 alkoxy; cyano; C _2-6 alkynyl; C _2-6 alkenyl; halo-C _1-6 alkyl; halo-C _1-6 alkoxy; C _3-6 cycloalkyl, wherein the C _3-6 cycloalkyl portion is optionally substituted with C _1-6 alkyl; C _3-6 cycloalkyl-C _1-6 alkyl, wherein the C _3-6 cycloalkyl portion is optionally substituted with C _1-6 alkyl; tetrahydrofuranyl; tetrahydrofuranyl-C _1-6 alkyl; acetyl; oxetanyl; or oxetanyl-C _1-6 alkyl;

R ³ is: -OR ⁴ ; halo; cyano; C _1-6 alkyl; halo-C _1-6 alkyl; C _3-6 cycloalkyl optionally substituted by C _1-6 alkyl; C _3-6 cycloalkyl-C _1-6 alkyl, wherein the C _3-6 cycloalkyl portion is optionally substituted by C _1-6 alkyl; tetrahydrofuranyl; tetrahydrofuranyl-C _1-6 alkyl; oxetanyl; or oxetanyl-C _1-6 alkyl;

R ⁴ is: hydrogen; C _1-6 alkyl; halo-C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; C _3-6 cycloalkyl optionally substituted by C _1-6 alkyl or halo; C _3-6 cycloalkyl-C _1-6 alkyl, wherein the C _3-6 cycloalkyl portion is optionally substituted by C _1-6 alkyl or halo; tetrahydrofuranyl; tetrahydrofuranyl-C _1-6 alkyl; oxetanyl; or oxetanyl-C _1-6 alkyl;

^R5 is: hydrogen; or _C1-6 alkyl;

R ⁶ is: hydrogen; C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; hydroxy-C _1-6 alkyl; amino-C _1-6 alkyl; C _3-6 cycloalkyl; C _3-6 cycloalkyl-C _1-6 alkyl; heteroaryl, heterocyclyl; or heterocyclyl-C _1-6 alkyl; wherein the C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-6 alkyl, heteroaryl, heterocyclyl and heterocyclyl-C _1-6 alkyl each may be optionally substituted with one, two, three or four groups independently selected from: C _1-6 alkyl; halo-C _1-6 alkyl; C _1-6 alkoxy; halo-C _1-6 alkoxy; hydroxy; hydroxy-C _1-6 alkyl; halo; nitrile; C _1-6 alkyl-carbonyl; C _1-6 alkyl-sulfonyl; C _3-6 cycloalkyl; C _3-6 cycloalkyl-C _1-6 alkyl; C _3-6 cycloalkyl-carbonyl; amino; or heterocyclyl; or two of said groups together with the atoms to which they are attached may form a five- or six-membered ring;

or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a three to seven membered ring, said three to seven membered ring optionally including additional heteroatoms selected from O, N and S(O) _n , and which is optionally substituted by one, two, three or four groups independently selected from: C _1-6 alkyl; halo-C _1-6 alkyl; C _1-6 alkoxy; halo-C _1-6 alkoxy; hydroxy; C _1-6 alkoxy-C _1-6 alkyl; hydroxy-C _1-6 alkyl; halo, nitrile; C _1-6 alkyl-carbonyl; C _1-6 alkyl-sulfonyl; C _3-6 cycloalkyl; C _3-6 cycloalkyl-C _1-6 alkyl; C _3-6 cycloalkyl-carbonyl; amino; or heterocyclyl; or two of said groups together with the atom to which they are attached may form a five or six membered ring; and

R ⁷ is: halo; C _1-6 alkyl; C _1-6 alkoxy; halo-C _1-6 alkyl; or halo-C _1-6 alkoxy;

wherein the compound is selected from:

[5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-[4-(2-methoxy-ethyl)-piperazin-1-yl]-methanone;

[5-Chloro-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[5-Methoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[2-Fluoro-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-methanone;

[2-Fluoro-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(1S,5R)-8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl-methanone;

[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-(1S,5R)-8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl-methanone;

2-Fluoro-5-methoxy-N-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-benzamide;

[2-Fluoro-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(4-morpholin-4-yl-piperidin-1-yl)-methanone;

[4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-3-hydroxy-phenyl]-morpholin-4-yl-methanone;

[5-Chloro-2-hydroxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[2-Fluoro-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-methanone;

[2,3-Difluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[4-(5-Chloro-4-methylamino-pyrimidin-2-ylamino)-2,3-difluoro-phenyl]-morpholin-4-yl-methanone;

[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-methanone;

[5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-methanone;

[2,5-Difluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[4-(5-Chloro-4-methylamino-pyrimidin-2-ylamino)-2,5-difluoro-phenyl]-morpholin-4-yl-methanone;

4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(2-hydroxy-2-methyl-propyl)-5-methoxy-benzamide;

4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(2-hydroxy-2-methyl-propyl)-5-methoxy-N-methyl-benzamide;

[5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(3-morpholin-4-yl-azetidin-1-yl)-methanone;

N-tert-Butyl-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methoxy-benzamide;

[3-Fluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(4-oxetan-3-yl-piperazin-1-yl)-methanone;

[5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(3,3-difluoro-pyrrolidin-1-yl)-methanone;

[4-(4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-morpholin-4-yl-methanone;

[4-(4-Azetidin-1-yl-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-morpholin-4-yl-methanone;

5-Fluoro-N-(2-hydroxy-2-methyl-propyl)-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide;

4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-N-(2-hydroxy-2-methyl-propyl)-2-methoxy-benzamide;

5-Fluoro-N-(2-hydroxy-2-methyl-propyl)-2-methoxy-N-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide;

4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-N-(2-hydroxy-2-methyl-propyl)-2-methoxy-N-methyl-benzamide;

[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,5-difluoro-phenyl]-morpholin-4-yl-methanone;

[2-Fluoro-4-(4-isopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-methoxy-phenyl]-morpholin-4-yl-methanone;

[3-Methoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-(1-oxa-6-aza-spiro[3.3]hept-6-yl)-methanone;

2-Fluoro-N-(2-hydroxy-2-methyl-propyl)-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide;

((3S,4S)-3,4-Difluoro-pyrrolidin-1-yl)-[2-fluoro-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-methanone;

4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-N-methyl-benzamide;

2-Fluoro-N-(2-hydroxy-2-methyl-propyl)-3-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide;

(3,3-Difluoro-pyrrolidin-1-yl)-[5-(2-fluoro-ethoxy)-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-methanone;

[5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(1-oxa-6-aza-spiro[3.3]hept-6-yl)-methanone;

[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-difluoro-phenyl]-morpholin-4-yl-methanone;

[4-(4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-methoxy-2-methyl-phenyl]-morpholin-4-yl-methanone;

[5-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-methoxy-phenyl]-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-methanone;

[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-methoxy-2-methyl-phenyl]-morpholin-4-yl-methanone;

4-(4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(2-hydroxy-2-methyl-propyl)-5-methoxy-benzamide;

N-tert-Butyl-4-(5-cyano-4-ethylamino-pyrimidin-2-ylamino)-3-methoxy-benzamide;

[3-Difluoromethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[2-Fluoro-5-(2-fluoro-ethoxy)-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-(2-fluoro-ethoxy)-phenyl]-morpholin-4-yl-methanone;

[2-Fluoro-5-methoxy-4-(4-methoxy-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[4-(4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-difluoro-phenyl]-morpholin-4-yl-methanone;

[4-(4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,5-difluoro-phenyl]-morpholin-4-yl-methanone;

[2-Chloro-5-fluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

4-Ethylamino-2-[4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-2-methoxy-phenylamino]-pyrimidine-5-carbonitrile;

5-Chloro-2-methoxy-N-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-N-(1-methyl-1H-pyrazol-4-yl)-benzamide;

(3,3-Difluoro-pyrrolidin-1-yl)-[4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,5-dimethoxy-phenyl]-methanone;

[4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-3-(2-fluoro-ethoxy)-phenyl]-morpholin-4-yl-methanone;

[2-Methoxy-5-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[2-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-phenyl]-morpholin-4-yl-methanone;

[3-Chloro-2-fluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

(3,3-Difluoro-pyrrolidin-1-yl)-[4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-(2-fluoro-ethoxy)-2-methoxy-phenyl]-methanone;

[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,6-difluoro-3-methoxy-phenyl]-morpholin-4-yl-methanone;

[2,6-Difluoro-3-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[4-(4-Ethoxy-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-morpholin-4-yl-methanone;

[2,5-Dimethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

(3,3-Difluoro-pyrrolidin-1-yl)-[4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoromethoxy-2-methoxy-phenyl]-methanone;

[5-Methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-trifluoromethyl-phenyl]-morpholin-4-yl-methanone;

[4-(5-Chloro-4-methylamino-pyrimidin-2-ylamino)-5-methoxy-2-trifluoromethyl-phenyl]-morpholin-4-yl-methanone;

[5-Chloro-2-fluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[4-(4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-(2-fluoro-ethoxy)-phenyl]-morpholin-4-yl-methanone;

[5-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-methyl-phenyl]-morpholin-4-yl-methanone;

[5-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoromethoxy-phenyl]-morpholin-4-yl-methanone;

[5-Fluoro-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[5-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-phenyl]-morpholin-4-yl-methanone;

{2-Fluoro-4-[4-((1R,2S)-2-fluoro-cyclopropylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-5-methoxy-phenyl}-morpholin-4-yl-methanone;

(2,2-Dimethyl-morpholin-4-yl)-[2-fluoro-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-methanone;

[3-Cyclopropyloxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[5-Chloro-2-difluoromethoxy-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[5-Chloro-2-difluoromethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

4-Ethylamino-2-[5-fluoro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-2-methoxy-phenylamino]-pyrimidine-5-carbonitrile;

4-Ethylamino-2-[2-fluoro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-5-methoxy-phenylamino]-pyrimidine-5-carbonitrile;

[3-Chloro-2,6-dimethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

(2,2-Dimethyl-morpholin-4-yl)-[3-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-methanone;

[5-(2-Fluoro-ethoxy)-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[5-(2-Fluoro-ethoxy)-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-pyrrolidin-1-yl-methanone;

(5-chloro-4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-methoxyphenyl)(perdeuteromorpholino)methanone;

[4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-2,5-dimethoxy-phenyl]-morpholin-4-yl-methanone;

[5-Fluoromethoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

{4-[Ethyl-(4-methylamino-5-trifluoromethyl-pyrimidin-2-yl)-amino]-5-fluoromethoxy-2-methyl-phenyl}-morpholin-4-yl-methanone;

[5-Fluoromethoxy-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-pyrrolidin-1-yl-methanone;

[4-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-morpholin-4-yl-methanone;

[2-Fluoro-5-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-5-methoxy-2-methyl-phenyl]-morpholin-4-yl-methanone;

[4-(5-Chloro-4-ethoxy-pyrimidin-2-ylamino)-5-methoxy-2-methyl-phenyl]-morpholin-4-yl-methanone;

[2-Fluoro-5-fluoromethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-pyrrolidin-1-yl-methanone;

4-Cyclopropylamino-2-[4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-2-methoxy-phenylamino]-pyrimidine-5-carbonitrile;

4-Ethylamino-2-[4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-2-methoxy-5-methyl-phenylamino]-pyrimidine-5-carbonitrile;

4-Ethylamino-2-[2-fluoro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-phenylamino]-pyrimidine-5-carbonitrile;

[5-Isopropoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[5-Ethoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[5-Fluoromethoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-pyrrolidin-1-yl-methanone;

[5-Chloro-4-(4-cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoromethoxy-phenyl]-morpholin-4-yl-methanone;

[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-2-methyl-phenyl]-morpholin-4-yl-methanone;

(5-methoxy-2-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)(perdeuteromorpholino)methanone;

4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-N-(2-hydroxy-2-methyl-propyl)-5-methoxy-2-methyl-benzamide;

4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(2-hydroxy-1,1-dimethyl-ethyl)-5-methoxy-benzamide;

2-[2-Chloro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-5-methyl-phenylamino]-4-ethylamino-pyrimidine-5-carbonitrile;

2-[2-Chloro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-phenylamino]-4-ethylamino-pyrimidine-5-carbonitrile;

[5-Cyclopropylmethoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

[5-Fluoromethoxy-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-piperidin-1-yl-methanone;

[5-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoromethoxy-phenyl]-pyrrolidin-1-yl-methanone;

[4-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-2-methoxy-phenyl]-morpholin-4-yl-methanone;

[5-Chloro-4-(4-cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-methoxy-phenyl]-morpholin-4-yl-methanone;

4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(1-hydroxymethyl-cyclopropyl)-5-methoxy-benzamide;

4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(1-hydroxy-cyclopropylmethyl)-5-methoxy-benzamide;

N-(2-Hydroxy-2-methyl-propyl)-5-methoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide;

2-[2-Chloro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-5-methoxy-phenylamino]-4-ethylamino-pyrimidine-5-carbonitrile;

[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methyl-phenyl]-morpholin-4-yl-methanone;

[4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-5-fluoromethoxy-2-methyl-phenyl]-pyrrolidin-1-yl-methanone;

5-Fluoromethoxy-2-methoxy-N,N-dimethyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide;

[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-2-fluoromethoxy-phenyl]-pyrrolidin-1-yl-methanone;

[3-Fluoro-2,6-dimethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

(4-(4-(2,3-tetradeuterio-cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxyphenyl)(morpholino)methanone;

[5-Methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-trifluoromethoxy-phenyl]-morpholin-4-yl-methanone;

[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,5-dimethoxy-phenyl]-morpholin-4-yl-methanone;

[2-Chloro-5-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;

(4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxyphenyl)(perdeuteromorpholino)methanone;

(5-bromo-2-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)(morpholino)methanone;

[4-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-methoxy-2-methyl-phenyl]-morpholin-4-yl-methanone; and

[2,5-Dimethyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone.

In another aspect of the present invention there is provided a compound of formula II:

or a pharmaceutically acceptable salt thereof,

A is a five- or six-membered ring optionally including one or two heteroatoms each independently selected from O, N and S, and ring A is optionally substituted one or more times by R ⁸ ;

m is 0 to 2;

X is: -NR ^a -; -O-; or -S(O) _r -, wherein r is 0 to 2 and ^Ra is hydrogen or C _1-6 alkyl;

R ¹ is: C _1-6 alkyl; C _2-6 alkenyl; C _2-6 alkynyl; halo-C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; hydroxy-C _1-6 alkyl; amino-C _1-6 alkyl; C _1-6 alkylsulfonyl-C _1-6 alkyl; C _3-6 cycloalkyl optionally substituted by C _1-6 alkyl; C _3-6 cycloalkyl-C _1-6 alkyl, wherein the C _3-6 cycloalkyl portion is optionally substituted by C _1-6 alkyl; tetrahydropyranyl; tetrahydrofuranyl; tetrahydrofuranyl-C _1-6 alkyl; oxetanyl; or oxetanyl-C _1-6 alkyl;

or R ¹ and R ^a together with the atoms to which they are attached may form a three to six membered ring, said three to six membered ring may optionally include additional heteroatoms selected from O, N and S, and which is substituted with oxo, halo or C _1-6 alkyl;

R ² is: halo; C _1-6 alkoxy; cyano; C _2-6 alkynyl; C _2-6 alkenyl; halo-C _1-6 alkyl; halo-C _1-6 alkoxy; C _3-6 cycloalkyl, wherein the C _3-6 cycloalkyl portion is optionally substituted with C _1-6 alkyl; C _3-6 cycloalkyl-C _1-6 alkyl, wherein the C _3-6 cycloalkyl portion is optionally substituted with C _1-6 alkyl; tetrahydrofuranyl; tetrahydrofuranyl-C _1-6 alkyl; acetyl; oxetanyl; or oxetanyl-C _1-6 alkyl;

^R5 is: hydrogen; or _C1-6 alkyl;

R ⁶ is: hydrogen; C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; hydroxy-C _1-6 alkyl; amino-C _1-6 alkyl; C _3-6 cycloalkyl; C _3-6 cycloalkyl-C _1-6 alkyl; heterocyclyl; or heterocyclyl-C _1-6 alkyl; wherein the C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-6 alkyl, heterocyclyl and heterocyclyl-C _1-6 alkyl each may be optionally substituted with one, two, three or four groups independently selected from: C _1-6 alkyl; halo-C _1-6 alkyl; C _1-6 alkoxy; halo-C _1-6 alkoxy; hydroxy; hydroxy-C _1-6 alkyl; halo; nitrile; C _1-6 alkyl-carbonyl; C _1-6 alkyl-sulfonyl; C _3-6 cycloalkyl; C _3-6 cycloalkyl-C _1-6 alkyl; C _3-6 cycloalkyl-carbonyl; amino; or heterocyclyl; or two of said groups together with the atoms to which they are attached may form a five- or six-membered ring;

or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a three to seven membered ring, said three to seven membered ring optionally including additional heteroatoms selected from O, N and S(O) _n , and which is optionally substituted by one, two, three or four groups independently selected from: C _1-6 alkyl; halo-C _1-6 alkyl; C _1-6 alkoxy; halo-C _1-6 alkoxy; hydroxy; C _1-6 alkoxy-C _1-6 alkyl; hydroxy-C _1-6 alkyl; halo, nitrile; C _1-6 alkyl-carbonyl; C _1-6 alkyl-sulfonyl; C _3-6 cycloalkyl; C _3-6 cycloalkyl-C _1-6 alkyl; C _3-6 cycloalkyl-carbonyl; amino; or heterocyclyl; or two of said groups together with the atom to which they are attached may form a five or six membered ring;

^R7 is: halo; _C1-6 alkyl; _C1-6 alkoxy; halo- _C1-6 alkyl; or halo- _C1-6 alkoxy; and

R ⁸ is: halo; C _1-6 alkyl; or oxo.

