HK1227387A1

HK1227387A1 - 2-phenylaminopyrimidine derivatives as kinase lrrk2 modulators for the treatment of parkinson's disease

Info

Publication number: HK1227387A1
Application number: HK17100838.7A
Authority: HK
Inventors: 查尔斯‧贝克-格伦; 丹尼尔‧乔恩‧伯狄克; 马克‧钱伯斯; 布赖恩‧K‧尚; 陈慧芬; 安东尼‧埃斯特拉德; 简纳‧格茨纳－托斯泰; 丹尼尔‧肖尔; 扎卡里‧斯威尼; 王淑梅; 赵桂玲
Original assignee: 健泰科生物技术公司
Priority date: 2011-11-29
Filing date: 2017-01-23
Publication date: 2017-10-20

Abstract

This invention disclose the specific compounds of formula (I): or pharmaceutically acceptable salts thereof, wherein m, X, R, R2, R3, R, R6 and R7 are as defined herein. Also disclosed are methods of making the compounds and using the compounds for treatment of diseases associated with LRRK2 receptor, such as Parkinson's disease.

Description

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

The application is a divisional application of applications of PCT international application with the date of 2012/28/11/2012, PCT international application number of PCT/EP2012/073762, Chinese national application number of 201280058444.X, and invention name of 2-phenylamino pyrimidine derivatives serving as kinase LRRK2 modulators for treating Parkinson's disease.

Technical Field

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

Background

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

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

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

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

Disclosure of Invention

The present invention provides compounds of formula I:

or a pharmaceutically acceptable salt thereof,

wherein:

m is 0 to 3;

x is: -NR^a-; -O-; or-S (O)_r-, where R is 0 to 2 and R^aIs hydrogen or C_1-6An alkyl group;

R¹comprises the following steps: c_1-6An alkyl group; c_2-6An alkenyl group; c_2-6An alkynyl group; halo-C_1-6An alkyl group; c_1-6alkoxy-C_1-6An alkyl group; hydroxy-C_1-6An alkyl group; amino-C_1-6An alkyl group; c_1-6alkylsulfonyl-C_1-6An alkyl group; optionally is covered with C_1-6Alkyl or halo-substituted C_3-6A cycloalkyl group; c_3-6cycloalkyl-C_1-6Alkyl radical, wherein C_3-6Cycloalkyl moiety being optionally substituted by C_1-6Alkyl substitution; a tetrahydropyranyl group; a tetrahydrofuranyl group; tetrahydrofuryl-C_1-6An alkyl group; an oxetanyl group; or oxetane-C_1-6An alkyl group;

or R¹And R^aTogether with the atoms to which they are attached may form a three-to six-membered ring, which may optionally include a further heteroatom selected from O, N and S, and which is oxo, halo or C_1-6Alkyl substitution；

R²Comprises the following steps: halogenating; c_1-6An alkoxy group; a cyano group; c_2-6An alkynyl group; c_2-6An alkenyl group; halo-C_1-6An alkyl group; halo-C_1-6An alkoxy group; c_3-6Cycloalkyl radicals, in which C_3-6Cycloalkyl moiety being optionally substituted by C_1-6Alkyl substitution; c_3-6cycloalkyl-C_1-6Alkyl radical, wherein C_3-6Cycloalkyl moiety being optionally substituted by C_1-6Alkyl substitution; a tetrahydrofuranyl group; tetrahydrofuryl-C_1-6An alkyl group; acetyl; an oxetanyl group; or oxetane-C_1-6An alkyl group;

R³comprises the following steps: -OR⁴(ii) a Halogenating; a cyano group; c_1-6An alkyl group; halo-C_1-6An alkyl group; optionally is covered with C_1-6Alkyl substituted C_3-6A cycloalkyl group; c_3-6cycloalkyl-C_1-6Alkyl radical, wherein C_3-6Cycloalkyl moiety being optionally substituted by C_1-6Alkyl substitution; a tetrahydrofuranyl group; tetrahydrofuryl-C_1-6An alkyl group; an oxetanyl group; or oxetane-C_1-6An alkyl group;

R⁴comprises the following steps: hydrogen; c_1-6An alkyl group; halo-C_1-6An alkyl group; c_1-6alkoxy-C_1-6An alkyl group; optionally is covered with C_1-6Alkyl or halo-substituted C_3-6A cycloalkyl group; c_3-6cycloalkyl-C_1-6Alkyl radical, wherein C_3-6Cycloalkyl moiety being optionally substituted by C_1-6Alkyl or halo substitution; a tetrahydrofuranyl group; tetrahydrofuryl-C_1-6An alkyl group; an oxetanyl group; or oxetane-C_1-6An alkyl group;

R⁵comprises the following steps: hydrogen; or C_1-6An alkyl group;

R⁶comprises the following steps: hydrogen; c_1-6An alkyl group; c_1-6alkoxy-C_1-6An alkyl group; hydroxy-C_1-6An alkyl group; amino-C_1-6An alkyl group; c_3-6A cycloalkyl group; c_3-6cycloalkyl-C_1-6An alkyl group; a heterocyclic group; or heterocyclyl-C_1-6An alkyl group; whereinSaid C is_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-6Alkyl, heterocyclyl and heterocyclyl-C_1-6Each alkyl group may be optionally substituted with one, two, three or four groups independently selected from: c_1-6An alkyl group; halo-C_1-6An alkyl group; c_1-6An alkoxy group; halo-C_1-6An alkoxy group; a hydroxyl group; hydroxy-C_1-6An alkyl group; halogenating; a nitrile; c_1-6Alkyl-carbonyl; c_1-6An alkyl-sulfonyl group; c_3-6A cycloalkyl group; c_3-6cycloalkyl-C_1-6An alkyl group; c_3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; or two of said groups together with the atoms to which they are attached may form a five or six membered ring;

or R⁵And R⁶Together with the nitrogen atom to which they are attached form a three-to seven-membered ring optionally including a nitrogen atom selected from O, N and S (O)_nAnd which is optionally substituted with one, two, three or four groups independently selected from: c_1-6An alkyl group; halo-C_1-6An alkyl group; c_1-6An alkoxy group; halo-C_1-6An alkoxy group; a hydroxyl group; c_1-6alkoxy-C_1-6An alkyl group; hydroxy-C_1-6An alkyl group; halo, nitrile; c_1-6Alkyl-carbonyl; c_1-6An alkyl-sulfonyl group; c_3-6A cycloalkyl group; c_3-6cycloalkyl-C_1-6An alkyl group; c_3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; or two of said groups together with the atoms to which they are attached may form a five or six membered ring; and is

R⁷Comprises the following steps: halogenating; c_1-6An alkyl group; c_1-6An alkoxy group; halo-C_1-6An alkyl group; or halo-C_1-6An alkoxy group;

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] oct-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] oct-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-cyclopropoxy-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) (deuteromorpholino) 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) (deuteromorpholino) 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-tetradeuterium-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) (deuteromorpholino) 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 invention also provides pharmaceutical compositions comprising the compounds, methods of using the compounds, and methods of making the compounds.

Detailed Description

Definition of

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

"alkyl" means a monovalent straight or branched chain saturated hydrocarbon moiety consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms. "lower alkyl" refers to alkyl of one to six carbon atoms, i.e., C_1-C₆An 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" means a straight chain monovalent hydrocarbon group of two to six carbon atoms or a branched monovalent hydrocarbon group of three to six carbon atoms containing at least one double bond, such as ethenyl, propenyl, and the like.

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

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

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

"alkoxyalkyl" means a group of the formula R^a-O-R^bA moiety of (a) wherein R^aAnd R^bRespectively, alkyl and alkylene as defined herein. Exemplary alkoxyalkyl groups include, for example, 2-methoxyethyl, 3-methoxypropyl, 1-methyl-2-methoxyethyl, 1- (2-methoxyethyl) -3-methoxypropyl, and 1- (2-methoxyethyl) -3-methoxypropyl.

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

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

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

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

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

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

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

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

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

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

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

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

"Alkylsulfonylalkyl" refers to a compound of the formula-R' -SO₂A moiety of-R ", wherein R' and R" are alkylene and alkyl, respectively, as defined herein.

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

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

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

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

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

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

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

"Alkylsulfonamido" refers to a compound of the formula-NR' SO₂A moiety of-R, wherein R is alkyl and R' is hydrogen or alkyl.

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

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

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

"arylalkyl" and "aralkyl" are used interchangeably to mean the group-R^aR^bWherein R is^aAnd R^bAlkylene and aryl, respectively, as defined herein; for example, phenylalkyl such as benzyl, phenethyl, 3- (3-chlorophenyl) -2-methylpentyl and the like are examples of arylalkyl groups.

"arylsulfonyl" means a compound of the formula-SO₂-R, wherein R is aryl as defined herein.

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

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

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

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

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

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

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

"heteroaryl" means a monocyclic or bicyclic group of 5 to 12 ring atoms having at least one aromatic ring containing one, two or three ring heteroatoms selected from N, O or S, the remaining ring atoms being C, wherein it is understood that the point of attachment of the heteroaryl group is on the aromatic ring. The heteroaryl ring may be optionally substituted as defined herein. Examples of heteroaryl moieties include, but are not limited to, optionally substituted imidazolyl,

oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thienyl, furyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuryl, benzothienyl, benzothiopyranyl, benzimidazolyl, benzoxazolyl, benzodiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, azazazolylRadical, diazaA group, acridinyl, and the like, each of which can be as defined hereinOptionally substituted.

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

"Heteroarylsulfonyl" means a compound of the formula-SO₂-R, wherein R is heteroaryl as defined herein.

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

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

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

"haloalkyl" refers to an alkyl group, as defined herein, wherein one or more hydrogens have been replaced with the same or different halogen. Exemplary haloalkyl groups include-CH₂Cl，-CH₂CF₃，-CH₂CCl₃Perfluoroalkyl (e.g. -CF)₃) And the like.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

"Sulfonamido (sulfonamide)" means a compound of the formula-SO₂A group of-NR ' R ', wherein R ', R ' and R ' are each independently hydrogen or alkyl.

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

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

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

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

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

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

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

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

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

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

"solvate" refers to a solvent addition form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thereby forming solvates. If the solvent is water, the solvate formed is a hydrate, and when the solvent is an alcohol, the solvate formed is an alcoholate. The hydrate maintains its molecular state as H with water therein via one or more water molecules₂O, such combination being capable of forming one or more hydrates.

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

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

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

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

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

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

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

Naming and Structure

In general, nomenclature and chemical names used in this application are based on Cambridge Soft^TMIs chembioooffice^TM. Unless otherwise indicated, any open valency appearing on a carbon, oxygen, sulfur or nitrogen atom in the structures herein indicates the presence of a hydrogen atom. The heteroaryl ring containing nitrogen exhibits an open valency at the nitrogen atom, and the variables are as R^a，R^bOr R^cWhere shown on the heteroaryl ring, such variables may be bound or joined to the open-valence nitrogen. In the case where a chiral center is present in a structure but no specific stereochemistry is shown for the chiral center, both enantiomers associated with the chiral center are encompassed by the structure. Where a structure shown herein can exist in multiple tautomeric forms, all such tautomers are encompassed by the structure. The atoms represented in the structures herein are intended to encompass all natural isotopes of such atoms. Thus, for example, a hydrogen atom as represented herein is meant to include deuterium and tritium, and a carbon atom is meant to include C¹³And C¹⁴An isotope.

