O-glycoprotein-2-acetamido-2-deoxy-3-d-glucopyranosidase inhibitors

Abstract

Described herein are compounds represented by Formula (IA) or Formula (IB), or pharmaceutically acceptable salts of such compounds, pharmaceutical compositions comprising them, and methods of making and using them. The variables R1, R3, R4, Y1, Y2, Ar, Z, and n are as defined herein. # imgabs0 #

Description

[0001] This application is a divisional application of Chinese invention patent application 201980060829.1 (the invention name is “O-glycoprotein-2-acetylamino-2-deoxy-3-D-pyranosidase inhibitors”, the application date is September 18, 2019, and the PCT application number is PCT / US2019 / 051661).

[0002] Related applications

[0003] This application claims priority to U.S. Provisional Patent Application No. 62 / 733,484, filed September 19, 2018, and U.S. Provisional Patent Application No. 62 / 750,000, filed October 24, 2018. The disclosures or contents of each of the foregoing two applications are incorporated herein by reference in their entirety. Background Art

[0004] A wide range of cellular proteins (nuclear and cytoplasmic) are post-translationally modified by adding the monosaccharide 2-acetylamino-2-deoxy-β-D-glucopyranoside (β-N-acetylglucosamine) connected via an O-glycosidic bond. This monosaccharide is generally referred to as the N-acetylglucosamine or O-GlcNAc connected by O-. The enzyme responsible for post-translationally connecting β-N-acetylglucosamine (GlcNAc) to the specific serine and threonine residues of numerous nuclear cytoplasmic proteins is O-GlcNAc transferase (OGTase). A second enzyme, called O-glycoprotein-2-acetylamino-2-deoxy-3-D-glucopyranosidase or O-GlcNAcase or OGA, removes this post-translational modification to release the protein, making the O-GlcNAc modification a dynamic cycle that occurs several times during the life of the protein.

[0005] O-GlcNAc-modified proteins regulate a wide range of crucial cellular functions, including, for example, transcription, proteasomal degradation, and cell signaling. O-GlcNAc is also found on many structural proteins, including the cytoskeletal protein "tau," which is responsible for stabilizing the critical cellular network of microtubules necessary for distributing proteins and nutrients within neurons. Importantly, tau has been clearly implicated in the etiology of several diseases, including tauopathies, Alzheimer's disease, Parkinson's disease, dementia, and cancer.

[0006] It is well established that Alzheimer's disease and many related tauopathies, including progressive supranuclear palsy (PSP) and amyotrophic lateral sclerosis (ALS), are characterized in part by the development of neurofibrillary tangles (NFTs). These NFTs are aggregates of paired helical filaments (PHFs) and are composed of abnormal forms of tau. In AD patients, tau becomes hyperphosphorylated, disrupting its normal function, forming PHFs and ultimately aggregated to form NFTs.

[0007] Six isoforms of tau are found in the human brain. In AD patients, all six tau isoforms are found in NFTs, and all are significantly hyperphosphorylated. While tau in healthy brain tissue carries only two or three phosphate groups, those found in the brains of AD patients carry an average of eight phosphate groups.

[0008] Recently found that the increase of phosphorylation level makes O-GlcNAc level reduce, and on the contrary, the O-GlcNAc level of increase is associated with the phosphorylation level of reduction.It has been shown that the glucose availability that reduces in the brain causes tau hyperphosphorylation.The gradual weakening of glucose transport and metabolism causes O-GlcNAc to reduce and tau (and other proteins) hyperphosphorylation.Therefore, by preventing from removing O-GlcNac from tau, prevent the O-GlcNAcase of tau hyperphosphorylation from suppressing the age-related weakening of glucose metabolism in the brain that should compensate healthy individuals and the patient suffering from Alzheimer's disease or related neurodegenerative diseases.

[0009] The present invention relates to the inhibitor of the function of the mammalian glycosidase that is used to block O-GlcNAcase, and the major challenge that development is used to block O-GlcNAcase is the large amount of function related enzymes existing in the tissue of higher eukaryotes.Therefore, the use of non-selective inhibitors is complicated in the cell and organism physiological effect of a kind of specific enzyme of research, and this is because complex phenotype is produced by the accompanying inhibition of this type of function related enzyme.In the case of β-N-acetyl glucosaminidase, the existing compound that acts on blocking-up O-GlcNAcase function is non-specific and acts on lysosomal β-hexosaminidase intensively.

[0010] In view of the aforementioned technical challenges and considering the potential of modulation of O-GlcNAcase for the treatment of AD, tauopathies and other neurological diseases, there is a need to develop potent and selective O-GlcNAcase inhibitors. Summary of the Invention

[0011] Described herein are compounds that are useful for treating various diseases, disorders, and medical conditions, including but not limited to those associated with proteins modified by O-GlcNAcase.

[0012] A first embodiment of the compound of the present invention is represented by the following structural formula:

[0013]

[0014] or a pharmaceutically acceptable salt of said compound, wherein:

[0015] Ar is optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl;

[0016] Y 1 and Y 2 Each is CR c or N, where Y 1 or Y 2 At least one of is N;

[0017] Z is CR 2 R 2 、C(=O)、(CR 2 R 2 )2 or CH2C(=O);

[0018] R c is -H, halo, C1-C4 alkyl or C1-C4 haloalkyl;

[0019] n is 0 or an integer from 1 to 8;

[0020] When n is not 0, R 1 is independently at each occurrence halo, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy;

[0021] R 2 Each occurrence is independently -H, halo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl or C3-C 10 Halogenated cycloalkyl groups;

[0022] Or alternatively, two R 2 Together with the carbon atoms to which they are attached, they form C3-C 10 Cycloalkyl;

[0023] R 3 is -H or C1-C4 alkyl; and

[0024] R 4 is -H, C1-C4 alkyl, C1-C4 haloalkyl or C3-C6 cycloalkyl;

[0025] Or alternatively, R 3 and R 4 Together with their intervening atoms they form an optionally substituted 5- to 7-membered heterocyclyl.

[0026] Another embodiment of the compound of the present invention is represented by the following structural formula:

[0027]

[0028] or a pharmaceutically acceptable salt of said compound, wherein:

[0029] Ar is optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl;

[0030] Y 1 and Y 2 Each is CR c or N, where Y 1 or Y 2 At least one of is N;

[0031] Z is CR 2 R 2 、C(=O)、(CR 2 R 2 )2 or CH2C(=O);

[0032] R c is -H, halo, C1-C4 alkyl or C1-C4 haloalkyl;

[0033] n is 0 or an integer from 1 to 7;

[0034] When n is not 0, R 1 is independently at each occurrence halo, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy;

[0035] R 2 Each occurrence is independently -H, halo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl or C3-C 10 Halogenated cycloalkyl groups;

[0036] Or alternatively, two R 2 Together with the carbon atoms to which they are attached, they form C3-C 10 Cycloalkyl;

[0037] R 3 is -H or C1-C4 alkyl; and

[0038] R 4 is -H, C1-C4 alkyl, C1-C4 haloalkyl or C3-C6 cycloalkyl;

[0039] Or alternatively, R 3 and R 4 Together with their intervening atoms they form an optionally substituted 5- to 7-membered heterocyclyl.

[0040] Provided is a pharmaceutical composition comprising at least one compound described herein or a pharmaceutically acceptable salt of the compound and at least one pharmaceutically acceptable excipient.

[0041] Also provided is a method of treating a subject having a disease or condition selected from a neurodegenerative disease, a tauopathy, diabetes, cancer, and stress, comprising administering to the subject an effective amount of a compound described herein or a pharmaceutically acceptable salt of the compound, or an effective amount of a pharmaceutical composition comprising at least one compound described herein or a pharmaceutically acceptable salt of the compound and at least one pharmaceutically acceptable excipient.

[0042] Also provided is a method of inhibiting O-GlcNAcase in a subject in need thereof, comprising administering to the subject an effective amount of a compound described herein or a pharmaceutically acceptable salt of the compound, or an effective amount of a pharmaceutical composition comprising at least one compound described herein or a pharmaceutically acceptable salt of the compound and at least one pharmaceutically acceptable excipient.

[0043] Also provided is a method of treating a disease or condition characterized by hyperphosphorylation of tau in the brain, comprising administering to a subject an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising at least one compound described herein or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. In one embodiment, the disease or condition characterized by hyperphosphorylation of tau in the brain is Alzheimer's disease. DETAILED DESCRIPTION

[0044] Described herein are compounds that are useful for treating various diseases, disorders, and medical conditions, including but not limited to those associated with proteins modified by O-GlcNAcase.

[0045] In a first embodiment, the compound of the present invention is represented by the following structural formula:

[0046]

[0047] or a pharmaceutically acceptable salt of said compound, wherein the variables are as defined above in the Summary of the Invention for the compound represented by Formula (IA).

[0048] In a second embodiment, the compound of the present invention is represented by the following structural formula:

[0049]

[0050] or a pharmaceutically acceptable salt of the compound; wherein R 1 is halogen, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy; R c is halo, C1-C4 alkyl or C1-C4 haloalkyl; and n is an integer from 1 to 7; wherein the remaining variables are as defined in the first embodiment.

[0051] In a third embodiment, the compound of the present invention is represented by the following structural formula:

[0052]

[0053] or a pharmaceutically acceptable salt of the compound, wherein R 1 is halo or C1-C4 alkyl; wherein the remaining variables are as defined in the first embodiment.

[0054] In a fourth embodiment, the compound of the present invention is represented by the following structural formula:

[0055]

[0056] or a pharmaceutically acceptable salt of the compound; wherein R 2 is independently at each occurrence -H or C1-C4 alkyl; and wherein the remaining variables are as defined for the variables in the first, second or third embodiment.

[0057] In a fifth embodiment, the compound of the present invention is represented by the following structural formula:

[0058]

[0059] or a pharmaceutically acceptable salt of the compound; wherein R 2 is independently -H or C1-C4 alkyl at each occurrence, R c is halo or C1-C4 alkyl; and n is an integer from 1 to 7; wherein the remaining variables are as defined in the first, second, third or fourth embodiment.

[0060] In a sixth embodiment, the compound of the present invention is represented by one of the following structural formulas:

[0061]

[0062] wherein the remaining variables are as defined in the first, second, third, fourth or fifth embodiment.

[0063] In a seventh embodiment, the compound of the present invention is represented by one of the following structural formulas:

[0064]

[0065] or a pharmaceutically acceptable salt of said compound; wherein n is an integer from 1 to 7; wherein the remaining variables are as defined in the first, second, third, fourth, fifth or sixth embodiment.

[0066] In an eighth embodiment, the compound of the present invention is represented by one of the following structural formulas:

[0067]

[0068] or a pharmaceutically acceptable salt of said compound; wherein n is 0 or an integer from 1 to 7; and wherein the remaining variables are as defined in the first, second, third, fourth, fifth, sixth or seventh embodiment.

[0069] In a ninth embodiment, the compound of the present invention is represented by one of the following structural formulas:

[0070]

[0071] or a pharmaceutically acceptable salt of said compound; wherein n is 0 or an integer from 1 to 6; and wherein the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh or eighth embodiment.

[0072] In a tenth embodiment, the compound of the present invention is represented by one of the following structural formulas:

[0073]

[0074] or a pharmaceutically acceptable salt of said compound; wherein n is 0 or an integer from 1 to 3; and wherein the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth or ninth embodiment.

[0075] In an eleventh embodiment, the compound of the present invention is represented by the following structural formula:

[0076]

[0077] or a pharmaceutically acceptable salt of said compound; wherein n is 0 or an integer from 1 to 3; and wherein the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth embodiment.

[0078] In a twelfth embodiment, the compound of the present invention is represented by the following structural formula:

[0079]

[0080] or a pharmaceutically acceptable salt of said compound; wherein n is 0, 1 or 2; and wherein the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth or eleventh embodiment.

[0081] In a thirteenth embodiment, the compound of the present invention is represented by the following structural formula:

[0082]

[0083] or a pharmaceutically acceptable salt of said compound; wherein n is 0, 1 or 2; and wherein the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiment.

[0084] In a fourteenth embodiment, the compound of the present invention is represented by the following structural formula:

[0085]

[0086] or a pharmaceutically acceptable salt of said compound; wherein the variables are as defined above in the Summary of the Invention for the compound represented by Formula (IB) or a pharmaceutically acceptable salt of said compound.

[0087] In a fifteenth embodiment, the compound of the present invention is represented by one of the following structural formulas:

[0088]

[0089] or a pharmaceutically acceptable salt of the compound; wherein R 1 is halo or C1-C4 alkyl; and wherein the remaining variables are as defined in the fourteenth embodiment.

[0090] In a sixteenth embodiment, the compound of the present invention is represented by one of the following structural formulas:

[0091]

[0092] or a pharmaceutically acceptable salt of the compound; wherein R 1 is halo or C1-C4 alkyl; and wherein the remaining variables are as defined in the fourteenth or fifteenth embodiment.

[0093] In a seventeenth embodiment, the compound of the present invention is represented by one of the following structural formulas:

[0094]

[0095] or a pharmaceutically acceptable salt of the compound; wherein R2 is independently at each occurrence -H or C1-C4 alkyl; wherein n is 0 or an integer from 1 to 3; and wherein the remaining variables are as defined in the fourteenth, fifteenth or sixteenth embodiment.

[0096] In an eighteenth embodiment, the compound of the present invention is represented by one of the following structural formulas:

[0097]

[0098] or a pharmaceutically acceptable salt of the compound; wherein R 2 is independently at each occurrence -H or C1-C4 alkyl; wherein n is 0 or an integer from 1 to 3; and wherein the remaining variables are as defined in the fourteenth, fifteenth, sixteenth or seventeenth embodiment.

[0099] In a nineteenth embodiment, the compound of the present invention is represented by one of the following structural formulas:

[0100]

[0101] or a pharmaceutically acceptable salt of said compound; wherein n is 0, 1 or 2; and wherein the remaining variables are as defined in the fourteenth, fifteenth, sixteenth, seventeenth or eighteenth embodiment.

[0102] In a twentieth embodiment, the compound of the present invention is represented by one of the following structural formulas:

[0103]

[0104] or a pharmaceutically acceptable salt of said compound; wherein n is 0, 1 or 2; and wherein the remaining variables are as defined in the fourteenth, fifteenth, sixteenth, seventeenth, eighteenth or nineteenth embodiment.

[0105] In a twenty-first embodiment, in the compounds of the invention according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth or twentieth embodiment, or a pharmaceutically acceptable salt thereof, Ar is an optionally substituted 5- or 6-membered monocyclic heteroaryl.

[0106] In a twenty-second embodiment, in the compounds of the invention according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth or twentieth embodiment, or a pharmaceutically acceptable salt thereof, Ar is an optionally substituted monocyclic heteroaryl comprising one or more nitrogen atoms.

[0107] In a twenty-third embodiment, in the compounds of the invention according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first or twenty-second embodiment, or a pharmaceutically acceptable salt thereof, Ar is optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl or optionally substituted pyridazinyl.

[0108] In a twenty-fourth embodiment, in the compounds of the invention according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second or twenty-third embodiment, or a pharmaceutically acceptable salt thereof, Ar is optionally substituted pyridinyl, optionally substituted pyrimidinyl or optionally substituted pyrazinyl.

[0109] In a twenty-fifth embodiment, in the compounds of the invention according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third or twenty-fourth embodiment, or pharmaceutically acceptable salts thereof, Ar is optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted or optionally substituted

[0110] In a twenty-sixth embodiment, in the compounds of the invention according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth or twenty-fifth embodiment, or pharmaceutically acceptable salts thereof, Ar is optionally substituted Optionally substituted Optionally substituted Optionally substituted or optionally substituted

[0111] In a twenty-seventh embodiment, in the compounds of the invention according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth or twenty-sixth embodiment, or pharmaceutically acceptable salts thereof, Ar is optionally substituted Optionally substituted or optionally substituted

[0112] In a twenty-eighth embodiment, in the compounds of the invention according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth or twenty-seventh embodiment, or pharmaceutically acceptable salts thereof, Ar is optionally substituted or optionally substituted

[0113] In a twenty-ninth embodiment, in the compounds of the invention according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth embodiment, or pharmaceutically acceptable salts thereof, Ar is optionally substituted with one or more groups selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, halo, -CN, -NO2, -OR z 、-NR x R y 、-S(O) i R x 、-NR x S(O) i R y 、-S(O) i NR x R y 、-C(=O)OR x 、-OC(=O)OR x 、-C(=S)OR y 、-O(C=S)R x 、-C(=O)NR x R y 、-NR x C(=O)R y 、-C(=S)NR x R y 、-NR x C(=S)R y 、-NR x (C=O)OR y 、-O(C=O)NR x R y 、-NR x (C=S)OR y 、-O(C=S)NR x R y 、-NR x (C=O)NR x R y 、-NR x (C=S)NR x R y 、-C(=S)R x 、-C(=O)R x , phenyl and monocyclic heteroaryl;

[0114] in

[0115] The C1-C4 alkyl substituents on Ar are optionally substituted with: -CN, -NO2, -OR z 、-NR x R y 、-S(O) i R x 、-NR x S(O) i R y 、-S(O) i NR x R y 、-C(=O)OR x 、-OC(=O)OR x 、-C(=S)OR x 、-O(C=S)R x 、-C(=O)NR x R y 、-NR x C(=O)R y 、-C(=S)NR x R y 、-NR x C(=S)R y 、-NR x (C=O)OR y 、-O(C=O)NR x R y 、-NR x (C=S)OR y 、-O(C=S)NR x R y 、-NR x (C=O)NR x R y 、-NR x (C=S)NR x R y 、-C(=S)R x 、-C(=O)R y , C3-C6 cycloalkyl (optionally substituted with one or more groups selected from -CH3, halomethyl, halo, methoxy and halomethoxy), monocyclic heteroaryl (optionally substituted with one or more groups selected from -CH3, halomethyl, halo, methoxy and halomethoxy), or phenyl (optionally substituted with one or more groups selected from -CH3, halomethyl, halo, methoxy and halomethoxy);

[0116] The C3-C6 cycloalkyl, C3-C6 heterocyclyl, phenyl and monocyclic heteroaryl substituents on Ar are optionally and independently substituted with C1-C4 alkyl, C1-C4 haloalkyl, halo, -CN, -NO2, -OR z 、-NRx R y 、-S(O) i R x 、-NR x S(O) i R y 、-S(O) i NR x R y 、-C(=O)OR x 、-OC(=O)OR x 、-C(=S)OR x 、-O(C=S)R y 、-C(=O)NR x R y 、-NR x C(=O)R y 、-C(=S)NR x R y 、-NR x C(=S)R y 、-NR x (C=O)OR y 、-O(C=O)NR x R y 、-NR x (C=S)OR y 、-O(C=S)NR x R y 、-NR x (C=O)NR x R y 、-NR x (C=S)NR x R y 、-C(=S)R x or -C(=O)R x ;

[0117] Each R x and each R y are independently -H, C1-C4 alkyl or C3-C8 cycloalkyl; wherein R x or R y The C1-C4 alkyl or C3-C8 cycloalkyl represented by is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl and phenyl (optionally substituted with one or more groups selected from the group consisting of -CH3, halomethyl, halo, methoxy and halomethoxy);

[0118] R z is -H, C1-C4 alkyl, C3-C8 cycloalkyl or C3-C8 heterocyclic group; wherein R zThe C1-C4 alkyl, C3-C8 cycloalkyl or C3-C8 heterocyclyl represented by is optionally substituted with one or more substituents selected from the group consisting of -CN, halo, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl and phenyl (optionally substituted with one or more groups selected from the group consisting of -CH3, halomethyl, halo, methoxy and halomethoxy); and

[0119] i is 0, 1 or 2.

[0120] In a thirtieth embodiment, in the compounds of the invention according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth embodiment, or a pharmaceutically acceptable salt thereof, Ar is optionally substituted with one or more groups selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, halo, -CN, -NO2, -OR z 、-NR x R y 、-S(O) i R x 、-NR x S(O) i R y 、-S(O) i NR x R y 、-C(=O)OR x 、-OC(=O)OR x 、-C(=S)OR y 、-O(C=S)R x 、-C(=O)NR x R y 、-NR x C(=O)R y 、-C(=S)NR x R y 、-NR x C(=S)R y 、-NR x (C=O)OR y 、-O(C=O)NR x R y 、-NR x (C=S)OR y 、-O(C=S)NR x R y 、-NRx (C=O)NR x R y 、-NR x (C=S)NR x R y 、-C(=S)R x 、-C(=O)R x , phenyl and monocyclic heteroaryl;

[0121] in

[0122] The C1-C4 alkyl substituents on Ar are optionally substituted with: -CN, -NO2, -OR z 、-NR x R y 、-S(O) i R x 、-NR x S(O) i R y 、-S(O) i NR x R y 、-C(=O)OR x 、-OC(=O)OR x 、-C(=S)OR x 、-O(C=S)R x 、-C(=O)NR x R y 、-NR x C(=O)R y 、-C(=S)NR x R y 、-NR x C(=S)R y 、-NR x (C=O)OR y 、-O(C=O)NR x R y 、-NR x (C=S)OR y 、-O(C=S)NR x R y 、-NR x (C=O)NR x R y 、-NR x (C=S)NR x R y 、-C(=S)R x 、-C(=O)R y, C3-C6 cycloalkyl (optionally substituted with one or more groups selected from -CH3, halomethyl, halo, methoxy and halomethoxy), monocyclic heteroaryl (optionally substituted with one or more groups selected from -CH3, halomethyl, halo, methoxy and halomethoxy), or phenyl (optionally substituted with one or more groups selected from -CH3, halomethyl, halo, methoxy and halomethoxy);

[0123] The C3-C6 cycloalkyl, C3-C6 heterocyclyl, phenyl and monocyclic heteroaryl substituents on Ar are optionally and independently substituted with C1-C4 alkyl, C1-C4 haloalkyl, halo, -CN, -NO2, -OR z 、-NR x R y 、-S(O) i R x 、-NR x S(O) i R y 、-S(O) i NR x R y 、-C(=O)OR x 、-OC(=O)OR x 、-C(=S)OR x 、-O(C=S)R y 、-C(=O)NR x R y 、-NR x C(=O)R y 、-C(=S)NR x R y 、-NR x C(=S)R y 、-NR x (C=O)OR y 、-O(C=O)NR x R y 、-NR x (C=S)OR y 、-O(C=S)NR x R y 、-NR x (C=O)NR x R y 、-NR x (C=S)NR x R y 、-C(=S)R x and -C(=O)R x ;

[0124] Each R x and each R yare independently -H, C1-C4 alkyl or C3-C8 cycloalkyl; wherein R x or R y The C1-C4 alkyl or C3-C8 cycloalkyl represented by is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, C3-C6 cycloalkyl and phenyl (optionally substituted with one or more groups selected from the group consisting of -CH3, halomethyl, halo, methoxy and halomethoxy);

[0125] R z is -H, C1-C4 alkyl, C1-C4 alkoxy, C3-C8 cycloalkyl or C3-C8 heterocyclic group; wherein R z The C1-C4 alkyl or C3-C8 cycloalkyl represented by is optionally substituted with one or more substituents selected from the group consisting of -CN, halo, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, and phenyl (optionally substituted with one or more groups selected from the group consisting of -CH3, halomethyl, halo, methoxy, and halomethoxy); and

[0126] i is 0, 1 or 2.

[0127] In a thirty-first embodiment, in the compounds of the invention according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth or thirtieth embodiment, or a pharmaceutically acceptable salt thereof, Ar is optionally substituted with one or more groups selected from optionally substituted C1-C4 alkyl, C1-C4 haloalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 heterocyclyl, halo, -CN, -OR z 、-NR x R y 、-C(=O)NR x R y 、-C(=S)NR x R y 、-O(C=O)NR x R y 、-O(C=S)NR x R y 、-C(=O)R x 、-C(=O)OR x 、-NR x C(=O)R y , phenyl and optionally substituted monocyclic heteroaryl.

[0128] In a thirty-second embodiment, in the compounds of the invention according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth or thirty-first embodiment, or a pharmaceutically acceptable salt thereof, Ar is optionally substituted with one or more groups selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, halo, -CN, -OR z 、-NR x R y 、-C(=O)NR x R y 、-C(=S)NR x R y 、-O(C=O)NR x R y 、-O(C=S)NR x R y 、-C(=O)OR x 、-NR x C(=O)R y , phenyl and optionally substituted monocyclic heteroaryl.

[0129] In a thirty-third embodiment, in the compounds of the invention according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth or thirty-first embodiment, or a pharmaceutically acceptable salt thereof, Ar is optionally substituted with one or more groups selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, halo, -CN, -OR z 、-NR x R y and -C(=O)R x wherein the C3-C6 cycloalkyl and C3-C6 heterocyclyl substituents on Ar are each optionally substituted by one or more independently selected halogen, C 1-4 Alkyl and C 1-4 Alkoxy group substitution; R x and R yEach independently represents -H, C1-C4 alkyl or C3-C6 cycloalkyl, wherein R x and R y The C1-C4 alkyl represented by 1-4 The alkoxy substituent is substituted; and R z is H, C1-C4 alkyl, C3-C8 cycloalkyl or C3-C6 heterocyclic group, wherein R z The C1-C4 alkyl, C3-C8 cycloalkyl and C3-C6 heterocyclyl represented are each optionally and independently substituted with one or more substituents independently selected from halo, -CN, C1-C4 alkyl and C1-C4 alkoxy.

[0130] In a thirty-fourth embodiment, in the compounds of the invention according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second or thirty-third embodiment, Ar is optionally replaced by one or more selected from C1-C4 alkyl, C1-C4 haloalkyl, halo, -CN and -OR z substituted by a group; wherein R z is a C1-C4 alkyl group optionally substituted by one or more halogen groups.

[0131] In a thirty-fifth embodiment, in the compounds of the invention according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second or thirty-third embodiment, or a pharmaceutically acceptable salt thereof, Ar is optionally substituted with one or more groups selected from: -CH3, -CF3, -CHF2, -F, -Cl, -CN, -OCH3, -OCHF2, -OC2H5, -OCH2CF3, -O(CH2)2(O)CH3, -OCH(CH3)2, -O-(3-methoxycyclobutyl), -O-cyclobutyl, -O-cyclopentyl, -COCH3, -N(H)CH3, -N(CH3)C2H5, -N(H)cyclobutyl, -NHCH2CH3, -NHCH(CH3)2, -N(CH3)2, -N(CH3)(CH2CH2(O)CH3), -OH, azetidinyl, oxetanyl, pyrrolidinyl, morpholinyl, 4-methylpiperazinyl and piperazinyl.

[0132] In a thirty-sixth embodiment, in the compounds of the invention according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth or thirty-fifth embodiment, or a pharmaceutically acceptable salt thereof, Ar is optionally substituted with one or more groups selected from -CH3, -CF3, -CHF2, -F, -Cl, -CN, -OCH3, -O(CH2)2(O)CH3, and -OCHF2.

[0133] In a thirty-seventh embodiment, in the compounds of the invention according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth or thirty-fifth embodiment, or a pharmaceutically acceptable salt thereof, Ar is optionally substituted with one or more groups selected from -CH3, -CF3, -CHF2, -F, -Cl, -CN, -OCH3, and -OCHF2.

[0134] In a thirty-eighth embodiment, in the compounds of the invention according to the eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth or thirty-seventh embodiment, n is 0.

[0135] In a thirty-ninth embodiment, the compound of the present invention is represented by one of the following structural formulas:

[0136] as well as

[0137]

[0138] or a pharmaceutically acceptable salt of the compound, wherein Ar is Each optionally substituted by a group selected from C1-C4 alkyl, C1-C4 haloalkyl, halo, -CN and -OR z The substituent R Ar Replacement; R z is H, C1-C4 alkyl, C3-C8 cycloalkyl or C3-C6 heterocyclic group, wherein R z The C1-C4 alkyl, C3-C8 cycloalkyl and C3-C6 heterocyclyl represented are each optionally and independently substituted with one or more substituents independently selected from halo, -CN, C1-C4 alkyl and C1-C4 alkoxy.

[0139] In the fortieth embodiment, in the compound of the present invention according to the thirty-ninth embodiment, Ar is represented by the formula:

[0140]

[0141] And the remaining variables are as defined in the thirty-ninth embodiment.

[0142] In the forty-first embodiment, in the compounds of the invention according to the thirty-ninth or fortieth embodiment, R Ar is C1-C4 alkyl or -OR z ; R z is H or C1-C4 alkyl optionally substituted with one to three substituents independently selected from halo, -CN, C1-C4 alkyl, and C1-C4 alkoxy; and the remaining variables are as defined in the thirty-ninth or fortieth embodiment.

[0143] In one embodiment, the compound of the present invention is selected from:

[0144]

[0145] or a pharmaceutically acceptable salt of the compound.

[0146] In another embodiment, the compound of the present invention is selected from:

[0147]

[0148] or a pharmaceutically acceptable salt of the compound.

[0149] In another embodiment, the compound of the present invention is selected from:

[0150]

[0151]

[0152] In another embodiment, the compounds of the present invention are selected from the compounds described in the exemplifications herein.

[0153] In yet another embodiment, the compound of the present invention is selected from the group consisting of:

[0154]

[0155] In one embodiment, the compound of the invention, e.g., according to the first or fourteenth embodiment, is selected from the group consisting of:

[0156] N-(5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0157] N-(5-(((2S,5R)-5-((5-fluoropyridin-2-yl)oxy)-2-methylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0158] N-(5-(((2S,5S)-5-((5-fluoropyridin-2-yl)oxy)-2-methylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0159] (R)-N-(5-((3-((5-fluoropyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0160] (S)-N-(5-((3-((5-fluoropyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0161] N-(5-(((2R,4S)-4-((5-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0162] N-(5-(((2S,4S)-4-((5-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0163] N-(5-(((2R,4R)-4-((5-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0164] N-(5-(((2S,4R)-4-((5-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0165] N-(5-(((2S,4R)-4-((6-methoxypyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0166] N-(5-(((2S,4R)-4-((5-(difluoromethyl)pyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0167] N-(5-(((2S,4R)-2-methyl-4-(pyridin-2-yloxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0168] N-(5-(((2S,4R)-4-((5-fluoro-6-methylpyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0169] N-(5-(((2S,4R)-4-((5-cyanopyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0170] N-(5-(((2S,4R)-4-((6-chloro-4-methylpyridin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0171] N-(5-(((2S,4R)-4-((6-(difluoromethyl)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0172] N-(5-(((2S,4R)-4-((5-fluoro-6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0173] N-(5-(((2S,4R)-4-((2-(difluoromethoxy)pyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0174] N-(4-fluoro-5-(((2S,4R)-4-((6-(2-methoxyethoxy)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0175] N-(5-(((2S,4R)-4-((6-(azetidin-1-yl)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[0176] N-(4-Fluoro-5-(((2S,4R)-4-((6-(3-fluoroazetidin-1-yl)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0177] N-(5-(((2S,4R)-4-((6-(3,3-difluoroazetidin-1-yl)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[0178] (S)-N-(4-fluoro-5-((3-((6-methoxypyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0179] (R)-N-(4-fluoro-5-((3-((6-methoxypyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0180] N-(4-Fluoro-5-(((2R,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0181] N-(4-fluoro-5-(((2S,4S)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0182] N-(4-fluoro-5-(((2R,4S)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0183] N-(4-fluoro-5-(((2S,5S)-5-((6-methoxypyrimidin-4-yl)oxy)-2-methylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0184] N-(4-fluoro-5-(((2S,5R)-5-((6-methoxypyrimidin-4-yl)oxy)-2-methylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0185] (S)-N-(5-((3-((6-methoxypyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0186] (R)-N-(5-((3-((6-methoxypyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0187] N-(5-(((2R,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0188] N-(5-(((2S,4S)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0189] N-(5-(((2R,4S)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0190] N-(5-(((2S,5S)-5-((6-methoxypyrimidin-4-yl)oxy)-2-methylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0191] N-(5-(((2S,5R)-5-((6-methoxypyrimidin-4-yl)oxy)-2-methylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0192] (R)-N-(4-fluoro-5-((3-((6-methoxypyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)propanamide;

[0193] N-(4-Fluoro-5-(((2S,4R)-4-((5-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0194] (S)-N-(5-((3-((2,6-dimethylpyridin-4-yl)oxy)pyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[0195] (R)-N-(5-((3-((2,6-dimethylpyridin-4-yl)oxy)pyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[0196] N-(5-(((2S,4R)-4-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[0197] N-(5-(((2R,4R)-4-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[0198] N-(5-(((2S,4S)-4-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[0199] N-(5-(((2R,4S)-4-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[0200] N-(5-(((2S,5S)-5-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpiperidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[0201] N-(5-(((2S,5R)-5-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpiperidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[0202] (S)-N-(5-((3-((2,6-dimethylpyridin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0203] (R)-N-(5-((3-((2,6-dimethylpyridin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0204] N-(5-(((2S,4R)-4-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0205] N-(5-(((2R,4R)-4-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0206] N-(5-(((2S,4S)-4-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0207] N-(5-(((2R,4S)-4-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0208] N-(5-(((2S,5S)-5-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0209] N-(5-(((2S,5R)-5-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0210] N-(5-(((2S,4R)-4-((6-methoxypyridazin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0211] N-(5-(((2S,4R)-2-methyl-4-((5-methylpyrazin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0212] N-(5-(((2S,4R)-2-methyl-4-((1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0213] N-(5-(((2S,4R)-4-((6-methoxy-5-methylpyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0214] N-(5-(((2S,4R)-4-((2,5-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0215] N-(5-(((2S,4R)-4-((5-methoxypyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0216] N-(4-fluoro-5-(((2S,4R)-4-((5-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0217] N-(5-(((2S,4R)-4-((2-methoxy-6-methylpyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0218] N-(5-(((2S,4R)-4-((6-acetylpyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[0219] N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0220] N-(5-(((2S,4R)-2-methyl-4-((6-(trifluoromethyl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0221] N-(5-(((2S,4R)-4-((3,5-dimethylpyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0222] N-(5-(((2S,4R)-2-methyl-4-((2-methylpyridin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0223] N-(5-(((2S,4R)-4-((6-fluoropyridazin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0224] N-(4-Fluoro-5-(((2S,4R)-4-((6-methoxypyridazin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0225] N-(4-Fluoro-5-(((2S,4R)-4-((6-fluoropyridin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0226] N-(5-(((2S,4R)-4-((5-fluoropyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0227] N-(5-(((2S,4R)-4-((5-fluoro-4-methylpyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0228] N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0229] N-(4-fluoro-5-(((2S,4R)-4-((5-methoxypyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0230] N-(5-(((2S,4R)-4-((5-chloropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[0231] N-(4-fluoro-5-(((2S,4R)-4-((4-methoxypyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0232] N-(4-Fluoro-5-(((2S,4R)-2-methyl-4-(pyrimidin-2-yloxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0233] N-(4-Fluoro-5-(((2S,4R)-4-((3-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0234] N-(5-(((2S,4R)-4-((5-chloropyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[0235] N-(4-Fluoro-5-(((2S,4R)-4-((4-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0236] N-(4-Fluoro-5-(((2S,4R)-4-((2-fluoropyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0237] N-(4-fluoro-5-(((2S,4R)-4-((5-methoxypyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0238] N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0239] N-(4-fluoro-5-(((2S,4R)-4-((2-methoxypyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0240] N-(5-(((2S,4R)-4-((4-chloropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[0241] N-(5-(((2S,4R)-4-((4,5-difluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[0242] N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((6-morpholinopyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0243] N-(5-(((2S,4R)-2-methyl-4-((2-methylpyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0244] N-(4-fluoro-5-(((2S,4R)-4-((5-methoxypyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0245] N-(5-(((2S,4R)-4-((3,5-dimethylpyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[0246] N-(5-(((2S,4R)-4-((2,5-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[0247] N-(4-Fluoro-5-(((2S,4R)-2-methyl-4-((5-methylpyrazin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0248] N-(4-Fluoro-5-(((2S,4R)-4-((6-hydroxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0249] N-(4-Fluoro-5-(((2S,4R)-2-methyl-4-((2-methylpyridin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0250] N-(4-Fluoro-5-(((2S,4R)-4-((6-fluoropyridazin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0251] N-(4-Fluoro-5-(((2S,4R)-4-((5-fluoropyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0252] N-(5-(((2S,4R)-4-((5-(difluoromethyl)pyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[0253] N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyridin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0254] N-(5-(((2S,4R)-4-((6-fluoropyridin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0255] N-(5-(((2R,4S)-2-methyl-4-((6-methylpyridin-3-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0256] N-(4-Fluoro-5-(((2S,4R)-4-((5-fluoro-4-methylpyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0257] N-(4-Fluoro-5-(((2S,4R)-4-((5-fluoro-4-methoxypyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0258] N-(4-Fluoro-5-(((2S,4R)-2-methyl-4-(pyrimidin-5-yloxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0259] N-(5-(((2S,4R)-4-((6-((1r,3R)-3-methoxycyclobutyloxy)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0260] N-(5-(((2S,4R)-4-((6-cyclobutoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0261] N-(5-(((2S,4R)-4-((6-(2-methoxyethoxy)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0262] N-(5-(((2S,4R)-2-methyl-4-((6-(oxetan-3-yloxy)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0263] N-(5-(((2S,4R)-2-methyl-4-((6-((1-methylazetidin-3-yl)oxy)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0264] N-(5-(((2S,4R)-4-((6-ethoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0265] N-(5-(((2S,4R)-4-((6-isopropoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0266] N-(5-(((2S,4R)-4-((2,6-dimethylpyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0267] N-(5-(((2S,4R)-2-methyl-4-((6-(pyrrolidin-1-yl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0268] N-(5-(((2S,4R)-2-methyl-4-((6-morpholinopyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0269] N-(5-(((2S,4R)-4-((6-(dimethylamino)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0270] N-(5-(((2S,4R)-4-((6-(ethyl(methyl)amino)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0271] N-(5-(((2S,4R)-4-((6-(azetidin-1-yl)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0272] N-(5-(((2S,4R)-4-((6-(cyclobutylamino)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0273] N-(5-(((2S,4R)-4-((6-(ethylamino)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0274] N-(5-(((2S,4R)-4-((6-(isopropylamino)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0275] N-(5-(((2S,4R)-2-methyl-4-((6-(methylamino)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0276] N-(5-(((2S,4R)-4-((6-(cyclopentyloxy)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0277] N-(5-(((2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[0278] N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((6-(oxetan-3-yloxy)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0279] N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((6-((1-methylazetidin-3-yl)oxy)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0280] N-(4-Fluoro-5-(((2S,4R)-2-methyl-4-((5-morpholinopyrazin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0281] N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((4-morpholinopyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0282] N-(4-fluoro-5-(((2S,4R)-4-((5-(2-methoxyethoxy)pyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0283] N-(4-fluoro-5-(((2S,4R)-4-((4-((2-methoxyethyl)(methyl)amino)pyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0284] N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((5-morpholinopyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0285] N-(4-fluoro-5-(((2S,4R)-4-((4-(2-methoxyethoxy)pyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0286] N-(4-Fluoro-5-(((2S,4R)-4-(4-fluorophenoxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0287] N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0288] N-(4-fluoro-5-(((2S,4R)-4-((5-(2-methoxyethoxy)pyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0289] N-(4-fluoro-5-(((2S,4R)-4-((5-((2-methoxyethyl)(methyl)amino)pyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0290] N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((4-(4-methylpiperazin-1-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0291] N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)-4,5,6- 13 C3)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0292] N-(5-(((2S,4R)-4-((6-(methoxy-d3)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0293] N-(4-Fluoro-5-(((2S,4R)-4-((6-(methoxy-d3)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0294] N-(5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide-2,2,2-d3;

[0295] N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide-2,2,2-d3;

[0296] N-(5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl-d)thiazol-2-yl)acetamide;

[0297] N-(4-Fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl-d)thiazol-2-yl)acetamide;

[0298] N-(5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl-d2)thiazol-2-yl)acetamide;

[0299] N-(4-Fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl-d2)thiazol-2-yl)acetamide;

[0300] N-(5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl-4-d)acetamide;

[0301] N-(5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl-4-d)methyl)thiazol-2-yl)acetamide;

[0302] N-(5-(((2S,4S)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl-4-d)methyl)thiazol-2-yl)acetamide;

[0303] N-(4-Fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0304] N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl-4-d)methyl)thiazol-2-yl)acetamide; and

[0305] N-(4-fluoro-5-(((2S,4S)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl-4-d)methyl)thiazol-2-yl)acetamide,

[0306] or a pharmaceutically acceptable salt of the compound.

