JP2014504362A - Assays and biomarkers for LRRK2 - Google Patents

Abstract

  Biomarkers to screen Parkinson's disease subjects and provide companion diagnostic tools for treatment using LRRK2 modulators, and assays for screening compounds and compositions for modulation of LRRK2 activity.

Description

(Related application)
This application claims priority from US Provisional Application No. 61 / 418,208, filed Nov. 30, 2010, which is incorporated by reference in its entirety.

(Field of Invention)
The present invention relates to assays for discovering compounds that modulate LRRK2 function and biomarkers for in vivo assessment of LRRK2 activity.

  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 musculoskeletal disorder that afflicts approximately one in 1,000 people, and hereditary Parkinson's disease accounts for 5-10% of all patients. Parkinson's disease is caused by the progressive loss of midbrain dopamine neurons, impairing the patient's ability to direct and control their movements. Primary Parkinson's disease symptoms are trembling, stiffness, slow motion, and balance disorder. Many Parkinson's patients also experience other symptoms such as emotional changes, memory loss, speech impairment, and sleep disorders.

  A 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 indicate that LRRK2 proteins with Parkinson's disease-related mutations generally have increased LRRK2 kinase activity and a reduced rate of GTP hydrolysis compared to the wild type protein (Guo et al., Experimental Cell Research, Vol. 313 (16), 2007, pp. 3658-3670 Anti-LRRK2 antibody has been used to label brainstem Lewy bodies associated with Parkinson's disease and cortical antibodies associated with Lewy body dementia Suggest that LRRK2 may play an important role in Lewy body formation and pathogenesis associated with these diseases (Zhou et al., Molecular Degeneration, 2006, 1:17 doi: 10.1186 / 1750-1326-1-17 LRRK2 has also been identified as a gene potentially associated with increased susceptibility to Crohn's disease and susceptibility to leprosy (Zhang et al., New England J. Med. Vol. 361 (2009) pp. 2609-2618). .

  Thus, compounds and compositions effective in modulating LRRK2 activity provide treatment for neurodegenerative diseases such as Parkinson's disease and Lewy body dementia, and for diseases such as leprosy and Crohn's disease. sell. In particular, there is a need for assays that can identify and evaluate compounds capable of inhibiting LRRK2 kinase activity in cells. There is also a significant need for biomarkers that allow the effects of inhibition of LRRK2 kinase activity to be evaluated in human patients and animal models of Parkinson's disease. Finally, there is a continuing need for technologies and biomarkers that can enable identification of subjects at risk for or having Parkinson's disease (PD) that can respond to treatment with LRRK2 inhibitors. The effector of LRRK2 activity is unknown, which impaired the ability of researchers to assess the ability of compounds to inhibit LRRK2 kinase activity in cells or in vivo. (N. Dzamko, 2010, Biochemical J.). It is known that autophosphorylation plays an important role in the biological activity of many kinases, and it has been established in the past that LRRK2 can autophosphorylate at many sites in vitro. (Gloekner, 2010, J. Proteosome Res .; Kamakikawaji, 2009, Biochemistry). Although these studies have found that LRRK2 functions primarily as a serine / threonine kinase, it has been suggested that phosphorylation at the threonine site is preferred. Importantly, however, dozens of autophosphorylation sites have been reported after in vitro studies, but most of these sites do not appear to be phosphorylated in cells (Reference). Furthermore, there are no reports describing sites of autophosphorylation that can be identified in animals. Confirmatory autophosphorylation sites that can be easily monitored in cells and animals, and assays that allow the degree of autophosphorylation to be monitored under various conditions are important tools in the development of treatments that target LRRK2. It will be.

  Mutations in the leucine rich repeat kinase 2 (LRRK2) gene are the most common cause of familial Parkinson's disease (PD). Mutations in the LRRK2 gene associated with Parkinson's disease regulate LRRK2 autophosphorylation. Therefore, monitoring changes in LRRK2 autophosphorylation provides a tool for identifying or evaluating inhibitors of LRRK2 in vitro and a potential biomarker for monitoring LRRK2 activity in vivo.

  The invention provides an assay / biomarker that can assess LRRK2 activity in the brain. Quantitative studies by the inventors indicate that LRRK2 autophosphorylation on Ser1292 is the most abundant autophosphorylation event in vitro and is detectable in transfected cells. A phosphorylation site-specific antibody against pSer1292 was generated and used to show that LRRK2 familial mutations, including R1441G, Y1699C, G2019S and I2020T, all show increased pSer1292. Ser1292 autophosphorylation depends on LRRK2 kinase activity and GTP binding and is most likely to occur in cis. Mutation of Ser1292 to alanine (S1292A) abolishes neurotoxicity caused by LRRK2 PD mutation in a cell-based model. In addition, expression of the LRRK2 PD mutant protein in neurons alters basal autophagy activity. The S1292A mutation also partially restores this phenotype. The use of an LRRK2 kinase inhibitor indicates that LRRK2 kinase inhibition effectively inhibits S1292 autophosphorylation in cultured cells and LRRK2 BAC transgenic animals. Thus, S1292 autophosphorylation represents a biomarker of LRRK2 kinase activity in vivo and may contribute to the mechanism by which LRRK2 causes Parkinson's disease. The terms “phosphorylation” and “autophosphorylation” are used interchangeably herein.

  In one aspect of the invention, a method for identifying a patient or subject suffering from or at risk for developing Parkinson's disease, wherein the level of S1292 phosphorylation or autophosphorylation in said patient is determined. A method is provided wherein the elevated level correlates with Parkinson's disease morbidity or risk of developing Parkinson's disease.

  The method can further comprise obtaining an LRRK2 containing sample from the subject;

  The method may further comprise measuring, monitoring or otherwise detecting the amount or level of S1292 autophosphorylation in the subject sample.

  The method may further comprise comparing the amount or level of S1292 autophosphorylation in the subject sample with the amount or level of S1292 autophosphorylation in one or more control samples.

  In one aspect of the invention, a method of predicting a subject's sensitivity to an LRRK2 modulator, or the effect of an LRRK2 modulator on the treatment of Parkinson's disease, comprising determining the level of S1292 phosphorylation or autophosphorylation in said patient And provided is a method in which elevated levels of S1292 phosphorylation or autophosphorylation correlate with the effect of the inhibitor for the treatment of the disease.

  The method can further include obtaining or obtaining a first LRRK2-containing sample from the subject.

  The method can further comprise administering an LRRK2 modulator to the subject.

  The method may further comprise obtaining or obtaining a second LRRK2 containing sample from the subject after administering the LRRK2 modulator to the subject.

  The method may further comprise measuring, monitoring or otherwise detecting the amount or level of S1292 autophosphorylation in the first subject sample.

  The method may further comprise measuring, monitoring or otherwise detecting the amount or level of S1292 autophosphorylation in the second subject sample.

  The method may further comprise comparing the amount or level of S1292 autophosphorylation in the first subject sample with the amount or level of S1292 autophosphorylation in the second subject sample.

  The invention also relates to a method of selecting a patient to receive an LRRK2 inhibitor comprising measuring a patient's S1292 phosphorylation or autophosphorylation profile, wherein a patient having an elevated S1292 autophosphorylation profile is selected. A method is provided. The term “S1292 profile” refers to the amount of S1292 autophosphorylation in a patient sample compared to the amount in a control sample. The S1292 profile can be a ratio (eg, amount of S1292 autophosphorylation in a patient sample or cell / S1292 autophosphorylation in a control sample or cell) or a difference (eg, amount of S1292 in a patient sample or cell-S1292 in a control sample or cell). The amount of autophosphorylation). “Increased S1292 profile” refers to the S1292 autophosphorylation profile determined to have a substantially higher S1292 autophosphorylation level in the control sample. In one example, the S1292 autophosphorylation profile is about 5% -100% higher than in the control sample.

  In the subject method, the LRRK2 modulator can be a compound of Formula I or Formula II, or one of the LRRK2 modulators disclosed herein.

In one aspect of the invention, a method for identifying a subject suffering from or at risk of developing Parkinson's disease comprising:
Obtaining or obtaining an LRRK2 containing sample from a subject;
Measuring, monitoring or otherwise detecting the amount or level of S1292 autophosphorylation in a subject sample; and determining the amount or level of S1292 autophosphorylation in a subject sample as measured by one or more control samples. A method comprising comparing to an amount or level is provided.

  The method can further include determining whether the amount or level of S1292 autophosphorylation in the subject sample is increased or greater than that of the control sample. If the amount or level of S1292 autophosphorylation in the subject sample is increased or greater compared to that of the control sample, the subject is at risk of developing Parkinson's disease or having Parkinson's disease Can be identified as having sex.

  By way of example, and not limitation, a LRRK2-containing subject sample can comprise cells, cell lysates, or solutions or suspensions thereof obtained from tissue or serum from a subject. In one embodiment, the subject sample may comprise monocytes (leukocytes) or lysates thereof. The sample can be obtained from the subject by a syringe or a tissue extraction device. The sample thus obtained can be subjected to cell separation, buffering, solvent extraction and / or exposure to a lytic enzyme to expose or make accessible the LRRK2 protein contained therein.

In some embodiments, measuring the level of S1292 autophosphorylation in a subject sample can be performed by detecting an antibody using an antibody associated with S1292 (ie, an anti-phosphate-S1292-LRRK2 antibody). . Thus, the measurement is
Transfer, attachment or fixation of cells or cell lysates from the subject sample onto the assay plate;
Application of anti-phosphate-S1292-LRRK2 antibody to the assay plate;
It may further comprise removal or washing of excess anti-phosphate-S1292-LRRK2 antibody; and detection of anti-phosphate-S1292-LRRK2 antibody bound to the assay plate.

  In certain embodiments, the anti-phosphate-S1292-LRRK2 antibody can be a monoclonal or polyclonal antibody that binds to an antigenic peptide or protein comprising the sequence PNEMGKLSKIWDLPL, or CPNEMGKLSKIWDLPL, or a fragment thereof. In the above sequence, the serine residue “S” is phosphorylated or phosphorylable. Thus, an antigenic peptide or protein can be represented as PNEMGKL-pS-KIWDLPL or CPNEMGKL-pS-KIWDLPL, where “pS” is phosphorylated serine.

  In another embodiment, the antigenic peptide or protein is between 12 and 20 residues in length or between 14 and 18 residues and comprises phosphorylated serine and 90% homology with PNEMGKL-pS-KIWDLPL Have In yet another embodiment, the antigenic peptide or protein is between 12 and 20 residues in length or between 14 and 18 residues, comprises phosphorylated serine and is at least 10 from within PNEMGKL-pS-KIWDLPL. Of consecutive residues. The anti-phosphate-S1292-LRRK2 antibody can be applied to the assay plate as a solution.

  In certain embodiments, detection of anti-phosphate-S1292-LRRK2 antibody may be performed by ELISA detection, DELFIA detection, fluorescence detection, electrochemiluminescence detection, or other electrometric capable of quantitative measurement or detection of antibodies on an assay plate. Optical or radioisotope techniques can be utilized.

  In certain embodiments, the comparison of the amount or level of S1292 autophosphorylation in a subject sample with the amount or level of S1292 autophosphorylation in one or more control samples can be determined using computer software stored on a computer readable medium. Can be incorporated into logic elements. The comparison may be, for example: input of data representing the amount or level of S1292 autophosphorylation in a subject sample by computer user interface; input of data representing the amount or level of S1292 autophosphorylation in a control sample by computer user interface; Including the execution of programming stored in computer memory to create a computer; and the display of comparison data in alphanumeric and / or graph format by a computer visual interface, wherein the comparison data is of S1292 autophosphorylation in a subject sample Displayed to determine whether the level indicates an increase or greater compared to that of the control sample.

The level of autophosphorylation of LRRK2 S1292 also determines whether the patient subject responds favorably to administration of a particular LRRK2 modulator therapy and / or what dose level of LRRK2 modulator or inhibitor may be optimal or desired for the subject. To determine, it can be used as a clinical pharmacodynamic marker or companion diagnostic tool. In this regard, the invention is a method for determining a subject that is responsive to a treatment comprising an LRRK2 modulator:
Obtaining or obtaining a first LRRK2 containing sample from a subject;
Administering an LRRK2 modulator to the subject;
Obtaining or obtaining a second LRRK2 containing sample from the subject after administering the LRRK2 modulator to the subject;
Measuring, monitoring or otherwise detecting the amount or level of S1292 autophosphorylation in the first subject sample;
Measuring, monitoring or otherwise detecting the amount or level of S1292 autophosphorylation in the second subject sample; and the amount or level of S1292 autophosphorylation in the first subject sample A method comprising comparing to the amount or level of phosphorylation is provided.

  The invention can further include determining whether the amount or level of S1292 autophosphorylation in the second subject sample is less than the amount or level of S1292 autophosphorylation in the first subject sample. A decrease in S1292 autophosphorylation in the second subject sample compared to the first subject sample indicates that the LRRK2 modulator is effective. The amount or level of reduction of S1292 autophosphorylation is further the use of how effective the LRRK2 modulator is in the subject, and thus what dosage level may be appropriate for the subject.

  By way of example and not limitation, the first and second LRRK2-containing subject samples may comprise cells, cell lysates, or solutions or suspensions thereof obtained from tissue or serum from the subject. In one embodiment, the subject sample may comprise monocytes (leukocytes) or lysates thereof. The sample can be obtained from the subject by a syringe or a tissue extraction device. The sample thus obtained can be subjected to cell separation, buffering, solvent extraction and / or exposure to a lytic enzyme in order to expose or make accessible the LRRK2 protein contained therein.

In certain embodiments, measuring the level of S1292 autophosphorylation in the first and second subject samples uses an antibody associated with S1292 (ie, an anti-phosphate-S1292-LRRK2 antibody) and detects the antibody Can be implemented. Thus, the measurement is
Transfer, attachment or fixation of cells or cell lysates from the first and second samples onto the assay plate or plate;
Application of anti-phosphate-S1292-LRRK2 antibody to the assay plate or plate;
It may further comprise removal or washing of excess anti-phosphate-S1292-LRRK2 antibody; and detection of anti-phosphate-S1292-LRRK2 antibody bound to the assay plate or plate.

  In one embodiment, the anti-phosphate-S1292-LRRK2 antibody binds to an antigenic peptide or protein comprising the sequence PNEMGKL-pS-KIWDLPL (PNEMGKLSKIWDLPL), CPNEMGKL-pS-KIWDLPL (CPNEMGKLSKIWDLPL), or a fragment thereof. Alternatively, it may be a polyclonal antibody and “pS” is phosphorylated serine as described above. In another embodiment, the antigenic peptide or protein is between 12 and 20 residues in length or between 14 and 18 residues in length, comprises phosphorylated serine, and 90% with PNEMGKL-pS-KIWDLPL Have homology. In another embodiment, the antigenic peptide or protein is between 12 and 20 residues in length or between 14 and 18 residues, comprises phosphorylated serine, and is at least 10 from within PNEMGKL-pS-KIWDLPL. Of consecutive residues. The anti-phosphate-S1292-LRRK2 antibody can be applied to the assay plate as a solution.

  In certain embodiments, detection of anti-phosphate-S1292-LRRK2 antibody from the first and second subject samples comprises ELISA detection, DELFIA detection, fluorescence detection, electrochemiluminescence detection, or an antibody on an assay plate or plate Other electrical, optical, or radioisotope techniques that can quantitatively measure or detect can be utilized.

  In certain embodiments, the comparison of the amount or level of S1292 autophosphorylation in the first subject sample with the amount or level of S1292 autophosphorylation in the second subject sample is performed by computer software stored on a computer readable medium. It can be embodied in a logic element. Thus, the comparison may be, for example: input of data representing the amount or level of S1292 autophosphorylation in the first subject sample by computer user interface; the amount or level of S1292 autophosphorylation in the second subject sample by computer user interface Input of representing data; execution of programming stored in computer memory to generate comparison data; and display of comparison data in alphanumeric and / or graph format by a computer visual interface, the comparison data being Displayed to determine whether the level of S1292 autophosphorylation in the body sample is less than or reduced in the first subject sample.

The subject invention is
One or more syringes or tools for obtaining a tissue sample or sample from a subject;
An assay plate; and a kit comprising a solution of anti-phosphate-S1292-LRRK2 antibody.

  The kit can further include a buffer solution for stabilizing the sample from the subject.

  The kit may further comprise a solution of cell lysis reagent.

  The kit may further comprise a solution or reagent capable of transferring, attaching or fixing cells or cell lysate from the subject sample to the assay plate.

  The kit may further comprise a solution for rinsing or removing excess anti-phosphate-S1292-LRRK2 antibody from the assay plate.

  The kit may further comprise an LRRK2 modulator solution and a syringe or other device for administration of the LRRK2 modulator solution.

  The invention also provides an anti-phosphate-S1292-LRRK2 antibody characterized by being capable of binding to the sequence CPNEMGKL-pS-KIWDLPL (CPNEMGKLSKIWDLPL), or an antigenic peptide or protein comprising a fragment thereof, "Is phosphorylated serine. In another embodiment, the anti-phosphate-S1292-LRRK2 antibody is capable of binding to an antigenic peptide or protein comprising the sequence PNEMGKL-pS-KIWDLPL (PNEMGKLSKIWDLPL), or a fragment thereof, "Is phosphorylated serine. In another embodiment, the antigenic peptide or protein is between 12 and 20 residues in length or between 14 and 18 residues and comprises phosphorylated serine and 90% homology with PNEMGKL-pS-KIWDLPL Have In another embodiment, the antigenic peptide or protein is between 12 and 20 residues in length or between 14 and 18 residues, comprises phosphorylated serine, and is at least 10 from within PNEMGKL-pS-KIWDLPL. Of consecutive residues.

  One aspect of the invention is an assay for screening compounds and compositions for inhibition of LRRK2 activity, the method comprising exposing LRRK2 or a fragment thereof to a potential inhibitory compound and phosphorylation sites on the LRRK2 protein. Detection of the level or amount of associated phosphorylation.

  In some embodiments, the LRRK2 phosphorylation site can be serine 1292 (Ser1292 or S1292).

  In certain embodiments, monitoring of phosphorylation at the LRRK2 phosphorylation site may be performed using an antibody associated with the LRRK2 autophosphorylation site (anti-phosphate-LRRK2 antibody). Detection of anti-phosphate antibodies may utilize ELISA, DELFIA, fluorescence, electrochemiluminescence, or other electrical, optical or radioisotope techniques. In one embodiment, the antibody used is an anti-phosphate-serine 1292-LRRK2 antibody.

  In certain embodiments, the LRRK2 used may be a wild type or a mutant form associated with Parkinson's disease, such as R1441G, R1441C, Y1699C, G2019S, I2020T mutation. In other embodiments, the LRRK2 protein used in the assay is characterized by a combination of Parkinson's disease-related mutations (ie, R1441G / G2019S or R1441G / Y1699C / G2019S). In a further embodiment, the assay is characterized by a mutation known to affect the kinase or GTPase activity of LRRK2 (ie D1994A). LRRK2 can be of human, rabbit, mouse or other mammalian origin. The LRRK2 protein used in the assay is prepared by recombinant techniques using HEK293, CHO or other suitable cell line transfected or virally transfected with cDNA encoding all or part of LRRK2. sell. LRRK2 can include an epitope tag to facilitate affinity purification, antibody detection, or immunoprecipitation.

  In one embodiment, the subject method comprises recombinant production of LRRK2 in a cell; exposure of the cell to one or more potential LRRK2 inhibitor compounds; lysis of the cell; exposure of the cell lysate to an anti-phosphate-LRRK2 antibody. And detection of anti-phosphate-LRRK2 antibodies bound to LRRK2 in cell lysates.

  In another embodiment, the method comprises recombinant production of LRRK2 in a cell; exposure of the cell to one or more potential LRRK2 inhibitor compounds; lysis of the cell; fixation of LRRK2 from lysed cells; anti-phosphate-LRRK2 Exposure of the cell lysate to the antibody; and detection of anti-phosphate-LRRK2 antibody bound to LRRK2 in the cell lysate.

  In another embodiment, the method comprises recombinant production of LRRK2 in cells; fixation of cells in multiple wells of the first plate; exposure of cells in each well to a potential LRRK2 inhibitor compound; lysis of cells in each well; Immobilization of LRRK2 from lysed cells from each well of the first plate; exposure of immobilized LRRK2 to anti-phosphate-LRRK2 antibody; and anti-phosphate-LRRK2 bound to LRRK2. Includes detection of antibodies. Immobilization of LRRK2 from lysed cells can be achieved, for example, by seeding or fixing antibodies against LRRK2 or epitog tag thereon in the second plate well, and cell lysate from the well of the first plate to the corresponding well of the second plate May include movements.

  Another aspect of the invention involves the use of the phosphorylation site of LRRK2 for in vivo detection of Parkinson's disease mutations in LRRK2 and as a biomarker method for assessing the in vivo effects of LRRK2 inhibitors. The method can include: administration of an LRRK2 inhibitor to a subject; obtaining a tissue or serum sample from the subject; and detecting the level or amount of phosphorylation associated with a phosphorylation site on LRRK2 from the sample.

  In one embodiment, the biomarker phosphorylation site can be serine 1292 (Ser1292 or S1292) of the LRRK2 protein.

  Monitoring of phosphorylation at the LRRK2 phosphorylation site can be performed by an antibody associated with the LRRK2 autophosphorylation site (anti-phosphate-LRRK2 antibody), eg, anti-phosphate-serine 1292-LRRK2 antibody. Anti-phosphate-serine 1292-LRRK2 is a standard in combination with anti-phosphate-serine 1292-LRRK2 antibody, such as ELISA, DELFIA, fluorescence, electrochemiluminescence, or other electrical, optical or radioisotope techniques Can be detected using a simple procedure.

  Another aspect of the invention is an antibody against an antigen comprising the sequence CPNEMGKL-pS-KIWDLPL, or a fragment thereof, wherein “pS” is phosphorylated serine. In another embodiment, the antigen is between 14 and 18 residues in length, comprises phosphorylated serine and has 90% homology with CPNEMGKL-pS-KIWDLPL.

  Another aspect of the invention is a kit for in vitro evaluation of LRRK2 inhibitors. Such a kit can include, for example, a solution having an LRRK2 protein; and a solution having an anti-phosphate-LRRK2 antibody, such as an anti-phosphate-Ser1292-LRRK2 antibody. The solution can be stored in a suitable tube or container. And the kit may further comprise containers, multiwell plates, buffer solutions and tools configured to perform the inventive assay and biomarker methods described herein.

  The invention will be more fully understood by reference to the following drawings for illustrative purposes.

Identification of in vivo LRRK2 autophosphorylation sites. (A) Schematic showing the domain structure of LRRK2. (B, C) Collected automated MS / MS spectra that clearly identify pSer1292 and pThr1343. Comparison of these spectra against MS / MS obtained from a synthetic internal standard provides further confirmation. (D, E) Extracted ion chromatograms of pSer1292 SFPNEGGKLS # K and pThr1343 LMVGNT # GSGK peptides from reactions of G2019S-LRRK2 at times ranging from 0 to 60 minutes. The isotopic labeled internal standards of pSer1292 ( ¹³ C ₆ ¹⁵ N ₁ Leu; +7.017 Da) and pThr1343 ( ¹³ C ₅ ¹⁵ N ₁ Val; +6.014 Da) are shown behind each 3D, and the forward signal is from the digested sample The resulting light analyte peptide is represented. (F, G) Extracted ion chromatograms of light and heavy pSer1292 peptides from FLAG-LRRK2 immunoprecipitated from transfected 293 cells. Light pSer1292 can be detected from G2019S-LRRK2, but is different in Kinase deadD1994A LRRK2. The kinase activity of LRRK2 is required for S1292 phosphorylation. (A) Western blot to detect LRRK2 autophosphorylation in lysates of HEK293 cells that transiently express the FLAG tag LRRK2 WT, S1292A and D1994A. (B) Western blot to detect LRRK2 autophosphorylation in brain lysates of BAC transgenic mice overexpressing LRRK2 WT or kinase-dead mutants. Familial Parkinson's disease mutations increase S1292 autophosphorylation. (A) Representative Western to detect pS1292 and total LRRK2 signal from lysates of HEK293 cells transiently transfected with WT, R1441G, Y1699C, G2019S, I2020T, G2385R and R1441G / G2019S (RG / GS) LRRK2. Blot image. (B) Quantification of the mean fold of the LRRK2 pS1292 signal in the mutant compared to the wild type, the signal being the average of 4 independent experiments. (C) Representative Western blot image detecting pS1292 and total LRRK2 from tissue lysates from different brain regions of BAC transgenic mice expressing Flag-tagged wild type (WT) and G2019S LRRK2. (D) Quantification of double pS1292 changes in whole brain lysates from BAC transgenic mice expressing Flag-tagged wild type (WT) and G2019S LRRK2. N = 5 animals for each genotype. Biochemical mechanism of LRRK2 autophosphorylation on S1292 (A) GTP binding is required for S1292 autophosphorylation. Representative Western blot images detecting pS1292 and total LRRK2 from lysates transiently expressing Flag-tag wild type, T1348N, G2019S and T1348N / G2019S LRRK2. (B) The LRRK2 S1292A protein cannot phosphorylate the S1292 residue on the LRRK2 kinase-dead mutant (D1994A). Schematic (left) of two constructs co-transfected in HEK293 cells. Representative Western blot image detecting pS1292 from lysates of HEK293 cells that transiently express Flag-tag LRRK2 R1441G / Y1699C / G2019S (3M), 3M / S1292A, D1994A, and D1994A + 3M / S1292A (right). (C) Full-length LRRK2 cannot phosphorylate the S1292 residue on truncated kinase-deadLRRK2 (D1994A). Schematic diagram of 2 co-transfected constructs (left). Representative Western blot image detecting pS1292 and total LRRK2 from HEK293 cells expressing full-length and truncated LRRK2 carrying the D1994A mutation. S1292 is required for neurite outgrowth failure by LRRK2 PD mutagenesis. (A) Neurolucida tracking of representative GFP transfected hippocampal neurons. The GFP signal was used for neurite tracking with Neurolucida software. A concentric overlay of 20 μm intervals centered on the cell body was used for the Hole analysis. (B) Representative Neurolucida tracing of hippocampal neurons co-transfected with GFP and LRRK2. GFP was co-transfected in vitro on day 6 (DIV6) with hippocampal cultures with empty vector, LRRK2 wild type, R1441G G2019S, S1292A R1441GG2019S and R1441G G2019S D1994A allele. At DIV17, neurons were fixed and stained with GFP and MAP2. Images of the transfected neurons were taken with a confocal microscope and the dendrites were followed by Neurolucida software by an observer who was blind for allelic identity. Scale bar: 100 μm. (C) Shall analysis. The average (± SEM) number of intersections with each circle in LRRK2 transfected cells was counted. Student's t-test p-value between R1441G G2019S and wild type, R1441G G2019S D1994A, S1292A R1441G G2019S was less than 0.05 (indicated by *). N = 22-30 cells for each construct. (D) Quantification of total dendrite length in (B). N = 40-85 in 3 experiments. Average diamond is shown for each group. Student's t-test p-value between R1441G G2019S (red circle) and wild type, R1441G G2019S D1994A, S1292A R1441G G2019S was less than 0.001. 6A-D. The S1292A mutation partially ameliorates the autophagic disorder induced by the LRRK2 PD mutation. LRRK2 kinase inhibitors block pS1292 autophosphorylation in cell-based assays. (A) LRRK2 cell lysate elicited with 1 ug / mL doxycline for 16 hours using pLRRK2 electrochemiluminescence 96 well plate-based assay and increased pLRRK (Ser1292) signal compared to uninduced LRRK cell lysate Detected in (B) Dose-dependent reduction of pS1292 signal in doxyclin-induced LRRK2 cells was incubated with Sutent (IC ₅₀ 0.10 uM) and G1023 (IC ₅₀ 0.0016 uM) for 16 hours. Inhibition was normalized to uninduced cell lysate as 100% inhibition. (C) 600 compound data showing a robust correlation between cellular pLRRK (Ser1292) inhibitor IC50 values and biochemical LRRK2Ki values. Slope = 0.95, R ² = 0.77. Hollow symbols were outside the range IC50 values and were excluded from the regression fit. The LRRK2 kinase inhibitor G1023 reduces pS1292 autophosphorylation in vivo. Image of Western blot detecting pS1292 and total LRRK2 from tissue lysates of spleen (A) and brain (B) from Flag-tag G2019S LRRK2 BAC transgenic animals. Animals were administered vehicle alone (2 animals), 10, 30 or 100 mg / kg G01581023 (3 animals each for compound administration groups). (C) Quantification of pS1292 / total LRRK2 signal in (A) and (B). (D), (E). 9A, 9B. The LRRK2 kinase inhibitor G1023 ameliorates neurite outgrowth in G2019S neuronal cultures from LRRK2 BAC transgenic mice.

(Detailed description of the invention)
Definitions Unless otherwise stated, the following terms used in this application, including the specification and claims, have the following definitions. As used in the specification and the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly indicates otherwise.

  Definitions of specific terms used in this specification are provided below. Definitions of other terms can be found in the glossary provided in the U.S. Department of Energy, Office of Science, Human Genome Project (http: www.ornl.gov/sci/techresources/Human_Genome/glossary/). Many common techniques in molecular biology, microbiology and recombinant DNA are used in the practice of the present invention. These techniques are well known, e.g. Current Protocols in Molecular Biology, Vols.I-III, Ausubel, ed. (1997); Sambrook et al., Molecular Cloning: A Laboratory Manual, Second Edition (Cold Spring Harbor Laboratory Press, (Cold Spring Harbor, NY, 1989); DNA Cloning: A Practical Approach, Vols. I and II, Glover D, ed. (1985); Oligonucleotide Synthesis, Gait, ed. (1984); Nucleic Acid Hybridization, Hames & Higgins, (1985); Transcription and Translation, Hames & Higgins, eds. (1984); Animal Cell Culture, Freshney, ed. (1986); Immobilized Cells and Enzymes (IRL Press, 1986); Perbal, A Practical Guide to Molecular Cloning; the series, Methods in Enzymol. (Academic Press, Inc., 1984); Gene Transfer Vectors for Mammalian Cells, Miller & Calos, eds. (Cold Spring Harbor Laboratory, NY, 1987); and Methods in Enzymology, Vols. 154 and 155, Wu & Grossman, and Wu, eds., Respectively.

  As used herein, the term “allele” refers to a particular form of a gene or DNA sequence at a particular chromosomal location (locus).

  As used herein, the term “antibody” includes, but is not limited to, polyclonal, monoclonal, humanized or chimeric antibodies, and biologically functional enough to bind antibody fragments to proteins. Antibody fragments. Antibodies can be used in assays to determine the presence of mutant proteins and peptides, and the genetic polymorphism of the invention is in the coding region of the gene.

  As used herein, the term “clinical response” refers to any or all of the following: quantitative measures of response, non-response, and adverse response (ie, side effects).

  As used herein, the term “clinical trial” means any research study designed to collect clinical data regarding response to a particular treatment, including but not limited to Phase I, Includes Phase II and Phase III clinical trials. Standard methods are used for patient population definition and subject enrollment.

  As used herein, the term “effective amount” of a compound is an amount sufficient to achieve the desired therapeutic and / or prophylactic effect, eg as described herein for the disease being treated, eg, An amount that results in the prevention or reduction of symptoms associated with diseases associated with LRRK2 mutant polynucleotides and mutant polypeptides (particularly Alzheimer's disease and Parkinson's disease). The amount of compound administered to a subject will depend on the type and severity of the disease and the characteristics of the individual, such as general health status, age, sex, weight and tolerance to drugs. It will also depend on the degree, severity and type of disease. A person skilled in the art will be able to determine the appropriate dose depending on these and other factors. Typically, an effective amount of a compound of the present invention sufficient to achieve a therapeutic or prophylactic effect ranges from about 0.000001 mg / kilogram body weight / day to about 10,000 mg / kilogram body weight / day. Preferably, the dosage range is from about 0.0001 mg / kilogram body weight / day to about 100 mg / kilogram body weight / day. The compounds of the invention can also be administered in combination with each other or with one or more additional therapeutic compounds.