In certain embodiments, the compound of Formula II may have Formula III:

or a pharmaceutically acceptable salt thereof,

in:

Y is -O- or -CHR ⁸ -;

Z is -O- or -CHR ⁸ -, or Z is absent; and

m, R ¹ , R ² , R ⁵ , R ⁶ , R ⁷ and R ⁸ are as defined herein for Formula II.

In certain embodiments of Formula II or Formula III, m is 0 or 1.

In certain embodiments of Formula II or Formula III, m is 0.

In certain embodiments of Formula II or Formula III, m is 1.

In certain embodiments of Formula II or Formula III, r is 0.

In certain embodiments of Formula II or Formula III, r is 2.

In certain embodiments of Formula II or Formula III, X is -NR ^a - or -O-.

In certain embodiments of Formula II or Formula III, X is -NR ^a .

In certain embodiments of Formula II or Formula III, X is -O-.

In certain embodiments of Formula II or Formula III, X is -S(O) _n- .

In certain embodiments of Formula II or Formula III, X is -NH- or -O-.

In certain embodiments of formula II or formula III, ^Ra is hydrogen.

In certain embodiments of formula II or formula III, ^Ra is _C1-6 alkyl.

In certain embodiments of formula II or formula III, R ¹ is: C _1-6 alkyl; halo-C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; amino-C _1-6 alkyl; C _1-6 alkylsulfonyl-C _1-6 alkyl; C _3-6 cycloalkyl; or C _3-6 cycloalkyl-C _1-6 alkyl.

In certain embodiments of formula II or formula III, R ¹ is: C _1-6 alkyl; C _3-6 cycloalkyl optionally substituted with C _1-6 alkyl; or C _3-6 cycloalkyl-C _1-6 alkyl, wherein the C _3-6 cycloalkyl portion is optionally substituted with C _1-6 alkyl.

In certain embodiments of formula II or formula III, R ¹ is: C _1-6 alkyl; halo-C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; amino-C _1-6 alkyl; C _1-6 alkylsulfonyl-C _1-6 alkyl; tetrahydrofuranyl; tetrahydrofuranyl-C _1-6 alkyl; oxetanyl; or oxetanyl-C _1-6 alkyl.

In certain embodiments of formula II or formula III, R ¹ is: C _1-6 alkyl; halo-C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; amino-C _1-6 alkyl; or C _1-6 alkylsulfonyl-C _1-6 alkyl.

In certain embodiments of formula II or formula III, R ¹ is C _1-6 alkyl.

In certain embodiments of formula II or formula III, R ¹ is halo-C _1-6 alkyl.

In certain embodiments of formula II or formula III, R ¹ is C _1-6 alkoxy-C _1-6 alkyl.

In certain embodiments of formula II or formula III, R ¹ is amino-C _1-6 alkyl.

In certain embodiments of formula II or formula III, R ¹ is C _1-6 alkylsulfonyl- _{C 1-6} alkyl optionally substituted with C 1-6 alkyl.

In certain embodiments of formula II or formula III, R ¹ is C _3-6 cycloalkyl optionally substituted with C _1-6 alkyl.

In certain embodiments of formula II or formula III, R ¹ is C _3-6 cycloalkyl-C _1-6 alkyl, wherein the C _3-6 cycloalkyl portion is optionally substituted with C _1-6 alkyl.

In certain embodiments of formula II or formula III, R ¹ is tetrahydropyranyl.

In certain embodiments of formula II or formula III, R ¹ is tetrahydrofuranyl.

In certain embodiments of formula II or formula III, R ¹ is tetrahydrofuranyl-C _1-6 alkyl; oxetanyl.

In certain embodiments of formula II or formula III, R ¹ is or oxetane-C _1-6 alkyl.

In certain embodiments of Formula II or Formula III, R ¹ is: methyl; ethyl; n-propyl; isopropyl; isobutyl; 3,3-dimethylpropyl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; cyclopropylmethyl; cyclobutylmethyl; cyclopentylmethyl; cyclopropylethyl; methoxyethyl; oxetanyl; or tetrahydrofuranylmethyl.

In certain embodiments of Formula II or Formula III, R ¹ is: methyl; ethyl; n-propyl; isopropyl; isobutyl; 3,3-dimethylpropyl; cyclopentyl; cyclohexyl; cyclopropylmethyl; cyclobutylmethyl; cyclopentylmethyl; cyclopropylethyl; methoxyethyl; oxetanyl; or tetrahydrofuranylmethyl.

In certain embodiments of Formula II or Formula III, R ¹ is: methyl; ethyl; n-propyl; isopropyl; isobutyl; 3,3-dimethylpropyl; cyclopentyl; cyclohexyl; cyclopentylmethyl; methoxyethyl; oxetanyl; or tetrahydrofuranylmethyl.

In certain embodiments of Formula II or Formula III, R ¹ is: methyl; ethyl; n-propyl; isopropyl; or isobutyl.

In certain embodiments of Formula II or Formula III, R ¹ is methyl or ethyl.

In certain embodiments of Formula II or Formula III, R ¹ is methyl.

In certain embodiments of Formula II or Formula III, R ¹ is ethyl.

In certain embodiments of formula II or formula III, R ¹ is: cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; cyclopropylmethyl; cyclobutylmethyl; cyclopentylmethyl; or cyclopropylethyl.

In certain embodiments of Formula II or Formula III, R ¹ is: cyclopentyl; cyclohexyl; or cyclopentylmethyl.

In certain embodiments of formula II or formula III, ^R2 is: halo; _C1-6 alkoxy; halo- _C1-6 alkyl; halo- _C1-6 alkoxy; _C3-6 cycloalkyl, wherein the _C3-6 cycloalkyl portion is optionally substituted with _C1-6 alkyl; _C3-6 cycloalkyl- _C1-6 alkyl, wherein the _C3-6 cycloalkyl portion is optionally substituted with _C1-6 alkyl; tetrahydrofuranyl; tetrahydrofuranyl- _C1-6 alkyl; oxetanyl; or oxetanyl- _C1-6 alkyl.

In certain embodiments of formula II or formula III, R ² is: halo; C _1-6 alkoxy; halo-C _1-6 alkyl; cyano; C _2-6 alkynyl; C _2-6 alkenyl; C _3-6 cycloalkyl; or C _3-6 cycloalkyl-C _1-6 alkyl.

In certain embodiments of formula II or formula III, R ² is: halo; C _1-6 alkoxy; halo-C _1-6 alkyl; cyano; C _3-6 cycloalkyl; or C _3-6 cycloalkyl-C _1-6 alkyl.

In certain embodiments of formula II or formula III, R ² is: halo; C _1-6 alkoxy; halo-C _1-6 alkyl; C _3-6 cycloalkyl; or C _3-6 cycloalkyl-C _1-6 alkyl.

In certain embodiments of formula II or formula III, R ² is: halo; halo-C _1-6 alkyl; or cyano.

In certain embodiments of formula II or formula III, R ² is: halo; or halo-C _1-6 alkyl.

In certain embodiments of Formula II or Formula III, R ² is halo.

In certain embodiments of formula II or formula III, R ² is C _1-6 alkoxy.

In certain embodiments of formula II or formula III, R ² is halo-C _1-6 alkoxy.

In certain embodiments of formula II or formula III, R ² is halo-C _1-6 alkyl.

In certain embodiments of formula II or formula III, R ² is C _3-6 cycloalkyl.

In certain embodiments of formula II or formula III, R ² is C _3-6 cycloalkyl-C _1-6 alkyl.

In certain embodiments of formula II or formula III, R ² is tetrahydrofuranyl.

In certain embodiments of formula II or formula III, R ² is tetrahydrofuranyl-C _1-6 alkyl.

In certain embodiments of Formula II or Formula III, R ² is oxetanyl.

In certain embodiments of formula II or formula III, R ² is oxetane-C _1-6 alkyl.

In certain embodiments of formula II or formula III, R ² is halo, trifluoromethyl, or cyano.

In certain embodiments of formula II or formula III, R ² is chloro, trifluoromethyl, or cyano.

In certain embodiments of formula II or formula III, R ² is fluoro, chloro, or bromo.

In certain embodiments of formula II or formula III, R ² is chloro.

In certain embodiments of Formula II or Formula III, R ² is fluoro.

In certain embodiments of formula II or formula III, R ² is bromo.

In certain embodiments of formula II or formula III, R ² is trifluoromethyl.

In certain embodiments of formula II or formula III, R ² is methoxy.

In certain embodiments of formula II or formula III, R ² is cyano.

In certain embodiments of formula II or formula III, R ² is C _2-6 alkynyl.

In certain embodiments of formula II or formula III, R ² is C _2-6 alkenyl.

In certain embodiments of Formula II or Formula III, R ⁵ is hydrogen.

In certain embodiments of formula II or formula III, R ⁵ is C _1-6 alkyl.

In certain embodiments of Formula II or Formula III, R ⁵ is methyl.

In certain embodiments of formula II or formula III, R ⁵ is ethyl.

In certain embodiments of formula II or formula III, R ⁶ is hydrogen.

In certain embodiments of formula II or formula III, R ⁶ is C _1-6 alkyl.

In certain embodiments of formula II or formula III, R ⁶ is C _1-6 alkoxy-C _1-6 alkyl.

In certain embodiments of formula II or formula III, R ⁶ is hydroxy-C _1-6 alkyl.

In certain embodiments of formula II or formula III, R ⁶ is amino-C _1-6 alkyl.

In certain embodiments of Formula II or Formula III, ^R6 is optionally substituted with one, two or three groups of _C3-6 cycloalkyl, said groups being independently selected from: _C1-6 alkyl; halo- _C1-6 alkyl; C1-6 alkoxy; halo- _C1-6 alkoxy; hydroxy; hydroxy- _C1-6 alkyl; halo; nitrile; _C1-6 alkyl-carbonyl _{; C1-6 alkyl} -sulfonyl; _C3-6 cycloalkyl; _C3-6 cycloalkyl- _C1-6 alkyl; _C3-6 cycloalkyl-carbonyl; amino; or heterocyclyl; or two of said groups together with the atoms to which they are attached may form a five- or six-membered ring.

In certain embodiments of formula II or formula III, ^R6 is _{C3-6cycloalkyl} - _C1-6alkyl , wherein the _{C3-6cycloalkyl} portion thereof is optionally substituted with one, two or three groups independently selected from: _C1-6alkyl ; halo-C1-6alkyl; C1-6alkoxy; halo- _C1-6alkoxy ; hydroxy; hydroxy- _C1-6alkyl ; halo; nitrile; _C1-6alkyl -carbonyl; _C1-6alkyl -sulfonyl; _{C3-6cycloalkyl} ; _{C3-6cycloalkyl} - _C1-6alkyl ; _{C3-6cycloalkyl} -carbonyl; amino; or _heterocyclyl ; or two of said groups, together with the atoms to which they are attached, may form a five- _or six-membered ring.

In the embodiment of Formula II or Formula III where ^R is a heterocyclic group, the heterocyclic group can be: azetidinyl; pyrrolidinyl; piperidinyl; piperazinyl; morpholinyl; thiomorpholinyl; 3-oxa-8-aza-bicyclo[3.2.1]octan-8-yl; 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl; or 8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl; each optionally substituted as defined herein.

In the embodiment of Formula II or Formula III where ^R is a heterocyclic group, the heterocyclic group can be: azetidinyl; pyrrolidinyl; piperidinyl; piperazinyl; or morpholinyl; each of which is optionally substituted as defined herein, that is, the heterocyclic group is optionally substituted with one, two or three groups independently selected from: C _1-6 alkyl; halo-C 1-6 alkyl; C _1-6 alkoxy; halo-C _1-6 alkoxy; hydroxy; hydroxy-C _1-6 alkyl; halo; nitrile; C _1-6 alkyl-carbonyl; C _1-6 alkyl-sulfonyl; C _3-6 cycloalkyl; C _{3-6 cycloalkyl-C 1-6 alkyl} ; C _3-6 cycloalkyl-carbonyl; amino; or heterocyclic group; or two of the groups, together with the atoms to which they are attached _, can form a five- or six-membered ring.

In certain embodiments of Formula II or Formula III, ^R6 is a heterocyclyl group optionally substituted with one, two or three groups independently selected from: _C1-6 alkyl; halo- _C1-6 alkyl; C1-6 alkoxy; halo- _C1-6 alkoxy; hydroxy; hydroxy- _C1-6 alkyl; halo; nitrile; _C1-6 alkyl-carbonyl; _C1-6 alkyl-sulfonyl; _C3-6 cycloalkyl; _C3-6 cycloalkyl- _C1-6 alkyl; _C3-6 cycloalkyl-carbonyl; amino; or _heterocyclyl ; or two of said groups, together with the atoms to which they are attached, may form a five- or six-membered ring.

In the embodiment of Formula II or Formula III where ^R is heterocyclyl- _{Ci_6alkyl} , the heterocyclyl portion thereof may be: azetidinyl; pyrrolidinyl; piperidinyl; piperazinyl; morpholinyl; thiomorpholinyl; 3-oxa-8-aza-bicyclo[3.2.1]octan-8-yl; 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl; or 8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl; each of which is optionally substituted as defined herein, i.e., the heterocyclyl portion is optionally substituted with one, two or three groups independently selected from: _{Ci_6alkyl} ; halo- _{Ci_6alkyl} ; _{Ci_6alkoxy} ; halo- _{Ci_6alkoxy} ; hydroxy; hydroxy- _{Ci_6alkyl} ; halo; nitrile; _{Ci_6alkyl} -carbonyl; _{Ci_6alkyl} -sulfon ... C _3-6 cycloalkyl; C _3-6 cycloalkyl-C _1-6 alkyl; C _3-6 cycloalkyl-carbonyl; amino; or heterocyclyl; or two of said groups together with the atoms to which they are attached may form a five- or six-membered ring.

In embodiments of Formula II or Formula III where R ⁶ is heterocyclyl-C _1-6 alkyl, the heterocyclyl portion thereof may be: azetidinyl; pyrrolidinyl; piperidinyl; piperazinyl; or morpholinyl; each optionally substituted as defined herein.

In certain embodiments of formula II or formula III, ^R6 is heterocyclyl- _C1-6 alkyl, wherein the heterocyclyl portion thereof is optionally substituted with one, two or three groups independently selected from: _C1-6 alkyl; halo- _C1-6 alkyl; C1-6 alkoxy; halo- _C1-6 alkoxy; hydroxy; hydroxy- _C1-6 alkyl; halo; nitrile; _C1-6 alkyl-carbonyl; _C1-6 alkyl-sulfonyl; _C3-6 cycloalkyl; _C3-6 cycloalkyl- _C1-6 alkyl; _C3-6 cycloalkyl-carbonyl; amino; or heterocyclyl; or two of said groups, together with the atoms to which they are attached, may form a five- or six-membered _ring .

In certain embodiments of Formula II or Formula III, R ⁶ is: hydrogen; methyl; ethyl; isopropyl; or cyclopropyl.

In certain embodiments of Formula II or Formula III, ^R6 is: hydrogen; methyl; ethyl; isopropyl; 2-amino-propyl; oxetan-3-yl; 2-methoxy-ethyl; 2-hydroxy-ethyl; cyclopropyl; piperidin-4-yl; 1-methyl-piperidin-4-yl; tert-butyl; 2-hydroxy-2-methyl-propyl; cyclobutyl; 1-methyl-cyclobutyl; 2-hydroxy-propyl; 1-cyano-cyclopropyl; 3,3-difluoro-cyclobutyl; cyclopropylmethyl; 3-fluoro-cyclobutyl; or 2,2-difluoroethyl;

In certain embodiments of formula II or formula III, R ⁶ is hydrogen.

In certain embodiments of Formula II or Formula III, R ⁶ is methyl.

In certain embodiments of formula II or formula III, R ⁶ is ethyl.