[0307] In another embodiment, the compound of the invention, e.g., according to the first or fourteenth embodiment, is selected from the group consisting of:

[0308] N-(4-fluoro-5-(((2S,4R)-4-((6-(2-methoxyethoxy)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0309] N-(5-(((2S,4R)-4-((6-(azetidin-1-yl)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[0310] N-(4-Fluoro-5-(((2S,4R)-4-((6-(3-fluoroazetidin-1-yl)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0311] N-(5-(((2S,4R)-4-((6-(3,3-difluoroazetidin-1-yl)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[0312] N-(4-fluoro-5-(((2S,5S)-5-((6-methoxypyrimidin-4-yl)oxy)-2-methylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0313] N-(4-Fluoro-5-(((2S,4R)-4-((5-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0314] N-(5-(((2S,4R)-4-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[0315] N-(4-fluoro-5-(((2S,4R)-4-((5-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0316] N-(5-(((2S,4R)-4-((6-acetylpyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[0317] N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0318] N-(4-Fluoro-5-(((2S,4R)-4-((6-methoxypyridazin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0319] N-(4-Fluoro-5-(((2S,4R)-4-((6-fluoropyridin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0320] N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0321] N-(4-fluoro-5-(((2S,4R)-4-((5-methoxypyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0322] N-(5-(((2S,4R)-4-((5-chloropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[0323] N-(4-fluoro-5-(((2S,4R)-4-((4-methoxypyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0324] N-(4-Fluoro-5-(((2S,4R)-2-methyl-4-(pyrimidin-2-yloxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0325] N-(4-Fluoro-5-(((2S,4R)-4-((3-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0326] N-(5-(((2S,4R)-4-((5-chloropyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[0327] N-(4-Fluoro-5-(((2S,4R)-4-((4-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0328] N-(4-Fluoro-5-(((2S,4R)-4-((2-fluoropyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0329] N-(4-fluoro-5-(((2S,4R)-4-((5-methoxypyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0330] N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0331] N-(4-fluoro-5-(((2S,4R)-4-((2-methoxypyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0332] N-(5-(((2S,4R)-4-((4-chloropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[0333] N-(5-(((2S,4R)-4-((4,5-difluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[0334] N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((6-morpholinopyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0335] N-(4-fluoro-5-(((2S,4R)-4-((5-methoxypyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0336] N-(5-(((2S,4R)-4-((3,5-dimethylpyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[0337] N-(5-(((2S,4R)-4-((2,5-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[0338] N-(4-Fluoro-5-(((2S,4R)-2-methyl-4-((5-methylpyrazin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0339] N-(4-Fluoro-5-(((2S,4R)-4-((6-hydroxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0340] N-(4-Fluoro-5-(((2S,4R)-2-methyl-4-((2-methylpyridin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0341] N-(4-Fluoro-5-(((2S,4R)-4-((6-fluoropyridazin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0342] N-(4-Fluoro-5-(((2S,4R)-4-((5-fluoropyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0343] N-(5-(((2S,4R)-4-((5-(difluoromethyl)pyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[0344] N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyridin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0345] N-(4-Fluoro-5-(((2S,4R)-4-((5-fluoro-4-methylpyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0346] N-(4-Fluoro-5-(((2S,4R)-4-((5-fluoro-4-methoxypyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0347] N-(4-Fluoro-5-(((2S,4R)-2-methyl-4-(pyrimidin-5-yloxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0348] N-(5-(((2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[0349] N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((6-(oxetan-3-yloxy)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0350] N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((6-((1-methylazetidin-3-yl)oxy)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0351] N-(4-Fluoro-5-(((2S,4R)-2-methyl-4-((5-morpholinopyrazin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0352] N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((4-morpholinopyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0353] N-(4-fluoro-5-(((2S,4R)-4-((5-(2-methoxyethoxy)pyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0354] N-(4-fluoro-5-(((2S,4R)-4-((4-((2-methoxyethyl)(methyl)amino)pyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0355] N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((5-morpholinopyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0356] N-(4-fluoro-5-(((2S,4R)-4-((4-(2-methoxyethoxy)pyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0357] N-(4-Fluoro-5-(((2S,4R)-4-(4-fluorophenoxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0358] N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0359] N-(4-fluoro-5-(((2S,4R)-4-((5-(2-methoxyethoxy)pyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0360] N-(4-fluoro-5-(((2S,4R)-4-((5-((2-methoxyethyl)(methyl)amino)pyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0361] N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((4-(4-methylpiperazin-1-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0362] N-(4-Fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[0363] N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl-4-d)methyl)thiazol-2-yl)acetamide; and

[0364] N-(4-fluoro-5-(((2S,4S)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl-4-d)methyl)thiazol-2-yl)acetamide,

[0365] or a pharmaceutically acceptable salt of the compound.

[0366] As used herein, the term "alkyl" refers to a fully saturated branched or straight chain hydrocarbon moiety. Unless otherwise specified, an alkyl group contains 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, or most preferably 1 to 4 carbon atoms. Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

[0367] As used herein, the term "alkoxy" refers to a group -OR, wherein R is an alkyl or cycloalkyl group as defined above. Non-limiting examples of alkoxy groups include: -OCH, -OCHCH, -OCHCHCH, -OCH(CH), -OCH(CH), -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, and -O-cyclohexyl.

[0368] As used herein, the terms "aryl", "aryl group", "aryl ring", "aromatic group" and "aromatic ring" are used interchangeably to refer to an aromatic 5- to 12-membered monocyclic or bicyclic carbocyclic ring system. Examples of monocyclic aryl systems include, but are not limited to, cyclopenta-1,3-dien-1-yl, phenyl, and the like.

[0369] The number of carbon atoms in a group is indicated herein by the prefix "C x-xx ", where x and xx are integers. For example, "C 1-4 "Alkyl" refers to an alkyl group having 1 to 4 carbon atoms.

[0370] The term "halogen" or "halo" as used herein may be fluorine, chlorine, bromine or iodine.

[0371] The term "haloalkyl" as used herein refers to an alkyl group, as defined herein, substituted with one or more halo groups, as defined herein.

[0372] As used herein, the terms "heterocyclyl," "heterocyclyl group," "heterocycle," and "heterocyclic ring" are used interchangeably to refer to a saturated, unsaturated, non-aromatic, monocyclic or bicyclic (e.g., fused) ring system having 3 to 12 ring members, or in particular 3 to 6 ring members or 5 to 7 ring members, at least one of which is a heteroatom, and up to 4 of which (e.g., 1, 2, 3, or 4) may be heteroatoms, wherein the heteroatoms are independently selected from O, S, and N, and wherein C may be oxidized (e.g., C(═O)), N may be oxidized (e.g., N(O)), or quaternized (e.g., N(C)). + ), and S can be optionally oxidized to sulfoxide and sulfone. Examples of non-aromatic heterocyclic groups include aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, isoxazolidinyl, isothiazolidinyl, piperidinyl, tetrahydropyranyl, thiolanyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithiolanyl, azepanyl, oxepanyl, thiolanyl, dihydrofuranyl, imidazolinyl, dihydropyranyl, hydantoinyl, pyrrolidonyl, tetrahydrothiopyranyl, tetrahydropyridinyl and thiopyranyl. Examples of bicyclic non-aromatic heterocyclic ring systems include benzo[1,3]dioxolyl, tetrahydroindolyl and 2-azaspiro[3.3]heptyl.

[0373] As used herein, the terms "heteroaryl", "heteroaryl group", "heteroaryl ring", "heteroaromatic" and "heteroaromatic ring" are used interchangeably to refer to an aromatic 5- to 12-membered monocyclic or bicyclic ring system having 1 to 4 heteroatoms independently selected from O, S and N, and wherein N can be oxidized (e.g., N(O)) or quaternized, and S can optionally be oxidized to sulfoxide and sulfone. "Heteroaryl" includes heteroaromatic groups fused to a phenyl or non-aromatic heterocycle, such as tetrahydrofuran, pyran, pyrrolidine, piperidine, and the like. As used herein, the heteroaryl Ar group can be attached to the remainder of the compound of the invention at any ring having an open valency. Examples of monocyclic heteroaryl ring systems include pyrrolyl, furanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, triazinyl, tetrazinyl, azepine, oxepinyl, thiepine, thiaazepine, 1-oxo-pyridinyl, thienyl, valerolactamyl, and the like.

[0374] As used herein, the term "cycloalkyl" refers to a fully saturated monocyclic or bicyclic (eg, fused) hydrocarbon group of 3-12 carbon atoms, 3-6 carbon atoms, or 5-7 carbon atoms.

[0375] The term "halocycloalkyl" as used herein refers to a cycloalkyl group, as defined herein, substituted with one or more halo groups, as defined herein.

[0376] Substituted alkyl, phenyl, heteroaryl, non-aromatic heterocyclyl or heterocyclyl groups are alkyl, phenyl, heteroaryl, non-aromatic heterocyclyl or heterocyclyl groups having one or more (e.g., two, three, four, five, six, etc.) substituents. In some embodiments, substituted alkyl, phenyl, heteroaryl, non-aromatic heterocyclyl or heterocyclyl groups are alkyl, phenyl, heteroaryl, non-aromatic heterocyclyl or heterocyclyl groups having one to six, one to three, or one to two substituents. Suitable substituents are those that do not significantly reduce the O-GlcNAcase inhibitory activity of a compound or a pharmaceutically acceptable salt of a compound of formula (IA), (IIA), (IIIA), (IVA-1), (IVA-2), (VA-1), (VA-2), (VIA-1), (VIA-2), (VIIA), (VIIA-2), (IB), (IIB-1), (IIB-2), (IIIB-1), (IIIB-2), (IVB-1), (IVB-2). Examples of suitable substituents for alkyl, phenyl, heteroaryl, non-aromatic heterocyclic or heterocyclic groups include, but are not limited to, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, halo ,-CN ,-NO2,-OR z 、-NR x R y 、-S(O) i R x 、-NR x S(O) i R y 、-S(O) i NR x R y 、-C(=O)OR x 、-OC(=O)OR x 、-C(=S)OR y 、-O(C=S)R x 、-C(=O)NR x R y 、-NR x C(=O)R y 、-C(=S)NR x R y 、-NR x C(=S)R y 、-NR x (C=O)OR y 、-O(C=O)NR x R y 、-NR x (C=S)OR y 、-O(C=S)NR x R y 、-NRx (C=O)NR x R y 、-NR x (C=S)NR x R y 、-C(=S)R x 、-C(=O)R x , phenyl and monocyclic heteroaryl. C1-C4 alkyl substituents are optionally substituted by: -CN, -NO2, -OR z 、-NR x R y 、-S(O) i R x 、-NR x S(O) i R y 、-S(O) i NR x R y 、-C(=O)OR x 、-OC(=O)OR x 、-C(=S)OR x 、-O(C=S)R x 、-C(=O)NR x R y 、-NR x C(=O)R y 、-C(=S)NR x R y 、-NR x C(=S)R y 、-NR x (C=O)OR y 、-O(C=O)NR x R y 、-NR x (C=S)OR y 、-O(C=S)NR x R y 、-NR x (C=O)NR x R y 、-NR x (C=S)NR x R y 、-C(=S)R x and -C(=O)R y, C3-C6 cycloalkyl (optionally substituted with one or more groups selected from -CH3, halomethyl, halo, methoxy and halomethoxy), monocyclic heteroaryl (optionally substituted with one or more groups selected from -CH3, halomethyl, halo, methoxy or halomethoxy) and phenyl (optionally substituted with one or more groups selected from -CH3, halomethyl, halo, methoxy and halomethoxy). C3-C6 cycloalkyl, phenyl and monocyclic heteroaryl substituents are optionally and independently substituted with C1-C4 alkyl, C1-C4 haloalkyl, halo, -CN, -NO2, -OR z 、-NR x R y 、-S(O) i R x 、-NR x S(O) i R y 、-S(O) i NR x R y 、-C(=O)OR x 、-OC(=O)OR x 、-C(=S)OR x 、-O(C=S)R y 、-C(=O)NR x R y 、-NR x C(=O)R y 、-C(=S)NR x R y 、-NR x C(=S)R y 、-NR x (C=O)OR y 、-O(C=O)NR x R y 、-NR x (C=S)OR y 、-O(C=S)NR x R y 、-NR x (C=O)NR x R y 、-NR x (C=S)NR x R y 、-C(=S)R x and -C(=O)R x In these substituents, each R x and each R y are independently -H, C1-C4 alkyl or C3-C8 cycloalkyl, wherein R x or R yThe C1-C4 alkyl or C3-C8 cycloalkyl represented by is optionally substituted by one or more substituents selected from the following: halogen, hydroxy, C3-C6 cycloalkyl and phenyl (optionally substituted by one or more groups selected from -CH3, halomethyl, halo, methoxy or halomethoxy). Among these substituents, R z is -H, C1-C4 alkyl or C3-C8 cycloalkyl, wherein R z The C1-C4 alkyl or C3-C8 cycloalkyl represented by is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, C3-C6 cycloalkyl, and phenyl (optionally substituted with one or more groups selected from the group consisting of -CH3, halomethyl, halo, methoxy, and halomethoxy). In these substituents, i is 0, 1, or 2.

[0377] Pharmaceutically acceptable salts of the compounds disclosed herein are also included in the present invention. In the case where the compounds provided herein have sufficient alkalinity or acidity to form stable, non-toxic acid salts or base salts, the preparation and administration of the compounds in the form of pharmaceutically acceptable salts may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids that form physiologically acceptable anions, for example, toluenesulfonate, mesylate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate, or α-glycerophosphate. Inorganic salts can also be formed, including hydrochlorides, sulfates, nitrates, bicarbonates, and carbonates.

[0378] Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example, by reacting a sufficiently basic compound (e.g., an amine) with a suitable acid to yield a physiologically acceptable anion. Alkali metal (e.g., sodium, potassium, or lithium) or alkaline earth metal (e.g., calcium) salts of carboxylic acids can also be prepared.

[0379] Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Suitable bases include, but are not limited to, alkali metal hydroxides, alkaline earth metal hydroxides, carbonates, bicarbonates, and the like.

[0380] The disclosed compound or the pharmaceutically acceptable salt of the compound may contain one or more asymmetric centers in the molecule. According to the present disclosure, any structure that does not specify stereochemistry is understood to encompass all various stereoisomers (e.g., diastereomers and enantiomers) in pure or substantially pure form, and mixtures thereof (e.g., racemic mixtures or mixtures enriched in enantiomers). It is well known in the art how to prepare such optically active forms (e.g., racemic forms are resolved by recrystallization techniques, synthesized from optically active starting materials, synthesized by chiral synthesis or chromatographic separation using chiral stationary phases). The disclosed compound may exist in tautomeric form, and encompasses mixtures and separate individual tautomers. Additionally, some compounds may exhibit polymorphism.

[0381] When a specific stereoisomer (e.g., enantiomer, diastereomer, etc.) of a compound used in the disclosed methods is depicted by name or structure, the stereochemical purity of the compound is at least 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5%, or 99.9%. "Stereochemical purity" means the weight percentage of the desired stereoisomer relative to the combined weight of all stereoisomers.

[0382] When the stereochemistry of a disclosed compound is named or depicted by a structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., in a diastereomeric pair), it is understood that any mixture of one of the encompassed stereoisomers or the encompassed stereoisomers is included. It is further understood that the stereoisomeric purity of the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight. In this case, stereoisomeric purity is determined by dividing the total weight of the stereoisomers encompassed by the name or structure in the mixture by the total weight of all stereoisomers in the mixture.

[0383] In one embodiment, the present invention also provides isotopically labeled compounds, which are identical to those described herein, but with one or more atoms replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. All isotopes of any particular atom or element specified are encompassed within the scope of the compounds of the present invention and their uses. Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, for example, 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O.17 O. 18 O. 32 P. 33 P. 35 S. 18 F. 36 Cl, 123 I and 125 I. Certain isotopically labeled compounds of the present invention (e.g., 3 H and 14 C-labeled ones) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e., 14 C) isotopes are useful for their ease of preparation and detectability. In addition, deuterium (i.e., 2 Substitution of heavier isotopes with H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. 15 O. 13 N. 11 C and 18 Positron-emitting isotopes of F are useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically-labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or in the Examples below, by substituting an isotopically-labeled reagent for a non-isotopically-labeled reagent.

[0384] In one embodiment, the invention provides deuterated compounds disclosed herein wherein any position occupied by hydrogen is meant to also include deuterium enrichment above the natural abundance of deuterium. For example, one or more hydrogen atoms are replaced with deuterium at an abundance of at least 3340 times (i.e., at least 50.1% deuterium incorporation), at least 3500 times (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 times (60% deuterium incorporation), at least 4500 times (67.5% deuterium incorporation), at least 5000 times (75% deuterium incorporation), at least 5500 times (82.5% deuterium incorporation), at least 6000 times (90% deuterium incorporation), at least 6333.3 times (95% deuterium incorporation), at least 6466.7 times (97% deuterium incorporation), at least 6600 times (99% deuterium incorporation), or at least 6633.3 times (99.5% deuterium incorporation) greater than the natural abundance of deuterium of 0.015%. In one embodiment, hydrogen is present in its natural abundance at all positions.Compounds as described herein or pharmaceutically acceptable salts of said compounds may exist in tautomeric forms, and both mixtures and separate individual tautomers are encompassed.

[0385] One aspect of the present invention includes a method for inhibiting glycosidases and / or glycosidase signaling pathways in a cell, the method comprising contacting the cell with an effective amount of a compound of Formula (IA), (IIA), (IIIA), (IVA-1), (IVA-2), (VA-1), (VA-2), (VIA-1), (VIA-2), (VIIA), (VIIA-2), (IB), (IIB-1), (IIB-2), (IIIB-1), (IIIB-2), (IVB-1), (IVB-2), or a pharmaceutically acceptable salt thereof. The glycosidase is preferably a glycoside hydrolase, more preferably a family 84 glycoside hydrolase, even more preferably an O-glycoprotein-2-acetamido-2-deoxy-3-D-pyranosidase (O-GlcNAcase or OGA), most preferably a mammalian O-GlcNAcase. In one embodiment, the cell is contacted in vitro or in vivo. In one embodiment, contacting the cell comprises administering a compound to a subject.

[0386] One aspect of the present invention includes a method of inhibiting a glycosidase and / or a glycosidase signaling pathway in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (IA), (IIA), (IIIA), (IVA-1), (IVA-2), (VA-1), (VA-2), (VIA-1), (VIA-2), (VIIA), (VIIA-2), (IB), (IIB-1), (IIB-2), (IIIB-1), (IIIB-2), (IVB-1), (IVB-2), or a pharmaceutically acceptable salt thereof, thereby activating a glycosidase in the subject. The glycosidase is preferably a glycoside hydrolase, more preferably a Family 84 glycoside hydrolase, even more preferably O-glycoprotein-2-acetamido-2-deoxy-3-D-pyranosidase (O-GlcNAcase or OGA), most preferably mammalian O-GlcNAcase.

[0387] One aspect of the present invention includes a method of promoting the survival of eukaryotic cells (e.g., mammalian cells) or increasing the lifespan of the cells, comprising administering to a subject a therapeutically effective amount of a compound of Formula (IA), (IIA), (IIIA), (IVA-1), (IVA-2), (VA-1), (VA-2), (VIA-1), (VIA-2), (VIIA), (VIIA-2), (IB), (IIB-1), (IIB-2), (IIIB-1), (IIIB-2), (IVB-1), (IVB-2) or a pharmaceutically acceptable salt thereof, thereby promoting the survival of the eukaryotic cells or increasing the lifespan of the cells.

[0388] One aspect of the present invention includes a method for treating a disease or illness caused, mediated and / or propagated by O-GlcNAcase activity in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (IA), (IIA), (IIIA), (IVA-1), (IVA-2), (VA-1), (VA-2), (VIA-1), (VIA-2), (VIIA), (VIIA-2), (IB), (IIB-1), (IIB-2), (IIIB-1), (IIIB-2), (IVB-1), (IVB-2) or a pharmaceutically acceptable salt thereof. Preferably, the disease or illness is a neurological disorder, diabetes, cancer or stress disorder. More preferably, the disease or illness is a neurological disorder.In one embodiment, the neurological disorder is one or more tauopathies selected from the group consisting of acute ischemic stroke (AIS), Alzheimer's disease, dementia, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis with cognitive impairment (ALSci), argyrophilic grain dementia, Bluit disease, corticobasal degeneration (CBP), dementia pugilistica, diffuse neurofibrillary tangles with calcifications, Down's syndrome, epilepsy, familial British dementia, familial Danish dementia, frontotemporal dementia with Parkinson's disease linked to chromosome 17 (FTDP-17), Gerstmann-Straussler-Scheinker disease, Guadeloupean parkinsonism, Hallevorden-Spatz disease, and tauopathies. disease (neurodegeneration with type 1 brain iron accumulation), ischemic stroke, mild cognitive impairment (MCI), multiple system atrophy, myotonic dystrophy, Niemann-Pick disease (type C), pallidum-ponto-nigral degeneration, Parkinsonism-dementia complex of Guam, Pick's disease (PiD), postencephalitis Parkinsonism (PEP), prion diseases (including Creutzfeldt-Jakob disease (GJD) and variant Creutzfeldt-Jakob disease (vCJD)), fatal familial insomnia, kuru, progressive supracortical gliomatosis, progressive supranuclear palsy (PSP), Steele-Richardson-Olszewski syndrome In another embodiment, the neurological disorder is one or more tau diseases selected from the group consisting of acute ischemic stroke (AIS), Alzheimer's disease, dementia, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis with cognitive impairment (ALSci), argyrophilic grain dementia, epilepsy, mild cognitive impairment (MCI), Huntington's disease, and Parkinson's disease. In yet another embodiment, the neurological disorder is Alzheimer's disease.

[0389] One aspect of the invention includes a method of treating a disease or condition characterized by hyperphosphorylation of tau (e.g., hyperphosphorylation of tau in the brain) in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (IA), (IIA), (IIIA), (IVA-1), (IVA-2), (VA-1), (VA-2), (VIA-1), (VIA-2), (VIIA), (VIIA-2), (IB), (IIB-1), (IIB-2), (IIIB-1), (IIIB-2), (IVB-1), (IVB-2), or a pharmaceutically acceptable salt thereof. In one embodiment, the disease or condition is selected from acute ischemic stroke (AIS), Alzheimer's disease, dementia, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis with cognitive impairment (ALSci), argyrophilic grain dementia, Bluit disease, corticobasal degeneration (CBP), dementia pugilistica, diffuse neurofibrillary tangles with calcifications, Down syndrome, epilepsy, familial British dementia, familial Danish dementia, frontotemporal dementia with Parkinson's disease linked to chromosome 17 (FTDP-17), Gerstmann-Straussler-Scheinker disease, Guadeloupe Parkinson's disease, Hallervorden-Spatz disease (neurodegeneration with Type 1 brain iron accumulation), ischemic stroke, mild cognitive impairment (MCI), multiple system atrophy, myotonic dystrophy, Niemann-Pick disease (type C), pallidopamine-ponto-nigral degeneration, Guam Parkinsonism-dementia complex, Pick's disease (PiD), postencephalitic Parkinsonism (PEP), prion diseases (including Creutzfeldt-Jakob disease (GJD) and variant Creutzfeldt-Jakob disease (vCJD)), fatal familial insomnia, kuru, progressive supracortical gliomatosis, progressive supranuclear palsy (PSP), Stille-Richardson-Oerstein syndrome, subacute sclerosing panencephalitis, simple entanglement dementia, Huntington's disease, and Parkinson's disease. In another embodiment, the disease or disorder is selected from acute ischemic stroke (AIS), Alzheimer's disease, dementia, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis with cognitive impairment (ALSci), argyrophilic grain dementia, epilepsy, ischemic stroke, mild cognitive impairment (MCI), Huntington's disease and Parkinson's disease. In yet another embodiment, the disease or disorder is Alzheimer's disease.

[0390] As used herein, the terms "subject" and "patient" are used interchangeably and refer to mammals in need of treatment, such as companion animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, pigs, horses, sheep, goats, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Typically, the subject is a human in need of treatment.

[0391] As used herein, the term "treat" or "treatment" refers to obtaining a desired pharmacological and / or physiological effect. The effect can be therapeutic, including partially or substantially achieving one or more of the following results: partially or completely alleviating the extent of the disease, disorder, or syndrome; improving or ameliorating clinical symptoms or indicators associated with the disorder; and delaying, inhibiting, or reducing the likelihood of progression of the disease, disorder, or syndrome.

[0392] The term "effective amount" means an amount of a compound of Formula (IA), (IIA), (IIIA), (IVA-1), (IVA-2), (VA-1), (VA-2), (VIA-1), (VIA-2), (VIIA), (VIIA-2), (IB), (IIB-1), (IIB-2), (IIIB-1), (IIIB-2), (IVB-1), (IVB-2), or a pharmaceutically acceptable salt thereof, e.g., 0.1 mg to 1000 mg per kg body weight, which, when administered to a subject, achieves a beneficial or desired result, including a clinical result, i.e., reverses, alleviates, inhibits, alleviates, or slows the effects of a drug indicated by Formula (IA), (IIA), (IIIA), (IVA-1), (IVA-2), (VA-1), (VA-2), (VIA-1), (VIA-2), (VIIA-2), (IB), (IIB-1), (IIB-2), (IIIB-1), (IIIB-2), (IVB-1), (IVB-2). The invention also includes but is not limited to: inhibiting the progression of a disease or condition treatable by a compound of Formula (IA), (IIA), (IIIA), (IVA-1), (IVA-2), (VA-1), (VA-2), (VIA-1), (VIA-2), (VIIA), (VIIA-2), (IB), (IIB-1), (IIB-2), (IIIB-1), (IIIB-2), (IVB-1), (IVB-2), or a pharmaceutically acceptable salt thereof, and reducing the likelihood of recurrence of a disease or condition treatable by a compound of Formula (IA), (IIA), (IIIA), (IVA-1), (IVA-2), (VA-1), (VA-2), (VIA-1), (VIA-2), (VIIA), (VIIA-2), (IB), (IIB-1), (IIB-2), (IIIB-1), (IIIB-2), (IVB-1), (IVB-2), or a pharmaceutically acceptable salt thereof, for example, as determined by clinical symptoms compared to a control. The expression "effective amount" also encompasses an amount effective to increase normal physiological function.

[0393] Another embodiment of the present invention is a pharmaceutical composition comprising at least one compound described herein or a pharmaceutically acceptable salt of said compound and at least one pharmaceutically acceptable carrier.

[0394] Also included are uses of a compound of Formula (IA), (IIA), (IIIA), (IVA-1), (IVA-2), (VA-1), (VA-2), (VIA-1), (VIA-2), (VIIA), (VIIA-2), (IB), (IIB-1), (IIB-2), (IIIB-1), (IIIB-2), (IVB-1), (IVB-2) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating one or more diseases or conditions described herein. Also included herein are pharmaceutical compositions comprising a compound of Formula (IA), (IIA), (IIIA), (IVA-1), (IVA-2), (VA-1), (VA-2), (VIA-1), (VIA-2), (VIIA), (VIIA-2), (IB), (IIB-1), (IIB-2), (IIIB-1), (IIIB-2), (IVB-1), (IVB-2), or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable carrier, for use in the manufacture of a medicament for treating one or more diseases or conditions described herein. Also included are compounds of Formula (IA), (IIA), (IIIA), (IVA-1), (IVA-2), (VA-1), (VA-2), (VIA-1), (VIA-2), (VIIA), (VIIA-2), (IB), (IIB-1), (IIB-2), (IIIB-1), (IIIB-2), (IVB-1), (IVB-2), or pharmaceutically acceptable salts thereof for use in treating a subject suffering from one or more diseases or conditions described herein. Also included are pharmaceutical compositions comprising a compound of Formula (IA), (IIA), (IIIA), (IVA-1), (IVA-2), (VA-1), (VA-2), (VIA-1), (VIA-2), (VIIA), (VIIA-2), (IB), (IIB-1), (IIB-2), (IIIB-1), (IIIB-2), (IVB-1), (IVB-2), or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable carrier, for use in treating one or more diseases or conditions described herein.

[0395] The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier, diluent, adjuvant, vehicle or excipient that does not adversely affect the pharmacological activity of the compound with which it is formulated and is safe for human use. Pharmaceutically acceptable carriers that can be used in the compositions of the present disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, magnesium stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based materials (e.g., microcrystalline cellulose, hydroxypropyl methylcellulose, lactose monohydrate, sodium lauryl sulfate, and crosscarmellose sodium), polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0396] Other excipients, such as flavoring agents, sweeteners, and preservatives, such as methylparaben, ethylparaben, propylparaben, and butylparaben, may also be included. A more complete list of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5th edition, Pharmaceutical Press (2005)). Those skilled in the art will know how to prepare formulations suitable for various types of routes of administration. Conventional procedures and ingredients for the selection and preparation of formulations suitable for use are described in, for example, Remington's Pharmaceutical Sciences (2003, 20th edition) and the United States Pharmacopeia published in 1999: National Formulary (USP 24NF19).

[0397] The compounds of Formula (IA), (IIA), (IIIA), (IVA-1), (IVA-2), (VA-1), (VA-2), (VIA-1), (VIA-2), (VIIA), (VIIA-2), (IB), (IIB-1), (IIB-2), (IIIB-1), (IIIB-2), (IVB-1), (IVB-2), or pharmaceutically acceptable salts thereof, or compositions of the present teachings can be administered, for example, orally, parenterally, sublingually, topically, rectally, nasally, buccally, vaginally, transdermally, by patch, by pump, or via an implantable reservoir, and the pharmaceutical compositions will be formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration can be by continuous infusion over a selected period of time.

[0398] Other administration forms encompassed by the present disclosure are described in WO 2013 / 075083, WO 2013 / 075084, WO 2013 / 078320, WO 2013 / 120104, WO 2014 / 124418, WO 2014 / 151142 and WO 2015 / 023915, the contents of which are incorporated herein by reference.

[0399] Useful dosages of the compounds as described herein or pharmaceutically acceptable salts of the compounds can be determined by comparing their in vitro activity with their in vivo activity in animal models. Methods for extrapolating effective doses in mice and other animals to humans are known in the art; for example, see U.S. Patent No. 4,938,949, which is incorporated by reference in its entirety.

[0400] example

[0401] General Methods

[0402] Silica gel chromatography was performed using a Teledyne ISCO Combiflash RF or Grace RevelerisX2 with an ELSD purification system using 20-40 uM (particle size), 250-400 mesh or 400-632 mesh silica gel.

[0403] Analytical HPLC

[0404] Acidic HPLC: performed on a Shimadza 20A instrument with an Ultimate C18 3.0 x 50 mm, 3 μm column eluting with 2.75 mL / 4 L TFA / water (solvent A) and 2.5 mL / 4 L TFA / acetonitrile (solvent B) by the following method:

[0405] Method A: The following elution gradient was used: 0%-60% (Solvent B) over 6 minutes and hold at 60% for 2 minutes, flow rate 1.2 ml / min. Wavelength: UV 220 nm, 215 nm and 254 nm.

[0406] Method B: The following elution gradient was used: 10%-80% (Solvent B) over 6 minutes and hold at 60% for 2 minutes, flow rate 1.2 ml / min. Wavelength: UV 220 nm, 215 nm and 254 nm.

[0407] Method C: The following elution gradient was used: 30%-90% (Solvent B) over 6 minutes and hold at 60% for 2 minutes, flow rate 1.2 ml / min. Wavelength: UV 220 nm, 215 nm and 254 nm.

[0408] Basic HPLC: performed on a Shimadza 20A instrument with an XbrigeShield RP-18, 5 μm, 2.1×50 mm column eluting with 2 mL / 4 L NH 3 H 2 O / water (solvent A) and acetonitrile (solvent B) by the following method:

[0409] Method D: The following elution gradient was used: 0%-60% (Solvent B) over 4.0 minutes and hold at 60% for 2 minutes, flow rate 1.2 ml / min.

[0410] Method E: The following elution gradient was used: 10%-80% (Solvent B) over 4.0 minutes and hold at 60% for 2 minutes, flow rate 1.2 ml / min.

[0411] Method F: The following elution gradient was used: 30%-90% (Solvent B) over 4.0 minutes and hold at 60% for 2 minutes, flow rate 1.2 ml / min.

[0412] Analytical LCMS

[0413] Acidic LCMS: Agilent 1100 Series LC / MSD system with DAD\ELSD, Agilent LC\MSD VL(G1956A)SL(G1956B) mass spectrometer, Agilent 1200 Series LC / MSD system with DAD\ELSD, Agilent LC\MSD SL(G6130A)SL(G6140A) mass spectrometer, equipped with a C18 column (2.1 mm×30 mm, 3.0 mm or 2.1 mm×50 mm, C18, 1.7 μm) eluted with 1.5 mL / 4 L TFA / water (solvent A) and 0.75 mL / 4 L TFA / acetonitrile (solvent B) or a Zorbax SB-C18 1.8 μm column with solvent A - acetonitrile (0.1% formic acid), solvent B - water (0.1% formic acid) The following method was used on a Shimadza 2010 series, Shimadza 2020 series, or Waters Acquity UPLC BEH. (MS ionization: ESI) instrument with a 4.6×15 mm rapid desorption cartridge:

[0414] 1.5 minute method:

[0415] General method: The following elution gradient was used: 5%-95% (Solvent B) over 0.7 min and hold at 95% for 0.4 min, flow rate 1.5 ml / min. Wavelength: UV 220 nm and 254 nm.

[0416] 2-minute method:

[0417] Method A: The following elution gradient was used: 0%-60% (Solvent B) over 0.9 minutes and held at 60% for 0.6 minutes, flow rate 1.2 ml / min. Wavelength: UV 220 nm and 254 nm.