  As used herein, “expression” includes, but is not limited to, one or more of the following: transcription of a gene into precursor mRNA; splicing of precursor mRNA to produce mature mRNA and other MRNA stabilization; translation of mature mRNA into protein (including codon usage and tRNA efficacy); and glycosylation and / or other modifications of the translation product as required for proper expression and function.

  As used herein, the term “gene” includes DNA that contains all information for the controlled biosynthesis of an RNA product, including promoters, exons, introns, and other untranslated regions that control expression. Means the segment.

  As used herein, the term “genotype” refers to an unphased 5'-3 'sequence of nucleotide pairs found at one or more polymorphic sites at a locus on a pair of homologous chromosomes in an individual. As used herein, genotype includes full genotype and / or subgenotype.

  As used herein, the term “locus” refers to a location on a chromosome or DNA molecule that corresponds to a gene or physical or phenotypic characteristic in a particular LRRK2 gene.

  As used herein, the term “LRRK2 modulator” refers to the expression level or biological activity of an LRRK2 polypeptide as compared to the expression level or biological activity level of the LRRK2 polypeptide in the absence of an LRRK2 modulator. Any compound that alters (eg, increases or decreases) the activity level. The LRRK2 modulator can be a small molecule, polypeptide, carbohydrate, lipid, nucleotide, or a combination thereof. The LRRK2 modulator can be an organic compound or an inorganic compound.

  As used herein, the term “mutant” refers to any genetic variation from the wild type that is the result of a mutation, such as a single nucleotide polymorphism. The term “mutant” is used interchangeably throughout the specification with the terms “marker”, “biomarker”, and “target”.

  As used herein, the term “medical condition” includes, but is not limited to, any condition or disease that manifests as one or more physical and / or psychological symptoms for which treatment is desired. Including past and newly identified diseases and other disorders.

  As used herein, the term “nucleotide pair” means a nucleotide found at a polymorphic site on two copies of a chromosome from an individual.

  As used herein, the term “polymorphic site” means a position within a locus where at least two alternative sequences are found in a population, the most frequent having a frequency of 99% or less.

  As used herein, the term “phased” when applied to the sequence of nucleotide pairs of two or more polymorphic sites at a locus, refers to the nucleotides present at those polymorphic sites in a single copy of the locus. Means the combination is known.

  As used herein, the term “polymorphism” refers to any sequence variant that is present at a frequency of> 1% in a population. Sequence variants may be present at a frequency significantly greater than 1%, such as 5% or 10% abnormalities. The term may also be used to refer to a sequence variant that is observed in an individual at a polymorphic site. Polymorphisms include nucleotide substitutions, insertions, deletions and microsatellite, but can result in detectable differences in gene expression or protein function, but not necessarily.

  As used herein, the term “polynucleotide” refers to any RNA or DNA that can be unmodified or modified RNA or DNA. A polynucleotide includes, but is not limited to, single and double stranded DNA, DNA that is a mixture of single and double stranded regions, single and double stranded RNA, RNA that is a mixture of single and double stranded regions, and It includes hybrid molecules comprising DNA and RNA that can be single stranded or, more typically, double stranded or a mixture of single and double stranded regions. In addition, polynucleotide refers to triple-stranded regions comprising RNA or DNA or both RNA and DNA. The term polynucleotide also includes DNAs or RNAs having one or more modified bases and DNAs or RNAs having backbones modified for stability or other reasons.

  As used herein, the term “polypeptide” refers to any polypeptide comprising two or more amino acids joined to each other by peptide bonds or modified peptide bonds, ie, peptide isosteres. Polypeptide refers to both short chains, commonly referred to as peptides, glycopeptides or oligomers, and to longer chains, generally referred to as proteins. The polypeptide can include amino acids other than the 20 gene-encoded amino acids. Polypeptides include amino acids modified by natural processes, such as post-translational processing or by chemical modification techniques well known in the art. Such modifications are well documented in basic texts, and in more detailed monographs and extensive research literature.

  As used herein, the terms “phosphorylation” and “autophosphorylation” are used interchangeably herein and include a phosphate group at its phosphorylation site to LRRK2, eg, serine 1292 (Ser1292 or S1292). Is generally referred to.

  As used herein, the term “SNP nucleic acid” refers to a nucleic acid sequence and includes nucleotides that are otherwise variable within an identical nucleotide sequence between individuals or populations, and thus exist as alleles. Such SNP nucleic acids are preferably about 15 to about 500 nucleotides in length. SNP nucleic acids can be part of a chromosome or they can be an exact copy of a part of a chromosome by amplification of such part of the chromosome, for example through PCR or cloning. The SNP nucleic acid is hereinafter simply referred to as “SNP”. SNP is the occurrence of nucleotide diversity at a single position in the genome, with two alternative bases occurring at an appropriate frequency (ie> 1%) in the human population. SNPs can occur within genes or within intergenic regions of the genome. The SNP probe according to the invention is an oligonucleotide complementary to a SNP nucleic acid.

  As used herein, administration of a substance or drug to a subject or patient includes self-administration and administration by others. The various modes of treatment or prevention of the described medical conditions are also understood to mean “substantial” and include not only complete but also less than complete treatment or prevention, and some biological Or a medically relevant result is obtained.

  As used herein, “Parkinson's disease” (“PD”) refers to a degenerative disorder of the central nervous system that impairs motor skills, speech, and / or cognitive function. Symptoms of Parkinson's disease can include, for example, muscle stiffness, tremors, slow movements of the body (slow movement), and loss of movements of the body (immobility).

  As used herein, “Lewy body disease”, also referred to as “Lewy body dementia”, “diffuse Lewy body disease”, or “cortical Lewy body disease” is anatomically the Lewy body in the brain. Means a neurodegenerative disorder characterized by the presence of

  As used herein, “subject” means mammals and non-mammals. Mammal means any member of the mammalian class, including but not limited to humans; non-human primates such as chimpanzees and other apes and monkeys; livestock animals such as cattle, horses, sheep, goats, And pigs; domestic animals such as rabbits, dogs, and cats; including laboratory animals, cats, mice, and rodents such as guinea pigs; and the like. Examples of non-human mammals include but are not limited to birds and the like. The term “subject” does not denote a particular age or sex.

  As used herein, a “therapeutically effective amount” when administered to a subject to treat a disease state is a compound that is sufficient for such treatment to act on the disease state. Means quantity. “Therapeutically effective amount” depends on the compound, the disease state being treated, the severity or disease being treated, the age and relative health of the subject, the route and form of administration, the attending physician or veterinarian, and other factors. Depending on it.

  When the terms “as defined above” and “as defined herein” refer to a variable, the broad definition of the variable, as well as the specific definition, if any, is incorporated by reference.

  “Treatment” or “treatment” of a disease state is, inter alia, inhibition of the disease state, ie suppression of the onset of the disease state or clinical symptoms thereof, and / or reduction of the disease state, ie temporary of the disease state or clinical symptoms thereof. Or including permanent retraction.

  All patents and publications mentioned herein are hereby incorporated by reference in their entirety.

LRRK2
In FIG. 1, a schematic representation of the LRRK2 protein is shown, with the N-terminus on the left and the C-terminus on the right. The LRRK2 protein is 2527 amino acids long and belongs to the ROCO-protein superfamily. LRRK2 contains an ANK (ankyrin repeat) domain, an LRR (leucine rich repeat) domain, an ROC (Ras in complex protein) domain, a COR (C-terminal to Roc) linker domain, a kinase domain, and a WD40 domain. The S1292 autophosphorylation site is generally located between the LRR and ROC domains as shown in FIG. The R1441G mutation occurs in the ROC domain, the Y1699C mutation occurs in the COR domain, and G2019S and I2020T are found in the kinase domain. Human LRRK2 proteins and corresponding nucleic acid sequences are well known and are disclosed, for example, as SEQ ID NO: 2 and SEQ ID NO: 1, respectively, in published application US2010 / 0035251.

Identification of S1292 as an in vivo autophosphorylation site In vitro kinase assay was performed using purified G2019S and kinase dead (D1994A) LRRK2. Reactions were performed in the presence or absence of ATP (1 mM) and GTPgS (10 mM) and then separated by SDS-PAGE. The Coomassie-stained LRRK2 band was subjected to in-gel trypsin digestion followed by liquid chromatography tandem mass spectrometry (LC-MS / MS, Aqua peptides (Sigma-Aldrich)). A database search showed a series of spectra that confidently matched the LRRK phosphopeptides. None of the identified sites were observed from reaction with kinase deadD1994A LRRK2. Of note is a cluster of phosphopeptides beginning at pSer1292 in the C-terminal part of the LRR domain and extending to the ROC domain (FIGS. 1B, 1C). Phosphorylation was also observed on at least one residue in the kinase activation loop (pSer2031; data not shown). These results support the foregoing that LRRK2 preferentially modifies Thr residues relative to Ser, at least in the context of autophosphorylation activity.

  Among the identified LRRK2 autophosphorylation sites, an unusual frequency of Met residues was shown in the vicinity of the LRRK2 phosphorylation sites, and the 9/14 peptide presented Met between positions 1 and 5 upstream of the modified residues. No phosphopeptide was observed in reactions lacking ATP and GTPgS, the only exception was spectral matching to the sequence SFPNEMGKLS # K corresponding to pSer1292 (FIG. 1B).

A series of internal standard peptides were synthesized to assess the relative abundance of phosphorylation in vitro and to assist in the verification of these modifications in vivo. These peptides contained the same sequence as the identified LRRK2 phosphopeptide, but contained a single amino acid enriched in stable isotopes. Included among these are isotope-labeled peptides directed to pSer1292, including SFPNEMGK L S # K ( ¹³ C ₆ ¹⁵ N ₁ Leu; +7.017 Da), pThr1343LMI V GNT # GSKK ( ¹³ C ₅ ¹⁵ N ₁ ^{Val; + 6.014Da), pThr1357TTLLQQ L} MKT # K (13 C 6 15 N 1 Leu + 7.017Da), and was _{^{pThr1368SDLGMQSAT # VGID V K (13 C}} 5 15 N 1 Val + 6.014Da). In order to comprehensively assess the phosphorylation status of pSer1357 and pSer1368, additional peptides were required for the ragged-end ends flanking these sequences.

  In vitro kinase reactions were then performed using purified WT, G2019S, and R1441C LRRK2 proteins. Time points were collected at 0, 5, 10, 30 and 60 minutes, separated by SDS-PAGE and stained with Coomassie. Extracted ion chromatograms of pSer1292 and pThr1343 peptides from the G2019S reaction are shown in comparison with their corresponding internal standards (FIGS. 1D, 1E). As described in the phosphomapping study, a small Ser1292 was phosphorylated in purified G2019S LRRK2 at the start of the kinase reaction. Raw MS data showed that each phosphopeptide increased in large amounts and pSer1292 showed a steady increase of 5-60 minutes compared to pThr1343 which increased 0-10 minutes before reaching the plateau rapidly. At each monitored position, G2019S appears to have undergone more rapid autophosphorylation than WT or R1441C LRRK2 (FIGS. 1E, 1F, 1G, 1H). Interestingly, the individual sites show unique kinetics, the autophosphorylation of pThr1343 and pThr1357 rapidly reaches a plateau, and the phosphorylation of Ser1292 and Thr1368 continues as robustly as reaching the 60 minute time point (FIG. 1E, 1F, 1G, 1H). A small but constant difference is also observed between the activity of WT and R1441C LRRK2 (FIGS. 1E, 1F, 1G, 1H).

To verify LRRK2 autophosphorylation activity in living cells, experiments on FLAG-LRRK2 overexpressed in HEK293 cells were performed using our quantitative LC-MS / MS assay. Most autophosphorylation events identified from in vitro kinase assays were undetectable in immunoprecipitated LRRK2 using the LRRK2 isotope standard as a sentry. One exception was pSer1292. The extracted ion chromatogram of the heavy pSer1292 signal exhibited low levels of pSer1292 in FLAG- ^G2019S LRRK2 (FIG. 1F), but was different in ^FLAG-D1994A LRRK2. The MS / MS obtained in the internal standard confirmed the identity of the heavy peptide, with a complete coresolution of the natural peptide that is essential for confirmation of the presence of pSer1292 from 293 cells. Appropriately, similar MS / MS spectra were collected from the light form of this peptide, but were co-isolated with another ion and entangled an automated identification attempt. Manual inspection and comparison of these two spectra allowed deconvolution and further verification of pSer1292 in this sample.

  Since pSer1292 was the most robust autophosphorylation site in vitro and in cultured cells, a rabbit polyclonal antibody that specifically recognizes this phosphate-epitope was generated (anti-pLRRK2 antibody). 293 cells were transfected with wild type, S1292A (phospho-site dead) and D1994A (kinase dead) LRRK2 constructs. It can be seen that the anti-pLRRK2 antibody detects a specific signal from the lysate of cells transfected with wild type LRRK2, but not with the S1292A or D1994A mutations (FIG. 2A), and the anti-pLRRK2 antibody is phosphorylated S1292 It is specific for the epitope. Furthermore, the anti-pLRRK2 antibody detected a specific signal from the brain lysate of a BAC transgenic mouse expressing wild type LRRK2, but was not detected in those expressing kinase-deadLRRK2 (FIG. 2B). These results indicate that LRRK2 kinase activity is required for phosphorylation of the S1292 residue in vivo.

Parkinson mutations increase LRRK2 autophosphorylation on Ser1292 The most common familial mutation of LRRK2 G2019S increases its kinase activity in various in vitro kinase assays, including MBP and LRRKtide phosphorylation, autophosphorylation It has been shown. Other than G2019S, the most published results show that other PD mutations including R1441G / C, Y1699C and I2020T do not increase LRRK2 kinase activity in vitro kinase. How PD mutations affect LRRK2 kinase activity in vivo remains unknown due to the lack of in vivo substrates.

  Since LRRK2 autophosphorylation on Ser1292 is dependent on its kinase activity, the effect of different LRRK2 PD mutations on LRRK2 autophosphorylation levels was tested by transfecting 293 cells with Flag-tag LRRK2 constructs with different Parkinson mutations did. Total LRRK2 and pS1292 levels in whole cell lysates were assessed by Western blotting. We have found that all four confirmed LRRK2 familial Parkinson mutations, including R1441G, Y1699C, G2019S and I2020T, show increased LRRK2 autophosphorylation at the S1292 site compared to wild type LRRK2. Furthermore, the combination of 2PD mutations R1441G and G2019S in the same construct increased the LRRK2 autophosphorylation level even higher (FIGS. 3A, B). Of note, G2385R, a PD risk factor mutation found in the Asian population, did not increase autophosphorylation at Ser1292.

  We also tested whether PD mutations increased LRRK2 autophosphorylation in transgenic animals. We compared LRRK2 autophosphorylation levels in brain tissue from wild-type or transgenic animals expressing G2019S LRRK2 protein. We found that total LRRK2 protein levels were comparable in the two lines of transgenic mice, and phosphate-LRRK2 levels were significantly higher in tissues from LRRK2 G2019S BAC transgenic mice in all brain regions tested (FIG. 3C). Quantitatively, LRRK2 autophosphorylation in S1292 is more than 10 times higher in whole brain lysates of transgenic animals expressing G2019S mutant LRRK2 than those expressing wild type LRRK2 (FIG. 3D). Taken together, these data indicate that LRRK2 Parkinson mutations increase LRRK2 autophosphorylation at S1292 in both cultured cells and animals.

Biochemical mechanism of LRRK2Ser1292 autophosphorylation It has been found that GTP binding is required for LRRK2 kinase activation in vitro. The LRRK2 T1348N mutation has been shown to abolish GTP binding in vitro. However, it is unclear how GTP binding affects LRRK2 kinase activity in vivo. To test whether GTP binding is required for LRRK2 autophosphorylation in vivo, the level of LRRK2 autophosphorylation in 293 cells transfected with LRRK2 T1348N and LRRK2 G2019S / T1348N mutant constructs was investigated. LRRK2 S1292 autophosphorylation was undetectable in lysates from cells expressing the T1348N mutation. S1292 phosphorylation is also greatly reduced in LRRK2 G2019S / T1348N transfected cells compared to those expressing LRRK2 G2019S (FIG. 4A). These results indicate that in vivo LRRK2 autophosphorylation at S1292 requires GTP binding.

  The mechanism of LRRK2 autophosphorylation can occur by two possible pathways. One possibility is that one LRRK2 molecule can phosphorylate S1292 on another LRRK2 molecule (ie, intermolecular phosphorylation). Another possibility is that the kinase domain of the LRRK2 molecule can phosphorylate its own S1292 (ie, intramolecular phosphorylation). To distinguish these two possibilities, the LRRK2 S1292A mutant mutant was transfected with the LRRK2 D1994A mutant. The S1292A mutation abolishes autophosphorylation sites and the D1994A mutation abolishes LRRK2 kinase activity. If LRRK2 autophosphorylation is intermolecular, LRRK2 S1292A could phosphorylate LRRK2 D1994A when these two constructs were co-transfected and a phosphate-LRRK2 signal would be observed. However, LRRK2 autophosphorylation was not observed in lysates of 293 cells co-transfected with S1292A and D1994A mutations (FIG. 4B). This data suggests that LRRK2 autophosphorylation may be intramolecular.

  To further verify intramolecular autophosphorylation, phosphorylation of N-terminal truncated LRRK2 by full-length wild type LRRK2 was tested. Wild type LRRK2 and N-terminal truncated LRRK2 (907-2527) were co-transfected with the D1994A mutation. Slight S1292 phosphorylation was detected in cleaved LRRK2 D1994A by Western blot (FIG. 4C). Therefore, full-length wild type LRRK2 failed to phosphorylate cleaved LRRK2. Taken together, these data indicate that LRRK2 autophosphorylation may be intramolecular.

Ser1292 is required for neurotoxicity induced by the LRRK2 Parkinson mutation.
Ser1292 residue is located at the junction of LRR domain and GTPase domain of LRRK2. Protein homology analysis showed that S1292 is conserved from worms to humans and overall amino acid identity is limited. Therefore, the importance of Ser1292 autophosphorylation of biological function was evaluated.

  Expression of LRRK2 protein carrying the PD mutation causes neurotoxicity in cultured primary neurons. Furthermore, the observed neurotoxicity requires the kinase activity of LRRK2. Transfection of cultured primary hippocampal neurons from E18 rat embryos with LRRK2 cDNA carrying the investigated neurite morphology and different PD mutations, hippocampal neurons expressing LRRK2 R1441G / G2019S double mutations were either wild-type LRRK2 or GFP This was done to show that it exhibits robust neurite outgrowth compared to those expressing only (FIG. 5A). Consistent with published reports, introduction of the kinase-dead mutation D1994A into the LRRK2 R1441G / G2019S double mutation abolished this phenotype. Furthermore, mutation of Ser 1292 to alanine in the LRRK2 R1441G / G2019S double mutation also abolished neurite outgrowth, and Ser1292 phosphorylation in the LRRK2 R1441G / G2019S-induced neurite outgrowth phenotype (FIGS. 5B, D) Suggests important.

  In addition to leading to a reduction in total neurite length, expression of the LRRK2 R1441G / G2019S double mutant protein also reduced the complexity of dendritic trees in cultured primary hippocampal neurons, as shown in the Sholl analysis. Furthermore, the LRRK2 G2019S / R1441G / D1994A mutant protein restores neuronal dendritic complexity, suggesting that LRRK2 kinase activity is required. Importantly, mutation of the LRRK2 autophosphorylation site serine 1292 to alanine also ameliorated this phenotype (FIG. 5C). Taken together, these data strongly suggest that Ser1292 autophosphorylation on LRRK2 plays an important role in mediating neurotoxicity through LRRK2 PD mutagenesis.

Ser1292 autophosphorylation is important for LRRK2 PD mutagenesis autophagy disorder The effect of Ser1292 autophosphorylation on neurotoxicity induced by LRRK2 PD mutation was investigated. We first considered whether Ser1292 autophosphorylation affects LRRK2 kinase activity. Flag-tag wt and S1292A LRRK2 protein were purified from transiently transfected 293 cells. Kinase activity was compared to LRRKtide as a substrate in an in vitro kinase assay. No significant difference was observed between LRRK2 WT and S1292A proteins.

  The cytoplasmic localization of the LRRK2 PD mutant protein was then investigated. A Flag-tag LRRK2 R1441G / G2019S double mutant construct was transfected into cultured primary cortical neurons. Immunofluorescent cytochemistry was used to detect Flag-tagged LRRK2 protein in transfected neurons. The WT LRRK2 protein was found to exhibit diffuse dispersion in neurons. However, in more than 80% neurons transfected with the LRRK2 R1441G / G2019S double mutant, the LRRK2 protein showed a filamentous dispersion of LRRK that co-localized with the microtubule markers (FIG. 6A). Furthermore, the LRRK2 mutant protein also formed large spots in some neurons (FIG. 6B). These neurons were co-stained with different cell markers to identify filament and dot properties. LRRK2 filaments were found to co-localize with microtubules as shown by co-staining with tubulin. Furthermore, both LRRK2 filaments and dots colocalized with the autophagy adapter protein p62 (FIGS. 6A, 6B). Additional cell markers for autophagy were investigated. LRRK2 points were also positive for LC3 and K63 poly-ubiquitin, markers of autophagosomes. These data suggest that the LRRK2 PD mutation impairs basal autophagy activity in neurons.

  To test whether LRRK2 kinase activity and / or LRRK2 S1292 autophosphorylation modulates the effect of LRRK2 PD mutation on autophagy, LRRK2 R1441G / G2019S / D1994A and LRRK2 R1441G / G2019S / S1292A mutant proteins were cultured It was expressed in cortical neurons. Lack of kinase activity (according to D1994A) abolishes LRRK2 localization to microtubules and autophagosomes (FIGS. 6C, 6D), indicating that kinase activity is important for impaired autophagy activity caused by LRRK2 PD mutations Show. Interestingly, the S1292A mutation significantly reduced LRRK2 localization in microtubules, but had less effect on the formation of LRRK2-positive autophagosomes (FIG. 6D). These data suggest that LRRK2 autophosphorylation in S1292 contributes to impaired autophagy activity induced by LRRK2 PD mutation.

LRRK2 Kinase Inhibitor Blocks S1292 Autophosphorylation in Cells To test whether LRRK2 kinase inhibitor blocks LRRK2 autophosphorylation in cells, express FLAG epitope-tag LRRK2 R1441G / Y1699C / G2019S triple mutant protein Induced HEK293 cell line (referred to herein as LRRK2 cells). This cell line was then used to develop a 96-well plate-based assay to quantify phosphate-S1292 in cell lysates. The assay uses electrochemiluminescence detection technology (Meso-Scale Discovery, MSD) and captures LRRK2 with a solid phase-immobilized anti-FLAG monoclonal antibody followed by detection with an anti-pSer1292 antibody and a ruthenium-conjugated anti-rabbit secondary antibody. did. Thus we were able to detect a significant increase in pS1292 signal in doxycycline-induced cell lysates (FIG. 7A). Furthermore, when doxycycline-induced LRRK2 cells were incubated with Sutent, a known LRRK2 kinase inhibitor (Ki ref), we observed a dose-dependent decrease in pS1292 signal, with maximal inhibition in lysates from uninduced cells It was equivalent to the detected signal (FIG. 7B). We then tested more than 600 compounds with various potencies in the LRRK2 kinase assay against these cells. The IC50 of the decrease in pS1292 signal was strongly correlated with the LRRK2 biochemistry Ki of the compound (FIG. 7C). These data indicate that LRRK2 kinase inhibitors block S1292 autophosphorylation in cells and that pS1292 can therefore be used as a marker for LRRK2 kinase inhibition in vivo.

LRRK2 kinase inhibitor that is potent, selective and brain penetrating blocks phosphate-S1292 in the LRRK2 G2019S BAC transgenic mouse brain. Through high-throughput chemical screening and lead optimization we are extremely potent and selective A novel LRRK2 small molecule inhibitor, [3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone (G1023) was identified. The biochemistry Ki of G1023 is about 4 nm. In the LRRK2 cell-based assay, G1023 effectively reduced pLRRK2 levels in a dose-dependent manner and the observed cell IC50 was 10 nM (FIG. 7B).

  To test whether G1023 can inhibit LRRK2 kinase activity in vivo, BAC transgenic mice expressing the LRRK2 G2019S protein were injected with a single dose of this compound at 10, 30 and 100 mg / kg. Peripheral and brain tissues were collected 6 hours after injection to determine compound concentrations and phosphate-LRRK2 levels.

  To investigate LRRK2 kinase inhibition in G1023 injected animals, spleen, lymph nodes and brain tissue were collected 6 hours after compound injection to determine phosphate-LRRK2 levels. In peripheral tissues, including spleen and lymph nodes, G1023 reduced phosphate-S1292 in a dose-dependent manner (FIGS. 8A, 8C). In brain tissue, G1023 also effectively reduced phosphate-S1292 levels, but the dose required for reduction is higher (FIGS. 8B, 8C). The calculated unbound concentration of G1023 in the brain required for phosphate-S1292 reduction was consistent with the cellular IC50 of this compound. These data indicate that G1023 has high brain exposure and blocks LRRK2 kinase activity in vivo. Furthermore, these data also indicate that LRRK2 autophosphorylation at Ser1292 can be used as a pharmacodynamic marker to measure the effects of LRRK2 kinase inhibitors in vivo.

LRRK2 kinase inhibitors reduce neurite outgrowth by Parkinson's mutagenesis To test whether inhibition of LRRK2 kinase activity ameliorates neurotoxicity by PD mutagenesis, we cultured embryos from LRRK2 BAC transgenic mice Sexual hippocampal neurons were used. These neurons showed neurite outgrowth as indicated by short total neurite length when compared to hippocampal neurons from non-transgenic littermates (FIG. 9). We treated neuronal cultures with the LRRK2 kinase inhibitor G1023. We have found that G1023 reverses neurite outgrowth in neurons from LRRK2 BAC transgenic mice in a dose-dependent manner. These data indicate that chemical inhibition of LRRK2 kinase activity can functionally block neurotoxicity due to LRRK2 PD mutagenesis.

S1292 is an in vivo LRRK2 autophosphorylation site The results disclosed herein indicate that S1292 is an in vivo LRRK2 autophosphorylation site. Several lines of evidence support that LRRK2 kinase activity is required for S1292 phosphorylation. First, the kinase-dead mutation causes S1292 phosphorylation in tissues from in vitro autophosphorylation assay (FIG. 1), transfected heterologous cells (FIG. 2A), and BAC transgenic mice overexpressing LRRK2 (FIG. 2B). Disabled. Second, highly specific LRRK2 inhibitors block S1292 phosphorylation in both the LRRK2 cell line (FIG. 7B) and LRRK2 transgenic mice (FIG. 8). Finally, many structurally diverse small molecule LRRK2 kinase inhibitors block S1292 phosphorylation in cell-based assays, providing chemical validation that LRRK2 kinase activity is required for S1292 phosphorylation in cells. Importantly, the concentration required for pLRRK2 reduction is closely related to the LRRK2 biochemistry Ki of the compound. Taken together, all evidence suggests that S1292 is an in vivo LRRK2 autophosphorylation site.

  Many other LRRK2 autophosphorylation sites have been reported in the past, but none were detectable in cell or animal models, even in overexpression situations. S1292 autophosphorylation is readily detectable in lysates from transfected cells and transgenic animals. S1292 is the only LRRK2 autophosphorylation site identified so far that is present in significant amounts in vivo. The identification of the S1292 autophosphorylation site provides a powerful biomarker tool for monitoring LRRK2 kinase activity in mammalian subjects.

Familial Parkinson mutations increase LRRK2 autophosphorylation on S1292 All confirmed familial Parkinson's disease mutations in LRRK2, including R1441G, Y1699C, G2019S and I2020T, when expressed in 293T cells, S1292 autophosphorylation Increase. Of these familial mutations, only G2019S has been specifically shown to increase LRRK2 kinase activity in vitro. G2019S is located in the kinase activation loop. It has been suggested that the G2019S mutation may change the conformation of the kinase activation loop, thereby activating LRRK2 kinase. However, I2020T, which is also near the kinase activation loop, was not consistently found to increase LRRK2 kinase activity in vitro. One possible explanation is that the substrate used in the biochemical assay was not an endogenous substrate. Thus, phosphorylation of these proteins may not accurately represent in vivo LRRK2 kinase activity. Here we show that both mutations can increase S1292 phosphorylation in a cell-based system, suggesting that both PD mutations in the LRRK2 kinase domain increase its kinase activity. The R1441G and Y1699C mutations are located in the ROC-COR domain. Both mutations have been shown to reduce LRRK2 GTPase activity. It has been shown that GTP binding is required for LRRK2 kinase activity in vitro. This disclosure shows that GTP binding is required for S1292 autophosphorylation in cell-based systems (FIG. 5A). Thus, the reduction in GTPase activity caused by the R1441G and Y1699C mutations will result in more LRRK2 protein in the GTP-bound state and increase S1292 autophosphorylation.

  Of note, the confirmed PD risk factor mutation G2385R located in the WD40 domain was not found to increase S1292 autophosphorylation. One simple explanation is that the G2385R mutation may not affect LRRK2 kinase activity or autophosphorylation. Alternatively, heterologous expression of LRRK2 in 293 cells may not provide a suitable cellular environment for LRRK2 autophosphorylation. When comparing S1292 autophosphorylation levels of the G2019S mutation in in vitro 293 cells and animal models, the levels of increase were 3, 5 and 10, respectively. This suggests that in vivo S1292 autophosphorylation is higher than in vitro.

Role of S1292 autophosphorylation in neurotoxicity due to LRRK2PD mutagenesis Given that increased S1292 autophosphorylation is a unified theme of all familial Parkinson mutations, S1292 autophosphorylation may be important for LRRK2 function and its role in PD pathogenesis It is reasonable to hypothesize. In the cell-based LRRK2 model, Parkinson mutations have been shown to cause cytotoxicity in both cell lines and primary neurons. Importantly, kinase activity has been shown to be necessary for toxicity. The fact that expression of the LRRK2 R1441G / G2019S mutation in embryonic hippocampal neurons reduces neurite length and complexity confirms the published results. Consistent with published data, the kinase-dead mutation was found to ameliorate the neurite outgrowth phenotype. Importantly, the S1292A mutation also reduced the neurite outgrowth phenotype. S1292 autophosphorylation may be part of the downstream mechanism of LRRK2 kinase activity that induces cytotoxicity. Of note, S1292 is located at the junction of the LRR domain and the ROC domain. Phosphorylation at this site can induce changes in protein conformation and can result in changes in protein-protein interactions.

  The mechanism by which the LRRK2 PD mutation induces neurotoxicity remains unknown. LRRK2 protein carrying a PD mutation was found to accumulate in microtubules when expressed in neurons. This is consistent with the results in cell lines and primary neurons. These aggregates are positive for the selective autophagy substrate p62 (SQSTM1). Accumulation of p62 positive aggregates is characteristic of autophagy dysfunction. Since autophagy cargo in neurons is thought to be transported along a microtubule network towards lysosomes, accumulation of p62 on microtubules may suggest an autophagy transport disorder in neurons expressing LRRK2 PD mutations. Since LRRK2 has been observed to accumulate at large spots that are positive for p62, LC3 and Lys-63 poly-ubiquitin, the autolysosomal degradation pathway can be impaired. Autophagy is an important “housekeeping” function in differentiated neurons, and loss of autophagy leads to neurodegeneration, leading to neurological abnormalities. This suggests that the LRRK2 PD mutation can lead to cytotoxicity through autophagic disorders. Interestingly, since the S1292A mutation does not ameliorate the appearance of LRRK2-positive autolysomes, Ser1292 phosphorylation may function upstream of autolysolysis. Importantly, the kinase-dead mutation (D1994A) abolishes both LRRK2 microtubules and autolysosomal accumulation, suggesting that kinase activity is required for both. The substrate for LRRK2 remains to be identified.

LRRK2 autophosphorylation as a marker of in vivo LRRK2 kinase activity S1292 autophosphorylation acts as a robust marker for in vivo LRRK2 kinase activity. Furthermore, S1292 autophosphorylation can be easily detected in tissue lysates from LRRK2 transgenic animals. This provides a pharmacodynamic assay to monitor LRRK2 kinase activity in vivo. In summary, S1292 autophosphorylation can be used to create a compound screening tool for LRRK2 kinase inhibitors.