In certain embodiments of Formula II or Formula III, R ⁶ is isopropyl.

In certain embodiments of formula II or formula III, ^R6 is 2-amino-propyl.

In certain embodiments of formula II or formula III, R ⁶ is oxetan-3-yl.

In certain embodiments of formula II or formula III, ^R6 is 2-methoxy-ethyl.

In certain embodiments of formula II or formula III, ^R6 is 2-hydroxy-ethyl.

In certain embodiments of formula II or formula III, R ⁶ is cyclopropyl.

In certain embodiments of formula II or formula III, R ⁶ is piperidin-4-yl.

In certain embodiments of formula II or formula III, ^R6 is 1-methyl-piperidin-4-yl.

In certain embodiments of formula II or formula III, R ⁶ is tert-butyl.

In certain embodiments of formula II or formula III, ^R6 is 2-hydroxy-2-methyl-propyl.

In certain embodiments of formula II or formula III, R ⁶ is cyclobutyl.

In certain embodiments of formula II or formula III, R ⁶ is 1-methyl-cyclobutyl.

In certain embodiments of formula II or formula III, ^R6 is 2-hydroxy-propyl.

In certain embodiments of formula II or formula III, R ⁶ is 1-cyano-cyclopropyl.

In certain embodiments of formula II or formula III, ^R6 is 3,3-difluoro-cyclobutyl.

In certain embodiments of formula II or formula III, R ⁶ is cyclopropylmethyl.

In certain embodiments of formula II or formula III, R ⁶ is 3-fluoro-cyclobutyl.

In certain embodiments of formula II or formula III, ^R6 is 2,2-difluoroethyl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a three- to seven-membered ring, said three- to seven-membered ring optionally including additional heteroatoms selected from O, N and S(O) _n , and which is optionally substituted with one, two or three groups independently selected from C _1-6 alkyl, halo-C _1-6 alkyl, C _1-6 alkoxy, halo-C _1-6 alkoxy, hydroxy, hydroxy-C _1-6 alkyl, halo, nitrile, C _1-6 alkyl-carbonyl, C _1-6 alkyl-sulfonyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-6 alkyl, C _3-6 cycloalkyl-carbonyl, or heterocyclyl, or two of said groups together with the atom to which they are attached can form a five- or six-membered ring.

In embodiments of Formula II or Formula III wherein R and ^R taken together with the nitrogen atom to which ^they are attached form a three to seven membered ring optionally including an additional heteroatom selected from O, N and S(O) _n , the ring may be: azetidinyl; pyrrolidinyl; piperidinyl; piperazinyl; morpholinyl; thiomorpholinyl; azepinyl; 3-oxa-8-aza-bicyclo[3.2.1]octan-8-yl; 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl; or 8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl; each optionally substituted as defined herein.

In embodiments of Formula II or Formula III wherein R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a three to seven membered ring, said three to seven membered ring optionally including additional heteroatoms selected from O, N and S(O) _n , said ring may be: azetidinyl; pyrrolidinyl; piperidinyl; piperazinyl; or morpholinyl; each optionally substituted as defined herein.

In certain embodiments of Formula II or Formula III, R ⁵ and R ^6, together with the nitrogen atom to which they are attached, form a morpholinyl group optionally substituted once or twice with a group independently selected from the group consisting of C _1-6 alkyl, halo-C _1-6 alkyl, C _1-6 alkoxy, halo-C _1-6 alkoxy, hydroxy, hydroxy-C _1-6 alkyl, halo, nitrile, C _1-6 alkyl-carbonyl, C _1-6 alkyl-sulfonyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-6 alkyl, C _3-6 cycloalkyl-carbonyl, amino, or heterocyclyl, or the two groups, together with the atom to which they are attached, can form a five- or six-membered ring.

In certain embodiments of Formula II or Formula III, R ⁵ and R ^6, together with the nitrogen atom to which they are attached, form a piperidinyl group optionally substituted once or twice with a group independently selected from the group consisting of C _1-6 alkyl, halo-C _1-6 alkyl, C _1-6 alkoxy, halo-C _1-6 alkoxy, hydroxy, hydroxy-C _1-6 alkyl, halo, nitrile, C _1-6 alkyl-carbonyl, C _1-6 alkyl-sulfonyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-6 alkyl, C _3-6 cycloalkyl-carbonyl, amino, or heterocyclyl, or the two groups, together with the atom to which they are attached, can form a five- or six-membered ring.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ , together with the nitrogen atom to which they are attached, form a piperazinyl group optionally substituted once or twice with a group independently selected from the group consisting of C _1-6 alkyl, halo-C _1-6 alkyl, C _1-6 alkoxy, halo-C _1-6 alkoxy, hydroxy, hydroxy-C _1-6 alkyl, halo, nitrile, C _1-6 alkyl-carbonyl, C _1-6 alkyl-sulfonyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-6 alkyl, C _3-6 cycloalkyl-carbonyl, amino, or heterocyclyl, or the two groups, together with the atom to which they are attached, can form a five- or six-membered ring.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ , together with the nitrogen atom to which they are attached, form a pyrrolidinyl group optionally substituted once or twice with a group independently selected from the group consisting of C _1-6 alkyl, halo-C _1-6 alkyl, C _1-6 alkoxy, halo-C _1-6 alkoxy, hydroxy, hydroxy-C _1-6 alkyl, halo, nitrile, C _1-6 alkyl-carbonyl, C _1-6 alkyl-sulfonyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-6 alkyl, C _3-6 cycloalkyl-carbonyl, amino, or heterocyclyl, or the two groups, together with the atom to which they are attached, can form a five- or six-membered ring.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a group selected from the group consisting of: morpholin-4-yl; 4-hydroxy-piperidin-1-yl; octahydro-pyrido[1,2-a]pyrazin-2-yl; 2-hydroxy-piperidin-1-yl; 4,4-dimethyl-piperidin-1-yl; 3,5-dimethyl-piperidin-1-yl; 1-hydroxy-1-methyl-ethyl)-piperidin-1-yl; 3-hydroxy-pyrrolidin-1-yl; 4-methyl-piperidin-1-yl; piperidin-1 -yl; azetidin-1-yl; 4,4-difluoro-piperidin-1-yl; 3-methyl-piperidin-1-yl; 4-methoxy-piperidin-1-yl; 3,3-difluoro-piperidin-1-yl; 4-cyano-piperidin-1-yl; 4-fluoro-piperidin-1-yl; 3-methoxy-piperidin-1-yl; 4-ethyl-piperazin-1-yl; 4-acetyl-piperazin-1-yl; 3-trifluoromethyl-piperidin-1-yl; 4-tert-butyl-piperidin-1-yl; 2 -hydroxy-ethyl)-piperazin-1-yl; 2-methyl-pyrrolidin-1-yl; 4-hydroxymethyl-piperidin-1-yl; 2-methyl-piperidin-1-yl; pyrrolidin-1-yl; 4-methanesulfonyl-piperazin-1-yl; 3-trifluoromethyl-pyrrolidin-1-yl; 4-(2,2,2-trifluoro-ethyl)-piperazin-1-yl; 2-methyl-morpholin-4-yl; (2,6-dimethyl-morpholin-4-yl; 2,2-diethyl-morpholin-4-yl) yl; 3-hydroxymethyl-morpholin-4-yl; 2-isobutyl-morpholin-4-yl; 2-hydroxymethyl-morpholin-4-yl; 3,3-dimethyl-morpholin-4-yl; 4-methyl-piperazin-1-yl; 4-isopropyl-piperazin-1-yl; piperazin-1-yl; 3-oxa-8-aza-bicyclo[3.2.1]octan-8-yl; (S)-3-methyl-morpholin-4-yl; 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl; 8-Oxa-3-aza-bicyclo[3.2.1]octan-3-yl; (R)-3-methyl-morpholin-4-yl; 4-cyclopropanecarbonyl-piperazin-1-yl; 4-(1-hydroxy-1-methyl-ethyl)-piperidin-1-yl; 4-cyclobutyl-piperazin-1-yl; (R)-3-hydroxy-pyrrolidin-1-yl; 4-oxetan-3-yl-piperazin-1-yl; 3-morpholin-4-yl-azetidin-1-yl; 4-(1-methyl -piperidin-4-yl)-piperazin-1-yl; 3,3-difluoro-azetidin-1-yl; 4-dimethylamino-piperidin-1-yl; 4-piperidin-4-yl-piperazin-1-yl; (4,4-difluoro-piperidin-1-yl; (3-morpholin-4-yl-azetidin-1-yl; 2-oxa-6-aza-spiro[3.3]hept-6-yl; 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl); 4-methoxy-piperidin -1-yl); [1,4]oxazepan-4-yl; 2R,6S)-2,6-dimethyl-morpholin-4-yl; 3-hydroxy-azetidin-1-yl; 3-cyano-pyrrolidin-1-yl; 3,5-dimethyl-piperazin-1-yl; (3R,5S)-dimethyl-piperazin-1-yl; 3-fluoro-pyrrolidin-1-yl; (S)-3-fluoro-pyrrolidin-1-yl; piperazin-1-yl; 3,3-difluoro-pyrrolidin-1-yl. yl; 3,3-difluoro-azetidin-1-yl; 2,2,6,6-tetrafluoro-morpholin-4-yl; 2-methoxymethyl-pyrrolidin-1-yl; (S)-2-methoxymethyl-pyrrolidin-1-yl; (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl; (3S,4S)-3,4-difluoropyrrolidin-1-yl; 3,4-difluoropyrrolidin-1-yl; and 3-methoxypyrrolidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a group selected from the group consisting of: morpholin-4-yl; 4-hydroxy-piperidin-1-yl; octahydro-pyrido[1,2-a]pyrazin-2-yl; 2-hydroxy-piperidin-1-yl; 4,4-dimethyl-piperidin-1-yl; 3,5-dimethyl-piperidin-1-yl; 1-hydroxy-1-methyl-ethyl)-piperidin-1-yl; 3-hydroxy-pyrrolidin-1-yl; 4-methyl-piperidin-1-yl; piperidin-1-yl; azetidin-1-yl; 4,4-difluoro-piperidin-1-yl; 3-methyl-piperidin-1-yl; 4-methoxy-piperidin-1-yl; 3,3 -difluoro-piperidin-1-yl; 4-cyano-piperidin-1-yl; 4-fluoro-piperidin-1-yl; 3-methoxy-piperidin-1-yl; 4-ethyl-piperazin-1-yl; 4-acetyl-piperazin-1-yl; 3-trifluoromethyl-piperidin-1-yl; 4-tert-butyl-piperidin-1-yl; 2-hydroxy-ethyl)-piperazin-1-yl; 2-methyl-pyrrolidin-1-yl; 4-hydroxymethyl-piperidin-1-yl; 2-methyl-piperidin-1-yl; pyrrolidin-1-yl; 4-methanesulfonyl-piperazin-1-yl; 3-trifluoromethyl-pyrrolidin-1-yl; 4-(2,2,2-trifluoro-ethyl)-piperazin- 1-yl; 2-methyl-morpholin-4-yl; (2,6-dimethyl-morpholin-4-yl; 2,2-diethyl-morpholin-4-yl; 3-hydroxymethyl-morpholin-4-yl; 2-isobutyl-morpholin-4-yl; 2-hydroxymethyl-morpholin-4-yl; 3,3-dimethyl-morpholin-4-yl; 4-methyl-piperazin-1-yl; 4-isopropyl-piperazin-1-yl; piperazin-1-yl; 3-oxa-8-aza-bicyclo[3.2.1]octan-8-yl; (S)-3-methyl-morpholin-4-yl; 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl; 8-oxa-3-aza -bicyclo[3.2.1]octan-3-yl; (R)-3-methyl-morpholin-4-yl; 4-cyclopropanecarbonyl-piperazin-1-yl; 4-(1-hydroxy-1-methyl-ethyl)-piperidin-1-yl; 4-cyclobutyl-piperazin-1-yl; (R)-3-hydroxy-pyrrolidin-1-yl; 4-oxetan-3-yl-piperazin-1-yl; 3-morpholin-4-yl-azetidin-1-yl; 4-(1-methyl-piperidin-4-yl)-piperazin-1-yl; 3,3-difluoro-azetidin-1-yl; 4-dimethylamino-piperidin-1-yl; and 4-piperidin-4-yl-piperazin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form morpholin-4-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 4-hydroxy-piperidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form octahydro-pyrido[1,2-a]pyrazin-2-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 2-hydroxy-piperidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 4,4-dimethyl-piperidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 3,5-dimethyl-piperidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 1-hydroxy-1-methyl-ethyl)-piperidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 3-hydroxy-pyrrolidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 4-methyl-piperidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form piperidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form azetidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 4,4-difluoro-piperidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 3-methyl-piperidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 4-methoxy-piperidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 3,3-difluoro-piperidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 4-cyano-piperidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 4-fluoro-piperidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 3-methoxy-piperidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 4-ethyl-piperazin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 4-acetyl-piperazin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 3-trifluoromethyl-piperidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ^{6 ,} together with the nitrogen atom to which they are attached, form 4-tert-butyl-piperidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 2-hydroxy-ethyl)-piperazin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 2-methyl-pyrrolidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 4-hydroxymethyl-piperidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 2-methyl-piperidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form pyrrolidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 4-methanesulfonyl-piperazin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 3-trifluoromethyl-pyrrolidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 4-(2,2,2-trifluoro-ethyl)-piperazin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 2-methyl-morpholin-4-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form (2,6-dimethyl-morpholin-4-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 2,2-diethyl-morpholin-4-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 3-hydroxymethyl-morpholin-4-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ^{6 ,} together with the nitrogen atom to which they are attached, form 2-isobutyl-morpholin-4-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 2-hydroxymethyl-morpholin-4-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 3,3-dimethyl-morpholin-4-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 4-methyl-piperazin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 4-isopropyl-piperazin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form piperazin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 3-oxa-8-aza-bicyclo[3.2.1]octan-8-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ^{6 ,} together with the nitrogen atom to which they are attached, form (S)-3-methyl-morpholin-4-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ^{6 ,} together with the nitrogen atom to which they are attached, form (R)-3-methyl-morpholin-4-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 4-cyclopropanecarbonyl-piperazin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 4-(1-hydroxy-1-methyl-ethyl)-piperidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 4-cyclobutyl-piperazin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ^{6 ,} together with the nitrogen atom to which they are attached, form (R)-3-hydroxy-pyrrolidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 4-oxetan-3-yl-piperazin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ^{6 ,} together with the nitrogen atom to which they are attached, form 3-morpholin-4-yl-azetidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 4-(1-methyl-piperidin-4-yl)-piperazin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 3,3-difluoro-azetidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 4-dimethylamino-piperidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 4-piperidin-4-yl-piperazin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form (4,4-difluoro-piperidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form (3-morpholin-4-yl-azetidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 2-oxa-6-aza-spiro[3.3]hept-6-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl). In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 4-methoxy-piperidin-1-yl).

In certain embodiments of Formula II or Formula III, R ⁵ and R ^{6 ,} together with the nitrogen atom to which they are attached, form [1,4]oxazepan-4-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 2R,6S)-2,6-dimethyl-morpholin-4-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ^{6 ,} together with the nitrogen atom to which they are attached, form 3-hydroxy-azetidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 3-cyano-pyrrolidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 3,5-dimethyl-piperazin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form (3R,5S)-dimethyl-piperazin-1-yl.

In certain embodiments of formula II or formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 3-fluoro-pyrrolidin-1-yl.

In certain embodiments of formula II or formula III, R ⁵ and R ^{6 ,} together with the nitrogen atom to which they are attached, form (S)-3-fluoro-pyrrolidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form piperazin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 3,3-difluoro-pyrrolidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 3,3-difluoro-azetidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 2,2,6,6-tetrafluoro-morpholin-4-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 2-methoxymethyl-pyrrolidin-1-yl. In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form (S)-2-methoxymethyl-pyrrolidin-1-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ^{6 ,} together with the nitrogen atom to which they are attached, form (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl.

In certain embodiments of Formula II or Formula III, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form (3S,4S)-3,4-difluoropyrrolidin-1-yl; 3,4-difluoropyrrolidin-1-yl; and 3-methoxypyrrolidin-1-yl.

In certain embodiments of formula II or formula III, R ⁷ is halo.

In certain embodiments of formula II or formula III, R ⁷ is C _1-6 alkyl.

In certain embodiments of formula II or formula III, R ⁷ is C _1-6 alkoxy.

In certain embodiments of formula II or formula III, R ⁷ is halo-C _1-6 alkyl.

In certain embodiments of formula II or formula III, R ⁷ is halo-C _1-6 alkoxy.

In certain embodiments of formula II or formula III, R ⁷ is halo or methoxy.

In certain embodiments of formula II or formula III, R ⁷ is fluoro, chloro, or methoxy.