[0418] Method B: The following elution gradient was used: 10%-80% (Solvent B) over 0.9 minutes and held at 60% for 0.6 minutes, flow rate 1.2 ml / min. Wavelength: UV 220 nm and 254 nm.

[0419] Method C: The following elution gradient was used: 30%-90% (Solvent B) over 0.9 minutes and hold at 60% for 0.6 minutes, flow rate 1.2 ml / min. Wavelength: UV 220 nm and 254 nm.

[0420] 3.5 minute method:

[0421] Initial conditions: solvent A 95%: solvent B 5%; initial hold 0.0-0.1 min; linear ramp to solvent A 5%: solvent B 95% between 0.1-3.25 min; hold solvent A 5%: solvent B 95% between 3.25-3.5 min. Diode array / MS detection.

[0422] 4-Minute Method:

[0423] Method A: The following elution gradient was used: 0%-60% (Solvent B) over 3 minutes and hold at 60% for 0.5 minutes, flow rate 0.8 ml / min. Wavelength: UV 220 nm and 254 nm.

[0424] Method B: The following elution gradient was used: 10%-80% (Solvent B) over 3 minutes and hold at 60% for 0.5 minutes, flow rate 0.8 ml / min. Wavelength: UV 220 nm and 254 nm.

[0425] Method C: The following elution gradient was used: 30%-90% (Solvent B) over 3 minutes and hold at 60% for 0.5 minutes, flow rate 0.8 ml / min. Wavelength: UV 220 nm and 254 nm.

[0426] 7-Minute Method:

[0427] Method A: The following elution gradient was used: 0%-60% (Solvent B) over 6 minutes and hold at 60% for 0.5 minutes, flow rate 0.8 ml / min. Wavelength: UV 220 nm and 254 nm.

[0428] Method B: The following elution gradient was used: 10%-80% (Solvent B) over 6 minutes and hold at 60% for 0.5 minutes, flow rate 0.8 ml / min. Wavelength: UV 220 nm and 254 nm.

[0429] Method C: The following elution gradient was used: 30%-900% (Solvent B) over 6 minutes and hold at 60% for 0.5 minutes, flow rate 0.8 ml / min. Wavelength: UV 220 nm and 254 nm.

[0430] Basic LCMS: performed on a Shimadza 2020 series or Waters Acquity UPLC BEH (MS ionization: ESI) instrument equipped with an XBridgeShield RP18, 5 μm column (2.1 mm × 30 mm, 3.0 mm inner diameter) or a 2.1 mm × 50 mm, C18, 1.7 μm column eluted with 2 mL / 4 L NH3·H2O / water (solvent A) and acetonitrile (solvent B) using the following method:

[0431] 3-minute method:

[0432] Method A: The following elution gradient was used: 0%-60% (Solvent B) over 2 minutes and hold at 60% for 0.48 minutes, flow rate 1 ml / min. Wavelength: UV 220 nm and 254 nm.

[0433] Method B: The following elution gradient was used: 10%-80% (Solvent B) over 2 minutes and hold at 60% for 0.48 minutes, flow rate 1 ml / min. Wavelength: UV 220 nm and 254 nm.

[0434] Method C: The following elution gradient was used: 30%-90% (Solvent B) over 2 minutes and hold at 60% for 0.48 minutes, flow rate 1 ml / min. Wavelength: UV 220 nm and 254 nm.

[0435] 3.5 minute method:

[0436] Initial conditions: solvent A 95%: solvent B 5%; initial hold 0.0-0.1 min; linear ramp to solvent A 5%: solvent B 95% between 0.1-3.25 min; hold solvent A 5%: solvent B 95% between 3.25-3.5 min. Diode array / MS detection.

[0437] 7-Minute Method:

[0438] Method A: The following elution gradient was used: 0%-60% (Solvent B) over 6 minutes and hold at 60% for 0.5 minutes, flow rate 0.8 ml / min. Wavelength: UV 220 nm and 254 nm.

[0439] Method B: The following elution gradient was used: 10%-80% (Solvent B) over 6 minutes and hold at 60% for 0.5 minutes, flow rate 0.8 ml / min. Wavelength: UV 220 nm and 254 nm.

[0440] Method C: The following elution gradient was used: 30%-90% (Solvent B) over 6 minutes and hold at 60% for 0.5 minutes, flow rate 0.8 ml / min. Wavelength: UV 220 nm and 254 nm.

[0441] SFC analytical preparation

[0442] Instrument: Waters UPC2 Analytical SFC (SFC-H). Column: ChiralCel OJ, 150 x 4.6 mm ID, 3 μm. Mobile phase: A for CO2 and B for ethanol (0.05% DEA). Gradient: B 40%. Flow rate: 2.5 mL / min. Back pressure: 100 bar. Column temperature: 35°C. Wavelength: 220 nm.

[0443] Preparative HPLC purification

[0444] General Methods: Preparative HPLC was performed on a Gilson UV / VIS-156 with UV detection at 220 / 254 nm Gilson 281 autocollection.

[0445] Acidic conditions: Two acid classification systems are used: hydrochloric acid and formic acid.

[0446] Method A: Hydrochloric acid: YMC-Actus Triart C18 150×30 mm×5 μm, gradient using 0-100% acetonitrile in water and the corresponding acid (0.05% HCl).

[0447] Method B: Formic acid: Phenomenex Synergi C18 150×30 mm×4 μm, gradient using 0-100% acetonitrile in water and the corresponding acid (0.225% formic acid), with the gradient shape optimized for the individual separation.

[0448] Neutral conditions: Xtimate C18 150×25 mm×5 μm, gradient 0-100% (water (10 mM NH 4 HCO 3 )-ACN), gradient shape optimized for individual separations.

[0449] Basic conditions: Waters Xbridge preparative OBD C18 150×30 10 μm, gradient using 0-100% water (0.04% NH 3 H 2 O + 10 mM NH 4 HCO 3 )-acetonitrile, gradient shape optimized for individual separations.

[0450] Preparative HPLC-MS purification

[0451] Column usage:

[0452] Acid: Waters SunFire preparative, C18 5um, OBD 19×100mm

[0453] Base: Waters XSelect CSH Preparative C18 5um OBD 19×100mm

[0454] Gradient profile: 12 minute run: initial conditions: A-95%:B-5%; initial hold 0.0-0.5 minute; linear ramp from A-5% to variable B-% (typical range is B-40% to B-75%) between 0.5-7.5 minutes; linear ramp from B-% to B-95% between 7.5-8.0 minutes; hold A-5%:B-95% between 8.0-10.0 minutes; end of DAD / MS detection; linear ramp to initial conditions between 10.0-10.5 minutes; and initial hold 1.5 minutes.

[0455] Mobile phase: Acid: A: 0.1% trifluoroacetic acid in water (v / v); Mobile phase B: 0.1% trifluoroacetic acid in acetonitrile (v / v). Base: A: 0.1% ammonia in water (v / v); Mobile phase B: 0.1% ammonia in acetonitrile (v / v)

[0456] Preparative SFC purification

[0457] Instrument: MG III preparative SFC (SFC-1). Column: ChiralCel OJ, 250 x 30 mm ID, 5 μm. Mobile phase: A for CO2 and B for ethanol (0.1% NH3H2O). Gradient: B 50%. Flow rate: 40 mL / min. Back pressure: 100 bar. Column temperature: 38°C. Wavelength: 220 nm. Cycle time: approximately 8 minutes.

[0458] 1 H-NMR

[0459] NMR spectra were recorded on a Bruker Avance III 600 MHz, Bruker AVANCE DRX 500, Bruker Avance III HD500 MHz, Bruker Avance III 500 MHz, Bruker Avance III 400 MHz, Varian UNITYplus400, Varian-400 VNMRS or Varian-400MR. Chemical shifts are expressed in parts per million (ppm). Coupling constants (J) are expressed in Hertz (Hz). Splitting patterns describe apparent multiplicity and are designated as s (singlet), d (doublet), t (triplet), dd (double of doublets), dt (double of triplets), dq (double of quartets), m (multiplet), br (broad).

[0460] The following general reaction schemes 1-6 provide useful details for preparing the compounds of the present invention. Necessary intermediates are commercially available in some cases, or can be prepared according to literature procedures. The illustrative reaction schemes are not limited by any specific substituents employed for illustrative purposes or by the listed compounds, and the substituent labels (i.e., R groups) shown in the reaction schemes are not necessarily associated with that group used in the claims, and for clarity, single substituents are often shown as being connected to compounds that allow multiple substituents under the definition of formula (IA) or formula (IB) above.

[0461] Process 1

[0462]

[0463] Process 2

[0464]

[0465] General Procedures

[0466] Intermediate 1

[0467]

[0468] tert-Butyl (2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidine-1-carboxylate: To a solution of tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate (5.00 g, 24.8 mmol) and 4-chloro-6-methoxypyrimidine (3.95 g, 27.3 mmol) in THF (125 mL) at 0° C. was added KHMDS solution (1.0 M in THF, 27.3 mL) over 10 minutes. The mixture was allowed to warm to room temperature and stirred for 3 hours. To the mixture was added 10 mL of saturated NH4Cl(aq), and the mixture was then concentrated in vacuo. The residue was taken up in EtOAc, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified on SiO2 (0-70% EtOAc / heptane) to afford the title compound (6.36 g, 82% yield).LCMS (ESI): [M+H]310. 1 HNMR: (500MHz, CDCl3) δ8.42(s,1H),6.04(s,1H),5.47-5.55(m,1H),3.98-4.13(m,1H),3.95(s,3H),3.76(br s,1H),3.45-3.65(m,1H),2.28-2.46(m,1H),1.90(br d,J=14.04Hz,1H),1.46(s,9H),1.32(br d,J=6.10Hz,3H).

[0469] or

[0470] At room temperature, (2S, 4R) -4- hydroxy -2- methyl - pyrrolidine -1- tert-butyl formate (150.00g, 745.3mmol) is added to a stirred mixture of 60% sodium hydride (44.7g, 1.12mol) in THF (800mL). The mixture is refluxed for 2 hours. A solution of 4- chloro -6- methoxy - pyrimidine (107.7g, 745.3mmol) in THF (200mL) is slowly added dropwise to the reflux mixture. After refluxing for 3 hours, the reactant is cooled and stirred at room temperature overnight. NH4 Cl (saturated) solution (300ml) is slowly added to the reactant cooled by ice bath. Each layer is separated, and aqueous layer (THF 100mL) is extracted. The combined organic layer is dried over MgSO4, filtered and concentrated in vacuo. The residue was purified in 35 g batches on SiO2 220 g (100% heptane 5 min, reaching 20% ​​3:1 EtOAc:EtOH over 30 min) to give the title compound (125 g, 54% yield). LCMS (ESI): [M+H]310. 1 HNMR: (500MHz, CDCl3) δ8.43(s,1H),6.05(s,1H),5.52(ddd,J=5.5,3.5,2.1Hz,1H),3.97-4.14(m,1H),3.90-3.97(m,3H),3.78(br d,J=17.5Hz,1H),3.56(brs,1H),2.37(br d,J=5.6Hz,1H),1.91(br d,J=14.2Hz,1H),1.43-1.51(m,9H),1.33(brd,J=5.2Hz,3H).

[0471] Intermediate 2

[0472]

[0473]

[0266] tert-Butyl (2S,4R)-4-((2-(difluoromethoxy)pyridin-4-yl)oxy)-2-methylpyrrolidine-1-carboxylate: A suspension of tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate (0.30 g, 1.49 mmol), 4-bromo-2-(difluoromethoxy)pyridine (0.33 mg, 1.49 mmol), Pd(dba)2 (0.086 g, 0.15 mmol), rac-BINAP (0.18 g, 0.298 mmol), and Cs2CO3 (0.97 g, 2.98 mmol) in toluene (3.75 mL) was heated to 120°C and stirred for 16 hours. The reaction was diluted with EtOAc, washed with saturated NH4Cl(aq), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified on SiO2 (0-100% EtOAc / heptane) to afford the title compound (0.37 g, 72% yield).LCMS (ESI): [M+H]345.

[0474] Intermediate 3

[0475]

[0476] (2S, 4R) -4- ((6- fluoropyridin-3-yl) oxy) -2-methylpyrrolidine -1- carboxylic acid tert-butyl ester: 6- fluoropyridin-3-ol (185 mg, 1.64 mmol) and (2S, 4S) -4- hydroxy -2-methylpyrrolidine -1- carboxylic acid tert-butyl ester (300 mg, 1.49 mmol) in THF (15.0 mL) were added DIAD (603 mg, 2.98 mmol) and triphenylphosphine (782 mg, 2.98 mmol). The mixture was stirred at 60 ° C for 2 hours. The solvent was removed and the residue was purified by column chromatography on eluted silica gel (petroleum ether / EtOAc = 3 / 1) to give the title compound (92.0 mg, 21% yield). 1 HNMR: (400MHz, CDCl3) δ7.78-7.79(m,1H),7.27-7.31(m,1H),6.87(dd,J=8.8,3.2Hz,1H),4.82-4.84(m,1H),4.03-4.09 (m,1H),3.75-3.76(m,1H),3.62-3.64(m,1H),2.33-2.36(m,1H),1.93-1.96(m,1H),1.47(s,9H),1.32(d,J=6.4Hz,3H).

[0477] Intermediate 4

[0478] Preparation 1

[0479]

[0480] 4-Methoxy-6-(((3R,5S)-5-methylpyrrolidin-3-yl)oxy)pyrimidine hydrochloride: Acetyl chloride (14.1mL, 197mmol) was added dropwise to MeOH (100mL) at 0°C over 10 minutes, and the mixture was stirred for an additional 20 minutes. A solution of (2S,4R)-tert-butyl 4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidine-1-carboxylate (6.09g, 19.69mmol) in MeOH (30mL) was added dropwise to anhydrous HCl solution at 0°C. The resulting mixture was allowed to warm to room temperature and stirred for an additional 2 hours. The mixture was concentrated in vacuo to give the title compound (4.84g, 99% yield). LCMS(ESI):[M+H]210. 1 HNMR: (500MHz, methanol-d4)δ8.56(s,1H),6.46(s,1H),5.70-5.78(m,1H),4.03(s,3H),3.83-3.92(m,1H),3.66-3.72(m,1H),3.5 7-3.63(m,1H),2.81(ddd,J=6.71,7.94,14.65Hz,1H),1.97(dddd,J=1.22,3.66,7.94,14.65Hz,1H),1.52(d,J=6.71Hz,3H).

[0481] Preparation 2

[0482]

[0483] 4-Methoxy-6-(((3R,5S)-5-methylpyrrolidin-3-yl)oxy)pyrimidine trifluoroacetate:

[0484] To a solution of (2S,4R)-4-(6-methoxypyrimidin-4-yl)oxy-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (868 mg, 2.81 mmol) in CH2Cl2 (10 mL) was added TFA (2.15 mL, 28.1 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated and co-evaporated with EtOAc to give the title compound (1.65 g, containing approximately 3 equivalents of TFA). LCMS (ESI): [M+H]210. 1H NMR (400 MHz, methanol-d4) δ 8.43 (d, J = 1.00 Hz, 1H), 6.22 (d, J = 1.00 Hz, 1H), 5.69 (dddd, J = 2.13, 3.51, 5.62, 6.81 Hz, 1H), 3.95 (s, 3H), 3.74-3.89 (m, 1H), 3.49-3.69 (m, 2H), 2.77 (ddd, J = 6.78, 7.97, 14.62 Hz, 1H), 1.85-2.01 (m, 1H), 1.49 (d, J = 6.78 Hz, 3H).

[0485] or

[0486] TFA (230g, 2.02mol, 154.4mL) is slowly added to a solution of (2S, 4R) -4- (6-methoxypyrimidin-4-yl) oxy-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (61.7g, 199.5mmol) in DCM (154mL) cooled in an ice bath. The reactants are allowed to warm to room temperature. After 2 hours, the mixture is concentrated in vacuo. The residue is diluted with water (80ml) and the mixture is cooled with an ice bath. 50% NaOH aqueous solution (about 20ml) is added dropwise to the mixture, maintaining the internal temperature below 30°C while allowing the mixture to reach a final pH value of about 11. The mixture is extracted with DCM, dried over NaSO4, filtered and concentrated in vacuo to give the title compound (45g, 100% yield). LCMS (ESI): [M+H] 210. 1 HNMR: (500MHz, CDCl3) δ8.41 (s, 1H), 6.04 (d, J = 0.6Hz, 1H), 5.47 (dtd, J = 6.8, 3.4, 3.4, 1.6Hz, 1H), 3.94 (s, 3H), 3.2 4-3.32(m,2H),3.14(dd,J=13.0,5.3Hz,1H),2.47(dt,J=14.2,7.2Hz,1H),1.50-1.61(m,1H),1.32(d,J=6.4Hz,4H).

[0487] Example 1-1

[0488]

[0489] N-(5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: To a suspension of 4-methoxy-6-(((3R,5S)-5-methylpyrrolidin-3-yl)oxy)pyrimidine hydrochloride (9.26 g, 37.7 mmol) and N-[5-(chloromethyl)thiazol-2-yl]acetamide (7.55 g, 39.6 mmol) in acetonitrile (95.0 mL) was added triethylamine (11.4 g, 113.1 mmol) and the mixture was warmed to 55 °C overnight. The reaction was cooled to room temperature and the mixture was filtered through celite and concentrated in vacuo. The residue was dissolved in EtOAc and washed with saturated NH4Cl (aq.). The aqueous layer was stripped with EtOAc, and the combined organic matter was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified on SiO2 (10-70% EtOAc: ethanol (3: 1 v / v) / heptane) to give a foamy white residue. The substance was dissolved in warm methanol and solid precipitated after cooling. The solid was filtered to give the title compound (4.32 g, 31% yield). LCMS (ESI): [M+H] 364. 1 HNMR: (500MHz, CDCl3) δ11.76 (br s,1H),8.38(s,1H),7.22(s,1H),6.06(s,1H),5.31-5.38(m,1H),4.08-4.17(m,1H),3.93(s,3H),3.59(d,J=14.65Hz,1H),3.14 (d,J=11.60Hz,1H),2.61(dd,J=6.10,11.60Hz,1H),2.48-2.57(m,2H),2.31(s,3H),1.64-1.72(m,1H),1.26(d,J=6.10Hz,3H).

[0490] Example 1-2

[0491]

[0492] (S)-N-(5-((3-((5-fluoropyridin-2-yl)oxy)piperidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 1 from tert-butyl (S)-3-hydroxypiperidine-1-carboxylate, 2,5-difluoropyridine and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 351. 1HNMR: (500MHz, CDCl3) δ12.55(s,1H),7.93(d,J=3.05Hz,1H),7.30(ddd,J=3.36,7.78,9.00Hz,1H),7.19(s,1H),6.68(d d,J=3.66,8.55Hz,1H),5.07(tt,J=3.97,8.24Hz,1H),3.68-3.82(m,2H),2.94-3.01(m,1H),2.62-2.72(m,1H),2.36(br t,J=9.16Hz,1H),2.31-2.33(m,3H),2.23-2.30(m,1H),1.94-2.06(m,1H),1.78-1.87(m,1H),1.58-1.72(m,1H),1.45-1.56(m,1H).

[0493] Examples 1-3

[0494]

[0495] (R)-N-(5-((3-((5-fluoropyridin-2-yl)oxy)piperidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a manner analogous to Scheme 1 from (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate, 2,5-difluoropyridine and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 351. 1 HNMR: (500MHz, CDCl3) δ12.50 (s, 1H), 7.93 (d, J = 3.05Hz, 1H), 7.28-7.33 (m, 1H), 7.1 9(s,1H),6.68(dd,J=3.36,8.85Hz,1H),5.07(tt,J=3.97,8.24Hz,1H),3.64-3.86(m, 2H),2.90-3.06(m,1H),2.61-2.76(m,1H),2.33-2.43(m,1H),2.32(s,3H),2.24-2.3 0(m,1H),1.93-2.07(m,1H),1.74-1.91(m,1H),1.61-1.70(m,1H),1.45-1.56(m,1H).

[0496] Examples 1-4

[0497]

[0498] N-(5-(((2S,5R)-5-((5-fluoropyridin-2-yl)oxy)-2-methylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 1 from tert-butyl (2S,5R)-5-hydroxy-2-methylpiperidine-1-carboxylate, 2,5-difluoropyridine and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 365. 1 HNMR: (500MHz, CDCl3)δ12.32(br s,1H),7.90(d,J=3.1Hz,1H),7.35-7.27(m,1H),7.18(s,1H),6.77(dd,J=3.7,9.2Hz,1H),5.17-5.03(m,1H),4.03-3.82(m ,2H),2.97(dd,J=4.3,12.2Hz,1H),2.60(m,2H),2.31(s,3H),1.95-1.82(m,1H),1.75-1.61(m,4H),1.21(d,J=6.1Hz,3H).

[0499] Examples 1-5

[0500]

[0501] N-(5-(((2S,5S)-5-((5-fluoropyridin-2-yl)oxy)-2-methylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 1 from tert-butyl (2S,5S)-5-hydroxy-2-methylpiperidine-1-carboxylate, 2,5-difluoropyridine and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 365. 1 HNMR: (500MHz, CDCl3)δ12.15(br s,1H),7.93(d,J=3.66Hz,1H),7.27-7.32(m,1H),7.19(s,1H),6.61(dd,J=3.36,8.85 Hz,1H),4.96-5.05(m,1H),4.00(d,J=14.65Hz,1H),3.89(d,J=14.65Hz,1H),3.17(br dd,J=2.75,10.68Hz,1H),2.33-2.41(m,1H),2.31(s,3H),2.21(t,J=10.07Hz,1H) ,2.13-2.18(m,1H),1.75-1.81(m,1H),1.33-1.53(m,2H),1.22(d,J=6.10Hz,3H).

[0502] Examples 1-6

[0503]

[0504] (R)-N-(5-((3-((5-fluoropyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 1 from (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate, 2,5-difluoropyridine and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 337. 1 HNMR: (500MHz, CDCl3) δ12.66 (s, 1H), 7.93 (d, J = 3.05Hz, 1H), 7.30 (ddd, J = 3.0 5,7.63,8.85Hz,1H),7.23(s,1H),6.68(dd,J=3.66,9.16Hz,1H),5.32-5.43(m, 1H),3.71-3.98(m,2H),2.96(dd,J=6.10,10.99Hz,1H),2.87(m,1H),2.78(dd, J=2.75,10.68Hz,1H),2.51-2.61(m,1H),2.20-2.42(m,4H),1.91-2.02(m,1H).

[0505] Examples 1-7

[0506]

[0507] (S)-N-(5-((3-((5-fluoropyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 1 from (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate, 2,5-difluoropyridine and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 337. 1HNMR: (500MHz, CDCl3) δ12.66 (s, 1H), 7.93 (d, J = 3.05Hz, 1H), 7.30 (ddd, J = 3.05 ,7.94,9.16Hz,1H),7.23(s,1H),6.68(dd,J=3.66,9.16Hz,1H),5.32-5.43(m,1H ),3.77-3.92(m,2H),2.96(dd,J=6.10,10.38Hz,1H),2.83-2.90(m,1H),2.78(dd ,J=2.75,10.68Hz,1H),2.51-2.62(m,1H),2.26-2.39(m,4H),1.90-2.02(m,1H).

[0508] Examples 1-8

[0509]

[0510] N-(5-(((2R,4S)-4-((5-Fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 1 from tert-butyl (2R,4S)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 2,5-difluoropyridine and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 351. 1 HNMR: (500MHz,CDCl3)δ11.57(br s,1H),7.92(d,J=3.05Hz,1H),7.27-7.33(m,1H),7.22(s,1H),6.71(dd,J =3.66,9.16Hz,1H),5.22-5.29(m,1H),4.13(d,J=14.65Hz,1H),3.60(d,J =14.04Hz,1H),3.14(d,J=10.99Hz,1H),2.61(dd,J=6.41,11.29Hz,1H),2 .47-2.57(m,2H),2.30(s,3H),1.63-1.72(m,1H),1.26(d,J=6.10Hz,3H).

[0511] Examples 1-9

[0512]

[0513] N-(5-(((2S,4S)-4-((5-Fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 1 from tert-butyl (2S,4S)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 2,5-difluoropyridine and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 351. 1 HNMR: (500MHz, CDCl3)δ12.04(br s,1H),7.93(d,J=3.05Hz,1H),7.27-7.34(m,1H),7.20(s,1H),6.63(dd,J=3.66,9 .16Hz,1H),5.22-5.33(m,1H),4.11(dd,J=1.22,14.04Hz,1H),3.55-3.67(m,2H),2 .79-2.88(m,1H),2.40(dd,J=4.58,10.68Hz,1H),2.31(s,3H),2.07(ddd,J=1.83, 6.26, 13.89Hz, 1H), 1.90 (ddd, J = 7.63, 9.92, 13.58Hz, 1H), 1.20 (d, J = 6.10Hz, 3H).

[0514] Examples 1-10

[0515]

[0516] N-(5-(((2R,4R)-4-((5-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 1 from tert-butyl (2R,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 2,5-difluoropyridine and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 351. 1 HNMR: (500MHz, CDCl3) δ12.14 (s, 1H), 7.93 (d, J = 3.05Hz, 1H), 7.28-7.33 (m ,1H),7.20(s,1H),6.63(dd,J=3.66,9.16Hz,1H),5.15-5.38(m,1H),4.02-4 .25(m,1H),3.46-3.78(m,2H),2.73-3.08(m,1H),2.40(dd,J=4.27,10.38H z,1H),2.31(s,3H),2.03-2.11(m,1H),1.90(m,1H),1.20(d,J=6.10Hz,3H).

[0517] Examples 1-11

[0518]

[0519] N-(5-(((2S,4R)-4-((5-Fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 1 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 2,5-difluoropyridine and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 351. 1 HNMR: (500MHz, CDCl3) δ12.07 (s, 1H), 7.92 (d, J = 3.05Hz, 1H), 7.27-7.33 (m, 1H) ,7.22(s,1H),6.71(dd,J=3.66,9.16Hz,1H),5.23-5.28(m,1H),4.06-4.18(m,1 H),3.59(d,J=14.65Hz,1H),3.14(d,J=10.99Hz,1H),2.61(dd,J=6.41,11.29Hz ,1H),2.48-2.56(m,2H),2.31(s,3H),1.65-1.73(m,1H),1.26(d,J=5.49Hz,3H).

[0520] Examples 1-12

[0521]

[0522] N-(5-(((2S,4R)-4-((6-methoxypyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 1 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 2-chloro-6-methoxypyrazine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 364. 1HNMR: (500MHz, CDCl3) δ 11.68 (br s,1H),7.78(s,1H),7.76(s,1H),7.23(s,1H),5.22-5.33(m,1H),4.12-4.17(m,1H),3.90(s,3H),3.61(d,J=14.04Hz,1H),3.19 (d,J=10.99Hz,1H),2.65(dd,J=6.10,10.99Hz,1H),2.52-2.60(m,2H),2.31(s,3H),1.68-1.77(m,1H),1.27(d,J=5.49Hz,3H).

[0523] Examples 1-13

[0524]

[0525] N-(5-(((2S,4R)-4-((5-(difluoromethyl)pyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 1 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 2-chloro-5-(difluoromethyl)pyridine and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 383. 1 HNMR: (500MHz,CDCl3)δ11.87(br s,1H),8.19-8.23(m,1H),7.69(dd,J=2.44,8.55Hz,1H),7.22(s,1H),6.82(d,J =9.16Hz,1H),6.61(t,J=56.20Hz,1H),5.34-5.40(m,1H),4.14(d,J=13.43Hz,1 H),3.59(d,J=14.65Hz,1H),3.15(d,J=10.99Hz,1H),2.63(dd,J=6.41,11.29Hz ,1H),2.50-2.59(m,2H),2.31(s,3H),1.66-1.75(m,1H),1.27(d,J=6.10Hz,3H).

[0526] Examples 1-14

[0527]

[0528] N-(5-(((2S,4R)-2-methyl-4-(pyridin-2-yloxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 1 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 2-fluoropyridine and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 333. 1 HNMR: (500MHz,CDCl3)δ11.85(br s,1H),8.06-8.12(m,1H),7.47-7.57(m,1H),7.22(s,1H),6.78-6.86(m, 1H),6.71-6.76(m,1H),5.28-5.40(m,1H),4.09-4.18(m,1H),3.61(d,J= 14.65Hz,1H),3.16(d,J=11.60Hz,1H),2.64(dd,J=6.71,10.99Hz,1H),2 .50-2.58(m,2H),2.30(s,3H),1.66-1.74(m,1H),1.26(d,J=5.49Hz,3H).

[0529] Examples 1-15

[0530]

[0531] N-(5-(((2S,4R)-4-((5-Fluoro-6-methylpyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 1 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 6-chloro-3-fluoro-2-methylpyridine and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 365. 1 HNMR: (500MHz, CDCl3) δ12.10(br s,1H),7.24(br s,1H),7.20(t,J=8.37Hz,1H),6.51(dd,J=2.75,8.85Hz,1H),5.25-5.32(m,1H),4.14(br d,J=14.04Hz,1H),3.55-3.67(m,1H),3.13(br d,J=10.99Hz,1H),2.57-2.69(m,1H),2.49-2.56(m,2H),2.35(d,J=3.05Hz,3H),2.31(s,3H),1.63-1.74(m,1H),1.24-1.29(m,3H).

[0532] Examples 1-16

[0533]

[0534] N-(5-(((2S,4R)-4-((5-cyanopyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a manner similar to that in Scheme 1 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 6-fluoronicotinonitrile, and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 358. 1 HNMR: (500MHz, CDCl3)δ11.82(br s,1H),8.42(d,J=2.44Hz,1H),7.68-7.78(m,1H),7.22(s,1H),6.82(d,J=8.55Hz,1H),5.32-5.43(m,1H),4.07-4.19(m,1H), 3.58(d,J=14.04Hz,1H),3.15(d,J=10.99Hz,1H),2.49-2.67(m,3H),2.31(s,3H),1.65-1.74(m,1H),1.26(d,J=5.49Hz,3H).

[0535] Examples 1-17

[0536]

[0537] N-(5-(((2S,4R)-4-((6-chloro-4-methylpyridin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 1 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 2-chloro-5-fluoro-4-methylpyridine and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 381. 1HNMR: (500MHz, CDCl3) δ11.50(br s,1H),7.72(s,1H),7.21(s,1H),7.08(s,1H),4.67-4.77(m,1H),4.12(d,J=14.04Hz,1H),3.57(br d,J=14.04Hz,1H),3.18(d,J=10.99Hz,1H),2.49-2.66(m,3H),2.31(s,3H), 2.23 (s, 3H), 1.74 (ddd, J = 3.97, 8.70, 12.97Hz, 1H), 1.26 (d, J = 6.10Hz, 3H).

[0538] Examples 1-18

[0539]

[0540] N-(5-(((2S,4R)-4-((6-(difluoromethyl)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a manner similar to that in Scheme 1 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4-chloro-6-(difluoromethyl)pyrimidine and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 384. 1 HNMR: (500MHz, CDCl3) δ11.98 (br s,1H),8.76(s,1H),7.23(s,1H),7.02(s,1H),6.47(t,J=55.55Hz,1H),5.37-5.49(m,1H),4.14(d,J=14.65Hz,1H),3.58 (d,J=14.04Hz,1H),3.16(d,J=11.60Hz,1H),2.50-2.73(m,3H),2.31(s,3H),1.66-1.75(m,1H),1.27(d,J=5.49Hz,3H).

[0541] Examples 1-19

[0542]

[0543] N-(5-(((2S,4R)-4-((5-fluoro-6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 1 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4-chloro-5-fluoro-6-methoxypyrimidine and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 382. 1 HNMR: (500MHz, CDCl3)δ12.07(br s,1H),8.10(s,1H),7.23(s,1H),5.31-5.41(m,1H),4.09-4.14(m,1H),4.02(s,3H),3.60(d,J=14.65Hz,1H),3.19(d,J= 10.99Hz, 1H), 2.68 (dd, J = 6.41, 11.29Hz, 1H), 2.51-2.61 (m, 2H), 2.31 (s, 3H), 1.73-1.82 (m, 1H), 1.26 (d, J = 6.10Hz, 3H).

[0544] Examples 1-20

[0545]

[0546] N-(5-(((2S,4R)-4-((2-(difluoromethoxy)pyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a manner analogous to that in Scheme 1 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4-bromo-2-(difluoromethoxy)pyridine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 399. 1 HNMR: (500MHz, CDCl3)δ11.38(br s,1H),7.95(d,J=5.49Hz,1H),7.44(t,J=72.64Hz,1H),7.23(s,1H),6.58-6.61(m,1H),6.22(d,J=2.44Hz,1H),4.66-4.75(m,1H),4.1 1-4.16(m,1H),3.61(d,J=14.04Hz,1H),3.18(d,J=10.99Hz,1H),2.49-2.68(m,3H),2.31(s,3H),1.70(m,1H),1.26(d,J=5.49Hz,3H).

[0547] Examples 1-21

[0548]

[0549] N-(5-(((2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 1 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 2,4-dichloropyridine and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 368. 1 HNMR: (500MHz, CDCl3)δ12.13(br s,1H),8.51(s,1H),7.22(s,1H),6.77(d,J=1.22Hz,1H),5.30-5.48(m,1H),4.13(d,J=14.04Hz,1H),3.56 (d,J=14.04Hz,1H),3.14(d,J=10.99Hz,1H),2.47-2.73(m,3H),1.66-1.72(m,1H),1.26(d,J=6.10Hz,3H).

[0550] Examples 1-22

[0551]

[0552] N-(4-Fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: To a mixture of crude 4-methoxy-6-[(3R,5S)-5-methylpyrrolidin-3-yl]oxy-pyrimidine trifluoroacetate (1.65 g, 2.81 mmol; Intermediate 3, Preparation 2) and N-(4-fluoro-5-formyl-thiazol-2-yl)acetamide (429 mg, 2.28 mmol, prepared according to the literature procedure described in WO2018 / 140299A1) in EtOAc (20 mL) was added N,N-diisopropylethylamine (1.19 mL, 6.84 mmol). The mixture was heated to 50 °C for 5 minutes and then cooled to room temperature. To the mixture, sodium triacetoxyborohydride (1.45g, 6.84mmol) was added. The mixture was heated to 50°C for 1 hour, then cooled to room temperature. Saturated NaHCO (aqueous solution) and EtOAc were added to the mixture. The water layer was removed and stripped with EtOAc. The combined organic matter was washed with salt water, dried over MgSO4, filtered, and concentrated in vacuo. The residue was wet-ground with heptane / EtOAc to obtain a pink solid (329mg). The mother liquor was concentrated in vacuo and the residue was purified on SiO2 (50% EtOAc / heptane) to obtain a yellow solid (98mg). The solid material (427mg) was dissolved in MeOH (30mL) and treated with charcoal. The suspension was filtered through diatomaceous earth and the eluent was concentrated in vacuo to obtain the title compound (402mg, 46% yield). LCMS (ESI): [M+H] 382. 1 H NMR (400MHz, methanol-d4) δ8.35(s,1H),6.13(s,1H),5.21-5.47(m,1H),3.85-4.03(m,4H),3.55(d,J=14.56Hz ,1H),3.13(d,J=11.29Hz,1H),2.47-2.73(m,3H),2.17(s,3H),1.52-1.72(m,1H),1.23(d,J=5.52Hz,3H).

[0553] or

[0554] N-(4-Fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: Sodium triacetoxyborohydride (100.3 g, 473.1 mmol) was added to a mixture of 4-methoxy-6-[(3R,5S)-5-methylpyrrolidin-3-yl]oxy-pyrimidine (33 g, 158 mmol) and acetic acid (18.9 g, 315 mmol, 18.0 mL) in EtOAc (743 mL) at 40 °C. After 5 minutes, N-(4-fluoro-5-formyl-thiazol-2-yl)acetamide (30.7 g, 163 mmol) was added to the mixture. After 2 hours at 40 °C, the mixture was cooled to room temperature and stirred overnight. 1N HCl solution (315mL) is slowly added into the reactant. The aqueous layer is separated, and the organic layer is extracted with 1N HCl (150mL). The combined HCl layer is processed with 50% NaOH to a final pH of about 11, while cooling with an ice bath. The mixture is extracted with DCM and dried over MgSO4 organic matter, filtered, and concentrated in a vacuum. The residue is wet-ground with MeOH to obtain a pink solid. On SiO2 (220g, 20% → 60% heptane / (3:1 EtOAc:EtOH 2% NH4OH)) with two batches of purified solids, title compound (29g, 48% yield) is obtained. LCMS (ESI): [M+H] 382. 1 HNMR: (500MHz, CDCl3)δ11.16(br s,1H),8.36-8.41(m,1H),6.04-6.08(m,1H),5.28-5.39(m,1H),3.98(d,J=14.6Hz,1H),3.89-3.94(m,3H),3.64(d,J=14.6Hz,1H) ,3.16(d,J=11.1Hz,1H),2.65(dd,J=11.1,6.1Hz,1H),2.48-2.57(m,2H),2.29-2.34(m,3H),1.60-1.72(m,2H),1.20-1.29(m,4H). 19 FNMR: (471MHz, CDCl3) δ-116 (s, 1F).