LRRK2 Modulator An LRRK2 modulator or inhibitor that can be used with the invention may comprise a compound of formula I or a compound of formula II.

又はその薬学的に許容可能な塩である
(上式中、
ｍは０〜３であり；
Ｘは：-ＮＲ^ａ-；-Ｏ-；又は-Ｓ(Ｏ)_ｒ-であり(ｒは０〜２であり、Ｒ^ａは水素又はＣ_１-６アルキル)；
Ｒ^１は：Ｃ_１-６アルキル；ハロ-Ｃ_１-６アルキル；Ｃ_２-６アルケニル；Ｃ_２-６アルキニル；ハロ-Ｃ_１-６アルキル；Ｃ_１-６アルコキシ-Ｃ_１-６アルキル；ヒドロキシ-Ｃ_１-６アルキル；アミノ-Ｃ_１-６アルキル；Ｃ_１-６アルキルスルホニル-Ｃ_１-６アルキル；Ｃ_１-６アルキル又はハロで置換されていてもよいＣ_３-６シクロアルキル；Ｃ_３-６シクロアルキル-Ｃ_１-６アルキル(Ｃ_３-６シクロアルキル部分はＣ_１-６アルキルで置換されていてもよい)；テトラヒドロピラニル；テトラヒドロフラニル；テトラヒドロフラニル-Ｃ_１-６アルキル；オキセタニル；又はオキセタン-Ｃ_１-６アルキルであり；
又はＲ^１及びＲ^ａはそれらが結合している原子と共に、Ｏ、Ｎ及びＳから選択される更なるヘテロ原子を含んでいてもよく、オキソ，ハロ又はＣ_１-６アルキルで置換される３〜６員の環を形成し得；
Ｒ^２は：ハロ；Ｃ_１-６アルコキシ；シアノ；Ｃ_２-６アルキニル；Ｃ_２-６アルケニル；ハロ-Ｃ_１-６アルキル；ハロ-Ｃ_１-６アルコキシ；Ｃ_３-６シクロアルキル(Ｃ_３-６シクロアルキル部分はＣ_１-６アルキルで置換されていてもよい)；Ｃ_３-６シクロアルキル-Ｃ_１-６アルキル(Ｃ_３-６シクロアルキル部分はＣ_１-６アルキルで置換されていてもよい)；テトラヒドロフラニル；テトラヒドロフラニル-Ｃ_１-６アルキル；アセチル；オキセタニル；又はオキセタン-Ｃ_１-６アルキルであり；
Ｒ^３は：-ＯＲ^４；ハロ；シアノ；Ｃ_１-６アルキル；ハロ-Ｃ_１-６アルキル；Ｃ_１-６アルキルで置換されていてもよいＣ_３-６シクロアルキル；Ｃ_３-６シクロアルキル-Ｃ_１-６アルキル(Ｃ_３-６シクロアルキル部分はＣ_１-６アルキルで置換されていてもよい)；テトラヒドロフラニル；テトラヒドロフラニル-Ｃ_１-６アルキル；オキセタニル；又はオキセタン-Ｃ_１-６アルキルであり；
Ｒ^４は：水素；Ｃ_１-６アルキル；ハロ-Ｃ_１-６アルキル；Ｃ_１-６アルコキシ-Ｃ_１-６アルキル；Ｃ_１-６アルキル又はハロで置換されていてもよいＣ_３-６シクロアルキル；Ｃ_３-６シクロアルキル-Ｃ_１-６アルキル(Ｃ_３-６シクロアルキル部分はＣ_１-６アルキル又はハロで置換されていてもよい)；テトラヒドロフラニル；テトラヒドロフラニル-Ｃ_１-６アルキル；オキセタニル；又はオキセタン-Ｃ_１-６アルキルであり；
Ｒ^５は：水素；又はＣ_１-６アルキルであり；
ｎは０又は１であり；
Ｒ^６は：水素；Ｃ_１-６アルキル；Ｃ_１-６アルコキシ-Ｃ_１-６アルキル；ヒドロキシ-Ｃ_１-６アルキル；アミノ-Ｃ_１-６アルキル；Ｃ_３-６シクロアルキル；Ｃ_３-６シクロアルキル-Ｃ_１-６アルキル；ヘテロシクリル；又はヘテロシクリル-Ｃ_１-６アルキルであり；Ｃ_３-６シクロアルキル，Ｃ_３-６シクロアルキル-Ｃ_１-６アルキル，ヘテロシクリル及びヘテロシクリル-Ｃ_１-６アルキル各々は：Ｃ_１-６アルキル；ハロ-Ｃ_１-６アルキル；Ｃ_１-６アルコキシ；ハロ-Ｃ_１-６アルコキシ；ヒドロキシ；ヒドロキシ-Ｃ_１-６アルキル；ハロ；ニトリル；Ｃ_１-６アルキル-カルボニル；Ｃ_１-６アルキル-スルホニル；Ｃ_３-６シクロアルキル；Ｃ_３-６シクロアルキル-Ｃ_１-６アルキル；Ｃ_３-６シクロアルキル-カルボニル；アミノ；又はヘテロシクリルから独立して選択される１、２、３又は４つの基で置換されていてもよく；又は２つの基はそれらが結合している原子と共に５又は６員の環を形成し得；
又はＲ^５及びＲ^６はそれらが結合している窒素原子と共に、Ｏ、Ｎ及びＳ(Ｏ)_ｎから選択される更なるヘテロ原子を含んでいてもよい３-〜７-員の環を形成し、それは：Ｃ_１-６アルキル；ハロ-Ｃ_１-６アルキル；Ｃ_１-６アルコキシ；ハロ-Ｃ_１-６アルコキシ；ヒドロキシ；Ｃ_１-６アルコキシ-Ｃ_１-６アルキル；ヒドロキシ-Ｃ_１-６アルキル；ハロ，ニトリル；Ｃ_１-６アルキル-カルボニル；Ｃ_１-６アルキル-スルホニル；Ｃ_３-６シクロアルキル；Ｃ_３-６シクロアルキル-Ｃ_１-６アルキル；Ｃ_３-６シクロアルキル-カルボニル；アミノ；又はヘテロシクリルから独立して選択される１、２、３又は４つの基で置換されていてもよく；又は２つの基はそれらが結合している原子と共に５又は６員の環を形成し得；そして
Ｒ^７は：ハロ；Ｃ_１-６アルキル；Ｃ_１-６アルコキシ；ハロ-Ｃ_１-６アルキル；又はハロ-Ｃ_１-６アルコキシである)。 In one embodiment, the LRRK2 modulator is of formula I:

Or a pharmaceutically acceptable salt thereof
(In the above formula,
m is 0-3;
X is: —NR ^a —; —O—; or —S (O) _r — (r is 0-2, R ^a is hydrogen or C _1-6 alkyl);
R ¹ is: C _1-6 alkyl; halo-C _1-6 alkyl; C _2-6 alkenyl; C _2-6 alkynyl; halo-C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; Hydroxy-C _1-6 alkyl; amino-C _1-6 alkyl; C _1-6 alkylsulfonyl-C _1-6 alkyl; C _1-6 alkyl or C _3-6 cycloalkyl optionally substituted with halo; C _3-6 cycloalkyl-C _1-6 alkyl (the C _3-6 cycloalkyl moiety may be substituted with C _1-6 alkyl); tetrahydropyranyl; tetrahydrofuranyl; tetrahydrofuranyl-C _1-6 alkyl Oxetanyl; or oxetane-C _1-6 alkyl;
Or R ¹ and R ^a together with the atoms to which they are attached may contain further heteroatoms selected from O, N and S and are substituted with oxo, halo or C _1-6 alkyl 3 Can form ˜6-membered rings;
R ² is: halo; C _1-6 alkoxy; cyano; C _2-6 alkynyl; C _2-6 alkenyl; halo-C _1-6 alkyl; halo-C _1-6 alkoxy; C _3-6 cycloalkyl (C _3-6 cycloalkyl moiety may be substituted with C _1-6 alkyl); C _3-6 cycloalkyl-C _1-6 alkyl (C _3-6 cycloalkyl moiety is substituted with C _1-6 alkyl) Tetrahydrofuranyl-C _1-6 alkyl; acetyl; oxetanyl; or oxetane-C _1-6 alkyl;
R ³ is: —OR ⁴ ; halo; cyano; C _1-6 alkyl; halo-C _1-6 alkyl; C _3-6 cycloalkyl optionally substituted with C _1-6 alkyl; C _3-6 cyclo Alkyl-C _1-6 alkyl (C _3-6 cycloalkyl moiety may be substituted with C _1-6 alkyl); tetrahydrofuranyl; tetrahydrofuranyl-C _1-6 alkyl; oxetanyl; or oxetane-C _{1- 6} alkyl;
R ⁴ is: hydrogen; C _1-6 alkyl; halo-C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; C _1-6 alkyl or C _3-6 optionally substituted with halo C _3-6 cycloalkyl-C _1-6 alkyl (the C _3-6 cycloalkyl moiety may be substituted with C _1-6 alkyl or halo); tetrahydrofuranyl; tetrahydrofuranyl-C _1-6 Alkyl; oxetanyl; or oxetane-C _1-6 alkyl;
R ⁵ is: hydrogen; or C _1-6 alkyl;
n is 0 or 1;
R ⁶ is: hydrogen; _{C 1-6} alkyl; _{C 1-6} alkoxy -C _1-6 alkyl; hydroxy -C _1-6 alkyl; amino -C _1-6 alkyl; _{C 3-6} cycloalkyl; _{C 3- 6} cycloalkyl-C _1-6 alkyl; heterocyclyl; or heterocyclyl-C _1-6 alkyl; C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-6 alkyl, heterocyclyl and heterocyclyl-C _{1- 6} alkyl each: _{C 1-6} alkyl; halo -C _1-6 alkyl; _{C 1-6} alkoxy; halo -C _1-6 alkoxy; hydroxy; hydroxyalkyl -C _1-6 alkyl; halo; nitrile; _{C 1- 6} alkyl - carbonyl; _{C 1-6} alkyl - sulfonyl; _{C 3-6} cycloalkyl; _{C 3-6} cycloalkyl -C _1-6 alkyl; _{C 3-6} cycloalkyl - carbonyl; amino; or het It may be substituted with one, two, three or four groups independently selected from cyclyl; or two groups form a ring of 5 or 6 membered together with the atoms to which they are attached obtain;
Or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a 3- to 7-membered ring which may contain further heteroatoms selected from O, N and S (O) _n and, it: _{C 1-6} alkyl; halo -C _1-6 alkyl; _{C 1-6} alkoxy; halo -C _1-6 alkoxy; hydroxy; _{C 1-6} alkoxy -C _1-6 alkyl; hydroxy -C _{1 -6} alkyl; halo, nitrile; _{C 1-6} alkyl - carbonyl; _{C 1-6} alkyl - sulfonyl; _{C 3-6} cycloalkyl; _{C 3-6} cycloalkyl -C _1-6 alkyl; _{C 3-6} cycloalkyl -Carbonyl; amino; or may be substituted with 1, 2, 3 or 4 groups independently selected from heterocyclyl; or the two groups may be 5- or 6-membered rings with the atoms to which they are attached. And R ⁷ is: halo; C _1-6 alkyl; C _1-6 alkoxy; halo-C _1-6 alkyl; or halo-C _1-6 alkoxy).

  In certain embodiments of formula I, n is 0.

  In certain embodiments of formula I, n is 1.

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

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

  In certain embodiments of formula I, m is 0.

  In certain embodiments of formula I, m is 1.

  In certain embodiments of formula I, r is 0.

  In certain embodiments of formula I, r is 2.

In certain embodiments of formula I, X is —NR ^a — or —O—.

In certain embodiments of formula I, X is —NR ^a .

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

In certain embodiments of formula I, X is —S (O) _n —.

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

In certain embodiments of formula I, R ^a is hydrogen.

In certain embodiments of formula I, R ^a is C _1-6 alkyl.

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

In certain embodiments of formula I, R ¹ is: C _1-6 alkyl; C _3-6 cycloalkyl optionally substituted with C _1-6 alkyl; or C _3-6 cycloalkyl-C _1-6 alkyl (The C _3-6 cycloalkyl moiety may be substituted with C _1-6 alkyl).

In certain embodiments of formula I, R ¹ is: C _1-6 alkyl; halo-C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; amino-C _1-6 alkyl; C _1-6 Alkylsulfonyl-C _1-6 alkyl; tetrahydrofuranyl; tetrahydrofuranyl-C _1-6 alkyl; oxetanyl; or oxetane-C _1-6 alkyl.

In certain embodiments of formula I, R ¹ is: C _1-6 alkyl; halo-C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; amino-C _1-6 alkyl; or C _{1- 6} alkylsulfonyl-C _1-6 alkyl.

In certain embodiments of formula I, R ¹ is C _1-6 alkyl.

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

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

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

In certain embodiments of formula I, ^{R 1} is _{C 1-6} optionally substituted by alkyl _{C 1-6} alkylsulfonyl -C _1-6 alkyl.

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

In certain embodiments of formula I, R ¹ is C _3-6 cycloalkyl-C _1-6 alkyl (the C _3-6 cycloalkyl moiety may be substituted with C _1-6 alkyl).

In certain embodiments of formula I, R ¹ is tetrahydropyranyl.

In certain embodiments of formula I, R ¹ is tetrahydrofuranyl.

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

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

In certain embodiments of formula I, R ¹ is: methyl; ethyl; n-propyl; isopropyl; isobutyl; 3,3-dimethylpropyl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; cyclopropylmethyl; Cyclopropylethyl; methoxyethyl; oxetanyl; or tetrahydrofuranylmethyl.

In certain embodiments of formula I, R ¹ is: methyl; ethyl; n-propyl; isopropyl; isobutyl; 3,3-dimethylpropyl; cyclopentyl; cyclohexyl; cyclopropylmethyl; cyclobutylmethyl; Methoxyethyl; oxetanyl; or tetrahydrofuranylmethyl.

In certain embodiments of formula I, R ¹ is: methyl; ethyl; n-propyl; isopropyl; isobutyl; 3,3-dimethylpropyl; cyclopentyl; cyclohexyl; cyclopentylmethyl; methoxyethyl; oxetanyl;

In certain embodiments of formula I, R ¹ is: methyl; ethyl; n-propyl; isopropyl; or isobutyl.

In certain embodiments of formula I, R ¹ is methyl or ethyl.

In certain embodiments of formula I, R ¹ is methyl.

In certain embodiments of formula I, R ¹ is ethyl.

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

In certain embodiments of formula I, R ¹ is: cyclopentyl; cyclohexyl; or cyclopentylmethyl.

In certain embodiments of formula I, R ² is: halo; C _1-6 alkoxy; halo-C _1-6 alkyl; halo-C _1-6 alkoxy; C _3-6 cycloalkyl (C _3-6 cycloalkyl moiety) _May be substituted with C _1-6 alkyl); C _3-6 cycloalkyl-C _1-6 alkyl (the C _3-6 cycloalkyl moiety may be substituted with C _1-6 alkyl); Tetrahydrofuranyl; tetrahydrofuranyl-C _1-6 alkyl; oxetanyl; or oxetane-C _1-6 alkyl.

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

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

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

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

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

In certain embodiments of formula I, R ² is halo.

In certain embodiments of formula I, R ² is C _1-6 alkoxy.

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

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

In certain embodiments of formula I, R ² is C _3-6 cycloalkyl.

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

In certain embodiments of formula I, R ² is tetrahydrofuranyl.

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

In certain embodiments of formula I, R ² is oxetanyl.

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

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

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

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

In certain embodiments of formula I, R ² is chloro.

In certain embodiments of formula I, R ² is fluoro.

In certain embodiments of formula I, R ² is bromo.

In certain embodiments of formula I, R ² is trifluoromethyl.

In certain embodiments of formula I, R ² is methoxy.

In certain embodiments of formula I, R ² is cyano.

In certain embodiments of formula I, R ² is C _2-6 alkynyl.

In certain embodiments of formula I, R ² is C _2-6 alkenyl.

In certain embodiments of formula I, R ³ is —OR ⁴ .

In certain embodiments of formula I, R ³ is: C _1-6 alkyl; or halo-C _1-6 alkyl.

In certain embodiments of formula I, R ³ is: halo; or —OR ⁴ .

In certain embodiments of formula I, R ³ is: halo; C _1-6 alkoxy; halo-C _1-6 alkoxy; C _3-6 cycloalkyloxy; or C _3-6 cycloalkyl-C _1-6 alkyloxy It is.

In certain embodiments of formula I, R ³ is: C _1-6 alkoxy; halo-C _1-6 alkoxy; C _3-6 cycloalkyloxy; or C _3-6 cycloalkyl-C _1-6 alkyloxy .

In certain embodiments of formula I, R ³ is: halo; C _1-6 alkoxy; cyano; or halo-C _1-6 alkoxy.

In certain embodiments of formula I, R ³ is: halo; C _1-6 alkoxy; or halo-C _1-6 alkoxy.

In certain embodiments of formula I, R ³ is: methoxy; halo; trifluoromethoxy; difluoromethoxy; 2-halo-ethoxy or 2,2,2-trihaloethoxy.

In certain embodiments of formula I, R ³ is: methoxy; or halo.

In certain embodiments of formula I, R ³ is: methoxy; chloro; or fluoro.

In certain embodiments of formula I, R ³ is methoxy.

In certain embodiments of formula I, R ³ is chloro.

In certain embodiments of formula I, R ³ is fluoro.

In certain embodiments of formula I, R ³ is: C _1-6 alkoxy; cyano; or halo-C _1-6 alkoxy.

In certain embodiments of formula I, R ³ is: C _1-6 alkoxy; or halo-C _1-6 alkoxy.

In certain embodiments of formula I, R ³ is C _1-6 alkoxy.

In certain embodiments of formula I, R ³ is methoxy.

In certain embodiments of formula I, R ³ is cyano.

In certain embodiments of formula I, R ³ is C _3-6 cycloalkyl.

In certain embodiments of formula I, R ³ is C _3-6 cycloalkyl-C _1-6 alkyl.

In certain embodiments of formula I, R ³ is tetrahydrofuranyl. In certain embodiments of formula I, R ³ is tetrahydrofuranyl-C _1-6 alkyl.

In certain embodiments of formula I, R ³ is oxetanyl.

In certain embodiments of formula I, R ³ is oxetane-C _1-6 alkyl.

In certain embodiments of formula I, R ⁴ is optionally substituted with: C _1-6 alkyl; halo-C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; C _1-6 alkyl C _3-6 cycloalkyl; C _3-6 cycloalkyl-C _1-6 alkyl (the C _3-6 cycloalkyl moiety may be substituted with C _1-6 alkyl); tetrahydrofuranyl; tetrahydrofuranyl-C _{1 -6} alkyl; oxetanyl; or oxetane-C _1-6 alkyl;

In certain embodiments of formula I, R ⁴ is: C _1-6 alkyl; halo-C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; C _3-6 cycloalkyl; or C _3-6 Cycloalkyl-C _1-6 alkyl.

In certain embodiments of formula I, R ⁴ is: C _1-6 alkyl; halo-C _1-6 alkyl; or C _3-6 cycloalkyl.

In certain embodiments of formula I, R ⁴ is C _1-6 alkyl.

In certain embodiments of formula I, R ⁴ is halo-C _1-6 alkyl.

In certain embodiments of formula I, R ⁴ is C _1-6 alkoxy-C _1-6 alkyl.

In certain embodiments of formula I, R ⁴ is C _3-6 cycloalkyl.

In certain embodiments of formula I, R ⁴ is C _3-6 cycloalkyl-C _1-6 alkyl.

In certain embodiments of formula I, R ⁴ is tetrahydrofuranyl.

In certain embodiments of formula I, R ⁴ is tetrahydrofuranyl-C _1-6 alkyl.

In certain embodiments of formula I, R ⁴ is oxetanyl.

In certain embodiments of formula I, R ⁴ is or oxetane-C _1-6 alkyl.

In certain embodiments of formula I, R ⁴ is: methyl; ethyl; isopropyl; cyclopropyl; cyclobutyl; cyclopropylmethyl; cyclobutylmethyl; 2-haloethyl; or 2,2,2-trihaloethyl.

In certain embodiments of formula I, R ⁴ is methyl.

In certain embodiments of formula I, R ⁵ is hydrogen.

In certain embodiments of formula I, R ⁵ is C _1-6 alkyl.

In certain embodiments of formula I, R ⁵ is methyl.

In certain embodiments of formula I, R ⁵ is ethyl.

In certain embodiments of formula I, R ⁶ is hydrogen.

In certain embodiments of formula I, R ⁶ is C _1-6 alkyl.

In certain embodiments of formula I, R ⁶ is C _1-6 alkoxy-C _1-6 alkyl.

In certain embodiments of formula I, R ⁶ is hydroxy-C _1-6 alkyl.

In certain embodiments of formula I, R ⁶ is amino-C _1-6 alkyl.

In certain embodiments of formula I, R ⁶ is C _1-6 alkyl; halo-C _1-6 alkyl; C _1-6 alkoxy; halo-C _1-6 alkoxy; hydroxy; hydroxy-C _1-6 alkyl; Halo; nitrile; C _1-6 alkyl-carbonyl; C _1-6 alkyl-sulfonyl; C _3-6 cycloalkyl; C _3-6 cycloalkyl-C _1-6 alkyl; C _3-6 cycloalkyl-carbonyl; Or C _3-6 cycloalkyl optionally substituted with 1, 2 or 3 groups independently selected from heterocyclyl; or two groups together with the atoms to which they are attached a 5- or 6-membered ring Can be formed.

In certain embodiments of formula I, R ⁶ is C _3-6 cycloalkyl-C _1-6 alkyl, wherein the C _3-6 cycloalkyl moiety is C _1-6 alkyl; halo-C _1-6 alkyl C _1-6 alkoxy; halo-C _1-6 alkoxy; hydroxy; hydroxy-C _1-6 alkyl; halo; nitrile; C _1-6 alkyl-carbonyl; C _1-6 alkyl-sulfonyl; C _3-6 cyclo Alkyl; C _3-6 cycloalkyl-C _1-6 alkyl; C _3-6 cycloalkyl-carbonyl; amino; or optionally substituted with 1, 2 or 3 groups independently selected from heterocyclyl; Or the two groups can form a 5- or 6-membered ring with the atoms to which they are attached.

In embodiments of formula I wherein R ⁶ is heterocyclyl, such heterocycles are: azetidinyl; pyrrolidinyl; piperidinyl; piperazinyl; morpholinyl; thiomorpholinyl; 3-oxa-8-aza-bicyclo [3.2.1] octa- 8-yl; 2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl; or 8-oxa-3-aza-bicyclo [3.2.1] oct-3-yl Each of which may be substituted as defined herein.

In embodiments of formula I wherein R ⁶ is heterocyclyl, such heterocycle may be: azetidinyl; pyrrolidinyl; piperidinyl; piperazinyl; or morpholinyl; each may be substituted as defined herein; That is, such heterocyclyl is: C _1-6 alkyl; halo-C _1-6 alkyl; C _1-6 alkoxy; halo-C _1-6 alkoxy; hydroxy; hydroxy-C _1-6 alkyl; halo; From C _1-6 alkyl-carbonyl; C _1-6 alkyl-sulfonyl; C _3-6 cycloalkyl; C _3-6 cycloalkyl-C _1-6 alkyl; C _3-6 cycloalkyl-carbonyl; amino; or from heterocyclyl Optionally substituted by 1, 2 or 3 independently selected groups; or two groups together with the atoms to which they are attached Or it can form a 6-membered ring.

In certain embodiments of formula I, R ⁶ is: C _1-6 alkyl; halo-C _1-6 alkyl; C _1-6 alkoxy; halo-C _1-6 alkoxy; hydroxy; hydroxy-C _1-6 alkyl; Halo; nitrile; C _1-6 alkyl-carbonyl; C _1-6 alkyl-sulfonyl; C _3-6 cycloalkyl; C _3-6 cycloalkyl-C _1-6 alkyl; C _3-6 cycloalkyl-carbonyl; Or a heterocyclyl optionally substituted by 1, 2 or 3 groups independently selected from heterocyclyl; or the two groups may form a 5- or 6-membered ring with the atoms to which they are attached.

In embodiments of Formula I wherein R ⁶ is heterocyclyl-C _1-6 alkyl, the heterocyclyl moiety is: azetidinyl; pyrrolidinyl; piperidinyl; piperazinyl; morpholinyl; thiomorpholinyl; 1) Oct-8-yl; 2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl; or 8-oxa-3-aza-bicyclo [3.2.1] oct-3 Each may be substituted as defined herein, ie, such heterocyclyl moieties are: C _1-6 alkyl; halo-C _1-6 alkyl; C _1-6 alkoxy Halo-C _1-6 alkoxy; hydroxy; hydroxy-C _1-6 alkyl; halo; nitrile; C _1-6 alkyl-carbonyl; C _1-6 alkyl-sulfonyl; C _3-6 cycloalkyl; C _3-6 Cyclo Alkyl -C _1-6 alkyl; C _3-6 cycloalkyl - carbonyl; amino; or heterocyclyl independently may be substituted with 1, 2 or 3 groups selected from; or two groups they A 5- or 6-membered ring can be formed with the atoms to be bonded.

In embodiments of formula I, wherein R ⁶ is heterocyclyl-C _1-6 alkyl, the heterocyclyl moiety can be: azetidinyl; pyrrolidinyl; piperidinyl; piperazinyl; or morpholinyl; each is substituted as defined herein May be.

In certain embodiments of formula I, R ⁶ is heterocyclyl-C _1-6 alkyl, wherein the heterocyclyl moiety is: C _1-6 alkyl; halo-C _1-6 alkyl; C _1-6 alkoxy; halo-C _{1 -6} alkoxy; hydroxy; hydroxyalkyl -C _1-6 alkyl; halo; nitrile; _{C 1-6} alkyl - carbonyl; _{C 1-6} alkyl - sulfonyl; _{C 3-6} cycloalkyl; _{C 3-6} cycloalkyl -C _{1 -6} alkyl; C _3-6 cycloalkyl-carbonyl; amino; or optionally substituted by 1, 2 or 3 groups independently selected from heterocyclyl; or two groups together with the atoms to which they are attached A 5- or 6-membered ring may be formed.

In certain embodiments of formula I, R ⁶ is: hydrogen; methyl; ethyl; isopropyl; or cyclopropyl.

In certain embodiments of formula I, R ⁶ is: hydrogen; methyl; ethyl; isopropyl; 2-amino-propyl; oxetane-3-yl; 2-methoxy-ethyl; 2-hydroxy-ethyl; 1-methyl-piperidin-4-yl; tert-butyl; 2-hydroxy-2-methyl-propyl; cyclobutyl; 1-methyl-cyclobutyl; 2-hydroxy-propyl; 1-cyano-cyclopropyl; 3-difluoro-cyclobutyl; cyclopropylmethyl; 3-fluoro-cyclobutyl; or 2,2-difluoroethyl;

In certain embodiments of formula I, R ⁶ is hydrogen.

In certain embodiments of formula I, R ⁶ is methyl.

In certain embodiments of formula I, R ⁶ is ethyl.

In certain embodiments of formula I, R ⁶ is isopropyl.

In certain embodiments of formula I, R ⁶ is 2-amino-propyl.

In certain embodiments of formula I, R ⁶ is oxetan-3-yl.

In certain embodiments of formula I, R ⁶ is 2-methoxy-ethyl.

In certain embodiments of formula I, R ⁶ is 2-hydroxy-ethyl.

In certain embodiments of formula I, R ⁶ is cyclopropyl.

In certain embodiments of formula I, R ⁶ is piperidin-4-yl.

In certain embodiments of formula I, R ⁶ is 1-methyl-piperidin-4-yl.

In certain embodiments of formula I, R ⁶ is tert-butl.

In certain embodiments of formula I, R ⁶ is 2-hydroxy-2-methyl-propyl.

In certain embodiments of formula I, R ⁶ is cyclobutyl.

In certain embodiments of formula I, R ⁶ is 1-methyl-cyclobutyl.

In certain embodiments of formula I, R ⁶ is 2-hydroxy-propyl.

In certain embodiments of formula I, R ⁶ is 1-cyano-cyclopropyl.

In certain embodiments of formula I, R ⁶ is 3,3-difluoro-cyclobutyl.

In certain embodiments of formula I, R ⁶ is cyclopropylmethyl.

In certain embodiments of formula I, R ⁶ is 3-fluoro-cyclobutyl.

In certain embodiments of formula I, R ⁶ is 2,2-difluoroethyl.

In certain embodiments of formula I, R ⁵ and R ⁶ may contain further heteroatoms selected from O, N and S (O) _n , together with the nitrogen atom to which they are attached. Forming a 7-membered ring, C _1-6 alkyl, halo-C _1-6 alkyl, C _1-6 alkoxy, halo-C _1-6 alkoxy, hydroxy, hydroxy-C _1-6 alkyl, halo, nitrile Independent from C _1-6 alkyl-carbonyl, C _1-6 alkyl-sulfonyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-6 alkyl, C _3-6 cycloalkyl-carbonyl, or heterocyclyl May be substituted with 1, 2 or 3 groups selected as above, or the two groups may form a 5- or 6-membered ring with the atoms to which they are attached.

R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a 3- to 7-membered ring which may contain further heteroatoms selected from O, N and S (O) _n In embodiments of Formula I, such rings are: azetidinyl; pyrrolidinyl; piperidinyl; piperazinyl; morpholinyl; thiomorpholinyl; azepinyl; May be -oxa-5-aza-bicyclo [2.2.1] hept-5-yl; or 8-oxa-3-aza-bicyclo [3.2.1] oct-3-yl; May be substituted as defined in

R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a 3- to 7-membered ring which may contain further heteroatoms selected from O, N and S (O) _n In embodiments of Formula I, such rings may be: azetidinyl; pyrrolidinyl; piperidinyl; piperazinyl; or morpholinyl; each may be substituted as defined herein.

In certain embodiments of formula I, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached are C _1-6 alkyl, halo-C _1-6 alkyl, C _1-6 alkoxy, halo-C _1-6. Alkoxy, hydroxy, hydroxy-C _1-6 alkyl, halo, nitrile, C _1-6 alkyl-carbonyl, C _1-6 alkyl-sulfonyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-6 Forms a morpholinyl which may be substituted once or twice with a group independently selected from alkyl, C _3-6 cycloalkyl-carbonyl, amino, or heterocyclyl, or two groups which are attached A 5- or 6-membered ring can be formed with the atom.

In certain embodiments of formula I, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached are C _1-6 alkyl, halo-C _1-6 alkyl, C _1-6 alkoxy, halo-C _1-6. Alkoxy, hydroxy, hydroxy-C _1-6 alkyl, halo, nitrile, C _1-6 alkyl-carbonyl, C _1-6 alkyl-sulfonyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-6 Forming a piperidinyl group which may be substituted once or twice with a group independently selected from alkyl, C _3-6 cycloalkyl-carbonyl, amino, or heterocyclyl, or the two groups are Can form a 5- or 6-membered ring with the atoms present.

In certain embodiments of formula I, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached are C _1-6 alkyl, halo-C _1-6 alkyl, C _1-6 alkoxy, halo-C _1-6. Alkoxy, hydroxy, hydroxy-C _1-6 alkyl, halo, nitrile, C _1-6 alkyl-carbonyl, C _1-6 alkyl-sulfonyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-6 Forming a piperazinyl group which may be substituted once or twice with a group independently selected from alkyl, C _3-6 cycloalkyl-carbonyl, amino, or heterocyclyl, or the two groups are joined together Can form a 5- or 6-membered ring with the atoms present.

In certain embodiments of formula I, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached are C _1-6 alkyl, halo-C _1-6 alkyl, C _1-6 alkoxy, halo-C _1-6. Alkoxy, hydroxy, hydroxy-C _1-6 alkyl, halo, nitrile, C _1-6 alkyl-carbonyl, C _1-6 alkyl-sulfonyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-6 Forms a pyrrolidinyl group which may be substituted once or twice with a group independently selected from alkyl, C _3-6 cycloalkyl-carbonyl, amino, or heterocyclyl, or the two groups are Can form a 5- or 6-membered ring with the atoms present.

