PYRAZOLE AMINOPYRIMIDINE DERIVATIVES, THEIR USE AND COMPOSITION INCLUDING THEM

专利摘要:
pyrazole aminopyrimidine derivatives as lrrk2 modulators. the present invention relates to compounds of formula i; or pharmaceutically acceptable salts thereof, wherein x, r1, r2, r3, r4, and r5 are as defined herein. Also described are methods of preparing the compounds and using the compounds for treating diseases associated with the lrrk2 receptor, such as parkinson's disease.
公开号:BR112013011600B1
申请号:R112013011600-5
申请日:2011-11-09
公开日:2022-01-11
发明作者:Charles Baker-Glenn；Daniel Jon Burdick；Mark Chambers；Huifen Chen；Anthony Estrada；Zachary Kevin Sweeney；Bryan K. Chan
申请人:Genentech, Inc；
IPC主号:

专利说明:

FIELD OF THE INVENTION
[001] This invention relates to compounds that modulate LRRK2 function and are useful for the treatment of LRRK2-mediated diseases and conditions such as Parkinson's disease. BACKGROUND OF THE INVENTION
[002] 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 that afflicts approximately one in every 1000 people, with hereditary Parkinson's disease accounting for 5-10% of all patients. Parkinson's disease is caused by the progressive loss of midbrain dopamine neurons, leaving patients with an impaired ability to direct and control their movements. The primary symptoms of Parkinson's disease are shaking, stiffness, slowness of movement, and impaired balance. Many Parkinson's disease patients also experience other symptoms such as emotional changes, memory loss, speech problems, and sleep disturbances.
[003] The gene encoding leucine-rich repeat kinase 2 protein (LRRK2) has been identified in association with hereditary Parkinson's disease (Paisan-Ruiz et al., Neuron, Vol. 44(4), 2004, pp 595 -600; Zimprich et al., Neuron, Vol. 44(4), 2004, 601-607 ). In vitro studies show that Parkinson's disease-associated mutation leads to increased LRRK2 kinase activity and decreased rate of GTP hydrolysis compared to wild type (Guo et al., Experimental Cell Research, Vol. 313(16), 2007, pp. 3658-3670. Anti-LRRK2 antibodies have been used to label the midbrain Lewy bodies associated with Parkinson's disease and cortical antibodies associated with Lewis body dementias suggesting that LRRK2 may play an important role in Lewie body formation and pathogenesis associated with these diseases (Zhou et al., Molecular Degeneration, 2006, 1:17 doi:10.1186/1750-1326-1-17) LRRK2 has likewise been identified potentially as a gene associated with increased susceptibility to Crohn's disease and leprosy susceptibility (Zhang et al., New England J. Med. Vol. 361 (2009) pp. 2609-2618.
[004] LRRK2 was similarly associated with the transition from mild cognitive impairment to Alzheimer's disease (WO2007/149789); L-dopa-induced dyskinesia (Hurley et al., Eur. J. Neurosci., Vol. 26, 2007, pp. 171-177; CNS disorders associated with neuronal progenitor differentiation (Milosevic et al., Neurodegen., Vol. 4 , 2009, p. 25); cancers such as renal, breast, prostate, blood and lung cancers and acute myelogenous leukemia (WO2011/038572); thyroid and papillary renal carcinomas (Looienga et al., www.pnas. org/cgi/doi/10.1073/pnas,1012500108); multiple myeloma (Chapman et al., Nature Vol. 471, 2011, pp. 467472); amyotrophic lateral sclerosis (Shtilbans et al, Amyotrophic Lateral Sclerosis "Early Online 2011, pp. 1-7); rheumatoid arthritis (Nakamura et al., DNA Res. Vol. 13(4), 2006, pp. 169-183); and ankylosing spondylitis (Danoy et al., PLoS Genetics, Vol. 6(12), 2010 , e1001195, pp. 1-5).
[005] Consequently, compounds and compositions effective in modulating LRRK2 activity may provide a treatment for neurodegenerative diseases such as Parkinson's disease and Lewie body dementia, for CNS disorders such as Alzheimer's disease and L -dopa, for cancers such as kidney, breast, prostate, blood, papillary and lung cancers, acute myelogenous leukemia and multiple myeloma, and for inflammatory diseases such as leprosy, Crohn's disease, amyotrophic lateral sclerosis, rheumatoid arthritis , and ankylosing spondylitis. Particularly, there is a need for compounds with LRRK2 affinity that are selective for LRRK2 in other kinases, such as JAK2 which can provide effective drugs for the treatment of neurodegenerative disorders such as PD. SUMMARY OF THE INVENTION
[006] The invention provides compounds of formula I:

[007] or pharmaceutically acceptable salts thereof,
[008] in which:
[009] X is: -NRa-; or -O- where Ra is hydrogen or C1-6alkyl;
[0010] R1 is: C1-6alkyl; C2-6alkenyl; C2-6alkynyl; halo-C1-6alkyl; C1-6alkoxy-C1-6alkyl; hydroxy-C1-6alkyl; amino-C1-6alkyl; C1-6alkylsulfonyl-C1-6alkyl; C3-6cycloalkyl optionally substituted one or more times with C1-6alkyl; C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted one or more times with C1-6alkyl; heterocyclyl optionally substituted one or more times with R7; or heterocyclyl-C1-6alkyl optionally substituted one or more times with R7;
[0011] or X and R1 together form C1-6alkyl; C1-6alkoxy-C1-6alkyl; C3-6cycloalkyl optionally substituted one or more times with R6; or C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted one or more times with R6;
[0012] or R1 and Ra together with the atoms to which they are attached may form a three to six membered heterocyclic ring optionally substituted one or more times with R7;
[0013] R2 is: C1-6alkyl; halo; C1-6alkoxy; cyan; C2-6alkynyl; C2-6alkenyl; halo-C1-6alkyl; halo-C1-6alkoxy; C3-6cycloalkyl optionally substituted one or more times with R6; C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted one or more times with R6; -ORb wherein Rb is C1-6alkyl, C3-6cycloalkyl optionally substituted one or more times with R6, or C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted one or more times with R6; or -C(O)-Rc wherein Rc is C1-6alkyl, C1-6alkoxy, amino, or heterocyclyl optionally substituted one or more times with R7;
[0014] R3 is: hydrogen; C1-6alkyl; halo-C1-6alkyl; C2-6alkenyl; C2-6alkynyl; hydroxy-C1-6alkyl; C1-6alkoxy-C1-6alkyl; cyano-C1-6alkyl; C1-6alkylsulfonyl; C1-6alkylsulfonylC1-6alkyl; amino-C1-6alkyl; C3-6cycloalkyl optionally substituted one or more times with R6; C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted one or more times with R6; C3-6cycloalkylsulfonyl wherein the C3-6cycloalkyl moiety is optionally substituted one or more times with R6; heterocyclyl optionally substituted one or more times with R7; heterocyclyl-C1-6alkyl wherein the heterocyclyl moiety is optionally substituted one or more times with R7; aryl optionally substituted one or more times with R8; aryl-C1-6alkyl wherein the aryl moiety is optionally substituted one or more times with R8; heteroaryl optionally substituted one or more times with R8; heteroaryl-C1-6alkyl wherein the heteroaryl moiety is optionally substituted one or more times with R8; or -Y-C(O)-Rd;
[0015] Y is C2-6alkylene or a bond;
[0016] Rd is C1-6alkyl, C1-6alkoxy, amino, C1-6alkyl-amino, di-C1-6alkyl-amino, halo-C1-6alkyl-amino, dihalo-C1-6alkyl-amino, halo- C1-6alkyl, hydroxy-C1-6alkyl, hydroxy, C1-6alkoxy-C1-6alkyl, cyano-C1-6alkyl, C1-6alkylsulfonylC1-6alkyl, amino-C1-6alkyl, C3-6cycloalkyl optionally substituted one or more times with R6, C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl portion is optionally substituted one or more times with R6, heterocyclyl optionally substituted one or more times with R7, or heterocyclyl-C1-6alkyl wherein the heterocyclyl portion is optionally substituted one or more times with R7;
[0017] R4 is: hydrogen; C1-6alkyl; halo; cyan; halo-C1-6alkyl; C2-6alkenyl; C2-6alkynyl; C1-6alkoxy; C1-6alkoxy-C1-6alkyl; hydroxy-C1-6alkyl; C3-6cycloalkyl optionally substituted one or more times with R6; C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted one or more times with R6; or -Y-C(O)-Rd;
[0018] R5 is: hydrogen; or C1-6alkyl;
[0019] each R6 is independently: C1-6alkyl; halo-C1-6alkyl; C1-6alkoxy; oxo; cyan; halo; or Y-C(O)-Rd;
[0020] each R7 is independently: C1-6alkyl; halo-C1-6alkyl; halo; oxo; C1-6alkoxy; C1-6alkylsulfonyl; C1-6alkoxy-C1-6alkyl; cyan; -Y-C(O)-Rd; heterocyclyl; heterocyclyl-C1-6alkyl; C3-6cycloalkyl; C3-6cycloalkyl-C1-6alkyl; or C3-6cycloalkylsulfonyl; and
[0021] each R8 is independently: oxo; C1-6alkyl; halo-C1-6alkyl; halo; C1-6alkylsulfonyl; C1-6alkoxy; C1-6alkoxy-C1-6alkyl; cyan; heteroeryclyl; heterocyclyl-C1-6alkyl; -Y-C(O)-Rd; C3-6cycloalkyl, C3-6cycloalkyl-C1-6alkyl, or C3-6cycloalkylsulfonyl.
[0022] The invention also provides pharmaceutical compositions comprising the compounds, methods of using the compounds, and methods of preparing the compounds. DETAILED DESCRIPTION OF THE INVENTION Definitions
[0023] Unless otherwise stated, the following terms used in this Order, including the specification and claims, have the definitions produced below. It should 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.
[0024] "Alkyl" means the saturated straight or branched monovalent hydrocarbon moiety, consisting only of carbon and hydrogen atoms, having from one to twelve carbon atoms. "Lower alkyl" refers to an alkyl group of one to six carbon atoms, i.e., C1-C6alkyl. 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.
[0025] "Alkenyl" means a linear monovalent hydrocarbon radical of two to six carbon atoms or linear monovalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g. ethenyl, propenyl , and the like.
[0026] "Alkynyl" means a linear monovalent hydrocarbon radical of two to six carbon atoms or linear monovalent hydrocarbon radical of three to six carbon atoms, containing at least one triple bond, e.g. ethynyl, propynyl , and the like.
[0027] "Alkylene" means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched divalent saturated hydrocarbon radical of three to six carbon atoms, for example, methylene, ethylene, 2,2- dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene, and the like.
[0028] "Alkoxy" and "alkyloxy", which may be used interchangeably, mean 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.
[0029] "Alkoxyalkyl" means a moiety of the formula Ra-O-Rb-, where Ra is alkyl and Rb is alkylene as defined herein. Exemplary alkoxyalkyl groups include, by way of example, 2-methoxyethyl, 3-methoxypropyl, 1-methyl-2-methoxyethyl, 1-(2-methoxyethyl)-3-methoxypropyl, and 1-(2-methoxyethyl)-3 -methoxypropyl.
[0030] "Alkoxyalkoxy" means a group of the formula -O-R-R' wherein R is alkylene and R' is alkoxy as defined herein.
[0031] "Alkylcarbonyl" means a moiety of the formula -C(O)-R, wherein R is alkyl as defined herein.
[0032] "Alkoxycarbonyl" means a group of the formula -C(O)-R wherein R is alkoxy as defined herein.
[0033] "Alkylcarbonylalkyl" means a group of the formula -R-C(O)-R wherein R is alkylene and R' is alkyl as defined herein.
[0034] "Alkoxycarbonylalkyl" means a group of the formula -R-C(O)-R wherein R is alkylene and R' is alkoxy as defined herein.
[0035] "Alkoxycarbonylalkoxy" means a group of the formula -O-R-C(O)-R wherein R is alkylene and R' is alkoxy as defined herein.
[0036] "Hydroxycarbonylalkoxy" means a group of the formula -O-R-C(O)-OH wherein R is alkylene as defined herein.
[0037] "Alkylaminocarbonylalkoxy" means a group of the formula - O-R-C(O)-NHR wherein R is alkylene and R' is alkyl as defined herein.
[0038] "Dialkylaminocarbonylalkoxy" means a group of the formula -O-R-C(O)-NR'R" wherein R is alkylene and R' and R" are alkyl as defined herein.
[0039] "Alkylaminoalkoxy" means a group of the formula -O-R-NHR wherein R is alkylene and R' is alkyl as defined herein.
[0040] "Dialkylaminoalkoxy" means a group of the formula -O-R-NR'R" wherein R is alkylene and R' and R" are alkyl as defined herein.
[0041] "Alkylsulfonyl" means a moiety of the formula -SO 2 -R, where R is alkyl as defined herein.
[0042] "Alkylsulfonylalkyl means a moiety of the formula -R'-SO2-R'' where R is alkylene and R'' is alkyl as defined herein.
[0043] "Alkylsulfonylalkoxy" means a group of the formula -O-R-SO 2 -R' wherein R is alkylene and R' is alkyl as defined herein.
[0044] "Amino" means a moiety of the formula -NRR' wherein 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).
[0045] "Aminocarbonyl" means a group of the formula -C(O)-R wherein R is amino as defined herein.
[0046] "Alkoxyamino" means a moiety of the formula -NR-OR' wherein R is hydrogen or alkyl and R' is alkyl as defined herein.
[0047] "Alkylsulfanyl" means a moiety of the formula -SR wherein R is alkyl as defined herein.
"Aminoalkyl" means a group -R-R' wherein R' is amino and R is alkylene as defined herein. "Aminoalkyl" includes aminomethyl, aminoethyl, 1-aminopropyl, 2-aminopropyl, and the like. The amino portion of "aminoalkyl" may be substituted one or two 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" means a group -OR-R' where R' is amino and R is alkylene as defined herein.
[0050] "Alkylsulfonylamido" means a moiety of the formula - NR'SO2-R wherein R is alkyl and R' is hydrogen or alkyl.
[0051] "Aminocarbonyloxyalkyl" or "carbamylalkyl" means a group of the formula -R-O-C(O)-NR'R" wherein R is alkylene and R, R" each is independently hydrogen or alkyl as defined herein.
[0052] "Alkynylalkoxy" means a group of the formula -O-R-R' wherein R is alkylene and R' is alkynyl as defined herein.
[0053] "Aryl" means a monovalent cyclic aromatic hydrocarbon moiety consisting of a mono-, bi- or tricyclic aromatic ring. The aryl group 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, diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzodioxylyl, benzopyranyl , benzoxazinyl, benzoxazinonyl, benzopiperadinyl, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, and the like, including partially hydrogenated derivatives thereof, each optionally substituted.
[0054] "Arylalkyl" and "Aralkyl", which may be used interchangeably, mean a radical -RaRb where Ra is an alkylene group and Rb is an aryl group as defined herein; for example, phenylalkyls such as benzyl, phenylethyl, 3-(3-chlorophenyl)-2-methylpentyl, and the like are examples of arylalkyl.
[0055] "Arylsulfonyl" means a group of the formula -SO 2 -R where R is aryl as defined herein.
[0056] "Aryloxy" means a group of the formula -O-R where R is aryl as defined herein.
[0057] "Aralkyloxy" means a group of the formula -O-R-R" wherein R is alkylene and R' is aryl as defined herein.
[0058] "Carboxy" or "hydroxycarbonyl" which may be used interchangeably means a group of the formula -C(O)-OH.
[0059] "Cyanoalkyl" means a moiety of the formula -R'-R" where R' is alkylene as defined herein and R" is cyano or nitrile.
[0060] "Cycloalkyl" means a monovalent saturated carbocyclic moiety consisting of mono or bicyclic rings. Particular cycloalkyl is unsubstituted or substituted with alkyl. Cycloalkyl may optionally be substituted with one or more substituents, each substituent independently being hydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, or dialkylamino, unless otherwise specifically indicated. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, including partially unsaturated (cycloalkenyl) derivatives thereof.
[0061] "Cycloalkylalkyl" means a moiety of the formula -R'-R" where R' is alkylene and R" is cycloalkyl as defined herein.
[0062] "Cycloalkylalkoxy" means a group of the formula -O-R-R' wherein R is alkylene and R' is cycloalkyl as defined herein.
[0063] "Heteroalkyl" means an alkyl radical as defined herein in which one, two, or three hydrogen atoms have been independently replaced with a substituent selected from the group consisting of -ORa, -NRbRc, and -S(O)nRd ( where n is an integer from 0 to 2), with the understanding that the point of attachment of the heteroalkyl radical is by a carbon atom, where Ra is hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; Rb and Rc are independently of one another hydrogen, acyl, alkyl, cycloalkyl or cycloalkylalkyl; and when n is 0, Rd is hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl, and when n is 1 or 2, Rd is alkyl, cycloalkyl, cycloalkylalkyl, amino, acylamino, monoalkylamino, or dialkylamino. Representative examples include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl, 1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl, 2-hydroxy-1-methylpropyl, 2-aminoethyl, 3-aminopropyl, 2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl, aminosulfonylpropyl, methylaminosulfonylmethyl, methylaminosulfonylethyl, methylaminosulfonylpropyl, and the like.
[0064] "Heteroaryl" means a monocyclic or bicyclic radical 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 are C, with the understanding that the point of attachment of the heteroaryl radical will be on an aromatic ring. The heteroaryl ring may be optionally substituted as defined herein. Examples of heteroaryl moieties include, but are not limited to, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl, isoquinolinyl , benzofuryl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbapinyl, dialyl, acriylinyl optionally substituted, and the like, including partially hydrogenated derivatives thereof, each optionally substituted.
[0065] "Heteroarylalkyl" or "heteroaralkyl" means a group of the formula -R-R' wherein R is alkylene and R' is heteroaryl as defined herein.
[0066] "Heteroarylsulfonyl" means a group of the formula -SO 2 -R where R is heteroaryl as defined herein.
[0067] "Heteroaryloxy" means a group of the formula -O-R wherein R is heteroaryl as defined herein.
[0068] "Heteroaralkyloxy" means a group of the formula -O-R-R" wherein R is alkylene and R' is heteroaryl as defined herein.
[0069] The terms "halo", "halogen" and "halide", which may be used interchangeably, refer to a fluorine, chlorine, bromine or iodine substituent.
[0070] "Haloalkyl" means alkyl as defined herein in which one or more hydrogens have been replaced with the same or different halogen. Exemplary haloalkyls include -CH2Cl, -CH2CF3, -CH2CCl3, perfluoroalkyl (e.g., -CF3), and the like.
[0071] "Haloalkoxy" means a moiety of the formula -OR, wherein R is a haloalkyl moiety as defined herein. An exemplary haloalkoxy is difluoromethoxy.
[0072] "Heterocycloamino" means a saturated ring in which at least one ring atom is N, NH or N-alkyl and the remaining ring atoms form an alkylene group.
[0073] "Heterocyclyl" means a monovalent saturated moiety, consisting of one to three rings, incorporating one, two, or three or four heteroatoms (chosen 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, piperidinyl, piperazinyl, homopiperazinyl, azepinyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyridinyl, pyridazinyl, pyrimidinyl, oxazolidinyl, isoxazolidinyl, morphoquinolinyl, thiazolidinyl, isothiazolidinyl, quinuclilinyl, quinuclidinyl , isoquinolinyl, benzimidazolyl, thiadiazolylidinyl, benzothiazolidinyl, benzoazolylidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfone, dihydroquinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, optionally substituted tetrahydrisoquinolinyl , and the like.
[0074] "Heterocyclylalkyl" means a moiety of the formula -R-R' wherein R is alkylene and R' is heterocyclyl as defined herein.
[0075] "Heterocyclyloxy" means a moiety of the formula -OR where R is heterocyclyl as defined herein.
[0076] "Heterocyclylalkoxy" means a moiety of the formula -OR-R' wherein R is alkylene and R' is heterocyclyl as defined herein.
[0077] "Hydroxyalkoxy" means a moiety of the formula -OR wherein R is hydroxyalkyl as defined herein.
[0078] "Hydroxyalkylamino" means a moiety of the formula -NR-R' wherein R is hydrogen or alkyl and R' is hydroxyalkyl as defined herein.
[0079] "Hydroxyalkylaminoalkyl" means a moiety of the formula -R-NR'-R" wherein R is alkylene, R' is hydrogen or alkyl, and R" is hydroxyalkyl as defined herein.
[0080] "Hydroxycarbonylalkyl" or "carboxyalkyl" means a group of the formula -R-(CO)-OH as where R is alkylene defined herein.
[0081] "Hydroxycarbonylalkoxy" means a group of the formula -O-R-C(O)-OH wherein R is alkylene as defined herein.
"Hydroxyalkyloxycarbonylalkyl" or "hydroxyalkoxycarbonylalkyl" means a group of the formula -R-C(O)-O-R-OH wherein each R is alkylene and may be the same or different.
[0083] "Hydroxyalkyl" means an alkyl moiety as defined herein substituted with one or more, for example one, two or three hydroxy groups, provided that the same carbon atom does not carry more than one hydroxy group. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3- dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl.
[0084] "Hydroxycycloalkyl" means a cycloalkyl moiety as defined herein wherein one, two or three hydrogen atoms on the cycloalkyl radical have been replaced with a hydroxy substituent. Representative examples include, but are not limited to, 2-, 3-, or 4-hydroxycyclohexyl, and the like.
[0085] "Alkoxy hydroxyalkyl" and "hydroxy alkoxyalkyl", which may be used interchangeably, mean an alkyl as defined herein which is substituted at least once with hydroxy and at least once with alkoxy. "Alkoxy hydroxyalkyl" and "hydroxy alkoxyalkyl" thus encompass, for example, 2-hydroxy-3-methoxy-propan-1-yl, and the like.
[0086] "Urea" or "Ureido" means a group of the formula -NR'-C(O)-NR''R"' wherein R', R'' and R"' are each independently hydrogen or alkyl.
[0087] "Carbamate" means a group of the formula -O-C(O)-NR'R" wherein R' and R'' are each independently hydrogen or alkyl.
[0088] "Carboxy" means a group of the formula -O-C(O)-OH.
[0089] "Sulfonamido" means a group of the formula -SO2-NR'R" wherein R', R'' and R"' are each independently hydrogen or alkyl.
[0090] "Optionally substituted", when used in association with "aryl", phenyl", "heteroaryl", "cycloalkyl" or "heterocyclyl", means an aryl, phenyl, heteroaryl, cycloalkyl or heterocyclyl that is optionally substituted independently with a to four substituents, for example one or two substituents selected from alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, hydroxyalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino, mono-alkylamino, dialkylamino, haloalkyl, haloalkoxy , heteroalkyl, -COR, -SO2R (where R is hydrogen, alkyl, phenyl or phenylalkyl), -(CR'R")n-COOR (where n is an integer from 0 to 5, R' and R" are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl, or phenylalkyl), or -(CR'R")n-CONRaRb (where n is an integer from 0 to 5, R' and R" are independently hydrogen or alkyl, and Ra and Rb are independently of each other hydrogen, alkyl, cycloalkyl phenyl, cycloalkylalkyl, phenyl or phenylalkyl). Certain particular optional substituents for "aryl", "phenyl", "heteroaryl", "cycloalkyl" or "heterocyclyl" include alkyl, halo, haloalkyl, alkoxy, cyano, amino and alkylsulfonyl. In one embodiment, substituents are methyl, fluorine, chlorine, trifluoromethyl, methoxy, amino and methanesulfonyl.
[0091] "Leaving group" means the group having the meaning conventionally associated with it in synthetic organic chemistry, that is, an atom or group leaving under substitution reaction conditions. Examples of leaving groups include, but are not limited to, halogen, alkane- or arylenesulfonyloxy, such as optionally substituted methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy, dialophosphinoyloxy, benzyloxy, isopropyloxy, acyloxy, and the like. .
[0092] "Modulator" means a molecule that interacts with a target. Interactions include, but are not limited to, agonist, antagonist, and the like, as defined herein.
[0093] "Optional" or "optionally" means that the event or circumstance subsequently described may, but not necessarily, occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
[0094] "Disease" and "Disease state" means any disease, condition, symptom, disorder or indication.
[0095] "Inert organic solvent" or "inert solvent" means that the solvent is inert under the conditions of the reaction which is described in conjunction therewith, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, chloroform, methylene chloride or dichloromethane, dichloroethane, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine, and the like. Unless otherwise specified, solvents used in the reactions of the present invention are inert solvents.
[0096] "Pharmaceutically acceptable" means one that is useful in the preparation of a pharmaceutical composition that is generally safe, non-toxic, neither biologically nor otherwise undesirable and includes one that is acceptable for veterinary as well as human pharmaceutical use.
"Pharmaceutically acceptable salts" of a compound means salts which are pharmaceutically acceptable, as defined herein, and which possess the desired pharmacological activity of the parent compound. Refers to salts that are suitable for use in contact with the tissues of humans and animals. Examples of suitable salts with inorganic and organic acids are, but are not limited to, acetic acid, citric acid, formic acid, fumaric acid, hydrochloric acid, lactic acid, maleic acid, malic acid, methanesulfonic acid, nitric acid, phosphoric acid. , p-toluenesulfonic acid, succinic acid, sulfuric acid, sulfuric acid, tartaric acid, trifluoroacetic acid, and the like. The terms "pharmaceutically acceptable carrier" and "pharmaceutically acceptable auxiliary substance" refer to carriers and auxiliary substances such as diluents or excipients that are compatible with the other ingredients of the formulation. Compounds of formula I can form pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to those salts which maintain the biological efficacy and properties of free bases or free acids which are not biologically or otherwise undesirable. In particular, pharmaceutically acceptable salts of compounds of formula I are acid addition salts with physiologically compatible mineral acids, such as hydrochloric acid, sulfuric acid, sulfurous acid or phosphoric acid; or with organic acids such as methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxylic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, malonic acid, tartaric acid, benzoic acid, cinnamic acid, mandelic acid, succinic acid or salicylic acid. Furthermore, pharmaceutically acceptable salts can be prepared from the addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, magnesium, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines which include naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polymine, and the like. The compound of formula I may likewise be present in the form of zwitterions. Particular pharmaceutically acceptable salts of compounds of formula I are acid addition salts such as the hydrochloride salts, the formate salts or the trifluoroacetate salts. Specific are formate salts (formic acid salts).
[0098] The corresponding pharmaceutically acceptable salts with acids can be obtained by standard methods known to the person skilled in the art, for example, by dissolving the compound of formula I in a suitable solvent such as, for example, dioxane or THF and adding an appropriate amount of the corresponding acid. The products can usually be isolated by filtration or chromatography. Conversion of a compound of formula I into a pharmaceutically acceptable salt with a base can be accomplished by treating such a compound with such a base. A possible method for forming such a salt is, for example, by adding 1/n equivalents of a basic salt such as, for example, a basic salt such as, for example, M(OH)n, where M = metal or ammonium cation en = number of hydroxide anions, to a solution of the compound in a suitable solvent (e.g. ethanol, ethanol-water mixture, tetrahydrofuran-water mixture) and to remove the solvent by evaporation or lyophilization . Particular salts are hydrochloride, formate and trifluoroacetate.
[0099] As their preparation is not described in the examples, the compounds of formula I as well as all intermediate products can be prepared according to the analogous methods or according to the methods mentioned herein. Starting materials are commercially available, known in the art or can be prepared by methods known in the art or in analogy thereto.
[00100] It will be appreciated that compounds of formula I in this invention may be derivatized at functional groups to provide derivatives which are capable of further conversion to the parent compound in vivo.
[00101] The term "near maximal inhibitory concentration" (IC50) denotes the concentration of a particular compound required to obtain 50% inhibition of a biological process in vitro. IC50 values can be converted logarithmically to pIC50 values (-log IC50) where higher values indicate exponentially greater power. The IC50 value is not an absolute value, but depends on experimental conditions, for example, the concentrations used. The IC50 value can be converted to an absolute inhibition constant (Ki) using the Cheng-Prusoff equation (Biochem. Pharmacol. (1973) 22:3099). The term "inhibition constant" (Ki) denotes the absolute binding affinity of a particular inhibitor to a receptor. It is measured using competition binding assays and is equal to the concentration where the particular inhibitor would occupy 50% of the receptors if no competing ligand (eg, a radioligand) were present. Ki values can be converted logarithmically to pKi values (-log Ki), where higher values indicate exponentially greater power.
[00102] The term "as defined herein" and "as described herein" when referring to a variable incorporates by reference the broad definition of the variable as well as preferred, more preferred, and even more preferred definitions, if any.
[00103] It should be understood that all references to pharmaceutically acceptable salts include the solvent addition forms (solvates) or crystalline forms (polymorphs) as defined herein, of the same acid addition salt.
[00104] "Protecting group" or "protecting group" means the group that selectively blocks a reactive site on a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Certain processes of this 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 the nitrogen atom against undesirable reactions during synthetic procedures. Exemplary nitrogen protecting groups include, but are not limited to, trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl (carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and the like. The artisan in the art will know how to choose a group in terms of ease of removal and ability to withstand the following reactions.
[00105] "Solvates" means the forms of solvent additions that contain stoichiometric or non-stoichiometric amounts of the solvent. Some compounds have a tendency to capture a fixed molar ratio of solvent molecules in the crystalline solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by combining one or more molecules of water with one of the substances in which water maintains its molecular state as H2O, such combination being able to form one or more hydrates.
[00106] "Parkinson's Disease" means a degenerative disorder of the central nervous system that impairs motor skills, speech, and/or cognitive function. Symptoms of Parkinson's disease can include, for example, muscle stiffness, tremor, slowness of physical movement (bradykinesia) and loss of physical movement (akinesia).
[00107] "Lewie corpuscle disease (Lewy)" also referred to as "Lewie corpuscle dementia", "diffuse Lewie corpuscle disease", "cortical Lewie corpuscle disease", means a neurogenerative disorder characterized anatomically by the presence of Lewie bodies in the brain.
[00108] "Individual" means mammals and non-mammals. Mammals means any member of the mammalia class including, but not limited to, humans; non-human primates such as chimpanzees and other apes and ape species; farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, and the like. The term "individual" does not denote a particular age or sex.
"Therapeutically effective amount" means an amount of a compound which, when administered to a subject to treat a disease state, is sufficient to effect such treatment for the disease state. The "therapeutically effective amount" will vary depending upon the compound, disease state being treated, the severity or disease treated, the age and relative health of the subject, the routine and manner of administration, the judgment of the attending physician or veterinarian, and other factors.
[00110] The terms "those defined above" and "those defined here" when referring to a variable incorporate by reference the broad definition of the variable as well as the particular definitions, if any.
[00111] "Treating" or "treatment" of a disease state includes, inter alia, inhibiting the disease state, i.e., halting the development of the disease state or its clinical symptoms, and/or alleviating the disease state, that is, to cause temporary or permanent regression of the disease state or its clinical symptoms.
[00112] The terms "treating", "contacting" and "reacting" when referring to a chemical reaction means adding or mixing two or more reactants under appropriate conditions to produce the indicated and/or desired product. It should be appreciated that the reaction that produces the indicated and/or desired product may not necessarily be the direct result of the combination of two reactants that were added initially, i.e. there may be one or more intermediates that are produced in the mixture that ultimately leads to the formation of the indicated and/or desired product. Nomenclature and Structures
[00113] In general, the nomenclature used in this Application is based on AUTONOM® v,4.0, a Beilstein Institute computerized system for generating IUPAC systematic nomenclature. Chemical structures shown here were prepared using ISIS® version 2.2. Any open valence that appears on a carbon, oxygen, sulfur, or nitrogen atom in the structures indicates the presence of a hydrogen atom unless otherwise indicated. Where a nitrogen-containing heteroaryl ring is shown with an open valence on a nitrogen atom, and variables such as Ra, Rb or Rc are shown on the heteroaryl ring, such variables may be bonded or joined to the nitrogen of open valence. Where one or more chiral centers exist in a structure, however, no specific stereochemistry is shown for the chiral centers, both enantiomers associated with each such chiral center are covered by the structure. Where a structure shown here may 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 naturally occurring isotopes of such atoms. Thus, for example, the hydrogen atoms depicted herein are intended to include deuterium and tritium, and the carbon atoms are intended to include isotopes of C13 and C14.
[00114] All patents and publications identified herein are hereby incorporated by reference in their entirety. Compounds of the Invention
[00115] The invention provides compounds of formula I:

[00116] or pharmaceutically acceptable salts thereof,
[00117] where:
[00118] X is: -NRa-; or -O- where Ra is hydrogen or C1-6alkyl;
[00119] R1 is: C1-6alkyl; C2-6alkenyl; C2-6alkynyl; halo-C1-6alkyl; C1-6alkoxy-C1-6alkyl; hydroxy-C1-6alkyl; amino-C1-6alkyl; C1-6alkylsulfonyl-C1-6alkyl; C3-6cycloalkyl optionally substituted one or more times with C1-6alkyl; C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted one or more times with C1-6alkyl; heterocyclyl optionally substituted one or more times with R7; or heterocyclyl-C1-6alkyl optionally substituted one or more times with R7;
[00120] or X and R1 together form C1-6alkyl; C1-6alkoxy-C1-6alkyl; C3-6cycloalkyl optionally substituted one or more times with R6; or C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted one or more times with R6;
[00121] or R1 and Ra together with the atoms to which they are attached may form a three to six membered heterocyclic ring optionally substituted one or more times with R7;
[00122] R2 is: C1-6alkyl; halo; C1-6alkoxy; cyan; C2-6alkynyl; C2-6alkenyl; halo-C1-6alkyl; halo-C1-6alkoxy; C3-6cycloalkyl optionally substituted one or more times with R6; C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted one or more times with R6; -ORb wherein Rb is C1-6alkyl, C3-6cycloalkyl optionally substituted one or more times with R6, or C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted one or more times with R6; or -C(O)-Rc wherein Rc is C1-6alkyl, C1-6alkoxy, amino, or heterocyclyl optionally substituted one or more times with R7;
[00123] R3 is: hydrogen; C1-6alkyl; halo-C1-6alkyl; C2-6alkenyl; C2-6alkynyl; hydroxy-C1-6alkyl; C1-6alkoxy-C1-6alkyl; cyano-C1-6alkyl; C1-6alkylsulfonyl; C1-6alkylsulfonylC1-6alkyl; amino-C1-6alkyl; C3-6cycloalkyl optionally substituted one or more times with R6; C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted one or more times with R6; C3-6cycloalkylsulfonyl wherein the C3-6cycloalkyl moiety is optionally substituted one or more times with R6; heterocyclyl optionally substituted one or more times with R7; heterocyclyl-C1-6alkyl wherein the heterocyclyl moiety is optionally substituted one or more times with R7; aryl optionally substituted one or more times with R8; aryl-C1-6alkyl wherein the aryl moiety is optionally substituted one or more times with R8; heteroaryl optionally substituted one or more times with R8; heteroaryl-C1-6alkyl wherein the heteroaryl moiety is optionally substituted one or more times with R8; or -Y-C(O)-Rd;
[00124] Y is C2-6alkylene or a bond;
[00125] Rd is C1-6alkyl, C1-6alkoxy, amino, C1-6alkyl-amino, di-C1-6alkyl-amino, halo-C1-6alkyl-amino, dihalo-C1-6alkyl-amino, halo -C1-6alkyl, hydroxy-C1-6alkyl, hydroxy, C1-6alkoxy-C1-6alkyl, cyano-C1-6alkyl, C1-6alkylsulfonylC1-6alkyl, amino-C1-6alkyl, C3-6cycloalkyl optionally substituted one or more times with R6, C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted one or more times with R6; heterocyclyl optionally substituted one or more times with R7, or heterocyclyl-C1-6alkyl wherein the heterocyclyl moiety is optionally substituted one or more times with R7;
[00126] R4 is: hydrogen; C1-6alkyl; halo; cyan; halo-C1-6alkyl; C2-6alkenyl; C2-6alkynyl; C1-6alkoxy; C1-6alkoxy-C1-6alkyl; hydroxy-C1-6alkyl; C3-6cycloalkyl optionally substituted one or more times with R6; C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted one or more times with R6; or -Y-C(O)-Rd;
[00127] R5 is: hydrogen; or C1-6alkyl;
[00128] each R6 is independently: C1-6alkyl; halo-C1-6alkyl; C1-6alkoxy; oxo; cyan; halo; or Y-C(O)-Rd;
[00129] each R7 is independently: C1-6alkyl; halo-C1-6alkyl; halo; oxo; C1-6alkoxy; C1-6alkylsulfonyl; C1-6alkoxy-C1-6alkyl; cyan; -Y-C(O)-Rd; heterocyclyl; heterocyclyl-C1-6alkyl; C3-6cycloalkyl; C3-6cycloalkyl-C1-6alkyl; or C3-6cycloalkylsulfonyl; and
[00130] each R8 is independently: oxo; C1-6alkyl; halo-C1-6alkyl; halo; C1-6alkylsulfonyl; C1-6alkoxy; C1-6alkoxy-C1-6alkyl; cyan; heteroeryclyl; heterocyclyl-C1-6alkyl; -Y-C(O)-Rd; C3-6cycloalkyl, C3-6cycloalkyl-C1-6alkyl, or C3-6cycloalkylsulfonyl.
[00131] In certain embodiments, the invention provides compounds of formula II:

[00132] or pharmaceutically acceptable salts thereof,
[00133] where:
[00134] X is: -NRa-; or -O- where Ra is hydrogen or C1-6alkyl;
[00135] R1 is: C1-6alkyl; C2-6alkenyl; C2-6alkynyl; halo-C1-6alkyl; C1-6alkoxy-C1-6alkyl; hydroxy-C1-6alkyl; amino-C1-6alkyl; C1-6alkylsulfonyl-C1-6alkyl; C3-6cycloalkyl optionally substituted with C1-6alkyl; C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted with C1-6alkyl; heterocyclyl; or heterocyclyl-C1-6alkyl;
[00136] or X and R1 together form C1-6alkyl; C3-6cycloalkyl optionally substituted with C1-6alkyl; or C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted with C1-6alkyl;
[00137] or R1 and Ra together with the atoms to which they are attached can form a three to six membered heterocyclic ring.
[00138] R2 is: C1-6alkyl; halo; C1-6alkoxy; cyan; C2-6alkynyl; C2-6alkenyl; halo-C1-6alkyl; halo-C1-6alkoxy; C3-6cycloalkyl optionally substituted with C1-6alkyl; C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted with C1-6alkyl; -ORb wherein Rb is C1-6alkyl, C3-6cycloalkyl optionally substituted with C1-6alkyl, or C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted with C1-6alkyl; or -C(O)-Rc wherein Rc is C1-6alkyl, C1-6alkoxy, amino, or heterocyclyl;
[00139] R3 is: hydrogen; C1-6alkyl; halo-C1-6alkyl; C2-6alkenyl; C2-6alkynyl; hydroxy-C1-6alkyl; C1-6alkoxy-C1-6alkyl; cyano-C1-6alkyl; C1-6alkylsulfonyl; C1-6alkylsulfonylalkyl; amino-C1-6alkyl; C3-6cycloalkyl optionally substituted with C1-6alkyl; C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted with C1-6alkyl; heterocyclyl; heterocyclyl-C1-6alkyl; aril; heteroaryl; or -C(O)-Rc wherein Rc is C1-6alkyl, C1-6alkoxy, amino, or heterocyclyl;
[00140] R4 is: hydrogen; C1-6alkyl; halo; cyan; halo-C1-6alkyl; C2-6alkenyl; C2-6alkynyl; C1-6alkoxy-C1-6alkyl; hydroxy-C1-6alkyl; C3-6cycloalkyl optionally substituted with C1-6alkyl; C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted with C1-6alkyl; or -C(O)-Rc wherein Rc is C1-6alkyl, C1-6alkoxy, amino, or heterocyclyl; and
[00141] R5 is: hydrogen; or C1-6alkyl.
[00142] In certain embodiments of formula I or formula II, X is -NRa- or -O-.
[00143] In certain embodiments of formula I or formula II, X is -NRa.
[00144] In certain embodiments of formula I or formula II, X is -O-.
[00145] In certain embodiments of formula I or formula II, X is -NH- or -O-.
[00146] In certain embodiments of formula I or formula II, X is -NH -.
[00147] In certain embodiments of formula I or formula II, X is -O-.
[00148] In certain embodiments of formula I or formula II, Ra is hydrogen.
[00149] In certain embodiments of formula I or formula II, Ra is C1-6alkyl.
[00150] In certain embodiments of formula I or formula II, R1 is: C1-6alkyl; C2-6alkenyl; C2-6alkynyl; halo-C1-6alkyl; C1-6alkoxy-C1-6alkyl; hydroxy-C1-6alkyl; amino-C1-6alkyl; C1-6alkylsulfonyl-C1-6alkyl; C3-6cycloalkyl optionally substituted with C1-6alkyl; C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted with C1-6alkyl; heterocyclyl; or heterocyclyl-C1-6alkyl.
[00151] In certain embodiments of formula I or formula II, R1 is: C1-6alkyl; halo-C1-6alkyl; C1-6alkoxy-C1-6alkyl; amino-C1-6alkyl; C1-6alkylsulfonyl-C1-6alkyl; C3-6cycloalkyl; or C3-6cycloalkyl-C1-6alkyl.
[00152] In certain embodiments of formula I or formula II, R1 is: C1-6alkyl; C3-6cycloalkyl optionally substituted with C1-6alkyl; or C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted with C1-6alkyl.
[00153] In certain embodiments of formula I or formula II, R1 is: C1-6alkyl; halo-C1-6alkyl; C1-6alkoxy-C1-6alkyl; amino-C1-6alkyl; C1-6alkylsulfonyl-C1-6alkyl; tetrahydrofuranyl; tetrahydrofuranyl-C1-6alkyl; oxetanil; or oxetan-C1-6alkyl.
[00154] In certain embodiments of formula I or formula II, R1 is: C1-6alkyl; halo-C1-6alkyl; C1-6alkoxy-C1-6alkyl; amino-C1-6alkyl; or C1-6alkylsulfonyl-C1-6alkyl.
[00155] In certain embodiments of formula I or formula II, R1 is C1-6alkyl or halo-C1-6alkyl.
[00156] In certain embodiments of formula I or formula II, R1 is C1-6alkyl.
[00157] In certain embodiments of formula I or formula II, R1 is halo-C1-6alkyl.
[00158] In certain embodiments of formula I or formula II, R1 is C1-6alkoxy-C1-6alkyl.
[00159] In certain embodiments of formula I or formula II, R1 is amino-C1-6alkyl.
[00160] In certain embodiments of formula I or formula II, R1 is C1-6alkylsulfonyl-C1-6alkyl.
[00161] In certain embodiments of formula I or formula II, R1 is C3-6cycloalkyl optionally substituted with C1-6alkyl.
[00162] In certain embodiments of formula I or formula II, R1 is C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted with C1-6alkyl.
[00163] In certain embodiments of formula I or formula II, R1 is heterocyclyl or heterocyclyl-C1-6alkyl.
[00164] In embodiments of formula I or formula II wherein R1 is heterocyclyl or heterocyclyl-C1-6alkyl, such heterocyclyl may be piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl or oxetanyl, each optionally replaced as defined here.
[00165] In embodiments of formula I or formula II wherein R 1 is heterocyclyl or heterocyclyl-C 1-6 alkyl, such heterocyclyl may be tetrahydropyranyl, piperidinyl, tetrahydrofuranyl or oxetanyl, each of which is optionally substituted as defined herein.
[00166] In certain embodiments of formula I or formula II, R1 is tetrahydrofuranyl.
[00167] In certain embodiments of formula I or formula II, R1 is tetrahydropyranyl.
[00168] In certain embodiments of formula I or formula II, R 1 is tetrahydrofuranyl-C 1-6 alkyl or oxetanyl.
[00169] In certain embodiments of formula I or formula II, R1 is tetrahydrofuranyl-C1-6alkyl.
[00170] In certain embodiments of formula I or formula II, R1 is oxetanyl.
[00171] In certain embodiments of formula I or formula II, R1 is oxetan-C1-6alkyl.
[00172] In certain embodiments of formula I or formula II, R1 is: methyl; ethyl; n-propyl; isopropyl; isobutyl; 3,3-dimethylpropyl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; cyclopropylmethyl; cyclobutylmethyl; cyclopentylmethyl; cyclopropylethyl; methoxyethyl; oxetanil; tetrahydropyranyl; 2,2-difluoroethyl; or tetrahydrofuranylmethyl.
[00173] In certain embodiments of formula I or formula II, R1 is: methyl; ethyl; n-propyl; isopropyl; isobutyl; 3,3-dimethylpropyl; cyclopentyl; cyclohexyl; cyclopropylmethyl; cyclobutylmethyl; cyclopentylmethyl; cyclopropylethyl; methoxyethyl; oxetanil; tetrahydropyranyl; 2,2-difluoroethyl; or tetrahydrofuranylmethyl.
[00174] In certain embodiments of formula I or formula II, R1 is: methyl; ethyl; n-propyl; isopropyl; isobutyl; 3,3-dimethylpropyl; cyclopentyl; cyclohexyl; cyclopentylmethyl; methoxyethyl; oxetanil; tetrahydropyranyl; or tetrahydrofuranylmethyl.
[00175] In certain embodiments of formula I or formula II, R1 is 2,2-difluoroethyl.
[00176] In certain embodiments of formula I or formula II, R1 is: methyl; ethyl; n-propyl; isopropyl; or isobutyl.
[00177] In certain embodiments of formula I or formula II, R1 is methyl or ethyl.
[00178] In certain embodiments of formula I or formula II, R1 is methyl.
[00179] In certain embodiments of formula I or formula II, R1 is ethyl.
[00180] In certain embodiments of formula I or formula II, R1 is: cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; cyclopropylmethyl; cyclobutylmethyl; cyclopentylmethyl; or cyclopropylethyl.
[00181] In certain embodiments of formula I or formula II, R1 is: cyclopentyl; cyclohexyl; or cyclopentylmethyl.
[00182] In certain embodiments of formula I or formula II, R1 is: cyclopropyl.
[00183] In certain embodiments of formula I or formula II, R1 and Ra together with the atoms to which they are attached may form a three to six membered heterocyclic ring.
[00184] In certain embodiments of formula I or formula II, R1 and Ra together with the atoms to which they are attached may form a three-membered heterocyclic ring.
[00185] In certain embodiments of formula I or formula II, R1 and Ra together with the atoms to which they are attached may form a four-membered heterocyclic ring.
[00186] In certain embodiments of formula I or formula II, R1 and Ra together with the atoms to which they are attached may form a five-membered heterocyclic ring.
[00187] In certain embodiments of formula I or formula II, R1 and Ra together with the atoms to which they are attached may form a six-membered heterocyclic ring.
[00188] In certain embodiments of formula I or formula II, X and R1 together form C1-6alkyl; C3-6cycloalkyl optionally substituted with C1-6alkyl; or C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted with C1-6alkyl.
[00189] In certain embodiments of formula I or formula II, X and R1 together form C1-6alkyl.
[00190] In certain embodiments of formula I or formula II, X and R1 together form C3-6cycloalkyl optionally substituted with C1-6alkyl.
[00191] In certain embodiments of formula I or formula II, X and R1 together form C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted with C1-6alkyl.
[00192] In certain embodiments of formula I or formula II, R2 is: C1-6alkyl; halo; C1-6alkoxy; cyan; C2-6alkynyl; C2-6alkenyl; halo-C1-6alkyl; halo-C1-6alkoxy; C3-6cycloalkyl optionally substituted with C1-6alkyl; C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted with C1-6alkyl; -ORb wherein Rb is C1-6alkyl, C3-6cycloalkyl optionally substituted with C1-6alkyl, or C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted with C1-6alkyl; or - C(O)-Rc.
[00193] In certain embodiments of formula I or formula II, R2 is: halo; C1-6alkoxy; halo-C1-6alkyl; halo-C1-6alkoxy; C3-6cycloalkyl wherein the C3-6cycloalkyl moiety is optionally substituted with C1-6alkyl; C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted with C1-6alkyl; tetrahydrofuranyl; tetrahydrofuranyl-C1-6alkyl; oxetanil; or oxetan-C1-6alkyl.
[00194] In certain embodiments of formula I or formula II, R2 is: halo; C1-6alkoxy; halo-C1-6alkyl; cyan; C2-6alkynyl; C2-6alkenyl; C3-6cycloalkyl; or C3-6cycloalkyl-C1-6alkyl.
[00195] In certain embodiments of formula I or formula II, R2 is: halo; C1-6alkoxy; halo-C1-6alkyl; cyan; C3-6cycloalkyl; or C3-6cycloalkyl-C1-6alkyl.
[00196] In certain embodiments of formula I or formula II, R2 is: halo; C1-6alkoxy; halo-C1-6alkyl; C3-6cycloalkyl; or C3-6cycloalkyl-C1-6alkyl.
[00197] In certain embodiments of formula I or formula II, R2 is: halo; halo-C1-6alkyl or cyano.
[00198] In certain embodiments of formula I or formula II, R2 is: fluorine; bromine; chlorine; iodine; trifluoromethyl; or cyan.
[00199] In certain embodiments of formula I or formula II, R2 is: chloro; trifluoromethyl; or cyan.
[00200] In certain embodiments of formula I or formula II, R2 is: halo; or halo-C1-6alkyl.
[00201] In certain embodiments of formula I or formula II, R2 is C1-6alkyl.
[00202] In certain embodiments of formula I or formula II, R2 is halo.
[00203] In certain embodiments of formula I or formula II, R2 is C1-6alkoxy.
[00204] In certain embodiments of formula I or formula II, R2 is halo-C1-6alkoxy.
[00205] In certain embodiments of formula I or formula II, R2 is halo-C1-6alkyl.
[00206] In certain embodiments of formula I or formula II, R2 is C3-6cycloalkyl.
[00207] In certain embodiments of formula I or formula II, R2 is C3-6cycloalkyl-C1-6alkyl.
[00208] In certain embodiments of formula I or formula II, R2 is tetrahydrofuranyl.
[00209] In certain embodiments of formula I or formula II, R2 is tetrahydrofuranyl-C1-6alkyl.
[00210] In certain embodiments of formula I or formula II, R2 is oxetanyl.
[00211] In certain embodiments of formula I or formula II, R2 is oxetan-C1-6alkyl.
[00212] In certain embodiments of formula I or formula II, R 2 is fluorine, chlorine or bromine.
[00213] In certain embodiments of formula I or formula II, R2 is chloro.
[00214] In certain embodiments of formula I or formula II, R2 is fluorine.
[00215] In certain embodiments of formula I or formula II, R2 is bromo.
[00216] In certain embodiments of formula I or formula II, R2 is iodine.
[00217] In certain embodiments of formula I or formula II, R2 is trifluoromethyl.
[00218] In certain embodiments of formula I or formula II, R2 is methoxy.
[00219] In certain embodiments of formula I or formula II, R2 is cyano.
[00220] In certain embodiments of formula I or formula II, R2 is C2-6alkynyl.
[00221] In certain embodiments of formula I or formula II, R2 is C2-6alkenyl.
[00222] In certain embodiments of formula I or formula II, R2 is -ORb where Rb is C1-6alkyl, C3-6cycloalkyl optionally substituted with C1-6alkyl, or C3-6cycloalkyl-C1-6alkyl wherein the C3- 6cycloalkyl is optionally substituted with C1-6alkyl.
[00223] In certain embodiments of formula I, R2 is -C(O)-Rc where Rc is C1-6alkyl, C1-6alkoxy, amino, or heterocyclyl.
[00224] In certain embodiments of formula I or formula II, R3 is: C1-6alkyl; halo-C1-6alkyl; C2-6alkenyl; C2-6alkynyl; hydroxy-C1-6alkyl; C1-6alkoxy-C1-6alkyl; cyano-C1-6alkyl; C1-6alkylsulfonyl; C1-6alkylsulfonylC1-6alkyl; amino-C1-6alkyl; C3-6cycloalkyl optionally substituted one or more times with R6; C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted one or more times with R6; heterocyclyl optionally substituted one or more times with R7; heterocyclyl-C1-6alkyl wherein the heterocyclyl moiety is optionally substituted one or more times with R7; aryl optionally substituted one or more times with R8; heteroaryl optionally substituted one or more times with R8; or -Y-C(O)-Rd.
[00225] In certain embodiments of formula I or formula II, R3 is: hydrogen; C1-6alkyl; halo-C1-6alkyl; C2-6alkenyl; C2-6alkynyl; hydroxy-C1-6alkyl; C1-6alkoxy-C1-6alkyl; cyano-C1-6alkyl; C1-6alkylsulfonyl; C1-6alkylsulfonylalkyl; amino-C1-6alkyl; C3-6cycloalkyl optionally substituted with C1-6alkyl; C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted with C1-6alkyl; heterocyclyl; heterocyclyl-C1-6alkyl; aril; heteroaryl; or -C(O)-Rc.
[00226] In certain embodiments of formula I or formula II, R3 is: C1-6alkyl; halo-C1-6alkyl; hydroxy-C1-6alkyl; C1-6alkoxy-C1-6alkyl; C3-6cycloalkyl optionally substituted with C1-6alkyl; C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted with C1-6alkyl; heterocyclyl; heterocyclyl-C1-6alkyl; or -C(O)-Rb wherein Rb is C1-6alkyl, C1-6alkoxy, amino, or heterocyclyl.
[00227] In certain embodiments of formula I or formula II, R3 is: C1-6alkyl; hydroxy-C1-6alkyl; C1-6alkoxy-C1-6alkyl; C3-6cycloalkyl optionally substituted with C1-6alkyl; C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted with C1-6alkyl; heterocyclyl; heterocyclyl-C1-6alkyl; or -C(O)-Rc where Rc is C1-6alkyl, C1-6alkoxy, amino, or heterocyclyl.
[00228] In certain embodiments of formula I or formula II, R3 is: C1-6alkyl; hydroxy-C1-6alkyl; C1-6alkoxy-C1-6alkyl; C3-6cycloalkyl optionally substituted one or more times with R6; C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted one or more times with R6; heterocyclyl optionally substituted one or more times with R7; heterocyclyl-C1-6alkyl wherein the heterocyclyl moiety is optionally substituted one or more times with R7; or -C(O)-Rd.
[00229] In certain embodiments of formula I or formula II, R3 is: C1-6alkyl; hydroxy-C1-6alkyl; C1-6alkoxy-C1-6alkyl; heterocyclyl; heterocyclyl-C1-6alkyl; or -C(O)-Rc wherein Rc is C1-6alkyl, C1-6alkoxy, amino, or heterocyclyl.
[00230] In certain embodiments of formula I or formula II, R3 is: C1-6alkyl; hydroxy-C1-6alkyl; C1-6alkoxy-C1-6alkyl; heterocyclyl; or heterocyclyl-C1-6alkyl.
[00231] In certain embodiments of formula I or formula II, R3 is: C1-6alkyl; hydroxy-C1-6alkyl; or C1-6alkoxy-C1-6alkyl.
[00232] In embodiments of formula I or formula II wherein R3 is heterocyclyl or heterocyclyl-C1-6alkyl, such heterocyclyl may be piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl or oxetanyl.
[00233] In embodiments of formula I or formula II wherein R3 is heterocyclyl or heterocyclyl-C1-6alkyl, such heterocyclyl may be piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, pyrrolidinyl, azetidinyl, tetrahydrofuranyl or oxetanyl , each optionally substituted one or more times, or once or twice, with R7 as defined herein.
[00234] In embodiments of formula I or formula II wherein R3 is heterocyclyl or heterocyclyl-C1-6alkyl, such heterocyclyl may be piperidinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl or oxetanyl.
[00235] In embodiments of formula I or formula II wherein R3 is heterocyclyl or heterocyclyl-C1-6alkyl, such heterocyclyl may be piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl or oxetanyl, each optionally substituted one or more times, or once or twice, with R7 as defined herein.
[00236] In certain embodiments of formula I or formula II, R3 is: methyl; ethyl; n-propyl; isopropyl; 2-methoxy-ethyl; oxetan-3-yl; 2-(morpholin-4-yl)-ethyl; 2-hydroxy-2-methyl-propan-1-yl; tetrahydropyran-4-yl; or morpholin-4-yl-carbonyl.
[00237] In certain embodiments of formula I, R3 is: methyl; ethyl; n-propyl; isopropyl; 2-methoxy-ethyl; oxetan-3-yl; 2-(morpholin-4-yl)-ethyl; 2-hydroxy-2-methyl-propan-1-yl; or tetrahydropyran-4-yl.
[00238] In certain embodiments of formula I or formula II, R3 is hydrogen.
[00239] In certain embodiments of formula I or formula II, R3 is C1-6alkyl.
[00240] In certain embodiments of formula I or formula II, R3 is halo-C1-6alkyl.
[00241] In certain embodiments of formula I or formula II, R3 is C2-6alkenyl.
[00242] In certain embodiments of formula I or formula II, R3 is C2-6alkynyl.
[00243] In certain embodiments of formula I or formula II, R3 is hydroxy-C1-6alkyl.
[00244] In certain embodiments of formula I or formula II, R3 is C1-6alkoxy-C1-6alkyl.
[00245] In certain embodiments of formula I or formula II, R3 is C3-6cycloalkyl optionally substituted one or more times with R6.
[00246] In certain embodiments of formula I or formula II, R3 is C3-6cycloalkyl optionally substituted with C1-6alkyl.
[00247] In certain embodiments of formula I or formula II, R3 is C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted one or more times with R6.
[00248] In certain embodiments of formula I or formula II, R3 is C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted with C1-6alkyl.
[00249] In certain embodiments of formula I or formula II, R3 is heterocyclyl optionally substituted one or more times with R7.
[00250] In certain embodiments of formula I or formula II, R3 is heterocyclyl.
[00251] In certain embodiments of formula I or formula II, R3 is heterocyclyl-C1-6alkyl wherein the heterocyclyl moiety is optionally substituted one or more times with R7.
[00252] In certain embodiments of formula I or formula II, R3 is heterocyclyl-C1-6alkyl.
[00253] In certain embodiments of formula I or formula II, R3 is -C(O)-Rc.
[00254] In certain embodiments of formula I or formula II, R3 is cyano-C1-6alkyl.
[00255] In certain embodiments of formula I or formula II, R3 is C1-6alkylsulfonyl.
[00256] In certain embodiments of formula I or formula II, R3 is C1-6alkylsulfonyl-C1-6alkyl.
[00257] In certain embodiments of formula I or formula II, R3 is amino-C1-6alkyl.
[00258] In certain embodiments of formula I or formula II, R3 is aryl optionally substituted one or more times with R8.
[00259] In certain embodiments of formula I or formula II, R3 is aryl.
[00260] In certain embodiments of formula I or formula II, R3 is phenyl optionally substituted one or more times, or once or twice, with R8.
[00261] In certain embodiments of formula I or formula II, R3 is heteroaryl optionally substituted one or more times, or once or twice, with R8.
[00262] In certain embodiments of formula I or formula II, R3 is heteroaryl.
[00263] In certain embodiments of formula I or formula II, R3 is C3-6cycloalkylsulfonyl wherein the C3-6cycloalkyl moiety is optionally substituted one or more times with R6.
[00264] In certain embodiments of formula I or formula II, R3 is: hydrogen; methyl; ethyl; propyl; isopropyl; butyl; cyclopropyl; cyclopropylmethyl; cyclobutyl; methanesulfonyl; ethylsulfonyl; cyclopropylsulfonyl; sec-butylsulfonyl; morpholin-4-yl-ethyl; oxetan-3-yl; 2-methoxyethyl; 2-hydroxy-2-methyl-propyl; 3-hydroxy-2-methyl-propan-2-yl; 2-methoxy-propyl; tetrahydro-2H-pyran-4-yl; tetrahydrofuran-3-yl; 2,6-dimethyltetrahydro-2H-pyran-4-yl; tetrahydro-2H-pyran-3-yl); phenyl; 4-(methylsulfonyl)phenyl); 4-cyano-phenyl; 4-fluoro-phenyl; 4-chloro-phenyl; 3,5-difluorophenyl; 4-(dimethylamino-carbonyl)-phenyl); 4-(cyclopropylsulfonyl)phenyl; 2,2,2-trifluoroethyl; 2-fluoroethyl; difluoromethyl; 2-dimethyl-1,3-dioxan-5-yl; 1-methyl-cyclopropyl-carbonyl; 3-methylpyridin-4-yl; 2-methylpyridin-4-yl; pyridin-2-yl; pyrimidin-2-yl; pyrimidin-5-yl; pyridin-2-ylmethyl; 1-(pyridin-2-yl)ethyl; cyclopropylsulfonyl; 1-cyano-1-methyl-ethyl (also referred to as 2-cyano-propan-2-yl); 2-cyano-ethyl; 1-cyano-ethyl; 2-cyano-2-methyl-propyl; 1-(2,2,2-trifluoroethyl)piperidin-4-yl; 1-(methylsulfonyl)azetidin-3-yl; (3-methyloxetan-3-yl)methyl; (1S,5S)-8-oxabicyclo[3,2,1]octan-3-yl; 1-(oxetan-3-yl)piperidin-4-yl; 1-acetyl-piperidin-4-yl; 1-(cyclopropylcarbonyl)-piperidin-4-yl; 1-methyl-piperidin-4-yl; 1-methyl-2-oxo-piperidin-5-yl; 2-oxo-piperidin-5-yl; 1-(isopropyl-carbonyl)-piperidin-4-yl; 1-(oxetan-3-yl)azetidin-3-yl; 1-(cyclopropyl-carbonyl)-piperidin-4-yl; 2-methoxycyclopentyl; 3-methoxycyclopentyl; 1-methoxy-2-methylpropan-2-yl; tetrahydro-2H-1,1-dioxo-thiopyran-4-yl; 3-fluoro-1-(oxetan-3-yl)piperidin-4-yl; 1-methoxypropan-2-yl; 1-(2,2,2-trifluoroethyl)azetidin-3-yl); 1-(oxetan-3-yl)pyrrolidin-3-yl; 1-isopropylazetidin-3-yl; 3-fluoro-1-methylpiperidin-4-yl; 1-ethyl-3-fluoropiperidin-4-yl; 1-methylpyrrolidin-3-yl; 2-methoxyethyl)piperidin-4-yl); 1-methyl-1-(methylamino-carbonyl)-ethyl; 2-methyl-2-morpholino-propyl; 4,4-difluorocyclohexyl; morpholin-4-yl-carbonyl; dimethylamino-carbonyl-methyl; methylamino-carbonyl-methyl; 1-methyl-1-(dimethylamino-carbonyl)-ethyl; pyrrolidin-1-yl-carbonyl; 1-cyanocyclopropyl; 1-(pyrrolidin-1-yl-carbonyl)-ethyl; 1-(dimethylamino-carbonyl)-ethyl; 1-(methoxycarbonyl)-ethyl; 1-(tert-butylamino-carbonyl)-1-methyl-ethyl; 1-(2,2,2-trifluoroethylamino-carbonyl)-1-methyl-ethyl; 1-(ethylamino-carbonyl)-1-methyl-ethyl; 1-(cyclopropylmethylamino-carbonyl)-1-methyl-ethyl; 1-(ethylamino-carbonyl)-cyclobutyl; 1-(isopropylamino-carbonyl)-1-methyl-ethyl; 1-cyano-cyclobutyl; 2-methoxy-1-methyl-ethyl; 1-methyl-1-(methoxycarbonyl)-ethyl; 2-methoxy-2-methyl-propan-1-yl; 1-(oxetan-3-yl)-pyrrolidin-3-yl; isopropylsulfonyl; butane-2-sulfonyl; 1-(2-fluoroethyl)-piperidin-4-yl; 3-fluoro-1-methyl-piperidin-4-yl; 1-ethyl-3-fluoro-piperidin-4-yl; pyridin-3-ylmethyl; 6-methyl-pyridin-2-ylmethyl; 2-(morpholin-1-yl)-1,1-dimethyl-ethyl; pyrimdin-2-yl-methyl; 3-fluoro-1-(oxetan-3-yl)-piperidin-4-yl; 1-(oxetan-3-yl)-piperidin-3-yl; 1-([1,3]Dioxolan-2-ylmethyl)-piperidin-4-yl; pyridazin-3-ylmethyl; piperidin-3-yl; pyrazin-2-ylmethyl; 2-hydroxy-3-methyl-butan-1-yl; 1-([1,3]Dioxolan-2-ylmethyl)-pyrrolidin-3-yl; pyrimidin-4-ylmethyl; 1-methyl-1H-pyrazol-3-ylmethyl; 1-methyl-1-(4H-[1,2,4]triazol-3-yl)-ethyl; 1-methyl-1-(5-methyl-4H-[1,2,4]triazol-3-yl)-ethyl; 3-fluoro-piperidin-4-yl; 2-hydroxy-cyclopentyl; dimethyl-[1,3]dioxan-5-yl, 2-(5-methyl-1,3,4-oxadiazol-2-yl)propan-2-yl; 2-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl; 2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl; 2-(1-methyl-1H-pyrazol-4-yl)propan-2-yl; 2-(1-methyl-1H-pyrazol-3-yl)propan-2-yl; 2-(1-methyl-1H-pyrazol-5-yl; 2-(4H-1,2,4-triazol-3-yl)propan-2-yl; or 1-methyl-1H-pyrazol-4-yl .
[00265] In certain embodiments of formula I or formula II, R3 is: methyl; ethyl; propyl; isopropyl; butyl; cyclopropyl; cyclopropylmethyl; cyclobutyl; methanesulfonyl; ethylsulfonyl; cyclopropylsulfonyl; sec-butylsulfonyl; morpholin-4-yl-ethyl; oxetan-3-yl; 2-methoxyethyl; 2-hydroxy-2-methyl-propyl; 3-hydroxy-2-methyl-propan-2-yl; 2-methoxy-propyl; tetrahydro-2H-pyran-4-yl; tetrahydrofuran-3-yl; 2,6-dimethyltetrahydro-2H-pyran-4-yl; tetrahydro-2H-pyran-3-yl); phenyl; 4-(methylsulfonyl)phenyl); 4-cyano-phenyl; 4-fluoro-phenyl; 4-chloro-phenyl; 3,5-difluorophenyl; 4-(dimethylamino-carbonyl)-phenyl); 4-(cyclopropylsulfonyl)phenyl; 2,2,2-trifluoroethyl; 2-fluoroethyl; difluoromethyl; 2-dimethyl-1,3-dioxan-5-yl; 1-methyl-cyclopropyl-carbonyl; 3-methylpyridin-4-yl; 2-methylpyridin-4-yl; pyridin-2-yl; pyrimidin-2-yl; pyrimidin-5-yl; pyridin-2-ylmethyl; 1-(pyridin-2-yl)ethyl; cyclopropylsulfonyl; 1-cyano-1-methyl-ethyl (also referred to as 2-cyano-propan-2-yl); 2-cyano-ethyl; 1-cyano-ethyl; 2-cyano-2-methyl-propyl; 1-(2,2,2-trifluoroethyl)piperidin-4-yl; 1-(methylsulfonyl)azetidin-3-yl; (3-methyloxetan-3-yl)methyl; (1S,5S)-8-oxabicyclo[3,2,1]octan-3-yl; 1-(oxetan-3-yl)piperidin-4-yl; 1-acetylpiperidin-4-yl; 1-(cyclopropyl-carbonyl)-piperidin-4-yl; 1-methyl-piperidin-4-yl; 1-methyl-2-oxo-piperidin-5-yl; 2-oxo-piperidin-5-yl; 1-(isopropylcarbonyl)-piperidin-4-yl; 1-(oxetan-3-yl)azetidin-3-yl; 1-(cyclopropylcarbonyl)-piperidin-4-yl; 2-methoxycyclopentyl; 3-methoxycyclopentyl; 1-methoxy-2-methylpropan-2-yl; tetrahydro-2H-1,1-dioxo-thiopyran-4-yl; 3-fluoro-1-(oxetan-3-yl)piperidin-4-yl; 1-methoxypropan-2-yl; 1-(2,2,2-trifluoroethyl)azetidin-3-yl); 1-(oxetan-3-yl)pyrrolidin-3-yl; 1-isopropylazetidin-3-yl; 3-fluoro-1-methylpiperidin-4-yl; 1-ethyl-3-fluoropiperidin-4-yl; 1-methylpyrrolidin-3-yl; 2-methoxyethyl)piperidin-4-yl); 1-methyl-1-(methylamino-carbonyl)-ethyl; 2-methyl-2-morpholino-propyl; 4,4-difluorocyclohexyl; morpholin-4-yl-carbonyl; dimethylaminocarbonylmethyl; methylamino-carbonyl-methyl; 1-methyl-1-(dimethylamino-carbonyl)-ethyl; pyrrolidin-1-yl-carbonyl; 1-cyano-cyclopropyl; 1-(pyrrolidin-1-yl-carbonyl)-ethyl; 1-(dimethylamino-carbonyl)-ethyl; 1-(methoxycarbonyl)-ethyl; 1-(tert-butylamino-carbonyl)-1-methyl-ethyl; 1-(2,2,2-trifluoroethylaminocarbonyl)-1-methyl-ethyl; 1-(ethylamino-carbonyl)-1-methyl-ethyl; 1-(cyclopropylmethylamino-carbonyl)-1-methyl-ethyl; 1-(ethylamino-carbonyl)-cyclobutyl; 1-(isopropylamino-carbonyl)-1-methyl-ethyl; 1-cyano-cyclobutyl; 2-methoxy-1-methyl-ethyl; 1-methyl-1-(methoxycarbonyl)-ethyl; 2-methoxy-2-methyl-propan-1-yl; 1-(oxetan-3-yl)-pyrrolidin-3-yl; isopropylsulfonyl; butane-2-sulfonyl; 1-(2-fluoroethyl)-piperidin-4-yl; 3-fluoro-1-methyl-piperidin-4-yl; 1-ethyl-3-fluoro-piperidin-4-yl; pyridin-3-ylmethyl; 6-methyl-pyridin-2-ylmethyl; 2-(morpholin-1-yl)-1,1,dimethyl-ethyl; pyrimdin-2-yl-methyl; 3-fluoro-1-(oxetan-3-yl)-piperidin-4-yl; 1-(oxetan-3-yl)-piperidin-3-yl; 1-([1,3]Dioxolan-2-ylmethyl)-piperidin-4-yl; pyridazin-3-ylmethyl; piperidin-3-yl; pyrazin-2-ylmethyl; 2-hydroxy-3-methyl-butan-1-yl; 1-([1,3]Dioxolan-2-ylmethyl)-pyrrolidin-3-yl; pyrimidin-4-ylmethyl; 1-methyl-1H-pyrazol-3-ylmethyl; 1-methyl-1-(4H-[1,2,4]triazol-3-yl)-ethyl; 1-methyl-1-(5-methyl-4H-[1,2,4]triazol-3-yl)-ethyl; 3-fluoro-piperidin-4-yl; 2-hydroxy-cyclopentyl; dimethyl-[1,3]dioxan-5-yl; 2-(5-methyl-1,3,4-oxadiazol-2-yl)propan-2-yl; 2-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl; 2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl; 2-(1-methyl-1H-pyrazol-4-yl)propan-2-yl; 2-(1-methyl-1H-pyrazol-3-yl)propan-2-yl; 2-(1-methyl-1H-pyrazol-5-yl; 2-(4H-1,2,4-triazol-3-yl)propan-2-yl; or 1-methyl-1H-pyrazol-4-yl .
[00266] In certain embodiments of formula I or formula II, R3 is: hydrogen; methyl; ethyl; n-propyl; isopropyl; 2-methoxy-ethyl; oxetan-3-yl; 2-hydroxy-2-methyl-propan-1-yl; tetrahydropyran-4-yl; or morpholin-4-yl-carbonyl.
[00267] In certain embodiments of formula I or formula II, R3 is: methyl; ethyl; n-propyl; isopropyl; 2-methoxy-ethyl; oxetan-3-yl; 2-hydroxy-2-methyl-propan-1-yl; or tetrahydropyran-4-yl.
[00268] In certain embodiments of formula I or formula II, R3 is: methyl; ethyl; isopropyl; 2-methoxy-ethyl; oxetan-3-yl; or 2-hydroxy-2-methyl-propan-1-yl.
[00269] In certain embodiments of formula I or formula II, R3 is: methyl; ethyl; isopropyl; 2-methoxy-ethyl; oxetan-3-yl; or 2-hydroxy-2-methyl-propan-1-yl.
[00270] In certain embodiments of formula I or formula II, R3 is: methyl; ethyl; or isopropyl.
[00271] In certain embodiments of formula I or formula II, R3 is hydrogen.
[00272] In certain embodiments of formula I or formula II, R3 is methyl.