[0555] Intermediate 5

[0556]

[0557] (2S, 4R) -4- ((6- chloropyrimidin-4-yl) oxy) -2-methylpyrrolidine -1- carboxylic acid tert-butyl ester: to a 1 L round-bottom flask containing THF (100 mL) containing (2S, 4R) -4-hydroxy-2-methyl-pyrrolidine -1- carboxylic acid tert-butyl ester (40 g, 198.75 mmol) was added LiHMDS solution (1 M, 198.75 mL) at room temperature, and the mixture was warmed to 60 ° C and stirred for 30 minutes. The reactants were cooled to 0 ° C and 4,6-dichloropyrimidine (29.61 g, 198.75 mmol) was added and stirred at 60 ° C for 2 hours, then at room temperature for 16 hours. The mixture was quenched with NH4Cl (saturated) at room temperature, diluted with EtOAc, and the layers were separated. The aqueous phase was extracted with EtOAc (2X), and the combined organics were dried over sodium sulfate and concentrated. The residue was adsorbed onto silica and purified using the following gradient EtOAc / heptane (0→20→100%) to afford the title compound (35.5 g, 113.3 mmol, 57% yield). LCMS (ESI): [M+H] 313.1. 1 HNMR: (500MHz, CDCl3) δ8.57(s,1H),6.78(s,1H),5.58(tt,J=5.5,2.1Hz,1H),3.95-4.14(m,1H),3.78(br s,1H),3.57(br s,1H),2.36-2.45(m,1H),1.92(brd,J=14.0Hz,1H),1.59(s,1H),1.43-1.49(m,9H),1.33ppm(brd,J=6.1Hz,3H).

[0558] Intermediate 6

[0559]

[0560]

[0268] tert-Butyl (2S,4R)-4-((6-(2-methoxyethoxy)pyrimidin-4-yl)oxy)-2-methylpyrrolidine-1-carboxylate: To a 500 mL round-bottom flask filled with THF (200 mL) containing 2-methoxyethanol (6.32 g, 83.08 mmol, 6.52 mL) was added potassium tert-butoxide (9.32 g, 83.08 mmol) at room temperature and the mixture was stirred at 60 °C for 30 minutes. The mixture was cooled to 0 °C and tert-butyl (2S,4R)-4-(6-chloropyrimidin-4-yl)oxy-2-methyl-pyrrolidine-1-carboxylate (23.70 g, 75.53 mmol) was added and stirred at room temperature for 16 hours. The mixture was quenched with water followed by addition of EtOAc and brine. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organics were dried over sodium sulfate and concentrated. The residue was purified on silica gel with a gradient of EtOAc / heptane (0→50%) to afford the title compound (16.5 g, 46.7 mmol, 62% yield). LCMS (ESI): [M+H] 354.2. 1 HNMR: (500MHz, CDCl3) δ8.40(s,1H),6.10(s,1H),5.48-5.53(m,1H),4.48-4.51(m,2H ),3.97-4.07(m,1H),3.68-3.79(m,3H),3.50-3.63(m,1H),3.42-3.44(m,3H),2.37(br s,1H),1.90(br d,J=14.0Hz,1H),1.47(s,9H),1.24-1.36(m,5H),0.86-0.90ppm(m,1H).

[0561] Intermediate 7

[0562]

[0563] 4-(2-Methoxyethoxy)-6-(((3R,5S)-5-methylpyrrolidin-3-yl)oxy)pyrimidine: A 2 L round-bottom flask containing (2S,4R)-4-[6-(2-methoxyethoxy)pyrimidin-4-yl]oxy-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (28.58 g, 80.87 mmol) in DCM was cooled to 0°C. Hydrogen chloride solution (4M in dioxane, 202.18 mL) was then added. After the reaction was complete, the mixture was concentrated, diluted with water, and the pH was adjusted to approximately 11 with 50% NaOH. The mixture was extracted with EtOAc, dried over sodium sulfate, filtered, and concentrated to obtain the title compound (19.21 g, 75.84 mmol, 93% yield). LCMS (ESI): [M+H] 254.1. 1HNMR: (500MHz, CDCl3) δ8.39 (s, 1H), 6.08 (s, 1H), 5.40 (dddd, J = 6.8, 5.1, 3.4, 1.2Hz, 1H), 4.47-4.51 (m, 2H), 3.70-3.74 (m, 2H),3.42-3.43(m,3H),3.22(d,J=12.8Hz,1H),3.12-3.19(m,1H),3.00-3.05(m,1H),2.42(dt,J=14.2,7.2Hz,1H),1.69(br s, 2H), 1.45 (dddd, J = 14.0, 7.9, 3.1, 1.2Hz, 1H), 1.27ppm (d, J = 6.7Hz, 3H).

[0564] Examples 1-23

[0565]

[0566]

[0149] N-(4-Fluoro-5-(((2S,4R)-4-((6-(2-methoxyethoxy)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: Sodium triacetoxyborohydride (48.22 g, 227.52 mmol) was added to a mixture of 4-(2-methoxyethoxy)-6-[(3R,5S)-5-methylpyrrolidin-3-yl]oxy-pyrimidine (19.21 g, 75.84 mmol) and acetic acid (9.11 g, 151.68 mmol, 8.7 mL) in EtOAc (321.48 g, 3.65 mol, 357 mL) at 40 °C. After 5 minutes, at 40 DEG C, N-(4-fluoro-5-formyl-thiazole-2-yl)acetamide (14.70g, 78.12mmol) was added to the mixture. The reactant turned pink after 30 minutes. After 2 hours at 40 DEG C, the reactant was cooled to room temperature and stirred at room temperature for 1 hour. 1M HCl (about 50mL is until bubbling stops) is added to quench the reactant. The aqueous layer is separated from the organic matter and the organic matter is extracted with about 75mL 1M HCl. The collected aqueous layer is adjusted to about 11-12 with 50% NaOH (about 75mL). The aqueous layer is extracted with EtOAc, dried over sodium sulfate and concentrated. The residue is purified on silica gel with gradient heptane / [EtOAc / EtOH (3: 1)] w / 1% TEA (0 → 50 → 100%) to obtain the title compound (25g, 58.76mmol, 77% yield). LCMS (ESI): [M+H] 426.1. 1HNMR: (400MHz, CDCl3)δ10.48(br s,1H),8.36(s,1H),6.10(s,1H),5.30-5.35(m,1H),4.45-4.48(m,2H),3.97(d,J= 14.7Hz,1H),3.70-3.73(m,2H),3.64(d,J=14.7Hz,1H),3.49(d,J=5.5Hz,1H),3.4 2(s,3H),3.15(d,J=11.0Hz,1H),2.66(dd,J=11.0,6.1Hz,1H),2.48-2.55(m,2H), 2.28-2.30(m,3H),1.57-1.62(m,6H),1.24(d,J=6.1Hz,3H),-0.12--0.01(m,1H).

[0567] Examples 1-24

[0568]

[0569] N-(5-(((2S,4R)-4-((6-(azetidin-1-yl)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide: The title compound was prepared in a manner analogous to Example 1-23 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4,6-dichloropyrimidine, azetidine, and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 407. 1 HNMR: (400MHz, methanol-d4) δ8.12(s,1H),5.73(s,1H),5.25-5.29(m,1H),4.05-4.09(m,4H),4.07-4.08(m,1H),3.64(d,J=14.5H z,1H),3.17(d,J=11.0Hz,1H),2.59-2.63(m,3H),2.43-2.47(m,2H),2.21(s,3H),1.64-1.67(m,1H),1.28(d,J=5.5Hz,3H).

[0570] Examples 1-25

[0571]

[0572] N-(4-Fluoro-5-(((2S,4R)-4-((6-(3-fluoroazetidin-1-yl)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a manner analogous to Example 1-23 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4,6-dichloropyrimidine, 3-fluoroazetidine and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 425. 1 HNMR: (500MHz, methanol-d4) δ8.12(s,1H),5.73(s,1H),5.25-5.29(m,1H),4.05-4.09(m,4H),4.07-4.08(m,1H),3.64(d,J=14.5H z,1H),3.17(d,J=11.0Hz,1H),2.59-2.63(m,3H),2.43-2.47(m,2H),2.21(s,3H),1.64-1.67(m,1H),1.28(d,J=5.5Hz,3H).

[0573] Examples 1-26

[0574]

[0575] N-(5-(((2S,4R)-4-((6-(3,3-difluoroazetidin-1-yl)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide: The title compound was prepared in a manner analogous to Example 1-23 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4,6-dichloropyrimidine, 3,3-difluoroazetidine and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 443.1. 1 HNMR: (500MHz, methanol-d4)δ8.20(s,1H),5.78(s,1H),5.26-5.29(m,1H),4.36-4.41(m,4H),3.93-3.97(m,1H),3. 51-3.58(m,1H),3.10-3.12(m,1H),2.45-2.65(m,3H),2.17(s,3H),1.57-1.62(m,1H),1.23(d,J=5.5Hz,3H).

[0576] Examples 1-27

[0577]

[0578] (S)-N-(4-Fluoro-5-((3-((6-methoxypyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 2 from (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate, 4-chloro-6-methoxypyrimidine and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 368. 1 HNMR: (400MHz, methanol-d4) δ8.36(s,1H),6.14(s,1H),5.42-5.47(m,1H),3.93(s,3H),3.75-3.78(m,2H),2.99-3.02(m,1H),2.83-2.90(m,2H),2.62-2.64(m,1H),2.36-2.38(m,1H),2.19(s,3H),1.96-1.98(m,1H).

[0579] Examples 1-28

[0580]

[0581] (R)-N-(4-Fluoro-5-((3-((6-methoxypyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate, 4-chloro-6-methoxypyrimidine and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 368. 1 HNMR: (500MHz, methanol-d4)δ8.36(s,1H),6.14(s,1H),5.46-5.42(m,1H),3.93(s,3H),3.78-3.71(m,2H),3.00-2.96(m ,1H),2.88-2.87(m,1H),2.83-2.80(m,1H),2.62-2.57(m,1H),2.40-2.32(m,1H),2.18(s,3H),1.99-1.93(m,1H).

[0582] Examples 1-29

[0583]

[0584] N-(4-Fluoro-5-(((2R,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl (2R,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4-chloro-6-methoxypyrimidine and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 382. 1 HNMR: (500MHz, CDCl3)δ:10.71(br.s,1H),8.39(s,1H),5.97(s,1H),5.33-5.35(m,1H),3.93-3.97(m,1H),3.92(s,3H),3.6 2-3.66(m,2H),2.81-2.86(m,1H),2.41-2.51(m,1H),2.29(s,3H),2.01-2.07(m,1H),1.83-1.91(m,1H),1.15-1.22(m,3H).

[0585] Examples 1-30

[0586]

[0587] N-(4-Fluoro-5-(((2S,4S)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl pyrazine(2S,4S)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4-chloro-6-methoxypyrimidine and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 382. 1 HNMR(400MHz, methanol-d4)δ8.35(d,J=0.75Hz,1H),6.07(d,J=1.00Hz,1H),5.28-5.37(m,1H),5 .28-5.37(m,1H),3.90-4.00(m,4H),3.67(d,J=14.81Hz,1H),3.57(dd,J=6.27,11.04Hz,1H ),2.88(td,J=6.02,10.29Hz,1H),2.53(dd,J=4.02,11.04Hz,1H),2.18(s,3H),2.09(ddd,J =1.76, 6.02, 13.80Hz, 1H), 1.87 (ddd, J = 7.28, 10.29, 13.80Hz, 1H), 1.20 (d, J = 6.27Hz, 3H).

[0588] Examples 1-31

[0589]

[0590] N-(4-Fluoro-5-(((2R,4S)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl (2R,4S)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4-chloro-6-methoxypyrimidine and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 382. 1 HNMR: (400MHz, methanol-d4)δ8.35(s,1H),6.14(s,1H),5.31-5.33(m,1H),3.96-4.00(m,1H),3.92(s,3H),3.55 -3.59(m,1H),3.13-3.16(m,1H),2.57-2.69(m,3H),2.18(s,3H),1.62-1.65(m,1H),1.25(d,J=5.6Hz,3H).

[0591] Examples 1-32

[0592]

[0593] (S)-N-(4-Fluoro-5-((3-((6-methoxypyrimidin-4-yl)oxy)piperidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate, 4-chloro-6-methoxypyrimidine and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 382. 1 HNMR: (400MHz, methanol-d4) δ8.33(s,1H),6.14(s,1H),5.17-5.13(m,1H),3.93(s,3H),3.67-3.65(m,2H),2.93-2.90(m,1H),2.66-2.65(m,1H),2.45-2.44(s,1H),2.36-2.35(s,1H),2.18(s,3H),1.96-1.95(m,1H),1.85-1.84(m,1H),1.67-1.58(m,2H).

[0594] Examples 1-33

[0595]

[0596] (R)-N-(4-Fluoro-5-((3-((6-methoxypyrimidin-4-yl)oxy)piperidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 2 from (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate, 4-chloro-6-methoxypyrimidine and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 382. 1 HNMR: (400 MHz, methanol-d4) δ8.33 (s, 1H), 6.14 (s, 1H), 5.16-5.12 (m, 1H), 3.93 (s, 3H), 3.65 (s, 2H), 2.91 (d, J = 8.4 Hz, 1H), 2.65 (d, J = 5.6 Hz, 1H), 2.44-2.35 (m, 2H), 2.18 (s, 3H), 1.99-1.85 (m, 2H), 1.66-1.57 (m, 2H).

[0597] Examples 1-34

[0598]

[0599] N-(4-Fluoro-5-(((2S,5S)-5-((6-methoxypyrimidin-4-yl)oxy)-2-methylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 2 from tert-butyl (2S,5S)-5-hydroxy-2-methylpiperidine-1-carboxylate, 4-chloro-6-methoxypyrimidine and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 396. 1 HNMR: (500 MHz, methanol-d4) δ 8.34 (s, 1H), 6.13 (s, 1H), 5.08-5.12 (m, 1H), 3.94 (s, 3H), 3.83-3.86 (m, 2H), 3.33-3.34 (m, 2H), 3.17-3.19 (m, 1H), 2.39-2.40 (m, 1H), 2.25-2.29 (m, 1H), 2.21 (s, 3H), 2.16 (m, 1H), 1.83-1.86 (m, 1H), 1.23 (d, J = 6.0 Hz, 3H).

[0600] Examples 1-35

[0601]

[0602] N-(4-Fluoro-5-(((2S,5R)-5-((6-methoxypyrimidin-4-yl)oxy)-2-methylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl (2S,5R)-5-hydroxy-2-methylpiperidine-1-carboxylate, 4-chloro-6-methoxypyrimidine and N-(5-(chloromethyl)-4-fluorothiazol-2-yl)acetamide. LCMS (ESI): [M+H] 396. 1 HNMR: (500MHz, CDCl3) δ10.95(brs,1H),8.37(s,1H),6.14(s,1H),5.20-5.24(m,1H),3.96(s,3H),3.90-3.94(m,1H),3.79(d, J=15.0Hz,1H),3.98-3.01(m,1H),2.55-2.63(m,2H),2.30(s,3H),1.88-1.91(m,1H),1.62-1.70(m,3H),1.20(d,J=6.5Hz,3H).

[0603] Examples 1-36

[0604]

[0605] (S)-N-(5-((3-((6-methoxypyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate, 4-chloro-6-methoxypyrimidine and N-(5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 350. 1 HNMR: (500MHz, methanol-d4)δ8.36(s,1H),7.26(s,1H),6.14(s,1H),5.42-5.46(m,1H),3.93(s,3H),3.80-3.88(m,2H),2.95- 2.98(m,1H),2.79-2.82(m,1H),2.58-2.60(m,1H),2.36-2.37(m,1H),2.06-2.11(m,1H)2.20(s,3H),1.83-1.94(m,1H).

[0606] Examples 1-37

[0607]

[0608] (R)-N-(5-((3-((6-methoxypyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 2 from (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate, 4-chloro-6-methoxypyrimidine and N-(5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 350. 1 HNMR: (500MHz, methanol-d4)δ8.39(s,1H),7.29(s,1H),6.17(s,1H),5.45-5.49(m,1H),3.96(s,3H),3.91-3.83(m,2H),3.01- 2.98(m,1H),2.93-2.88(m,1H),2.85-2.82(m,1H),2.64-2.59(m,1H),2.43-2.36(m,1H),2.22(s,3H),2.02-1.96(m,1H).

[0609] Examples 1-38

[0610]

[0611] N-(5-(((2R,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl (2R,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4-chloro-6-methoxypyrimidine and N-(5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 364. 1 HNMR: (500MHz, methanol-d4) δ8.34(s,1H),7.24(s,1H),6.08(s,1H),5.31-5.33(m,1H),4.12(d,J=14.5Hz,1H),3.92(s,3H),3.68(d,J=14.0Hz ,1H),3.52-3.56(m,1H),2.85-2.87(m,1H),2.46-2.49(m,1H),2.20(s,3H),2.07-2.11(m,1H),1.85-1.94(m,1H),1.21(d,J=6.0Hz,3H).

[0612] Examples 1-39

[0613]

[0614] N-(5-(((2S,4S)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl (2S,4S)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4-chloro-6-methoxypyrimidine and N-(5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 364. 1 HNMR: (400MHz, methanol-d4) δ8.37(s,1H),7.27(s,1H),6.11(s,1H),5.34-5.36(m,1H),4.15(d,J=14.4Hz,1H),3.95(s,3H),3.71(d,J=14.0Hz ,1H),3.55-3.60(m,1H),2.88-2.91(m,1H),2.49-2.53(m,1H),2.23(s,3H),2.11-2.14(m,1H),1.92-1.94(m,1H),1.24(d,J=6.0Hz,3H).

[0615] Examples 1-40

[0616]

[0617] N-(5-(((2R,4S)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl (2R,4S)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4-chloro-6-methoxypyrimidine and N-(5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 364. 1 HNMR: (500MHz, methanol-d4)δ8.34(s,1H),7.26(s,1H),6.13(s,1H),5.30-5.33(m,1H),4.11-4.15(m,1H),3.92(s,3H) ,3.52-3.55(m,1H),3.08-3.11(m,1H),2.54-2.65(m,3H),2.19(s,3H),1.61-1.65(m,1H),1.24(d,J=5.5Hz,3H).

[0618] Example 1-41

[0619]

[0620] (S)-N-(5-((3-((6-methoxypyrimidin-4-yl)oxy)piperidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate, 4-chloro-6-methoxypyrimidine and N-(5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 364. 1 HNMR: (500 MHz, methanol-d4) δ 8.17 (s, 1H), 7.13 (s, 1H), 5.98 (s, 1H), 5.05 (br s, 1H), 3.76 (s, 3H), 3.74-3.76 (m, 2H), 2.84-2.85 (m, 1H), 2.60-2.61 (m, 1H), 2.28-2.46 (m, 2H), 2.03 (s, 3H), 1.71-1.75 (m, 2H), 1.51-1.55 (m, 2H).

[0621] Examples 1-42

[0622]

[0623] (R)-N-(5-((3-((6-methoxypyrimidin-4-yl)oxy)piperidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate, 4-chloro-6-methoxypyrimidine and N-(5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 364. 1 HNMR: (400 MHz, methanol-d4) δ8.32 (s, 1H), 7.23 (s, 1H), 6.13 (s, 1H), 5.13-5.17 (m, 1H), 3.92 (s, 3H), 3.77-3.80 (m, 2H), 2.93 (d, J = 10.4 Hz, 1H), 2.67-2.69 (m, 1H), 2.43-2.44 (m, 2H), 2.19 (s, 3H), 1.86-2.00 (m, 2H), 1.59-1.67 (m, 2H).

[0624] Examples 1-43

[0625]

[0626] N-(5-(((2S,5S)-5-((6-methoxypyrimidin-4-yl)oxy)-2-methylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl (2S,5S)-5-hydroxy-2-methylpiperidine-1-carboxylate, 4-chloro-6-methoxypyrimidine and N-(5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 378. 1 HNMR: (500MHz, methanol-d4) δ8.34(s,1H),7.28(s,1H),6.12(s,1H),5.11-5.21(m,1H),4.07-4.17(m,1H),3.97(s,3H),3.89-3.90(m,1H),3.17-3. 19(m,1H),2.44-2.45(m,1H),2.22(s,3H),2.17-2.18(m,1H),2.01-2. 02(m,1H),1.87-1.88(m,1H),1.48-1.52(m,2H),1.26(d,J=6.0Hz,3H).

[0627] Examples 1-44

[0628]

[0629] N-(5-(((2S,5R)-5-((6-methoxypyrimidin-4-yl)oxy)-2-methylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl (2S,5R)-5-hydroxy-2-methylpiperidine-1-carboxylate, 4-chloro-6-methoxypyrimidine and N-(5-(chloromethyl)thiazol-2-yl)acetamide. LCMS (ESI): [M+H] 378. 1 HNMR: (500MHz, CDCl3) δ11.4(brs,1H),8.36(s,1H),7.18(s,1H),6.12(s,1H),5.19-5.21(m,1H),3.96(d,J=15.0Hz,1H),3.93(s,3H), 3.87(d,J=15.0Hz,1H),2.93-2.96(m,1H),2.60-2.63(m,2H),2.29(s,3H),1.85-1.89(m,1H),1.63-1.74(m,3H),1.20(d,J=6.0Hz,3H).

[0630] Examples 1-45

[0631]

[0632] (R)-N-(4-Fluoro-5-((3-((6-methoxypyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)propanamide: The title compound was prepared in a similar manner to Scheme 2 from (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate, 4-chloro-6-methoxypyrimidine and N-(4-fluoro-5-formylthiazol-2-yl)propanamide. LCMS (ESI): [M+H] 382. 1 HNMR (400MHz, methanol-d4) δ8.36(s,1H),6.13(d,J=0.75Hz,1H),5.38-5.49(m,1H),3.93(s,3H),3.68-3.82(m,2H),2.99(dd,J=6.15,11.1 7Hz,1H),2.79-2.93(m,2H),2.55-2.66(m,1H),2.46(q,J=7.53Hz,2H),2.29-2.40(m,1H),1.91-2.03(m,1H),1.19(t,J=7.65Hz,3H).

[0633] Examples 1-46

[0634]

[0635] N-(4-Chloro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4-chloro-2-methylpyridine and N-(4-chloro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 398. 1 HNMR: (400MHz, methanol-d4) δ8.34(d,J=1.00Hz,1H),6.13(d,J=0.75Hz,1H),5.28-5.40(m,1H),4.04(d,J=14.56Hz,1H),3.92(s, 3H), 3.56 (d, J = 14.56Hz, 1H), 3.07-3.17 (m, 1H), 2.51-2.73 (m, 3H), 2.18 (s, 3H), 1.56-1.69 (m, 1H), 1.24 (d, J = 5.52Hz, 3H).

[0636] Examples 1-47

[0637]

[0638] N-(4-Fluoro-5-(((2S,4R)-4-((5-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 2,5-difluoropyridine and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 369. 1 HNMR: (400MHz, methanol-d4) δ7.95(d,J=2.4Hz,1H),7.45-7.49(m,1H),6.77(dd,J=9.2,3.2Hz,1H),5.21-5.24(m,1H),3.96(d,J=14 .8Hz,1H),3.56(d,J=14.8Hz,1H),3.10-3.13(m,1H),2.54-2.68(m,3H),2.18(s,3H),1.56-1.64(m,1H),1.24(d,J=6.0Hz,3H).

[0639] Examples 1-48

[0640]

[0641] (S)-N-(5-((3-((2,6-dimethylpyridin-4-yl)oxy)pyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from 4-chloro-2,6-dimethylpyridine, (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 365.0. 1 HNMR: (500MHz, CDCl3) δ10.27(br.,s.,1H),6.44(s,2H),4.82-4.86(m,1H),3.76-3.79(m,2H),2.99-3.03( m,1H),2.94-2.98(m,1H),2.82-2.86(m,1H),2.76-2.78(m,1H),2.48(s,6H),2.29-2.34(m,4H),1.95-2.01.

[0642] Examples 1-49

[0643]

[0644] (R)-N-(5-((3-((2,6-dimethylpyridin-4-yl)oxy)pyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 2 from 4-chloro-2,6-dimethylpyridine, (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate, and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 365.0. 1 HNMR: (400MHz, CDCl3) δ10.71(br.,s.,1H),6.43(s,2H),4.82-4.83(m,1H),3.75(s,2H),2.84-3.0 1(m,1H),2.75-2.82(m,2H),2.63-2.64(m,1H),2.47(s,6H),1.97-2.31(m,4H),1.86-1.95(m,1H).

[0645] Examples 1-50

[0646]

[0647] N-(5-(((2S,4R)-4-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide: The title compound was prepared in a manner similar to that in Scheme 2 from 4-chloro-2,6-dimethylpyridine, tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 379.1. 1 HNMR: (400MHz, CDCl3) δ10.67(br.s.,1H),6.45(s,2H),4.71-4.73(m,1H),3.96(d,J=15.2Hz,1H),3.65(d,J=14.8Hz ,1H),3.17(d,J=10.8Hz,1H),2.53-2.65(m,3H),2.50(s,6H),2.30(s,3H),1.66-1.69(m,1H),1.24(d,J=6.0Hz,3H).

[0648] Example 1-51

[0649]

[0650] N-(5-(((2R,4R)-4-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from 4-chloro-2,6-dimethylpyridine, tert-butyl (2R,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 379.0. 1 HNMR: (400MHz, CDCl3) δ10.09(br.s,1H),6.39(d,J=2.8Hz,2H),4.75-4.79(m,1H),3.93-3.97(m,1H),3.57-3.64(m, 2H),2.80-2.83(m,1H),2.45-2.50(m,7H),2.28(s,3H),2.03-2.05(m,1H),1.82-1.86(m,1H),1.17(d,J=5.6Hz,3H).

[0651] Examples 1-52

[0652]

[0653] N-(5-(((2S,4S)-4-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl (2S,4S)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4-bromo-2,6-dimethylpyridine and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 379. 1 HNMR(400MHz, methanol-d4)δ7.19(s,2H),5.35-5.49(m,1H),4.62-4.74(m,1H),4.50-4.61(m,1H),4.19(br dd,J=5.14,13.68Hz,1H),3.93(td,J=5.99,11.86Hz,1H),3.63(br d,J=13.80Hz,1H),2.54-2.72(m,7H),2.22(s,4H),1.56(d,J=6.27Hz,3H).

[0654] Examples 1-53

[0655]

[0656] N-(5-(((2R,4S)-4-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl 2,6-dimethylpyridin-4-ol (2R,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate and N-(5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 379.0. 1 HNMR: (400 MHz, methanol-d4) δ 6.58 (s, 2H), 4.83-4.89 (m, 1H), 3.97 (d, J = 14.4 Hz, 1H), 3.58 (d, J = 14.4 Hz, 1H), 3.12-3.13 (m, 1H), 2.55-2.69 (m, 3H), 2.41 (s, 6H), 2.18 (s, 3H), 1.56-1.61 (m, 1H), 1.23 (d, J = 5.6 Hz, 3H).

[0657] Examples 1-54

[0658]

[0659] (S)-N-(5-((3-((2,6-dimethylpyridin-4-yl)oxy)piperidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from 4-chloro-2,6-dimethylpyridine, (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 379.1. 1 HNMR: (500 MHz, methanol-d4) δ 6.70 (s, 2H), 4.57-4.53 (m, 1H), 3.72-3.68 (m, 2H), 2.97 (d, J = 9.5 Hz, 1H), 2.76-2.73 (m, 1H), 2.41-2.35 (m, 6H), 2.33-2.32 (m, 2H), 2.21-2.04 (m, 3H), 1.88 (d, J = 4.5 Hz, 1H), 1.70 (m, 1H), 1.69-1.68 (m, 1H), 1.56 (m, 1H).

[0660] Examples 1-55

[0661]

[0662] (R)-N-(5-((3-((2,6-dimethylpyridin-4-yl)oxy)piperidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from 4-chloro-2,6-dimethylpyridine, (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 379.1. 1 HNMR: (500MHz, CDCl3) δ6.65(s,2H),4.57-4.52(m,1H),3.71-3.68(m,2H),2.98-2.96(m,1H),2.76-2.73(m,1H),2.4 1(s,6H),2.33-2.31(m,2H),2.21(s,3H),2.02-1.99(m,1H),1.88-1.87(m,1H),1.71-1.69(m,1H),1.67-1.55(m,1H).

[0663] Examples 1-56

[0664]

[0665] N-(5-(((2S,5S)-5-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpiperidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from 4-chloro-2,6-dimethylpyridine, tert-butyl (2S,5S)-5-hydroxy-2-methylpiperidine-1-carboxylate and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 393.1. 1 HNMR: (400 MHz, methanol-d4) δ 6.68 (s, 2H), 4.47-4.48 (m, 1H), 3.92-3.96 (m, 1H), 3.72-3.75 (m, 1H), 3.13-3.15 (m, 1H), 2.41 (s, 6H), 2.36-2.37 (m, 1H), 2.19 (s, 3H), 2.14-2.17 (m, 2H), 1.83-1.84 (m, 1H), 1.43-1.48 (m, 2H), 1.22 (d, J = 6.4 Hz, 3H).

[0666] Examples 1-57

[0667]

[0668] N-(5-(((2S,5R)-5-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpiperidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide: The title compound was prepared in a manner similar to that in Scheme 2 from 2,6-dimethylpyridin-4-ol, tert-butyl (2S,5S)-5-hydroxy-2-methylpiperidine-1-carboxylate, and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 393.1. 1 HNMR: (500 MHz, methanol-d4) δ 6.66 (s, 2H), 4.61-4.63 (m, 1H), 3.78 (dd, J = 15.0, 12.5 Hz, 2H), 2.93-2.96 (m, 1H), 2.55-2.62 (m, 2H), 2.39 (s, 6H), 2.18 (s, 3H), 1.83-1.95 (m, 1H), 1.66-1.73 (m, 3H), 1.20 (d, J = 6.0 Hz, 3H).

[0669] Examples 1-58

[0670]

[0671] (S)-N-(5-((3-((2,6-dimethylpyridin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide. The title compound was prepared in a manner similar to that described in Scheme 2 from 4-chloro-2,6-dimethylpyridine, tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 347.1. 1 HNMR: (400MHz, CDCl3) δ11.25(br.,s.,1H),7.16(s,1H),6.35(s,2H),4.75-4.79(m,1H),3.73-3.81(m,2H),2.94-2.9 8(m,1H),2.71-2.77(m,1H),2.65-2.68(m,1H),2.56-2.62(m,1H),2.38(s,6H),2.21-2.26(m,4H),1.88-1.95(m,1H).

[0672] Examples 1-59

[0673]

[0674] (R)-N-(5-((3-((2,6-dimethylpyridin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from 4-chloro-2,6-dimethylpyridine, (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate and N-(5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 347.0. 1 HNMR: (500MHz, CDCl3)δ11.43(br s,1H),7.23(s,1H),6.42(s,2H),4.85-4.82(m,1H),3.88-3.84(m,2H),3.02-3.01(m,1H),3.04-3. 03(m,1H),2.82-2.80(m,1H),2.74-2.73(m,1H),2.72(s,6H),2.45-2.32(m,4H),2.30-1.99(m,1H).

[0675] Examples 1-60

[0676]

[0677] N-(5-(((2S,4R)-4-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from 4-bromo-2,6-dimethylpyridine, tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate and N-(5-(chloromethyl)thiazol-2-yl)acetamide. LCMS (ESI): [M+H] 361. 1 HNMR: (400 MHz, methanol-d4) δ7.29 (s, 1H), 6.58 (s, 2H), 4.70-4.85 (m, 1H), 4.16 (dd, J = 1.00, 14.06 Hz, 1H), 3.52-3.64 (m, 1H), 3.04-3.16 (m, 1H), 2.50-2.72 (m, 3H), 2.42 (s, 6H), 2.21 (s, 3H), 1.56-1.71 (m, 1H), 1.26 (d, J = 5.77 Hz, 3H).

[0678] Example 1-61

[0679]

[0680] N-(5-(((2R,4R)-4-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from 4-chloro-2,6-dimethylpyridine, tert-butyl (2R,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate and N-(5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 361.0. 1 HNMR: (500MHz, CDCl3) δ11.94 (br s,1H),7.20(s,1H),6.42(s,2H),4.77-4.79(m,1H),4.10-4.12(m,1H),3.53-3.60(m,2H),2.46-2.48(m,1H ), 2.46 (s, 6H), 2.40-2.43 (m, 1H), 2.30 (s, 3H), 2.07-2.10 (m, 1H), 1.86-1.89 (m, 1H), 1.20 (d, J = 6.0Hz, 3H).

[0681] Example 1-62

[0682]

[0683] N-(5-(((2S,4S)-4-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from 2,6-dimethylpyridin-4-ol, tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate and N-(5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 361.0. 1 HNMR: (500MHz, methanol-d4) δ7.10(s,1H),6.69(s,2H),4.86(d,J=3.5Hz,1H),4.01(d,J=13.5Hz,1H),3.60(d,J=14.5Hz,1H),3.44(dd,J=11.5 ,6.5Hz,1H),2.78-2.80(m,1H),2.44-2.49(m,1H),2.36(s,6H),2.05(s,3H),1.96-2.00(m,1H),1.77-1.83(m,1H),1.07(d,J=6.0Hz,3H).

[0684] Examples 1-63

[0685]

[0686] N-(5-(((2R,4S)-4-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from 4-chloro-2,6-dimethylpyridine, tert-butyl (2R,4S)-4-hydroxy-2-methylpyrrolidine-1-carboxylate and N-(5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 361.0. 1 HNMR: (500 MHz, methanol-d4) δ7.30 (s, 1H), 6.60 (s, 2H), 4.88-4.94 (m, 1H), 4.15-4.18 (m, 1H), 3.58-3.61 (m, 1H), 3.11-3.13 (m, 1H), 2.61-2.68 (m, 3H), 2.43 (s, 6H), 2.22 (s, 3H), 1.60-1.63 (m, 1H), 1.27 (d, J = 5.5 Hz, 3H).

[0687] Examples 1-64

[0688]

[0689] (S)-N-(5-((3-((2,6-dimethylpyridin-4-yl)oxy)piperidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from 4-chloro-2,6-dimethylpyridine, (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate and N-(5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 361.0. 1 HNMR: (500MHz, CDCl3)δ11.02(br s,1H),7.18(s,1H),6.50(s,2H),4.44-4.41(m,1H),3.78-3.70(m,2H),3.03(d,J=9.0Hz,1H),2.78(d,J=11.5Hz,1H),2.4 6-2.44(m,6H),2.30-2.28(m,3H),2.18-2.15(m,2H),2.05(d,J=9.5Hz,1H),1.84-1.82(m,1H),1.68(m,1H),1.46(m,1H).

[0690] Example 1-65

[0691]

[0692] (R)-N-(5-((3-((2,6-dimethylpyridin-4-yl)oxy)piperidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from 4-chloro-2,6-dimethylpyridine, (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate and N-(5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 361.0. 1 HNMR: (400MHz, CDCl3)δ11.01(br s,1H),7.18(s,1H),6.54(s,2H),4.44-4.46(m,1H),3.68-3.78(m,2H),2.94-2.96(m,1H),2.74- 2.76(m,1H),2.47(s,6H),2.30(s,3H),2.15-2.30(m,2H),2.02-2.14(m,2H),1.51-1.68(m,2H).

[0693] Example 1-66

[0694]

[0695] N-(5-(((2S,5S)-5-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from 4-chloro-2,6-dimethylpyridine, tert-butyl (2S,5S)-5-hydroxy-2-methylpiperidine-1-carboxylate and N-(5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 375.1. 1 HNMR: (400MHz, methanol-d4) δ7.23(s,1H),6.55(s,2H),4.38-4.42(m,1H),4.09-4.13(m,1H),3.70-3.74(m,1H),3.13-3.15(m,1H),2.35(s, 6H),2.33-2.34(m,1H),2.20(s,3H),2.13-2.14(m,1H),2.01-2.07(m,1H),1.83-1.86(m,1H),1.45-1.53(m,2H),1.24(d,J=6.4Hz,3H).

[0696] Example 1-67

[0697]

[0698] N-(5-(((2S,5R)-5-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from 2,6-dimethylpyridin-4-ol, tert-butyl (2S,5S)-5-hydroxy-2-methylpiperidine-1-carboxylate and N-(5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 375.1. 1 HNMR: (400MHz, methanol-d4) δ7.22(s,1H),6.62(s,2H),4.57-4.59(m,1H),3.91-3.95(m,1H),3.79-3.85(m,1H),2.87-2.90(m,1H) ,2.65-2.67(m,1H),2.53-2.58(m,1H),2.38(s,6H),2.19(s,3H),1.83-1.92(m,1H),1.68-1.80(m,3H),1.20(d,J=6.0Hz,3H).

[0699] Examples 1-68

[0700]

[0701] N-(5-(((2S,4R)-4-((6-methoxypyridazin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 3-chloro-6-methoxypyridazine, and N-(5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 364. 1 HNMR: (500 MHz, methanol-d4) δ7.11 (s, 2H), 5.33-5.37 (m, 1H), 3.98-4.02 (m, 1H), 3.99 (s, 3H), 3.57-3.60 (m, 1H), 3.20-3.22 (m, 1H), 2.62-2.74 (m, 3H), 2.20 (s, 3H), 1.66-1.68 (m, 1H), 1.27 (d, J = 5.5 Hz, 3H).