In certain embodiments of formula I, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached: morpholin-4-yl; 4-hydroxy-piperidin-1-yl; octahydro-pyrido [1,2-a] Pyrazin-2-yl; 2-hydroxy-piperidin-1-yl; 4,4-dimethyl-piperidin-1-yl; 3,5-dimethyl-piperidin-1-yl; 1-hydroxy-1-methyl-ethyl) -Piperidin-1-yl; 3-hydroxy-pyrrolidin-1-yl; 4-methyl-piperidin-1-yl; piperidin-1-yl; azetidin-1-yl; 4,4-difluoro-piperidin-1-yl 3-methyl-piperidin-1-yl; 4-methoxy-piperidin-1-yl; 3,3-difluoro-piperidin-1-yl; 4-cyano-piperidin-1-yl; 4-fluoro-piperidin-1 -Il; 3-methoxy-piperidin-1-yl; 4-ethyl-piperazine-1-y 4-acetyl-piperazin-1-yl; 3-trifluoromethyl-piperidin-1-yl; 4-tert-butyl-piperidin-1-yl; 2-hydroxy-ethyl) -piperazin-1-yl; 4-hydroxymethyl-piperidin-1-yl; 2-methyl-piperidin-1-yl; pyrrolidin-1-yl; 4-methanesulfonyl-piperazin-1-yl; 3-trifluoro Methyl-pyrrolidin-1-yl; 4- (2,2,2-trifluoro-ethyl) -piperazin-1-yl; 2-methyl-morpholin-4-yl; (2,6-dimethyl-morpholine-4- 2,2-diethyl-morpholin-4-yl; 3-hydroxymethyl-morpholin-4-yl; 2-isobutyl-morpholin-4-yl; 2-hydroxymethyl-morpholin-4-yl; Dimethyl-morpholin-4-yl; 4-methyl-piperazin-1-yl; 4 -Isopropyl-piperazin-1-yl; piperazin-1-yl; 3-oxa-8-aza-bicyclo [3.2.1] oct-8-yl; (S) -3-methyl-morpholin-4-yl 2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl; 8-oxa-3-aza-bicyclo [3.2.1] oct-3-yl; (R) -3 4-Methyl-morpholin-4-yl; 4-cyclopropanecarbonyl-piperazin-1-yl; 4- (1-hydroxy-1-methyl-ethyl) -piperidin-1-yl; 4-cyclobutyl-piperazin-1-yl (R) -3-hydroxy-pyrrolidin-1-yl; 4-oxetane-3-yl-piperazin-1-yl; 3-morpholin-4-yl-azetidin-1-yl; 4- (1-methyl- Piperidin-4-yl) -piperazin-1-yl; 3,3-difluoro-azetidin-1-yl; 4-dimethylamino-piperidin-1-yl; 4-piperidin-4-yl-piperazi (4,4-difluoro-piperidin-1-yl; (3-morpholin-4-yl-azetidin-1-yl; 2-oxa-6-aza-spiro [3.3] hepta-6 -Yl; 2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl); 4-methoxy-piperidin-1-yl); [1,4] oxazepan-4-yl; 2R, 6S) -2,6-Dimethyl-morpholin-4-yl; 3-hydroxy-azetidin-1-yl; 3-cyano-pyrrolidin-1-yl; 3,5-dimethyl-piperazin-1-yl; (3R, 5S) -dimethyl-piperazin-1-yl; 3-fluoro-pyrrolidin-1-yl; (S) -3-fluoro-pyrrolidin-1-yl; piperazin-1-yl; 3,3-difluoro-pyrrolidin-1 3,3-difluoro-azetidin-1-yl; 2,2,6,6-tetrafluoro-morpholin-4-yl; 2-methoxymethyl-pyrrolidin-1-yl; (S) -2-methoxy Methyl-pyrrolidin-1-yl; (1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl; (3S, 4S) -3,4-difluoropyrrolidin-1-yl Forming a group selected from 3,4-difluoropyrrolidin-1-yl; and 3-methoxypyrrolidin-1-yl;

In certain embodiments of formula I, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached: morpholin-4-yl; 4-hydroxy-piperidin-1-yl; octahydro-pyrido [1,2-a] Pyrazin-2-yl; 2-hydroxy-piperidin-1-yl; 4,4-dimethyl-piperidin-1-yl; 3,5-dimethyl-piperidin-1-yl; 1-hydroxy-1-methyl-ethyl) -Piperidin-1-yl; 3-hydroxy-pyrrolidin-1-yl; 4-methyl-piperidin-1-yl; piperidin-1-yl; azetidin-1-yl; 4,4-difluoro-piperidin-1-yl 3-methyl-piperidin-1-yl; 4-methoxy-piperidin-1-yl; 3,3-difluoro-piperidin-1-yl; 4-cyano-piperidin-1-yl; 4-fluoro-piperidin-1 -Il; 3-methoxy-piperidin-1-yl; 4-ethyl-piperazine-1-y 4-acetyl-piperazin-1-yl; 3-trifluoromethyl-piperidin-1-yl; 4-tert-butyl-piperidin-1-yl; 2-hydroxy-ethyl) -piperazin-1-yl; 4-hydroxymethyl-piperidin-1-yl; 2-methyl-piperidin-1-yl; pyrrolidin-1-yl; 4-methanesulfonyl-piperazin-1-yl; 3-trifluoro Methyl-pyrrolidin-1-yl; 4- (2,2,2-trifluoro-ethyl) -piperazin-1-yl; 2-methyl-morpholin-4-yl; (2,6-dimethyl-morpholine-4- 2,2-diethyl-morpholin-4-yl; 3-hydroxymethyl-morpholin-4-yl; 2-isobutyl-morpholin-4-yl; 2-hydroxymethyl-morpholin-4-yl; Dimethyl-morpholin-4-yl; 4-methyl-piperazin-1-yl; 4 -Isopropyl-piperazin-1-yl; piperazin-1-yl; 3-oxa-8-aza-bicyclo [3.2.1] oct-8-yl; (S) -3-methyl-morpholin-4-yl 2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl; 8-oxa-3-aza-bicyclo [3.2.1] oct-3-yl; (R) -3 4-Methyl-morpholin-4-yl; 4-cyclopropanecarbonyl-piperazin-1-yl; 4- (1-hydroxy-1-methyl-ethyl) -piperidin-1-yl; 4-cyclobutyl-piperazin-1-yl (R) -3-hydroxy-pyrrolidin-1-yl; 4-oxetane-3-yl-piperazin-1-yl; 3-morpholin-4-yl-azetidin-1-yl; 4- (1-methyl- Piperidin-4-yl) -piperazin-1-yl; 3,3-difluoro-azetidin-1-yl; 4-dimethylamino-piperidin-1-yl; and 4-piperidin-4-yl-pipe Form a group selected from 1-yl.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

In certain embodiments of formula I, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 4-tert-butyl-piperidin-1-yl.

In certain embodiments of formula I, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached.

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

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

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

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

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

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

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

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

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

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

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

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

In certain embodiments of formula I, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 2-isobutyl-morpholin-4-yl.

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

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

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

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

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

In certain embodiments of formula I, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 3-oxa-8-aza-bicyclo [3.2.1] oct-8-yl.

In certain embodiments of formula I, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form (S) -3-methyl-morpholin-4-yl.

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

In certain embodiments of formula I, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 8-oxa-3-aza-bicyclo [3.2.1] oct-3-yl.

In certain embodiments of formula I, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form (R) -3-methyl-morpholin-4-yl.

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

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

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

In certain embodiments of formula I, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form (R) -3-hydroxy-pyrrolidin-1-yl.

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

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

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

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

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

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

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

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

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

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

In certain embodiments of formula I, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form [1,4] oxazepan-4-yl.

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

In certain embodiments of formula I, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 3-hydroxy-azetidin-1-yl.

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

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

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

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

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

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

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

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

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

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

In certain embodiments of formula I, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form (1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl. To do.

In certain embodiments of formula I, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached are (3S, 4S) -3,4-difluoropyrrolidin-1-yl; 3,4-difluoropyrrolidin-1-yl And 3-methoxypyrrolidin-1-yl is formed.

In certain embodiments of formula I, R ⁷ is halo.

In certain embodiments of formula I, R ⁷ is C _1-6 alkyl.

In certain embodiments of formula I, R ⁷ is C _1-6 alkoxy.

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

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

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

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

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

In certain embodiments of formula I, R ⁷ is methoxy.

In certain embodiments of formula I, R ⁷ is chloro.

In certain embodiments of formula I, R ⁷ is fluoro.

In certain embodiments of formula I, the LRRK2 modulator compound is:
[4- (5-Fluoro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl] -morpholin-4-yl-methanone
[4- (5-Fluoro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(4-hydroxy-piperidin-1-yl) -methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl] -morpholin-4-yl-methanone
4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-N, N-dimethyl-benzamide
4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -N-cyclopropyl-3-methoxy-benzamide
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(4-hydroxy-piperidin-1-yl) -methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-difluoromethoxy-phenyl] -morpholin-4-yl-methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(octahydro-pyrido [1,2-a] pyrazin-2-yl) -methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(2-hydroxy-piperidin-1-yl) -methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(4,4-dimethyl-piperidin-1-yl) -methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(3,5-dimethyl-piperidin-1-yl) -methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-[4- (1-hydroxy-1-methyl-ethyl) -piperidin-1-yl] -methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(3-hydroxy-pyrrolidin-1-yl) -methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(4-methyl-piperidin-1-yl) -methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl] -piperidin-1-yl-methanone
Azetidin-1-yl- [4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl] -methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(4,4-difluoro-piperidin-1-yl) -methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(3-methyl-piperidin-1-yl) -methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(4-methoxy-piperidin-1-yl) -methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(3,3-difluoro-piperidin-1-yl) -methanone
1- [4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-benzoyl] -piperidine-4-carbonitrile
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(4-fluoro-piperidin-1-yl) -methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(3-methoxy-piperidin-1-yl) -methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(4-ethyl-piperazin-1-yl) -methanone
1- {4- [4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-benzoyl] -piperazin-1-yl} -ethanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(3-trifluoromethyl-piperidin-1-yl) -methanone
(4-tert-butyl-piperidin-1-yl)-[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl] -methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-[4- (2-hydroxy-ethyl) -piperazin-1-yl] -methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(2-methyl-pyrrolidin-1-yl) -methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(4-hydroxymethyl-piperidin-1-yl) -methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(2-methyl-piperidin-1-yl) -methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl] -pyrrolidin-1-yl-methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(4-methanesulfonyl-piperazin-1-yl) -methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(3-trifluoromethyl-pyrrolidin-1-yl) -methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-[4- (2,2,2-trifluoro-ethyl) -piperazin-1-yl]- Methanon
[4- (5-Bromo-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl] -morpholin-4-yl-methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(2-methyl-morpholin-4-yl) -methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(2,6-dimethyl-morpholin-4-yl) -methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(2,2-diethyl-morpholin-4-yl) -methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(3-hydroxymethyl-morpholin-4-yl) -methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(2-isobutyl-morpholin-4-yl) -methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(2-hydroxymethyl-morpholin-4-yl) -methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(3,3-dimethyl-morpholin-4-yl) -methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(4-methyl-piperazin-1-yl) -methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(4-isopropyl-piperazin-1-yl) -methanone
[4- (5-Bromo-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl] -morpholin-4-yl-methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl] -piperazin-1-yl-methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-difluoromethoxy-phenyl]-(4-hydroxy-piperidin-1-yl) -methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-ethoxy-phenyl] -morpholin-4-yl-methanone
[3-Methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-benzamide
4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -N-ethyl-3-methoxy-benzamide
4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -N-isopropyl-3-methoxy-benzamide
4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-N-methyl-benzamide
[4- (5-Chloro-4-propoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl] -morpholin-4-yl-methanone
[4- (5-Chloro-4-ethylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl] -morpholin-4-yl-methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(3-oxa-8-aza-bicyclo [3.2.1] oct-8-yl) -Methanone
[4- (5-Chloro-4-ethoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl] -morpholin-4-yl-methanone
[4- (5-Chloro-4-isopropoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl] -morpholin-4-yl-methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-((S) -3-methyl-morpholin-4-yl) -methanone
[4- (5-Chloro-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl] -morpholin-4-yl-methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl) -Methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(8-oxa-3-aza-bicyclo [3.2.1] oct-3-yl) -Methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-((R) -3-methyl-morpholin-4-yl) -methanone
N- (3-amino-propyl) -4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-benzamide
[4- (5-Cyclopropyl-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl] -morpholin-4-yl-methanone
[4- (5-Chloro-4-isobutylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl] -morpholin-4-yl-methanone
[4- (5-Chloro-4-propylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl] -morpholin-4-yl-methanone
[4- (5-Chloro-4-isopropylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl] -morpholin-4-yl-methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(4-cyclopropanecarbonyl-piperazin-1-yl) -methanone
[4- (5-Bromo-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-[4- (1-hydroxy-1-methyl-ethyl) -piperidin-1-yl] -methanone
[4- (5-Bromo-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(3-trifluoromethyl-pyrrolidin-1-yl) -methanone
1- [4- (5-Bromo-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-benzoyl] -piperidine-4-carbonitrile
[4- (5-Bromo-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(4-cyclobutyl-piperazin-1-yl) -methanone
[4- (5-Bromo-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-[4- (2,2,2-trifluoro-ethyl) -piperazin-1-yl]- Methanon
[4- (5-Bromo-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(4-methoxy-piperidin-1-yl) -methanone
[4- (5-Bromo-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-((R) -3-hydroxy-pyrrolidin-1-yl) -methanone
[4- (5-Bromo-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(4-oxetan-3-yl-piperazin-1-yl) -methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-isopropoxy-phenyl] -morpholin-4-yl-methanone
{4- [5-Chloro-4- (cyclopropylmethyl-amino) -pyrimidin-2-ylamino] -3-methoxy-phenyl} -morpholin-4-yl-methanone
[4- (5-Chloro-4-cyclobutylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl] -morpholin-4-yl-methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-hydroxy-phenyl] -morpholin-4-yl-methanone
[4- (5-Bromo-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(4-ethyl-piperazin-1-yl) -methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-phenyl] -morpholin-4-yl-methanone
[4- (5-Bromo-4-methoxy-pyrimidin-2-ylamino) -3-cyclobutoxy-phenyl] -morpholin-4-yl-methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-cyclobutoxy-phenyl] -morpholin-4-yl-methanone
[4- (5-Chloro-4-ethylamino-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-phenyl] -morpholin-4-yl-methanone
[4- (5-Bromo-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(3-morpholin-4-yl-azetidin-1-yl) -methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(3-morpholin-4-yl-azetidin-1-yl) -methanone
[4- (5-Chloro-4-cyclopentylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl] -morpholin-4-yl-methanone
{4- [5-Chloro-4- (1-methyl-cyclobutylamino) -pyrimidin-2-ylamino] -3-methoxy-phenyl} -morpholin-4-yl-methanone
[4- (5-Chloro-4-cyclohexylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl] -morpholin-4-yl-methanone
(4- {5-Chloro-4-[(tetrahydro-furan-3-ylmethyl) -amino] -pyrimidin-2-ylamino} -3-methoxy-phenyl) -morpholin-4-yl-methanone
[4- (5-Iodo-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl] -morpholin-4-yl-methanone
[4- (5-Bromo-4-isopropoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl] -morpholin-4-yl-methanone
[4- (5-Bromo-4-ethoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl] -morpholin-4-yl-methanone
[4- (5-Bromo-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(4,4-difluoro-piperidin-1-yl) -methanone
(4- {5-Chloro-4-[(tetrahydro-furan-2-ylmethyl) -amino] -pyrimidin-2-ylamino} -3-methoxy-phenyl) -morpholin-4-yl-methanone
{4- [5-Chloro-4- (cyclobutylmethyl-amino) -pyrimidin-2-ylamino] -3-methoxy-phenyl} -morpholin-4-yl-methanone
[4- (5-Iodo-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl] -morpholin-4-yl-methanone
[4- (5-Cyclobutyl-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl] -morpholin-4-yl-methanone
[4- (5-Cyclopropyl-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl] -morpholin-4-yl-methanone
{4- [5-Chloro-4- (2-cyclopropyl-ethylamino) -pyrimidin-2-ylamino] -3-methoxy-phenyl} -morpholin-4-yl-methanone
{4- [5-Chloro-4- (2-methoxy-ethylamino) -pyrimidin-2-ylamino] -3-methoxy-phenyl} -morpholin-4-yl-methanone
{4- [5-Chloro-4- (cyclopentylmethyl-amino) -pyrimidin-2-ylamino] -3-methoxy-phenyl} -morpholin-4-yl-methanone
[4- (5-Bromo-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl]-((R) -2,2-di-deutero-3-methyl-morpholin-4-yl)- Methanon
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3- (2,2,2-trifluoro-ethoxy) -phenyl] -morpholin-4-yl-methanone
[4- [5-Chloro-4- (2-methoxy-ethylamino) -pyrimidin-2-ylamino] -3- (2,2,2-trifluoro-ethoxy) -phenyl] -morpholin-4-yl- Methanon
[4- (5-Bromo-4-methoxy-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-phenyl] -morpholin-4-yl-methanone
[4- (5-Bromo-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl]-((S) -2,2-di-deutero-3-methyl-morpholin-4-yl)- Methanon
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-[4- (1-methyl-piperidin-4-yl) -piperazin-1-yl] -methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-trifluoromethoxy-phenyl] -morpholin-4-yl-methanone
[4- (5-Cyclobutyl-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl] -morpholin-4-yl-methanone
[3-Chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[4- (5-Bromo-4-methoxy-pyrimidin-2-ylamino) -3-ethoxy-phenyl] -morpholin-4-yl-methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(3,3-difluoro-azetidin-1-yl) -methanone
{4- [5-Bromo-4- (2-methoxy-ethylamino) -pyrimidin-2-ylamino] -3-ethoxy-phenyl} -morpholin-4-yl-methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(4-dimethylamino-piperidin-1-yl) -methanone
4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-N-oxetane-3-yl-benzamide
4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-N- (tetrahydro-pyran-3-yl) -benzamide
{4- [5-Chloro-4- (tetrahydro-pyran-3-ylamino) -pyrimidin-2-ylamino] -3-methoxy-phenyl} -morpholin-4-yl-methanone
{4- [5-Chloro-4- (2-methoxy-ethylamino) -pyrimidin-2-ylamino] -3-cyclobutoxy-phenyl} -morpholin-4-yl-methanone
{4- [5-Bromo-4- (2-methoxy-ethylamino) -pyrimidin-2-ylamino] -3-cyclobutoxy-phenyl} -morpholin-4-yl-methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(4-piperidin-4-yl-piperazin-1-yl) -methanone
{4- [5-Chloro-4- (2,2,2-trifluoro-ethylamino) -pyrimidin-2-ylamino] -3-methoxy-phenyl} -morpholin-4-yl-methanone
{4- [5-Chloro-4- (2,2-difluoro-ethylamino) -pyrimidin-2-ylamino] -3-methoxy-phenyl} -morpholin-4-yl-methanone
[4- (5-Bromo-4-methoxy-pyrimidin-2-ylamino) -3-isopropoxy-phenyl] -morpholin-4-yl-methanone
[3-Bromo-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[4- (5-Bromo-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl]-[4- (1-hydroxy-1-methyl-ethyl) -piperidin-1-yl] -methanone
(4- (5-Bromo-4-methoxypyrimidin-2-ylamino) -3-methoxyphenyl) (3- (trifluoromethyl) pyrrolidin-1-yl) methanone
1- (4- (5-Bromo-4-methoxypyrimidin-2-ylamino) -3-methoxybenzoyl) piperidine-4-carbonitrile
(3-Methoxy-4- (5-methoxy-4- (methylamino) pyrimidin-2-ylamino) phenyl) (morpholino) methanone
N- (3-aminopropyl) -4- (5-chloro-4- (methylamino) pyrimidin-2-ylamino) -3-methoxybenzamide
[3-Methoxy-4- (4-methylamino-5-prop-1-ynyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[3-Methoxy-4- (4-methoxy-5-prop-1-ynyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[5-Chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl] -morpholin-4-yl-methanone
{4- [5-Bromo-4- (2-methoxy-ethoxy) -pyrimidin-2-ylamino] -3-methoxy-phenyl} -morpholin-4-yl-methanone
5-Chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-N, N-dimethyl-benzamide
5-Chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-benzamide
5-Chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -N- (2-hydroxy-ethyl) -2-methoxy-benzamide
5-Chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-N- (2-methoxy-ethyl) -benzamide
5-Chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-N-methyl-benzamide
5-Chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -N-cyclopropyl-2-methoxy-benzamide
[5-Chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl]-(4,4-difluoro-piperidin-1-yl) -methanone
[5-Chloro-4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-methoxy-phenyl] -morpholin-4-yl-methanone
5-Chloro-N-cyclopropyl-4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-methoxy-benzamide
5-Chloro-4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-methoxy-N- (2-methoxy-ethyl) -benzamide
[5-Chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl] -piperazin-1-yl-methanone
[5-Chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl]-(4-dimethylamino-piperidin-1-yl) -methanone
[5-Chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl]-(3-hydroxy-pyrrolidin-1-yl) -methanone
5-Chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-N-oxetane-3-yl-benzamide
5-Chloro-N-cyclopropyl-2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide
5-Chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-N- (1-methyl-piperidin-4-yl) -benzamide
[5-Chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl] -pyrrolidin-1-yl-methanone
N-tert-butyl-5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-benzamide
5-Chloro-2-methoxy-N, N-dimethyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide
5-Chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-N- (2-methoxy-ethyl) -N-methyl-benzamide
5-Chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -N- (2-hydroxy-2-methyl-propyl) -2-methoxy-benzamide
[5-Chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl]-(4-hydroxy-piperidin-1-yl) -methanone
[5-Chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl]-(2-hydroxymethyl-morpholin-4-yl) -methanone
5-Chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -N- (2-hydroxy-ethyl) -2-methoxy-N-methyl-benzamide
5-Chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-N- (1-methyl-cyclobutyl) -benzamide
[5-Chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl]-[1,4] oxazepan-4-yl-methanone
[5-Chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl]-((2R, 6S) -2,6-dimethyl-morpholin-4-yl) -Methanone
1- [5-Chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-benzoyl] -piperidine-4-carbonitrile
5-Chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -N- (2-hydroxy-propyl) -2-methoxy-benzamide
[5-Chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl]-(3-hydroxy-azetidin-1-yl) -methanone
5-Chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -N- (1-cyano-cyclopropyl) -2-methoxy-benzamide
1- [5-Chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-benzoyl] -pyrrolidine-3-carbonitrile
[5-Chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl]-((3R, 5S) -dimethyl-piperazin-1-yl) -methanone
5-Chloro-2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -N- (1-methyl-piperidin-4-yl) -benzamide
5-Chloro-2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -N-oxetane-3-yl-benzamide
5-Chloro-N- (2-hydroxy-2-methyl-propyl) -2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide
[5-Chloro-2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -piperazin-1-yl-methanone
1- [5-Chloro-2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzoyl] -pyrrolidine-3-carbonitrile
1- [2-Fluoro-5-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzoyl] -pyrrolidine-3-carbonitrile
[5-Chloro-2-ethoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
2-Fluoro-5-methoxy-N-methyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide
5-Chloro-N- (2-hydroxy-2-methyl-propyl) -2-methoxy-N-methyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide
(4- (5-Cyclopropyl-4-methoxypyrimidin-2-ylamino) -3-methoxyphenyl) (morpholino) methanone
1- {2- [2-methoxy-4- (morpholine-4-carbonyl) -phenylamino] -4-methylamino-pyrimidin-5-yl} -ethanone
{4- [5-Chloro-4- (2-methoxy-ethoxy) -pyrimidin-2-ylamino] -3-methoxy-phenyl} -morpholin-4-yl-methanone
{4- [5-Bromo-4- (2-methoxy-ethylamino) -pyrimidin-2-ylamino] -2-fluoro-5-methoxy-phenyl} -morpholin-4-yl-methanone
{4- [5-Bromo-4- (2-methoxy-ethylamino) -pyrimidin-2-ylamino] -3-isopropoxy-phenyl} -morpholin-4-yl-methanone
{4- [5-Chloro-4- (2-methoxy-ethoxy) -pyrimidin-2-ylamino] -3-cyclobutoxy-phenyl} -morpholin-4-yl-methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-cyclopentyloxy-phenyl]-(2-oxa-6-aza-spiro [3.3] hept-6-yl)- Methanon
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-cyclopentyloxy-phenyl] -morpholin-4-yl-methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-(2-oxa-6-aza-spiro [3.3] hept-6-yl) -methanone
2- (2-Methoxy-4- (2,2,6,6-tetrafluoromorpholine-4-carbonyl) phenylamino) -4- (methylamino) pyrimidine-5-carbonitrile
2- (4- (4,4-Difluoropiperidine-1-carbonyl) -2-methoxyphenylamino) -4- (methylamino) pyrimidine-5-carbonitrile
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-cyclopropyl-phenyl] -morpholin-4-yl-methanone
4- (5-Cyano-4-methylamino-pyrimidin-2-ylamino) -N- (3,3-difluoro-cyclobutyl) -3-methoxy-benzamide
4- (5-Cyano-4-methylamino-pyrimidin-2-ylamino) -N-cyclopropylmethyl-3-methoxy-benzamide
2- [4-((S) -3-Fluoro-pyrrolidine-1-carbonyl) -2-methoxy-phenylamino] -4-methylamino-pyrimidine-5-carbonitrile
4- (5-Cyano-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-N-methyl-benzamide
4- (5-Cyano-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-N, N-dimethyl-benzamide
4- (5-Cyano-4-methylamino-pyrimidin-2-ylamino) -N, N-diethyl-3-methoxy-benzamide
4- (5-Cyano-4-methylamino-pyrimidin-2-ylamino) -N-isopropyl-3-methoxy-benzamide
2- [2-Methoxy-4- (pyrrolidine-1-carbonyl) -phenylamino] -4-methylamino-pyrimidine-5-carbonitrile
2- [4- (3-Fluoro-azetidine-1-carbonyl) -2-methoxy-phenylamino] -4-methylamino-pyrimidine-5-carbonitrile
4- (5-Cyano-4-methylamino-pyrimidin-2-ylamino) -N-ethyl-3-methoxy-benzamide
2- [2-Methoxy-4- (piperidine-1-carbonyl) -phenylamino] -4-methylamino-pyrimidine-5-carbonitrile
4- (5-Cyano-4-methylamino-pyrimidin-2-ylamino) -N- (2,2-difluoro-ethyl) -3-methoxy-benzamide
N-tert-butyl-4- (5-cyano-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-benzamide
4- (5-Cyano-4-methylamino-pyrimidin-2-ylamino) -N-ethyl-N-isopropyl-3-methoxy-benzamide
2- [4- (3,3-Difluoro-pyrrolidine-1-carbonyl) -2-methoxy-phenylamino] -4-methylamino-pyrimidine-5-carbonitrile
2- [4- (3,3-Difluoro-azetidine-1-carbonyl) -2-methoxy-phenylamino] -4-methylamino-pyrimidine-5-carbonitrile
2- [4-((R) -3-Fluoro-pyrrolidine-1-carbonyl) -2-methoxy-phenylamino] -4-methylamino-pyrimidine-5-carbonitrile
4- (5-Cyano-4-methylamino-pyrimidin-2-ylamino) -N-ethyl-3-methoxy-N-methyl-benzamide
2- [4- (Azetidine-1-carbonyl) -2-methoxy-phenylamino] -4-methylamino-pyrimidine-5-carbonitrile
4- (5-Cyano-4-methylamino-pyrimidin-2-ylamino) -N-isopropyl-3-methoxy-N-methyl-benzamide
{4- [5-Chloro-4- (tetrahydro-furan-3-ylamino) -pyrimidin-2-ylamino] -3-methoxy-phenyl} -morpholin-4-yl-methanone
[3-Isopropoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[3-Ethoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-cyclopropoxy-phenyl] -morpholin-4-yl-methanone
[4- (5-Bromo-4-methoxy-pyrimidin-2-ylamino) -3-cyclopropoxy-phenyl] -morpholin-4-yl-methanone
{4- [5-Chloro-4- (2-methanesulfonyl-ethylamino) -pyrimidin-2-ylamino] -3-methoxy-phenyl} -morpholin-4-yl-methanone
2- [4- (5-Bromo-4-methylamino-pyrimidin-2-ylamino) -2,5-dimethoxy-phenyl] -1-morpholin-4-yl-ethanone
2- [4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -2,5-dimethoxy-phenyl] -1-morpholin-4-yl-ethanone
2- [4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl] -1-morpholin-4-yl-ethanone
2- [3-Methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -1-morpholin-4-yl-ethanone
2- [4- (5-Chloro-4-methoxy-pyrimidin-2-ylamino) -2,5-dimethoxy-phenyl] -1-morpholin-4-yl-ethanone
2- [4- (5-Chloro-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl] -1-morpholin-4-yl-ethanone
2- [4- (5-Bromo-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl] -1-morpholin-4-yl-ethanone
2- [2,5-Dimethoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -1-morpholin-4-yl-ethanone
N- (3-Amino-propyl) -5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-benzamide
{4- [5-Bromo-4- (2-methoxy-ethylamino) -pyrimidin-2-ylamino] -3-methoxy-phenyl} -morpholin-4-yl-methanone
{4- [5-Chloro-4- (2-methoxy-propylamino) -pyrimidin-2-ylamino] -3-methoxy-phenyl} -morpholin-4-yl-methanone
4- (5-Chloro-4- (methylamino) pyrimidin-2-ylamino) -N, N, 3-trimethylbenzamide
(4- (5-Chloro-4- (methylamino) pyrimidin-2-ylamino) -3-methylphenyl) (morpholino) methanone
(4- (5-Chloro-4- (methylamino) pyrimidin-2-ylamino) -3-methylphenyl) (4-hydroxypiperidin-1-yl) methanone
(4- (4- (Ethylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -3- (trifluoromethoxy) phenyl) (morpholino) methanone
(4- (4- (Methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -3- (trifluoromethoxy) phenyl) (morpholino) methanone
(5-Chloro-2-methoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) (perdeuteromorpholino) methanone
(5-Fluoro-2-methoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) (morpholino) methanone
(4- (4- (Ethylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -5-fluoro-2-methoxyphenyl) (morpholino) methanone
[2-Fluoro-5-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
4- (5-Cyano-4-ethylamino-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-N, N-dimethyl-benzamide
(4- (4- (Ethylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -2-fluoro-3-methoxyphenyl) (morpholino) methanone
(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl (4- (4- (ethylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino)- 2-Fluoro-3-methoxyphenyl) methanone
(1S, 4S) -2-Oxa-5-azabicyclo [2.2.1] heptan-5-yl (2-fluoro-3-methoxy-4- (4- (methylamino) -5- (trifluoromethyl ) Pyrimidin-2-ylamino) phenyl) methanone
5-Chloro-4- (5-chloro-4-methoxypyrimidin-2-ylamino) -2-methoxy-N-methylbenzamide
2- (4-((3S, 4S) -3,4-Difluoropyrrolidine-1-carbonyl) -2-methoxyphenylamino) -4- (methylamino) pyrimidine-5-carbonitrile
(5-Chloro-2-methoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) (3-methoxypyrrolidin-1-yl) methanone
(2-Fluoro-5-methoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) (3-methoxypyrrolidin-1-yl) methanone
2-Fluoro-N- (2-hydroxy-2-methylpropyl) -5-methoxy-N-methyl-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) benzamide
((2S, 6R) -2,6-dimethylmorpholino) (2-fluoro-5-methoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) methanone
(2-Fluoro-5-methoxy-4- (4- (2-methoxyethoxy) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) (morpholino) methanone
(2-Ethoxy-5-fluoro-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) (morpholino) methanone
(4- (4- (Ethylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -3-isopropoxyphenyl) (morpholino) methanone
(4- (4- (Ethylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -2-fluoro-3-isopropoxyphenyl) (morpholino) methanone
(4- (5-Chloro-4- (piperidin-1-yl) pyrimidin-2-ylamino) -3-methoxyphenyl) (morpholino) methanone
(4- (5-Chloro-4- (pyrrolidin-1-yl) pyrimidin-2-ylamino) -3-methoxyphenyl) (morpholino) methanone
[4- (4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-phenyl] -morpholin-4-yl-methanone
4- (4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -3-methoxy-phenyl] -morpholin-4-yl-methanone
[5-Chloro-4- (5-chloro-4-ethylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl] -morpholin-4-yl-methanone
[4- (5-Chloro-4-methoxy-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-phenyl] -morpholin-4-yl-methanone
[5-Chloro-4- (5-chloro-4-methoxy-pyrimidin-2-ylamino) -2-methoxy-phenyl] -morpholin-4-yl-methanone
[3-Chloro-4- (5-chloro-4-methoxy-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[2-Chloro-5-methoxy-4- (4-methoxy-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[3-Methoxy-4- (4-methoxy-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
{4- [5-Chloro-4- (tetrahydro-pyran-4-yloxy) -pyrimidin-2-ylamino] -3-methoxy-phenyl} -morpholin-4-yl-methanone
5-Chloro-N- (1-cyano-cyclopropyl) -2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide
5-Chloro-N- (1-cyano-cyclopropyl) -2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide
[5-Chloro-2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl]-(2,6-dimethyl-morpholin-4-yl) -methanone
[3-Methoxy-4- (4-pyrrolidin-1-yl-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[3-Cyclobutoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
N- (3,3-Difluoro-cyclobutyl) -3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide
3-Methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -N-oxetane-3-yl-benzamide
[3-Methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl]-(8-oxa-3-aza-bicyclo [3.2.1] oct-3- Il) -methanone
[3-Methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl]-(2-oxa-5-aza-bicyclo [2.2.1] hepta-5- Il) -methanone
[3-Methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -pyrrolidin-1-yl-methanone
N, N-diethyl-3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide
(4-Dimethylamino-piperidin-1-yl)-[3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -methanone
(2,6-Dimethyl-morpholin-4-yl)-[3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -methanone
1- [3-Methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzoyl] -piperidine-4-carbonitrile
[3-Methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl]-[4- (2,2,2-trifluoro-ethyl) -piperazin-1-yl ] -Methanone
[3-Methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl]-(4-methoxy-piperidin-1-yl) -methanone
3-Methoxy-N- (2-methoxy-ethyl) -4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide
3-Methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -N- (1-methyl-piperidin-4-yl) -benzamide
N- (4,4-Difluoro-cyclohexyl) -3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -3- (oxetane-3-yloxy) -phenyl] -morpholin-4-yl-methanone
[3-Cyclopropylmethoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[3-Cyclobutylmethoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
N-ethyl-3-methoxy-N-methyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide
[4- (5-Bromo-4-methylamino-pyrimidin-2-ylamino) -5-chloro-2-methoxy-phenyl] -morpholin-4-yl-methanone
[3-Cyclopropyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[3-Bromo-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[3-Chloro-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[2-Chloro-5-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[2-Chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -5-methoxy-phenyl] -morpholin-4-yl-methanone
[4- (5-Bromo-4-methoxy-pyrimidin-2-ylamino) -2-chloro-5-methoxy-phenyl] -morpholin-4-yl-methanone
(5-Chloro-4- (5-chloro-4- (methylamino) pyrimidin-2-ylamino) -2-methoxyphenyl) (morpholino) methanone
[5-Chloro-2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[2-Fluoro-3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[3- (2-Fluoro-ethoxy) -4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
(4- (5-Chloro-4-methoxypyrimidin-2-ylamino) -3-methoxyphenyl) (pyrrolidin-1-yl) methanone
[5-Ethoxy-2-fluoro-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
3-Methoxy-N- (2-methoxy-ethyl) -N-methyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide
4- (4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -3-methoxy-N- (2-methoxy-ethyl) -N-methyl-benzamide
2-Fluoro-5-methoxy-N- (2-methoxy-ethyl) -N-methyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide
4- (4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-N- (2-methoxy-ethyl) -N-methyl-benzamide
[2-Fluoro-5-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl]-((S) -2-methoxymethyl-pyrrolidin-1-yl)- Methanon
[4- (4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-phenyl]-((S) -2-methoxymethyl-pyrrolidin-1-yl)- Methanon
N-ethyl-4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-N- (2-methoxy-ethyl) -benzamide
N-ethyl-2-fluoro-5-methoxy-N- (2-methoxy-ethyl) -4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide
[5-Ethoxy-4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoro-phenyl] -morpholin-4-yl-methanone
(4- (4- (Ethylamino) -5- (trifluoromethyl) pyrimidin-2-yl-amino) -3-isopropoxyphenyl) (morpholino) methanone
(2-Fluoro-3-isopropoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) (morpholino) methanone
(4- (4- (Ethylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -3- (trifluoromethoxy) phenyl) (morpholino) methanone
(2-Fluoro-3-isopropoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) (morpholino) methanone
2- (2-Methoxy-4- (morpholine-4-carbonyl) phenylamino) -4- (methylamino) pyrimidine-5-carbonitrile
4-Methoxy-2- [2-methoxy-4- (morpholine-4-carbonyl) -phenylamino] -pyrimidine-5-carbonitrile
4-Ethylamino-2- [5-fluoro-2-methoxy-4- (morpholine-4-carbonyl) -phenylamino] -pyrimdine-5-carbonitrile
2- [5-Fluoro-2-methoxy-4- (morpholine-4-carbonyl) -phenylamino] -4-methylamino-pyrimidine-5-carbonitrile
2- [4-((2R, 6S) -2,6-Dimethyl-morpholine-4-carbonyl) -5-fluoro-2-methoxy-phenylamino] -4-methylamino-pyrimidine-5-carbonitrile
2- [4-((2R, 6S) -2,6-Dimethyl-morpholine-4-carbonyl) -5-fluoro-2-methoxy-phenylamino] -4-ethylamino-pyrimidine-5-carbonitrile
4- (5-Cyano-4-methylamino-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-N, N-dimethyl-benzamide
[5-Chloro-2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl]-[4- (2-methoxy-ethyl) -piperazin-1-yl] -Methanone
[5-Chloro-2-methyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[5-Methoxy-2-methyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[2-Fluoro-5-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl]-(hexahydro-pyrrolo [1,2-a] pyrazin-2-yl) -Methanone
[2-Fluoro-5-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl]-(1S, 5R) -8-oxa-3-aza-bicyclo [3 .2.1] Oct-3-yl-methanone
[4- (4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-phenyl]-(1S, 5R) -8-oxa-3-aza-bicyclo [3 .2.1] Oct-3-yl-methanone
2-Fluoro-5-methoxy-N-methyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -N- (1-methyl-piperidin-4-yl) -benzamide
[2-Fluoro-5-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl]-(4-morpholin-4-yl-piperidin-1-yl) -methanone
[4- (5-Chloro-4-methoxy-pyrimidin-2-ylamino) -3-hydroxy-phenyl] -morpholin-4-yl-methanone
[5-Chloro-2-hydroxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[2-Fluoro-5-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl]-(1S, 4S) -2-oxa-5-aza-bicyclo [2 2.2.1] Hepta-5-yl-methanone
[2,3-Difluoro-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -2,3-difluoro-phenyl] -morpholin-4-yl-methanone
[4- (4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-phenyl]-(1S, 4S) -2-oxa-5-aza-bicyclo [2 2.2.1] Hepta-5-yl-methanone
[5-Chloro-2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl]-(1S, 4S) -2-oxa-5-aza-bicyclo [2 2.2.1] Hepta-5-yl-methanone
[2,5-Difluoro-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -2,5-difluoro-phenyl] -morpholin-4-yl-methanone
4- (4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoro-N- (2-hydroxy-2-methyl-propyl) -5-methoxy-benzamide
4- (4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoro-N- (2-hydroxy-2-methyl-propyl) -5-methoxy-N-methyl-benzamide
[5-Chloro-2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl]-(3-morpholin-4-yl-azetidin-1-yl) -methanone
N-tert-butyl-4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -3-methoxy-benzamide
[3-Fluoro-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[5-Chloro-2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl]-(4-oxetan-3-yl-piperazin-1-yl) -methanone
[5-Chloro-2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl]-(3,3-difluoro-pyrrolidin-1-yl) -methanone
[4- (4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-phenyl] -morpholin-4-yl-methanone
[4- (4-Azetidin-1-yl-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-phenyl] -morpholin-4-yl-methanone
5-Fluoro-N- (2-hydroxy-2-methyl-propyl) -2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide
4- (4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -5-fluoro-N- (2-hydroxy-2-methyl-propyl) -2-methoxy-benzamide
5-Fluoro-N- (2-hydroxy-2-methyl-propyl) -2-methoxy-N-methyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide
4- (4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -5-fluoro-N- (2-hydroxy-2-methyl-propyl) -2-methoxy-N-methyl-benzamide
[4- (4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2,5-difluoro-phenyl] -morpholin-4-yl-methanone
[2-Fluoro-4- (4-isopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -5-methoxy-phenyl] -morpholin-4-yl-methanone
[3-Methoxy-2-methyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[4- (4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-phenyl]-(1-oxa-6-aza-spiro [3.3] hepta- 6-yl) -methanone
2-Fluoro-N- (2-hydroxy-2-methyl-propyl) -5-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide
((3S, 4S) -3,4-Difluoro-pyrrolidin-1-yl)-[2-fluoro-5-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)- Phenyl] -methanone
4- (4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-N-methyl-benzamide
2-Fluoro-N- (2-hydroxy-2-methyl-propyl) -3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide
(3,3-difluoro-pyrrolidin-1-yl)-[5- (2-fluoro-ethoxy) -2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)- Phenyl] -methanone
[5-Chloro-2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl]-(1-oxa-6-aza-spiro [3.3] hepta- 6-yl) -methanone
[4- (4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2,3-difluoro-phenyl] -morpholin-4-yl-methanone
[4- (4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -5-methoxy-2-methyl-phenyl] -morpholin-4-yl-methanone
[5-Chloro-4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-methoxy-phenyl]-(2-oxa-6-aza-spiro [3.3] hepta- 6-yl) -methanone
[4- (4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -5-methoxy-2-methyl-phenyl] -morpholin-4-yl-methanone
4- (4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoro-N- (2-hydroxy-2-methyl-propyl) -5-methoxy-benzamide
N-tert-butyl-4- (5-cyano-4-ethylamino-pyrimidin-2-ylamino) -3-methoxy-benzamide
[3-Difluoromethoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[2-Fluoro-5- (2-fluoro-ethoxy) -4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[4- (4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoro-5- (2-fluoro-ethoxy) -phenyl] -morpholin-4-yl-methanone
[2-Fluoro-5-methoxy-4- (4-methoxy-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[4- (4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2,3-difluoro-phenyl] -morpholin-4-yl-methanone
[4- (4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2,5-difluoro-phenyl] -morpholin-4-yl-methanone
[2-Chloro-5-fluoro-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
4-Ethylamino-2- [4-((S) -3-fluoro-pyrrolidine-1-carbonyl) -2-methoxy-phenylamino] -pyrimidine-5-carbonitrile
5-Chloro-2-methoxy-N-methyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -N- (1-methyl-1H-pyrazol-4-yl) -benzamide
(3,3-Difluoro-pyrrolidin-1-yl)-[4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2,5-dimethoxy-phenyl] -methanone
[4- (5-Chloro-4-methoxy-pyrimidin-2-ylamino) -3- (2-fluoro-ethoxy) -phenyl] -morpholin-4-yl-methanone
[2-Methoxy-5-methyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[2-Chloro-4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -5-fluoro-phenyl] -morpholin-4-yl-methanone
[3-Chloro-2-fluoro-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
(3,3-Difluoro-pyrrolidin-1-yl)-[4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -5- (2-fluoro-ethoxy) -2-methoxy- Phenyl] -methanone
[4- (4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2,6-difluoro-3-methoxy-phenyl] -morpholin-4-yl-methanone
[2,6-Difluoro-3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[4- (4-Ethoxy-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-phenyl] -morpholin-4-yl-methanone
[2,5-Dimethoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
(3,3-Difluoro-pyrrolidin-1-yl)-[4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -5-fluoromethoxy-2-methoxy-phenyl] -methanone
[5-Methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-trifluoromethyl-phenyl] -morpholin-4-yl-methanone
[4- (5-Chloro-4-methylamino-pyrimidin-2-ylamino) -5-methoxy-2-trifluoromethyl-phenyl] -morpholin-4-yl-methanone
[5-Chloro-2-fluoro-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[4- (4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoro-5- (2-fluoro-ethoxy) -phenyl] -morpholin-4-yl-methanone
[5-Chloro-4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-methyl-phenyl] -morpholin-4-yl-methanone
[5-Chloro-4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoromethoxy-phenyl] -morpholin-4-yl-methanone
[5-Fluoro-2-methyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[5-Chloro-4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoro-phenyl] -morpholin-4-yl-methanone
{2-Fluoro-4- [4-((1R, 2S) -2-fluoro-cyclopropylamino) -5-trifluoromethyl-pyrimidin-2-ylamino] -5-methoxy-phenyl} -morpholine-4- Il-methanone
(2,2-Dimethyl-morpholin-4-yl)-[2-fluoro-5-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -methanone
[3-Cyclopropoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[5-Chloro-2-difluoromethoxy-4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[5-Chloro-2-difluoromethoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
4-Ethylamino-2- [5-fluoro-4-((S) -3-fluoro-pyrrolidine-1-carbonyl) -2-methoxy-phenylamino] -pyrimidine-5-carbonitrile
4-Ethylamino-2- [2-fluoro-4-((S) -3-fluoro-pyrrolidine-1-carbonyl) -5-methoxy-phenylamino] -pyrimidine-5-carbonitrile
[3-Chloro-2,6-dimethoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
(2,2-Dimethyl-morpholin-4-yl)-[3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -methanone
[5- (2-Fluoro-ethoxy) -2-methyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[5- (2-Fluoro-ethoxy) -2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -pyrrolidin-1-yl-methanone
(5-Chloro-4- (4- (ethylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -2-methoxyphenyl) (perdeuteromorpholino) methanone
[4- (5-Chloro-4-methoxy-pyrimidin-2-ylamino) -2,5-dimethoxy-phenyl] -morpholin-4-yl-methanone
[5-Fluoromethoxy-2-methyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
{4- [Ethyl- (4-methylamino-5-trifluoromethyl-pyrimidin-2-yl) -amino] -5-fluoromethoxy-2-methyl-phenyl} -morpholin-4-yl-methanone
[5-Fluoromethoxy-2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -pyrrolidin-1-yl-methanone
[4- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-phenyl] -morpholin-4-yl-methanone
[2-Fluoro-5-methyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[4- (5-Chloro-4-methoxy-pyrimidin-2-ylamino) -5-methoxy-2-methyl-phenyl] -morpholin-4-yl-methanone
[4- (5-Chloro-4-ethoxy-pyrimidin-2-ylamino) -5-methoxy-2-methyl-phenyl] -morpholin-4-yl-methanone
[2-Fluoro-5-fluoromethoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -pyrrolidin-1-yl-methanone
4-Cyclopropylamino-2- [4-((S) -3-fluoro-pyrrolidine-1-carbonyl) -2-methoxy-phenylamino] -pyrimidine-5-carbonitrile
4-Ethylamino-2- [4-((S) -3-fluoro-pyrrolidine-1-carbonyl) -2-methoxy-5-methyl-phenylamino] -pyrimidine-5-carbonitrile
4-Ethylamino-2- [2-fluoro-4-((S) -3-fluoro-pyrrolidine-1-carbonyl) -phenylamino] -pyrimidine-5-carbonitrile
[5-Isopropoxy-2-methyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[5-Ethoxy-2-methyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[5-Fluoromethoxy-2-methyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -pyrrolidin-1-yl-methanone
[5-Chloro-4- (4-cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoromethoxy-phenyl] -morpholin-4-yl-methanone
[4- (4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -5-fluoro-2-methyl-phenyl] -morpholin-4-yl-methanone
(5-Methoxy-2-methyl-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) (perdeuteromorpholino) methanone
4- (4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -N- (2-hydroxy-2-methyl-propyl) -5-methoxy-2-methyl-benzamide
4- (4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoro-N- (2-hydroxy-1,1-dimethyl-ethyl) -5-methoxy-benzamide
2- [2-Chloro-4-((S) -3-fluoro-pyrrolidine-1-carbonyl) -5-methyl-phenylamino] -4-ethylamino-pyrimidine-5-carbonitrile
2- [2-Chloro-4-((S) -3-fluoro-pyrrolidine-1-carbonyl) -phenylamino] -4-ethylamino-pyrimidine-5-carbonitrile
[5-Cyclopropylmethoxy-2-methyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
[5-Fluoromethoxy-2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -piperidin-1-yl-methanone
[5-Chloro-4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoromethoxy-phenyl] -pyrrolidin-1-yl-methanone
[4- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -5-fluoro-2-methoxy-phenyl] -morpholin-4-yl-methanone
[5-Chloro-4- (4-cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-methoxy-phenyl] -morpholin-4-yl-methanone
4- (4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoro-N- (1-hydroxymethyl-cyclopropyl) -5-methoxy-benzamide
4- (4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoro-N- (1-hydroxy-cyclopropylmethyl) -5-methoxy-benzamide
N- (2-hydroxy-2-methyl-propyl) -5-methoxy-2-methyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide
2- [2-Chloro-4-((S) -3-fluoro-pyrrolidine-1-carbonyl) -5-methoxy-phenylamino] -4-ethylamino-pyrimidine-5-carbonitrile
[4- (4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoro-5-methyl-phenyl] -morpholin-4-yl-methanone
[4- (5-Chloro-4-methoxy-pyrimidin-2-ylamino) -5-fluoromethoxy-2-methyl-phenyl] -pyrrolidin-1-yl-methanone
5-Fluoromethoxy-2-methoxy-N, N-dimethyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide
[4- (4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -5-fluoro-2-fluoromethoxy-phenyl] -pyrrolidin-1-yl-methanone
[3-Fluoro-2,6-dimethoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
(4- (4- (2,3-tetradeutero-cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -2-fluoro-5-methoxyphenyl) (morpholino) methanone
[5-Methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-trifluoromethoxy-phenyl] -morpholin-4-yl-methanone
[4- (4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2,5-dimethoxy-phenyl] -morpholin-4-yl-methanone
[2-Chloro-5-methyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone
(4- (4- (Ethylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -2-fluoro-5-methoxyphenyl) (perdeuteromorpholino) methanone
(5-Bromo-2-methoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) (morpholino) methanone
[4- (4-cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -5-methoxy-2-methyl-phenyl] -morpholin-4-yl-methanone or
[2,5-Dimethyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone.