Compounds of the invention

The present invention provides compounds of formula a:

or a pharmaceutically acceptable salt thereof,

wherein:

m is 0 to 3;

R¹comprises the following steps: c_1-6An alkyl group; c_2-6An alkenyl group; c_2-6An alkynyl group; halo-C_1-6An alkyl group; c_1-6alkoxy-C_1-6An alkyl group; hydroxy-C_1-6An alkyl group; amino group-C_1-6An alkyl group; c_1-6alkylsulfonyl-C_1-6An alkyl group; optionally is covered with C_1-6Alkyl or halo-substituted C_3-6A cycloalkyl group; c_3-6cycloalkyl-C_1-6Alkyl radical, wherein C_3-6Cycloalkyl moiety being optionally substituted by C_1-6Alkyl substitution; a tetrahydropyranyl group; a tetrahydrofuranyl group; tetrahydrofuryl-C_1-6An alkyl group; an oxetanyl group; or oxetane-C_1-6An alkyl group;

or R¹And R^aTogether with the atoms to which they are attached may form a three-to six-membered ring, which may optionally include a further heteroatom selected from O, N and S, and which is oxo, halo or C_1-6Alkyl substitution;

R^3acomprises the following steps: -OR⁴(ii) a Halogenating; a cyano group; c_1-6An alkyl group; halo-C_1-6An alkyl group; optionally is covered with C_1-6Alkyl substituted C_3-6A cycloalkyl group; c_3-6cycloalkyl-C_1-6Alkyl radical, wherein C_3-6Cycloalkyl moiety being optionally substituted by C_1-6Alkyl substitution; a tetrahydrofuranyl group; tetrahydrofuryl-C_1-6An alkyl group; an oxetanyl group; or oxetane-C_1-6An alkyl group;

R^3bcomprises the following steps: the presence of hydrogen in the presence of hydrogen,

or R^3aAnd R^3bTogether with the atoms to which they are attached may form a five or six membered ring, optionally including oneOne or two heteroatoms each independently selected from O, N and S, said ring being optionally substituted by R⁸One or more substitutions;

R⁵comprises the following steps: hydrogen; or C_1-6An alkyl group;

R⁶comprises the following steps: hydrogen; c_1-6An alkyl group; c_1-6alkoxy-C_1-6An alkyl group; hydroxy-C_1-6An alkyl group; amino-C_1-6An alkyl group; c_3-6A cycloalkyl group; c_3-6cycloalkyl-C_1-6An alkyl group; heteroaryl, heterocyclyl; or heterocyclyl-C_1-6An alkyl group; wherein said C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-6Alkyl, heteroaryl, heterocyclyl and heterocyclyl-C_1-6Each alkyl group may be optionally substituted with one, two, three or four groups independently selected from: c_1-6An alkyl group; halo-C_1-6An alkyl group; c_1-6An alkoxy group; halo-C_1-6An alkoxy group; a hydroxyl group; hydroxy-C_1-6An alkyl group; halogenating; a nitrile; c_1-6Alkyl-carbonyl; c_1-6An alkyl-sulfonyl group; c_3-6A cycloalkyl group; c_3-6cycloalkyl-C_1-6An alkyl group; c_3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; or two of said groups together with the atoms to which they are attached may form a five or six membered ring;

or R⁵And R⁶Together with the nitrogen atom to which they are attached form a three-to seven-membered ring optionally including a nitrogen atom selected from O, N and S (O)_nAnd which is optionally mono-, di-, tri-orSubstituted with four groups independently selected from: c_1-6An alkyl group; halo-C_1-6An alkyl group; c_1-6An alkoxy group; halo-C_1-6An alkoxy group; a hydroxyl group; c_1-6alkoxy-C_1-6An alkyl group; hydroxy-C_1-6An alkyl group; halo, nitrile; c_1-6Alkyl-carbonyl; c_1-6An alkyl-sulfonyl group; c_3-6A cycloalkyl group; c_3-6cycloalkyl-C_1-6An alkyl group; c_3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; or two of said groups together with the atoms to which they are attached may form a five or six membered ring; and is

R⁸comprises the following steps: halogenating; c_1-6An alkyl group; or oxo.

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

Wherein R is¹，R²，R³，R⁴，R⁵，R⁶，R⁷，R⁸X, Y, Z, A and m are as defined herein.

The present invention provides a compound of formula (A),

wherein:

m is 0 to 1;

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

R¹comprises the following steps: c_1-6Alkyl or C_3-6A cycloalkyl group;

or R¹And R^aTogether with the atoms to which they are attached may form threeTo a six membered ring;

R²comprises the following steps: halogenating; cyano or halo-C_1-6An alkyl group;

R^3acomprises the following steps: -OR⁴(ii) a Halo or C_1-6An alkyl group;

or R^3aAnd R^3bTogether with the atoms to which they are attached may form a five or six membered ring optionally including one or two heteroatoms each independently selected from O, N and S, said ring optionally being substituted with R⁸One or more substitutions;

R⁴comprises the following steps: hydrogen; c_1-6An alkyl group; halo-C_1-6An alkyl group; optionally is covered with C_1-6Alkyl or halo-substituted C_3-6A cycloalkyl group; c_3-6cycloalkyl-C_1-6Alkyl radical, wherein C_3-6Cycloalkyl moiety being optionally substituted by C_1-6Alkyl or halo substitution;

R⁵comprises the following steps: hydrogen or C_1-6An alkyl group;

R⁶comprises the following steps: c_1-6An alkyl group; hydroxy-C_1-6An alkyl group; c_3-6A cycloalkyl group; c_3-6cycloalkyl-C_1-6An alkyl or heterocyclic group; wherein said C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-6Each of the alkyl and heterocyclyl groups may be optionally substituted with one, two, three or four groups independently selected from: c_1-6An alkyl group; hydroxy and hydroxy-C_1-6An alkyl group;

or R⁵And R⁶Together with the nitrogen atom to which they are attached form a three-to seven-membered ring, optionally including an additional heteroatom selected from O and N, and which is optionally substituted with one, two, three or four groups independently selected from: c_1-6An alkyl group; c_1-6alkoxy-C_1-6An alkyl group; halogenating; or a heterocyclic group; or two of said radicals, together with the atoms to which they are attached, may form a five or six membered ringA ring; and is

R⁸comprises the following steps: halogenating; c_1-6An alkyl group; or oxo.

The present invention provides compounds of formula I:

or a pharmaceutically acceptable salt thereof,

wherein:

m is 0 to 3;

R⁵comprises the following steps: hydrogen; or C_1-6An alkyl group;

wherein the compound is selected from:

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

or a pharmaceutically acceptable salt thereof,

a is a five or six membered ring optionally comprising one or two heteroatoms each independently selected from O, N and S, ring A is optionally substituted with R⁸One or more substitutions;

m is 0 to 2;

R¹comprises the following steps: c_1-6An alkyl group; c_2-6An alkenyl group; c_2-6An alkynyl group; halo-C_1-6An alkyl group; c_1-6alkoxy-C_1-6An alkyl group; hydroxy-C_1-6An alkyl group; amino-C_1-6An alkyl group; c_1-6alkylsulfonyl-C_1-6An alkyl group; optionally is covered with C_1-6Alkyl substituted C_3-6A cycloalkyl group; c_3-6Cycloalkyl-C_1-6Alkyl radical, wherein C_3-6Cycloalkyl moiety being optionally substituted by C_1-6Alkyl substitution; a tetrahydropyranyl group; a tetrahydrofuranyl group; tetrahydrofuryl-C_1-6An alkyl group; an oxetanyl group; or oxetane-C_1-6An alkyl group;

R⁵comprises the following steps: hydrogen; or C_1-6An alkyl group;

R⁶comprises the following steps: hydrogen; c_1-6An alkyl group; c_1-6alkoxy-C_1-6An alkyl group; hydroxy-C_1-6An alkyl group; amino-C_1-6An alkyl group; c_3-6A cycloalkyl group; c_3-6cycloalkyl-C_1-6An alkyl group; a heterocyclic group; or heterocyclyl-C_1-6An alkyl group; wherein said C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-6Alkyl, heterocyclyl and heterocyclyl-C_1-6Each alkyl group may be optionally substituted with one, two, three or four groups independently selected from: c_1-6An alkyl group; halo-C_1-6An alkyl group; c_1-6An alkoxy group; halo-C_1-6An alkoxy group; a hydroxyl group; hydroxy-C_1-6An alkyl group; halogenating; a nitrile; c_1-6Alkyl-carbonyl; c_1-6An alkyl-sulfonyl group; c_3-6CycloalkanesA group; c_3-6cycloalkyl-C_1-6An alkyl group; c_3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; or two of said groups together with the atoms to which they are attached may form a five or six membered ring;

or R⁵And R⁶Together with the nitrogen atom to which they are attached form a three-to seven-membered ring optionally including a nitrogen atom selected from O, N and S (O)_nAnd which is optionally substituted with one, two, three or four groups independently selected from: c_1-6An alkyl group; halo-C_1-6An alkyl group; c_1-6An alkoxy group; halo-C_1-6An alkoxy group; a hydroxyl group; c_1-6alkoxy-C_1-6An alkyl group; hydroxy-C_1-6An alkyl group; halo, nitrile; c_1-6Alkyl-carbonyl; c_1-6An alkyl-sulfonyl group; c_3-6A cycloalkyl group; c_3-6cycloalkyl-C_1-6An alkyl group; c_3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; or two of said groups together with the atoms to which they are attached may form a five or six membered ring;

R⁷comprises the following steps: halogenating; c_1-6An alkyl group; c_1-6An alkoxy group; halo-C_1-6An alkyl group; or halo-C_1-6An alkoxy group; and is

R⁸Comprises the following steps: halogenating; c_1-6An alkyl group; or oxo.

In certain embodiments the compound of formula II may have formula III:

or a pharmaceutically acceptable salt thereof,

wherein:

y is-O-or-CHR⁸-；

Z is-O-or-CHR⁸-, or Z is absent; and is

m，R¹，R²，R⁵，R⁶，R⁷And R⁸As 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, R^aIs hydrogen.

In certain embodiments of formula II or formula III, R^aIs C_1-6An alkyl group.

In certain embodiments of formula II or formula III, R¹Comprises the following steps: c_1-6An alkyl group; halo-C_1-6An alkyl group; c_1-6alkoxy-C_1-6An alkyl group; amino-C_1-6An alkyl group; c_1-6alkylsulfonyl-C_1-6An alkyl group; c_3-6A cycloalkyl group; or C_3-6cycloalkyl-C_1-6An alkyl group.

In certain embodiments of formula II or formula IIIIn the scheme, R¹Comprises the following steps: c_1-6An alkyl group; optionally is covered with C_1-6Alkyl substituted C_3-6A cycloalkyl group; or C_3-6cycloalkyl-C_1-6Alkyl radical, wherein C_3-6Cycloalkyl moiety being optionally substituted by C_1-6Alkyl substitution.

In certain embodiments of formula II or formula III, R¹Comprises the following steps: c_1-6An alkyl group; halo-C_1-6An alkyl group; c_1-6alkoxy-C_1-6An alkyl group; amino-C_1-6An alkyl group; c_1-6alkylsulfonyl-C_1-6An alkyl group; a tetrahydrofuranyl group; tetrahydrofuryl-C_1-6An alkyl group; an oxetanyl group; or oxetane-C_1-6An alkyl group.

In certain embodiments of formula II or formula III, R¹Comprises the following steps: c_1-6An alkyl group; halo-C_1-6An alkyl group; c_1-6alkoxy-C_1-6An alkyl group; amino-C_1-6An alkyl group; or C_1-6alkylsulfonyl-C_1-6An alkyl group.

In certain embodiments of formula II or formula III, R¹Is C_1-6An alkyl group.

In certain embodiments of formula II or formula III, R¹Is halo-C_1-6An alkyl group.

In certain embodiments of formula II or formula III, R¹Is C_1-6alkoxy-C_1-6An alkyl group.

In certain embodiments of formula II or formula III, R¹Is amino-C_1-6An alkyl group.

In certain embodiments of formula II or formula III, R¹Is optionally substituted by C_1-6Alkyl substituted C_1-6alkylsulfonyl-C_1-6An alkyl group.

In certain embodiments of formula II or formula III, R¹Is optionally substituted by C_1-6Alkyl substituted C_3-6A cycloalkyl group.

In-situ typeIn certain embodiments of II or formula III, R¹Is C_3-6cycloalkyl-C_1-6Alkyl radical, wherein C_3-6Cycloalkyl moiety being optionally substituted by C_1-6Alkyl substitution.

In certain embodiments of formula II or formula III, R¹Is tetrahydropyranyl.

In certain embodiments of formula II or formula III, R¹Is tetrahydrofuranyl.