In certain embodiments of formula II or formula III, R ⁷ is fluoro or chloro.

In certain embodiments of formula II or formula III, R ⁷ is methoxy.

In certain embodiments of formula II or formula III, R ⁷ is chloro.

In certain embodiments of formula II or formula III, R ⁷ is fluoro.

In certain embodiments of Formula II or Formula III, Y is -O-.

In certain embodiments of formula II or formula III, Y is ^-CHR8- .

In certain embodiments of Formula II or Formula III, Z is -O-.

In certain embodiments of formula II or formula III, Z is ^-CHR8- .

In certain embodiments of Formula II or Formula III, Z is absent.

In certain embodiments of formula II or formula III, R ⁸ is halo.

In certain embodiments of formula II or formula III, R ⁸ is C _1-6 alkyl.

In certain embodiments of formula II or formula III, R ⁸ is oxo.

In certain embodiments of Formula II or Formula III, the target compound may be:

[5-Fluoro-7-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzofuran-4-yl]-morpholin-4-yl-methanone;

8-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxin-5-carboxylic acid ethylamide;

8-(4-Methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxin-5-carboxylic acid isopropylamide;

8-(4-Methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxin-5-carboxylic acid ethylamide;

[8-(4-Methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxin-5-yl]-morpholin-4-yl-methanone;

(3,3-Difluoro-pyrrolidin-1-yl)-[8-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxin-5-yl]-methanone;

8-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxin-5-carboxylic acid methylamide;

[8-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxin-5-yl]-pyrrolidin-1-yl-methanone;

[8-(4-Methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxin-5-yl]-pyrrolidin-1-yl-methanone; or

[8-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxin-5-yl]-morpholin-4-yl-methanone.

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 treating Parkinson's disease, comprising administering an effective amount of a compound as described herein to a subject in need thereof.

The present invention also relates to compounds of formula A 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 it is useful for preventing or treating Parkinson's disease.

The present invention also relates to compounds of formula A as described herein for use in the preparation of medicaments for the prevention or treatment of Parkinson's disease.

The present invention also provides a method for treating a disease or condition mediated by or otherwise associated with the LRRK2 receptor, comprising 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 a cancer or a proliferative disorder such as renal, breast, prostate, leukemia, 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 according to the methods of the present invention are shown in the following experimental examples.

synthesis

The compounds of the present invention can be prepared by a variety of 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 can be prepared by methods known to those skilled in the art according to the procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, 1991, Volumes 1-15; Rodd's Chemistry of Carbon compounds, Elsevier Science Publishers, 1989, Volumes 1-5 and Supplements; and Organic Reactions, Wiley & Sons: New-York, 1991, Volumes 1-40. The following synthetic reaction schemes are merely illustrative of some of the methods by which the compounds of the present invention can be synthesized, and various modifications to these synthetic reaction schemes are possible and will be suggested to those skilled in the art having reference 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, etc. Such materials can be characterized using conventional means, including physical constants and spectral data.

Unless stated to the contrary, the reactions described herein can be carried out under an inert atmosphere at atmospheric pressure at a temperature range of about -78°C to about 150°C, such as about 0°C to about 125°C, or conveniently at about room temperature (ambient temperature), such as about 20°C.

Scheme A below illustrates one synthetic procedure that can be used to prepare specific compounds of Formula I or Formula II, wherein X, m, ^R1 , ^R2 , ^R3 , ^R5 , ^R6 and ^R7 are as defined herein.

Plan A

In step 1 of Scheme A, dichloropyrimidine compound a reacts with reagent b to obtain pyrimidine compound c . The reaction in step 1 can occur under polar solvent conditions. In embodiments of the present invention where X is -O- (reagent b is an alcohol), the reaction in step 1 can be carried out in the presence of a base.

In step 2, pyrimidine compound c is reacted with aminobenzoic acid compound d to provide aminopyridine compound e . The reaction of step 2 can occur in a polar protic solvent and in the presence of an acid such as HCl.

In step 3, an amide coupling reaction is carried out, wherein compound e is reacted with amine f to obtain a compound of formula I or formula II according to the present invention. The amide coupling reaction in step 3 can employ various well-known amide coupling reagents such as carbodiimides (e.g., DCC, DIC, EDC, etc.), amine onium salts (e.g., HATU, HBTU, TBTU, etc.), or phosphonium salts (e.g., BOP, PyBOP, etc.), in the presence or absence of benzotriazole derivatives such as HOBt, HOAt, DhbtOH, etc. In other embodiments, amide formation can be achieved using an acid chloride or anhydride intermediate (not shown).

Many variations on the procedure of Scheme A are possible and will suggest themselves to those skilled in the art. Specific details for preparing 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 present invention are administered in a therapeutically effective amount by any of the modes of administration for the acceptance of agents for similar purposes. Suitable dosage ranges are typically 1-500 mg/ days, such as 1-100 mg/ days, and most preferably 1-30 mg/ days, depending on many factors such as the severity of the disease being treated, the age and relative health of the patient, the effectiveness of the compound used, the route and form of administration, the indications to which administration is related, and the preference and experience of the medical practitioners involved. Those of ordinary skill in the art of treating such diseases will be able to determine the therapeutically effective amount of the compounds of the present invention for a given disease without excessive experimentation and relying on personal knowledge and the disclosure of this application.

The compounds of the present 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. A particular route of administration is generally oral, using a convenient daily dosage regimen which can be adjusted according to the severity of the affliction.

The compound or compounds of the present invention, together with one or more conventional adjuvants, carriers or diluents, may be placed in the form of pharmaceutical compositions and unit dosage forms. Pharmaceutical compositions and unit dosage forms may be composed of conventional ingredients in conventional proportions (with or without additional active compounds or ingredients), and the unit dosage form may contain any suitable effective amount of the active ingredient commensurate with the desired daily dosage range to be employed. 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 about 0.01 to about one hundred (100) milligrams, are accordingly suitable representative unit dosage forms.

The compounds of the present invention can be formulated into a wide variety of oral dosage forms. Pharmaceutical compositions and dosage forms can contain one or more compounds of the present invention or pharmaceutically acceptable salts thereof as the active ingredient. Pharmaceutical carriers can be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances that can also act as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, preservative, tablet disintegrant, or encapsulating material. In powders, the carrier is typically a finely divided solid that is in admixture with the finely divided active ingredient. In tablets, the active ingredient is typically mixed in suitable proportions with a carrier having the necessary binding capacity and compacted into the desired shape and size. Powders and tablets can 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, methylcellulose, sodium carboxymethylcellulose, low melting waxes, cocoa butter, and the like. The term "preparation" 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 (which is in association with it). Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used 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 expected to be converted into liquid form preparations before use. Emulsions can be prepared with solutions, for example in propylene glycol aqueous solutions, or can contain emulsifiers, such as lecithin, sorbitan monooleate or gum arabic. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable colorants, spices, stabilizers and thickeners. Aqueous suspensions can be prepared by dispersing the subdivided active ingredient in water with viscous materials 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 in addition to the active ingredient, can contain colorants, spices, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, etc.

The compounds of the present invention can be formulated for parenteral administration (e.g., by injection, such as bolus or continuous infusion) and can be present in unit dose form in ampules, prefilled syringes, small volume infusions, or multi-dose containers with preservatives added. The composition can be in such a form as a suspension, solution, or emulsion in an oily or aqueous medium, such as a solution in aqueous polyethylene glycol solution. Examples of oily or non-aqueous carriers, diluents, solvents, or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and organic esters for injection (e.g., ethyl oleate), and can contain formulation agents such as preservatives, wetting agents, emulsifiers, or suspending agents, stabilizers, and/or dispersants. Alternatively, the active ingredient can be in powder form, obtained by aseptic isolation of a sterile solid, or by lyophilization from a solution that is constructed prior to use with a suitable medium, such as sterile, pyrogen-free water.

The compounds of the present invention can be formulated for topical administration to the epidermis as ointments, creams or lotions, or as transdermal patches. Ointments and creams can be formulated, for example, with aqueous or oily bases, with the addition of suitable thickeners and/or gelling agents. Lotions can be formulated with aqueous or oily bases and typically also contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners or colorants. Formulations suitable for topical administration in the mouth include lozenges containing the active agent in a flavored base, typically sucrose and arabinose or tragacanth; pastilles containing the active ingredient in an inert base such as gelatin and glycerol or sucrose and gum arabic; and mouthwashes containing the active ingredient in a suitable liquid carrier.

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

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

The subject compounds can be formulated for nasal administration. The solution or suspension is administered directly to the nasal cavity by conventional means, such as with a dropper, pipette, or sprayer. The formulation can be provided in single or multiple doses. In the latter case of a dropper or pipette, this can be achieved by administering an appropriate, predetermined amount of the solution or suspension to the patient. In the case of a sprayer, this can be achieved, for example, with the aid of a metered atomizing spray pump.

The compounds of the present invention can be formulated for aerosol administration, particularly administration to the respiratory tract, and including intranasal administration. The compounds typically have a small particle size, for example, on the order of five (5) microns or less. Such particle sizes can be obtained by means known in the art, for example, by micronization. The active ingredient is provided in a pressurized pack having a suitable propellant such as a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. The aerosol can conveniently also contain a surfactant such as lecithin. The dose of the drug can be controlled by a metering valve. Alternatively, the active ingredient can be provided in the form of a dry powder, for example, a powder mixture of the compound in a suitable powder matrix such as lactose, starch, a starch derivative such as hydroxypropylmethylcellulose and polyvinylpyrrolidone (PVP). The powder carrier forms a gel in the nasal cavity. The powder composition can be presented in a unit dose form, for example, in a capsule or cartridge in, for example, gelatin or a film pack, from which the powder can be administered by an inhaler.

When needed, preparation can be prepared with the enteric coating that is applicable to the sustained release of active component or controlled release administration.For example, compound of the present invention can be prepared in percutaneous or subcutaneous drug delivery device.These delivery systems are advantageous when the sustained release of compound is needed and patient compliance with treatment regimen is key.Compound in percutaneous delivery system often adheres to skin adhesive solid carrier.Interested compound can also combine penetration enhancer, such as azone (1-dodecylazacycloheptane-2-one).Sustained release delivery system is inserted into subcutaneous layer by surgery or injection subcutaneously.Described compound is encapsulated in fat-soluble film, such as silicone rubber, or biodegradable polymer such as polylactic acid by this subcutaneous implant.

Pharmaceutical formulations can be in unit dosage form. In such form, the formulation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be a packaged formulation, a package containing discrete quantities of the formulation, such as packaged tablets, capsules, and powders in vials or ampoules. Furthermore, 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 Pharmacy 1995, 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

The compounds of the present 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, as well as for enhancing cognitive memory in subjects generally in need thereof.

Example

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 to limit the scope of the present invention, but are merely examples and representatives thereof.

Unless otherwise indicated, all temperatures, including melting points (i.e., MP), are in degrees Celsius (° C.). It should be understood that the reaction to produce a 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 lead to 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-methylpropionitrile)

Atm. atmospheric pressure

(BOC) ₂ O Di-tert-butyl dicarbonate

DCM Dichloromethane/Methylene Chloride

DIAD Diisopropyl azodicarboxylate

DIPEA Diisopropylethylamine

DMAP 4-dimethylaminopyridine

DME 1,2-dimethoxyethane

DMF N,N-dimethylformamide

DMSO dimethyl sulfoxide

DPPF 1,1′-bis(diphenylphosphino)ferrocene

Et ₂ O diethyl ether

EtOH ethanol/ethyl alcohol

EtOAc

HATU 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium methylammonium hexafluorophosphate

HBTU O-Benzotriazol-1-yl-N,N,N’,N’-tetramethyluronium hexafluorophosphate

HOBT 1-Hydroxybenzotriazole

HPLC High-pressure liquid chromatography

RP HPLC Reversed-phase high-pressure liquid chromatography

i-PrOH Isopropyl alcohol/Isopropyl alcohol

LCMS liquid chromatography/mass spectrometry

MeOH Methanol/Methyl Alcohol

MW microwave

NBS N-bromosuccinimide

NMP 1-Methyl-2-pyrrolidone

PSI pounds per square inch

RT Room temperature

TBDMS tert-butyldimethylsilyl

TFA trifluoroacetic acid

THF Tetrahydrofuran

TLC thin layer chromatography

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

To a 250 mL round-bottom flask equipped with a stir bar was added 9.0 g of 5-fluoro-2,4-dichloro-pyrimidine, 40 mL of methanol, and 15 mL of an 8 M ethanolic solution of methylamine. The reaction was exothermic (mildly exothermic) and stirred at room temperature for ~30 minutes. TLC (1:1 EtOAc:heptane) and LCMS indicated the reaction was complete. The reaction was concentrated to give 9.77 g of crude material, which was purified on a silica column running a gradient of 1% to 10% MeOH in DCM over 35 minutes to give 6.77 g 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-pyrimidines and amines.

Table 1

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

1g 5-chloro-2,4-dichloro-pyrimidine and 15mL of diethyl ether were added to a 250mL round-bottom flask equipped with a stirring rod. The mixture was cooled to 0°C in an ice bath and then slowly added to 1 equivalent of a methanolic sodium methoxide solution (prepared from 120mg of sodium and 4mL of methanol at room temperature). The reactant was stirred at room temperature 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 was obtained and the material was 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

Preparation 3: 4-(5-Fluoro-4-(methylamino)pyrimidin-2-ylamino)-3-methoxybenzoic acid

A mixture of 50 mg of 2-chloro-5-fluoro-N-methylpyrimidin-4-amine, 57 mg of 4-amino-3-methoxybenzoic acid, 0.1 mL of 4N HCl in 1,4-dioxane, and 1 mL of n-butanol was placed in a 10 mL snap-top microwave vial (CEM Corp.) and heated to 120° C. in a microwave for 40 min. The reaction was monitored by LC/MS. The precipitated solid was filtered to obtain 80 mg of 4-(5-fluoro-4-(methylamino)pyrimidin-2-ylamino)-3-methoxybenzoic acid.

The same procedure was used to prepare the compounds shown in Table 3 below using the appropriate amine and the appropriately substituted 2-chloropyrimidine.

Table 3

Preparation 4: 4-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-3-(difluoromethoxy)benzoic acid

To 1g 3-hydroxy-4-nitrobenzoic acid methyl ester, the cooling solution of cesium carbonate of 3.31g in 20mL DMF, carefully add 1.5 equivalents of difluoroiodomethane.Allow reactant to be warming up to room temperature and follow the tracks of by TLC.When the reaction is complete, the mixture is concentrated and purified by silica gel chromatography, provides 1.2g of 3-(difluoromethoxy)-4-nitrobenzoic acid methyl ester.

3-(difluoromethoxy)-4-nitrobenzoic acid methyl ester (0.9g) is placed in a 250mL round-bottomed flask and dissolved in the ethanol of 30mL. Pd/C (0.15g, 10%Pd) is carefully added and a hydrogen balloon is connected to the flask. Reactant is stirred vigorously overnight. After checking through TLC, reactant is filtered and concentrated through a celite pad to provide 0.6g of 4-amino-3-(difluoromethoxy)benzoic acid methyl ester, which is used without further purification.

By 4-amino-3-(difluoromethoxy) methyl benzoate (70mg), 2,5-dichloro-N-methylpyrimidine-4-amine, 0.1mL of 4N HCl/ dioxane and 1mL of n-butyl alcohol are placed in microwave vial.Reactant was heated 30 minutes at 150 ℃ and monitored by LCMS.Mixture is concentrated and, by silica gel chromatography purification, provides 100mg of pure 4-(5-chloro-4-(methylamino) pyrimidine-2-base amino)-3-(difluoromethoxy) methyl benzoate.

4-(5-chloro-4-(methylamino) pyrimidin-2-ylamino)-3-(difluoromethoxy) methyl benzoate (500mg) is dissolved in the water of 5mL THF and 5mL.After dissolving, add the lithium hydroxide of 234mg and react and spend the night at stirring at room temperature.Check mixture by LCMS, then carefully use 1N HCl acidifying and distribute with ethyl acetate.The organic layer is concentrated and by silica gel chromatography purification, provide 250mg of 4-(5-chloro-4-(methylamino) pyrimidin-2-ylamino)-3-(difluoromethoxy) benzoic acid.

The compounds shown in Table 4 were prepared similarly.