又はその薬学的に許容可能な塩である
(上式中、
Ｘは：-ＮＲ^ａ-；又は-Ｏ-(Ｒ^ａは水素又はＣ_１-６アルキル)であり；
Ｒ^１は：Ｃ_１-６アルキル；Ｃ_２-６アルケニル；Ｃ_２-６アルキニル；ハロ-Ｃ_１-６アルキル；Ｃ_１-６アルコキシ-Ｃ_１-６アルキル；ヒドロキシ-Ｃ_１-６アルキル；アミノ-Ｃ_１-６アルキル；Ｃ_１-６アルキルスルホニル-Ｃ_１-６アルキル；Ｃ_１-６アルキルで一又は複数回置換されていてもよいＣ_３-６シクロアルキル；Ｃ_３-６シクロアルキル-Ｃ_１-６アルキル(Ｃ_３-６シクロアルキル部分はＣ_１-６アルキルで一又は複数回置換されていてもよい)；Ｒ^７で一又は複数回置換されていてもよいヘテロシクリル；又はＲ^７で一又は複数回置換されていてもよいヘテロシクリル-Ｃ_１-６アルキルであり；
又はＸ及びＲ^１は共にＣ_１-６アルキル；Ｃ_１-６アルコキシ-Ｃ_１-６アルキル；Ｒ^６で一又は複数回置換されていてもよいＣ_３-６シクロアルキル；又はＣ_３-６シクロアルキル-Ｃ_１-６アルキル(Ｃ_３-６シクロアルキル部分はＲ^６で一又は複数回置換されていてもよい)を形成し；
又はＲ^１及びＲ^ａはそれらが結合している原子と共に、Ｒ^７で一又は複数回置換されていてもよい３〜６員の複素環を形成し得；
Ｒ^２は：Ｃ_１-６アルキル；ハロ；Ｃ_１-６アルコキシ；シアノ；Ｃ_２-６アルキニル；Ｃ_２-６アルケニル；ハロ-Ｃ_１-６アルキル；ハロ-Ｃ_１-６アルコキシ；Ｒ^６で一又は複数回置換されていてもよいＣ_３-６シクロアルキル；Ｃ_３-６シクロアルキル-Ｃ_１-６アルキル(Ｃ_３-６シクロアルキル部分はＲ^６で一又は複数回置換されていてもよい)；-ＯＲ^ｂ(Ｒ^ｂはＣ_１-６アルキル、Ｒ^６で一又は複数回置換されていてもよいＣ_３-６シクロアルキル、又はＣ_３-６シクロアルキル-Ｃ_１-６アルキル(Ｃ_３-６シクロアルキル部分はＲ^６で一又は複数回置換されていてもよい))；又は-Ｃ(Ｏ)-Ｒ^ｃ(Ｒ^ｃはＣ_１-６アルキル、Ｃ_１-６アルコキシ、アミノ、又はＲ^７で一又は複数回置換されていてもよいヘテロシクリル)であり；
Ｒ^３は：水素；Ｃ_１-６アルキル；ハロ-Ｃ_１-６アルキル；Ｃ_２-６アルケニル；Ｃ_２-６アルキニル；ヒドロキシ-Ｃ_１-６アルキル；Ｃ_１-６アルコキシ-Ｃ_１-６アルキル；シアノ-Ｃ_１-６アルキル；Ｃ_１-６アルキルスルホニル；Ｃ_１-６アルキルスルホニルＣ_１-６アルキル；アミノ-Ｃ_１-６アルキル；Ｒ^６で一又は複数回置換されていてもよいＣ_３-６シクロアルキル；Ｃ_３-６シクロアルキル-Ｃ_１-６アルキル(Ｃ_３-６シクロアルキル部分はＲ^６で一又は複数回置換されていてもよい)；Ｃ_３-６シクロアルキル-スルホニル(Ｃ_３-６シクロアルキル部分はＲ^６で一又は複数回置換されていてもよい)；Ｒ^７で一又は複数回置換されていてもよいヘテロシクリル；ヘテロシクリル-Ｃ_１-６アルキル(ヘテロシクリル部分Ｒ^７で一又は複数回置換されていてもよい)；Ｒ^８で一又は複数回置換されていてもよいアリール；アリール-Ｃ_１-６アルキル(アリール部分はＲ^８で一又は複数回置換されていてもよい)；Ｒ^８で一又は複数回置換されていてもよいヘテロアリール；ヘテロアリール-Ｃ_１-６アルキル(ヘテロアリール部分はＲ^８で一又は複数回置換されていてもよい)；又は-Ｙ-Ｃ(Ｏ)-Ｒ^ｄであり；
ＹはＣ_２-６アルキレン又は結合であり；
Ｒ^ｄはＣ_１-６アルキル、Ｃ_１-６アルコキシ、アミノ、Ｃ_１-６アルキル-アミノ、ジ-Ｃ_１-６アルキル-アミノ、ハロ-Ｃ_１-６アルキル-アミノ、ジ-ハロ-Ｃ_１-６アルキル-アミノ、ハロ-Ｃ_１-６アルキル、ヒドロキシ-Ｃ_１-６アルキル、ヒドロキシ、Ｃ_１-６アルコキシ-Ｃ_１-６アルキル、シアノ-Ｃ_１-６アルキル、Ｃ_１-６アルキルスルホニルＣ_１-６アルキル、アミノ-Ｃ_１-６アルキル、Ｒ^６で一又は複数回置換されていてもよいＣ_３-６シクロアルキル、Ｃ_３-６シクロアルキル-Ｃ_１-６アルキル(Ｃ_３-６シクロアルキル部分はＲ^６で一又は複数回置換されていてもよい)、Ｒ^７で一又は複数回置換されていてもよいヘテロシクリル、又はヘテロシクリル-Ｃ_１-６アルキル(ヘテロシクリル部分Ｒ^７で一又は複数回置換されていてもよい)であり；
Ｒ^４は：水素；Ｃ_１-６アルキル；ハロ；シアノ；ハロ-Ｃ_１-６アルキル；Ｃ_２-６アルケニル；Ｃ_２-６アルキニル；Ｃ_１-６アルコキシ；Ｃ_１-６アルコキシ-Ｃ_１-６アルキル；ヒドロキシ-Ｃ_１-６アルキル；Ｒ^６で一又は複数回置換されていてもよいＣ_３-６シクロアルキル；Ｃ_３-６シクロアルキル-Ｃ_１-６アルキル(Ｃ_３-６シクロアルキル部分はＲ^６で一又は複数回置換されていてもよい)；又は-Ｙ-Ｃ(Ｏ)-Ｒ^ｄであり；
Ｒ^５は：水素；又はＣ_１-６アルキルであり；
各Ｒ^６は独立して：Ｃ_１-６アルキル；ハロ-Ｃ_１-６アルキル；Ｃ_１-６アルコキシ；オキソ；シアノ；ハロ；又はＹ-Ｃ(Ｏ)-Ｒ^ｄであり；
各Ｒ^７は独立して：Ｃ_１-６アルキル；ハロ-Ｃ_１-６アルキル；ハロ；オキソ；Ｃ_１-６アルコキシ；Ｃ_１-６アルキルスルホニル；Ｃ_１-６アルコキシ-Ｃ_１-６アルキル；シアノ；-Ｙ-Ｃ(Ｏ)-Ｒ^ｄ；ヘテロシクリル；ヘテロシクリル-Ｃ_１-６アルキル；Ｃ_３-６シクロアルキル；Ｃ_３-６シクロアルキル-Ｃ_１-６アルキル；又はＣ_３-６シクロアルキルスルホニルであり；そして
各Ｒ^８は独立して：オキソ；Ｃ_１-６アルキル；ハロ-Ｃ_１-６アルキル；ハロ；Ｃ_１-６アルキル-スルホニル；Ｃ_１-６アルコキシ；Ｃ_１-６アルコキシ-Ｃ_１-６アルキル；シアノ；ｈｅｔｏｅｒｙｃｌｙｌ；ヘテロシクリル-Ｃ_１-６アルキル；-Ｙ-Ｃ(Ｏ)-Ｒ^ｄ；Ｃ_３-６シクロアルキル、Ｃ_３-６シクロアルキル-Ｃ_１-６アルキル、又はＣ_３-６シクロアルキル-スルホニルである)。 In another embodiment, the LRRK2 modulator is of formula II

Or a pharmaceutically acceptable salt thereof
(In the above formula,
X is: —NR ^a —; or —O— (R ^a is hydrogen or C _1-6 alkyl);
R ¹ is: C _1-6 alkyl; C _2-6 alkenyl; C _2-6 alkynyl; halo-C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; hydroxy-C _1-6 alkyl; Amino-C _1-6 alkyl; C _1-6 alkylsulfonyl-C _1-6 alkyl; C _3-6 cycloalkyl optionally substituted one or more times with C _1-6 alkyl; C _3-6 cycloalkyl -C _1-6 alkyl (the C _3-6 cycloalkyl moiety may be substituted one or more times with C _1-6 alkyl); a heterocyclyl optionally substituted one or more times with R ⁷ ; or R ⁷ is heterocyclyl-C _1-6 alkyl optionally substituted one or more times;
Or X and R ¹ are both C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; C _3-6 cycloalkyl optionally substituted one or more times with R ⁶ ; or C _3-6 Forming a cycloalkyl-C _1-6 alkyl (the C _3-6 cycloalkyl moiety may be substituted one or more times by R ⁶ );
Or R ¹ and R ^a together with the atoms to which they are attached may form a 3-6 membered heterocycle that may be substituted one or more times with R ⁷ ;
R ² is: _{C 1-6} alkyl; halo; _{C 1-6} alkoxy; cyano; _{C 2-6} alkynyl; _{C 2-6} alkenyl; halo -C _1-6 alkyl; halo -C _1-6 alkoxy; ^{R 6} C _3-6 cycloalkyl optionally substituted one or more times by: C _3-6 cycloalkyl-C _1-6 alkyl (wherein the C _3-6 cycloalkyl moiety is substituted one or more times by R ⁶ -OR ^b (R ^b is C _1-6 alkyl, C _3-6 cycloalkyl optionally substituted one or more times with R ⁶ , or C _3-6 cycloalkyl-C _1-6 alkyl) (C _3-6 cycloalkyl moiety may be substituted one or more times with R ⁶ ); or —C (O) —R ^c (R ^c is C _1-6 alkyl, C _1-6 alkoxy, Amino, or heterocyclyl optionally substituted one or more times by R ⁷ );
R ³ is: hydrogen; C _1-6 alkyl; halo-C _1-6 alkyl; C _2-6 alkenyl; C _2-6 alkynyl; hydroxy-C _1-6 alkyl; C _1-6 alkoxy-C _1-6 Alkyl; cyano-C _1-6 alkyl; C _1-6 alkylsulfonyl; C _1-6 alkylsulfonyl C _1-6 alkyl; amino-C _1-6 alkyl; _optionally substituted one or more times by R ⁶ C _3-6 cycloalkyl; C _3-6 cycloalkyl-C _1-6 alkyl (the C _3-6 cycloalkyl moiety may be substituted one or more times by R ⁶ ); C _3-6 cycloalkyl- Sulfonyl (C _3-6 cycloalkyl moiety may be substituted one or more times with R ⁶ ); Heterocyclyl optionally substituted one or more times with R ⁷ ; Heterocyclyl-C _1-6 alkyl (heterocyclyl moiety) one or more times by R ⁷ Conversion is may be); by R ⁸ may be substituted one or more times aryl; aryl -C _1-6 alkyl (the aryl moiety may be substituted one or more times by R ^8); R Heteroaryl optionally substituted one or more times by ⁸ ; heteroaryl-C _1-6 alkyl (the heteroaryl moiety may be substituted one or more times by R ⁸ ); or —Y—C (O ) -R ^d ;
Y is C _2-6 alkylene or a bond;
R ^d is C _1-6 alkyl, C _1-6 alkoxy, amino, C _1-6 alkyl-amino, di-C _1-6 alkyl-amino, halo-C _1-6 alkyl-amino, di-halo-C _1-6 alkyl-amino, halo-C _1-6 alkyl, hydroxy-C _1-6 alkyl, hydroxy, C _1-6 alkoxy-C _1-6 alkyl, cyano-C _1-6 alkyl, C _1-6 alkyl Sulfonyl C _1-6 alkyl, amino-C _1-6 alkyl, C _3-6 cycloalkyl optionally substituted one or more times with R ⁶ , C _3-6 cycloalkyl-C _1-6 alkyl (C _{3 The -6} cycloalkyl moiety may be substituted one or more times by R ⁶ ), a heterocyclyl optionally substituted one or more times by R ⁷ , or a heterocyclyl-C _1-6 alkyl (in the heterocyclyl moiety R ⁷⁾ . (It may be substituted one or more times) Yes;
R ⁴ is: hydrogen; C _1-6 alkyl; halo; cyano; halo-C _1-6 alkyl; C _2-6 alkenyl; C _2-6 alkynyl; C _1-6 alkoxy; C _1-6 alkoxy-C _{1 -6} alkyl; hydroxy-C _1-6 alkyl; C _3-6 cycloalkyl optionally substituted one or more times with R ⁶ ; C _3-6 cycloalkyl-C _1-6 alkyl (C _3-6 cyclo The alkyl moiety may be substituted one or more times with R ⁶ ); or —Y—C (O) —R ^d ;
R ⁵ is: hydrogen; or C _1-6 alkyl;
Each R ⁶ is independently: C _1-6 alkyl; halo-C _1-6 alkyl; C _1-6 alkoxy; oxo; cyano; halo; or Y—C (O) —R ^d ;
Each R ⁷ is independently: C _1-6 alkyl; halo-C _1-6 alkyl; halo; oxo; C _1-6 alkoxy; C _1-6 alkylsulfonyl; C _1-6 alkoxy-C _1-6 alkyl Cyano; —YC (O) —R ^d ; heterocyclyl; heterocyclyl-C _1-6 alkyl; C _3-6 cycloalkyl; C _3-6 cycloalkyl-C _1-6 alkyl; or C _3-6 cyclo; And each R ⁸ is independently: oxo; C _1-6 alkyl; halo-C _1-6 alkyl; halo; C _1-6 alkyl-sulfonyl; C _1-6 alkoxy; C _1-6 alkoxy -C _1-6 alkyl; cyano; Hetoeryclyl; heterocyclyl -C _1-6 ^{alkyl; -Y-C (O) -R} d; C 3-6 cycloalkyl, _{C 3-6} cycloalkyl -C _1-6 alkyl , or _{C 3-6} cycloalkyl - scan It is a Honiru).