In certain embodiments of formula II or formula III, R¹Is tetrahydrofuryl-C_1-6An alkyl group; an oxetanyl group.

In certain embodiments of formula II or formula III, R¹Is or oxetane-C_1-6An alkyl group.

In certain embodiments of formula II or formula III, R¹Comprises the following steps: a methyl group; an ethyl group; n-propyl; isopropyl group; an isobutyl group; 3, 3-dimethylpropyl; a cyclopropyl group; a cyclobutyl group; a cyclopentyl group; a cyclohexyl group; a cyclopropyl methyl group; a cyclobutylmethyl group; a cyclopentyl methyl group; a cyclopropyl ethyl group; a methoxyethyl group; an oxetanyl group; or tetrahydrofurylmethyl.

In certain embodiments of formula II or formula III, R¹Comprises the following steps: a methyl group; an ethyl group; n-propyl; isopropyl group; an isobutyl group; 3, 3-dimethylpropyl; a cyclopentyl group; a cyclohexyl group; a cyclopropyl methyl group; a cyclobutylmethyl group; a cyclopentyl methyl group; a cyclopropyl ethyl group; a methoxyethyl group; an oxetanyl group; or tetrahydrofurylmethyl.

In certain embodiments of formula II or formula III, R¹Comprises the following steps: a methyl group; an ethyl group; n-propyl; isopropyl group; an isobutyl group; 3, 3-dimethylpropyl; a cyclopentyl group; a cyclohexyl group; a cyclopentyl methyl group; a methoxyethyl group; an oxetanyl group; or tetrahydrofurylmethyl.

In certain embodiments of formula II or formula III, R¹Comprises the following steps: a methyl group; an ethyl group; n-propyl; isopropyl group; or an isobutyl group.

In certain embodiments of formula II or formula III, R¹Is methyl or ethyl.

In certain embodiments of formula II or formula III, R¹Is methyl.

In certain embodiments of formula II or formula III, R¹Is ethyl.

In certain embodiments of formula II or formula III, R¹Comprises the following steps: a cyclopropyl group; a cyclobutyl group; a cyclopentyl group; a cyclohexyl group; a cyclopropyl methyl group; a cyclobutylmethyl group; a cyclopentyl methyl group; or a cyclopropylethyl group.

In certain embodiments of formula II or formula III, R¹Comprises the following steps: a cyclopentyl group; a cyclohexyl group; or a cyclopentylmethyl group.

In certain embodiments of formula II or formula III, R²Comprises the following steps: halogenating; c_1-6An alkoxy group; halo-C_1-6An alkyl group; halo-C_1-6An alkoxy group; c_3-6Cycloalkyl radicals, in which C_3-6Cycloalkyl moiety being optionally substituted by C_1-6Alkyl substitution; c_3-6cycloalkyl-C_1-6Alkyl radical, wherein C_3-6Cycloalkyl moiety being optionally substituted by C_1-6Alkyl substitution; a tetrahydrofuranyl group; tetrahydrofuryl-C_1-6An alkyl group; an oxetanyl group; or oxetane-C_1-6An alkyl group.

In certain embodiments of formula II or formula III, R²Comprises the following steps: halogenating; c_1-6An alkoxy group; halo-C_1-6An alkyl group; a cyano group; c_2-6An alkynyl group; c_2-6An alkenyl group; c_3-6A cycloalkyl group; or C_3-6cycloalkyl-C_1-6An alkyl group.

In certain embodiments of formula II or formula III, R²Comprises the following steps: halogenating; c_1-6An alkoxy group; halo-C_1-6An alkyl group; a cyano group; c_3-6A cycloalkyl group; or C_3-6cycloalkyl-C_1-6An alkyl group.

In certain embodiments of formula II or formula III, R²Comprises the following steps: halogenGeneration; c_1-6An alkoxy group; halo-C_1-6An alkyl group; c_3-6A cycloalkyl group; or C_3-6cycloalkyl-C_1-6An alkyl group.

In certain embodiments of formula II or formula III, R²Comprises the following steps: halogenating; halo-C_1-6An alkyl group; or a cyano group.

In certain embodiments of formula II or formula III, R²Comprises the following steps: halogenating; or halo-C_1-6An alkyl group.

In certain embodiments of formula II or formula III, R²Is halo.

In certain embodiments of formula II or formula III, R²Is C_1-6An alkoxy group.

In certain embodiments of formula II or formula III, R²Is halo-C_1-6An alkoxy group.

In certain embodiments of formula II or formula III, R²Is halo-C_1-6An alkyl group.

In certain embodiments of formula II or formula III, R²Is C_3-6A cycloalkyl group.

In certain embodiments of formula II or formula III, R²Is C_3-6cycloalkyl-C_1-6An alkyl group.

In certain embodiments of formula II or formula III, R²Is tetrahydrofuranyl.

In certain embodiments of formula II or formula III, R²Is tetrahydrofuryl-C_1-6An alkyl group.

In certain embodiments of formula II or formula III, R²Is an oxetanyl group.

In certain embodiments of formula II or formula III, R²Is oxetane-C_1-6An alkyl group.

In certain embodiments of formula II or formula III, R²Is halo, trifluoromethyl or cyano.

In certain embodiments of formula II or formula III, R²Is chloro, trifluoromethyl or cyano.

In certain embodiments of formula II or formula III, R²Is fluorine, chlorine or bromine.

In certain embodiments of formula II or formula III, R²Is chlorine.

In certain embodiments of formula II or formula III, R²Is fluorine.

In certain embodiments of formula II or formula III, R²Is bromine.

In certain embodiments of formula II or formula III, R²Is trifluoromethyl.

In certain embodiments of formula II or formula III, R²Is methoxy.

In certain embodiments of formula II or formula III, R²Is cyano.

In certain embodiments of formula II or formula III, R²Is C_2-6Alkynyl.

In certain embodiments of formula II or formula III, R²Is C_2-6An alkenyl group.

In certain embodiments of formula II or formula III, R⁵Is hydrogen.

In certain embodiments of formula II or formula III, R⁵Is C_1-6An alkyl group.

In certain embodiments of formula II or formula III, R⁵Is methyl.

In certain embodiments of formula II or formula III, R⁵Is ethyl.

In certain embodiments of formula II or formula III, R⁶Is hydrogen.

In certain embodiments of formula II or formula III, R⁶Is C_1-6An alkyl group.

In certain embodiments of formula II or formula III, R⁶Is C_1-6alkoxy-C_1-6An alkyl group.

In certain embodiments of formula II or formula III, R⁶Is hydroxy-C_1-6An alkyl group.

In certain embodiments of formula II or formula III, R⁶Is amino-C_1-6An alkyl group.

In certain embodiments of formula II or formula III, R⁶Optionally substituted by one, two or three groups C_3-6Cycloalkyl independently selected from: c_1-6An alkyl group; halo-C_1-6An alkyl group; c_1-6An alkoxy group; halo-C_1-6An alkoxy group; a hydroxyl group; hydroxy-C_1-6An alkyl group; halogenating; a nitrile; c_1-6Alkyl-carbonyl; c_1-6An alkyl-sulfonyl group; c_3-6A cycloalkyl group; c_3-6cycloalkyl-C_1-6An alkyl group; c_3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; 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, R⁶Is C_3-6cycloalkyl-C_1-6Alkyl radical, wherein C_3-6The cycloalkyl moiety is optionally substituted with one, two or three groups independently selected from: c_1-6An alkyl group; halo-C_1-6An alkyl group; c_1-6An alkoxy group; halo-C_1-6An alkoxy group; a hydroxyl group; hydroxy-C_1-6An alkyl group; halogenating; a nitrile; c_1-6Alkyl-carbonyl; c_1-6An alkyl-sulfonyl group; c_3-6A cycloalkyl group; c_3-6cycloalkyl-C_1-6An alkyl group; c_3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; or two of said groups together with the atoms to which they are attached may form a five or six membered ring.

In which R is⁶Is a heterocyclic ringIn embodiments of formula II or formula III, the heterocycle may be: an azetidinyl group; a pyrrolidinyl group; a piperidinyl group; a piperazinyl group; morpholinyl; a thiomorpholinyl group; 3-oxa-8-aza-bicyclo [3.2.1]Oct-8-yl; 2-oxa-5-aza-bicyclo [2.2.1]Hept-5-yl; or 8-oxa-3-aza-bicyclo [3.2.1]Oct-3-yl; each optionally substituted as defined herein.

In which R is⁶In embodiments of formula II or formula III that are heterocyclyl, the heterocycle may be: an azetidinyl group; a pyrrolidinyl group; a piperidinyl group; a piperazinyl group; or a morpholinyl group; each optionally substituted as defined herein, i.e. the heterocyclyl is optionally substituted by one, two or three groups independently selected from: c_1-6An alkyl group; halo-C_1-6An alkyl group; c_1-6An alkoxy group; halo-C_1-6An alkoxy group; a hydroxyl group; hydroxy-C_1-6An alkyl group; halogenating; a nitrile; c_1-6Alkyl-carbonyl; c_1-6An alkyl-sulfonyl group; c_3-6A cycloalkyl group; c_3-6cycloalkyl-C_1-6An alkyl group; c_3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; 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, R⁶Is heterocyclyl optionally substituted with one, two or three groups independently selected from: c_1-6An alkyl group; halo-C_1-6An alkyl group; c_1-6An alkoxy group; halo-C_1-6An alkoxy group; a hydroxyl group; hydroxy-C_1-6An alkyl group; halogenating; a nitrile; c_1-6Alkyl-carbonyl; c_1-6An alkyl-sulfonyl group; c_3-6A cycloalkyl group; c_3-6cycloalkyl-C_1-6An alkyl group; c_3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; or two of said groups together with the atoms to which they are attached may form a five or six membered ring.

In which R is⁶Is heterocyclyl-C_1-6In embodiments of formula II or formula III of alkyl, the heterocyclyl portion thereof may be: an azetidinyl group; a pyrrolidinyl group; a piperidinyl group; piperazine derivativesA group; morpholinyl; a thiomorpholinyl group; 3-oxa-8-aza-bicyclo [3.2.1]Oct-8-yl; 2-oxa-5-aza-bicyclo [2.2.1]Hept-5-yl; or 8-oxa-3-aza-bicyclo [3.2.1]Oct-3-yl; each optionally substituted as defined herein, i.e., the heterocyclyl moiety is optionally substituted with one, two or three groups independently selected from: c_1-6An alkyl group; halo-C_1-6An alkyl group; c_1-6An alkoxy group; halo-C_1-6An alkoxy group; a hydroxyl group; hydroxy-C_1-6An alkyl group; halogenating; a nitrile; c_1-6Alkyl-carbonyl; c_1-6An alkyl-sulfonyl group; c_3-6A cycloalkyl group; c_3-6cycloalkyl-C_1-6An alkyl group; c_3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; or two of said groups together with the atoms to which they are attached may form a five or six membered ring.

In which R is⁶Is heterocyclyl-C_1-6In embodiments of formula II or formula III of alkyl, the heterocyclyl portion thereof may be: an azetidinyl group; a pyrrolidinyl group; a piperidinyl group; a piperazinyl group; or a morpholinyl group; each optionally substituted as defined herein.

In certain embodiments of formula II or formula III, R⁶Is heterocyclyl-C_1-6Alkyl, wherein the heterocyclyl portion thereof is optionally substituted with one, two or three groups independently selected from: c_1-6An alkyl group; halo-C_1-6An alkyl group; c_1-6An alkoxy group; halo-C_1-6An alkoxy group; a hydroxyl group; hydroxy-C_1-6An alkyl group; halogenating; a nitrile; c_1-6Alkyl-carbonyl; c_1-6An alkyl-sulfonyl group; c_3-6A cycloalkyl group; c_3-6cycloalkyl-C_1-6An alkyl group; c_3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; 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, R⁶Comprises the following steps: hydrogen; a methyl group; an ethyl group; isopropyl group; or a cyclopropyl group.