Table 4

Preparation 5: (4-amino-5-methoxy-2-methylphenyl)(morpholino)methanone

Step 1: 5-Methoxy-2-methyl-4-nitrobenzonitrile

To 5-methoxy-2-methyl-4-nitroaniline (4.9g, 26.8mmol) in the mixture of acetone (17.5mL) and water (19mL) at 0 ℃, add concentrated HCl (5.6mL).Drop the solution of sodium nitrite (2.25g, 32.6mmol) in water (7.5mL) and allow the mixture to stir 30min at 0 ℃.Then the mixture is added dropwise to a mixture of cupric cyanide (3.75g, 42mmol) and sodium cyanide (5.5g, 112mmol) in water (25mL) and EtOAc (12.5mL).Allow the mixture to stir 2h at RT, then add water (50mL).Mixture is extracted with EtOAc (3 × 100mL) and the organic portion merged is washed with 2M NaOH (aqueous solution) (50mL) and salt solution (50mL).Organic portion is passed through hydrophobic glass frit and solvent is removed in vacuo. The residue was triturated with isohexane and dried to give 5-methoxy-2-methyl-4-nitrobenzonitrile (4.62 g, 90%) as an off-white solid. LCMS (10 cm-ESCI-Bicarb-MeCN): [M] ⁻ = 192 at 3.19 min. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.72 (s, 1H), 7.31 (s, 1H), 3.98 (s, 3H), 2.55 (s, 3H).

Step 2: 5-Methoxy-2-methyl-4-nitrobenzoic acid

A mixture of 5-methoxy-2-methyl-4-nitrobenzonitrile (2.0 g, 10.4 mmol) in AcOH (20 mL), water (20 mL), and concentrated sulfuric acid (20 mL) was heated to 120° C. for 10 h. Water (100 mL) and DCM (100 mL) were added and the mixture was passed through a hydrophobic frit. The solvent was removed in vacuo to give 5-methoxy-2-methyl-4-nitrobenzoic acid (2.0 g, 91%) as an off-white solid. LCMS (10 cm-ESCI-Formic-MeCN): [MH] ⁻ = 210 at 3.37 min. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.75 (s, 1H), 7.70 (s, 1H), 3.99 (s, 3H), 2.62 (s, 3H).

Step 3: (5-Methoxy-2-methyl-4-nitrophenyl)(morpholino)methanone

To 5-methoxy-2-methyl-4-nitrobenzoic acid (2.0 g, 9.47 mmol) in DCM (50 mL) was added DIPEA (8.3 mL, 47 mmol) and HATU (3.96 g, 10.4 mmol), followed by morpholine (0.83 mL, 9.47 mmol). The mixture was allowed to stir at RT for 5 h, then water (50 mL) and DCM (50 mL) were added. The aqueous phase was extracted with DCM (3 x 25 mL) and the combined organic phases were passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by silica gel column chromatography (0-100% EtOAc in isohexane) to give (5-methoxy-2-methyl-4-nitrophenyl)(morpholino)methanone (2.5 g, 94%) as an off-white solid. LCMS (10 cm-ESCI-Formic-MeCN): [M+H] ⁺ = 281 at 3.17 min. ¹ H NMR (400MHz, CDCl ₃ ): δ 7.72 (s, 1H), 6.90 (s, 1H), 3.94 (s, 3H), 3.85-3.76 (m, 4H), 3.61 (dd, 2H), 3.23 (dd, 2H), 2.30 (s, 3H).

Step 4: (4-Amino-5-methoxy-2-methylphenyl)(morpholino)methanone (Method 1)

To (5-methoxy-2-methyl-4-nitrophenyl)(morpholino)methanone (324 mg, 1.16 mmol) in ethanol (20 mL) and water (2 mL) was added _SnCl2.2H2O ( _1.05 g, 4.64 mmol). The mixture was heated to 65°C for 36 h, then 2M aqueous sodium hydroxide solution (20 mL) and DCM (20 mL) were added. The organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo to give (4-amino-5-methoxy-2-methylphenyl)(morpholino)methanone (268 mg, 92%) as an off-white solid. LCMS (10 cm-ESCI_Formic_MeCN): [M+H] ⁺ = 251 at 2.14 min. ¹ H NMR (400MHz, CDCl ₃ ): δ 6.60 (s, 1H), 6.52 (s, 1H), 3.87-3.52 (br m, 6H), 3.84 (br s, 2H), 3.82 (s, 3H), 3.36-3.23 (br m, 2H), 2.17 (s, 3H).

Step 4: (4-Amino-5-methoxy-2-methylphenyl)(morpholino)methanone (Method 2)

To (5-methoxy-2-methyl-4-nitrophenyl) (morpholino) ketone (1.76 g, 6.3 mmol) in ethanol (25 mL) and water (25 mL) was added ammonium chloride (1.72 g, 31.5 mmol) and iron powder (1.41 g, 25.2 mmol). The mixture was heated to 90 ° C for 2 hours, then filtered through diatomaceous earth and washed with ethanol. The solvent was removed in a vacuum and the residue was distributed between water (50 mL) and DCM (50 mL). The layers were separated and the aqueous phase was washed with DCM (3 × 50 mL). The combined organic phases were dried with MgSO ₄ , filtered and the solvent was removed in a vacuum. The residue was ground with diethyl ether/40-60 petroleum ether and dried to give (4-amino-5-methoxy-2-methylphenyl) (morpholino) ketone (1.31 g, 82%) as a pale white solid.

Preparation 6: (4-amino-5-chloro-2-methylphenyl)(morpholino)methanone

Step 1: 5-Chloro-2-methyl-4-nitrobenzonitrile

To 5-chloro-2-methyl-4-nitroaniline (5g, 26.8mmol) in the mixture of acetone (17.5mL) and water (19mL) at 0 ℃, add concentrated HCl (5.6mL).Drop the solution of sodium nitrite (2.25g, 32.6mmol) in water (7.5mL) and allow the mixture to stir 30min at 0 ℃.Then the mixture is added dropwise to a mixture of cupric cyanide (3.75g, 42mmol) and sodium cyanide (5.5g, 112mmol) in water (25mL) and EtOAc (12.5mL).Allow the mixture to stir 1h at RT, then add water (50mL).Mixture is extracted with EtOAc (3 × 100mL) and the organic portion merged is washed with 2M NaOH (aqueous solution) (50mL) and salt solution (50mL).Organic portion is passed through hydrophobic glass frit and solvent is removed in a vacuum. The residue was suspended in a 1:1 mixture of diethyl ether:isohexane. The resulting solid was removed by filtration, washed with isohexane, and dried. An additional fraction was separated from the filtrate and combined with the initial solid fraction to give 5-chloro-2-methyl-4-nitrobenzonitrile (3.22 g, 61%) as an off-white solid. LCMS (10 cm_ESCI_Formic_MeCN): [M+H] ⁺ = 197 at 3.97 min. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.80 (s, 1H), 7.80 (s, 1H), 2.63 (s, 3H).

Step 2: 5-Chloro-2-methyl-4-nitrobenzoic acid

A mixture of 5-chloro-2-methyl-4-nitrobenzonitrile (1 g, 5 mmol) in AcOH (10 mL), water (10 mL), and concentrated sulfuric acid (10 mL) was heated to 120° C. for 5 h. Water (100 mL) was added, and the solid was removed by filtration and dried to afford 5-chloro-2-methyl-4-nitrobenzoic acid (905 mg, 84%) as an off-white solid. LCMS (10 cm-ESCI-Bicarb-MeCN): [MH] ⁻ = 214 at 2.12 min. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.22 (s, 1H), 7.76 (s, 1H), 2.70 (s, 3H).

Step 3: (5-Chloro-2-methyl-4-nitrophenyl)(morpholino)methanone

To 5-chloro-2-methyl-4-nitrobenzoic acid (197 mg, 0.91 mmol) in DMF (5 mL) was added triethylamine (0.13 mL, 0.91 mmol) and HATU (345 mg, 0.91 mmol), followed by morpholine (0.08 mL, 0.91 mmol). The mixture was allowed to stir at RT for 18 h, then water (10 mL) and DCM were added. The organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (0-100% EtOAc in isohexane) to give (5-chloro-2-methyl-4-nitrophenyl)(morpholino)methanone (244 mg, 95%) as an off-white solid. LCMS (10 cm-ESCI-Bicarb-MeCN): [M+H] ⁺ = 285 at 3.05 min. ¹ H NMR (400MHz, CDCl ₃ ): δ 7.76 (s, 1H), 7.36 (s, 1H), 3.83-3.76 (m, 4H), 3.66-3.58 (m, 2H), 3.28-3.20 (m, 2H), 2.37 (s, 3H).

Step 4: (4-Amino-5-chloro-2-methylphenyl)(morpholino)methanone

To (5-chloro-2-methyl-4-nitrophenyl)(morpholino)methanone (244 mg, 0.86 mmol) in ethanol (6 mL) and water (0.6 mL) was _{added SnCl2.2H2O} (776 mg, 3.44 mmol). The mixture was heated to 65°C for 5 h, then 2M aqueous sodium hydroxide solution (10 mL) and DCM (10 mL) were added. The organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo to give (4-amino-5-chloro-2-methylphenyl)(morpholino)methanone (203 mg, 93%) as an off-white solid. LCMS (10 cm-ESCI_Formic_MeCN): [M+H] ⁺ = 255 at 2.84 min. ¹ H NMR (400MHz, CDCl ₃ ): δ 7.07 (s, 1H), 6.60 (s, 1H), 4.10 (br s, 2H), 3.84-3.53 (br m, 6H), 3.36-3.24 (br m, 2H), 2.21 (s, 3H).

Preparation 7: 2-chloro-N-cyclopropyl-5-(trifluoromethyl)pyrimidin-4-amine

To 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.25 g, 5.8 mmol) in methanol (4 mL) at 0° C. was added cyclopropylamine (0.69 mL, 10 mmol). The mixture was allowed to stir at RT for 4 h., then DCM (20 mL) and water (20 mL) were added. The mixture was passed through a hydrophobic frit and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (0-100% DCM in isohexane) to give 2-chloro-N-cyclopropyl-5-(trifluoromethyl)pyrimidin-4-amine (472 mg, 34%) as an off-white solid. LCMS (10 cm-ESCI-Bicarb-MeCN): [M+H] ⁺ = 238 at 3.64 min. ¹ H NMR (400MHz, CDCl ₃ ): δ 8.27 (d, J=1.1Hz, 1H), 5.56 (br s, 1H), 3.03-2.93 (m, 1H), 0.99-0.89 (m, 2H), 0.65-0.60 (m, 2H).

Preparation 8: (4-amino-5-methoxy-2-(trifluoromethyl)phenyl)(morpholino)methanone

Step 1: (5-Methoxy-4-nitro-2-(trifluoromethyl)phenyl)(morpholino)methanone

To 5-fluoro-2-(trifluoromethyl)benzoic acid (1g, 4.8mmol) in concentrated sulfuric acid (5mL) at 0 ℃, carefully drop concentrated nitric acid (5mL). The mixture is heated to 100 ℃ and lasts for 18h. The cooling mixture is poured into an ice/water mixture (75mL), then extracted with EtOAc (75mL). The organic layer is washed with salt water (75mL) and passed through a hydrophobic glass frit. The solvent is removed in a vacuum and half the residue is added to a solution of sodium methoxide in THF [by adding sodium hydride (220mg, 60% in oil, 5.5mmol) to a mixture of THF (5mL) and methanol (0.12mL, 2.9mmol) to form]. The mixture is stirred for 3h at RT, then DCM (20mL) and the 2MHCl aqueous solution (5mL) are added. The mixture is passed through a hydrophobic glass frit and the solvent is removed in a vacuum. The residue was dissolved in DCM (24 mL) and DIPEA (0.48 mL, 7.2 mmol) and HATU (1.1 g, 2.9 mmol) were added, followed by morpholine (0.15 mL, 2.9 mmol). The mixture was allowed to stir at RT for 4 h, and then saturated aqueous sodium bicarbonate solution (25 mL) was added. The mixture was passed through a hydrophobic glass frit and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (0-10% EtOAc in isohexane) to give (5-methoxy-4-nitro-2-(trifluoromethyl)phenyl)(morpholino)methanone (350 mg, 4%) as a yellow solid. LCMS (10 cm-ESCI-Bicarb-MeCN): [M+H] ⁺ =335 at 3.33 min. ¹ H NMR (400MHz, CDCl ₃ ): δ 8.21 (s, 1H), 7.02 (s, 1H), 4.04 (s, 3H), 3.96-3.59 (m, 4H), 3.64-3.59 (m, 2H), 3.22-3.17 (m, 2H).

Step 2: (4-amino-5-methoxy-2-(trifluoromethyl)phenyl)(morpholino)methanone

[0266] To (5-methoxy-4-nitro-2-(trifluoromethyl)phenyl)(morpholino)methanone (349 mg, 1.04 mmol) in ethanol (20 mL) and water (2 mL) was added _SnCl2.2H2O (941 mg, 4.16 _mmol ). The mixture was heated to 65°C for 2 h, then 2M aqueous sodium hydroxide solution (20 mL) and DCM (20 mL) were added. The organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo to give (4-amino-5-methoxy-2-(trifluoromethyl)phenyl)(morpholino)methanone (250 mg, 79%) as an off-white solid. LCMS (10 cm-ESCI-Bicarb-MeCN): [M+H] ⁺ = 305 at 2.87 min. ¹ H NMR (400MHz, CDCl ₃ ): δ 6.94 (s, 1H), 6.64 (s, 1H), 4.07 (s, 2H), 3.92-3.67 (m, 4H), 3.89 (s, 3H), 3.62-3.52 (m, 2H), 3.25-3.19 (m, 2H).

Preparation 9: tert-Butyl 4-amino-5-chloro-2-fluorobenzoate and tert-butyl 4-amino-3-chloro-2-fluorobenzoate

To N-chlorosuccinimide (950mg, 7.1mmol) in N, the solution of tert-butyl 4-amino-2-fluorobenzoate (1.5g, 7.1mmol) in N, N-dimethylformamide (22mL) was added dropwise. The gained mixture was stirred at room temperature for 3 hours, then saline solution (80mL) and ethyl acetate (100mL) were added. The organic phase was collected and washed three times with salt water (50mL). The organic phase merged was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (4% EtOAc in isohexane) to give tert-butyl 4-amino-5-chloro-2-fluorobenzoate (400 mg, 23%, ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.63 (d, J=7.6 Hz, 1H), 6.55 (d, J=13.2 Hz, 1H), 6.46 (brs, 2H), 1.52 (s, 9H)) and tert-butyl 4-amino-3-chloro-2-fluorobenzoate (490 mg, 28%, ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.52 (t, J = 8.4 Hz, 1H), 6.64 (dd, J = 1.2 Hz and J = 8.4 Hz, 1H), 6.50 (brs, 2H), 1.53 (s, 9H)), all were white solids.

Preparation 10: Methyl 4-amino-3-fluoro-2,6-dimethoxybenzoate

To a solution of methyl 4-amino-2,6-dimethoxybenzoate (510 mg, 2.42 mmol) in acetonitrile (10 mL) at 0°C was added 4-nitro-2,6-dimethoxybenzoic acid (940 mg, 2.66 mmol). The mixture was stirred at 0°C for 30 minutes, then water (10 mL) was added. The reaction was extracted twice with ethyl acetate (30 mL). The organic phases were combined, passed through a hydrophobic frit, and the solvent removed in vacuo. The residue was purified by silica gel column chromatography (0-100% EtOAc in isohexane) to give methyl 4-amino-3-fluoro-2,6-dimethoxybenzoate (114 mg, 20%) as a yellow solid. ^1H NMR (400 MHz, CDCl ₃ ): δ 6.05 (d, J = 6.4 Hz, 1H), 3.93 (s, 3H), 3.88 (s, 3H), 3.75 (s, 3H).

Preparation 11: (2-Bromo-4-((2,4-dimethoxybenzyl)amino)-5-fluorophenyl)(morpholino)methanone

Step 1: (2-Bromo-4,5-difluorophenyl)(morpholino)methanone

2-Bromo-4,5-difluorobenzoic acid (2.00g, 8.44mmol), DIPEA (2.18g, 16.88mmol) and HATU (3.85g, 10.13mmol) were stirred at room temperature in dichloromethane (120mL) for 20min. Morpholine (0.88g, 10.13mmol) was added and the reactant was stirred for 2 hours. The dichloromethane was removed and the resulting residue was distributed between ethyl acetate and water. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were passed through a phase separation cartridge and concentrated. The resulting residue was purified by silica gel column chromatography (0-100% ethyl acetate/isohexane) to provide (2-bromo-4,5-difluorophenyl) (morpholino) ketone (2.5g, 97%). ¹ H NMR (400MHz, CDCl ₃ ): δ 7.44 (dd, J=9.42, 6.99Hz, 1H), 7.14 (dd, J=9.57, 7.88Hz, 1H), 3.88-3.69 (m, 5H), 3.64-3.57 (m, 1H), 3.33-3.17 (m, 2H).