[00273] In certain embodiments of formula I or formula II, R3 is ethyl.
[00274] In certain embodiments of formula I or formula II, R3 is n-propyl.
[00275] In certain embodiments of formula I or formula II, R3 is iso-propyl.
[00276] In certain embodiments of formula I or formula II, R3 is 2-methoxy-ethyl.
[00277] In certain embodiments of formula I or formula II, R3 is oxetan-3-yl.
[00278] In certain embodiments of formula I or formula II, R3 is 2-hydroxy-2-methyl-propan-1-yl.
[00279] In certain embodiments of formula I or formula II, R3 is tetrahydropyran-4-yl.
[00280] In certain embodiments of formula I or formula II, R3 is morpholin-4-yl-carbonyl.
[00281] In certain embodiments of formula I or formula II, R3 is butyl.
[00282] In certain embodiments of formula I or formula II, R3 is cyclopropyl.
[00283] In certain embodiments of formula I or formula II, R3 is cyclopropylmethyl.
[00284] In certain embodiments of formula I or formula II, R3 is cyclobutyl.
[00285] In certain embodiments of formula I or formula II, R3 is methanesulfonyl.
[00286] In certain embodiments of formula I or formula II, R3 is ethylsulfonyl.
[00287] In certain embodiments of formula I or formula II, R3 is cyclopropylsulfonyl.
[00288] In certain embodiments of formula I or formula II, R3 is sec-butylsulfonyl.
[00289] In certain embodiments of formula I or formula II, R3 is morpholin-4-yl-ethyl.
[00290] In certain embodiments of formula I or formula II, R3 is 2-hydroxy-2-methyl-propyl.
[00291] In certain embodiments of formula I or formula II, R3 is 3-hydroxy-2-methyl-propan-2-yl.
[00292] In certain embodiments of formula I or formula II, R3 is 2-methoxy-propyl.
[00293] In certain embodiments of formula I or formula II, R3 is tetrahydro-2H-pyran-4-yl.
[00294] In certain embodiments of formula I or formula II, R3 is tetrahydrofuran-3-yl.
[00295] In certain embodiments of formula I or formula II, R3 is 2,6-dimethyltetrahydro-2H-pyran-4-yl.
[00296] In certain embodiments of formula I or formula II, R3 is tetrahydro-2H-pyran-3-yl).
[00297] In certain embodiments of formula I or formula II, R3 is phenyl.
[00298] In certain embodiments of formula I or formula II, R3 is 4-(methylsulfonyl)phenyl).
[00299] In certain embodiments of formula I or formula II, R3 is 4-cyano-phenyl.
[00300] In certain embodiments of formula I or formula II, R3 is 4-fluoro-phenyl.
[00301] In certain embodiments of formula IV, R3 is 4-chloro-phenyl.
[00302] In certain embodiments of formula I or formula II, R3 is 3,5-difluorophenyl.
[00303] In certain embodiments of formula I or formula II, R3 is 4-(dimethylamino-carbonyl)-phenyl).
[00304] In certain embodiments of formula I or formula II, R3 is 4-(cyclopropylsulfonyl)phenyl.
[00305] In certain embodiments of formula I or formula II, R3 is 2,2,2-trifluoroethyl.
[00306] In certain embodiments of formula I or formula II, R3 is 2-fluoroethyl.
[00307] In certain embodiments of formula I or formula II, R3 is difluoromethyl.
[00308] In certain embodiments of formula I or formula II, R3 is 2-dimethyl-1,3-dioxan-5-yl.
[00309] In certain embodiments of formula I or formula II, R3 is 1-methyl-cyclopropyl-carbonyl.
[00310] In certain embodiments of formula I or formula II, R3 is 3-methylpyridin-4-yl.
[00311] In certain embodiments of formula I or formula II, R3 is 2-methylpyridin-4-yl.
[00312] In certain embodiments of formula I or formula II, R3 is pyridin-2-yl.
[00313] In certain embodiments of formula I or formula II, R3 is pyrimidin-2-yl.
[00314] In certain embodiments of formula I or formula II, R3 is pyrimidin-5-yl.
[00315] In certain embodiments of formula I or formula II, R3 is pyridin-2-ylmethyl.
[00316] In certain embodiments of formula I or formula II, R3 is 1-(pyridin-2-yl)ethyl.
[00317] In certain embodiments of formula I or formula II, R3 is cyclopropylsulfonyl.
[00318] In certain embodiments of formula I or formula II, R 3 is 1-cyano-1-methyl-ethyl (also referred to as 2-cyano-propan-2-yl).
[00319] In certain embodiments of formula I or formula II, R3 is 2-cyano-ethyl.
[00320] In certain embodiments of formula I or formula II, R3 is 1-cyano-ethyl.
[00321] In certain embodiments of formula I or formula II, R3 is 2-cyano-2-methyl-propyl.
[00322] In certain embodiments of formula I or formula II, R3 is 1-(2,2,2-trifluoroethyl)piperidin-4-yl.
[00323] In certain embodiments of formula I or formula II, R3 is 1-(methylsulfonyl)azetidin-3-yl.
[00324] In certain embodiments of formula I or formula II, R3 is (3-methyloxetan-3-yl)methyl.
[00325] In certain embodiments of formula I or formula II, R3 is (1S,5S)-8-oxabicyclo[3,2,1]octan-3-yl.
[00326] In certain embodiments of formula I or formula II, R3 is 1-(oxetan-3-yl)piperidin-4-yl.
[00327] In certain embodiments of formula I or formula II, R3 is 1-acetyl-piperidin-4-yl.
[00328] In certain embodiments of formula I or formula II, R3 is 1-(cyclopropyl-carbonyl)-piperidin-4-yl.
[00329] In certain embodiments of formula I or formula II, R3 is 1-methyl-piperidin-4-yl.
[00330] In certain embodiments of formula I or formula II, R3 is 1-methyl-2-oxo-piperidin-5-yl.
[00331] In certain embodiments of formula I or formula II, R3 is 2-oxo-piperidin-5-yl.
[00332] In certain embodiments of formula I or formula II, R3 is 1-(isopropyl-carbonyl)-piperidin-4-yl.
[00333] In certain embodiments of formula I or formula II, R3 is 1-(oxetan-3-yl)azetidin-3-yl.
[00334] In certain embodiments of formula I or formula II, R3 is 1-(cyclopropyl-carbonyl)-piperidin-4-yl.
[00335] In certain embodiments of formula I or formula II, R3 is 2-methoxycyclopentyl.
[00336] In certain embodiments of formula I or formula II, R3 is 3-methoxycyclopentyl.
[00337] In certain embodiments of formula I or formula II, R3 is 1-methoxy-2-methylpropan-2-yl.
[00338] In certain embodiments of formula I or formula II, R3 is tetrahydro-2H-1,1-dioxo-thiopyran-4-yl.
[00339] In certain embodiments of formula I or formula II, R3 is 3-fluoro-1-(oxetan-3-yl)piperidin-4-yl.
[00340] In certain embodiments of formula I or formula II, R3 is 1-methoxypropan-2-yl.
[00341] In certain embodiments of formula I or formula II, R3 is 1-(2,2,2-trifluoroethyl)azetidin-3-yl).
[00342] In certain embodiments of formula I or formula II, R3 is 1-(oxetan-3-yl)pyrrolidin-3-yl.
[00343] In certain embodiments of formula I or formula II, R3 is 1-isopropylazetidin-3-yl.
[00344] In certain embodiments of formula I or formula II, R3 is 3-fluoro-1-methylpiperidin-4-yl.
[00345] In certain embodiments of formula I or formula II, R3 is 1-ethyl-3-fluoropiperidin-4-yl.
[00346] In certain embodiments of formula I or formula II, R3 is 1-methylpyrrolidin-3-yl.
[00347] In certain embodiments of formula I or formula II, R3 is 2-methoxyethyl)piperidin-4-yl).
[00348] In certain embodiments of formula I or formula II, R3 is 1-methyl-1-(methylamino-carbonyl)ethyl.
[00349] In certain embodiments of formula I or formula II, R3 is 2-methyl-2-morpholino-propyl.
[00350] In certain embodiments of formula I or formula II, R3 is 4,4-difluorocyclohexyl.
[00351] In certain embodiments of formula I or formula II, R 3 is dimethylamino-carbonyl-methyl.
[00352] In certain embodiments of formula I or formula II, R3 is methylamino-carbonyl-methyl.
[00353] In certain embodiments of formula I or formula II, R3 is 1-methyl-1-(dimethylamino-carbonyl)-ethyl.
[00354] In certain embodiments of formula I or formula II, R3 is pyrrolidin-1-yl-carbonyl.
[00355] In certain embodiments of cyano-cyclopropyl formula.
[00356] In certain embodiments of formula (pyrrolidin-1-yl-carbonyl)-ethyl.
[00357] In certain embodiments of formula (dimethylamino-carbonyl)-ethyl.
[00358] In certain embodiments of formula (methoxy-carbonyl)-ethyl.
[00359] In certain embodiments of formula (tert-butylamino-carbonyl)-1-methyl-ethyl.
[00360] In certain embodiments of formula (2,2,2-trifluoroethylamino-carbonyl)-1-methyl-ethyl.
[00361] In certain embodiments of formula (ethylamino-carbonyl)-1-methyl-ethyl.
[00362] In certain embodiments of formula (cyclopropylmethylamino-carbonyl)-1-methyl-ethyl.
[00363] In certain embodiments of formula I or formula II, R3 is 1-(ethylamino-carbonyl)-cyclobutyl.
[00364] In certain embodiments of formula I or formula II, R3 is 1-(isopropylamino-carbonyl)-1-methyl-ethyl.
[00365] In certain embodiments of formula I or formula II, R3 is 1-cyano-cyclobutyl.
[00366] In certain embodiments of formula I or formula II, R3 is dimethyl-[1,3]dioxan-5-yl.
[00367] In certain embodiments of formula I or formula II, R3 is 2-methoxy-2-methyl-propan-1-yl.
[00368] In certain embodiments of formula I or formula II, R3 is 2-methoxy-1-methyl-ethyl.
[00369] In certain embodiments of formula I or formula II, R3 is 1-methyl-1-(methoxycarbonyl)-ethyl.
[00370] In certain embodiments of formula I or formula II, R3 is 1-oxetan-3-yl-pyrrolidin-3-yl.
[00371] In certain embodiments of formula I or formula II, R3 is isopropylsulfonyl.
[00372] In certain embodiments of formula I or formula II, R3 is butane-2-sulfonyl.
[00373] In certain embodiments of formula I or formula II, R3 is 1-(2-fluoroethyl)-piperidin-4-yl.
[00374] In certain embodiments of formula I or formula II, R3 is 3-fluoro-1-methyl-piperidin-4-yl.
[00375] In certain embodiments of formula I or formula II, R3 is 1-ethyl-3-fluoro-piperidin-4-yl.
[00376] In certain embodiments of formula I or formula II, R3 is pyridin-3-ylmethyl.
[00377] In certain embodiments of formula I or formula II, R3 is 6-methyl-pyridin-2-ylmethyl.
[00378] In certain embodiments of formula I or formula II, R3 is 2-(morpholin-1-yl)-1,1-dimethyl-ethyl.
[00379] In certain embodiments of formula I or formula II, R3 is pyrimdin-2-yl-methyl.
[00380] In certain embodiments of formula I or formula II, R3 is 3-fluoro-1-(oxetan-3-yl)-piperidin-4-yl.
[00381] In certain embodiments of formula I or formula II, R3 is 1-(oxetan-3-yl)-piperidin-3-yl.
[00382] In certain embodiments of formula I or formula II, R3 is 1-([1,3]Dioxolan-2-ylmethyl)-piperidin-4-yl.
[00383] In certain embodiments of formula I or formula II, R3 is pyridazin-3-ylmethyl.
[00384] In certain embodiments of formula I or formula II, R3 is piperidin-3-yl.
[00385] In certain embodiments of formula I or formula II, R3 is pyrazin-2-ylmethyl.
[00386] In certain embodiments of formula I or formula II, R3 is 2-hydroxy-3-methyl-butan-1-yl.
[00387] In certain embodiments of formula I or formula II, R3 is 1-([1,3]dioxolan-2-ylmethyl)-pyrrolidin-3-yl.
[00388] In certain embodiments of formula I or formula II, R3 is pyrimidin-4-ylmethyl.
[00389] In certain embodiments of formula I or formula II, R3 is 1-methyl-1H-pyrazol-3-ylmethyl.
[00390] In certain embodiments of formula I or formula II, R3 is 1-methyl-1-(5-methyl-4H-[1,2,4]triazol-3-yl)-ethyl.
[00391] In certain embodiments of formula I or formula II, R3 is 1-methyl-1-(4H-[1,2,4]triazol-3-yl)-ethyl.
[00392] In certain embodiments of formula I or formula II, R3 is 3-fluoro-piperidin-4-yl; 2-hydroxy-cyclopentyl.
[00393] In certain embodiments of formula I or formula II, R3 is 2-(5-methyl-1,3,4-oxadiazol-2-yl)propan-2-yl.
[00394] In certain embodiments of formula I or formula II, R3 is 2-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl.
[00395] In certain embodiments of formula I or formula II, R3 is 2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl.
[00396] In certain embodiments of formula I or formula II, R3 is 2-(1-methyl-1H-pyrazol-4-yl)propan-2-yl; 2-(1-methyl-1H-pyrazol-3-yl)propan-2-yl.
[00397] In certain embodiments of formula I or formula II, R3 is 2-(1-methyl-1H-pyrazol-5-yl.
[00398] In certain embodiments of formula I or formula II, R3 is 2-(4H-1,2,4-triazol-3-yl)propan-2-yl.
[00399] In certain embodiments of formula I or formula II, R3 is 1-methyl-1H-pyrazol-4-yl.
[00400] In embodiments of formula I or formula II wherein R3 is aryl, such aryl may be unsubstituted phenyl or phenyl substituted one or more times with R8, or in certain embodiments, once, twice, or three times with a group or groups independently selected from C1-6alkyl, halo, halo-C1-6alkyl, C1-6alkoxy, hydroxy or cyano.
[00401] In embodiments of formula I or formula II wherein R3 is heteroaryl or heteroaryl-C1-6alkyl, such heteroaryl moiety may be pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, isoxazolyl, isothiazolyl , triazolyl, oxadiaolyl, thiadiazolyl or tetrazolyl, each of which is unsubstituted or sometimes substituted with R8, or in certain embodiments sometimes substituted with C1-6alkyl.
[00402] In embodiments of formula I or formula II wherein R3 is heteroaryl or heteroaryl-C1-6alkyl, such heteroaryl moiety may be pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl or oxa-diazolyl each of which is unsubstituted or substituted once or twice with R8, or in certain embodiments substituted once or twice with C1-6alkyl.
[00403] In embodiments of formula I or formula II wherein R3 is heteroaryl or heteroaryl-C1-6alkyl, such heteroaryl moiety may be pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, each of which is not substituted or substituted one or more times with R8.
[00404] In embodiments of formula I or formula II wherein R 3 is heterocyclyl, such heterocyclyl moiety may be piperidinyl, pyrrolidinyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, [1,3]dioxolanyl or tetra- hydrothiopyranyl, each unsubstituted or substituted one or more times with R7.
[00405] In embodiments of formula I or formula II wherein R3 is heterocyclyl-C1-6alkyl, such heterocyclyl moiety may be piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, [ 1,3]dioxolanyl or tetrahydrothiopyranyl, each unsubstituted or substituted one or more times with R7 .
[00406] In certain embodiments of formula I or formula II, R3 is -Y-C(O)-Rd.
[00407] In certain embodiments of formula I or formula II, Y is a bond.
[00408] In certain embodiments of formula I or formula II, Y is C2-6alkylene.
[00409] In certain embodiments of formula I or formula II, Y is iso-propylidine.
[00410] In certain embodiments of formula I or formula II, Y is methylene.
[00411] In certain embodiments of formula I or formula II, Y is ethylene.
[00412] In certain embodiments of formula I C(CH3)2-.
[00413] In certain embodiments of formula I CH2-.
[00414] In certain embodiments of formula I CH(CH3)-.
[00415] In certain embodiments of formula I CH2-C(CH3)2-.
[00416] In certain embodiments of formula I C(CH3)2-CH2-.
[00417] In certain embodiments of formula I or formula II, Rd is C1-6alkyl, C1-6alkoxy, amino, or heterocyclyl.
[00418] In certain embodiments of formula I or formula II, Rd is C1-6alkyl.
[00419] In certain embodiments of formula I or formula II, Rd is C1-6alkoxy.
[00420] In certain embodiments of formula I or formula II, Rd is amino.
[00421] In certain embodiments of formula I or formula II, Rd is halo-C1-6alkyl.
[00422] In certain embodiments of formula I or formula II, Rd is hydroxy-C1-6alkyl.
[00423] In certain embodiments of formula I or formula II, Rd is C1-6alkoxy-C1-6alkyl.
[00424] In certain embodiments of formula I or formula II, Rd is cyano-C1-6alkyl.
[00425] In certain embodiments of formula I or formula II, Rd is C1-6alkylsulfonylC1-6alkyl.
[00426] In certain embodiments of formula I or formula II, Rd is amino-C1-6alkyl.
[00427] In certain embodiments of formula I or formula II, Rd is C3-6cycloalkyl optionally substituted one or more times with R6.
[00428] In certain embodiments of formula I or formula II, Rd is C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted one or more times with R6.
[00429] In certain embodiments of formula I or formula II, Rd is heterocyclyl optionally substituted one or more times with R7.
[00430] In certain embodiments of formula I or formula II, Rd is heterocyclyl-C1-6alkyl wherein the heterocyclyl moiety is optionally substituted one or more times with R7.
[00431] In certain embodiments of formula I or formula II, Rd is 1-methyl-cyclopropyl; methylamino; dimethylamino; pyrrolidin-1-yl; methoxy; cyclopropyl-methyl; ethyl; 2,2,2-trifluoro-ethyl; tert-butyl; or isopropyl.
[00432] In certain embodiments of formula I or formula II, Rd is 1-methyl-cyclopropyl.
[00433] In certain embodiments of formula I or formula II, Rd is methylamino.
[00434] In certain embodiments of formula I or formula II, Rd is dimethylamino.
[00435] In certain embodiments of formula I or formula II, Rd is pyrrolidin-1-yl.
[00436] In certain embodiments of formula I or formula II, Rd is methoxy.
[00437] In certain embodiments of formula I or formula II, Rd is cyclopropyl-methyl.
[00438] In certain embodiments of formula I or formula II, Rd is ethyl.
[00439] In certain embodiments of formula I or formula II, Rd is 2,2,2-trifluoro-ethyl.
[00440] In certain embodiments of formula I or formula II, Rd is tert-butyl.
[00441] In certain embodiments of formula I or formula II, Rd is iso-propyl.
[00442] In embodiments of formula I or formula II where Rd is heterocyclyl or heterocyclyl-C1-6alkyl, such heterocyclyl may be piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, pyrrolidinyl, azetidinyl, tetrahydrofuranyl or oxetanyl , each optionally substituted one or more times, or once or twice, with R7 as defined herein.
[00443] In embodiments of formula I or formula II wherein Rd is heterocyclyl, such heterocyclyl moiety may be piperidinyl, pyrrolidinyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, [1,3]dioxolanyl or tetra- hydrothiopyranyl, each unsubstituted or substituted one or more times with R7.
[00444] In embodiments of formula I or formula II wherein Rd is heterocyclyl-C1-6alkyl, such heterocyclyl moiety may be piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, [ 1,3]dioxolanyl or tetrahydrothiopyranyl, each unsubstituted or substituted one or more times with R7 .
[00445] In certain embodiments of formula I or formula II, R4 is: hydrogen; C1-6alkyl; halo; halo-C1-6alkyl; C1-6alkoxy-C1-6alkyl; hydroxy-C1-6alkyl; C3-6cycloalkyl optionally substituted with C1-6alkyl; C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted with C1-6alkyl; or -C(O)-Rc where Rc is C1-6alkyl, C1-6alkoxy, amino, or heterocyclyl.
[00446] In certain embodiments of formula I or formula II, R4 is: C1-6alkyl; halo; halo-C1-6alkyl; C1-6alkoxy-C1-6alkyl; hydroxy-C1-6alkyl; C3-6cycloalkyl optionally substituted with C1-6alkyl; C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted with C1-6alkyl; or -C(O)-Rc wherein Rc is C1-6alkyl, C1-6alkoxy, amino, or heterocyclyl.
[00447] In certain embodiments of formula I or formula II, R4 is: hydrogen; C1-6alkyl; halo; C3-6cycloalkyl optionally substituted with C1-6alkyl; C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted with C1-6alkyl; or - C(O)-Rc wherein Rc is C1-6alkyl, C1-6alkoxy, amino, or heterocyclyl.
[00448] In certain embodiments of formula I or formula II, R4 is: hydrogen; C1-6alkyl; halo; or C3-6cycloalkyl optionally substituted with C1-6alkyl.
[00449] In certain embodiments of formula I or formula II, R4 is hydrogen or C1-6alkyl.
[00450] In certain embodiments of formula I or formula II, R4 is hydrogen.
[00451] In certain embodiments of formula I or formula II, R4 is C1-6alkyl.
[00452] In certain embodiments of formula I or formula II, R4 is halo.
[00453] In certain embodiments of formula I or formula II, R4 is cyano.
[00454] In certain embodiments of formula I or formula II, R4 is halo-C1-6alkyl.
[00455] In certain embodiments of formula I or formula II, R4 is C1-6alkoxy-C1-6alkyl.
[00456] In certain embodiments of formula I or formula II, R4 is hydroxy-C1-6alkyl.
[00457] In certain embodiments of formula I or formula II, R4 is C3-6cycloalkyl optionally substituted with C1-6alkyl.
[00458] In certain embodiments of formula I or formula II, R4 is hydrogen or methyl.
[00459] In certain embodiments of formula I or formula II, R4 is C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted with C1-6alkyl.
[00460] In certain embodiments of formula I or formula II, R4 is -C(O)-Rc where Rc is C1-6alkyl, C1-6alkoxy, amino, or heterocyclyl.
[00461] In certain embodiments of formula I or formula II, R4 is -C(O)-Rc where Rc is heterocyclyl.
[00462] In embodiments of formula I or formula II where Rc is heterocyclyl, such heterocyclyl may be pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.
[00463] In embodiments of formula I or formula II where Rc is heterocyclyl, such heterocyclyl may be piperidinyl, piperazinyl or morpholinyl.
[00464] In certain embodiments of formula I or formula II, R4 is: hydrogen; methyl; isopropyl; cyclopropyl; chlorine; or morpholin-4-yl-carbonyl.
[00465] In certain embodiments of formula I or formula II, R4 is: hydrogen; methyl; isopropyl; cyclopropyl; or chlorine.
[00466] In certain embodiments of formula I or formula II, R4 is hydrogen.
[00467] In certain embodiments of formula I or formula II, R4 is methyl.
[00468] In certain embodiments of formula I or formula II, R4 is iso-propyl.
[00469] In certain embodiments of formula I or formula II, R4 is cyclopropyl.
[00470] In certain embodiments of formula I or formula II, R4 is chloro.
[00471] In certain embodiments of formula I or formula II, R4 is morpholin-4-yl-carbonyl.
[00472] In certain embodiments of formula I or formula II, R4 is 2-fluoroethyl.
[00473] In certain embodiments of formula I or formula II, R4 is C3-6cycloalkyl optionally substituted one or more times, or once or twice, with R6.
[00474] In certain embodiments of formula I or formula II, R4 is C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted one or more times, or once or twice, with R6.
[00475] In certain embodiments of formula I or formula II, R4 is -Y-C(O)-Rd.
[00476] In certain embodiments of formula I or formula II, either R3 and R4 together with the atoms to which they are attached may form a 5- or 6-membered ring that optionally includes a heteroatom selected from O, N and S.
[00477] In certain embodiments of formula I or formula II, R5 is hydrogen.
[00478] In certain embodiments of formula I or formula II, R5 is C1-6alkyl.
[00479] In certain embodiments of formula I or formula II, R5 is methyl.
[00480] In certain embodiments of formula I or formula II, each R6 is independently C1-6alkyl; halo-C1-6alkyl; C1-6alkoxy; cyan; or halo.
[00481] In certain embodiments of formula I or formula II, R6 is C1-6alkyl; halo-C1-6alkyl; C1-6alkoxy; or halo.
[00482] In certain embodiments of formula I or formula II, R6 is C1-6alkyl; halo-C1-6alkyl; or halo.
[00483] In certain embodiments of formula I or formula II, R6 is C1-6alkyl.
[00484] In certain embodiments of formula I or formula II, R6 is halo-C1-6alkyl.
[00485] In certain embodiments of formula I or formula II, R6 is C1-6alkoxy.
[00486] In certain embodiments of formula I or formula II, R6 is cyano.
[00487] In certain embodiments of formula I or formula II, R6 is halo.
[00488] In certain embodiments of formula I or formula II, R6 is Y-C(O)-Rd.
[00489] In certain embodiments of formula I or formula II, R6 is oxo.
[00490] In certain embodiments of formula I or formula II, each R7 is independently C1-6alkyl; halo-C1-6alkyl; halo; C1-6alkylsulfonyl; C1-6alkoxy-C1-6alkyl; cyan; heterocyclyl; or C3-6cycloalkylsulfonyl wherein the C3-6cycloalkyl moiety is optionally substituted one or more times with R6.
[00491] In certain embodiments of formula I or formula II, R7 is C1-6alkyl.
[00492] In certain embodiments of formula I or formula II, R7 is halo-C1-6alkyl.
[00493] In certain embodiments of formula I or formula II, R7 is halo.
[00494] In certain embodiments of formula I or formula II, R7 is C1-6alkylsulfonyl.
[00495] In certain embodiments of formula I or formula II, R7 is C1-6alkoxy-C1-6alkyl.
[00496] In certain embodiments of formula I or formula II, R7 is cyano.
[00497] In certain embodiments of formula I or formula II, R7 is -Y-C(O)-Rd.
[00498] In certain embodiments of formula I or formula II, R7 is heterocyclyl.
[00499] In certain embodiments of formula I or formula II, R7 is C3-6cycloalkylsulfonyl wherein the C3-6cycloalkyl moiety is optionally substituted one or more times with R6.
[00500] In certain embodiments of formula I or formula II, R7 is oxo.
[00501] In certain embodiments of formula I or formula II, R7 is C1-6alkoxy.
[00502] In certain embodiments of formula I or formula II, R7 is heterocyclyl-C1-6alkyl.
[00503] In certain embodiments of formula I or formula II, R7 is C3-6cycloalkyl.
[00504] In certain embodiments of formula I or formula II, R7 is C3-6cycloalkyl-C1-6alkyl.
[00505] In embodiments of formula I or formula II wherein R7 is heterocyclyl, such heterocyclyl moiety may be piperidinyl, pyrrolidinyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, [1,3]dioxolanyl or tetra- hydrothiopyranyl.
[00506] In embodiments of formula I or formula II wherein R7 is heterocyclyl-C1-6alkyl, such heterocyclyl moiety may be piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, [ 1,3]dioxolanyl or tetrahydrothiopyranyl.
[00507] In certain embodiments of formula I or formula II, each R8 is independently oxo; C1-6alkyl; halo-C1-6alkyl; halo; C1-6alkoxy; C1-6alkoxy-C1-6alkyl; cyan; C3-6cycloalkyl optionally substituted one or more times with R6, C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted one or more times with R6, or C3-6cycloalkylsulfonyl wherein the C3- 6cycloalkyl is optionally substituted one or more times with R6.
[00508] In certain embodiments of formula I or formula II, R8 is oxo.
[00509] In certain embodiments of formula I or formula II, R7 is C1-6alkyl.
[00510] In certain embodiments of formula I or formula II, R7 is halo-C1-6alkyl
[00511] In certain embodiments of formula I or formula II, R7 is halo.
[00512] In certain embodiments of formula I or formula II, R7 is C1-6alkoxy.
[00513] In certain embodiments of formula I or formula II, R7 is C1-6alkoxy-C1-6alkyl.
[00514] In certain embodiments of formula I or formula II, R7 is cyano.
[00515] In certain embodiments of formula I or formula II, R7 is heterocyclyl.
[00516] In certain embodiments of formula I or formula II, R7 is -Y-C(O)-Rd.
[00517] In certain embodiments of formula I or formula II, R7 is C3-6cycloalkyl optionally substituted one or more times with R6.
[00518] In certain embodiments of formula I or formula II, R7 is C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl moiety is optionally substituted one or more times with R6.
[00519] In certain embodiments of formula I or formula II, R7 is C3-6cycloalkylsulfonyl wherein the C3-6cycloalkyl moiety is optionally substituted one or more times with R6.
[00520] In certain embodiments of formula I or formula II, R8 is oxo.
[00521] In certain embodiments of formula I or formula II, R8 is C1-6alkyl.
[00522] In certain embodiments of formula I or formula II, R8 is halo-C1-6alkyl.
[00523] In certain embodiments of formula I or formula II, R8 is halo.
[00524] In certain embodiments of formula I or formula II, R8 is C1-6alkylsulfonyl.
[00525] In certain embodiments of formula I or formula II, R8 is C1-6alkoxy.
[00526] In certain embodiments of formula I or formula II, R8 is C1-6alkoxy-C1-6alkyl.
[00527] In certain embodiments of formula I or formula II, R8 is cyano; heterocyl.
[00528] In certain embodiments of formula I or formula II, R8 is heterocyclyl-C1-6alkyl.
[00529] In certain embodiments of formula I or formula II, R8 is -Y-C(O)-Rd.
[00530] In certain embodiments of formula I or formula II, R8 is C3-6cycloalkyl.
[00531] In certain embodiments of formula I or formula II, R8 is C3-6cycloalkyl-C1-6alkyl, C3-6cycloalkylsulfonyl.
[00532] In embodiments of formula I or formula II wherein R8 is heterocyclyl, such heterocyclyl moiety may be piperidinyl, pyrrolidinyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, [1,3]dioxolanyl or tetra- hydrothiopyranyl.
[00533] In embodiments of formula I or formula II wherein R8 is heterocyclyl-C1-6alkyl, such heterocyclyl moiety may be piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, [ 1,3]dioxolanyl or tetrahydrothiopyranyl.
[00534] In certain embodiments of the invention, compounds of formulas III, IV and V are provided:

[00535] wherein X, R1, R, R2, R3, R4 and R5 are as defined herein.
[00536] In certain embodiments of the invention, the object compounds are of formula III.
[00537] In certain embodiments of the invention, the object compounds are of formula IV.
[00538] In certain embodiments of the invention, the subject compounds are of formula V.
[00539] Where any of R1, R2, R3, R4, R5, R6, R7, R8 Ra, Rb, Rc and Rd is alkyl or contains an alkyl moiety, such alkyl may be lower alkyl, i.e. C1-C6alkyl , and in many embodiments may be C1-C4alkyl.
[00540] In a certain embodiment, the invention relates to the compound as described herein which is selected from the group consisting of
[00541] N2-(1-isopropyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00542] N2-(1,5-Dimethyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00543] N4-Methyl-N2-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00544] N4-Methyl-N2-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00545] 5-Chloro-N2-(1-isopropyl-1H-pyrazol-4-yl)-N4-methylpyrimidine-2,4-diamine,
[00546] N4-Methyl-N2-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00547] N4-Methyl-N2-(1-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00548] N2-(1,3-dimethyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00549] 5-Chloro-N-(1,5-dimethyl-1H-pyrazol-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)pyrimidin-2-amine,
[00550] N4-Methyl-5-(trifluoromethyl)-N2-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine,
[00551] 5-Chloro-N-(1-isopropyl-1H-pyrazol-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)pyrimidin-2-amine,
[00552] 5-Chloro-N-(1,5-dimethyl-1H-pyrazol-4-yl)-4-methoxypyrimidin-2-amine,
[00553] N-(1,5-dimethyl-1H-pyrazol-4-yl)-4-(pyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-amine,
[00554] N2-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00555] 5-Chloro-N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-methoxypyrimidin-2-amine,
[00556] N4-Methyl-N2-(3-methyl-1-(oxetan-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00557] N2-(5-Chloro-1-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00558] 5-Chloro-4-methoxy-N-(3-methyl-1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine,
[00559] 5-Chloro-4-methoxy-N-(1-(2-methoxyethyl)-3-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine,
[00560] 5-Chloro-4-methoxy-N-(1-(2-methoxyethyl)-5-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine,
[00561] 5-Chloro-N-(5-chloro-1-methyl-1H-pyrazol-4-yl)-4-methoxypyrimidin-2-amine,
[00562] 2-Methyl-1-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propan-2-ol,
[00563] 2-Methyl-1-(3-methyl-4-(4-(methylamino)-5-chloro-pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propan-2-ol,
[00564] N2-(1-(2-Methoxyethyl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00565] N2-(1-(2-Methoxyethyl)-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00566] 5-Chloro-N-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-4-methoxypyrimidin-2-amine,
[00567] 5-Chloro-N4-methyl-N2-(3-methyl-1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine,
[00568] N2-(1-Isopropyl-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00569] 5-Chloro-N-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-4-methoxypyrimidin-2-amine,
[00570] 5-Chloro-N2-(1,3-dimethyl-1H-pyrazol-4-yl)-N4-methylpyrimidine-2,4-diamine,
[00571] 5-Chloro-N2-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-N4-methylpyrimidine-2,4-diamine,
[00572] N4-Methyl-N2-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4- diamine,
[00573] N4-Methyl-N2-(5-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4- diamine,
[00574] N2-(2-Ethyl-2H-pyrazol-3-yl)-5-fluoro-N4-methyl-pyrimidine-2,4-diamine,
[00575] 5-Fluoro-N4-methyl-N2-(2-methyl-2H-pyrazol-3-yl)-pyrimidine-2,4-diamine,
[00576] 5-Fluoro-N4-methyl-N4-(2-propyl-2H-pyrazol-3-yl)-pyrimidine-2,4-diamine,
[00577] N2-(2,5-Dimethyl-2H-pyrazol-3-yl)-5-fluoro-N4-methyl-pyrimidine-2,4-diamine,
[00578] N2-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00579] 5-Chloro-N-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-4-methoxypyrimidin-2-amine,
[00580] N2-(3-Cyclopropyl-1-methyl-1H-pyrazol-5-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00581] 5-Chloro-N-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-4-methoxypyrimidin-2-amine,
[00582] 5-Chloro-N2-(5-isopropyl-2-methyl-2H-pyrazol-3-yl)-N4-methyl-pyrimidine-2,4-diamine,
[00583] 5-Chloro-4-methoxy-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrimidin-2-amine,
[00584] 5-Chloro-N4-methyl-N2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-pyrimidine-2,4-diamine,
[00585] 5-Chloro-N2-(5-cyclopropyl-2-methyl-2H-pyrazol-3-yl)-N4-methyl-pyrimidine-2,4-diamine,
[00586] N4-Methyl-N2-(5-methyl-1-oxetan-3-yl-1H-pyrazol-4-yl)-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00587] N2-(1-isopropyl-1H-pyrazol-5-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00588] 5-Chloro-N-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-4-methoxypyrimidin-2-amine,
[00589] 5-Chloro-N2-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-N4-methylpyrimidine-2,4-diamine,
[00590] N2-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00591] 5-Chloro-N2-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-N4-methylpyrimidine-2,4-diamine,
[00592] 5-Chloro-N2-(1-isopropyl-1H-pyrazol-5-yl)-N4-methylpyrimidine-2,4-diamine,
[00593] 5-Chloro-N-(1-isopropyl-1H-pyrazol-5-yl)-4-methoxypyrimidin-2-amine,
[00594] 5-Chloro-4-methoxy-N-(3-methyl-1-(methylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-2-amine,
[00595] N2-(1-ethyl-1H-pyrazol-3-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00596] 5-Chloro-4-methoxy-N-(5-methyl-1-phenyl-1H-pyrazol-4-yl)pyrimidin-2-amine,
[00597] N2-(1-isopropyl-1H-pyrazol-3-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00598] N4-Methyl-N2-(5-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00599] N2-(1-(2,2-dimethyl-1,3-dioxan-5-yl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine- 2,4-diamine,
[00600] 5-Chloro-4-methoxy-N-(5-methyl-1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)pyrimidin-2-amine,
[00601] N4-Ethyl-N2-(1-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00602] 5-Chloro-N-(1,5-dimethyl-1H-pyrazol-4-yl)-4-(oxetan-3-yloxy)pyrimidin-2-amine,
[00603] 5-Chloro-4-(2,2-difluoroethoxy)-N-(1,5-dimethyl-1H-pyrazol-4-yl)pyrimidin-2-amine,
[00604] 5-Chloro-N-(1,5-dimethyl-1H-pyrazol-4-yl)-4-(2,2,2-trifluoroethoxy)pyrimidin-2-amine,
[00605] 5-Chloro-4-methoxy-N-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine,
[00606] (4-(4-(5-chloro-4-methoxypyrimidin-2-ylamino)-3-methyl-1H-pyrazol-1-yl)piperidin-1-yl)(1-methylcyclopropyl)methanone,
[00607] (4-(4-(5-chloro-4-methoxypyrimidin-2-ylamino)-5-methyl-1H-pyrazol-1-yl)piperidin-1-yl)(1-methylcyclopropyl)methanone,
[00608] 4-(4-(5-Chloro-4-methoxypyrimidin-2-ylamino)-3-methyl-1H-pyrazol-1-yl)benzonitrile,
[00609] 5-Chloro-4-methoxy-N-(3-methyl-1-(3-methylpyridin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine,
[00610] 5-Chloro-N-(1-(cyclopropylsulfonyl)-5-methyl-1H-pyrazol-4-yl)-4-methoxypyrimidin-2-amine,
[00611] 5-Chloro-N-(1-(cyclopropylsulfonyl)-3-methyl-1H-pyrazol-4-yl)-4-methoxypyrimidin-2-amine,
[00612] 2-(4-(5-Chloro-4-methoxypyrimidin-2-ylamino)-5-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile,
[00613] 2-(4-(5-Chloro-4-methoxypyrimidin-2-ylamino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile,
[00614] 5-Chloro-4-ethoxy-N-(5-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine,
[00615] (5-Chloro-4-methoxy-pyrimidin-2-yl)-[1-(4-methanesulfonyl-phenyl)-3-methyl-1H-pyrazol-4-yl]-amine,
[00616] (5-Chloro-4-methoxy-pyrimidin-2-yl)-(3-methyl-1-phenyl-1H-pyrazol-4-yl)-amine,
[00617] (4-Methoxy-5-trifluoromethyl-pyrimidin-2-yl)-(3-methyl-1-phenyl-1H-pyrazol-4-yl)-amine,
[00618] (4-Methoxy-5-trifluoromethyl-pyrimidin-2-yl)-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-amine,
[00619] (5-Chloro-4-methoxy-pyrimidin-2-yl)-(1-methanesulfonyl-3-methyl-1H-pyrazol-4-yl)-amine,
[00620] (5-Chloro-4-methoxy-pyrimidin-2-yl)-[5-methyl-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-amine,
[00621] 4-[4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-3-methyl-pyrazol-1-yl]-N,N-dimethyl-benzamide,
[00622] 4-[4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-5-methyl-pyrazol-1-yl]-N,N-dimethyl-benzamide,
[00623] 4-[4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-5-methyl-pyrazol-1-yl]-benzonitrile,
[00624] N2-(5-Methoxy-1-methyl-1H-pyrazol-4-yl)-N4-methyl-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00625] (5-Chloro-4-methoxy-pyrimidin-2-yl)-[5-chloro-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-amine,
[00626] (5-Chloro-4-methoxy-pyrimidin-2-yl)-{1-[1-(2-fluoro-ethyl)-piperidin-4-yl]-3-methyl-1H-pyrazol-4- yl}-amine,
[00627] N2-[1-(1-[1,3]Dioxolan-2-ylmethyl-piperidin-4-yl)-5-methyl-1H-pyrazol-4-yl]-N4-ethyl-5-trifluoromethyl- pyrimidine-2,4-diamine,
[00628] N2-[1-(1-[1,3]Dioxolan-2-ylmethyl-piperidin-4-yl)-3-methyl-1H-pyrazol-4-yl]-N4-ethyl-5-trifluoromethyl- pyrimidine-2,4-diamine,
[00629] 5-Bromo-N2-(1,5-dimethyl-1H-pyrazol-4-yl)-N4-methylpyrimidine-2,4-diamine,
[00630] N2-(1,3-Dimethyl-1H-pyrazol-4-yl)-5-iodo-N4-methyl-pyrimidine-2,4-diamine,
[00631] N4-Methyl-N2-(5-methyl-1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine -2,4-diamine,
[00632] N4-Methyl-N2-(3-methyl-1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine -2,4-diamine,
[00633] 5-bromo-N4-methyl-N2-(5-methyl-1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine-2 ,4-diamine,
[00634] 5-bromo-N4-methyl-N2-(3-methyl-1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine-2 ,4-diamine,
[00635] 5-bromo-N4-methyl-N2-(3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine,
[00636] 5-bromo-N4-methyl-N2-(5-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine,
[00637] N4-Ethyl-N2-(3-methyl-1-(oxetan-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00638] 5-Chloro-N4-ethyl-N2-(3-methyl-1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine,
[00639] 5-bromo-N4-methyl-N2-(1-methyl-1H-pyrazol-5-yl)pyrimidine-2,4-diamine,
[00640] 2-Methyl-1-(5-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propan-2-ol,
[00641] 5-Chloro-N4-methyl-N2-(3-methyl-1-(methylsulfonyl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine,
[00642] N4-Methyl-N2-(3-methyl-1-(methylsulfonyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00643] N4-Methyl-N2-(3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00644] 5-bromo-N4-ethyl-N2-(3-methyl-1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine,
[00645] N2-(1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00646] N2-(1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00647] 5-bromo-N4-ethyl-N2-(1-ethyl-5-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine,
[00648] 5-bromo-N2-(1-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl)-N4-methylpyrimidine-2,4-diamine,
[00649] 5-bromo-N4-methyl-N2-(3-methyl-1-phenyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine,
[00650] 5-bromo-N4-methyl-N2-(5-methyl-1-phenyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine,
[00651] 5-bromo-N4-methyl-N2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine,
[00652] N4-Methyl-N2-(3-methyl-1-(1-(methylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine ,
[00653] 5-bromo-N4-methyl-N2-(3-methyl-1-propyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine,
[00654] 5-Chloro-N4-methyl-N2-(3-methyl-1-((3-methyloxetan-3-yl)methyl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine,
[00655] 5-bromo-N2-(1-(3,5-difluorophenyl)-5-methyl-1H-pyrazol-4-yl)-N4-methylpyrimidine-2,4-diamine,
[00656] 5-bromo-N2-(1-(3,5-difluorophenyl)-3-methyl-1H-pyrazol-4-yl)-N4-methylpyrimidine-2,4-diamine,
[00657] N4-Methyl-N2-(3-methyl-1-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00658] N4-Methyl-N2-(3-methyl-1-((3-methyloxetan-3-yl)methyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine ,
[00659] N4-Methyl-N2-(5-methyl-1-propyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00660] N4-Methyl-N2-(3-methyl-1-propyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00661] 5-bromo-N2-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-N4-methylpyrimidine-2,4-diamine,
[00662] 5-bromo-N2-(1-(4-chlorophenyl)-5-methyl-1H-pyrazol-4-yl)-N4-methylpyrimidine-2,4-diamine,
[00663] N2-(1-(4-chlorophenyl)-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00664] N4-Methyl-N2-(3-methyl-1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00665] N4-Methyl-N2-(5-methyl-1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00666] N2-(1-((1S,5S)-8-oxabicyclo[3.2.1]octan-3-yl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5 -(trifluoromethyl)pyrimidine-2,4-diamine,
[00667] N2-(1-Butyl-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00668] N4-Methyl-N2-(3-methyl-1-(pyrimidin-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00669] N2-(1-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00670] N2-(1-(2-fluoroethyl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00671] N4-Methyl-N2-(3-methyl-1-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2 ,4-diamine,
[00672] N4-Methyl-N2-(5-methyl-1-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2 ,4-diamine,
[00673] N2-(1-(2-Fluoroethyl)-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00674] 1-(4-(4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-3-methyl-1H-pyrazol-1-yl)piperidin-1-yl)ethanone,
[00675] cyclopropyl(4-(5-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)piperidin-1-yl)methanone,
[00676] cyclopropyl(4-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)piperidin-1-yl)methanone,
[00677] 1-(4-(4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-5-methyl-1H-pyrazol-1-yl)piperidin-1-yl)ethanone,
[00678] N2-(5-Chloro-1-isopropyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00679] N2-(5-Chloro-1-ethyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00680] N4-Methyl-N2-(3-methyl-1-(pyrimidin-5-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00681] N4-Methyl-N2-(4-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00682] N4-Methyl-N2-(5-methyl-1-(2-methylpyridin-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00683] N4-Methyl-N2-(3-methyl-1-(2-methylpyridin-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00684] N4-ethyl-N2-(3-methyl-1-((3-methyloxetan-3-yl)methyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine ,
[00685] N2-(5-Chloro-1-cyclopropyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00686] N2-(5-Chloro-1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00687] 4-(5-Methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)benzonitrile,
[00688] 4-(3-Methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)benzonitrile,
[00689] N4-Methyl-N2-(3-methyl-1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00690] N4-Methyl-N2-(5-methyl-1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00691] 5-(4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-5-methyl-1H-pyrazol-1-yl)-1-methylpiperidin-2-one,
[00692] 5-(4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-3-methyl-1H-pyrazol-1-yl)-1-methylpiperidin-2-one,
[00693] 5-(3-Methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)piperidin-2-one,
[00694] 5-(5-Methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)piperidin-2-one,
[00695] N2-(1-Isopropyl-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00696] N,N-dimethyl-4-(5-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)benzamide,
[00697] 4-(4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-5-methyl-1H-pyrazol-1-yl)-N,N-dimethylbenzamide,
[00698] N4-Ethyl-N2-(5-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4- diamine,
[00699] N4-ethyl-N2-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4- diamine,
[00700] N4-ethyl-N2-(3-methyl-1-(methylsulfonyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00701] N2-(1-(4-(cyclopropylsulfonyl)phenyl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00702] 4-(4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-5-methyl-1H-pyrazol-1-yl)benzonitrile,
[00703] N4-ethyl-N2-(5-methyl-1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00704] N,N-dimethyl-4-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)benzamide,
[00705] N2-(1-(cyclopropylmethyl)-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00706] N2-(1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00707] N2-(1-(4-(cyclopropylsulfonyl)phenyl)-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00708] N2-(5-Chloro-1-(oxetan-3-yl)-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00709] N4-ethyl-N2-(5-methyl-1-((3-methyloxetan-3-yl)methyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine ,
[00710] N2-(1-(cyclopropylsulfonyl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00711] N2-(1-(cyclopropylsulfonyl)-3-methyl-1H-pyrazol-4-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00712] 5-Chloro-N4-(2,2-difluoroethyl)-N2-(1,5-dimethyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine,
[00713] 5-Chloro-4-methyl-N-(3-methyl-1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)pyrimidin-2-amine,
[00714] N2-(1-(4-(cyclopropylsulfonyl)phenyl)-5-methyl-1H-pyrazol-4-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00715] 2-Methyl-1-(4-(5-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)piperidin-1- il)propan-1-one,
[00716] N4-Ethyl-N2-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00717] N2-(3-cyclopropyl-1-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00718] N2-(5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00719] N4-Methyl-N2-(5-methyl-1-((3-methyloxetan-3-yl)methyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine ,
[00720] N2-(5-Chloro-1-((3-methyloxetan-3-yl)methyl)-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine ,
[00721] 1-(4-(4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-5-methyl-1H-pyrazol-1-yl)piperidin-1-yl)-2 -methylpropan-1-one,
[00722] N4-ethyl-N2-(3-methyl-1-(1-(oxetan-3-yl)azetidin-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2 ,4-diamine,
[00723] cyclopropyl(4-(4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-3-methyl-1H-pyrazol-1-yl)piperidin-1-yl)methanone,
[00724] cyclopropyl(4-(4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-5-methyl-1H-pyrazol-1-yl)piperidin-1-yl)methanone,
[00725] 1-(5-Chloro-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)-2-methylpropan-2-ol,
[00726] N4-ethyl-N2-(1-ethyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00727] (S)-N2-(1-(2-methoxypropyl)-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00728] N2-(1-(2-methoxycyclopentyl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00729] (S)-N2-(1-(2-methoxypropyl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00730] N2-(1-(1-Methoxy-2-methylpropan-2-yl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4- diamine,
[00731] N2-(1-(2,6-dimethyltetrahydro-2H-pyran-4-yl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine- 2,4-diamine,
[00732] (R)-N2-(1-(2-methoxypropyl)-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00733] N2-(1-(3-methoxycyclopentyl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00734] N4-Methyl-N2-(1-methyl-5-(methylamino)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00735] N4-Methyl-N2-(5-methyl-1-(methylsulfonyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00736] N4-Methyl-N2-(5-methyl-1-(tetrahydro-2H-1,1-dioxo-thiopyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl) pyrimidine-2,4-diamine,
[00737] 2-Methyl-1-(4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-5-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-ol ,
[00738] 2-Methyl-1-(4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-3-(trifluoromethyl)-1H-pyrazol-1-yl)propan-2-ol ,
[00739] N2-(1-(3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl) )pyrimidine-2,4-diamine,
[00740] (R)-N2-(1-(1-methoxypropan-2-yl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4- diamine,
[00741] 1-(3-tert-butyl-4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)-2-methylpropan-2-ol,
[00742] N4-Methyl-N2-(3-methyl-1-(1-(2,2,2-trifluoroethyl)azetidin-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine -2,4-diamine,
[00743] N2-(1-(1-Methoxy-2-methylpropan-2-yl)-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4- diamine,
[00744] (R)-N4-methyl-N2-(3-methyl-1-(1-(oxetan-3-yl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl) ) pyrimidine-2,4-diamine,
[00745] (R)-N2-(1-(1-methoxypropan-2-yl)-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4- diamine,
[00746] N4-Methyl-N2-(4-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00747] N4-Ethyl-N2-(5-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00748] N4-ethyl-N2-(3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00749] N4-Methyl-N2-(3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00750] N4-Methyl-N2-(5-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00751] (R)-N4-methyl-N2-(5-methyl-1-(1-(oxetan-3-yl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl) ) pyrimidine-2,4-diamine,
[00752] N4-Methyl-N2-(5-methyl-1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00753] N4-Methyl-N2-(3-methyl-1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00754] N2-(1-(1-isopropylazetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00755] 1-Methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-5-carbonitrile,
[00756] N4-Ethyl-N2-(1-(isopropylsulfonyl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00757] N2-(1-(isopropylsulfonyl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00758] N2-(1-(isopropylsulfonyl)-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00759] N2-(1-(sec-butylsulfonyl)-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00760] N2-(1-(sec-butylsulfonyl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00761] 1-(4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-3-isopropyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol,
[00762] N2-(1-(3-fluoro-1-methylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4- diamine,
[00763] N2-(5-Isopropyl-1-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00764] N4-Methyl-N2-(3-methyl-1-(1-(pyridin-2-yl)ethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine ,
[00765] N4-Methyl-N2-(5-methyl-1-(1-(pyridin-2-yl)ethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine ,
[00766] N2-(5-Chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4- diamine,
[00767] N2-(3-isopropyl-1-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00768] N2-(3-cyclobutyl-1-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00769] N2-(5-cyclobutyl-1-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00770] N4-Methyl-N2-(3-methyl-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4- diamine,
[00771] N4-Methyl-N2-(5-methyl-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4- diamine,
[00772] N2-(1,5-dimethyl-1H-pyrazol-4-yl)-N4-((tetrahydro-2H-pyran-4-yl)methyl)-5-(trifluoromethyl)pyrimidine-2,4 -diamine,
[00773] (R)-N4-methyl-N2-(3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4- diamine,
[00774] 1-(5-Chloro-4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)-2-methylpropan-2-ol,
[00775] 1-(3-Cyclopropyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)-2-methylpropan-2-ol,
[00776] 1-(3-Cyclopropyl-4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)-2-methylpropan-2-ol,
[00777] 2-(5-Chloro-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)-N,2-dimethylpropanamide,
[00778] N2-(1-(1-(2-Methoxyethyl)piperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4 -diamine,
[00779] N2-(1-(1-(2-methoxyethyl)piperidin-4-yl)-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4 -diamine,
[00780] (R)-N4-methyl-N2-(5-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4- diamine,
[00781] N2-(5-Chloro-1-(3-fluoro-1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4- diamine,
[00782] N2-(5-Chloro-1-(1-ethyl-3-fluoropiperidin-4-yl)-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4- diamine,
[00783] N4-Ethyl-N2-(1-(ethylsulfonyl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00784] N4-ethyl-N2-(1-(ethylsulfonyl)-5-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00785] N4-Methyl-N2-(3-methyl-1-(2-methyl-2-morpholinopropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00786] N2-(1-(1-ethyl-3-fluoropiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4- diamine,
[00787] N2-(5-(dimethylamino)-1-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00788] 2-(5-Chloro-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)-2-methylpropan-1-ol,
[00789] N2-(1-(ethylsulfonyl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00790] 2-Methyl-1-[3-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-pyrazol-1-yl]-propan-2-ol,
[00791] N2-[1-(2-Methoxy-ethyl)-3-methyl-1H-pyrazol-4-yl]-N4-methyl-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00792] N2-[1-(2-Methoxy-ethyl)-5-methyl-1H-pyrazol-4-yl]-N4-methyl-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00793] 5-Bromo-N2-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-N4-methyl-pyrimidine-2,4-diamine,
[00794] N4-Methyl-N2-[3-methyl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-4-yl]-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00795] 5-Bromo-N2-(1-Difluoromethyl-5-methyl-1H-pyrazol-4-yl)-N4-methyl-pyrimidine-2,4-diamine,
[00796] 5-Bromo-N2-(1-Difluoromethyl-3-methyl-1H-pyrazol-4-yl)-N4-methyl-pyrimidine-2,4-diamine,
[00797] 5-Bromo-N2-(1,5-dimethyl-1H-pyrazol-4-yl)-N4-ethyl-pyrimidine-2,4-diamine,
[00798] 5-Bromo-N2-[1-(4-fluoro-phenyl)-5-methyl-1H-pyrazol-4-yl]-N4-methyl-pyrimidine-2,4-diamine,
[00799] 5-Bromo-N4-methyl-N2-(5-methyl-1-propyl-1H-pyrazol-4-yl)-pyrimidine-2,4-diamine,
[00800] 5-Bromo-N2-[1-(4-chloro-phenyl)-3-methyl-1H-pyrazol-4-yl]-N4-methyl-pyrimidine-2,4-diamine,
[00801] N2-(1,5-Dimethyl-1H-pyrazol-4-yl)-N4-ethyl-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00802] 5-[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methyl-pyrazol-1-yl]-piperidin-2-one,
[00803] 4-[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methyl-pyrazol-1-yl]-N,N-dimethyl-benzamide,
[00804] N2-[1-(4-Cyclopropanesulfonyl-phenyl)-3-methyl-1H-pyrazol-4-yl]-N4-ethyl-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00805] 4-[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methyl-pyrazol-1-yl]-benzonitrile,
[00806] N4-Ethyl-N2-[1-(4-methanesulfonyl-phenyl)-3-methyl-1H-pyrazol-4-yl]-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00807] 1-{4-[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-methyl-pyrazol-1-yl]-piperidin-1-yl}-2-methyl-propan -1-one,
[00808] 1-{4-[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methyl-pyrazol-1-yl]-piperidin-1-yl}-2-methyl-propan -1-one,
[00809] N4-Methyl-N2-[3-methyl-1-(3-methyl-pyridin-4-yl)-1H-pyrazol-4-yl]-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00810] N2-[1-((R)-2-Methoxy-propyl)-3-methyl-1H-pyrazol-4-yl]-N4-methyl-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00811] N2-[1-(2,6-Dimethyl-tetrahydro-pyran-4-yl)-5-methyl-1H-pyrazol-4-yl]-N4-methyl-5-trifluoromethyl-pyrimidine-2 ,4-diamine,
[00812] N2-[1-(1,1-Dioxo-hexahydro-1H-thiopyran-4-yl)-3-methyl-1H-pyrazol-4-yl]-N4-methyl-5-trifluoromethyl-pyrimidine -2,4-diamine,
[00813] N2-[1-((R)-2-Methoxy-1-methyl-ethyl)-5-methyl-1H-pyrazol-4-yl]-N4-methyl-5-trifluoromethyl-pyrimidine-2,4 -diamine,
[00814] N2-[1-((S)-2-Methoxy-1-methyl-ethyl)-3-methyl-1H-pyrazol-4-yl]-N4-methyl-5-trifluoromethyl-pyrimidine-2,4 -diamine,
[00815] N4-Methyl-N2-[3-methyl-1-((S)-1-oxetan-3-yl-pyrrolidin-3-yl)-1H-pyrazol-4-yl]-5-trifluoromethyl-pyrimidine -2,4-diamine,
[00816] N4-Methyl-N2-[5-methyl-1-((S)-1-oxetan-3-yl-pyrrolidin-3-yl)-1H-pyrazol-4-yl]-5-trifluoromethyl-pyrimidine -2,4-diamine,
[00817] N2-[1-(1-Isopropyl-azetidin-3-yl)-5-methyl-1H-pyrazol-4-yl]-N4-methyl-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00818] N4-Ethyl-N2-[5-methyl-1-(propane-2-sulfonyl)-1H-pyrazol-4-yl]-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00819] N2-(5-Cyclobutyl-1-methyl-1H-pyrazol-4-yl)-N4-ethyl-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00820] N2-(3-Cyclobutyl-1-methyl-1H-pyrazol-4-yl)-N4-ethyl-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00821] N4-ethyl-N2-{1-[1-(2-methoxy-ethyl)-piperidin-4-yl]-3-methyl-1H-pyrazol-4-yl}-5-trifluoromethyl-pyrimidine-2 ,4-diamine,
[00822] N4-ethyl-N2-{1-[1-(2-methoxy-ethyl)-piperidin-4-yl]-5-methyl-1H-pyrazol-4-yl}-5-trifluoromethyl-pyrimidine-2 ,4-diamine,
[00823] N2-{1-[1-(2-Fluoro-ethyl)-piperidin-4-yl]-5-methyl-1H-pyrazol-4-yl}-N4-methyl-5-trifluoromethyl-pyrimidine-2 ,4-diamine,
[00824] N2-{1-[1-(2-Fluoro-ethyl)-piperidin-4-yl]-3-methyl-1H-pyrazol-4-yl}-N4-methyl-5-trifluoromethyl-pyrimidine-2 ,4-diamine,
[00825] N2-[5-Chloro-1-(3-fluoro-1-methyl-piperidin-4-yl)-1H-pyrazol-4-yl]-N4-methyl-5-trifluoromethyl-pyrimidine-2,4 -diamine,
[00826] N2-(1-Ethanesulfonyl-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00827] N4-Methyl-N2-[5-methyl-1-(2-methyl-2-morpholin-4-yl-propyl)-1H-pyrazol-4-yl]-5-trifluoromethyl-pyrimidine-2,4 -diamine,
[00828] N4-Methyl-N2-(3-methyl-1-pyridin-3-ylmethyl-1H-pyrazol-4-yl)-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00829] N2-(1-Cyclopropanesulfonyl-3-cyclopropyl-1H-pyrazol-4-yl)-N4-methyl-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00830] N4-Methyl-N2-(5-methyl-1-pyridin-3-ylmethyl-1H-pyrazol-4-yl)-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00831] (5-Chloro-4-methoxy-pyrimidin-2-yl)-{1-[1-(2-fluoro-ethyl)-piperidin-4-yl]-5-methyl-1H-pyrazol-4- yl}-amine,
[00832] N4-Methyl-N2-[3-methyl-1-(6-methyl-pyridin-2-ylmethyl)-1H-pyrazol-4-yl]-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00833] N4-ethyl-N2-[1-(2-methoxy-ethyl)-3-methyl-1H-pyrazol-4-yl]-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00834] N4-ethyl-N2-[1-(2-methoxy-ethyl)-5-methyl-1H-pyrazol-4-yl]-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00835] 1-[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-methyl-pyrazol-1-yl]-2-methyl-propan-2-ol,
[00836] 1-[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methyl-pyrazol-1-yl]-2-methyl-propan-2-ol,
[00837] N2-[1-(1,1-Dimethyl-2-morpholin-4-yl-ethyl)-3-methyl-1H-pyrazol-4-yl]-N4-ethyl-5-trifluoromethyl-pyrimidine-2 ,4-diamine,
[00838] N2-[1-(1,1-Dimethyl-2-morpholin-4-yl-ethyl)-3-methyl-1H-pyrazol-4-yl]-N4-methyl-5-trifluoromethyl-pyrimidine-2 ,4-diamine,
[00839] N4-Cyclopropyl-N2-(1-methanesulfonyl-3-methyl-1H-pyrazol-4-yl)-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00840] N4-Cyclopropyl-N2-(1-methanesulfonyl-5-methyl-1H-pyrazol-4-yl)-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00841] 1-[3-Chloro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-pyrazol-1-yl]-2-methyl-propan-2-ol,
[00842] 2-[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methyl-pyrazol-1-yl]-N-methyl-isobutyramide,
[00843] N4-Methyl-N2-(3-methyl-1-pyrimidin-2-ylmethyl-1H-pyrazol-4-yl)-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00844] N2-[5-Chloro-1-(3-fluoro-1-oxetan-3-yl-piperidin-4-yl)-1H-pyrazol-4-yl]-N4-methyl-5-trifluoromethyl-pyrimidine -2,4-diamine,
[00845] N2-[5-Chloro-1-(3-fluoro-1-oxetan-3-yl-piperidin-4-yl)-1H-pyrazol-4-yl]-N4-ethyl-5-trifluoromethyl-pyrimidine -2,4-diamine,
[00846] N4-Ethyl-N2-[5-methyl-1-((S)-1-oxetan-3-yl-piperidin-3-yl)-1H-pyrazol-4-yl]-5-trifluoromethyl-pyrimidine -2,4-diamine,
[00847] N4-ethyl-N2-[3-methyl-1-((S)-1-oxetan-3-yl-piperidin-3-yl)-1H-pyrazol-4-yl]-5-trifluoromethyl-pyrimidine -2,4-diamine,
[00848] N4-Methyl-N2-(5-methyl-1-pyridazin-3-ylmethyl-1H-pyrazol-4-yl)-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00849] N4-Methyl-N2-(3-methyl-1-pyridazin-3-ylmethyl-1H-pyrazol-4-yl)-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00850] N4-ethyl-N2-[5-methyl-1-((S)-1-methyl-piperidin-3-yl)-1H-pyrazol-4-yl]-5-trifluoromethyl-pyrimidine-2,4 -diamine,
[00851] N4-Ethyl-N2-[3-methyl-1-((S)-1-methyl-piperidin-3-yl)-1H-pyrazol-4-yl]-5-trifluoromethyl-pyrimidine-2,4 -diamine,
[00852] 3-[5-Chloro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-pyrazol-1-yl]-2,2-dimethyl-propionitrile,
[00853] N4-Methyl-N2-[5-methyl-1-(6-methyl-pyridin-2-ylmethyl)-1H-pyrazol-4-yl]-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00854] N4-Methyl-N2-(5-methyl-1-pyrimidin-2-ylmethyl-1H-pyrazol-4-yl)-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00855] N4-Methyl-N2-(5-methyl-1-pyrazin-2-ylmethyl-1H-pyrazol-4-yl)-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00856] N4-Methyl-N2-(3-methyl-1-pyrazin-2-ylmethyl-1H-pyrazol-4-yl)-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00857] 3-[5-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-pyrazol-1-yl]-2,2-dimethyl-propionitrile,
[00858] N4-Ethyl-N2-[1-(3-fluoro-1-oxetan-3-yl-piperidin-4-yl)-3-methyl-1H-pyrazol-4-yl]-5-trifluoromethyl-pyrimidine -2,4-diamine,
[00859] 3-Methyl-1-[5-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-pyrazol-1-yl]-butan-2-ol,
[00860] 3-Methyl-1-[3-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-pyrazol-1-yl]-butan-2-ol,
[00861] N2-[1-(1-[1,3]Dioxolan-2-ylmethyl-pyrrolidin-3-yl)-3-methyl-1H-pyrazol-4-yl]-N4-ethyl-5-trifluoromethyl- pyrimidine-2,4-diamine,
[00862] N4-Methyl-N2-(5-methyl-1-pyrimidin-4-ylmethyl-1H-pyrazol-4-yl)-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00863] N4-Methyl-N2-[5-methyl-1-(1-methyl-1H-pyrazol-3-ylmethyl)-1H-pyrazol-4-yl]-5-trifluoromethyl-pyrimidine-2,4-diamine ,
[00864] N4-Methyl-N2-[3-methyl-1-(1-methyl-1H-pyrazol-3-ylmethyl)-1H-pyrazol-4-yl]-5-trifluoromethyl-pyrimidine-2,4-diamine ,
[00865] 3-[3-Chloro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-pyrazol-1-yl]-2,2-dimethyl-propionitrile,
[00866] N4-Ethyl-N2-{3-methyl-1-[1-methyl-1-(4H-[1,2,4]triazol-3-yl)-ethyl]-1H-pyrazol-4-yl }-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00867] N2-[1-(1-[1,3]Dioxolan-2-ylmethyl-pyrrolidin-3-yl)-5-methyl-1H-pyrazol-4-yl]-N4-ethyl-5-trifluoromethyl- pyrimidine-2,4-diamine,
[00868] N4-Methyl-N2-(3-methyl-1-pyrimidin-4-ylmethyl-1H-pyrazol-4-yl)-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00869] N2-(5-Fluoromethyl-1-methyl-1H-pyrazol-4-yl)-N4-methyl-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00870] N4-ethyl-N2-{3-methyl-1-[1-methyl-1-(5-methyl-4H-[1,2,4]triazol-3-yl)-ethyl]-1H-pyrazole -4-yl}-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00871] N4-Methyl-N2-{3-methyl-1-[1-methyl-1-(4H-[1,2,4]triazol-3-yl)-ethyl]-1H-pyrazol-4-yl }-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00872] N4-Ethyl-N2-[1-(3-fluoro-piperidin-4-yl)-3-methyl-1H-pyrazol-4-yl]-5-trifluoromethyl-pyrimidine-2,4-diamine,
[00873] 2-[5-Methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-pyrazol-1-yl]-cyclopentanol,
[00874] 2-[3-Methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-pyrazol-1-yl]-cyclopentanol,
[00875] N4-Ethyl-N2-(3-methyl-1-(2-(5-methyl-1,3,4-oxadiazol-2-yl)propan-2-yl)-1H-pyrazol-4-yl )-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00876] N4-Ethyl-N2-(3-methyl-1-(2-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4 -yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00877] N4-Ethyl-N2-(3-methyl-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4 -yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00878] N4-Methyl-N2-(3-methyl-1-(2-(5-methyl-1,3,4-oxadiazol-2-yl)propan-2-yl)-1H-pyrazol-4-yl )-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00879] N4-Methyl-N2-(3-methyl-1-(2-(1-methyl-1H-pyrazol-4-yl)propan-2-yl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidine-2,4-diamine,
[00880] N4-Methyl-N2-(5-methyl-1-(2-(1-methyl-1H-pyrazol-4-yl)propan-2-yl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidine-2,4-diamine,
[00881] N4-ethyl-N2-(3-methyl-1-(2-(1-methyl-1H-pyrazol-3-yl)propan-2-yl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidine-2,4-diamine,
[00882] N4-ethyl-N2-(3-methyl-1-(2-(1-methyl-1H-pyrazol-5-yl)propan-2-yl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidine-2,4-diamine,
[00883] N4-Methyl-N2-(3-methyl-1-(2-(1-methyl-1H-pyrazol-5-yl)propan-2-yl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidine-2,4-diamine,
[00884] N4-Methyl-N2-(3-methyl-1-(2-(1-methyl-1H-pyrazol-3-yl)propan-2-yl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidine-2,4-diamine,
[00885] N2-(1',5-dimethyl-1'H-1,4'-bipyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00886] N2-(1',3-dimethyl-1'H-1,4'-bipyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00887] N2-(1-(2-(4H-1,2,4-triazol-3-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl- 5-(trifluoromethyl)pyrimidine-2,4-diamine,
[00888] 2-(1,5-Dimethyl-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile,
[00889] 2-(1,3-Dimethyl-1H-pyrazol-4-ylamino)-4-methylamino-pyrimidine-5-carbonitrile,
[00890] 2-(1-Ethyl-5-methyl-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile,
[00891] 2-(1-Isopropyl-3-methyl-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile,
[00892] 2-(1-Ethyl-3-methyl-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile,
[00893] 2-(3-Methyl-1-phenyl-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile,
[00894] 2-(3-Methyl-1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile ,
[00895] 2-(5-Methyl-1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile ,
[00896] 2-(1-Methyl-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile,
[00897] 2-(5-Methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile,
[00898] 2-(3-Methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile,
[00899] 2-(5-Methyl-1-phenyl-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile,
[00900] 2-(5-Methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile,
[00901] 2-(3-Methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile,
[00902] 2-(1-Ethyl-5-methyl-1H-pyrazol-4-ylamino)-4-(ethylamino)pyrimidine-5-carbonitrile,
[00903] 2-(1-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile,
[00904] 2-(1-(Difluoromethyl)-3-methyl-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile,
[00905] 2-(5-Methyl-1-propyl-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile,
[00906] 2-(1-(3,5-Difluorophenyl)-3-methyl-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile,
[00907] 2-(1-(4-Chlorophenyl)-3-methyl-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile,
[00908] 2-(1-(4-Chlorophenyl)-5-methyl-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile,
[00909] 2-(3-Methyl-1-(pyridin-2-yl)-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile,
[00910] 4-(ethylamino)-2-(5-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-ylamino)pyrimidine-5-carbonitrile,
[00911] 4-(ethylamino)-2-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-ylamino)pyrimidine-5-carbonitrile,
[00912] 4-(ethylamino)-2-(3-methyl-1-(oxetan-3-yl)-1H-pyrazol-4-ylamino)pyrimidine-5-carbonitrile,
[00913] 2-(1-Isopropyl-5-methyl-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile,
[00914] 2-(1,5-Dimethyl-1H-pyrazol-4-ylamino)-4-methoxypyrimidine-5-carbonitrile,
[00915] 2-(1,5-Dimethyl-1H-pyrazol-4-ylamino)-4-(2,2,2-trifluoroethylamino)pyrimidine-5-carbonitrile,
[00916] 2-(1-Ethyl-5-methyl-1H-pyrazol-4-ylamino)-4-methoxypyrimidine-5-carbonitrile,
[00917] 4-(2,2-Difluoroethylamino)-2-(1,5-dimethyl-1H-pyrazol-4-ylamino)pyrimidine-5-carbonitrile,
[00918] 2-(1,5-Dimethyl-1H-pyrazol-4-ylamino)-4-(2,2,2-trifluoroethoxy)pyrimidine-5-carbonitrile,
[00919] 2-(1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile,
[00920] 2-(1-(4,4-Difluorocyclohexyl)-5-methyl-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile,
[00921] 2-(3-Methyl-1-(oxetan-3-yl)-1H-pyrazol-4-ylamino)-4-(2,2,2-trifluoroethylamino)pyrimidine-5-carbonitrile,
[00922] 2-(5-Chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile,
[00923] 2-(1-Difluoromethyl-5-methyl-1H-pyrazol-4-ylamino)-4-methylamino-pyrimidine-5-carbonitrile,
[00924] 2-(1,5-Dimethyl-1H-pyrazol-4-ylamino)-4-ethylamino-pyrimidine-5-carbonitrile,
[00925] 2-[1-(4-Fluoro-phenyl)-5-methyl-1H-pyrazol-4-ylamino]-4-methylamino-pyrimidine-5-carbonitrile,
[00926] 4-Methylamino-2-(3-methyl-1-propyl-1H-pyrazol-4-ylamino)-pyrimidine-5-carbonitrile,
[00927] 4-Methylamino-2-(5-methyl-1-oxetan-3-yl-1H-pyrazol-4-ylamino)-pyrimidine-5-carbonitrile,
[00928] 4-Methylamino-2-(3-methyl-1-oxetan-3-yl-1H-pyrazol-4-ylamino)-pyrimidine-5-carbonitrile,
[00929] 2-[1-(3,5-Difluoro-phenyl)-5-methyl-1H-pyrazol-4-ylamino]-4-methylamino-pyrimidine-5-carbonitrile,
[00930] 4-(2,2-Difluoro-ethoxy)-2-(1,5-dimethyl-1H-pyrazol-4-ylamino)-pyrimidine-5-carbonitrile,
[00931] 2-[1-(4,4-Difluoro-cyclohexyl)-3-methyl-1H-pyrazol-4-ylamino]-4-methylamino-pyrimidine-5-carbonitrile,
[00932] (5-(5-Chloro-4-(methylamino)pyrimidin-2-ylamino)-1-methyl-1H-pyrazol-3-yl)(morpholino)methanone,
[00933] 2-Methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile,
[00934] N,N-dimethyl-2-(5-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)acetamide,
[00935] N,N-dimethyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)acetamide,
[00936] N-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)acetamide,
[00937] N-methyl-2-(5-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)acetamide,
[00938] N,N,2-Trimethyl-2-(5-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanamide,
[00939] 2-Methyl-2-(5-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)-1-(pyrrolidin-1) - yl)propan-1-one,
[00940] 2-Methyl-2-(5-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile,
[00941] 1-(3-Methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)cyclopropanecarbonitrile,
[00942] (R)-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)-1-(pyrrolidin-1) -yl)propan-1-one,
[00943] (R)-N,N-dimethyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanamide ,
[00944] (S)-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)-1-(pyrrolidin-1) -yl)propan-1-one,
[00945] 3-(5-Methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile,
[00946] 3-(3-Methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile,
[00947] methyl 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanoate,
[00948] methyl 2-methyl-2-(5-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanoate,
[00949] 2-(3-Ethyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)-2-methylpropanenitrile,
[00950] (R)-2-(5-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)-1-(pyrrolidin-1) -yl)propan-1-one,
[00951] (R)-N,N-dimethyl-2-(5-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanamide ,
[00952] (S)-2-(5-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)-1-(pyrrolidin-1) -yl)propan-1-one,
[00953] (S)-N,N-dimethyl-2-(5-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanamide ,
[00954] (S)-2-(5-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile,
[00955] (S)-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile,
[00956] 2-(4-(5-Chloro-4-(methylamino)pyrimidin-2-ylamino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile,
[00957] 2-(5-Chloro-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)-2-methylpropanenitrile,
[00958] 2-(3-Cyclopropyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)-2-methylpropanenitrile,
[00959] 2,2-Dimethyl-3-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile,
[00960] 2,2-Dimethyl-3-(5-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile,
[00961] 1-(5-Chloro-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)cyclopropanecarbonitrile,
[00962] N-tert-butyl-2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanamide ,
[00963] 2-Methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)-N-(2,2 ,2-trifluoroethyl)propanamide,
[00964] 2-(5-Chloro-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)-N-ethyl-2-methyl propanamide,
[00965] N-(cyclopropylmethyl)-2-methyl-2-(5-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanamide ,
[00966] N-(cyclopropylmethyl)-2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanamide ,
[00967] N-ethyl-1-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)cyclobutanecarboxamide,
[00968] N-isopropyl-2-methyl-2-(5-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanamide,
[00969] 1-(3-Methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)cyclobutanecarbonitrile,
[00970] 2-(4-(4-(cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile,
[00971] N,2-Dimethyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanamide,
[00972] 1-(5-Chloro-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)cyclopropanecarbonitrile,
[00973] 2-[4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-5-methyl-pyrazol-1-yl]-2-methyl-propionic acid methyl ester,
[00974] 2-[4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-3-methyl-pyrazol-1-yl]-2-methyl-propionic acid methyl ester,
[00975] (S)-N,N-Dimethyl-2-[3-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-pyrazol-1-yl]-propionamide,
[00976] R)-2-[3-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-pyrazol-1-yl]-propionitrile,
[00977] 2-[4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-3-cyclopropyl-pyrazol-1-yl]-2-methyl-propionitrile,
[00978] (R)-2-[5-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-pyrazol-1-yl]-propionitrile,
[00979] N-ethyl-2-[3-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-pyrazol-1-yl]-isobutyramide,
[00980] N-ethyl-2-[5-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-pyrazol-1-yl]-isobutyramide,
[00981] 1-[5-Methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-pyrazol-1-yl]-cyclobutanecarboxylic acid ethylamide,
[00982] 2-[5-Methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-pyrazol-1-yl]-N-(2,2,2-trifluoro-ethyl)-isobutyramide ,
[00983] N-Isopropyl-2-[3-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-pyrazol-1-yl]-isobutyramide,
[00984] N-methyl-2-[5-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-pyrazol-1-yl]-isobutyramide,
[00985] 1-[5-Methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-pyrazol-1-yl]-cyclobutanecarbonitrile,
[00986] N-tert-Butyl-2-[5-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-pyrazol-1-yl]-isobutyramide,
[00987] 2-[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-methyl-pyrazol-1-yl]-N-methyl-isobutyramide,
[00988] 2-[4-(4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methyl-pyrazol-1-yl]-N-methyl-isobutyramide,
[00989] 2-[4-(4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-methyl-pyrazol-1-yl]-N-methyl-isobutyramide,
[00990] 2-[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methyl-pyrazol-1-yl]-2-methyl-propionitrile,
[00991] 2-(3-Chloro-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)-2-methylpropanenitrile, and
[00992] 2-[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methyl-pyrazol-1-yl]-N-methyl-isobutyramide,
[00993] or a pharmaceutically acceptable salt thereof.
[00994] In a certain embodiment, the invention relates to the compound as described herein for use as a medicine.
[00995] In a certain embodiment, the invention relates to the compound as described herein for use in the therapeutic and/or prophylactic treatment of Parkinson's disease.
[00996] In a certain embodiment, the invention relates to the use of a compound as described herein for the preparation of medicaments for the therapeutic and/or prophylactic treatment of Parkinson's disease.
[00997] In a certain embodiment, the invention relates to a composition comprising: (a) a pharmaceutically acceptable carrier; and (b) a compound as described herein.
[00998] In a certain embodiment, the invention relates to a method of treating Parkinson's disease, said method comprising administering to a subject in need thereof an effective amount of a compound as described herein.
[00999] The invention also provides a method of treating a disease or condition mediated by or otherwise associated with the LRRK2 receptor, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention.
[001000] The disease may be a neurodegenerative disease such as Parkinson's disease, Huntington's disease or Lewie body dementia.
[001001] The disease may be a CNS disorder such as Alzheimer's disease or L-dopa-induced dyskinesia.
[001002] The disease may be a cancer or proliferative disorder such as kidney, breast, prostate, blood, papillary or lung cancer, acute myelogenous leukemia, or multiple myeloma.
[001003] The disease may be an inflammatory disease such as leprosy, Crohn's disease, amyotrophic lateral sclerosis, rheumatoid arthritis, or ankylosing spondylitis.
[001004] The invention also provides a method of increasing cognitive memory, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention.
[001005] Representative compounds according to the methods of the invention are shown in the experimental examples below. Synthesis
[001006] Compounds of the present invention can be made by a variety of methods described in the illustrative synthetic reaction schemes shown and described below.
[001007] The starting materials and reagents used in the preparation of these compounds are generally available from their commercial suppliers such as Aldrich Chemical Co. or are prepared by methods known to those skilled in the art following procedures mentioned in references such as Fieser's and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, 1991, Volumes 1-15; Rodd's Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5 and Supplementals; and Organic Reactions, Wiley & Sons: New York, 1991, Volumes 1-40. The following synthetic reaction schemes are merely illustrative of some methods by which the compounds of the present invention may be synthesized, and various modifications to these synthetic reaction schemes may be made and will be suggested by one skilled in the art having referred to the description contained in this Application .
[001008] The starting materials and intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.
[001009] Unless otherwise specified, the reactions described herein may be conducted under an inert atmosphere at atmospheric pressure at a reaction temperature range from about -78°C to about 150°C, for example from about 0°C at about 125°C, or conveniently at about local (or ambient) temperature, for example about 20°C.
[001010] Scheme A below illustrates a synthetic procedure usable to prepare the specific compounds of formula I, wherein X, R1, R2, R3, R4 and R5 are as defined herein.
SCHEME A
[001011] In step 1 of Scheme A, dichloropyrimidine compound a is reacted with reagent b to provide pyrimidine compound c. The step 1 reaction can take place under polar solvent conditions. In embodiments of the invention where X is -O- (reactant b is an alcohol), the reaction of step 1 can be carried out in the presence of base.
[001012] Following Step 1, one of steps 2a, 2b and 2c are performed. In step 2a, pyrimidine compound c is reacted with 4-amino-pyrazole compound d1 to provide an aminopyrimidine compound of formula III. In step 2b, the pyrimidine compound c is reacted with the 5-amino-pyrazole compound d2 to provide an aminopyrimidine compound of formula IV. In step 2c, the pyrimidine compound c is treated with the 3-amino-pyrazole compound d3 to produce an aminopyrimidine compound of formula V. The reaction of steps 2a-2c can take place in polar protic solvent and in the presence of such acid. as HCl.
[001013] Many variations on the Scheme A procedure are possible and will be suggested to those skilled in the art. Specific details for producing the compounds of the invention in the Examples below are described. Administration and Pharmaceutical Composition
[001014] The invention includes pharmaceutical compositions comprising at least one compound of the present invention, or an individual isomer, 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.
[001015] In general, compounds of the invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Suitable dosage ranges are typically 1-500 mg per day, for example 1-100 mg per day, and in some embodiments 130 mg per day, depending on numerous factors such as the severity of the disease being treated, age and relative health. of the individual, the potency of the compound used, the routine and form of administration, the indication to which the administration is directed, and the preferences and experience of the physician involved. One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and on reliance on personal knowledge, and the description of this Application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease.
[001016] The compounds of the invention may be administered as pharmaceutical formulations which include those suitable for oral (including buccal and sublingual), rectal, nasal, topical, pulmonary, vaginal or parenteral (including intramuscular, intra-arterial, intrathecal, subcutaneous and intravenous) or in a form suitable for administration by inhalation or insufflation. A particular way of administration is generally oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.
[001017] A compound or compounds of the invention, together with one or more conventional adjuvants, carriers or diluents, can be placed in the form of pharmaceutical compositions and unit dosages. Pharmaceutical compositions and unit dosage forms of the conventional ingredients may be comprised in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the planned daily dosage range. to be employed. The pharmaceutical compositions can be employed as solids, such as filled tablets or capsules, semi-solids, 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, or more broadly, about 0.01 to about (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.
[001018] The compounds of the invention can be formulated into a wide variety of oral dosage forms. Pharmaceutical compositions and dosage forms may comprise a compound or compounds of the present invention or pharmaceutically acceptable salts as the active ingredient. Pharmaceutically acceptable carriers can be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, seals, suppositories, and dispersible granules. A solid carrier can be one or more substances that can similarly act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is generally a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component is generally mixed with the carrier having the requisite binding capacity in suitable proportions and compacted into the desired shape and size. Powders and tablets may contain from about one (1) to about seventy (70) percent of the active compound. Suitable carriers include, however, are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low-melting wax, cocoa butter, and the like. The term "preparation" is intended to include formulating the active compound with encapsulating material as a carrier, providing a capsule in which the active component, with or without carriers, is surrounded by a carrier which is in association therewith. Similarly, seals and inserts are included. Tablets, powders, capsules, pills, seals and lozenges may be solid forms suitable for oral administration.
[001019] Other forms suitable for oral administration include liquid preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted shortly before use to liquid form preparations. Emulsions may be prepared in solutions, for example in aqueous propylene glycol solutions, or they may contain emulsifying agents, for example, such as lecithin, sorbitan monooleate or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorings, flavors, stabilizers, and thickening agents. Aqueous suspensions can 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 component, colorings, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
[001020] 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 dose form in ampoules, pre-filled syringes, small volume infusion or in containers of multiple doses with an added condom. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or non-aqueous 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 formulating agents. such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization of the solution for constitution before use with a suitable vehicle, for example, sterile, pyrogen-free water.
[001021] The compounds of the invention may be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable gelling agents and/or thickeners. Lotions may be formulated with an aqueous or oily base and generally likewise 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 agents in a flavored base, typically sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprise the active ingredient in a suitable liquid carrier.
[001022] The compounds of the invention may be formulated for administration as suppositories. A low melting wax such as a mixture of fatty acid glycerides or cocoa butter is melted first, and the active component is evenly spread out, for example by stirring. The molten homogeneous mixture is then poured into molds of suitable size, allowed to cool and solidify.
[001023] The compounds of the invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays which contain in addition to the active ingredient such carriers as are known in the art to be appropriate.
[001024] The subject compounds may be formulated for nasal administration. Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The formulations may be provided in a multiple or single dose form. In the more recent case of a dropper or pipette, this can be achieved by the patient administering an appropriate, predetermined volume of solution or suspension. In the case of a spray, this can be achieved, for example, by means of an atomizing spray pump with a dosimeter.
[001025] The compounds of the invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration. The compound will generally have a small particle size, for example on the order of five (5) microns or less. Such a particle size can be obtained by means known in the art, for example by micronization. The active ingredient is supplied in a pressurized package with a suitable propellant such as a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. The aerosol may also conveniently contain a surfactant such as lecithin. The drug dose can be controlled by a dosimeter valve. Alternatively, the active ingredients may be provided in a dry powder form, for example a powder mixture of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP). The powdered vehicle will form a gel in the nasal cavity. The powder composition may be presented, for example, in unit dose form in capsules or cartridges of, for example, gelatin or blister packs from which the powder can be administered by means of an inhaler.
[001026] When desired, formulations may be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient. For example, compounds of the present invention can be formulated in transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when prolonged release of the compound is required and when patient compliance with a treatment regimen is crucial. Compounds in transdermal delivery systems are often attached to an adhesive solid support to the skin. The compound of interest can be combined in the same way with a penetration enhancer, for example Azone (1-dodecylazacycloheptan-2-one). Extended delivery and delivery systems are inserted subcutaneously into the subdermal layer by surgery or injection. Subdermal implants encapsulate the compound in a lipid-soluble membrane, eg silicone rubber, or a biodegradable polymer, eg polylactic acid.
[001027] Pharmaceutical preparations may be in unit dosage forms. In such forms, the preparation is subdivided into unit doses containing appropriate amounts of the active component. The unit dosage form can be a packaged preparation, the package containing discrete amounts of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Likewise, the unit dosage form can be a capsule, tablet, seal or lozenge itself, or it can be the appropriate number of any of these in packaged form.
[001028] Other suitable pharmaceutical carriers and formulations thereof 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 a compound of the present invention are described below. Utility
[001029] The compounds of the invention are useful for the treatment of diseases or conditions mediated by LRRK2, including neurodegenerative diseases such as Parkinson's disease, Lewy body dementia, and Huntington's disease, and for the enhancement of cognitive memory generally. in individuals in need thereof. Examples
[001030] The following preparations and examples are produced 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 only as illustrative and representative thereof.
[001031] Unless otherwise stated, all temperatures including melting points (ie MP) are in degrees Celsius (°C). It should be appreciated that the reaction that produces the indicated and/or desired product may not necessarily result directly from the combination of two reactants that are initially added, i.e., there may be one or more intermediates that are produced in the mixture that ultimately leads to the formation of the indicated and/or desired product. The following abbreviations may be used in the Preparations and Examples. Abbreviations AcOH Acetic Acid AIBN 2,2'-Azobis(2-methylpropionitrile) Atm. Atmosphere (BOC)2O di-tert-Butyl dicarbonate dba tris(dibenzylideneacetone) 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 Diethylether EtOH Ethanol/Ethyl Alcohol EtOAc Ethyl Acetate HATU 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-Tetramethyluronium Hexafluorophosphate Methananium HBTU O-Benzotriazol-1-yl-N,N,N',N'-Tetramethyluronium Hexafluorophosphate HOBT 1-Hydroxybenzotriazole HPLC High Pressure Liquid Chromatography RP HPLC Reverse Phase High Pressure Liquid Chromatography i-PrOH Isopropanol/Isopropyl Alcohol LCMS Liquid Chromatography/Mass Spectroscopy MeOH Methanol/Methyl Alcohol MW Microwave NBS N-Bromosuccinimide NMP 1-Methyl-2-pyrrolidinone PSI Pound Per Square Inch RT Room Temperature SFC Supercritical Fluid Chromatography TBDMS tert-Butyldimethylsilyl TF A Trifluoroacetic acid THF Tetrahydrofuran TLC Thin layer chromatography Xphos 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl Liquid Chromatography-Mass Spectrometry Method A
[001032] LC-MS was performed on an Agilent 1200 Series LC coupled to an Agilent 6140 quadrupole mass spectrometer using an Agilent SD-C18 column (1.8 μm, 2.1 x 30 mm) with a linear gradient of acetonitrile/ 3-95% water (with 0.05% trifluoroacetic acid in each mobile phase) within 8.5 minutes and held at 95% for 2.5 minutes. Liquid Chromatography-Mass Spectrometry Method B
[001033] LC-MS was performed on a Waters 2795 Alliance HT HPLC with Waters 2996 Diode Array Detector coupled to a Micromass ZQ simple quadrupole mass spectrometer using a Phenomenex Luna C18 (2) column (5 µm, 100 x 4.6mm plus guard cartridge) with a linear gradient of 5-95% acetonitrile/water (with 0.1% formic acid in each mobile phase) within 3.5 minutes and held at 95% for 2 .0 minutes. Liquid Chromatography Method-Mass Spectrometry C
[001034] LC-MS was performed on a Waters 2795 Alliance HT HPLC with Waters 2996 Diode Array Detector coupled to a Micromass ZQ simple quadrupole mass spectrometer using a Waters Xterra MS C18 column (5 µm, 100 x 4.6mm plus guard cartridge) being initially held in 5% acetonitrile/water (with 10 mM ammonium bicarbonate in the aqueous mobile phase) for 0.5 min, followed by a linear gradient from 5-95% within 3 .5 minutes, and then held at 95% for 1.5 minutes. Analytical Methods
[001035] 1H nuclear magnetic resonance (NMR) spectroscopy was performed using a Bruker instrument operating at 400 or 500 MHz, using the stated solvent at around room temperature, unless otherwise stated. In all cases, the NMR data were compatible with the proposed structures. The characteristic chemical shifts (δ) are given in parts-per-million using conventional abbreviations for designating major peaks: eg s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; br, wide. Where thin layer chromatography (TLC) was used, it refers to TLC on silica gel using 60° MK6F silica gel plates, Rf is the distance traveled by the compound divided by the distance traveled by the solvent on a TLC plate . Flash chromatography refers to silica gel chromatography, and is performed using an Isolara 4 or SP4 MPLC system (manufactured by Biotage); pre-packaged silica gel cartridges (supplied by Biotage); or using conventional glass column chromatography. compost preparation
[001036] Where the preparation of starting materials is not described, these are commercially available, known in the literature, or readily obtainable by those skilled in the art using standard procedures. Where it is stated that the compounds were prepared analogously to the intermediates or examples above, it will be appreciated by the skilled person that the reaction time, number of reagent equivalents and temperature may be modified for each specific reaction, and that it may be necessary or desirable. employ different preparation or purification techniques. Where reactions are carried out using microwave irradiation, the microwave used is an Initiator 60 supplied by Biotage. The current power supplied varies during the course of the reaction to maintain a constant temperature.
[001037] The compounds made in the following examples are summarized in the Tables below, which show affinity values for LRRK2 (Ki, micromolar) for representative compounds along with LCMS method (M), LC retention time (RT) in minu - Mass Spectrometry values and values m/z (molecular weight). Intermediate 1 2,5-Dichloro-4-methoxypyrimidine