In certain embodiments of formula II or formula III, R⁶Comprises the following steps: hydrogen; a methyl group; an ethyl group; isopropyl group; 2-amino-propyl; oxetan-3-yl; 2-methoxy-ethyl; 2-hydroxy-ethyl; a cyclopropyl group; piperidin-4-yl; 1-methyl-piperidin-4-yl; a tertiary butyl group; 2-hydroxy-2-methyl-propyl; a cyclobutyl group; 1-methyl-cyclobutyl; 2-hydroxy-propyl; 1-cyano-cyclopropyl; 3, 3-difluoro-cyclobutyl; a cyclopropyl methyl group; 3-fluoro-cyclobutyl; or 2, 2-difluoroethyl;

in certain embodiments of formula II or formula III, R⁶Is hydrogen.

In certain embodiments of formula II or formula III, R⁶Is methyl.

In certain embodiments of formula II or formula III, R⁶Is ethyl.

In certain embodiments of formula II or formula III, R⁶Is isopropyl.

In certain embodiments of formula II or formula III, R⁶Is 2-amino-propyl.

In certain embodiments of formula II or formula III, R⁶Is oxetan-3-yl.

In certain embodiments of formula II or formula III, R⁶Is 2-methoxy-ethyl.

In certain embodiments of formula II or formula III, R⁶Is 2-hydroxy-ethyl.

In certain embodiments of formula II or formula III, R⁶Is cyclopropyl.

In certain embodiments of formula II or formula III, R⁶Is piperidin-4-yl.

In certain embodiments of formula II or formula III, R⁶Is 1-methyl-piperidin-4-yl.

In certain embodiments of formula II or formula III, R⁶Is a tert-butyl group.

In certain of formula II or formula IIIIn embodiments, R⁶Is 2-hydroxy-2-methyl-propyl.

In certain embodiments of formula II or formula III, R⁶Is a cyclobutyl group.

In certain embodiments of formula II or formula III, R⁶Is 1-methyl-cyclobutyl.

In certain embodiments of formula II or formula III, R⁶Is 2-hydroxy-propyl.

In certain embodiments of formula II or formula III, R⁶Is 1-cyano-cyclopropyl.

In certain embodiments of formula II or formula III, R⁶Is 3, 3-difluoro-cyclobutyl.

In certain embodiments of formula II or formula III, R⁶Is cyclopropylmethyl.

In certain embodiments of formula II or formula III, R⁶Is 3-fluoro-cyclobutyl.

In certain embodiments of formula II or formula III, R⁶Is 2, 2-difluoroethyl.

In certain embodiments of formula II or formula III, R⁵And R⁶Together with the nitrogen atom to which they are attached form a three-to seven-membered ring optionally including a nitrogen atom selected from O, N and S (O)_nAnd which is optionally substituted by one, two or three groups independently selected from C_1-6Alkyl, halo-C_1-6Alkyl radical, C_1-6Alkoxy, halo-C_1-6Alkoxy, hydroxy-C_1-6Alkyl, halo, nitrile, C_1-6Alkyl-carbonyl, C_1-6Alkyl-sulfonyl radical, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-6Alkyl radical, C_3-6Cycloalkyl-carbonyl, 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 which R is⁵And R⁶Together with the nitrogen atom to which they are attached form a three-to seven-membered ring optionally including a nitrogen atom selected from O, N and S (O)_nIn embodiments of formula II or formula III of additional heteroatoms, the ring may be: an azetidinyl group; a pyrrolidinyl group; a piperidinyl group; a piperazinyl group; morpholinyl; a thiomorpholinyl group; aza derivativesA group; 3-oxa-8-aza-bicyclo [3.2.1]Oct-8-yl; 2-oxa-5-aza-bicyclo [2.2.1]Hept-5-yl; or 8-oxa-3-aza-bicyclo [3.2.1]Oct-3-yl; each optionally substituted as defined herein.

In which R is⁵And R⁶Together with the nitrogen atom to which they are attached form a three-to seven-membered ring optionally including a nitrogen atom selected from O, N and S (O)_nIn embodiments of formula II or formula III of additional heteroatoms, the ring may be: an azetidinyl group; a pyrrolidinyl group; a piperidinyl group; a piperazinyl group; or a morpholinyl group; each optionally substituted as defined herein.

In certain embodiments of formula II or formula III, R⁵And R⁶Together with the nitrogen atom to which they are attached form a morpholinyl radical optionally substituted once or twice by radicals independently selected from C_1-6Alkyl, halo-C_1-6Alkyl radical, C_1-6Alkoxy, halo-C_1-6Alkoxy, hydroxy-C_1-6Alkyl, halo, nitrile, C_1-6Alkyl-carbonyl, C_1-6Alkyl-sulfonyl radical, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-6Alkyl radical, C_3-6Cycloalkyl-carbonyl, amino, or heterocyclyl, or both 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, R⁵And R⁶Together with the nitrogen atom to which they are attached form a piperidinyl group optionally substituted once or twice by groups independently selected from C_1-6Alkyl, halo-C_1-6Alkyl radical, C_1-6Alkoxy, halogeneration-C_1-6Alkoxy, hydroxy-C_1-6Alkyl, halo, nitrile, C_1-6Alkyl-carbonyl, C_1-6Alkyl-sulfonyl radical, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-6Alkyl radical, C_3-6Cycloalkyl-carbonyl, amino, or heterocyclyl, or both 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, R⁵And R⁶Together with the nitrogen atom to which they are attached form a piperazinyl group optionally substituted once or twice with groups independently selected from C_1-6Alkyl, halo-C_1-6Alkyl radical, C_1-6Alkoxy, halo-C_1-6Alkoxy, hydroxy-C_1-6Alkyl, halo, nitrile, C_1-6Alkyl-carbonyl, C_1-6Alkyl-sulfonyl radical, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-6Alkyl radical, C_3-6Cycloalkyl-carbonyl, amino, or heterocyclyl, or both 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, R⁵And R⁶Together with the nitrogen atom to which they are attached form a pyrrolidinyl group optionally substituted once or twice with groups independently selected from C_1-6Alkyl, halo-C_1-6Alkyl radical, C_1-6Alkoxy, halo-C_1-6Alkoxy, hydroxy-C_1-6Alkyl, halo, nitrile, C_1-6Alkyl-carbonyl, C_1-6Alkyl-sulfonyl radical, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-6Alkyl radical, C_3-6Cycloalkyl-carbonyl, amino, or heterocyclyl, or both 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, R⁵And R⁶Together with the nitrogen atom to which they are attached form a group selected from: 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; 3-oxa-8-aza-bicyclo [3.2.1]Oct-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]Oct-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; 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, R⁵And R⁶Together with the nitrogen atom to which they are attached form a group selected from: 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; 3-oxa-8-aza-bicyclo [3.2.1]Oct-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]Oct-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 group-piperidin-1-yl; and 4-piperidin-4-yl-piperazin-1-yl.

In certain embodiments of formula II or formula III, R⁵And R⁶Together with the nitrogen atom to which they are attached form morpholin-4-yl.

In certain embodiments of formula II or formula III, R⁵And R⁶Together with the nitrogen atom to which they are attached form a 4-hydroxy-piperidin-1-yl group.

In certain embodiments of formula II or formula III, R⁵And R⁶Together 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, R⁵And R⁶Together with the nitrogen atom to which they are attached form a 2-hydroxy-piperidin-1-yl group.

In certain embodiments of formula II or formula III, R⁵And R⁶Together with the nitrogen atom to which they are attached form a 4, 4-dimethyl-piperidin-1-yl group.

In certain embodiments of formula II or formula III, R⁵And R⁶Together with the nitrogen atom to which they are attached form a 3, 5-dimethyl-piperidin-1-yl group.

In certain embodiments of formula II or formula III, R⁵And R⁶Together 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, R⁵And R⁶Together with the nitrogen atom to which they are attached form a 3-hydroxy-pyrrolidin-1-yl group.

In certain embodiments of formula II or formula III, R⁵And R⁶Together with the nitrogen atom to which they are attached form 4-methyl-piperidin-1-yl.

In certain embodiments of formula II or formula III, R⁵And R⁶Together with the nitrogen atom to which they are attached form piperidin-1-yl.

In certain embodiments of formula II or formula III, R⁵And R⁶Together with the nitrogen atom to which they are attached form azetidin-1-yl.

In certain embodiments of formula II or formula III, R⁵And R⁶Together 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, R⁵And R⁶Together with the nitrogen atom to which they are attached form a 3-methyl-piperidin-1-yl group.

In certain embodiments of formula II or formula III, R⁵And R⁶Together with the nitrogen atom to which they are attached form 4-methoxy-piperidin-1-yl.

In certain embodiments of formula II or formula III, R⁵And R⁶Together with the nitrogen atom to which they are attached form a 3, 3-difluoro-piperidin-1-yl group.

In certain embodiments of formula II or formula III, R⁵And R⁶Together with the nitrogen atom to which they are attached form 4-cyano-piperidin-1-yl.

In certain embodiments of formula II or formula III, R⁵And R⁶Together with the nitrogen atom to which they are attached form a 4-fluoro-piperidin-1-yl group.

In certain embodiments of formula II or formula III, R⁵And R⁶Together with the nitrogen atom to which they are attached form a 3-methoxy-piperidin-1-yl group.

In certain embodiments of formula II or formula III, R⁵And R⁶Together with the nitrogen atom to which they are attached form a 4-ethyl-piperazin-1-yl group.

In certain embodiments of formula II or formula III, R⁵And R⁶Together with the nitrogen atom to which they are attached form a 4-acetyl-piperazin-1-yl group.

In certain embodiments of formula II or formula III, R⁵And R⁶To which they are connectedThe nitrogen atoms taken together form 3-trifluoromethyl-piperidin-1-yl.

In certain embodiments of formula II or formula III, R⁵And R⁶Together 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, R⁵And R⁶Together with the nitrogen atom to which they are attached.

In certain embodiments of formula II or formula III, R⁵And R⁶Together 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, R⁵And R⁶Together with the nitrogen atom to which they are attached form 2-methyl-pyrrolidin-1-yl.

In certain embodiments of formula II or formula III, R⁵And R⁶Together with the nitrogen atom to which they are attached form 4-hydroxymethyl-piperidin-1-yl.

In certain embodiments of formula II or formula III, R⁵And R⁶Together with the nitrogen atom to which they are attached form 2-methyl-piperidin-1-yl.

In certain embodiments of formula II or formula III, R⁵And R⁶Together with the nitrogen atom to which they are attached form pyrrolidin-1-yl.

In certain embodiments of formula II or formula III, R⁵And R⁶Together with the nitrogen atom to which they are attached form 4-methanesulfonyl-piperazin-1-yl.

In certain embodiments of formula II or formula III, R⁵And R⁶Together with the nitrogen atom to which they are attached form 3-trifluoromethyl-pyrrolidin-1-yl.

In certain embodiments of formula II or formula III, R⁵And R⁶Together 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, R⁵And R⁶Together with the nitrogen atom to which they are attached form a 2-methyl-morpholin-4-yl group.

In certain embodiments of formula II or formula III, R⁵And R⁶Together 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, R⁵And R⁶Together with the nitrogen atom to which they are attached form a 2, 2-diethyl-morpholin-4-yl group.

In certain embodiments of formula II or formula III, R⁵And R⁶Together with the nitrogen atom to which they are attached form a 3-hydroxymethyl-morpholin-4-yl group.

In certain embodiments of formula II or formula III, R⁵And R⁶Together with the nitrogen atom to which they are attached form a 2-isobutyl-morpholin-4-yl group.

In certain embodiments of formula II or formula III, R⁵And R⁶Together with the nitrogen atom to which they are attached form a 2-hydroxymethyl-morpholin-4-yl group.

In certain embodiments of formula II or formula III, R⁵And R⁶Together with the nitrogen atom to which they are attached form a 3, 3-dimethyl-morpholin-4-yl group.

In certain embodiments of formula II or formula III, R⁵And R⁶Together with the nitrogen atom to which they are attached form a 4-methyl-piperazin-1-yl group.

In certain embodiments of formula II or formula III, R⁵And R⁶Together with the nitrogen atom to which they are attached form 4-isopropyl-piperazin-1-yl.

In certain embodiments of formula II or formula III, R⁵And R⁶Together with the nitrogen atom to which they are attached form piperazin-1-yl.