Step 2: (2-Bromo-4-((2,4-dimethoxybenzyl)amino)-5-fluorophenyl)(morpholino)methanone

By (2- bromo-4,5-difluorophenyl) (morpholino) ketone (1.00g, 3.27mmol) and 3,4-dimethoxybenzylamine (601mg, 3.60mmol) in dimethyl sulfoxide (10mL) solution with dipotassium hydrogen phosphate (2.88g, 13.07mmol) under nitrogen atmosphere.Then the mixture is heated to 80 DEG C for 48h.Allow the reaction to cool, then dilute with water (50mL) and extract with dichloromethane (3x50mL).The combined extracts are washed with salt water (50mL), then passed through a phase separation cartridge, then evaporated, and a yellow oil is provided.The crude product is adsorbed on silica and purified by silica gel column chromatography (0-100% ethyl acetate/isohexane), there is provided (2- bromo-4-((2,4-dimethoxybenzyl) amino)-5-fluorophenyl)-(morpholino) ketone (200mg, 13%). ¹ HNMR (400MHz, CDCl ₃ ): δ7.16-7.14(m, 1H), 6.89-6.85(m, 2H), 6.49-6.42(m, 2H), 4.50(br s, 1H), 4.28-4.22 (m, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.75-3.65 (m, 5H), 3.67-3.56 (m, 1H), 3.35-3.25 (br s, 1H), 3.25 (br s, 1H).

Example 1: (4-(5-Fluoro-4-(methylamino)pyrimidin-2-ylamino)-3-methoxyphenyl)(morpholino)methanone

By 100mg 4-(5-fluoro-4-(methylamino) pyrimidine-2-ylamino)-3-methoxybenzoic acid, 47 μ L morpholine, 205mg HATU, the mixture of 188mL diisopropylethylamine in 1mL dimethylformamide was stirred at room temperature overnight.By LCMS, check reaction and find that the reaction is complete.Reactant is diluted with EtOAc, and organic layer is used saturated NaHCO ₃ and salt water washing.Organic layer is concentrated and by preparative reversed-phase HPLC purification, obtain 12mg of (4-(5-fluoro-4-(methylamino) pyrimidine-2-ylamino)-3-methoxyphenyl) (morpholino) ketone.

Example 2: 5-Chloro-2-methoxy-4-N,N-dimethyl-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) 1-Benzamide

A mixture of 4-amino-5-chloro-2-methoxy-N,N-dimethylbenzamide (110 mg, 0.48 mmol), 2-chloro-4-(methylamino)-5-trifluoromethylpyrimidine (50 mg, 0.23 mmol), tris(dibenzylideneacetone)dipalladium (11 mg, 0.012 mmol), xantphos (14 mg, 0.024 mmole) and cesium carbonate (235 mg, 0.72 mmol) in 1,4-dioxane was degassed with nitrogen for 5 minutes and then heated to 100°C for 2 hours. The cooled mixture was diluted with DCM (10 ml), washed with water, dried ( _MgSO4 ) and concentrated to dryness in vacuo. The residue was triturated in diethyl ether to provide the title compound as a light yellow solid, 45 mg, 47%.

Example 3 (2-fluoro-3-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl) (Morpholino)ketone

To a suspension of 2-fluoro-3-methoxy-4-nitrobenzoic acid (180 mg, 0.97 mmol) in DCM (8 mL) were added morpholine (0.17 mL, 1.9 mmol), DIEA (0.25 mL) and HBTU (0.4 g, 1.05 mmol). The reaction was stirred at room temperature for 18 hours. The reaction was then diluted with water and extracted with DCM (3x). The combined extracts were washed with water, dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by flash chromatography to give (2-fluoro-3-methoxy-4-nitrophenyl) (morpholino)methanone (0.20 g, 83%).

A suspension of (2-fluoro-3-methoxy-4-nitrophenyl)(morpholino)methanone (0.20 g) and palladium on carbon (0.1 g, 10 wt%) in ethanol was stirred under hydrogen for 18 hours. The reaction was then filtered through celite and concentrated to give (4-amino-2-fluoro-3-methoxyphenyl)(morpholino)methanone.

A mixture of (4-amino-2-fluoro-3-methoxyphenyl)(morpholino)methanone (0.18 g, 0.72 mmol) and 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (0.10 g, 0.47 mmol) in a solution of 2-methoxyethanol (2 mL) and TFA (0.055 mL) was stirred for 2 hours at 95° C. The reaction was concentrated and purified by reverse phase HPLC to give the title compound.

Example 4: 2-[2-Methoxy-4-(morpholine-4-carbonyl)-phenylamino]-4-methylamino-pyrimidine-5-carbonitrile

By (4-(5-bromo-4-(methylamino)pyrimidin-2-ylamino)-3-methoxyphenyl)(morpholino)methanone (80mg, 0.19mmol), zinc cyanide (50mg, 0.42mmol), tris(dibenzylideneacetone)dipalladium (9mg, 0.09mmol), DPPF (11mg, 0.02mmol) in DMF (3mL) was stirred at 105 DEG C for 18 hours in a pressure tube. The reaction mixture was filtered and concentrated. The crude product was purified by reverse phase HPLC to give the title compound (70mg, 82%). The additional compounds prepared using the above procedure are shown in Table 5 below.

Example 5

(5-methoxy-2-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)(morpholine (substituted) ketone

A mixture of (4-amino-5-methoxy-2-methylphenyl)(morpholino)methanone (2.12 g, 8.47 mmol), 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (1.79 g, 8.47 mmol), and p-toluenesulfonic acid (1.62 g, 8.47 mmol) in dioxane (80 mL) was heated to 100° C. for 18 h. Saturated aqueous sodium bicarbonate solution (100 mL) and DCM (100 mL) were added, the organic phase was passed through a hydrophobic frit, and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (0-100% EtOAc in isohexane) to give (5-methoxy-2-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)(morpholino)methanone (2.1 g, 58%) as an off-white solid. LCMS (10cm_ESCI_Bicarb_MeCN): [M+H] ⁺ =426 at 2.59 min. ¹ H NMR (400MHz, CDCl ₃ ): δ 8.47 (s, 1H), 8.18 (s, 1H), 7.74 (s, 1H), 6.71 (s, 1H), 5.25 (br s, 1H), 3.88 (s, 3H), 3.80 (br d, 4H), 3.59 (br s, 2H), 3.31 (br s, 2H), 3.12 (d, 3H), 2.28 (s, 3H).

Example 6: (5-chloro-2-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl) (Morpholino)ketone

A mixture of (4-amino-5-chloro-2-methylphenyl)(morpholino)methanone (79 mg, 0.31 mmol), 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (66 mg, 0.31 mmol), and p-toluenesulfonic acid (59 mg, 0.31 mmol) in dioxane (4 mL) was heated to 100° C. for 4 h. Saturated aqueous sodium bicarbonate solution (10 mL) and DCM (10 mL) were added, and the organic phase was passed through a hydrophobic frit. The solvent was removed in vacuo, and the residue was purified by reverse phase HPLC to give (5-chloro-2-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)(morpholino)methanone (71 mg, 53%) as an off-white solid. LCMS (10 cm-ESCI-Bicarb-MeCN): [M+H] ⁺ = 430 at 3.47 min. ¹ H NMR (400MHz, CDCl ₃ ): δ 8.55 (s, 1H), 8.21 (d, 1H), 7.57 (s, 1H), 7.22 (s, 1H), 5.30 (br s, 1H), 3.79 (br d, 4H), 3.60 (br s, 2H), 3.32 (br s, 2H), 3.11 (d, 3H), 2.32 (s, 3H).

Example 7: (4-(4-(cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxybenzene (Morpholino)methanone

To the chloro-N-cyclopropyl-5-(trifluoromethyl) pyrimidine-4-amine (237mg, 1mmol) of 2-in dioxane (3mL), pTSA (190mg, 1mmol) and 4-amino-2-fluoro-5-methoxybenzoic acid (185mg, 1mmol) are added. The mixture is heated to 100 ℃ for 5h, then the mixture is allowed to cool to RT. The precipitated solid is collected by filtration, washed with dioxane and diethyl ether, then dried. The residue is suspended in DCM (5mL), then DIPEA (0.1mL, 1.5mmol) and HATU (228mg, 0.6mmol) are added, followed by addition of morpholine (0.03mL, 0.6mmol). The mixture is allowed to stir 4h at RT, then DCM (10mL) and saturated sodium bicarbonate aqueous solution (15mL) are added. The organic phase separated is passed through a hydrophobic glass frit and the solvent is removed in a vacuum. The residue was purified by silica gel column chromatography (0-10% methanol in DCM) to give (4-(4-(cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxyphenyl)(morpholino)methanone (36 mg, 16%) as an off-white solid. LCMS (10cm-ESCI-Bicarb-MeCN): [M+H] ⁺ = 456 at 2.93 min. ¹ H NMR (400MHz, CDCl ₃ ): δ8.77 (d, J=12.6Hz, 1H), 8.20 (s, 1H), 7.94 (s, 1H), 6.91 (d, J=6.0Hz, 1H), 5.48(s, 1H), 3.92(s, 3H), 3.84-3.76(m, 4H), 3.68(t, J=4.5Hz, 2H), 3.44(br s, 2H), 2.94-2.87 (m, 1H), 1.03-0.96 (m, 2H), 0.70-0.65 (m, 2H).

Example 8: (4-(4-(cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino-2-fluoro-5-methoxy-benzene (Morpholino)methanone

To a solution of (4-(4-chloro-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxyphenyl)-(morpholino)methanone (120 mg, 0.28 mmol) in dioxane (2 mL) was added pTSA (52 mg, 0.28 mmol) and D4-cyclopropylamine (17 mg, 0.28 mmol). The mixture was heated to 100 ° C for 2 hours. LSMS of the crude sample showed only 10% of the desired substance. DIPEA (100 μL, 0.56 mmol) and D4-cyclopropylamine (17 mg, 0.28 mmol) were added and the mixture was heated to 100 ° C for one hour. After returning to room temperature, DCM (20 mL) and saturated aqueous sodium bicarbonate solution (15 mL) were added. The separated organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo. The residue was purified by reverse phase HPLC to give (4-(4-(cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxyphenyl)(morpholino)-methanone (42 mg, 33%) as an off-white solid. LCMS (10cm_ESCI_Bicarb_MeCN): [M+H] ⁺ = 460 at 3.41 min. ¹ H NMR (400MHz, CDCl ₃ ): δ8.77 (d, J=12.8Hz, 1H), 8.20 (s, 1H), 7.94 (s, 1H), 6.91 (d, J=5.6Hz, 1H), 5.4 8(s, 1H), 3.92(s, 3H), 3.80-3.74(m, 4H), 3.69-3.67(m, 2H), 3.44-3.43(m, 2H).

Example 9: (5-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-(trifluoromethyl)pyrimidin-2-ylamino)- methyl)phenyl)(morpholino)methanone

A mixture of (4-amino-5-methoxy-2-(trifluoromethyl)phenyl)(morpholino)methanone (94 mg, 0.31 mmol), 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (66 mg, 0.31 mmol) and p-toluenesulfonic acid (59 mg, 0.31 mmol) in dioxane (4 mL) was heated to 100° C. for 2 h. Saturated aqueous sodium bicarbonate solution (10 mL) and DCM (10 mL) were added and the organic phase was passed through a hydrophobic frit. The solvent was removed in vacuo and the residue was purified by reverse phase HPLC to give (5-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-(trifluoromethyl)phenyl)(morpholino)methanone (111 mg, 75%) as an off-white solid. LCMS (10cm_ESCI_Bicarb_MeCN): [M+H] ⁺ =480 at 3.32 min. ¹ HNMR (400MHz, CDCl ₃ ): δ9.13 (s, 1H), 8.19 (s, 1H), 7.82 (s, 1H), 6.77 (s, 1H), 5.34 (q, J=4.7Hz, 1H), 3.97 (s, 3H), 3.9 5-3.88 (m, 1H), 3.83-3.68 (m, 3H), 3.65-3.55 (m, 2H), 3.27-3.21 (m, 2H), 3.13 (d, J=4.7Hz, 3H).

Example 10: (4-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-5-methoxy-2-(trifluoromethyl)benzene (Morpholino)methanone

A mixture of (4-amino-5-methoxy-2-(trifluoromethyl)phenyl)(morpholino)methanone (94 mg, 0.31 mmol), 2,5-dichloro-N-methylpyrimidin-4-amine (55 mg, 0.31 mmol) and p-toluenesulfonic acid (59 mg, 0.31 mmol) in dioxane (4 mL) was heated to 100° C. for 36 h. Saturated aqueous sodium bicarbonate solution (10 mL) and DCM (10 mL) were added and the organic phase was passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by silica gel column chromatography (0-10% EtOAc in isohexane) to give (4-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-5-methoxy-2-(trifluoromethyl)phenyl)(morpholino)methanone (11 mg, 8%) as an off-white solid. LCMS (10cm_ESCI_Bicarb_MeCN): [M+H] ⁺ =446 at 3.60 min. ¹ H NMR (400MHz, CDCl ₃ ): δ8.97 (s, 1H), 8.40 (br s, 1H), 7.90 (s, 1H), 6.76 (s, 1H), 5.59 (q, J=4.9Hz, 1H), 3.96 (s, 3H), 3.95-3.87 (m, 1H), 3.82-3.69 (m, 3H), 3.62-3.56 (m, 2H), 3.26-3.20 (m, 2H), 3.13 (d, J=4.9Hz, 3H).

Example 11: (5-chloro-2-fluoro-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)- (Morpholino)ketone

By solution of 4-amino-5-chloro-2-fluorobenzoic acid tert-butyl ester (50mg, 0.20mmol) in dichloromethane (2mL) and trifluoroacetic acid (2mL) at room temperature stirring 3 hours, then reactant is evaporated to dryness.Residue is put into dioxane (3mL), then add 2-chloro-N-methyl-5-(tri-fluoromethyl) pyrimidine-4-amine (42mg, 0.20mmol) and p-toluenesulfonic acid (38mg, 0.20mmol).Gained mixture is heated to 100 ℃ and lasts 2h.After returning to room temperature, add DCM (10mL) and water (10m) and organic phase is passed through hydrophobic glass frit.Solvent is removed in a vacuum and residue is dissolved in DCM (3mL), then add DIPEA (140 μ L, 0.8mmol) and HATU (85mg, 0.22mmol), then add morpholine (18 μ L, 0.2mmol). The mixture was allowed to stir at RT for 4 h, then saturated aqueous sodium bicarbonate solution (25 mL) was added. The mixture was passed through a hydrophobic glass frit and the solvent was removed in vacuo. The residue was purified by reverse phase HPLC to give (5-chloro-2-fluoro-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-(morpholino)methanone (25 mg, 28%) as a pale solid. LCMS (10 cm-ESCI-Bicarb-MeCN): [M+H] ⁺ =434 at 3.02 min. ¹ H NMR (400MHz, CDCl ₃ ): δ8.64 (d, J=12.8Hz, 1H), 8.22 (s, 1H), 7.72 (brs, 1H), 7.48 (d, J=6.8Hz, 1H), 5.30 (br s, 1H), 3.80-3.77 (m, 4H), 3.66-3.68 (m, 2H), 3.41-3.39 (m, 2H), 3.12 (d, J=4.8Hz, 3H).

Example 12: (3-Fluoro-2,6-dimethoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino) methyl)-phenyl)(morpholino)methanone

By 4-amino-3-fluoro-2, the mixture of 6-dimethoxybenzoic acid methyl esters (114mg, 0.5mmol) and 1N NaOH (1.5mL) in ethanol (5mL) was heated at 60 ℃ for 18 hours.Solvent is removed in a vacuum.Resistate is dissolved in water (2mL), cools in an ice bath and is acidified to pH 3 by dropping 2NHCl.Reactant is evaporated to dryness and residue is dissolved in DCM (10mL), then DIPEA (260 μ L, 1.5mmol) and HATU (208mg, 0.6mmol) are added, then morpholine (66 μ L, 0.75mmol) are added.Allow mixture to stir one hour at RT, then add saturated sodium bicarbonate aqueous solution (10mL).Mixture is passed through hydrophobic glass frit and solvent is removed in a vacuum. The residue was taken up in dioxane (2 mL), followed by the addition of 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (105 mg, 0.5 mmol) and p-toluenesulfonic acid (95 mg, 0.50 mmol). The resulting mixture was heated to 100° C. for 30 minutes. After returning to room temperature, DCM (10 mL) and water (10 mL) were added and the organic phase was passed through a hydrophobic frit. The solvent was removed in vacuo and the residue was purified by reverse phase HPLC to give (3-fluoro-2,6-dimethoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-phenyl)(morpholino)methanone (18 mg, 8% over three steps) as an off-white solid. LCMS (10 cm-ESCI-Formic-MeCN): [M+H] ⁺ =460 at 3.32 min. ¹ H NMR (400MHz, CDCl ₃ ): δ8.20 (s, 1H), 8.04 (d, J = 6.0Hz, 1H), 7.36 (brs, 1H), 5.30 (brs, 1H), 3.97 (s, 3H), 3.85-3 .82 (m, 5H), 3.80-3.78 (m, 2H), 3.75-3.73 (m, 2H), 3.29-3.27 (m, 2H), 3.11 (d, J=4.8Hz, 3H).