In certain embodiments of formula II, X is —NR ^a — or —O—.

In certain embodiments of formula II, X is —NR ^a .

  In certain embodiments of formula II, X is —O—.

  In certain embodiments of formula II, X is —NH— or —O—.

  In certain embodiments of formula II, X is —NH—.

  In certain embodiments of formula II, X is —O—.

In certain embodiments of formula II, R ^a is hydrogen.

In certain embodiments of formula II, R ^a is C _1-6 alkyl.

In certain embodiments of formula II, R ¹ is: C _1-6 alkyl; C _2-6 alkenyl; C _2-6 alkynyl; halo-C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; Hydroxy-C _1-6 alkyl; Amino-C _1-6 alkyl; C _1-6 alkylsulfonyl-C _1-6 alkyl; C _3-6 cycloalkyl optionally substituted with C _1-6 alkyl; C _{3 -6} cycloalkyl-C _1-6 alkyl (the C _3-6 cycloalkyl moiety may be substituted with C _1-6 alkyl); heterocyclyl; or heterocyclyl-C _1-6 alkyl.

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

In certain embodiments of formula II, R ¹ is: C _1-6 alkyl; C _3-6 cycloalkyl optionally substituted with C _1-6 alkyl; or C _3-6 cycloalkyl-C _1-6 alkyl (The C _3-6 cycloalkyl moiety may be substituted with C _1-6 alkyl).

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

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

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

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

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

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

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

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

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

In certain embodiments of formula II, R ¹ is C _3-6 cycloalkyl-C _1-6 alkyl (the C _3-6 cycloalkyl moiety _optionally substituted with C _1-6 alkyl).

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

In embodiments of Formula II wherein R ¹ is heterocyclyl or heterocyclyl-C _1-6 alkyl, such heterocyclyl can be piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl or oxetanyl, each of which May be substituted as defined in

In embodiments of Formula II wherein R ¹ is heterocyclyl or heterocyclyl-C _1-6 alkyl, such heterocyclyl can be tetrahydropyranyl, piperidinyl, tetrahydrofuranyl or oxetanyl, each as defined herein. May be substituted.

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

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

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

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

In certain embodiments of formula II, R ¹ is oxetanyl.

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

In certain embodiments of Formula II, R ¹ is: methyl; ethyl; n-propyl; isopropyl; isobutyl; 3,3-dimethylpropyl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; cyclopropylmethyl; Cyclopropylethyl; methoxyethyl; oxetanyl; tetrahydropyranyl; 2,2-difluoroethyl; or tetrahydrofuranylmethyl.

In certain embodiments of formula II, R ¹ is: methyl; ethyl; n-propyl; isopropyl; isobutyl; 3,3-dimethylpropyl; cyclopentyl; cyclohexyl; cyclopropylmethyl; cyclobutylmethyl; Methoxyethyl; oxetanyl; tetrahydropyranyl; 2,2-difluoroethyl; or tetrahydrofuranylmethyl.

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

In certain embodiments of formula II, R ¹ is 2,2-difluoroethyl.

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

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

In certain embodiments of formula II, R ¹ is methyl.

In certain embodiments of formula II, R ¹ is ethyl.

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

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

In certain embodiments of formula II, R ¹ is: cyclopropyl.

In certain embodiments of formula II, R ¹ and R ^a together with the atoms to which they are attached can form a 3- to 6-membered heterocycle.

In certain embodiments of formula II, R ¹ and R ^a together with the atoms to which they are attached can form a 3-membered heterocycle.

In certain embodiments of formula II, R ¹ and R ^a together with the atoms to which they are attached can form a 4-membered heterocycle.

In certain embodiments of formula II, R ¹ and R ^a together with the atoms to which they are attached can form a 5-membered heterocycle.

In certain embodiments of formula II, R ¹ and R ^a together with the atoms to which they are attached can form a 6-membered heterocycle.

In certain embodiments of formula II, X and R ¹ are both C _1-6 alkyl; C _3-6 cycloalkyl optionally substituted with C _1-6 alkyl; or C _3-6 cycloalkyl-C _{1- 6} alkyl (C _3-6 cycloalkyl moiety may be _optionally substituted with C _1-6 alkyl).

In certain embodiments of formula II, X and R ¹ together form C _1-6 alkyl.

In certain embodiments of formula II, X and R ¹ together form a C _3-6 cycloalkyl optionally substituted with C _1-6 alkyl.

In certain embodiments of formula II, X and R ¹ together form C _3-6 cycloalkyl-C _1-6 alkyl (the C _3-6 cycloalkyl moiety may be substituted with C _1-6 alkyl). To do.

In certain embodiments of formula II, R ² is: C _1-6 alkyl; halo; C _1-6 alkoxy; cyano; C _2-6 alkynyl; C _2-6 alkenyl; halo-C _1-6 alkyl; C _1-6 alkoxy; C _3-6 cycloalkyl optionally substituted with C _1-6 alkyl; C _3-6 cycloalkyl-C _1-6 alkyl (the C _3-6 cycloalkyl moiety is C _1-6 -OR ^b (R ^b is C _1-6 alkyl, C _3-6 cycloalkyl optionally substituted with C _1-6 alkyl, or C _3-6 cycloalkyl- C _1-6 alkyl (the C _3-6 cycloalkyl moiety may be substituted with C _1-6 alkyl)); or —C (O) —R ^c .

In certain embodiments of formula II, R ² is: halo; C _1-6 alkoxy; halo-C _1-6 alkyl; halo-C _1-6 alkoxy; C _3-6 cycloalkyl (C _3-6 cycloalkyl moiety) _May be substituted with C _1-6 alkyl); C _3-6 cycloalkyl-C _1-6 alkyl (the C _3-6 cycloalkyl moiety may be substituted with C _1-6 alkyl); Tetrahydrofuranyl; tetrahydrofuranyl-C _1-6 alkyl; oxetanyl; or oxetane-C _1-6 alkyl.

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

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

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

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

In certain embodiments of formula II, R ² is: fluoro; bromo; chloro; iodo; trifluoromethyl; or cyano.

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

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

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

In certain embodiments of formula II, R ² is halo.

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

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

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

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

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

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

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

In certain embodiments of formula II, R ² is oxetanyl.

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

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

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

In certain embodiments of formula II, R ² is fluoro.

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

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

In certain embodiments of formula II, R ² is iodo.

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

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

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

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

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

In certain embodiments of formula II, ^{R 2} is -OR ^{b (R b} is _{C 1-6} alkyl, _{C 1-6} alkyl optionally substituted by _{C 3-6} cycloalkyl, or _{C 3-6} cycloalkyl -C _1-6 alkyl (the C _3-6 cycloalkyl moiety may be substituted with C _1-6 alkyl)).

In certain embodiments of formula I, R ² is —C (O) —R ^{c, where} R ^c is C _1-6 alkyl, C _1-6 alkoxy, amino, or heterocyclyl.

In certain embodiments of formula II, R ³ is: C _1-6 alkyl; halo-C _1-6 alkyl; C _2-6 alkenyl; C _2-6 alkynyl; hydroxy-C _1-6 alkyl; C _1-6 Alkoxy-C _1-6 alkyl; cyano-C _1-6 alkyl; C _1-6 alkylsulfonyl; C _1-6 alkylsulfonyl C _1-6 alkyl; amino-C _1-6 alkyl; one or more times at R ⁶ Optionally substituted C _3-6 cycloalkyl; C _3-6 cycloalkyl-C _1-6 alkyl (the C _3-6 cycloalkyl moiety may be substituted one or more times by R ⁶ ); R Heterocyclyl optionally substituted one or more times by ⁷ ; Heterocyclyl-C _1-6 alkyl (optionally substituted one or more times by heterocyclyl moiety R ⁷ ); One or more times substituted by R ⁸ Good aryl; one at R ⁸ Is heteroaryl optionally substituted multiple times; or —Y—C (O) —R ^d .

In certain embodiments of formula II, ^{R 3} is: hydrogen; _{C 1-6} alkyl; halo -C _1-6 alkyl; _{C 2-6} alkenyl; _{C 2-6} alkynyl; hydroxy -C _1-6 alkyl; _{C 1} Substituted with _6-6 alkoxy-C _1-6 alkyl; cyano-C _1-6 alkyl; C _1-6 alkylsulfonyl; C _1-6 alkylsulfonylalkyl; amino-C _1-6 alkyl; C _1-6 alkyl C _3-6 cycloalkyl; C _3-6 cycloalkyl-C _1-6 alkyl (the C _3-6 cycloalkyl moiety may be substituted with C _1-6 alkyl); heterocyclyl; heterocyclyl-C _1-6 alkyl; aryl; heteroaryl; or -C (O) -R ^c .

In certain embodiments of formula II, R ³ is: C _1-6 alkyl; halo-C _1-6 alkyl; hydroxy-C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; C _1-6 C _3-6 cycloalkyl optionally substituted with alkyl; C _3-6 cycloalkyl-C _1-6 alkyl (the C _3-6 cycloalkyl moiety may be substituted with C _1-6 alkyl); Heterocyclyl; heterocyclyl-C _1-6 alkyl; or —C (O) —R ^{b, where} R ^b is C _1-6 alkyl, C _1-6 alkoxy, amino, or heterocyclyl.

In certain embodiments of formula II, R ³ is optionally substituted with: C _1-6 alkyl; hydroxy-C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; C _1-6 alkyl C _3-6 cycloalkyl; C _3-6 cycloalkyl-C _1-6 alkyl (the C _3-6 cycloalkyl moiety may be substituted with C _1-6 alkyl); heterocyclyl; heterocyclyl-C _1-6 Alkyl; or —C (O) —R ^{c, where} R ^c is C _1-6 alkyl, C _1-6 alkoxy, amino, or heterocyclyl.

In certain embodiments of formula II, R ³ is: C _1-6 alkyl; hydroxy-C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; optionally substituted one or more times by R ⁶ Good C _3-6 cycloalkyl; C _3-6 cycloalkyl-C _1-6 alkyl (the C _3-6 cycloalkyl moiety may be substituted one or more times by R ⁶ ); one or more at R ⁷ Heterocyclyl optionally substituted; heterocyclyl-C _1-6 alkyl (optionally substituted one or more times with a heterocyclyl moiety R ⁷ ); or —C (O) —R ^d .

In certain embodiments of formula II, R ³ is: C _1-6 alkyl; hydroxy-C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; heterocyclyl; heterocyclyl-C _1-6 alkyl; C (O) —R ^{c, where} R ^c is C _1-6 alkyl, C _1-6 alkoxy, amino, or heterocyclyl.

In certain embodiments of formula II, R ³ is: C _1-6 alkyl; hydroxy-C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; heterocyclyl; or heterocyclyl-C _1-6 alkyl. .

In certain embodiments of formula II, R ³ is: C _1-6 alkyl; hydroxy-C _1-6 alkyl; or C _1-6 alkoxy-C _1-6 alkyl.

In embodiments of formula II wherein R ³ is heterocyclyl or heterocyclyl-C _1-6 alkyl, such heterocyclyl can be piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl or oxetanyl.

In embodiments of Formula II wherein R ³ is heterocyclyl or heterocyclyl-C _1-6 alkyl, such heterocyclyl can be piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, pyrrolidinyl, azetidinyl, tetrahydrofuranyl or oxetanyl, each R ⁷ as defined herein may be substituted one or more times, or once or twice.

In embodiments of formula II wherein R ³ is heterocyclyl or heterocyclyl-C _1-6 alkyl, such heterocyclyl can be piperidinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl or oxetanyl.

In embodiments of Formula II wherein R ³ is heterocyclyl or heterocyclyl-C _1-6 alkyl, such heterocyclyl can be piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl or oxetanyl, each of which R ⁷ as defined may be substituted one or more times, or once or twice.

In certain embodiments of formula II, R ³ is: methyl; ethyl; n-propyl; isopropyl; 2-methoxy-ethyl; oxetan-3-yl; 2- (morpholin-4-yl) -ethyl; 2-methyl-propan-1-yl; tetrahydropyran-4-yl; or morpholin-4-yl-carbonyl.

In certain embodiments of formula I, R ³ is: methyl; ethyl; n-propyl; isopropyl; 2-methoxy-ethyl; oxetan-3-yl; 2- (morpholin-4-yl) -ethyl; 2-methyl-propan-1-yl; or tetrahydropyran-4-yl.

In certain embodiments of formula II, R ³ is hydrogen.

In certain embodiments of formula II, R ³ is C _1-6 alkyl.

In certain embodiments of formula II, R ³ is halo-C _1-6 alkyl.

In certain embodiments of formula II, R ³ is C _2-6 alkenyl.

In certain embodiments of formula II, R ³ is C _2-6 alkynyl.

In certain embodiments of formula II, R ³ is hydroxy-C _1-6 alkyl.

In certain embodiments of formula II, R ³ is C _1-6 alkoxy-C _1-6 alkyl.

In certain embodiments of formula II, R ³ is C _3-6 cycloalkyl optionally substituted one or more times with R ⁶ .

In certain embodiments of formula II, R ³ is C _3-6 cycloalkyl optionally substituted with C _1-6 alkyl.

In certain embodiments of formula II, R ³ is C _3-6 cycloalkyl-C _1-6 alkyl (the C _3-6 cycloalkyl moiety may be substituted one or more times with R ⁶ ).

In certain embodiments of formula II, R ³ is C _3-6 cycloalkyl-C _1-6 alkyl (the C _3-6 cycloalkyl moiety _optionally substituted with C _1-6 alkyl).

In certain embodiments of formula II, R ³ is heterocyclyl optionally substituted one or more times with R ⁷ .

In certain embodiments of formula II, R ³ is heterocyclyl.

In certain embodiments of formula II, R ³ is heterocyclyl-C _1-6 alkyl (optionally substituted one or more times with a heterocyclyl moiety R ⁷ ).

In certain embodiments of formula II, R ³ is heterocyclyl-C _1-6 alkyl.

In certain embodiments of formula II, R ³ is —C (O) —R ^{c, where} R ^c is C _1-6 alkyl, C _1-6 alkoxy, amino, or heterocyclyl.

In certain embodiments of formula II, R ³ is cyano-C _1-6 alkyl.

In certain embodiments of formula II, R ³ is C _1-6 alkylsulfonyl.

In certain embodiments of formula II, ^{R 3} is _{C 1-6} alkylsulfonyl -C _1-6 alkyl.

In certain embodiments of formula II, R ³ is amino-C _1-6 alkyl.

In certain embodiments of formula II, R ³ is aryl optionally substituted one or more times with R ⁸ .

In certain embodiments of formula II, R ³ is aryl.

In certain embodiments of formula II, R ³ is phenyl optionally substituted one or more times, or once or twice with R ⁸ .

In certain embodiments of formula II, R ³ is heteroaryl optionally substituted one or more times, or once or twice with R ⁸ .

In certain embodiments of formula II, R ³ is heteroaryl.

In certain embodiments of formula II, R ³ is C _3-6 cycloalkyl-sulfonyl (the C _3-6 cycloalkyl moiety may be substituted one or more times with R ⁶ ).

In certain embodiments of formula II, R ³ is: hydrogen; methyl; ethyl; propyl; isopropyl; butyl; cyclopropyl; cyclopropylmethyl; cyclobutyl; methanesulfonyl; ethylsulfonyl; cyclopropylsulfonyl; 4-Oxy-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 4- (cyclopropylsulfonyl) phenyl; 2,2,2-trifluoroethyl; 2-fluoroethyl; difluoromethyl; 2-dimethyl-1,3-dioxan-5-yl; 3-methylpyridin-4-yl; 2-methylpyridin-4-yl; pyridin-2-yl; pyrimidin-2-yl; pyrimidin-5-yl; pyridin-2-ylmethyl; -(Pyridin-2-yl) ethyl; cyclopropylsulfonyl; 1-cyano-1-methyl-ethyl (also called 2-cyano-propan-2-yl); 2-cyano-ethyl; 1-cyano-ethyl; -Cyano-2-methyl-propyl; 1- (2,2,2-trifluoroethyl) piperidin-4-yl; 1- (methylsulfonyl) azetidin-3-yl; (3-methyloxetane-3-yl) Methyl; (1S, 5S) -8-oxabicyclo [3. .1] Octane-3-yl; 1- (oxetane-3-yl) piperidin-4-yl; 1-acetyl-piperidin-4-yl; 1- (cyclopropyl-carbonyl) -piperidin-4-yl; -Methyl-piperidin-4-yl; 1-methyl-2-oxo-piperidin-5-yl; 2-oxo-piperidin-5-yl; 1- (isopropyl-carbonyl) -piperidin-4-yl; Oxetane-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- (oxetane-3-yl) piperidin-4-yl; 1-methoxypropan-2-yl; 1- (2,2 , 2-trifluoroethyl) azetidin-3-yl); 1- (oxetane-3-yl) Lolidine-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 -｀- yl-carbonyl; 1-siamo-cyclopropyl; Pyrrolidin -｀- yl-carbonyl) -ethyl; 1- (dimethylamino-carbonyl) -ethyl; 1- (methoxy-carbonyl) -ethyl; 1- (tert-butylamino-carbonyl) -1-methyl-ethyl; -(2,2,2-trifluoroethylamino-carbonyl) -1-methyl-ethyl; 1- (ethylamino-carbonyl) -1-methyl-ethyl; 1- (cyclopropylmethylamino-carbonyl) -1- 1- (ethylamino-carbonyl) -cyclobutyl; 1- (isopropylamino-carbonyl) -1-methyl-ethyl; 1-cyano-cyclobutyl; 2-methoxy-1-methyl-ethyl; 1-methyl- 1- (methoxy-carbonyl) -ethyl; 2-methoxy-2-methyl-propan-1-yl; 1- (oxetane-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; Methyl-pyridin-2-ylmethyl; 2- (morpholine- -Yl) -1,1, dimethyl-ethyl; pyrimdin-2-yl-methyl; 3-fluoro-1- (oxetane-3-yl) -piperidin-4-yl; 1- (oxetane-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 1-([1,3] dioxolan-2-ylmethyl) -pyrrolidin-3-yl; pyrimidin-4-ylmethyl; 1-methyl-1H-pyrazol-3-ylmethyl; Methyl-1- (4H- [1,2,4] triazol-3-yl) -ethyl; 1-methyl-1- (5-methyl-4H- [1,2,4] triazol-3-yl)- 3-fluoro-piperidin-4-yl; 2-hydroxy-cyclopentyl; dimethyl- [1,3] dioxane-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.

In certain embodiments of formula II, R ³ is: methyl; ethyl; propyl; isopropyl; butyl; cyclopropyl; cyclopropylmethyl; cyclobutyl; methanesulfonyl; ethylsulfonyl; cyclopropylsulfonyl; Oxetane-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-fluoro-phenyl; 4-chloro-phenyl; 3,5-difluorophenyl; 4- (dimethylamino-carb 4- (cyclopropylsulfonyl) phenyl; 2,2,2-trifluoroethyl; 2-fluoroethyl; difluoromethyl; 2-dimethyl-1,3-dioxane-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; (Pyridin-2-yl) ethyl; cyclopropylsulfonyl; 1-cyano-1-methyl-ethyl (also called 2-cyano-propan-2-yl); 2-cyano-ethyl; 1-cyano-ethyl; Cyano-2-methyl-propyl; 1- (2,2,2-trifluoroethyl) piperidin-4-yl; 1- (methylsulfonyl) azetidin-3-yl; (3-methyloxetane-3-yl) methyl ; (1S, 5S) -8-oxabicyclo [3.2.1] 1- (Oxetane-3-yl) piperidin-4-yl; 1-acetyl-piperidin-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- (isopropyl-carbonyl) -piperidin-4-yl; 1- (oxetane-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- (oxetane-3-yl) piperidin-4-yl; 1-methoxypropan-2-yl; 1- (2,2,2- Trifluoroethyl) azetidin-3-yl); 1- (oxetane-3-yl) pyrrole 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 -｀- yl-carbonyl; 1-siamo-cyclopropyl; Pyrrolidin -｀- yl-carbonyl) -ethyl; 1- (dimethylamino-carbonyl) -ethyl; 1- (methoxy-carbonyl) -ethyl; 1- (tert-butylamino-carbonyl) -1-methyl-ethyl; -(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- (methoxy- Carbonyl) -ethyl; 2-methoxy-2-methyl-propan-1-yl; 1- (oxetane-3-yl) -pyrrolidin-3-yl; isopropylsulfonyl; butane-2-sulfonyl; 1- (2-fluoro) Ethyl) -piperidin-4-yl; 3-fluoro-1-methyl-piperidin-4-yl; 1-ethyl-3-fluoro-piperidin-4-yl; pyridin-3-ylmethyl; 6-methyl-pyridin-2 -Ilmethyl; 2- (morpholin-1-yl ) -1,1, dimethyl-ethyl; pyrimdin-2-yl-methyl; 3-fluoro-1- (oxetan-3-yl) -piperidin-4-yl; 1- (oxetane-3-yl) -piperidine- 1-([1,3] dioxolan-2-ylmethyl) -piperidin-4-yl; pyridazine-3-ylmethyl; piperidin-3-yl; pyrazin-2-ylmethyl; 2-hydroxy-3-methyl 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-o Sadiazol-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.

In certain embodiments of formula II, R ³ 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.

In certain embodiments of Formula II, R ³ is: methyl; ethyl; n-propyl; isopropyl; 2-methoxy-ethyl; oxetane-3-yl; 2-hydroxy-2-methyl-propan-1-yl; It is pyran-4-yl.

In certain embodiments of formula II, R ³ is: methyl; ethyl; isopropyl; 2-methoxy-ethyl; oxetan-3-yl; or 2-hydroxy-2-methyl-propan-1-yl.

In certain embodiments of formula II, R ³ is: methyl; ethyl; isopropyl; 2-methoxy-ethyl; oxetan-3-yl; or 2-hydroxy-2-methyl-propan-1-yl.

In certain embodiments of formula II, R ³ is: methyl; ethyl; or isopropyl.

In certain embodiments of formula II, R ³ is hydrogen.

In certain embodiments of formula II, R ³ is methyl.

In certain embodiments of formula II, R ³ is ethyl.

In certain embodiments of formula II, R ³ is n-propyl.

In certain embodiments of formula II, R ³ is isopropyl.

In certain embodiments of formula II, R ³ is 2-methoxy-ethyl.

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

In certain embodiments of formula II, R ³ is 2-hydroxy-2-methyl-propan-1-yl.

In certain embodiments of formula II, R ³ is tetrahydropyran-4-yl.

In certain embodiments of formula II, R ³ is morpholin-4-yl-carbonyl.

In certain embodiments of formula II, R ³ is butyl.

In certain embodiments of formula II, R ³ is cyclopropyl.

In certain embodiments of formula II, R ³ is cyclopropylmethyl.

In certain embodiments of formula II, R ³ is cyclobutyl.

In certain embodiments of formula II, R ³ is methanesulfonyl.

In certain embodiments of formula II, R ³ is ethylsulfonyl.

In certain embodiments of formula II, R ³ is cyclopropylsulfonyl.

In certain embodiments of formula II, R ³ is sec-butylsulfonyl.

In certain embodiments of formula II, R ³ is morpholin-4-yl-ethyl.

In certain embodiments of formula II, R ³ is 2-hydroxy-2-methyl-propyl.

In certain embodiments of formula II, R ³ is 3-hydroxy-2-methyl-propan-2-yl.

In certain embodiments of formula II, R ³ is 2-methoxy-propyl.

In certain embodiments of formula II, R ³ is tetrahydro-2H-pyran-4-yl.

In certain embodiments of formula II, R ³ is tetrahydrofuran-3-yl.

In certain embodiments of formula II, R ³ is 2,6-dimethyltetrahydro-2H-pyran-4-yl.

In certain embodiments of formula II, R ³ is tetrahydro-2H-pyran-3-yl).

In certain embodiments of formula II, R ³ is phenyl.

In certain embodiments of formula II, R ³ is 4- (methylsulfonyl) phenyl).

In certain embodiments of formula II, R ³ is 4-cyano-phenyl.

In certain embodiments of formula II, R ³ is 4-fluoro-phenyl.

In certain embodiments of formula Iv, R ³ is 4-chloro-phenyl.

In certain embodiments of formula II, R ³ is 3,5-difluorophenyl.

In certain embodiments of formula II, R ³ is 4- (dimethylamino-carbonyl) -phenyl).

In certain embodiments of formula II, R ³ is 4- (cyclopropylsulfonyl) phenyl.

In certain embodiments of formula II, R ³ is 2,2,2-trifluoroethyl.

In certain embodiments of formula II, R ³ is 2-fluoroethyl.

In certain embodiments of formula II, R ³ is difluoromethyl.

In certain embodiments of formula II, R ³ is 2-dimethyl-1,3-dioxane-5-yl.

In certain embodiments of formula II, R ³ is 1-methyl-cyclopropyl-carbonyl.

In certain embodiments of formula II, R ³ is 3-methylpyridin-4-yl.

In certain embodiments of formula II, R ³ is 2-methylpyridin-4-yl.

In certain embodiments of formula II, R ³ is pyridin-2-yl.

In certain embodiments of formula II, R ³ is pyrimidin-2-yl.

In certain embodiments of formula II, R ³ is pyrimidin-5-yl.

In certain embodiments of formula II, R ³ is pyridin-2-ylmethyl.

In certain embodiments of formula II, R ³ is 1- (pyridin-2-yl) ethyl.

In certain embodiments of formula II, R ³ is cyclopropylsulfonyl.

In certain embodiments of formula II, R ³ is 1-cyano-1-methyl-ethyl (also referred to as 2-cyano-propan-2-yl).

In certain embodiments of formula II, R ³ is 2-cyano-ethyl.

In certain embodiments of formula II, R ³ is 1-cyano-ethyl.

In certain embodiments of formula II, R ³ is 2-cyano-2-methyl-propyl.

In certain embodiments of formula II, R ³ is 1- (2,2,2-trifluoroethyl) piperidin-4-yl.

In certain embodiments of formula II, R ³ is 1- (methylsulfonyl) azetidin-3-yl.

In certain embodiments of formula II, R ³ is (3-methyloxetane-3-yl) methyl.

In certain embodiments of formula II, R ³ is (1S, 5S) -8-oxabicyclo [3.2.1] octane-3-yl.

In certain embodiments of formula II, R ³ is 1- (oxetane-3-yl) piperidin-4-yl.

In certain embodiments of formula II, R ³ is 1-acetyl-piperidin-4-yl.

In certain embodiments of formula II, R ³ is 1- (cyclopropyl-carbonyl) -piperidin-4-yl.

In certain embodiments of formula II, R ³ is 1-methyl-piperidin-4-yl.

In certain embodiments of formula II, R ³ is 1-methyl-2-oxo-piperidin-5-yl.

In certain embodiments of formula II, R ³ is 2-oxo-piperidin-5-yl.

In certain embodiments of formula II, R ³ is 1- (isopropyl-carbonyl) -piperidin-4-yl.

In certain embodiments of formula II, R ³ is 1- (oxetane-3-yl) azetidin-3-yl.

In certain embodiments of formula II, R ³ is 1- (cyclopropyl-carbonyl) -piperidin-4-yl.

In certain embodiments of formula II, R ³ is 2-methoxycyclopentyl.

In certain embodiments of formula II, R ³ is 3-methoxycyclopentyl.

In certain embodiments of formula II, R ³ is 1-methoxy-2-methylpropan-2-yl.

In certain embodiments of formula II, R ³ is tetrahydro-2H-1,1-dioxo-thiopyran-4-yl.

In certain embodiments of formula II, R ³ is 3-fluoro-1- (oxetan-3-yl) piperidin-4-yl.

In certain embodiments of formula II, R ³ is 1-methoxypropan-2-yl.

In certain embodiments of formula II, R ³ is 1- (2,2,2-trifluoroethyl) azetidin-3-yl).

In certain embodiments of formula II, R ³ is 1- (oxetane-3-yl) pyrrolidin-3-yl.

In certain embodiments of formula II, R ³ is 1-isopropylazetidin-3-yl.

In certain embodiments of formula II, R ³ is 3-fluoro-1-methylpiperidin-4-yl.

In certain embodiments of formula II, R ³ is 1-ethyl-3-fluoropiperidin-4-yl.

In certain embodiments of formula II, R ³ is 1-methylpyrrolidin-3-yl.

In certain embodiments of formula II, R ³ is 2-methoxyethyl) piperidin-4-yl).

In certain embodiments of formula II, R ³ is 1-methyl-1- (methylamino-carbonyl) -ethyl.

In certain embodiments of formula II, R ³ is 2-methyl-2-morpholino-propyl.

In certain embodiments of formula II, R ³ is 4,4-difluorocyclohexyl.

In certain embodiments of formula II, R ³ is dimethylamino-carbonyl-methyl.

In certain embodiments of formula II, R ³ is methylamino-carbonyl-methyl.

In certain embodiments of formula II, R ³ is 1-methyl-1- (dimethylamino-carbonyl) -ethyl.

In certain embodiments of formula II, R ³ is pyrrolidin -｀- yl-carbonyl.

In certain embodiments of formula II, R ³ is 1-cyano-cyclopropyl.

In certain embodiments of formula II, R ³ is 1- (pyrrolidin -｀- yl-carbonyl) -ethyl.

In certain embodiments of formula II, R ³ is 1- (dimethylamino-carbonyl) -ethyl.

In certain embodiments of formula II, R ³ is 1- (methoxy-carbonyl) -ethyl.

In certain embodiments of formula II, R ³ is 1- (tert-butylamino-carbonyl) -1-methyl-ethyl.

In certain embodiments of formula II, R ³ is 1- (2,2,2-trifluoroethylamino-carbonyl) -1-methyl-ethyl.

In certain embodiments of formula II, R ³ is 1- (ethylamino-carbonyl) -1-methyl-ethyl.

In certain embodiments of formula II, R ³ is 1- (cyclopropylmethylamino-carbonyl) -1-methyl-ethyl.

In certain embodiments of formula II, R ³ is 1- (ethylamino-carbonyl) -cyclobutyl.

In certain embodiments of formula II, R ³ is 1- (isopropylamino-carbonyl) -1-methyl-ethyl.

In certain embodiments of formula II, R ³ is 1-cyano-cyclobutyl.

In certain embodiments of formula II, R ³ is dimethyl- [1,3] dioxan-5-yl.

In certain embodiments of formula II, R ³ is 2-methoxy-2-methyl-propan-1-yl.

In certain embodiments of formula II, R ³ is 2-methoxy-1-methyl-ethyl.

In certain embodiments of formula II, R ³ is 1-methyl-1- (methoxy-carbonyl) -ethyl.

In certain embodiments of formula II, R ³ is 1-oxetan-3-yl-pyrrolidin-3-yl.

In certain embodiments of formula II, R ³ is isopropylsulfonyl.

In certain embodiments of formula II, R ³ is butane-2-sulfonyl.

In certain embodiments of formula II, R ³ is 1- (2-fluoroethyl) -piperidin-4-yl.

In certain embodiments of formula II, R ³ is 3-fluoro-1-methyl-piperidin-4-yl.

In certain embodiments of formula II, R ³ is 1-ethyl-3-fluoro-piperidin-4-yl. In certain embodiments of formula II, R ³ is pyridin-3-ylmethyl.

In certain embodiments of formula II, R ³ is 6-methyl-pyridin-2-ylmethyl.