In certain embodiments of formula II or formula III, R⁵And R⁶Together with the nitrogen atom to which they are attached form a 3-oxa-8-aza-bicyclo [3.2.1]Oct-8-yl.

In certain embodiments of formula II or formula III, R⁵And R⁶Together 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, R⁵And R⁶Together 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, R⁵And R⁶Together with the nitrogen atom to which they are attached form 8-oxa-3-aza-bicyclo [3.2.1]Oct-3-yl.

In certain embodiments of formula II or formula III, R⁵And R⁶Together 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, R⁵And R⁶Together with the nitrogen atom to which they are attached form 4-cyclopropanecarbonyl-piperazin-1-yl.

In certain embodiments of formula II or formula III, R⁵And R⁶Together 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, R⁵And R⁶Together with the nitrogen atom to which they are attached form a 4-cyclobutyl-piperazin-1-yl group.

In certain embodiments of formula II or formula III, R⁵And R⁶Together 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, R⁵And R⁶Together 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, R⁵And R⁶Together 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, R⁵And R⁶Together 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, R⁵And R⁶Together with the nitrogen atom to which they are attached form a 3, 3-difluoro-azetidin-1-yl group.

In certain embodiments of formula II or formula III, R⁵And R⁶Together with the nitrogen atom to which they are attached form 4-dimethylamino-piperidin-1-yl.

In certain embodiments of formula II or formula III, R⁵And R⁶Together 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, R⁵And R⁶Together 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, R⁵And R⁶Together 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, R⁵And R⁶Together with the nitrogen atom to which they are attached form a 2-oxa-6-aza-spiro [3.3]Hept-6-yl.

In certain embodiments of formula II or formula III, R⁵And R⁶Together 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, R⁵And R⁶Together with the nitrogen atom to which they are attached form 4-methoxy-piperidin-1-yl).

In certain embodiments of formula II or formula III, R⁵And R⁶Together with the nitrogen atom to which they are attached form [1,4]oxazepan-4-yl.

In certain embodiments of formula II or formula III, R⁵And R⁶Together with the nitrogen atom to which they are attached form a 2R, 6S) -2, 6-dimethyl-morpholin-4-yl group.

In certain embodiments of formula II or formula III, R⁵And R⁶Together with the nitrogen atom to which they are attached form a 3-hydroxy-azetidin-1-yl group.

In certain embodiments of formula II or formula III, R⁵And R⁶Together with the nitrogen atom to which they are attached form 3-cyano-pyrrolidin-1-yl.

In certain embodiments of formula II or formula III, R⁵And R⁶Together with the nitrogen atom to which they are attached form a 3, 5-dimethyl-piperazin-1-yl group.

In certain embodiments of formula II or formula III, R⁵And R⁶Together 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, R⁵And R⁶Together with the nitrogen atom to which they are attached form a 3-fluoro-pyrrolidin-1-yl group.

In certain embodiments of formula II or formula III, R⁵And R⁶Together 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, R⁵And R⁶Together 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, R⁵And R⁶Together with the nitrogen atom to which they are attached form a 2, 2, 6, 6-tetrafluoro-morpholin-4-yl group.

In certain embodiments of formula II or formula III, R⁵And R⁶Together with the nitrogen atom to which they are attached form 2-methoxymethyl-pyrrolidin-1-yl. In certain embodiments of formula II or formula III, R⁵And R⁶Together 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, R⁵And R⁶Together with the nitrogen atom to which they are attached form (1S, 4S) -2-oxa-5-azabicyclo [2.2.1]Heptane-5-yl.

In certain embodiments of formula II or formula III, R⁵And R⁶Together 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, R⁷Is halo.

In certain embodiments of formula II or formula III, R⁷Is C_1-6An alkyl group.

In certain embodiments of formula II or formula III, R⁷Is C_1-6An alkoxy group.

In certain embodiments of formula II or formula III, R⁷Is halo-C_1-6An alkyl group.

In certain embodiments of formula II or formula III, R⁷Is halo-C_1-6An alkoxy group.

In certain embodiments of formula II or formula III, R⁷Is halo or methoxy.

In certain embodiments of formula II or formula III, R⁷Is fluorine, chlorine or methoxy.

In certain embodiments of formula II or formula III, R⁷Is fluorine or chlorine.

In certain embodiments of formula II or formula III, R⁷Is methoxy.

In certain embodiments of formula II or formula III, R⁷Is chlorine.

In certain embodiments of formula II or formula III, R⁷Is fluorine.

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, R⁸Is halo.

In certain embodiments of formula II or formula III, R⁸Is C_1-6An alkyl group.

In certain embodiments of formula II or formula III, R⁸Is 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] dioxine-5-carboxylic acid ethylamide;

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

8- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2, 3-dihydro-benzo [1, 4] dioxine-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] dioxine-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 the treatment of parkinson's disease, said method comprising administering to a subject in need thereof an effective amount of a compound as described herein.

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

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

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

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

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

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

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

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

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

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

Synthesis of

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

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

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

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

Scheme A below illustrates one synthetic procedure that may be used to prepare a particular compound of formula I or formula II, wherein X, m, R¹，R²，R³，R⁵，R⁶And R⁷As defined herein.

Scheme A

In step 1 of scheme A, dichloropyrimidine compoundaWith reagentsbReacted to give a pyrimidine compoundc. The reaction of step 1 may occur under polar solvent conditions. In which X is-O- (reagent)bIs an alcohol), the reaction of step 1 may be carried out in the presence of a base.

In step 2, a pyrimidine compoundcBy reaction with aminobenzoic acid compoundsdReaction to provide aminopyridine compoundse. The reaction of step 2 may be carried out inIn polar protic solvents and in the presence of acids such as HCl.

In step 3, an amide coupling reaction is carried out, wherein the compound iseWith aminesfTo obtain a compound of formula I or formula II according to the invention. The amide coupling reaction of step 3 can be carried out using various well-known amide coupling reagents such as carbodiimides (e.g., DCC, DIC, EDC, etc.), aminium (aminium) 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 may be achieved using acid chloride or anhydride intermediates (not shown).

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

Administration and pharmaceutical compositions

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Other suitable pharmaceutical carriers and their formulations are described in Remington: the Science and practice of 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 of

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

Examples

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

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

List of abbreviations

AcOH acetic acid

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

Atm. atmospheric pressure

(BOC)₂Di-tert-butyl O 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

Et₂O diethyl ether

EtOH ethanol/Ethyl alcohol

EtOAc ethyl acetate

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

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 Isopropanol/Isopropanol

LCMS liquid chromatography/Mass Spectrometry

MeOH methanol/methyl alcohol

MW microwave

NBS N-bromosuccinimide

NMP 1-methyl-2-pyrrolidone

PSI PSI

RT Room temperature

TBDMS tert-butyldimethylsilyl group

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

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

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

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

TABLE 1

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

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

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

TABLE 2

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

A mixture of 50mg 2-chloro-5-fluoro-N-methylpyrimidin-4-amine, 57mg 4-amino-3-methoxybenzoic acid, 0.1mL of 4NHCl in 1, 4-dioxane and 1mL of N-butanol was placed in a 10mL sprung microwave vial (CEMCorp.) and heated to 120 ℃ for 40min in the microwave. The reaction was monitored by LC/MS. The precipitated solid was filtered to obtain 80mg 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 a cooled solution of 1g of methyl 3-hydroxy-4-nitrobenzoate, 3.31g of cesium carbonate in 20mL of DMF, 1.5 equivalents of difluoromethane iodide were carefully added. The reaction was allowed to warm to room temperature and was followed by TLC. When the reaction was complete, the mixture was concentrated and purified by silica gel chromatography to give 1.2g of methyl 3- (difluoromethoxy) -4-nitrobenzoate.

Methyl 3- (difluoromethoxy) -4-nitrobenzoate (0.9g) was placed in a 250mL round bottom flask and dissolved in 30mL of ethanol. Pd/C (0.15g, 10% Pd) was carefully added and a hydrogen balloon was attached to the flask. The reaction was stirred vigorously overnight. After checking by TLC, the reaction was filtered through a pad of celite and concentrated to give 0.6g of methyl 4-amino-3- (difluoromethoxy) benzoate, which was used without further purification.

Methyl 4-amino-3- (difluoromethoxy) benzoate (70mg), 2, 5-dichloro-N-methylpyrimidin-4-amine, 0.1mL of 4N HCl/dioxane and 1mL of N-butanol were placed in a microwave vial. The reaction was heated at 150 ℃ for 30min and monitored by LCMS. The mixture was concentrated and purified by silica gel chromatography to give 100mg of pure methyl 4- (5-chloro-4- (methylamino) pyrimidin-2-ylamino) -3- (difluoromethoxy) benzoate.

Methyl 4- (5-chloro-4- (methylamino) pyrimidin-2-ylamino) -3- (difluoromethoxy) benzoate (500mg) was dissolved in 5mL of THF and 5mL of water. After dissolution, 234mg of lithium hydroxide was added and the reaction was stirred at room temperature overnight. The mixture was checked by LCMS, then carefully acidified with 1N HCl and partitioned with ethyl acetate. The organic layer was concentrated and purified by silica gel chromatography to give 250mg of 4- (5-chloro-4- (methylamino) pyrimidin-2-ylamino) -3- (difluoromethoxy) benzoic acid.

The compounds shown in table 4 were prepared analogously.

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 a mixture of acetone (17.5mL) and water (19mL) at 0 deg.C was added concentrated HCl (5.6 mL). A solution of sodium nitrite (2.25g, 32.6mmol) in water (7.5mL) was added dropwise and the mixture was allowed to stir at 0 ℃ for 30 min. The mixture was then added dropwise to copper cyanide (3.75g, 42mmol) and sodium cyanide (5.5g, 112mmol) in water (2)5mL) and EtOAc (12.5mL) the mixture was allowed to stir at RT for 2h, then water (50mL) was added, the mixture was extracted with EtOAc (3 × 100mL) and the combined organic portions were washed with 2M NaOH (aq) (50mL) and brine (50mL), the organic portions were passed through a hydrophobic frit and the solvent was removed in vacuo, the residue was triturated with isohexane and dried to give 5-methoxy-2-methyl-4-nitrobenzonitrile (4.62g, 90%) as an off-white solid, LCMS (10cm _ ESCI _ Bicarb _ MeCN) [ M]^-192 at 3.19 min.¹H NMR(400MHz，CDCl₃)：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 (2.0g, 10.4mmol) in AcOH (20mL), water (20mL) and concentrated sulfuric acid (20mL) was heated to 120 ℃ for 10 h. Water (100mL) and DCM (100mL) 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 (2.0g, 91%) as an off-white solid. LCMS (10cm _ ESCI _ Formic _ MeCN): [ M-H ]]^-210 at 3.37 min.¹H NMR(400MHz，CDCl₃)：7.75(s，1H)，7.70(s，1H)，3.99(s，3H)，2.62(s，3H)。

And step 3: (5-methoxy-2-methyl-4-nitrophenyl) (morpholino) methanone

To 5-methoxy-2-methyl-4-nitrobenzoic acid (2.0g, 9.47mmol) in DCM (50mL) was added DIPEA (8.3mL, 47mmol) and HATU (3.96g, 10.4mmol), followed by morpholine (0.83mL, 9.47 mmol). The mixture was allowed to stir at RT for 5h, then water (50mL) and DCM (50mL) were added. Mixing the aqueous phase with DCM (3 × 25mL) was extracted and the combined organic phases passed through a hydrophobic frit and the solvent was removed in vacuo purification of the residue by silica gel column chromatography (0-100% EtOAc in isohexane) gave (5-methoxy-2-methyl-4-nitrophenyl) (morpholino) methanone (2.5g, 94%) as an off-white solid LCMS (10CM _ ESCI _ Formic _ MeCN) [ M + H: [ M + H ] M]⁺281 at 3.17 min.¹H NMR(400MHz，CDCl₃)：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)。

And 4, step 4: (4-amino-5-methoxy-2-methylphenyl) (morpholino) methanone (method 1)