Example 13: (5-Fluoro-2-methyl-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-benzene (Morpholino)methanone

Trifluoroacetic acid (2mL) is added to a solution of 2-bromo-4-((2,4-dimethoxybenzyl)amino)-5-fluorophenyl)(morpholino)methanone (205mg, 0.45mmol). The resulting mixture is stirred at room temperature for 2h. The reactant is then evaporated to dryness. The resulting residue is dissolved in dichloromethane and washed with saturated sodium bicarbonate solution. The organic phase is collected and filtered through a phase separation cartridge and evaporated in a vacuum. The residue is added to a mixture of 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidine-4-amine (77mg, 0.36mmol) and p-toluenesulfonic acid (68.5mg g, 0.36mmol) in dioxane (3mL). The mixture is stirred at 100°C for 2h. Saturated sodium bicarbonate aqueous solution (20mL) and DCM (20mL) are added and the organic phase is passed through a hydrophobic glass frit and the solvent is removed in a vacuum. The residue was purified by silica gel column chromatography (0-50% EtOAc in isohexane) to give a solid, which was then added to a mixture of methylboric acid (75 mg, 1.26 mol), potassium carbonate (124 mg, 0.9 mmol) and palladium tetrakis (31 mg, 0.027 mmol) in degassed water (0.8 mL) and degassed dioxane (5.5 mL). The resulting mixture was purged with nitrogen and then heated at 100° C. for 18 h. Volatiles were removed under reduced pressure and the resulting residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate and the combined organic phases were filtered through a hydrophobic frit and evaporated. The crude product was purified by reverse phase HPLC to give (5-fluoro-2-methyl-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)(morpholino)methanone (30 mg, 16% over 3 steps). LCMS (10cm_ESCI_Formic_MeCN): [M+H] ⁺ =415 at 3.12 min. ¹ H NMR (400MHz, DMSO-d ₆ ): δ9.17 (s, 1H), 8.19 (s, 1H), 7.80 (d, J = 7.69Hz, 1H), 7.20-7.11 (m, 2H), 3.68-3.64 (m, 4H), 3.58-3.53 (m, 2H), 3.22-3.18 (m, 2H), 2.89 (d, J=4.27Hz, 3H), 2.21 (s, 3H).

Example 14: 5-Bromo-2-methoxy-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzene (Morpholino)methanone

4-Amino-5-bromo-2-methoxybenzoic acid (1.09 g, 4.42 mmol), DIPEA (1.14 g, 8.84 mmol) and HATU (2.02 g, 5.3 mmol) were stirred at room temperature in dichloromethane (60 mL) for 20 min. Morpholine (0.77 g, 8.84 mmol) was added and the reaction was stirred for 2 h. The dichloromethane was removed and the resulting residue was distributed between ethyl acetate and water. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were passed through a phase separation cartridge and concentrated. The resulting material was purified by silica gel column chromatography (50-100% ethyl acetate/isohexane) to give a solid, which was added to a mixture of 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidine-4-amine (671 mg, 3.17 mmol) and p-toluenesulfonic acid (603 mg, 3.17 mmol) in dioxane (70 mL). The reaction was stirred at 100°C for 2 h. The resulting solution was evaporated to dryness and the residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate and the combined organic fractions were filtered through a phase separation cartridge and evaporated to provide a residue that was purified by silica gel column chromatography (25-75% ethyl acetate/isohexane) and the resulting residue was triturated with diethyl ether:petroleum ether (1:1) to provide 5-bromo-2-methoxy-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)(morpholino)methanone (340 mg, 15% yield) as a white solid.

Example 15 (2-methoxy-5-methyl-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino methyl)-phenyl)(morpholino)methanone

5-Bromo-2-methoxy-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)(morpholino)-methanone (340 mg, 0.69 mmol) was added to a mixture of methylboric acid (217 mg, 3.64 mmol), potassium carbonate (359 mg, 2.6 mmol) and palladium tetrakis (90 mg, 0.078 mmol) in degassed water (3 mL) and degassed dioxane (20 mL) in a reaction tube. The reaction tube was purged with nitrogen, sealed, and then heated at 100° C. for 18 h. The volatiles were removed under reduced pressure and the resulting residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate and the combined organic portions were filtered through a phase separation cartridge and evaporated. The crude material was purified by silica gel column chromatography (25-75% ethyl acetate/isohexane) and the resulting impure material was purified by reverse phase HPLC to give (2-methoxy-5-methyl-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)(morpholino)methanone (16 mg, 6%). LCMS (10 cm-ESCI-bicarb-MeOH): [M+H] ⁺ = 426 at 3.32 min. ¹ H NMR (400MHz, CDCl ₃ ): δ8.17(s, 1H), 8.01(s, 1H), 7.10(s, 1H), 7.04(s, 1H), 5.27(s, 1H), 3.84(s, 3H), 3.80- 3.70 (m, 4H), 3.64-3.59 (m, 2H), 3.36-3.19 (m, 2H), 3.09 (d, J=4.73Hz, 3H), 2.27 (s, 3H).

Example 16: (4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxybenzene (D8-morpholino)methanone

(4-(4-(Ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxyphenyl)(D8-morpholino)methanone was prepared as described above using perdeuterated morpholine: LCMS (10 cm-ESCI_Formic_MeCN): [M+H] ⁺ = 452 at 3.77 min. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.43 (d, J = 12 Hz, 1 H), 8.20 (s, 1 H), 7.84 (s, 1 H), 6.92 (d, J = 6 Hz, 1 H), 5.2 (1 H, brs), 3.92 (s, 3 H), 3.64-3.58 (m, 2 H), 1.33 (t, J = 7.2 Hz, 3 H).

Compounds according to the invention prepared using the above procedure are shown in Table 5 along with LRRK2 Ki values (micromolar concentrations).

Table 5

Example 17; 8-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-N-methyl-2,3-dihydrobenzene [b][1,4]dioxin-5-

Step 1: 6,7-Dibromo-2,3-dihydrobenzo[b][1,4]dioxin-5-carboxylic acid

A 20-mL round-bottom flask was charged with 2,3-dihydrobenzo[b][1,4]dioxin-5-carboxylic acid (1.8 g, 1.0 mmol), bromine (3.16 g, 2.0 mmol), and acetic acid (2 mL). The reaction mixture was stirred at 120° C. for 2 h and then cooled to 15° C. It was filtered and the solid was washed with acetic acid to provide the title compound as a white solid (3.0 g, 60%). LCMS: ESI (3 minute run), m/z = 337 [M+1] ⁺ ; retention time: 1.21 minutes.

Step 2: 6,7-Dibromo-8-nitro-2,3-dihydrobenzo[b][1,4]dioxin-5-carboxylic acid

A 20-mL round-bottom flask was charged with 6,7-dibromo-2,3-dihydrobenzo[b][1,4]dioxin-5-carboxylic acid (3.0 g, 0.61 mmol) and acetic acid (2 mL). The mixture was heated to 37°C, followed by the addition of a solution of nitric acid (d = 1.4 g, 1.0 mL), acetic acid (1.0 mL) and concentrated sulfuric acid (1.0 mL). After heating at 50°C for 1 h, the mixture was poured into cold water while stirring. It was then filtered and the solid was washed with water to provide the title compound (1.91 g, 83%). LCMS: ESI (3 minute run), m/z = 382 [M+1] +; retention time: 1.05 minutes.

Step 3: 8-amino-2,3-dihydrobenzo[b][1,4]dioxin-5-carboxylic acid

The autoclave vessel was charged with water (4.0 mL), 6,7-dibromo-8-nitro-1,4-benzodioxane-5-carboxylic acid (1.9 g, 0.5 mmol), saturated sodium carbonate (1.0 mL), and Pd/C (500 mg). The mixture was hydrogenated at 40 kg/ ^cm2 at 50°C overnight. It was then filtered and the filtrate was treated with hydrochloric acid (3.0 mL). The suspension was filtered and the solid was washed with water to provide the title compound (253 mg, 26%). LCMS: ESI (3 minute run), m/z = 196 [M+1] +; retention time: 0.30 min.

Step 4: 8-amino-N-methyl-2,3-dihydrobenzo[b][1,4]dioxin-5-carboxamide

A 50-mL round-bottom flask was charged with 8-amino-2,3-dihydrobenzo[b][1,4]dioxin-5-carboxylic acid (200 mg, 1.025 mmol), methylamine hydrochloride (138 mg, 2.05 mmol), HATU (467 mg, 1.23 mmol), TEA (0.5 mL), and DMF (5.0 mL). The reaction mixture was stirred at room temperature for 15 h. It was then purified by reverse phase Combi-Flash eluting _with 0.1% _NH4HCO3 in water/ _CH3CN to provide the title compound as a red oil (250 mg, 88%). LCMS: ESI (3 minute run), m/z = 209.1 [M+1]+; retention time: 1.53 min.

Step 5: 8-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-N-methyl-2,3-dihydrobenzo [b][1,4]Dioxin-5-carboxamide

A microwave vial equipped with a magnetic stirrer was charged with 8-amino-N-methyl-2,3-dihydrobenzo[b][1,4]dioxin-5-carboxamide (50 mg, 0.18 mmol), 2-chloro-N-ethyl-5-(trifluoromethyl)pyrimidin-4-amine (40 mg, 0.18 mmol), and t-BuOH (1.0 mL). The mixture was heated at 100° C. under microwave irradiation for 2 h. It was then concentrated and the residue was purified by reverse phase preparative HPLC to provide the title compound as a white solid (15.4 mg, 32%). LCMS: ESI (10 minute run), m/z=398.1 retention time: 5.471 minutes. 1H NMR (500MHz, CDCl ₃ )δ8.19 (d, J=9.0Hz, 1H), 8.17 (s, 1H), 7.82 (d, J=4.5Hz, 1H), 7.67~7.62 (m, 1H), 7.50~7.47 (m, 1H), 5.20 (s, 1H), 4.46~4.44(m, 2H), 4.41~4.40(m, 2H), 3.63~3.56(m, 2H), 3.01(d, J=5.0Hz, 3H), 1.31(t, J=7.5Hz, 3H).

Compounds according to the invention prepared using the above procedure are shown in Table 6 along with LRRK2 Ki values (micromolar concentrations).

Table 6

Example 18 In vitro LRRK2 LabChip assay

This assay is used to determine the potency of a compound in inhibiting LRRK2 activity by determining the Ki _app , IC ₅₀ , or percent inhibition value. LRRK2, a fluorescently labeled peptide substrate, ATP, and the test compound are incubated together in a polypropylene plate. Following the reaction, the substrate is separated by capillary electrophoresis into two populations: phosphorylated and unphosphorylated, using a LabChip 3000 (Caliper Life Sciences). The relative amounts of each are quantified by fluorescence intensity. The LRRK2 Ki 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 μM.

The assay conditions and materials used are as follows:

Final measurement conditions :

ATP ^app Kms :

Material :

Complete reaction buffer: _H2O /25 mM Tris, pH 8.0/5 mM _MgCl2 /2 mM DTT/0.01% Triton X-100.

Stop solution: _H2O /100 mM HEPES, pH 7.2/0.015% Brij-35/0.2% Coating Reagent #3/20 mM EDTA.

Isolation buffer: _H2O /100 mM HEPES, pH 7.2/0.015% Brij-35/0.1% Coating Reagent #3/1:200 Coating Reagent #8/10 mM EDTA/5% DMSO.

Compound plate preparation:

For serial dilutions, add 34.6 μl of DMSO to columns 3-24. For assay controls, add 37.5 μl of DMSO to columns 1 and 2 of rows A and P, and add 50 μl of 25 μM G-028831 (Staurosporine) to columns 1 and 2 of row B. For samples: starting at 100 μM, add 37.5 μl of DMSO to columns 1 and 2, followed by 12.5 μl of 10 mM compound; starting at 10 μM, add 78 μl of DMSO to columns 1 and 2, followed by 2 μl of 10 mM compound; and starting at 1 μM, add 25 μM compound (2 μl of 10 mM compound + 798 μl of DMSO) to empty columns 1 and 2. A precision instrument was used to perform a 1:3.16 serial dilution ("PLK_BM_serial_halflog").

ATP preparation :

ATP was diluted to 282.1 μM in complete kinase buffer (final concentration 130 μM).

Overall and blank preparation :

Dilute substrate to 4 μM in complete reaction buffer. Combine equal volumes of complete reaction buffer and 4 μM substrate to create a blank. Combine equal volumes of complete reaction buffer and 4 μM substrate and add 2X final LRRK2 concentration to this combined solution.

Assay procedure :

To a 50 μl polypropylene plate, 5 μl/well buffer/substrate was added by hand to a blank well. A Biomek FX was used to start the kinase reaction ("PLK SAR 23ATP"). The following were added to the appropriate wells:

2 μl compound + 23 μl ATP;

5 μl/well compound/ATP in the assay plate;

5 μl/well kinase/substrate in the assay plate;

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

Lab Chip 3000 Protocol :

The LabChip 3000 was run using the job "LRRK2 IC50" with the following working settings:

Example 19 In vitro LRRK2 Lanthascreen binding assay

This assay is used to determine the potency of compounds in inhibiting the activity of LRRK2 by determining Ki _app , IC ₅₀ or percent inhibition values. In 384-well proxiplates F black shallow well plates, LRRK2, Eu-anti-GST-antibody, Alexa Kinase tracer 236 and test compounds are incubated together.

Binding of the Alexa "tracer" to the kinase is detected by the addition of an Eu-labeled anti-GST antibody. Binding of the tracer and antibody to the kinase results in a high degree of FRET, while displacement of the tracer by the kinase inhibitor results in a loss of FRET.

The assay conditions and materials used are as follows:

Final measurement conditions :

Material :

Reaction buffer solution: H ₂ O/50 mM Tris, pH 7.4/10 mM MgCl ₂ /1 mM EGTA/0.01% Brij35.

Compound plate preparation:

Serially dilute the test compound (10 mM stock) 1:3.16 (20 μl + 43.2 μl) in 100% DMSO. 12pt curve. Dilute each concentration 1:33.3 (3 μl + 97 μl) in reaction buffer. Print 5 μl onto the assay plate. Final highest test concentration 100 μM.

Overall and blank preparation :

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

Assay procedure :

5ul of LRRK2 (30nM)/Eu-labeled anti-GST antibody (6nM) mixture was added to the compound and all wells. 5ul of kinase tracer (25.5nM) was added to all wells. The plate was incubated at room temperature on a plate shaker (gentle shaking) for 1 hour. The plate was read using the Perkin Elmer EnVision reader HTRF protocol.

Data processing:

Calculate the ratio: (665/620)*10000. Subtract the average background value from all data points. Calculate the % of control for each test value. Plot the % of control against the compound concentration. Calculate the Ki value (xlfit curve fit - Morrison equation).

The results are expressed as Ki in μM. 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)))

Where Et = 4 nM

kd(tracer) = 8.5 nM

Tracer concentration (S) = 8.5 nM.

Example 20 Parkinson's disease animal model

Parkinson's disease can be replicated in mice and primates by administering 1-methyl-4-phenyltetrahydropyridine (MPTP), a selective nigrostriatal dopaminergic neurotoxin that produces a marked loss of striatal dopamine (DA) nerve terminals. Using MPTP-induced neurodegeneration, the efficacy of the compounds of the present invention in treating Parkinson's disease can be evaluated generally according to the protocol described by Saporito et al., J. Pharmacology (1999) Vol. 288, pp. 421-427.

In brief, MPTP is dissolved in PBS with a concentration of 2-4mg/ml, and mice (male C57, weighing 20-25g) are subcutaneously injected with 20 to 40mg/kg. Compound of the present invention is solubilized with polyethylene glycol hydroxystearate and dissolved in PBS. 4 to 6h before MPTP administration, mice are administered 10ml/kg of compound solution by subcutaneous injection, and then administered every day for 7 days. On the last injection day, mice are killed and midbrain is sealed and postfixed in paraformaldehyde. Excise the striatum, weigh and store at -70 ℃.

The striatum thus collected is evaluated for 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 can also be evaluated using the tyrosine hydroxylase assay of Okunu et al., Anal Biochem (1987) Vol. 129, pp. 405-411, by measuring ¹⁴ CO ₂ evolution associated with the tyrosine hydroxylase-mediated conversion of labeled tyrosine to L-dopa. The striatum can also be evaluated using the monoamine oxidase-B assay as described by White et al., Life Sci. (1984) Vol. 35, pp. 827-833, and by measuring dopamine uptake as described by Saporito et al., (1992) Vol. 260, pp. 1400-1409.