[001038] 2,4,5-trichloro-pyrimidine (1 g) and diethyl ether (15 ml) were added to a 250 mL round-bottomed flask equipped with a stir bar. The mixture was cooled to 0°C in an ice bath, then 1 equivalent of sodium methoxide in methanol (prepared by reacting 120 mg of sodium with 4 mL of methanol at room temperature) was slowly added. The reaction was stirred overnight at room temperature and checked by LCMS. The white precipitate was filtered, and the solid washed with cold methanol. After drying, 0.98 g of pure 2,5-dichloro-4-methoxypyrimidine was obtained and this material was used without further purification. 1H-NMR (DMSO): δ 8.61 (s, 1H), 4.05 (s, 3H). Intermediate 2 2,5-Dichloro-N-methylpyrimidin-4-amine

[001039] To a cooled (0°C) solution of 2,4,5-trichloropyrimidine (2.0 g, 11 mmol) in methanol (30 mL) was added dropwise a 2 M solution of methylamine in methanol ( 6.3 ml). The reaction was allowed to warm to room temperature and stirred overnight. The reaction was then concentrated and redissolved in DCM. The solution was washed with sat. NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (0-40% EtOAc in heptane) to yield 2,5-dichloro-N-methylpyrimidin-4-amine (0.9 g, 50%). 1H-NMR (DMSO): δ 8.13 (s, 1H), 7.89 (s, 1H), 2.86 (d, J = 4.5, 3H). Intermediate 3 5-Bromo-2-chloro-N-methylpyrimidin-4-amine

[001040] To a cooled (0 °C) solution of 5-bromo-2,4-dichloropyrimidine (5.0 g, 22 mmol) in methanol (42 mL) was added dropwise a 33% by weight solution of methylamine in ethanol (3.3 mL). The reaction was allowed to warm to room temperature. The reaction was then concentrated. The crude product was purified by column chromatography (0-10% methanol in DCM) to yield 5-bromo-2-chloro-N-methylpyrimidin-4-amine (1.8 g, 39%). 1H-NMR (DMSO): δ 8.22 (s, 1H), 7.75 (s, 1H), 2.85 (d, J = 3.9, 3H). Intermediate 4 5-Bromo-2-chloro-4-methoxypyrimidine

[001041] To a cooled (-78°C) solution of 5-bromo-2,4-dichloropyrimidine (1.7 g, 7.3 mmol) in THF (30 mL) was added a 25% solution dropwise. by weight of methylamine in ethanol (1.7 ml). The reaction was allowed to warm to 0°C and stirred for 1 h. The reaction was then concentrated and redissolved in EtOAc. The solution was washed with brine, dried over Na2SO4, filtered and concentrated to yield 5-bromo-2-chloro-4-methoxypyrimidine (1.25 g, 76%). 1H-NMR (CDCl3): δ 8.43 (s, 1H), 4.10 (s, 3H). Intermediate 5 2-chloro-5-fluoro-N-methylpyrimidin-4-amine

[001042] In a 250 mL round bottom flask equipped with a stir bar were added 5-fluoro-2,4-dichloropyrimidine (9 g), methanol (40 mL) and 8M methylamine in ethanol (15 mL) . The reaction was heated (moderate exotherm) and allowed to stir at room temperature for 30 minutes. A check by TLC (1:1 EtOAc: heptane) and LCMS showed complete reaction. The reaction was concentrated to yield 9.77 g of crude material, which was purified on a silica column driving a gradient of 1% to 10% MeOH in DCM over 35 minutes to yield 2-chloro-5-fluoro-N - methylpyrimidin-4-amine (6.77 g). Intermediate 6 2-Chloro-5-iodo-N-methylpyrimidin-4-amine

[001043] 2-Chloro-5-iodo-N-methylpyrimidin-4-amine was prepared following the procedure for Intermediate 5, however using 2,4-dichloro-5-iodopyrimidine. 1H-NMR (DMSO): δ 8.26 (s, 1H), 5.47 (s, 1H), 3.07 (d, J = 4.9, 3H). Intermediate 7 2-Chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine

[001044] To a cooled (-10°C) solution of 2,4-dichloro-5-trifluoromethylpyrimidine (20 g, 0.089 mol) in methanol (100 ml) was added triethylamine (12.5 ml, 0.089 mol) and a 2M solution of methylamine in methanol (45 mL). The reaction was allowed to warm to room temperature and stirred overnight. The reaction was then concentrated and redissolved in ethyl acetate. The solution was washed with sat. NaHCO3 , brine, dried over MgSO4 , filtered and concentrated. The crude product was purified by column chromatography (525% EtOAc in heptane) to yield 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (8.6 g, 45%). 1H-NMR (DMSO): δ 8.37 (s, 1H), 7.90 (s, 1H), 2.90 (s, 3H). Intermediate 8 2-Chloro-4-(pyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidine

[001045] 2-Chloro-4-(pyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidine was prepared according to the procedure described for intermediate 7 using pyrrolidine. Intermediate 9 2,5-Dichloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrimidine

[001046] To a solution of tetrahydro-4-pyranol (0.36 g, 3.54 mmol) in DMF (5 mL) was added sodium hydride (60% dispersion, 0.17 g, 4.25 mmol). The resulting mixture was added to a solution of 2,4,5-trichloropyrimidine (650 mg, 3.5 mmol) in THF at 0°C. The combined mixture was then allowed to warm to room temperature. To the reaction was then added water, and the product was extracted with a 1:1 mixture of EtOAc-Heptane. The extract was then dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (0-30% EtOAc in heptane) to yield 2,5-dichloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrimidine. 1H-NMR (CDCl3): δ 8.33 (s, 1H), 5.42 (m, 1H), 4.09 - 3.90 (m, 2H), 3.65 (m, 2H), 2. 19-1.99 (m, 2H), 1.87 (m, 2H).
[001047] Additional intermediates prepared using similar methods as described above are listed in Table 1 below: TABLE 1

Intermediates 19 and 20 5-Methyl-1-(oxetan-3-yl)-1H-pyrazol-4-amine and 3-methyl-1-(oxetan-3-yl)-1H-pyrazol-4-amine
Step 1 5-Methyl-4-nitro-1-(oxetan-3-yl)-1H-pyrazole and 3-methyl-4-nitro-1-(oxetan-3-yl)-1H-pyrazole
[001048] To a mixture of 3-methyl-4-nitro-pyrazole (0.80 g, 6.3 mmol), cesium carbonate (4.1 g, 12 mmol) in DMF (10 mL) was added 3- iodo-oxetane (3.47 g, 19 mmol). The mixture was stirred at 100°C for 3 h. The reaction was diluted with water and extracted with ethyl acetate (3x). The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (20-100% EtOAc-heptane) to yield a mixture of 5-methyl-4-nitro-1-(oxetan-3-yl)-1H-pyrazole and 3-methyl- 4-nitro-1-(oxetan-3-yl)-1H-pyrazole (0.85 g, 74%). Step 2 5-Methyl-1-(oxetan-3-yl)-1H-pyrazol-4-amine and 3-methyl-1-(oxetan-3-yl)-1H-pyrazol-4-amine
[001049] In a solution of 5-methyl-4-nitro-1-(oxetan-3-yl)-1H-pyrazole and 3-methyl-4-nitro-1-(oxetan-3-yl)-1H-pyrazole (0.137 g, 0.75 mmol) in ethanol (2 mL) was added Pd-C (10 wt%, 0.10 g). The mixture was stirred under an atmosphere of hydrogen for 24 hours. The reaction was filtered through Celite® and concentrated to yield a mixture of 5-methyl-1-(oxetan-3-yl)-1H-pyrazol-4-amine and 3-methyl-1-(oxetan-3-yl)- 1H-pyrazol-4-amine (83 mg, 73%), which were used together in the following Examples.
[001050] Additional intermediates made using the above procedure are shown in Table 2 below. TABLE 2



Intermediate 49 5-Chloro-1-methyl-1H-pyrazol-4-amine

[001051] To a suspension of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid (1.0 g, 6.2 mmol) in toluene (15 mL) was added triethylamine (1.7 mL, 12 mmol) and diphenylphosphonic azide (2 mL, 9.3 mmol). The resulting solution was stirred at room temperature for 30 minutes before heating to 95°C for 1 h. After cooling to room temperature, the reaction was diluted with water and extracted with ethyl acetate (3x). The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated to yield a yellow syrup. The crude product was purified by column chromatography (0-50% EtOAc in heptane) to yield 5-chloro-1-methyl-1H-pyrazol-4-amine. 1H-NMR (CDCl3): δ 7.90 (s, 1H), 3.88 (s, 2H), 1.55 (s, 3H). Intermediates 50 and 51 (S)-3-methyl-1-(1-(oxetan-3-yl)pyrrolidin-3-yl)-1H-pyrazol-4-amine and (S)-5-methyl-1-( 1-(oxetan-3-yl)pyrrolidin-3-yl)-1H-pyrazol-4-amine
Step 1: (R)-tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate
[001052] (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (5.0 g, 26.7 mmol) and Et 3 N (8.0 g, 80.2 mmol) were dissolved in dichloromethane (50 mL). The mixture was stirred at 0°C for 30 minutes, then methanesulfonyl chloride (4.5 g, 40.1 mmol) was added dropwise. It was stirred at room temperature for 2 h and concentrated under reduced pressure. DCM (50 ml) and water (50 ml) were added. The organic phase was washed with saturated NaHCO 3 (30 mL) and H 2 O (2 x 30 mL) and concentrated to provide the title compound as an oil (6 g, 100%). Step 2: (S)-tert-butyl 3-(3-methyl-4-nitro-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate and (S)-tert-butyl 3-(5-methyl-4) -nitro-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate
[001053] A microwave flask equipped with a magnetic stirrer was charged with (R)-tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (6.0 g, 22.5 mmol), 5-methyl- 4-nitro-1H-pyrazole (2 g, 15.1 mmol), K2CO3 (6.2g, 45.3 mmol) and DMF (50 mL). The reaction mixture was heated at 100 °C for 1 h under microwave irradiation. It was then filtered to get rid of K2CO3, and the filtrate was concentrated. The residue was purified by chromatography on silica gel eluting with petroleum ether/ethyl acetate (2:1) to give the mixture of the two title compounds as brown oil (5 g, 100%). m/z (ES+APCI)+: [M+H]+ 241.
[001054] Alternatively, (S)-tert-butyl 3-(3-methyl-4-nitro-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (049-3) and (S)-tert-butyl 3 -(5-methyl-4-nitro-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate or related analogs such as tert-butyl 3-fluoro-4-(3-methyl-4-nitro-1H-pyrazole -1-yl)piperidine-1-carboxylate, can be prepared by the following procedure: In a solution of 5-methyl-4-nitro-1H-pyrazole (0.99 g, 7.8 mmol), tert-butyl 3- fluoro-4-hydroxypiperidine-1-carboxylate (1.7 g, 7.8 mmol) and triphenylphosphine (2.3 g, 8.5 mmol) in THF (8 mL) was added diisopropyl azodicarboxylate ( 2 g, 9.3 mmol). The reaction was stirred at room temperature for 2 hours before being diluted with water and extracted with EtOAc (4x). The organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by chromatography to give tert-butyl 3-fluoro-4-(3-methyl-4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate (2.25 g, 88%). Step 3: (S)-3-methyl-4-nitro-1-(pyrrolidin-3-yl)-1H-pyrazole and (S)-5-methyl-4-nitro-1-(pyrrolidin-3-yl) -1H-pyrazole
[001055] The mixture of (S)-tert-butyl 3-(3-methyl-4-nitro-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate and (S)-tert-butyl 3-(5- methyl-4-nitro-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (5 g, 16.9 mmol) was dissolved in dichloromethane (40 mL). CF3COOH (10 mL) was added, and the mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure to provide the mixture of the two title compounds as brown oil (4.0 g, 100%). m/z (ES+APCI)+: [M+H]+ 197. Step 4: (S)-3-methyl-4-nitro-1-(1-(oxetan-3-yl)pyrrolidin-3-yl)-1H-pyrazole and (S)-5-methyl-4-nitro- 1-(1-(oxetan-3-yl)pyrrolidin-3-yl)-1H-pyrazole
[001056] To the mixture of (S)-3-methyl-4-nitro-1-(pyrrolidin-3-yl)-1H-pyrazole and (S)-5-methyl-4-nitro-1-(pyrrolidin-3 -yl)-1H-pyrazole (4 g, 20.4 mmol), oxetan-3-one (4.4 g, 61.2 mmol) and ZnCl 2 (8.3 g, 61.2 mmol) in MeOH (50 mL) was added NaBH4 (3.8 g, 61.2 mmol). The mixture was stirred at 50°C for 5 h. Then the solvent was removed in vacuo. Dichloromethane (100 mL) was added, and the mixture was washed with water (2 x 50 mL). It was then concentrated in vacuo and purified by chromatography on silica gel eluting with dichloromethane/methanol (25/1) to give the mixture of the two title compounds as a yellow oil (3.8g, 75%). m/z (ES+APCI)+: [M+H]+ 253. Step 5: (S)-3-Methyl-1-(1-(oxetan-3-yl)pyrrolidin-3-yl)-1H-pyrazol-4-amine and (S)-5-methyl-1-(1 -(oxetan-3-yl)pyrrolidin-3-yl)-1H-pyrazol-4-amine
[001057] To the mixture of (S)-3-methyl-4-nitro-1-(1-(oxetan-3-yl)pyrrolidin-3-yl)-1H-pyrazole and (S)-5-methyl-4 -nitro-1-(1-(oxetan-3-yl)pyrrolidin-3-yl)-1H-pyrazole (500 mg, 1.98 mmol), and Zn (506 mg, 7.94 mmol) in methanol (20 mL) THF (20 mL) and NH4Cl (841 mg, 15.9 mmol) were added. The mixture was stirred at 50°C for 2 h. It was then concentrated and purified by prep. phase to give the mixture of the two title compounds as a yellow solid (200 mg, 45%). m/z (ES+APCI)+: [M+H]+ 223.
[001058] Additional intermediates made using the above procedure are shown in Table 3 below. TABLE 3


Intermediates 67 and 68: 3-Methyl-1-(4-(methylsulfonyl)phenyl)-4-nitro-1H-pyrazole compound with 5-methyl-1-(4-(methylsulfonyl)phenyl)-4-nitro-1H- pyrazole
Step 1: Compound 3-Methyl-1-(4-(methylsulfonyl)phenyl)-4-nitro-1H-pyrazole and 5-methyl-1-(4-(methylsulfonyl)phenyl)-4-nitro- 1H-pyrazole
[001059] A mixture of 3-methyl-4-nitro-1H-pyrazole (2.1 g, 17 mmol) and 4-methylsulfonylphenylboronic acid (5.0 g, 25 mmol), copper(II) acetate monohydrate ( 0.91 g, 5.0 mmol) and pyridine (0.5 g, 6.6 mmol) in DMF was stirred at 95°C under an atmosphere of oxygen for 7 hours. The reaction was diluted with water, extracted with EtOAc (3x). The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography to yield a mixture of 3-methyl-1-(4-(methylsulfonyl)phenyl)-4-nitro-1H-pyrazole and 5-methyl-1-(4-(methylsulfonyl) compound. )phenyl)-4-nitro-1H-pyrazole (1.3 g, 28%). Step 2: 3-Methyl-1-(4-(methylsulfonyl)phenyl)-4-nitro-1H-pyrazole compound with 5-methyl-1-(4-(methylsulfonyl)phenyl)-4-nitro-1H-pyrazole
[001060] A suspension of 3-methyl-1-(4-(methylsulfonyl)phenyl)-4-nitro-1H-pyrazole and 5-methyl-1-(4-(methylsulfonyl)phenyl)-4-nitro-1H compound -pyrazole (0.57 g, 2.0 mmol) and palladium on carbon (10% by weight, 0.2 g) in ethanol was stirred under a hydrogen atmosphere at 55°C for 18 hours. The reaction mixture was filtered through celite and concentrated to yield the title compounds as a mixture of regioisomers (446 mg, 87%).
[001061] Additional intermediates made using the above procedure are shown in Table 4 below TABLE 4


Intermediate 85: 5-Chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine
Step 1: 5-Chloro-4-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole
[001062] To a solution of 4-nitro-1-tetrahydropyran-4-yl-pyrazole (1.32 g; 6.69 mmol) in THF (15 mL) was added LHMDS (1 mol/L) dropwise. ) in THF (2.0 equiv.; 13.4 mmol) at -78°C. The reaction was stirred at -78°C for 30 minutes before hexachloroethane (2.4 g, 10 mmol) in THF (5 mL) was added. The reaction was stirred at -78°C before warming to room temperature. The reaction was diluted with sat. NaCl. and extracted with EtOAc (3x). The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography to yield 5-chloro-4-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (0.98 g, 63%). Step 2: 5-Chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine
[001063] In a solution of 5-chloro-4-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (0.4 g, 2 mmol) in ethanol (10 mL) was ammonium chloride (0.3 g, 5 mmol) and iron (0.3 g) are added. The reaction was stirred at 90°C for 30 minutes before being filtered through Celite® and concentrated. The residue was triturated in EtOAc and filtered. The filtrates were concentrated to give the title compound (0.34 g, quant.)
[001064] Additional intermediates made using the above procedure are shown in Table 5 below. TABLE 5

Intermediates 96: 3-Cyclopropyl-4-nitro-1H-pyrazole
Step 1: 3-cyclopropyl-1H-pyrazole
[001065] Ethynylcyclopropane (660 mg, 10 mmol) mixed with (diazomethyl)trimethylsilane (5 mL, 2M in hexane) in a 30 mL microwave tube was microwaved at 135°C for 1 h. This reaction was then concentrated in vacuo to yield a light yellow oily product (1.02 g, 94%). This product was pure enough to be used in the next step reaction without further purification. MS: [M+H]+ 109. Step 2: 3-Cyclopropyl-4-nitro-1H-pyrazole
[001066] To a cooled (0°C) solution of 3-cyclopropyl-1H-pyrazole (1.5 g, 13.89 mmol) in concentrated H2SO4 (20 mL, 98%) was added concentrated HNO3 (20 mL, 65 %) for 2 min. The reaction mixture was stirred for 1 hr at this temperature. It was then diluted with ice water and extracted with EA (30 mL X 4). The organic phase was combined and washed with saturated sodium bicarbonate (50 mL). It was dried over Na2SO4 and concentrated in vacuo to yield a crude product (1.5 g, 70%). This crude product was pure enough to be released or used in the next step reaction. MS: [M+H]+ 154. 1H NMR (500 MHz, CDCl 3 ) δ 0.97 (m, 2H), 1.22 (m, 2H), 2.66 (m, 1H), 8.20 ( s, 1H), 8.38 (s, 1H).
[001067] Intermediates made using the above procedure are shown in Table 6 below TABLE 6
Example 1 N2-(1-isopropyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine

[001068] In a microwave tube was added 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (112 mg, 0.53 mmol), 1-isopropyl-1H-pyrazol-4- amine (55mg, 0.44mmol), cesium carbonate (0.287g, 0.88mmol), XPhos (21mg, 0.044mmol), Pd2(dba)3 (20mg, 0.02mmol) and dioxane ( 2.5 ml). The tube was sealed, and the reaction was irradiated in the microwave at 140°C for 30 minutes. The reaction mixture was then filtered and concentrated. The crude product was purified by reverse phase HPLC to yield N2-(1-isopropyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (22 mg, 16% ). LCMS (Method A): [MH+] = 301.1 to 3.2 min. 1H-NMR (DMSO): δ 9.43 (m, 2H), 8.08 (s, 1H), 7.89 (s, 1H), 7.54 (s, 1H), 6.96 (m, 1H), 2H), 4.43 (m, 1H), 2.92 (d, J = 8.0, 3H), 1.39 (d, J = 6.6, 6H).
[001069] Compounds made using the above procedure are shown in Table 7 below, along with low resolution mass spectrometry (M+H), proton NMR and LRRK2 Ki (micromolar) data for selected compounds determined at from the assay described below. TABLE 7














Example 89 5-Bromo-N2-(1,5-dimethyl-1H-pyrazol-4-yl)-N4-methylpyrimidine-2,4-diamine
[001070] In a mixture of 5-bromo-2-chloro-N-methylpyrimidin-4-amine (0.201 g, 0.903 mmol) and 1,5-dimethyl-1H-pyrazol-4-amine (0.12 g, 1 .08 mmol) in 2-methoxyethanol (2 mL) was added TFA (0.070 mL, 0.9 mmol). The reaction was stirred in a sealed tube at 100°C for 90 minutes. The resulting precipitate was collected by filtration. The isolated solid was also purified by reverse phase HPLC to yield 5-bromo-N2-(1,5-dimethyl-1H-pyrazol-4-yl)-N4-methylpyrimidine-2,4-diamine (46 mg, 17% ). LCMS (Method A): [MH+] = 297.0 to 2.57 min. 1H-NMR (DMSO): δ 8.28 (s, 1H), 7.84 (s, 1H), 7.49 (s, 1H), 6.79 (d, J = 3.4, 1H), 3.67 (s, 3H), 2.82 (d, J = 3.6, 3H), 2.14 (s, 3H). Ki = 0.017 μM.
[001071] Compounds made using the above procedure are shown in Table 8 below, along with low resolution mass spectrometry (M+H), proton NMR and LRRK2 Ki (micromolar) data for selected compounds determined from the assay described below. TABLE 8
























































Example 349 2-(1,5-Dimethyl-1H-pyrazol-4-ylamino)-4h(methylamino)pyrimidine-5-carbonitrile

[001072] In a mixture of 5-bromo-N2-(1,5-dimethyl-1H-pyrazol-4-yl)-N4-methylpyrimidine-2,4-diamine (95 mg, 0.32 mmol), sodium cyanide zinc (70mg, 0.60mmol), Pd2(dba)3 (11mg, 0.012mmol), DPPF (13mg, 0.023mmol) was added DMF (3.5mL). The reaction was then heated in a sealed tube at 105°C for 18 h. The reaction mixture was filtered and concentrated. The crude product was purified by reverse phase HPLC to yield 2-(1,5-dimethyl-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile (19 mg, 25%). LCMS (Method A): [MH+] = 244.1 to 2.53 min. 1H-NMR (DMSO): δ 8.96 (m, 1H), 8.21 (m, 1H), 7.49 (m, 2H), 3.69 (s, 3H), 2.84 (m, 3H), 3H), 2.14 (m, 3H). KI = 0.025 μM.
[001073] Compounds made using the above procedure are shown in Table 9 below, along with low resolution mass spectrometry (M+H), proton NMR and LRRK2 Ki (micromolar) data for selected compounds determined at from the assay described below. TABLE 9