To (5-methoxy-2-methyl-4-nitrophenyl) (morpholino) methanone (324mg, 1.16mmol) in ethanol (20mL) and water (2mL) was added SnCl₂·2H₂O (1.05g, 4.64 mmol). The mixture was heated to 65 ℃ for 36h, then 2M aqueous sodium hydroxide (20mL) and DCM (20mL) 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 (268mg, 92%) as an off-white solid. LCMS (10cm _ ESCI _ Formic _ MeCN): [ M + H ]]⁺251 at 2.14 min.¹H NMR(400MHz，CDCl₃)：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)。

And 4, step 4: (4-amino-5-methoxy-2-methylphenyl) (morpholino) methanone (method 2)

To (5-methoxy-2-methyl-4-nitrophenyl) (morpholino) methanone (1.76g, 6.3mmol) in ethanol (25mL) and water (25mL) was added ammonium chloride (1.72g, 3.3 mmol)1.5mmol) and iron powder (1.41g, 25.2 mmol). the mixture was heated to 90 ℃ for 2 hours, then filtered through celite, washed with ethanol, the solvent was removed in vacuo and the residue was partitioned between water (50mL) and DCM (50mL), the layers were separated and the aqueous phase was washed with DCM (3 × 50mL), the combined organic phases were MgSO 3₄Dry, filter and remove the solvent in vacuo. The residue was triturated with diethyl ether/40-60 petroleum ether and dried to give (4-amino-5-methoxy-2-methylphenyl) (morpholino) methanone (1.31g, 82%) as an off-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 a mixture of acetone (17.5mL) and water (19mL) at 0 deg.C was added concentrated HCl (5.6mL), a solution of sodium nitrite (2.25g, 32.6mmol) in water (7.5mL) was added dropwise and the mixture was allowed to stir at 0 deg.C for 30min, then the mixture was added dropwise to a mixture of copper cyanide (3.75g, 42mmol) and sodium cyanide (5.5g, 112mmol) in water (25mL) and EtOAc (12.5mL), the mixture was allowed to stir at RT for 1H, then water (50mL) was added, the mixture was extracted with EtOAc (3 × 100mL) and the combined organic fractions were washed with 2M aqueous NaOH (50mL) and brine (50mL), the organic fraction was passed through a hydrophobic glass frit residue and the solvent was removed in vacuo, the mixture of isohexane was suspended in diethyl ether, the combined organic fraction was removed by filtration to form an off-white solid fraction (MCH-dry) and the off-white fraction was separated from the mixture by filtration and the off-white solid (MCH-white solid) and filtered off-white]⁺197 at 3.97 min.¹HNMR(400MHz，CDCl₃)：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 (1g, 5mmol) in AcOH (10mL), water (10mL) and concentrated sulfuric acid (10mL) was heated to 120 ℃ for 5 h. Water (100mL) was added and the solid was removed by filtration and dried to give 5-chloro-2-methyl-4-nitrobenzoic acid (905mg, 84%) as an off-white solid. LCMS (10cm _ ESCI _ Bicarb _ MeCN): [ M-H ]]^-214 at 2.12 min.¹H NMR(400MHz，CDCl₃)：8.22(s，1H)，7.76(s，1H)，2.70(s，3H)。

And step 3: (5-chloro-2-methyl-4-nitrophenyl) (morpholino) methanone

To 5-chloro-2-methyl-4-nitrobenzoic acid (197mg, 0.91mmol) in DMF (5mL) was added triethylamine (0.13mL, 0.91mmol) and HATU (345mg, 0.91mmol), followed by morpholine (0.08mL, 0.91 mmol). The mixture was allowed to stir at RT for 18h, then water (10mL) 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 (244mg, 95%) as an off-white solid. LCMS (10cm _ ESCI _ Bicarb _ MeCN): [ M + H ]]⁺285 in 3.05 min.¹H NMR(400MHz，CDCl₃)：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)。

And 4, step 4: (4-amino-5-chloro-2-methylphenyl) (morpholino) methanone

To (5-chloro-2-methyl-4-nitrophenyl) (morpholino) methanone (244mg, 0.86mmol) in ethanol (6mL) and water (0.6mL) was added SnCl₂·2H₂O (776mg, 3.44 mmol). The mixture was heated to 65 ℃ for 5h, then 2M aqueous sodium hydroxide (10mL) and DCM (10mL) 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 (203mg, 93%) as an off-white solid. LCMS (10cm _ ESCI _ Formic _ MeCN): [ M + H ]]⁺255 at 2.84 min.¹H NMR(400MHz，CDCl₃)：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 (1.25g, 5.8mmol) in methanol (4mL) at 0 deg.C was added cyclopropylamine (0.69mL, 10 mmol). The mixture was allowed to stir at RT for 4h, then DCM (20mL) and water (20mL) 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 (472mg, 34%) as an off-white solid. LCMS (10cm _ ESCI _ Bicarb _ MeCN): [ M + H ]]⁺At 3.64min, 238.¹H NMR(400MHz，CDCl₃)：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

Concentrated nitric acid (5mL) was carefully added dropwise to 5-fluoro-2- (trifluoromethyl) benzoic acid (1g, 4.8mmol) in concentrated sulfuric acid (5mL) at 0 ℃. The mixture was heated to 100 ℃ for 18 h. The cooled mixture was poured into an ice/water mixture (75mL) and extracted with EtOAc (75 mL). The organic layer was washed with brine (75mL) and passed through a hydrophobic frit. The solvent was removed in vacuo and half of the residue was added to a solution of sodium methoxide in THF [ formed by adding sodium hydride (220mg, 60% in oil, 5.5mmol) to a mixture of THF (5mL) and methanol (0.12mL, 2.9mmol)]In (1). The mixture was stirred at RT for 3h, then DCM (20mL) and 2M aqueous Cl (5mL) were added. The mixture was passed through a hydrophobic frit and the solvent was removed in vacuo. The residue was dissolved in DCM (24mL), then DIPEA (0.48mL, 7.2mmol) and HATU (1.1g, 2.9mmol) were added, followed by morpholine (0.15mL, 2.9 mmol). The mixture was allowed to stir at RT for 4h, then saturated aqueous sodium bicarbonate (25mL) was 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 (0-10% EtOAc in isohexane) to give (5-methoxy-4-nitro-2- (trifluoromethyl) phenyl) (morpholino) methanone (350mg, 4%) as a yellow solid. LCMS (10cm _ ESCI _ Bicarb _ MeCN): [ M + H ]]⁺335 at 3.33 min.¹H NMR(400MHz，CDCl₃)：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

To (5-methoxy-4-nitro-2- (trifluoromethyl) phenyl) (morpholino) methanone (349mg, 1.04mmol) in ethanol (20mL) and water (2mL) was added SnCl₂·2H₂O (941mg, 4.16 mmol). The mixture was heated to 65 ℃ for 2h, then 2M aqueous sodium hydroxide (20mL) and DCM (20mL) 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 (250mg, 79%) as an off-white solid. LCMS (10cm _ ESCI _ Bicarb _ MeCN): [ M + H ]]⁺305 in 2.87 min.¹H NMR(400MHz，CDCl₃)：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: 4-amino-5-chloro-2-fluorobenzoic acid tert-butyl ester and 4-amino-3-chloro-2-fluorobenzoic acid tert-butyl ester

To a solution of N-chlorosuccinimide (950mg, 7.1mmol) in N, N-dimethylformamide (25mL) was added dropwise a solution of tert-butyl 4-amino-2-fluorobenzoate (1.5g, 7.1mmol) in N, N-dimethylformamide (22 mL). The resulting mixture was stirred at room temperature for 3 hours, then brine solution (80mL) and ethyl acetate (100mL) were added. The organic phase was collected and washed three times with brine (50 mL). The combined organic phases were dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (4% EtOAc in isohexane) to give tert-butyl 4-amino-5-chloro-2-fluorobenzoate (400mg, 23%,¹HNMR(400MHz，DMSO-d₆): 7.63(d, J ═ 7.6Hz, 1H), 6.55(d, J ═ 13.2Hz, 1H), 6.46(brs, 2H), 1.52(s, 9H)) and tert-butyl 4-amino-3-chloro-2-fluorobenzoate (490mg, 28%,¹H NMR(400MHz，DMSO-d₆): 7.52(t, J ═ 8.4Hz, 1H), 6.64(dd, J ═ 1.2Hz and J ═ 8.4Hz, 1H), 6.50(brs, 2H), 1.53(s, 9H)), all white solids.

Preparation 10: 4-amino-3-fluoro-2, 6-dimethoxybenzoic acid methyl ester

To a solution of methyl 4-amino-2, 6-dimethoxybenzoate (510mg, 2.42mmol) in acetonitrile (10mL) at 0 deg.C was added(940mg, 2.66 mmol). The mixture was stirred at 0 ℃ for 30 minutes, then water (10mL) 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 was removed in vacuo. Purification of the residue by silica gel column chromatography (0-100% EtOAc in isohexane) afforded methyl 4-amino-3-fluoro-2, 6-dimethoxybenzoate (114mg, 20%) as a yellow solid.¹H NMR(400MHz，CDCl₃)：6.05(d，J＝6.4Hz，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 in dichloromethane (120mL) at room temperature for 20 min. Morpholine (0.88g, 10.13mmol) was added and the reaction stirred for 2 hours. The dichloromethane was removed and the resulting residue partitioned 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 give (2-bromo-4, 5-difluorophenyl) (morpholino) methanone (2.5g, 97%).¹H NMR(400MHz，CDCl₃)：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

A solution of (2-bromo-4, 5-difluorophenyl) (morpholino) methanone (1.00g, 3.27mmol) and 3, 4-dimethoxybenzylamine (601mg, 3.60mmol) in dimethyl sulfoxide (10mL) was treated with dipotassium hydrogen phosphate (2.88g, 13.07mmol) under a nitrogen atmosphere. The mixture was then heated to 80 ℃ for 48 h. The reaction was allowed to cool, then diluted with water (50mL) and extracted with dichloromethane (3x50 mL). The combined extracts were washed with brine (50mL) and then passed through a phase separation cartridge and then evaporated to give a yellow oil. The crude product was adsorbed onto silica and purified by silica gel column chromatography (0-100% ethyl acetate/isohexane) to give (2-bromo-4- ((2, 4-dimethoxybenzyl) amino) -5-fluorophenyl) - (morpholino) methanone (200mg, 13%).¹HNMR(400MHz，CDCl₃)：7.16-7.14(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

A mixture of 100mg of 4- (5-fluoro-4- (methylamino) pyrimidin-2-ylamino) -3-methoxybenzoic acid, 47. mu.L of morpholine, 205mg of HATU, 188mL of diisopropylethylamine in 1mL of dimethylformamide was stirred at room temperature overnight. The reaction was checked by LCMS and found complete. Will be reversedThe reaction was diluted with EtOAc and the organic layer was washed with saturated NaHCO₃And a brine wash. The organic layer was concentrated and purified by preparative reverse phase HPLC to give 12mg of (4- (5-fluoro-4- (methylamino) pyrimidin-2-ylamino) -3-methoxyphenyl) (morpholino) methanone.

Example 2: 5-chloro-2-methoxy-4-N, N-dimethyl- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) Phenyl) -benzamides

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

Example 3 (2-fluoro-3-methoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) (morpholino) methanones

To a suspension of 2-fluoro-3-methoxy-4-nitrobenzoic acid (180mg, 0.97mmol) in DCM (8mL) was added morpholine (0.17mL, 1.9mmol), DIEA (0.25mL) and HBTU (0.4g, 1.05 mmol). The reaction was stirred at room temperature for 18 hours. The reaction was then diluted with water and extracted with DCM (3 ×). Combining the extractsWashed with water and Na₂SO₄Dried, filtered and concentrated. The crude product was purified by flash chromatography to give (2-fluoro-3-methoxy-4-nitrophenyl) (morpholino) methanone (0.20g, 83%).