Although the present 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 present invention. In addition, many modifications may be made to adapt specific circumstances, materials, compositions of matter, methods, method steps, or multiple 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 (11)

1. A pharmaceutical salt of a compound, wherein the compound is selected from: [5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-[4-(2-methoxy-ethyl)-piperazin-1-yl]-methyl ketone; [5-Chloro-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methyl ketone; [5-Methoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methyl ketone; [2-Fluoro-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-methyl ketone; [2-Fluoro-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(1S,5R)-8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl-methyl ketone; [4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-(1S,5R)-8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl-methyl ketone; 2-Fluoro-5-methoxy-N-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-benzamide; [2-Fluoro-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(4-morpholino-4-yl-piperidin-1-yl)-methyl ketone; [4-(5-chloro-4-methoxy-pyrimidin-2-ylamino)-3-hydroxy-phenyl]-morpholin-4-yl-methyl ketone; [5-Chloro-2-hydroxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methyl ketone; [2-Fluoro-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-methyl ketone; [2,3-Difluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methyl ketone; [4-(5-chloro-4-methylamino-pyrimidin-2-ylamino)-2,3-difluoro-phenyl]-morpholin-4-yl-methyl ketone; [4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-methyl ketone; [5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-methyl ketone; [2,5-Difluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methyl ketone; [4-(5-chloro-4-methylamino-pyrimidin-2-ylamino)-2,5-difluoro-phenyl]-morpholin-4-yl-methyl ketone; 4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(2-hydroxy-2-methyl-propyl)-5-methoxy-benzamide; 4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(2-hydroxy-2-methyl-propyl)-5-methoxy-N-methyl-benzamide; [5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(3-morpholin-4-yl-azacyclobutane-1-yl)-methyl ketone; N-tert-butyl-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methoxy-benzamide; [3-Fluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholino-4-yl-methyl ketone; [5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(4-oxetane-3-yl-piperazin-1-yl)-methyl ketone; [5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(3,3-difluoro-pyrrolidone-1-yl)-methyl ketone; [4-(4-cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-morpholin-4-yl-methyl ketone; [4-(4-azacyclobutane-1-yl-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-morpholin-4-yl-methyl ketone; 5-Fluoro-N-(2-hydroxy-2-methyl-propyl)-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide; 4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-N-(2-hydroxy-2-methyl-propyl)-2-methoxy-benzamide; 5-Fluoro-N-(2-hydroxy-2-methyl-propyl)-2-methoxy-N-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide; 4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-N-(2-hydroxy-2-methyl-propyl)-2-methoxy-N-methyl-benzamide; [4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,5-difluoro-phenyl]-morpholin-4-yl-methyl ketone; [2-Fluoro-4-(4-isopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-methoxy-phenyl]-morpholino-4-yl-methyl ketone; [3-Methoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methyl ketone; [4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-(1-oxa-6-aza-spiro[3.3]hept-6-yl)-methyl ketone; 2-Fluoro-N-(2-hydroxy-2-methyl-propyl)-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide; ((3S,4S)-3,4-difluoro-pyrrolidone-1-yl)-[2-fluoro-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-methyl ketone; 4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-N-methyl-benzamide; 2-Fluoro-N-(2-hydroxy-2-methyl-propyl)-3-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide; (3,3-Difluoro-pyrrolidone-1-yl)-[5-(2-fluoro-ethoxy)-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-methyl ketone; [5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(1-oxa-6-aza-spiro[3.3]hept-6-yl)-methyl ketone; [4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-difluoro-phenyl]-morpholin-4-yl-methyl ketone; [4-(4-cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-methoxy-2-methyl-phenyl]-morpholin-4-yl-methyl ketone; [5-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-methoxy-phenyl]-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-methyl ketone; [4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-methoxy-2-methyl-phenyl]-morpholin-4-yl-methyl ketone; 4-(4-cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(2-hydroxy-2-methyl-propyl)-5-methoxy-benzamide; N-tert-butyl-4-(5-cyano-4-ethylamino-pyrimidin-2-ylamino)-3-methoxy-benzamide; [3-Difluoromethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methyl ketone; [2-Fluoro-5-(2-Fluoro-ethoxy)-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholino-4-yl-methyl ketone; [4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-(2-fluoro-ethoxy)-phenyl]-morpholin-4-yl-methyl ketone; [2-Fluoro-5-methoxy-4-(4-methoxy-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholino-4-yl-methyl ketone; [4-(4-cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-difluoro-phenyl]-morpholin-4-yl-methyl ketone; [4-(4-cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,5-difluoro-phenyl]-morpholin-4-yl-methyl ketone; [2-Chloro-5-fluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methyl ketone; 4-Ethylamino-2-[4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-2-methoxy-phenylamino]-pyrimidine-5-carboxynitrile; 5-Chloro-2-methoxy-N-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-N-(1-methyl-1H-pyrazol-4-yl)-benzamide; (3,3-Difluoro-pyrrolidone-1-yl)-[4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,5-dimethoxy-phenyl]-methyl ketone; [4-(5-chloro-4-methoxy-pyrimidin-2-ylamino)-3-(2-fluoro-ethoxy)-phenyl]-morpholin-4-yl-methyl ketone; [2-Methoxy-5-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methyl ketone; [2-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-phenyl]-morpholin-4-yl-methyl ketone; [3-Chloro-2-fluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methyl ketone; (3,3-Difluoro-pyrrolidone-1-yl)-[4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-(2-fluoro-ethoxy)-2-methoxy-phenyl]-methyl ketone; [4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,6-difluoro-3-methoxy-phenyl]-morpholin-4-yl-methyl ketone; [2,6-Difluoro-3-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methyl ketone; [4-(4-ethoxy-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-morpholin-4-yl-methyl ketone; [2,5-Dimethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methyl ketone; (3,3-Difluoro-pyrrolidone-1-yl)-[4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoromethoxy-2-methoxy-phenyl]-methyl ketone; [5-Methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-trifluoromethyl-phenyl]-morpholin-4-yl-methyl ketone; [4-(5-chloro-4-methylamino-pyrimidin-2-ylamino)-5-methoxy-2-trifluoromethyl-phenyl]-morpholin-4-yl-methyl ketone; [5-Chloro-2-fluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methyl ketone; [4-(4-cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-(2-fluoro-ethoxy)-phenyl]-morpholin-4-yl-methyl ketone; [5-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-methyl-phenyl]-morpholin-4-yl-methyl ketone; [5-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoromethoxy-phenyl]-morpholin-4-yl-methyl ketone; [5-Fluoro-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholino-4-yl-methyl ketone; [5-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-phenyl]-morpholin-4-yl-methyl ketone; {2-Fluoro-4-[4-((1R,2S)-2-fluoro-cyclopropylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-5-methoxy-phenyl}-morpholino-4-yl-methyl ketone; (2,2-Dimethylmorpholino-4-yl)-[2-fluoro-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-methyl ketone; [3-Cyclopropoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methyl ketone; [5-Chloro-2-difluoromethoxy-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methyl ketone; [5-Chloro-2-difluoromethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methyl ketone; 4-Ethylamino-2-[5-fluoro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-2-methoxy-phenylamino]-pyrimidine-5-carboxynitrile; 4-Ethylamino-2-[2-fluoro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-5-methoxy-phenylamino]-pyrimidine-5-carboxynitrile; [3-Chloro-2,6-dimethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methyl ketone; (2,2-Dimethylmorpholino-4-yl)-[3-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-methyl ketone; [5-(2-fluoro-ethoxy)-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methyl ketone; [5-(2-fluoro-ethoxy)-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-pyrrolidine-1-yl-methyl ketone; (5-Chloro-4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-methoxyphenyl)(per-deuterated morpholino) methyl ketone; [4-(5-chloro-4-methoxy-pyrimidin-2-ylamino)-2,5-dimethoxy-phenyl]-morpholin-4-yl-methyl ketone; [5-Fluoromethoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methyl ketone; {4-[ethyl-(4-methylamino-5-trifluoromethyl-pyrimidin-2-yl)-amino]-5-fluoromethoxy-2-methyl-phenyl}-morpholin-4-yl-methyl ketone; [5-Fluoromethoxy-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-pyrrolidine-1-yl-methyl ketone; [4-(4-cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-morpholin-4-yl-methyl ketone; [2-Fluoro-5-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholino-4-yl-methyl ketone; [4-(5-chloro-4-methoxy-pyrimidin-2-ylamino)-5-methoxy-2-methyl-phenyl]-morpholin-4-yl-methyl ketone; [4-(5-chloro-4-ethoxy-pyrimidin-2-ylamino)-5-methoxy-2-methyl-phenyl]-morpholin-4-yl-methyl ketone; [2-Fluoro-5-fluoromethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-pyrrolidine-1-yl-methyl ketone; 4-Cyclopropylamino-2-[4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-2-methoxy-phenylamino]-pyrimidine-5-carboxynitrile; 4-Ethylamino-2-[4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-2-methoxy-5-methyl-phenylamino]-pyrimidine-5-carboxynitrile; 4-Ethylamino-2-[2-fluoro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-phenylamino]-pyrimidin-5-carboxynitrile; [5-Isopropoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methyl ketone; [5-ethoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methyl ketone; [5-Fluoromethoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-pyrrolidine-1-yl-methyl ketone; [5-Chloro-4-(4-cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoromethoxy-phenyl]-morpholin-4-yl-methyl ketone; [4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-2-methyl-phenyl]-morpholin-4-yl-methyl ketone; (5-Methoxy-2-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)(per-deuterated morpholino) methyl ketone; 4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-N-(2-hydroxy-2-methyl-propyl)-5-methoxy-2-methyl-benzamide; 4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(2-hydroxy-1,1-dimethyl-ethyl)-5-methoxy-benzamide; 2-[2-chloro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-5-methyl-phenylamino]-4-ethylamino-pyrimidine-5-carboxynitrile; 2-[2-chloro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-phenylamino]-4-ethylamino-pyrimidine-5-carboxynitrile; [5-Cyclopropylmethoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methyl ketone; [5-Fluoromethoxy-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-piperidin-1-yl-methyl ketone; [5-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoromethoxy-phenyl]-pyrrolidine-1-yl-methyl ketone; [4-(4-cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-2-methoxy-phenyl]-morpholin-4-yl-methyl ketone; [5-Chloro-4-(4-cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-methoxy-phenyl]-morpholin-4-yl-methyl ketone; 4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(1-hydroxymethyl-cyclopropyl)-5-methoxy-benzamide; 4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(1-hydroxy-cyclopropylmethyl)-5-methoxy-benzamide; N-(2-hydroxy-2-methyl-propyl)-5-methoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide; 2-[2-chloro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-5-methoxy-phenylamino]-4-ethylamino-pyrimidine-5-carboxynitrile; [4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methyl-phenyl]-morpholin-4-yl-methyl ketone; [4-(5-chloro-4-methoxy-pyrimidin-2-ylamino)-5-fluoromethoxy-2-methyl-phenyl]-pyrrolidine-1-yl-methyl ketone; 5-Fluoromethoxy-2-methoxy-N,N-dimethyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide; [4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-2-fluoromethoxy-phenyl]-pyrrolidine-1-yl-methyl ketone; [3-Fluoro-2,6-dimethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholino-4-yl-methyl ketone; (4-(4-(2,3-tetradeuterium-cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxyphenyl, (morpholino) methyl ketone; [5-Methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-trifluoromethoxy-phenyl]-morpholin-4-yl-methyl ketone; [4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,5-dimethoxy-phenyl]-morpholin-4-yl-methyl ketone; [2-Chloro-5-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methyl ketone; (4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxyphenyl)(per-deuterated morpholino) methyl ketone; (5-Bromo-2-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)(morpholino) methyl ketone; [4-(4-cyclobutylamino-5-trifluoromethylpyrimidin-2-ylamino)-5-methoxy-2-methyl-phenyl]-morpholin-4-yl-methyl ketone; and [2,5-Dimethyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methyl ketone. 2. A pharmaceutical salt of the compound according to claim 1, wherein said compound is [4-(4-cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-morpholin-4-yl-methyl ketone. 3. A pharmaceutical salt of the compound according to claim 1, wherein the compound is [4-(4-cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-methoxy-2-methyl-phenyl]-morpholin-4-yl-methyl ketone. 4. A pharmaceutical composition comprising: Pharmaceutical carriers; and A pharmaceutical salt of the compound according to any one of claims 1-3. 5. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition is used for the prevention or treatment of Parkinson's disease. 6. Use of a pharmaceutical salt of a compound according to any one of claims 1-3 in the preparation of a medicament for the prevention or treatment of Parkinson's disease. 7. Compounds of Formula III: Or its medicinal salt, in: Y is either -O- or -CHR ⁸ -; Z is -O- or -CHR ⁸ -, or Z does not exist; m is between 0 and 2; X is: -NR ^a- ; -O-; or -S(O) _r- , where r is 0 to 2 and ^Ra is hydrogen or _C1-6 alkyl; ^R1 is: _C1-6 alkyl; _C2-6 alkenyl; _C2-6 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 portion is optionally substituted with _C1-6 alkyl; tetrahydropyranyl; tetrahydrofuranyl; tetrahydrofuranyl- _C1-6 alkyl; oxetane-butane; or oxetane- _C1-6 alkyl; ^R2 is: halogenated; _C1-6 alkoxy; cyano; _C2-6 alkynyl; _C2-6 alkenyl; halo- _C1-6 alkyl; halo- _C1-6 alkoxy; _C3-6 cycloalkyl, wherein the _C3-6 cycloalkyl portion is optionally substituted with a _C1-6 alkyl; _C3-6 cycloalkyl- _C1-6 alkyl, wherein the _C3-6 cycloalkyl portion is optionally substituted with a _C1-6 alkyl; tetrahydrofuranyl; tetrahydrofuranyl- _C1-6 alkyl; acetyl; oxetane-C1-6 alkyl; or oxetane- _C1-6 alkyl; R ⁵ represents: hydrogen; or _C1-6 alkyl; ^R6 is: hydrogen; _C1-6 alkyl; _C1-6 alkoxy- _C1-6 alkyl; hydroxy- _C1-6 alkyl; amino- _C1-6 alkyl; _C3-6 cycloalkyl; or _C3-6 cycloalkyl- _C1-6 alkyl; or ^R5 and ^R6 together with the nitrogen atom to which they are attached form a three- to seven-membered ring, said three- to seven-membered ring optionally including additional heteroatoms selected from O, N and S(O) _n , said ring being: azirrobutyl; pyrrolidinyl; piperidinyl; piperazinyl; or morpholinyl, and optionally substituted by one, two, three or four groups, said groups being independently selected from: _C1-6 alkyl; halo- _C1-6 alkyl; _C1-6 alkoxy; halo- _C1-6 alkoxy; hydroxy; _C1-6 alkoxy- _C1-6 alkyl; hydroxy- _C1-6 alkyl; halo, nitrile; _C1-6 alkyl-carbonyl; C _1-6 alkyl-sulfonyl; _C3-6 cycloalkyl; _C3-6 cycloalkyl- _C1-6 alkyl; _C3-6 cycloalkyl-carbonyl; or amino; R ⁷ is: halogenated; _C1-6 alkyl; _C1-6 alkoxy; halo- _C1-6 alkyl; or halo- _C1-6 alkoxy; and ^R8 represents: hydrogen; halogenated; _C1-6 alkyl; or oxo-substituted. 8. The compound according to claim 7, wherein the compound is: [5-Fluoro-7-(4-methylamino-5-trifluoromethylpyrimidin-2-ylamino)-2,3-dihydro-benzofuran-4-yl]-morpholino-4-yl-methyl ketone; 8-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxin-5-carboxyethylamide; 8-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxin-5-carboxylic acid isopropylamide; 8-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxin-5-carboxyethylamide; [8-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxin-5-yl]-morpholin-4-yl-methyl ketone; (3,3-Difluoro-pyrrolidone-1-yl)-[8-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxin-5-yl]-methyl ketone; 8-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxin-5-carboxymethylamide; [8-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxin-5-yl]-pyrrolidine-1-yl-methyl ketone; [8-(4-methylamino-5-trifluoromethylpyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxin-5-yl]pyrrolidine-1-yl-methyl ketone; or [8-(5-chloro-4-methoxy-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxin-5-yl]-morpholin-4-yl-methyl ketone, Or its medicinal salt. 9. A pharmaceutical composition comprising: Pharmaceutical carriers; and The compound or its pharmaceutical salt according to any one of claims 7-8. 10. The pharmaceutical composition of claim 9, wherein the pharmaceutical composition is used for the prevention or treatment of Parkinson's disease. 11. Use of a compound or a pharmaceutical salt thereof according to any one of claims 7-8 in the preparation of a medicament for the prevention or treatment of Parkinson's disease.