Example 393 (5-(5-Chloro-4-(methylamino)pyrimidin-2-ylamino)-1-methyl-1H-pyrazol-3-yl)(morpholino)methanone
Step 1 Methyl 5-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-1-methyl-1H-pyrazole-3-carboxylate
[001074] To a 30 mL microwave flask was added 0.98 g of 2,5-dichloro-N-methylpyrimidin-4-amine, 0.78 g of methyl 5-amino-1-methyl-1H- pyrazole-3-carboxylate, 10 ml of 1-butanol and 0.13 ml of 4M hydrogen chloride in dioxane. The vial was capped, and the reaction was heated in a microwave for 30 minutes at 130°C. When the reaction cooled, a precipitate dispersed. Filter the precipitate and rinse with a small amount of n-butanol. Dry the mass produced of 0.964 g of methyl 5-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-1-methyl-1H-pyrazole-3-carboxylate which was used without further purification. Step 2 5-(5-Chloro-4-(methylamino)pyrimidin-2-ylamino)-1-methyl-1H-pyrazole-3-carboxylic acid
[001075] In a 100 mL round-bottomed flask equipped with a stir bar, 0.964 g of methyl 5-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-1-methyl-1H-pyrazole was added -3-carboxylate, 0.28 g of LiOH, 15 ml of tetrahydrofuran and 10 ml of water. The reaction was stirred at room temperature for 18 hours. The tetrahydrofuran was removed in vacuo, and the aqueous layer was acidified to pH 5 with 1N HCl. The aqueous layer was partitioned with ethyl acetate, and the organic layer washed with brine, dried over MgSO4, filtered and concentrated to yield 0.58 g of 5-(5-chloro-4-(methylamino)pyrimidin-2-ylamino acid )-1-methyl-1H-pyrazole-3-carboxylic acid, which was used without further purification. Step 3 (5-(5-Chloro-4-(methylamino)pyrimidin-2-ylamino)-1-methyl-1H-pyrazol-3-yl)(morpholino)methanone
[001076] 0.116 g of 5-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-1-methyl-1H-pyrazol- 3-carboxylic acid, 0.19 g of o-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate, 0.14 ml of diisopropylethylamine and 2 ml of dimethylformamide. After preactivating for 10 minutes, 0.05 mL of morpholine was added, and the reaction stirred at room temperature for 2 hours. The reaction was concentrated and purified by preparative reversed-phase HPLC to yield 53.2 mg of (5-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-1-methyl-1H-pyrazol-3-yl )(morpholino)methanone. LCMS (Method A): [MH+] = 352.0 to 2.80 min. 1H-NMR (DMSO): δ 9.47 (s, 1H), 7.86 (s, 1H), 7.15 (s, 1H), 6.78 (s, 1H), 3.74 (s, 1H), 3H), 3.61 (m, 8H), 2.88 (d, 3H). KI = 0.16 μM. Example 394 2-Methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile
Step 1: 2-Methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanamide.
[001077] In a solution of 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanoic acid (2.5 g, 11.7 mmol) in CH2Cl2 (50 mL) was Oxalyl chloride (2.97 g, 23.4 mmol) is added dropwise. The reaction was stirred at room temperature for about 2 hours, then concentrated under reduced pressure to remove the solvent, the remaining solid was dissolved in THF (30 mL) and added dropwise in NH4OH (50 mL), the reaction was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure and partitioned between EtOAc (50 mL) and water (100 mL), the aqueous phase was extracted with EtOAc, and the combined organic was washed with sat. (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to give crude 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanamide (2.5 g, 100%) as white solid, which was used in the next step without further purification. Step 2: 2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanamide.
[001078] To a solution of 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanamide (2.5 g, 11.7 mmol) in MeOH (50 mL) was added Pd/C (1 g), exchanged with nitrogen three times, then with hydrogen, and the reaction was stirred in a hydrogen atmosphere (1 atm) for 1 h at room temperature. The solution was filtered, and the filtrate was concentrated under reduced pressure to yield crude 2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanamide (2.0 g, 93%), which was used in the next step without further purification. Step 3: 2-Methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanamide
[001079] To a solution of 2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanamide (250 mg, 1.37 mmol) in 2-methoxyethanol (5 mL) were added 2 -chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (290 mg, 1.37 mmol) and trifluoroacetic acid (156 mg, 1.37 mmol), the reaction was stirred at 70°C for ca. 0.5 h. The reaction mixture was cooled to room temperature, followed by the addition of water (10 mL), and the pH of the solution was adjusted to 8 with sat. Na2CO3. The aqueous phase was extracted with ethyl acetate (10 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to dryness to yield a residue, which was purified by silica gel column chromatography (CH2Cl2:MeOH = 20:1) to yield 2-methyl-2 -(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanamide (250 mg, 51%) as white solid. LCMS (m/z) ES+ 358 (m+H). Step 4: 2-Methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile
[001080] A stirred solution of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanamide (250 mg, 0.7 mmol) in POCl 3 (5 mL) was stirred at 90°C for 1 hour. POCl3 was removed by evaporation, the mixture was added in ice/H2O (10 ml), and the pH of the solution was adjusted to 8 with sat. Na2CO3, the aqueous phase was extracted with ethyl acetate (5 ml x 3). The combined organic phase was washed with sat. sodium chloride. (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness to yield a residue, which was purified by recrystallization to yield 2-methyl-2-(3-methyl-4-(4-(methylamino) )-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile (100 mg, 42%) as a white solid. 1H-NMR (300 MHz, DMSO-d6) δ ppm 9.18 (s, 1H), 8.29 (s, 1H), 8.14 (s, 1H), 7.10 (s, 1H), 2 .91 (d, 3H), 2.22 (s, 3H), 1.94 (s, 2H). LCMS (m/z) ES+ 340 (m+1). Purity, 99.3% (HPLC at 214 nm); Ki = 0.0005 μM.
[001081] Compounds made using the above procedure are shown in Table 10 below, along with low resolution mass spectrometry (M+H), proton NMR and LRRK2 Ki (micromolar) data for selected compounds determined at from the assay described below. TABLE 10












Example 454: LRRK2 In Vitro Lantascreen Binding Assay
[001082] This assay was used to determine the potency of a compound in inhibiting LRRK2 activity by determining Kiapp, IC50 or percent inhibition values. On LRRK2 shallow well plates, black 384-well F proxies, black Eu-anti-GST-antibody, Alexa Fluor® 236 Kinase tracer, and test compound were incubated together.
[001083] Binding of the Alexa Fluor® "tracer" to a kinase is detected by addition of an Eu-labeled anti-GST antibody. Binding of the tracer and antibody to a kinase results in a high degree of FRET, whereas the displacement of the tracer with a kinase inhibitor results in a loss of FRET.
[001084] The test conditions and materials used were as follows: Final Test Conditions:
Materials: Perkin Elmer black shallow cavity 384-well F proxies cat # 6008260 Kinase: LRRK2 G2019S, Invitrogen cat # PV4882(LOT 567054A). Eu-labeled anti-GST antibody Invitrogen cat # PV5594 Kinase 236 tracer Alexa Fluor® Invitrogen cat # PV5592 TRIS - HCl Sigma cat # T3253 EGTA Sigma cat # E3889 Brij-35: Sigma cat # B4184 (30% w/v) DMSO: Sigma cat # D8418 MgCl2 Sigma cat # M9272 Reaction Buffer: H2O/50 mM Tris, pH 7.4/10 mM MgCl2/1 mM EGTA/0.01% Brij 35 Compound Plate Preparation:
[001085] Serially dilute test compounds (10 mM raw material) 1:3.16 (20 ul + 43.2 ul) in 100% DMSO. 12pt curve. Dilute each concentration 1:33.3 (3 µl + 97 µl) in reaction buffer. Fix 5 ul to the assay plate. Final top test concentration 100 uM Total and Blank Preparation:
[001086] In Reaction Buffer, 5 ul of DMSO (3%) was added to total and blank wells and 5 ul of Eu-labeled anti-GST antibody (6 nM) was added to blank wells. Add 5 µl LRRK2 (30nM) / Eu-labeled anti-GST antibody (6 nM), mix to compound and total wells. Test Procedure:
[001087] Add 5 ul of kinase tracer (25.5 nM) to all wells. Incubate plates at room temperature for 1 hour on a plate shaker (gentle shaking). Read on a Perkin Elmer EnVision reader, HTRF protocol Data Handling:
[001088] Calculate the ratio: (665/620)*10000. Subtract the average base values from all data points. Calculate the % of control for each test value. Plot the % Control Concentration VS Compound. Calculate the Ki Value (xlfit curve fitting - Morrison equation). The eresults are expressed as a Ki in μM. Equation for Ki: Y=V0*(1-((x+Ki*(1+S/Km)+Et)/(2*Et)- (((x+Ki* (1+S/Km)+Et)^2-(4*Et*x))^0.5)/(2*Et))) Where Et = 4 nM kd (Tracer) = 8.5 nM Concentration of tracer (S) = 8.5 nM Example 455: In Vitro LRRK2 Assay
[001089] This assay was used to determine the potency of a compound in inhibiting LRRK2 activity by determining Kiapp, IC50, or percent inhibition values. On a polypropylene plate, LRRK2, fluorescently labeled peptide substrate, ATP and test compound were incubated together. Using a LabChip 3000 (Caliper Life Sciences), after the reaction, the substrate was separated by capillary electrophoresis into two populations: phosphorylated and non-phosphorylated. The relative amounts of each were quantified by fluorescence intensity. Ki of LRRK2 was determined according to the 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))).
[001090] The Ki values in Table 4 and elsewhere here are shown in μM.
[001091] Assay conditions and materials used were as follows: Final Assay Conditions: LRRK2 G2019S in 5 mM MgCl2: 5.2 nM (Invitrogen lo te # 567054A) LRRK2 G2019S in 1 mM MnCl2: 11 nM (Invitrogen lot # 567054A) Wild type LRRK2 in MgCl2 at 5 mM: 15 nM (Invitrogen lot # 500607F) LRRK2 I2020T in MgCl2 at 5 mM: 25 nM (Invitrogen lot # 43594) Substrate: 1 μM ATP: 130 μM Time kinase reaction time: 2 hours Temperature: ambient Total volume: 20 μl ATPapp Kms: G2019S in 5 mM MgCl2: 130 μM G2019S in 1 mM MnCl2: 1 μM Wild type in 5 mM MgCl2: 80 μM I2020T in MgCl2 a 5 mM: 14 μM Materials: Solid support: Black volume 50 μL polypropylene 384-well plate (MatriCal cat # MP101-1-PP) Kinase: LRRK2 G2019S (Invitrogen cat # PV4882). Wild type LRRK2 (Invitrogen cat # PV4874). Substrate: 5FAM-GAGRLGRDKYKTLRQIRQ-CONH2 Non-Binding Plate: 384-well clear V-base polypropylene plate (Greiner cat # 781280). ATP: 10 mM ATP (Cell Signaling cat # 9804). Triton X-100: Triton X-100. Brij-35: Brij-35 (Pierce cat # 20150). Coating Reagent #3: Coating Reagent #3 (Caliper). DMSO: DMSO (Sigma cat # 34869-100ML). Complete Reaction Buffer: H2O/25mM Tris, pH 8.0/5mM MgCl2/2mM DTT/0.01% Triton X-100. Stopping Solution: H2O/100 mM HEPES, pH 7.2/0.015% Brij-35/0.2% Coating Reagent #3/20 mM EDTA. Separation Buffer: H2O/100 mM HEPES, pH 7.2/0.015% Brij-35/0.1% Coating Reagent #3/1:200 Coating Reagent #8/10 mM EDTA/ 5% DMSO. Compound Plate Preparation:
[001092] For serial dilutions, 34.6 μl of DMSO was added to columns 3-24. For assay controls, 37.5 μl of DMSO was added to columns 1 and 2 of rows A and P. For samples: to start at 100 μM, 37.5 μl of DMSO went to columns 1 and 2, then 12.5 μl of compounds at 10 mM; to start at 10 µM, 78 µl of DMSO was added to columns 1 & 2, then 2 µl of 10 mM compounds; and to start at 1 μM, 25 μM compounds (2 μl of comp. at 10 mM + 798 μl of DMSO) were added to empty columns 1 and 2. A Precision instrument was used to perform 1:3, 16 serial dilutions ("PLK_BM_serial_halflog"). ATP preparation:
[001093] ATP was diluted to 282.1 μM in Complete Kinase Buffer (final concentration was 130 μM). Full and Blank Preparation:
[001094] In Complete Reaction Buffer, the substrate was diluted to 4 μM. Equal volumes of Complete Reaction Buffer and 4 μM substrate were combined to obtain the blank. Equal volumes of Complete Reaction Buffer and 4 µM substrate were combined and 2X final LRRK2 concentration was added to the combined solution. Test Procedure:
[001095] In a 50 μl polypropylene plate, 5 μl/well of buffer/substrate was manually added to the Blank wells. A Biomek FX was used to start the kinase reaction ("PLK SAR 23 ATP"). The following were added to the appropriate wells: 2 µl of compounds + 23 µl of ATP; 5 µl/well of compound/ATP on Assay Plate; 5 µl/well kinase/substrate on Assay Plate;
[001096] The plate was incubated for 2 hours in the dark. Biomek FX was used to stop the kinase reaction ("PLK Stop"), and 10 μl/well of Stop solution was added to the Assay Plate. The results were read on the LabChip 3000. Lab Chip 3000 Protocol: The LabChip 3000 was conducted using the "LRRK2 IC50" task with the following task settings: Pressure: -1.4 psi Downstream Voltage: -500 V Upstream Voltage: -2350 V Post-Sample Buffer Proof Sample: 75 seconds Post-Dye Buffer Proof Time: 75 seconds Final Delay Time: 200 seconds Example 456 Mouse model with Parkinson's disease
[001097] Parkinson's disease can be reproduced in mice and primates by administration of 1-methyl-4-phenyl tetrahydropyridine (MPTP), a selective nigrostriatal dopaminergic neurotoxin that produces a loss of striatal dopamine nerve terminal markers ( GIVES). Compounds of the invention can be evaluated for efficacy in the treatment of Parkinson's disease using MPTP-induced neurodegeneration following the protocol described by Saporito et al., J. Pharmacology (1999) Vol. 288, pp. 421-427.
[001098] Briefly, MPTP is dissolved in PBS at concentrations of 2-4 mg/ml, and mice (C57 males weighing 20-25 g) are given a subcutaneous injection of 20 to 40 mg/kg. Compounds of the invention are solubilized with polyethylene glycol hydroxystearate and dissolved in PBS. Mice are given 10 ml/kg of compound solution by subcutaneous injection 4 to 6 h prior to MPTP administration, then daily for 7 days thereafter. On the day of the last injection, mice are sacrificed and the midbrain blocked and post-fixed in paraformaldehyde. Stria are dissected free, weighed and stored at -70°C.
[001099] The striatum thus collected are evaluated for the content of dopamine and its metabolites, dihydroxyphenylacetic acid and homovanillic acid, by HPL
[001100] C with electrochemical detection as described by Sonsalla et al., J.Pharmacol. Exp. Ther. (1987) Vol. 242, pp. 850-857. The striatum can also be evaluated using the tyrosine hydroxylase assay of Okunu et al., Anal Biochem (1987) Vol. 129, pp. 405-411 measuring the evolution of 14CO2 associated with the tyrosine hydroxylase-mediated conversion of labeled tyrosine to L-dopa. The striatum can also be evaluated using the Monoamine oxidase-B assay as described by White et al., Life Sci. (1984), Vol. 35, pp. 827-833, and monitoring dopamine uptake as described by Saporito et al., (1992) Vol. 260, pp. 827-833. 1400-1409.
[001101] While the present invention has been described with reference to specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the spirit and scope of the invention. Furthermore, many modifications may be made to adapt a particular situation, material, composition of matter, process, step or process 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 thus far.