[0702] Examples 1-69

[0703]

[0704] N-(5-(((2S,4R)-2-methyl-4-((5-methylpyrazin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 2-chloro-5-methylpyrazine and N-(5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 348.1. 1 HNMR: (500MHz, methanol-d4)δ8.05(s,1H),7.99(s,1H),7.26(s,1H),5.27-5.30(m,1H),4.13-4.15(m,1H),3.54-3.57( m,1H),3.09-3.12(m,1H),2.57-2.66(m,3H),2.41(s,3H),2.19(s,3H),1.64-1.67(m,1H),1.25(d,J=6.0Hz,3H).

[0705] Examples 1-70

[0706]

[0707] N-(5-(((2S,4R)-2-methyl-4-((1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 6-chloro-3-methylpyrimidin-4(3H)-one and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 363.1. 1 HNMR: (500MHz, DMSO-d6) δ11.95(br s,1H),8.32(s,1H),7.26(s,1H),5.52(s,1H),4.99(br d,J=4.3Hz,1H),4.02(d,J=14.0Hz,1H),2.89(d,J=11.6Hz,1H),2.37-2.49(m,3H),2 .07-2.13(m,4H),1.45(s,1H),1.24(s,1H),1.14(d,J=6.1Hz,4H),0.01-0.05(m,1H).

[0708] Example 1-71

[0709]

[0710] N-(5-(((2S,4R)-4-((6-methoxy-5-methylpyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4-chloro-6-methoxy-5-methylpyrimidine and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 378.1. 1 HNMR: (500MHz, DMSO-d6) δ12.30(s,1H),7.64(s,1H),5.53(br s,1H),4.77(br d,J=12.8Hz,2H),4.52(br dd,J=13.7,5.2Hz,1H),3.92(s,4H),3.60-3.79(m,2H),2.82(dt,J=14.2,7 .2Hz,1H),2.16(s,4H),1.96(s,3H),1.85-1.93(m,1H),1.38-1.48(m,4H).

[0711] Example 1-72

[0712]

[0713] N-(5-(((2S,4R)-4-((2,5-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4-chloro-2,5-dimethylpyridine and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 361. 1 HNMR: (400MHz, methanol-d4) δ8.00(s,1H),7.28(s,1H),6.71(s,1H),4.90-4.91(m,1H),4.15(d,J=14.0Hz,1H),3.61(d,J=14.4Hz,1 H),3.14(d,J=10.8Hz,1H),2.62-2.73(m,3H),2.43(s,3H),2.19(s,3H),2.13(s,3H),1.61-1.68(m,1H),1.26(d,J=5.6Hz,3H).

[0714] Examples 1-73

[0715]

[0716] N-(5-(((2S,4R)-4-((5-methoxypyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 2-chloro-5-methoxypyrazine and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 364. 1 HNMR: (400MHz, DMSO-d6) δ7.85-7.86(m,2H),7.25(s,1H),5.09-5.14(m,1H),4.01-4.04(m,1H),3.84(s,3H),3 .42-3.46(m,1H),2.90-2.93(m,1H),2.39-2.44(m,3H),2.10(s,3H),1.47-1.52(m,1H),1.14(d,J=6.0Hz,3H).

[0717] Examples 1-74

[0718]

[0719] N-(4-Fluoro-5-(((2S,4R)-4-((5-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4-chloro-5-methoxy-pyrimidine and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 364.1. 1 HNMR: (500MHz, DMSO-d6) δ11.95(br s,1H),8.31(s,1H),8.20(s,1H),7.26(s,1H),5.29-5.36(m,1H),4.03(d,J=14.0Hz,1H),3.85(s,3H),3.47(br d,J=14.0Hz,1H),2.95(d,J=11.6Hz,1H),2.51-2.65(m,3H),2.36-2.48(m,1H),2.07 -2.13(m,4H),1.52(ddd,J=13.3,9.3,4.3Hz,1H),1.23(s,1H),1.15(d,J=6.1Hz,4H).

[0720] Examples 1-75

[0721]

[0722] N-(5-(((2S,4R)-4-((2-methoxy-6-methylpyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4-chloro-6-methoxy-2-methylpyrimidine and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 378.1. 1 HNMR: (500MHz, DMSO-d6) δ12.30(s,1H),7.63(s,2H),6.06(s,1H),5.44-5.60(m,2H),4.75(br d,J=13.4Hz,2H),4.49(br dd,J=13.1,4.6Hz,2H),3.45-3.68(m,3H),2.83(dt,J=14.6,7.3Hz,2H), 2.54-2.62(m,2H),2.44(s,5H),2.16(s,3H),1.75-1.87(m,2H),1.40(br d,J=6.7Hz,3H).

[0723] Examples 1-76

[0724]

[0725] N-(5-(((2S,4R)-4-((6-acetylpyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 1-(6-chloropyrimidin-4-yl)ethanone and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 376.1. 1 HNMR: (500MHz, DMSO-d6) δ12.27-12.45(m,1H),9.01(s,1H),7.63(s,1H),7.19-7.29(m,1H),5.26(s,1H),4.67(br d,J=14.0Hz,1H),4.51(br s,1H),4.35-4.48(m,2H),3.12(br s,1H),2.80-3.00(m,2H),2.60-2.65(m,3H),2.16(br s,3H),1.90(br s,2H),1.36(br d,J=6.1Hz,3H).

[0726] Example 1-77

[0727]

[0728] N-(4-Fluoro-5-(((2S,4R)-2-methyl-4-((6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate 2,2,2-trifluoroethanol and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 432. 1 HNMR: (500MHz, DMSO-d6)δ12.30(br s,1H),7.63(br s,1H),6.46-6.55(m,1H),5.55(br s,1H),5.02-5.15(m,2H),4.76(br d,J=12.8Hz,1H),3.49-3.71(m,1H),2.74-2.96(m,1H),2.52-2.71(m,3H),2.16(s,3H),1.78-1.93(m,1H),1.41(br d,J=6.1Hz,4H).

[0729] Examples 1-78

[0730]

[0731] N-(5-(((2S,4R)-4-((6-fluoropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4,6-difluoropyrimidine and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 352.1. 1 HNMR: (500MHz, DMSO-d6) δ12.30(br s,1H),8.66(d,J=1.8Hz,1H),7.63(s,1H),6.80(s,1H),5.52-5.68(m,1H),4.76(br d,J=14.0Hz,1H),4.42-4.62(m,1H),3.50-3.82(m,2H),2.87(dt,J=14.6,7.3Hz,1H),2.16(s,3H),1.77-1.97(m,1H),1.37-1.48(m,4H).

[0732] Examples 1-79

[0733]

[0734] N-(5-(((2S,4R)-2-methyl-4-((6-(trifluoromethyl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4-chloro-6-(trifluoromethyl)pyrimidine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 402.1. 1 HNMR: (500MHz, DMSO-d6) δ12.26-12.37(m,1H),7.55-7.73(m,1H),7.47(s,1H),5.67(br s,2H),4.77(br d,J=12.8Hz,1H),4.40-4.62(m,1H),2.81-2.95(m,2H),2.13-2.19(m,5H),2.07(s,1H),1.87-2.00(m,1H),1.44(br d,J=6.1Hz,5H).

[0735] Example 1-80

[0736]

[0737] N-(5-(((2S,4R)-4-((5-(difluoromethoxy)pyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a manner analogous to Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 2-chloro-5-(difluoromethoxy)pyrimidine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 400.1. 1 HNMR: (500MHz, DMSO-d6) δ11.95(s,1H),8.55(s,1H),7.26(s,1H),7.19(s,1H),7.33(s,1H),5.17-5.24(m,1H),4.06(s,1H),4.03(s,1H),3.47(br d,J=14.0Hz,1H),2.95(d,J=11.6Hz,1H),2.52-2.62(m,3H),2.42-2.49(m,1H) ,2.08-2.15(m,3H),1.52(ddd,J=13.0,8.7,4.0Hz,1H),1.17(d,J=6.1Hz,4H).

[0738] Example 1-81

[0739]

[0740] N-(5-(((2S,4R)-4-((3,5-dimethylpyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 2-chloro-3,5-dimethylpyrazine and N-(5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 362. 1 HNMR: (400MHz, methanol-d4)δ7.81(s,1H),7.32(s,1H),5.32-5.33(m,1H),4.22-4.23(m,1H),3.69-3.70(m,1H),3.13- 3.19(m,1H),2.57-2.65(m,3H),2.41(s,3H),2.37(s,3H),2.19(s,3H),1.72-1.73(m,1H),1.31(d,J=4.4Hz,3H).

[0741] Example 1-82

[0742]

[0743] N-(5-(((2S,4R)-2-methyl-4-((2-methylpyridin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4-chloro-2-methylpyridine and N-(5-(chloromethyl)thiazol-2-yl)acetamide. LCMS (ESI): [M+H] 347. 1 HNMR: (400MHz, methanol-d4) δ8.18(d,J=5.77Hz,1H),7.29(s,1H),6.67-6.82(m,2H),4.78-4.92(m,1H),4.16(d,J=15.06Hz,1H),3.5 2-3.66(m,1H),3.13(d,J=11.29Hz,1H),2.53-2.73(m,3H),2.46(s,3H),2.21(s,3H),1.57-1.71(m,1H),1.26(d,J=6.02Hz,3H).

[0744] Example 1-83

[0745]

[0746] N-(5-(((2S,4R)-4-((6-Fluoropyridazin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 2 from 3,6-difluoropyridazine, tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate and N-(5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 352.0. 1 HNMR: (400MHz, methanol-d4) δ7.40 (d, J = 9.2Hz, 1H), 7.29-7.33 (m, 1H), 7.27 (s, 1H), 5.39-5.43 (m, 1H), 4.13-4.17 (m, 1H) ),3.53-3.57(m,1H),3.16-3.18(m,1H),2.57-2.68(m,3H),2.19(s,3H),1.67-1.71(m,1H),1.26(d,J=6.0Hz,3H).

[0747] Examples 1-84

[0748]

[0749] N-(4-Fluoro-5-(((2S,4R)-4-((6-methoxypyridazin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 3-chloro-6-methoxypyridazine and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 382.1. 1 HNMR: (500 MHz, methanol-d4) δ7.11 (s, 2H), 5.33-5.37 (m, 1H), 3.98-4.02 (m, 1H), 3.99 (s, 3H), 3.57-3.60 (m, 1H), 3.20-3.22 (m, 1H), 2.62-2.74 (m, 3H), 2.20 (s, 3H), 1.66-1.68 (m, 1H), 1.27 (d, J = 5.5 Hz, 3H).

[0750] Example 1-85

[0751]

[0752] N-(4-Fluoro-5-(((2S,4R)-4-((6-fluoropyridin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 6-fluoropyridin-3-ol and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 369. 1 HNMR: (500MHz, methanol-d4)δ7.75(s,1H),7.46-7.50(m,1H),6.98(dd,J=8.8,3.2Hz,1H),4.78-4.80(m,1H),3.96-4.00(m ,1H),3.57-3.60(m,1H),3.15-3.18(m,1H),2.58-2.68(m,3H),2.18(s,3H),1.56-1.63(m,1H),1.25(d,J=5.6Hz,3H).

[0753] Example 1-86

[0754]

[0755] N-(5-(((2S,4R)-4-((5-fluoropyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from 2-chloro-5-fluoropyrimidine, tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate and N-(5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 352.0. 1 HNMR: (500MHz, CDCl3)δ12.14(br s,1H),8.26(s,2H),7.14(s,1H),5.05-5.19(m,1H),4.02(d,J=14.50Hz,1H),3.52(d,J=14.50Hz,1H),3.10(d,J=11.14Hz,1H),2.62(dd,J= 11.22,6.48Hz,1H),2.40-2.55(m,2H),2.19-2.28(m,3H),1.70(ddd,J=13.01,8.66,4.27Hz,1H),1.10-1.26(m,5H),0.81(t,J=6.94Hz,1H).

[0756] Example 1-87

[0757]

[0758] N-(5-(((2S,4R)-4-((5-fluoro-4-methylpyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 2-bromo-5-fluoro-4-methylpyridine and N-(5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 365. 1 HNMR: (500MHz, CDCl3) δ11.46(brs,1H),7.79(s,1H),7.20(s,1H),6.56(d,J=5.0Hz,1H),5.20-5.23(m,1H),4.10-4.13(m,1H),3.56-3. 59(m,1H),3.09-3.12(m,1H),2.56-2.61(m,1H),2.48-2.52(m,2H),2.29(s,3H),2.22(s,3H),1.62-1.66(m,1H),1.24(d,J=5.5Hz,3H).

[0759] Example 1-88

[0760]

[0761] N-(4-Fluoro-5-(((2S,4R)-4-((6-methoxypyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 2-chloro-6-methoxypyrazine, and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 382.1. 1 HNMR: (500 MHz, methanol-d4) δ7.70 (s, 2H), 5.29-5.31 (m, 1H), 3.97-4.00 (m, 1H), 3.94 (s, 3H), 3.56-3.60 (m, 1H), 3.18-3.20 (m, 1H), 2.73-2.77 (m, 1H), 2.60-2.65 (m, 2H), 2.18 (s, 3H), 1.64-1.69 (m, 1H), 1.25 (d, J = 5.2 Hz, 3H).

[0762] Example 1-89

[0763]

[0764] N-(4-Fluoro-5-(((2S,4R)-4-((5-methoxypyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 2-chloro-5-methoxypyrimidine and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 382. 1 HNMR: (400 MHz, methanol-d4) δ 8.26 (s, 2H), 5.29-5.30 (m, 1H), 4.07-4.11 (m, 1H), 3.87 (s, 3H), 3.70-3.73 (m, 1H), 3.24-3.25 (m, 1H), 2.64-2.89 (m, 3H), 2.18 (s, 3H), 1.73-1.75 (m, 1H), 1.30 (d, J = 5.6 Hz, 3H).

[0765] Example 1-90

[0766]

[0767] N-(5-(((2S,4R)-4-((5-chloropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 5-chloro-2-fluoropyridine and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 385. 1 HNMR: (400MHz, CDCl3) δ10.57(br.s,1H),8.03(d,J=2.4Hz,1H),7.48(dd,J=8.8,2.4Hz,1H),6.70(d,J=8.8Hz,1H),5.25-5.27(m,1H),3.97(d,J=1 4.4Hz,1H),3.64(d,J=14.8Hz,1H),3.14-3.17(m,1H),2.62-2.67(m,1H), 2.49-2.55(m,2H),2.29(s,3H),1.63-1.67(m,1H),1.24(d,J=5.2Hz,3H).

[0768] Example 1-91

[0769]

[0770] N-(4-Fluoro-5-(((2S,4R)-4-((4-methoxypyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 2-chloro-4-methoxypyrimidine and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 382. 1 HNMR: (400MHz, CDCl3)δ10.57(br s,1H),8.13(d,J=5.5Hz,1H),6.33(d,J=5.5Hz,1H),5.22-5.28(m,1H),3.95-3.96(m,1H),3.94(s,3H),3.62(d,J=14.5Hz ,1H),3.22(d,J=11.0Hz,1H),2.68-2.73(m,1H),2.47-2.58(m,2H),2.29(s,3H),1.73-1.79(m,1H),1.23(d,J=5.5Hz,3H).

[0771] Example 1-92

[0772]

[0773] N-(4-Fluoro-5-(((2S,4R)-4-((2-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4-chloro-2-methoxypyrimidine and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 382.0. 1 HNMR: (400MHz, methanol-d4) δ8.18 (d, J=6.0Hz 1H),6.45(d,J=6.0Hz,1H),5.36-5.40(m,1H),3.97-3.98(m,1H),3.93(s,3H),3.55-3.58(m,1H ),3.15-3.18(m,1H),2.59-2.74(m,3H),2.18(s,3H),1.61-1.67(m,1H),1.23(d,J=5.6Hz,3H).

[0774] Example 1-93

[0775]

[0776] N-(4-Fluoro-5-(((2S,4R)-2-methyl-4-(pyrimidin-2-yloxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 2-chloropyrimidine and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 352.0. 1 HNMR: (500MHz, methanol-d4)δ8.53(d,J=5.0Hz,2H),7.06(t,J=5.0Hz,1H),5.30-5.34(m,1H),3.93-3.97(m,1H),3. 53-3.57(m,1H),3.15-3.18(m,1H),2.58-2.73(m,3H),2.17(s,3H),1.65-1.70(m,1H),1.25(d,J=6.0Hz,3H).

[0777] Examples 1-94

[0778]

[0779] N-(4-Fluoro-5-(((2S,4R)-4-((3-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 2,3-difluoropyridine and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 369.0. 1 HNMR: (500MHz, methanol-d4) δ7.87 (d, J = 5.0Hz, 1H), 7.40-7.44 (m, 1H), 6.88-6.92 (m, 1H), 5.34-5.37 (m, 1H), 3.93-3.97 (m, 1H), 3.5 6-3.59(m,1H),3.15-3.17(m,1H),2.70-2.74(m,1H),2.55-2.61(m,2H),2.18(s,3H),1.66-1.70(m,1H),1.25(d,J=5.5Hz,3H).

[0780] Example 1-95

[0781]

[0782] N-(5-(((2S,4R)-4-((5-chloropyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 2,5-dichloropyrimidine and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 385.9. 1 HNMR: (500MHz, CDCl3)δ10.82(br s,1H),8.41(s,2H),5.21-5.22(m,1H),3.93(d,J=14.5Hz,1H),3.62(d,J=14.5Hz,1H),3.18-3.20( m,1H),2.69-2.72(m,1H),2.50-2.54(m,2H),2.29(s,3H),1.73-1.74(m,1H),1.24(d,J=6.0Hz,3H).

[0783] Example 1-96

[0784]

[0785] N-(4-Fluoro-5-(((2S,4R)-4-((4-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 2,4-difluoropyridine and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 368.9. 1 HNMR: (500MHz, methanol-d4) δ8.07-8.10(m,1H),6.73-6.76(m,1H),6.50-6.53(m,1H),5.29-5.32(m,1H),3.95-3.98(m,1 H),3.55-3.58(m,1H),3.12-3.14(m,1H),2.56-2.69(m,3H),2.18(s,3H),1.58-1.64(m,1H),1.23(d,J=5.5Hz,3H).

[0786] Example 1-97

[0787]

[0788] N-(4-Fluoro-5-(((2S,4R)-4-((2-fluoropyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 2,4-difluoropyridine and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 368.9. 1 HNMR: (500MHz, methanol-d4) δ7.96(d,J=4.5Hz,1H),6.82(d,J=6.0Hz,1H),6.55(d,J=1.5Hz,1H),4.89-4.92(m,1H),3.96-4.00(m,1H),3.57 -3.60(m,1H),3.16-3.18(m,1H),2.61-2.71(m,3H),2.18(s,3H),1.58-1.62(m,1H),1.28(d,J=5.5Hz,3H).

[0789] Examples 1-98

[0790]

[0791] N-(4-Fluoro-5-(((2S,4R)-4-((5-methoxypyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 2-fluoro-5-methoxypyridine and N-(5-(chloromethyl)-4-fluorothiazol-2-yl)acetamide. LCMS (ESI): [M+H] 381.1. 1 HNMR: (500MHz, methanol-d4) δ7.74(d,J=3.0Hz,1H),7.31(dd,J=3.0Hz,9.0Hz,1H),6.70-6.76(m,1H),5.18-5.19(m,1H),3.96(d,J=15.0Hz,1H),3.79(s ,3H),3.56(d,J=14.5Hz,1H),3.11(d,J=11.0Hz,1H),2.65-2.68(m,1H), 2.54-2.57(m,2H),2.18(s,3H),1.58-1.63(m,1H),1.24(d,J=5.5Hz,3H).

[0792] Examples 1-99

[0793]

[0794] N-(4-Fluoro-5-(((2S,4R)-4-((6-methoxypyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 2-chloro-6-methoxypyridine and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 381.0. 1 HNMR: (500 MHz, methanol-d4) δ7.53 (t, J = 8.0 Hz, 1H), 6.30 (d, J = 7.5 Hz, 2H), 5.27-5.30 (m, 1H), 3.98-4.01 (m, 1H), 3.87 (s, 3H), 3.58-3.61 (m, 1H), 3.17-3.20 (m, 1H), 2.75-2.78 (m, 1H), 2.57-2.62 (m, 2H), 2.20 (s, 3H), 1.64-1.69 (m, 1H), 1.26 (d, J = 5.5 Hz, 3H).

[0795] Example 1-100

[0796]

[0797] N-(4-Fluoro-5-(((2S,4R)-4-((2-methoxypyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4-chloro-2-methoxypyridine and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 381.0. 1 HNMR: (500MHz, methanol-d4)δ7.88(d,J=6.0Hz,1H),6.50(d,J=4.5Hz,1H),6.20(s,1H),4.81-4.82(m,1H),3.95-3.98(m,1H),3. 85(s,3H),3.55-3.58(m,1H),3.13-3.15(m,1H),2.57-2.67(m,3H),2.18(s,3H),1.56-1.61(m,1H),1.23(d,J=5.5Hz,3H).

[0798] Example 1-101

[0799]

[0800] N-(5-(((2S,4R)-4-((4-chloropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4-chloro-2-fluoropyridine and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 384.9. 1 HNMR: (500MHz, CDCl3)δ11.18(br s,1H),7.99(d,J=5.5Hz,1H),6.83(dd,J=5.5,2.0Hz,1H),6.76(d,J=1.5Hz,1H),5.30-5.31(m,1H),3.97(d,J=15.0Hz,1H),3.63 (d,J=14.5Hz,1H),3.14-.16(m,1H),2.64-2.67(m,1H),2.49-2.53(m,2H),2.30(s,3H),1.62-1.66(m,1H),1.24(d,J=5.5Hz,3H).

[0801] Intermediate 8

[0802]

[0803] (2S, 4R) -4- ((5-fluoropyridin-2-yl) oxy) -2-methylpyrrolidine -1- carboxylic acid tert-butyl ester: to a mixture of (2S, 4R) -4-hydroxy -2-methyl- pyrrolidine -1- carboxylic acid tert-butyl ester (262.33 mg, 1.30 mmol) in THF (3.00 mL) was added NaH (104 mg, 2.61 mmol, 60% purity). After 30 minutes at room temperature, 2,5-difluoropyridine (150 mg, 1.30 mmol, 118 uL) was added to the mixture. The resulting mixture was stirred at 90 ° C for 2 hours. The reactants were concentrated under reduced pressure and the residue was purified on silica gel by column chromatography (petroleum ether / EtOAc = 5 / 1) to give the title compound (286 mg, 0.965 mmol, 74% yield).

[0804] Intermediate 9

[0805]

[0806] Tert-Butyl (2S,4R)-4-((4-chloro-5-fluoropyridin-2-yl)oxy)-2-methylpyrrolidine-1-carboxylate: n-BuLi (2.5 M, 1.94 mL) was added dropwise to a mixture of tert-butyl (2S,4R)-4-[(5-fluoro-2-pyridin-2-yl)oxy]-2-methyl-pyrrolidine-1-carboxylate (720 mg, 2.43 mmol) in THF (20.0 mL) at -78°C under N2. After 0.5 h, hexachloroethane (1.73 g, 7.29 mmol, 826 uL) was added and the mixture was stirred for an additional hour. NH4Cl (saturated aqueous solution, 15 mL) was added to the mixture, extracted with EtOAc (3 x 15 mL), and the combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether / EtOAc=10 / 1) to give the title compound (430 mg). LCMS (ESI): [M-tBu+H]275.

[0807] Intermediate 10

[0808]

[0809] (2S,4R)-4-((4,5-difluoropyridin-2-yl)oxy)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester: A mixture of (2S,4R)-4-[(4-chloro-5-fluoro-2-pyridinyl)oxy]-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 0.604 mmol) and cesium fluoride (459 mg, 3.02 mmol) in DMSO (3.00 mL) was stirred at 160 ° C. under N2 in a microwave for 2 hours. Water (10 mL) was added and the mixture was extracted with EtOAc (3×10 mL), and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150×25 mm×5 μm; conditions: water (10 mM NH 4 HCO 3 )-CAN; start B: 48; end B: 78; gradient time (min): 10; 100% B hold time (min)) to give the title compound (101 mg, 0.321 mmol, 53% yield). LCMS (ESI): [M-tBu+H] 259.

[0810] Example 1-102

[0811]

[0812] N-(5-(((2S,4R)-4-((4,5-difluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 2 from tert-butyl (2S,4R)-4-((4,5-difluoropyridin-2-yl)oxy)-2-methylpyrrolidine-1-carboxylate and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 387.0. 1 HNMR: (500MHz, CDCl3)δ11.5(br s,1H),7.9(d,1H),6.5(d,1H),5.25(m,1H),3.9(d,J=14Hz,1H),3.54(d,J=14Hz,1H),3.10 (d,J=11.14Hz,1H),2.6(dd,J=11,6.5Hz,1H),2.40(m,2H),2.19(s,3H),1.10-1.26(d,3H).

[0813] Intermediate 11

[0814]

[0815] 4-(6-chloropyrimidin-4-yl)morpholine: To a solution of 4,6-dichloropyrimidine (500 mg, 3.53 mmol) in EtOH (15.0 mL) was added morpholine (585 mg, 6.71 mmol) and triethylamine (747.2 mg, 7.38 mmol). The mixture was stirred at 20 ° C for 3 hours. The reaction mixture was filtered and the residue was washed with EtOH (30 mL) to give the title compound (826 mg, 62% yield). 1 HNMR: (500MHz, CDCl3) δ: 8.38 (s, 1H), 6.48 (s, 1H), 3.76-3.80 (m, 4H), 3.62-3.63 (m, 4H).

[0816] Example 1-103

[0817]

[0818] N-(4-Fluoro-5-(((2S,4R)-2-methyl-4-((6-morpholinopyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4-(6-chloropyrimidin-4-yl)morpholine and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 437.1. 1HNMR: (400MHz, CDCl3) δ10.28(br.,s.,1H),8.26(s,1H),5.85(s,1H),5.27-5.35(m,1H),3.75-3.97(m,1H), 3.64-3.74(m,5H),3.52-3.59(m,5H),3.12-3.16(m,1H),2.51-2.61(m,3H),2.29(s,3H),1.24-1.25(m,3H).

[0819] Example 1-104

[0820]

[0821] N-(5-(((2S,4R)-2-methyl-4-((2-methylpyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4-chloro-2-methyl-pyrimidine and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 348.1. 1 HNMR: (500MHz, DMSO-d6) δ12.30(s,1H),8.45(d,J=5.5Hz,1H),7.59-7.69(m,1H),5.57(br s,1H),4.75(br s,2H),4.46-4.62(m,2H),2.85(br d,J=7.3Hz,1H),2.59-2.73(m,2H),2.52-2.55(m,5H),2.12-2.19(m,4H),2.07(s,1H),1.84(br s,1H),1.41(br d,J=6.7Hz,4H).

[0822] Example 1-105

[0823]

[0824] N-(4-Fluoro-5-(((2S,4R)-4-((5-methoxypyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 2-chloro-5-methoxypyrazine and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 382. 1HNMR: (400MHz, DMSO-d6)δ7.85(s,2H),5.10-5.14(m,1H),3.86-3.89(m,1H),3.81(s,3H),3.42-3.46(m,1H),2 .94-2.97(m,1H),2.53-2.54(m,2H),2.41-2.46(m,1H),2.10(s,3H),1.44-1.49(m,1H),1.12(d,J=6.0Hz,3H).

[0825] Example 1-106

[0826]

[0827] N-(5-(((2S,4R)-4-((3,5-dimethylpyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 2-chloro-3,5-dimethylpyrazine and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 380. 1 HNMR: (400MHz, methanol-d4) δ7.82(s,1H),5.29-5.30(m,1H),3.39-3.40(m,1H),3.63-3.64(m,1H),3.16-3.17( m,1H),2.60-2.76(m,3H),2.42(s,3H),2.38(s,3H),2.18(s,3H),1.67-1.68(m,1H),1.28(d,J=5.0Hz,3H).

[0828] Example 1-107

[0829]

[0830] N-(5-(((2S,4R)-4-((2,5-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4-chloro-2,5-dimethylpyridine and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 379. 1HNMR: (400MHz, methanol-d4) δ7.99(s,1H),6.69(s,1H),4.86-4.89(m,1H),3.97(d,J=14.5Hz,1H),3.60(d,J=15.0Hz,1H),3.16(d,J=11.0Hz ,1H),2.73(dd,J=11.0,5.5Hz,1H),2.61-2.64(m,2H),2.43(s,3H),2.18(s,3H),2.12(s,3H),1.60-1.63(m,1H),1.24(d,J=5.5Hz,3H).

[0831] Example 1-108

[0832]

[0833] N-(4-Fluoro-5-(((2S,4R)-2-methyl-4-((5-methylpyrazin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 2-chloro-5-methylpyrazine and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 366. 1 HNMR: (400MHz, methanol-d4)δ8.05(s,1H),8.00(s,1H),5.27-5.29(m,1H),3.96-3.98(m,1H),3.55-3.58(m,1H) ,3.12-3.15(m,1H),2.57-2.69(m,3H),2.42(s,3H),2.18(s,3H),1.60-1.66(m,1H),1.24(d,J=6.0Hz,3H).

[0834] Example 1-109

[0835]

[0836] N-(4-Fluoro-5-(((2S,4R)-4-((6-hydroxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound (byproduct isolated from Example 1-22) was prepared in a manner similar to that described in Scheme 2. LCMS (ESI): [M+H] 368. 1HNMR: (400MHz, methanol-d4) δ8.04(d,J=0.75Hz,1H),5.61(d,J=0.75Hz,1H),5.08-5.23(m,1H),3.95(dd,J=0.88,14.68Hz,1H ),3.55(d,J=14.56Hz,1H),3.13(d,J=11.55Hz,1H),2.47-2.70(m,3H),2.17(s,3H),1.53-1.71(m,1H),1.16-1.31(m,3H)

[0837] Example 1-110

[0838]

[0839] N-(4-Fluoro-5-(((2S,4R)-2-methyl-4-((2-methylpyridin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4-chloro-2-methylpyridine and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 365. 1 HNMR: (400MHz, methanol-d4) δ8.17(d,J=6.02Hz,1H),6.66-6.85(m,2H),4.87-4.93(m,1H),3.97(dd,J=1.00,14.56Hz,1H),3.58(d,J =14.56Hz,1H),3.15(d,J=11.04Hz,1H),2.52-2.76(m,3H),2.45(s,3H),2.18(s,3H),1.49-1.70(m,1H),1.24(d,J=6.02Hz,3H)

[0840] Example 1-111

[0841]

[0842] N-(4-Fluoro-5-(((2S,4R)-4-((6-fluoropyridazin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from 3,6-difluoropyridazine, tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate and N-(5-(chloromethyl)-4-fluorothiazol-2-yl)acetamide. LCMS (ESI): [M+H] 370. 1HNMR: (400MHz, methanol-d4) δ7.40 (d, J=9.2, 1.6Hz, 1H), 7.31-7.33 (m, 1H), 5.39-5.43 (m, 1H), 3.96-4.00 (m, 1H), 3 .55-3.58(m,1H),3.19-3.22(m,1H),2.57-2.72(m,3H),2.18(s,3H),1.64-1.69(m,1H),1.25(d,J=6.0Hz,3H).

[0843] Example 1-112

[0844]

[0845] N-(4-Fluoro-5-(((2S,4R)-4-((5-fluoropyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from 2-chloro-5-fluoropyrimidine, tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 370.0. 1 HNMR: (400 MHz, methanol-d4) δ8.46 (s, 2H), 5.20-5.29 (m, 1H), 3.93 (d, J = 14.4 Hz, 1H), 3.53 (d, J = 14.4 Hz, 1H), 3.14 (d, J = 11.2 Hz, 1H), 2.64-2.70 (m, 1H), 2.50-2.62 (m, 2H), 2.15 (s, 3H), 1.59-1.68 (m, 1H), 1.22 (d, J = 6.0 Hz, 3H).

[0846] Example 1-113

[0847]

[0848] N-(5-(((2S,4R)-4-((5-(difluoromethyl)pyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from 2-chloro-5-(difluoromethyl)pyrazine, tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 402.0. 1HNMR: (400MHz, methanol-d4) δ8.8(s,1H),8.4(s,1H),6.4(t),5.6(m,1H),3.93(d,J=14.4Hz,1H),3.53(d,J=14 .4Hz,1H),3.3(d,J=11.2Hz,1H),2.64-2.70(m,3H),2.2(s,3H),1.59-1.68(m,1H),1.22(d,J=6.0Hz,3H).

[0849] Example 1-114

[0850]

[0851] N-(4-Fluoro-5-(((2S,4R)-4-((6-methoxypyridin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl (2S,4S)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 6-methoxypyridin-3-ol and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 380.9. 1 HNMR: (500MHz, methanol-d4) δ7.68(d,J=2.5Hz,1H),7.29(dd,J=9.0,3.0Hz,1H),6.72(d,J=9.0Hz,1H),4.72-4.74(m,1H),3.96-3.99(m ,1H),3.83(s,3H),3.56-3.59(m,1H),3.14-3.16(m,1H),2.54-2.63(m,3H),2.18(s,3H),1.58-1.64(m,1H),1.23(d,J=6.0Hz,3H).

[0852] Example 1-115

[0853]

[0854] N-(5-(((2S,4R)-4-((6-Fluoropyridin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 2 from 6-fluoropyridin-3-ol, tert-butyl (2S,4S)-4-hydroxy-2-methylpyrrolidine-1-carboxylate and N-(5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 351.1. 1HNMR: (500MHz, methanol-d4) δ7.75 (s, 1H), 7.46-7.49 (m, 1H), 7.28 (s, 1H), 6.97 (dd, J = 9.0, 3.0Hz, 1H), 4.79-4.82 (m, 1H), 4.13-4 .17(m,1H),3.56-3.59(m,1H),3.12-3.15(m,1H),2.59-2.64(m,3H),2.20(s,3H),1.61-1.65(m,1H),1.26(d,J=5.5Hz,3H).

[0855] Example 1-116

[0856]

[0857] N-(5-(((2R,4S)-2-methyl-4-((6-methylpyridin-3-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 2 from 6-methylpyridin-3-ol, tert-butyl (2S,4S)-4-hydroxy-2-methylpyrrolidine-1-carboxylate and N-(5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 347. 1 HNMR: (400MHz, methanol-d4) δ8.02(d,J=2.76Hz,1H),7.29(s,1H),7.24-7.28(m,1H),7.18-7.22(m,1H),4.77-4.84(m,1H),4.16(dd,J=14.18,0.8 8Hz,1H),3.59(d,J=14.31Hz,1H),3.14(d,J=11.04Hz,1H),2.54-2.68(m,3H),2.45(s,3H),2.21(s,3H),1.64(s,1H),1.27(d,J=5.77Hz,3H).

[0858] Example 1-117

[0859]

[0860] N-(4-Fluoro-5-(((2S,4R)-4-((5-fluoro-4-methylpyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from 2-bromo-5-fluoro-4-methylpyridine, tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate and N-(5-(chloromethyl)-4-fluorothiazol-2-yl)acetamide. LCMS (ESI): [M+H] 383. 1HNMR: (400MHz, methanol-d4) δ11.08(brs,1H),7.81(s,1H),6.57(d,J=4.8Hz,1H),5.20-5.25(m,1H),3.95-3.99(m,1H),3.61-3.65(m, 1H),3.12-3.15(m,1H),2.61-2.65(m,1H),2.47-2.52(m,2H),2.30(s,3H),2.22(s,3H),1.59-1.62(m,1H),1.24(d,J=5.6Hz,3H).

[0861] Example 1-118

[0862]

[0863] N-(4-Fluoro-5-(((2S,4R)-4-((5-fluoro-4-methoxypyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from 2-bromo-5-fluoro-4-methoxypyridine, tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 399.0. 1 HNMR: (400MHz, methanol-d4) δ7.75(s,1H),6.45(s,1H),5.25(m,1H),3.9(d,J=14Hz,1H),3.5(d,J=14H z,1H),3.1(d,J=11Hz,1H),2.49-2.6(m,3H),2.2(s,3H),1.5-1.6(m,1H),1.25(d,J=6.0Hz,3H).

[0864] Example 1-119

[0865]

[0866] N-(4-Fluoro-5-(((2S,4R)-2-methyl-4-(pyrimidin-5-yloxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from 5-bromopyrimidine, tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 352.0. 1HNMR: (400 MHz, methanol-d4) δ8.7 (s, 1H), 8.3 (s, 2H), 5.3 (m, 1H), 3.93 (d, J = 14.4 Hz, 1H), 3.53 (d, J = 14.4 Hz, 1H), 3.3 (d, J = 11.2 Hz, 1H), 2.5-2.7 (m, 3H), 2.2 (s, 3H), 1.5-1.6 (m, 1H), 1.2 (d, J = 6.0 Hz, 3H).