In certain embodiments of formula II, R ³ is 2- (morpholin-1-yl) -1,1, dimethyl-ethyl.

In certain embodiments of formula II, R ³ is pyrimdin-2-yl-methyl.

In certain embodiments of formula II, R ³ is 3-fluoro-1- (oxetan-3-yl) -piperidin-4-yl.

In certain embodiments of formula II, R ³ is 1- (oxetane-3-yl) -piperidin-3-yl.

In certain embodiments of formula II, R ³ is 1-([1,3] dioxolan-2-ylmethyl) -piperidin-4-yl.

In certain embodiments of formula II, R ³ is pyridazin-3-ylmethyl.

In certain embodiments of formula II, R ³ is piperidin-3-yl.

In certain embodiments of formula II, R ³ is pyrazin-2-ylmethyl.

In certain embodiments of formula II, R ³ is 2-hydroxy-3-methyl-butan-1-yl.

In certain embodiments of formula II, R ³ is 1-([1,3] dioxolan-2-ylmethyl) -pyrrolidin-3-yl.

In certain embodiments of formula II, R ³ is pyrimidin-4-ylmethyl.

In certain embodiments of formula II, R ³ is 1-methyl-1H-pyrazol-3-ylmethyl.

In certain embodiments of formula II, R ³ is 1-methyl-1- (5-methyl-4H- [1,2,4] triazol-3-yl) -ethyl.

In certain embodiments of formula II, R ³ is 1-methyl-1- (4H- [1,2,4] triazol-3-yl) -ethyl.

In certain embodiments of formula II, R ³ is 3-fluoro-piperidin-4-yl; 2-hydroxy-cyclopentyl.

In certain embodiments of formula II, R ³ is 2- (5-methyl-1,3,4-oxadiazol-2-yl) propan-2-yl.

In certain embodiments of formula II, R ³ is 2- (4-methyl-4H-1,2,4-triazol-3-yl) propan-2-yl.

In certain embodiments of formula II, R ³ is 2- (1-methyl-1H-1,2,4-triazol-3-yl) propan-2-yl.

In certain embodiments of formula II, R ³ is 2- (1-methyl-1H-pyrazol-4-yl) propan-2-yl; 2- (1-methyl-1H-pyrazol-3-yl) propane-2 -Ill.

In certain embodiments of formula II, R ³ is 2- (1-methyl-1H-pyrazol-5-yl.

In certain embodiments of formula II, R ³ is 2- (4H-1,2,4-triazol-3-yl) propan-2-yl.

In certain embodiments of formula II, R ³ is 1-methyl-1H-pyrazol-4-yl.

In embodiments of Formula II where R ³ is aryl, such aryl is unsubstituted phenyl or one or more times in R ⁸ , in certain embodiments, C _1-6 alkyl, halo, halo-C It may be phenyl substituted 1, 2 or 3 times with a group (s) independently selected from _1-6 alkyl, C _1-6 alkoxy, hydroxy or cyano.

In embodiments of Formula II wherein R ³ is heteroaryl or heteroaryl-C _1-6 alkyl, such heteroaryl moieties are pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, isoxazolyl, It can be isothiazolyl, triazolyl, oxadialyl, thiadiazolyl or tetrazolyl, each of which is unsubstituted or substituted once or twice with R ⁸ , or in certain embodiments, once or twice with C _1-6 alkyl. Has been replaced.

In embodiments of formula II wherein R ³ is heteroaryl or heteroaryl-C _1-6 alkyl, such heteroaryl moieties can be pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl or oxadialyl, each It is substituted or substituted once or twice with R ⁸ , or in certain embodiments, substituted once or twice with C _1-6 alkyl.

In embodiments of Formula II wherein R ³ is heteroaryl or heteroaryl-C _1-6 alkyl, such heteroaryl moieties can be pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl. Each is unsubstituted or substituted one or more times by R ⁸ .

In embodiments of Formula II wherein R ³ is heterocyclyl, such heterocyclyl moieties can be piperidinyl, pyrrolidinyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, [1,3] dioxolanyl or tetrahydrothiopyranyl, each Is unsubstituted or substituted one or more times by R ⁷ .

In embodiments of Formula II wherein R ³ is heterocyclyl-C _1-6 alkyl, such heterocyclyl moieties are piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, [1,3 ] be a dioxolanyl or tetrahydrothiopyranyl, each of which is substituted one or more times with or is R ⁷ is unsubstituted.

In certain embodiments of formula II, R ³ is —Y—C (O) —R ^d .

  In certain embodiments of formula II, Y is a bond.

In certain embodiments of formula II, Y is C _2-6 alkylene.

  In certain embodiments of formula II, Y is isopropylidine.

  In certain embodiments of formula II, Y is methylene.

  In certain embodiments of formula II, Y is ethylene.

In certain embodiments of formula II, Y is —C (CH ₃ ) ₂ —.

In certain embodiments of formula II, Y is —CH ₂ —.

In certain embodiments of formula II, Y is —CH (CH ₃ ) —.

In certain embodiments of formula II, Y is —CH ₂ —C (CH ₃ ) ₂ —.

In certain embodiments of formula II, Y is —C (CH ₃ ) ₂ —CH ₂ —.

In certain embodiments of formula II, R ^d is C _1-6 alkyl, C _1-6 alkoxy, amino, or heterocyclyl.

In certain embodiments of formula II, R ^d is C _1-6 alkyl.

In certain embodiments of formula II, R ^d is C _1-6 alkoxy.

In certain embodiments of formula II, R ^d is amino.

In certain embodiments of formula II, R ^d is halo-C _1-6 alkyl.

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

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

In certain embodiments of formula II, R ^d is cyano-C _1-6 alkyl.

In certain embodiments of formula II, R ^d is C _1-6 alkylsulfonyl C _1-6 alkyl.

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

In certain embodiments of formula II, R ^d is C _3-6 cycloalkyl optionally substituted one or more times with R ⁶ .

In certain embodiments of formula II, R ^d is C _3-6 cycloalkyl-C _1-6 alkyl (the C _3-6 cycloalkyl moiety may be substituted one or more times with R ⁶ ).

In certain embodiments of formula II, R ^d is heterocyclyl optionally substituted one or more times with R ⁷ .

In certain embodiments of formula II, R ^d is heterocyclyl-C _1-6 alkyl (optionally substituted one or more times with a heterocyclyl moiety R ⁷ ).

In certain embodiments of formula II, R ^d is 1-methyl-cyclopropyl; methylamino; dimethylamino; pyrrolidin-1-yl; methoxy; cyclopropyl-methyl; ethyl; 2,2,2-trifluoro-ethyl; tert-butyl; or isopropyl.

In certain embodiments of formula II, R ^d is 1-methyl-cyclopropyl.

In certain embodiments of formula II, R ^d is methylamino.

In certain embodiments of formula II, R ^d is dimethylamino.

In certain embodiments of formula II, R ^d is pyrrolidin-1-yl.

In certain embodiments of formula II, R ^d is methoxy.

In certain embodiments of formula II, R ^d is cyclopropyl-methyl.

In certain embodiments of formula II, R ^d is ethyl.

In certain embodiments of formula II, R ^d is 2,2,2-trifluoro-ethyl.

In certain embodiments of formula II, R ^d is tert-butyl.

In certain embodiments of formula II, R ^d is isopropyl.

In embodiments of Formula II wherein R ^d is heterocyclyl or heterocyclyl-C _1-6 alkyl, such heterocyclyl can be piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, pyrrolidinyl, azetidinyl, tetrahydrofuranyl or oxetanyl, each R ⁷ as defined herein may be substituted one or more times, or once or twice.

In embodiments of Formula II wherein R ^d is heterocyclyl, such heterocyclyl moieties can be piperidinyl, pyrrolidinyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, [1,3] dioxolanyl, or tetrahydrothiopyranyl, each Is unsubstituted or substituted one or more times by R ⁷ .

In embodiments of Formula II wherein R ^d is heterocyclyl-C _1-6 alkyl, such heterocyclyl moieties are piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, [1,3 ] be a dioxolanyl or tetrahydrothiopyranyl, each of which is substituted one or more times with or is R ⁷ is unsubstituted.

In certain embodiments of formula II, R ⁴ is: hydrogen; C _1-6 alkyl; halo; halo-C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; hydroxy-C _1-6 alkyl; C _3-6 cycloalkyl optionally substituted with C _1-6 alkyl; C _3-6 cycloalkyl-C _1-6 alkyl (the C _3-6 cycloalkyl moiety is substituted with C _1-6 alkyl; Or —C (O) —R ^{c, where} R ^c is C _1-6 alkyl, C _1-6 alkoxy, amino, or heterocyclyl.

In certain embodiments of formula II, ^{R 4} is: _{C 1-6} alkyl; halo; halo -C _1-6 alkyl; _{C 1-6} alkoxy -C _1-6 alkyl; hydroxy -C _1-6 alkyl; _{C 1} C _3-6 cycloalkyl optionally substituted with _-6 alkyl; C _3-6 cycloalkyl-C _1-6 alkyl (the C _3-6 cycloalkyl moiety may be substituted with C _1-6 alkyl) Or —C (O) —R ^{c, where} R ^c is C _1-6 alkyl, C _1-6 alkoxy, amino, or heterocyclyl.

In certain embodiments of formula II, R ⁴ is: hydrogen; C _1-6 alkyl; halo; C _3-6 cycloalkyl optionally substituted with C _1-6 alkyl; C _3-6 cycloalkyl-C _{1 -6} alkyl (C _3-6 cycloalkyl moiety may be substituted with C _1-6 alkyl); or -C (O) -R ^c (R ^c is C _1-6 alkyl, C _1-6 alkoxy) , Amino, or heterocyclyl).

In certain embodiments of formula II, R ⁴ is: hydrogen; C _1-6 alkyl; halo; or C _3-6 cycloalkyl optionally substituted with C _1-6 alkyl.

In certain embodiments of formula II, R ⁴ is hydrogen or C _1-6 alkyl.

In certain embodiments of formula II, R ⁴ is hydrogen.

In certain embodiments of formula II, R ⁴ is C _1-6 alkyl.

In certain embodiments of formula II, R ⁴ is halo.

In certain embodiments of formula II, R ⁴ is cyano.

In certain embodiments of formula II, R ⁴ is halo-C _1-6 alkyl.

In certain embodiments of formula II, R ⁴ is C _1-6 alkoxy-C _1-6 alkyl.

In certain embodiments of formula II, R ⁴ is hydroxy-C _1-6 alkyl.

In certain embodiments of formula II, R ⁴ is C _3-6 cycloalkyl optionally substituted with C _1-6 alkyl.

In certain embodiments of formula II, R ⁴ is hydrogen or methyl.

In certain embodiments of formula II, R ⁴ is C _3-6 cycloalkyl-C _1-6 alkyl (the C _3-6 cycloalkyl moiety _optionally substituted with C _1-6 alkyl).

In certain embodiments of formula II, R ⁴ is —C (O) —R ^{c, where} R ^c is C _1-6 alkyl, C _1-6 alkoxy, amino, or heterocyclyl.

In certain embodiments of formula II, R ⁴ is —C (O) —R ^{c, where} R ^c is heterocyclyl.

In embodiments of Formula II where R ^c is heterocyclyl, such heterocyclyl can be pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.

In embodiments of Formula II wherein R ^c is heterocyclyl, such heterocyclyl can be piperidinyl, piperazinyl or morpholinyl.

In certain embodiments of formula II, R ⁴ is: hydrogen; methyl; isopropyl; cyclopropyl; chloro; or morpholin-4-yl-carbonyl.

In certain embodiments of formula II, R ⁴ is: hydrogen; methyl; isopropyl; cyclopropyl; or chloro.

In certain embodiments of formula II, R ⁴ is hydrogen.

In certain embodiments of formula II, R ⁴ is methyl.

In certain embodiments of formula II, R ⁴ is isopropyl.

In certain embodiments of formula II, R ⁴ is cyclopropyl.

In certain embodiments of formula II, R ⁴ is chloro.

In certain embodiments of formula II, R ⁴ is morpholin-4-yl-carbonyl.

In certain embodiments of formula II, R ⁴ is 2-fluoro-ethyl.

In certain embodiments of formula II, R ⁴ is C _3-6 cycloalkyl optionally substituted one or more times, or once or twice with R ⁶ .

In certain embodiments of formula II, R ⁴ is C _3-6 cycloalkyl-C _1-6 alkyl (the C _3-6 cycloalkyl moiety may be substituted one or more times, or once or twice, with R ^6. Good).

In certain embodiments of formula II, R ⁴ is —Y—C (O) —R ^d .

In certain embodiments of formula II, or R ³ and R ⁴ together with the atoms to which they are attached, a 5- or 6-membered ring optionally containing a heteroatom selected from O, N and S Can be formed.

In certain embodiments of formula II, R ⁵ is hydrogen.

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

In certain embodiments of formula II, R ⁵ is methyl.

In certain embodiments of formula II, each R ⁶ is independently C _1-6 alkyl; halo-C _1-6 alkyl; C _1-6 alkoxy; cyano; or halo.

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

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

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

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

In certain embodiments of formula II, R ⁶ is cyano.

In certain embodiments of formula II, R ⁶ is halo.

In certain embodiments of formula II, R ⁶ is Y—C (O) —R ^d .

In certain embodiments of formula II, R ⁶ is oxo.

In certain embodiments of formula II, each R ⁷ is independently C _1-6 alkyl; halo-C _1-6 alkyl; halo; C _1-6 alkylsulfonyl; C _1-6 alkoxy-C _1-6 alkyl; Cyano; heterocyclyl; or C _3-6 cycloalkylsulfonyl (the C _3-6 cycloalkyl moiety may be substituted one or more times by R ⁶ ).

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

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

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

In certain embodiments of formula II, R ⁷ is C _1-6 alkylsulfonyl.

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

In certain embodiments of formula II, R ⁷ is cyano.

In certain embodiments of formula II, R ⁷ is —Y—C (O) —R ^d .

In certain embodiments of formula II, R ⁷ is heterocyclyl.

In certain embodiments of formula II, R ⁷ is C _3-6 cycloalkylsulfonyl (the C _3-6 cycloalkyl moiety may be substituted one or more times with R ⁶ ).

In certain embodiments of formula II, R ⁷ is oxo.

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

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

In certain embodiments of formula II, R ⁷ is C _3-6 cycloalkyl.

In certain embodiments of formula II, R ⁷ is C _3-6 cycloalkyl-C _1-6 alkyl.

In certain embodiments of formula II wherein R ⁷ is heterocyclyl, such heterocyclyl moieties can be piperidinyl, pyrrolidinyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, [1,3] dioxolanyl or tetrahydrothiopyranyl. .

In certain embodiments of formula II wherein R ⁷ is heterocyclyl-C _1-6 alkyl, such heterocyclyl moieties are piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, [1 , 3] dioxolanyl or tetrahydrothiopyranyl.

In certain embodiments of formula II, each R ⁸ is independently oxo; C _1-6 alkyl; halo-C _1-6 alkyl; halo; C _1-6 alkoxy; C _1-6 alkoxy-C _1-6 alkyl Cyano; C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-6 alkyl optionally substituted one or more times with R ⁶ (wherein the C _3-6 cycloalkyl moiety is one or more with R ⁶ ; C _3-6 cycloalkyl-sulfonyl (the C _3-6 cycloalkyl moiety may be substituted one or more times with R ⁶ ).

In certain embodiments of formula II, R ⁸ is oxo. In certain embodiments of formula II, R ⁷ is C _1-6 alkyl.

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

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

In certain embodiments of formula II, R ⁷ is cyano.

In certain embodiments of formula II, R ⁷ is heterocycle.

In certain embodiments of formula II, R ⁷ is —Y—C (O) —R ^d .

In certain embodiments of formula II, R ⁷ is C _3-6 cycloalkyl optionally substituted one or more times with R ⁶ .

In certain embodiments of formula II, R ⁷ is C _3-6 cycloalkyl-C _1-6 alkyl (the C _3-6 cycloalkyl moiety may be substituted one or more times with R ⁶ ).

In certain embodiments of formula II, R ⁷ is C _3-6 cycloalkyl-sulfonyl (the C _3-6 cycloalkyl moiety may be substituted one or more times with R ⁶ ).

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

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

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

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

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

In certain embodiments of formula II, R ⁸ is C _1-6 alkoxy.

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

In certain embodiments of formula II, R ⁸ is cyano; heterocycle.

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

In certain embodiments of formula II, R ⁸ is —Y—C (O) —R ^d .

In certain embodiments of formula II, R ⁸ is C _3-6 cycloalkyl.

In certain embodiments of formula II, R ⁸ is C _3-6 cycloalkyl-C _1-6 alkylC _3-6 cycloalkyl-sulfonyl.

In embodiments of Formula II wherein R ⁸ is heterocyclyl, such a heterocyclyl moiety can be piperidinyl, pyrrolidinyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, [1,3] dioxolanyl, or tetrahydrothiopyranyl.

R ⁸ is heterocyclyl -C 1 _- In the formula II embodiments from ₆ alkyl, such heterocyclyl moiety, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, [1, 3] Dioxolanyl or tetrahydrothiopyranyl.

In certain embodiments of formula II, the compound is
N ² -(1,5-Dimethyl-1H-pyrazol-4-yl) -N ⁴ -Methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine
N ⁴ -Methyl-N ² -(1- (2-morpholinoethyl) -1H-pyrazol-4-yl) -5- (trifluoromethyl) pyrimidine-2,4-diamine
N ⁴ -Methyl-N ² -(1-Methyl-1H-pyrazol-4-yl) -5- (trifluoromethyl) pyrimidine-2,4-diamine
5-Chloro-N ² -(1-Isopropyl-1H-pyrazol-4-yl) -N ⁴ -Methylpyrimidine-2,4-diamine
N ⁴ -Methyl-N ² -(1-Methyl-1H-pyrazol-5-yl) -5- (trifluoromethyl) pyrimidine-2,4-diamine
N ⁴ -Methyl-N ² -(1-Methyl-1H-pyrazol-3-yl) -5- (trifluoromethyl) pyrimidine-2,4-diamine
N ² -(1,3-Dimethyl-1H-pyrazol-4-yl) -N ⁴ -Methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine
5-Chloro-N- (1,5-dimethyl-1H-pyrazol-4-yl) -4- (tetrahydro-2H-pyran-4-yloxy) pyrimidin-2-amine
N ⁴ -Methyl-5- (trifluoromethyl) -N ² -(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
N ² -(1-Ethyl-5-methyl-1H-pyrazol-4-yl) -N ⁴ -Methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine
5-Chloro-N- (1,3-dimethyl-1H-pyrazol-4-yl) -4-methoxypyrimidin-2-amine
N ⁴ -Methyl-N ² -(3-Methyl-1- (oxetane-3-yl) -1H-pyrazol-4-yl) -5- (trifluoromethyl) pyrimidine-2,4-diamine
N ² -(5-Chloro-1-methyl-1H-pyrazol-4-yl) -N ⁴ -Methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine
5-Chloro-4-methoxy-N- (3-methyl-1- (oxetane-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-amine
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
N ² -(1- (2-Methoxyethyl) -3-methyl-1H-pyrazol-4-yl) -N ⁴ -Methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine
N ² -(1- (2-Methoxyethyl) -5-methyl-1H-pyrazol-4-yl) -N ⁴ -Methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine
5-Chloro-N- (1-ethyl-3-methyl-1H-pyrazol-4-yl) -4-methoxypyrimidin-2-amine
5-Chloro-N ⁴ -Methyl-N ² -(3-Methyl-1- (oxetane-3-yl) -1H-pyrazol-4-yl) pyrimidine-2,4-diamine
N ² -(1-Isopropyl-3-methyl-1H-pyrazol-4-yl) -N ⁴ -Methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine
5-Chloro-N- (1-isopropyl-3-methyl-1H-pyrazol-4-yl) -4-methoxypyrimidin-2-amine
5-Chloro-N ² -(1,3-Dimethyl-1H-pyrazol-4-yl) -N ⁴ -Methylpyrimidine-2,4-diamine
5-Chloro-N ² -(1-Isopropyl-3-methyl-1H-pyrazol-4-yl) -N ⁴ -Methylpyrimidine-2,4-diamine
N ⁴ -Methyl-N ² -(3-Methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) -5- (trifluoromethyl) pyrimidine-2,4-diamine
N ⁴ -Methyl-N ² -(5-Methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) -5- (trifluoromethyl) pyrimidine-2,4-diamine
N ² -(2-Ethyl-2H-pyrazol-3-yl) -5-fluoro-N ⁴ -Methyl-pyrimidine-2,4-diamine
5-Fluoro-N ⁴ -Methyl-N ² -(2-Methyl-2H-pyrazol-3-yl) -pyrimidine-2,4-diamine
5-Fluoro-N ⁴ -Methyl-N ⁴ -(2-Propyl-2H-pyrazol-3-yl) -pyrimidine-2,4-diamine
N ² -(2,5-Dimethyl-2H-pyrazol-3-yl) -5-fluoro-N ⁴ -Methyl-pyrimidine-2,4-diamine
N ² -(3-Isopropyl-1-methyl-1H-pyrazol-5-yl) -N ⁴ -Methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine
5-Chloro-N- (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) -4-methoxypyrimidin-2-amine
N ² -(3-Cyclopropyl-1-methyl-1H-pyrazol-5-yl) -N ⁴ -Methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine
5-Chloro-N- (3-isopropyl-1-methyl-1H-pyrazol-5-yl) -4-methoxypyrimidin-2-amine
5-Chloro-N ² -(5-Isopropyl-2-methyl-2H-pyrazol-3-yl) -N ⁴ -Methyl-pyrimidine-2,4-diamine
5-Chloro-4-methoxy-N- (1,3,5-trimethyl-1H-pyrazol-4-yl) pyrimidin-2-amine
5-Chloro-N ⁴ -Methyl-N ² -(1,3,5-Trimethyl-1H-pyrazol-4-yl) -pyrimidine-2,4-diamine
5-Chloro-N ² -(5-Cyclopropyl-2-methyl-2H-pyrazol-3-yl) -N ⁴ -Methyl-pyrimidine-2,4-diamine
N ⁴ -Methyl-N ² -(5-Methyl-1-oxetane-3-yl-1H-pyrazol-4-yl) -5-trifluoromethyl-pyrimidine-2,4-diamine
N ² -(1-Isopropyl-1H-pyrazol-5-yl) -N ⁴ -Methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine
5-Chloro-N- (1-ethyl-5-methyl-1H-pyrazol-4-yl) -4-methoxypyrimidin-2-amine
5-Chloro-N ² -(1-Ethyl-5-methyl-1H-pyrazol-4-yl) -N ⁴ -Methylpyrimidine-2,4-diamine
N ² -(1-Ethyl-3-methyl-1H-pyrazol-4-yl) -N ⁴ -Methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine
5-Chloro-N ² -(1-Ethyl-3-methyl-1H-pyrazol-4-yl) -N ⁴ -Methylpyrimidine-2,4-diamine
5-Chloro-N ² -(1-Isopropyl-1H-pyrazol-5-yl) -N ⁴ -Methylpyrimidine-2,4-diamine
5-Chloro-N- (1-isopropyl-1H-pyrazol-5-yl) -4-methoxypyrimidin-2-amine
5-Chloro-4-methoxy-N- (3-methyl-1- (methylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-2-amine
N ² -(1-Ethyl-1H-pyrazol-3-yl) -N ⁴ -Methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine
5-Chloro-4-methoxy-N- (5-methyl-1-phenyl-1H-pyrazol-4-yl) pyrimidin-2-amine
N ² -(1-Isopropyl-1H-pyrazol-3-yl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine
N ⁴ -Methyl-N ² -(5-Methyl-1- (2,2,2-trifluoroethyl) -1H-pyrazol-4-yl) -5- (trifluoromethyl) pyrimidine-2,4-diamine
N ² -(1- (2,2-dimethyl-1,3-dioxan-5-yl) -3-methyl-1H-pyrazol-4-yl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine
5-Chloro-4-methoxy-N- (5-methyl-1- (4- (methylsulfonyl) phenyl) -1H-pyrazol-4-yl) pyrimidin-2-amine
N ⁴ -Ethyl-N ² -(1-Methyl-1H-pyrazol-3-yl) -5- (trifluoromethyl) pyrimidine-2,4-diamine
5-Chloro-N- (1,5-dimethyl-1H-pyrazol-4-yl) -4- (oxetane-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- (cyclopropylsulfonyl) -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- (tetrahydro-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
N ² -(5-Methoxy-1-methyl-1H-pyrazol-4-yl) -N ⁴ -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
N ² -[1- (1- [1,3] Dioxolan-2-ylmethyl-piperidin-4-yl) -5-methyl-1H-pyrazol-4-yl] -N ⁴ -Ethyl-5-trifluoromethyl-pyrimidine-2,4-diamine
N ² -[1- (1- [1,3] Dioxolan-2-ylmethyl-piperidin-4-yl) -3-methyl-1H-pyrazol-4-yl] -N ⁴ -Ethyl-5-trifluoromethyl-pyrimidine-2,4-diamine
N ² -(1,3-Dimethyl-1H-pyrazol-4-yl) -5-iodo-N ⁴ -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) Pyrimidine-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- (oxetane-3-yl) -1H-pyrazol-4-yl) -5- (trifluoromethyl) pyrimidine-2,4-diamine
5-Chloro-N4-ethyl-N2- (3-methyl-1- (oxetane-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
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- (oxetane-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-pyrazol-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-methyloxetane-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-methyloxetane-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-((1S, 5S) -8-oxabicyclo [3.2.1] octane-3-yl) -3-methyl-1H-pyrazol-4-yl) -N4-methyl-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- (oxetane-3-yl) piperidin-4-yl) -1H-pyrazol-4-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine
N4-methyl-N2- (5-methyl-1- (1- (oxetane-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-pyrazol-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-methyloxetane-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-pyrazol-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- (methylsulfonyl) 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- (oxetane-3-yl) -1H-pyrazol-4-yl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2,4-diamine
N4-ethyl-N2- (5-methyl-1-((3-methyloxetane-3-yl) methyl) -1H-pyrazol-4-yl) -5- (trifluoromethyl) pyrimidine-2,4-diamine
N2- (1- (cyclopropylsulfonyl) -3-methyl-1H-pyrazol-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
5-Chloro-4-methyl-N- (3-methyl-1- (4- (methylsulfonyl) phenyl) -1H-pyrazol-4-yl) pyrimidin-2-amine
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) piperidine-1- Il) 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-methyloxetane-3-yl) methyl) -1H-pyrazol-4-yl) -5- (trifluoromethyl) pyrimidine-2,4-diamine
N2- (5-Chloro-1-((3-methyloxetane-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- (oxetane-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
N4-ethyl-N2- (1-ethyl-1H-pyrazol-3-yl) -5- (trifluoromethyl) pyrimidine-2,4-diamine
(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
2-Methyl-1- (4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -5- (trifluoromethyl) -1H-pyrazol-1-yl) propane-2 -All
2-Methyl-1- (4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -3- (trifluoromethyl) -1H-pyrazol-1-yl) propane-2 -All
N2- (1- (3-Fluoro-1- (oxetane-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
1- (3-tert-butyl-4- (4- (ethylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -1H-pyrazol-1-yl) -2-methylpropan-2-ol
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- (oxetane-3-yl) pyrrolidin-3-yl) -1H-pyrazol-4-yl) -5- (trifluoromethyl) Pyrimidine-2,4-diamine
(R) -N2- (1- (1-methoxypropan-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- (oxetane-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-pyrazole-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- (pyridin-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) pyrimidine-2,4- Diamine
1- (5-Chloro-4- (4- (ethylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -1H-pyrazol-1-yl) -2-methylpropan-2-ol
1- (3-Cyclopropyl-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -1H-pyrazol-1-yl) -2-methylpropan-2-ol
1- (3-Cyclopropyl-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
N4-methyl-N2- (3-methyl-1- (2-methyl-2-morpholinopropyl) -1H-pyrazol-4-yl) -5- (trifluoromethyl) pyrimidine-2,4-diamine
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
N ² -(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-pyrazol-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-propane -1-on
1- {4- [4- (4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -3-methyl-pyrazol-1-yl] -piperidin-1-yl} -2-methyl-propane -1-on
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-oxetane-3-yl-pyrrolidin-3-yl) -1H-pyrazol-4-yl] -5-trifluoromethyl-pyrimidine- 2,4-diamine
N4-methyl-N2- [5-methyl-1-((S) -1-oxetane-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- [5-methyl-1- (2-methyl-2-morpholin-4-yl-propyl) -1H-pyrazol-4-yl] -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
N2- (1-cyclopropanesulfonyl-3-cyclopropyl-1H-pyrazol-4-yl) -N4-methyl-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-pyrazol-1-yl] -2-methyl-propan-2-ol
N2- [1- (1,1-dimethyl-2-morpholin-4-yl-ethyl) -3-methyl-1H-pyrazol-4-yl] -N4-ethyl-5-trifluoromethyl-pyrimidine-2, 4-diamine
N2- [1- (1,1-dimethyl-2-morpholin-4-yl-ethyl) -3-methyl-1H-pyrazol-4-yl] -N4-methyl-5-trifluoromethyl-pyrimidine-2, 4-diamine
N2- [1- (3-Fluoro-1-methyl-piperidin-4-yl) -3-methyl-1H-pyrazol-4-yl] -N4-methyl-5-trifluoromethyl-pyrimidine-2,4- Diamine
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-isobutyric acid amide
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-oxetane-3-yl-piperidin-4-yl) -1H-pyrazol-4-yl] -N4-methyl-5-trifluoromethyl-pyrimidine- 2,4-diamine
N2- [5-Chloro-1- (3-fluoro-1-oxetane-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-oxetane-3-yl-piperidin-3-yl) -1H-pyrazol-4-yl] -5-trifluoromethyl-pyrimidine- 2,4-diamine
N4-ethyl-N2- [3-methyl-1-((S) -1-oxetane-3-yl-piperidin-3-yl) -1H-pyrazol-4-yl] -5-trifluoromethyl-pyrimidine- 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-trifluoromethyl-pyrimidin-2-ylamino) -pyrazol-1-yl] -2,2-dimethyl-propionitrile
N4-ethyl-N2- [1- (3-fluoro-1-oxetane-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) -pyrazol-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] triazol-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-pyrazole-4- Il} -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- (trifluoro Methyl) 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- (trifluoro Methyl) 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- (trifluoro Methyl) 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- (trifluoro Methyl) 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- (trifluoro Methyl) 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- (trifluoro Methyl) 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- (4 (H-1,2,4-triazol-3-yl) propan-2-yl) -3-methyl-1H-pyrazol-4-yl) -N4-methyl-5- ( Trifluoromethyl) pyrimidine-2,4-diamine
2- (1,3-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-carbo Nitrile
2- (5-Methyl-1- (1- (2,2,2-trifluoroethyl) piperidin-4-yl) -1H-pyrazol-4-ylamino) -4- (methylamino) pyrimidine-5-carbo Nitrile
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- (Difluoromethyl) -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- (oxetane-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- (oxetane-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-pyrimidine-5-carbonitrile
4-Methylamino-2- (3-methyl-1-propyl-1H-pyrazol-4-ylamino) -pyrimidine-5-carbonitrile
4-Methylamino-2- (5-methyl-1-oxetane-3-yl-1H-pyrazol-4-ylamino) -pyrimidine-5-carbonitrile
4-Methylamino-2- (3-methyl-1-oxetane-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
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-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- (pyrrolidine-1 -Il) 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-pyrazol-1-yl) cyclopropanecarbonitrile
(R) -2- (3-Methyl-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -1H-pyrazol-1-yl) -1- (pyrrolidine-1 -Il) Propan-1-one
(R) -N, N-dimethyl-2- (3-methyl-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -1H-pyrazol-1-yl) propane Amide
(S) -2- (3-Methyl-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -1H-pyrazol-1-yl) -1- (pyrrolidine-1 -Il) Propan-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
2- (3-Ethyl-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -1H-pyrazol-1-yl) -2-methylpropanenitrile
(R) -2- (5-Methyl-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -1H-pyrazol-1-yl) -1- (pyrrolidine-1 -Il) Propan-1-one
(R) -N, N-dimethyl-2- (5-methyl-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -1H-pyrazol-1-yl) propane Amide
(S) -2- (5-Methyl-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -1H-pyrazol-1-yl) -1- (pyrrolidine-1 -Il) Propan-1-one
(S) -N, N-dimethyl-2- (5-methyl-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -1H-pyrazol-1-yl) propane Amide
(S) -2- (5-Methyl-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -1H-pyrazol-1-yl) propanenitrile
(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- (3-Cyclopropyl-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) propane Amide
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-pyrazol-1-yl) -N-ethyl-2-methylpropanamide
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- [4- (5-Chloro-4-methoxy-pyrimidin-2-ylamino) -5-methyl-pyrazol-1-yl] -2-methyl-propionic acid methyl ester
2- [4- (5-Chloro-4-methoxy-pyrimidin-2-ylamino) -3-methyl-pyrazol-1-yl] -2-methyl-propionic acid methyl ester
(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] -isobutyric acid amide
N-ethyl-2- [5-methyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -pyrazol-1-yl] -isobutyric acid amide
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)- Isobutyric acid amide
N-isopropyl-2- [3-methyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -pyrazol-1-yl] -isobutyric acid amide
N-methyl-2- [5-methyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -pyrazol-1-yl] -isobutyric acid amide
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] -isobutyric acid amide
2- [4- (4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -5-methyl-pyrazol-1-yl] -N-methyl-isobutyric acid amide
2- [4- (4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -3-methyl-pyrazol-1-yl] -N-methyl-isobutyric acid amide
2- [4- (4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -5-methyl-pyrazol-1-yl] -N-methyl-isobutyric acid amide
2- [4- (4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -3-methyl-pyrazol-1-yl] -2-methyl-propionitrile or
2- (3-Chloro-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -1H-pyrazol-1-yl) -2-methylpropanenitrile
It can be.