权利要求:
Claims (7)
[0001]
A compound, characterized in that it is selected from the group consisting of: N2-(1,5-dimethyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4- diamine, N4-methyl-N2-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-methyl-N2-(1-methyl-1H-pyrazol- 5-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-methyl-N2-(1-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine , N2-(1,3-dimethyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-methyl-5-(trifluoromethyl)-N2-(1 ,3,5-Trimethyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine, 5-Chloro-N-(1-isopropyl-1H-pyrazol-4-yl)-4-(tetrahydro- 2H-Pyran-4-yloxy)pyrimidin-2-amine, 5-Chloro-N-(1,5-dimethyl-1H-pyrazol-4-yl)-4-methoxypyrimidin-2-amine, N-(1,5 -dimethyl-1H-pyrazol-4-yl)-4-(pyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-amine, N2-(1-ethyl-5-methyl-1H-pyrazol-4- yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, 5-Chloro-N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-methoxypyrimidin-2-amine, N4- methyl-N2-(3-methyl-1-(oxetan-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N2-(5-chloro-1- methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, 5-Chloro-4-methoxy-N-(3-methyl-1-(oxetan-3- yl)-1H-pyrazol-4-yl)pyrimidin-2-amine, 5-Chloro-4-methoxy-N-(1-(2-methoxyethyl)-3-methyl-1H-pyrazol-4-yl)pyrimidin- 2-amino, 5-chloro-4-methoxy-N-(1-(2-methoxyethyl)-5-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine, 5-Chloro-N-(5- chloro-1-methyl-1H-pyrazol-4-yl)-4-methoxypyrimidin-2-amine, 2-methyl-1-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin- 2-ylamino)-1H-pyrazol-1-yl)propan-2-ol, 2-methyl-1-(3-methyl-4-(4-(methylamino)-5-chloro-pyrimidin-2-ylamino)- 1H-pyrazol-1-yl)propan-2-ol, N2-(1-(2-methoxyethyl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2 ,4-diamine, N2-(1-(2-methoxyethyl)-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, 5-Chloro- N-(1-Ethyl-3-methyl-1H-pyrazol-4-yl)-4-methoxypyrimidin-2-amine, 5-Chloro-N4-methyl-N2-(3-methyl-1-(ox) ethan-3-yl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine, N2-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-( trifluoromethyl)pyrimidine-2,4-diamine, 5-Chloro-N-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-4-methoxypyrimidin-2-amine, 5-Chloro-N2-(1 ,3-Dimethyl-1H-pyrazol-4-yl)-N4-methylpyrimidine-2,4-diamine, 5-Chloro-N2-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-N4- methylpyrimidine-2,4-diamine, N4-methyl-N2-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine -2,4-diamine, N4-methyl-N2-(5-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine- 2,4-diamine, 5-Fluoro-N4-methyl-N2-(2-methyl-2H-pyrazol-3-yl)-pyrimidine-2,4-diamine, N2-(2,5-Dimethyl-2H-pyrazole -3-yl)-5-fluoro-N4-methyl-pyrimidine-2,4-diamine, N2-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-N4-methyl-5-(trifluoromethyl) )pyrimidine-2,4-diamine, 5-Chloro-N-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-4-methoxypyrimidin-2-amine, N2-(3-Cyclopropyl-1- methyl-1H-pyrazol-5-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine- 2,4-diamine, 5-Chloro-N-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-4-methoxypyrimidin-2-amine, 5-Chloro-N2-(5-isopropyl-2 -methyl-2H-pyrazol-3-yl)-N4-methyl-pyrimidine-2,4-diamine, 5-Chloro-4-methoxy-N-(1,3,5-trimethyl-1H-pyrazol-4-yl) )pyrimidin-2-amine, 5-Chloro-N4-methyl-N2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-pyrimidine-2,4-diamine, 5-Chloro-N2-( 5-cyclopropyl-2-methyl-2H-pyrazol-3-yl)-N4-methyl-pyrimidine-2,4-diamine, N4-methyl-N2-(5-methyl-1-oxetan-3-yl-1H- pyrazol-4-yl)-5-trifluoromethyl-pyrimidine-2,4-diamine, 5-Chloro-N-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-4-methoxypyrimidin-2-amine , 5-Chloro-N2-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-N4-methylpyrimidine-2,4-diamine, N2-(1-ethyl-3-methyl-1H-pyrazol- 4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, 5-Chloro-N2-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-N4-methylpyrimidine- 2,4-diamine, 5-chloro-4-methoxy-N-(3-methyl-1-(methylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-2-amine, 5-chloro-4-methoxy-N -(5-methyl-1-phenyl-1H-pyrazol-4-yl)pyrimidin-2-amine, N4-methyl-N2-(5-methyl-1-(2,2,2-tri fluoroethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, 5-chloro-4-methoxy-N-(5-methyl-1-(4-(methylsulfonyl)phenyl) -1H-pyrazol-4-yl)pyrimidin-2-amine, N4-ethyl-N2-(1-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, 5- chloro-N-(1,5-dimethyl-1H-pyrazol-4-yl)-4-(oxetan-3-yloxy)pyrimidin-2-amine, 5-chloro-4-(2,2-difluoroethoxy)-N -(1,5-dimethyl-1H-pyrazol-4-yl)pyrimidin-2-amine, 5-chloro-N-(1,5-dimethyl-1H-pyrazol-4-yl)-4-(2,2 ,2-trifluoroethoxy)pyrimidin-2-amine, 5-chloro-4-methoxy-N-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl) pyrimidin-2-amine, (4-(4-(5-chloro-4-methoxypyrimidin-2-ylamino)-3-methyl-1H-pyrazol-1-yl)piperidin-1-yl)(1-methylcyclopropyl)methanone , (4-(4-(5-chloro-4-methoxypyrimidin-2-ylamino)-5-methyl-1H-pyrazol-1-yl)piperidin-1-yl)(1-methylcyclopropyl)methanone, 4-(4 -(5-chloro-4-methoxypyrimidin-2-ylamino)-3-methyl-1H-pyrazol-1-yl)benzonitrile, 5-chloro-4-methoxy-N-(3-methyl-1-(3-methylpyridin) -4-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine, 5-chloro-N-(1-(cyclopro phenylsulfonyl)-5-methyl-1H-pyrazol-4-yl)-4-methoxypyrimidin-2-amine, 5-chloro-N-(1-(cyclopropylsulfonyl)-3-methyl-1H-pyrazol-4-yl)- 4-methoxypyrimidin-2-amine, 2-(4-(5-chloro-4-methoxypyrimidin-2-ylamino)-5-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile, 2-(4-( 5-chloro-4-methoxypyrimidin-2-ylamino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile, 5-chloro-4-ethoxy-N-(5-methyl-1-(tetra- hydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine, (5-Chloro-4-methoxy-pyrimidin-2-yl)-[1-(4-methanesulfonyl-phenyl) )-3-methyl-1H-pyrazol-4-yl]-amine, (5-Chloro-4-methoxy-pyrimidin-2-yl)-(3-methyl-1-phenyl-1H-pyrazol-4-yl) -amine, (4-Methoxy-5-trifluoromethyl-pyrimidin-2-yl)-(3-methyl-1-phenyl-1H-pyrazol-4-yl)-amine, (4-Methoxy-5-trifluoromethyl-pyrimidin- 2-yl)-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-amine, (5-Chloro-4-methoxy-pyrimidin-2-yl)-(1-methanesulfonyl-3-methyl- 1H-pyrazol-4-yl)-amine, (5-Chloro-4-methoxy-pyrimidin-2-yl)-[5-methyl-1-(tetrahydro-pyran-4-yl)-1H-pyrazol- 4-yl]-amine, 4-[4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-3- methyl-pyrazol-1-yl]-N,N-dimethyl-benzamide, 4-[4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-5-methyl-pyrazol-1-yl]-N ,N-Dimethyl-benzamide, 4-[4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-5-methyl-pyrazol-1-yl]-benzonitrile, N2-(5-Methoxy-1- methyl-1H-pyrazol-4-yl)-N4-methyl-5-trifluoromethyl-pyrimidine-2,4-diamine, (5-Chloro-4-methoxy-pyrimidin-2-yl)-[5-chloro-1- (tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-amine, (5-Chloro-4-methoxy-pyrimidin-2-yl)-{1-[1-(2-fluoro- ethyl)-piperidin-4-yl]-3-methyl-1H-pyrazol-4-yl}-amine, N2-[1-(1-[1,3]Dioxolan-2-ylmethyl-piperidin-4-yl) -5-methyl-1H-pyrazol-4-yl]-N4-ethyl-5-trifluoromethyl-pyrimidine-2,4-diamine, N2-[1-(1-[1,3]Dioxolan-2-ylmethyl-piperidin -4-yl)-3-methyl-1H-pyrazol-4-yl]-N4-ethyl-5-trifluoromethyl-pyrimidine-2,4-diamine, 5-Bromo-N2-(1,5-dimethyl-1H- pyrazol-4-yl)-N4-methylpyrimidine-2,4-diamine, N2-(1,3-Dimethyl-1H-pyrazol-4-yl)-5-iodo-N4-methyl-pyrimidine-2,4-diamine , N4-methyl-N2-(5-methyl-1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)p irimidine-2,4-diamine, N4-methyl-N2-(3-methyl-1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazol-4-yl)-5 -(trifluoromethyl)pyrimidine-2,4-diamine, 5-bromo-N4-methyl-N2-(5-methyl-1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H- pyrazol-4-yl)pyrimidine-2,4-diamine, 5-bromo-N4-methyl-N2-(3-methyl-1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)- 1H-pyrazol-4-yl)pyrimidine-2,4-diamine, 5-bromo-N4-methyl-N2-(3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl )pyrimidine-2,4-diamine, 5-bromo-N4-methyl-N2-(5-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidine-2,4- diamine, N4-ethyl-N2-(3-methyl-1-(oxetan-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, 5-chloro-N4 -ethyl-N2-(3-methyl-1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine, 5-bromo-N4-methyl-N2-(1-methyl -1H-pyrazol-5-yl)pyrimidine-2,4-diamine, 2-methyl-1-(5-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H -pyrazol-1-yl)propan-2-ol, 5-chloro-N4-methyl-N2-(3-methyl-1-(methylsulfonyl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine a, N4-methyl-N2-(3-methyl-1-(methylsulfonyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-methyl-N2-(3- methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, 5-bromo-N4-ethyl-N2-(3-methyl-1-(oxetan-3-yl)-1H -pyrazol-4-yl)pyrimidine-2,4-diamine, N2-(1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2, 4-diamine, N2-(1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, 5-bromo-N4-ethyl -N2-(1-ethyl-5-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine, 5-bromo-N2-(1-(4-fluorophenyl)-3-methyl-1H-pyrazole -4-yl)-N4-methylpyrimidine-2,4-diamine, 5-bromo-N4-methyl-N2-(3-methyl-1-phenyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine , 5-bromo-N4-methyl-N2-(5-methyl-1-phenyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine, 5-bromo-N4-methyl-N2-(1-methyl -1H-pyrazol-4-yl)pyrimidine-2,4-diamine, N4-methyl-N2-(3-methyl-1-(1-(methylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl )-5-(trifluoromethyl)pyrimidine-2,4-diamine, 5-bromo-N4-methyl-N2-(3-methyl -1-propyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine, 5-chloro-N4-methyl-N2-(3-methyl-1-((3-methyloxetan-3-yl)methyl) -1H-pyrazol-4-yl)pyrimidine-2,4-diamine, 5-bromo-N2-(1-(3,5-difluorophenyl)-5-methyl-1H-pyrazol-4-yl)-N4-methylpyrimidine -2,4-diamine, 5-bromo-N2-(1-(3,5-difluorophenyl)-3-methyl-1H-pyrazol-4-yl)-N4-methylpyrimidine-2,4-diamine, N4-methyl -N2-(3-Methyl-1-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-methyl-N2-(3-methyl -1-((3-methyloxetan-3-yl)methyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-methyl-N2-(5-methyl-1 -propyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-methyl-N2-(3-methyl-1-propyl-1H-pyrazol-4-yl)-5 - (trifluoromethyl)pyrimidine-2,4-diamine, 5-bromo-N2-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-N4-methylpyrimidine-2,4-diamine, 5-bromo- N2-(1-(4-chlorophenyl)-5-methyl-1H-pyrazol-4-yl)-N4-methylpyrimidine-2,4-diamine, N2-(1-(4-chlorophenyl)-5-methyl-1H -pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-methyl- N2-(3-methyl-1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-methyl-N2-(5-methyl -1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N2-(1-butyl-5-methyl-1H-pyrazol-4 -yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-methyl-N2-(3-methyl-1-(pyrimidin-2-yl)-1H-pyrazol-4-yl) -5-(trifluoromethyl)pyrimidine-2,4-diamine, N2-(1-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2 ,4-diamine, N2-(1-(2-fluoroethyl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-methyl- N2-(3-Methyl-1-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4- methyl-N2-(5-methyl-1-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N2-(1-(2-fluoroethyl)-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, 1-(4-(4-( 4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-3-methyl-1H-pyrazo 1-1-yl)piperidin-1-yl)ethanone, cyclopropyl(4-(5-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1- yl)piperidin-1-yl)methanone, cyclopropyl(4-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)piperidin- 1-yl)methanone, 1-(4-(4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-5-methyl-1H-pyrazol-1-yl)piperidin-1-yl )ethanone, N2-(5-chloro-1-isopropyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, N2-(5-chloro-1-ethyl -1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-methyl-N2-(3-methyl-1-(pyrimidin-5-yl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-methyl-N2-(4-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-3-yl )-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-methyl-N2-(5-methyl-1-(2-methylpyridin-4-yl)-1H-pyrazol-4-yl)-5-( trifluoromethyl)pyrimidine-2,4-diamine, N4-methyl-N2-(3-methyl-1-(2-methylpyridin-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2 ,4-diamine, N4-ethyl-N2-(3- methyl-1-((3-methyloxetan-3-yl)methyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N2-(5-chloro-1-cyclopropyl- 1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, N2-(5-chloro-1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-N4- methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, 4-(5-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl )benzonitrile, 4-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)benzonitrile, N4-methyl-N2-(3- methyl-1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-methyl-N2-(5-methyl-1-( tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, 5-(4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin- 2-ylamino)-5-methyl-1H-pyrazol-1-yl)-1-methylpiperidin-2-one, 5-(4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)- 3-methyl-1H-pyrazol-1-yl)-1-methylpiperidin-2-one, 5-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H -pyraz ol-1-yl)piperidin-2-one, 5-(5-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)piperidin- 2-one, N2-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, N,N-dimethyl-4-( 5-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)benzamide, 4-(4-(4-(ethylamino)-5-( trifluoromethyl)pyrimidin-2-ylamino)-5-methyl-1H-pyrazol-1-yl)-N,N-dimethylbenzamide, N4-ethyl-N2-(5-methyl-1-(tetrahydro-2H-pyran- 4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-ethyl-N2-(3-methyl-1-(tetrahydro-2H-pyran-4) -yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-ethyl-N2-(3-methyl-1-(methylsulfonyl)-1H-pyrazol-4-yl )-5-(trifluoromethyl)pyrimidine-2,4-diamine, N2-(1-(4-(cyclopropylsulfonyl)phenyl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl) )pyrimidine-2,4-diamine, 4-(4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-5-methyl-1H-pyrazol-1-yl)benzonitrile, N4-ethyl -N2-(5-methyl-1-(4-(methylsulf) onyl)phenyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N,N-dimethyl-4-(3-methyl-4-(4-(methylamino)-5 -(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)benzamide, N2-(1-(cyclopropylmethyl)-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-( trifluoromethyl)pyrimidine-2,4-diamine, N2-(1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, N2 -(1-(4-(cyclopropylsulfonyl)phenyl)-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, N2-(5-chloro- 1-(oxetan-3-yl)-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-ethyl-N2-(5-methyl-1-( (3-methyloxetan-3-yl)methyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N2-(1-(cyclopropylsulfonyl)-3-methyl-1H-pyrazole -4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, N2-(1-(cyclopropylsulfonyl)-3-methyl-1H-pyrazol-4-yl)-N4-ethyl-5 - (trifluoromethyl)pyrimidine-2,4-diamine, 5-chloro-N4-(2,2-difluoroethyl)-N2-(1,5-dimethyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine , N2-(1-(4-(cyclopropylsulfonyl)phenyl)-5-methyl-1H-pyrazol-4-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, 2-methyl-1- (4-(5-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)piperidin-1-yl)propan-1-one, N4 -ethyl-N2-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N2-(3-cyclopropyl-1-methyl-1H-pyrazol-4-yl )-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, N2-(5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine- 2,4-diamine, N4-methyl-N2-(5-methyl-1-((3-methyloxetan-3-yl)methyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2, 4-diamine, N2-(5-chloro-1-((3-methyloxetan-3-yl)methyl)-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4- diamine, 1-(4-(4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-5-methyl-1H-pyrazol-1-yl)piperidin-1-yl)-2- methylpropan-1-one, N4-ethyl-N2-(3-methyl-1-(1-(oxetan-3-yl)azetidin-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl) pyrimidine-2,4-diamine, cyclopropyl(4-(4-(4-(ethylamino)) -5-(trifluoromethyl)pyrimidin-2-ylamino)-3-methyl-1H-pyrazol-1-yl)piperidin-1-yl)methanone, cyclopropyl(4-(4-(4-(ethylamino)-5-( trifluoromethyl)pyrimidin-2-ylamino)-5-methyl-1H-pyrazol-1-yl)piperidin-1-yl)methanone, 1-(5-chloro-4-(4-(methylamino)-5-(trifluoromethyl) pyrimidin-2-ylamino)-1H-pyrazol-1-yl)-2-methylpropan-2-ol, (S)-N2-(1-(2-methoxypropyl)-5-methyl-1H-pyrazol-4-yl )-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, N2-(1-(2-methoxycyclopentyl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-( trifluoromethyl)pyrimidine-2,4-diamine, (S)-N2-(1-(2-methoxypropyl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2 ,4-diamine, N2-(1-(1-methoxy-2-methylpropan-2-yl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2, 4-diamine, N2-(1-(2,6-dimethyltetrahydro-2H-pyran-4-yl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine -2,4-diamine, (R)-N2-(1-(2-methoxypropyl)-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4- diamine, N2-(1-(3-methoxycyclopentyl)-3 -methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-methyl-N2-(1-methyl-5-(methylamino)-1H-pyrazol- 4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-methyl-N2-(5-methyl-1-(methylsulfonyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine -2,4-diamine, N4-methyl-N2-(5-methyl-1-(tetrahydro-2H-1,1-dioxo-thiopyran-4-yl)-1H-pyrazol-4-yl)-5 -(trifluoromethyl)pyrimidine-2,4-diamine, N2-(1-(3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-3-methyl-1H-pyrazol-4-yl) -N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, (R)-N2-(1-(1-methoxypropan-2-yl)-3-methyl-1H-pyrazol-4-yl)- N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-methyl-N2-(3-methyl-1-(1-(2,2,2-trifluoroethyl)azetidin-3-yl)-1H - pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N2-(1-(1-methoxy-2-methylpropan-2-yl)-5-methyl-1H-pyrazol-4- yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, (R)-N4-methyl-N2-(3-methyl-1-(1-(oxetan-3-yl)pyrrolidin-3 -yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, (R)-N2-(1-(1-m ethoxypropan-2-yl)-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-methyl-N2-(4-methyl-1H- pyrazol-5-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-ethyl-N2-(5-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl )-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-ethyl-N2-(3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-( trifluoromethyl)pyrimidine-2,4-diamine, N4-methyl-N2-(3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2 ,4-diamine, N4-methyl-N2-(5-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, (R)-N4-methyl-N2-(5-methyl-1-(1-(oxetan-3-yl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine- 2,4-diamine, N4-methyl-N2-(5-methyl-1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4 -methyl-N2-(3-methyl-1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N2-(1-(1- isopropylazetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl- 5-(trifluoromethyl)pyrimidine-2,4-diamine, 1-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-5-carbonitrile, N4-ethyl- N2-(1-(isopropylsulfonyl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N2-(1-(isopropylsulfonyl)-3-methyl-1H- pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, N2-(1-(isopropylsulfonyl)-5-methyl-1H-pyrazol-4-yl)-N4-methyl- 5-(trifluoromethyl)pyrimidine-2,4-diamine, N2-(1-(sec-butylsulfonyl)-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2, 4-diamine, N2-(1-(sec-butylsulfonyl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, 1-(4- (4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-3-isopropyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol, N2-(1-(3-fluoro- 1-methylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, N2-(5-isopropyl-1-methyl- 1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-methyl-N2-(3-methyl-1-(1-(pyridinium) n-2-yl)ethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-methyl-N2-(5-methyl-1-(1-(pyridin- 2-yl)ethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N2-(5-chloro-1-(tetrahydro-2H-pyran-4-yl) )-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, N2-(3-isopropyl-1-methyl-1H-pyrazol-4-yl)-N4- methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, N2-(3-cyclobutyl-1-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4- diamine, N2-(5-cyclobutyl-1-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-methyl-N2-(3-methyl- 1-(Tetrahydro-2H-pyran-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-methyl-N2-(5-methyl-1 -(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N2-(1,5-dimethyl-1H-pyrazol- 4-yl)-N4-((tetrahydro-2H-pyran-4-yl)methyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, (R)-N4-methyl-N2-(3- methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrim idine-2,4-diamine, 1-(5-chloro-4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)-2-methylpropan-2 -ol, 2-(5-chloro-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)-N,2-dimethylpropanamide, N2-(1 -(1-(2-methoxyethyl)piperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, N2-(1 -(1-(2-methoxyethyl)piperidin-4-yl)-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, (R)- N4-methyl-N2-(5-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N2-(5- chloro-1-(3-fluoro-1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, N2-(5-chloro -1-(1-ethyl-3-fluoropiperidin-4-yl)-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-ethyl-N2-( 1-(Ethylsulfonyl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-ethyl-N2-(1-(ethylsulfonyl)-5-methyl-1H -pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine a, N2-(1-(1-ethyl-3-fluoropiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine , N2-(5-(dimethylamino)-1-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, 2-(5-chloro-4-( 4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)-2-methylpropan-1-ol, N2-(1-(ethylsulfonyl)-3-methyl-1H- pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, 2-methyl-1-[3-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2- ylamino)-pyrazol-1-yl]-propan-2-ol, N2-[1-(2-Methoxy-ethyl)-3-methyl-1H-pyrazol-4-yl]-N4-methyl-5-trifluoromethyl- pyrimidine-2,4-diamine, N2-[1-(2-Methoxy-ethyl)-5-methyl-1H-pyrazol-4-yl]-N4-methyl-5-trifluoromethyl-pyrimidine-2,4-diamine, 5-Bromo-N2-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-N4-methyl-pyrimidine-2,4-diamine, N4-methyl-N2-[3-methyl-1-( 2,2,2-trifluoro-ethyl)-1H-pyrazol-4-yl]-5-trifluoromethyl-pyrimidine-2,4-diamine, 5-Bromo-N2-(1-difluoromethyl-5-methyl-1H-pyrazole -4-yl)-N4-methyl-pyrimidine-2,4-diamine, 5-Bromo-N2-(1 -difluoromethyl-3-methyl-1H-pyrazol-4-yl)-N4-methyl-pyrimidine-2,4-diamine, 5-Bromo-N2-(1,5-dimethyl-1H-pyrazol-4-yl)- N4-Ethyl-pyrimidine-2,4-diamine, 5-Bromo-N2-[1-(4-fluoro-phenyl)-5-methyl-1H-pyrazol-4-yl]-N4-methyl-pyrimidine-2, 4-diamine, 5-Bromo-N4-methyl-N2-(5-methyl-1-propyl-1H-pyrazol-4-yl)-pyrimidine-2,4-diamine, 5-Bromo-N2-[1-( 4-Chloro-phenyl)-3-methyl-1H-pyrazol-4-yl]-N4-methyl-pyrimidine-2,4-diamine, N2-(1,5-Dimethyl-1H-pyrazol-4-yl)- N4-Ethyl-5-trifluoromethyl-pyrimidine-2,4-diamine, 5-[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methyl-pyrazol-1-yl]-piperidin- 2-one, 4-[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methyl-pyrazol-1-yl]-N,N-dimethyl-benzamide, N2-[1-( 4-Cyclopropanesulfonyl-phenyl)-3-methyl-1H-pyrazol-4-yl]-N4-ethyl-5-trifluoromethyl-pyrimidine-2,4-diamine, 4-[4-(4-Ethylamino-5-trifluoromethyl- pyrimidin-2-ylamino)-3-methyl-pyrazol-1-yl]-benzonitrile, N4-ethyl-N2-[1-(4-methanesulfonyl-phenyl)-3-methyl-1H-pyrazol-4-yl]- 5-trifluoromethyl-pyrimidine-2,4-diamine, 1-{4-[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-methyl-pyrazol-1-yl]-piperidin-1-yl}-2-methyl-propan-1- one, 1-{4-[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methyl-pyrazol-1-yl]-piperidin-1-yl}-2-methyl-propan- 1-one, N4-methyl-N2-[3-methyl-1-(3-methyl-pyridin-4-yl)-1H-pyrazol-4-yl]-5-trifluoromethyl-pyrimidine-2,4-diamine, N2-[1-((R)-2-Methoxy-propyl)-3-methyl-1H-pyrazol-4-yl]-N4-methyl-5-trifluoromethyl-pyrimidine-2,4-diamine, N2-[1 -(2,6-Dimethyl-tetrahydro-pyran-4-yl)-5-methyl-1H-pyrazol-4-yl]-N4-methyl-5-trifluoromethyl-pyrimidine-2,4-diamine, N2- [1-(1,1-Dioxo-hexahydro-1$1%6&-thiopyran-4-yl)-3-methyl-1H-pyrazol-4-yl]-N4-methyl-5-trifluoromethyl-pyrimidine- 2,4-diamine, N2-[1-((R)-2-Methoxy-1-methyl-ethyl)-5-methyl-1H-pyrazol-4-yl]-N4-methyl-5-trifluoromethyl-pyrimidine- 2,4-diamine, N2-[1-((S)-2-Methoxy-1-methyl-ethyl)-3-methyl-1H-pyrazol-4-yl]-N4-methyl-5-trifluoromethyl-pyrimidine- 2,4-diamine, N4-methyl-N2-[3-methyl-1-((S)-1-oxetan-3-yl-pyrrolidin-3-yl)-1H-pyrazol-4-yl]-5- triflu oromethyl-pyrimidine-2,4-diamine, N4-methyl-N2-[5-methyl-1-((S)-1-oxetan-3-yl-pyrrolidin-3-yl)-1H-pyrazol-4-yl ]-5-trifluoromethyl-pyrimidine-2,4-diamine, N2-[1-(1-Isopropyl-azetidin-3-yl)-5-methyl-1H-pyrazol-4-yl]-N4-methyl-5- trifluoromethyl-pyrimidine-2,4-diamine, N4-ethyl-N2-[5-methyl-1-(propane-2-sulfonyl)-1H-pyrazol-4-yl]-5-trifluoromethyl-pyrimidine-2,4- diamine, N2-(5-Cyclobutyl-1-methyl-1H-pyrazol-4-yl)-N4-ethyl-5-trifluoromethyl-pyrimidine-2,4-diamine, N2-(3-Cyclobutyl-1-methyl-1H -pyrazol-4-yl)-N4-ethyl-5-trifluoromethyl-pyrimidine-2,4-diamine, N4-ethyl-N2-{1-[1-(2-methoxy-ethyl)-piperidin-4-yl] -3-methyl-1H-pyrazol-4-yl}-5-trifluoromethyl-pyrimidine-2,4-diamine, N4-ethyl-N2-{1-[1-(2-methoxy-ethyl)-piperidin-4- yl]-5-methyl-1H-pyrazol-4-yl}-5-trifluoromethyl-pyrimidine-2,4-diamine, N2-{1-[1-(2-Fluoro-ethyl)-piperidin-4-yl] -5-methyl-1H-pyrazol-4-yl}-N4-methyl-5-trifluoromethyl-pyrimidine-2,4-diamine, N2-{1-[1-(2-Fluoro-ethyl)-piperidin-4- yl]-3-methyl-1H-pyrazol-4-yl}-N4-methyl-5-trifluoromethyl-pyrimidine- 2,4-diamine, N2-[5-Chloro-1-(3-fluoro-1-methyl-piperidin-4-yl)-1H-pyrazol-4-yl]-N4-methyl-5-trifluoromethyl-pyrimidine- 2,4-diamine, N2-(1-Ethanesulfonyl-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-trifluoromethyl-pyrimidine-2,4-diamine, N4-methyl-N2-(3 -methyl-1-pyridin-3-ylmethyl-1H-pyrazol-4-yl)-5-trifluoromethyl-pyrimidine-2,4-diamine, N4-methyl-N2-(5-methyl-1-pyridin-3-ylmethyl -1H-pyrazol-4-yl)-5-trifluoromethyl-pyrimidine-2,4-diamine, (5-Chloro-4-methoxy-pyrimidin-2-yl)-{1-[1-(2-fluoro-ethyl) )-piperidin-4-yl]-5-methyl-1H-pyrazol-4-yl}-amine, N4-methyl-N2-[3-methyl-1-(6-methyl-pyridin-2-ylmethyl)-1H -pyrazol-4-yl]-5-trifluoromethyl-pyrimidine-2,4-diamine, N4-ethyl-N2-[1-(2-methoxy-ethyl)-3-methyl-1H-pyrazol-4-yl]- 5-Trifluoromethyl-pyrimidine-2,4-diamine, N4-ethyl-N2-[1-(2-methoxy-ethyl)-5-methyl-1H-pyrazol-4-yl]-5-trifluoromethyl-pyrimidine-2, 4-diamine, 1-[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-methyl-pyrazol-1-yl]-2-methyl-propan-2-ol, 1-[4 -(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methyl-p irazol-1-yl]-2-methyl-propan-2-ol, N4-Cyclopropyl-N2-(1-methanesulfonyl-3-methyl-1H-pyrazol-4-yl)-5-trifluoromethyl-pyrimidine-2,4 -diamine, N4-Cyclopropyl-N2-(1-methanesulfonyl-5-methyl-1H-pyrazol-4-yl)-5-trifluoromethyl-pyrimidine-2,4-diamine, 1-[3-Chloro-4-(4 -methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-pyrazol-1-yl]-2-methyl-propan-2-ol, 2-[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) )-3-methyl-pyrazol-1-yl]-N-methyl-isobutyramide, N4-methyl-N2-(3-methyl-1-pyrimidin-2-ylmethyl-1H-pyrazol-4-yl)-5-trifluoromethyl -pyrimidine-2,4-diamine, N2-[5-Chloro-1-(3-fluoro-1-oxetan-3-yl-piperidin-4-yl)-1H-pyrazol-4-yl]-N4-methyl -5-Trifluoromethyl-pyrimidine-2,4-diamine, N2-[5-Chloro-1-(3-fluoro-1-oxetan-3-yl-piperidin-4-yl)-1H-pyrazol-4-yl] -N4-ethyl-5-trifluoromethyl-pyrimidine-2,4-diamine, N4-ethyl-N2-[5-methyl-1-((S)-1-oxetan-3-yl-piperidin-3-yl)- 1H-Pyrazol-4-yl]-5-trifluoromethyl-pyrimidine-2,4-diamine, N4-ethyl-N2-[3-methyl-1-((S)-1-oxetan-3-yl-piperidin-3 -yl)-1H-pyrazol-4-yl]-5-trifluoromethyl-py rimidine-2,4-diamine, N4-methyl-N2-(5-methyl-1-pyridazin-3-ylmethyl-1H-pyrazol-4-yl)-5-trifluoromethyl-pyrimidine-2,4-diamine, N4- methyl-N2-(3-methyl-1-pyridazin-3-ylmethyl-1H-pyrazol-4-yl)-5-trifluoromethyl-pyrimidine-2,4-diamine, N4-ethyl-N2-[5-methyl-1 -((S)-1-methyl-piperidin-3-yl)-1H-pyrazol-4-yl]-5-trifluoromethyl-pyrimidine-2,4-diamine, N4-ethyl-N2-[3-methyl-1 -((S)-1-methyl-piperidin-3-yl)-1H-pyrazol-4-yl]-5-trifluoromethyl-pyrimidine-2,4-diamine, 3-[5-Chloro-4-(4- methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-pyrazol-1-yl]-2,2-dimethyl-propionitrile, N4-methyl-N2-[5-methyl-1-(6-methyl-pyridin-2- ylmethyl)-1H-pyrazol-4-yl]-5-trifluoromethyl-pyrimidine-2,4-diamine, N4-methyl-N2-(5-methyl-1-pyrimidin-2-ylmethyl-1H-pyrazol-4-yl )-5-trifluoromethyl-pyrimidine-2,4-diamine, N4-methyl-N2-(5-methyl-1-pyrazin-2-ylmethyl-1H-pyrazol-4-yl)-5-trifluoromethyl-pyrimidine-2, 4-diamine, N4-methyl-N2-(3-methyl-1-pyrazin-2-ylmethyl-1H-pyrazol-4-yl)-5-trifluoromethyl-pyrimidine-2,4-diamine, 3-[5-Chloro -4-(4-ethylamino-5-trifluoro romethyl-pyrimidin-2-ylamino)-pyrazol-1-yl]-2,2-dimethyl-propionitrile, N4-ethyl-N2-[1-(3-fluoro-1-oxetan-3-yl-piperidin-4- yl)-3-methyl-1H-pyrazol-4-yl]-5-trifluoromethyl-pyrimidine-2,4-diamine, 3-methyl-1-[5-methyl-4-(4-methylamino-5-trifluoromethyl- pyrimidin-2-ylamino)-pyrazol-1-yl]-butan-2-ol, 3-methyl-1-[3-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-pyrazole -1-yl]-butan-2-ol, N2-[1-(1-[1,3]Dioxolan-2-ylmethyl-pyrrolidin-3-yl)-3-methyl-1H-pyrazol-4-yl] -N4-ethyl-5-trifluoromethyl-pyrimidine-2,4-diamine, N4-methyl-N2-(5-methyl-1-pyrimidin-4-ylmethyl-1H-pyrazol-4-yl)-5-trifluoromethyl-pyrimidine -2,4-diamine, N4-methyl-N2-[5-methyl-1-(1-methyl-1H-pyrazol-3-ylmethyl)-1H-pyrazol-4-yl]-5-trifluoromethyl-pyrimidine-2 ,4-diamine, N4-methyl-N2-[3-methyl-1-(1-methyl-1H-pyrazol-3-ylmethyl)-1H-pyrazol-4-yl]-5-trifluoromethyl-pyrimidine-2,4 -diamine, 3-[3-Chloro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-pyrazol-1-yl]-2,2-dimethyl-propionitrile, N4-ethyl-N2-{ 3-methyl-1-[1-methyl-1-(4H-[1,2,4]tria zol-3-yl)-ethyl]-1H-pyrazol-4-yl}-5-trifluoromethyl-pyrimidine-2,4-diamine, N2-[1-(1-[1,3]Dioxolan-2-ylmethyl- pyrrolidin-3-yl)-5-methyl-1H-pyrazol-4-yl]-N4-ethyl-5-trifluoromethyl-pyrimidine-2,4-diamine, N4-methyl-N2-(3-methyl-1-pyrimidin -4-ylmethyl-1H-pyrazol-4-yl)-5-trifluoromethyl-pyrimidine-2,4-diamine, N2-(5-Fluoromethyl-1-methyl-1H-pyrazol-4-yl)-N4-methyl- 5-Trifluoromethyl-pyrimidine-2,4-diamine, N4-ethyl-N2-{3-methyl-1-[1-methyl-1-(5-methyl-4H-[1,2,4]triazol-3- yl)-ethyl]-1H-pyrazol-4-yl}-5-trifluoromethyl-pyrimidine-2,4-diamine, N4-methyl-N2-{3-methyl-1-[1-methyl-1-(4H- [1,2,4]triazol-3-yl)-ethyl]-1H-pyrazol-4-yl}-5-trifluoromethyl-pyrimidine-2,4-diamine, N4-ethyl-N2-[1-(3- fluoro-piperidin-4-yl)-3-methyl-1H-pyrazol-4-yl]-5-trifluoromethyl-pyrimidine-2,4-diamine, 2-[5-methyl-4-(4-methylamino-5- trifluoromethyl-pyrimidin-2-ylamino)-pyrazol-1-yl]-cyclopentanol, 2-[3-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-pyrazol-1-yl]- cyclopentanol, N4-ethyl-N2-(3-methyl-1-(2-(5-methyl-1,3,4-oxadiazol-2- yl)propan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-ethyl-N2-(3-methyl-1-(2-(4- methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-ethyl-N2 -(3-methyl-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl) ) pyrimidine-2,4-diamine, N4-methyl-N2-(3-methyl-1-(2-(5-methyl-1,3,4-oxadiazol-2-yl)propan-2-yl)-1H -pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-methyl-N2-(3-methyl-1-(2-(1-methyl-1H-pyrazol-4-yl)) propan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-methyl-N2-(5-methyl-1-(2-(1-methyl- 1H-pyrazol-4-yl)propan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-ethyl-N2-(3-methyl-1- (2-(1-methyl-1H-pyrazol-3-yl)propan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-ethyl-N2 -(3-methyl-1-(2-(1-methyl-1H-pyrazol-5-yl)propan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4 -diamine, N4-methyl-N2-(3-methyl-1-(2-(1-methyl- 1H-pyrazol-5-yl)propan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N4-methyl-N2-(3-methyl-1- (2-(1-methyl-1H-pyrazol-3-yl)propan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine, N2-(1' ,5-dimethyl-1'H-1,4'-bipyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, N2-(1',3-dimethyl-1' H-1,4'-bipyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, N2-(1-(2-(4H-1,2,4-triazol- 3-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, 2-(1,5-Dimethyl- 1H-Pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile, 2-(1,3-Dimethyl-1H-pyrazol-4-ylamino)-4-methylamino-pyrimidine-5-carbonitrile, 2- (1-ethyl-5-methyl-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile, 2-(1-isopropyl-3-methyl-1H-pyrazol-4-ylamino)-4 - (methylamino)pyrimidine-5-carbonitrile, 2-(1-ethyl-3-methyl-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile, 2-(3-methyl-1- phenyl-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine- 5-carbonitrile, 2-(3-methyl-1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5- carbonitrile, 2-(5-methyl-1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile, 2-(1-Methyl-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile, 2-(5-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol- 4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile, 2-(3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine -5-carbonitrile, 2-(5-methyl-1-phenyl-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile, 2-(5-methyl-1-(tetrahydro- 2H-pyran-4-yl)-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile, 2-(3-methyl-1-(tetrahydro-2H-pyran-4-yl) )-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile, 2-(1-ethyl-5-methyl-1H-pyrazol-4-ylamino)-4-(ethylamino)pyrimidine-5 -carbonitrile, 2-(1-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile, 2-(1-(difl) fluoromethyl)-3-methyl-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile, 2-(5-methyl-1-propyl-1H-pyrazol-4-ylamino)-4-( methylamino)pyrimidine-5-carbonitrile, 2-(1-(3,5-difluorophenyl)-3-methyl-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile, 2-(1- (4-chlorophenyl)-3-methyl-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile, 2-(1-(4-chlorophenyl)-5-methyl-1H-pyrazol-4 -ylamino)-4-(methylamino)pyrimidine-5-carbonitrile, 2-(3-methyl-1-(pyridin-2-yl)-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5- carbonitrile, 4-(ethylamino)-2-(5-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-ylamino)pyrimidine-5-carbonitrile, 4-(ethylamino) -2-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-ylamino)pyrimidine-5-carbonitrile, 4-(ethylamino)-2-(3-methyl -1-(oxetan-3-yl)-1H-pyrazol-4-ylamino)pyrimidine-5-carbonitrile, 2-(1-isopropyl-5-methyl-1H-pyrazol-4-ylamino)-4-(methylamino) pyrimidine-5-carbonitrile, 2-(1,5-dimethyl-1H-pyrazol-4-ylamino)-4-methoxypyrimidine-5-carbonitrile, 2- (1,5-dimethyl-1H-pyrazol-4-ylamino)-4-(2,2,2-trifluoroethylamino)pyrimidine-5-carbonitrile, 2-(1-ethyl-5-methyl-1H-pyrazol-4- ylamino)-4-methoxypyrimidine-5-carbonitrile, 4-(2,2-difluoroethylamino)-2-(1,5-dimethyl-1H-pyrazol-4-ylamino)pyrimidine-5-carbonitrile, 2-(1,5 -dimethyl-1H-pyrazol-4-ylamino)-4-(2,2,2-trifluoroethoxy)pyrimidine-5-carbonitrile, 2-(1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-ylamino) -4-(methylamino)pyrimidine-5-carbonitrile, 2-(1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile , 2-(3-methyl-1-(oxetan-3-yl)-1H-pyrazol-4-ylamino)-4-(2,2,2-trifluoroethylamino)pyrimidine-5-carbonitrile, 2-(5-chloro -1-(Tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile, 2-(1-Difluoromethyl-5-methyl-1H- pyrazol-4-ylamino)-4-methylamino-pyrimidine-5-carbonitrile, 2-(1,5-Dimethyl-1H-pyrazol-4-ylamino)-4-ethylamino-pyrimidine-5-carbonitrile, 2-[1- (4-Fluoro-phenyl)-5-methyl-1H-pyrazol-4-ylamino]-4-methylamino-pyrimidin α-5-carbonitrile, 4-Methylamino-2-(3-methyl-1-propyl-1H-pyrazol-4-ylamino)-pyrimidine-5-carbonitrile, 4-Methylamino-2-(5-methyl-1-oxetan -3-yl-1H-pyrazol-4-ylamino)-pyrimidine-5-carbonitrile, 4-Methylamino-2-(3-methyl-1-oxetan-3-yl-1H-pyrazol-4-ylamino)-pyrimidine- 5-carbonitrile, 2-[1-(3,5-Difluoro-phenyl)-5-methyl-1H-pyrazol-4-ylamino]-4-methylamino-pyrimidine-5-carbonitrile, 4-(2,2-Difluoro -ethoxy)-2-(1,5-dimethyl-1H-pyrazol-4-ylamino)-pyrimidine-5-carbonitrile, 2-[1-(4,4-Difluoro-cyclohexyl)-3-methyl-1H -pyrazol-4-ylamino]-4-methylamino-pyrimidine-5-carbonitrile, (5-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-1-methyl-1H-pyrazol-3-yl) (morpholino)methanone, 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile, N,N -dimethyl-2-(5-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)acetamide, N,N-dimethyl-2-( 3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)acetamide, N-methyl-2-(3-methyl 1-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)acetamide, N-methyl-2-(5-methyl-4-(4-( methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)acetamide, N,N,2-trimethyl-2-(5-methyl-4-(4-(methylamino)-5 - (trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanamide, 2-methyl-2-(5-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2- ylamino)-1H-pyrazol-1-yl)-1-(pyrrolidin-1-yl)propan-1-one, 2-methyl-2-(5-methyl-4-(4-(methylamino)-5-( trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile, 1-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazole -1-yl)cyclopropanecarbonitrile, (R)-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)-1- (pyrrolidin-1-yl)propan-1-one, (R)-N,N-dimethyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino) -1H-pyrazol-1-yl)propanamide, (S)-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl )-1-(pyrrolidin-1-yl)pr opan-1-one, 3-(5-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile, 3-(3-methyl -4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile, methyl 2-methyl-2-(3-methyl-4-(4-( methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanoate, methyl 2-methyl-2-(5-methyl-4-(4-(methylamino)-5-(trifluoromethyl) )pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanoate, (R)-2-(5-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)- 1H-pyrazol-1-yl)-1-(pyrrolidin-1-yl)propan-1-one, (R)-N,N-dimethyl-2-(5-methyl-4-(4-(methylamino)- 5-(Trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanamide, (S)-2-(5-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2 - ylamino)-1H-pyrazol-1-yl)-1-(pyrrolidin-1-yl)propan-1-one, (S)-N,N-dimethyl-2-(5-methyl-4-(4- (methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanamide, (S)-2-(5-methyl-4-(4-(methylamino)-5-(trifluoromethyl) )pyrimidin-2-ylamino)-1H-pyrazol-1-yl)p ropanonitrile, (S)-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile, 2-(4-( 5-chloro-4-(methylamino)pyrimidin-2-ylamino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile, 2-(5-chloro-4-(4-(methylamino)-5 -(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)-2-methylpropanenitrile, 2,2-dimethyl-3-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl) )pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile, 2,2-dimethyl-3-(5-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino )-1H-pyrazol-1-yl)propanenitrile, 1-(5-chloro-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)cyclopropanecarbonitrile, N-tert-butyl-2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanamide, 2- methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)-N-(2,2,2-trifluoroethyl) propanamide, 2-(5-Chloro-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H propanamide -pyrazol-1-yl)-N-ethyl-2-methyl, N-(cyclopropylmethyl)-2-methyl-2-(5-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2 -ylamino)-1H-pyrazol-1-yl)propanamide, N-(cyclopropylmethyl)-2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino )-1H-pyrazol-1-yl)propanamide, N-ethyl-1-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1- yl)cyclobutanecarboxamide, N-isopropyl-2-methyl-2-(5-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanamide, 1-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)cyclobutanecarbonitrile, 2-(4-(4-(cyclopropylamino)- 5-(trifluoromethyl)pyrimidin-2-ylamino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile, N,2-dimethyl-2-(3-methyl-4-(4-(methylamino) -5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanamide, 1-(5-chloro-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino) -1H-pyrazol-1-yl)cyclopropanecarbonitrile, 2-[ Propionic Acid Methylester 4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-5-methyl-pyrazol-1-yl]-2-methyl-, Propionic Acid Methylester 2-[4-(5-Chloro-4- methoxy-pyrimidin-2-ylamino)-3-methyl-pyrazol-1-yl]-2-methyl-, (S)-N,N-Dimethyl-2-[3-methyl-4-(4-methylamino-5 -trifluoromethyl-pyrimidin-2-ylamino)-pyrazol-1-yl]-propionamide, (R)-2-[3-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-pyrazol- 1-yl]-propionitrile, 2-[4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-3-cyclopropyl-pyrazol-1-yl]-2-methyl-propionitrile, (R)-2 -[5-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-pyrazol-1-yl]-propionitrile, N-ethyl-2-[3-methyl-4-(4-methylamino) -5-Trifluoromethyl-pyrimidin-2-ylamino)-pyrazol-1-yl]-isobutyramide, N-ethyl-2-[5-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)- pyrazol-1-yl]-isobutyramide, 1-[5-Methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-pyrazol-1-yl]-cyclobutanecarboxylic acid ethylamide, 2-[5 -methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-pyrazol-1-yl]-N-(2,2, 2-Trifluoro-ethyl)-isobutyramide, N-Isopropyl-2-[3-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-pyrazol-1-yl]-isobutyramide, N-methyl -2-[5-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-pyrazol-1-yl]-isobutyramide, 1-[5-methyl-4-(4-methylamino-5 -trifluoromethyl-pyrimidin-2-ylamino)-pyrazol-1-yl]-cyclobutanecarbonitrile, N-tert-Butyl-2-[5-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)- pyrazol-1-yl]-isobutyramide, 2-[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-methyl-pyrazol-1-yl]-N-methyl-isobutyramide, 2-[ 4-(4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methyl-pyrazol-1-yl]-N-methyl-isobutyramide, 2-[4-(4-Cyclopropylamino-5-trifluoromethyl-pyrimidin -2-ylamino)-5-methyl-pyrazol-1-yl]-N-methyl-isobutyramide, 2-[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methyl-pyrazol- 1-yl]-2-methyl-propionitrile, 2-(3-chloro-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)-2- methylpropanenitrile, and 2-[4-(4-Ethi lamino-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methyl-pyrazol-1-yl]-N-methyl-isobutyramide, or a pharmaceutically acceptable salt thereof. 1.
[0002]
2. Compound according to claim 1, characterized in that it is N2-[5-chloro-1-(3-fluoro-1-oxetan-3-yl-piperidin-4-yl)-1H-pyrazol- 4-yl]-N4-methyl-5-trifluoromethylpyrimidine-2,4-diamine, or a pharmaceutically acceptable salt thereof.
[0003]
3. Compound according to claim 1, characterized in that it is 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H -pyrazol-1-yl)propanenitrile, or a pharmaceutically acceptable salt thereof.
[0004]
4. A compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3, characterized in that it is for use as a medicine.
[0005]
5. A compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3, characterized in that it is for use in the therapeutic and/or prophylactic treatment of Parkinson's disease.
[0006]
6. Use of a compound, as defined in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, characterized in that it is for the preparation of medicaments for the therapeutic and/or prophylactic treatment of Parkinson's disease.
[0007]
7. Composition, characterized in that it comprises: (a) a pharmaceutically acceptable carrier; and (b) a compound as defined in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.

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法律状态:
2017-07-11| B25A| Requested transfer of rights approved|Owner name: GENENTECH, INC. (US) |

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2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2019-02-26| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|

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2019-05-21| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

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2020-05-19| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2021-05-18| B07A| Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]|

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2021-10-26| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2022-01-11| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 09/11/2011, OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME ADI 5.529/DF, QUE DETERMINA A ALTERACAO DO PRAZO DE CONCESSAO. |

优先权:

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申请号 | 申请日 | 专利标题

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US41227310P| true| 2010-11-10|2010-11-10|

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US61/412,273|2010-11-10|

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US201161546613P| true| 2011-10-13|2011-10-13|

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US61/546,613|2011-10-13|

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