[0867] Process 3

[0868]

[0869] Representative Procedure A: To a solution of the alcohol (3 eq) in DMSO (0.6 mL) was added tBuOK (2.5 eq). The mixture was stirred at ambient temperature for 30 min, followed by the addition of N-(5-(((2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide. Stirring was continued at 60°C for 16-72 h. Upon completion, the mixture was subjected to C18 preparative HPLC-MS (gradient mixtures of HO / MeOH or HO / MeCN) to afford the desired product.

[0870] Example 1-120

[0871]

[0872] N-(5-(((2S,4R)-4-((6-((1r,3R)-3-methoxycyclobutoxy)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 2 from N-(5-(((2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide and (1r,3r)-3-methoxycyclobutan-1-ol. LCMS (ESI): [M+H] 434.2.

[0873] Example 1-121

[0874]

[0875] N-(5-(((2S,4R)-4-((6-cyclobutoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 3 from N-(5-(((2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide and cyclobutanol. LCMS (ESI): [M+H] 404.2.

[0876] Example 1-122

[0877]

[0878] N-(5-(((2S,4R)-4-((6-(2-methoxyethoxy)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 3 from N-(5-(((2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide and 2-methoxyethan-1-ol. LCMS (ESI): [M+H] 408.2.

[0879] Example 1-123

[0880]

[0881] N-(5-(((2S,4R)-4-((6-((1s,3S)-3-methoxycyclobutoxy)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 3 from N-(5-(((2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide and (1s,3s)-3-methoxycyclobutan-1-ol. LCMS (ESI): [M+H] 434.2. 1HNMR: (400MHz, DMSO+CCl4) δ11.81(s,1H),8.24(s,1H),7.11(s,1H),5.99(s,1H),5.31 -5.26(m,1H),4.83-4.75(m,1H),4.01(d,J=14.0Hz,1H),3.62-3.55(m,1H),3.46(d,J=1 4.0Hz,1H),3.17(s,3H),2.98-2.94(m,1H),2.82-2.78(m,2H),2.59-2.52(m,2H),2.48 -2.45(m,1H),2.10(s,3H),1.96-1.92(m,2H),1.59-1.54(m,1H),1.20(d,J=5.4Hz,3H).

[0882] Example 1-124

[0883]

[0884] N-(5-(((2S,4R)-2-methyl-4-((6-(oxetan-3-yloxy)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 3 from N-(5-(((2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide and (1s,3s)-3-methoxycyclobutan-1-ol. LCMS (ESI): [M+H] 406.2.

[0885] Example 1-125

[0886]

[0887] N-(5-(((2S,4R)-2-methyl-4-((6-((1-methylazetidin-3-yl)oxy)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 3 from N-(5-(((2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide and 1-methylazetidin-3-ol. LCMS (ESI): [M+H] 419.0. 1HNMR: (400MHz, DMSO+CCl4) δ12.12-11.73(m,1H),8.67(s,1H),7.16(s,1H),6.47(s,1H),5.44-5.40(m,1H),4.40-4.36(m,2H),4.1 9-4.01(m,0H),3.83-3.69(m,2H),3.50-3.40(m,5H),3.17-3.16(m,3H),2.60(s,2H),2.12(s,3H),1.68-1.50(m,1H),1.23(s,3H).

[0888] Example 1-126

[0889]

[0890] N-(5-(((2S,4R)-4-((6-ethoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 3 from N-(5-(((2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide and ethanol. LCMS (ESI): [M+H] 378.2.

[0891] Example 1-127

[0892]

[0893] N-(5-(((2S,4R)-4-((6-Isopropoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 3 from N-(5-(((2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide and isopropanol. LCMS (ESI): [M+H] 392.2.

[0894] Process 4

[0895]

[0896] Representative Procedure B: To a solution of N-(5-(((2S,4R)-4-hydroxy-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide (1 eq) in DMSO (0.6 mL) was added tBuOK (1.2 eq). The mixture was stirred at ambient temperature for 30 min, followed by the addition of aryl halide (1.2 eq). The mixture was stirred at 60 °C for 16-72 h. Upon completion, the mixture was subjected to C18 preparative HPLC-MS (gradient mixture HO / MeOH or HO / MeCN) to give the desired product.

[0897] Intermediate 12

[0898]

[0899] (2S,4R)-4-((tert-Butyldimethylsilyl)oxy)-2-methylpyrrolidine: A 1 L round-bottom flask was charged with (3R,5S)-5-methylpyrrolidin-3-ol (6.21 g, 45.13 mmol, hydrochloride) and DCM (150 mL). Triethylamine (4.57 g, 45.13 mmol, 6.26 mL) was added and stirred for 10 minutes, followed by the addition of imidazole (737.35 mg, 10.83 mmol) and tert-butyl-chloro-dimethyl-silane (8.16 g, 54.16 mmol). The reaction was stirred at room temperature for 16 hours. The reaction was diluted with DCM and NaCHO (saturated) was added, the layers were separated and extracted with DCM (2×). The organics were dried over sodium sulfate, filtered and concentrated to give the title compound (9.72 g, 100% yield). LCMS (ESI): [M+H] 216.12. 1 HNMR:(500MHz,CDCl3)δ4.34(br dd,J=4.9,2.4Hz,1H),3.11-3.32(m,2H),2.88-3.03(m,1H),2.83(ddd,J=11.9,4.9,1.5Hz ,1H),2.15(ddd,J=13.3,7.5,6.1Hz,1H),1.25-1.33(m,4H),0.88(s,9H),0.05ppm(s,6H).

[0900] Intermediate 13

[0901]

[0902] N-(5-(((2S,4R)-4-((tert-Butyldimethylsilyl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: (2S,4R)-4-((tert-Butyldimethylsilyl)oxy)-2-methylpyrrolidine was dissolved in acetonitrile (100 mL) and triethylamine (11.25 g, 111.2 mmol, 15.41 mL) was added. N-[5-(chloromethyl)thiazol-2-yl]acetamide (5.30 g, 27.79 mmol) was added and stirred at room temperature for 16 hours. The reaction was filtered through celite and concentrated. Purification; gradient heptane / [Ea / EtOH (3:1)] (0→20→50%) gave the desired product (7.2 g, 19.5 mmol, 70% yield). LCMS (ESI): [M+H] 369.1. 1 HNMR: (500MHz, CDCl3) δ7.20 (s, 1H), 4.21-4.41 (m, 1H), 4.01-4.06 (m, 1H), 3.59 (d, J = 14.7Hz, 1H), 2.87 (dd, J = 10.1, 2.1Hz, 1H), 2.43-2.57 (m, 2H), 2.30(s,3H),2.24(dt,J=12.8,7.0Hz,1H),1.44-1.68(m,3H),1.22-1.31( m, 3H), 1.18 (d, J = 6.1Hz, 3H), 0.84-0.89 (m, 11H), -0.02-0.02ppm (m, 8H).

[0903] Intermediate 14

[0904]

[0905] N-(5-(((2S,4R)-4-hydroxy-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: A 250 ml round-bottom flask was charged with N-[5-[[(2S,4R)-4-[tert-butyl(dimethyl)silanyl]oxy-2-methyl-pyrrolidin-1-yl]methyl]thiazol-2-yl]acetamide (11.1 g, 29.90 mmol). MeOH (119.6 mL) and KHF (5.84 g, 74.8 mmol, 2.46 mL) were added and stirred at 60° C. for 16 hours. The reaction was cooled to room temperature and filtered through celite and concentrated. Purification on silica gel with [[heptane / EtOH (3:1)] containing 1% TEA; gradient (0→20→50→100%)] gave the title compound (5.30 g, 20.76 mmol, 69.42% yield). LCMS (ESI): [M+H] 256.1. 1HNMR: (500MHz, MeOD) δ7.24 (s, 1H), 4.17-4.22 (m, 1H), 4.05-4.10 (m, 1H), 3.48 (d, J = 14.0Hz, 1H), 2 .89(d,J=10.4Hz,1H),2.34-2.49(m,3H),2.19(s,3H),1.39-1.46(m,1H),1.21ppm(d,J=6.1Hz,3H).

[0906] Intermediate 15

[0907]

[0908] N-(5-(((2S,4S)-4-hydroxy-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: To a solution of (3S,5S)-5-methylpyrrolidin-3-ol (700 mg, 5.09 mmol, HCl) and N-[5-(chloromethyl)thiazol-2-yl]acetamide (953 mg, 5.00 mmol) in DMF (10.0 mL) was added Hunigs base (1.29 g, 10.0 mmol, 1.75 mL). The mixture was stirred at room temperature overnight and concentrated in vacuo. A few drops (about 10 drops) of saturated NaHCO were added to the mixture and evaporated with MeCN. The residue was purified on SiO (EtOAc / EtOH 3 / 1) to give the title compound (430 mg, 34% yield).

[0909] Example 1-128

[0910]

[0911] N-(5-(((2S,4R)-4-((2,6-dimethylpyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: To a mixture of 2,6-dimethylpyrimidin-4-ol (20 mg, 0.163 mmol), N-(5-(((2S,4S)-4-hydroxy-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide (38 mg, 0.149 mmol) and triphenylphosphine (51 mg, 0.193 mmol) in THF (1.0 mL) was added diisopropyl azodicarboxylate (42 mg, 0.208 mmol, 41 uL). The mixture was stirred at room temperature for 40 minutes. The mixture was purified on SiO2 (EtOAc 100% to EtOAc / EtOH 3 / 1) to give the title compound (23 mg, 43% yield).

[0912] LCMS (ESI): [M+H] 362.1 H NMR (400 MHz, methanol-d4) δ 7.28 (s, 1H), 6.53 (s, 1H), 5.35-5.46 (m, 1H), 4.15 (dd, J = 1.00, 14.31 Hz, 1H), 3.56 (d, J = 14.31 Hz, 1H), 3.10 (d, J = 11.55 Hz, 1H), 2.54-2.71 (m, 3H), 2.51 (s, 3H), 2.38 (s, 3H), 2.21 (s, 3H), 1.58-1.72 (m, 1H), 1.23-1.32 (m, 3H)

[0913] Example 1-129

[0914]

[0915] N-(5-(((2S,4R)-2-methyl-4-((6-(pyrrolidin-1-yl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 4 from N-(5-(((2S,4R)-4-hydroxy-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide and 4-chloro-6-(pyrrolidin-1-yl)pyrimidine. LCMS (ESI): [M+H] 403.

[0916] Example 1-130

[0917]

[0918] N-(5-(((2S,4R)-2-methyl-4-((6-morpholinopyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 4 from N-(5-(((2S,4R)-4-hydroxy-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide and 4-(6-chloropyrimidin-4-yl)morpholine. LCMS (ESI): [M+H] 419.0.

[0919] Process 5

[0920]

[0921] Representative Procedure C: A mixture of N-(5-(((2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide (1 eq), an amine (1.5 eq), and DIPEA (2 eq) in DMSO (0.6 mL) was stirred at 90 °C for 16-72 h. Upon completion, the mixture was subjected to C18 preparative HPLC-MS (gradient mixture HO / MeOH or HO / MeCN) to give the desired product.

[0922] Example 1-131

[0923]

[0924] N-(5-(((2S,4R)-4-((6-(Dimethylamino)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 5 from N-(5-(((2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide and dimethylamine. LCMS (ESI): [M+H] 377. 1 HNMR: (400MHz, DMSO+CCl4) δ11.81(s,1H),8.04(s,1H),7.11(s,1H),5.73(s,1H),5.29-5.25(m,1H),4.01(d,J=14.0Hz,1H),3. 42(d,J=13.9Hz,1H),3.02(s,6H),2.98-2.91(m,2H),2.49-2.41(m,2H),2.10(s,3H),1.58-1.49(m,1H),1.20(d,J=5.3Hz,3H).

[0925] Example 1-132

[0926]

[0927] N-(5-(((2S,4R)-4-((6-(ethyl(methyl)amino)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 5 from N-(5-(((2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide and N-methylethylamine. LCMS (ESI): [M+H] 391.2. 1HNMR: (400MHz, DMSO+CCl4)δ11.81(s,1H),8.03(s,1H),7.11(s,1H),5.70( s,1H),5.29-5.24(m,1H),4.01(d,J=13.9Hz,1H),3.53(q,J=7.3,6.5,6.5H z,2H),3.42(d,J=14.0Hz,1H),2.99-2.91(m,4H),2.50-2.42(m,3H),2.10( s, 3H), 1.55-1.51 (m, 1H), 1.20 (d, J = 5.3Hz, 3H), 1.10 (t, J = 7.0, 7.0Hz, 3H).

[0928] Example 1-133

[0929]

[0930] N-(5-(((2S,4R)-4-((6-(azetidin-1-yl)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 5 from N-(5-(((2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide and azetidine. LCMS (ESI): [M+H] 389.2. 1 HNMR: (400MHz, DMSO+CCl4) δ11.77-11.73(m,1H),8.01(s,1H),7.11(s,1H),5.47(s,1H),5.29-5.22(m,1H),4.05-3.93(m,5H),3.42( d,J=13.9Hz,1H),2.93(d,J=11.1Hz,1H),2.51-2.41(m,3H),2.41-2.32(m,2H),2.11(s,3H),1.54-1.46(m,1H),1.19(d,J=5.4Hz,3H).

[0931] Example 1-134

[0932]

[0933] N-(5-(((2S,4R)-4-((6-(cyclobutylamino)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 5 from N-(5-(((2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide and cyclobutane. LCMS (ESI): [M+H] 403.2. 1 HNMR: (400MHz, DMSO+CCl4)δ11.81(s,1H),7.95(s,1H),7.11(s,1H),7.04(d,J=7.2Hz ,1H),5.51(s,1H),5.25-5.18(m,1H),4.36-4.03(m,1H),4.00(d,J=14.0Hz,1H),3.42( d,J=13.9Hz,1H),2.93(d,J=11.2Hz,1H),2.51-2.38(m,3H),2.30-2.26(m,2H),2.10( s,3H),1.96-1.86(m,2H),1.74-1.63(m,2H),1.59-1.48(m,1H),1.19(d,J=5.3Hz,3H).

[0934] Example 1-135

[0935]

[0936] N-(5-(((2S,4R)-4-((6-(ethylamino)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 5 from N-(5-(((2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide and ethylamine hydrochloride. LCMS (ESI): [M+H] 377.2. 1HNMR: (400MHz, DMSO+CCl4)δ11.81(s,1H),7.96(s,1H),7.11(s,1H),6.74(t,J =5.6,5.6Hz,1H),5.57(s,1H),5.25-5.19(m,1H),4.01(d,J=14.0Hz,1H),3.42 (d,J=14.0Hz,1H),3.02(s,2H),2.93(d,J=11.1Hz,1H),2.49-2.38(m,3H),2.1 0(s,3H),1.59-1.48(m,1H),1.20(d,J=5.3Hz,3H),1.14(t,J=7.2,7.2Hz,3H).

[0937] Example 1-136

[0938]

[0939] N-(5-(((2S,4R)-4-((6-(Isopropylamino)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 5 from N-(5-(((2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide and isopropylamine. LCMS (ESI): [M+H] 391.2. 1 HNMR: (400MHz, DMSO+CCl4)δ11.81(s,1H),7.96(s,1H),7.11(s,1H),6.59(d,J =7.8Hz,1H),5.56(s,1H),5.25-5.18(m,1H),4.01(d,J=14.0Hz,1H),3.43(d,J =13.9Hz,1H),3.19(d,J=5.2Hz,1H),2.93(d,J=11.1Hz,1H),2.47-2.42(m,3H) ,2.10(s,3H),1.61-1.47(m,1H),1.20(d,J=5.3Hz,3H),1.14(d,J=6.4Hz,6H).

[0940] Example 1-137

[0941]

[0942] N-(5-(((2S,4R)-2-methyl-4-((6-(methylamino)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 5 from N-(5-(((2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide and methylamine. LCMS (ESI): [M+H] 363.2. 1 HNMR: (400MHz, DMSO+CCl4)δ11.82(s,1H),7.97(s,1H),7.12(s,1H),6.76(s,1H),5.57(s,1H),5.24(s,1H),4.02-3.98(m,1H) ,3.44-3.40(m,1H),2.94-2.90(m,2H),2.75(d,J=4.8Hz,3H),2.50-2.37(m,2H),2.11(s,3H),1.56-1.52(m,1H),1.21(s,3H).

[0943] Process 6

[0944]

[0945] Representative Procedure D: To a solution of the alcohol (1.3 eq) in THF (2 mL) was added KHMDS (1.2 eq) and the solution was stirred at ambient temperature for 1 hour. N-(5-(((2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide (1 eq) was added and stirring was continued at room temperature for 2 hours before the temperature was raised to 60° C. Upon completion, the mixture was then neutralized with AcOH (1 eq), concentrated under reduced pressure, and subjected to C18 preparative HPLC-MS (gradient mixture HO / MeOH or HO / MeCN) to give the desired product.

[0946] Example 1-138

[0947]

[0948] N-(5-(((2S,4R)-4-((6-(cyclopentyloxy)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 6 from N-(5-(((2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide and cyclopentanol. LCMS (ESI): [M+H] 418.2.

[0949] Example 1-139

[0950]

[0951] N-(5-(((2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4,6-dichloropyrimidine and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 385.9.

[0952] Example 1-140

[0953]

[0954] N-(4-Fluoro-5-(((2S,4R)-2-methyl-4-((6-(oxetan-3-yloxy)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 6 from N-(5-(((2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide and oxetan-3-ol. LCMS (ESI): [M+H] 424. 1 HNMR: (500MHz, CDCl3)δ10.78(br s,1H),8.30(s,1H),6.09(s,1H),5.55-5.60(m,1H),5.32-5.35(m,1H),4.94-4.97(m,2H),4.70-4.73(m,2H),3.97(d,J=15.0Hz,1H),3.6 3(d,J=14.5Hz,1H),3.15(d,J=11.5Hz,1H),2.63-2.66(m,1H),2.49-2.55(m,2H),2.30(s,3H),1.64-1.66(m,1H),1.24(d,J=5.5Hz,3H).

[0955] Example 1-141

[0956]

[0957] N-(4-Fluoro-5-(((2S,4R)-2-methyl-4-((6-((1-methylazetidin-3-yl)oxy)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 6 from N-(5-(((2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide and 1-methylazetidin-3-ol. LCMS (ESI): [M+H] 437.1. 1 HNMR: (400 MHz, methanol-d4) δ 8.32 (s, 1H), 6.13 (s, 1H), 5.30-5.33 (m, 1H), 5.17-5.23 (m, 1H), 3.94-3.96 (m, 1H), 3.77-3.81 (m, 2H), 3.53-3.56 (m, 1H), 3.23-3.25 (m, 2H), 3.10-3.22 (m, 1H), 2.55-2.58 (m, 3H), 2.40 (s, 3H), 2.18 (s, 3H), 1.59-1.64 (m, 1H), 1.24 (d, J = 6.0 Hz, 3H).

[0958] Example 1-142

[0959]

[0960] (2S, 4R) -4- (5-chloropyrazin-2-yl) oxy-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester: To a solution of (2S, 4R) -4-hydroxy-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (676 mg, 3.36 mmol) in THF (10.0 mL) was added sodium hydride (202 mg, 5.04 mmol, 60% purity) and then 2,5-dichloropyrazine (500 mg, 3.36 mmol) was added to the mixture. The resulting mixture was stirred at 90 ° C. After 2 hours, the reactants were concentrated under reduced pressure and the residue was purified by SiO2 (PE / EtOAc = 10 / 1) to give (2S, 4R) -4- (5-chloropyrazin-2-yl) oxy-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (785 mg, 74% yield).

[0961] (2S,4R)-2-Methyl-4-(5-morpholinopyrazin-2-yl)oxy-pyrrolidine-1-carboxylic acid tert-butyl ester: A mixture of (2S,4R)-4-(5-chloropyrazin-2-yl)oxy-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 0.64 mmol), morpholine (278 mg, 3.19 mmol, 277 uL), Pd2(dba)3 (58 mg, 63.74 umol), t-BuONa (122 mg, 1.27 mmol) and BINAP (40 mg, 63.7 umol) in toluene (10.0 mL) was stirred at 110 °C under N2 for 2 hours. The reaction was concentrated under reduced pressure and the residue was purified on SiO2 (PE / EtOAc=3 / 1) to give (2S,4R)-2-methyl-4-(5-morpholinopyrazin-2-yl)oxy-pyrrolidine-1-carboxylic acid tert-butyl ester (157 mg, 430.80 μmol, 68% yield) as a yellow solid.

[0962] N-(4-Fluoro-5-(((2S,4R)-2-methyl-4-((5-morpholinopyrazin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that described in Example 1-22 from tert-butyl (2S,4R)-2-methyl-4-((5-morpholinopyrazin-2-yl)oxy)pyrrolidine-1-carboxylate and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 437. 1 HNMR: (400MHz, methanol-d4) δppm 7.81(d,J=1.17Hz,1H),7.70(d,J=1.57Hz,1H),5.13-5.23(m,1H),3.97(d,J=14. 48Hz,1H),3.74-3.84(m,4H),3.56(d,J=14.48Hz,1H),3.32-3.38(m,4H),3.12(br d,J=10.96Hz,1H),2.65(dd,J=11.35,6.26Hz,1H),2.49-2.61(m,2H),2.18(s,3H),1.54-1.69(m,1H),1.25(d,J=5.48Hz,3H).

[0963] Example 1-143

[0964]

[0965] N-(4-Fluoro-5-(((2S,4R)-2-methyl-4-((4-morpholinopyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from 4-(2-fluoropyridin-4-yl)morpholine, tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 436. 1 HNMR: (500 MHz, methanol-d4) δ ppm 7.75(d,J=6.26Hz,1H),6.51(dd,J=6.26,2.29Hz,1H),6.13(d,J=2.14Hz,1H), 5.09-5.24(m,1H),3.96(d,J=14.65Hz,1H),3.71-3.84(m,4H),3.55(d,J=14.65 Hz,1H),3.21-3.29(m,4H),3.10(d,J=11.14Hz,1H),2.64(dd,J=11.14,6.26Hz, 1H), 2.50-2.59 (m, 2H), 2.18 (s, 3H), 1.54-1.67 (m, 1H), 1.24 (d, J = 5.49Hz, 3H).

[0966] Example 1-144

[0967]

[0968] N-(4-Fluoro-5-(((2S,4R)-4-((5-(2-methoxyethoxy)pyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 2 from 2-chloro-5-(2-methoxyethoxy)pyrazine, tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 426. 1HNMR: (400MHz,CDCl3)δ9.95(br s,1H),7.71(d,J=1.47Hz,1H),7.68(d,J=1.47Hz,1H),5.07-5.17(m,1H),4.25- 4.39(m,2H),3.91(d,J=15.16Hz,1H),3.66(dd,J=5.26,3.79Hz,2H),3.58(d,J= 14.67Hz,1H),3.36(s,3H),3.09(d,J=11.00Hz,1H),2.57(dd,J=11.13,6.24Hz, 1H), 2.36-2.50 (m, 2H), 2.21 (s, 3H), 1.54-1.64 (m, 1H), 1.18 (d, J = 5.62Hz, 3H).

[0969] Example 1-145

[0970]

[0971] N-(4-Fluoro-5-(((2S,4R)-4-((4-((2-methoxyethyl)(methyl)amino)pyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 2 from 2-fluoro-N-(2-methoxyethyl)-N-methylpyridin-4-amine, tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 438. 1 HNMR: (400MHz, CDCl3) δppm9.72(br s,2H),7.75(d,J=6.11Hz,2H),6.19(dd,J=6.11,2.45Hz,1H),5.89(d,J=2.20Hz,2H),5.30(br d,J=3.91Hz,2H),3.95(br d,J=14.67Hz,2H),3.63(d,J=14.67Hz,1H),3.41-3.55(m,3H),3.32(s,3H),3.13(br d,J=11.00Hz,1H),2.95(s,3H),2.56-2.66(m,1H),2.41-2.54(m,2H),2.25(s,3H),1.22(d,J=5.62Hz,4H)

[0972] Example 1-146

[0973]

[0974] (2S, 4R) -4- [(5- bromo-2-pyridyl) oxy] -2-methyl - pyrrolidine -1- carboxylic acid tert-butyl ester: To a solution of 5- bromo-2-fluoro-pyridine (315 mg, 1.79 mmol, 184 uL) in THF (5.0 mL) was added NaH (119 mg, 2.98 mmol, 60% purity) and (2S, 4R) -4-hydroxy -2-methyl - pyrrolidine -1- carboxylic acid tert-butyl ester (300 mg, 1.49 mmol) and the mixture was stirred at 90 ° C for 2 hours. The reactants were quenched with saturated NH4Cl (4 mL aqueous solution). The mixture was concentrated, then treated with H2O (10 mL) and extracted with EtOAc (20 mL × 3). The organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified on SiO2 (petroleum ether / EtOAc=15 / 1 to 5 / 1) to give (2S,4R)-4-[(5-bromo-2-pyridinyl)oxy]-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (458 mg, 86% yield).

[0975] To a solution of morpholine (243.87 mg, 2.80 mmol, 243.87 uL) in toluene (8.00 mL) was added tert-butyl (2S,4R)-4-[(5-bromo-2-pyridinyl)oxy]-2-methyl-pyrrolidine-1-carboxylate (200 mg, 560 μmol), [2-(2-aminophenyl)phenyl]-methanesulfonyloxy-palladium; dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (51 mg, 56 μmol), and Cs2CO3 (365 mg, 1.12 mmol). The mixture was stirred at 110° C. under N2 for 15 hours. The mixture was concentrated and purified on SiO2 (petroleum ether / EtOAc=15 / 1 to 5 / 1) to give tert-butyl (2S,4R)-2-methyl-4-[(5-morpholino-2-pyridinyl)oxy]pyrrolidine-1-carboxylate (197 mg, 97% yield). LCMS (ESI): [M+H] 359.

[0976] N-(4-Fluoro-5-(((2S,4R)-2-methyl-4-((5-morpholinopyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that described in Example 1-22 from tert-butyl (2S,4R)-2-methyl-4-[(5-morpholinopyridin-2-yl)oxy]pyrrolidine-1-carboxylate and N-(4-fluoro-5-formyl-thiazol-2-yl)acetamide. LCMS (ESI): [M+H] 436. 1HNMR: (400MHz, methanol-d4) δppm 7.72(d,J=2.93Hz,1H),7.41(dd,J=9.05,3.18Hz,1H),6.70(d,J=9.05Hz,1H),5.12-5. 24(m,1H),3.95(d,J=14.67Hz,1H),3.75-3.87(m,4H),3.55(d,J=14.43Hz,1H),3.10(br d,J=11.25Hz,1H),2.99-3.07(m,4H),2.65(dd,J=11.13,6.24Hz,1H),2.48-2.60(m ,2H),2.18(s,3H),1.61(ddd,J=15.77,11.86,3.91Hz,1H),1.24(d,J=5.62Hz,3H).

[0977] Example 1-147

[0978]

[0979] (2S,4R)-4-[[5-(2-methoxyethoxy)-2-pyridinyl]oxy]-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester: A mixture of (2S,4R)-4-[[5-fluoro-2-pyridinyl)oxy]-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 675 μmol), 2-methoxyethanol (257 mg, 3.37 mmol, 264 μL), and potassium tert-butoxide (152 mg, 1.35 mmol) in DMSO (8.00 mL) was stirred at 120° C. for 12 hours. The reaction was extracted (EtOAc 3×10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified on SiO2 (petroleum ether / EtOAc=3 / 1) to give (2S,4R)-4-[[5-(2-methoxyethoxy)-2-pyridinyl]oxy]-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (79 mg, 33% yield). LCMS (ESI): [M+H]353.

[0980] N-(4-Fluoro-5-(((2S,4R)-4-((4-(2-methoxyethoxy)pyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that described in Example 1-22 from (2S,4R)-4-[[5-(2-methoxyethoxy)-2-pyridinyl]oxy]-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester and N-(4-fluoro-5-formyl-thiazol-2-yl)acetamide. LCMS (ESI): [M+H] 425. 1HNMR: (400MHz, methanol-d4) δppm 7.87(d,J=5.87Hz,1H),6.54(dd,J=5.87,1.96Hz,1H),6.29(d,J=1.71Hz,1H),5.12-5.29(m,1H),4.08-4.21(m,2H),3.96(br d,J=14.43Hz,1H),3.69-3.79(m,2H),3.55(br d,J=14.43Hz,1H),3.40(s,3H),3.11(br d,J=11.25Hz,1H),2.65(br dd,J=11.13,6.24Hz,1H),2.47-2.61(m,2H),2.18(s,3H),1.52-1.69(m,1H),1.24(br d,J=5.38Hz,3H).

[0981] Example 1-148

[0982]

[0983] (2S, 4R) -4- (4- fluorophenoxy) -2-methyl - pyrrolidine -1- carboxylic acid tert-butyl ester: To a solution of 4-fluorophenol (50 mg, 446 umol) in DMF (5.00 mL) was added sodium hydride (36 mg, 892 umol, 60% purity) at 25 ° C and stirred for 30 minutes. (2S, 4S) -2-methyl -4-methylsulfonyloxy - pyrrolidine -1- carboxylic acid tert-butyl ester (83 mg, 297 umol) was added and the mixture was stirred at 90 ° C for 3 hours. The reaction mixture was quenched with water (15 mL) and extracted with EtOAc (2 × 15 mL). The combined organic phase was washed with water (2 × 15 mL), brine (15 mL), dried over Na2SO4, filtered and concentrated. The residue was purified on SiO 2 (PE:EtOAc=3:1) to give (2S,4R)-4-(4-fluorophenoxy)-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (35 mg, 40% yield).

[0984] N-(4-Fluoro-5-(((2S,4R)-4-(4-fluorophenoxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a manner analogous to that described in Example 1-22 from (2S,4R)-4-(4-fluorophenoxy)-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester and N-(4-fluoro-5-formyl-thiazol-2-yl)acetamide. LCMS (ESI): [M+H] 368. 1HNMR: (400MHz, CDCl3)δ10.73(br s,1H),6.88-6.99(m,2H),6.70-6.80(m,2H),4.53-4.67(m,1H),3.98(d,J=14.48Hz,1H),3.66(d,J=14.87Hz,1H),3.19(d,J=10.56H z,1H),2.61(dd,J=10.56,5.87Hz,1H),2.50-2.58(m,1H),2.41-2.49(m,1H),2.30(s,3H),1.66-1.73(m,1H),1.24(d,J=5.87Hz,3H).

[0985] Example 1-149

[0986]

[0987] N-(4-Fluoro-5-(((2S,4R)-2-methyl-4-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Example 1-146 from 1-methylpiperazine, tert-butyl (2S,4R)-4-((5-bromopyridin-2-yl)oxy)-2-methylpyrrolidine-1-carboxylate and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 449. 1 HNMR: (400MHz, methanol-d4) δppm 7.73(d,J=2.88Hz,1H),7.42(dd,J=9.01,3.00Hz,1H),6.70(d,J=9.01Hz,1H),5.13-5.23(m,1H),3.95(d,J=14.51Hz,1H),3.56(d ,J=14.51Hz,1H),3.06-3.15(m,5H),2.49-2.70(m,7H),2.34(s,3H),2.15-2.21(m,4H),1.52-1.69(m,1H),1.23(d,J=5.63Hz,3H).

[0988] Example 1-150

[0989]

[0990] (2S,4R)-4-[[4-(2-methoxyethoxy)-2-pyridinyl]oxy]-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester: (2S,4R)-4-[(4-fluoro-2-pyridinyl)oxy]-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 337 μmol) was added to a mixture of 2-methoxyethanol (51 mg, 675 μmol, 53 uL) and NaH (34 mg, 844 μmol, 60% purity) in THF (5.00 mL). The mixture was stirred at 80° C. for 12 hours. The mixture was quenched (aqueous NH4Cl), extracted (EtOAc 3×10 mL), washed with brine (2×20 mL), dried over Na2SO4, filtered and concentrated to give (2S,4R)-4-[[4-(2-methoxyethoxy)-2-pyridinyl]oxy]-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (106 mg, 88% yield).

[0991] N-(4-Fluoro-5-(((2S,4R)-4-((5-(2-methoxyethoxy)pyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 2 from (2S,4R)-4-[[4-(2-methoxyethoxy)-2-pyridinyl]oxy]-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 425. 1 HNMR: (500MHz, methanol-d4) δppm 7.76(d,J=3.05Hz,1H),7.33(dd,J=9.00,3.05Hz,1H),6.70(d,J=9.00Hz,1H),5.10-5.2 4(m,1H),4.09(dd,J=5.26,3.74Hz,2H),3.97(d,J=14.65Hz,1H),3.71(dd,J=5.34,3.66H z,2H),3.58(d,J=14.65Hz,1H),3.41(s,3H),3.12(d,J=11.29Hz,1H),2.68(dd,J=11.22 ,6.33Hz,1H),2.49-2.62(m,2H),2.18(s,3H),1.55-1.68(m,1H),1.24(d,J=5.65Hz,3H).

[0992] Example 1-151

[0993]

[0994] N-(4-Fluoro-5-(((2S,4R)-4-((5-((2-methoxyethyl)(methyl)amino)pyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Example 1-146 from tert-butyl (2S,4R)-4-((5-bromopyridin-2-yl)oxy)-2-methylpyrrolidine-1-carboxylate, 2-methoxy-N-methylethan-1-amine, and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 438. 1 HNMR: (400 MHz, methanol-d4) δ ppm 7.56 (d, J = 3.18 Hz, 1H), 7.26 (dd, J = 9.05, 3.18 Hz, 1H), 6.66 (d, J = 8.80 Hz, 1H), 5.08-5.17 (m, 1H), 3.95 (d, J = 14.67 Hz, 1H), 3.48-3.60 (m, 3H), 3.35-3.45 (m, 2H), 3.32 (s, 2H), 3.10 (br d,J=11.25Hz,1H),2.89(s,3H),2.65(dd,J=11.00,6.36Hz,1H),2.48-2.59(m,2H),2.18(s,3H),1.54-1.67(m,1H),1.24(d,J=5.62Hz,3H).

[0995] Example 1-152

[0996]

[0997] N-(4-Fluoro-5-(((2S,4R)-2-methyl-4-((4-(4-methylpiperazin-1-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that described in Example 1-22 from 1-(2-fluoropyridin-4-yl)-4-methylpiperazine, tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, and N-(4-fluoro-5-formylthiazol-2-yl)acetamide. LCMS (ESI): [M+H] 449. 1HNMR: (400MHz, methanol-d4) δppm 7.74 (d, J=6.11Hz, 1H), 6.51 (dd, J=6.36, 2.20Hz, 1H), 6.13 (d, J=1.96Hz, 1H), 5.14-5.21 (m, 1H), 3.97 (br d,J=14.67Hz,1H),3.56(br d,J=14.67Hz,1H),3.33-3.39(m,4H),3.11(br d,J=11.00Hz,1H),2.65(br dd,J=11.13,6.24Hz,1H),2.51-2.60(m,5H),2.35(s,3H),2.18(s,3H),1.54-1.67(m,2H),1.24(d,J=5.62Hz,3H).

[0998] Intermediate 16

[0999]

[1000] Pyrimidine-4,6-diol-4,5,6- 13 C3: To a mixture of formamide (2.48 g, 2.19 mL, 55.2 mmol) and a solution of sodium ethoxide (26.0 g, 30 mL, 80.9 mmol) in ethanol (21 wt%) was added diethyl malonate- 13 C3 (4.00 g, 3.72 mL, 24.5 mmol). The mixture was stirred at reflux overnight, then cooled to room temperature and concentrated under reduced pressure. The residue was treated with concentrated aqueous HCl (5.6 mL) and water (8.8 mL) at 0°C. The resulting precipitate was filtered, washed with cold water, and dried under reduced pressure to give the title compound (2.81 g; 99%).

[1001] Intermediate 17

[1002]

[1003] 4,6-Dichloropyrimidine-4,5,6- 13 C3: To a solution of phosphorus oxychloride (40.4 g, 24.5 mL, 263 mmol) was added pyrimidine-4,6-diol-4,5,6- 13C3 (2.82 g, 24.5 mmol) was added, followed by N,N-dimethylaniline (4.75 g, 4.97 mL, 39.2 mmol). The resulting mixture was heated to reflux for 2 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and poured into water (50 mL). The solid was filtered and dried to give 1.26 g of the title compound. The remaining solution was extracted with EtOAc (2 × 100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give another 1.2 g. The crude products were combined and purified on SiO2 to give the title compound (1.85 g; 50%).

[1004] Intermediate 18

[1005]

[1006] 4-Chloro-6-methoxypyrimidine-4,5,6- 13 C3: A sodium methoxide solution prepared from sodium (95 mg, 4.11 mmol) and methanol (1.2 g, 1.53 mL, 38 mmol) was added dropwise to 4,6-dichloropyrimidine-4,5,6- 13 To a solution of C3 (624 mg, 4.11 mmol) in methanol (4.6 mL), the temperature was maintained at room temperature. The resulting solution was stirred at room temperature for 1 hour, and then sodium methoxide (0.5 equiv) was added. The mixture was stirred for 30 minutes, then diluted with DCM (12 mL) and washed with water (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (426 mg, 70%).