Experimental Example Mass Spectroscopy The excised gel pieces were reduced, alkylated and subjected to trypsin digestion overnight. For phosphomapping analysis, digested peptides were extracted, dried and resuspended in 10% acetonitrile / 5% formic acid. For quantitative analysis, a mixture of isotopically labeled internal standard peptides (Cell Signaling Technologies, Danvers, MA) was introduced into a digested gel piece prior to peptide extraction, and then after extraction, for complete oxidation of peptides with methionine. The dried peptide was resuspended in 3% acetonitrile / 5% formic acid / 10% H ₂ O ₂ at least 30 minutes prior to analysis. Peptides were separated using a standard gradient consisting of H ₂ O / acetonitrile / formic acid delivered by nanoAcquity UPLC (Waters, Milford MA) and LTQ-Orbitrap XL (Thermo, San Jose, CA) using the conditions described above. It was analyzed in a mass spectrometer (Phu and Kirkpatrick, Mol cell Proteomics 2011). In this study, the mass spectrometer was performed in a data dependent mode with a 60,000 resolution full MS scan collected in an Orbitrap and MS / MS for the eight highest intensity ions collected in an ion trap. Spectral data was converted to mzxml, searched against the human Uniprot database using a target-decoy strategy, and approximately filtered to 5% FDR using linear discriminant analysis (Huttlin and Gygi, Cell 2011). The localization of putative phosphorylation sites was optimized and a confidence score was assigned using the AScore algorithm (Beausoliel and Gygi, Nat Biotech 2006), with scores of 13 and 19 representing 95% and 99% confidence levels, respectively. No consensus phosphopeptide (Ascore <13) with uncertain localization was reported. The remaining peptide-spectrum match required manual validation of at least one representative spectrum for each unique phosphopeptide sequence for inclusion here. For quantitative analysis, full MS scans were integrated using Qualbrowser software (Thermo, San Jose, Calif.) To determine peak areas for the most abundant charged state heavy and light m / z ions of each LRRK2 phosphopeptide.

Western blotting Cultured cells and mouse brain were treated with RIPA buffer (25 mM Tris-HCl (pH 7.6), 150 mM NaCl, 1% NP-40, 1% sodium deoxycholate, 0.1% with Complete protease and phosphotase inhibitor cocktail (Roche). Homogenized in SDS). Cell / tissue lysates were cleared by centrifugation at 20,000 g for 30 minutes at 4 ° C. The protein concentration of the supernatant was measured using the BCA assay (Pierce). 20 ug of lysate was loaded on 3-8% Tris-Acetate gel or 4-12% Bis-Tris gel (Invitrogen) and the following antibodies: Phosphate-LRRK2 (Custom generated), LRRK2 (Epitomics), FLAG, Tubulin (Sigma) was immunoblotted. The Li-CorOdyssey system was used for Western blot detection.

Generation of a stable LRRK2 cell line FLAG-tag full-length human LRRK2 was inserted into the pTre2Hygro vector (Clontech). A QuickChange site-directed mutagenesis kit was used to introduce three Parkinson mutations, R1441G, Y1699C and G2019S (Stratagene). A tetracycline-controlled Tet-On system was used to generate an LRRK2 stable cell line (Gossen et al.). HEK293Tet-On cells (Clontech) were transfected with the LRRK2 plasmid described above with GFP. Hygromycin was used for stable cell selection and 48 single clones were selected using clone-disk. Western blots were used to compare LRRK2 expression levels to identify the highest expresser strains. The concentration of hygromycin used for selection was determined by a death curve assay. Gossen, M., el al. (1995) Science 268: 1766-1769.

Treatment of LRRK2 cells with inhibitor HEK293 Tet-On LRRK2 G2019S / R144G / Y1699C-induced stable cell line complete media (High Glucose DMEM, 10% Tet System FBS, 1% Glutamax, 1% NEAA, 100ug / mL G418, 30ug / mL Grow in hygromycin B). Cells were induced with 1 ug / mL doxycycline for 16 hours at 37 ° C. Cells were treated with inhibitors for 1 hour and then lysed with chilled MSD Tris Lysis Buffer.

Am's assay Anti-FLAG M2 antibody (Sigma, Saint Louis, MO, USA) was immobilized on a standard Binding 96 Well Small Spot Plate (MSD, Gaithersburg, MD, USA). The antibody was diluted to 333 ug / mL in low salt TBS buffer (16.6 mM Tris, 50 mM NaCl, 16.6 mM HEPES, 0.015% Triton X-100), spotted 5 ul and dried overnight. Plates were blocked with Sea Block (Thermo Scientific, Rockford, IL, USA) for 1 hour and washed with MSD Tris Wash Buffer.

  Cell lysates were transferred to assay plates and incubated for 2 hours at room temperature. After washing with MSD Wash Buffer, anti-phosphate-Ser 1292 pLRRK antibody was added to 0.370 ug / mL in Complete Assay Buffer (20 mM Tris, 150 mM NaCl, 0.05% Tween 20, 10% Sea Block, 1% normal mouse serum) Diluted, added and incubated for 1 hour at room temperature. After washing, the SULFOTAG goat anti-rabbit antibody was diluted to 1 ug / mL in Complete Assay Buffer, added, and incubated at room temperature for 1 hour. After washing the plate with MSD Wash Buffer, 1x MSD Read Buffer T was added and the plate was measured on an MSD Sector Imager 6000 according to the manufacturer's instructions.

Hippocampal culture and transfection Dissociated hippocampal neuronal cultures were prepared as described (Brewer et al.). Briefly, 200 hippocampal neurons mm- ² were plated in 8-well culture chamber (BD) or coated 24-well clear plates using 30 μg / ml poly-D-lysine and 2 μg / ml laminin. For IHC, cells were fixed in 4% formaldehyde, 4% sucrose in PBS for 10 minutes at room temperature. The antibody was applied to GDB buffer (0.1% gelatin, 0.3% TX-100, 450 mM NaCl, 32% 0.1 M phosphate buffer [pH 7.4]). Images were acquired using an LSM710 confocal system or a GE InCell automatic imager. Image analysis was performed using an InCell Developer. GJ Brewer et al., “Optimizing survival of hippocampal neurons in B27-supplemented Neurobasal, a new serum-free medium combination”. J. Neuro. Meth. 170: 181-187. Neurons were co-transfected with GFP and LRRK2 (1:20 ratio) in 6 days in vitro using Lipofectamine 2000.

Immunofluorescence Cells were fixed with 4% paraformaldehyde / 4% sucrose in phosphate buffered saline (PBS, pH 7.4). After permeabilization (0.1% Triton-X PBS), blocking (5% NGS, 0.1% Triton X-100 PBS) and primary antibody incubation, the antibody was secondary conjugated to Alexa 405, Alexa 488 or Alexa 568 (Invitrogen). Visualized using antibodies. The following antibodies were used for primary immunostaining: mouse anti-FLAG (Sigma), rabbit anti-Flag (Cell signaling), chicken anti-GFP (Invitrogen), rabbit anti-MAP2 (Millipore), rabbit β-tubulin (Abcam), rabbit anti-antibody. P62 (Santa Cruz), rabbit anti-LC3 (Cell signaling), rabbit Lys63-specific anti-ubiquitin (Millipore).

Image acquisition and quantitative analysis For neurite outgrowth quantification, neurons were fixed 11 days after transfection. Cells were stained with GFP and MAP2 for dendritic observation. Confocal images of transfected neurons were obtained using a Zeiss LSM 710 20X (NA?) Objective. Dendrites from neurons were traced using Neurolucida software (MicroBrightField). Sholl analysis and total dendrite length were analyzed with Neurolucida Explorer (MicroBrightField). Statistical analysis was performed using JMP9 software. P values were obtained using (non-paired Student's t test, one way ANOVA test?). All image acquisition and analysis were performed in a blinded manner.

  For LRRK2 cell localization, neurons were fixed 3-4 days after transfection. Confocal images of transfected neurons were obtained using a Zeiss LSM 710 100X (NA?) Or Leica SP5 confocal microscope 63X (NA) (Z-section size of?). Quantitative analysis of the subcellular localization of various LRRK2 constructs was performed blinded to experimental conditions.

Animal test G1023 was dissolved in 1% RC591 in water. Mice in the treatment group (n = 3 / group) received 10, 30, or 100 mg / kg intraperitoneal injection. The vehicle group (n = 2) received 1% RC591. The dose volume was calculated based on the animal body weight and did not exceed 500 ul. The animals were dismantled 6 hours after administration. The brain, spleen, and lymph nodes were quickly collected and dissected. All animals were handled according to IACUC guidelines.

Cell-based assay using MSD pellet form Based on the foregoing, a cell-based assay was performed using anti-phosphate-serine 1292-LRRK2 antibody and anti-FLAG antibody capture of LRRK2 in MesoScale Discovery (MSD, Gaithersburg MD) plates. The captured anti-phosphate-serine 1292-LRRK2 antibody was detected with the MSD sulfotag goat anti-rabbit antibody using the MSD sector leader according to the procedure in the example below. FIG. 5A shows a Western blot for a tetracycline-On induced LRRK2 R1441G / Y1699C / G2019S triple mutant cell line expressing LRRK2 by treatment with 1 ug / mL doxycycline, anti-phosphate-serine 1292-LRRK2 antibody Are shown in the first (top) row and anti-FLAG epitope (control) in the second (bottom) row. FIG. 5B is a graphical representation of the Western blot diagram of FIG. 5A, with relative luminescence shown on the vertical axis.

  LRRK2 activity was measured by detection of anti-phosphate-serine 1292-LRRK2 antibody using an assay with LRRK2 inhibitor Sutent (SU-11248 or Sunitinib, American Custom Chemicals Inc.).

Inhibition of LRRK2 autophosphorylation in vivo In vivo effects of LRRK2 inhibitors on S1292 autophosphorylation, and thus LRRK2 inhibition, is possible by the invention. A 3-year-old BAC transgenic mouse overexpressing LRRK2 G2019S was treated with an LRRK2 inhibitor [3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl] -morpholine-4. -Il-methanone was orally administered at 10 mg / kg, 30 mg / kg and 100 mg / kg. After 6 hours, hippocampal, lymph node and spleen tissues were collected and the level of S1292 autophosphorylation was determined by detecting anti-phosphate-serine 1292-LRRK2 antibody as described.

HEK293 R1441G / Y1699C / G2019S LRRK2 HEK 293 Tet-On cell line Using standard mutagenesis techniques, R1441G, Y1699C, G2019S mutation and N-terminal FLAG tag were introduced into the full-length human LRRK2 sequence (hereinafter “LRRK2-3M”) ). LRRK2-3M was cloned into the pTre2Hyg vector (Clontech, Cat. No. 631014) using NotI and EcoRV restriction sites. PTre2Hyg-LRRK2-3M in combination with pCaggs_GFP was then introduced into Clontech's Tet-OnHEK293 cells according to their standard protocol (http://www.clontech.com/images/pt/PT3898-1.pdf).

LRRK2-3M cell line handling and induction procedure Materials:
High glucose DMEM (Site Service) *
Glutamax 100X (Invitrogen 35050) *
NEAA 100X (Invitrogen 11140) *
Tet system FBS (Clontech 631105) *
H2O dissolved G418 100 mg / ml stock (Clontech 631308) *
Pen / Strep (Invitrogen) *
H2O dissolved doxycycline 1mg / ml (Clontech) *
Hygromycin B 100 mg / ml stock (Invivogen)
* DMEM medium for HEK293 Tet_OnLRRK2 Triple MutantGFP cells available online:
Glutamine-containing DMEM (1000 ml)
Add 100 ml Tet system FBS, fc 10% Add 10 ml 100 × pen / strep solution Add 10 ml 100 × Glutamax Add 10 ml 100 × NEAA 1 ml 100 mg / ml G418, fc 100 ug / Addition of ml 300 ul of 100 mg / ml hygromycin B, fc 30 ug / ml addition day 1:
Plate cells at 20% confluence (differs depending on differences in surface area of different plates)
Day 2:
16-20 hours after plating, 1 ug / ml f. c. Doxycycline (1 mg / ml stock) was added directly to culture wells that yielded Dox. (If handling volume is too small, first dilute stock Dox to 10X or 100X in culture medium)
Day 3:
24 hours after Dox induction, the cells can be compound treated.

pLRRK2 antibody Rabbits were immunized with the peptide CPNEMGKL-pS-KIWDLPL-amide according to standard procedures (Yenzyme). Serum from the immunized rabbit was first purified by passing through an agarose column conjugated with the peptide CPNEMGKL-pS-KIWDLPL-amide. The antibody bound to the column was eluted. The purified material was then passed through an agarose column conjugated with the peptide CPNEMGKLSKIWDLPL-amide to absorb non-phosphorylated peptide cross-reacting antibodies.

BAC mice BAC mice overexpressing G2019S and / or other Parkinson's disease mutations are described in Marshall et al. In "Generation of BAC transgenic mice", Methods in Mol. Biol. Vol. 256 (2004) pp. 159-182. Generally prepared by procedures.

Assay using Meso Scale Discovery platform HEK293 cells were transiently transfected with a plasmid carrying the FLAG epitope-tag full length LRRK2 cDNA under the control of the CMV promoter. Transfections were performed in 10-cm dishes using Fugene 6 reagent (Roche Applied Science, Mannheim, Germany) according to manufacturer's instructions. Twenty-four hours after transfection, cells were collected, counted, seeded in 96-well plates and allowed to attach for 1 hour prior to compound addition.

  Cells are treated with compound for 1 hour, medium is then removed, and cells are placed in MSD (Meso Scale Discovery, Gaithersburg, MD) lysis buffer (Meso Scale Discovery, Gaithersburg, MD) supplemented with proteases and phosphorylation inhibitors. Dissolved.

  Assay detection plates are prepared by spotting 2 ug of anti-FLAG monoclonal antibody (Sigma Aldrich, St Louis, MO) to each well of a 96-well MSD plate and blocking with Sea-Block (Thermo Fisher, Rockford, IL). did. Cell lysates were transferred to MSD plates, incubated for 2 hours and then washed. Captured phosphate-LRRK2 was detected by the addition of anti-phosphate-Ser1292-LRRK2, a 2 hour incubation followed by a wash. Detection of capture antibody with MSD Sulfotag goat anti-rabbit antibody using an MSD Sector reader was performed according to the manufacturer's instructions.

Other Assay Formats In a variation of the above assay format, the determination of phosphate-Ser (1292) in cell lysates was transfected with cDNA encoding all or part of the LRRK2 protein (with or without fusion to an epitope tag protein). Obtained using cells transduced (stable or transient) or virally. Capture of overexpressed LRRK2 or a fragment of LRRK2 (with or without fusion epitope tag or fusion protein partner) from cell lysates is performed using immobilized proteins to the LRRK2 sequence, other epitope tags or fusion proteins. Capture solid phase matrices include ELISA plates, MesoScale Discovery plates (Meso Scale Discovery, Gaithersberg, MD), membranes (eg, nitrocellulose, PVDF). Detection of captured phosphate-Ser1292-LRRK2 using antibodies against phosphate-Ser1292 by methods includes ELISA, DELFIA, electrochemiluminescence, and fluorescence.

  Another variation of the above assay format is the capture of phosphate-Ser1292-LRRK2 from cell lysates using immobilized anti-phosphate-Ser1292-LRRK2 antibody followed by antibodies to LRRK2 sequence, epitope tag or fusion protein partner Detection of captured LRRK2 using is used.

  Plate-based detection of endogenous phosphate-Ser (1292) from cell lysates in any of the above formats can use anti-LRRK2 and anti-phosphate-Ser (1292) antibodies.

  Plate-based detection of phosphate-Ser (1292) in intact cells can be achieved by microfluorescence detection and quantification of fluorescence intensity and by immunofluorescence detection of phosphate-Ser (1292) in permeabilized cells or by bulk fluorescence (Eg LiCor “In-Cell Western”).

  Plate-based detection of phosphate-Ser (1292) in intact cells is a colorimetric / immunohistochemical detection and quantification of anti-phosphate-Ser (1292) binding to immobilized and permeabilized cells; Western blotting of immunoprecipitated endogenous or transfected LRRK2 or whole cell lysates with Ser (1292); or Western blotting of proteins immunoprecipitated with anti-phosphate Ser (1292) antibody followed by antibody to fusion protein / epitope tag Alternatively, detection by anti-LRRK can be utilized.

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

Claims (16)

  A method of identifying a patient or subject suffering from or at risk of developing Parkinson's disease, comprising determining the level of S1292 autophosphorylation in said subject, wherein the elevated level Is correlated with the risk of developing Parkinson's disease or the risk of developing Parkinson's disease.   The method of claim 1, further comprising obtaining or obtaining an LRRK2-containing sample from a subject.   3. The method of claim 2, further comprising measuring, monitoring or otherwise detecting the amount or level of S1292 autophosphorylation in the subject sample.   4. The method of claim 3, further comprising comparing the amount or level of S1292 autophosphorylation in the subject sample with the amount or level of S1292 autophosphorylation in one or more control samples.   A method of predicting the sensitivity of a subject to an LRRK2 modulator, or the effect of an LRRK2 modulator for the treatment of Parkinson's disease, comprising determining the level of S1292 autophosphorylation in said subject, wherein said level of S1292 self is increased. A method wherein phosphorylation correlates with the effect of the inhibitor for the treatment of the disease.   6. The method of claim 5, further comprising obtaining or obtaining a first LRRK2-containing sample from a subject.   7. The method of claim 6, further comprising administering an LRRK2 modulator to the subject.   8. The method of claim 7, further comprising obtaining or obtaining a second LRRK2-containing sample from the subject after administering the LRRK2 modulator to the subject.   9. The method of claim 8, further comprising measuring, monitoring or otherwise detecting the amount or level of S1292 autophosphorylation in the first subject sample.   10. The method of claim 9, further comprising measuring, monitoring or otherwise detecting the amount or level of S1292 autophosphorylation in the second subject sample.   11. The method of claim 10, further comprising comparing the amount or level of S1292 autophosphorylation in the first subject sample with the amount or level of S1292 autophosphorylation in the second subject sample. Said LRRK2 modulator is of formula I:

Or a pharmaceutically acceptable salt thereof.
(In the above formula,
m is 0-3;
X is: —NR ^a —; —O—; or —S (O) _r — (r is 0-2, R ^a is hydrogen or C _1-6 alkyl);
R ¹ is: C _1-6 alkyl; halo-C _1-6 alkyl; C _2-6 alkenyl; C _2-6 alkynyl; halo-C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; Hydroxy-C _1-6 alkyl; amino-C _1-6 alkyl; C _1-6 alkylsulfonyl-C _1-6 alkyl; C _1-6 alkyl or C _3-6 cycloalkyl optionally substituted with halo; C _3-6 cycloalkyl-C _1-6 alkyl (the C _3-6 cycloalkyl moiety may be substituted with C _1-6 alkyl); tetrahydropyranyl; tetrahydrofuranyl; tetrahydrofuranyl-C _1-6 alkyl Oxetanyl; or oxetane-C _1-6 alkyl;
Or R ¹ and R ^a together with the atoms to which they are attached may contain further heteroatoms selected from O, N and S and are substituted with oxo, halo or C _1-6 alkyl 3 Can form ˜6-membered rings;
R ² is: halo; C _1-6 alkoxy; cyano; C _2-6 alkynyl; C _2-6 alkenyl; halo-C _1-6 alkyl; halo-C _1-6 alkoxy; C _3-6 cycloalkyl (C _3-6 cycloalkyl moiety may be substituted with C _1-6 alkyl); C _3-6 cycloalkyl-C _1-6 alkyl (C _3-6 cycloalkyl moiety is substituted with C _1-6 alkyl) Tetrahydrofuranyl-C _1-6 alkyl; acetyl; oxetanyl; or oxetane-C _1-6 alkyl;
R ³ is: —OR ⁴ ; halo; cyano; C _1-6 alkyl; halo-C _1-6 alkyl; C _3-6 cycloalkyl optionally substituted with C _1-6 alkyl; C _3-6 cyclo Alkyl-C _1-6 alkyl (C _3-6 cycloalkyl moiety may be substituted with C _1-6 alkyl); tetrahydrofuranyl; tetrahydrofuranyl-C _1-6 alkyl; oxetanyl; or oxetane-C _{1- 6} alkyl;
R ⁴ is: hydrogen; C _1-6 alkyl; halo-C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; C _1-6 alkyl or C _3-6 optionally substituted with halo C _3-6 cycloalkyl-C _1-6 alkyl (the C _3-6 cycloalkyl moiety may be substituted with C _1-6 alkyl or halo); tetrahydrofuranyl; tetrahydrofuranyl-C _1-6 Alkyl; oxetanyl; or oxetane-C _1-6 alkyl;
R ⁵ is: hydrogen; or C _1-6 alkyl;
n is 0 or 1;
R ⁶ is: hydrogen; _{C 1-6} alkyl; _{C 1-6} alkoxy -C _1-6 alkyl; hydroxy -C _1-6 alkyl; amino -C _1-6 alkyl; _{C 3-6} cycloalkyl; _{C 3- 6} cycloalkyl-C _1-6 alkyl; heterocyclyl; or heterocyclyl-C _1-6 alkyl; C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-6 alkyl, heterocyclyl and heterocyclyl-C _{1- 6} alkyl each: _{C 1-6} alkyl; halo -C _1-6 alkyl; _{C 1-6} alkoxy; halo -C _1-6 alkoxy; hydroxy; hydroxyalkyl -C _1-6 alkyl; halo; nitrile; _{C 1- 6} alkyl - carbonyl; _{C 1-6} alkyl - sulfonyl; _{C 3-6} cycloalkyl; _{C 3-6} cycloalkyl -C _1-6 alkyl; _{C 3-6} cycloalkyl - carbonyl; amino; or het It may be substituted with one, two, three or four groups independently selected from cyclyl; or two groups form a ring of 5 or 6 membered together with the atoms to which they are attached obtain;
Or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a 3- to 7-membered ring which may contain further heteroatoms selected from O, N and S (O) _n and, it: _{C 1-6} alkyl; halo -C _1-6 alkyl; _{C 1-6} alkoxy; halo -C _1-6 alkoxy; hydroxy; _{C 1-6} alkoxy -C _1-6 alkyl; hydroxy -C _{1 -6} alkyl; halo, nitrile; _{C 1-6} alkyl - carbonyl; _{C 1-6} alkyl - sulfonyl; _{C 3-6} cycloalkyl; _{C 3-6} cycloalkyl -C _1-6 alkyl; _{C 3-6} cycloalkyl -Carbonyl; amino; or may be substituted with 1, 2, 3 or 4 groups independently selected from heterocyclyl; or the two groups may be 5- or 6-membered rings with the atoms to which they are attached. And R ⁷ is: halo; C _1-6 alkyl; C _1-6 alkoxy; halo-C _1-6 alkyl; or halo-C _1-6 alkoxy). Said LRRK2 modulator is of formula II

Or a pharmaceutically acceptable salt thereof.
(In the above formula,
X is: —NR ^a —; or —O— (R ^a is hydrogen or C _1-6 alkyl);
R ¹ is: C _1-6 alkyl; C _2-6 alkenyl; C _2-6 alkynyl; halo-C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; hydroxy-C _1-6 alkyl; Amino-C _1-6 alkyl; C _1-6 alkylsulfonyl-C _1-6 alkyl; C _3-6 cycloalkyl optionally substituted one or more times with C _1-6 alkyl; C _3-6 cycloalkyl -C _1-6 alkyl (the C _3-6 cycloalkyl moiety may be substituted one or more times with C _1-6 alkyl); a heterocyclyl optionally substituted one or more times with R ⁷ ; or R ⁷ is heterocyclyl-C _1-6 alkyl optionally substituted one or more times;
Or X and R ¹ are both C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; C _3-6 cycloalkyl optionally substituted one or more times with R ⁶ ; or C _3-6 Forming a cycloalkyl-C _1-6 alkyl (the C _3-6 cycloalkyl moiety may be substituted one or more times by R ⁶ );
Or R ¹ and R ^a together with the atoms to which they are attached may form a 3-6 membered heterocycle that may be substituted one or more times with R ⁷ ;
R ² is: _{C 1-6} alkyl; halo; _{C 1-6} alkoxy; cyano; _{C 2-6} alkynyl; _{C 2-6} alkenyl; halo -C _1-6 alkyl; halo -C _1-6 alkoxy; ^{R 6} C _3-6 cycloalkyl optionally substituted one or more times by: C _3-6 cycloalkyl-C _1-6 alkyl (wherein the C _3-6 cycloalkyl moiety is substituted one or more times by R ⁶ -OR ^b (R ^b is C _1-6 alkyl, C _3-6 cycloalkyl optionally substituted one or more times with R ⁶ , or C _3-6 cycloalkyl-C _1-6 alkyl) (C _3-6 cycloalkyl moiety may be substituted one or more times with R ⁶ ); or —C (O) —R ^c (R ^c is C _1-6 alkyl, C _1-6 alkoxy, Amino, or heterocyclyl optionally substituted one or more times by R ⁷ );
R ³ is: hydrogen; C _1-6 alkyl; halo-C _1-6 alkyl; C _2-6 alkenyl; C _2-6 alkynyl; hydroxy-C _1-6 alkyl; C _1-6 alkoxy-C _1-6 Alkyl; cyano-C _1-6 alkyl; C _1-6 alkylsulfonyl; C _1-6 alkylsulfonyl C _1-6 alkyl; amino-C _1-6 alkyl; _optionally substituted one or more times by R ⁶ C _3-6 cycloalkyl; C _3-6 cycloalkyl-C _1-6 alkyl (the C _3-6 cycloalkyl moiety may be substituted one or more times by R ⁶ ); C _3-6 cycloalkyl- Sulfonyl (C _3-6 cycloalkyl moiety may be substituted one or more times with R ⁶ ); Heterocyclyl optionally substituted one or more times with R ⁷ ; Heterocyclyl-C _1-6 alkyl (heterocyclyl moiety) one or more times by R ⁷ Conversion is may be); by R ⁸ may be substituted one or more times aryl; aryl -C _1-6 alkyl (the aryl moiety may be substituted one or more times by R ^8); R Heteroaryl optionally substituted one or more times by ⁸ ; heteroaryl-C _1-6 alkyl (the heteroaryl moiety may be substituted one or more times by R ⁸ ); or —Y—C (O ) -R ^d ;
Y is C _2-6 alkylene or a bond;
R ^d is C _1-6 alkyl, C _1-6 alkoxy, amino, C _1-6 alkyl-amino, di-C _1-6 alkyl-amino, halo-C _1-6 alkyl-amino, di-halo-C _1-6 alkyl-amino, halo-C _1-6 alkyl, hydroxy-C _1-6 alkyl, hydroxy, C _1-6 alkoxy-C _1-6 alkyl, cyano-C _1-6 alkyl, C _1-6 alkyl Sulfonyl C _1-6 alkyl, amino-C _1-6 alkyl, C _3-6 cycloalkyl optionally substituted one or more times with R ⁶ , C _3-6 cycloalkyl-C _1-6 alkyl (C _{3 The -6} cycloalkyl moiety may be substituted one or more times by R ⁶ ), a heterocyclyl optionally substituted one or more times by R ⁷ , or a heterocyclyl-C _1-6 alkyl (in the heterocyclyl moiety R ⁷⁾ . (It may be substituted one or more times) Yes;
R ⁴ is: hydrogen; C _1-6 alkyl; halo; cyano; halo-C _1-6 alkyl; C _2-6 alkenyl; C _2-6 alkynyl; C _1-6 alkoxy; C _1-6 alkoxy-C _{1 -6} alkyl; hydroxy-C _1-6 alkyl; C _3-6 cycloalkyl optionally substituted one or more times with R ⁶ ; C _3-6 cycloalkyl-C _1-6 alkyl (C _3-6 cyclo The alkyl moiety may be substituted one or more times with R ⁶ ); or —Y—C (O) —R ^d ;
R ⁵ is: hydrogen; or C _1-6 alkyl;
Each R ⁶ is independently: C _1-6 alkyl; halo-C _1-6 alkyl; C _1-6 alkoxy; oxo; cyano; halo; or Y—C (O) —R ^d ;
Each R ⁷ is independently: C _1-6 alkyl; halo-C _1-6 alkyl; halo; oxo; C _1-6 alkoxy; C _1-6 alkylsulfonyl; C _1-6 alkoxy-C _1-6 alkyl Cyano; —YC (O) —R ^d ; heterocyclyl; heterocyclyl-C _1-6 alkyl; C _3-6 cycloalkyl; C _3-6 cycloalkyl-C _1-6 alkyl; or C _3-6 cyclo; And each R ⁸ is independently: oxo; C _1-6 alkyl; halo-C _1-6 alkyl; halo; C _1-6 alkyl-sulfonyl; C _1-6 alkoxy; C _1-6 alkoxy -C _1-6 alkyl; cyano; Hetoeryclyl; heterocyclyl -C _1-6 ^{alkyl; -Y-C (O) -R} d; C 3-6 cycloalkyl, _{C 3-6} cycloalkyl -C _1-6 alkyl , or _{C 3-6} cycloalkyl - scan It is a Honiru). A method of identifying a subject suffering from Parkinson's disease or a subject at risk of developing Parkinson's disease, comprising:
Obtaining or obtaining an LRRK2 containing sample from a subject;
Measuring, monitoring or otherwise detecting the amount or level of S1292 autophosphorylation in a subject sample; and the amount or level of S1292 autophosphorylation in a subject sample to determine the amount or level of S1292 autophosphorylation in one or more control samples Comparing to an amount or level. A method of determining a subject responsive to treatment with an LRRK2 modulator comprising:
Obtaining or obtaining a first LRRK2 containing sample from a subject;
Administering an LRRK2 modulator to the subject;
Obtaining or obtaining a second LRRK2 containing sample from the subject after administering the LRRK2 modulator to the subject;
Measuring, monitoring or otherwise detecting the amount or level of S1292 autophosphorylation in the first subject sample;
Measuring, monitoring or otherwise detecting the amount or level of S1292 autophosphorylation in the second subject sample; and the amount or level of S1292 autophosphorylation in the first subject sample Comparing to the amount or level of phosphorylation. An assay for screening compounds and compositions for inhibition of LRRK2 activity comprising:
A method comprising exposing LRRK2 or a fragment thereof to a potential inhibitory compound; and detecting the level or amount of phosphorylation associated with S1292 on LRRK2.

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