A suspension of (2-fluoro-3-methoxy-4-nitrophenyl) (morpholino) methanone (0.20g) and palladium on charcoal (0.1g, 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 (0.18g, 0.72mmol) and 2-chloro-N-methyl-5- (trifluoromethyl) pyrimidin-4-amine (0.10g, 0.47mmol) in a solution of 2-methoxyethanol (2mL) and TFA (0.055mL) was stirred at 95 ℃ for 2 hours. 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

A mixture of (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 in a pressure tube at 105 ℃ for 18 hours. The reaction mixture was filtered and concentrated. The crude product was purified by reverse phase HPLC to give the title compound (70mg, 82%). 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 (2.12g, 8.47mmol), 2-chloro-N-methyl-5- (trifluoromethyl) pyrimidin-4-amine (1.79g, 8.47mmol) and p-toluenesulfonic acid (1.62g, 8.47mmol) in dioxane (80mL) was heated to 100 ℃ for 18 h. Saturated aqueous sodium bicarbonate (100mL) and DCM (100mL) 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 (2.1g, 58%) as an off-white solid. LCMS (10cm _ ESCI _ Bicarb _ MeCN): [ M + H ]]⁺426 at 2.59 min.¹H NMR(400MHz，CDCl₃)：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) methanones

A mixture of (4-amino-5-chloro-2-methylphenyl) (morpholino) methanone (79mg, 0.31mmol), 2-chloro-N-methyl-5- (trifluoromethyl) pyrimidin-4-amine (66mg, 0.31mmol) and p-toluenesulfonic acid (59mg, 0.31mmol) in dioxane (4mL) was heated to 100 ℃ for 4h. Saturated aqueous sodium bicarbonate (10mL) and DCM (10mL) 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 (71mg, 53%) as an off-white solid. LCMS (10cm _ ESCI _ Bicarb _ MeCN): [ M + H ]]⁺430 at 3.47 min.¹H NMR(400MHz，CDCl₃)：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 Yl) (morpholino) methanone

To 2-chloro-N-cyclopropyl-5- (trifluoromethyl) pyrimidin-4-amine (237mg, 1mmol) in dioxane (3mL) was added pTSA (190mg, 1mmol) and 4-amino-2-fluoro-5-methoxybenzoic acid (185mg, 1 mmol). The mixture was heated to 100 ℃ for 5h, then the mixture was allowed to cool to RT. The precipitated solid was collected by filtration, washed with dioxane and diethyl ether, and then dried. The residue was suspended in DCM (5mL), then DIPEA (0.1mL, 1.5mmol) and HATU (228mg, 0.6mmol) were added, followed by morpholine (0.03mL, 0.6 mmol). The mixture was allowed to stir at RT for 4h, then DCM (10mL) and saturated aqueous sodium bicarbonate solution (15mL) were added. The separated organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (0-10% methanol in DCM) to give (4- (4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -2-fluoro-5-methoxyphenyl) (morpholino) methanone (36mg, 16%) as an off-white solid. LCMS (10cm _ ESCI _ Bicarb _ MeCN): [ M + H ]]⁺456 at 2.93 min.¹H NMR(400MHz，CDCl₃)：8.77(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) Yl) (morpholino) methanone

To a solution of (4- (4-chloro-5- (trifluoromethyl) pyrimidin-2-ylamino) -2-fluoro-5-methoxyphenyl) - (morpholino) methanone (120mg, 0.28mmol) in dioxane (2mL) was added pTSA (52mg, 0.28mmol) and D4-cyclopropylamine (17mg, 0.28 mmol). The mixture was heated to 100 ℃ for 2 hours. LSMS of the crude sample showed only 10% of the desired material. DIPEA (100. mu.L, 0.56mmol) and D4-cyclopropylamine (17mg, 0.28mmol) were added and the mixture was heated to 100 ℃ for one hour. After returning to room temperature, DCM (20mL) and saturated aqueous sodium bicarbonate (15mL) 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 (42mg, 33%) as an off-white solid. LCMS (10cm _ ESCI _ Bicarb _ MeCN): [ M + H ]]⁺460 at 3.41 min.¹H NMR(400MHz，CDCl₃)：8.77(d，J＝12.8Hz，1H)，8.20(s，1H)，7.94(s，1H)，6.91(d，J＝5.6Hz，1H)，5.48(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- (trifluoro-methyl) pyrimidine derivatives Methyl) phenyl) (morpholino) methanone

A mixture of (4-amino-5-methoxy-2- (trifluoromethyl) phenyl) (morpholino) methanone (94mg, 0.31mmol), 2-chloro-N-methyl-5- (trifluoromethyl) pyrimidin-4-amine (66mg, 0.31mmol) and p-toluenesulfonic acid (59mg, 0.31mmol) in dioxane (4mL) was heated to 100 ℃ for 2 h. Saturated aqueous sodium bicarbonate (10mL) and DCM (10mL) 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 (111mg, 75%) as an off-white solid. LCMS (10cm _ ESCI _ Bicarb _ MeCN): [ M + H ]]⁺480 at 3.32 min.¹HNMR(400MHz，CDCl₃)：9.13(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)，3.95-3.88(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 Yl) (morpholino) methanone

A mixture of (4-amino-5-methoxy-2- (trifluoromethyl) phenyl) (morpholino) methanone (94mg, 0.31mmol), 2, 5-dichloro-N-methylpyrimidin-4-amine (55mg, 0.31mmol) and p-toluenesulfonic acid (59mg, 0.31mmol) in dioxane (4mL) was heated to 100 ℃ for 36 h. Saturated aqueous sodium bicarbonate (10mL) and DCM (10mL) were added and 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 (0-10% EtOAc in isohexane) to give (4- (5-chloro-4- (methylamino) pyrimidin-2-ylamino) -5-methoxy-2- (trifluoromethyl) phenyl) (morpholino) methanone (11mg, 8%) as an off-white solid. LCMS (10cm _ ESCI _ Bicarb _ MeCN): [ M + H ]]⁺446 at 3.60 min.¹H NMR(400MHz，CDCl₃)：8.97(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) methanones

A solution of tert-butyl 4-amino-5-chloro-2-fluorobenzoate (50mg, 0.20mmol) in dichloromethane (2mL) and trifluoroacetic acid (2mL) was stirred at room temperature for 3h, then the reaction was evaporated to dryness. The residue was taken up in dioxane (3mL) and then 2-chloro-N-methyl-5- (tri-fluoromethyl) pyrimidin-4-amine (42mg, 0.20mmol) and p-toluenesulfonic acid (38mg, 0.20mmol) were added. The resulting mixture was heated to 100 ℃ for 2 h. After returning to room temperature, DCM (10mL) and water (10m) were added and the organic phase was passed through a hydrophobic frit. The solvent was removed in vacuo and the residue was dissolved in DCM (3mL) and then DIPEA (140. mu.L, 0.8mmol) and HATU (85mg, 0.22mmol) were added followed by morpholine (18. mu.L, 0.2 mmol). The mixture was allowed to stir at RT for 4h, then saturated aqueous sodium bicarbonate (25mL) was added. The mixture was passed through a hydrophobic 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 (25mg, 28%) as an off-white solid. LCMS (10cm _ ESCI _ Bicarb _ MeCN): [ M + H ]]⁺434 at 3.02 min.¹H NMR(400MHz，CDCl₃)：8.64(d，J＝12.8Hz，1H)，8.22(s，1H)，7.72(brs，1H)，7.48(d，J＝6.8Hz，1H)，5.30(brs，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) Phenyl) (morpholino) methanones

A mixture of methyl 4-amino-3-fluoro-2, 6-dimethoxybenzoate (114mg, 0.5mmol) and 1N NaOH (1.5mL) in ethanol (5mL) was heated at 60 ℃ for 18 h. The solvent was removed in vacuo. The residue was dissolved in water (2mL), cooled in an ice bath and acidified to pH 3 by dropwise addition of 2n hcl. The reaction was evaporated to dryness and the residue was dissolved in DCM (10mL) and then DIPEA (260. mu.L, 1.5mmol) and HATU (208mg, 0.6mmol) were added followed by morpholine (66. mu.L, 0.75 mmol). The mixture was allowed to stir at RT for one hour, then saturated aqueous sodium bicarbonate (10mL) was added. The mixture was passed through a hydrophobic frit and the solvent was removed in vacuo. The residue was taken up in dioxane (2mL) and then 2-chloro-N-methyl-5- (trifluoromethyl) pyrimidin-4-amine (105mg, 0.5mmol) and p-toluenesulfonic acid (95mg, 0.50mmol) were added. The resulting mixture was heated to 100 ℃ for 30 minutes. After returning to room temperature, DCM (10mL) and water (10m) 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 (18mg, 8% in three steps) as an off-white solid. LCMS (10cm _ ESCI _ Formic _ MeCN): [ M + H ]]⁺460 at 3.32 min.¹H NMR(400MHz，CDCl₃)：8.20(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 Yl) (morpholino) methanone

Trifluoroacetic acid (2mL) was added to a solution of 2-bromo-4- ((2, 4-dimethoxybenzyl) amino) -5-fluorophenyl) (morpholino) methanone (205mg, 0.45 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction was then evaporated to dryness. The resulting residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate solution. The organic phase was collected and filtered through a phase separation cartridge and evaporated in vacuo. The residue was added to a mixture of 2-chloro-N-methyl-5- (trifluoromethyl) pyrimidin-4-amine (77mg, 0.36mmol) and p-toluenesulfonic acid (68.5mg g, 0.36mmol) in dioxane (3 mL). The mixture was stirred at 100 ℃ for 2 h. Saturated aqueous sodium bicarbonate (20mL) and DCM (20mL) were added and 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 (0-50% EtOAc in isohexane) to give a solid which was then added to a mixture of methylboronic acid (75mg, 1.26mol), potassium carbonate (124mg, 0.9mmol) and palladium tetrakis (31mg, 0.027mmol) in degassed water (0.8mL) and degassed dioxane (5.5 mL). The resulting mixture was purged with nitrogen and then heated at 100 ℃ 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 phases were filtered through a hydrophobic frit and evaporated. The crude was purified by reverse phase HPLC to give (5-fluoro-2-methyl-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) (morpholino) methanone (30mg, 16% over 3 steps). LCMS (10cm _ ESCI _ Formic _ MeCN): [ M + H ]]⁺415 at 3.12 min.¹H NMR(400MHz，DMSO-d₆)：9.17(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 Yl) (morpholino) methanone

4-amino-5-bromo-2-methoxybenzoic acid (1.09g, 4.42mmol), DIPEA (1.14g, 8.84mmol) and HATU (2.02g, 5.3mmol) were stirred in dichloromethane (60mL) at room temperature for 20 min. Morpholine (0.77g, 8.84mmol) was added and the reaction stirred for 2 h. The dichloromethane was removed and the resulting residue partitioned 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) pyrimidin-4-amine (671mg, 3.17mmol) and p-toluenesulfonic acid (603mg, 3.17mmol) in dioxane (70 mL). The reaction was stirred at 100 ℃ 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 give a residue which was purified by silica gel column chromatography (25-75% ethyl acetate/isohexane) and the resulting residue triturated with diethyl ether to petroleum ether (1: 1) to afford 5-bromo-2-methoxy-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) (morpholino) methanone (340mg, 15% yield) as a white solid.

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

5-bromo-2-methoxy-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) (morpholino) -methanone (340mg, 0.69mmol) was added to a mixture of methylboronic acid (217mg, 3.64mmol), potassium carbonate (359mg, 2.6mmol) and palladium tetrakis (90mg, 0.078mmol) in a reaction tube combined in degassed water (3mL) and degassed dioxane (20 mL). The reaction tube was purged with nitrogen, sealed, and then heated at 100 ℃ 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 fractions were filtered through a phase separation cartridge and evaporated. The crude was purified by silica gel column chromatography (25-75% ethyl acetate/isohexane) and the resulting impurity was purified by reverse phase HPLC to give (2-methoxy-5-methyl-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) (morpholino) methanone (16mg, 6%). LCMS (10cm _ ESCI _ bicarb _ MeOH): [ M + H ]]⁺426 at 3.32 min.¹H NMR(400MHz，CDCl₃)：8.17(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 Yl) (D8-morpholino) methanone

Preparation of (4- (4- (ethylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -2-fluoro-5-methoxyphenyl) (D8-morpholino) methanone as described above using deuterated morpholine: LCMS (10cm _ ESCI _ Formic _ MeCN): [ M + H ]]⁺452 at 3.77 min.¹H NMR(400MHz，CDCl₃)：8.43(d，J＝12Hz，1H)，8.20(s，1H)，7.84(s，1H)，6.92(d，J＝6Hz，1H)，5.2(1H，brs)，3.92(s，3H)，3.64-3.58(m，2H)，1.33(t，J＝7.2Hz，3H)。

The compounds according to the invention, prepared using the above procedure, are shown in table 5 together with LRRK2 Ki values (micromolar concentrations).