[1007] Intermediate 19

[1008]

[1009] (2S,4R)-4-((6-methoxypyrimidin-4-yl)-4,5,6- 13 C3) tert-Butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate: A three-necked round-bottom flask was charged with THF (10.3 mL) and NaH (60% in mineral oil, 0.43 g, 10.8 mmol) was slowly added. tert-Butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate (1.60 g, 7.71 mmol) was added and the mixture was stirred for 30 minutes. A mixture containing 4-chloro-6-methoxypyrimidine-4,5,6- 13C3 (1.14 g, 7.71 mmol) in THF (3.43 mL). The solution was heated to 60° C., and the previously mentioned mixture was slowly added at this temperature. The resulting mixture was heated to 60° C. for 1.5 hours, then the mixture was cooled to room temperature and saturated NH4Cl aqueous solution (4 mL) was added. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified on SiO2 to give the title compound (1.30 g, 54%).

[1010] Intermediate 20

[1011]

[1012] 4-Methoxy-6-(((3R,5S)-5-methylpyrrolidin-3-yl)oxy)pyrimidine-4,5,6- 13 C3: In a three-necked round-bottom flask, (2S,4R)-4-((6-methoxypyrimidin-4-yl)-4,5,6- 13 C3) oxy) -2-methylpyrrolidine -1- acid tert-butyl ester (1.30g, 4.20mmol) was dissolved in DCM. The solution was cooled to 0 ° C and TFA (2.90g, 1.9mL, 25.0mmol) was added dropwise. The mixture was stirred at room temperature overnight. Another portion of TFA (1.5 equivalents) was added and stirring was continued at room temperature overnight. The mixture was cooled to 0 ° C. 2M NaOH (aqueous solution) was added until pH = 11. The layers were separated and the alkaline aqueous layer was extracted with DCM (2×50mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give 786mg of the title compound.

[1013] Example 1-153

[1014]

[1015] N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)-4,5,6- 13 C3) oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: sodium triacetoxyborohydride (2.40 g, 11.1 mmol), 4-methoxy-6-(((3R,5S)-5-methylpyrrolidin-3-yl)oxy)pyrimidine-4,5,6- 13C3 (0.786 g, 3.70 mmol) and acetic acid (445 mg, 424 μL, 7.41 mmol) were dissolved in ethyl acetate (15.7 g, 17 mL, 178 mmol). The mixture was warmed to 40 ° C and stirred at that temperature for 5 minutes. N- (4-fluoro-5-formylthiazol-2-yl) acetamide (718 mg, 3.81 mmol) was then added in one portion. The reaction was stirred between 40-50 ° C for 2 hours. 1M HCl aqueous solution (5 mL) was slowly added. The layers were separated and the organic layer was extracted again with 1M HCl aqueous solution (10 mL). The combined acidic layers were cooled to 0 ° C and basified with 2M NaOH aqueous solution (20 mL) until pH = 11. A solid precipitated; the mixture was stirred and cooled to room temperature, and then DCM (50 mL) was added to the mixture; the layers were separated. The aqueous layer is extracted with DCM (50mL) again, and the organic layer merged through sodium sulfate drying is filtered and concentrated to give a crude product (1.36g). The solid is suspended in MeOH (5mL) and stirred at reflux for 10 minutes. The mixture is filtered off and the solid is washed with cold MeOH to give 485mg of the title compound. Concentrated solution and more solid precipitation are obtained. This solid is filtered to give 217mg more. A total of 702mg of the title compound is obtained. LCMS (EI): [M+H] 385.4.

[1016] Intermediate 21

[1017]

[1018] N-(5-Formylthiazol-2-yl)acetamide-2,2,2-d3: To a solution of 2-aminothiazole-5-carboxaldehyde (491 mg, 3.83 mmol) and pyridine (930 uL, 11 mmol) in DCM (10. mL) was added acetyl-d3 chloride (550 uL, 7.7 mmol) dropwise at 0 ° C. The reaction mixture was stirred at room temperature for 3 days and then evaporated to dryness. The residue was purified by silica gel chromatography using dichloromethane containing ethyl acetate as eluent to give the title compound (452 ​​mg, 68% yield). LCMS (ESI): [M+H] 174.1. 1 HNMR: (400 MHz, methanol-d4) δ 9.93 (s, 1H), 8.23 ​​(s, 1H).

[1019] Intermediate 22

[1020]

[1021] N-(4-fluoro-5-formylthiazol-2-yl)acetamide-2,2,2-d3:

[1022] Step 1: 2-amino-4-fluorothiazole-5-carboxaldehyde: Zinc bromide (1.38 g, 6.13 mmol) was added to a mixture of tert-butyl (4-fluoro-5-formylthiazol-2-yl)carbamate (503 mg, 2.04 mmol) in DCM (12.5 mL) at room temperature. The reaction was stirred at 40 ° C overnight and then cooled to room temperature. 20% of the mixture was removed. The remaining mixture was diluted with ether and filtered, then washed with ether to give the title compound as a light yellow solid (376 mg, 158% yield, adjusted), which was used in the next step without further purification. LCMS (ESI): [M+H] 146.9. 1 HNMR: (400 MHz, methanol-d4) δ 9.60 (s, 1H). 19 F NMR (376 MHz, methanol-d4) δ -95.27 (br s, 1F).

[1023] Step 2: N-(4-Fluoro-5-formylthiazol-2-yl)acetamide-2,2,2-d3: 2-Amino-4-fluorothiazole-5-carbaldehyde (100 mg, 0.684 mmol) and pyridine (170 uL, 2.1 mmol) in DCM (2.5 mL) were cooled to 0°C. Acetic anhydride (130 uL, 1.4 mmol) was slowly added and then stirred at room temperature for 1 day. The reaction was evaporated and the residue was partitioned between water and ethyl acetate. The organics were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated. The sample was purified by silica gel chromatography to give the title compound (23 mg, 18% yield or 28% yield over 2 steps). 1 HNMR: (600 MHz, methanol-d4) δ 9.89 (s, 1H). 19 FNMR: (565 MHz, methanol-d4) δ-100.90 (br s, 1F).

[1024] Intermediate 23

[1025]

[1026] N-(5-(Chloromethyl-d)thiazol-2-yl)acetamide:

[1027] Step 1: N-(5-(Hydroxymethyl-d)thiazol-2-yl)acetamide: To a solution of N-(5-formylthiazol-2-yl)acetamide (300. mg, 1.76 mmol) in MeOH (3.3 mL) and THF (5.0 mL) stirred at 0 ° C., sodium borodeuteride (147 mg, 3.51 mmol) was slowly added, and the mixture was stirred at room temperature for 2 hours. The reaction was quenched by the addition of saturated aqueous NH4Cl. The reaction was concentrated and treated with aqueous NH4Cl, extracted with EtOAc (3×), washed with saturated NaCl solution, dried over MgSO4, filtered and evaporated to give the title compound (221 mg, 72% yield). LCMS (ESI): [M+H] 174.1. 1 HNMR: (400 MHz, methanol-d4) δ 7.28 (d, J = 1.00 Hz, 1H), 4.68-4.70 (m, 1H), 2.20 (s, 3H).

[1028] Intermediate 24

[1029]

[1030] N-(5-(Chloromethyl-d)thiazol-2-yl)acetamide:

[1031] Step 1: N-(5-(Hydroxymethyl-d)thiazol-2-yl)acetamide: To a solution of N-(5-formylthiazol-2-yl)acetamide (300. mg, 1.76 mmol) in MeOH (3.3 mL) and THF (5.0 mL) stirred at 0 ° C., sodium borodeuteride (147 mg, 3.51 mmol) was slowly added, and the mixture was stirred at room temperature for 2 hours. The reaction was quenched by the addition of saturated aqueous NH4Cl. The reaction was concentrated and treated with aqueous NH4Cl, extracted with EtOAc (3×), washed with saturated NaCl solution, dried over MgSO4, filtered and evaporated to give the title compound (221 mg, 72% yield). LCMS (ESI): [M+H] 174.1. 1 HNMR: (400 MHz, methanol-d4) δ 7.28 (d, J = 1.00 Hz, 1H), 4.68-4.70 (m, 1H), 2.20 (s, 3H).

[1032] Intermediate 25

[1033]

[1034] 2-Acetylamino-4-fluorothiazole-5-carboxylic acid: To a stirred mixture of N-(4-fluoro-5-formylthiazol-2-yl)acetamide (500.mg, 2.66mmol), potassium dihydrogen phosphate (1.09g, 7.98mmol) in water (5.0mL) and 2-methyl-2-butene (3.7mL, 35mmol) in tert-butanol (28mL) was added dropwise water (3.0mL) containing sodium chlorite (1.80g, 16.0mmol, 80% purity). The mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 5% citric acid solution and then with saturated sodium chloride. The organic matter was dried over sodium sulfate, filtered and evaporated. The sample was purified by silica gel chromatography using dichloromethane containing 0-50% methanol as eluent. 450mg of the separated material was isolated, containing 25% starting material. An additional 320 mg was purified by preparative HPLC (ACN / H2O, 0.1% TFA modifier) ​​to afford the title compound (174 mg, 45% yield, adjusted). LCMS (ESI): [M+H] 205.0. 1 HNMR: (400 MHz, methanol-d4) δ 2.22 (s, 3H). 19 FNMR: (376 MHz, methanol-d4) δ-97.03 (s, 1F).

[1035] Intermediate 26

[1036]

[1037] 2-Acetamido-4-fluorothiazole-5-methyl carboxylate: In a 20mL vial, 2-acetamido-4-fluorothiazole-5-carboxylic acid (50.mg, 0.25mmol) and oxalyl chloride (26uL, 0.31mmol) were dissolved in acetonitrile (1.0mL). After 5 minutes, DMF (10.uL, 0.13mmol) was added dropwise at room temperature with a large amount of gas evolution. The reaction was stirred at room temperature for 2 hours. Methanol (1.0mL) was added as a whole and the reaction was stirred at room temperature overnight. The solvent was removed in vacuo, and the resulting residue was then diluted with EtOAc and washed with NaHCO solution, followed by brine washing. The organic matter was dried over NaSO, filtered and evaporated under vacuum to give the crude title compound (33mg, 63% yield). LCMS (ESI): [M+H] 219.1. 1 HNMR: (400 MHz, methanol-d4) δ 3.83 (s, 3H), 2.22 (s, 3H). 19 FNMR: (376 MHz, methanol-d4) δ-96.25 (s, 1F).

[1038] Intermediate 27

[1039]

[1040] N-(4-Fluoro-5-(hydroxymethyl-d2)thiazol-2-yl)acetamide: To a stirred mixture of methyl 2-acetamido-4-fluorothiazole-5-carboxylate (33 mg, 0.15 mmol) in toluene (1.0 mL) was slowly added lithium triethylborodeuteride (310 uL, 1 M in THF) at 0°C. The reaction mixture was stirred at room temperature for 1 hour, then cooled to 0°C, and lithium triethylborodeuteride (310 uL, 1 M in THF) was slowly added, and the reaction was stirred at room temperature for 3 days. The reaction was cooled to 0°C, and methanol (0.2 mL) was added very slowly, followed by 5% citric acid solution (4 mL) (with gas evolution). The mixture was stirred at room temperature for 10 minutes, then extracted with ethyl acetate, washed with saturated sodium chloride, dried over sodium sulfate, filtered, and evaporated. Purification was performed by silica gel chromatography using heptane containing ethyl acetate as eluent to give the title compound (11 mg, 38% yield). LCMS (ESI): [M+H] 193.1. 1 HNMR (400 MHz, methanol-d4) δ 2.18 (s, 3H). 19 FNMR: (376 MHz, methanol-d4) δ-118.83 (s, 1F).

[1041] Intermediate 28

[1042]

[1043] N-(4-Fluoro-5-(hydroxymethyl-d2)thiazol-2-yl)acetamide: To a stirred mixture of methyl 2-acetamido-4-fluorothiazole-5-carboxylate (33 mg, 0.15 mmol) in toluene (1.0 mL) was slowly added lithium triethylborodeuteride (310 uL, 1 M in THF) at 0°C. The reaction mixture was stirred at room temperature for 1 hour, then cooled to 0°C, and lithium triethylborodeuteride (310 uL, 1 M in THF) was slowly added, and the reaction was stirred at room temperature for 3 days. The reaction was cooled to 0°C, and methanol (0.2 mL) was added very slowly, followed by 5% citric acid solution (4 mL) (with gas evolution). The mixture was stirred at room temperature for 10 minutes, then extracted with ethyl acetate, washed with saturated sodium chloride, dried over sodium sulfate, filtered, and evaporated. Purification was performed by silica gel chromatography using heptane containing ethyl acetate as eluent to give the title compound (11 mg, 38% yield). LCMS (ESI): [M+H] 193.1. 1 HNMR (400 MHz, methanol-d4) δ 2.18 (s, 3H).19 FNMR: (376 MHz, methanol-d4) δ-118.83 (s, 1F).

[1044] Intermediate 29

[1045]

[1046] N-(4-Fluoro-5-(hydroxymethyl-d2)thiazol-2-yl)acetamide: To a stirred mixture of methyl 2-acetamido-4-fluorothiazole-5-carboxylate (33 mg, 0.15 mmol) in toluene (1.0 mL) was slowly added lithium triethylborodeuteride (310 uL, 1 M in THF) at 0°C. The reaction mixture was stirred at room temperature for 1 hour, then cooled to 0°C, and lithium triethylborodeuteride (310 uL, 1 M in THF) was slowly added, and the reaction was stirred at room temperature for 3 days. The reaction was cooled to 0°C, and methanol (0.2 mL) was added very slowly, followed by 5% citric acid solution (4 mL) (with gas evolution). The mixture was stirred at room temperature for 10 minutes, then extracted with ethyl acetate, washed with saturated sodium chloride, dried over sodium sulfate, filtered, and evaporated. Purification was performed by silica gel chromatography using heptane containing ethyl acetate as eluent to give the title compound (11 mg, 38% yield). LCMS (ESI): [M+H] 193.1. 1 HNMR (400 MHz, methanol-d4) δ 2.18 (s, 3H). 19 FNMR: (376 MHz, methanol-d4) δ-118.83 (s, 1F).

[1047] Example 1-154

[1048]

[1049] N-(5-(((2S,4R)-4-((6-(methoxy-d3)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a manner analogous to that in Scheme 1 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4-bromo-6-(methoxy-d3)pyrimidine and N-(5-(chloromethyl)thiazol-2-yl)acetamide. LCMS (ESI): [M+H] 367.2. 1HNMR: (400MHz, methanol-d4) δ8.33(d,J=1.00Hz,1H),7.26(s,1H),6.12(d,J=0.75Hz,1H),5.29-5.36(m,1H),4.13(dd,J=1.13,14.18Hz ,1H),3.54(d,J=14.31Hz,1H),3.10(d,J=11.55Hz,1H),2.50-2.66(m,3H),2.19(s,3H),1.57-1.67(m,1H),1.24(d,J=5.77Hz,3H).

[1050] Example 1-155

[1051]

[1052] N-(4-Fluoro-5-(((2S,4R)-4-((6-(methoxy-d3)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a manner analogous to that in Scheme 1 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4-bromo-6-(methoxy-d3)pyrimidine, and N-(5-(chloromethyl)-4-fluorothiazol-2-yl)acetamide. LCMS (ESI): [M+H] 385.2. 1 HNMR: (400MHz, methanol-d4) δ8.35(d,J=1.00Hz,1H),6.13(d,J=1.00Hz,1H),5.28-5.37(m,1H),3.96(dd,J=1.00,14.56Hz,1H),3.56(d,J=14.31 Hz,1H),3.13(d,J=11.29Hz,1H),2.67(dd,J=5.77,11.04Hz,1H),2.51-2.63(m,2H),2.18(s,3H),1.56-1.66(m,1H),1.24(d,J=5.77Hz,3H). 19 FNMR: (376 MHz, methanol-d4) δ-117.94 (s, 1F).

[1053] Example 1-156

[1054]

[1055] N-(5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide-2,2,2-d3: The title compound was prepared in a similar manner to that in Scheme 1 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4-chloro-6-methoxypyrimidine and N-(5-formylthiazol-2-yl)acetamide-2,2,2-d3. LCMS (ESI): [M+H] 367.2. 1 HNMR: (400MHz, methanol-d4) δ8.34(d,J=0.75Hz,1H),7.26(s,1H),6.13(d,J=0.75Hz,1H),5.27-5.37(m,1H),4.13(dd,J=1.00,14.31Hz ,1H),3.92(s,3H),3.55(d,J=14.31Hz,1H),3.10(d,J=11.29Hz,1H),2.51-2.67(m,3H),1.57-1.69(m,1H),1.25(d,J=6.02Hz,3H).

[1056] Example 1-157

[1057]

[1058] N-(4-Fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide-2,2,2-d3 trifluoroacetate: The title compound was prepared in a similar manner to that in Scheme 1 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4-chloro-6-methoxypyrimidine and N-(4-fluoro-5-formylthiazol-2-yl)acetamide-2,2,2-d3. LCMS (ESI): [M+H] 385.2. 1 HNMR: (600MHz, methanol-d4) δ8.43(br s,1H),6.21(br s,1H),5.66(br s,1H),4.70(br d,J=14.67Hz,1H),4.46(br d,J=14.67Hz,1H),3.95(br s,3H),3.60-3.81(m,3H),2.95(br s,1H),1.94-2.05(m,1H),1.55(br s,3H). 19 FNMR: (565 MHz, methanol-d4) δ -77.14 (br s, 3F), -110.91 (br s, 1F).

[1059] Example 1-158

[1060]

[1061] N-(5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl-d)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 1 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4-chloro-6-methoxypyrimidine and N-(5-(chloromethyl-d)thiazol-2-yl)acetamide. LCMS (ESI): [M+H] 365.1. 1 HNMR: (400 MHz, methanol-d4) δ8.34 (d, J = 1.00 Hz, 1H), 7.26 (d, J = 0.75 Hz, 1H), 6.13 (s, 1H), 5.28-5.37 (m, 1H), 4.11 (s, 0.5H), 3.92 (s, 3H), 3.53 (s, 0.5H), 3.10 (d, J = 11.29 Hz, 1H), 2.51-2.69 (m, 3H), 2.19 (s, 3H), 1.58-1.68 (m, 1H), 1.25 (dd, J = 0.75, 5.77 Hz, 3H).

[1062] Example 1-159

[1063]

[1064] N-(4-Fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl-d)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 1 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4-chloro-6-methoxypyrimidine and N-(5-(chloromethyl-d)-4-fluorothiazol-2-yl)acetamide. LCMS (ESI): [M+H] 383.1. 1 HNMR: (400MHz, methanol-d4) δ8.35(d,J=1.00Hz,1H),6.14(d,J=1.00Hz,1H),5.29-5.37(m,1H),3.95(s,0.5H),3.92(s,3H),3.54(s,0. 5H),3.10-3.16(m,1H),2.68(td,J=5.55,11.23Hz,1H),2.53-2.64(m,2H),2.18(s,3H),1.56-1.67(m,1H),1.24(d,J=5.52Hz,3H). 19FNMR: (376 MHz, methanol-d4) δ-117.92 (br s, 1F).

[1065] Intermediate 30

[1066]

[1067] tert-Butyl (5-(hydroxymethyl-d2)thiazol-2-yl)carbamate: Lithium aluminum deuteride (54 mg, 1.3 mmol) was added to a 0°C solution of ethyl 2-((tert-butoxycarbonyl)amino)thiazole-5-carboxylate (300. mg, 1.10 mmol) in THF (5.0 mL). The reaction mixture was stirred at room temperature for 1 hour, then diluted with 5 mL of ether, cooled to 0°C, and carefully quenched by the dropwise addition of water (55 uL). After 10 minutes, 15% aqueous NaOH (55 uL) was added, followed by 165 uL of water. After another 10 minutes, the mixture was stirred at room temperature for 1 hour. The mixture was stirred at room temperature for 1 hour. The mixture was then diluted with 5 mL of ether, cooled to 0°C, and carefully quenched by the dropwise addition of water (55 uL). After 10 minutes, 15% aqueous NaOH (55 uL) was added, followed by 165 uL of water. After another 10 minutes, the mixture was stirred at room temperature for 1 hour. The mixture was filtered through a pad of Celite®, washed with ether and the filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatography using heptane containing EtOAc as eluent to give the title compound (93 mg, 37% yield). LCMS (ESI): [M+Na] 255.1. 1 HNMR: (400 MHz, methanol-d4) δ 7.19 (s, 1H), 1.54 (s, 9H).

[1068] Intermediate 31

[1069]

[1070] tert-Butyl (5-(chloromethyl-d2)thiazol-2-yl)carbamate: Thionyl chloride (120 uL, 1.6 mmol) was added to a 0°C mixture of tert-butyl (5-(hydroxymethyl-d2)thiazol-2-yl)carbamate (93 mg, 0.40 mmol) in DCM (1.0 mL). The reaction mixture was stirred at 0°C for 2 hours and then concentrated in vacuo to give the title compound (111 mg). LCMS (ESI) for the methyl ether: [M-C4H8+H] 191.1 (LCMS sample in MeOH).

[1071] Intermediate 32

[1072]

[1073] Tert-Butyl (5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl-d2)thiazol-2-yl)carbamate: 4-Methoxy-6-(((3R,5S)-5-methylpyrrolidin-3-yl)oxy)pyrimidine (93 mg, 0.44 mmol) was dissolved in acetonitrile (1.0 mL) and TEA (250 uL, 1.8 mmol) was added dropwise. A solution of tert-butyl (5-(chloromethyl-d2)thiazol-2-yl)carbamate (111 mg, 0.44 mmol) in acetonitrile (2.0 mL) was added dropwise. After 2 hours, the reaction was evaporated to dryness and partitioned between water and ethyl acetate. The organics were washed with saturated sodium chloride, dried over MgSO4, filtered, and evaporated. The residue was purified by silica gel chromatography using 3:1 ethyl acetate / ethanol (containing 2% NH4OH) in heptane as eluent to give the title compound (110 mg, 59% yield). LCMS (ESI): [M+H] 424.2. 1 HNMR: (600MHz, methanol-d4) δ8.34(s,1H),7.17(s,1H),6.14(s,1H),5.29-5.38(m,1H),3.92(s,3H),3.10(d,J=1 1.74Hz, 1H), 2.53-2.68 (m, 3H), 1.63 (ddd, J=3.67, 8.99, 13.02Hz, 1H), 1.54 (s, 9H), 1.25 (d, J=5.87Hz, 3H).

[1074] Intermediate 33

[1075]

[1076]

[0266] 5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl-d2)thiazol-2-amine hydrochloride: tert-Butyl (5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl-d2)thiazol-2-yl)carbamate (50. mg, 0.12 mmol) was dissolved in DCM (1.0 mL) and hydrogen chloride (0.30 mL, 4 M in dioxane) was added. The reaction was stirred at room temperature for 4 h, then evaporated to dryness and co-distilled with DCM to give the title compound as the hydrochloride salt. LCMS (ESI): [M+H] 324.1.

[1077] Example 1-160

[1078]

[1079] N-(5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl-d2)thiazol-2-yl)acetamide: 5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl-d2)thiazol-2-amine (0.12 mmol, x hydrochloride) was dissolved in DCM (2.0 mL) and pyridine (50. μL, 0.62 mmol). To this was added acetic anhydride (27 uL, 0.29 mmol), followed by pyridine (1 mL, 12 mmol) and acetic anhydride (35 uL, 0.38 mmol). The reaction was stirred at room temperature overnight, then evaporated to dryness, diluted with water, extracted with EtOAc, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated. The sample was purified by silica gel chromatography using 3:1 ethyl acetate / ethanol (containing 2% NH4OH) in heptane as eluent to give the title compound (17 mg, 32% yield over 2 steps). LCMS (ESI): [M+H] 366.1. 1 HNMR: (600MHz, methanol-d4) δ8.34(s,1H),7.27(s,1H),6.13(s,1H),5.29-5.36(m,1H),3.92(s,3H),3. 09(d,J=11.01Hz,1H),2.52-2.68(m,3H),2.19(s,3H),1.58-1.68(m,1H),1.25(d,J=5.14Hz,3H).

[1080] Example 1-161

[1081]

[1082] N-(4-Fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl-d2)thiazol-2-yl)acetamide: The title compound was prepared in a manner similar to that in Scheme 1 from tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate, 4-chloro-6-methoxypyrimidine and N-(5-(chloromethyl-d2)-4-fluorothiazol-2-yl)acetamide. LCMS (ESI): [M+H] 384.2. 1HNMR: (400 MHz, methanol-d4) δ 8.35 (d, J = 0.75 Hz, 1H), 6.13 (d, J = 1.00 Hz, 1H), 5.27-5.38 (m, 1H), 3.92 (s, 3H), 3.13 (d, J = 11.55 Hz, 1H), 2.68 (dd, J = 6.27, 11.29 Hz, 1H), 2.51-2.63 (m, 2H), 2.18 (s, 3H), 1.56-1.66 (m, 1H), 1.24 (d, J = 5.77 Hz, 3H). 19 FNMR: (376 MHz, methanol-d4) δ-117.92 (s, 1F).

[1083] Intermediate 34

[1084]

[1085] tert-Butyl (4-bromo-5-formylthiazol-2-yl)carbamate: To a solution of diisopropylamine (3.3 mL, 23 mmol) in THF (20. mL) was slowly added n-butyl lithium (14.8 mL, 1.6 M in hexane) at 0°C. The reactants were stirred for 20 minutes, and then a solution of tert-butyl (5-bromothiazol-2-yl)carbamate (2.00 g, 7.16 mmol) in THF (20. mL) was slowly added. The mixture was stirred at 0°C for 30 minutes, and then DMF (1.8 mL, 23 mmol) was added. The solution was stirred at room temperature for 2 hours. EA and water were added, the layers were separated, and the organics were washed with brine. The organics were dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography using heptane containing ethyl acetate as eluent to give the title compound (1.53 g, 70% yield). 81 Br, LCMS (ESI): [M+H] 308.9. 1 HNMR: (400 MHz, methanol-d4) δ 9.83 (s, 1H), 1.56 (s, 9H).

[1086] Intermediate 35

[1087]

[1088] (5-formylthiazole-2-yl-4-d) tert-butyl carbamate: Under nitrogen, palladium / carbon (91 mg, 10%) and anhydrous methanol-d4 (5.0 mL) were added to a flask containing a mixture of (4-bromo-5-formylthiazole-2-yl) tert-butyl carbamate (202 mg, 0.66 mmol) and sodium acetate (113 mg, 1.38 mmol). Deuterium was slowly bubbled into the suspension for 15 minutes under stirring, and the reaction flask was then connected to a balloon filled with deuterium under vigorous stirring overnight. Palladium black was filtered off and rinsed with methanol. The filtrate was concentrated. The residue was dissolved in water and EtOAc. The organic matter was washed with saturated sodium chloride, dried over sodium sulfate, filtered and evaporated to give the title compound (131 mg, 87% yield). LCMS (ESI): [M-C4H8+H] 174.1. 1 HNMR: (400 MHz, methanol-d4) δ 9.87 (s, 1H), 1.56 (s, 9H).

[1089] Intermediate 36

[1090]

[1091] tert-Butyl (5-(hydroxymethyl)thiazol-2-yl-4-d)carbamate: To a stirred 0 ° C solution of tert-butyl (5-formylthiazol-2-yl-4-d)carbamate (131 mg, 0.57 mmol) in MeOH (1.4 mL) and THF (2.2 mL) was slowly added sodium borohydride (58 mg, 1.5 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction was quenched by dropwise addition of saturated NH4Cl aqueous solution (2 mL). The reaction was concentrated and treated with NH4Cl aqueous solution, extracted with EtOAc (3×), washed with saturated NaCl solution, dried over MgSO4, filtered and evaporated to give the title compound (128 mg, 97% yield). LCMS (ESI): [M+Na] 254.1. 1 HNMR: (400 MHz, methanol-d4) δ 4.68 (s, 2H), 1.54 (s, 9H).

[1092] Intermediate 37

[1093]

[1094] tert-Butyl (5-(chloromethyl)thiazol-2-yl-4-d)carbamate: Thionyl chloride (160 μL, 2.2 mmol) was added to a 0°C mixture of tert-butyl (5-(hydroxymethyl)thiazol-2-yl-4-d)carbamate (128 mg, 0.55 mmol) in DCM (1.4 mL). The reaction mixture was stirred at 0°C for 2 hours and then concentrated in vacuo to give the crude title compound. LCMS (ESI) for the methyl ether: [M-C4H8+H] 190.1 (LCMS sample in methanol).

[1095] Intermediate 38

[1096]

[1097] tert-Butyl (5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl-4-d)carbamate: 4-Methoxy-6-(((3R,5S)-5-methylpyrrolidin-3-yl)oxy)pyrimidine (128 mg, 0.61 mmol) was dissolved in acetonitrile (1.5 mL) and TEA (340 uL, 2.45 mmol) was added dropwise. A solution of tert-butyl (5-(chloromethyl)thiazol-2-yl-4-d)carbamate (0.55 mmol) in acetonitrile (1.5 mL) was added dropwise with stirring. After 2 hours, the reaction was evaporated to dryness and partitioned between water and ethyl acetate. The organics were washed with saturated sodium chloride, dried over MgSO4, filtered, and evaporated. The crude material was purified by silica gel chromatography using 3:1 ethyl acetate / ethanol (containing 2% NH4OH) in heptane as eluent to give the title compound (177 mg, 68% yield over 2 steps). LCMS (ESI): [M+H] 423.2. 1 HNMR: (400MHz, methanol-d4) δ8.34(d,J=0.75Hz,1H),6.14(d,J=0.75Hz,1H),5.29-5.35(m,1H),4.11(d,J=14.06Hz,1H),3.92(s,3H ), 3.54 (d, J = 14.31Hz, 1H), 3.11 (d, J = 11.29Hz, 1H), 2.50-2.68 (m, 3H), 1.57-1.66 (m, 1H), 1.54 (s, 9H), 1.24 (d, J = 5.77Hz, 3H).

[1098] Intermediate 39

[1099]

[1100] 5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-4-d-2-amine hydrochloride: Tert-butyl (5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl-4-d)carbamate (78 mg, 0.18 mmol) was dissolved in DCM (1.5 mL) and hydrogen chloride (460 uL, 4 M in dioxane) was added. The reaction was stirred at room temperature for 4 hours, then evaporated to dryness and co-distilled once with MeOH and twice with DCM to give the title compound. LCMS (ESI): [M+H] 323.1.

[1101] Example 1-162

[1102]

[1103] N-(5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl-4-d)acetamide: 5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-4-d-2-amine (0.18 mmol, x hydrochloride salt) was dissolved in DCM (1.5 mL) and pyridine (1.0 mL). Acetic anhydride (52 uL, 0.55 mmol) was added. The reaction was stirred at room temperature overnight, then evaporated to dryness, diluted with water, extracted with EtOAc, washed with saturated sodium chloride, dried over sodium sulfate, filtered, and evaporated. The residue was purified by silica gel chromatography using 3:1 ethyl acetate / ethanol (containing 2% NH4OH) in heptane as eluent to give the title compound (22 mg, 32% yield over 2 steps). LCMS (ESI): [M+H] 365.2. 1 HNMR: (400MHz, methanol-d4) δ8.33(d,J=1.00Hz,1H),6.13(d,J=0.75Hz,1H),5.29-5.35(m,1H),4.13(d,J=14.06Hz,1H),3.92(s,3H ),3.55(d,J=14.05Hz,1H),3.10(d,J=11.55Hz,1H),2.50-2.67(m,3H),2.19(s,3H),1.58-1.67(m,1H),1.24(d,J=5.77Hz,3H).

[1104] Example 1-163

[1105]

[1106] N-(5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl-4-d)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 1 from tert-butyl (2S)-4-hydroxy-2-methylpyrrolidine-1-carboxylate-4-d, 4-chloro-6-methoxypyrimidine and N-(5-(chloromethyl)thiazol-2-yl)acetamide. The product mixture was separated into its individual diastereomers by HPLC [XSelect CSH Preparative C18 OBD 5 μm 30×100 mm; method: (A) 95% {H2O} / (B) 5% {acetonitrile} w / 0.2% NH4OH (initial conditions held for 0.5 min), followed by a 12-min linear gradient to 50% (A) / 50% (B) (flow rate: 50 mL / min)], followed by SFC [CHIRALPAK AD-H 30×250 mm, 5 μm; method: 40% IPA w / 0.1% DEA in CO2 (flow rate: 100 mL / min, ABPR 120 bar, MBPR 60 psi, column temperature 40°C)]. LCMS (ESI): [M+H] 365.2. 1 HNMR: (400MHz, methanol-d4) δ8.33(d,J=0.75Hz,1H),7.26(s,1H),6.13(d,J=0.75Hz,1H),4.13(dd,J=0.88,14.18Hz,1H),3.92(s,3H),3.54(d ,J=14.06Hz,1H),3.09(d,J=11.29Hz,1H),2.63(d,J=11.55Hz,1H),2.51-2.60(m,2H),2.19(s,3H),1.56-1.67(m,1H),1.23-1.27(m,3H).

[1107] Example 1-164

[1108]

[1109] N-(5-(((2S,4S)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl-4-d)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 1 from tert-butyl (2S)-4-hydroxy-2-methylpyrrolidine-1-carboxylate-4-d, 4-chloro-6-methoxypyrimidine and N-(5-(chloromethyl)thiazol-2-yl)acetamide. The product mixture was separated into its individual diastereomers by HPLC [XSelect CSH Preparative C18 OBD 5 μm 30×100 mm; method: (A) 95% {H2O} / (B) 5% {acetonitrile} w / 0.2% NH4OH (initial conditions held for 0.5 min), followed by a 12-min linear gradient to 50% (A) / 50% (B) (flow rate: 50 mL / min)], followed by SFC [CHIRALPAK AD-H 30×250 mm, 5 μm; method: 40% IPA w / 0.1% DEA in CO2 (flow rate: 100 mL / min, ABPR 120 bar, MBPR 60 psi, column temperature 40°C)]. LCMS (ESI): [M+H] 365.2. 1 HNMR: (400MHz, methanol-d4) δ8.34 (s, 1H), 7.24 (s, 1H), 6.08 (d, J = 0.75Hz, 1H), 4. 13(d,J=14.05Hz,1H),3.92(s,3H),3.69(d,J=14.31Hz,1H),3.54(d,J=11.04 Hz,1H),2.84-2.93(m,1H),2.50(d,J=11.29Hz,1H),2.20(s,3H),2.10(dd,J= 6.15, 13.93Hz, 1H), 1.89 (dd, J = 10.29, 13.80Hz, 1H), 1.21 (d, J = 6.02Hz, 3H).

[1110] Example 1-165

[1111]

[1112] N-(4-Fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl-4-d)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a manner similar to that described in Scheme 1 from tert-butyl (2S)-4-hydroxy-2-methylpyrrolidine-1-carboxylate-4-d, 4-chloro-6-methoxypyrimidine, and N-(5-(chloromethyl)-4-fluorothiazol-2-yl)acetamide. The product mixture was separated into its individual diastereomers by SFC [CHIRALPAK AD-H 30×250 mm, 5 μm; method: 45% MeOH w / 0.1% DEA in CO (flow rate: 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40°C)]. LCMS (ESI): [M+H] 383.2. 1 HNMR: (400MHz, methanol-d4) δ8.35(d,J=1.00Hz,1H),6.13(d,J=1.00Hz,1H),3.96(dd,J=1.00,14.56Hz,1H),3.92(s,3H),3.55(d,J=14.56 Hz,1H),3.12(d,J=11.29Hz,1H),2.66(d,J=11.29Hz,1H),2.50-2.62(m,2H),2.18(s,3H),1.55-1.66(m,1H),1.24(d,J=5.77Hz,3H). 19 FNMR: (376 MHz, methanol-d4) δ-117.94 (s, 1F).

[1113] Example 1-166

[1114]

[1115] N-(4-Fluoro-5-(((2S,4S)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl-4-d)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a manner similar to that described in Scheme 1 from tert-butyl (2S)-4-hydroxy-2-methylpyrrolidine-1-carboxylate-4-d, 4-chloro-6-methoxypyrimidine, and N-(5-(chloromethyl)-4-fluorothiazol-2-yl)acetamide. The product mixture was separated into its individual diastereomers by SFC (CHIRALPAK AD-H 30×250 mm, 5 μm; method: 45% MeOH w / 0.1% DEA in CO (flow rate: 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40°C)). LCMS (ESI): [M+H] 383.2. 1HNMR: (400MHz, methanol-d4) δ8.34(d,J=0.75Hz,1H),6.07(d,J=1.00Hz,1H),3.95( dd,J=0.75,14.81Hz,1H),3.92(s,3H),3.66(d,J=14.56Hz,1H),3.56(d,J=10. 79Hz,1H),2.80-2.92(m,1H),2.52(d,J=10.79Hz,1H),2.18(s,3H),2.08(dd,J =6.15, 13.93Hz, 1H), 1.86 (dd, J = 10.16, 13.93Hz, 1H), 1.20 (d, J = 6.02Hz, 3H). 19 FNMR: (376 MHz, methanol-d4) δ-118.18 (s, 1F).