TABLE 5

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

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

A20-mL round-bottom flask was charged with 2, 3-dihydrobenzo [ b ]][1，4]Dioxin-5-carboxylic acid (1.8g, 1.0mmol), bromine (3.16g, 2.0mmol), and acetic acid (2 mL). The reaction mixture was stirred at 120 ℃ for 2h and then cooled to 15 ℃. It was filtered and the solid was washed with acetic acid to afford the title compound as a white solid (3.0g, 60%). LCMS: ESI (3minuterun), M/z 337[ M +1]]⁺(ii) a Retention time: 1.21 minutes.

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

A20-mL round-bottom flask was charged with 6, 7-dibromo-2, 3-dihydrobenzo [ b ] [1, 4] dioxin-5-carboxylic acid (3.0g, 0.61mmol) and acetic acid (2 mL). The mixture was heated to 37 ℃, followed by addition of a solution of nitric acid (d ═ 1.49, 1.0mL), acetic acid (1.0mL) and concentrated sulfuric acid (1.0 mL). After heating at 50 ℃ for 1h, the mixture was poured into cold water while stirring. It was then filtered and the solid was washed with water to give the title compound (1.91g, 83%). LCMS: ESI (3min run), M/z 382[ M +1] +; retention time: 1.05 minutes.

And step 3: 8-amino-2, 3-dihydrobenzo [ b ]][1，4]Dioxin-5-carboxylic acid

The autoclave vessel was charged with water (4.0mL), 6, 7-dibromo-8-nitro-1, 4-benzodioxane-5-carboxylic acid (1.9g, 0.5mmol), saturated sodium carbonate (1.0mL), and Pd/C (500 mg). Mixing the mixture at 40kg/cm²Hydrogenation was carried out at 50 ℃ 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 (253mg, 26%). LCMS: ESI (3min run), M/z 196[ M +1]]+; retention time: 0.30 minutes.

And 4, step 4: 8-amino-N-methyl-2, 3-dihydrobenzo [ b ]][1，4]Dioxin-5-carboxamides

A50-mL round-bottom flask was charged with 8-amino-2, 3-dihydrobenzo [ b ]][1，4]Dioxin-5-carboxylic acid (200mg, 1.025mmol), methylamine hydrochloride (138mg, 2.05mmol), HATU (467mg, 1.23mmol), TEA (0.5mL), and DMF (5.0 mL). The reaction mixture was stirred at room temperature for 15 h. Then passing it through water/CH₃0.1% NH in CN₄HCO₃Eluted reverse phase Combi-Flash was purified to afford the title compound as a red oil (250mg, 88%). LCMS: ESI (3min run), M/z 209.1[ M +1]]+; retention time: 1.53 minutes.

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

Filling a microwave vial equipped with a magnetic stirrer with 8-amino-N-methyl-2, 3-dihydrobenzo [ b][1，4]Dioxin-5-carboxamide (50mg, 0.18mmol), 2-chloro-N-ethyl-5- (trifluoromethyl) pyrimidin-4-amine (40mg, 0.18mmol), and t-BuOH (1.0 mL). The mixture was heated at 100 ℃ for 2h under microwave irradiation. It was then concentrated and the residue was purified by reverse phase preparative HPLC to provide the title compound as a white solid (15.4mg, 32%). LCMS: ESI (10 min run), m/z 398.1 retention time: 5.471 minutes. 1H NMR (500MHz, CDCl)₃)8.19(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)。

The compounds according to the invention, prepared using the above procedure, are shown in table 6 together with LRRK2 Ki values (micromolar concentrations).

TABLE 6

Example 18 in vitro LRRK2 LabChip assay

The assay is used to determine Ki_app、IC₅₀Or percent inhibition value to determine the efficacy of the compound in inhibiting the activity of LRRK 2. In polypropylene plates, LRRK2, fluorescently labeled peptide substrate, ATP, and test compound were incubated together. Using LabChip 3000(Caliper Life Sciences), after the reaction, the substrate was separated into two populations by capillary electrophoresis: phosphorylated and unphosphorylated. The relative amounts of each are quantified by fluorescence intensity. LRRK2 Ki was determined according to the following equation:

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

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

The assay conditions and materials used were as follows:

final assay conditions：

ATP ^app Kms：

Material：

Complete reaction buffer: h₂O/25mM Tris，pH 8.0/5mM MgCl₂/2mM DTT/0.01％Triton X-100。

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

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

Compound plate preparation:

for serial dilutions, 34.6. mu.l DMSO was added to columns 3-24. For assay controls, 37.5. mu.l DMSO was added to columns 1 and 2 of rows A and P, and 50. mu.l 25. mu. M G-028831(Staurosporine) was added to columns 1 and 2 of row B. For the samples: starting at 100. mu.M, 37.5. mu.l DMSO was added to columns 1 and 2, followed by 12.5. mu.l 10mM compound; starting at 10. mu.M, 78. mu.l DMSO was added to columns 1 and 2, followed by 2. mu.l 10mM compound; and starting at 1. mu.M, 25. mu.M compound (2. mu.l of 10mM compound + 798. mu.l DMSO) was added to empty columns 1 and 2. A1: 3.16 serial dilution ("PLK _ BM _ serial _ halfiog") was performed using precision instrumentation.

ATP preparation：

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

Bulk and blank preparation：

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

Measurement procedure：

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

2 μ l compound +23 μ l ATP;

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

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

the plates were incubated for 2 hours in the dark. The kinase reaction ("PLKStop") was terminated using Biomek FX, and 10 μ l/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 "LRRK 2 IC 50" with the following job settings:

example 19 in vitro LRRK2 Lanthascreen binding assay

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

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

The assay conditions and materials used were as follows:

final assay conditions：

Material：

Reaction buffer solution: h₂O/50mM Tris，pH 7.4/10mM MgCl₂/l mM EGTA/0.01％Brij35。

Compound plate preparation:

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

Bulk and blank preparation：

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

Measurement procedure：

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

Data processing:

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

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

Wherein Et is 4nM

kd (tracer) ═ 8.5nM

Tracer concentration (S) 8.5 nM.

Example 20 animal models of Parkinson's disease

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

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

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

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

Claims

1. A compound of formula A:

or a pharmaceutically acceptable salt thereof,

wherein:

m is 0 to 3;

or R^3aAnd R^3bAtoms attached to themTogether may form a five or six membered ring optionally including one or two heteroatoms each independently selected from O, N and S, said ring optionally being substituted by R⁸One or more substitutions;

R⁵comprises the following steps: hydrogen; or C_1-6An alkyl group;

or R⁵And R⁶Together with the nitrogen atom to which they are attached form a three-to seven-membered ring optionally including a nitrogen atom selected from O, N and S (O)_nAnd which is optionally substituted by one, two, three or four radicals, saidThe groups are independently selected from: c_1-6An alkyl group; halo-C_1-6An alkyl group; c_1-6An alkoxy group; halo-C_1-6An alkoxy group; a hydroxyl group; c_1-6alkoxy-C_1-6An alkyl group; hydroxy-C_1-6An alkyl group; halo, nitrile; c_1-6Alkyl-carbonyl; c_1-6An alkyl-sulfonyl group; c_3-6A cycloalkyl group; c_3-6cycloalkyl-C_1-6An alkyl group; c_3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; or two of said groups together with the atoms to which they are attached may form a five or six membered ring; and is

R⁸comprises the following steps: halogenating; c_1-6An alkyl group; or oxo.

2. A compound of formula A according to claim 1, selected from the group consisting of formulae I, II and III,

wherein R is¹，R²，R³，R⁴，R⁵，R⁶，R⁷，R⁸X, Y, Z, A and m are as defined in claim 1.

3. The compound according to any one of claims 1-2, having formula I:

or a pharmaceutically acceptable salt thereof,

wherein:

m is 0 to 3;

x is: -NR^a-; -O-; or-S (O)_r-wherein R is 0 to 2 and R^aIs hydrogen or C_1-6An alkyl group;

R⁵comprises the following steps: hydrogen; or C_1-6An alkyl group;

or R⁵And R⁶Together with the nitrogen atom to which they are attached form a three-to seven-membered ring optionally including a nitrogen atom selected from O, N and S (O)_nAnd which is optionally substituted with one, two, three or four groups independently selected from: c_1-6An alkyl group; halo-C_1-6An alkyl group; c_1-6An alkoxy group; halo-C_1-6An alkoxy group; a hydroxyl group; c_1-6alkoxy-C_1-6An alkyl group; hydroxy-C_1-6An alkyl group; halo, nitrile; c_1-6Alkyl-carbonyl; c_1-6Alkyl-A sulfonyl group; c_3-6A cycloalkyl group; c_3-6cycloalkyl-C_1-6An alkyl group; c_3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; or two of said groups together with the atoms to which they are attached may form a five or six membered ring; and is

the compound is selected from:

[ 5-chloro-2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] - (1-oxa-6-aza-spiro [33] hept-6-yl) -methanone;

[4- (4-cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoro-5- (2-fluoro-ethoxy) -phenyl-1-morpholin-4-yl-methanone;

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

4. A compound according to any one of claims 1-2, having formula II

Or a pharmaceutically acceptable salt thereof,

wherein:

m is 0 to 2;

or R¹And R^aTogether with the atoms to which they are attached may form a three-to six-membered ring, which may optionally include an additional heteroatom selected from O, N and S, and which is oxo substitutedHalogen or C_1-6Alkyl substitution;

R⁵comprises the following steps: hydrogen; or C_1-6An alkyl group;

R⁶comprises the following steps: hydrogen; c_1-6An alkyl group; c_1-6alkoxy-C_1-6An alkyl group; hydroxy-C_1-6An alkyl group; amino-C_1-6An alkyl group; c_3-6A cycloalkyl group; c_3-6cycloalkyl-C_1-6An alkyl group; a heterocyclic group; or heterocyclyl-C_1-6An alkyl group; wherein said C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-6Alkyl, heterocyclyl and heterocyclyl-C_1-6Each alkyl group may be optionally substituted with one, two, three or four groups independently selected from: c_1-6An alkyl group; halo-C_1-6An alkyl group; c_1-6An alkoxy group; halo-C_1-6An alkoxy group; a hydroxyl group; hydroxy-C_1-6An alkyl group; halogenating; a nitrile; c_1-6Alkyl-carbonyl; c_1-6An alkyl-sulfonyl group; c_3-6A cycloalkyl group; c_3-6cycloalkyl-C_1-6An alkyl group; c_3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; or two of said groups together with the atoms to which they are attached may form a five or six membered ring;

R⁸Comprises the following steps: halogenating; c_1-6An alkyl group; or oxo.

5. The compound according to any one of claims 1-2, wherein the compound is of formula III:

or a pharmaceutically acceptable salt thereof,

wherein:

y is-O-or-CHR⁸-; and is

Z is-O-or-CHR⁸-, or Z is absent.

6. The compound according to claim 5, wherein said compound is:

7. A composition, comprising:

a pharmaceutically acceptable carrier; and

a compound according to any one of claims 1 to 6.

8. A method for treating parkinson's disease, said method comprising administering to a subject in need thereof an effective amount of a compound of any of claims 1-6.

9. A compound of formula a according to any one of claims 1 to 6 for use in the prevention or treatment of parkinson's disease.

10. The pharmaceutical composition according to claim 7, wherein the pharmaceutical composition is for the prevention or treatment of Parkinson's disease.

11. The use of a compound of formula a according to any one of claims 1 to 6 in the manufacture of a medicament for the prevention or treatment of parkinson's disease.

12. The invention as hereinbefore described.