[1116] Biological data

[1117] OGA enzyme inhibition biochemical assay

[1118] Recombinant full-length human OGA enzyme was purchased from Origene. 4-MUGlcNAc substrate was purchased from Sigma. All other reagents were purchased from Sigma or Fisher. The assay buffer consisted of McIlvaine buffer system pH 6.4 (0.2 M Na2HPO4 mixed with 0.1 M citric acid) and 0.01% BSA. The reaction consisted of 1 nM OGA, 100 μM 4-MUGlcNAc (K m ) and compound in a final volume of 10 μl. Reactions were incubated at room temperature for 90 minutes and quenched with 40 μl 3M glycine (pH 10) and read on a PerkinElmer Envision plate reader (excitation: 355 nm / emission: 460 nm). Compounds were tested starting at 20 μM in 4-fold dilutions using a 10-point dose response. Data were fitted using GraphPad Prism using a 4-parameter fit with variable slope.

[1119] Description of the Cellular OGA-Tau MSD Assay

[1120] HEK-293T cells were transfected with OGT and Tau-V5 plasmids using Lipofectamine and grown overnight. The next day, cells were collected and cultured at 1×10 5Cells / well were then plated in 96-well plates. The cells were incubated at 37°C for 4 hours, followed by the addition of 1uM compound, diluted 3-fold in a 10-point titration. The cell plates were incubated with compounds overnight at 37°C. The next day, the culture medium was removed from the wells by gentle aspiration, and 120ul of 1× cell lysis buffer mixed with a protease and phosphatase cocktail was added to each well. Freeze-thawed at -80°C, then mixed, and 50ul was transferred to an MSD plate coated with a V5-tag antibody to capture Tau. The MSD plate was incubated overnight at 4°C on a plate shaker. The next day, the plates were washed and incubated with a Tau-S400-GlcNAc antibody for 2 hours, followed by development with a rabbit Sulfo-tag antibody. The final readout was performed on an MSD600 reader. Data were analyzed using Graph Pad or Genedata, normalized, and the % activity was plotted against the logarithm of the compound concentration. IC was obtained from a 4-parameter fit 50 value.

[1121] Description of the rat liver microsome stability assay

[1122] Compounds (1 μM final concentration) were incubated with rat liver microsomes (0.5 mg / mL) in 0.1 M sodium phosphate buffer (pH 7.4) plus 3.3 mM magnesium chloride in the presence or absence of 1 mM nicotinamide adenine dinucleotide phosphate (NADPH) at 37° C. At 0, 5, 10, 15, 25, and 40 minutes after NADPH addition (or compound addition for reaction in the absence of NADPH), aliquots (40 μL) were transferred to individual wells of a 96-well plate containing 160 μL of acetonitrile:methanol (1:1 v / v) containing 40 ng / ml 8-cyclopentyl-1,3-dipropylxanthine (CPDPX, internal standard). The sample-containing plates were centrifuged (10 min, 3220 x g) and 50 μL of supernatant from each well was transferred to a well of a clean analytical sample 96-well plate containing 300 μL of 20:80:0.1 acetonitrile / water / formic acid, mixed, and then injected directly onto the LC / MS / MS system for sample analysis.

[1123] HPLC and mass spectrometry conditions for stability determination

[1124] The LC / MS / MS system consisted of an ultra-high throughput LC / MS / MS system coupled to a triple quadrupole 5500 mass spectrometer (ABSciex, Foster City, CA). 300 system (Agilent Technologies, Santa Clara, CA). On the C4 cartridge, 0.1% formic acid in water was used as mobile phase A for sample loading and washing, and 0.1% formic acid in acetonitrile:methanol (1:1 v / v) was used as mobile phase B for sample elution.

[1125] Operating conditions:

[1126]

[1127] Mass spectrometer operating conditions:

[1128]

[1129] Source Parameters Parameter settings CAD gas 9 Curtain gas 30 Ion source gas 1 60 Ion source gas 2 70 Ion spray voltage 5500 temperature 600

[1130] Data Analysis:

[1131] CLint,app (apparent intrinsic clearance) was calculated using the following equation for microsomal stability.

[1132]

[1133] in" a ” means 45 g liver / kg rat body weight.

[1134] CL int,app Apparent intrinsic clearance was calculated using the following equation for hepatocyte stability:

[1135] CL hep (Hepatic clearance) was calculated using the following equation for microsomes:

[1136]

[1137] 55 ml / min / kg was used as Qh (hepatic blood flow) for rats.

[1138] Description of the MDR1-MDCK efflux ratio assay

[1139] MDR1-MDCK cell monolayers were grown to confluence on microporous polyester membranes in 96-well Corning insert plates. The permeability assay buffer was a Hanks' Balanced Salt Solution containing 10 mM HEPES (pH 7.4). Loperamide (1 μM) was used as a positive control P-gp substrate. Propranolol and Bestatin (1 μM) were used as high permeability and low permeability comparators, respectively.

[1140] Test compound or positive control P-gp substrate / permeability comparator is added to the corresponding top and base side chamber for the two-way assessment of permeability. Receiver buffer (transport buffer supplemented with 1% bovine serum albumin) is added to the corresponding receiver chamber. MDR1-MDCK cells are incubated with the test compound for 2 hours at 37°C with 5% CO2. Samples are collected from the donor chamber and from the receiver chamber at 120 minutes at 0 and 120 minutes. LC-MS / MS analysis is used to determine the concentration of the test and control compounds. Each determination is carried out in triplicate. app ), effluent ratio, and mass balance (percent recovery) were calculated as follows:

[1141] P app =(dC r / dt)×V r / (A×C E )

[1142] Mass balance = 100 × ((V r ×C r 最终 )+(V d ×C d 最终 )) / (V d ×C E )

[1143] Outflow ratio = P app(B-A) / P app(A-B)

[1144] in:

[1145] dC r / dt is the cumulative concentration in the receptor compartment versus time, μM s -1

[1146] V r is the volume of the receptor compartment, cm 3

[1147] V d is the volume of the donor compartment, cm 3

[1148] A is the embedding area (for 96-well embedding, 0.143 cm 2 )

[1149] C E is the estimated experimental concentration of the dosing solution (time = 0)

[1150] C r 最终 is the concentration of the acceptor at the end of the incubation period

[1151] C d 最终 is the concentration of the donor at the end of the incubation period.

[1152] Table 1 below shows the activity data of some compounds of the present invention.In some cases, repeat OGA suppression, MDR1-MDCK efflux ratio and rat liver microsome stability determination, and whenever the final data in subsequent determination are different, data are provided in hereinafter and indicate with asterisk (*).Symbol "-" indicator data are unavailable.

[1153]

[1154]

[1155]

[1156]

[1157]

[1158] In summary, the present invention relates to the following aspects:

[1159] 1. A compound represented by the following structural formula:

[1160]

[1161] or a pharmaceutically acceptable salt of said compound, wherein:

[1162] Ar is an optionally substituted monocyclic aryl or an optionally substituted monocyclic heteroaryl; Y 1 and Y 2 Each is CR c or N, where Y 1 or Y 2 At least one of them is N; Z is CR 2 R 2 、C(=O)、(CR 2 R 2 )2 or CH2C(=O);

[1163] R c is -H, halo, C1-C4 alkyl or C1-C4 haloalkyl;

[1164] n is 0 or an integer from 1 to 8;

[1165] When n is not 0, R 1 is independently at each occurrence halo, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy;

[1166] R 2Each occurrence is independently -H, halo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl or C3-C 10 Halogenated cycloalkyl groups;

[1167] Or alternatively, two R 2 Together with the carbon atoms to which they are attached, they form C3-C 10 Cycloalkyl;

[1168] R 3 is -H or C1-C4 alkyl; and

[1169] R 4 is -H, C1-C4 alkyl, C1-C4 haloalkyl or C3-C6 cycloalkyl;

[1170] Or alternatively, R 3 and R 4 Together with their intervening atoms they form an optionally substituted 5- to 7-membered heterocyclyl.

[1171] 2. The compound according to item 1, wherein the compound is represented by the following structural formula:

[1172]

[1173] or a pharmaceutically acceptable salt of the compound; wherein R 1 is halogen, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy; R c is a halogen group, a C1-C4 alkyl group or a C1-C4 haloalkyl group; and n is an integer from 1 to 7.

[1174] 3. The compound according to item 1, wherein the compound is represented by the following structural formula:

[1175]

[1176] or a pharmaceutically acceptable salt of the compound; wherein R 1 It is a halogen group or a C1-C4 alkyl group.

[1177] 4. The compound according to any one of items 1 to 3, wherein the compound is represented by the following structural formula:

[1178]

[1179] or a pharmaceutically acceptable salt of the compound; wherein R 2 is independently at each occurrence -H or C1-C4 alkyl.

[1180] 5. The compound according to any one of items 1 to 4, wherein the compound is represented by the following structural formula:

[1181]

[1182]

[1183] or a pharmaceutically acceptable salt of the compound; wherein R 2 is independently -H or C1-C4 alkyl at each occurrence, R c is a halogen group or a C1-C4 alkyl group; and n is an integer from 1 to 7.

[1184] 6. The compound according to any one of items 1 to 5, wherein the compound is represented by one of the following structural formulas:

[1185]

[1186] or a pharmaceutically acceptable salt of the compound.

[1187] 7. The compound according to any one of items 1 to 6, wherein the compound is represented by the following structural formula:

[1188]

[1189] or a pharmaceutically acceptable salt of the compound; wherein n is an integer from 1 to 7.

[1190] 8. The compound according to any one of items 1 to 7, wherein the compound is represented by one of the following structural formulas:

[1191]

[1192] or a pharmaceutically acceptable salt of the compound; wherein n is 0 or an integer from 1 to 7.

[1193] 9. The compound according to any one of items 1 to 8, wherein the compound is represented by the following structural formula:

[1194]

[1195] or a pharmaceutically acceptable salt of the compound; wherein n is 0 or an integer from 1 to 6.

[1196] 10. The compound according to any one of items 1 to 9, wherein the compound is represented by the following structural formula:

[1197]

[1198] or a pharmaceutically acceptable salt of the compound; wherein n is 0 or an integer from 1 to 3.

[1199] 11. The compound according to any one of items 1 to 10, wherein the compound is represented by the following structural formula:

[1200]

[1201] or a pharmaceutically acceptable salt of the compound; wherein n is 0 or an integer from 1 to 3.

[1202] 12. The compound according to any one of items 1 to 11, wherein the compound is represented by one of the following structural formulas:

[1203]

[1204] or a pharmaceutically acceptable salt of the compound; wherein n is 0, 1 or 2.

[1205] 13. The compound according to any one of items 1 to 12, wherein the compound is represented by the following structural formula:

[1206]

[1207] or a pharmaceutically acceptable salt of the compound; wherein n is 0, 1 or 2.

[1208] 14. A compound represented by the following structural formula:

[1209]

[1210]

[1211] or a pharmaceutically acceptable salt of said compound, wherein:

[1212] Ar is optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl;

[1213] Y 1 and Y 2 Each is CR c or N, where Y 1 or Y 2 At least one of is N;

[1214] Z is CR 2 R 2 、C(=O)、(CR 2 R 2 )2 or CH2C(=O);

[1215] R c is -H, halo, C1-C4 alkyl or C1-C4 haloalkyl;

[1216] n is 0 or an integer from 1 to 7;

[1217] When n is not 0, R 1 is independently at each occurrence halo, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy;

[1218] R 2 Each occurrence is independently -H, halo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl or C3-C 10 Halogenated cycloalkyl groups;

[1219] Or alternatively, two R 2 Together with the carbon atoms to which they are attached, they form C3-C 10 Cycloalkyl;

[1220] R 3 is -H or C1-C4 alkyl; and

[1221] R 4 is -H, C1-C4 alkyl, C1-C4 haloalkyl or C3-C6 cycloalkyl;

[1222] Or alternatively, R 3 and R 4 Together with their intervening atoms they form an optionally substituted 5- to 7-membered heterocyclyl.

[1223] 15. The compound according to item 14, wherein the compound is represented by one of the following structural formulas:

[1224]

[1225] or a pharmaceutically acceptable salt of the compound; wherein R 1 It is a halogen group or a C1-C4 alkyl group.

[1226] 16. The compound according to item 14 or 15, wherein the compound is represented by the following structural formula:

[1227]

[1228] or a pharmaceutically acceptable salt of the compound; wherein R 1 It is a halogen group or a C1-C4 alkyl group.

[1229] 17. The compound according to any one of items 14 to 16, wherein the compound is represented by the following structural formula:

[1230]

[1231] or a pharmaceutically acceptable salt of the compound; wherein R2 is independently at each occurrence -H or C1-C4 alkyl; and wherein n is 0 or an integer from 1 to 3.

[1232] 18. The compound according to any one of items 14 to 17, wherein the compound is represented by the following structural formula:

[1233]

[1234] or a pharmaceutically acceptable salt of the compound; wherein R 2 is independently at each occurrence -H or C1-C4 alkyl; and wherein n is 0 or an integer from 1 to 3.

[1235] 19. The compound according to any one of items 14 to 18, wherein the compound is represented by one of the following structural formulas:

[1236]

[1237] or a pharmaceutically acceptable salt of the compound; wherein n is 0, 1 or 2.

[1238] 20. The compound according to any one of items 14 to 19, wherein the compound is represented by the following structural formula:

[1239]

[1240] or a pharmaceutically acceptable salt of the compound; wherein n is 0, 1 or 2.

[1241] 21. The compound according to any one of items 1 to 20, wherein Ar is an optionally substituted 5-membered or 6-membered monocyclic heteroaryl.

[1242] 22. The compound according to any one of items 1 to 20, wherein Ar is an optionally substituted monocyclic heteroaryl group comprising one or more nitrogen atoms.

[1243] 23. The compound or pharmaceutically acceptable salt of any one of items 1 to 22, wherein Ar is optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, or optionally substituted pyridazinyl.

[1244] 24. The compound or pharmaceutically acceptable salt of any one of items 1 to 23, wherein Ar is pyridinyl, optionally substituted pyrimidinyl or optionally substituted pyrazinyl.

[1245] 25. A compound according to any one of items 1-24, or a pharmaceutically acceptable salt thereof, wherein Ar is optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted or optionally substituted

[1246] 26. A compound according to any one of items 1-25, or a pharmaceutically acceptable salt thereof, wherein Ar is optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted

[1247] 27. A compound according to any one of items 1-26, or a pharmaceutically acceptable salt thereof, wherein Ar is optionally substituted Optionally substituted or optionally substituted

[1248] 28. A compound according to any one of items 1-27, or a pharmaceutically acceptable salt thereof, wherein Ar is optionally substituted or optionally substituted

[1249] 29. A compound according to any one of items 1 to 28, or a pharmaceutically acceptable salt thereof, wherein Ar is optionally substituted with one or more groups selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, halo, -CN, -NO2, -OR z 、-NR x R y 、-S(O) i R x 、-NR x S(O) i R y 、-S(O) i NR x R y 、-C(=O)OR x 、-OC(=O)OR x 、-C(=S)OR y 、-O(C=S)R x 、-C(=O)NR x R y 、-NR x C(=O)R y 、-C(=S)NR x R y、-NR x C(=S)R y 、-NR x (C=O)OR y 、-O(C=O)NR x R y 、-NR x (C=S)OR y 、-O(C=S)NR x R y 、-NR x (C=O)NR x R y 、-NR x (C=S)NR x R y 、-C(=S)R x 、-C(=O)R x , phenyl and monocyclic heteroaryl;

[1250] in

[1251] The C1-C4 alkyl substituents on Ar are optionally substituted with: -CN, -NO2, -OR z 、-NR x R y 、-S(O) i R x 、-NR x S(O) i R y 、-S(O) i NR x R y 、-C(=O)OR x 、-OC(=O)OR x 、-C(=S)OR x 、-O(C=S)R x 、-C(=O)NR x R y 、-NR x C(=O)R y 、-C(=S)NR x R y 、-NR x C(=S)R y 、-NR x (C=O)OR y 、-O(C=O)NR x R y 、-NR x (C=S)OR y 、-O(C=S)NR x R y 、-NR x(C=O)NR x R y 、-NR x (C=S)NR x R y 、-C(=S)R x 、-C(=O)R y , C3-C6 cycloalkyl (optionally substituted with one or more groups selected from -CH3, halomethyl, halo, methoxy and halomethoxy), monocyclic heteroaryl (optionally substituted with one or more groups selected from -CH3, halomethyl, halo, methoxy and halomethoxy), or phenyl (optionally substituted with one or more groups selected from -CH3, halomethyl, halo, methoxy and halomethoxy);

[1252] The C3-C6 cycloalkyl, the C3-C6 heterocyclyl, the phenyl and the monocyclic heteroaryl substituents on Ar are optionally and independently substituted with C1-C4 alkyl, C1-C4 haloalkyl, halo, -CN, -NO2, -OR z 、-NR x R y 、-S(O) i R x 、-NR x S(O) i R y 、-S(O) i NR x R y 、-C(=O)OR x 、-OC(=O)OR x 、-C(=S)OR x 、-O(C=S)R y 、-C(=O)NR x R y 、-NR x C(=O)R y 、-C(=S)NR x R y 、-NR x C(=S)R y 、-NR x (C=O)OR y 、-O(C=O)NR x R y 、-NR x (C=S)OR y 、-O(C=S)NR x R y 、-NR x (C=O)NR x R y 、-NR x(C=S)NR x R y 、-C(=S)R x or -C(=O)R x ;

[1253] Each R x and each R y are independently -H, C1-C4 alkyl or C3-C8 cycloalkyl; wherein R x or R y The C1-C4 alkyl group or the C3-C8 cycloalkyl group represented by is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl and phenyl (optionally substituted with one or more groups selected from the group consisting of -CH3, halomethyl, halo, methoxy and halomethoxy);

[1254] R z is -H, C1-C4 alkyl, C3-C8 cycloalkyl or C3-C8 heterocyclic group; wherein R z The C1-C4 alkyl, the C3-C8 cycloalkyl or the C3-C8 heterocyclyl represented by is optionally substituted with one or more substituents selected from the group consisting of -CN, halo, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl and phenyl (optionally substituted with one or more groups selected from the group consisting of -CH3, halomethyl, halo, methoxy and halomethoxy); and

[1255] i is 0, 1 or 2.

[1256] 30. A compound according to any one of items 1-29, or a pharmaceutically acceptable salt thereof, wherein Ar is optionally substituted with one or more groups selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, halo, -CN, -NO2, -OR z 、-NR x R y 、-S(O) i R x 、-NR x S(O) i R y 、-S(O) i NR x R y 、-C(=O)OR x 、-OC(=O)OR x 、-C(=S)OR y 、-O(C=S)R x 、-C(=O)NR x R y 、-NRx C(=O)R y 、-C(=S)NR x R y 、-NR x C(=S)R y 、-NR x (C=O)OR y 、-O(C=O)NR x R y 、-NR x (C=S)OR y 、-O(C=S)NR x R y 、-NR x (C=O)NR x R y 、-NR x (C=S)NR x R y 、-C(=S)R x 、-C(=O)R x , phenyl and monocyclic heteroaryl;

[1257] in

[1258] The C1-C4 alkyl substituents on Ar are optionally substituted with: -CN, -NO2, -OR z 、-NR x R y 、-S(O) i R x 、-NR x S(O) i R y 、-S(O) i NR x R y 、-C(=O)OR x 、-OC(=O)OR x 、-C(=S)OR x 、-O(C=S)R x 、-C(=O)NR x R y 、-NR x C(=O)R y 、-C(=S)NR x R y 、-NR x C(=S)R y 、-NR x (C=O)OR y 、-O(C=O)NR x R y 、-NR x (C=S)ORy 、-O(C=S)NR x R y 、-NR x (C=O)NR x R y 、-NR x (C=S)NR x R y 、-C(=S)R x 、-C(=O)R y , C3-C6 cycloalkyl (optionally substituted with one or more groups selected from -CH3, halomethyl, halo, methoxy and halomethoxy), monocyclic heteroaryl (optionally substituted with one or more groups selected from -CH3, halomethyl, halo, methoxy and halomethoxy), or phenyl (optionally substituted with one or more groups selected from -CH3, halomethyl, halo, methoxy and halomethoxy);

[1259] The C3-C6 cycloalkyl, the C3-C6 heterocyclyl, the phenyl and the monocyclic heteroaryl substituents on Ar are optionally and independently substituted with C1-C4 alkyl, C1-C4 haloalkyl, halo, -CN, -NO2, -OR z 、-NR x R y 、-S(O) i R x 、-NR x S(O) i R y 、-S(O) i NR x R y 、-C(=O)OR x 、-OC(=O)OR x 、-C(=S)OR x 、-O(C=S)R y 、-C(=O)NR x R y 、-NR x C(=O)R y 、-C(=S)NR x R y 、-NR x C(=S)R y 、-NR x (C=O)OR y 、-O(C=O)NR x R y 、-NR x (C=S)OR y 、-O(C=S)NR x R y 、-NRx (C=O)NR x R y 、-NR x (C=S)NR x R y 、-C(=S)R x or -C(=O)R x ;

[1260] Each R x and each R y are independently -H, C1-C4 alkyl or C3-C8 cycloalkyl; wherein R x or R y The C1-C4 alkyl group or the C3-C8 cycloalkyl group represented by is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, C3-C6 cycloalkyl and phenyl (optionally substituted with one or more groups selected from the group consisting of -CH3, halomethyl, halo, methoxy and halomethoxy);

[1261] R z is -H, C1-C4 alkyl, C1-C4 alkoxy, C3-C8 cycloalkyl or C3-C8 heterocyclic group; wherein R z The C1-C4 alkyl group or the C3-C8 cycloalkyl group represented by is optionally substituted with one or more substituents selected from the group consisting of -CN, halo, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl and phenyl (optionally substituted with one or more groups selected from the group consisting of -CH3, halomethyl, halo, methoxy and halomethoxy); and

[1262] i is 0, 1 or 2.

[1263] 31. A compound according to any one of items 1 to 30, or a pharmaceutically acceptable salt thereof, wherein Ar is optionally substituted with one or more groups selected from the group consisting of optionally substituted C1-C4 alkyl, C1-C4 haloalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 heterocyclyl, halo, -CN, -OR z 、-NR x R y 、-C(=O)NR x R y 、-C(=S)NR x R y 、-O(C=O)NR x R y 、-O(C=S)NR x R y 、-C(=O)R x 、-C(=O)OR x 、-NRx C(=O)R y , phenyl and optionally substituted monocyclic heteroaryl.

[1264] 32. A compound according to any one of items 1 to 31, or a pharmaceutically acceptable salt thereof, wherein Ar is optionally substituted with one or more groups selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, halo, -CN, -OR z 、-NR x R y 、-C(=O)NR x R y 、-C(=S)NR x R y 、-O(C=O)NR x R y 、-O(C=S)NR x R y 、-C(=O)OR x 、-NR x C(=O)R y , phenyl and optionally substituted monocyclic heteroaryl.

[1265] 33. A compound according to any one of items 1 to 31, or a pharmaceutically acceptable salt thereof, wherein Ar is optionally substituted with one or more groups selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, halo, -CN, -OR z 、-NR x R y and -C(=O)R x wherein the C3-C6 cycloalkyl and the C3-C6 heterocyclyl substituents on Ar are each optionally substituted by one or more independently selected halogen, C 1-4 Alkyl and C 1-4 Alkoxy group substitution; R x and R y Each independently represents -H, C1-C4 alkyl or C3-C6 cycloalkyl, wherein R x and R y The C1-C4 alkyl represented by the present invention is optionally substituted by one or more independently selected halogen and C 1-4 The alkoxy substituent is substituted; and R z is H, C1-C4 alkyl, C3-C8 cycloalkyl or C3-C6 heterocyclic group, wherein R zThe C1-C4 alkyl, the C3-C8 cycloalkyl and the C3-C6 heterocyclyl represented are each optionally and independently substituted with one or more substituents independently selected from halogen, -CN, C1-C4 alkyl and C1-C4 alkoxy.

[1266] 34. A compound according to any one of items 1 to 33, or a pharmaceutically acceptable salt thereof, wherein Ar is optionally substituted with one or more groups selected from C1-C4 alkyl, C1-C4 haloalkyl, halo, -CN and -OR z substituted by a group; wherein R z is a C1-C4 alkyl group optionally substituted by one or more halogen groups.

[1267] 35. A compound according to any one of items 1 to 33, or a pharmaceutically acceptable salt thereof, wherein Ar is optionally substituted with one or more groups selected from the group consisting of -CH3, -CF3, -CHF2, -F, -Cl, -CN, -OCH3, -OCHF2, -OC2H5, -OCH2CF3, -O(CH2)2(O)CH3, -OCH(CH3)2, -O-(3-methoxycyclobutyl), -O-cyclobutyl, -O-cyclopentyl, -COCH3, -N(H)CH3, -N(CH3)C2H5, -N(H)cyclobutyl, -NHCH2CH3, -NHCH(CH3)2, -N(CH3)2, -N(CH3)(CH2CH2(O)CH3), -OH, azetidinyl, oxetanyl, pyrrolidinyl, morpholinyl, 4-methylpiperazinyl and piperazinyl.

[1268] 36. A compound according to any one of items 1 to 35, or a pharmaceutically acceptable salt thereof, wherein Ar is optionally substituted with one or more groups selected from -CH3, -CF3, -CHF2, -F, -Cl, -CN, -OCH3, -O(CH2)2(O)CH3 and -OCHF2.

[1269] 37. A compound according to any one of items 1 to 36, or a pharmaceutically acceptable salt thereof, wherein Ar is optionally substituted with one or more groups selected from -CH3, -CF3, -CHF2, -F, -Cl, -CN, -OCH3 and -OCHF2.

[1270] 38. The compound according to any one of items 8-37, wherein n is 0.

[1271] 39. The compound according to item 1, wherein the compound is represented by one of the following structural formulas:

[1272]

[1273]

[1274] or a pharmaceutically acceptable salt of the compound, wherein Ar is Each optionally substituted by a group selected from C1-C4 alkyl, C1-C4 haloalkyl, halo, -CN and -OR z The substituent R Ar Replacement; R z is H, C1-C4 alkyl, C3-C8 cycloalkyl or C3-C6 heterocyclic group, wherein R z The C1-C4 alkyl, the C3-C8 cycloalkyl and the C3-C6 heterocyclyl represented are each optionally and independently substituted with one or more substituents independently selected from halogen, -CN, C1-C4 alkyl and C1-C4 alkoxy.

[1275] 40. The compound according to item 39, wherein Ar is represented by the following formula:

[1276]

[1277] 41. The compound according to item 38 or 39, wherein R Ar is C1-C4 alkyl or -OR z ; R z is H or C1-C4 alkyl optionally substituted with one to three substituents independently selected from halo, -CN, C1-C4 alkyl and C1-C4 alkoxy.

[1278] 42. The compound according to item 1, wherein the compound is selected from

[1279] N-(4-fluoro-5-(((2S,4R)-4-((6-(2-methoxyethoxy)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1280] N-(5-(((2S,4R)-4-((6-(azetidin-1-yl)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[1281] N-(4-Fluoro-5-(((2S,4R)-4-((6-(3-fluoroazetidin-1-yl)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1282] N-(5-(((2S,4R)-4-((6-(3,3-difluoroazetidin-1-yl)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[1283] N-(4-fluoro-5-(((2S,5S)-5-((6-methoxypyrimidin-4-yl)oxy)-2-methylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1284] N-(4-Fluoro-5-(((2S,4R)-4-((5-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1285] N-(5-(((2S,4R)-4-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[1286] N-(4-fluoro-5-(((2S,4R)-4-((5-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1287] N-(5-(((2S,4R)-4-((6-acetylpyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[1288] N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1289] N-(4-Fluoro-5-(((2S,4R)-4-((6-methoxypyridazin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1290] N-(4-Fluoro-5-(((2S,4R)-4-((6-fluoropyridin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1291] N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1292] N-(4-fluoro-5-(((2S,4R)-4-((5-methoxypyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1293] N-(5-(((2S,4R)-4-((5-chloropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[1294] N-(4-fluoro-5-(((2S,4R)-4-((4-methoxypyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1295] N-(4-Fluoro-5-(((2S,4R)-2-methyl-4-(pyrimidin-2-yloxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1296] N-(4-Fluoro-5-(((2S,4R)-4-((3-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1297] N-(5-(((2S,4R)-4-((5-chloropyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[1298] N-(4-Fluoro-5-(((2S,4R)-4-((4-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1299] N-(4-Fluoro-5-(((2S,4R)-4-((2-fluoropyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1300] N-(4-fluoro-5-(((2S,4R)-4-((5-methoxypyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1301] N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1302] N-(4-fluoro-5-(((2S,4R)-4-((2-methoxypyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1303] N-(5-(((2S,4R)-4-((4-chloropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[1304] N-(5-(((2S,4R)-4-((4,5-difluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[1305] N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((6-morpholinopyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1306] N-(4-fluoro-5-(((2S,4R)-4-((5-methoxypyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1307] N-(5-(((2S,4R)-4-((3,5-dimethylpyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[1308] N-(5-(((2S,4R)-4-((2,5-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[1309] N-(4-Fluoro-5-(((2S,4R)-2-methyl-4-((5-methylpyrazin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1310] N-(4-Fluoro-5-(((2S,4R)-4-((6-hydroxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1311] N-(4-Fluoro-5-(((2S,4R)-2-methyl-4-((2-methylpyridin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1312] N-(4-Fluoro-5-(((2S,4R)-4-((6-fluoropyridazin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1313] N-(4-Fluoro-5-(((2S,4R)-4-((5-fluoropyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1314] N-(5-(((2S,4R)-4-((5-(difluoromethyl)pyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[1315] N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyridin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1316] N-(4-Fluoro-5-(((2S,4R)-4-((5-fluoro-4-methylpyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1317] N-(4-Fluoro-5-(((2S,4R)-4-((5-fluoro-4-methoxypyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1318] N-(4-Fluoro-5-(((2S,4R)-2-methyl-4-(pyrimidin-5-yloxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1319] N-(5-(((2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;

[1320] N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((6-(oxetan-3-yloxy)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1321] N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((6-((1-methylazetidin-3-yl)oxy)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1322] N-(4-Fluoro-5-(((2S,4R)-2-methyl-4-((5-morpholinopyrazin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1323] N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((4-morpholinopyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1324] N-(4-fluoro-5-(((2S,4R)-4-((5-(2-methoxyethoxy)pyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1325] N-(4-fluoro-5-(((2S,4R)-4-((4-((2-methoxyethyl)(methyl)amino)pyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1326] N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((5-morpholinopyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1327] N-(4-fluoro-5-(((2S,4R)-4-((4-(2-methoxyethoxy)pyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1328] N-(4-Fluoro-5-(((2S,4R)-4-(4-fluorophenoxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1329] N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1330] N-(4-fluoro-5-(((2S,4R)-4-((5-(2-methoxyethoxy)pyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1331] N-(4-fluoro-5-(((2S,4R)-4-((5-((2-methoxyethyl)(methyl)amino)pyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1332] N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((4-(4-methylpiperazin-1-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1333] N-(4-Fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;

[1334] N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl-4-d)methyl)thiazol-2-yl)acetamide; and

[1335] N-(4-fluoro-5-(((2S,4S)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl-4-d)methyl)thiazol-2-yl)acetamide,

[1336] or a pharmaceutically acceptable salt of the compound.

[1337] 43. A pharmaceutical composition comprising the compound according to any one of items 1 to 42 or a pharmaceutically acceptable salt of the compound and a pharmaceutically acceptable carrier or diluent.

[1338] 44. A method of treating a subject having a disease or condition selected from a neurodegenerative disease, a tauopathy, diabetes, cancer, and stress, the method comprising administering to the subject an effective amount of a compound according to any one of items 1 to 42 or an effective amount of a pharmaceutical composition according to item 43.

[1339] 45. The method of claim 44, wherein the disease or condition is selected from the group consisting of acute ischemic stroke (AIS), Alzheimer's disease, dementia, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis with cognitive impairment (ALSci), argyrophilic grain dementia, Bluit disease, corticobasal degeneration (CBP), dementia pugilistica, diffuse neurofibrillary tangles with calcifications, Down syndrome, epilepsy, familial British dementia, familial Danish dementia, and chromosomal agenesis. Frontotemporal dementia with Parkinson's disease associated with body 17 (FTDP-17), Gerstmann-Straussler-Scheinker disease, Guadeloupe Parkinson's disease, Hallervorden-Spatz disease (neurodegeneration with type 1 brain iron accumulation), ischemic stroke, mild cognitive impairment (MCI), multiple system atrophy, myotonic dystrophy, Niemann-Pick disease (type C), pallidum-pontine-nigral degeneration, Guam Parkinsonism-dementia complex, Pick's disease disease)(PiD), postencephalitis Parkinson's disease (PEP), prion diseases (including Creutzfeldt-Jakob disease (GJD) and variant Creutzfeldt-Jakob disease (vCJD)), fatal familial insomnia, kuru, progressive supracortical gliomatosis, progressive supranuclear palsy (PSP), Stills-Richardson-Oerstein syndrome, subacute sclerosing panencephalitis, simple entanglement dementia, Huntington's disease, and Parkinson's disease.

[1340] 46. ​​The method of any one of items 44 and 45, wherein the disease or disorder is selected from acute ischemic stroke (AIS), Alzheimer's disease, dementia, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis with cognitive impairment (ALSci), argyrophilic grain dementia, epilepsy, ischemic stroke, mild cognitive impairment (MCI), Huntington's disease and Parkinson's disease.

[1341] 47. The method of any one of items 44-46, wherein the disease or disorder is Alzheimer's disease.

[1342] 48. A method of inhibiting O-GlcNAcase in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of items 1-42 or an effective amount of a pharmaceutical composition according to item 43.

[1343] 49. A method of treating a disease or condition characterized by hyperphosphorylation of tau in the brain, the method comprising administering to a subject an effective amount of a compound according to any one of items 1 to 42 or an effective amount of a pharmaceutical composition according to item 43.

[1344] Although we have described many embodiments herein, it is apparent that our basic examples can be modified to provide other embodiments utilizing the compounds and methods of the present disclosure. Therefore, it should be understood that the scope of the present disclosure will be defined by the appended claims rather than by the specific embodiments shown by way of example.

[1345] The contents of all references cited throughout this application (including literature references, issued patents, published patent applications, and co-pending patent applications) are hereby expressly incorporated herein by reference in their entirety. Unless otherwise specified, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art.

Claims

1. A compound represented by the following structural formula: or a pharmaceutically acceptable salt of the compound, wherein: Ar is an optionally substituted monocyclic aryl or an optionally substituted monocyclic heteroaryl; Y 1 and Y 2 Each is CR c or N, where Y 1 or Y 2 At least one of is N; Z is CR 2 R 2 , C(=O), (CR 2 R 2 )2 or CH2C(=O); R c is -H, halo, C1-C4 alkyl or C1-C4 haloalkyl; n is 0 or an integer from 1 to 8; When n is not 0, R 1 is independently at each occurrence halo, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy; R 2 is independently -H, halo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl or C3-C 10 Halogenated cycloalkyl; Or alternatively, two R 2 Together with the carbon atom to which they are attached, they form C3-C 10 Cycloalkyl; R 3 is -H or C1-C4 alkyl; and R 4 is -H, C1-C4 alkyl, C1-C4 haloalkyl or C3-C6 cycloalkyl; Or alternatively, R 3 and R 4 Together with their intervening atoms they form an optionally substituted 5- to 7-membered heterocyclyl.

2. A compound represented by the following structural formula: or a pharmaceutically acceptable salt of the compound, wherein: Ar is an optionally substituted monocyclic aryl or an optionally substituted monocyclic heteroaryl; Y 1 and Y 2 Each is CR c or N, where Y 1 or Y 2 At least one of is N; Z is CR 2 R 2 , C(=O), (CR 2 R 2 )2 or CH2C(=O); R c is -H, halo, C1-C4 alkyl or C1-C4 haloalkyl; n is 0 or an integer from 1 to 7; When n is not 0, R 1 is independently at each occurrence halo, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy; R 2 is independently -H, halo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl or C3-C 10 Halogenated cycloalkyl; Or alternatively, two R 2 Together with the carbon atom to which they are attached, they form C3-C 10 Cycloalkyl; R 3 is -H or C1-C4 alkyl; and R 4 is -H, C1-C4 alkyl, C1-C4 haloalkyl or C3-C6 cycloalkyl; Or alternatively, R 3 and R 4 Together with their intervening atoms they form an optionally substituted 5- to 7-membered heterocyclyl.

3. A pharmaceutical composition comprising the compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt of the compound and a pharmaceutically acceptable carrier or diluent.

4. A method for treating a subject suffering from a disease or disorder selected from a neurodegenerative disease, a tauopathy, diabetes, cancer, and stress, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1-2 or an effective amount of a pharmaceutical composition according to claim 3.

5. A method for inhibiting O-GlcNAcase in a subject in need thereof, the method comprising: An effective amount of the compound according to any one of claims 1-2 or an effective amount of the pharmaceutical composition according to claim 3 is administered to the subject.

6. A method for treating a disease or disorder characterized by hyperphosphorylation of tau in the brain, the method comprising administering to a subject an effective amount of a compound according to any one of claims 1-2 or an effective amount of a pharmaceutical composition according to claim 3.

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